MYELOPROLIFERATIVE SYNDROMES: MYELOPROLIFERATIVE NEOPLASMS - CLINICAL FEATURES AND THERAPEUTICS
An Open-Label Study of CEP-701 in Patients with JAK2 V617F-Positive PV and ET: Update of 39 Enrolled Patients.
Alison R Moliterno, MD1,
Elizabeth Hexner, MD2,
Gail J. Roboz, MD3,
Martin Carroll, MD4,
Selina Luger, MD5,
John Mascarenhas, MD6,
Ronald Hoffman, MD6 and
Debra M Bensen-Kennedy7
1 Medicine, Johns Hopkins University School of Medicince, Baltimore, MD, USA, 2 3400 Civic Center Boulevard, University of Pennsylvania, Philadelphia, PA, USA, 3 Department of Medicine, Leukemia Program, Weill-Cornell College of Medicine, New York, NY, USA, 4 Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA, USA, 5 Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA, 6 Department of Medicine, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA, 7 Cephalon, Frazer, PA
Since the seminal discovery of the JAK2V617F mutation, smallmolecule inhibitors of JAK2 to treat patients with myeloproliferativeneoplasms have been recently evaluated in a growing number ofclinical trials. To date, there has been limited evaluationof the utility of such JAK2 inhibitors in patients with PV orET. CEP-701 is an orally available, potent, low nanomolar inhibitorof both the wild-type and mutated JAK2 tyrosine kinase, withits inhibitory effect being demonstrated both in enzymatic andcellular assays. The present study is the first JAK2 inhibitorstudy to test the safety and efficacy of such an agent in highrisk JAK2 V617F positive ET and PV patients. The primary endpointwas reduction in JAK2 V617F neutrophil allele burden. Secondaryendpoints included reduction in phlebotomy rates; improvementin hemoglobin, white cell and platelet counts; reduction inhydroxyurea (HU) dose and spleen size; and the pharmacokineticsand pharmacodynamics of CEP-701. Enrollment was completed with39 JAK2V617F-positive subjects, 27 PV and 12 ET, 22 femalesand 17 males, ages 38 to 80. The PV patients were a high riskgroup as defined by a median age of 65 years, neutrophil JAK2V617Fallele burden of 76%, prevalence of prior thrombotic eventsof 19%, prior HU use in 44% and an average white cell countof 19,600/ul (range 3,500-78,600). The ET patients were alsoconsidered to be a high risk group as defined by a median ageof 61.5 years, the prior use of HU in 100% of cases, and prevalenceof prior thrombotic events of 25%; the median neutrophil JAK2V617Fallele burden was 40%. More than half the patients had had theirdisease for 5 years or longer. To date, 15 of the patients havecompleted 18 weeks of treatment and 13 of these patients continueon the extension phase of the trial. Within 18 weeks, responsesincluded a reduction spleen size of > 5cm or to non-palpablein 15/18 (83%) subjects and amelioration of pruritus in 5/5patients studied. While reduction in phlebotomy requirementoccurred in a number of phlebotomy dependent patients (3/5 evaluableat time of report), this effect was not evident in these patientsuntil 6 months of therapy, and was not associated with concomitantreductions in white cell or platelet count. In fact, in manypatients, platelet and white cell counts increased while ondrug. A reduction in the JAK2 V617F allele burden of 15% ormore was observed in 3 of the 15 patients at the 18 week assessment.The most common adverse events were gastrointestinal, whichwere dose related and improved over time. Serious adverse eventshave occurred, including 5 patients experiencing thromboticevents (3 venous (1 DVT, 1DVT/PE, 1 PVT), 2 arterial (1 TIA,1 PAT)), and one non-serious DVT. We conclude that CEP-701 isbiologically active agent in patients with JAK2 V617F positivePV and ET. Serious adverse events related to thrombosis, however,have occurred which to date have not been reported with theuse of other JAK2 inhibitor trials involving patients with PMF.Though substantial symptomatic improvements have occurred, ourdata suggest, at a minimum, that JAK2 inhibitor therapy maynot prevent thrombosis in high-risk patients with PV and ET.This risk of thrombosis may be a disease specific interactionin PV and ET patients since thrombosis has not been a frequentcomplication of CEP 701 therapy for other malignancies. Final18 week data and cumulative extension data will be updated atthe annual meeting.
Disclosures:Roboz:Cephalon: Consultancy. Carroll:Cephalon consultancy:Consultancy; Sanofi Aventis Corporation: Research Funding; KyowaHakko Kirin Pharmaceutical: Research Funding. Bensen-Kennedy:cephalon: Employment.
* Asterisk with author names denotes non-ASH members.
M. B. Sonbol, B. Firwana, A. Zarzour, M. Morad, V. Rana, and R. V. Tiu Comprehensive review of JAK inhibitors in myeloproliferative neoplasms
Therapeutic Advances in Hematology,
February 1, 2013;
15 - 35.