Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera.

Interferon-alpha (IFN-alpha) is a nonleukemogenic treatment of polycythemia vera (PV) able to induce cytogenetic remissions. Its use is limited by toxicity, leading to treatment discontinuation in approximately 20% of patients. We completed a phase 2 multicenter study of pegylated IFN-alpha-2a in 40 PV patients. Objectives included evaluation of efficacy, safety, and monitoring of residual disease using JAK2V617F quantification (%V617F). Median follow-up was 31.4 months. At 12 months, all 37 evaluable patients had hematologic response, including 94.6% complete responses (CRs). Only 3 patients (8%) had stopped treatment. After the first year, 35 patients remained in hematologic CR, including 5 who had stopped pegylated IFN-alpha-2a. Sequential samples for %V617F monitoring, available in 29 patients, showed %V617F decrease in 26 (89.6%). Median %V617F decreased from 45% before pegylated IFN-alpha-2a to 22.5%, 17.5%, 5%, and 3% after 12, 18, 24, and 36 months, respectively. Molecular CR (JAK2V617F undetectable) was achieved in 7 patients, lasting from 6(+) to 18(+) months, and persisted after pegylated IFN-alpha-2a discontinuation in 5. No vascular event was recorded. These results show that pegylated IFN-alpha-2a yields high rates of hematologic and molecular response in PV with limited toxicity, and could even eliminate the JAK2 mutated clone in selected cases. Available at www.clinicaltrials.gov as #NCT00241241.

[1]  R. Silver,et al.  JAK2 Mutations are present in all cases of polycythemia vera , 2008, Leukemia.

[2]  R. A. Etten,et al.  Bedside to bench: Interfering with leukemic stem cells , 2008, Nature Medicine.

[3]  A. Pardanani.  JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials , 2008, Leukemia.

[4]  H. Kantarjian,et al.  Pegylated Interferon-alfa-2a (PEG-IFN-α-2A; PEGASYS™) for Essential Thrombocythemia (ET) and Polycythemia Vera (PV): An Update of an Ongoing Phase II Study. , 2007 .

[5]  H. Kantarjian,et al.  PEG‐IFN‐α‐2b therapy in BCR‐ABL–negative myeloproliferative disorders , 2007 .

[6]  C. Bloomfield,et al.  Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. , 2007, Blood.

[7]  A. Tefferi,et al.  Leucocytosis in polycythaemia vera predicts both inferior survival and leukaemic transformation , 2007, British journal of haematology.

[8]  S. Pestka.  The Interferons: 50 Years after Their Discovery, There Is Much More to Learn* , 2007, Journal of Biological Chemistry.

[9]  T. Barbui,et al.  Prospective identification of high-risk polycythemia vera patients based on JAK2V617F allele burden , 2007, Leukemia.

[10]  T. Barbui,et al.  How I treat patients with polycythemia vera. , 2007, Blood.

[11]  T. Barbui,et al.  V617F JAK-2 mutation in patients with essential thrombocythemia: relation to platelet, granulocyte, and plasma hemostatic and inflammatory molecules. , 2007, Experimental hematology.

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

[13]  R. Hoffman,et al.  Recurrence of clonal hematopoiesis after discontinuing pegylated recombinant interferon-α 2a in a patient with polycythemia vera , 2007, Leukemia.

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

[15]  H. Kantarjian,et al.  PEG-IFN-alpha-2b therapy in BCR-ABL-negative myeloproliferative disorders: final result of a phase 2 study. , 2007, Cancer.

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

[17]  J. Jelinek,et al.  Polycythemia vera is not initiated by JAK2V617F mutation. , 2007, Experimental hematology.

[18]  R. Mesa.  Navigating the evolving paradigms in the diagnosis and treatment of myeloproliferative disorders. , 2007, Hematology. American Society of Hematology. Education Program.

[19]  S. Verstovsek,et al.  An Unconventional Antigen Translated by a Novel Internal Ribosome Entry Site Elicits Antitumor Humoral Immune Reactions1 , 2006, The Journal of Immunology.

