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.

Evaluation of Absolute Neutrophil, Lymphocyte and Platelet Count and Their Ratios as Predictors of Thrombotic Risk in Patients with Prefibrotic and Overt Myelofibrosis

“…Thrombosis imposes a substantial morbidity burden on MF patients [42,43] and mandates the introduction of specific therapies that may further make it difficult to optimize care [44]. Myelodepletive phenotype, low platelet count and developed complications of portal hypertension that are encountered in subsets of MF patients further challenge the delivery of specific primary and secondary prevention measures [45][46][47][48][49][50]. Thrombosis also significantly increases healthcare resource utilization and treatment costs [51], which are already high in patients with MF [52].…”

Molecular Genetic Profile of Myelofibrosis: Implications in the Diagnosis, Prognosis, and Treatment Advancements

“…However, the biologic ramifications and phenotypic associations with mutation profiles, particularly the impact of additional mutations in individuals with the same driver mutation, remain poorly understood. Studies have indicated that a higher allelic burden of JAK2 V617F and type 2 CALR mutations is correlated with elevated blood cell counts (reviewed by Chifortides et al [50]). A study by Grinfeld et al on 2035 MPN patients suggested that genetic mutations and germline polymorphisms contribute, at least partially, to the determination of the phenotype [25].…”

ACVR1: A Novel Therapeutic Target to Treat Anemia in Myelofibrosis

“…Fedratinib presents a possible option for MF patients who are refractory/intolerant to ruxolitinib [ 74 ]. Importantly, there was a critical unmet need for MF patients with cytopenias prior to the regulatory approval of pacritinib and momelotinib, the preferable non-myelosuppressive JAK inhibitors to treat cytopenic patients with MF [ 75 ], because both ruxolitinib [ 60 , 76 ] and fedratinib [ 77 ] may worsen cytopenias.…”