Bone Marrow Cell Depletion in Myelofibrosis Is Associated With High-Risk Features and Shortened Survival: A Bone...

Fibrosis is a key histologic finding in the bone marrow (BM) of patients with advanced BCR::ABL1-negative myeloproliferative neoplasms (MPN). Fibrotic MPN can be associated with variable BM cellularity ranging from hypercellular to severe cell depletion. The significance of BM cellularity in the assessment of patients with advanced stage myelofibrosis (MF) is largely unknown. The current study compares cell-depleted MF patients with cellular MF controls in terms of morphologic, genetic, laboratory, and clinical features, including patient outcome. BMs that fulfilled the diagnostic criteria for advanced fibrotic phase MF (with MF-3 or osteosclerosis) including cases of primary myelofibrosis, post-polycythemia myelofibrosis and post-essential thrombocythemia myelofibrosis were collected from eleven participating institutions. BM hematopoietic cellularity was defined as depleted if cellularity was <30% in patients <70 and <20% for those >70 years old, and cellular if normocellular or hypercellular for age. Only cases with an adequate BM core biopsy and available clinical information including long-term follow-up were included. Data from 141 patients with cell-depleted MF and 100 patients with cellular MF were available. Thirty-three (26%) patients had depleted MF at diagnosis. Cell-depleted MF group had significantly lower hemoglobin and platelet counts, and higher peripheral blasts and basophils compared to cellular MF, although it was not independently prognostic. Patients had an increased prevalence of osteosclerosis (p<0.001). Depleted MF cases were enriched in ASXL1 (p=0.007), U2AF1 (p=0.01), EZH2 (p=0.026) and MPL (p=0.029) mutations. Finally, patients with depleted MF had significantly shorter overall survival (p=0.001). Cell-depletion in MF-3 patients is strongly associated with high-risk hematological and molecular features. These patients exhibit a distinct molecular signature compared to the cellular MF group, suggesting both underlying biological differences and features of more advanced disease. Thus, morphologic evaluation of bone marrow cellularity, fibrosis and osteosclerosis in MF patients may lead to a more accurate assessment of the disease status and guide clinical management.