Biological drivers of clinical phenotype in myelofibrosis

Myelofibrosis (MF) is a myeloproliferative disorder that exhibits considerable biological and clinical heterogeneity. At the two ends of the disease spectrum are the myelodepletive or cytopenic phenotype and the myeloproliferative phenotype. The cytopenic phenotype has a high prevalence in primary MF (PMF) and is characterized by low blood counts. The myeloproliferative phenotype is typically associated with secondary MF (SMF), mild anemia, minimal need for transfusion support, and normal to mild thrombocytopenia. Differences in somatic driver mutations and allelic burden, as well as the acquisition of non-driver mutations further influences these phenotypic differences, prognosis, and response to therapies such as JAK2 inhibitors. The outcome of patients with the cytopenic phenotype are comparatively worse and frequently pose a challenge to treat given the inherent exacerbation of cytopenias. Recent data indicate that an innate immune deregulated state that hinges on the myddosome-IRAK-NF kappa B axis favors the cytopenic myelofibrosis phenotype and offers opportunity for novel treatment approaches. We will review the biological and clinical features of the MF disease spectrum and associated treatment considerations.

Automated summary

Myelofibrosis is a myeloproliferative disorder with significant biological and clinical heterogeneity. It can manifest as a cytopenic phenotype or a myeloproliferative phenotype, each with different prognosis and response to treatment. Patients with the cytopenic phenotype have worse outcomes and pose challenges in treatment. Recent data suggest that an innate immune deregulated state may be associated with the cytopenic phenotype, providing potential for novel treatment approaches.