Lenalidomide-Epoetin Alfa Versus Lenalidomide Monotherapy in Myelodysplastic Syndromes Refractory to Recombinant Erythropoietin

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 ).

Navigating Myelodysplastic and Myelodysplastic/Myeloproliferative Overlap Syndromes

“…44 Lenalidomide may restore the sensitivity of primitive erythroid precursors to erythropoietin, as evidenced by the superior erythroid response rates observed from the combined use of lenalidomide with erythropoietin alfa compared with lenalidomide alone in a French study 45 and a recently published phase III U.S. intergroup study. 46…”

Dual pyroptotic biomarkers predict erythroid response in lower-risk non-del(5q) myelodysplastic syndromes treated with lenalidomide and recombinant erythropoietin

“…Symptomatic anemia is the most common manifestation in patients with lower risk myelodysplastic syndrome (MDS) that requires treatment. Although both recombinant erythropoietin and lenalidomide show modest effectiveness as single agents, combined treatment yields a significantly higher and durable erythroid response 1,2 . However, less than 50% of patients respond, therefore predictive biomarkers may assist in treatment selection for these patients.…”

“…Ineffective erythropoiesis is a hallmark of lower risk MDS, and NLRP3 inflammasome-directed pyroptosis serves as a common underlying driver licensed by both extrinsic proinflammatory cytokine milieu and intrinsic somatic mutations 3,4 . Lenalidomide with recombinant erythropoietin yields a higher erythroid response compared to single agent 1,2 . Our study showed that elevation of ASC specks, a specific and measurable surrogate of pyroptosis, was predictive of this response independently.…”

“…Other baseline parameters, including bone marrow blast percentage, karyotype classification and numbers of mutations, were also not significantly different between responders and non-responders (Table). In the multivariate analysis including ASC specks and serum erythropoietin, and adjusted for DNMT3A mutational status1,12 and treatment arm, both elevated ASC specks (odds ratio [OR] 4.963, 95% confidence interval [CI] 1.445-17.045, p = 0.011) and serum erythropoietin (OR 0.119, 95% CI 0.025-0.561, p = 0.007) were independently associated with HI-E. As expected, combined treatment remained significant (OR 6.535, 95% CI 1.622-26.334, p = 0.008). Of note, therewas no significant interaction between each of these two biomarkers and treatment arm.…”

Targeting ineffective hematopoiesis in myelodysplastic syndromes

“…11 Lenalidomide also has activity in lower-risk, non-del5q MDS (26%-30% response rates) patients, 12 with a recent randomized phase 3 trial demonstrating synergy with ESA, regardless of prior exposure, or high endogenous EPO levels (major erythroid response 28.3% vs. 11.5%). 13,14 SMAD2-SMAD3 signaling is constitutively increased in patients with lower-risk MDS and impacts erythroid maturation. Luspatercept is a recombinant fusion protein that traps GDF11 and activin ligands belonging to the TGF-beta superfamily, thereby decreasing SMAD2 and SMAD3 signaling, enabling late-stage erythroid maturation.…”