Since the development of the JAK1/2 inhibitor ruxolitinib, our understanding of MPNs has come a long way. Researchers Bing Li, Raajit K. Rampal, and Zhijian Xiao document the targeted therapies currently in various stages of development, with the promising effects of reducing myelosuppression, greater selectivity for JAK1/2, and the ability to overcome JAK inhibitor persistence.
“Targeted therapies for myeloproliferative neoplasms”
“In particular, treatment for patients with MF and extensive splenomegaly and symptomatic burden has been significantly improved following the introduction of the ruxolitinib. However, ruxolitinib for MPNs is still largely inadequate to cope with significant challenges including reduction of mutated allele burden, reversion of fibrosis, normalization of life span and prevention of hematological progression . Recently, some clinical trials of novel type I JAK inhibitors showed the equal, even better effect of reduction in splenomegaly and transfusion and improvement in symptomatic burden and these results really shed light on treatment options for ruxolitinib-resistant or ruxolitinib-intolerant MPN patients. However, some of the major challenges of JAK2 inhibition: the first, to achieve potent catalytic inhibition without off-target effects; the second, to reach a high degree of selectivity for JAK2 against the other JAKs; the third, to specifically or preferentially target mutated forms against JAK2 WT, thus directly targeting the MPN clone and sparing normal hematopoiesis; finally, to specifically disrupt JAK2 function in defined cytokine receptor complexes were not overcame. Combinatorial approaches of ruxolitinib and various agents may lower toxicity and provide more effective disease control, yet more preclinical data are needed to define the most effective and synergistic combinations.”