Impact of bone marrow pathology on the clinical management of Philadelphia chromosome-negative myeloproliferative neoplasms.

Abstract

Philadelphia chromosome-negative myeloproliferative neoplasms include primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET). Although these 3 entities share many pathogenic characteristics, such as dysregulated Janus kinase (JAK)/signal transducer and activator of transcription signaling, they differ substantially regarding prognosis, progression to myelofibrosis (MF), risk of leukemic transformation, and specific medical needs. Accurate diagnosis and classification of myeloproliferative neoplasms are prerequisites for appropriate risk-based therapy and should be based on an integrated approach following the World Health Organization guidelines that, in addition to clinical, molecular, and cytogenetic evaluation, includes the examination of bone marrow morphology. Reticulin fibrosis at presentation in ET and PV is associated with increased risk of myelofibrotic transformation, and higher fibrosis grade in patients with MF is associated with worse prognosis. Additional assessment of collagen deposition and osteosclerosis may further increase diagnostic and prognostic precision. Moreover, the evaluation of bone marrow pathology has become very important in the new era of disease-modifying agents. In randomized controlled phase 3 studies, the JAK1/JAK2 inhibitor ruxolitinib provided rapid and lasting improvement in MF-related splenomegaly and symptom burden as well as a survival advantage compared with placebo or best available therapy. Follow-up for up to 5 years of patients who participated in a phase 1/2 study of ruxolitinib, revealed stabilization or reversal of bone marrow fibrosis in a proportion of patients with MF. Combinations of JAK inhibitors with other therapies, including agents with antifibrotic and/or anti-inflammatory properties, may possibly decrease bone marrow fibrosis further and favorably influence clinical outcomes.