Clinical Parameters, Anemia, and Spleen Response in Patients with MF-Related Anemia Treated with Luspatercept: Efficacy Sub-Analysis from the ACE-536-MF-001 Study
Authors: Gerds Aaron T. , Harrison Claire N , Kiladjian Jean-Jacques , Mesa Ruben , Komrokji Rami S. , Bose Prithviraj , Sanabria Fabian , Marsousi Niloufar , Lai Yinzhi , Passamonti Francesco 
Published: December 2023

Introduction: Approximately 24% of patients with myelofibrosis (MF) have anemia requiring red blood cell (RBC) transfusion at initial diagnosis. For patients with MF, chronic anemia and RBC transfusion dependence (TD) often increase throughout the disease course and are an indicator of poor prognosis. Luspatercept (LUSPA) is an erythroid maturation agent approved to treat anemia in adults with β-thalassemia and myelodysplastic syndrome requiring RBC transfusions. Primary results from the phase 2 ACE-536-MF-001 study (NCT03194542) demonstrated reductions in MF-related anemia and transfusion dependence (Gerds et al. ASCO 2023 7016). Here we provide an extended analysis of the impact of LUSPA on clinical parameters and transfusion burden over time, and associated management of MF disease symptoms.
Methods: Patients were enrolled into cohorts based on TD and ruxolitinib (RUX) treatment. Patients received LUSPA 1.0 mg/kg subcutaneously (with titration up to 1.75 mg/kg), administered on day 1 of each 21-day cycle (starting dose was 1.33 mg/kg for cohort 3B expansion). Patients were defined as TD if receiving an average of 4-12 RBC units/84 days immediately up to cycle 1 day 1 (C1D1). For non-transfusion dependent (NTD) patients, anemia was defined as 3 or more hemoglobin (Hgb) level measurements of ≤ 9.5 g/dL recorded on at least 3 different days in the 84-day period immediately preceding C1D1.
The primary endpoint was anemia response, assessed at day 169 (week 24) and defined as 84 consecutive days without RBC transfusion for TD patients, and 84 consecutive days with Hgb increase of ≥ 1.5 g/dL from baseline without transfusion for NTD patients. Treatment was extended if clinical benefit was observed at day 169. Secondary and exploratory endpoints included anemia response for the entire treatment period, transfusion burden, and clinical and laboratory parameters.
Results: A total of 95 patients were enrolled: cohort 1 (NTD, no RUX, n = 22), cohort 2 (TD, no RUX, n = 21), cohort 3A (NTD, RUX, n = 14), and cohort 3B (TD, RUX, n = 38). A total of 63 (66.3%) patients continued to the follow-up period. The mean (SD)/median (range) duration of treatment was 42.8 (47.6)/24.0 (2.0-232.0) weeks and mean/median (range) follow-up duration after first dose was 101.1/78.0 (2.1-232.1) weeks. Anemia response was seen across all cohorts. Among transfusion-dependent patients (cohorts 2 and 3B), transfusion independence ≥ 12 weeks was observed in 4 (19.0%, 95% CI 5.45-41.91) and 12 (31.6%, 95% CI 17.5-48.7) patients, respectively, in the entire treatment period. Additionally, approximately half of patients with TD achieved a 50% reduction in transfusion burden; 10 (47.6%) patients in cohort 2 and 20 (52.6%) patients in cohort 3B had ≥ 50% reduction in transfusion burden over any 84-day period in the entire treatment period, including 16 patients from cohorts 2 and 3B who achieved transfusion independence (100% reduction) (Figure).
Changes in laboratory parameters of Hgb, serum erythropoietin, serum ferritin, and platelet count at day 169 are summarized in the Table; in addition, patients with clinical benefit continuing LUSPA treatment after day 169 showed ferritin decreases with longer follow-up from cycle 13 (n = 20) to cycle 33 (n = 6). Additionally, there was minimal (~1 cm) to no increase in median spleen size across patients in all cohorts. Of the 3 patients in cohort 3B who increased their RUX dose during LUSPA treatment, spleen size remained stable, with a -4.0 cm, 1.0 cm, and 3.0 cm change from baseline during the entire treatment period, respectively.
Conclusions: In the phase 2 ACE-536-MF-001 study, LUSPA demonstrated improvements in anemia and transfusion burden in patients with MF. Further analysis of clinical and laboratory parameters may reveal differences between responders and non-responders. Spleen size stability was observed in all patients; this suggests that LUSPA does not worsen splenomegaly and may support continual use of RUX for MF disease and symptoms.
Study support: Bristol Myers Squibb.