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

[21]  R. Kralovics,et al.  Acquisition of the V617F mutation of JAK2 is a late genetic event in a subset of patients with myeloproliferative disorders. , 2006, Blood.

[22]  R. Silver.  Long‐term effects of the treatment of polycythemia vera with recombinant interferon‐α , 2006 .

[23]  P. Fenaux,et al.  Long-term incidence of hematological evolution in three French prospective studies of hydroxyurea and pipobroman in polycythemia vera and essential thrombocythemia. , 2006, Seminars in thrombosis and hemostasis.

[24]  O. Linder,et al.  A phase II trial of pegylated interferon alpha-2b therapy for polycythemia vera and essential thrombocythemia: feasibility, clinical and biologic effects, and impact on quality of life. , 2006, Cancer.

[25]  P. Fenaux,et al.  Essential thrombocythemias without V617F JAK2 mutation are clonal hematopoietic stem cell disorders , 2006, Leukemia.

[26]  M. Cazzola,et al.  Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders. , 2006, Blood.

[27]  W. Vainchenker,et al.  Detection of JAK2 V617F as a first intention diagnostic test for erythrocytosis , 2006, Leukemia.

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

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

[30]  P. Campbell,et al.  Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis , 2005, British journal of haematology.

[31]  T. Barbui,et al.  Leukocyte-platelet interaction in patients with essential thrombocythemia and polycythemia vera. , 2005, Experimental hematology.

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

[33]  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.

[34]  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.

[35]  T. Barbui,et al.  Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. , 2005 .

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

[37]  W. Vainchenker,et al.  A unique activating mutation in JAK2 (V617F) is at the origin of polycythemia vera and allows a new classification of myeloproliferative diseases. , 2005, Hematology. American Society of Hematology. Education Program.

[38]  M. Griesshammer,et al.  Pegylated interferon for the treatment of high risk essential thrombocythemia: results of a phase II study. , 2005, Haematologica.

[39]  T. Barbui,et al.  Efficacy and safety of low-dose aspirin in polycythemia vera. , 2004, The New England journal of medicine.

[40]  T. Barbui,et al.  Practice guidelines for the therapy of essential thrombocythemia. A statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. , 2004, Haematologica.

[41]  J. Jelinek,et al.  Discrimination of polycythemias and thrombocytoses by novel, simple, accurate clonality assays and comparison with PRV-1 expression and BFU-E response to erythropoietin. , 2003, Blood.

[42]  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.

[43]  R. Kralovics,et al.  Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera. , 2002, Experimental hematology.

[44]  Z. Estrov,et al.  Pilot study of pegylated interferon-alpha 2b in patients with essential thrombocythemia , 2002, Cancer Chemotherapy and Pharmacology.

[45]  R. Hehlmann,et al.  Interferon α in the treatment of polycythemia vera , 2000, Annals of Hematology.

[46]  R. Hehlmann,et al.  Interferon alpha in the treatment of polycythemia vera. , 2000, Annals of hematology.

[47]  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.

[48]  C. Clerici,et al.  Polycythemia vera treated with recombinant interferon‐alpha 2a: Evidence of a selective effect on the malignant clone , 1997, American journal of hematology.

[49]  Y. Najean,et al.  Treatment of polycythemia vera: use of 32P alone or in combination with maintenance therapy using hydroxyurea in 461 patients greater than 65 years of age. The French Polycythemia Study Group. , 1997, Blood.

[50]  S. Sacchi,et al.  Cytogenetic conversion in a case of polycythaemia vera treated with interferon‐alpha , 1994, British journal of haematology.

[51]  R. Silver.  RECOMBINANT INTERFERON-ALPHA FOR TREATMENT OF POLYCYTHAEMIA VERA , 1988, The Lancet.

[52]  S. Schwartz.  Myeloproliferative Disorders , 1975, Annals of surgery.

[53]  B. Dallapiccola,et al.  Letter: X long-arm deletion with features of Turner's syndrome. , 1974, Lancet.