A Phase-Ib/II Study of Ruxolitinib Plus Pomalidomide in Myelofibrosis

Background: Myelofibrosis (MF) patients (pts) frequently suffer from constitutional symptoms, splenomegaly, and cytopenia. While ruxolitinib (RUX) is available for the treatment of symptomatic splenomegaly and constitutional symptoms in MF, therapeutic options for the treatment of cytopenia are limited. Recent data indicate that the immunomodulatory drug pomalidomide (POM) may improve anemia and thrombocytopenia in a subset of MF pts (e.g. Tefferi et al., J Clin Oncol 2009). We designed a single arm, multicenter phase-Ib/II combination study of RUX and POM (MPNSG-0212 trial, NCT01644110) to evaluate potential synergistic effects of both drugs in MF.

Study Design: Primary endpoints are response rate after 12 treatment cycles (28 days each) according to IWG-MRT criteria (Tefferi et al., Blood 2006) and achievement of red blood cell (RBC) transfusion independence (Gale et al., Leuk Res 2011). Secondary endpoints are safety, quality of life, progression-free survival, and overall survival. Main inclusion criterion is pre-treated or untreated primary or secondary (post-ET / post-PV) MF with anemia (Hb <10 g/dL and/or RBC transfusion dependency). Key exclusion criteria are suitability for allotransplant, low platelet count (<100 /nL), and severe neutropenia (ANC <0.5 /nL). While POM is given at the fixed dosage of 0.5 mg QD, RUX is started at 10 mg BID with dose modifications being allowed to optimize efficacy and to manage myelosuppression. According to a Simon´s two-stage design, recruitment will be extended to a total number of 72 pts if response is achieved in a minimum of 12/37 pts tested initially.

Results: Safety of the combination therapy was evaluated favorably by an independent safety monitoring committee after treatment of the first 6 pts as reported previously (Stegelmann et al, ASH 2014). Here, we present follow-up data from 25 pts. Median age of the study population was 75 years (range 51-82). Ten of 25 pts (40%) had one or more previous therapies. The most frequent previous drugs were hydroxyurea (n=6), ruxolitinib (n=3), EPO (n=2), pomalidomide (n=2), and steroids (n=2). Median Hb at study entry was 8.6 g/dL (range 6.8-10.6); 6 pts (24%) were RBC transfusion dependent. Median spleen size measured by ultrasound was 18 cm (range 13-28). Eight pts (32%) were intermediate-1, 10 pts (40%) intermediate-2, and 7 pts (28%) high-risk according to the dynamic international prognostic scoring system (DIPSS). Mutation frequencies of JAK2 V617F, MPL W515L, and CALR exon 9 were 72%, 12%, and 16%, respectively. ASXL1 was mutated in 5 pts (20%). Regarding safety, 287 adverse events (AE) of any grade (CTCAE 1-5) were recorded. Among these, worsening of anemia (°3/°4) was the most frequent AE (n=35 in 9 pts), followed by musculoskeletal pain (n=25 in 6 pts; °1-°3), and constitutional symptoms (n=13 in 2 pts; °1-°3). In total, 11 serious AE (SAE) CTCAE °2-5 were recorded. While 9 SAE (pneumonia °3, n=3; cardiac decompensation °5, malignant melanoma °2, septic shock °5, syncope °3, and TIA °2, worsening of general condition °3, n=1 each) were considered non-related to the study drugs, 2 SAE (hemoglobin °4, neuropathy °3) were considered related. Of note, neuropathy resolved after end of study. Treatment interruptions and dose reductions of RUX were uncommon. RUX could be step-wise increased to 15 or 20 mg BID in 10 pts (40%). Median time on treatment was 8 28-days cycles (range 1-13) in 24 pts, while one patient has not yet started therapy; 14 pts (56%) are still on study treatment. A total of 10 pts (40%) discontinued, due to death (n=2), no response after 12 cycles (n=5), or withdrawal of informed consent (n=3). Within this short observation time, 3 pts experienced ´clinical improvement´ (CI) according to IWG-MRT criteria in the following categories: i) spleen reduction, ii) spleen reduction + increase of Hb, and iii) increase of both Hb and ANC. RBC transfusion independency criteria have not yet been fulfilled in transfusion dependent pts. None of the study pts progressed during treatment.

Conclusions: Taking into account that the majority of study pts were pre-treated and at advanced risk, the combination therapy of RUX and POM was well tolerated and is feasible. First efficacy evaluation shows that clinical improvement regarding reduction of splenomegaly and improvement of cytopenia is achieved in a subset of MF pts. Recruitment of the study continues. An update on safety and efficacy will be presented at the meeting.