Elsevier

Leukemia Research

Volume 37, Issue 9, September 2013, Pages 1041-1045
Leukemia Research

Long term molecular responses in a cohort of Danish patients with essential thrombocythemia, polycythemia vera and myelofibrosis treated with recombinant interferon alpha

https://doi.org/10.1016/j.leukres.2013.06.012Get rights and content

Abstract

Within recent years data has accumulated demonstrating the efficacy of recombinant interferon alpha2 (rIFN-alpha2) in the treatment of chronic myeloproliferative neoplasms (MPNs). We report on clinical and molecular data in the largest cohort of JAK2 V617F mutant MPN Danish patients (n = 102) being treated long-term with rIFN-alpha2 (rIFN-alpha2a and rIFN-alpha2b in a non-clinical trial setting. The median follow-up was 42 months. We substantiate the capacity of rIFN-alpha2 to induce complete hematologic remissions (ET 95%, PV 68%) and molecular response. In total 76 patients (74.5%) had a decline in JAK2 V617F allele burden with a median reduction from baseline of 59% (95% c.i. 50–73%, range 3–99%). A decline in JAK2 V617F allele burden was recorded in both ET (median 24–10% (95% c.i.: 8–16%), and PV (median 59–35% (95% c.i.: 17–33%). Patients with the lowest pre-treatment JAK2 V617F allele burdens tend to achieve the most favourable responses on long term treatment with rIFN-alpha2. Eleven patients (10%) had deep molecular remissions with ≤2% JAK2 V617F mutant DNA. Finally, long term treatment with rIFN-alpha2 was associated with a very low thrombosis rate. Our observations are supportive of the concept of early up-front treatment with rIFN-alpha2.

Introduction

Identification of the JAK2 V617F somatic point mutation is now a well established part of the diagnostic work up in the Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) (essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF)). Apart from being an important and robust marker of clonal neoplastic disease, the quantification of the JAK2 V617F mutant allele burden can be used as a marker of treatment response and monitoring of minimal residual disease (MRD) [1], [2]. A reduction of the JAK2 V617F allele burden is a response criterion in MPNs according to the European LeukemiaNet (ELN) Working Group guidelines [3]. The pathogenetic and prognostic significance of a reduction of the JAK2 V617F allele burden still remains to be established. However, an increasing enthusiasm towards rIFN-alpha2 as a promising agent with a potential to change the natural history of MPNs has been supported by the very impressive results published by among others by the French group, demonstrating solid hematologic response rates and deep molecular responses on pegylated interferon alfa 2a (peg-IFN2a) treatment [2], [4], [5]. These interesting results on interferon as well as data on new agents such as histone-deacetylase inhibitors (HDACi) and JAK2 kinase inhibitors are changing the landscape of cytoreductive treatment of MPNs these years. Whereas the new agents and in particular the JAK1-2 kinase inhibitor (Ruxolitinib) has demonstrated impressive results on constitutional symptoms and splenomegaly in PMF, the JAK2 allele burden has not been significantly reduced in most studies [6], [7]. Results from ongoing studies on ET and PV are being awaited, as are the results from future studies on combination treatment with other agents. In this regard combination with IFN-alpha2 is of particular interest. The clinical efficacy of this agent in the treatment of ET, PV and hyperproliferative myelofibrosis has been recognized for decades, [8], [9], [10], [11], [12]. The molecular effects of IFN are not fully understood, but this agent has a wide range of well known attractive biological effects such as antiproliferative, pro-apoptotic, anti-angiogenic and immunomodulating properties [12], [13], [14], [15]. In particular the immunomodulating capacity of IFN is a focus of intense investigation, in part motivated by the observation of long term deep molecular responses and clinical remissions being sustained and durable after cessation of therapy, which might indicate an immune response to the minimal JAK2 V617F clone [16], [17].

However, the use of IFN-alpha2 in clinical practice has been dampened by toxicity issues causing drop-off rates in the range of 20–30% [18], [19]. In many countries off-label use of pegylated IFNs is impossible outside clinical trials. In Denmark we have had the opportunity to treat patients with MPNs outside clinical trials with pegylated IFNs for many years and the use of these agents has increased dramatically over the last years. Most recently, the routine clinical experience with off-protocol use of rIFN-alpha2a (Pegasys) in advanced myeloproliferative neoplasms in an international cohort of 118 patients has been published [20]. Herein, we report on clinical and molecular data in the largest cohort of JAK2 V617F mutant MPN patients being treated long-term with rIFN-alpha2 (rIFN-alpha2a and rIFN-alpha2b in a similar non-clinical trial setting.

Section snippets

Patients and methods

We collected data from 8 Danish centres. In the period from 2008 to 2011 102 patients met the inclusion criteria, (i) JAK2 V617F mutated ET, PV or PMF according to either the WHO 2001 or 2008 criteria and (ii) treatment with IFN-alpha2a for a period of at least 12 months.

Fifty-two patients had received prior treatment with other agents (hydroxyurea, anagrelide and busulfan) before being treated with interferon. The large majority of the 52 patients were treated with hydroxyurea or anagrelide,

Demographics

In total 102 patients with JAK2 V617F mutated MPN patients were evaluable and included in the study encompassing 19 patients with ET, 75 patients with PV, 4 patients with proliferative myelofibrosis of whom 2 had PMF and 2 had post-polycythemic MF, and 4 patients with MPN unclassified (MPNu). Patients fulfilled the WHO criteria (2001 or 2008). No patients transformed to myelofibrosis or acute leukaemia during follow-up. There was an equal gender distribution (49 males and 53 females), with a

Discussion

We here report the largest series of JAK2 V617F mutated MPN patients being treated long-term (>12 months) with rIFN-alpha2, which mostly was Peg-rIFN-alpha2. The primary objective of our study was to describe the molecular response on long-term treatment with rIFN-alpha2a. The majority of patients – 74.5% obtained a decline in JAK2 V617F allele burden, and 74% of molecular responders met the criteria of partial molecular response according to ELN guidelines. We did record complete

Conflicts of interest statement

The authors have no conflicts of interest to declare.

Acknowledgements

We are indebted to our patients who allowed drawing and analysis of blood after informed consent for analysis. We would like acknowledge personal at the 8 centres participating in the study.

Contributions. Contributors T.S.L and H.C.H provided the conception and design of the study, acquisition of data, analysis and interpretation of the data and drafted the manuscript. K.I, E.H, A.M, C.M, H.L, I.H, D.R-J, M.F, O.W.B, H.V and C.H.R supplied the acquisition of data. M.B.M and K.d.S. performed the

References (27)

  • S. Verstovsek et al.

    Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis

    N Engl J Med

    (2010)
  • C. Harrison et al.

    JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis

    N Engl J Med

    (2012)
  • H. Ludwig et al.

    Interferon-alfa corrects thrombocytosis in patients with myeloproliferative disorders

    Cancer Immunol Immunother

    (1987)
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