Eltrombopag for Post-Transplant Thrombocytopenia: Results of Phase II Randomized Double Blind Placebo Controlled Trial

Background: Delayed platelet recovery and secondary thrombocytopenia, defined as a drop in platelet count not due to disease relapse after initial platelet recovery, occur in 5-25% of patients after hematopoietic cell transplantation (HCT) and indicate adverse prognosis. Platelet transfusion to prevent bleeding remains a mainstay of therapy and role of thrombopoietic agents is not known. Eltrombopag, a non-peptide small molecule, thrombopoietin receptor agonist, is licensed for use in refractory ITP and aplastic anemia. In this phase II randomized double blind placebo controlled study, we investigated the safety and efficacy of eltrombopag for post HCT thrombocytopenia.

Methods: Patients 35 days or more after HCT were eligible for the study if they had 1) platelet count ≤ 20 x 109/l sustained for 7 days or if they were platelet transfusion dependent, and 2) neutrophil count ≥ 1.5 x 109/l with or without G-CSF in the previous 7 days. Patients were excluded if they had abnormal liver function tests (ALT ≥ 2.5 ULN, or Bilirubin >2mg/dl) or had prior venous thrombosis. Patients were randomized to receive placebo or eltrombopag using a Bayesian adaptive algorithm in which the probability of randomization to each arm was based upon the ongoing response rate. Eltrombopag was started at a dose of 50mgs and escalated every 2 weeks to 75mgs, 125 mgs and 150mgs if platelet count was < 50 x 109/l. The primary endpoint was platelet count at end of the treatment (8 weeks). A patient was considered responsive if platelet count was ≥ 30 x 109/l. The primary endpoint was evaluated by calculating the Bayesian posterior probability in each arm that the response rate was higher than the other arm.  A Beta (0.4, 1.6) prior distribution was assumed for each arm. Given the observed study data, the probability of response in each arm was calculated and the probability that Eltrombopag is superior was computed.

Results: Sixty patients were randomized to eltrombopag (n=42) or placebo (n=18) and received at least one dose of drug. 7 patients had an autograft and 53 patients had an allograft. Donor was related for 22 and unrelated for 31 patients. Stem cell source was peripheral blood in 36 patients, bone marrow in 23 patients and cord blood in 1 patient. There were no significant differences in patient characteristics between the 2 treatment arms.

The probability that the response rate in the Eltrombopag arm is superior to the response rate in the placebo arm was 0.75, given the observed data. The protocol required this probability to be > 0.975 to declare a winner; thus, the results are inconclusive. Fifteen (36%) of patients in eltrombopag arm responded compared to 5 (28%) of patients in placebo arm. A 95% credible interval for response in the Eltrombopag arm is 22% to 50%, and a 95% credible interval for response in the placebo arm is 11% to 48%. 37 patients completed all 8 weeks of therapy; however, all patients (n=60) who received at least one dose of study treatment were included in the intention to treat evaluation of this endpoint.

A secondary objective was to compare proportion of patients achieving a platelet count ≥ 50 x 109/l. Response rate was higher in the eltrombopag arm for this endpoint as well: 9 (21.4%) patients achieved success compared with 0 (0%) patients in the placebo arm (p=0.0466; Fisher’s exact test). OS, PFS, relapse rate, and non-relapse mortality were similar in two arms.

Conclusion: Eltrombopag improves platelet count in patients with post-transplant thrombocytopenia.