Review Examines Ruxolitinib's Role in the Evolving MPN Treatment Landscape

Myeloproliferative neoplasms are linked by activation of cytokine-independent signaling through the Janus kinase/signal transducers and activators of transcription (JAK/STAT) cascade. Ruxolitinib, a tyrosine kinase inhibitor (TKI) that inhibits JAK1 and JAK2, is approved for use in intermediate- to high-risk patients with the MPNs primary myelofibrosis (MF) and polycythemia vera (PV) who are resistant to or intolerant of other treatment options. A recent review describes the current understanding of the clinical and molecular effects of ruxolitinib in MPNs, as well as the future of improved therapy for MPNs in the era of JAK inhibition.

Ruxolitinib has shown efficacy in reducing spleen volume and symptom burden versus other available treatments. However, the efficacy of the drug is variable across MPNs, and transformations to secondary MF and acute leukemia have been observed in patients receiving the drug. In MF, the treatment improves the odds of stabilization of bone marrow fibrosis and reduces the chance of worsening fibrosis in some patients, but it does not produce disease reversal, suggesting the need for further advancements in therapies.

Developing such therapies will require better understanding the genomic complexity of MPNs. A range of genes are found to be mutated in patients with MPNs; cooperating oncogenic mutations found alongside driver mutations may impact on disease phenotype and prognosis. The driver mutation JAK2 V617F is understood to result in higher thrombotic risk, for example, while the calreticulin gene (CALR) driver mutation appears to carry a lower risk of thrombosis and has been linked with better overall survival.

Mutated cooperating oncogenes also have important roles; in primary MF, mutations in the genes ASXL1, EZH2, SRSF2, for example, have been observed to independently predict shortened survival. Better understanding such molecular markers will help to provide individualized prognosis for patients, and to understand phenotype as well as thrombosis and transformation risk. “It is in this spectrum of disease that the role of [JAK inhibition and ruxolitinib] in particular will need to be defined,” write the authors, noting that molecular data from clinical trials of ruxolitinib is limited.

Another key issue for further investigation is the fact that MPN clones can persist despite JAK inhibition. This persistence may be because TKI therapy allows resistance to TKIs to develop. Another potential mechanism of resistance to ruxolitinib is recruitment of alternative cell signaling pathways. Reduced DNA repair mechanisms may also allow for clonal selection during ruxolitinib monotherapy.

Furthermore, JAK inhibition may not be able to overcome the effects of histone modification—a key mechanism of epigenetic regulation that can enhance or repress gene transcription—so the role of combined epigenetic manipulation and JAK inhibition should be explored in trials.

Finally, inflammation is linked with neoplastic disease, and patients with MPNs have been shown to have higher levels of circulating cytokines. Ruxolitinib has shown good efficacy in an anti-inflammatory role, and this effect could be augmented through the use of Bromodomain and Extra-Terminal motif (BET) inhibitors. BET inhibition together with ruxolitinib has also been shown to result in reversal of bone marrow fibrosis and a reduction of disease burden.

JAK inhibition “has demonstrated good efficacy in symptom relief but more limited impact on disease modification,” conclude the authors. “Understanding how [JAK inhibition] affects and is affected by each of the key features of pathogenesis…is key to understanding how best to augment this therapy and establish an optimal therapeutic approach to this complex disease state.”

Reference

Greenfield G, McPherson S, Mills K, McMullin MF. The ruxolitinib effect: understanding how molecular pathogenesis and epigenetic dysregulation impact therapeutic efficacy in myeloproliferative neoplasms. J Transl Med. 2018;16: 360. doi: 10.1186/s12967-018-1729-7.