Luspatercept Under Exploration in Myeloproliferative Neoplasm–Associated Myelofibrosis


The safety and efficacy of luspatercept vs placebo is under exploration in patients with myeloproliferative neoplasm–associated myelofibrosis who are receiving concomitant JAK2 inhibitor therapy and who require red blood cell transfusions, as part of the phase 3 INDEPENDENCE trial.

Ruben Mesa, MD, FACP

Ruben Mesa, MD, FACP

The safety and efficacy of luspatercept-aamt (Reblozyl) vs placebo is under exploration in patients with myeloproliferative neoplasm (MPN)–associated myelofibrosis who are receiving concomitant JAK2 inhibitor therapy and who require red blood cell transfusions (RBCs), as part of the phase 3 INDEPENDENCE trial (NCT04717414).1

A first-in-class erythroid maturation agent, luspatercept-aamt binds to select TGF-β superfamily ligands to diminish Smad2/3 signaling and enhance late-stage erythropoiesis.

In November 2019, the agent was approved by the FDA for the treatment of anemia in adult patients with β-thalassemia who need regular RBCs, based on findings from the phase 3 BELIEVE trial (NCT02604433).2 Among the 336 adult patients who received luspatercept, 21.4% achieved RBC transfusion burden reduction from baseline vs 4.5% of those who were given placebo (risk difference, 17.0; 95% CI, 10.4-23.6; P < .0001).

The following year, in April 2020, the FDA greenlit luspatercept for the treatment of anemia failing an erythropoiesis-stimulating agent (ESA) and requiring 2 or more RBC units over 8 weeks in adult patients with very low– to intermediate-risk myelodysplastic syndromes with ring sideroblasts or with myelodysplastic/MPN with ring sideroblasts and thrombocytosis.3 This decision was based on findings from the phase 3 MEDALIST trial (NCT02631070), which revealed that among 153 patients who received the agent, 37.9% (95% CI, 30.2-46.1) had RBC transfusion independence for at least 8 weeks vs 13.2% (95% CI, 14.5-34.6) of those who received placebo (P < .0001).

Results from the preliminary analysis of a phase 2 trial (NCT03194542) evaluating luspatercept in patients with myelofibrosis-associated anemia indicated that 27% of patients achieved at least one 12-week or longer episode of RBC transfusion independence within the first 24 weeks of treatment with the agent.4

“[INDEPENDENCE] is currently enrolling patients with myelofibrosis,” study author Ruben Mesa, MD, FACP, of the UT Health San Antonio Cancer Center, said in a poster presentation during the 2021 ASH Annual Meeting. “It started in February of 2021. Enrollment is currently ongoing, with 150 planned sites in Europe, North America, Asia, and Australia.”

The double-blind, randomized INDEPENDENCE trial is enrolling patients who are at least 18 years of age and who have a diagnosis of primary myelofibrosis, post-essential thrombocythemia myelofibrosis, or post-polycythemia myelofibrosis.

To be eligible for enrollment, patients must require regular RBC transfusions of 4 to 12 RBC units per 12 weeks prior to randomization. Furthermore, patients must have received concomitant JAK2 inhibitor therapy for at least 32 weeks prior to randomization, with a stable daily dose for at least 16 weeks, and have an ECOG performance status ranging from 0 to 2.

If patients had anemia due to causes other than MPN-associated myelofibrosis or JAK2 inhibitor therapy, if they previously received hydroxyurea (Hydrea), ESAs, androgenic steroids, immunomodulatory compounds like pomalidomide (Pomalyst) or thalidomide (Thalomid), or they received other drugs with potential hematopoiesis effects 8 weeks or less before randomization, they were excluded.

Other key exclusion criteria included having uncontrolled hypertension, heart disease, or systemic fungal, bacterial, or viral infection; a history of malignancies—except for basal or squamous cell skin carcinoma, cervix carcinoma, breast carcinoma, or prostate cancer; planned or prior hematopoietic cell transplant; stroke, myocardial infarction, or deep venous thrombosis, or pulmonary or arterial embolism within 6 months of randomization. Prior use of sotatercept (ACE-011) or luspatercept-aamt is also not permitted.

Following a 4-week screening period, approximately 309 patients will be randomized 2:1 to receive luspatercept-aamt plus best supportive care (BSC) every 21 days for 168 days (n = ~206)or placebo plus BSC (n = ~103). The starting dose of luspatercept will be 1.33 mg/kg with titration allowed up to 1.75 mg/kg. BSC can include transfusions, iron chelation therapy, and antibiotic, antiviral, or antifungal therapy. During the treatment phase, dose reductions are permitted.

Stratification factors include RBC transfusion burden at baseline (4 to 5 RBC units/12 weeks prior to randomization vs 6 to 12 RBC unites) and Dynamic International Prognostic Scoring System score at baseline (intermediate-1/intermediate-2 vs high risk).

Disease response assessment will be done on day 169 to determine clinical benefit, which will be defined as RBC transfusion independence for any consecutive 12-week period or more during the first 24 weeks of treatment, a reduction of RBC transfusion burden by at least 50% and by at least 4 RBC units for at least 12 weeks through day 169, and an incomplete duration of response of at least 4 weeks of RBC transfusion independence.

After 24 weeks, and following the assessment, patients will proceed to a blinded extension phase of the treatment period. Post-treatment follow-up will occur 5 years following the first dose of treatment received or 3 years following the final dose received, whichever happens later.

The primary end point of the study is the proportion of patients who achieve RBC transfusion independence for any period of at least 12 weeks during the first 24 weeks of treatment. The key secondary end point of the trial is the proportion of patients who become RBC transfusion independent over any period of at least 16 weeks during the first 24 weeks following randomization.

Other secondary end points include maximum duration of RBC transfusion independence, cumulative duration of 12-week RBC transfusion independence episodes for patients experiencing multiple episodes, proportion of patients achieving at least a 50% reduction in RBC transfusion burden with a reduction of at least 4 units during any 12-week interval, mean hemoglobin increase of at least 1 g/dL over any 12-week period without RBC transfusions, and any change in serum ferritin levels from baseline.

Safety assessments will include frequency, severity, and seriousness of adverse events, prior or concomitant medicines or procedures, serum chemistry, hematology assessments, urinalysis and urine chemistry, electrocardiogram, vital signs and body weight, and monitoring for transformation to blast phase and other malignancies or premalignancies.


  1. Mesa RA, Harrison C, Kiladjian J, et al. INDEPENDENCE: a phase 3 study of efficacy and safety of luspatercept versus placebo in patients with myeloproliferative neoplasm-associated myelofibrosis on JAK2 inhibitor therapy and requiring red blood cell transfusions. Presented at: 2021 ASH Annual Meeting; December 9-14, 2021; Atlanta, GA. Poster 1490.
  2. FDA approves luspatercept-aamt for anemia in patients with beta thalassemia. News release. FDA; November 8, 2019. Accessed January 17, 2022.
  3. FDA approves luspatercept-aamt for anemia in adults with MDS. News release. FDA; April 3, 2020. Accessed January 17, 2022.
  4. Gerds AT, Vannucchi A, Passamonti F, et al. Duration of response to luspatercept in patients (Pts) requiring red blood cell (RBC) transfusions with myelofibrosis (MF) – updated data from the phase 2 ACE-536-MF-001 study. Blood. 2020;136(suppl 1):47-48. doi:10.1182/blood-2020-137265
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