Conference Coverage

Adding epoetin alfa to lenalidomide boosted myelodysplastic syndrome responses

 

Key clinical point: Dual therapy with lenalidomide and epoetin alfa was more effective than lenalidomide monotherapy in patients with erythropoietin-refractory, lower-risk, non-del(5q) myelodysplastic syndrome.

Major finding: After 16 weeks of treatment, 33% of patients who received both agents met International Working Group 2000 criteria for major erythroid response, compared with 14% of patients receiving lenalidomide monotherapy (P = .03).

Data source: An interim analysis of 163 patients in the phase III ECOG-ACRIN E2905 Intergroup Study.

Disclosures: The National Institutes of Health supported the study. Dr. List had no relevant financial disclosures.


 

– Dual therapy with lenalidomide and epoetin alfa was safe and led to freedom from transfusion significantly more often than lenalidomide alone in patients with erythropoietin-refractory, lower-risk, non-del(5q) myelodysplastic syndromes, according to a randomized phase III head-to-head trial.

After 16 weeks of treatment, 33% of patients who received both lenalidomide and epoetin alfa met International Working Group 2000 criteria for major erythroid response, compared with only 14% of patients receiving lenalidomide monotherapy (P = .03), Alan F. List, MD, reported at the annual meeting of the American Society of Hematology.

Dr. Alan F. List H. Lee Moffitt Cancer Center
Dr. Alan F. List
Combination therapy also worked longer – median duration of response was 25 months, versus 13 months for lenalidomide only, said Dr. List of H. Lee Moffitt Cancer Center and Research Institute in Tampa. These results illustrate the power of lenalidomide to restore sensitivity to epoetin alfa in patients with lower-risk, non-del(5q) myelodysplastic syndrome (MDS), he emphasized.

Recombinant human erythropoietin improves anemia in some cases of MDS, but salvage options are limited. “Cytokine therapy is generally ineffective in patients with high transfusion burden or elevated serum erythropoietin level,” Dr. List said.

Lenalidomide (Revlimid) promotes the in vitro expansion of primitive erythroid precursors, and in a recent phase III, placebo-controlled trial, the immunomodulator improved erythropoiesis in about 25% of lower-risk, non-del(5q) MDS patients who were azanucleoside-naïve and transfusion-dependent, with effects lasting about 8 months. In another pilot study, adding epoetin alfa to lenalidomide induced erythroid responses in 28% of MDS patients who were not responding to lenalidomide alone. “This suggests that lenalidomide overcomes resistance and augments response to recombinant human erythropoietin,” Dr. List explained.

For their phase III trial, he and his associates randomly assigned erythropoietin-refractory, lower-risk, non-del(5q) MDS patients with hemoglobin levels under 9.5 g/dL to receive lenalidomide (10 mg per day for 21 days every 28 days) with or without epoetin alfa (weekly dose, 60,000 units subcutaneously). A total of 14% of patients had previously received azanucleoside therapy, about 92% had received erythropoietic stimulating agents, and median serum erythropoietin levels were 167 and 143 mU per mL in the monotherapy and dual therapy arms, respectively.

In accordance with International Working Group 2000 criteria, the researchers defined major erythroid response as transfusion independence for least 8 consecutive weeks, with at least a 1 g/dL increase in hemoglobin levels if patients were transfusion-dependent at baseline, and at least a 2 g/dL rise in hemoglobin if they were transfusion-independent.

In an interim analysis of 163 patients, 26% of the dual therapy group and 11% of lenalidomide-only patients met this primary endpoint (P = .02). These results met predefined criteria for stopping the study, after which 34 lenalidomide nonresponders crossed over to dual therapy. In all, 21% of these patients also had a major erythroid response, Dr. List said.

A multivariable analysis that included disease duration, International Prognostic Scoring System low versus intermediate-1 risk status, baseline erythropoietin level, and prior azanucleoside exposure showed that only dual lenalidomide–epoetin alfa therapy predicted major erythroid response. Specifically, dual therapy increased the odds of this outcome by about 63% when compared with lenalidomide monotherapy (P = .03).

Secondary analyses linked major erythroid response to having more low than high molecular weight CD45 isoform. In fact, the median ratio of high to low molecular weight CD45 was 1.5 among responders and 4.2 among nonresponders (P = .04) This finding fits the hypothesis that larger CD45 isoforms keep lenalidomide from enhancing erythropoietin receptor signaling, Dr. List said. Indeed, rates of major erythroid response to lenalidomide–epoetin alfa therapy were 73% when patients had a low isoform ratio, but were only 18% when they had a high isoform ratio (P = .03). The CD45 isoform ratio distinguished responders from nonresponders with a sensitivity and specificity of 80% and 75%, respectively, Dr. List said.

Grade 3 or higher nonhematologic events affected about a quarter of patients in each arm, and rates of individual events were similar. The most common serious adverse event was fatigue (5% of patients), followed by elevated serum creatinine (3.7%). About 10% of patients in each arm died while on study.

The National Institutes of Health supported the study. Dr. List had no relevant financial disclosures.

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