Bio

Clinical Focus


  • Cancer > Hematology
  • Hematology

Academic Appointments


Honors & Awards


  • Charles Dorsey Armstrong Award for Excellence in Patient Care, Stanford Internal Medicine Residency Program (1998)
  • Hematology Division Faculty Teaching Award, Stanford Division of Hematology/Department of Medicine (2005, 2007, 2009)
  • NIH K23 Mentored Patient-Oriented Research Career Development Award (#HL04409), National Institutes of Health (2001-2006)

Professional Education


  • Board Certification: Hematology, American Board of Internal Medicine (2001)
  • Fellowship:Stanford University School of Medicine (2003) CA
  • Residency:Stanford University School of Medicine (1998) CA
  • Internship:Stanford University School of Medicine (1996) CA
  • Medical Education:Stanford University School of Medicine (1995) CA
  • B.A., Franklin & Marshall College, Biology; HAPOS (1990)
  • M.D., Stanford, Medicine (1995)
  • M.S., Stanford, Clinical Epidemiology (2003)

Research & Scholarship

Current Research and Scholarly Interests


My research interests include phase I/II clinical trial evaluation of novel therapies for the following diseases:
--Myelodysplastic syndromes (MDS)
--Chronic myelogenous leukemia (CML)
--Acute myelogenous leukemia (AML)
--Myeloproliferative disorders (MPDs) including:
Hypereosinophilic syndrome
Systemic mastocytosis
BCR-ABL-negative MPDs

Clinical Trials


  • Mothers With a History of Depression and Their 10-14 Year Old Daughters Not Recruiting

    The purpose of this study is to investigate risk factors associated with depression and how such factors might be transmitted cross-generationally. The investigators are conducting an integrative assessment of emotion regulation and stress reactivity in a group of mothers with and without a history of depression and their daughters.

    Stanford is currently not accepting patients for this trial. For more information, please contact Maria Lemus, (650) 723 - 0804.

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  • Efficacy and Safety of ON 01910.Na in Myelodysplastic Syndrome (MDS) Patients With Trisomy 8 or Classified as Intermediate-1, -2 or High Risk Not Recruiting

    This study will explore the efficacy and safety of a regimen of ON 01910.Na as a 48-hour continuous intravenous infusion once a week for 3 weeks of a 4-week cycle in MDS patients with Trisomy 8 or classified as Intermediate-1, -2 or High Risk who are not responding to current therapeutic options. The rationale for this trial is based upon data from laboratory studies with ON 01910.Na and upon activity that has been observed in other clinical trials with ON 01910.Na in patients with MDS.

    Stanford is currently not accepting patients for this trial. For more information, please contact Mai Tran, (650) 723 - 8594.

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  • Azacitidine and Gemtuzumab Ozogamicin in Treating Older Patients With Previously Untreated Acute Myeloid Leukemia Not Recruiting

    This phase II trial is studying the side effects of giving azacitidine together with gemtuzumab ozogamicin to see how well it works in treating older patients with previously untreated acute myeloid leukemia. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Azacitidine may also stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as gemtuzumab ozogamicin, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving azacitidine together with gemtuzumab ozogamicin may kill more cancer cells.

    Stanford is currently not accepting patients for this trial. For more information, please contact Joselene Sipin-Sayno, (650) 736 - 8113.

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  • Biomarker To Evaluate Protein Profiles of Neutropenic Fever/Infection With Acute or Chronic Leukemias Not Recruiting

    The purpose of this study is to measure, in pilot/observational study, panels of circulating proteins in real time at the onset of neutropenic fever/infection in patients with acute or chronic leukemias undergoing chemotherapy or other biologic treatment. And to generate preliminary trend results in panels of circulating proteins longitudinally during the period of neutropenia and to correlate those values to clinical/laboratory data and patient outcomes.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • Phase 1-2 of Azacitidine + Lenalidomide for Previously Untreated Elderly Patients With Acute Myeloid Leukemia (AML) Not Recruiting

    This study has a phase 1 and a phase 2 component. In phase 1, the objective is to determine the maximum tolerated dose (MTD) of lenalidomide when after azacitidine. In phase 2, the objective is to determine the efficacy of the combination treatment.

    Stanford is currently not accepting patients for this trial. For more information, please contact Leonel Gallegos, (650) 723 - 2781.

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  • A Randomized, Double-Blind, Placebo-Controlled Study of Idelalisib in Combination With Rituximab for Previously Treated Chronic Lymphocytic Leukemia (CLL) Not Recruiting

    This Phase 3, randomized, double-blind, placebo-controlled study is to evaluate the effect of idelalisib in combination with rituximab on the onset, magnitude, and duration of tumor control in participants previously treated for chronic lymphocytic leukemia (CLL). Eligible patients will be randomized with a 1:1 ratio into 1 of the 2 treatment arms to receive either idelalisib plus rituximab or placebo plus rituximab. Participants who are tolerating primary study therapy but experience definitive CLL progression are eligible to receive active idelalisib therapy in the extension study, GS-US-312-0117.

    Stanford is currently not accepting patients for this trial. For more information, please contact Tessa Hunter, (650) 736 - 4032.

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  • Extension Study of Idelalisib for Patients With Chronic Lymphocytic Leukemia Who Participated in GS-US-312-0116 Not Recruiting

    This study (GS-US-312-0117) is a multicenter, 2-arm, double-blind, parallel-group extension study that is a companion study to Study GS-US-312-0116, to evaluate the effect of idelalisib on the onset, magnitude, and duration of tumor control.

    Stanford is currently not accepting patients for this trial. For more information, please contact Tessa Hunter, (650) 736 - 4032.

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  • Efficacy Study of Oral Sapacitabine to Treat Acute Myeloid Leukemia in Elderly Patients Not Recruiting

    The main objective of this study is to learn which sapacitabine treatment is more likely to keep the cancer in check for at least one year in AML patients who are at least 70 years of age or older and in MDS patients who are at least 60 years of age.

    Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Takahashi, (650) 736 - 4032.

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  • Allogeneic HCT Using Nonmyeloablative Host Conditioning With TLI & ATG vs SOC in AML Not Recruiting

    Acute myeloid leukemia (AML) is a cancer of the bone marrow that mostly affects older adults. Even with the best chemotherapy, two-year disease-free survival is achieved in a minority of patients. Bone marrow transplantation from a sibling donor may improve cure rates; however, patients over 50 years of age have a high risk of complications and therefore generally are excluded from this treatment option. Recently our group developed a transplantation strategy for older cancer patients that protects against transplant-associated complications, yet does not interfere with the ability of the transplanted donor cells to destroy cancer cells. With this new method, we can now safely evaluate transplantation as a curative therapy for AML patients over the age of 50. We have assembled clinical and scientific researchers throughout the state of California to study and compare bone marrow transplantation using our new approach with the best standard of care chemotherapy in AML patients over the age of 50. The results of this study have the potential to establish a new treatment standard that will improve survival of older AML patients.

    Stanford is currently not accepting patients for this trial. For more information, please contact BMT Referrals, 650-725-1647.

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  • Vorinostat, Azacitidine, and Gemtuzumab Ozogamicin for Older Patients With Relapsed or Refractory AML Not Recruiting

    The purpose of this study is to test the safety of vorinostat (Zolinza) and azacitidine (Vidaza) when combined with gemtuzumab ozogamicin (GO) at different dose levels. These drugs increase the effect of GO against leukemia cells in the test tube, but we don't know yet whether they also increase the anti-leukemia effect of GO in people.

    Stanford is currently not accepting patients for this trial. For more information, please contact Leonel Gallegos, (650) 723 - 2781.

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  • A Long-Term Study of the Effects of Orally Administered SAR302503 in Patients With Myelofibrosis Not Recruiting

    The purpose of this study is to evaluate the long-term effects of orally administered SAR302503 (TG101348) in patients with myelofibrosis who have completed the MF-TG101348-001 study.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • To Demonstrate Superiority of Decitabine Over Azacitidine in Subjects With Intermediate- or High-risk MDS. Not Recruiting

    The purpose of this study is to compare the response of patients with Intermediate or High Risk myelodysplastic syndromes (MDS) following treatment with decitabine or azacitidine.

    Stanford is currently not accepting patients for this trial. For more information, please contact Mai Tran, (650) 723 - 8594.

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  • Evaluating the Safety of Long Term Dosing of Romiplostim (Formerly AMG 531) in Thrombocytopenic Subjects With Myelodysplastic Syndromes (MDS) Not Recruiting

    This is an open label extension study of romiplostim for treatment of thrombocytopenia (platelet count ≤ 50 x 10^9/L) in MDS subjects. The study is designed to assess the long-term safety of treatment with romiplostim, as measured by incidence of overall adverse events, the incidence of bleeding events, the utilization of platelet transfusions, and the duration of platelet response. The study will further describe the time to disease progression to acute myeloid leukemia (AML) and survival.

    Stanford is currently not accepting patients for this trial. For more information, please contact Mai Tran, (650) 723 - 8594.

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  • Phase III Study of SAR302503 in Intermediate-2 and High Risk Patients With Myelofibrosis Not Recruiting

    Primary Objective: - To evaluate the efficacy of daily oral doses of 400 mg or 500 mg of SAR302503 (Investigational Medicinal Product, IMP) compared to placebo in the reduction of spleen volume as determined by magnetic resonance imaging (MRI) (or computed tomography scan in patients with contraindications for MRI). Secondary Objectives: - To evaluate the effect on Myelofibrosis (MF)-associated symptoms (key MF symptoms) as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) diary. - To evaluate the Overall Survival of patients treated with either 400 mg/day or 500 mg/day of IMP as compared to placebo. - To evaluate the Progression Free Survival of patients treated with either 400 mg/day or 500 mg/day of IMP as compared to placebo. - To evaluate the durability of splenic response. - To evaluate the safety of IMP.

    Stanford is currently not accepting patients for this trial. For more information, please contact Harshdeep Kaur, (650) 723 - 3589.

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  • A Study of Darbepoetin Alfa in Patients With Myelodysplastic Syndrome (MDS) Not Recruiting

    The primary objectives of the trial are to assess erythroid response to darbepoetin alfa, as determined by changes in hemoglobin and/or red blood cell (RBC) transfusion-dependence and to describe the safety profile of darbepoetin alfa in patients with MDS. The secondary objective is to assess bone marrow progenitor BFU-E growth before and after treatment with darbepoetin alfa.

    Stanford is currently not accepting patients for this trial. For more information, please contact Mai Tran, (650) 723 - 8594.

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  • Myelodysplastic Syndromes (MDS) Event Free Survival With Iron Chelation Therapy Study Not Recruiting

    The primary purpose of this study is to prospectively assess the efficacy and safety of iron chelation therapy with deferasirox compared to placebo in patients with myelodysplastic syndromes (low/int-1 risk) and transfusional iron overload.

    Stanford is currently not accepting patients for this trial. For more information, please contact Savita Kamble, (650) 723 - 8594.

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  • A Dose-escalation Study of the Safety and Tolerability of Orally Administered TG101348 in Patients With Myelofibrosis Not Recruiting

    The purpose of this study is to evaluate the safety and tolerability of orally administered TG101348 in patients with myelofibrosis.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • Dose Escalation Study of CAL-101 in Select Relapsed or Refractory Hematologic Malignancies Not Recruiting

    The purpose of this study is to determine the dose that can be safely given to see what effect it may have on your cancer and to determine how the drug is distributed in the body.

    Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Takahashi, (650) 736 - 4032.

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  • Lenalidomide With or Without Epoetin Alfa in Treating Patients With Myelodysplastic Syndrome and Anemia Not Recruiting

    This randomized phase III trial studies lenalidomide to see how well it works with or without epoetin alfa in treating patients with myelodysplastic syndrome and anemia. Lenalidomide may stop the growth of myelodysplastic syndrome by blocking blood flow to the cells. Colony stimulating factors, such as epoetin alfa, may increase the number of immune cells found in bone marrow or peripheral blood. It is not yet known whether lenalidomide is more effective with or without epoetin alfa in treating patients with myelodysplastic syndrome and anemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Mai Tran, (650) 723 - 8594.

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  • Safety, Efficacy, & Pharmacokinetic Study of Tamibarotene to Treat Patients With Relapsed or Refractory APL Not Recruiting

    This is a Phase II, open-label, non-randomized study to evaluate the safety, efficacy, and pharmacokinetics of tamibarotene in adult patients with relapsed or refractory acute promyelocytic leukemia (APL) following treatment with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Patients must have received and failed therapy with ATRA and ATO. Treatment may have been administered either as combination therapy or sequentially as single agents. Patients who are intolerant to either drug are eligible for this study.

    Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Takahashi, (650) 736 - 4032.

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  • Safety Study of CAT-8015 Immunooxin in Patients With HCL With Advance Disease Not Recruiting

    RATIONALE: The CAT-8015 immunotoxin can bind tumor cells and kill them without harming normal cells. This may be an effective treatment for hairy cell leukemia(HCL) that has not responded to chemotherapy, surgery or radiation therapy. PURPOSE: Phase I dose escalation study to determine the maximum tolerated dose of CAT-8015 immunotoxin in treating patients who have hairy cell leukemia (HCL) that has not responded to treatment.

    Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Takahashi, (650) 736 - 4032.

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  • A Study of Idelalisib and Rituximab in Elderly Patients With Untreated CLL or SLL Not Recruiting

    This study is to evaluate the safety and clinical activity of idelalisib alone and in combination with rituximab in patients with CLL or SLL. This Phase 2 study will be the first time that idelalisib is administered to previously untreated patients with hematologic malignancies. Idelalisib has demonstrated clinical activity as a single agent in relapsed or refractory CLL and SLL with acceptable toxicity, which supports its evaluation in previously untreated patients. The study population is limited to patients over 65 years of age because younger patients are generally appropriate for standard immunochemotherapy regimens that are highly active. Since the mechanism of action of idelalisib is distinct from rituximab, it is hypothesized that the combination will be more active than either agent alone. This study will establish initial safety and clinical activity of idelalisib in combination with rituximab in patients with CLL or SLL. Cohort 2 of this study will establish safety and clinical activity of idelalisib alone in subjects with untreated CLL or SLL.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, (650) 725 - 4041.

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  • Efficacy and Safety of Midostaurin in Patients With Aggressive Systemic Mastocytosis or Mast Cell Leukemia Not Recruiting

    This study will investigate if the drug midostaurin taken orally twice daily is effective and safe in treating patients with aggressive systemic mastocytosis or mast cell leukemia with or without an additional hematological neoplasm.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • Integrated Whole-Genome Analysis of Hematologic Disorders Recruiting

    We will use new technologies to look at the DNA, RNA, proteins, and metabolites in the disease-containing blood, bone marrow, or tissue and normal cells from the skin. Our goal is to analyze all of the genes in the diseased and normal skin sample. By comparing the results of the diseased sample and normal skin cells and the results of the two types of genetic information (DNA and RNA), we should be able to identify genetic changes that are important for the initiation, progression, or treatment response of that particular disorder.

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  • Bortezomib and Dexamethasone With or Without Lenalidomide in Treating Patients With Multiple Myeloma Previously Treated With Dexamethasone Not Recruiting

    This randomized phase III trial compares bortezomib, dexamethasone, and lenalidomide with bortezomib and dexamethasone to see how well they work in treating patients with multiple myeloma previously treated with dexamethasone. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. It is not yet known whether giving bortezomib and dexamethasone is more effective with or without lenalidomide in treating multiple myeloma.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nancy Mori, (650) 724 - 0201.

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  • Phase II Midostaurin in Aggressive Systemic Mastocytosis and Mast Cell Leukemia Not Recruiting

    The safety and efficacy of midostaurin (PKC412), a novel investigational drug, will be evaluated on the basis of response rate, when administered to patients with aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL)

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • Study of Lenalidomide to Evaluate Safety and Efficacy in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia Not Recruiting

    The purpose of this study is to determine the safety and effectiveness of different dose regimen of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Tessa Hunter, (650) 736 - 4032.

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  • Azacitidine With or Without Entinostat in Treating Patients With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia Not Recruiting

    This randomized phase II trial studies azacitidine with or without entinostat to see how well they work compared to azacitidine alone in treating patients with myelodysplastic syndromes, chronic myelomonocytic leukemia, or acute myeloid leukemia. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Entinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine together with entinostat may work better in treating patients with myelodysplastic syndromes, chronic myelomonocytic leukemia, or acute myeloid leukemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Mai Tran, (650) 723 - 8594.

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  • A Phase 2 Study With IPI-926 in Patients With Myelofibrosis Not Recruiting

    The purpose of this study is to determine the safety and efficacy of IPI-926 in patients with myelofibrosis (MF) (primary myelofibrosis [PMF], post-polycythemia vera myelofibrosis [post-PV MF], or post-essential thrombocythemia myelofibrosis [post-ET MF]).

    Stanford is currently not accepting patients for this trial. For more information, please contact Harshdeep Kaur, (650) 723 - 3589.

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  • Safety Study of Human Myeloid Progenitor Cells (CLT-008) After Chemotherapy for Leukemia Not Recruiting

    Ex vivo expanded human myeloid progenitor cells (hMPCs; CLT-008) have the potential to accelerate neutrophil recovery and decrease the risk of febrile neutropenia and infection in patients receiving chemotherapy for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or high-risk myelodysplasia (MDS). In this study, the safety, tolerability and activity of CLT-008 administered after "standard of care" cytarabine-based consolidation or induction/re-induction chemotherapy will be determined by monitoring for adverse reactions, infusion reactions, graft-versus host disease (GVHD), neutrophil and platelet recovery, hMPC persistence, infections and complications.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • A Dose Escalation Study of Lenalidomide in Relapsed or Refractory B-cell Chronic Lymphocytic Leukemia Not Recruiting

    The purpose of this study is to evaluate the safety of lenalidomide and to define the maximum tolerated escalation dose level (MTEDL) when administered by a stepwise dose-escalation schedule in subjects with relapsed or refractory B-cell CLL.

    Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Takahashi, (650) 736 - 4032.

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  • Pilot Lenalidomide in Adult Diamond-Blackfan Anemia Patients w/ RBC Transfusion-Dependent Anemia Recruiting

    This is a single-center, single arm, open-label study of oral lenalidomide monotherapy administered to red blood cell (RBC) transfusion dependent adult subjects with Diamond-Blackfan Anemia (DBA). Primary Objective: To evaluate the erythroid response rate as measured by rate of red blood cell transfusion independence (MDS IWG 2000 Criteria will be applied) Secondary Objective: 1)To evaluate the tolerability and safety profile of lenalidomide in patients with DBA and other inherited marrow failure syndromes 2) To correlate response to lenalidomide with biologic surrogates of DBA including ribosomal protein mutation status, ex vivo erythroid colony growth, and microarray gene expression

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  • Determination of Safe and Effective Dose of Romiplostim (AMG 531) in Subjects With Myelodysplastic Syndrome (MDS)Receiving Hypomethylating Agents Not Recruiting

    The purpose of this study is to evaluate the effect of Romiplostim (AMG 531) on the incidence of clinically significant thrombocytopenic events (grade 3 or 4 and/or receipt of platelet transfusions) in subjects with low or intermediate risk Myelodysplastic Syndrome (MDS) receiving hypomethylating agents. It is hypothesized that Romiplostim administration, at the appropriate dose and schedule, will result in reduction in the incidence of clinically significant thrombocytopenic events in low or intermediate risk MDS subjects receiving hypomethylating agents.

    Stanford is currently not accepting patients for this trial. For more information, please contact Mai Tran, (650) 723 - 8594.

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  • Phase II Study of VELCADE for Relapsed or Refractory T-cell Prolymphocytic Leukemia Not Recruiting

    We hope to learn more about the clinical efficacy of bortezomib in T-cell prolymphocytic leukemia. Patients will be selected as a possible participant in this study because they have a bone marrow disorder known as T-cell prolymphocytic leukemia (T-cell PLL) which does not tend to respond well to conventional treatment with chemotherapy.

    Stanford is currently not accepting patients for this trial. For more information, please contact Richa Rajwanshi, (650) 736 - 4031.

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  • Extension Study Evaluating the Long Term Safety and Efficacy Study of CYT387 in Primary Myelofibrosis (PMF) or Post-polycythemia Vera (PV) or Post-essential Thrombocythemia (ET) Not Recruiting

    This extension protocol to the core study CCL09101 allows patients who have tolerated the drug and derived a clinical benefit, to continue to receive treatment beyond the 9 cycles of the core protocol. Long term safety and efficacy of CYT387 will be evaluated.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4027.

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  • Single Agent Lenalidomide in Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia Not Recruiting

    Time-to-Progression (TTP)

    Stanford is currently not accepting patients for this trial. For more information, please contact Leonel Gallegos, (650) 723 - 2781.

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  • MLN4924 for the Treatment of Acute Myelogenous Leukemia, Myelodysplastic Syndrome, and Acute Lymphoblastic Leukemia Not Recruiting

    An open-label, multicenter, phase 1, dose escalation study of MLN4924 in adult patients with acute myelogenous leukemia (AML), high-grade myelodysplastic syndrome (MDS). The patient population will consist of adults previously diagnosed with AML including high-grade MDS for which standard curative, life-prolonging treatment does not exist or is no longer effective.

    Stanford is currently not accepting patients for this trial. For more information, please contact Leonel Gallegos, (650) 723 - 2781.

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  • Phase 2 Study of Temozolomide to Treat Poor Risk / Refractory Acute Myeloid Leukemia Not Recruiting

    Open-label, non-randomized, parallel assignment, phase 2 trial assessing the safety and efficacy of distinct temozolomide treatment regimens for patients with AML and poor prognosis

    Stanford is currently not accepting patients for this trial. For more information, please contact Richa Rajwanshi, (650) 736 - 4031.

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  • Efficacy and Safety of Simtuzumab in Adults With Primary, Post Polycythemia Vera or Post Essential Thrombocythemia Myelofibrosis Not Recruiting

    This study is to evaluate the efficacy and safety of simtuzumab (GS-6624) on bone marrow fibrosis either alone or in combination with ruxolitinib in participants with Primary myelofibrosis (PMF) and Post Polycythemia Vera or Post Essential Thrombocythemia Myelofibrosis (ET/PV MF). The study is designed as a two stage trial. In the stage 1, patients will be randomized into two cohorts to receive either 200 or 700 mg of study drug. In the stage 2, patients on ruxolitinib will be randomized to receive either 200 or 700 mg of study drug.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • Vorinostat and Gemtuzumab Ozogamicin in Treating Older Patients With Previously Untreated Acute Myeloid Leukemia Not Recruiting

    RATIONALE: Vorinostat may stop the growth of cancer cells by interfering with various proteins needed for cell growth. Monoclonal antibodies, such as gemtuzumab ozogamicin (GO), can block cancer growth in different ways. GO finds cancer cells and helps kill them by carrying a cancer-killing substance to them. Giving vorinostat together with gemtuzumab ozogamicin may kill more cancer cells. PURPOSE: This phase II trial is studying how well giving vorinostat together with gemtuzumab ozogamicin works in treating older patients with previously untreated acute myeloid leukemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Richa Rajwanshi, (650) 736 - 4031.

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  • Clofarabine, Cytarabine, and Filgrastim in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia, Advanced Myelodysplastic Syndrome, and/or Advanced Myeloproliferative Neoplasm Not Recruiting

    This phase II trial is studying how well giving clofarabine and cytarabine together with filgrastim works in treating patients with newly diagnosed acute myeloid leukemia (AML), advanced myelodysplastic syndrome (MDS), and/or advanced myeloproliferative neoplasm. Drugs used in chemotherapy, such as clofarabine and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving the drugs in different doses may kill more cancer cells. Colony stimulating factors, such as filgrastim, may increase the number of immune cells found in bone marrow or peripheral blood and may help the immune system recover from the side effects of chemotherapy.

    Stanford is currently not accepting patients for this trial. For more information, please contact Leonel Gallegos, (650) 723 - 2781.

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  • Safety & Efficacy Study of Oral Panobinostat (LBH589) With Chemotherapy in Patients < 65 Years Old With Acute Myeloid Leukemia (AML) Not Recruiting

    This study will be conducted to assess the maximum tolerated dose (MTD) of panobinostat given 3 times a week (administered on weeks 2 and 3 of a 4 week cycle) in combination with induction chemotherapy (idarubicin and cytarabine) in newly diagnosed patients with a cytopathologically confirmed diagnosis of high-risk AML, and to investigate the safety of the combination in this regimen.

    Stanford is currently not accepting patients for this trial. For more information, please contact Jack Taw, (650) 723 - 2781.

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  • An Extension Study for Subjects Who Are Deriving Benefit With Idelalisib (GS-1101; CAL-101) Following Completion of a Prior Idelalisib Study Recruiting

    This is a long-term safety extension study of idelalisib (GS-1101; CAL-101) in patients with hematologic malignancies who complete other idelalisib studies. It provides the opportunity for patients to continue treatment as long as the patient is deriving clinical benefit. Patients will be followed according to the standard of care as appropriate for their type of cancer. The dose of idelalisib will generally be the same as the dose that was administered at the end of the prior study, but may be titrated up to improve clinical response or down for toxicity. Patients will be withdrawn from the study if they develop progressive disease, unacceptable toxicity related to idelalisib, or if they no longer derive clinical benefit in the opinion of the investigator.

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  • Study to Determine the Maximum Tolerated Dose and Evaluate the Efficacy and Safety of CEP-18770 (Delanzomib) in Patients With Relapsed Multiple Myeloma Refractory to the Most Recent Therapy Not Recruiting

    The primary objective for part 1 of the study is to determine the maximum tolerated dose (MTD) of CEP-18770 in patients with relapsed and refractory multiple myeloma. The primary objective for part 2 is to evaluate the antitumor activity of CEP-18770 in patients treated at the MTD.

