Efficacy and Safety of Luspatercept: a Study by Fondazione Italiana Sindromi Mielodisplastiche

Myelodysplastic syndromes (MDS) are a group of malignancies characterized by reduced differentiation and increased apoptosis of hematopoietic progenitor cells, leading to ineffective hematopoiesis. The incidence of MDS ranges from 1.5 to 4 cases per 100,000 individuals per year. Prognosis is determined by a number of factors, including age, cytogenetic abnormalities, and cytopenia as determined by the Revised International Prognostic Scoring System (IPSS-R), but also by the occurrence of molecular aberrations (eg, gene mutations) and red blood cell (RBC) transfusion dependence.

Treatment of MDS varies according to prognosis. Patients with low IPSS-R risk have a low probability of progression to acute myeloid leukemia (AML) and the treatment is aimed at controlling cytopenia and improving quality of life (QOL), whereas patients with high-risk disease have a shorter life expectancy and treatment is aimed at modifying the natural course of the disease.

Anemia is the most common disease feature, occurring in 80%-85% of low-risk patients, 40% of whom eventually become RBC transfusion-dependent (TD).

Besides lenalidomide, which is exclusively approved for patients with deletion of chromosome 5q, erythropoiesis-stimulating agents (ESAs) constitute the first option for patients with low risk disease. Patients who do not respond to ESAs have very limited options and ultimately require long-term RBC transfusions. Chronic transfusions lead to secondary iron overload and have a deleterious effect on the patient's QOL.

On April 26, 2019, Celgene Europe BV applied for a marketing authorization via the European Medicines Agency (EMA) centralized procedure for luspatercept (trade name Reblozyl). Luspatercept is a recombinant fusion protein that selectively binds to ligands belonging to the transforming growth factor-beta (TGF-beta) superfamily. Luspatercept binds to GDF11, GDF8, activin B, and other ligands. This binding leads to inhibition of Smad2/3 signaling, which is abnormally high in disease models of ineffective erythropoiesis such as MDS, resulting in erythroid maturation and differentiation.

The review of the benefit-risk balance was conducted by the Committee for Medicinal Products for Human Use (CHMP), and the positive opinion was issued on April 30, 2020. The indication approved in the EU is as follows: "Reblozyl is indicated for the treatment of adult patients with TD anemia due to very low-, low-, and intermediate-risk MDS with ring sideroblasts, who had an unsatisfactory response to or are ineligible for erythropoietin-based therapy.

The clinical development program for luspatercept in MDS consists of 3 clinical trials, including the phase 3, randomized, double-blind, placebo-controlled study ACE-536-MDS-001 (MEDALIST) and 2 supportive phase 2, open-label, single-arm trials (A536-03 and A536-05).

In the MEDALIST trial, adult patients with very low, low, or intermediate IPSS-R risk MDS with ring sideroblasts who required RBC transfusions were randomized 2:1 to luspatercept (1mg/kg) or placebo by the SC route every 3 weeks.16 In both treatment groups, best supportive care could be used when clinically indicated, including RBC transfusions or iron chelation therapy, but excluding ESAs or other MDS-directed agents. The primary endpoint of the trial was the proportion of subjects who were RBC transfusion-independent (RBC-TI) over any 56-day period from week 1 to week 24.

In the MEDALIST trial, 229 subjects very low, low or intermediate IPSS-R risk MDS with ring sideroblasts were randomized: 153 to luspatercept and 76 to placebo (ITT population). Forty-nine (21.4%) patients discontinued from the study, with no differences between arms. Patients' baseline characteristics and prior medication use were well balanced across treatment arms. The percentage of responders (RBC-TI during 56 d through week 24) was 37.91% versus 13.16% (P < 0.0001) for patients receiving luspatercept versus placebo, respectively (Table 1). When the assessment period was extended to 84 days, the proportion of responders was 33.33% versus 11.84% through week 48 and 28.10% versus 7.89% through week 24.

The safety database comprised 571 subjects who received luspatercept. The mean luspatercept treatment duration was 49 weeks (median 45.6). Treatment emergent adverse events (TEAEs) were documented in 95.3% of patients in the pooled luspatercept group, compared to 91.2% of patients in the placebo group. Incidence rates of serious TEAEs (23.8% versus 15.0%), grade ≥3 TEAEs (34.9% versus 25.9%) and TEAEs leading to permanent drug discontinuation (8.8% versus 3.6%) were higher in the pooled luspatercept group. In the MDS cohort, the most frequent TEAEs leading to discontinuation were progression to high-risk MDS, transformation to AML, general physical deterioration and sepsis. Fatal TEAEs were observed in 1.8% versus 2.6% of patients receiving luspatercept versus placebo. The most frequently reported TEAEs (≥15%) in the MDS group were fatigue, diarrhea, nausea, cough, dizziness, hypertension, peripheral edema, headache, viral upper respiratory tract infection, and back pain.

Overall, luspatercept significantly reduced red blood cell (RBC) transfusion requirements in patients with MDS with ring sideroblasts and had a generally manageable tolerability profile in clinical trials. Thus, luspatercept is an emerging treatment option in adults with transfusion-dependent anaemia due to MDS.

Despite that luspatercept is approved based on data of safety and efficacy from a large randomized clinical trial, the authors know that especially for human diseases arising in elderly people, features of subjects included in those randomized trials often do not reflect those of the population in which a therapy is intended to be used. Compliance to treatment and safety in clinical trials can also differ from real world settings. Consequently, in order to drive clinical decision-making process, data from randomized clinical trials should be integrated with evidence generated in a real world setting.

To date, no information is available on the efficacy and safety luspatercept in the treatment of MDS in real world populations. FiSIM (Fondazione Italiana Sindromi Mielodisplastiche) promotes a multicenter, retrospective observational study to collect information on the efficacy and safety of luspatercept in a real world Italian population of adult patients with transfusion-dependent anemia due to very low- and intermediate-risk MDS with ring sideroblasts, who had an unsatisfactory response to or are ineligible for erythropoietin-based therapy.