Introduction Myelofibrosis (MF), either primary or post–polycythemia vera/ essential thrombocythemia, is a Philadelphia chromosome–nega- tive, myeloproliferative neoplasm characterized by bone marrow fibrosis and extramedullary hematopoiesis. 1 Most patients present with systemic constitutional symptoms such as fatigue, night sweats, and weight loss, as well as with hepatosplenomegaly, anemia, and a leukoerythroblastic picture in peripheral blood smears. Life expec- tancy is shortened to an average of 5-7 years after diagnosis. The contemporary management of patients with MF is largely palliative and consists of hydroxyurea, danazol, interferon-α, and prednisone, with the more recent addition of thalidomide and lenalidomide. 2 Allogeneic stem cell transplantation (SCT) is the only curative modality of treatment. However, most patients are not candidates for SCT because of their advanced age and medical comorbidi- ties. 3 New therapies are needed to tackle the biologic abnormalities characteristic of the disease and possibly alter its natural history. A recently described gain-of-function Janus kinase 2 (JAK2) mutation, V617F, is present in about 50% of patients with MF. 4-7 Constitutive activation of the JAK receptor complex leads to the recruitment and phosphorylation of substrate molecules, including signal transducer and activator of transcription (STAT) proteins, and particularly STAT5. 8,9 The STAT5 protein plays a crucial role in antiapoptotic signaling by mediating the transcription of BCL-X L , thereby providing cells with a survival advantage. Moreover, BCL-X L and MCL-1 form part of the BCL-2 antiapop- totic family of proteins that inhibit the mitochondrial pathway of Abstract Phase II Study of Obatoclax Mesylate (GX15-070), a Small-Molecule BCL-2 Family Antagonist, for Patients With Myelofibrosis Sameer A. Parikh, 1 Hagop Kantarjian, 1 Aaron Schimmer, 2 William Walsh, 3 Ekatherine Asatiani, 4 Khaled El-Shami, 4 Elliott Winton, 5 Srdan Verstovsek 1 Background: Myelofibrosis (MF) is a disease characterized by the overexpression of the antiapoptotic BCL-2 family of proteins (eg, BCL-X L and MCL-1). Patients and Methods: We conducted a multicenter, open-label, noncomparative phase II study of obatoclax mesylate, a small-molecule pan–BCL-2 antagonist, in patients with MF. Obatoclax was ad- ministered as a 24-hour infusion (on an outpatient basis) every 2 weeks at a fixed dose of 60 mg. Results: A total of 22 patients were enrolled, with a median age of 63 years (range, 43-89 years). Twelve were men, and all 22 patients were previously treated (median of 2 previous therapies). Ten patients (45%) had a Lille score of 1, and 9 patients (41%) had a Lille score of 2. Thirteen (59%) were red blood cell transfusion dependent. A median of 7 cycles of obatoclax were administered. No patient achieved complete or partial response according to International Working Group criteria. One patient (4%) demonstrated a clinical improvement (in terms of hemoglobin and platelet count) after 7 cycles of therapy. The improvement was sustained for 4 cycles of therapy, after which he underwent allogeneic stem cell transplantation. The most common adverse events included low-grade ataxia and fatigue in 50% of the patients. Dose reduction because of toxicity was required in 1 patient, whereas 2 patients were taken off the study because of grade 3 ataxia and grade 3 heart failure. Grade 3/4 anemia and thrombocytopenia were evident in 6 (27%) and 4 (18%) patients, respectively. Conclusion: Obatoclax exhibits no significant clinical activity in patients with MF at the dose and schedule evaluated. Clinical Lymphoma, Myeloma & Leukemia, Vol. 10, No. 4, 285-289, 2010; DOI: 10.3816/CLML.2010.n.059 Keywords: Ataxia, Post–essential thrombocythemia myelofibrosis, Polycythemia vera, Targeted therapy Original Study Clinical Lymphoma, Myeloma & Leukemia August 2010 | 285 1 Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston 2 Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada 3 Division of Hematology and Oncology, University of Massachusetts Medical Center, Worcester, MA 4 Lombardi Cancer Center, Georgetown University, Washington, DC 5 Winship Cancer Center, Emory University, Atlanta, GA Submitted: Dec 22, 2009; Revised: Jan 28, 2010; Accepted: Feb 1, 2010 Address for correspondence: Srdan Verstovsek, MD, PhD, Department of Leukemia, Unit 428, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 Fax: 713-794-4297; e-mail: sverstov@mdanderson.org This summary may include the discussion of investigational and/or unlabeled uses of drugs and/or devices that may not be approved by the FDA. Electronic forwarding or copying is a violation of US and International Copyright Laws. 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