    Stanford is currently not accepting patients for this trial. For more information, please contact Leonel Gallegos, (650) 723 - 2781.

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  • S0535, Gemtuzumab and Combination Chemotherapy in Treating Patients With Previously Untreated Acute Promyelocytic Leukemia Not Recruiting

    RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as gemtuzumab, can block cancer growth in different ways. Some find cancer cells and help kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Gemtuzumab may also stop the growth of promyelocytic leukemia by blocking blood flow to the cancer. Giving gemtuzumab together with combination chemotherapy may be more effective in treating promyelocytic leukemia. PURPOSE: This phase II trial is studying how well giving gemtuzumab together with combination chemotherapy works in treating patients with previously untreated promyelocytic leukemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, (650) 725 - 4041.

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  • S0910 Epratuzumab, Cytarabine, and Clofarabine in Treating Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia Not Recruiting

    RATIONALE: Monoclonal antibodies, such as epratuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such as cytarabine and clofarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving epratuzumab together with cytarabine and clofarabine may kill more cancer cells. PURPOSE: This phase II trial is studying the side effects and how well giving epratuzumab together with cytarabine and clofarabine works in treating patients with relapsed or refractory acute lymphoblastic leukemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, (650) 725 - 4041.

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  • Phase I Bortezomib (VELCADE) in Combo With Pralatrexate in Relapsed/Refractory MM Not Recruiting

    The purpose of this trial is to find out the maximum tolerated dose (MTD) of bortezomib (VELCADE) in combination with pralatrexate in patients with previously treated multiple myeloma, AL amyloid and Waldenstroem's macroglobulinemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Ying Hao, 650-723-0646.

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  • Study to Investigate Idelalisib in Combination With Chemotherapeutic Agents, Immunomodulatory Agents and Anti-CD20 Monoclonal Antibody (mAb) in Subjects With Relapsed or Refractory Indolent B-cell Non-Hodgkin's Lymphoma, Mantle Cell Lymphoma or Chronic Lymphocytic Leukemia Not Recruiting

    This study will evaluate the safety and clinical activity of idelalisib in combination with an anti-CD20 monoclonal antibody (mAb), a chemotherapeutic agent, an mTOR inhibitor, a protease inhibitor, an antiangiogenic agent, and/or an immunomodulatory agent in participants with relapsed or refractory indolent B-cell non-Hodgkin lymphoma (NHL), mantle cell lymphoma (MCL), or chronic lymphocytic leukemia (CLL).

    Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, 650725-4041.

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  • COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment: The COMFORT-I Trial Not Recruiting

    This was a randomized, double-blind study comparing the efficacy and safety of ruxolitinib (INCB018424) tablets to matching placebo tablets in patients diagnosed with Myelofibrosis (either Primary Myelofibrosis (PMF) or Post-Polycythemia Vera Myelofibrosis (PPV-MF) or Post-Essential Thrombocythemia Myelofibrosis (PET-MF).

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • Phase 3 Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (CRd) vs Lenalidomide and Dexamethasone (Rd) in Subjects With Relapsed Multiple Myeloma Not Recruiting

    To compare progression-free survival in subjects with relapsed multiple myeloma who are receiving CRd vs subjects receiving Rd in a randomized multicenter setting.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, (650) 725 - 4041.

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  • Efficacy and Safety Study of Idelalisib in Subjects With Indolent B-Cell Non-Hodgkin Lymphoma Not Recruiting

    The purpose of this study is to evaluate the efficacy and safety of idelalisib in patients with previously treated indolent Non-Hodgkin Lymphoma (iNHL) that is refractory both to rituximab and to alkylating-agent-containing chemotherapy. The primary objective will be to assess the overall response rate. Eligible patients will initiate oral therapy with idelalisib at a starting dose of 150 mg taken twice per day. Treatment with idelalisib can continue in compliant patients as long as the study is still ongoing and the patients appear to be benefiting from treatment with acceptable safety.

    Stanford is currently not accepting patients for this trial. For more information, please contact Tessa St.Rose, (650) 736 - 4032.

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  • Safety and Efficacy Study of CYT387 in Primary Myelofibrosis (PMF) or Post-polycythemia Vera (PV) or Post-essential Thrombocythemia (ET) Not Recruiting

    This study seeks to (i) determine a safe and tolerated dose of CYT387 given to patients with PMF, post-PV or post-ET and, (ii) assess the effectiveness of orally-administered CYT387 as a treatment for PMF, post-PV or post-ET.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Lymphoblastic Leukemia Not Recruiting

    RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. PURPOSE: This phase II trial is studying how well combination chemotherapy works in treating young patients with newly diagnosed acute lymphoblastic leukemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Joselene Sipin-Sayno, (650) 736 - 8113.

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  • Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia Not Recruiting

    The purpose of this study is to compare the effects, good and/or bad, of a standard chemotherapy regimen for AML that includes the drugs daunorubicin and cytarabine combined with or without midostaurin (also known as PKC412), to find out which is better. This research is being done because it is unknown whether the addition of midostaurin to chemotherapy treatment is better than chemotherapy treatment alone. Midostaurin has been tested in over 400 patients and is being studied in a number of illnesses, including AML, colon cancer, and lung cancer. Midostaurin blocks an enzyme, produced by a gene known as FLT3, that may have a role in the survival and growth of AML cells. Not all leukemia cells will have the abnormal FLT3 gene. This study will focus only on patients with leukemia cells with the abnormal FLT3 gene.

    Stanford is currently not accepting patients for this trial. For more information, please contact Leonel Gallegos, (650) 723 - 2781.

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  • Phase II Temozolomide + Vorinostat in Patients (>60) w/ Newly Diagnosed or Relapse/Refractory AML Not Recruiting

    The purpose of the study is to first determine if Temozolomide plus Vorinostat in combination can control relapsed or refractory AML and determine if this combination can be safely taken. The study will look at the side effects of the Temozolomide plus Vorinostat in combination and whether the treatment schedule is tolerated.

    Stanford is currently not accepting patients for this trial. For more information, please contact Diana Dobbs, 650-736-6295.

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  • Investigation of Dysregulated Signaling in MPD Via Multiparameter Phospho-specific Flow Cytometry Not Recruiting

    The objective of this study is to better understand the underlying pathogenetic mechanisms of MPDs. We will collect peripheral blood samples from MPD patients and utilize multiparameter phospho-specific flow cytometry to investigate dysregulated signaling in blood cells from these patients. This will provide deeper insights into the pathogenesis of MPDs and may lead to the identification of novel targets for therapeutic intervention.

    Stanford is currently not accepting patients for this trial. For more information, please contact Stephen Oh, 650-723-7875.

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  • Compare Bosutinib To Imatinib In Subjects With Newly Diagnosed Chronic Phase Philadelphia Chromosome Positive CML Not Recruiting

    Two-arm, randomized, open-label trial designed to evaluate the efficacy and safety of bosutinib alone compared to imatinib alone in subjects newly diagnosed with chronic phase Chronic Myelogenous Leukemia (CML). The primary endpoint is cytogenetic response rate at one year.

    Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Takahashi, (650) 736 - 4032.

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  • Study to Determine Efficacy and Safety of Lenalidomide Plus Low-dose Dexamethasone Versus Melphalan, Prednisone, Thalidomide in Patients With Previously Untreated Multiple Myeloma Not Recruiting

    The purpose of this study is to compare the safety and efficacy of Lenalidomide plus low dose dexamethasone to that of the combination of melphalan, prednisone and thalidomide.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, (650) 725 - 4041.

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  • Panobinostat or Placebo With Bortezomib and Dexamethasone in Patients With Relapsed Multiple Myeloma Not Recruiting

    Panobinostat (LBH589) is a highly potent pan-deacetylase inhibitor (pan-DACi), inclusive of HDAC6, which disrupts aggresome function, promotes accumulation of cytotoxic misfolded protein aggregates and triggers myeloma cell death. Combination of pan-DAC and protease inhibition by co-treatment with panobinostat (PAN) and bortezomib (BTZ) has demonstrated synergistic cytotoxicity in vitro and in vivo in pre-clinical experiments. Furthermore, clinical experience in advanced multiple myeloma (MM) patients treated by oral panobinostat and i.v bortezomib ± dexamethasone showed very encouraging results for efficacy and manageable toxicity profile. Given the medical need for improved treatment strategies for patients with previously treated and relapsed MM, the purpose of this prospective, multinational, randomized, double-blind, placebo-controlled, parallel group Phase III study is to compare the results in progression-free survival of 2 combination therapies, panobinostat with bortezomib and dexamethasone or placebo with bortezomib and dexamethasone, in patients with previously treated MM whose disease has recurred or progressed.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, (650) 725 - 4041.

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  • Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis NEW ENGLAND JOURNAL OF MEDICINE Gotlib, J., Kluin-Nelemans, H. C., George, T. I., Akin, C., Sotlar, K., Hermine, O., Awan, F. T., Hexner, E., Mauro, M. J., Sternberg, D. W., Villeneuve, M., Labed, A. H., Stanek, E. J., Hartmann, K., Horny, H., Valent, P., Reiter, A. 2016; 374 (26): 2530-2541

    Abstract

    Advanced systemic mastocytosis comprises rare hematologic neoplasms that are associated with a poor prognosis and lack effective treatment options. The multikinase inhibitor midostaurin inhibits KIT D816V, a primary driver of disease pathogenesis.We conducted an open-label study of oral midostaurin at a dose of 100 mg twice daily in 116 patients, of whom 89 with mastocytosis-related organ damage were eligible for inclusion in the primary efficacy population; 16 had aggressive systemic mastocytosis, 57 had systemic mastocytosis with an associated hematologic neoplasm, and 16 had mast-cell leukemia. The primary outcome was the best overall response.The overall response rate was 60% (95% confidence interval [CI], 49 to 70); 45% of the patients had a major response, which was defined as complete resolution of at least one type of mastocytosis-related organ damage. Response rates were similar regardless of the subtype of advanced systemic mastocytosis, KIT mutation status, or exposure to previous therapy. The median best percentage changes in bone marrow mast-cell burden and serum tryptase level were -59% and -58%, respectively. The median overall survival was 28.7 months, and the median progression-free survival was 14.1 months. Among the 16 patients with mast-cell leukemia, the median overall survival was 9.4 months (95% CI, 7.5 to not estimated). Dose reduction owing to toxic effects occurred in 56% of the patients; re-escalation to the starting dose was feasible in 32% of those patients. The most frequent adverse events were low-grade nausea, vomiting, and diarrhea. New or worsening grade 3 or 4 neutropenia, anemia, and thrombocytopenia occurred in 24%, 41%, and 29% of the patients, respectively, mostly in those with preexisting cytopenias.In this open-label study, midostaurin showed efficacy in patients with advanced systemic mastocytosis, including the highly fatal variant mast-cell leukemia. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT00782067.).

    View details for DOI 10.1056/NEJMoa1513098

    View details for Web of Science ID 000378727200005

    View details for PubMedID 27355533

  • Clinical activity of ponatinib in a patient with FGFR1-rearranged mixed-phenotype acute leukemia. Leukemia Khodadoust, M. S., Luo, B., Medeiros, B. C., Johnson, R. C., Ewalt, M. D., Schalkwyk, A. S., Bangs, C. D., Cherry, A. M., Arai, S., Arber, D. A., Zehnder, J. L., Gotlib, J. 2016; 30 (4): 947-950

    View details for DOI 10.1038/leu.2015.136

    View details for PubMedID 26055304

  • A phase 1, open-label, dose-escalation study of pralatrexate in combination with bortezomib in patients with relapsed/refractory multiple myeloma. British journal of haematology Dunn, T. J., Dinner, S., Price, E., Coutré, S. E., Gotlib, J., Hao, Y., Berube, C., Medeiros, B. C., Liedtke, M. 2016; 173 (2): 253-259

    Abstract

    Pralatrexate inhibits folic acid metabolism, and preclinical studies have shown that it is cytotoxic to multiple myeloma cells. This phase 1 study investigated the safety and efficacy of pralatrexate in combination with bortezomib in adults with relapsed or refractory multiple myeloma. A standard 3 + 3 design was used. Patients received intravenous pralatrexate at doses ranging from 10 to 30 mg/m(2) and intravenous bortezomib at a dose of 1·3 mg/m(2) on days 1, 8 and 15 of each 4-week cycle. Eleven patients were enrolled and completed a median of two cycles. The maximum tolerated dose was 20 mg/m(2) . Two patients experienced dose-limiting toxicity of mucositis. The most frequent non-haematological toxicities were fatigue (55%) and mucositis (45%). There were three serious adverse events in three patients: rash, sepsis and hypotension. One patient (9%) had a very good partial response, 1 (9%) had a partial response, 1 (9%) had minimal response and two (18%) had progressive disease. The median duration of response was 4 months, the median time to next treatment was 3·4 months and the median time to progression was 4 months. Pralatrexate, in combination with bortezomib, was generally safe and demonstrated modest activity in relapsed or refractory multiple myeloma. Clinicaltrials.gov identifier: NCT01114282.

    View details for DOI 10.1111/bjh.13946

    View details for PubMedID 27040320

  • Age-related mutations and chronic myelomonocytic leukemia LEUKEMIA Mason, C. C., Khorashad, J. S., Tantravahi, S. K., Kelley, T. W., Zabriskie, M. S., Yan, D., Pomicter, A. D., Reynolds, K. R., Eiring, A. M., Kronenberg, Z., Sherman, R. L., Tyner, J. W., Dalley, B. K., Dao, K., Yandell, M., Druker, B. J., Gotlib, J., O'Hare, T., Deininger, M. W. 2016; 30 (4): 906-913

    Abstract

    Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy nearly confined to the elderly. Previous studies to determine incidence and prognostic significance of somatic mutations in CMML have relied on candidate gene sequencing, although an unbiased mutational search has not been conducted. As many of the genes commonly mutated in CMML were recently associated with age-related clonal hematopoiesis (ARCH) and aged hematopoiesis is characterized by a myelomonocytic differentiation bias, we hypothesized that CMML and aged hematopoiesis may be closely related. We initially established the somatic mutation landscape of CMML by whole exome sequencing followed by gene-targeted validation. Genes mutated in ⩾10% of patients were SRSF2, TET2, ASXL1, RUNX1, SETBP1, KRAS, EZH2, CBL and NRAS, as well as the novel CMML genes FAT4, ARIH1, DNAH2 and CSMD1. Most CMML patients (71%) had mutations in ⩾2 ARCH genes and 52% had ⩾7 mutations overall. Higher mutation burden was associated with shorter survival. Age-adjusted population incidence and reported ARCH mutation rates are consistent with a model in which clinical CMML ensues when a sufficient number of stochastically acquired age-related mutations has accumulated, suggesting that CMML represents the leukemic conversion of the myelomonocytic-lineage-biased aged hematopoietic system.

    View details for DOI 10.1038/leu.2015.337

    View details for Web of Science ID 000374123100017

    View details for PubMedID 26648538

  • Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome LEUKEMIA & LYMPHOMA Narayan, R., Garcia, J. S., Percival, M. M., Berube, C., Coutre, S., Gotlib, J., Greenberg, P., Liedtke, M., Hewitt, R., Regan, K., Williamson, C., Doykan, C., Cardone, M. H., McMillan, A., Medeiros, B. C. 2016; 57 (3): 609-615
  • Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome. Leukemia & lymphoma Narayan, R., Garcia, J. S., Percival, M. M., Berube, C., Coutre, S., Gotlib, J., Greenberg, P., Liedtke, M., Hewitt, R., Regan, K., Williamson, C., Doykan, C., Cardone, M. H., McMillan, A., Medeiros, B. C. 2016; 57 (3): 609-615

    Abstract

    The outcome of sequential azacitidine with lenalidomide has not been reported in previously treated patients with acute myeloid leukemia (AML) and higher risk myelodysplastic syndrome (MDS). We describe a phase 2 study evaluating the safety and efficacy of this combination in elderly patients with AML and MDS with prior hypomethylating agent (HMA) and/or immunomodulatory agent exposure. Patients were treated on a 42-day cycle with azacitidine at 75 mg/m2 SQ/IV daily on days 1-7, followed by lenalidomide 50 mg orally daily on days 8-28. Median number of treatment cycles on study was two (range, 1-11). Of 32 evaluable patients, the overall response rate was 25%. Neutropenic fever was the most common serious adverse event, but overall the combination was well-tolerated. The median overall survival (OS) for responders versus non-responders was 9.8 versus 4.0 months, respectively (HR 0.36, p=0.016). In conclusion, this combination demonstrated modest clinical activity in this poor risk population.

    View details for DOI 10.3109/10428194.2015.1091930

    View details for PubMedID 26374199

  • The Colony-Stimulating Factor 3 Receptor T640N Mutation Is Oncogenic, Sensitive to JAK Inhibition, and Mimics T618I. Clinical cancer research Maxson, J. E., Luty, S. B., Macmaniman, J. D., Paik, J. C., Gotlib, J., Greenberg, P., Bahamadi, S., Savage, S. L., Abel, M. L., Eide, C. A., Loriaux, M. M., Stevens, E. A., Tyner, J. W. 2016; 22 (3): 757-764

    Abstract

    Colony-stimulating factor 3 receptor (CSF3R) mutations have been identified in the majority of chronic neutrophilic leukemia (CNL) and a smaller percentage of atypical chronic myeloid leukemia (aCML) cases. Although CSF3R point mutations (e.g., T618I) are emerging as key players in CNL/aCML, the significance of rarer CSF3R mutations is unknown. In this study, we assess the importance of the CSF3R T640N mutation as a marker of CNL/aCML and potential therapeutic target.Sanger sequencing of leukemia samples was performed to identify CSF3R mutations in CNL and aCML. The oncogenicity of the CSF3R T640N mutation relative to the T618I mutation was assessed by cytokine independent growth assays and by mouse bone marrow transplant. Receptor dimerization and O-glycosylation of the mutants was assessed by Western blot, and JAK inhibitor sensitivity was assessed by colony assay.Here, we identify a CSF3R T640N mutation in two patients with CNL/aCML, one of whom was originally diagnosed with MDS and acquired the T640N mutation upon evolution of disease to aCML. The T640N mutation is oncogenic in cellular transformation assays and an in vivo mouse bone marrow transplantation model. It exhibits many similar phenotypic features to T618I, including ligand independence and altered patterns of O-glycosylation-despite the transmembrane location of T640 preventing access by GalNAc transferase enzymes. Cells transformed by the T640N mutation are sensitive to JAK kinase inhibition to a similar degree as cells transformed by CSF3R T618I.Because of its similarities to CSF3R T618I, the T640N mutation likely has diagnostic and therapeutic relevance in CNL/aCML. Clin Cancer Res; 1-8. ©2015 AACR.

    View details for DOI 10.1158/1078-0432.CCR-14-3100

    View details for PubMedID 26475333

  • Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Hartmann, K., Escribano, L., Grattan, C., Brockow, K., Carter, M. C., Alvarez-Twose, I., Matito, A., Broesby-Olsen, S., Siebenhaar, F., Lange, M., Niedoszytko, M., Castells, M., Oude Elberink, J. N., Bonadonna, P., Zanotti, R., Hornick, J. L., Torrelo, A., Grabbe, J., Rabenhorst, A., Nedoszytko, B., Butterfield, J. H., Gotlib, J., Reiter, A., Radia, D., Hermine, O., Sotlar, K., George, T. I., Kristensen, T. K., Kluin-Nelemans, H. C., Yavuz, S., Hagglund, H., Sperr, W. R., Schwartz, L. B., Triggiani, M., Maurer, M., Nilsson, G., Horny, H., Arock, M., Orfao, A., Metcalfe, D. D., Akin, C., Valent, P. 2016; 137 (1): 35-45
  • Tyrosine Kinase Inhibitors and Therapeutic Antibodies in Advanced Eosinophilic Disorders and Systemic Mastocytosis CURRENT HEMATOLOGIC MALIGNANCY REPORTS Gotlib, J. 2015; 10 (4): 351-361
  • Effect of treatment with a JAK2-selective inhibitor, fedratinib, on bone marrow fibrosis in patients with myelofibrosis JOURNAL OF TRANSLATIONAL MEDICINE Jamieson, C., Hasserjian, R., Gotlib, J., Cortes, J., Stone, R., Talpaz, M., Thiele, J., Rodig, S., Pozdnyakova, O. 2015; 13
  • A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis HAEMATOLOGICA Vannucchi, A. M., Kantarjian, H. M., Kiladjian, J., Gotlib, J., Cervantes, F., Mesa, R. A., Sarlis, N. J., Peng, W., Sandor, V., Gopalakrishna, P., Hmissi, A., Stalbovskaya, V., Gupta, V., Harrison, C., Verstovsek, S. 2015; 100 (9): 1139-1145
  • Phase II evaluation of IPI-926, an oral Hedgehog inhibitor, in patients with myelofibrosis LEUKEMIA & LYMPHOMA Sasaki, K., Gotlib, J. R., Mesa, R. A., Newberry, K. J., Ravandi, F., Cortes, J. E., Kelly, P., Kutok, J. L., Kantarjian, H. M., Verstovsek, S. 2015; 56 (7): 2092-2097

    Abstract

    The clinical safety and efficacy of IPI-926 was evaluated in 14 patients with myelofibrosis in a phase II study. Patients received 160 mg IPI-926 orally in continuous 28-day cycles. The median treatment duration was 5.1 months, and all patients had discontinued treatment by 7.5 months. Nine patients discontinued due to lack of response as determined by the treating physician, two after developing acute leukemia and one due to disease progression/loss of response. Twelve patients had slight reductions in spleen size (less than 50% from baseline), but symptoms did not improve consistently. One patient achieved transfusion independence lasting 5 months. Reductions in GLI1 mRNA and protein levels, JAK2V617F allele burden, degree of fibrosis or cytokine levels were observed in some patients, but were not significant when evaluated for the cohort. Low-grade gastrointestinal/liver abnormalities were the most common toxicities. The results did not support continued evaluation of IPI-926 as a monotherapy in myelofibrosis.

    View details for DOI 10.3109/10428194.2014.984703

    View details for Web of Science ID 000359888700028

    View details for PubMedID 25641433

  • KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis LEUKEMIA Arock, M., Sotlar, K., Akin, C., Broesby-Olsen, S., Hoermann, G., Escribano, L., Kristensen, T. K., Kluin-Nelemans, H. C., Hermine, O., Dubreuil, P., Sperr, W. R., Hartmann, K., Gotlib, J., Cross, N. C., Haferlach, T., Garcia-Montero, A., Orfao, A., Schwaab, J., Triggiani, M., Horny, H., Metcalfe, D. D., Reiter, A., Valent, P. 2015; 29 (6): 1223-1232
  • Next-generation sequencing of acute myeloid leukemia identifies the significance of TP53, U2AF1, ASXL1, and TET2 mutations MODERN PATHOLOGY Ohgami, R. S., Ma, L., Merker, J. D., Gotlib, J. R., Schrijver, I., Zehnder, J. L., Arber, D. A. 2015; 28 (5): 706-714

    Abstract

    We assessed the frequency and clinicopathologic significance of 19 genes currently identified as significantly mutated in myeloid neoplasms, RUNX1, ASXL1, TET2, CEBPA, IDH1, IDH2, DNMT3A, FLT3, NPM1, TP53, NRAS, EZH2, CBL, U2AF1, SF3B1, SRSF2, JAK2, CSF3R, and SETBP1, across 93 cases of acute myeloid leukemia (AML) using capture target enrichment and next-generation sequencing. Of these cases, 79% showed at least one nonsynonymous mutation, and cases of AML with recurrent genetic abnormalities showed a lower frequency of mutations versus AML with myelodysplasia-related changes (P<0.001). Mutational analysis further demonstrated that TP53 mutations are associated with complex karyotype AML, whereas ASXL1 and U2AF1 mutations are associated with AML with myelodysplasia-related changes. Furthermore, U2AF1 mutations were specifically associated with trilineage morphologic dysplasia. Univariate analysis demonstrated that U2AF1 and TP53 mutations are associated with absence of clinical remission, poor overall survival (OS), and poor disease-free survival (DFS; P<0.0001), whereas TET2 and ASXL1 mutations are associated with poor OS (P<0.03). In multivariate analysis, U2AF1 and TP53 mutations retained independent prognostic significance in OS and DFS, respectively. Our results demonstrate unique relationships between mutations in AML, clinicopathologic prognosis, subtype categorization, and morphologic dysplasia.Modern Pathology advance online publication, 21 November 2014; doi:10.1038/modpathol.2014.160.

