Benefits and pitfalls of pegylated interferon-α2a therapy in patients with myeloproliferative neoplasm-associated myelofibrosis: a French Intergroup of Myeloproliferative neoplasms (FIM) study

Jean-Christophe Ianotto, Aurélie Chauveau, Françoise Boyer-Perrard, Emmanuel Gyan, Kamel Laribi, Pascale Cony-Makhoul, Jean-Loup Demory, Benoit de Renzis, Christine Dosquet, Jerome Rey, Lydia Roy, Brigitte Dupriez, Laurent Knoops, Laurence Legros, Mohamed Malou, Pascal Hutin, Dana Ranta, Omar Benbrahim, Valérie Ugo, Eric Lippert, Jean-Jacques Kiladjian, Jean-Christophe Ianotto, Aurélie Chauveau, Françoise Boyer-Perrard, Emmanuel Gyan, Kamel Laribi, Pascale Cony-Makhoul, Jean-Loup Demory, Benoit de Renzis, Christine Dosquet, Jerome Rey, Lydia Roy, Brigitte Dupriez, Laurent Knoops, Laurence Legros, Mohamed Malou, Pascal Hutin, Dana Ranta, Omar Benbrahim, Valérie Ugo, Eric Lippert, Jean-Jacques Kiladjian

Abstract

We have previously described the safety and efficacy of pegylated interferon-α2a therapy in a cohort of 62 patients with myeloproliferative neoplasm-associated myelofibrosis followed in centers affiliated to the French Intergroup of Myeloproliferative neoplasms. In this study, we report their long-term outcomes and correlations with mutational patterns of driver and non-driver mutations analyzed by targeted next generation sequencing. The median age at diagnosis was 66 years old, the median follow-up since starting pegylated interferon was 58 months. At the time of analysis, 30 (48.4%) patients were alive including 16 still being treated with pegylated interferon. The median survival of patients with intermediate and high-risk prognostic Lille and dynamic International Prognostic Scoring System scores treated with pegylated interferon was increased in comparison to that of historical cohorts. In addition, overall survival was significantly correlated with the duration of pegylated interferon therapy (70 versus 30 months after 2 years of treatment, P<10-12). JAK2V617F allele burden was decreased by more than 50% in 58.8% of patients and two patients even achieved complete molecular response. Next-generation sequencing analyses performed in 49 patients showed that 28 (57.1%) of them carried non-driver mutations. The presence of at least one additional mutation was associated with a reduction of both overall and leukemia-free survival. These findings in a large series of patients with myelofibrosis suggest that pegylated interferon therapy may provide a survival benefit for patients with intermediate- or high-risk Lille and dynamic International Prognostic Scoring System scores. It also reduced the JAK2V617F allele burden in most patients. These results further support the use of pegylated interferon in selected patients with myelofibrosis.

Copyright© 2018 Ferrata Storti Foundation.

Figures

Figure 1.
Figure 1.
Survival of the whole study cohort. (A) Overall and (B) leukemia-free survival of the whole cohort and survivals according to the prognostic (C) Lille and (D) DIPSS scores.
Figure 2.
Figure 2.
Survival according to treatment status. Kaplan-Meier estimated (A) overall and (B) leukemia-free survival differentiating patients who were still being treated with pegylated-interferon from patients who had stopped interferon because of intolerance or resistance.
Figure 3.
Figure 3.
Patients’ treatment. ASCT: allogeneic stem cell transplantation; disc: discontinuation (of Peg-Ifn); dur: duration; FU: follow-up; m: months; n: number; Peg-Ifn: pegylated-interferon.
Figure 4.
Figure 4.
Variations of the JAK2V617F allele burden during the follow-up. Relative variation of the JAK2V617F allele burden for each of the 27 patients for whom sequential testing was done.
Figure 5.
Figure 5.
Non-driver mutations identified by next-generation sequencing among 49 tested patients. The black color indicates high molecular risk (HMR) mutations. (A) Number of patients with each mutation; (B) number of additional mutations identified per patient. The percentages correspond to the proportion of HMR mutations among additional mutations.
Figure 6.
Figure 6.
Survival according to non-driver mutation status. (A) Overall survival and (B) leukemia-free survival according to the presence of at least one mutation. (C) Overall survival and (B) leukemia-free survival according to the presence of one of the high molecular risk mutations. High molecular risk is defined by the presence of one of the five following mutations: ASXL1, SRSF2, EZH2 or IDH1/2.

