Clinical trial NCT05520749: Efficacy and Safety of Luspatercept: a Study by Fondazione Italiana Sindromi Mielodisplastiche
Official title: Efficacy and Safety of Luspatercept in Adult Patients with Transfusion-dependent Anemia Due to Very Low-, Low- and Intermediate-risk (IPSS-R) Myelodysplastic Syndrome with Ring Sideroblasts: a Retrospective Multicenter Study by FISiM-ETS
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Myeloid Dysplasia
Keywords: Luspatercept safety
Luspatercept efficacy
Real World Study
Lead sponsor: Fondazione Italiana Sindromi Mielodisplastiche-ETS
Sponsor class: OTHER
Collaborators: name: Istituto Clinico Humanitas
First posted: 2022-08-30
Enrollment: 215
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: All patients treated with luspatercept in Italy between November 2020 and January 2022 will be included in this study (i.e., around 215 subjects).

Brief summary: Myelodysplastic syndromes (MDS) are a group of malignancies characterized by reduced differentiation and increased apoptosis of hematopoietic progenitor cells, leading to ineffective hematopoiesis. 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). Anemia is the most common disease feature, occurring in 80%-85% of low-risk patients, 40% of whom eventually become RBC transfusion-dependent (TD).

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.

Luspatercept is now approved 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.

FISiM (Fondazione Italiana Sindromi Mielodidplastiche) 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

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

Adult patients (i.e. aged \>=18 years) with diagnosis of MDS according to WHO 2016 classification that met IPSS-R criteria for very low, low, or intermediate-risk MDS along with the following additional criteria:

* Ring Sideroblasts (RS) ≥15% of erythroid precursors in bone marrow in the absence of SF3B1 mutation, or ≥5% in the presence of SF3B1 mutation;
* Bone marrow blasts \<5%;
* Peripheral white blood cell count \<13,000/μL;
* ECOG PS 0-2;
* Refractory or intolerant to, or ineligible for prior ESA therapy.
* Required RBC transfusions per the following criteria:
* Mean RBC transfusion requirement ≥2 units/8 weeks in the 16 weeks before the start of luspatercept treatment
* No consecutive 56-day period free from RBCTs in the 16 weeks before the start of luspatercept treatment
* Treatment with luspatercept

Exclusion Criteria:

Any prior treatment with the following therapies:

* Prior therapy with disease modifying agents for MDS including immunomodulatory drugs (eg, lenalidomide), hypomethylating agents (eg, azacitidine or decitabine), and immunosuppressive therapy.
* Presence of the following conditions:
* Pregnancy
* The following blood and laboratory parameters: ANC \<500/μL and Platelets \<50,000/μL

Primary outcomes:
measure: Transfusion independence for 8 weeks or longer during weeks 1 through 24
timeFrame: From week 1 through week 24 of treatment
Secondary outcomes:
measure: Transfusion independence for 12 weeks or longer, assessed during weeks 1 through 24
timeFrame: From Week 1 through Week 24 of treatment
measure: Transfusion independence for 12 weeks or longer, assessed during weeks 1 through 48
timeFrame: From Week 1 through Week 48 of treatment
measure: Transfusion independence for 8 weeks or longer from week 1 through week 48
timeFrame: From Week 1 through Week 48 of treatment
Other outcomes:
measure: Erythroid response
timeFrame: Week 1 through 24 or Week 1 Through Week 48
measure: Longest duration of primary response (week 1 through week 24)
timeFrame: From start of study treatment to 16 weeks after last dose, up to approximately 93 weeks
measure: Longest duration of primary response (week 1 through week 48)
timeFrame: From start of study treatment to 16 weeks after last dose, up to approximately 93 weeks
measure: Mean increase in hemoglobin levels
timeFrame: Week 1 though Week 24 and Week 1 through 48
measure: Hematologic Improvement in Neutrophil Response
timeFrame: Week 1 through Week 24 or Week 1 Through Week 48 of study treatment
measure: Hematologic Improvement in Platelet Response
timeFrame: Week 1 through Week 24 or Week 1 Through Week 48 of study treatment
measure: Progression to acute myeloid leukemia
timeFrame: From randomization to study completion (up to approximately 57 months)
measure: Time to Acute Myeloid Leukemia (AML) Progression
timeFrame: From randomization to study completion (up to approximately 57 months)
measure: Overall Survival
timeFrame: From randomization to study completion (up to approximately 57 months)
measure: Mean change in the serum ferritin level
timeFrame: Baseline and Week 9 through Week 24 and Week 33 through Week 48
measure: Safety analyses
timeFrame: From date of first dose up to 42 days after the last dose (up to approximately 83 weeks)
measure: Change from baseline in RBC Units Transfused over fixed 16-week Period
timeFrame: At Baseline (16 weeks prior to first dose of study treatment) and Weeks 9 to 24 or Weeks 33 to 48
measure: Time to Red Blood Cell Transfusion Independence Week 1 Through Week 24
timeFrame: From first dose to Week 24 of treatment
measure: Time to Red Blood Cell Transfusion Independence Week 1 Through Week 48
timeFrame: From first dose to Week 48 of treatment
Locations:
city: Milan
country: Italy
facility: Istituto Clinico Humanitas
state: Rozzano
Study officials:
affiliation: Istituto Clinico Humanitas
name: Matteo Della Porta, MD
role: STUDY_DIRECTOR
affiliation: Università degli studi di Firenze - AOU Careggi
name: Valeria Santini, MD
role: STUDY_CHAIR
affiliation: ASST-MONZA
name: Lorenza Borin, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Aziena Ospedaliera Mauriziano - Torino
name: Daniela Cilloni, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ospedale Policlinico di Milano
name: Bruno Fattizzo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Policlinico di Bari
name: Pellegrino Musto, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli di Reggio Calabria
name: Esther Oliva, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: ASST Grande Ospedale Metropolitano Niguarda
name: Marta Riva, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Presidio Ospedaliero Pescara
name: Prassede Salutari, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Università Cattolica del Sacro Cuore - Roma
name: Maria Teresa Voso, MD
role: PRINCIPAL_INVESTIGATOR
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