    View details for DOI 10.1038/modpathol.2014.160

    View details for Web of Science ID 000353774200010

  • Mast Cells in Systemic Mastocytosis Have Distinctly Brighter CD45 Expression by Flow Cytometry AMERICAN JOURNAL OF CLINICAL PATHOLOGY Chisholm, K. M., Merker, J. D., Gotlib, J. R., Gitana, G., Lefterova, M., Zehnder, J. L., George, T. I., Arber, D. A., Ohgami, R. S. 2015; 143 (4): 527-534

    Abstract

    We sought to determine the significance of bright CD45 expression on mast cells in cases of systemic mastocytosis vs mast cells in bone marrows uninvolved by systemic mastocytosis and compare this CD45 expression with CD25 and CD2 expression on mast cells.Multiparameter flow cytometry was performed on 31 cases of systemic mastocytosis and 70 bone marrow cases that were not involved by systemic mastocytosis. Bright expression of CD45 was defined as more than 20% of CD117+ mast cells showing brighter CD45 expression than the average expression level of lymphocytes.Mast cells with bright CD45 expression were seen in 26 systemic mastocytosis cases and three bone marrows uninvolved by systemic mastocytosis (sensitivity, 84%; specificity, 96%). CD25 alone had a greater sensitivity (100%) but lower specificity (93%) compared with bright CD45 for identifying abnormal mast cells, while CD2 alone had lower sensitivity but higher specificity. To reach a specificity of 100%, CD25 together with bright CD45 on mast cells was the optimal combination to detect cases of systemic mastocytosis.A combination of bright CD45 and CD25 appears to specifically identify abnormal mast cells in cases of systemic mastocytosis. Further studies will be necessary to confirm these results.

    View details for DOI 10.1309/AJCPZ3J4GEEYIRRA

    View details for Web of Science ID 000351331200009

  • Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I. Haematologica Verstovsek, S., Mesa, R. A., Gotlib, J., Levy, R. S., Gupta, V., DiPersio, J. F., Catalano, J. V., Deininger, M. W., Miller, C. B., Silver, R. T., Talpaz, M., Winton, E. F., Harvey, J. H., Arcasoy, M. O., Hexner, E. O., Lyons, R. M., Raza, A., Vaddi, K., Sun, W., Peng, W., Sandor, V., Kantarjian, H. 2015; 100 (4): 479-488

    Abstract

    In the phase III COMFORT-I study, the Janus kinase 1 (JAK1)/JAK2 inhibitor ruxolitinib provided significant improvements in splenomegaly, key symptoms, and quality-of-life measures and was associated with an overall survival benefit relative to placebo in patients with intermediate-2 or high-risk myelofibrosis. This planned analysis assessed the long-term efficacy and safety of ruxolitinib at a median follow-up of 149 weeks. At data cutoff, approximately 50% of patients originally randomized to ruxolitinib remained on treatment whereas all patients originally assigned to placebo had discontinued or crossed over to ruxolitinib. At week 144, mean spleen volume reduction was 34% with ruxolitinib. Previously observed improvements in quality-of-life measures were sustained with longer-term ruxolitinib therapy. Overall survival continued to favor ruxolitinib despite the majority of placebo patients crossing over to ruxolitinib [hazard ratio 0.69 (95% confidence interval: 0.46-1.03); P=0.067]. Exploratory analyses suggest that crossover may have contributed to an underestimation of the true survival difference between the treatment groups. Ruxolitinib continued to be generally well tolerated; there was no pattern of worsening grade ≥3 anemia or thrombocytopenia with longer-term ruxolitinib exposure. These longer-term data continue to support the efficacy and safety of ruxolitinib in patients with myelofibrosis. The study is registered at clinicaltrials.gov: NCT00952289.

    View details for DOI 10.3324/haematol.2014.115840

    View details for PubMedID 25616577

  • Effects of Ruxolitinib Treatment on Metabolic and Nutritional Parameters in Patients With Myelofibrosis From COMFORT-I CLINICAL LYMPHOMA MYELOMA & LEUKEMIA Mesa, R. A., Verstoysek, S., Gupta, V., Mascarenhas, J. O., Atallah, E., Burn, T., Sun, W., Sandor, V., Gotlib, J. 2015; 15 (4): 214-221

    Abstract

    In the COMFORT (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy)-I study, the Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib provided significant reductions in splenomegaly, improvements in myelofibrosis (MF)-related symptoms, and a survival advantage relative to placebo in patients with intermediate-2 or high-risk MF. In this post hoc analysis, we assessed the effects of ruxolitinib treatment on measures of metabolic and nutritional status.Patients were randomized to receive ruxolitinib (n = 155; 15 or 20 mg twice a day for patients with baseline platelet counts of 100-200 × 10(9)/L or > 200 × 10(9)/L, respectively) or placebo (n = 154). The primary end point was the proportion of patients with a ≥ 35% spleen volume reduction from baseline to week 24. A secondary end point was the proportion of patients with ≥ 50% improvement in Total Symptom Score (TSS) from baseline to week 24, measured using the modified Myelofibrosis Symptom Assessment Form version 2.0. Weight, cholesterol, and albumin were measured at specified time points throughout the study.Compared with placebo, ruxolitinib treatment was associated with increased weight (mean change: 3.9 kg vs. -1.9 kg), total cholesterol (mean percentage change: 26.4% vs. -3.3%), and albumin levels (mean percentage change: 5.8% vs. -1.7%) at week 24; sustained improvements were observed with longer-term ruxolitinib therapy. Relative to placebo, increases in mean weight, total cholesterol, and albumin levels were observed with ruxolitinib treatment regardless of the degree of spleen volume and TSS reductions at 24 weeks.Treatment with ruxolitinib improved measures of metabolic and nutritional status of patients with intermediate-2 or high-risk MF.

    View details for DOI 10.1016/j.clml.2014.12.008

    View details for Web of Science ID 000352659300004

    View details for PubMedID 25682576

  • Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I HAEMATOLOGICA Verstovsek, S., Mesa, R. A., Gotlib, J., Levy, R. S., Gupta, V., DiPersio, J. F., Catalano, J. V., Deininger, M. W., Miller, C. B., Silver, R. T., Talpaz, M., Winton, E. F., Harvey, J. H., Arcasoy, M. O., Hexner, E. O., Lyons, R. M., Raza, A., Vaddi, K., Sun, W., Peng, W., Sandor, V., Kantarjian, H. 2015; 100 (4): 482-491
  • Historical Views, Conventional Approaches, and Evolving Management Strategies for Myeloproliferative Neoplasms JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Stein, B. L., Gotlib, J., Arcasoy, M., Nguyen, M. H., Shah, N., Moliterno, A., Jamieson, C., Pollyea, D. A., Scott, B., Wadleigh, M., Levine, R., Komrokji, R., Klisovic, R., Gundabolu, K., Kropf, P., Wetzler, M., Oh, S. T., Ribeiro, R., Paschal, R., Mohan, S., Podoltsev, N., Prchal, J., Talpaz, M., Snyder, D., Verstovsek, S., Mesa, R. A. 2015; 13 (4): 424-434

    Abstract

    The classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPN), which include essential thrombocythemia, polycythemia vera, and myelofibrosis (MF), are in a new era of molecular diagnosis, ushered in by the identification of the JAK2(V617F) and cMPL mutations in 2005 and 2006, respectively, and the CALR mutations in 2013. Coupled with increased knowledge of disease pathogenesis and refined diagnostic criteria and prognostic scoring systems, a more nuanced appreciation has emerged of the burden of MPN in the United States, including the prevalence, symptom burden, and impact on quality of life. Biological advances in MPN have translated into the rapid development of novel therapeutics, culminating in the approval of the first treatment for MF, the JAK1/JAK2 inhibitor ruxolitinib. However, certain practical aspects of care, such as those regarding diagnosis, prevention of vascular events, choice of cytoreductive agent, and planning for therapies, present challenges for hematologists/oncologists, and are discussed in this article.

    View details for Web of Science ID 000352962200008

    View details for PubMedID 25870379

  • Mutations in G protein beta subunits promote transformation and kinase inhibitor resistance NATURE MEDICINE Yoda, A., Adelmant, G., Tamburini, J., Chapuy, B., Shindoh, N., Yoda, Y., Weigert, O., Kopp, N., Wu, S., Kim, S. S., Liu, H., Tivey, T., Christie, A. L., Elpek, K. G., Card, J., Gritsman, K., Gotlib, J., Deininger, M. W., Makishima, H., Turley, S. J., Javidi-Sharifi, N., Maciejewski, J. P., Jaiswal, S., Ebert, B. L., Rodig, S. J., Tyner, J. W., Marto, J. A., Weinstock, D. M., Lane, A. A. 2015; 21 (1): 71-75

    Abstract

    Activating mutations in genes encoding G protein α (Gα) subunits occur in 4-5% of all human cancers, but oncogenic alterations in Gβ subunits have not been defined. Here we demonstrate that recurrent mutations in the Gβ proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling. Multiple mutations in GNB1 affect the protein interface that binds Gα subunits as well as downstream effectors and disrupt Gα interactions with the Gβγ dimer. Different mutations in Gβ proteins clustered partly on the basis of lineage; for example, all 11 GNB1 K57 mutations were in myeloid neoplasms, and seven of eight GNB1 I80 mutations were in B cell neoplasms. Expression of patient-derived GNB1 variants in Cdkn2a-deficient mouse bone marrow followed by transplantation resulted in either myeloid or B cell malignancies. In vivo treatment with the dual PI3K-mTOR inhibitor BEZ235 suppressed GNB1-induced signaling and markedly increased survival. In several human tumors, mutations in the gene encoding GNB1 co-occurred with oncogenic kinase alterations, including the BCR-ABL fusion protein, the V617F substitution in JAK2 and the V600K substitution in BRAF. Coexpression of patient-derived GNB1 variants with these mutant kinases resulted in inhibitor resistance in each context. Thus, GNB1 and GNB2 alterations confer transformed and resistance phenotypes across a range of human tumors and may be targetable with inhibitors of G protein signaling.

    View details for DOI 10.1038/nm.3751

    View details for Web of Science ID 000348408000015

    View details for PubMedID 25485910

  • Salvage therapy with mitoxantrone, etoposide and cytarabine in relapsed or refractory acute lymphoblastic leukemia LEUKEMIA RESEARCH Liedtke, M., Dunn, T., Dinner, S., Coutre, S. E., Berubea, C., Gotlib, J., Patel, S., Medeiros, B. 2014; 38 (12): 1441-1445
  • Chronic Myelogenous Leukemia, Version 1.2015 Clinical Practice Guidelines in Oncology JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK O'Brien, S., Radich, J. P., Abboud, C. N., Akhtari, M., Altman, J. K., Berman, E., Curtin, P., DeAngelo, D. J., Deininger, M., Devine, S., Fathi, A. T., Gotlib, J., Jagasia, M., Kropf, P., Moore, J. O., Pallera, A., Reddy, V. V., Shah, N. P., Smith, B. D., Snyder, D. S., Wetzler, M., Gregory, K., Sundar, H. 2014; 12 (11): 1590-1609
  • The serum tryptase test: an emerging robust biomarker in clinical hematology EXPERT REVIEW OF HEMATOLOGY Valent, P., Sperr, W. R., Sotlar, K., Reiter, A., Akin, C., Gotlib, J., Horny, H., Arock, M. 2014; 7 (5): 683-690
  • Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis ALLERGY Valent, P., Escribano, L., Broesby-Olsen, S., Hartmann, K., Grattan, C., Brockow, K., Niedoszytko, M., NEDOSZYTKO, B., Elberink, J. N., Kristensen, T., Butterfield, J. H., Triggiani, M., Alvarez-Twose, I., Reiter, A., Sperr, W. R., Sotlar, K., Yavuz, S., Kluin-Nelemans, H. C., Hermine, O., Radia, D., van Doormaal, J. J., Gotlib, J., Orfao, A., Siebenhaar, F., SCHWARTZ, L. B., Castells, M., Maurer, M., Horny, H., Akin, C., Metcalfe, D. D., Arock, M. 2014; 69 (10): 1267-1274

    View details for DOI 10.1111/all.12436

    View details for Web of Science ID 000342759700003

  • Janus Kinase Inhibitors and Allogeneic Stem Cell Transplantation for Myelofibrosis BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Gupta, V., Gotlib, J., Radich, J. P., Kroeger, N. M., Rondelli, D., Verstovsek, S., Deeg, H. J. 2014; 20 (9): 1274-1281

    Abstract

    Myelofibrosis (MF) is a manifestation of several disorders of hematopoiesis, collectively referred to as myeloproliferative neoplasms. Allogeneic hematopoietic stem cell transplantation (ASCT) is the only therapy with proven curative potential. However, most patients with MF are in their 6th or 7th decade of life, and only some of these patients have been considered suitable transplantation candidates. The development of reduced-intensity conditioning regimens with limited toxicity has allowed clinicians to offer ASCT to a growing number of older patients. The availability of Janus Kinase (JAK) 1/2 inhibitors allows clinicians to provide symptom relief and improved quality of life for MF patients. These drugs may also affect the decision regarding, in particular, the timing of ASCT. Future studies need to address the role of JAK1/2 inhibitors in patients who are transplantation candidates and determine their role before and, possibly, after transplantation. The identification of indications for the use of JAK1/2 inhibitors in the context of transplantation may lead to new therapeutic strategies for patients with MF.

    View details for DOI 10.1016/j.bbmt.2014.03.017

    View details for Web of Science ID 000340986200004

    View details for PubMedID 24680977

  • Refined diagnostic criteria and classification of mast cell leukemia (MCL) and myelomastocytic leukemia (MML): a consensus proposal ANNALS OF ONCOLOGY Valent, P., Sotlar, K., Sperr, W. R., Escribano, L., Yavuz, S., Reiter, A., George, T. I., Kluin-Nelemans, H. C., Hermine, O., Butterfield, J. H., Hagglund, H., Ustun, C., Hornick, J. L., Triggiani, M., Radia, D., Akin, C., Hartmann, K., Gotlib, J., SCHWARTZ, L. B., Verstovsek, S., Orfao, A., Metcalfe, D. D., Arock, M., Horny, H. 2014; 25 (9): 1691-1700
  • Acute Myeloid Leukemia With Monosomal Karyotype Morphologic, Immunophenotypic, and Molecular Findings AMERICAN JOURNAL OF CLINICAL PATHOLOGY Weinberg, O. K., Ohgami, R. S., Ma, L., Seo, K., Ren, L., Gotlib, J. R., Seetharam, M., Cherry, A., Arber, D. A. 2014; 142 (2): 190-195

    Abstract

    Acute myeloid leukemia (AML) with monosomal karyotype (MK) recently has been reported to be associated with worse outcome than the traditional complex karyotype.In this retrospective study of 111 patients with AML, we identified 14 patients with MK (13% of all patients with AML) using the definition proposed by Breems et al.Five (36%) of these 14 patients had a loss of a single chromosome in the presence of other structural abnormalities, and nine (64%) had a loss of two or more autosomal chromosomes. Patients with AML-MK presented at an older age, with lower bone marrow blasts, and their blasts less frequently expressed CD34. Most patients with AML-MK had morphologic multilineage dysplasia and were predominantly subclassified as having AML with myelodysplasia-related changes (AML-MRC). Molecular analysis showed a significant absence of NPM1 and FLT3 in patients with AML-MK.Outcome data showed that patients with AML-MK had significantly worse overall survival, disease-free survival, and complete response compared with the rest of the patients with AML as well as within the AML-MRC group.

    View details for DOI 10.1309/AJCPMLO84JDNVLNK

    View details for Web of Science ID 000339415400009

  • Altered translation of GATA1 in Diamond-Blackfan anemia NATURE MEDICINE Ludwig, L. S., Gazda, H. T., Eng, J. C., Eichhorn, S. W., Thiru, P., Ghazvinian, R., George, T. I., Gotlib, J. R., Beggs, A. H., Sieff, C. A., Lodish, H. F., Lander, E. S., Sankaran, V. G. 2014; 20 (7): 748-753

    Abstract

    Ribosomal protein haploinsufficiency occurs in diverse human diseases including Diamond-Blackfan anemia (DBA), congenital asplenia and T cell leukemia. Yet, how mutations in genes encoding ubiquitously expressed proteins such as these result in cell-type- and tissue-specific defects remains unknown. Here, we identify mutations in GATA1, encoding the critical hematopoietic transcription factor GATA-binding protein-1, that reduce levels of full-length GATA1 protein and cause DBA in rare instances. We show that ribosomal protein haploinsufficiency, the more common cause of DBA, can lead to decreased GATA1 mRNA translation, possibly resulting from a higher threshold for initiation of translation of this mRNA in comparison with other mRNAs. In primary hematopoietic cells from patients with mutations in RPS19, encoding ribosomal protein S19, the amplitude of a transcriptional signature of GATA1 target genes was globally and specifically reduced, indicating that the activity, but not the mRNA level, of GATA1 is decreased in patients with DBA associated with mutations affecting ribosomal proteins. Moreover, the defective hematopoiesis observed in patients with DBA associated with ribosomal protein haploinsufficiency could be partially overcome by increasing GATA1 protein levels. Our results provide a paradigm by which selective defects in translation due to mutations affecting ubiquitous ribosomal proteins can result in human disease.

    View details for DOI 10.1038/nm.3557

    View details for Web of Science ID 000338689500017

    View details for PubMedID 24952648

  • Hereditary erythrocytosis, thrombocytosis and neutrophilia BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY Hong, W., Gotlib, J. 2014; 27 (2): 95-106

    Abstract

    Hereditary erythrocytosis, thrombocytosis, and neutrophilia are rare inherited syndromes which exhibit Mendelian inheritance. Some patients with primary hereditary erythrocytosis exhibit a mutation in the erythropoietin receptor (EPOR) which is associated with low serum erythropoietin (EPO) levels. Secondary congenital erythrocytosis may be characterized by normal or high serum EPO levels, and is related to high oxygen affinity haemoglobin variants, mutation of the enzyme biphosphoglycerate mutase (BPGM), or defects in components of the oxygen-sensing pathway. Hereditary thrombocytosis was first linked to mutations in genes encoding thrombopoietin (THPO) or the thrombopoietin receptor, MPL. More recently, germline mutations in JAK2, distinct from JAK2 V617F, and mutation of the gelsolin gene, were uncovered in several pedigrees of hereditary thrombocytosis. Hereditary neutrophilia has been described in one family with an activating germline mutation in CSF3R. The mutational basis for most hereditary myeloproliferative disorders has yet to be identified.

    View details for DOI 10.1016/j.beha.2014.07.002

    View details for Web of Science ID 000342534800003

    View details for PubMedID 25189721

  • CME Information: World Health Organization-defined eosinophilic disorders: 2014 update on diagnosis, risk stratification, and management AMERICAN JOURNAL OF HEMATOLOGY Gotlib, J. 2014; 89 (3): 325-337

    View details for DOI 10.1002/ajh.23664

    View details for Web of Science ID 000331941600016

  • Comparison of placebo and best available therapy for the treatment of myelofibrosis in the phase 3 COMFORT studies HAEMATOLOGICA Mesa, R. A., Kiladjian, J., Verstovsek, S., Al-Ali, H. K., Gotlib, J., Gisslinger, H., Levy, R., Siulnik, A., Gupta, V., Khan, M., DiPersio, J. F., McQuitty, M., Catalano, J. V., Hunter, D. S., Knoops, L., Deininger, M., Cervantes, F., Miller, C., Vannucchi, A. M., Silver, R. T., Barbui, T., Talpaz, M., Barosi, G., Winton, E. F., Mendeson, E., Harvey, J. H., Arcasoy, M. O., Hexner, E., Lyons, R. M., Paquette, R., Raza, A., Sun, W., Sandor, V., Kantarjian, H. M., Harrison, C. 2014; 99 (2): 292-298

    Abstract

    Prior to Janus kinase inhibitors, available therapies for myelofibrosis were generally supportive and did not improve survival. This analysis compares efficacy outcomes of patients with myelofibrosis in the control arms (placebo [n=154] and best available therapy [n=73]) from the two phase 3 COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment (COMFORT) studies. Spleen volume was assessed by magnetic resonance imaging/computed tomography at baseline and every 12 weeks through week 72; spleen length was assessed by palpation at each study visit. Health-related quality of life and symptoms were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Items at baseline and in weeks 4, 8, 12, 16 and 24 in COMFORT-I and in weeks 8, 16, 24 and 48 in COMFORT-II. The demographic and baseline characteristics were similar between the control arms of the two studies. One patient who received placebo and no patients who received best available therapy had a ≥35% reduction in spleen volume from baseline at week 24. At 24 weeks, neither placebo nor best available therapy had produced clinically meaningful changes in global quality of life or symptom scales. Non-hematologic adverse events were mostly grade 1/2; the most frequently reported adverse events in each group were abdominal pain, fatigue, peripheral edema and diarrhea. These data suggest that non-Janus kinase inhibitor therapies provide little improvement in splenomegaly, symptoms or quality of life as compared with placebo. Both COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544) studies have been appropriately registered with clinicaltrials.gov.

    View details for DOI 10.3324/haematol.2013.087650

    View details for Web of Science ID 000336253900021

    View details for PubMedID 23911705

  • Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes ONCOTARGETS AND THERAPY Verstovsek, S., Gotlib, J., Gupta, V., Atallah, E., Mascarenhas, J., Quintas-Cardama, A., Sun, W., Sarlis, N. J., Sandor, V., Levy, R. S., Kantarjian, H. M., Mesa, R. A. 2014; 7: 13-21

    View details for DOI 10.2147/OTT.S53348

    View details for Web of Science ID 000328610100001

  • JAK inhibition in the myeloproliferative neoplasms: lessons learned from the bench and bedside HEMATOLOGY-AMERICAN SOCIETY OF HEMATOLOGY EDUCATION PROGRAM Gotlib, J. 2013: 529-537

    Abstract

    The discovery of the JAK2 V617F mutation in the classic BCR-ABL1-negative myeloproliferative neoplasms in 2005 catalyzed a burst of research efforts that have culminated in substantial dividends for patients. Beyond JAK2 V617F, a more detailed picture of the pathobiologic basis for activated JAK-STAT signaling has emerged. In some patients with myelofibrosis (MF), next-generation sequencing technologies have revealed a complex clonal architecture affecting both genetic and epigenetic regulators of cell growth and differentiation. Although these bench-top findings have informed the clinical development of JAK inhibitors in MF, they have also provided scientific context for some of their limitations. The JAK1/JAK2 inhibitor ruxolitinib is approved for treatment of MF in North America and Europe and other lead JAK inhibitors discussed herein (fedratinib [SAR302503], momelotinib [CYT387], and pacritinib [SB1518]), have entered advanced phases of trial investigation. Uniformly, these agents share the ability to reduce spleen size and symptom burden. A major challenge for practitioners is how to optimize dosing of these agents to secure clinically relevant and durable benefits while minimizing myelosuppression. Suboptimal responses have spurred a "return to the bench" to characterize the basis for disease persistence and to inform new avenues of drug therapy.

    View details for Web of Science ID 000331900300075

    View details for PubMedID 24319228

  • Efficacy, safety and survival with ruxolitinib in patients with myelofibrosis: results of a median 2-year follow-up of COMFORT-I HAEMATOLOGICA Verstovsek, S., Mesa, R. A., Gotlib, J., Levy, R. S., Gupta, V., DiPersio, J. F., Catalano, J. V., Deininger, M. W., Miller, C. B., Silver, R. T., Talpaz, M., Winton, E. F., Harvey, J. H., Arcasoy, M. O., Hexner, E. O., Lyons, R. M., Paquette, R., Raza, A., Vaddi, K., Erickson-Viitanen, S., Sun, W., Sandor, V., Kantarjian, H. M. 2013; 98 (12): 1865-1871

    Abstract

    COMFORT-I is a randomized, double-blind, placebo-controlled trial of the Janus kinase 1/Janus kinase 2 inhibitor ruxolitinib in 309 patients with intermediate-2 or high-risk myelofibrosis. This analysis of COMFORT-I describes the long-term efficacy and safety of ruxolitinib (median follow-up, 2 years). Spleen volume was measured by magnetic resonance imaging, and quality of life was evaluated using the EORTC QLQ-C30. Overall survival was determined according to randomized treatment group. At the time of this analysis, 100 of 155 patients randomized to ruxolitinib were still receiving treatment. All patients randomized to placebo crossed over to ruxolitinib or discontinued within 3 months of the primary analysis (median time to crossover, 41 weeks). Mean spleen volume reductions in the ruxolitinib group were 31.6% at week 24 and 34.9% at week 96; improvements in quality of life measures were also maintained. Improved survival was observed for ruxolitinib (n=27 deaths) versus placebo (n=41 deaths) (hazard ratio=0.58; 95% confidence interval: 0.36, 0.95; P=0.03). The incidence of new-onset grade 3 or 4 anemia and thrombocytopenia decreased over time to levels observed in patients receiving placebo. These data indicate that ruxolitinib treatment provides durable reductions in spleen volume and improvements in quality of life and suggest a continued survival advantage for ruxolitinib over placebo.

    View details for DOI 10.3324/haematol.2013.092155

    View details for Web of Science ID 000328545500014

    View details for PubMedID 24038026

  • Comprehensive whole-genome sequencing of an early-stage primary myelofibrosis patient defines low mutational burden and non-recurrent candidate genes. Haematologica Merker, J. D., Roskin, K. M., Ng, D., Pan, C., Fisk, D. G., King, J. J., Hoh, R., Stadler, M., Okumoto, L. M., Abidi, P., Hewitt, R., Jones, C. D., Gojenola, L., Clark, M. J., Zhang, B., Cherry, A. M., George, T. I., Snyder, M., Boyd, S. D., Zehnder, J. L., Fire, A. Z., Gotlib, J. 2013; 98 (11): 1689-1696

    Abstract

    In order to identify novel somatic mutations associated with classic BCR/ABL1-negative myeloproliferative neoplasms, we performed high-coverage genome sequencing of DNA from peripheral blood granulocytes and cultured skin fibroblasts from a patient with MPL W515K-positive primary myelofibrosis. The primary myelofibrosis genome had a low somatic mutation rate, consistent with that observed in similar hematopoietic tumor genomes. Interfacing of whole-genome DNA sequence data with RNA expression data identified three somatic mutations of potential functional significance: a nonsense mutation in CARD6, implicated in modulation of NF-kappaB activation; a 19-base pair deletion involving a potential regulatory region in the 5'-untranslated region of BRD2, implicated in transcriptional regulation and cell cycle control; and a non-synonymous point mutation in KIAA0355, an uncharacterized protein. Additional mutations in three genes (CAP2, SOX30, and MFRP) were also evident, albeit with no support for expression at the RNA level. Re-sequencing of these six genes in 178 patients with polycythemia vera, essential thrombocythemia, and myelofibrosis did not identify recurrent somatic mutations in these genes. Finally, we describe methods for reducing false-positive variant calls in the analysis of hematologic malignancies with a low somatic mutation rate. This trial is registered with ClinicalTrials.gov (NCT01108159).

