Romiplostim Improves Platelet Recovery after UCB Transplant

Abstract

Background Prolonged thrombocytopenia after hematopoietic stem cell transplant is a common complication, especially after umbilical cord blood transplant (UCBT). Romiplostim is a thrombopoietin receptor agonist that is FDA approved for chronic ITP. Its effect on platelet recovery after UCBT remains unknown. Objectives The primary objective of the study was to determine the maximum tolerated dose (MTD) of romiplostim in patients who failed to achieve platelet recovery by day +28 after UCBT. Secondary objectives were to determine if romiplostim influences the speed of platelet recovery, decreases the risk of thrombocytopenia related complications or affects the incidence of bone marrow fibrosis or relapse. Methods This was a single center dose escalation trial of weekly romiplostim in patients >18 years who failed to achieve an untransfused platelet count (PLT) of 20 × 109/L by day +28 after myeloablative (MA) or non-myeloablative (NMA) UCBT. A total of 20 patients were enrolled. Romiplostim was administered at the assigned dose as 6 weekly injections beginning by day +42 post UCBT with an end date by day +100. Four dose levels (4, 6, 8, and 10 mcg/kg/dose) were evaluated. There was no intra-patient dose escalation. The MTD of romiplostim was determined by the Continual Reassessment Method, with a goal to identify a dose level with desired toxicity rate of ≤ 20%. Historical controls were selected from our database based on age, gender, underlying disease, and transplant type (1:1 matching). Results Median age of the patients was 59.5 years and 40% were male. Ten patients had AML, 5 ALL, 3 MDS, 1 NHL and 1 MM. Two patients received 4, two 6, four 8 and the remaining 12 received 10 mcg/kg/dose. Only 5 patients completed the full 6 doses. Of the 15 patients who received less than 6 doses, 12 were due to a PLT>100, 2 due to PLT>400 (× 109/L), and 1 was due to the subject developed right upper extremity edema (no thrombosis). All romiplostim treated patients achieved platelet engraftment to 20 × 10^9/L at a median of 45 days post UCBT compared to 85% of controls at a median of 49 days (p=0.07). Similarly, 90% of romiplostim treated patients achieved platelet engraftment to 50 × 10^9/L at a median of 48 days compared to 70% of controls at a median of 52 days (p=0.04) (fig 1). Three patients experienced serious AEs requiring discontinuation of the drug: 2 had a PLT>400 × 109 /L and 1 developed right upper extremity edema. Bleeding episodes or transfusions improved with the use of the drug. All dose levels appear to be effective with low toxicity. Therefore, the MTD of romiplostim was 10mcg/kg/dose. There were no BM findings suggestive of increased fibrosis or relapse by day +100. Conclusion Our results indicate that romiplostim is safe and potentially effective therapy to improve platelet recovery after UCBT, with the MTD being 10mcg/kg/dose. Further studies in larger numbers of patients are needed to confirm these observations.