Background: Although ruxolitinib (RUX) reduces constitutional symptoms and splenomegaly in myelofibrosis (MF) therapy options for anemia are limited. In our prior MPNSG-0109 trial of pomalidomide (POM) in MF with cytopenia, anemia responses were reported in 14% and 29% of subjects receiving POM 0.5 mg/d and 2 mg/d, respectively (Schlenk RF et al., ASH 2013, abstract #2822). We designed a phase-Ib/-II combination study of RUX plus POM to evaluate synergistic effects in subjects with anemia and splenomegaly (MPNSG-0212 trial, NCT01644110; Stegelmann et al., ASH 2015, abstract #826).

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 RBC transfusion independence (Gale et al., Leuk Res 2011). Secondary endpoints are safety, quality-of-life, progression-free survival (PFS) and survival. Main inclusion criterion is pre-treated or untreated MF with anemia (Hb <10 g/dL and/or RBC transfusion dependence). Key exclusion criteria are transplant-eligibility, platelets <100x10E+9/L and neutrophils <0.5x10E+9/L). POM is given at 0.5 mg/d QD. RUX is started at 10 mg BID with dose modifications to optimize efficacy and to manage toxicity. According to a 2-stage design, 37 subjects will be tested in the 1st cohort before starting a 2ndcohort of 38 subjects.

Results: Data from 37 subjects are reported. Median age was 73 years (range, 49-83 years). 17 subjects (46%) previously received therapy such as hydroxyurea, ruxolitinib, EPO, pomalidomide, and/or steroids. Median hemoglobin at study entry was 8.6 g/dL (range, 5.4-11.7 g/dL); 11 subjects (30%) were RBC-transfusion-dependent. Median spleen size by ultrasound was 18 cm (range, 13-28 cm). 29 subjects (78%) had constitutional symptoms at baseline; 25 (68%) were intermediate-2 risk and 9 (24%) high-risk according to the ´Dynamic International Prognostic Scoring System´ (DIPSS). Adverse prognosis of the study cohort was underlined by the detection of one or more high-molecular risk markers in 21 subjects (57%) [i.e. mutation in ASXL1, EZH2, IDH1/2 and/or SRSF2].

Median time on-treatment is 11 cycles (range, 1-26 cycles). 563 adverse events (AE) of any grade (CTCAE 1-5) were recorded. Worsening of anemia within the first 6 cycles was the most frequent AE occurring in 13 subjects (35%) followed by fatigue in 11 (30%). Treatment interruptions and dose reductions of RUX and/or POM were rare. There were 26 serious AE (SAE) CTCAE grade 2-5. Pneumonia (N=3), leukemia transformation (N=3), thoracic pain (N=3), abdominal pain (N=2) and septic shock (N=2) occurred in 13 subjects (35%) of which 4 were fatal (cardiac decompensation, pneumonia, and septic shock [N=2]). Only 2 SAE (hemoglobin, grade 4 and neuropathy, grade 3) were considered therapy-related.

18 subjects (49%) are on-study treatment; 19 (51%) discontinued because of AE (N=5), leukemia transformation (N=3), stable disease (SD) without objective response after 12 cycles (N=4), death (N=3) or withdrawal of consent (N=3). 6 subjects (16%) responded with spleen reduction (N=3) or ≥2 mg/dL hemoglobin increase / RBC transfusion independence (N=3). Mean hemoglobin increased from 8.6 g/dL at baseline to 9.3 g/dL at the end of cycle 12. 12 subjects (32%) continued treatment after cycle 12 because of response or SD plus clinical benefit (hemoglobin increase <2g/dL or prolongation of RBC-transfusion intervals and/or improvement of symptoms). 3 subjects (8%) are on treatment for >24 cycles.

Conclusions: Combined RUX and POM was safe and feasible and achieved an objective response rate of 16%. One third of the subjects had clinical benefit with the combination therapy. Based on these results and our MPNSG-0109 data a step-wise increase of POM dose to 2 mg QD is intended for the 2nd study cohort to further improve anemia response.


Koschmieder:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. von Bubnoff:Amgen: Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria. Hochhaus:Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Scheid:Janssen: Other: funding outside this work; Celgene: Other: funding outside this work; Novartis: Other: funding outside this work. Schlenk:Pfizer: Honoraria, Research Funding; Amgen: Research Funding.

Author notes


Asterisk with author names denotes non-ASH members.