    View details for DOI 10.3324/haematol.2013.092379

    View details for PubMedID 23872309

  • Chronic Myelogenous Leukemia, Version 1.2014 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK O'Brien, S., Radich, J. P., Abboud, C. N., Akhtari, M., Altman, J. K., Berman, E., DeAngelo, D. J., Deininger, M., Devine, S., Fathi, A. T., Gotlib, J., Jagasia, M., Kropf, P., Moore, J. O., Pallera, A., Pinilla-Ibarz, J., Reddy, V. V., Shah, N. P., Smith, B. D., Snyder, D. S., Wetzler, M., Gregory, K., Sundar, H. 2013; 11 (11): 1327-1340
  • Hidden Mastocytosis in Acute Myeloid Leukemia With t(8;21)(q22;q22) AMERICAN JOURNAL OF CLINICAL PATHOLOGY Johnson, R. C., Savage, N. M., Chiang, T., Gotlib, J. R., Cherry, A. M., Arber, D. A., George, T. I. 2013; 140 (4): 525-535

    Abstract

    Objectives: To assess the frequency of systemic mastocytosis (SM) in a large series of acute myeloid leukemia (AML) with t(8;21)(q22;q22). Methods: We retrospectively characterized 40 bone marrow aspirate smears and biopsy specimens from patients with AML with t(8;21) for the presence of SM. Cases were assessed for mast cell morphology and immunohistochemistry, as well as KIT exon 8 and 17 mutational assessment by reverse transcription polymerase chain reaction. Results: Four patients met criteria for SM, 1 met criteria for myelomastocytic leukemia, and 8 demonstrated the benign finding of mast cell hyperplasia. Conclusions: We recommend examining all cases of AML with t(8;21) for the presence of SM via morphology, immunophenotyping, and KIT mutational analysis studies.

    View details for DOI 10.1309/AJCP1Q0YSXEAHNKK

    View details for Web of Science ID 000330099800010

    View details for PubMedID 24045550

  • Myeloid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, and FGFR1: a review INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY Savage, N., George, T. I., Gotlib, J. 2013; 35 (5): 491-500

    Abstract

    Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of platelet-derived growth factor receptor alpha (PDGFRA), platelet-derived growth factor receptor beta (PDGFRB), and fibroblast growth factor receptor-1 (FGFR1) are a group of hematologic neoplasms resulting from the formation of abnormal fusion genes that encode constitutively activated tyrosine kinases. These entities are now separated into their own major category in the 2008 World Health Organization classification of hematolymphoid tumors. Although eosinophilia is characteristic of these diseases, the clinical presentation of the three entities is variable. Conventional cytogenetics (karyotyping) will detect the majority of abnormalities involving PDGFRB and FGFR1, but florescence in situ hybridization (FISH)/molecular studies are required to detect factor interacting with PAP (FIP1L1)-PDGFRA as the characteristic 4q12 interstitial deletion is cryptic. Imatinib mesylate (imatinib) is the first-line therapy for patients with abnormalities of PDGFRA/B, whereas patients with FGFR1 fusions are resistant to this therapy and carry a poor prognosis. The discovery of novel gene rearrangements associated with eosinophilia will further guide our understanding of the molecular pathobiology of these diseases and aid in the development of small-molecule inhibitors that inhibit deregulated hematopoiesis.

    View details for DOI 10.1111/ijlh.12057

    View details for Web of Science ID 000325079000016

    View details for PubMedID 23489324

  • Practical management of patients with myelofibrosis receiving ruxolitinib EXPERT REVIEW OF HEMATOLOGY Harrison, C., Mesa, R., Ross, D., Mead, A., Keohane, C., Gotlib, J., Verstovsek, S. 2013; 6 (5): 511-523

    Abstract

    Myelofibrosis (MF) is characterized by bone marrow fibrosis, progressive anemia and extramedullary hematopoiesis, primarily manifested as splenomegaly. Patients also experience debilitating constitutional symptoms, including sequelae of splenomegaly, night sweats and fatigue. Ruxolitinib (INC424, INCB18424, Jakafi, Jakavi), a JAK1 and JAK2 inhibitor, was approved in November 2011 by the US FDA for the treatment of intermediate- or high-risk MF, and more recently in Europe and Canada for the treatment of MF-related splenomegaly or symptoms. These approvals were based on data from two randomized Phase III studies: COMFORT-I randomized against placebo, and COMFORT-II randomized against best available therapy. In these studies, ruxolitinib rapidly improved multiple disease manifestations of MF, reducing splenomegaly and improving quality of life of patients and potentially prolonging survival. However, as with other chemotherapies, ruxolitinib therapy is associated with some adverse events, such as anemia and thrombocytopenia. The aims of this article are to provide a brief overview of ruxolitinib therapy, to discuss some common adverse events associated with ruxolitinib therapy and to provide clinical management recommendations to maximize patients' benefit from ruxolitinib.

    View details for DOI 10.1586/17474086.2013.827413

    View details for Web of Science ID 000325547100007

    View details for PubMedID 24083419

  • The new genetics of chronic neutrophilic leukemia and atypical CML: implications for diagnosis and treatment. Blood Gotlib, J., Maxson, J. E., George, T. I., Tyner, J. W. 2013; 122 (10): 1707-1711

    Abstract

    Although activation of tyrosine kinase pathways is a shared theme among myeloproliferative neoplasms, the pathogenetic basis of chronic neutrophilic leukemia (CNL) has remained elusive. Recently, we identified high-frequency oncogenic mutations in the granulocyte-colony stimulating factor receptor (CSF3R) in CNL and in some patients with atypical chronic myeloid leukemia. Inhibition of Janus kinase 2 or SRC kinase signaling downstream of mutated CSF3R is feasible and should be explored therapeutically. Herein, we discuss the potential impact of these findings for the classification and treatment of these disorders.

    View details for DOI 10.1182/blood-2013-05-500959

    View details for PubMedID 23896413

  • Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report BLOOD Tefferi, A., Cervantes, F., Mesa, R., Passamonti, F., Verstovsek, S., Vannucchi, A. M., Gotlib, J., Dupriez, B., Pardanani, A., Harrison, C., Hoffman, R., Gisslinger, H., Kroeger, N., Thiele, J., Barbui, T., Barosi, G. 2013; 122 (8): 1395-1398

    Abstract

    The current document is a revision of the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria for treatment response in myelofibrosis (MF) and represents a collaborative effort by the IWG-MRT and the European LeukemiaNet to objectively assess the value of new drugs in inducing morphologic remission or improvement in MF-associated symptomatic burden (MF-SB). Some of the changes in the current revision include stricter definitions of red cell transfusion dependency and independency and consideration of the Myeloproliferative Neoplasm Symptom Assessment Form as a tool to quantify meaningful changes in disease-related symptoms. Six response categories are listed: complete remission (CR) and partial remission signify treatment effects that are consistent with disease modification, whereas drug-induced improvements in MF-SB were annotated as clinical improvement, anemia response, spleen response, or symptoms response. Additional criteria are provided for progressive disease, stable disease, and relapse. The document also includes recommendations for assessing cytogenetic and molecular remissions, without mandating their inclusion for CR assignment.

    View details for DOI 10.1182/blood-2013-03-488098

    View details for Web of Science ID 000323394300016

    View details for PubMedID 23838352

  • Editorial. Therapeutic advances in hematology Gotlib, J. 2013; 4 (4): 235-236

    View details for DOI 10.1177/2040620713498057

    View details for PubMedID 23926456

  • Oncogenic CSF3R Mutations in Chronic Neutrophilic Leukemia and Atypical CML NEW ENGLAND JOURNAL OF MEDICINE Maxson, J. E., Gotlib, J., Pollyea, D. A., Fleischman, A. G., Agarwal, A., Eide, C. A., Bottomly, D., Wilmot, B., McWeeney, S. K., Tognon, C. E., Pond, J. B., Collins, R. H., Goueli, B., Oh, S. T., Deininger, M. W., Chang, B. H., Loriaux, M. M., Druker, B. J., Tyner, J. W. 2013; 368 (19): 1781-1790

    Abstract

    The molecular causes of many hematologic cancers remain unclear. Among these cancers are chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL1-negative) chronic myeloid leukemia (CML), both of which are diagnosed on the basis of neoplastic expansion of granulocytic cells and exclusion of genetic drivers that are known to occur in other myeloproliferative neoplasms and myeloproliferative-myelodysplastic overlap neoplasms.To identify potential genetic drivers in these disorders, we used an integrated approach of deep sequencing coupled with the screening of primary leukemia cells obtained from patients with CNL or atypical CML against panels of tyrosine kinase-specific small interfering RNAs or small-molecule kinase inhibitors. We validated candidate oncogenes using in vitro transformation assays, and drug sensitivities were validated with the use of assays of primary-cell colonies.We identified activating mutations in the gene encoding the receptor for colony-stimulating factor 3 (CSF3R) in 16 of 27 patients (59%) with CNL or atypical CML. These mutations segregate within two distinct regions of CSF3R and lead to preferential downstream kinase signaling through SRC family-TNK2 or JAK kinases and differential sensitivity to kinase inhibitors. A patient with CNL carrying a JAK-activating CSF3R mutation had marked clinical improvement after the administration of the JAK1/2 inhibitor ruxolitinib.Mutations in CSF3R are common in patients with CNL or atypical CML and represent a potentially useful criterion for diagnosing these neoplasms. (Funded by the Leukemia and Lymphoma Society and others.).

    View details for DOI 10.1056/NEJMoa1214514

    View details for Web of Science ID 000318540000006

    View details for PubMedID 23656643

  • The clinical benefit of ruxolitinib across patient subgroups: analysis of a placebo-controlled, Phase III study in patients with myelofibrosis BRITISH JOURNAL OF HAEMATOLOGY Verstovsek, S., Mesa, R. A., Gotlib, J., Levy, R. S., Gupta, V., DiPersio, J. F., Catalano, J. V., Deininger, M., Miller, C., Silver, R. T., Talpaz, M., Winton, E. F., Harvey, J. H., Arcasoy, M. O., Hexner, E., Lyons, R. M., Paquette, R., Raza, A., Vaddi, K., Erickson-Viitanen, S., Sun, W., Sandor, V., Kantarjian, H. M. 2013; 161 (4): 508-516

    Abstract

    Myelofibrosis (MF) patients can present with a wide spectrum of disease characteristics. We analysed the consistency of ruxolitinib efficacy across patient subgroups in the COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment (COMFORT-I,) a double-blind trial, where patients with intermediate-2 or high-risk MF were randomized to twice-daily oral ruxolitinib (n = 155) or placebo (n = 154). Subgroups analysed included MF subtype (primary, post-polycythaemia vera, post-essential thrombocythaemia), age (≤65, > 65 years), International Prognostic Scoring System risk group, baseline Eastern Cooperative Oncology Group performance status (0, 1, ≥2), JAK2 V617F mutation (positive, negative), baseline haemoglobin level (≥100, <100 g/l), baseline platelet count (100-200 × 10(9)/l, >200 × 10(9)/l), baseline palpable spleen size (≤10, >10 cm), and baseline quartile of spleen volume and Total Symptom Score (TSS; Q1 = lowest, Q4 = highest). Mean percentage change from baseline to week 24 in spleen volume and TSS were calculated for ruxolitinib and placebo in each subgroup. Overall survival was estimated by Kaplan-Meier method according to original randomization group. In ruxolitinib-treated patients, reductions in spleen volume and TSS and evidence of improved survival relative to placebo across subgroups were consistent with those seen in the COMFORT-I population, confirming that ruxolitinib is an effective therapy for the spectrum of MF patients studied in COMFORT-I.

    View details for DOI 10.1111/bjh.12274

    View details for Web of Science ID 000318172300007

    View details for PubMedID 23480528

  • Myeloid and lymphoid Neoplasms with FGFR1 abnormalities: diagnostic and therapeutic challenges AMERICAN JOURNAL OF HEMATOLOGY Savage, N. M., Johnson, R. C., Gotlib, J., George, T. I. 2013; 88 (5): 427-430

    View details for DOI 10.1002/ajh.23296

    View details for Web of Science ID 000318043500430

    View details for PubMedID 22886804

  • Effect of Ruxolitinib Therapy on Myelofibrosis-Related Symptoms and Other Patient-Reported Outcomes in COMFORT-I: A Randomized, Double-Blind, Placebo-Controlled Trial JOURNAL OF CLINICAL ONCOLOGY Mesa, R. A., Gotlib, J., Gupta, V., Catalano, J. V., Deininger, M. W., Shields, A. L., Miller, C. B., Silver, R. T., Talpaz, M., Winton, E. F., Harvey, J. H., Hare, T., Erickson-Viitanen, S., Sun, W., Sandor, V., Levy, R. S., Kantarjian, H. M., Verstovsek, S. 2013; 31 (10): 1285-1292

    Abstract

    To assess the effects of ruxolitinib on symptom burden and quality of life (QoL) and to evaluate the ability of the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 to measure meaningful changes in myelofibrosis-related symptoms in patients with myelofibrosis.COMFORT-I (Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment-I) is a double-blind, placebo-controlled phase III study evaluating ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis. Exploratory analyses were conducted on the following patient-reported outcomes (PROs) assessments: modified MFSAF v2.0 (individual symptoms and Total Symptom Score [TSS]), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale, and Patient Global Impression of Change (PGIC).Patients receiving ruxolitinib experienced improvements in individual myelofibrosis-related symptoms, although patients receiving placebo experienced worsening (P < .001). The majority (91%) of ruxolitinib-treated patients designated as ? 50% TSS responders (? 50% TSS improvement) self-reported their condition as either "Much improved" or "Very much improved" on the PGIC. These patients achieved significant improvements in the EORTC QLQ-C30 functional domains and Global Health Status/QoL versus patients receiving placebo, who experienced worsening on these measures (P ? .0135). Ruxolitinib-treated patients with a lesser degree of symptom improvement (< 50% TSS responders) also achieved improvements over placebo on these measures. The degree of spleen volume reduction with ruxolitinib correlated with improvements in TSS, PGIC, PROMIS Fatigue Scale, and EORTC Global Health Status/QoL. Ruxolitinib-treated patients who achieved a ? 35% reduction in spleen volume experienced the greatest improvements in these PROs.Ruxolitinib-treated patients achieved clinically meaningful improvements in myelofibrosis-related symptoms and QoL, but patients receiving placebo reported worsening of symptoms and other PROs.

    View details for DOI 10.1200/JCO.2012.44.4489

    View details for Web of Science ID 000317003300015

    View details for PubMedID 23423753

  • Sequential azacitidine plus lenalidomide combination for elderly patients with untreated acute myeloid leukemia HAEMATOLOGICA Pollyea, D. A., Zehnder, J., Coutre, S., Gotlib, J. R., Gallegos, L., Abdel-Wahab, O., Greenberg, P., Zhang, B., Liedtke, M., Berube, C., Levine, R., Mitchell, B. S., Medeiros, B. C. 2013; 98 (4): 591-596

    Abstract

    There are limited treatment options for older patients with acute myeloid leukemia and prognosis of these patients remains poor, thereby warranting development of novel therapies. We evaluated the efficacy and safety of azacitidine in combination with lenalidomide as front-line therapy for older patients with acute myeloid leukemia. Patients ≥ 60 years of age with untreated acute myeloid leukemia received azacitidine 75 mg/m2 for 7 days followed by escalating doses of lenalidomide daily for 21 days starting on day 8 of each cycle every 6 weeks. Patients received continued therapy until disease progression, unacceptable toxicity, or completion of 12 cycles. Forty-two patients (median age, 74 years) were enrolled with equal distribution according to European LeukemiaNet risk. The overall response rate was 40% (rate of complete remission with or without complete recovery of blood counts = 28%). The median time to complete remission with or without complete recovery of blood counts was 12 weeks, and duration of this status was 28 weeks (range, 4 - >104 weeks). Therapy-related acute myeloid leukemia and a high score on the Hematopoietic Cell Transplantation Comorbidity Index were negative predictors of response. Early death was noted in 17% of patients. Grades ≥ 3 toxicities were uncommon and most adverse events were gastrointestinal, fatigue and myelosuppression. In conclusion, a sequential combination of azacitidine plus lenalidomide has clinical activity in older patients with acute myeloid leukemia, and further studies of this combination are underway.

    View details for DOI 10.3324/haematol.2012.076414

    View details for Web of Science ID 000319897700026

    View details for PubMedID 23242596

  • International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis BLOOD Gotlib, J., Pardanani, A., Akin, C., Reiter, A., George, T., Hermine, O., Kluin-Nelemans, H., Hartmann, K., Sperr, W. R., Brockow, K., Schwartz, L. B., Orfao, A., DeAngelo, D. J., Arock, M., Sotlar, K., Horny, H., Metcalfe, D. D., Escribano, L., Verstovsek, S., Tefferi, A., Valent, P. 2013; 121 (13): 2393-2401

    Abstract

    Systemic mastocytosis (SM) is characterized by accumulation of neoplastic mast cells and is classified into indolent and aggressive forms. The latter include aggressive SM (ASM), mast cell leukemia (MCL), and SM associated with a myeloid neoplasm wherein 1 or both disease compartments exhibit advanced features. These variants, henceforth collectively referred to as advanced SM for the purposes of this report, are typically characterized by organ damage and shortened survival duration. In contrast to indolent SM, in which symptoms are usually managed by noncytotoxic antimediator therapy, cytoreduction is usually necessary for disease control in advanced SM. Unfortunately, current drug treatment of these patients rarely results in complete clinical and histopathologic remissions or improved survival time. Previously defined response criteria were adapted to the heterogeneous presentations of advanced SM and the limited effects of available drugs. However, recent advances in understanding the molecular pathogenesis of SM and the corresponding prospect in targeted therapy make it a priority to modify these criteria. Our current study is the product of an international group of experts and summarizes the challenges in accomplishing this task and forwards a new proposal for response criteria, which builds on prior proposals and should facilitate response evaluation in clinical trials.

    View details for DOI 10.1182/blood-2012-09-458521

    View details for Web of Science ID 000321762400009

    View details for PubMedID 23325841

  • A Pan-BCL2 Inhibitor Renders Bone-Marrow-Resident Human Leukemia Stem Cells Sensitive to Tyrosine Kinase Inhibition CELL STEM CELL Goff, D. J., Recart, A. C., Sadarangani, A., Chun, H., Barrett, C. L., Krajewska, M., Leu, H., Low-Marchelli, J., Ma, W., Shih, A. Y., Wei, J., Zhai, D., Geron, I., Pu, M., Bao, L., Chuang, R., Balaian, L., Gotlib, J., Minden, M., Martinelli, G., Rusert, J., Dao, K., Shazand, K., Wentworth, P., Smith, K. M., Jamieson, C. A., Morris, S. R., Messer, K., Goldstein, L. S., Hudson, T. J., Marra, M., Frazer, K. A., Pellecchia, M., Reed, J. C., Jamieson, C. H. 2013; 12 (3): 316-328

    Abstract

    Leukemia stem cells (LSCs) play a pivotal role in the resistance of chronic myeloid leukemia (CML) to tyrosine kinase inhibitors (TKIs) and its progression to blast crisis (BC), in part, through the alternative splicing of self-renewal and survival genes. To elucidate splice-isoform regulators of human BC LSC maintenance, we performed whole-transcriptome RNA sequencing, splice-isoform-specific quantitative RT-PCR (qRT-PCR), nanoproteomics, stromal coculture, and BC LSC xenotransplantation analyses. Cumulatively, these studies show that the alternative splicing of multiple prosurvival BCL2 family genes promotes malignant transformation of myeloid progenitors into BC LSCS that are quiescent in the marrow niche and that contribute to therapeutic resistance. Notably, sabutoclax, a pan-BCL2 inhibitor, renders marrow-niche-resident BC LSCs sensitive to TKIs at doses that spare normal progenitors. These findings underscore the importance of alternative BCL2 family splice-isoform expression in BC LSC maintenance and suggest that the combinatorial inhibition of prosurvival BCL2 family proteins and BCR-ABL may eliminate dormant LSCs and obviate resistance.

    View details for DOI 10.1016/j.stem.2012.12.011

    View details for Web of Science ID 000329569400010

    View details for PubMedID 23333150

  • A Detailed Flow Cytometry Analysis of the Immune System in Non-Leukemic Cells of Acute Myeloid Leukemia Demonstrates the Prognostic Significance of Lymphocyte Subsets Ohgami, R. S., Alcasid, M., Ren, L., Gotlib, J. R., Arber, D. A. NATURE PUBLISHING GROUP. 2013: 353A-354A
  • Accessory splenules in autoimmune hemolytic anemia. American journal of hematology Logan, A., Berube, C., Gotlib, J. 2013; 88 (2): 156-?

    View details for DOI 10.1002/ajh.23335

    View details for PubMedID 23027373

  • Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes. OncoTargets and therapy Verstovsek, S., Gotlib, J., Gupta, V., Atallah, E., Mascarenhas, J., Quintas-Cardama, A., Sun, W., Sarlis, N. J., Sandor, V., Levy, R. S., Kantarjian, H. M., Mesa, R. A. 2013; 7: 13-21

    Abstract

    Ruxolitinib is an oral Janus kinase (JAK) 1/JAK2 inhibitor approved in the US for the treatment of intermediate-or high-risk myelofibrosis (MF). Because thrombopoietin and erythropoietin signal through JAK2, dose-dependent cytopenias are expected with treatment. In the COMFORT-I (COntrolled Myelofibrosis study with ORal JAK inhibitor Treatment I) trial, these cytopenias were effectively managed with dose adjustments. These analyses were conducted to evaluate the relationship between ruxolitinib titrated doses and changes in platelet count and hemoglobin level as well as efficacy measures.COMFORT-I was a randomized, placebo-controlled trial in 309 patients with intermediate-2 or high-risk MF and a platelet count ≥100 × 10(9)/L. Ruxolitinib starting doses were 15 and 20 mg twice daily (bis in die [BID]) for patients with baseline platelet counts of 100-200 × 10(9)/L and >200 × 10(9)/L, respectively. Percentage changes from baseline to week 24 in spleen volume and MF-related symptoms were assessed in subgroups defined by final titrated dose (average daily dose during weeks 21 to 24).The median final titrated doses for patients starting at doses of 15 and 20 mg BID were 10 and 20 mg BID, respectively, at week 24. Most dose reductions occurred in the first 8-12 weeks of treatment and coincided with decreases in platelet count and hemoglobin level. Subsequently, platelet counts stabilized and hemoglobin levels gradually returned to near baseline levels (red blood cell transfusion rates followed a similar trend). Final titrated doses of ≥10 mg BID were associated with clinically meaningful improvements in MF-related symptoms that were comparable across doses, while marginally greater reductions in spleen volume were observed at higher doses.This COMFORT-I analysis shows that dose-dependent cytopenias were effectively managed with ruxolitinib dose adjustments, and titrated doses of ≥10 mg BID were associated with clinically meaningful reductions in spleen volume and symptom improvement at week 24.

    View details for DOI 10.2147/OTT.S53348

    View details for PubMedID 24368888

  • Kinase Pathway Dependence in Primary Human Leukemias Determined by Rapid Inhibitor Screening CANCER RESEARCH Tyner, J. W., Yang, W. F., Bankhead, A., Fan, G., Fletcher, L. B., Bryant, J., Glover, J. M., Chang, B. H., Spurgeon, S. E., Fleming, W. H., Kovacsovics, T., Gotlib, J. R., Oh, S. T., Deininger, M. W., Zwaan, C. M., den Boer, M. L., van den Heuvel-Eibrink, M. M., O'Hare, T., Druker, B. J., Loriaux, M. M. 2013; 73 (1): 285-296

    Abstract

    Kinases are dysregulated in most cancers, but the frequency of specific kinase mutations is low, indicating a complex etiology in kinase dysregulation. Here, we report a strategy to rapidly identify functionally important kinase targets, irrespective of the etiology of kinase pathway dysregulation, ultimately enabling a correlation of patient genetic profiles to clinically effective kinase inhibitors. Our methodology assessed the sensitivity of primary leukemia patient samples to a panel of 66 small-molecule kinase inhibitors over 3 days. Screening of 151 leukemia patient samples revealed a wide diversity of drug sensitivities, with 70% of the clinical specimens exhibiting hypersensitivity to one or more drugs. From this data set, we developed an algorithm to predict kinase pathway dependence based on analysis of inhibitor sensitivity patterns. Applying this algorithm correctly identified pathway dependence in proof-of-principle specimens with known oncogenes, including a rare FLT3 mutation outside regions covered by standard molecular diagnostic tests. Interrogation of all 151 patient specimens with this algorithm identified a diversity of kinase targets and signaling pathways that could aid prioritization of deep sequencing data sets, permitting a cumulative analysis to understand kinase pathway dependence within leukemia subsets. In a proof-of-principle case, we showed that in vitro drug sensitivity could predict both a clinical response and the development of drug resistance. Taken together, our results suggested that drug target scores derived from a comprehensive kinase inhibitor panel could predict pathway dependence in cancer cells while simultaneously identifying potential therapeutic options.

