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Lenalidomide-Epoetin Alfa Versus Lenalidomide Monotherapy in Myelodysplastic Syndromes Refractory to Recombinant Erythropoietin
List AF, Sun Z, Verma A, Bennett JM, Komrokji RS, McGraw K, Maciejewski J, Altman JK, Cheema PS, Claxton DF, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2021;:Jco2001691
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Abstract
PURPOSE Impaired response to erythropoietin underlies ineffective erythropoiesis and anemia in myelodysplastic syndromes (MDS). We investigated whether treatment with lenalidomide (LEN), which augments erythropoietin receptor signaling in vitro, can restore and improve hemoglobin response to epoetin (EPO) alfa in patients with lower-risk, non-del(5q) MDS who have anemia that is refractory to or have low probability of benefit from treatment with recombinant erythropoietin. METHODS In a phase III, US intergroup trial, we randomly assigned patients to receive either LEN and EPO alfa or LEN alone following stratification by serum erythropoietin concentration and prior erythropoietin treatment. RESULTS A total of 195 evaluable patients were randomly assigned: 99 patients to the LEN-EPO alfa cohort and 96 to LEN alone. After four cycles of treatment, the primary end point of major erythroid response (MER) was significantly higher (28.3%) with the combination compared with LEN alone (11.5%) (P = .004). Among 136 patients who completed 16 weeks of study treatment, 38.9% and 15.6% achieved MER, respectively (P = .004). Additionally, minor erythroid response was achieved in 18.2% and 20.8% of patients, for an overall erythroid response rate of 46.5% versus 32.3%. Among LEN nonresponders, 38 crossed over to the addition of EPO alfa with 10 patients (26.3%) achieving a MER. Responses to the combined treatment were highly durable with a median MER duration of 23.8 months compared with 13 months with LEN alone. CONCLUSION LEN restores sensitivity to recombinant erythropoietin in growth factor-insensitive, lower-risk, non-del(5q) MDS, to yield a significantly higher rate and duration of MER compared with LEN alone (funded by the National Cancer Institute; E2905 ClinicalTrials.gov identifier: NCT02048813).
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Azacitidine with or without eltrombopag for first-line treatment of intermediate- or high-risk MDS with thrombocytopenia
Dickinson M, Cherif H, Fenaux P, Mittelman M, Verma A, Portella MSO, Burgess P, Ramos PM, Choi J, Platzbecker U
Blood. 2018;132((25):):2629-2638.
Abstract
Azacitidine treatment for (MDS) generally exacerbates thrombocytopenia during the first treatment cycles. SUPPORT, a Phase III, randomized, double-blind, placebo-controlled study (NCT02158936), investigated the platelet supportive effects of eltrombopag given concomitantly with azacitidine. IPSS intermediate-1, intermediate-2 or high-risk MDS patients with baseline platelets <75x10(9)/L were randomized 1:1 to eltrombopag (starting 200 mg/day [East Asians: 100 mg/day], maximum 300 mg/day [East Asians: 150 mg/day]) or placebo, plus azacitidine (75 mg/m(2) sc once daily for 7 days, every 28 days). Primary endpoint was the proportion of patients platelet transfusion-free during cycles 1-4 of azacitidine therapy. Based on planned interim analyses, an independent data monitoring committee recommended stopping the study prematurely as efficacy outcomes crossed the predefined futility threshold, and for safety reasons. At final termination, 28/179 (16%) eltrombopag and 55/177 (31%) placebo patients met the primary endpoint (OR 0.37; 95%CI 0.21, 0.65; two-sided P=0.001). Overall response (IWG criteria; complete, marrow or partial response) occurred in 20% and 35% of eltrombopag and placebo patients, respectively, by investigator assessment (OR 0.51; 95%CI 0.30, 0.86; nominal P=0.005). There was no difference in hematologic improvement in any cell lineage between the two arms. There was no improvement in overall survival (HR 1.42; 95%CI 0.97, 2.08; nominal P=0.164) or progression-free survival (HR 1.47; 95%CI 1.05, 2.07; nominal P=0.060). AEs with greater occurrence (≥10%) in the eltrombopag versus placebo arm were febrile neutropenia and diarrhea. Compared with azacitidine alone, eltrombopag plus azacitidine worsened platelet recovery, with lower response rates and a trend toward increased progression to AML.