A Multicenter Phase-Ib/II Study of Ruxolitinib/Pomalidomide Combination Therapy in Patients with Primary and Secondary Myelofibrosis: Safety Data from the Mpnsg-0212 Trial (NCT01644110)

Background: Myelofibrosis (MF) is characterized by poor prognosis, and patients (pts) frequently present with constitutional symptoms, splenomegaly, and anemia. Although ruxolitinib (RUX) is available for the treatment of constitutional symptoms and splenomegaly, therapeutic options for the treatment of anemia are limited. Recent data indicate that immunmodulatory drugs such as lenalidomide or pomalidomide (POM) can improve anemia and/or thrombocytopenia. We designed a multicenter phase-Ib/II combination study of RUX and POM (MPNSG-0212) to evaluate potential synergistic effects in MF.

Aims: Based on data from the first 6 pts,we performed a safety assessment to evaluate feasibility and toxicity of combination therapy. Primary study-endpoint is response rate after 12 treatment cycles (28 days each) according to IWG-MRT criteria (Tefferi et al., Blood 2006) and red blood cell (RBC) transfusion independence (Gale et al., Leuk Res 2011). Secondary endpoints are safety, response duration, quality of life, progression-free survival and overall survival.

Study Design: Key inclusion criteria are primary or secondary (post-ET / post-PV) MF, anemia with hemoglobin level <10 g/dL, and splenomegaly. Key exclusion criteria are MF pts suitable for allotransplant, platelets <100x10E+9/L, and neutrophils <0.5x10E+9/L. POM is given at a fixed dosage of 0.5 mg QD. RUX was started at 10 mg BID. Dose modifications of RUX were allowed to increase efficacy and to manage myelosuppression. Safety assessment is done after treatment of the first 6 pts for ≥1 cycle. The safety profile is defined favourable if ≤1 of the first 6 pts had a treatment limiting toxicity associated with one of the study drugs (non-hematological toxicity CTCAE ≥°3 and/or hematological toxicity CTCAE ≥°4).

Results: Between August 2013 and March 2014, 6 pts were registered. Database lock for the safety analysis was April 22, 2014. Median time on treatment was 4.3 months (range, 1.0-9.4 months). RUX dose was maintained at 10 mg BID in 5 pts, and increased stepwise to 20 mg BID until cycle 6 in 1 pt (ID001). POM was administered continuously. In total, 8 hematological toxicities CTCAE °3 (anemia) were recorded in the 6 pts over the total period of 26 cycles; 3 events already pre-existed before study entry and affected the same pt (ID005). In contrast, anemia increased in 5 pts and made RBC transfusions necessary. However, no CTCAE °4 anemia, no CTCAE °3/4 thrombocytopenia, and no CTCAE °3/4 neutropenia occurred.

Study treatment was stopped in 2/6 pts, in ID003 at cycle 3 (cardiac decompensation) and in ID002 at cycle 6 (withdrawal). The following events of non-hematological toxicities CTCAE °3 (n=2) and °5 (n=1) were observed in these 2 pts: 2 SAEs (neuropathy and pneumonia) in ID002 and 1 SUSAR (cardiac decompensation) in ID003 who died during an in-hospital stay. No causal relationship with the study drugs was seen for pneumonia, whereas neuropathy was considered POM-associated. After discontinuation of POM, neuropathy resolved. ID003 was hospitalized for cardiac decompensation with immediate stop of study drugs and died 13 days later. Therefore, causal relationship between study treatment and the SUSAR is unlikely. Three additional unrelated non-hematological adverse events CTCAE °3 occurred in the remaining pts: 1 was pre-existing without aggravation (muscle cramps) and 2 represented MF symptoms not meeting seriousness criteria (musculoskeletal pain, reduced general condition).

Conclusion: Based on our safety analysis, the combination therapy was well tolerated. The observed toxicities were within the expected range according to the reported toxicity profiles for the respective single agents and with regard to the general condition of the pts. Therefore, the safety profile of 6 pts treated within the MPNSG-0212 trial was favourably evaluated by the investigators and by an independent data safety monitoring committee. Recruitment of the study continues. An update on safety and first efficacy data will be presented.