Mutation Clearance After Transplant Linked to Better Outcomes in Myelofibrosis

Clearance of driver mutations at day 30 after transplantation was associated with a reduced risk of relapse and better survival among patients with myelofibrosis, a German study showed.

The cumulative incidence of relapse at 1 year was 6% among patients with clearance of JAK2, CALR, and MPL mutations at day 30 after transplantation, and 21% among those without mutation clearance at this time point, reported Nicolaus Kröger, MD, of the University Medical Center Hamburg-Eppendorf in Germany, and colleagues in the New England Journal of Medicine.

Disease-free and overall survival rates at 6 years were 61% and 74%, respectively, among patients with mutation clearance at day 30 after transplantation, and 41% and 60%, respectively, among those without mutation clearance at day 30.

Kröger and colleagues determined that mutation clearance 30 days after transplantation was independently associated with a reduced risk of relapse or progression (HR 0.36, 95% CI 0.21-0.61) and a reduced risk of death, relapse, or progression (HR 0.49, 95% CI 0.34-0.69).

While mutation clearance at day 30 appeared to be the best predictor of response, mutation clearance at day 100 or 180 was also associated with a reduced risk of relapse or progression and a reduced risk of death compared with persistence of mutations at day 180.

“Myelofibrosis is harbored in 90% of one of three so-called driver mutations — JAK2, CALR, and MPL — which can be detected in peripheral blood,” Kröger told MedPage Today. “Disappearance of this driver mutation is necessary to cure the disease, which can be achieved only by hematopoietic stem cell transplantation. Here we could show that clearance of driver mutations on day 30 after allogeneic stem cell transplantation was the most predictive factor for relapse, followed by clearance at day 100.”

“The study clearly showed that driver mutation monitoring is needed to counsel patients properly, and will become clinical practice,” he added.

In explaining the rationale behind the study, the authors noted that while driver mutations “are the pathophysiological hallmark of the disease,” the role of mutation clearance after transplantation has been unclear.

They included 324 patients with myelofibrosis — 73% with JAK2 mutations, 23% with CALR mutations, and 4% with MPL mutations. The median age of the study population was 60 years, and 58% were men. Of these patients, 62% underwent transplantation for primary myelofibrosis, and more than half had received prior JAK inhibitor therapy.

At day 30 after transplantation, mutation clearance was found in 42% of patients who had JAK2 mutations, 73% of those who had CALR mutations, and 54% of those who had MPL mutations. At day 100, these proportions were 63%, 82%, and 100%, respectively.

Kröger and colleagues also reported that mutation clearance at 30 days “appeared to outperform traditional donor chimerism as a measure of response.”

Specifically, the 1-year cumulative incidence of relapse or progression was 6% among patients with full donor chimerism and mutation clearance at day 30 after transplantation, 6% among those with mixed chimerism and mutation clearance, 16% among patients with full donor chimerism and a lack of mutation clearance, and 36% among patients with mixed chimerism and a lack of mutation clearance.

The authors acknowledged that there were limitations to their study, including the fact that the study population was made up primarily of German citizens who were mainly white, which “may not fully capture the diversity of the broader population of patients with myelofibrosis, including groups such as Black or Hispanic patients.”