Romiplostim in Thrombocytopenic Patients with Low- or Int-1- Risk MDS Results in Reduced Bleeding without Impacting Leukemic Progression: Final Follow-up Results from a Randomized, Double-Blind, Placebo-Controlled Study
Authors: Kantarjian Hagop , Fenaux Pierre , Sekeres Mikkael A. , Szer Jeffrey , Platzbecker Uwe , Kuendgen Andrea , Gaidano Gianluca , Wiktor-Jedrzejczak Wieslaw , Carpenter Nancy , Mehta Bhakti , Franklin Janet , Giagounidis Aristoteles 
Published: October 2019

Abstract

Background: Thrombocytopenia occurs in ~50% of patients with low/int-1 risk myelodysplastic syndrome (MDS) and is associated with reduced survival. In a placebo (PBO)-controlled study, 250 patients with MDS were randomized 2:1 to receive weekly romiplostim or PBO. In the original June 2011 analysis, romiplostim reduced clinically significant bleeding events [hazard ratio (HR) romiplostim vs PBO 0.83, 95% CI: 0.66−1.05, P = 0.13] and platelet transfusions (relative risk 0.77, 95% CI: 0.66−0.88, P<0.001) and increased IWG hematologic improvement platelets (HI-P) incidence (odds ratio 15.6, 95% CI: 4.7−51.8, P<0.001). Peripheral blast count increases >10% were more frequent with romiplostim (25/167, 15%) than PBO (3/83, 3.6%) and resolved after discontinuation in most cases. In February 2011, the DMC recommended that treatment with study drug be discontinued as 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 patients at risk for diagnosis of and treatment for AML. Patients were moved into long-term follow-up (LTFU). Previously reported (Giagounidis et al, Cancer 2014) 58-week incidence of AML was 6.0% (N = 10) for romiplostim and 4.9% for PBO (N = 4); HR 1.20 (95% CI: 0.38−3.84). This report provides final 5-year LTFU data.
Methods: Eligible patients were receiving only supportive care and had IPSS low/int-1 risk MDS and platelets 1) ≤20 × 109/L or 2) ≤50 × 109/L with a history of bleeding. Disease progression to AML was defined as 1) ≥20% blasts in bone marrow or peripheral blood after 4 weeks following discontinuation of romiplostim; 2) pathology consistent with leukemia; or 3) antileukemic treatment. Results are presented by treatment group.
Results: At baseline, median (Q1, Q3) age was 70 (61, 77) years, the majority (59%) of patients were male; 27.6% were IPSS low risk and 72.4% were int-1 risk. WHO classifications were RCMD: 67.6%, RAEB-1: 13.2%, MDS-U: 11.2%, RA: 4.4%, RCMD-RS: 2.4%, RARS: 0.8%, and RAEB-2: 0.4%. Of 250 patients in the study, 210 entered LTFU and 66 completed the 5 years of LTFU; median (Q1, Q3) follow-up was 27.5 (10.8, 58.7) months. Reasons for discontinuation (death, lost to follow-up, and consent withdrawal) during LTFU were similar in both groups. During the active study period and LTFU, death was reported in 93 (55.7%) patients in the romiplostim group and 45 (54.2%) patients in the PBO group (HR romiplostim vs PBO 1.03, 95% CI: 0.72−1.47) (Figure); mortality rates were greater in those with IPSS int-1 vs low risk for both groups (Table). AML was reported in 20 (11.9%) patients in the romiplostim group and 9 (11.0%) patients in the PBO group (HR 1.06, 95% CI: 0.48−2.33). The proportions of patients who either died or developed AML were 56.9% (N = 95) in the romiplostim group and 55.4% (N = 46) in the PBO group (HR for AML-free survival 1.04, 95% CI: 0.73−1.48) (Figure). Nearly half (N = 14, 48%) of the 29 AML cases occurred in patients who were RAEB-1 at screening (none RAEB-2), and 6 cases were diagnosed because of anti-AML treatment use alone (Table). In LTFU, patient-reported use of MDS therapy (eg, azacitidine or cyclosporine) was 42.8% (N = 59, 95% CI: 34.4%−51.5%) in the romiplostim group and 31.4% (N = 22, 95% CI: 20.9%−43.6%) in the PBO group. AML therapy (eg, chemotherapy) was used in 14 (10.2%) patients in the romiplostim group and 7 (10.0%) patients in the PBO group.
Conclusions: Following the decision in 2011 to stop study drug secondary to increased AML rates at that time and transient blasts increases, final 5-year LTFU HRs (romiplostim vs placebo) for death or progression to AML, respectively, are 1.03 (95% CI: 0.72−1.47) and 1.06 (95% CI: 0.48−2.33). In conclusion, romiplostim reduced bleeding events and platelet transfusions, with no increase in AML incidence or impact on survival.

Disclosures
Kantarjian: Amgen Inc.: Research Funding. 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; Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees. Szer:Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Australia: Consultancy, Honoraria; Amgen Inc.: 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; Shire: 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:Celgene Corporation: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Kuendgen:Celgene: Research Funding. Gaidano:Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wiktor-Jedrzejczak:Angelini: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Consultancy; Janssen-Cilag: Consultancy; Novartis: Consultancy, Research Funding; BMS: Research Funding; Sandoz: Consultancy; Amgen Inc.: Research Funding. Carpenter:Amgen Inc.: Employment, Equity Ownership. Mehta:Amgen Inc.: Employment, Equity Ownership. Franklin:Amgen Inc.: Employment, Equity Ownership. Giagounidis:Amgen Inc.: Consultancy, Honoraria.