    View details for DOI 10.1158/0008-5472.CAN-12-1906

    View details for Web of Science ID 000313019800029

    View details for PubMedID 23087056

  • Next-generation sequencing in hematologic malignancies: what will be the dividends? Therapeutic advances in hematology Merker, J. D., Valouev, A., Gotlib, J. 2012; 3 (6): 333-339

    Abstract

    The application of high-throughput, massively parallel sequencing technologies to hematologic malignancies over the past several years has provided novel insights into disease initiation, progression, and response to therapy. Here, we describe how these new DNA sequencing technologies have been applied to hematolymphoid malignancies. With further improvements in the sequencing and analysis methods as well as integration of the resulting data with clinical information, we expect these technologies will facilitate more precise and tailored treatment for patients with hematologic neoplasms.

    View details for DOI 10.1177/2040620712458948

    View details for PubMedID 23606936

  • ICON: Eosinophil Disorders. The World Allergy Organization journal Valent, P., Klion, A. D., Rosenwasser, L. J., Arock, M., Bochner, B. S., Butterfield, J. H., Gotlib, J., Haferlach, T., Hellmann, A., Horny, H., Leiferman, K. M., Metzgeroth, G., Matsumoto, K., Reiter, A., Roufosse, F., Rothenberg, M. E., Simon, H., Sotlar, K., Vandenberghe, P., Weller, P. F., Gleich, G. J. 2012; 5 (12): 174-181

    View details for DOI 10.1097/WOX.0b013e31827f4192

    View details for PubMedID 23282419

  • Whole Genome Sequence Analysis of Primary Myelofibrosis. Merker, J. D., Roskin, K., Ng, D., Pan, C., Fisk, D. G., Jones, C. D., Gojenola, L., Clark, M. J., Zhang, B., Cherry, M., Snyder, M., Boyd, S. D., Zehnder, J. L., Fire, A. Z., Gotlib, J. AMER SOC HEMATOLOGY. 2012
  • A Phase I/II Study of Bortezomib (VELCADE) in Combination with Pralatrexate in Relapsed/Refractory Multiple Myeloma Dunn, T. J., Dinner, S. N., Berube, C., Gotlib, J., Coutre, S. E., Medeiros, B. C., Liedtke, M. AMER SOC HEMATOLOGY. 2012
  • Amrubicin, a Novel Investigational Anthracycline, in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: Results of a Phase 1 Dose-Escalation Study Dinner, S. N., Dunn, T. J., Medeiros, B. C., Coutre, S. E., Berube, C., Gotlib, J., Liedtke, M. AMER SOC HEMATOLOGY. 2012
  • Sabutoclax, a Novel Pan BCL2 Family Inhibitor, Sensitizes Dormant Blast Crisis Chronic Myeloid Leukemia Stem Cells to Dasatinib Leu, H. S., Goff, D. J., Low-Marchelli, J., Recart, A. C., Smith, K. M., Ma, W., Sadarangani, A., Shih, A. Y., Wei, J., Zhai, D., Gotlib, J., Minden, M. D., Martinelli, G., Marra, M. A., Frazer, K. A., Pellecchia, M., Reed, J. C., Jamieson, C. AMER SOC HEMATOLOGY. 2012
  • Estimation of JAK2 V617F Prevalence by Detection of the Mutation in Saliva Samples From Online MPN and General Population Cohorts Barnholt, K. E., Hinds, D. A., Kiefer, A. K., Do, C. B., Eriksson, N., Mountain, J. L., Francke, U., Tung, J. A., Nguyen, H. (., Levine, R. L., Mesa, R. A., Gotlib, J., Zehnder, J. L. AMER SOC HEMATOLOGY. 2012
  • Correlation of Symptom Assessment with Genotyping Analysis of Saliva Samples in a Large Cohort of Myeloproliferative Neoplasm Patients Nguyen, H. (., Hinds, D. A., Barnholt, K. E., Kiefer, A. K., Do, C. B., Eriksson, N., Mountain, J. L., Francke, U., Tung, J. A., Levine, R. L., Zehnder, J. L., Gotlib, J., Mesa, R. A. AMER SOC HEMATOLOGY. 2012
  • FDA-Approved Ruxolitinib in Patients with Myelofibrosis: the Stanford Experience Nguyen, H. (., Anh Pham, A., Perkins, C., Linder, A., Fechter, L., Gotlib, J. AMER SOC HEMATOLOGY. 2012
  • DNA methylation analysis of ALOX12 and GSTM1 in acute myeloid leukaemia identifies prognostically significant groups BRITISH JOURNAL OF HAEMATOLOGY Ohgami, R. S., Ma, L., Ren, L., Weinberg, O. K., Seetharam, M., Gotlib, J. R., Arber, D. A. 2012; 159 (2): 182-190

    Abstract

    To determine the role of DNA methylation in the progression of acute myeloid leukaemia (AML), we analysed the methylation status of ALOX12, GSTM1, HS3ST2 and FZD9 in 127 AML patients. Aberrant methylation of ALOX12 was associated with the subcategory AML with myelodysplasia-related changes (P = 0·0439) and specifically with megakaryocytic dysplasia (P = 0·0003). An association between HS3ST2 and AML patients with favourable cytogenetic risk was identified (P = 0·0469). In univariate and multivariate analysis, methylation of GSTM1 was associated with worse overall survival (OS) and disease-free survival (DFS), with hazard ratios of 2·57 and 1·86, respectively. Furthermore, the significance of methylation of GSTM1 in predicting poor prognosis was maintained within the subcategories of AML not otherwise specified (NOS), AML with intermediate cytogenetic risk and normal karyotype AML. Finally, patients with both GSTM1 and ALOX12 methylated, demonstrated worse outcomes when all AML patients were assessed (OS; P = 0·000411) as well as within AML NOS (DFS; P = 0·0023), AML with intermediate cytogenetic risk (OS; P = 0·0104) and normal karyotype AML (OS; P = 0·00636). This study implicates methylation of specific genes in the classification and prognostication of AML and suggests that the morphological feature of multilineage dysplasia may be a surrogate marker of gene methylation in at least a subset of AML cases.

    View details for DOI 10.1111/bjh.12029

    View details for Web of Science ID 000309242000009

    View details for PubMedID 22924777

  • World Health Organization-defined eosinophilic disorders: 2012 update on diagnosis, risk stratification, and management. American journal of hematology Gotlib, J. 2012; 87 (9): 903-914

    Abstract

    DISEASE OVERVIEW: The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage.Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm(3) and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ-hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. RISK STRATIFICATION: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semimolecular classification scheme of disease subtypes including "myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1," chronic eosinophilic leukemia, not otherwise specified' (CEL, NOS), lymphocyte-variant hypereosinophilia, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion. RISK-ADAPTED THERAPY: The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g., <1,500/mm(3) ) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant hypereosinophilia and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as initial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited numbers of patients. Although clinical trials have been performed with anti IL-5 (mepolizumab) and anti-CD52 (alemtuzumab) antibodies, their therapeutic role in primary eosinophilic diseases and HES has yet to be established.

    View details for DOI 10.1002/ajh.23293

    View details for PubMedID 22926771

  • Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Valent, P., Klion, A. D., Horny, H., Roufosse, F., Gotlib, J., Weller, P. F., Hellmann, A., Metzgeroth, G., Leiferman, K. M., Arock, M., Butterfield, J. H., Sperr, W. R., Sotlar, K., Vandenberghe, P., Haferlach, T., Simon, H., Reiter, A., Gleich, G. J. 2012; 130 (3): 607-?

    Abstract

    Eosinophilia is an important indicator of various neoplastic and nonneoplastic conditions. Depending on the underlying disease and mechanisms, eosinophil infiltration can lead to organ dysfunction, clinical symptoms, or both. During the past 2 decades, several different classifications of eosinophilic disorders and related syndromes have been proposed in various fields of medicine. Although criteria and definitions are, in part, overlapping, no global consensus has been presented to date. The Year 2011 Working Conference on Eosinophil Disorders and Syndromes was organized to update and refine the criteria and definitions for eosinophilic disorders and to merge prior classifications in a contemporary multidisciplinary schema. A panel of experts from the fields of immunology, allergy, hematology, and pathology contributed to this project. The expert group agreed on unifying terminologies and criteria and a classification that delineates various forms of hypereosinophilia, including primary and secondary variants based on specific hematologic and immunologic conditions, and various forms of the hypereosinophilic syndrome. For patients in whom no underlying disease or hypereosinophilic syndrome is found, the term hypereosinophilia of undetermined significance is introduced. The proposed novel criteria, definitions, and terminologies should assist in daily practice, as well as in the preparation and conduct of clinical trials.

    View details for DOI 10.1016/j.jaci.2012.02.019

    View details for Web of Science ID 000308463500005

    View details for PubMedID 22460074

  • Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia LEUKEMIA Pollyea, D. A., Kohrt, H. E., Gallegos, L., Figueroa, M. E., Abdel-Wahab, O., Zhang, B., Bhattacharya, S., Zehnder, J., Liedtke, M., Gotlib, J. R., Coutre, S., Berube, C., Melnick, A., Levine, R., Mitchell, B. S., Medeiros, B. C. 2012; 26 (5): 893-901

    Abstract

    Acute myeloid leukemia (AML) is a disease of the elderly. Poor outcomes with standard therapies necessitate novel approaches. Outpatient regimens sufficiently potent and well tolerated to induce remissions and enable continuation therapy may be beneficial. In this phase-1 study, we determined the maximum tolerated dose (MTD) and the efficacy for sequential azacitidine and lenalidomide as remission induction and continuation therapy in elderly, previously untreated patients. We investigated the impact on global DNA methylation and bone marrow cytokines, and sought biological predictors of response. Eighteen patients were enrolled. The MTD was not reached. Median follow-up was 8.2 months (10.3 months for survivors). Common adverse events included fatigue, injection site reactions, constipation, nausea, pruritus and febrile neutropenia. Ten patients responded (56%), and the rate of complete remissions (CRs) or CRs with incomplete recovery of blood counts for evaluable patients was 44% (7/16). The median response duration was 6.2 months. DNA demethylation and changes in bone marrow cytokines were observed; responders had a unique cytokine profile and a trend towards lower methylation levels. Sequential azacitidine and lenalidomide was well tolerated with encouraging clinical and biological activity in previously untreated elderly AML patients. This trial is registered at ClinicalTrials.gov (NCT00890929).

    View details for DOI 10.1038/leu.2011.294

    View details for Web of Science ID 000303883500005

    View details for PubMedID 22033493

  • Unraveling the genetic underpinnings of myeloproliferative neoplasms and understanding their effect on disease course and response to therapy: Proceedings from the 6th international post-ASH symposium AMERICAN JOURNAL OF HEMATOLOGY Abdel-Wahab, O., Pardanani, A., Bernard, O. A., Finazzi, G., Crispino, J. D., Gisslinger, H., Kralovics, R., Odenike, O., Bhalla, K., Gupta, V., Barosi, G., Gotlib, J., Guglielmelli, P., Kiladjian, J., Noel, P., Cazzola, M., Vannucchi, A. M., Hoffman, R., Barbui, T., Thiele, J., Van Etten, R. A., Mughal, T., Tefferi, A. 2012; 87 (5): 562-568

    Abstract

    Immediately after the annual scientific meeting of the American Society of Hematology (ASH), a select group of clinical and laboratory investigators in myeloproliferative neoplasms (MPN) is summoned to a post-ASH conference on chronic myeloid leukemia and the BCR-ABL1-negative MPN. The 6th such meeting occurred on December 13–14,2011, in La Jolla, California, USA, under the direction of its founder,Dr. Tariq Mughal. The current document is the first of two reports on this post-ASH event and summarizes the most recent preclinical and clinical advances in polycythemia vera, essential thrombocythemia,and primary myelofibrosis.

    View details for DOI 10.1002/ajh.23169

    View details for Web of Science ID 000302899900028

    View details for PubMedID 22460584

  • Mast Cells and Eosinophils in Mastocytosis, Chronic Eosinophilic Leukemia, and Non-clonal Disorders SEMINARS IN HEMATOLOGY Gotlib, J., Akin, C. 2012; 49 (2): 128-137

    Abstract

    Mast cells and eosinophils often travel in the same biologic circles. In non-clonal states, such as allergic and inflammatory conditions, cell-to-cell contact and the pleiotropic actions of multiple cytokines and chemokines, derived from local tissues or mast cells themselves, foster the co-recruitment of these cells to the same geographic cellular niche. While eosinophils and mast cells serve critical roles as part of the host immune response and in maintenance of normal homeostasis, these cell types can undergo neoplastic transformation due to the development of clonal molecular abnormalities that arise in early hematopoietic progenitors. The dysregulated tyrosine kinases, D816V KIT and FIP1L1-PDGFRA, are the prototypic oncogenic lesions resulting in systemic mastocytosis (SM) and chronic eosinophilic leukemia, respectively. We review the pathobiology of these myeloproliferative neoplasms (MPNs) with a focus on the relationship between mast cells and eosinophils, and discuss murine models, which further elucidate how the phenotype of these diseases can be influenced by stem cell factor (SCF) and expression of the potent eosinophilopoietic cytokine, interleukin-5 (IL-5). Therapy of SM and FIP1L1-PDGFRA-positive disease and the prognostic relevance of increased peripheral blood and tissue mast cells in hematolymphoid malignancies will also be addressed.

    View details for DOI 10.1053/j.seminhematol.2012.01.007

    View details for Web of Science ID 000302427300004

    View details for PubMedID 22449623

  • Pathogenesis and classification of eosinophil disorders: a review of recent developments in the field EXPERT REVIEW OF HEMATOLOGY Valent, P., Gleich, G. J., Reiter, A., Roufosse, F., Weller, P. F., Hellmann, A., Metzgeroth, G., Leiferman, K. M., Arock, M., Sotlar, K., Butterfield, J. H., Cerny-Reiterer, S., Mayerhofer, M., Vandenberghe, P., Haferlach, T., Bochner, B. S., Gotlib, J., Horny, H., Simon, H., Klion, A. D. 2012; 5 (2): 157-176

    Abstract

    Eosinophils and their products play an essential role in the pathogenesis of various reactive and neoplastic disorders. Depending on the underlying disease, molecular defect and involved cytokines, hypereosinophilia may develop and may lead to organ damage. In other patients, persistent eosinophilia is accompanied by typical clinical findings, but the causative role and impact of eosinophilia remain uncertain. For patients with eosinophil-mediated organ pathology, early therapeutic intervention with agents reducing eosinophil counts can be effective in limiting or preventing irreversible organ damage. Therefore, it is important to approach eosinophil disorders and related syndromes early by using established criteria, to perform all appropriate staging investigations, and to search for molecular targets of therapy. In this article, we review current concepts in the pathogenesis and evolution of eosinophilia and eosinophil-related organ damage in neoplastic and non-neoplastic conditions. In addition, we discuss classifications of eosinophil disorders and related syndromes as well as diagnostic algorithms and standard treatment for various eosinophil-related disorders.

    View details for DOI 10.1586/EHM.11.81

    View details for Web of Science ID 000303629400013

    View details for PubMedID 22475285

  • A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis NEW ENGLAND JOURNAL OF MEDICINE Verstovsek, S., Mesa, R. A., Gotlib, J., Levy, R. S., Gupta, V., DiPersio, J. F., Catalano, J. V., Deininger, M., Miller, C., Silver, R. T., Talpaz, M., Winton, E. F., Harvey, J. H., Arcasoy, M. O., Hexner, E., Lyons, R. M., Paquette, R., Raza, A., Vaddi, K., Erickson-Viitanen, S., Koumenis, I. L., Sun, W., Sandor, V., Kantarjian, H. M. 2012; 366 (9): 799-807

    Abstract

    Ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2, has clinically significant activity in myelofibrosis.In this double-blind trial, we randomly assigned patients with intermediate-2 or high-risk myelofibrosis to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients). The primary end point was the proportion of patients with a reduction in spleen volume of 35% or more at 24 weeks, assessed by means of magnetic resonance imaging. Secondary end points included the durability of response, changes in symptom burden (assessed by the total symptom score), and overall survival.The primary end point was reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the placebo group (P<0.001). A reduction in spleen volume was maintained in patients who received ruxolitinib; 67.0% of the patients with a response had the response for 48 weeks or more. There was an improvement of 50% or more in the total symptom score at 24 weeks in 45.9% of patients who received ruxolitinib as compared with 5.3% of patients who received placebo (P<0.001). Thirteen deaths occurred in the ruxolitinib group as compared with 24 deaths in the placebo group (hazard ratio, 0.50; 95% confidence interval, 0.25 to 0.98; P=0.04). The rate of discontinuation of the study drug because of adverse events was 11.0% in the ruxolitinib group and 10.6% in the placebo group. Among patients who received ruxolitinib, anemia and thrombocytopenia were the most common adverse events, but they rarely led to discontinuation of the drug (in one patient for each event). Two patients had transformation to acute myeloid leukemia; both were in the ruxolitinib group.Ruxolitinib, as compared with placebo, provided significant clinical benefits in patients with myelofibrosis by reducing spleen size, ameliorating debilitating myelofibrosis-related symptoms, and improving overall survival. These benefits came at the cost of more frequent anemia and thrombocytopenia in the early part of the treatment period. (Funded by Incyte; COMFORT-I ClinicalTrials.gov number, NCT00952289.).

    View details for Web of Science ID 000300874300006

    View details for PubMedID 22375971

  • Loss of CD25 Expression in Advanced Systemic Mastocytosis Patients Treated with Midostaurin (PKC412) Kunder, C. A., DeAngelo, D. J., Gotlib, J. R., Gitana, G., Atwater, S. K., George, T. I. NATURE PUBLISHING GROUP. 2012: 349A-349A
  • Systemic mastocytosis with associated clonal hematological non-mast-cell lineage disease: A case review AMERICAN JOURNAL OF HEMATOLOGY Ustun, C., Savage, N. M., Gotlib, J., Bhalla, K., Manaloor, E., George, T. I. 2012; 87 (2): 191-193

    View details for DOI 10.1002/ajh.22208

    View details for Web of Science ID 000299098100014

    View details for PubMedID 22081475

  • Tailored temozolomide therapy according to MGMT methylation status for elderly patients with acute myeloid leukemia AMERICAN JOURNAL OF HEMATOLOGY Medeiros, B. C., Kohrt, H. E., Gotlib, J., Coutre, S. E., Zhang, B., Arber, D. A., Zehnder, J. L. 2012; 87 (1): 45-50

    Abstract

    Temozolomide sensitivity is determined by methylation of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter. This study assessed whether the temozolomide dose can be tailored by MGMT promoter status and whether protracted, low-dose temozolomide can "prime" blasts in patients with unmethylated MGMT (unMGMT). Elderly patients with high-risk AML were stratified by MGMT methylation. Patients with methylated MGMT (mMGMT) received temozolomide 200 mg/m(2) orally for 7 days every 4 weeks, while patients with unMGMT received temozolomide 100 mg/m(2) orally for 14 days followed by 200 mg/m(2) orally for 7 days every 6weeks. Of 36 patients (median age, 75 years), 31 (86%) had an unMGMT promoter. Overall response rate for the entire cohort was 36%. Patients with mMGMT and unMGMT had similar response rates (40% vs. 29%). Median duration of response and overall survival (OS) among responders were 29 and 35 weeks, respectively. Induction deaths (ID) occurred in 25% of patients, mostly caused by disease progression. Hematological toxicities were the most common adverse event. Toxicities were similar between patients on conventional versus protracted schedules. High HCT-CI scores were predictive of lower CR rate, higher ID, and shorter OS, while bone marrow blast count <50% at screening predicted for improved responses. Temozolomide, dosed according to MGMT methylation status, demonstrated modest clinical activity in elderly patients with AML, especially in those presenting with fewer comorbidities and low disease burden. The trial was registered on www.ClinicalTrials.gov as #NCT00611247.

    View details for DOI 10.1002/ajh.22191

    View details for Web of Science ID 000298257700010

    View details for PubMedID 22052619

  • Insights into the molecular genetics of myeloproliferative neoplasms. American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting Nguyen, H. M., Gotlib, J. 2012: 411-418

    Abstract

    The molecular biology of the BCR-ABL1-negative chronic myeloproliferative neoplasms (MPNs) has witnessed unprecedented advances since the discovery of the acquired JAK2 V617F mutation in 2005. Despite the high prevalence of JAK2 V617F in polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), and the common finding of dysregulated JAK-STAT signaling in these disorders, it is now appreciated that MPN pathogenesis can reflect the acquisition of multiple genetic mutations that alter several biologic pathways, including epigenetic control of gene expression. Although certain gene mutations are identified at higher frequencies with disease evolution to the blast phase, MPN initiation and progression are not explained by a single, temporal pattern of clonal changes. A complex interplay between acquired molecular abnormalities and host genetic background, in addition to the type and allelic burden of mutations, contributes to the phenotypic heterogeneity of MPNs. At the population level, an inherited predisposition to developing MPNs is linked to a relatively common JAK2-associated haplotype (referred to as '46/1'), but it exhibits a relatively low penetrance. This review details the current state of knowledge of the molecular genetics of the classic MPNs PV, ET, and PMF and discusses the clinical implications of these findings.

    View details for DOI 10.14694/EdBook_AM.2012.32.411

    View details for PubMedID 24451773

  • Treatment advances have not improved the early death rate in acute promyelocytic leukemia HAEMATOLOGICA-THE HEMATOLOGY JOURNAL McClellan, J. S., Kohrt, H. E., Coutre, S., Gotlib, J. R., Majeti, R., Alizadeh, A. A., Medeiros, B. C. 2012; 97 (1): 133-136

    Abstract

    Early mortality in acute promyelocytic leukemia has been reported to occur in less than 10% of patients treated in clinical trials. This study reports the incidence and clinical features of acute promyelocytic leukemia patients treated at Stanford Hospital, CA, USA since March 1997, focusing on early mortality. We show that the risk of early death in acute promyelocytic leukemia patients is higher than previously reported. In a cohort of 70 patients who received induction therapy at Stanford Hospital, 19% and 26% died within seven and 30 days of admission, respectively. High early mortality was not limited to our institution as evaluation of the Surveillance, Epidemiology and End Results Database demonstrated that 30-day mortality for acute promyelocytic leukemia averaged 20% from 1977-2007 and did not improve significantly over this interval. Our findings show that early death is now the greatest contributor to treatment failure in this otherwise highly curable form of leukemia.

    View details for DOI 10.3324/haematol.2011.046490

    View details for Web of Science ID 000299870500022

    View details for PubMedID 21993679

  • Chronic Myelogenous Leukemia JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK O'Brien, S., Abboud, C. N., Akhtari, M., Altman, J., Berman, E., DeAngelo, D. J., Devine, S., Fathi, A. T., Gotlib, J., Jagasia, M., Moore, J. O., Pinilla-Ibarz, J., Radich, J. P., Reddy, V. V., Shah, N. P., Shami, P. J., Smith, B. D., Snyder, D. S., Wetzler, M., Yunus, F. 2012; 10 (1): 64-110

    View details for Web of Science ID 000299007500009

    View details for PubMedID 22223870

  • Phase I trial of a novel human monoclonal antibody mAb216 in patients with relapsed or refractory B-cell acute lymphoblastic leukemia HAEMATOLOGICA-THE HEMATOLOGY JOURNAL Liedtke, M., Twist, C. J., Medeiros, B. C., Gotlib, J. R., Berube, C., Bieber, M. M., Bhat, N. M., Teng, N. N., Coutre, S. E. 2012; 97 (1): 30-37

    Abstract

    This phase I trial was conducted to determine the safety and pharmacokinetics of monoclonal antibody 216, a human monoclonal Immunoglobulin M antibody targeting a linear B-cell lactosamine antigen, administered alone and in combination with vincristine in patients with relapsed or refractory B-cell acute lymphoblastic leukemia, and to preliminarily assess tumor targeting and efficacy.Three cohorts of patients received escalating doses of monoclonal antibody 216 administered as an intravenous infusion. In the case of poor response to the first dose of monoclonal antibody 216 alone, defined as less than 75% reduction in peripheral blood blast count, a second dose of the antibody with vincristine was given between days 4 and 7. Responses were assessed weekly until day 35. Serum concentration of monoclonal antibody 216 was measured before and after infusion. Monoclonal antibody 216 targeting was determined with an anti-idiotypic antibody to monoclonal antibody 216 and preliminary efficacy was analyzed by changes in peripheral blood blasts.Thirteen patients were enrolled. One episode of grade 3 epistaxis was the only dose-limiting toxicity observed. All patients showed a poor response to the first monoclonal antibody 216 infusion with a decrease in peripheral blasts from 6-65% in 9 patients. In 8 patients, addition of vincristine to monoclonal antibody 216 resulted in an average reduction of the peripheral blasts of 81%. One patient without peripheral blasts achieved a hypoplastic marrow without evidence of leukemia after one infusion of monoclonal antibody 216 and monoclonal antibody 216/vincristine each. Monoclonal antibody 216 was detected on peripheral blasts in all patients.Treatment with monoclonal antibody 216 in combination with vincristine is feasible and well tolerated in patients with relapsed or refractory B-cell acute lymphoblastic leukemia. Binding of monoclonal antibody 216 to leukemic blasts was efficient, and favorable early responses were observed.

