Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis.

PURPOSE 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. PATIENTS AND METHODS 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. CONCLUSION TG101348 is well tolerated and produces significant reduction in disease burden and durable clinical benefit in patients with myelofibrosis.

[1]  Erin F. Simonds,et al.  Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms. , 2010, Blood.

[2]  D. Birnbaum,et al.  Mutations of ASXL1 gene in myeloproliferative neoplasms , 2009, Leukemia.

[3]  H. Deeg,et al.  International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT). , 2006, Blood.

[4]  A. Green,et al.  Somatic mutations of IDH1 and IDH2 in the leukemic transformation of myeloproliferative neoplasms. , 2010, The New England journal of medicine.

[5]  D. Gilliland,et al.  IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis , 2010, Leukemia.

[6]  Stefan N. Constantinescu,et al.  A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera , 2005, Nature.

[7]  M. Cazzola,et al.  Deletions of the transcription factor Ikaros in myeloproliferative neoplasms , 2010, Leukemia.

[8]  J. Soulier,et al.  Mutation in TET2 in myeloid cancers. , 2009, The New England journal of medicine.

[9]  A. Tefferi,et al.  Clinical correlates of JAK2V617F allele burden in essential thrombocythemia , 2007, Cancer.

[10]  Sandra A. Moore,et al.  MPLW515L Is a Novel Somatic Activating Mutation in Myelofibrosis with Myeloid Metaplasia , 2006, PLoS medicine.

[11]  H. Drexler,et al.  Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders , 2010, Nature Genetics.

[12]  K. Bhalla,et al.  Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. , 2007, Blood.

[13]  D. Gilliland,et al.  MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. , 2006, Blood.

[14]  A. Tefferi.  Myelofibrosis with myeloid metaplasia. , 2000, The New England journal of medicine.

[15]  A. Tefferi,et al.  Age and platelet count are IPSS‐independent prognostic factors in young patients with primary myelofibrosis and complement IPSS in predicting very long or very short survival , 2010, European journal of haematology.

[16]  G. Noronha,et al.  Selective inhibition of JAK2-driven erythroid differentiation of polycythemia vera progenitors. , 2008, Cancer cell.

[17]  Sandra A. Moore,et al.  Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. , 2008, Cancer cell.

[18]  Michael G. Kharas,et al.  Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells. , 2010, Cancer cell.

[19]  D. Gilliland,et al.  TG101348, a JAK2-selective antagonist, inhibits primary hematopoietic cells derived from myeloproliferative disorder patients with JAK2V617F, MPLW515K or JAK2 exon 12 mutations as well as mutation negative patients , 2008, Leukemia.

[20]  A. Hall,et al.  Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. , 2008, Blood.

[21]  A. Tefferi,et al.  International Prognostic Scoring System-independent cytogenetic risk categorization in primary myelofibrosis. , 2010, Blood.

[22]  A. Tefferi,et al.  Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic algorithms , 2008, Leukemia.

[23]  M. Stratton,et al.  JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. , 2007, The New England journal of medicine.

[24]  R. Mesa,et al.  New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. , 2008, Blood.

[25]  A. Tefferi,et al.  LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2, IDH, JAK2 or MPL mutations , 2010, Leukemia.