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.

Summary Myeloproliferative neoplasm‐related myelofibrosis is associated with cytopenic or proliferative phases, splenomegaly and constitutional symptoms. Few effective treatments are available and small series suggested that interferon could be an option for myelofibrosis therapy. We performed a retrospective study of pegylated‐interferon α‐2a (Peg‐IFNα‐2a) therapy in myelofibrosis. Sixty‐two patients treated with Peg‐IFNα‐2a at 17 French and Belgian centres were included. Responses were determined based on the criteria established by the International Working Group for Myelofibrosis Research and Treatment. Mean follow‐up was 26 months. Sixteen of 25 anaemic patients (64%) (eight concomitantly receiving recombinant erythropoietin) achieved a complete response and transfusion‐independence was obtained in 5/13 patients (38·5%). Constitutional symptoms resolved in 82% of patients. All five leucopenic patients normalized their leucocyte counts, whereas a normal platelet count was obtained in 5/8 thrombocytopenic patients. Splenomegaly was reduced in 46·5% of patients, and complete resolution of thrombocytosis and leucocytosis were observed in 82·8% and 68·8% of patients, respectively. Side effects (mostly haematological) were mainly of grade 1–2. The only factor independently associated with treatment failure was a spleen enlargement of more than 6 cm below the costal margin. In conclusion, Peg‐IFNα‐2a induced high response rates with acceptable toxicity in a large proportion of patients with primary and secondary myelofibrosis, especially in early phases.

EEXPAND (phase Ib, dose-finding study) evaluated the starting dose of ruxolitinib in patients with myelofibrosis with baseline platelet counts of 50-99×10 9 /L. The study consisted of dose-escalation and safety-expansion phases. Based on the baseline platelet counts, patients were assigned to stratum 1 (75-99×10 9 /L) or stratum 2 (50-74×10 9 /L), with the primary objective of determining the maximum safe starting dose (MSSD); key secondary objectives included safety and efficacy. At week 48 data cutoff (stratum 1, n=44; stratum 2, n=25), 24.6% (17 out of 69) of patients were still receiving treatment. The MSSD was established as ruxolitinib 10 mg twice daily in both strata. Thrombocytopenia [grade 4 (stratum 1, n=1; stratum 2, n=2)] was the only reported dose-limiting toxicity (study drug related) at 10 mg twice daily. In the MSSD cohort (stratum 1, n=20; stratum 2, n=18), adverse events (regardless of study drug relationship) led to treatment discontinuation in 15.0% and 33.3% of patients in stratum 1 and stratum 2, respectively, and dose adjustment/interruption in 45.0% and 66.7% of patients in stratum 1 and stratum 2, respectively. Three cases of on-treatment deaths were reported at the MSSD. Spleen response was achieved at week 48 in 33.3% and 30.0% of patients in stratum 1 and stratum 2, respectively. Improvements in the Total Symptom Score were also observed. In this study, ruxolitinib demonstrated acceptable tolerability in both the strata at the MSSD of 10 mg twice daily. (Registered at: clinicaltrials.gov identifier: 01317875 ).

Myeloproliferative neoplasms (MPN) are chronic disorders that can sometimes evolve into accelerated or leukemic phases. We retrospectively identified 122 patients with such blastic phases. The overall median survival was four months: 10.2 months for patients treated with intensive treatments compared to three months for best supportive care (p = .005). Azacytidine, intensive chemotherapies, or allogeneic stem cell transplantation gave the highest median survivals with 9, 10.2, and 19.4 months, respectively. Accelerated phases (AP) had a longer median survival compared to acute leukemia (4.8 months vs. 3.1 months; p = .02). In this retrospective and observational study, we observe that the longest survivals are seen in patients eligible for intensive treatments. Azacytidine shows interesting results in patients non-fit for intensive chemotherapy. Supportive care should probably be restricted to elderly patients and those with unfavorable karyotype. An early diagnosis of AP could also result in a better survival rate.

