In comparison with conventional chemotherapeutic drugs, the expectations of targeted therapies are high. Imatinib, which targets BCR-ABL, and all-trans retinoic acid (ATRA) that targets PML-RARa, have made major impacts on medicine. It was expected that JAK1/2 inhibitors would have similar, almost magical, effects in JAK-positive myeloproliferative neoplasms. However, the data to date have shown that ruxolitinib, the first of the JAK1/2 inhibitors, has failed to live up to these expectations.

Ruxolitinib reduces constitutional symptoms and reduces spleen size in PMF [2]. However, the observations of reduction in constitutional symptoms and the decrease in spleen size after treatment with a JAK1/2 inhibitor in patients with wild-type JAK2 create doubts about the targeted nature of this drug and the role of JAK2 in the pathogenesis of PMF. In addition, it is hard to imagine how ruxolitinib reduces mortality without having a significant impact on the peripheral blood blast count, marrow fibrosis, cytogenetic remission, or reduction of JAK2 V617F allele burden. How does a targeted drug reduce mortality without having a significant effect on the disease biology? It would have been enlightening had this question been addressed; previous articles have not touched upon this topic.

Severe splenomegaly has been associated with poor outcomes after hematopoietic stem cell transplant (HSCT). Given this, the study author predicts that ruxolitinib administered prior to HSCT may improve the outcomes of HSCT in PMF. However, as mentioned in the penultimate section of the article, it is difficult to understand how this drug would have any impact on the outcome of HSCT by decreasing the proinflammatory cytokine levels when the mechanism of action for this effect is still unknown.

The outcomes of trials of ruxolitinib in PMF have raised many questions and provided a few answers. What is the specificity of ruxolitinib as a targeted drug? Are there any other undiscovered pathways in the pathogenesis of PMF that hinder the action of ruxolitinib? These are some of the many questions that further studies need to answer. In my opinion, then and only then will the question "Will JAK1/2 inhibitors change the standard of care for myelofibrosis?" be answered appropriately.