Real-Life Experience of Luspatercept in Transfusion-Dependent Lower-Risk Myelodysplastic Syndrome Patients

Introduction. Luspatercept has been recently approved for the treatment of red blood cell (RBC) transfusion-dependent (TD) Lower-Risk (LR) Myelodysplastic Syndrome (MDS) patients and can be administered either in the frontline or after erythropoietin failure. Our aim is to report its efficacy and safety in this study population in the everyday clinical practice using the well-defined IWG 2018 criteria for hematological response.

Methods. We retrospectively studied LR, TD MDS patients from 15 Greek and 2 Turkish sites since October 2020. Transfusion burden was defined as high (HTB), intermediate (ITB) and low (LTB) if they had received ≥8, 3-7 or 1-2 RBC transfusions in the last 16 weeks before luspatercept onset respectively. Response was defined as transfusion independence (TI) for at least 8 weeks. Therefore, date of response was set at 8 weeks after the date of last recorded transfusion or after the date of luspatercept onset, if no more RBC transfusions were administered afterwards. If relapses were noted before the completion of 16 weeks since these timepoints, those responses were not considered meaningful and were excluded. All variables were reported as median (5-95% range). Fisher's exact test and Wilcoxon signed-rank test were performed for comparison of discrete and continuous variables respectively and the Kaplan-Meier method with log-rank test was used for time-to-event data.

Results. A total of 98 patients, 59 male and 39 female, aged 75 ± 8 years were studied. 80 patients had bone marrow ring sideroblasts (RS) and 18 did not. In addition, 95 patients had prior erythropoietin failure and 3 were erythropoietin naive. There were 48 HTB, 37 ITB and 13 LTB patients. Out of 54 patients with available molecular results, 39 were SF3B1 positive and 15 were SF3B1 negative. 74 patients received maximum luspatercept dose (1.75 mg/kg), 12 received intermediate dose (1.33 mg/kg) and 12 received minimum dose (1 mg/kg). Median number of luspatercept doses was 14 (5-95% range: 4- 54). Median follow-up time was 13.1 (4.2-39,8) months and 20 deaths were observed within this time period. During follow-up, 57 patients stopped treatment, 8 due to adverse events (2 due to musculoskeletal pain, and the rest due to vertigo, hypertension, orthostatic hypotension, soft tissue infections, bleeding diathesis and one undetermined case), 8 because of death unrelated to treatment, 2 proceeded to transplantation and 36 stopped due to inadequate response. Notably, 3 patients stopped because of persistent hemoglobin levels>11g/dL.

Out of 98 patients, 42 responded to treatment, 25% in the HTB, 57% in the ITB and 69% in the LTB group respectively (p=0.002). All LTB who became TI also exhibited >1,5g/dL increase in hemoglobin. There was 48.7% response in the SF3B1 positive vs 20% response in the SF3B1 negative group (p=0.051). HTB remained significant after controlling for SF3B1 status (Mantel-Haenszel p=0.002). On the other hand, there was no difference in response in the non-RS group (33,3%) compared with the RS group (45%, p=0.366). 29 and 33 patients who responded had ferritin and lymphocyte levels available upon response respectively. There was a significant decrease in ferritin upon response vs baseline (691 (52, 4375) vs 880 (93, 6291) ng/dL, p=0.008) and a significant increase in lymphocytes (1700 (748, 3902) vs 1635 (453, 2972) cells/uL p=0.05). For the 42 responders, time to response was 14.8 (8, 30) weeks and duration of response was 44.9 (4.3, 170.4) weeks at the time of data collection. 10 out of 42 patients lost response after having experienced 59 (10.3- 142) weeks of TI. Overall, patients who achieved response had better chances of survival (log-rank p=0.048).

Conclusions. Luspatercept is tolerable and effective in the treatment of LR-TD MDS patients. Response depends mainly on transfusion burden at baseline and the presence of SF3B1 mutations. Most responses occur within the first six months of treatment and they are long lasting. Response to luspatercept treatment favorably affects overall survival in TD LR MDS patients.

Gavriilaki:AstraZeneca Pharmaceuticals: Honoraria; Omeros Pharmaceuticals: Honoraria; Sanofi Pharmaceuticals: Honoraria; Sobi Pharmaceuticals: Honoraria; Jazz Pharmaceuticals: Research Funding. Christoulas:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas: Research Funding; Genesis Pharma: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Janssen-Cilag: Research Funding, Speakers Bureau; Laboratories SMB SA: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Sandoz: Speakers Bureau; Takeda: Speakers Bureau. Pappa:Celgene: Research Funding; Janssen: Honoraria, Research Funding; Genesis Pharma: Honoraria; Roche: Honoraria; Servier: Honoraria; Novartis: Honoraria; Gilead: Honoraria; BMS: Honoraria; AstraZeneca: Honoraria; GSK: Honoraria; Amgen: Honoraria; Sobi: Honoraria; Pfizer: Honoraria; Abbvie: Honoraria, Research Funding.