Background MPN-associated myelofibrosis (MF) is a condition characterized by splenomegaly, anemia, bone marrow (BM) fibrosis and debilitating symptoms. About 80% of patients (pts) harbor a driver mutations in JAK2, CALR or MPL genes that can be used as biomarkers for minimal residual disease assessment. Ruxolitinib (Rux) is a JAK inhibitor approved in intermediate or high risk (HR) MF to improve symptoms and splenomegaly but with little impact on the malignant clone and fibrosis. Interferon alpha (IFNa) can reduce mutant allele burden and fibrosis but is often poorly tolerated in highly symptomatic pts. The RUXOPEG study was designed to assess the efficacy and safety of the combination of Rux + IFNa in MF (NCT02742324). Methods RUXOPEG is a multi-center Bayesian Phase 1/2 adaptive trial. Phase 1 includes up to 9 cohorts of 3 pts with increasing doses of both drugs. Tested doses of Rux and IFNa are 10, 15 and 20 mg BID, and 45, 90 and 135 mcg/week, respectively. Phase 2 will randomize between the 2 best dose combinations selected from phase 1. Primary objective: identify the most efficacious dose combination that also satisfies safety requirements. Primary tolerance criterion is the occurrence of dose limiting toxicities (DLT) within 45 days; primary efficacy criterion is >50% reduction in spleen length within 6 months. Secondary objectives include molecular response, reduction of BM fibrosis, quality of life and symptoms evolution, event-free and overall survival. The planned total enrollment is 42 pts. Key inclusion criteria are: diagnosis of MF (WHO criteria), intermediate or HR (IPSS), need of active therapy, presence of a driver mutation. Key exclusion criteria: prior treatment (or contra-indication) with Rux or IFNa, eligibility for stem cell transplantation, inadequate liver, cardiac or renal function, autoimmune disease, history of depression. Enrolment in 5 cohorts was completed in June 2018, and the last cohort for phase 1 will be opened in August. This abstract reports the current available data for the 5 cohorts who have completed the primary endpoint, but the presentation will provide the detailed analysis of primary and secondary endpoints of phase 1, which will be available in October 2018. Results Among the 15 pts currently enrolled in phase 1, 6 were females, mean age was 60.9 years (range: 38-72), 8 had primary MF, 5 post ET and 2 post PV MF. Median spleen size was 6 cm (range 0 - 18) by palpation and 18 cm (range 10-25) by imaging. Mean (range) blood counts were: hemoglobin 12 g/dL (8.5 - 13.8), WBC 18.3 G/L (8 - 35.5), platelets 457 G/L (157 - 906) and 6 pts had circulating blasts. 12 pts had JAK2V617F and 2 had CALR mutations; karytotype was normal in 9 pts, abnormal in 5 (very HR in 3). In 10 pts analyzed by NGS so far, 8 had additional mutations (1 in 5 pts, 3 in 1, and 4 in 2) in TET2 (n= 5), ASXL1 (4), DNMT3A (2), TP53 (2), SF3B1 (1) and SRSF2 (1) genes. Safety: No DLT was observed in the 5 cohorts (primary safety criterion), the highest tested dose combination being Rux 15 mg BID + IFNa 135 mcg/week. The last cohort will test Rux 20 mg BID + IFNa 135 mcg/week. 4 serious adverse events have been reported: 1 AML transformation (very HR cytogenetics, 3% circulating blasts at baseline), 1 thrombotic event, 1 squamous cell carcinoma and 1 aggravation of Raynaud's phenomenon. Efficacy: preliminary data show a clear decrease in spleen size at 6 months (median 0 cm by palpation, range 0-9; 12.1 cm by imaging, range 10-21) and improvement in blood counts (mean, range): hemoglobin 10.5 g/dL (9.7 - 12.5), WBC 8.6 G/L (5.4 - 11.1), platelets 267 G/L (80 - 486). According to IWG criteria, all the 10 pts evaluable at time of abstract preparation responded (3 partial response, 7 hematological improvement). JAK2V617F allele burden decreased from a mean of 75% (range 43- 96) at baseline to 46% (range 24 - 84) at 6 months. Encouraging results were also found in a patient with 5 mutations (figure1) with a clear decrease in JAK2V617F, ASXL1, DNMT3A and EZH2 mutations after 12 months of treatment. Conclusion RUXOPEG is the first study to formally assess the safety and efficacy of Rux + IFNa combination in MF patients never exposed to either drugs before. The first 5 dose combinations tested showed no DLT, confirming that this combination was generally well tolerated. Preliminary efficacy results are encouraging, including in patients who received very low doses of both drugs. Full results of the 6 cohorts tested in phase 1 and doses selected for phase 2 will be presented. Disclosures Kiladjian: Novartis: 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; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Giraudier:Novartis: Research Funding. Cassinat:Novartis: Research Funding; AOP Orphan: Research Funding.