AUTHORS
Mikkael A. Sekeres, MD, Hetty Carraway, MD, MBA2, Isildinha Reis3, Yazan F. Madanat, MD4, Richard Stone, MD5, Yolanda P. Davis, CCRP6, Rami Komrokji, MD7, Sangeetha Venugopal, MD, MS8, Namrata Sonia Chandhok I, MD9, Jibran Durrani, MD10, Terrence Bradley, MD11, Justin Taylor, MD12, Anastasia Santiago, NP13, Justin M Watts, MD14, Amy DeZern, MD, MHS15
AFFILIATIONS
1 Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, United States
2 Cleveland Clinic, Cleveland, Ohio, United States
3 Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, United States
4 UT Southwestern Medical Center, Dallas, Texas, United States
5 Dana-Farber Cancer Institute, Boston, Massachusetts, United States
6 Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, United States
7 Moffitt Cancer Center, Tampa, Florida, United States
8 Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, United States
9 Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, United States
10 Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, United States
11 Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, United States
12 Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, United States
13 Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, United States
14 Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, United States
15 Johns Hopkins University, Baltimore, Maryland, United States
ABSTRACT
Background: Standard, up-front monotherapy for lower-risk myelodysplastic syndromes (LR-MDS) associated with anemia includes erythropoiesis stimulating agents (ESAs) or luspatercept (Lusp), a modified form of the human activin receptor IIB linked to the human immunoglobulin G1, which works on late-stage erythropoiesis and has also been approved for MDS with ring sideroblasts (RS) following ESAs. Lenalidomide (Len) degrades CK1 alpha and works through immunomodulatory mechanisms, and is approved to treat anemia of LR-MDS with the del(5q) cytogenetic abnormality, though is used off-label for LR-MDS without del(5q). Whether combination therapy can improve on responses from either drug alone remains to be shown.
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, which has already been reported (Sekeres et al. ASH 2024), 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 recommended Phase II (RP2D) 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 II portion was response per 2006 International Working Group criteria.
Results: Of 21 total patients, the median age was 69 years (range, 49-88), 20% were female, and 38% were Hispanic. ECOG performance status was 0, 1, and 2 in 6 (28.6%), 13 (61.9%, and 2 (9.5%) patients, respectively. IPSS-R categories included 12 (57.1%) Low and 9 (42.9%) Intermediate risk; 15 pts (71.4%) were previously treated: 7 (33.3%) with ESAs, 3 (14.3%) with HMAs, and 5 (23.8%) with HMAs + ESAs. Baseline molecular characteristics (n) included ASXL1 (8), TET2 (8), SF3B1 (5), SRSF2 (3), U2AF1 (3), DNMT3A (2), EP300 (2), EZH2 (2), JAK2 V617F (2), and ATM, BCOR, CALR, ETV6, FLT3, IDH2, KMT2D, KRAS, NRAS (1 each). Ten pts had MDS-RS, 1 MDS/unclassifiable, and 10 had MDS with multilineage dysplasia. Baseline blood counts included a median WBC = 3.9/L (range 0.7-14.6); hemoglobin 8.1 g/dl (range, 5.9-10.3); platelet (plt) count 143/L (range 25-870); and absolute neutrophil count 2.38/L (range, 0.14-12.5). The median baseline pRBC transfusion need/16 wk was 3 (range, 1-16). During the phase 1b study, 3 pts were treated at Len 2.5mg, 3 at 5mg, and 3 pts at Len 10mg, which was the RPTD; there were no DLTs, though 16 Grade 1, 7 grade 2, and 1 non-heme grade 3 adverse events (AEs) occurred. Among all 21 pts, there were 31 grade >3 non-hematologic AEs, the most common being GI hemorrhage (3) and Hypertension (3). The most common hematological AE was decreased plt counts. Lusp was dose escalated for 8 pts, and Len was dose reduced (post-cycle 1) for 1 pt in the 5mg dosing cohort and 3 pts in the 10mg cohort. A total of 8 pts of 21 evaluable (38%) responded: 1 trilineage, 1 bilineage, and 6 hematologic improvement-erythroid; 6 achieved pRBC transfusion independence. Among the 8 responders, 5 were treated previously with HMA and 3 with ESA; mutations in responders (n) included SF3B1 (3), TET2 (3), SRSF2 (2), JAK2 (2), and U2AF1, IDH2 (1). Among non-responders, the most common mutations were ASXL1 (8) and TET2 (8). The 36-month survival rate was 77.3% (95%CI 51.9 -91.3%).
Conclusions: The combination of Len + Lusp (L2) was well-tolerated with a recommended phase II dose of LEN 10mg daily established. Response rates appeared at least similar to either monotherapy in the second- or third-line setting for this heavily pre-treated cohort.
DISCLOSURES
Mikkael A. Sekeres, MD: Takeda - Consultancy (Includes expert testimony); Geron - Consultancy (Includes expert testimony); BMS - Consultancy (Includes expert testimony); Agios - Consultancy (Includes expert testimony)