Bio

Clinical Focus


  • Hematology
  • Cancer > Hematology

Academic Appointments


Honors & Awards


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

Professional Education


  • 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 GS-6624 in Adults With Primary, Post Polycythemia Vera or Post Essential Thrombocythemia Myelofibrosis Recruiting

    This study is to evaluate the efficacy and safety of 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.

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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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  • 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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  • Study to Determine the Maximum Tolerated Dose and Evaluate the Efficacy and Safety of CEP-18770 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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  • 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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  • 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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  • 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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  • 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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  • 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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  • 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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  • 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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  • 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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  • 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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  • S0703 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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  • 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 cell. 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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  • 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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  • Vorinostat, Azacitidine, and Gemtuzumab Ozogamicin in Treating Older Patients With Relapsed or Refractory Acute Myeloid Leukemia 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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  • Phase I Bortezomib (VELCADE) in Combo With Pralatrexate in Relapsed/Refractory MM Not Recruiting

    This is an open-label Phase I dose-escalation safety study of VELCADE in combination with pralatrexate in patients with previously treated multiple myeloma. In a standard 3+3 dose escalation trial design, escalating doses of pralatrexate in combination with VELCADE will be studied sequentially, with at least 3 patients in each dose level until the MTD is determined. Dose limiting toxicity (DLT) and MTD are determined during cycle 1 of treatment.

    Stanford is currently not accepting patients for this trial. For more information, please contact Vani Jain, (650) 725 - 5459.

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

    This randomized phase III trial is studying bortezomib, dexamethasone, and lenalidomide to see how well they work compared with bortezomib and dexamethasone 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 together with 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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  • 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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  • 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 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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  • Safety & Efficacy Study of Oral Panobinostat (LBH589) With Chemotherapy in Patients < 65 Years Old With Acute Myeloid Leukemia (AML) 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.

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  • ON 01910.Na for Intermediate1-2, or High Risk Trisomy 8 Myelodysplastic Syndrome (MDS) Not Recruiting

    This is a phase 2 single arm study in which fourteen MDS patients with Trisomy 8 or classified as Intermediate-1, 2, or High risk who meet all other inclusion/exclusion criteria will receive ON 01910.Na 1800 mg/24h as an intravenous continuous infusion (IVCI) over 72 hours every other week for the first four 2-week cycles and every 4 weeks afterwards.

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

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  • Phase I/II of Azacitidine + Lenalidomide for Previously Untreated Elderly Patients With Acute Myeloid Leukemia Not Recruiting

    The purpose of this study is to first determine the highest dose of the drugs that can be safely taken. The study will look at the side effects of the combination and whether the treatment schedule is tolerated. After the right dose is determined, the study will look at whether the combination is effective in patients with AML who are older than 60 and have never been treated before.

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

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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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  • 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 Recruiting

    The purpose of this study is to evaluate the safety and clinical activity of idelalisib in combination with CD20 mAb chemotherapeutic agents, Immunomodulatory Agents, mTOR inhibitors and proteasome inhibitor in participants with hematologic malignancies.

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

    RATIONALE: Drugs used in chemotherapy, such as daunorubicin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Midostaurin may help daunorubicin and cytarabine work better by making cancer cells more sensitive to the drugs. Midostaurin also may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether combination chemotherapy is more effective with or without midostaurin in treating acute myeloid leukemia. PURPOSE: This randomized phase III trial is studying giving daunorubicin and cytarabine with or without midostaurin followed by high-dose cytarabine and midostaurin to see how well it works in treating patients with newly diagnosed acute myeloid leukemia.

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

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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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  • 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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  • A Randomized, Double-Blind and 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 on the onset, magnitude, and duration of tumor control, combined with rituximab, 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 or placebo and 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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  • 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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  • 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 is studying azacitidine and 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 or by stopping them from dividing. Entinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine together with entinostat may kill more cancer cells.

    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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  • 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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  • Integrated Whole-Genome Analysis of Hematologic Disorders Recruiting

    To identify mutations, changes in DNA copy number, structural rearrangements, or altered microRNA/mRNA expression that are important for the initiation, progression, or treatment response of hematologic disorders.

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  • Phase II Temozolomide + Vorinostat in Patients (>60) w/ Newly Diagnosed or Relapse/Refractory AML Recruiting

    The primary endpoint of the study is to determine the clinical efficacy as determined by the rate of morphological complete remission, of 2 different treatment regimens of temozolomide and vorinostat in patients with AML and poor prognostic features.

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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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  • 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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  • Efficacy and Safety Study of Idelalisib in Patients 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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  • Phase II PKC412 in Aggressive Systemic Mastocytosis and Mast Cell Leukemia Not Recruiting

    To evaluate the efficacy of twice-daily oral doses of PKC412 when administered to patients with ASM/MCL and AHNMD (associated hematological clonal non-mast cell lineage disease) by measuring response rate.

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

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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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  • 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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  • 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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  • 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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  • 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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  • Investigation of Dysregulated Signaling in MPD Via Multiparameter Phospho-specific Flow Cytometry 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.

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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.

    View full details

  • 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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  • 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 Study of Idelalisib and Rituximab in Elderly Patients With Untreated CLL or SLL 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.

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

    Primary Objective: • Determine the complete response (CR) rate, duration of remission of single agent lenalidomide in patients with relapsed/refractory Acute Lymphoblastic Leukemia (ALL), after at least one previous treatment regimen. Secondary Objective: • Establish the toxicity profile for lenalidomide in this patient population

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

    View full details

  • 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.

    View full details

Teaching

2013-14 Courses


Graduate and Fellowship Programs


Publications

Journal Articles


  • 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

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

    View details for DOI 10.1177/2040620713498057

    View details for PubMedID 23926456

  • 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

  • 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

  • Accessory splenules in autoimmune hemolytic anemia AMERICAN JOURNAL OF HEMATOLOGY Logan, A., Berube, C., Gotlib, J. 2013; 88 (2): 156-156

    View details for DOI 10.1002/ajh.23335

    View details for Web of Science ID 000314149700015

    View details for PubMedID 23027373

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

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