Association of Myelofibrosis Phenotypes with Clinical Manifestations, Molecular Profiles, and Treatments

Abstract

Myelofibrosis (MF) presents an array of clinical manifestations and molecular profiles. The two distinct phenotypes- myeloproliferative and myelodepletive or cytopenic- are situated at the two poles of the disease spectrum and are largely defined by different degrees of cytopenias, splenomegaly, and distinct molecular profiles. The myeloproliferative phenotype is characterized by normal/higher peripheral blood counts or mildly decreased hemoglobin, progressive splenomegaly, and constitutional symptoms. The myeloproliferative phenotype is typically associated with secondary MF, higher JAK2 V617F burden, fewer mutations, and superior overall survival (OS). The myelodepletive phenotype is usually associated with primary MF, ≥2 cytopenias, modest splenomegaly, lower JAK2 V617F burden, higher fibrosis, greater genomic complexity, and inferior OS. Cytopenias are associated with mutations in epigenetic regulators/splicing factors, clonal evolution, disease progression, and shorter OS. Clinical variables, in conjunction with the molecular profiles, inform integrated prognostication and disease management. Ruxolitinib/fedratinib and pacritinib/momelotinib may be more suitable to treat patients with the myeloproliferative and myelodepletive phenotypes, respectively. Appreciation of MF heterogeneity and two distinct phenotypes, the different clinical manifestations and molecular profiles associated with each phenotype alongside the growing treatment expertise, the development of non-myelosuppressive JAK inhibitors, and integrated prognostication are leading to a new era in patient management. Physicians can increasingly tailor personalized treatments that will address the unique unmet needs of MF patients, including those presenting with the myelodepletive phenotype, to elicit optimal outcomes and extended OS across the disease spectrum.

Keywords: MPN; PMF; anemia; cytopenic; high molecular risk mutations; momelotinib; myelodepletive; myelofibrosis; myeloproliferative neoplasm; pacritinib; phenotype; thrombocytopenia.

Figure 1

MF phenotypes (myeloproliferative and myelodepletive), clinical and molecular characteristics, and suggested treatment options with JAK inhibitors. Abbreviations. BM: bone marrow; OS: overall survival; RBC: red blood cell; VAF: variant allele frequency; WBC: white blood cell.