Treatment with Romiplostim, a Thrombopoietin-Receptor Agonist, in Thrombocytopenic Patients (Pts) with Low or Intermediate-1 (Int-1) Risk Myelodysplastic Syndrome (MDS): Updated Follow-up Results for Acute Myeloid Leukemia (AML) and Survival from a Randomized, Double-Blind, Placebo (PBO)-Controlled Study
Authors: Kantarjian Hagop M. , Mufti Ghulam , Fenaux Pierre , Sekeres Mikkael , Szer Jeffrey , Platzbecker Uwe , Kuendgen Andrea , Gaidano Gianluca , Wiktor-Jedrzejczak Wieslaw , Orejudos Amelia , Lopez Angela , Giagounidis Aristoteles 
Published: October 2019

Abstract
Background: Thrombocytopenia in MDS occurs in ~50% of pts with low/int-1 MDS and is associated with reduced survival; few therapies are available for these thrombocytopenic MDS pts. In a randomized PBO-controlled study, 250 pts with MDS were randomized 2:1 to receive weekly romiplostim or PBO. In the original June 2011 analysis, romiplostim reduced clinically significant bleeding events (HR romiplostim vs. PBO 0.83, 95% CI: 0.66, 1.05, P = 0.13) and platelet transfusions (RR 0.77, 95% CI: 0.66, 0.88, P <0.001), and increased IWG HI-P incidence (OR 15.6, 95% CI: 4.7, 51.8, P < 0.001). Increases in peripheral blast counts to >10% were more frequent with romiplostim (25/167, 15%) than PBO (3/83, 3.7%), and in most cases resolved after discontinuation. Due to concerns of the safety data monitoring committee that the potential benefit seen in the reduction of bleeding did not outweigh the potential risk for disease progression to AML and that transient increases in blast cell counts might put pts at risk for diagnosis of and treatment for AML, treatment with study drug was discontinued in February 2011. Pts were then moved into the long-term follow-up (LTFU) portion of the study. Previously reported (Giagounidis et al, Cancer 2014) 58-week incidence of AML was romiplostim: 6.0% (10 pts), PBO: 4.9% (4 pts), HR 1.20 (95% CI: 0.38, 3.84). This report provides additional data on LTFU of these pts up to March 2014, with a particular emphasis on AML incidence.
Methods: Eligible pts had IPSS low/int-1 MDS and platelets 1) ≤20x109/L or 2) ≤50x109/L with a history of bleeding, and were receiving only supportive care. Disease progression to AML was defined as 1) ≥20% blasts in the bone marrow or peripheral blood after 4 weeks following discontinuation of romiplostim, 2) pathology consistent with leukemia including chloroma or leukemia cutis, or 3) anti-leukemic treatment initiation. Results are presented by treatment group.
Results: Of 250 pts in the study, 210 entered LTFU, and 83 of these pts remained on study as of March 2014; the median (Q1, Q3) follow-up was 27.5 (10.8, 41.2) months. Reasons for discontinuation during LTFU were similar in the romiplostim and PBO groups and included death, lost to follow-up, and withdrawal of consent. During the active study period or during LTFU, death was reported in 50.9% (N = 85) of pts in the romiplostim group and 48.2% (N = 40) of pts in the PBO group (HR romiplostim vs. PBO 1.04, 95% CI: 0.71, 1.52) (Figure); mortality rates were greater in those with int-1 vs. low IPSS status for both the PBO and romiplostim groups (Table 1). AML was reported in 11.9% (N = 20) of pts in the romiplostim group and 9.8% (N = 8) of pts in the PBO group (HR 1.21, 95% CI: 0.53, 2.76). The proportions of pts who either died or developed AML were 52.7% (N = 88) in the romiplostim group and 48.2% (N = 40) in the PBO group (HR 1.10, 95% CI: 0.75, 1.60) (Figure). Fourteen of the 28 AML cases occurred in pts who were RAEB-1 at screening (none were RAEB-2) and 5 cases were diagnosed due to anti-AML treatment use alone (Table 2). In LTFU, the rate of pt-reported use of MDS therapy (e.g., azacitidine or cyclosporine) in the romiplostim group was 42.8% (N = 59, 95% CI: 34.4%, 51.5%) and 28.2% (N = 20, 95% CI: 18.1%, 40.1%) in the PBO group. Reported use of AML therapy (e.g., chemotherapy) occurred at a rate of 10.2% (N = 14) in the romiplostim group and 8.5% (N = 6) in the PBO group.
Conclusion:Following the 2011 decision to stop study drug, results have been updated with more observational time on study. Specifically, the HRs for death or progression to AML (romiplostim vs. PBO) are 1.04 (95% CI: 0.71, 1.52) and 1.21 (95% CI: 0.53, 2.76), respectively, compared with 2013 HRs of 1.04 (95% CI: 0.70, 1.54) and 1.14 (95% CI: 0.49, 2.62), respectively. As LTFU continues, additional data will be evaluated. Safety concerns regarding risk of disease progression to AML are still being investigated.
Table 1: Survival by Baseline IPSS n (%) RomiplostimN = 167 PBON = 83 Low 14/46 (30.4%) 3/23 (13.0%) 95% CI (%) 17.7, 45.8 2.8, 33.6 Int-1 71/121 (58.7%) 37/60 (61.7%) 95% CI (%) 49.4, 67.6 48.2, 73.9
Table 2: Progression to AML to Date Study-defined AML, n (%) RomiplostimN = 20 PBON = 8 TotalN = 28 Baseline WHO classification RAEB-1/2 11 (55%) 3 (37.5%) 14 (50%) Non-RAEB 9 (45%) 5 (62.5%) 14 (50%) AML diagnosis by Bone marrow/peripheral blast >20% 17 (85%) 6 (75%) 23 (82.1%) Anti-AML therapy alone 3 (15%) 2 (25%) 5 (17.9%)
Figure
Figure 1 Figure 1.

Disclosures
Kantarjian: Amgen Inc.: Research Funding. Off Label Use: Romiplostim is indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. The use of romiplostim in myelodysplastic syndromes is under investigation.. Mufti:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Fenaux:Amgen Inc.: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees. Szer:Sandoz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Platzbecker:Amgen Inc.: Honoraria. Kuendgen:Celgene: Research Funding. Gaidano:Amgen Inc.: Consultancy, Honoraria. Wiktor-Jedrzejczak:Amgen Inc.: Research Funding. Orejudos:Amgen Inc.: Consultancy. Lopez:Amgen Inc.: Employment, Equity Ownership. Giagounidis:Amgen Inc.: Consultancy, Honoraria.