Emerging treatments for classical myeloproliferative neoplasms

Abstract

There has been a major revolution in the management of patients with myeloproliferative neoplasms (MPN), and in particular those with myelofibrosis and extensive splenomegaly and symptomatic burden, after the introduction of the JAK1 and JAK2 inhibitor ruxolitinib. The drug also has been approved as second-line therapy for polycythemia vera (PV). However, the therapeutic armamentarium for MPN is still largely inadequate for coping with patients’ major unmet needs, which include normalization of life span (myelofibrosis and some patients with PV), reduction of cardiovascular complications (mainly PV and essential thrombocythemia), prevention of hematological progression, and improved quality of life (all MPN). In fact, none of the available drugs has shown clear evidence of disease-modifying activity, even if some patients treated with interferon and ruxolitinib showed reduction of mutated allele burden, and ruxolitinib might extend survival of patients with higher-risk myelofibrosis. Raised awareness of the molecular abnormalities and cellular pathways involved in the pathogenesis of MPN is facilitating the development of clinical trials with novel target drugs, either alone or in combination with ruxolitinib. Although for most of these molecules a convincing preclinical rationale was provided, the results of early phase 1 and 2 clinical trials have been quite disappointing to date, and toxicities sometimes have been limiting. In this review, we critically illustrate the current landscape of novel therapies that are under evaluation for patients with MPN on the basis of current guidelines, patient risk stratification criteria, and previous experience, looking ahead to the chance of a cure for these disorders.

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…It is prescribed as a targeted therapy for treatment of patients with primary MF, PV, and ET [155]. During clinical trials, it was shown to reduce spleen size, abdominal discomfort, bone pain, night sweats, and itching, as well as diminish the level of inflammatory cytokines in MPN patients.…”

An acquired NRAS mutation contributes to neutrophilic progression in a patient with primary myelofibrosis

“…Pharmacological inhibitors of MEK have shown considerable efficacy in BRAF ‐mutated metastatic melanoma, with case reports demonstrating significant clinical responses of these agents, such as trametinib, in NRAS ‐mutated haematological malignancies, including aCML with a similar neutrophilic hyperleucocytosis (Khanna et al , ). In context of the emerging array of treatments for MPN (Vannucchi & Harrison, ) such cases support the rationale for considering clinical trials of MEK inhibitors in the treatment of NRAS ‐mutated MPN.…”

Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms

“…94 However, a few studies have examined at molecular level the effect of compounds that can target the mutant myeloproliferative clone. These studies have shown that pegylated or regular interferon a can induce significant reduction in mutant allele burden in patients with JAK2 (V617F)-mutant ET or PV, 95,96 and in those with CALR-mutant ET.…”