Luspatercept for the treatment of transfusion-dependent anemia in patients with myelodysplastic neoplasms with del5q, refractory/resistant/intolerant to prior treatments (QOL-ONE Phoenix)

Abstract Background: Myelodysplastic neoplasms (MDS) with deletion 5q (del5q) are characterized by <5% bone marrow blasts and either isolated del5q or with one additional cytogenetic abnormality, other than monosomy 7 or del7q. Most patients develop severe anemia and transfusion dependence. Treatment goals for patients with lower-risk MDS include transfusion independence (TI), increase in hemoglobin (Hb) levels, and maintenance of or improvement in quality of life (QoL). Lenalidomide is the targeted treatment for MDS with del5q able to abrogate RBC TD with a median duration of response of 2-3 years. However, about a third of patients are refractory/resistant/ ineligible to lenalidomide and will remain RBC TD. Luspatercept has been recently approved for lower risk MDS requiring transfusions. We present interim results on an Italian multicenter single arm trial to evaluate the efficacy of luspatercept in RBC TD patients with MDS with del5q refractory/resistant/intolerant to prior treatments. Methods:In this study, 22 patients ≥ 18 years of age with anemia due to MDS with del5q, with <5 % bone marrow blasts and IPSS-R very low, low, or intermediate risk who are refractory/intolerant/ineligible to erythropoietin and lenalidomide treatment and who required at least 2 units/8 weeks of red blood cell RBC transfusions have been included. The primary endpoint is transfusion independence (TI) defined as absence of transfusions for 8 consecutive weeks within the first 24 weeks. Secondary endpoints include duration of RBC-TI, safety, tolerability, and changes in quality of life (QoL) using QOL-E and HM-PRO measures. Patients received luspatercept at a starting dose of 1.0 mg/kg every 3 weeks for up to 2 years, with dose titrations up to a maximum of 1.75 mg/kg or reduced, as appropriate. Non-responders at 24 weeks and those losing response interrupt treatment and continue a follow-up up to 5 years from study start.Results:Enrolment has been concluded with the inclusion of 22 patients (16 females) of median age 76 years (range 40-94). Median baseline hemoglobin (Hb) is 8.7 (6.4–9.7) g/dL with median RBC transfusion requirement of 4 (2-14) units in the preceding 8 weeks. Ten cases had a high transfusion burden (HTB). 20 patients had baseline isolated del(5q) and 2 had an additional cytogenetic abnormality.At enrolment, 9 cases were intolerant to lenalidomide, 8 were not responders, 4 were refractory, and 1 was ineligible. Nineteen cases had received erythropoietin and 3 were ineligible.At interim, 18 cases have reached 24 weeks in the trial, 1 non responsive case is in the study at week 22, 1 (non responsive) case withdrew consent, 1 non responsive patient died due to pneumonia and 1 non responsive case evolved to acute leukemia before 24 weeks.A total of 8 patients (38%) has reached RBC-TI with concurrent increase in Hb>10 g/dL. Six responders had baseline HTB (75.0%) and a median baseline Hb of 8.8 (7.4-9.4) g/dL.Overall, the median follow-up is 35 (15-102) weeks. Time to response is 13 (10-19) weeks at the median dose of 1.33 (1.00 – 1.75) mg/kg. Only one responder lost RBC-TI after 39 weeks, five patients continue on therapy, and 1 responsive patient interrupted to receive a stem cell transplantation at week 24. Currently the median duration of response is 41 (14-76) weeks.Changes in QOL-E fatigue correlate with improvements in hemoglobin levels (r2=0.497; p=0.042). Responders showed a clinically meaningful improvement in QOL-E physical functioning in 6 cases and QOL-E fatigue in 5 cases. One responder experienced an unrelated grade 3 paresthesia, 1 non-responder evolved to acute leukemia, and two deaths occurred due to pneumonia (one during response). Conclusion:This interim analysis shows that luspatercept is an effective treatment in a substantial proportion of cases with MDS with del5q, with concurrent improvements in Hb levels, while maintaining a favourable safety profile. Additionally, a notable improvement in QoL is reported. Longer follow-up is required to confirm the durability of these benefits.