Activation of the erythroid K-Cl cotransporter Kcc1 enhances sickle cell disease pathology in a humanized mouse model

Background : Thrombocytopenia occurs in ~50% of pts with low/int-1 MDS and is associated with reduced survival; few therapies are available for thrombocytopenic MDS pts. In a 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 P 10% were more frequent with romiplostim (25/167, 15%) than PBO (3/83, 3.7%) and resolved after discontinuation in most cases. In February 2011, the data monitoring committee recommended that treatment with study drug be discontinued over safety concerns 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. 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 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 additional data on LTFU of these pts through January 2015, with emphasis on AML incidence. Methods : Eligible pts had IPSS low/int-1 MDS and platelets 1) ≤20 × 10 9 /L or 2) ≤50 × 10 9 /L with a history of bleeding and were receiving only supportive care. 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, including chloroma or leukemia cutis; or 3) antileukemic treatment initiation. Results are presented by treatment group. Results : Of 250 pts in the study, 210 entered LTFU and 71 of these pts remained on study as of January 2015; median (Q1, Q3) follow-up was 27.5 (10.8, 50.2) months. Reasons for discontinuation (death, lost to follow-up, and consent withdrawal) during LTFU were similar in the romiplostim and PBO groups. During the active study period or during LTFU, death was reported in 89 (53.3%) pts in the romiplostim group and 44 (53.0%) pts in the PBO group (HR romiplostim vs PBO 1.01, 95% CI: 0.70-1.45) (Figure 1A) ; mortality rates were greater in those with int-1 vs low IPSS status for both groups (Table 1) . AML was reported in 19 (11.3%) pts in the romiplostim group and 9 (11.0%) pts in the PBO group (HR 1.02, 95% CI: 0.46-2.27). The proportions of pts who either died or developed AML were 54.5% (n=91) in the romiplostim group and 54.2% (n=45) in the PBO group (HR for AML-free survival 1.03, 95% CI: 0.72-1.47) (Figure 1B) . One half (n=14, 50%) of the 28 AML cases occurred in pts who were RAEB-1 at screening (none were RAEB-2), and 5 cases were diagnosed because of anti-AML treatment use alone (Table 2) . In LTFU, pt-reported use of MDS therapy (eg, 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. AML therapy (eg, chemotherapy) was used in 13 (9.5%) patients in the romiplostim group and 7 (9.9%) patients in the PBO group. Conclusions: Following the decision in 2011 to stop study drug, LTFU results have been updated with more observational time on study. Specifically, the 2015 HRs (romiplostim vs PBO) for death or progression to AML, respectively, are 1.01 (95% CI: 0.70-1.45) and 1.02 (95% CI: 0.46-2.27), compared with 2014 HRs of 1.04 (95% CI: 0.71-1.52) and 1.21 (95% CI: 0.53-2.76). Risks of disease progression to AML continue to be investigated. A final data analysis will be completed next year. Disclosures Off Label Use: Romiplostim is indicated for use in adults with chronic immune thrombocytopenia who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. The use of romiplostim in MDS is investigational.. Mufti: GlaxoSmithKline: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Fenaux: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Sekeres: TetraLogic: Membership on an entity9s Board of Directors or advisory committees; Amgen: Membership on an entity9s Board of Directors or advisory committees; Celgene Corporation: Membership on an entity9s Board of Directors or advisory committees. Szer: Pfizer: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Alexion: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Alexion: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Alexion Australia: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Platzbecker: Novartis: Honoraria; Celgene: Honoraria; Amgen, Inc.: Honoraria; GlaxoSmithKline: Honoraria, Research Funding. Gaidano: Amgen: Honoraria, Other: Advisory boards; Novartis: Honoraria, Other: Advisory boards; GlaxoSmithKline: Honoraria, Other: Advisory boards; Celgene: Research Funding; Morphosys: Honoraria, Other: Advisory boards; Roche: Honoraria, Other: Advisory boards; Janssen: Honoraria, Other: Advisory boards; Karyopharm: Honoraria, Other: Advisory boards. Wiktor-Jedrzejczak: Roche: Other: Advisory Board, Research Funding; Onconova: Other: Advisory Board; Pfizer: Other: Advisory Board; Amgen, Inc.: Research Funding; Novartis: Research Funding; Jansen: Other: Advisory Board; Celgene: Other: Advisory Board. Franklin: Amgen, Inc.: Employment, Other: shareholder.