    View details for DOI 10.3324/haematol.2011.045997

    View details for Web of Science ID 000299870500009

    View details for PubMedID 21993685

  • A novel splice donor mutation in the thrombopoietin gene leads to exon 2 skipping in a Filipino family with hereditary thrombocythemia. Blood Zhang, B., Ng, D., Jones, C., Oh, S. T., Nolan, G. P., Salehi, S., Wong, W., Zehnder, J. L., Gotlib, J. 2011; 118 (26): 6988-6990

    View details for DOI 10.1182/blood-2011-10-386177

    View details for PubMedID 22194398

  • A novel splice donor mutation in the thrombopoietin gene leads to exon 2 skipping in a Filipino family with hereditary thrombocythemia BLOOD Ng, D., Jones, C., Oh, S. T., Nolan, G. P., Salehi, S., Wong, W., Zehnder, J. L., Gotlib, J. 2011; 118 (26): 6988-?
  • Consistent Benefit of Ruxolitinib Over Placebo in Spleen Volume Reduction and Symptom Improvement Across Subgroups and Overall Survival Advantage: Results From COMFORT-I Verstovsek, S., Mesa, R. A., Gotlib, J., Levy, R. S., Gupta, V., DiPersio, J. F., Catalano, J., Deininger, M. W., Miller, C. B., Silver, R. T., Talpaz, M., Winton, E. F., Harvey, J. H., Arcasoy, M. O., Hexner, E., Lyons, R. M., Paquette, R., Raza, A., Vaddi, K., Erickson-Viitanen, S., Sun, W., Sandor, V. A., Kantarjian, H. M. AMER SOC HEMATOLOGY. 2011: 128-129
  • BCL2 Splice Isoform Switching Promotes Leukemia Stem Cell Survival and Sensitivity to a Novel Pan BCL2 Inhibitor Goff, D., Smith, K. M., Shih, A. Y., Court-Recart, A., Sadarangani, A., Geron, I., Chuang, R., Balaian, L., Wei, J., Kitada, S., Zhai, D., Gotlib, J., Minden, M. D., Martinelli, G., Schairer, A., Leu, H., Ma, W., Jiang, Q., Rusert, J., Dao, K. T., Shazand, K., Volar, M., De Borja, R., McPherson, J. D., Hudson, T. J., Barrett, C. L., Frazer, K. A., Wentworth, P., Jamieson, C., Morris, S. R., Goldstein, L. S., Pellechia, M., Reed, J. C., Jamieson, C. AMER SOC HEMATOLOGY. 2011: 1176-1176
  • SAR302503: Interim Safety, Efficacy and Long-Term Impact on JAK2 V617F Allele Burden in a Phase I/II Study in Patients with Myelofibrosis Pardanani, A., Gotlib, J., Jamieson, C., Cortes, J. E., Talpaz, M., Stone, R., Gao, G., Zhang, J. (., Neumann, F., Tefferi, A. AMER SOC HEMATOLOGY. 2011: 1640-1640
  • Impact of TET2 mutations on mRNA expression and clinical outcomes in MDS patients treated with DNA methyltransferase inhibitors HEMATOLOGICAL ONCOLOGY Pollyea, D. A., Raval, A., Kusler, B., Gotlib, J. R., Alizadeh, A. A., Mitchell, B. S. 2011; 29 (3): 157-160

    View details for DOI 10.1002/hon.976

    View details for Web of Science ID 000300148700010

    View details for PubMedID 21922510

  • KIT-D816V-independent oncogenic signaling in neoplastic cells in systemic mastocytosis: role of Lyn and Btk activation and disruption by dasatinib and bosutinib BLOOD Gleixner, K. V., Mayerhofer, M., Cerny-Reiterer, S., Hoermann, G., Rix, U., Bennett, K. L., Hadzijusufovic, E., Meyer, R. A., Pickl, W. F., Gotlib, J., Horny, H., Reiter, A., Mitterbauer-Hohendanner, G., Superti-Furga, G., Valent, P. 2011; 118 (7): 1885-1898

    Abstract

    Systemic mastocytosis (SM) either presents as a malignant neoplasm with short survival or as an indolent disease with normal life expectancy. In both instances, neoplastic mast cells (MCs) harbor D816V-mutated KIT, suggesting that additional oncogenic mechanisms are involved in malignant transformation. We here describe that Lyn and Btk are phosphorylated in a KIT-independent manner in neoplastic MCs in advanced SM and in the MC leukemia cell line HMC-1. Lyn and Btk activation was not only detected in KIT D816V-positive HMC-1.2 cells, but also in the KIT D816V-negative HMC-1.1 subclone. Moreover, KIT D816V did not induce Lyn/Btk activation in Ba/F3 cells, and deactivation of KIT D816V by midostaurin did not alter Lyn/Btk activation. siRNAs against Btk and Lyn were found to block survival in neoplastic MCs and to cooperate with midostaurin in producing growth inhibition. Growth inhibitory effects were also obtained with 2 targeted drugs, dasatinib which blocks KIT, Lyn, and Btk activation in MCs, and bosutinib, a drug that deactivates Lyn and Btk without blocking KIT activity. Together, KIT-independent signaling via Lyn/Btk contributes to growth of neoplastic MCs in advanced SM. Dasatinib and bosutinib disrupt Lyn/Btk-driven oncogenic signaling in neoplastic MC, which may have clinical implications and explain synergistic drug interactions.

    View details for DOI 10.1182/blood-2010-06-289959

    View details for Web of Science ID 000294011500028

    View details for PubMedID 21680801

  • World Health Organization-defined eosinophilic disorders: 2011 update on diagnosis, risk stratification, and management. American journal of hematology Gotlib, J. 2011; 86 (8): 677-688

    Abstract

    DISEASE OVERVIEW: The eosinophilias encompass a broad range of non-hematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage.Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm(3) and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ-hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. RISK STRATIFICATION: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semi-molecular classification scheme of disease subtypes including myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1, chronic eosinophilic leukemia, not otherwise specified (CEL, NOS), lymphocyte-variant hypereosinophilia, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion. RISK-ADAPTED THERAPY: The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g. < 1,500/mm(3) ) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant hypereosinophilia and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as initial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited numbers of patients. Although clinical trials have been performed with anti IL-5 (mepolizumab) and anti-CD52 (alemtuzumab) antibodies, their therapeutic niche in primary eosinophilic diseases and HES have yet to be established.

    View details for DOI 10.1002/ajh.22062

    View details for PubMedID 21761433

  • World Health Organization-defined eosinophilic disorders: 2011 update on diagnosis, risk stratification, and management AMERICAN JOURNAL OF HEMATOLOGY Gotlib, J. 2011; 86 (8): 678-688

    View details for DOI 10.1002/ajh.22062

    View details for Web of Science ID 000293508600009

  • Safety and Efficacy of TG101348, a Selective JAK2 Inhibitor, in Myelofibrosis JOURNAL OF CLINICAL ONCOLOGY Pardanani, A., Gotlib, J. R., Jamieson, C., Cortes, J. E., Talpaz, M., Stone, R. M., Silverman, M. H., Gilliland, D. G., Shorr, J., Tefferi, A. 2011; 29 (7): 789-796

    Abstract

    Myelofibrosis is a myeloid malignancy associated with anemia, splenomegaly, and constitutional symptoms. Patients frequently harbor JAK-STAT activating mutations that are sensitive to TG101348, a selective small-molecule Janus kinase 2 (JAK2) inhibitor.In a multicenter phase I trial, oral TG101348 was administered once a day to patients with high- or intermediate-risk primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Results: Fifty-nine patients were treated, including 28 in the dose-escalation phase. The maximum-tolerated dose was 680 mg/d, and dose-limiting toxicity was a reversible and asymptomatic increase in the serum amylase level. Forty-three patients (73%) continued treatment beyond six cycles; the median cumulative exposure to TG101348 was 380 days. Adverse events included nausea, vomiting, diarrhea, anemia, and thrombocytopenia; corresponding grades 3 to 4 incidence rates were 3%, 3%, 10%, 35%, and 24%. TG101348 treatment had modest effect on serum cytokine levels, but greater than half of the patients with early satiety, night sweats, fatigue, pruritus, and cough achieved rapid and durable improvement in these symptoms. By six and 12 cycles of treatment, 39% and 47% of patients, respectively, had achieved a spleen response per International Working Group criteria. The majority of patients with leukocytosis or thrombocytosis at baseline (n = 28 and n = 10, respectively) achieved normalization of blood counts after six (57% and 90%, respectively) and 12 (56% and 88%, respectively) cycles. A significant decrease in JAK2 V617F allele burden was observed at 6 months in mutation-positive patients (n = 51; P = .04), particularly in the subgroup with allele burden greater than 20% (n = 23; P < .01); the decrease was durable at 12 months.TG101348 is well tolerated and produces significant reduction in disease burden and durable clinical benefit in patients with myelofibrosis.

    View details for DOI 10.1200/JCO.2010.32.8021

    View details for Web of Science ID 000287729900018

    View details for PubMedID 21220608

  • Mutations with epigenetic effects in myeloproliferative neoplasms and recent progress in treatment: Proceedings from the 5th International Post-ASH Symposium BLOOD CANCER JOURNAL Tefferi, A., Abdel-Wahab, O., Cervantes, F., Crispino, J. D., Finazzi, G., Girodon, F., Gisslinger, H., Gotlib, J., Kiladjian, J., Levine, R. L., Licht, J. D., Mullally, A., Odenike, O., Pardanani, A., Silver, R. T., Solary, E., Mughal, T. 2011; 1

    Abstract

    Immediately following the 2010 annual American Society of Hematology (ASH) meeting, the 5th International Post-ASH Symposium on Chronic Myelogenous Leukemia and BCR-ABL1-Negative Myeloproliferative Neoplasms (MPNs) took place on 7-8 December 2010 in Orlando, Florida, USA. During this meeting, the most recent advances in laboratory research and clinical practice, including those that were presented at the 2010 ASH meeting, were discussed among recognized authorities in the field. The current paper summarizes the proceedings of this meeting in BCR-ABL1-negative MPN. We provide a detailed overview of new mutations with putative epigenetic effects (TET oncogene family member 2 (TET2), additional sex comb-like 1 (ASXL1), isocitrate dehydrogenase (IDH) and enhancer of zeste homolog 2 (EZH2)) and an update on treatment with Janus kinase (JAK) inhibitors, pomalidomide, everolimus, interferon-α, midostaurin and cladribine. In addition, the new 'Dynamic International Prognostic Scoring System (DIPSS)-plus' prognostic model for primary myelofibrosis (PMF) and the clinical relevance of distinguishing essential thrombocythemia from prefibrotic PMF are discussed.

    View details for DOI 10.1038/bcj.2011.4

    View details for Web of Science ID 000298815400001

    View details for PubMedID 23471017

  • Identification of Novel LNK Mutations In Patients with Chronic Myeloproliferative Neoplasms and Related Disorders Oh, S. T., Zahn, J. M., Jones, C. D., Zhang, B., Loh, M. L., Kantarjian, H., Simonds, E. F., Bruggner, R. V., Abidi, P., Natsoulis, G., Bell, J., Buenrostro, J., Nolan, G. P., Zehnder, J. L., Ji, H. P., Gotlib, J. AMER SOC HEMATOLOGY. 2010: 143-144
  • Identification of a Novel Splice Donor Mutation In the Thrombopoietin Gene In a Philippine Family with Hereditary Thrombocythemia Gotlib, J., Zhang, B., Jones, C. D., Riess, J., Wong, W. B., Simonds, E. F., Hale, M. B., Abidi, P., McClung, J., Nolan, G. P., Oh, S. T., Zehnder, J. L. AMER SOC HEMATOLOGY. 2010: 1272-1272
  • A Phase I Study of Sequential Azacitidine and Lenalidomide for Elderly Patients with Acute Myeloid Leukemia (AML) Pollyea, D. A., Kohrt, H. E., Gallegos, L., Berube, C., Coutre, S., Gotlib, J., Liedtke, M., Mitchell, B. S., Medeiros, B. C. AMER SOC HEMATOLOGY. 2010: 1347-1347
  • Temozolomide In Acute Myeloid Leukemia: A MGMT Promoter Methylation Status-Based Treatment Stratification Medeiros, B. C., Kohrt, H. E., Rajwanshi, R., Gotlib, J., Coutre, S., Liedtke, M., Berube, C., Zhang, M., Arber, D. A., Zehnder, J. L. AMER SOC HEMATOLOGY. 2010: 1357-1358
  • Second-line mitoxantrone, etoposide, and cytarabine for acute myeloid leukemia: A single-center experience AMERICAN JOURNAL OF HEMATOLOGY Kohrt, H. E., Patel, S., Ho, M., Owen, T., Pollyea, D. A., Majeti, R., Gotlib, J., Coutre, S., Liedtke, M., Berube, C., Alizadeh, A. A., Medeiros, B. C. 2010; 85 (11): 877-881

    Abstract

    The majority of patients with acute myeloid leukemia (AML) will require second-line chemotherapy for either relapsed or refractory disease. Currently, only allogeneic hematopoietic cell transplantation (HCT) offers a curative option in this setting and no preferred regimen has been established. The reported efficacy of second-line regimens is widely disparate, thus limiting informed clinical decision making. A retrospective review of 77 patients receiving therapy between 2001 and 2008 with relapsed, 42, and refractory, 35, AML was performed to determine overall response rate and survival following mitoxantrone (8 mg/m(2)/day), etoposide (100 mg/m(2)/day), and cytarabine (1,000 mg/m(2)/day) chemotherapy administered over 5 days. Among 77 patients (median age of 54 years and 64% intermediate risk karyotype) with median follow-up of 153 days, 18% achieved a complete response and 8% a morphologic leukemia-free state. Fifty-seven (74%) experienced treatment failure, 10 of whom achieved a remission after additional therapy. Median overall survival (OS) was 6.8 months. Among patients achieving a response, 50% received consolidation with allogeneic HCT, autologous HCT (5%), or consolidation chemotherapy alone (45%). A nonsignificant trend in overall response (50%, 27%, and 23.8%) and median OS (8.3, 6.8, and 4.7 months) was observed by cytogenetic stratification into favorable, intermediate, and unfavorable risk. Patients with refractory versus relapsed disease had similar overall responses (20% and 31%, P = 0.41) and median OS (5.3 and 7.6 months, P = 0.36). Despite risk stratification by the European Prognostic Index, our series demonstrates inferior rates of response and survival, illustrating the limited activity of this regimen in our cohort.

    View details for DOI 10.1002/ajh.21857

    View details for Web of Science ID 000283568200010

    View details for PubMedID 20872554

  • LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2, IDH, JAK2 or MPL mutations LEUKEMIA Pardanani, A., Lasho, T., Finke, C., Oh, S. T., Gotlib, J., Tefferi, A. 2010; 24 (10): 1713-1718

    Abstract

    LNK mutation analysis was performed in 61 patients with blast-phase myeloproliferative neoplasms (MPN); post-primary myelofibrosis (PMF) in 41, post-polycythemia vera in 11 and post-essential thrombocythemia in 9 patients. Paired chronic-blast phase sample analysis was possible in 26 cases. Nine novel heterozygous LNK mutations were identified in eight (13%) patients: six exon 2 missense mutations involving codons 215, 220, 223, 229 and 234, a synonymous mutation involving codon 208, and two deletion mutations involving exon 2 (685-691_delGGCCCCG) or exon 5 (955_delA); eight affected the pleckstrin homology (PH) domain. Mutations were detected in six (9.8%) blast-phase samples; chronic-phase sample analysis in four of these revealed the same mutation in one. Mutant LNK was detected in chronic-phase only in two patients and in both chronic-blast phases in one. JAK2V617F was documented in three and IDH2R140Q in one LNK-mutated patients. LNK mutations were not detected in 78 additional patients with chronic-phase MPN enriched for TET2, IDH, JAK2V617F, or MPL-mutated cases. We conclude that LNK mutations (i) target an exon 2 'hot spot' in the PH domain spanning residues E208-D234, (ii) might be more prevalent in blast-phase PMF and (iii) are not mutually exclusive of other MPN-associated mutations but rarely occur in their presence in chronic-phase disease.

    View details for DOI 10.1038/leu.2010.163

    View details for Web of Science ID 000283056200006

    View details for PubMedID 20724988

  • Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms BLOOD Oh, S. T., Simonds, E. F., Jones, C., Hale, M. B., Goltsev, Y., Gibbs, K. D., Merker, J. D., Zehnder, J. L., Nolan, G. P., Gotlib, J. 2010; 116 (6): 988-992

    Abstract

    Dysregulated Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling due to activation of tyrosine kinases is a common feature of myeloid malignancies. Here we report the first human disease-related mutations in the adaptor protein LNK, a negative regulator of JAK-STAT signaling, in 2 patients with JAK2 V617F-negative myeloproliferative neoplasms (MPNs). One patient exhibited a 5 base-pair deletion and missense mutation leading to a premature stop codon and loss of the pleckstrin homology (PH) and Src homology 2 (SH2) domains. A second patient had a missense mutation (E208Q) in the PH domain. BaF3-MPL cells transduced with these LNK mutants displayed augmented and sustained thrombopoietin-dependent growth and signaling. Primary samples from MPN patients bearing LNK mutations exhibited aberrant JAK-STAT activation, and cytokine-responsive CD34(+) early progenitors were abnormally abundant in both patients. These findings indicate that JAK-STAT activation due to loss of LNK negative feedback regulation is a novel mechanism of MPN pathogenesis.

    View details for DOI 10.1182/blood-2010-02-270108

    View details for Web of Science ID 000280881700021

    View details for PubMedID 20404132

  • Myelomastocytic leukemia versus mast cell leukemia versus systemic mastocytosis associated with acute myeloid leukemia: A diagnostic challenge AMERICAN JOURNAL OF HEMATOLOGY Arredondo, A. R., Gotlib, J., Shier, L., Medeiros, B., Wong, K., Cherry, A., Corless, C., Arber, D. A., Valent, P., George, T. I. 2010; 85 (8): 600-606

    View details for DOI 10.1002/ajh.21713

    View details for Web of Science ID 000280562800011

    View details for PubMedID 20658589

  • JAK2 V617F and beyond: role of genetics and aberrant signaling in the pathogenesis of myeloproliferative neoplasms EXPERT REVIEW OF HEMATOLOGY Oh, S. T., Gotlib, J. 2010; 3 (3): 323-337

    Abstract

    Dysregulated signaling is a hallmark of chronic myeloproliferative neoplasms (MPNs), as evidenced by the identification of the activating JAK2 V617F somatic mutation in almost all patients with polycythemia vera (PV) and 50-60% of essential thrombocythemia and primary myelofibrosis patients. These disorders are clinically distinct, raising the question of how a single mutation can result in such phenotypic diversity. Mouse models have demonstrated that the level of JAK2 V617F expression can modulate the phenotype, and clinical studies of JAK2 V617F allele burden have reported similar findings. It has also been hypothesized that one or more pre-JAK2 V617F events may modify the MPN phenotype. However, the molecular basis of JAK2 V617F-negative essential thrombocythemia and primary myelofibrosis remains largely unexplained. Mutations in the TET2 gene have been identified in both JAK2 V617F-positive and -negative MPNs and other myeloid neoplasms, but their functional and clinical significance have yet to be clarified. In addition, recent reports have identified a specific germline haplotype that increases the predisposition to MPNs. The role of inhibitory pathways (e.g., SOCS and LNK) in regulating JAK-STAT signaling in MPNs is being increasingly recognized. The implications of these findings and their clinical relevance are the focus of this article.

    View details for DOI 10.1586/EHM.10.28

    View details for Web of Science ID 000284801600015

    View details for PubMedID 21082983

  • Eosinophilic myeloid disorders: new classification and novel therapeutic strategies CURRENT OPINION IN HEMATOLOGY Gotlib, J. 2010; 17 (2): 117-124

    Abstract

    The aim of this brief review is to evaluate recent developments in the classification and treatment of eosinophilic myeloid disorders in the context of reactive, lymphocyte-variant, and idiopathic eosinophilias.The revised 2008 WHO classification recognizes both molecularly defined ('myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1') and undefined (chronic eosinophilic leukemia, not otherwise specified) eosinophilic myeloid disorders. An increasingly sophisticated understanding of the molecular underpinnings of eosinophilia has translated into rational use of biologically targeted therapies such as imatinib mesylate. Conventional cytotoxics and interferon-alpha still have an established role in treating these diseases. Although studied in idiopathic hypereosinophilic syndrome, the therapeutic niche of anti-interleukin-5 (mepolizumab) and anti-CD52 (alemtuzumab) antibody therapy in eosinophilic myeloid diseases has yet to be established.Molecular/genetic analysis is now mandatory for the diagnosis, classification, and treatment of eosinophilic myeloid disorders. The finding of rearranged, constitutively activated PDGFRA/B identifies patients who are eminently treatable with tyrosine kinase inhibitors.

    View details for DOI 10.1097/MOH.0b013e3283366c70

    View details for Web of Science ID 000275198000008

    View details for PubMedID 20071982

  • Hypereosinophilic Syndrome and Clonal Eosinophilia: Point-of-Care Diagnostic Algorithm and Treatment Update MAYO CLINIC PROCEEDINGS Tefferi, A., Gotlib, J., Pardanani, A. 2010; 85 (2): 158-164

    Abstract

    Acquired eosinophilia is operationally categorized into secondary, clonal, and idiopathic types. Causes of secondary eosinophilia include parasite infections, allergic or vasculitis conditions, drugs, and lymphoma. Clonal eosinophilia is distinguished from idiopathic eosinophilia by the presence of histologic, cytogenetic, or molecular evidence of an underlying myeloid malignancy. The World Health Organization classification system for hematologic malignancies recognizes 2 distinct subcategories of clonal eosinophilia: chronic eosinophilic leukemia, not otherwise specified and myeloid/lymphoid neoplasms with eosinophilia and mutations involving platelet-derived growth factor receptor alpha/beta or fibroblast growth factor receptor 1. Clonal eosinophilia might also accompany other World Health Organization-defined myeloid malignancies, including chronic myelogenous leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and systemic mastocytosis. Hypereosinophilic syndrome, a subcategory of idiopathic eosinophilia, is defined by the presence of a peripheral blood eosinophil count of 1.5 x 10(9)/L or greater for at least 6 months (a shorter duration is acceptable in the presence of symptoms that require eosinophil-lowering therapy), exclusion of both secondary and clonal eosinophilia, evidence of organ involvement, and absence of phenotypically abnormal and/or clonal T lymphocytes. The presence of the latter defines lymphocytic variant hyper eosinophilia, which is best classified under secondary eosinophilia. In the current review, we provide a simplified algorithm for distinguishing the various causes of clonal and idiopathic eosinophilia and discuss current therapy, including new drugs (imatinib mesylate, alemtuzumab, and mepolizumab).

    View details for DOI 10.4065/mcp.2009.0503

    View details for Web of Science ID 000274607200009

    View details for PubMedID 20053713

  • Design and Evaluation of a Real-Time PCR Assay for Quantification of JAK2 V617F and Wild-Type JAK2 Transcript Levels in the Clinical Laboratory JOURNAL OF MOLECULAR DIAGNOSTICS Merker, J. D., Jones, C. D., Oh, S. T., Schrijver, I., Gotlib, J., Zehnder, J. L. 2010; 12 (1): 58-64

    Abstract

    The somatic mutation JAK2 V617F is associated with BCR-ABL1-negative myeloproliferative neoplasms. Detection of this mutation aids diagnosis of these neoplasms, and quantification of JAK2 V617F may provide a method to monitor response to therapy. For these reasons, we designed a clinical assay that uses allele-specific PCR and real-time detection with hydrolysis probes for the quantification of JAK2 V617F, wild-type JAK2, and GAPDH transcripts. Mutant and wild-type JAK2 were quantified by using external plasmid standards that contain the relevant JAK2 V617F or JAK2 sequence, respectively. We tested 55 peripheral blood specimens from patients with suspected myeloproliferative neoplasms and 55 peripheral blood specimens from patients not known to have myeloproliferative neoplasms. Low-level, nonspecific amplification was detected in reactions containing a high copy number of plasmid standards and in specimens from patients not known to have myeloproliferative neoplasms, necessitating the use of a laboratory-established mutant to wild-type cutoff. The limit of detection established by using cell line dilutions is 0.1%, and this method identified three JAK2 V617F-positive patients who were not detected by a less sensitive method. The assay characteristics and our initial evaluation indicate this method can be used for the detection and quantification of JAK2 V617F, which should be useful for diagnosis of myeloproliferative neoplasms and potentially for monitoring minimal residual disease in future trials of therapies targeted to myeloproliferative neoplasms.

    View details for DOI 10.2353/jmoldx.2010.090068

    View details for Web of Science ID 000273664100009

    View details for PubMedID 19959796

  • Fusion of PDGFRB to two distinct loci at 3p21 and a third at 12q13 in imatinib-responsive myeloproliferative neoplasms BRITISH JOURNAL OF HAEMATOLOGY Hidalgo-Curtis, C., Apperley, J. F., Stark, A., Jeng, M., Gotlib, J., Chase, A., Cross, N. C., Grand, F. H. 2010; 148 (2): 268-273

    Abstract

    We identified four patients who presented with BCR-ABL1 negative myeloproliferative neoplasms and cytogenetically visible abnormalities of chromosome band 5q31-35. Fluorescence in situ hybridization indicated that the platelet-derived growth factor receptor beta gene (PDGFRB) was disrupted in all four cases and 5' rapid amplification of cDNA ends identified in-frame mRNA fusions between PDGFRB and WDR48 (3p21), GOLGA4 (3p21) and BIN2 (12q13). Strikingly, all three genes encode proteins involving intracellular trafficking. Imatinib, a known inhibitor of PDGFRbeta, selectively blocked the growth of t(3;5) myeloid colonies and produced clinically significant responses in all patients. We conclude that PDGFRB fuses to diverse partner genes in atypical myeloproliferative neoplasms (MPNs). Although very rare, identification of these fusions is critical for proper management of affected individuals.

