Luspatercept for the Treatment of Transfusion-Dependent Anemia in Patients with Myelodysplastic Neoplasms with del5q, Refractory/Resistant/Intolerant to Prior Treatments (QOL-ONE Phoenix)
Authors: Oliva Esther Natalie , Poloni Antonella , Frairia Chiara , Riva Marta , Capodanno Isabella , Delfino Ilaria Maria , D'Errigo Maria Grazia , Mammì Corrado , Ianni' Giuseppe , Zini Gina , Griguolo Davide , Marchetti Monia , Gurnari Carmelo , Voso Maria Teresa , Fattizzo Bruno 
Published: December 2024

Background: Myelodysplastic neoplasms (MDS) with deletion 5q (del5q) are characterized by &lt;5% bone marrow blasts and either with 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 first targeted treatment in MDS able to abrogate RBC TD, hallmark of the disease, 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. Furthermore, they are generally excluded from clinical trials so there is an unmet need in such patients. Luspatercept has been recently approved for lower risk MDS requiring transfusions. We present interim results of a multicenter single arm trial to evaluate the efficacy of luspatercept in RBC TD patients with del5q MDS refractory/resistant/intolerant to prior treatments.

Methods: As per protocol, a total of 22 patients aged ≥ 18 years with anemia due to del5q MDS and &lt; 5% bone marrow blasts with IPSS-R very low, low, or intermediate risk MDS who are refractory/intolerant/ineligible to erythropoietin and lenalidomide treatment and who require at least 2 units/8 weeks of RBC transfusions will be included. Primary endpoint is to evaluate the effect of luspatercept on RBC TI (lack of transfusions for 8 consecutive weeks) within the first 24 weeks. Secondary endpoints are to evaluate safety and tolerability of luspatercept, RBC-TI at 48 weeks and end of study; the time to and duration of RBC-TI, the reduction in RBC transfusions; the increase in Hb; the change in quality of life (QOL) scores using QOL-E and HM-PRO. Higher QOL-E and lower HM-PRO reflect a better QoL. Patients receive luspatercept at a starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks for up to 2.5 years,with dose levels either increased in a stepwise manner beyond the starting dose up to a maximum of 1.75 mg/kg or reduced, as appropriate. Response assessment according to the International Working Group (IWG) 2018 criteria is performed at every visit and, at 24 weeks. Non-responders interrupt treatment and continue a follow up for 5 years.

Results: At the present pre-determined interim analysis, 12 patients (10 females) of median age 78 years (range 65-90) have been enrolled. Two cases have additional cytogenetic abnormalities: del20(q) and monosomy 17, respectively. Median baseline Hb was 8.6 (6.4 - 9.7) g/dL with median RBC transfusion requirement of 4 (3-14) units in the preceding 8 weeks. Transfusion burden was equally distributed (N=6 low burden/ 6 high). Nine cases had received prior epoetin alfa, 7 were refractory to lenalidomide and 5 were intolerant. At the time of the present report, 5 cases have reached 24 weeks in study and are evaluable for efficacy: 2 low transfusion burden cases have responded at a 1.33 mg/kg dose: 1 case at week 16, reaching Hb 10.3 g/d at week 24, and 1 case at week 19, with Hb 10.1 at a 43 week follow-up. Eight cases have received at least 3 cycles with a first dose increase in all patients and 7 have received at least 5 cycles with a dose increase to 1.75 in all patients but the 2 responders who continue at 1.33 mg/kg. Median QOL-E baseline scores highlighted a significant burden of disease: physical 31.2 (IQR 12.5 - 50.0), functional 55.6 (IQR 22.2 - 83.3), social 50.0 (IQR 25.0 - 75.0), sexual 70.8 (IQR 10.4 - 100.0), fatigue 76.2 (IQR 66.7 - 88.1), MDS-specific 47.6 (IQR 38.1 - 58,5)), general 67.3 (IQR 55.6 - 90.8), All 68.2 (IQR 57.3 - 87.9)] and Treatment-outcome index 51.6 (IQR 28.7 - 66.6). Median HM-PRO baseline scores were: Physical Behaviour 39.3 (IQR 5.3 - 60.7), Social Well-being 47.7 (IQR 31.8 - 54.5), Emotional Behaviour 8.3 (IQR 0 - 33.3)), Eating and Drinking 12.5 (IQR 0 - 50.0)], PART-A 32.3 (IQR 26.6 - 40.5) and PART-B 2.8 (IQR 0 - 7.6). The 2 responders are experiencing stability or improvement in QoL. One responder experienced grade 3 paresthesia, an unrelated adverse event, which resolved after one week of dose delay.

Conclusion: Preliminary interim results show a positive signal of efficacy and safety of luspatercept in MDS with del5q resistant, refractory, intolerant or ineligible to other treatments. Final trial results will inform on the value of luspatercept for the benefit of TD patients.