References

    1. Mesa RA, Verstovsek S, Cervantes F, et al. Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofibrosis (post-ET MF), blast phase PMF (PMF-BP): consensus on terminology by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). Leuk Res. 2007;31(6):737–740.
    1. Tefferi A. Primary myelofibrosis: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol. 2016;91(12):1262–1271.
    1. Cervantes F, Tassies D, Salgado C, Rovira M, Pereira A, Rozman C. Acute transformation in nonleukemic chronic myeloproliferative disorders: actuarial probability and main characteristics in a series of 218 patients. Acta Haematol. 1991;85(3):124–127.
    1. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379–2390.
    1. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369(25):2391–2405.
    1. Vannucchi AM, Lasho TL, Guglielmelli P, et al. Mutations and prognosis in primary myelofibrosis. Leukemia. 2013;27(9):1861–1869.
    1. Guglielmelli P, Lasho TL, Rotunno G, et al. The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients. Leukemia. 2014;28(9):1804–1810.
    1. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–798.
    1. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799–807.
    1. Vannucchi AM, Kantarjian HM, Kiladjian JJ, et al. ; COMFORT Investigators. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis. Haematologica. 2015;100(9):1139–1145.
    1. Passamonti F, Vannucchi AM, Cervantes F, et al. Ruxolitinib and survival improvement in patients with myelofibrosis. Leukemia. 2015;29(3):739–740.
    1. Cervantes F, Pereira A. Does ruxolitinib prolong the survival of patients with myelofibrosis? Blood. 2016;129(7):832–837.
    1. Alchalby H, Kröger N. Allogeneic stem cell transplant vs. Janus kinase inhibition in the treatment of primary myelofibrosis or myelofibrosis after essential thrombocythemia or polycythemia vera. Clin Lymphoma Myeloma Leuk. 2014;14(Suppl):S36–41.
    1. Kröger NM, Deeg JH, Olavarria E, et al. Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN International Working Group. Leukemia. 2015;29(11):2126–2133.
    1. Kröger N, Giorgino T, Scott BL, et al. Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis. Blood. 2015;125(21):3347–3350.
    1. Robin M, Porcher R, Wolschke C, et al. Outcome after transplantation according to reduced-intensity conditioning regimen in patients undergoing transplantation for myelofibrosis. Biol Blood Marrow Transplant. 2016;22(7):1206–1211.
    1. Ianotto JC, Kiladjian JJ, Demory JL, et al. PEG-IFN-alpha-2a therapy in patients with myelofibrosis: a study of the French Groupe d’Etudes des Myelofibroses (GEM) and France Intergroupe des syndromes Myéloprolifératifs (FIM). Br J Haematol. 2009;146(2):223–225.
    1. Ianotto JC, Boyer-Perrard F, Gyan E, et al. Efficacy and safety of pegylated-interferon α-2a in myelofibrosis: a study by the FIM and GEM French cooperative groups. Br J Haematol. 2013;162(6):783–791.
    1. Lippert E, Boissinot M, Kralovics R, et al. The JAK2-V617F mutation is frequently present at diagnosis in patients with essential thrombocythemia and polycythemia vera. Blood. 2006;108(6):1865–1867.
    1. Dupriez B, Morel P, Demory JL, et al. Prognostic factors in agnostic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood. 1996;88(3):1013–1018.
    1. Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood. 2010;115(9):1703–1708.
    1. Harrison CN, Vannucchi AM, Kiladjian JJ, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016;30(8):1701–1707.
    1. Barosi G, Zhang MJ, Gale PR. Does ruxolitinib improve survival of persons with MPN-associated myelofibrosis? Should-it? Leukemia. 2014;28(11):2267–2270.
    1. Martí-Carvajal AJ, Anand V, Solà I. Janus kinase-1 and Janus kinase-2 inhibitors for treating myelofibrosis. Cochrane Database Syst Rev. 2015;(4):CD010298.
    1. Scott BL, Gooley TA, Sorror ML, et al. The Dynamic International Prognostic Scoring System for myelofibrosis predicts outcomes after hematopoietic cell transplantation. Blood. 2012;119(11):2657–2664.
    1. Gupta V, Malone AK, Hari PN, et al. Reduced-intensity hematopoietic cell transplantation for patients with primary myelofibrosis: a cohort analysis from the center for international Blood and Marrow Transplant Research. Biol Blood Marrow Transplant. 2014;20(1):89–97.
    1. Pigneux A, Tanguy ML, Michallet M, et al. ; Société Française de Greffe de Moelle. Prior treatment with alpha interferon does not adversely affect the outcome of allogeneic transplantation for chronic myeloid leukaemia. Br J Haematol. 2002;116(1):193–201.
    1. Kiladjian JJ, Cassinat B, Turlure P, et al. High molecular response rate of polycythemia vera patients treated with pegylated interferon alpha-2a. Blood. 2006;108(6):2037–2040.
    1. Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112(8):3065–3072.
    1. Masarova L, Patel KP, Newberry KJ, et al. Pegylated interferon alfa-2a in patients with essential thrombocythaemia or polycythaemia vera: a post-hoc, median 83 months follow-up of an open-label, phase 2 trial. Lancet Haematol. 2017;4(4):e165–e175.
    1. Silver RT, Barel AC, Lascu E, et al. The effect of initial molecular profile on response to recombinant interferon-α (rIFNα) treatment in early myelofibrosis. Cancer. 2017;123(14):2680–2687.
    1. Verger E, Cassinat B, Chauveau A, et al. Clinical and molecular response to interferon-α therapy in essential thrombocythemia patients with CALR mutations. Blood. 2015;126(24):2585–2591.
    1. Rotunno G, Pacilli A, Artusi V, et al. Epidemiology and clinical relevance of mutations in post polycythemia vera and post essential thrombocythemia myelofibrosis: a study on 359 patients of the AGIMM group. Am J Hematol. 2016;91(7):681–686.
    1. Pizzi M, Silver RT, Barel A, Orazi A. Recombinant interferon-α in myelofibrosis reduces bone marrow fibrosis, improves its morphology and is associated with clinical response. Mod Pathol. 2015;28(10):1315–1323.

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