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By Binod Dhakal, MD, MS

In 1951 a renowned hematologist from Harvard University, William Dameshek, MD, wrote an editorial in Blood providing seminal insight into myeloproliferative neoplasms (MPNs) — a group of disorders characterized by expansion of different myeloid lineages, with important clinical sequelae. Despite the brilliance of his hypothesis, he described an “undiscovered stimulus” as the biologic basis for these disorders. The hematology world had to wait another five decades for Dameshek’s vision to materialize. In 2005, over a span of just four weeks, four different groups independently published their findings on the identification of the somatic JAK2 V617F mutation in MPNs. Janus is the Roman god of portals and of duality — thus, the metaphor for JAKs possessing two near-identical phosphate-transferring domains. The importance of the discovery was soon realized as the mutation made a rapid transition into the clinic. Nearly two decades since JAK2’s discovery, we have now identified several players in the field including JAK2 exon 12, CALR, and MPL. Most importantly, with this understanding, JAK2 inhibitors were developed and approved. Novel JAK inhibitors have revolutionized the current landscape of MPN clinical trials.

Recognizing the significance of these developments in MPNs, this year’s ASH annual meeting offers the Education Program session Myeloproliferative Neoplasms: Managing the Cup that Runneth Over (offered twice on Saturday), chaired by Brady Lee Stein, MD, of Northwestern University. This session was dedicated to the novel understanding of the risk factors and treatment strategies in MPNs. Mary Frances McMullin, MD, of Queens University in the UK, reviewed several causes of thrombocytosis and erythrocytosis. Familial MPNs, which comprise 2 to 10 percent of cases, consist mainly of two types: true hereditary MPNs and hereditary MPN-like disorders with clinical symptoms of MPN. Explaining the role of familial factors in MPNs, she described the diagnostic pathway to investigate for a hereditary erythrocytosis or thrombocytosis. Thrombosis (arterial and venous), a major cause of morbidity and mortality, results from a complex interplay of clinical and disease-related factors. Dr. Stein discussed both the traditional and novel risk factors for MPN thrombosis. He highlighted treatment strategies for newly diagnosed and recurrent thrombosis including special clinical situations such as unusual-site thrombosis, pregnancy, and bleeding due to acquired von Willebrand syndrome.

Finally, Aaron T. Gerds, MD, of Cleveland Clinic, reviewed several treatment strategies that focus on JAK-STAT pathways in MPNs. JAK inhibition alone is insufficient for long-term remission and offers modest, if any, disease-modifying effects; therefore, it is essential to identify mechanisms that cooperate with JAK-STAT signaling to predict disease progression. This will help guide the development of novel therapies. Beyond ruxolitinib, three other JAK inhibitors are available: momelotinib, pacritinib, and recently approved fedratinib. Also, several clinical trials are now underway to investigate novel combinations with ruxolitinib for increased efficacy and potentially disease-modifying effects. Another therapeutic avenue under investigation centers around the hypothesis that reversal of the altered bone marrow microenvironment and fibrosis will restore normal hematopoiesis in myelofibrosis (MF). These include direct inhibition of TGF-β signaling with AVID2000, or indirect with inhibition of aurora kinase (MLN8237 or alisertib). He touched upon various other novel targets, including hedgehog-smoothened inhibitor, PI3K inhibitor, SMAC, and MDM2. Finally, immunotherapy is gaining attention in the field given the “graft-versus-tumor” effect observed with donor transplantation in MF. Dr. Gerds discussed the potential role of several immunotherapeutic approaches in the therapeutic armamentarium for MF.

Since the discovery of JAK2 V617F mutations in MPNs more than 10 years ago, significant advancements have been made in understanding the biology of these disorders. Ongoing efforts include understanding the initiating events to identify novel targets, improving risk models, and developing molecularly targeted therapies for mutations beyond JAK kinases. This session had it all!

Dr. Dhakal indicated no relevant conflicts of interest.

 

 

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