Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera.

PURPOSE We conducted a phase II study of pegylated interferon alfa-2a (PEG-IFN-alpha-2a) in patients with essential thrombocythemia (ET) and polycythemia vera (PV). PATIENTS AND METHODS Seventy-nine patients (40 with PV and 39 with ET) have been treated. Median time from diagnosis to PEG-IFN-alpha-2a was 54 months in patients with PV and 33 months in patients with ET. Eighty-one percent of patients had received prior therapy. The first three patients received PEG-IFN-alpha-2a at 450 microg weekly. As a result of poor tolerance, this dose was decreased in a stepwise manner to a current starting dose of 90 microg weekly. Seventy-seven patients are evaluable and have been observed for a median of 21 months. RESULTS The overall hematologic response rate was 80% in PV and 81% in ET (complete in 70% and 76% of patients, respectively). The JAK2(V617F) mutation was detected in 18 patients with ET and 38 patients with PV; sequential measurements by a pyrosequencing assay were available in 16 patients with ET and 35 patients with PV. The molecular response rate was 38% in ET and 54% in PV, being complete (undetectable JAK2(V617F)) in 6% and 14%, respectively. The JAK2(V617F) mutant allele burden continued to decrease with no clear evidence for a plateau. The tolerability of PEG-IFN-alpha-2a at 90 microg weekly was excellent. CONCLUSION PEG-IFN-alpha-2a resulted in remarkable clinical activity, high rates of molecular response, and acceptable toxicity in patients with advanced ET or PV. The ability of PEG-IFN-alpha-2a to induce complete molecular responses suggests selective targeting of the malignant clone.

[1]  M. Griesshammer,et al.  Response criteria for essential thrombocythemia and polycythemia vera: result of a European LeukemiaNet consensus conference. , 2009, Blood.

[2]  W. Vainchenker,et al.  Can Peg-Interferon (IFN) α-2a Eradicate JAK2V617F-Positive Bone Marrow Progenitors in Polycythemia Vera (PV)? , 2008 .

[3]  S. Serrano,et al.  Major Hematological Response Is the Main Factor for Achieving a Major Molecular Response in JAK2V617F-Positive Essential Thrombocythemia and Polycythemia Vera Patients Treated with Hydroxyurea , 2008 .

[4]  A. Falanga,et al.  Thrombosis in myeloproliferative disorders: pathogenetic facts and speculation , 2008, Leukemia.

[5]  S. Chevret,et al.  Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. , 2008, Blood.

[6]  T. Barbui,et al.  Evidence and expertise in the management of polycythemia vera and essential thrombocythemia , 2008, Leukemia.

[7]  P. Fenaux,et al.  SPOTLIGHT REVIEW Interferon-a therapy in bcr-abl-negative myeloproliferative neoplasms , 2008 .

[8]  T. Barbui,et al.  Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. , 2007, Blood.

[9]  A. Tefferi,et al.  Risk stratification for survival and leukemic transformation in essential thrombocythemia: a single institutional study of 605 patients , 2007, Leukemia.

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

[11]  J. Lipton,et al.  Phase II, randomized, multicenter, comparative study of peginterferon–α–2a (40 kD) (Pegasys®) versus interferon α-2a (Roferon®-A) in patients with treatment-naïve, chronic-phase chronic myelogenous leukemia , 2007 .

[12]  S. Verstovsek,et al.  Novel tumor antigens elicit anti-tumor humoral immune reactions in a subset of patients with polycythemia vera. , 2007, Clinical immunology.

[13]  J. Lipton,et al.  Phase II, randomized, multicenter, comparative study of peginterferon-alpha-2a (40 kD) (Pegasys) versus interferon alpha-2a (Roferon-A) in patients with treatment-naïve, chronic-phase chronic myelogenous leukemia. , 2007, Leukemia & lymphoma.

[14]  G. Massonnet,et al.  High molecular response rate of polycythemia vera patients treated with pegylated interferon alpha-2a. , 2006, Blood.

[15]  H. Kantarjian,et al.  Pegylated interferon therapy for patients with Philadelphia chromosome-negative myeloproliferative disorders. , 2006, Seminars in thrombosis and hemostasis.

[16]  D. Oscier,et al.  Minimal molecular response in polycythemia vera patients treated with imatinib or interferon alpha. , 2005, Blood.

[17]  P. Campbell,et al.  Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study , 2005, The Lancet.

[18]  D. Oscier,et al.  Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. , 2005, Blood.

[19]  H. Kantarjian,et al.  Phase I Evaluation of a 40-kDa Branched-Chain Long-Acting Pegylated IFN-α-2a With and Without Cytarabine in Patients with Chronic Myelogenous Leukemia , 2005, Clinical Cancer Research.

[20]  J. D. van der Walt,et al.  Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. , 2005, The New England journal of medicine.

[21]  Qingshan Li,et al.  Identification of an Acquired JAK2 Mutation in Polycythemia Vera* , 2005, Journal of Biological Chemistry.

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

[23]  Mario Cazzola,et al.  A gain-of-function mutation of JAK2 in myeloproliferative disorders. , 2005, The New England journal of medicine.

[24]  Sandra A. Moore,et al.  Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. , 2005, Cancer cell.

[25]  T. Barbui,et al.  Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  P. Campbell,et al.  Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders , 2005, The Lancet.

[27]  Y. Nishizawa,et al.  Possible selective effects of Interferon α-2b on a malignant clone in a case of polycythemia vera , 1993, Annals of Hematology.

[28]  C. Gardin,et al.  Long-term outcomes of polycythemia vera patients treated with pipobroman as initial therapy. , 2003, The hematology journal : the official journal of the European Haematology Association.

[29]  T. Barbui,et al.  Second malignancies in patients with essential thrombocythaemia treated with busulphan and hydroxyurea: long‐term follow‐up of a randomized clinical trial , 2000, British journal of haematology.

[30]  E. Wattel,et al.  Acute myeloid leukemia and myelodysplastic syndromes following essential thrombocythemia treated with hydroxyurea: high proportion of cases with 17p deletion. , 1998, Blood.

[31]  Y. Najean,et al.  Treatment of polycythemia vera: the use of hydroxyurea and pipobroman in 292 patients under the age of 65 years. , 1997, Blood.

[32]  I. Pannacciulli,et al.  The in vitro and in vivo effect of recombinant interferon α‐2a on circulating haemopoietic progenitors in polycythaemia vera , 1994, British journal of haematology.

[33]  T. Pearson,et al.  Primary polycythaemia: positive diagnosis using the differential response of primitive and mature erythroid progenitors to erythropoietin, interleukin 3 and alpha‐interferon , 1990, British journal of haematology.

[34]  T. Barbui,et al.  Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia. , 1990, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  M. Cazzola,et al.  Effects of recombinant alpha and gamma interferons on the in vitro growth of circulating hematopoietic progenitor cells (CFU-GEMM, CFU-Mk, BFU-E, and CFU-GM) from patients with myelofibrosis with myeloid metaplasia. , 1987, Blood.