Myeloproliferative Neoplasms: Focus on Myelofibrosis
Dr. Lynda Foltz - University of British Columbia
There continues to be progress in understanding molecular pathogenesis in myelofibrosis (MF). Most patients harbour a driver mutation that activates the Jak2 signaling pathway, either a mutation in Jak2, CALR or MPL. It had been unclear exactly how CALR, a protein usually found in the endoplasmic reticulum, activated Jak2. Recent studies now suggest that the mutant CALR protein can bind MPL, leading to Jak2 pathway activation. Interestingly, there appear to be different clinical features associated with different CALR mutations. CALR type 1 mutation (deletion) has been associated with a better prognosis than CALR type 2 mutations (insertion) in MF, even though both result in the same frameshift. Triple negativity (negative for Jak2, CALR and MPL) has the poorest prognosis, likely due to association with other high molecular risk mutations.
Ruxolitinib continues to be the only Heath Canada approved medication for MF. 5 year data from the COMFORT trial demonstrates an ongoing survival benefit for patients randomized to ruxolitinib, despite cross-over at 24 weeks. Average duration of splenic response was 168 weeks and 27% of patients remain on trial. No new adverse events are apparent. Risk of herpes zoster is 3.5 per 100 patient years. Further analysis of the COMFORT data set supports benefit of ruxolitinib in patients with and without baseline anemia. Ruxolitinib associated anemia does not appear to carry the same adverse prognostic impact as disease associated anemia. Management of anemia and thrombocytopenia continues to be a challenge in MF. Phase 2 studies of momelotinib had suggested improvements in hemoglobin in some patients, but peripheral neuropathy was also reported. The phase 3 RCT of momelotinib vs ruxolitinib for first line treatment of MF has completed accrual, and we await report of results.