    View details for DOI 10.1111/j.1365-2141.2009.07955.x

    View details for Web of Science ID 000272884100009

    View details for PubMedID 20085582

  • When yellow jackets attack: recurrent and severe anaphylactic reactions to insect bites and stings AMERICAN JOURNAL OF HEMATOLOGY Pollyea, D. A., George, T. I., Corless, C., Gotlib, J. 2009; 84 (12): 843-846

    View details for DOI 10.1002/ajh.21551

    View details for Web of Science ID 000272481500015

    View details for PubMedID 19862831

  • On being metachromatic: mystique and misunderstanding in mastocytosis AMERICAN JOURNAL OF HEMATOLOGY Gotlib, J. 2009; 84 (12): 779-781

    View details for DOI 10.1002/ajh.21575

    View details for Web of Science ID 000272481500001

    View details for PubMedID 19899132

  • NPM1 Haploinsufficiency Results in Increased Numbers of Hematopoietic Stem Cells and Progenitor Cells Raval, A., Park, C. Y., Pang, W. W., Kusler, B., Sridhar, K. J., Gotlib, J. R., Greenberg, P. L., Weissman, I. L., Mitchell, B. S. AMER SOC HEMATOLOGY. 2009: 307-307
  • Is Time of the Essence in Adult Acute Myeloid Leukemia (AML)? Time to Blast Clearance and Time to Induction Therapy Fail to Predict Overall Survival (OS). Kohrt, H. E., Patel, S., Ho, M., Owen, T., Majeti, R., Gotlib, J. R., Coutre, S., Medeiros, B. C., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2009: 646-647
  • Early Mortality in Acute Promyelocytic Leukemia May Be Higher Than Previously Reported. Alizadeh, A. A., McClellan, J. S., Gotlib, J. R., Coutre, S., Majeti, R., Kohrt, H. E., Medeiros, B. C. AMER SOC HEMATOLOGY. 2009: 420-421
  • Chronic Myelogenous Leukemia JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK O'Brien, S., Berman, E., Borghaei, H., DeAngelo, D. J., Devetten, M. P., Devine, S., Erba, H. P., Gotlib, J., Jagasia, M., Moore, J. O., Mughal, T., Mughal, T., Radich, J. P., Radich, J. P., Shah, N. P., Smith, B. D., Snyder, D. S., Snyder, D. S., Talpaz, M., Wetzler, M. 2009; 7 (9): 984-1023
  • NCCN clinical practice guidelines in oncology: chronic myelogenous leukemia. Journal of the National Comprehensive Cancer Network O'Brien, S., Berman, E., Borghaei, H., DeAngelo, D. J., Devetten, M. P., Devine, S., Erba, H. P., Gotlib, J., Jagasia, M., Moore, J. O., Mughal, T., Pinilla-Ibarz, J., Radich, J. P., Shah Md, N. P., Shami, P. J., Smith, B. D., Snyder, D. S., Tallman, M. S., Talpaz, M., Wetzler, M. 2009; 7 (9): 984-1023

    View details for PubMedID 19878641

  • Monoclonal antibodies against IREM-1: potential for targeted therapy of AML LEUKEMIA Korver, W., Zhao, X., Singh, S., Pardoux, C., Zhao, J., Guzman, M. L., Sen, S., Yonkovich, S., Liu, S., Zhan, X., Tomasevic, N., Zhou, C., Gros, D., Jordan, C. T., Gotlib, J., Hsi, E. D., Abo, A. 2009; 23 (9): 1587-1597

    Abstract

    IREM-1 is an inhibitory cell surface receptor with an unknown function and is expressed on myeloid cell lineages, including cell lines derived from acute myeloid leukemia (AML) patients. We have generated a series of monoclonal antibodies (mAbs) against the extracellular domain of IREM-1 and further assessed its expression in normal and AML cells. IREM-1 was restricted to cells from myeloid origin and extensive expression analysis in primary cells obtained from AML patients showed IREM-1 expression in leukemic blasts of 72% (39/54) of samples. We therefore searched for specific IREM-1 mAbs with activity in functional complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Lead mAbs against IREM-1 showed specific cytotoxic activity against a variety of AML-derived cell lines and freshly isolated blasts from AML patients. Internalization of mAbs upon IREM-1 binding was also shown. In vivo anticancer activity of lead mAbs was observed in an established HL-60 xenograft model with a tumor growth delay of up to 40% and in a model using primary human AML cells, where treatment with anti-IREM-1 mAb resulted in a significant reduction of engrafted human cells. These results demonstrate IREM-1 as a potential novel target for immunotherapy of AML.

    View details for DOI 10.1038/leu.2009.99

    View details for Web of Science ID 000269674200007

    View details for PubMedID 19440216

  • RNAi screen for rapid therapeutic target identification in leukemia patients PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Tyner, J. W., Deininger, M. W., Loriaux, M. M., Chang, B. H., Gotlib, J. R., Willis, S. G., Erickson, H., Kovacsovics, T., O'Hare, T., Heinrich, M. C., Druker, B. J. 2009; 106 (21): 8695-8700

    Abstract

    Targeted therapy has vastly improved outcomes in certain types of cancer. Extension of this paradigm across a broad spectrum of malignancies will require an efficient method to determine the molecular vulnerabilities of cancerous cells. Improvements in sequencing technology will soon enable high-throughput sequencing of entire genomes of cancer patients; however, determining the relevance of identified sequence variants will require complementary functional analyses. Here, we report an RNAi-assisted protein target identification (RAPID) technology that individually assesses targeting of each member of the tyrosine kinase gene family. We demonstrate that RAPID screening of primary leukemia cells from 30 patients identifies targets that are critical to survival of the malignant cells from 10 of these individuals. We identify known, activating mutations in JAK2 and K-RAS, as well as patient-specific sensitivity to down-regulation of FLT1, CSF1R, PDGFR, ROR1, EPHA4/5, JAK1/3, LMTK3, LYN, FYN, PTK2B, and N-RAS. We also describe a previously undescribed, somatic, activating mutation in the thrombopoietin receptor that is sensitive to down-stream pharmacologic inhibition. Hence, the RAPID technique can quickly identify molecular vulnerabilities in malignant cells. Combination of this technique with whole-genome sequencing will represent an ideal tool for oncogenic target identification such that specific therapies can be matched with individual patients.

    View details for DOI 10.1073/pnas.0903233106

    View details for Web of Science ID 000266432700052

    View details for PubMedID 19433805

  • Interim results of protracted low doses of temozolomide in high-risk acute myeloid leukemia Medeiros, B. C., Gotlib, J. R., Coutre, S. E., Jones, C., Khan, S. A., Rajwanshi, R., Rajwanshi, R., Zehnder, J., Zehnder, J. AMER SOC CLINICAL ONCOLOGY. 2009
  • Nanofluidic proteomic assay for serial analysis of oncoprotein activation in clinical specimens NATURE MEDICINE Fan, A. C., Deb-Basu, D., Orban, M. W., Gotlib, J. R., Natkunam, Y., O'Neill, R., Padua, R., Xu, L., Taketa, D., Shirer, A. E., Beer, S., Yee, A. X., Voehringer, D. W., Felsher, D. W. 2009; 15 (5): 566-571

    Abstract

    Current methods of protein detection are insensitive to detecting subtle changes in oncoprotein activation that underlie key cancer signaling processes. The requirement for large numbers of cells precludes serial tumor sampling for assessing a response to therapeutics. Therefore, we have developed a nanofluidic proteomic immunoassay (NIA) to quantify total and low-abundance protein isoforms in nanoliter volumes. Our method can quantify amounts of MYC oncoprotein and B cell lymphoma protein-2 (BCL2) in Burkitt's and follicular lymphoma; identify changes in activation of extracellular signal-related kinases-1 (ERK1) and ERK2, mitogen-activated kinase-1 (MEK), signal transducer and activator of transcription protein-3 (STAT3) and STAT5, c-Jun N-terminal kinase (JNK) and caspase-3 in imatinib-treated chronic myelogeneous leukemia (CML) cells; measure an unanticipated change in the phosphorylation of an ERK2 isomer in individuals with CML who responded to imatinib; and detect a decrease in STAT3 and STAT5 phosphorylation in individuals with lymphoma who were treated with atorvastatin. Therefore, we have described a new and highly sensitive method for determining oncoprotein expression and phosphorylation in clinical specimens for the development of new therapeutics for cancer.

    View details for DOI 10.1038/nm.1903

    View details for Web of Science ID 000265889300036

    View details for PubMedID 19363496

  • Glycogen synthase kinase 3 beta missplicing contributes to leukemia stem cell generation PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Abrahamsson, A. E., Geron, I., Gotlib, J., Dao, K. T., Barroga, C. F., Newton, I. G., Giles, F. J., Durocher, J., Creusot, R. S., Karimi, M., Jones, C., Zehnder, J. L., Keating, A., Negrin, R. S., Weissman, I. L., Jamieson, C. H. 2009; 106 (10): 3925-3929

    Abstract

    Recent evidence suggests that a rare population of self-renewing cancer stem cells (CSC) is responsible for cancer progression and therapeutic resistance. Chronic myeloid leukemia (CML) represents an important paradigm for understanding the genetic and epigenetic events involved in CSC production. CML progresses from a chronic phase (CP) in hematopoietic stem cells (HSC) that harbor the BCR-ABL translocation, to blast crisis (BC), characterized by aberrant activation of beta-catenin within granulocyte-macrophage progenitors (GMP). A major barrier to predicting and inhibiting blast crisis transformation has been the identification of mechanisms driving beta-catenin activation. Here we show that BC CML myeloid progenitors, in particular GMP, serially transplant leukemia in immunocompromised mice and thus are enriched for leukemia stem cells (LSC). Notably, cDNA sequencing of Wnt/beta-catenin pathway regulatory genes, including adenomatous polyposis coli, GSK3beta, axin 1, beta-catenin, lymphoid enhancer factor-1, cyclin D1, and c-myc, revealed a novel in-frame splice deletion of the GSK3beta kinase domain in the GMP of BC samples that was not detectable by sequencing in blasts or normal progenitors. Moreover, BC CML progenitors with misspliced GSK3beta have enhanced beta-catenin expression as well as serial engraftment potential while reintroduction of full-length GSK3beta reduces both in vitro replating and leukemic engraftment. We propose that CP CML is initiated by BCR-ABL expression in an HSC clone but that progression to BC may include missplicing of GSK3beta in GMP LSC, enabling unphosphorylated beta-catenin to participate in LSC self-renewal. Missplicing of GSK3beta represents a unique mechanism for the emergence of BC CML LSC and might provide a novel diagnostic and therapeutic target.

    View details for DOI 10.1073/pnas.0900189106

    View details for Web of Science ID 000264036900051

    View details for PubMedID 19237556

  • Clinical characterization of acute myeloid leukemia with myelodysplasia-related changes as defined by the 2008 WHO classification system BLOOD Weinberg, O. K., Seetharam, M., Ren, L., Seo, K., Ma, L., Merker, J. D., Gotlib, J., Zehnder, J. L., Arber, D. A. 2009; 113 (9): 1906-1908

    Abstract

    Although some studies have validated the 2001 World Health Organization (WHO) classification of acute myeloid leukemia (AML), including the importance of multilineage dysplasia, others have suggested that multilineage dysplasia correlates with unfavorable cytogenetics but has no independent impact on prognosis. In 2008, the revised WHO classification has expanded this category into "AML with myelodysplasia-related changes" (AML-MRC). We evaluated the clinical, pathologic, cytogenetic, and molecular features of 100 AML patients using the 2008 WHO criteria. Patients underwent genetic screening for NPM1, FLT3-ITD, FLT3-D835, and CEBPA mutations. Compared with patients with AML, not otherwise specified, patients with AML-MRC were significantly older (P= .014), presented with a lower hemoglobin (P= .044), more frequently expressed CD14 (P= .048), and exhibited a decreased frequency of CEBPA mutations (P= .001). Multivariate analysis indicated that patients with AML-MRC had a significantly worse overall survival, progression-free survival, and complete response compared with AML-not otherwise specified (all P< .001). These data support the clinical, morphologic, and cytogenetic criteria for this 2008 WHO AML category.

    View details for DOI 10.1182/blood-2008-10-182782

    View details for Web of Science ID 000263723700007

    View details for PubMedID 19131546

  • Myelomastocytic Leukemia: A Clinical, Pathologic, and Molecular Genetic Study McGuire, A., Shier, L. R., Gotlib, J., Medeiros, B., Wong, K., Corless, C., Arber, D. A., George, T. I. NATURE PUBLISHING GROUP. 2009: 277A-277A
  • Molecular stratification of patients with normal karyotype acute myeloid leukemia based on initial assessment of FLT3-internal tandem duplication status at first complete remission LEUKEMIA & LYMPHOMA Medeiros, B. C., Gotlib, J., Zehnder, J. 2009; 50 (5): 851-853

    View details for DOI 10.1080/10428190902838400

    View details for Web of Science ID 000266201800029

    View details for PubMedID 19452323

  • A phase II intra-patient dose-escalation trial of weight-based darbepoetin alfa with or without granulocyte-colony stimulating factor in myelodysplastic syndromes AMERICAN JOURNAL OF HEMATOLOGY Gotlib, J., Lavori, P., Quesada, S., Stein, R. S., Shahnia, S., Greenberg, P. L. 2009; 84 (1): 15-20

    Abstract

    This Phase II study evaluated darbepoetin alfa (DA) in 24 patients with predominantly low or intermediate-1 risk myelodysplastic syndrome (MDS). Intra-patient dose escalation of DA was undertaken in three 6-week dose cohorts until a major erythroid response was achieved: 4.5 mcg/kg/week, 9 mcg/kg/week, and 9 mcg/kg/week plus granulocyte-colony stimulating factor (G-CSF) 2.5 mcg/kg twice weekly. Patients with refractory anemia with ringed sideroblasts (RARS) commenced DA at 9 mcg/kg/week. The weight-based dosing regimen translated into a median starting DA dose of 390 mcg/week. Erythroid responses were observed in 16/24 patients (67%; 12 major and 4 minor), with a median response duration of 11 months in major responders. Addition of G-CSF generated a major erythroid response in 7/15 patients (47%) who suboptimally responded to DA alone. DA was well tolerated, except for worsening of baseline mild hypertension and renal insufficiency in one patient with diabetes. IPSS score <0.5 and RBC transfusions <2 units/month increased the probability of an erythroid response. A minority of subjects (12%) developed low-level non-neutralizing anti-DA antibodies. Our data indicate that weekly weight-based dosing of DA, with the addition of G-CSF in selected individuals, can be an effective erythropoietic option in a high proportion of lower-risk MDS patients.

    View details for DOI 10.1002/ajh.21316

    View details for Web of Science ID 000262219900004

    View details for PubMedID 19006226

  • Acute Myeloid Leukemia with Myelodysplasia-Related Changes as Defined by the 2008 WHO Classification System Weinberg, O. K., Seetharam, M., Ren, L., Ma, L., Seo, K., Merker, J., Gotlib, J., Zehnder, J., Arber, D. A. NATURE PUBLISHING GROUP. 2009: 291A-291A
  • Clinical Characterization of Acute Myeloid Leukemia with Myelodysplasia-Related Changes as Defined by the 2008 WHO Classification System Weinberg, O. K., Seetharam, M., Ren, L., Ma, L., Seo, K., Merker, J. D., Gotlib, J. R., Zehnder, J. L., Arber, D. A. AMER SOC HEMATOLOGY. 2008: 341-342
  • Design and Validation of a Real-Time PCR Assay for Quantification of JAK2 V617F and Wild-type JAK2 Transcript Levels Merker, J. D., Jones, C. D., Oh, S. T., Khan, S., Schrijver, I., Gotlib, J., Zehnder, J. L. ELSEVIER SCIENCE INC. 2008: 581-581
  • Five years since the discovery of FIP1L1-PDGFRA: what we have learned about the fusion and other molecularly defined eosinophilias LEUKEMIA Gotlib, J., Cools, J. 2008; 22 (11): 1999-2010

    Abstract

    The year 2008 marks the fifth anniversary since the publication which identified the FIP1L1-PDGFRA fusion gene in patients with idiopathic hypereosinophilia. With the benefit of time, a more comprehensive picture has emerged regarding several characteristics of the fusion, including its incidence, biological features and the clinical profile of patients who carry the molecular rearrangement. A few prospective trials have now better defined the natural history of imatinib-treated FIP1L1-PDGFRA-positive patients, from which some basic conclusions can be drawn: the prognosis is outstanding, acquired resistance is exceedingly rare, but ongoing imatinib treatment is likely required to prevent relapse. The emergence of genetically assigned eosinophilias has led the World Health Organization in 2008 to adopt a semi-molecular classification scheme, with one subcategory named 'myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1.' Molecular rearrangements involving other partner genes, such as ETV6 and JAK2, have also been associated with eosinophilic disorders, and will likely be assimilated into such classifications over time. Despite the molecularly defined eosinophilias comprising a small proportion of cases compared to the aggregate of other subtypes of hypereosinophilia, their recognition is critical because of the availability of highly effective molecularly targeted therapy.

    View details for DOI 10.1038/leu.2008.287

    View details for Web of Science ID 000260832800003

    View details for PubMedID 18843283

  • Selective inhibition of JAK2-Driven erythroid differentiation of polycythemia vera progenitors CANCER CELL Geron, I., Abrahamsson, A. E., Barroga, C. F., Kavalerchik, E., Gotlib, J., Hood, J. D., Durocher, J., Mak, C. C., Noronha, G., Soll, R. M., Tefferi, A., Kaushansky, K., Jamieson, C. H. 2008; 13 (4): 321-330

    Abstract

    Polycythemia Vera (PV) is a myeloproliferative disorder (MPD) that is commonly characterized by mutant JAK2 (JAK2V617F) signaling, erythrocyte overproduction, and a propensity for thrombosis, progression to myelofibrosis, or acute leukemia. In this study, JAK2V617F expression by human hematopoietic progenitors promoted erythroid colony formation and erythroid engraftment in a bioluminescent xenogeneic immunocompromised mouse transplantation model. A selective JAK2 inhibitor, TG101348 (300 nM), significantly inhibited JAK2V617F+ progenitor-derived colony formation as well as engraftment (120 mg/kg) in xenogeneic transplantation studies. TG101348 treatment decreased GATA-1 expression, which is associated with erythroid-skewing of JAK2V617F+ progenitor differentiation, and inhibited STAT5 as well as GATA S310 phosphorylation. Thus, TG101348 may be an effective inhibitor of JAK2V617F+ MPDs in clinical trials.

    View details for DOI 10.1016/j.ccr.2008.02.017

    View details for Web of Science ID 000254817400007

    View details for PubMedID 18394555

  • A 2-gene classifier for predicting response to the famesyltransferase inhibitor tipifarnib in acute myeloid leukemia BLOOD Raponi, M., Lancet, J. E., Fan, H., Dossey, L., Lee, G., Gojo, I., Feldman, E. J., Gotlib, J., Morris, L. E., Greenberg, P. L., Wright, J. J., Harousseau, J., Loewenberg, B., Stone, R. M., De Porre, P., Wang, Y., Karp, J. E. 2008; 111 (5): 2589-2596

    Abstract

    At present, there is no method available to predict response to farnesyltransferase inhibitors (FTIs). We analyzed gene expression profiles from the bone marrow of patients from a phase 2 study of the FTI tipifarnib in older adults with previously untreated acute myeloid leukemia (AML). The RASGRP1/APTX gene expression ratio was found to predict response to tipifarnib with the greatest accuracy using a "leave one out" cross validation (LOOCV; 96%). RASGRP1 is a guanine nucleotide exchange factor that activates RAS, while APTX (aprataxin) is involved in DNA excision repair. The utility of this classifier for predicting response to tipifarnib was validated in an independent set of 58 samples from relapsed or refractory AML, with a negative predictive value (NPV) and positive predictive value (PPV) of 92% and 28%, respectively (odds ratio of 4.4). The classifier also predicted for improved overall survival (154 vs 56 days; P < .001), which was independent of other covariates, including a previously described prognostic gene expression classifier. Therefore, these data indicate that a 2-gene expression assay may have utility in categorizing a population of patients with AML who are more likely to respond to tipifarnib.

    View details for DOI 10.1182/blood-2007-09-112730

    View details for Web of Science ID 000253671600023

    View details for PubMedID 18160667

  • Gene expression and pathway analysis of immune thrombocytopenic purpura BRITISH JOURNAL OF HAEMATOLOGY Sood, R., Wong, W., Gotlib, J., Jeng, M., Zehnder, J. L. 2008; 140 (1): 99-103

    Abstract

    A global expression profile of peripheral blood from patients with immune thrombocytopenic purpura (ITP) was performed that identified an ITP-specific signature, which also included interferon (IFN)-induced genes. Several genes correlated with ITP have been shown to be associated with expression signatures in systemic lupus erythematosis and rheumatoid arthritis, indicating an overlap with other autoimmune disorders. Pathway analysis demonstrated that IFN signalling, death receptor and protein ubiquitination pathways were associated with ITP. These results provide the first glimpse of the genes and pathways consistently aberrant in ITP, identifying new targets for investigations of pathogenesis and treatment of ITP.

    View details for DOI 10.1111/j.1365-2141.2007.06881.x

    View details for Web of Science ID 000251502700011

    View details for PubMedID 18005267

  • Antiangiogenic therapy in myelodysplastic syndromes: is there a role? Current hematologic malignancy reports Oh, S. T., Gotlib, J. 2008; 3 (1): 10-18

    Abstract

    Angiogenesis has been shown to play a pivotal role in the growth and metastasis of solid tumors. Numerous in vitro and translational research studies have implicated a role for angiogenesis in the pathogenesis of myelodysplastic syndrome (MDS). Although the role of angiogenesis inhibitors in the treatment of solid tumors has evolved significantly over the past 5 years, their role in the treatment of hematologic malignancies such as MDS remains investigational. MDS treatment historically has been challenging, but the US Food and Drug Administration in the past 4 years has approved the hypomethylating agents 5-azacitidine and decitabine and the immunomodulatory agent lenalidomide for the 5q-syndrome. These approvals highlight recent successes in identifying and targeting pathobiologic abnormalities that contribute to MDS. Drugs such as lenalidomide and the first-generation analogue from which it was derived, thalidomide, exert multiple mechanisms of action but partially act via inhibition of angiogenesis. Over the next 5 to 10 years, preclinical and clinical evaluation of agents with more strictly defined antiangiogenic activity, such as inhibitors of vascular endothelial growth factor, or agents with partial antiangiogenesis activity, such as multitargeted tyrosine kinase inhibitors, will ultimately help define the utility of angiogenic blockade in MDS.

    View details for DOI 10.1007/s11899-008-0003-0

    View details for PubMedID 20425441

  • Chronic eosinophilic leukemia/hypereosinophilic syndrome. Cancer treatment and research Gotlib, J. 2008; 142: 69-106

    Abstract

    Although HES and CEL are indeed rare clinical entities, interest in these disorders has been reborn due to a renaissance in uncovering the biologic basis of previously idiopathic cases. Unmasking the molecular basis for such cases has, in turn, led to the development of semimolecular classification schemes for categorizing patients based on recurrent genetic alterations, usually related to constitutively activated tyrosine kinases. In turn, increasing sophistication in unmasking the molecular underpinnings of eosinophilia in patients heretofore classified as idiopathic HES now permits the rationale use biologically targeted therapies such as imatinib mesylate and recombinant anti-IL-5 antibody. The WHO convenes in 2007 to review prior diagnostic criteria for both HES and CEL. It will be of interest to see how the new genetic information becomes integrated with traditional histopathologic criteria in establishing a practical road map for clinicians who treat these diseases.

