Reduction in Red Blood Cell Transfusion Burden: A Novel Longitudinal Time-Dependent Analysis in Patients With Transfusion-Dependent Myelofibrosis Treated With Momelotinib

Topic: 16. Myeloproliferative neoplasms - Clinical Background: In addition to splenomegaly and constitutional symptoms, anemia is a high medical need in patients with myelofibrosis (MF). Although anemia in patients with MF is commonly managed with red blood cell (RBC) transfusions, their use can be detrimental to survival and quality of life as well as a burden on the healthcare system. A recently developed clinical prognostic model supports the negative prognostic impact of requiring RBC transfusions during the initial 6 months of ruxolitinib (RUX) treatment on survival (Maffioli et al, 2022). Momelotinib (MMB) is a small-molecule inhibitor of activin receptor type 1 (ACVR1), Janus kinase 1 (JAK1), and JAK2, with clinical activity against anemia, constitutional symptoms, and splenomegaly. Prespecified anemia endpoints in MMB phase 3 studies have prioritized achievement of a strict transfusion independence response (TI-R), defined as no transfusions for ≥12 weeks immediately before the end of week 24, with all hemoglobin (Hb) levels ≥8 g/dL. However, this binominal response/nonresponse endpoint does not fully characterize the changes in transfusion burden in patients with MF. Aims: In a phase 2 translational biology study of MMB in transfusion-dependent (TD) patients with MF, 34% of patients (14/41) achieved a TI-R by week 24 (Oh et al, 2020). However, the transfusion burden and treatment effect on overall transfusion burden of the entire study population has not been reported. Novel transfusion burden analyses presented here examine transfusion frequency over time in TD patients with MF treated with MMB. Methods: All RBC units transfused and Hb levels associated with transfusions were collected during the 24-week study period and for the 56 days before initiation of MMB on study. Eligible patients were to be TD at baseline, defined as ≥4 RBC units in the 56 days before start of MMB study treatment, which for this analysis was defined as a prestudy average of ≥2 units per 28 days. Time-dependent transfusion burden was quantified by number of RBC units administered, in a tabular display of baseline- and treatment-period intensity. Patients were grouped jointly based on the baseline- and treatment-period intensity of RBC units per 28 days into ordinal bins: exactly zero units, >0 to 1 unit, >1 to 2 units, >2 to 3 units, >3 to 4 units, and >4 units. Results: At baseline, 98% of patients (40/41) enrolled were TD and 88% (36/41) were JAK inhibitor naive, with a mean Hb of 8.3 g/dL and a mean platelet count of 181×103/µL. The mean RBC transfusion requirement was 3.2 units per 28 days before MMB treatment, with a range of 1.5 to 6.0 units per 28 days; 98% of patients (40/41) had transfusion needs of ≥2.0 units per 28 days. The mean transfusion requirement after MMB initiation was reduced from 3.2 to 1.7 units per 28 days (range, 0-6 units per 28 days), with 85% of patients (35/41) achieving a numeric reduction in transfusions. Using the ordinal bins, 90% of patients (37/41) showed improved (26/41) or stable (11/41) transfusion intensity with MMB treatment (Figure). Nine patients (22%) became transfusion free for the entire treatment period, while transfusion requirements modestly increased in 4 patients (10%). Summary/Conclusion: These data demonstrate that nearly all RBC TD patients treated with MMB (90%) experience a decline or stabilization of transfusion requirements, which further supports the differentiated activity of MMB against ACVR1, JAK1, and JAK2, resulting in decreased plasma hepcidin, improved iron homeostasis, and increased erythropoiesis, in addition to symptomatic and splenic benefits. FigureKeywords: Anemia, Transfusion, Myelofibrosis