Romiplostim (AMG531, Nplate^®) for Secondary Failure of Platelet Recovery After Allogeneic Stem-Cell Transplantation

Abstract 1994

Romiplostim (Rm), a protein that binds to and stimulates the thrombopoietin receptor, has been shown to increase and maintain platelet counts in splenectomised and non-splenectomised adult patients with chronic immune thrombocytopenic purpura (ITP), and few adverse events have been reported. Thrombocytopenia after allogeneic stem cell transplantation (allo-SCT) is a common complication which can sometimes be severe. All patients are thrombocytopenic until the primary recovery of platelet counts at engraftment, although some patients present with secondary failure of platelet recovery (SFPR) defined by the Seattle group as a decline of platelet counts below 20,000/μL for 7 consecutive days or requiring transfusion support after achieving sustained platelet counts ≥50,000/μL without transfusions for 7 consecutive days after allo-SCT. SFPR is associated with a greater number of complications and a worse outcome indicating that rapid correction of severe thrombocytopenia in these patients is essential.

We report on seven patients treated with Rm after allo-SCT for a SFPR not due to disease relapse. The first day of the 7 consecutive days when platelet counts were <20,000/μL was considered the day of SFPR onset. Our therapeutic strategy was to start Rm at 1μg/kg and to increase dose weekly by 1μg/kg until platelet count had reached 50,000/μL. The dose was then reduced as quickly as possible until discontinuation, providing platelet counts remained >50,000/μL, to avoid unnecessary Rm exposure.

Transplantations were performed between January 2009 and January 2011. The median age of the patients was 57 years (range, 25 to 60). There were 4 males and 3 females. Diseases were distributed as follow: acute myeloid leukemia (n=2), acute lymphoid leukemia (n=1), myelodysplastic syndrome (n=1), non-Hodgkin lymphoma (n=2), severe aplastic anemia (n=1). Conditioning regimes were reduced in 5 patients. Donors were siblings in 2 cases, matched unrelated in 4 cases and mismatched unrelated in 1 case (C mismatch). The sources of stem cells were peripheral blood in 4 patients and bone marrow in 3 patients. At the onset of SFPR, all patients had severe thrombocytopenia (<10,000/μL) that required transfusion support. At bone marrow aspiration, 2 patients had numerous megakaryocytes while they were rare in the other 4 patients. The median time between allo-SCT and onset of SFPR was 3 months (range, 2 to 18). The median time between onset of SFPR and start of Rm was 27 days (range, 7 to 61). Thrombocytopenia was corrected in all patients. There was a median time of 54 days (range, 24 to 84) between onset of Rm and the first day when platelet count was >50,000/μL. Median duration of treatment was 13 weeks (range, 4 to 16). Maximum dose ranged from 1 to 10μg/kg. Rm was well tolerated and no patient needed to discontinue drug treatment because of adverse events. Four patients developed SFPR within 2 months of developing acute GvHD II-IV. Another patient had an acute GvHD II-IV at 15 months before the onset of SFPR. He also had 2 episodes of CMV infection at 16 and 4 months before SFPR and 2 episodes of EBV infection at 12 and 1 month before SFPR. Moreover, the same patient developed bronchiolitis obliterans organizing pneumonia (BOOP) not due to infection at 1 month before SFPR. Another patient developed acute GvHD II-IV 6 months before SFPR. She also had 2 episodes of CMV infection at 5 and 3 months before the onset of SFPR. The last patient did not develop acute GvHD II-IV or chronic GvHD but had a CMV infection at 1 month before SFPR. Taken together, these observations underline the occurrence of SFPR shortly after episodes of acute GvHD II-IV, BOOP, EBV or CMV infections. At the last follow-up, one patient had died of a relapse of acute myeloid leukemia while others were alive and in remission without recurrence of SFPR after discontinuation of Rm.

We conclude that Rm can be a therapeutic option after allo-SCT for patients with severe thrombocytopenia caused by SFPR. However, these preliminary data need to be confirmed in larger studies with a longer follow-up time to improve assessment of efficacy and safety profiles within this setting. In the meantime, if Rm is prescribed, it seems reasonable to use it at the minimally effective dose and to avoid unnecessary prolonged exposure.