JAK Inhibitor Treatment in Myelofibrosis May Depend on Treatment Line, Risk of AEs

Researchers have shared their findings from a meta-analysis comparing the efficacy and tolerability of various Janus kinase (JAK) inhibitors in myelofibrosis. The findings offer guidance for the use of JAK inhibitors in this setting and suggest that deciding on an inhibitor may depend on the line of treatment and the risk of adverse events like severe anemia and/or thrombocytopenia.

The data also offer novel insights, as comparable data on the treatment class is scarce despite 2 JAK inhibitors being approved for use in myelofibrosis and others having shown benefit. Ruxolitinib has been approved for a decade for the treatment of intermediate-2 or high-risk primary or secondary myelofibrosis, and fedratinib was recently approved in 2019 for the same patients.

“All JAK inhibitors have shown a significant effect on splenomegaly reduction compared to either placebo, best available treatment or ruxolitinib in different clinical trials,” noted the researchers. “Interestingly, tolerance and adverse events seem to be different according to JAK inhibitors. However, there is a lack of data regarding direct comparison of anti-JAKs to each other.”

With a lack of direct comparisons between JAK inhibitors, the researchers collected data from 7 studies, comprising of nearly 2000 patients receiving 1 of the 2 approved JAK inhibitors, pacritinib, or momelotinib. The findings support the use of ruxolitnib as the reference JAK inhibitor for these patients while also suggesting that fedratinib is a viable alternative to ruxolitinib in the frontline setting.

Both fedratinib and momelotinib showed similar efficacy to ruxolitinib, with fedratinib demonstrating comparable reduction in splenomegaly and improvement in disease-related symptoms. The treatment was also less toxic on platelets than ruxolitinib.

“Among investigational agents, momelotinib as first-line or second-line therapy after ruxolitinib appears to be a valuable option to reduce splenomegaly, although it was not possible to obtain results on its relative efficacy on constitutional symptoms,” explained the researchers.

They added that momelotinib may also be a viable option when onset of severe anemia is a concern. Throughout the studies, the treatment was associated with significantly lower rates of grade 3/4 anemia compared with the other 3 JAK inhibitors. According to the group, this could be due to the treatment’s ability to decrease hepcidin production.

Meanwhile, say the researchers, pacritinib seemed to be less effective than ruxolitinib in the frontline setting but showed promise in the second line setting following treatment with ruxolitinib. The researchers wrote: “Concerning pacritinib, our results showed better efficacy to reduce spleen volume in patients with prior ruxolitinib exposure than in patients naïve to JAK inhibitors.”

Reference

Sureau L, Orvain C, Ianotto J, et al. Efficacy and tolerability of Janus kinase inhibitors in myelofibrosis: a systematic review and network meta-analysis. Blood Cancer J. 2021;11(7):135. doi:10.1038/s41408-021-00526-z