Myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) can occur as a de novo (Primary MF, PMF), or as secondary MF (SMF) resulting from transformation of Polycythemia Vera or Essential Thrombocythemia. In all cases, altered hematopoiesis results in abnormal blood counts (either hyperproliferation or cytopenias), splenomegaly and general symptoms related to inflammation, all of which are the intended targets of treatments.

Unfortunately, few therapeutic options exist and, besides allogeneic stem cell transplantation (ASCT), none is curative. We previously reported that pegylated-interferon-a2a (Peg-Ifn-α2a ) treatment in MF was able to induce significant clinical and hematological responses (1). We now present the long-term follow-up of this prospective cohort and correlations with driver and non-driver mutations.

Sixty-two MF patients (pts) treated with Peg-Ifn-α2a were included between 2006 and 2011 in a prospective observational study in 17 centers of the FIM group. Clinical and biological parameters and treatments were collected at Peg-Ifn-α2a initiation, every 3 months during two years and every 6 months thereafter. All 62 pts were genotyped for the 3 major MPN mutations (JAK2V617F, CALR, MPL), and 49 were also screened by next generation sequencing (NGS) for mutations in the whole coding sequence of 25 genes frequently mutated in chronic myeloid disorders.

The median age at Peg-Ifn-α2a initiation was 64 and 70.5 years-old, in PMF (n=29) and SMF (n=33) pts, respectively. The median follow-up was 58 months (range: 9-107) after Peg-Ifn-α2a initiation and 69.6 months (range: 10-178) from MF diagnosis. Median Peg-Ifn-α2a treatment duration was 39 months (range: 6-107). At the time of analysis, 30 patients (48.4%) were still alive. The median overall survival (OS) was 7.4 years from MF diagnosis. The Lille and the DIPSS scores clearly differentiated pts in terms of OS, but median OS observed in this cohort was clearly longer than that reported in the reference cohorts used for the establishment of these prognostic scores, especially in higher risk categories: according to the Lille score (8.9 vs. 7.75 yrs for low, 5.42 vs. 2.17 yrs for intermediate and 4.46 vs. 1.08 yrs for high risks) and to the DIPSS score (6.9 vs. 4 yrs for intermediate-2 and 4.58 vs. 1.5 yrs for high-risk pts).

The type of driver mutation statistically impacted survival: CALR -mutated pts had 13.5 yrs of median OS compared to 7 yrs for JAK2 -mutated pts (p<0.0001). Forty-five pts (72.6%) discontinued Peg-Ifn-α2a: 25 (55.6%) due to resistance and 20 (44.4%) due to intolerance. Patients developing intolerance to Peg-Ifn-α2a had longer median OS and leukemia-free survival (LFS) than those with resistance (p=10-5 and p=0.048, respectively). The median survival after Peg-Ifn-α2a cessation was 17 months (3-62m), but differed according to the subsequent treatment received: 22 months for those who received ruxolitinib compared to 14 months for those who received another drug (p=0.12) and 10 months for pts who underwent ASCT (p=0.003).

Sequential quantification of JAK2V617F allele burden was available in 27 pts, showing a decrease of mutant allele burden of more than 50% in 10/27 pts (37%). Four pts (15%) achieved a reduction over 90% including 3 complete molecular responses. Of the 49 pts analyzed with targeted NGS, 28 (57.1%) carried at least one additional mutation. Patients who harbored at least one non-driver mutation had shorter OS (6.1 vs. not reached, p=0.06) and LFS (not reached both, p=0.026) than those with only driver mutations. The presence of "high molecular risk" mutations previously associated with poorer prognosis (in ASXL1, EZH2, SRSF2, IDH1/2) was not associated with a poorer OS or LFS than other mutations in this series of pts treated with interferon.

In conclusion, this large cohort of MF pts treated with Peg-Ifn-α2a demonstrates that a long-term use of this treatment is safe, and is associated with improved OS compared to historical series as well as significant decrease in driver mutation allele burden. The presence of additional mutations remains associated with poorer prognosis. The role of interferon therapy should be discussed in pts with MF, optimal target population possibly being high-risk pts without ASCT project and with a proliferative disease.

Disclosures

Ianotto: Novartis: Other: Grant. Laribi: MUNDIPHARMA: Research Funding; NOVARTIS: Honoraria, Research Funding; ROCHE: Research Funding; TEVA: Research Funding; HOSPIRA: Research Funding; AMGEN: Honoraria; TAKEDA: Honoraria, Research Funding. Cony-Makhoul: BMS: Speakers Bureau. Kiladjian: AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Author notes

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Asterisk with author names denotes non-ASH members.