    View details for PubMedID 18283783

  • Significance of NPM1 and FLT3 mutations in acute myeloid leukemia with multilineage dysplasia: Does NPM1 identify a lower risk group? Weinberg, O., Merker, J., Beck, A., Seetharam, M., Gotlib, J., Zehnder, J., Arber, D. A. NATURE PUBLISHING GROUP. 2008: 281A-281A
  • Missplicing of glycogen synthase kinase 3 beta: A potential mechanism of blast crisis chronic myeloid leukemia stem cell generation Abrahamsson, A., Geron, I., Gotlib, J., Dao, K., Giles, F., Newton, I., Kavaterchik, E., Durocher, J., Creusot, R., Karimi, M., Jones, C., Zehnder, J., Keating, A., Negrin, R., Weissman, I. L., Jamieson, C. H. AMER SOC HEMATOLOGY. 2007: 238A-239A
  • The KIT tyrosine kinase inhibitor midostaurine (PKC412) exhibits a high response rate in aggressive systemic mastocytosis (ASM): Interim results of a phase II trial Gotlib, J., George, T. I., Corless, C., Linder, A., Ruddell, A., Akin, C., DeAngelo, D. J., Kepten, I., Lanza, C., Heinemann, H., Yin, O., Gallagher, N., Graubert, T. AMER SOC HEMATOLOGY. 2007: 1035A-1035A
  • A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia BLOOD Lancet, J. E., Gojo, I., Gotlib, J., Feldman, E. J., Greer, J., Liesveld, J. L., Bruzek, L. M., Morris, L., Park, Y., Adjei, A. A., Kaufmann, S. H., Garrett-Mayer, E., Greenberg, P. L., Wright, J. J., Karp, J. E. 2007; 109 (4): 1387-1394

    Abstract

    Outcomes for older adults with acute myelogenous leukemia (AML) are poor due to both disease and host-related factors. In this phase 2 study, we tested the oral farnesyltransferase inhibitor tipifarnib in 158 older adults with previously untreated, poor-risk AML. The median age was 74 years, and a majority of patients had antecedent myelodysplastic syndrome. Complete remission (CR) was achieved in 22 patients (14%); partial remission or hematologic improvement occurred in 15 patients, for an overall response rate of 23%. The median duration of CR was 7.3 months and the median survival of complete responders was 18 months. Adverse karyotype, age 75 years or older, and poor performance status correlated negatively with survival. Early death in the absence of progressive disease was rare, and drug-related nonhematologic serious adverse events were observed in 74 patients (47%). Inhibition of farnesylation of the surrogate protein HDJ-2 occurred in the large majority of marrow samples tested. Baseline levels of phosphorylated mitogen-activated protein kinase and AKT did not correlate with clinical response. Tipifarnib is active and well tolerated in older adults with poor-risk AML and may impart a survival advantage in those patients who experience a clinical response.

    View details for DOI 10.1182/blood-2006-04-014357

    View details for Web of Science ID 000244219400013

    View details for PubMedID 17082323

  • Gene expression profile of idiopathic thrombocytopenic purpura (ITP) reveals elevated expression of interferon regulated genes. Sood, R., Wong, W., Gotlib, J., Jeng, M., Zehnder, J. L. AMER SOC HEMATOLOGY. 2006: 211A-211A
  • Inhibition of JAK2 V617F-Induced erythroid skewing of hematopoietic stem cell differentiation with a selective JAK2 antagonist. Geron, I., Barroga, C., Gotlib, J., Kavalerchik, E., Abrahamsson, A., Goff, D., Cacalano, N., Hood, J., Soll, R., Noronha, G., Tefferi, A., Weissman, I. L., Kaushansky, K., Jamieson, C. AMER SOC HEMATOLOGY. 2006: 1033A-1033A
  • Aberrant regulation of Wnt/beta-catenin pathway mediators in chronic myelogenous leukemia stem cells Abrahamsson, A., Geron, I., Gotlib, J., Durocher, J., Creusot, R., Kavalerchik, E., Goff, D., Fathman, C. G., Lilleberg, S. L., Giles, F., Weissman, I., Jamieson, C. AMER SOC HEMATOLOGY. 2006: 605A-605A
  • Inhibition of chronic myelogenous leukemia stem cells with novel wnt antagonists. Kavalerchik, E., Gotlib, J., Geron, I., Abrahamsson, A., Wrasidlo, W., Goff, D., Lu, D., Molinski, T., Giles, F., Weissman, I., Carson, D., Jamieson, C. AMER SOC HEMATOLOGY. 2006: 74A-75A
  • A patient with paroxysmal nocturnal hemoglobinuria, T cell large granular lymphocyte clonal expansion, and monoclonal gammopathy of undetermined significance AMERICAN JOURNAL OF HEMATOLOGY Fukumoto, J. S., Gotlib, J. 2006; 81 (11): 870-874

    Abstract

    Paroxysmal nocturnal hemoglobinuria (PNH) has been described in association separately with T cell large granular lymphocyte (LGL) clonal expansions and plasma cell dyscrasias. We describe a patient with anemia related to hemolytic PNH, with concurrent T cell LGL oligoclonal expansion and IgG lambda monoclonal gammopathy of undetermined significance. Peripheral blood flow cytometry revealed decreased expression of CD55 and CD59 on erythrocytes and decreased expression of CD55 and CD66 on neutrophils. An LGL population was present in the peripheral blood and was characterized as oligoclonal by polymerase chain reaction-based analysis of the T cell receptor gamma-chain variable region. Serum protein electrophoresis with immunofixation showed a low level IgG lambda monoclonal protein. We describe the diagnostic evaluation of this patient and provide a brief review of the reported associations among PNH, LGL clonal expansion, and monoclonal gammopathy.

    View details for DOI 10.1002/ajh.20634

    View details for Web of Science ID 000241906700010

    View details for PubMedID 16929542

  • Use of urine flow cytometry to verify relapse of Burkitt's lymphoma in the genitourinary system JOURNAL OF CLINICAL ONCOLOGY Dormady, S. P., Mariappan, M. R., Kao, D., Gotlib, J. 2006; 24 (27): 4515-4516

    View details for DOI 10.1200/JCO.2006.06.1598

    View details for Web of Science ID 000240708200023

    View details for PubMedID 16983121

  • KIT mutations in mastocytosis and their potential as therapeutic targets IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA Gotlib, J. 2006; 26 (3): 575-?

    Abstract

    Deregulation of the KIT receptor TK by the prevalent activation loop mutation D816V has served as a focal point in therapeutic strategies aimed curbing neoplastic mast cell growth. Perhaps the most important development in this era of targeted therapy, and certainly relevant to KIT-driven diseases like mastocytosis, is the realization that small molecule inhibitors with varied chemical structure (eg, PKC412, dasatinib, AP23464) can circumvent the resistance of TKs to first-generation agents such as imatinib. Genuine opportunity now exists to effectively treat mastocytosis, and the arsenal consists of several orally bioavailable drugs with promising preclinical activity against D816V and other KIT mutants that promote mast cell growth. Because KIT mutations may not act as fully transforming oncogenic events in SM, it is prudent to evaluate combinations of TK inhibitors with drugs with activity in mast cell disease, such as cladribine, interferon-alpha, and corticosteroids. The identification of novel "drug-able" targets within mast cells should aid in the development of complementary therapies that promote enhanced cytotoxicity of mast cells through blockade of nonredundant signaling pathways. In addition, the generation of murine models that recapitulate human mastocytosis should accelerate preclinical testing of novel agents.

    View details for DOI 10.1016/j.iac.2006.05.003

    View details for Web of Science ID 000240967200012

    View details for PubMedID 16931294

  • Detection of the JAK2 V617F mutation by LightCycler PCR and probe dissociation analysis JOURNAL OF MOLECULAR DIAGNOSTICS Lay, M., Mariappan, R., Gotlib, J., Dietz, L., Sebastian, S., Schrijver, I., Zehnder, J. L. 2006; 8 (3): 330-334

    Abstract

    A point mutation in the JAK2 gene, a member of the tyrosine kinase family, was recently identified and shown to be associated with several myeloproliferative disorders. Several studies identified the same JAK2 point mutation (1,849G>T), resulting in the substitution of a valine to phenylalanine at codon 617 (V617F). We developed a simple and sensitive method to detect this mutation via polymerase chain reaction and probe dissociation analysis using the LightCycler platform, and we compared this method to existing restriction fragment-length polymorphism, direct sequencing, and amplification refractory mutation system methods. We found that the LightCycler method offered advantages of speed, reliability, and more straightforward interpretation over the restriction fragment-length polymorphism and sequencing approaches.

    View details for DOI 10.2353/jmoldx.2006.050130

    View details for Web of Science ID 000239106800006

    View details for PubMedID 16825505

  • Eosinophilic disorders: Molecular pathogenesis, new classification, and modern therapy BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY Gotlib, J., Cross, N. C., Gilliland, D. G. 2006; 19 (3): 535-569

    Abstract

    Before the 1990s, lack of evidence for a reactive cause of hypereosinophilia or chronic eosinophilic leukemia (e.g. presence of a clonal cytogenetic abnormality or increased blood or bone marrow blasts) resulted in diagnosticians characterizing such nebulous cases as 'idiopathic hypereosinophilic syndrome (HES)'. However, over the last decade, significant advances in our understanding of the molecular pathophysiology of eosinophilic disorders have shifted an increasing proportion of cases from this idiopathic HES 'pool' to genetically defined eosinophilic diseases with recurrent molecular abnormalities. The majority of these genetic lesions result in constitutively activated fusion tyrosine kinases, the phenotypic consequence of which is an eosinophilia-associated myeloid disorder. Most notable among these is the recent discovery of the cryptic FIP1L1-PDGFRA gene fusion in karyotypically normal patients with systemic mast cell disease with eosinophilia or idiopathic HES, redefining these diseases as clonal eosinophilias. Rearrangements involving PDGFRA and PDGFRB in eosinophilic chronic myeloproliferative disorders, and of fibroblast growth factor receptor 1 (FGFR1) in the 8p11 stem cell myeloproliferative syndrome constitute additional examples of specific genetic alterations linked to clonal eosinophilia. The identification of populations of aberrant T-lymphocytes secreting eosinophilopoietic cytokines such as interleukin-5 establish a pathophysiologic basis for cases of lymphocyte-mediated hypereosinophilia. This recent revival in understanding the biologic basis of eosinophilic disorders has permitted more genetic specificity in the classification of these diseases, and has translated into successful therapeutic approaches with targeted agents such as imatinib mesylate and recombinant anti-IL-5 antibody.

    View details for DOI 10.1016/j.beha.2005.07.013

    View details for Web of Science ID 000238903900012

    View details for PubMedID 16781488

  • Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation BLOOD Gotlib, J., Berube, C., Growney, J. D., Chen, C. C., George, T. I., Williams, C., Kajiguchi, T., Ruan, J., Lilleberg, S. L., Durocher, J. A., Lichy, J. H., Wang, Y. F., Cohen, P. S., Arber, D. A., Heinrich, M. C., Neckers, L., GALLI, S. J., Gilliland, D. G., Coutre, S. E. 2005; 106 (8): 2865-2870

    Abstract

    The majority of patients with systemic mast cell disease express the imatinib-resistant Asp816Val (D816V) mutation in the KIT receptor tyrosine kinase. Limited treatment options exist for aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL). We evaluated whether PKC412, a small-molecule inhibitor of KIT with a different chemical structure from imatinib, may have therapeutic use in advanced SM with the D816V KIT mutation. We treated a patient with MCL (with an associated myelodysplastic syndrome (MDS)/myeloproliferative disorder [MPD]) based on in vitro studies demonstrating that PKC412 could inhibit D816V KIT-transformed Ba/F3 cell growth with a 50% inhibitory concentration (IC50) of 30 nM to 40 nM. The patient exhibited a partial response with significant resolution of liver function abnormalities. In addition, PKC412 treatment resulted in a significant decline in the percentage of peripheral blood mast cells and serum histamine level and was associated with a decrease in KIT phosphorylation and D816V KIT mutation frequency. The patient died after 3 months of therapy due to progression of her MDS/MPD to acute myeloid leukemia (AML). This case indicates that KIT tyrosine kinase inhibition is a feasible approach in SM, but single-agent clinical efficacy may be limited by clonal evolution in the advanced leukemic phase of this disease.

    View details for DOI 10.1182/blood-2005-04-1568

    View details for Web of Science ID 000232466000047

    View details for PubMedID 15972446

  • Farnesyltransferase inhibitor therapy in acute myelogenous leukemia. Current hematology reports Gotlib, J. 2005; 4 (1): 77-84

    Abstract

    Acute myelogenous leukemia (AML) remains a clinical challenge with poor long-term survival. Low remission rates and high treatment-related mortality persist as major obstacles, particularly in older patients. The design of novel agents based on the identification of genetic lesions and aberrant signaling pathways provides opportunity to improve the standard treatment paradigm of intensive cytotoxic chemotherapy. Farnesyltransferase inhibitors (FTIs) show potential to fill this niche. The preclinical concept of farnesyltransferase blockade as a targeted therapy against oncogenic Ras has clearly evolved with the recognition that many proteins involved signaling pathways in tumor cells undergo farnesylation. Phase I/II trials of FTI monotherapy in AML demonstrate encouraging responses and good tolerability. The FTI tipifarnib (R115777, Zarnestra; Johnson & Johnson, Titusville, NJ) has advanced the furthest in clinical trials, with the most promising activity in previously untreated, high-risk AML patients. A major emphasis of current clinical studies has been to analyze potential candidate genes and signaling pathways modified by FTIs in order to identify mechanisms of response and resistance. Preclinical concepts related to the development of FTIs, the rationale for their use in AML, and efficacy and safety results from recent clinical trials are evaluated in this paper.

    View details for PubMedID 15610664

  • Molecular classification and pathogenesis of eosinophilic disorders: 2005 update ACTA HAEMATOLOGICA Gotlib, J. 2005; 114 (1): 7-25

    Abstract

    Use of the term "idiopathic hypereosinophilic syndrome (HES)" has highlighted our basic lack of understanding of the molecular pathophysiology of eosinophilic disorders. However, over the last 10 years, the study of hypereosinophilia has enjoyed a revival. This interest has been rekindled by two factors: (1) the development of increasingly sophisticated molecular biology techniques that have unmasked recurrent genetic abnormalities linked to eosinophilia, and (2) the successful application of targeted therapy with agents such as imatinib to treat eosinophilic diseases. To date, most of these recurrent molecular abnormalities have resulted in constitutively activated fusion tyrosine kinases whose phenotypic consequence is an eosinophilia-associated myeloid disorder. Most notable among these are rearrangements of platelet-derived growth factor receptors alpha and beta (PDGFRalpha, PDGFRbeta), which define a small subset of patients with eosinophilic chronic myeloproliferative disorders (MPDs) and/or overlap myelodysplastic syndrome/MPD syndromes, including chronic myelomonocytic leukemia. Discovery of the cryptic FIP1L1-PDGFRA gene fusion in cytogenetically normal patients with systemic mast cell disease with eosinophilia or idiopathic HES has redefined these diseases as clonal eosinophilias. A growing list of fibroblast growth factor receptor 1 fusion partners has similarly emerged in the 8p11 myeloproliferative syndromes, which are often characterized by elevated eosinophil counts. Herein the focus is on the molecular gains made in these MPD-type eosinophilias, and the classification and clinicopathological issues related to hypereosinophilic syndromes, including the lymphocyte variant. Success in establishing the molecular basis of a group of once seemingly heterogeneous diseases has now the laid the foundation for establishing a semi-molecular classification scheme of eosinophilic disorders.

    View details for DOI 10.1159/000085559

    View details for Web of Science ID 000230306500002

    View details for PubMedID 15995322

  • Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML NEW ENGLAND JOURNAL OF MEDICINE Jamieson, C. H., Ailles, L. E., Dylla, S. J., Muijtjens, M., Jones, C., Zehnder, J. L., Gotlib, J., Li, K., Manz, M. G., Keating, A., Sawyers, C. L., Weissman, I. L. 2004; 351 (7): 657-667

    Abstract

    The progression of chronic myelogenous leukemia (CML) to blast crisis is supported by self-renewing leukemic stem cells. In normal mouse hematopoietic stem cells, the process of self-renewal involves the beta-catenin-signaling pathway. We investigated whether leukemic stem cells in CML also use the beta-catenin pathway for self-renewal.We used fluorescence-activated cell sorting to isolate hematopoietic stem cells, common myeloid progenitors, granulocyte-macrophage progenitors, and megakaryocyte-erythroid progenitors from marrow during several phases of CML and from normal marrow. BCR-ABL, beta-catenin, and LEF-1 transcripts were compared by means of a quantitative reverse-transcriptase-polymerase-chain-reaction assay in normal and CML hematopoietic stem cells and granulocyte-macrophage progenitors. Confocal fluorescence microscopy and a lymphoid enhancer factor/T-cell factor reporter assay were used to detect nuclear beta-catenin in these cells. In vitro replating assays were used to identify self-renewing cells as candidate leukemic stem cells, and the dependence of self-renewal on beta-catenin activation was tested by lentiviral transduction of hematopoietic progenitors with axin, an inhibitor of the beta-catenin pathway.The granulocyte-macrophage progenitor pool from patients with CML in blast crisis and imatinib-resistant CML was expanded, expressed BCR-ABL, and had elevated levels of nuclear beta-catenin as compared with the levels in progenitors from normal marrow. Unlike normal granulocyte-macrophage progenitors, CML granulocyte-macrophage progenitors formed self-renewing, replatable myeloid colonies, and in vitro self-renewal capacity was reduced by enforced expression of axin.Activation of beta-catenin in CML granulocyte-macrophage progenitors appears to enhance the self-renewal activity and leukemic potential of these cells.

    View details for Web of Science ID 000223225500008

    View details for PubMedID 15306667

  • Targeted treatment of hypereosinophilic syndromes and chronic eosinophilic leukemias with imatinib mesylate. Seminars in cancer biology Coutré, S., Gotlib, J. 2004; 14 (4): 307-315

    Abstract

    Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilia leukemia (CEL) represent the most recent additions to the list of molecularly defined chronic myeloproliferative disorders. Beginning with the observation that imatinib mesylate (Gleevec) could elicit rapid and complete hematologic remissions in a proportion of patients with HES, a reverse bedside-to-bench translational research effort led to the discovery of FIP1L1-PDGFRA, a novel fusion gene on chromosome 4q12 whose product is an imatinib-sensitive protein tyrosine kinase. FIP1L1-PDGFRA is the first description of a gain-of-function fusion gene derived from an interstitial chromosomal deletion rather than a reciprocal translocation. Empiric use of imatinib in HES and CEL provides a dramatic example of how the development of targeted therapeutics can provide tremendous insight into the molecular etiology of what appear to be a diverse and otherwise indecipherable collection of diseases. In this review, we discuss the role of imatinib in HES/CEL and other malignancies characterized by constitutively activated tyrosine kinases, and examine molecular features of the FIP1L1-PDGFRA fusion.

    View details for PubMedID 15305431

  • The HP1L1-PDIGFR alpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management BLOOD Gotlib, J., Cools, J., Malone, J. M., Schrier, S. L., Gilliland, D. G., Coutre, S. E. 2004; 103 (8): 2879-2891

    Abstract

    Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL) comprise a spectrum of indolent to aggressive diseases characterized by unexplained, persistent hypereosinophilia. These disorders have eluded a unique molecular explanation, and therapy has primarily been oriented toward palliation of symptoms related to organ involvement. Recent reports indicate that HES and CEL are imatinib-responsive malignancies, with rapid and complete hematologic remissions observed at lower doses than used in chronic myelogenous leukemia (CML). These BCR-ABL-negative cases lack activating mutations or abnormal fusions involving other known target genes of imatinib, implicating a novel tyrosine kinase in their pathogenesis. A bedside-to-benchtop translational research effort led to the identification of a constitutively activated fusion tyrosine kinase on chromosome 4q12, derived from an interstitial deletion, that fuses the platelet-derived growth factor receptor-alpha gene (PDGFRA) to an uncharacterized human gene FIP1-like-1 (FIP1L1). However, not all HES and CEL patients respond to imatinib, suggesting disease heterogeneity. Furthermore, approximately 40% of responding patients lack the FIP1L1-PDGFRA fusion, suggesting genetic heterogeneity. This review examines the current state of knowledge of HES and CEL and the implications of the FIP1L1-PDGFRA discovery on their diagnosis, classification, and management.

    View details for DOI 10.1182/blood-2003-06-1824

    View details for Web of Science ID 000222163500012

    View details for PubMedID 15070659

  • Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis BLOOD Loh, M. L., Vattikuti, S., Schubbert, S., Reynolds, M. G., Carlson, E., Lieuw, K. H., Cheng, J. W., Lee, C. M., Stokoe, D., Bonifas, J. M., Curtiss, N. P., Gotlib, J., Meshinchi, S., Le Beau, M. M., Emanuel, P. D., Shannon, K. M. 2004; 103 (6): 2325-2331

    Abstract

    The PTPN11 gene encodes SHP-2 (Src homology 2 domain-containing protein tyrosine Phosphatase), a nonreceptor tyrosine protein tyrosine phosphatase (PTPase) that relays signals from activated growth factor receptors to p21Ras (Ras) and other signaling molecules. Mutations in PTPN11 cause Noonan syndrome (NS), a developmental disorder characterized by cardiac and skeletal defects. NS is also associated with a spectrum of hematologic disorders, including juvenile myelomonocytic leukemia (JMML). To test the hypothesis that PTPN11 mutations might contribute to myeloid leukemogenesis, we screened the entire coding region for mutations in 51 JMML specimens and in selected exons from 60 patients with other myeloid malignancies. Missense mutations in PTPN11 were detected in 16 of 49 JMML specimens from patients without NS, but they were less common in other myeloid malignancies. RAS, NF1, and PTPN11 mutations are largely mutually exclusive in JMML, which suggests that mutant SHP-2 proteins deregulate myeloid growth through Ras. However, although Ba/F3 cells engineered to express leukemia-associated SHP-2 proteins cells showed enhanced growth factor-independent survival, biochemical analysis failed to demonstrate hyperactivation of the Ras effectors extracellular-regulated kinase (ERK) or Akt. We conclude that SHP-2 is an important cellular PTPase that is mutated in myeloid malignancies. Further investigation is required to clarify how these mutant proteins interact with Ras and other effectors to deregulate myeloid growth.

    View details for DOI 10.1182/blood-2003-09-3287

    View details for Web of Science ID 000220123400053

    View details for PubMedID 14644997

  • Targeted treatment of hypereosinophilic syndromes and chronic eosinophilic leukemias with imatinib mesylate SEMINARS IN CANCER BIOLOGY Coutre, S., Gotlib, J. 2004; 14 (1): 23-31

    Abstract

    Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilia leukemia (CEL) represent the most recent additions to the list of molecularly defined chronic myeloproliferative disorders. Beginning with the observation that imatinib mesylate (Gleevec) could elicit rapid and complete hematologic remissions in a proportion of patients with HES, a reverse bedside-to-bench translational research effort led to the discovery of FIP1L1-PDGFRA, a novel fusion gene on chromosome 4q12 whose product is an imatinib-sensitive protein tyrosine kinase. FIP1L1-PDGFRA is the first description of a gain-of-function fusion gene derived from an interstitial chromosomal deletion rather than a reciprocal translocation. Empiric use of imatinib in HES and CEL provides a dramatic example of how the development of targeted therapeutics can provide tremendous insight into the molecular etiology of what appear to be a diverse and otherwise indecipherable collection of diseases. In this review, we discuss the role of imatinib in HES/CEL and other malignancies characterized by constitutively activated tyrosine kinases, and examine molecular features of the FIP1L1-PDGFRA fusion.

    View details for DOI 10.1016/j.semcancer.2003.11.004

    View details for Web of Science ID 000189081200004

    View details for PubMedID 14757533

  • PTPN11 mutations are rare in adult patients with chronic myelomonocytic leukemia (CMML). Loh, M. L., Vattikuti, S., Reynolds, M. G., Cheng, J. W., Lee, C. M., Gotlib, J., Beran, M. AMER SOC HEMATOLOGY. 2003: 328B-328B
  • Novel biospecific agents for the treatment of myelodysplastic syndromes. Journal of the National Comprehensive Cancer Network Gotlib, J., Greenberg, P. L. 2003; 1 (4): 473-480

    Abstract

    Levels of treatment for patients with myelodysplastic syndromes (MDS) fall within 3 broad categories: supportive care, low- and high-intensity therapy. Most approaches remain experimental, and supportive care remains the standard of treatment in MDS. In parallel with the growing knowledge of the multiple pathobiologic abnormalities in MDS, increasing numbers of low-intensity, biospecific agents that target these pathogenetic lesions have entered clinical trial testing. Although the term "biospecific" has been applied to many of these investigational drugs, they often exert pleiotropic effects, many of which remain to be identified. An ongoing challenge will be to more fully characterize the mechanisms of action of these drugs and to characterize biologic correlates of response. With these data in hand, it will be increasingly feasible to treat patients with combinations of biospecific drugs with non-overlapping actions and toxicities, a therapeutic approach that is likely required to effectively overcome the barriers posed by the biologic heterogeneity of MDS. This review focuses on recent therapeutic approaches using such biologic response modifiers to treat MDS.

    View details for PubMedID 19774739

  • Soluble TNF receptor fusion protein (etanercept) for the treatment of myelodysplastic syndrome: A pilot study LEUKEMIA Deeg, H. J., Gotlib, J., Beckham, C., Dugan, K., Holmberg, L., Schubert, M., Appelbaum, F., Greenberg, P. 2002; 16 (2): 162-164

    Abstract

    Blockade of tumor necrosis factor (TNF)alpha by a soluble TNF receptor fusion protein (etanercept; Enbrel) improved in vitro hemopoiesis from the marrow of patients with myelodysplastic syndrome (MDS). Therefore, we enrolled 14 MDS patients (4 RA, 2 RARS, 6 RAEB, 2 CMML), 44-80 (median 60) years old, in a pilot trial. Etanercept, 25 mg, was given twice a week s.c. for 16 weeks (increased to three times a week if no response at 8 weeks). Among 12 evaluable patients, four had rises in hemoglobin by 1-1.5 gm/dl (three) or decreased transfusion requirements (one). Two patients had increased platelet counts (54% and 73%), and two increased neutrophils (63% and 120%). Baseline TNFalpha levels, determined in all patients, did not correlate with responses. Among eight marrows available for sequential in vitro assays, four showed increases in CFU-GM of 1.5- to 5-fold at 8 weeks, whereas three showed 3- to 10-fold decrements relative to baseline. Thus, etanercept treatment resulted in moderate improvements of cytopenias in some patients, while cell counts declined in others. Additional trials are needed to evaluate its clinical efficacy in MDS.

    View details for Web of Science ID 000173710800003

    View details for PubMedID 11840280