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

Background: Standard, up-front monotherapy for lower-risk myelodysplastic syndromes/neoplasms (LR-MDS) associated with anemia includes erythropoiesis stimulating agents (ESAs). Additionally, luspatercept (Lusp), a modified form of the human activin receptor IIB linked to the human immunoglobulin G1, works on late-stage erythropoiesis and has been approved both for up-front treatment of MDS-associated anemia, and for MDS with ring sideroblasts (RS) following ESAs. Lenalidomide (Len), which degrades CK1 alpha and works through immunomodulatory effects and direct cytotoxicity, is approved to treat anemia of LR-MDS with the del(5q) cytogenetic abnormality, and is used off-label for LR-MDS without del(5q). The next frontier in treating LR-MDS is combination therapy.

Methods: This multicenter, Phase Ib/II trial combined Lusp and Len to treat anemia due to revised International Prognostic Scoring System (IPSS-R) very low, low, or intermediate risk (<5% blasts) non-del(5q) MDS. For the Phase Ib study portion, Len was given in escalating doses of 2.5 mg, 5 mg, and 10 mg PO daily of a 21-day cycle, in a traditional 3+3 design, until a maximum tolerated dose (MTD) was identified. Dose-limiting toxicity (DLT) was defined as non-hematologic events grade 3 or higher per NCI CTCAE version 5.0 criteria that did not resolve to grade 1 or lower within 21 days, or Grade 4 neutropenia or thrombocytopenia lasting >10 days, during the first treatment cycle. Lusp was given at a starting dose of 1.0 mg/kg SC on Day 1 of the 21-day cycle, with standard dose titration within each cohort for insufficient response (increases to 1.33 and 1.75mg/kg). Patients (pts) had to be transfusion-dependent, defined as receiving 2 units packed red blood cells (pRBC) over a 16-week period, and either treatment-naïve or following ESA or hypomethylating agent (HMA), but not previously treated with Len or Lusp. The primary endpoint of the Phase Ib trial portion was to determine the MTD and recommended Phase II dosing; secondary endpoints included safety, tolerability, and response per International Working Group criteria.

Results: Among 12 enrolled pts, the median age was 69 years (range, 49-84). Median ECOG performance status was 1 (range, 0-2), and 20% were female. IPSS-R categories included 67% Low and 33 % Intermediate risk; 50% were previously treated with ESAs, 33% with HMAs, and 33% naive. Molecular characteristics (n) included SF3B1 (3) and DNMT3A, TET2, ASXL1, CALR, U2AF1, NRAS, IDH2, and JAK2 (1 each). Three pts had MDS-RS and 4 had MDS with multilineage dysplasia. Baseline blood counts included a median WBC = 2.2/L (range 1.2-4.8); hemoglobin 8.3 g/dl (range, 8.2-9.5); platelet count 247/L (range 97-510); and absolute neutrophil count 1.28/L (range, 0.49-3.19). The median baseline pRBC transfusion need/16 wk was 4 (range, 2-15). There were no DLTs, and the MTD was not reached. During the DLT assessment period, 49 Grade 1 and 30 grade 2 adverse events (AEs) occurred. The most common hematologic AEs were decreased neutrophil count (n=16 instances), decreased platelet count (n=9), and anemia (n=6); non-hematologic AEs were diarrhea (n=5), muscle cramps (n=4), fatigue (n=3), and lung infection (n=3). With a median follow-up of 22.5 weeks on study (range, 9-30), 62 non-hematologic AEs occurred: 39 Grade 1, 19 grade 2, and 4 grade 3 or higher (2 pneumonia, 1 fall, and 1 agitation). The most common were gastrointestinal and infectious. Lusp was dose escalated for 8 patients, and Len was dose reduced (post-cycle 1) for 1 patient in the 5mg dosing cohort and 3 patients in the 10mg cohort. A total of 5 pts of 10 evaluable (50%) had a hematologic improvement (HI) response: 4 an erythroid HI (3 of whom achieved transfusion independence) and 1 a platelet HI. Responders had the following mutations: SF3B1 (1 pt), TET2 (1 pt), U2AF1/JAK2/IDH2 (1 pt), and no mutations (2 pts). The recommended Phase II dosing of Len + Lusp (L2) was Len 10 mg PO daily and Lusp 1.0 mg/kg SC on Day 1 of a 21-day cycle.

Conclusions: The combination of Len + Lusp (L2) was well-tolerated, and a recommended phase II dose was established, with that trial ongoing. The preliminary response rate appeared at least similar to either monotherapy.