SAN DIEGO, CA—In patients with low or intermediate-1 (int-1) risk myelodysplastic syndrome (MDS) and thrombocytopenia, use of the thrombopoietin (TPO)-receptor agonist, romiplostim, resulted in a 15-fold increase in platelet response as defined by the International Working Group’s (IWG) 2006 criteria for hematologic improvement-platelets (HI-P). The data from this randomized, double-blind, placebo-controlled study was presented at the 53rd American Society of Hematology Annual Meeting and Exposition.

International Prognostic Scoring System (IPSS) low/int-1 MDS patients receiving supportive care with platelets ≤20×109/L or ≤50×109/L and with a history of bleeding were included in the trial. Patient demographics included the following WHO classes: refractory cytopenia with multilineage dysplasia (RCMD; 68%), refractory anemia with excess blasts (RAEB) type 1 (13%), unclassifiable (MDS-U; 11%), refractory anemia (RA; 4.4%), RCMD with ringed sideroblasts (RCMD-RS; 2.4%), refractory anemia with ringed sideroblasts (RARS; 0.8%), RAEB-2 (1%), IPSS status low (25%), int-1 (71%), int-2 (0.4%), and IPSS cytogenetics good (78%), intermediate (18%), poor (1.6%).

A total of 250 patients enrolled in the trial, with a median age of 70 years. Patients were randomized 2:1 to 750mcg romiplostim (n=167) or placebo (n=83) for 26 weeks in combination with MDS supportive care, followed by a 4-week washout period then a bone marrow biopsy. Patients then continued with any MDS therapy for 24 weeks with an additional 4-week washout followed by a bone marrow biopsy. In February 2011, due to Data Monitoring Committee concerns with the possibility for transitory escalations in blast cell counts and the risk for advancement to or treatment for AML, study drug was discontinued, affecting 28% of patients. The median time on romiplostim therapy was 21.5 weeks (range 1–50).

The study’s primary endpoint was the number of clinically significant bleeding events (CSBE, Grade ≥2 as defined by the modified World Health Organization scale). Other endpoints evaluated in the trial included protocol-defined platelet transfusion events (PTE), platelet response per IWG 2006 HI-P, survival, safety, antibodies to romiplostim and TPO, and progression to acute myeloid leukemia (AML). Progression to AML was defined as having ≥20% blasts in the bone marrow or peripheral blood four weeks following romiplostim discontinuation, or pathology consistent with leukemia (e.g, chloroma or leukemia cutis), or the start of anti-leukemic treatment.

The average number of CSBE per patient was 1.47 for romiplostim and 1.94 for placebo (HR 0.83, 95% CI: 0.66–1.05, P=0.13); rates of CSBE were 18.6% for romiplostim and 26.5% for placebo. The overall number of bleeding events was reduced with romiplostim (RR 0.92, 95% CI: 0.86–0.99, P=0.026). PTE rates/100 patient-year were 748.9 for romiplostim and 1013.5 for placebo (RR 0.77, 95% CI: 0.66–1.05, P<0.001). HI-P rates were 36.5% for romiplostim (61 patients) and 3.6% for placebo (3 patients) (OR 15.6, 95% CI: 4.7–51.8, P<0.001). Including and following Week 4, median platelets were consistently higher with romiplostim treatment than with placebo (P<0.001). The overall 1-year Kaplan-Meier survival was 80% with romiplostim, 78% with placebo (HR 1.03, 95% CI: 0.54–1.95). Twenty-eight deaths occurred in the romiplostim group and 14 deaths occurred in the placebo group.

Forty percent of romiplostim patients and 27% of placebo patients experienced serious adverse events. Serious adverse events experienced by ≥5% of patients and occurring twice as much in romiplostim patients were pneumonia, pyrexia, thrombocytopenia, and atrial fibrillation. Increases in peripheral blasts >10% occurred more frequently with romiplostim (n=25, 15%) compared with placebo (n=3, 3.6%) but generally resolved after romiplostim discontinuation. Progression to AML arose in 6% of romiplostim patients and 2.4% of placebo patients through Week 58 (HR 2.54, 95% CI: 0.6–11.5). AML-free survival rates were similar between both groups (HR 1.13, 95% CI: 0.60–2.13).

There was a trend for more clinically significant bleeding events with placebo (P=0.13) than romiplostim, concluded Aristoteles Giagounidis, MD, PhD, of St. Johannes Hospital, Duisburg, Germany, and colleagues, indicating a suggested benefit of romiplostim in patients with MDS.