Clinical features and outcomes of myelofibrosis patients with MPL mutations

Abstract Background Myelofibrosis (MF) is a type of myeloproliferative neoplasm (MPN) characterized by clonal proliferation of hematopoietic stem cells. MF may arise de novo (PMF) or progress from underlying essential thrombocythemia (ET) or polycythemia vera (PV). Mutations in JAK2, CALR, or MPL commonly drive the disease. Among these, JAK2 mutations are the most prevalent, occurring in approximately 55% of ET and 60% of PMF cases. CALR mutations are seen in 25-30% of ET and 20-30% of PMF cases. MPL mutations are less common, found in 5-7% of ET and 7-10% of PMF cases. Due to the rarity of MPL mutations, the clinical characteristics and outcomes associated with MPL-mutated MF remain poorly understood. This study aims to characterize the presentation and outcomes of MF patients harboring MPL mutations. Method This retrospective case series was conducted at Massachusetts General Hospital (MGH) and Moffitt Cancer Center (MCC) between 2010-2022. Patients with a confirmed diagnosis of MF and MPL mutations identified through next-generation sequencing were included. Those with less than six months of clinical follow-up were excluded. Collected data included patient demographics, disease characteristics, molecular profiles, and treatment history. Prognostic risk scores were manually calculated using MIPSS70v2 when available. Clinical outcomes evaluated included progression to acute myeloid leukemia (AML), duration of follow-up, and survival. Descriptive statistical methods were applied to summarize baseline characteristics and clinical outcomes. Results A total of 73 patients were identified, 58 from MCC and 15 from MGH. The median age at diagnosis was 70 years (range 44–98), with a median follow-up of 36 months (range 3–158), 43 (58.9%) were male. 61 patients were White, 6 Black, 5 Hispanic, and 1 Asian. At diagnosis, 72.6% had primary MF, and 1 patient had unclassified MPN. Among 17 post-ET MF patients, the median time from ET to MF progression was 9.4 years (range, 1–20). The most common MPL mutations were W515L (n=48), W515K (n=10), and S505N (n=4), with 11 patients carrying other variants. High molecular risk (HMR) mutations were found in 41 (56.2%) patients, most commonly ASXL1 (n=23), SRSF2 (n=14), and U2AF1 (n=11), with an average of 1.7 HMR mutations per patient (range, 1–6). 61 patients were noted to have additional non-HMR driver mutations. Among the 60 patients with available data to calculate MIPSS70v2 scores, 31 (51.7%) were classified as high-risk, 21 (35%) as intermediate-risk, and 8 (13.3%) as low-risk. Median blood counts at diagnosis were WBC 8.7 × 10³/μL, hemoglobin 10.0 g/dL, and platelets 299 × 10³/μL. Treatment regimens included JAK inhibitors, most commonly Ruxolitinib (n=31), Momelotinib (n=4), Fedratinib (n=2), and Pacritinib (n=1). Anemia-directed therapies included erythropoietin-stimulating agents (ESA) in 21 patients, Danazol (n=9), and Luspatercept (n=2). At the time of analysis, 6 progressed to accelerated-phase disease, 5 patients to AML. 14 patients (19.2%) had undergone stem cell transplantation, with 3 having a diagnosis of AML progression. At the time of last contact, 41 patients were alive, and 32 patients were deceased. Conclusion Little is known about the clinical outcomes and molecular characteristics of MPN patients with MPL mutations. Although prior work has characterized ET patients with MPL mutations, less is known about the outcomes for MPL-mutated MF patients. This dual-institutional retrospective study represents the largest cohort of patients with MPL-mutated MF reported to date. Our findings show that MPL-mutated MF is associated with a high prevalence of HMR mutations, with >50% of patients harboring an HMR mutation. A significant subset of patients progressed to accelerated-phase disease or AML (n=11, 15%). Despite this, only one-fifth underwent hematopoietic stem cell transplantation. These results highlighted the need for improved risk stratification and the development of targeted therapeutic strategies for this rare and understudied population.