Luspatercept/Lenalidomide Combo Demonstrates Safety and Early Efficacy in Lower-Risk, Non-Del(5q) MDS

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The combination of lenalidomide (Revlimid) and luspatercept-aamt (Reblozyl) demonstrated safety, tolerability, and preliminary efficacy in patients with non-del(5q) myelodysplastic syndrome (MDS), according to data from a phase 1b trial (NCT04532936) presented at the 2024 ASH Annual Meeting.¹

Findings showed that at a median follow-up of 22.5 weeks, no dose-limiting toxicities (DLTs) were observed in treated patients (n = 12), and the maximum tolerated dose (MTD) was not reached.

Efficacy data showed that among evaluable patients (n = 10), 50% experienced hematologic improvement. The rates of hematologic improvement–erythroid (HI-E), red blood cell (RBC) transfusion independence, and HI-platelet were 40%, 30%, and 10%, respectively.

“The next step forward is to start to combine drugs for patients with lower-risk MDS, and that's what we've done with this trial.” lead study author, Mikkael A. Sekeres, MD, MS, said in an interview with OncLive^®.

Sekeres is a professor of medicine, chief of the Division of Hematology in the Leukemia Section at University of Miami Health System, Sylvester Comprehensive Cancer Center, in Florida,

Study Rational and Design

Both luspatercept and lenalidomide are approved as monotherapy within the MDS field. Luspatercept was initially approved by the FDA in April 2020 for the treatment of anemia failing an ESA and requiring 2 or more RBC units over 8 weeks in adult patients with very low- to intermediate-risk MDS with ring sideroblasts or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.² The indication for the agent was then expanded in August 2023 to include the treatment of anemia without prior erythropoiesis-stimulating agent (ESA) use in adult patients with very low– to intermediate-risk MDS who may require regular RBC transfusions.

Lenalidomide previously received FDA approval for transfusion-dependent anemia due to low- or intermediate-1-risk MDS associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities.3

“We wondered what would happen if we combined the drugs. Could [we] get a higher transfusion independence response rate than either drug alone? We initiated a phase 1b /2 trial to try to answer that question,” Sekeres said.

The phase 1b/2, multicenter study included patients with very low–, low-, or intermediate-risk MDS per Revised International Prognostic Scoring System (IPSS-R) criteria.¹ Patients could not harbor del(5q), and they also needed to be transfusion dependent, defined as receiving 2 packed RBC units over a 16-week period. Prior treatment with an ESA or a hypomethylating agent (HMA) was allowed; however, previous treatment with either lenalidomide or luspatercept was not permitted. An ECOG performance status of 0 to 2 was also necessary.

During phase 1b, 3 regimens were evaluated using different doses of lenalidomide. The agent was given at 2.5 mg per day (dose level 1), 5 mg per day (dose level 2), or 10 mg per day (dose level 3) once per day during each 21-day cycle. In all 3 cohorts, patients received luspatercept subcutaneously at a starting dose of 1.0 mg/kg on day 1 of each cycle. Dose titrations of luspatercept to 1.33 mg/kg and 1,75 mg/kg were allowed within each cohort based on insufficient response. Luspatercept was discontinued if no reduction in transfusion burden was observed after 9 weeks of treatment.

DLTs were defined as grade 3 or higher non-hematologic adverse effects (AEs) that did not resolve to grade 1 or lower within 21 days; or grade 4 neutropenia or thrombocytopenia that lasted more than 10 days during the first treatment cycle.

The primary objective of the phase 1b study was to determine the MTD and recommended phase 2 dose (RP2D). Secondary end points included safety, tolerability, and response assessment based on International Working Group criteria.

Baseline Patient Characteristics

The median age of the study population (n = 12) was 69 years (range, 49-84). Patients had low-risk (67%) or intermediate-risk (33%) disease according to IPSS-R criteria. Half of the patients had previously been treated with ESAs, and 33% had received HMAs.

Next-generation sequencing (NGS) revealed that 25% of patients had SF3B1 mutations; DNMT3A, TET2, ASXL1, CALR, U2AF1, NRAS, IDH2, and JAK2 alterations were each reported in 8% of patients. According to WHO classification, 25% of patients had MDS with ring sideroblasts, and 33% had MDS with multilineage dysplasia.

Baseline hematologic parameters included a median hemoglobin level of 8.3 g/dL (range, 8.2-9.5), a median absolute neutrophil count of 1.28 × 10⁹/L (range, 0.49-3.19), and a median platelet count of 247 × 10⁹/L (range, 97-510). Patients required a median of 4 units of packed RBC transfusions over 16 weeks (range, 2-15).

Safety Observations

“In the phase 1 study portion, the most common AEs we saw were drop in blood counts, [which is] very common in patients who have MDS. However, we actually didn't reach any DLTs,” Sekeres notes.

The most common hematologic AEs included decreased absolute neutrophil count (total events, n = 16), decreased platelet count (n = 9), and decreased hemoglobin (n = 6). Non-hematologic AEs reported included diarrhea (n = 5), muscle cramps (n = 4), fatigue (n = 3), and lung infection (n = 3).

Throughout the course of the study, 62 non-hematologic AEs were observed, including 39 at grade 1, 19 at grade 2 effects, and 4 at grade 3. Grade 3 AEs consisted of pneumonia (n = 2), agitation (n = 1), and a fall (n = 1). The most common non-hematologic AEs during this period were gastrointestinal or infectious in nature.

These findings led to the establishment of the RP2D of lenalidomide at 10 mg orally once per day and luspatercept at 1.0 mg/kg subcutaneously on day 1 of a 21-day cycle. Enrollment for the phase 2 arm of this trial is ongoing.

References

1. Sekeres MA, Carraway HE, Stone RM, et al. A Multicenter, Phase Ib/II Study That Combines Luspatercept and Lenalidomide (L2) in Lower-Risk, Non-Del(5q) Patients with Myelodysplastic Syndromes: Phase Ib Results. Blood. 2024;144:1821. doi:https://doi.org/10.1182/blood-2024-203965
2. Rebozyl. Prescribing information. May 2024. Accessed January 6, 2025. https://packageinserts.bms.com/pi/pi_reblozyl.pdf
3. Revlimid. Prescribing information. March 2023. Accessed January 6, 2025. https://packageinserts.bms.com/pi/pi_revlimid.pdf