Time without Transfusion Reliance or Anemia Worsening: A Novel Method for Integrating Transfusion Dependence, Anemia, and Survival with Myelofibrosis Therapies Based on the Phase 3 Simplify-1 and Simplify-2 Trials

Introduction: While approved Janus kinase inhibitors (JAKi) have improved overall survival (OS) in myelofibrosis (MF), traditional survival analyses do not consider individual patient (pt) experience, which may be negatively impacted by factors such as persistent symptoms, adverse events (AEs), and red blood cell (RBC) transfusion dependence. In particular, RBC transfusions, an important component of anemia management in MF with currently approved JAKi, are associated with negative quality of life (QOL), increased healthcare resource utilization, and poor prognosis. Momelotinib (MMB), a JAK1/JAK2/activin A receptor type 1 inhibitor, has demonstrated consistent anemia benefits, including increased transfusion independence and reduced transfusion burden, as well as spleen and symptom improvements across 3 phase 3 trials in MF. In the SIMPLIFY-1 (NCT01969838) and SIMPLIFY-2 (NCT02101268) trials, achieving transfusion independence with MMB was associated with prolonged OS (Mesa R, et al. Leukemia. 2022). Here we apply time without transfusion reliance (TWiTR) analyses, integrating transfusion-dependent (TD) status and OS, to further characterize the benefits of MMB on survival quality. Methods: Analyses were performed in the safety populations, by treatment arm, over the randomized 24-wk treatment period of SIMPLIFY-1 (n/N=430/432; MMB vs ruxolitinib [RUX], JAKi naive) and SIMPLIFY-2 (N=156; MMB vs best available therapy [BAT; 88.5% RUX], JAKi experienced). TWiTR (Zeidner JF, et al. Haematologica. 2023) was based on the established time without symptoms and toxicity (TWiST) analysis, replacing toxicity with TD status. The analysis partitioned survival duration into 3 health states: (1) TD, defined as the number of days on which pts were TD (defined per protocol in the SIMPLIFY studies as requiring ≥4 units of RBC transfusions or having a hemoglobin level