For patients with myelofibrosis (MF) undergoing hematopoietic cell transplantation, clearance of driver mutations at day 30 was the most predictive factor influencing relapse and survival, according to study results published in the New England Journal of Medicine.
“Historically, after transplant we look for chimerism [as a measure of response], but these molecular markers were more sensitive for predicting relapse and cure than chimerism,” said study researcher Nicolaus Kröger, MD, of University Medical Center Hamburg-Eppendorf in Hamburg, Germany. “Based on these practice-changing results, it should now become standard of care to monitor these patients with molecular markers post-transplant.”
Dr. Kröger and colleagues used peripheral blood samples from 324 patients with MF and analyzed the dynamics of driver mutations using polymerase chain reaction technology. Mutations were analyzed prior to transplant and again at 30, 100, and 180 days after transplant. Patients in the study had MF with JAK2 mutations (73%), CALR mutations (23%), and MPL mutations (4%).
At day 30, mutation clearance was observed in 42% of patients with JAK2 mutations, 73% of patients with CALR mutations, and 54% of patients with MPL mutations.
There were data available for 271 patients at day 100. At that time, 63% of patients with JAK2 mutations, 82% of patients with CALR mutations, and 100% of patients with MPL mutations had mutation clearance. By day 180, 79% of patients with JAK2 and 90% of patients with CALR mutation had clearance, and clearance was maintained among those with MPL mutations.
“Patients who were negative by day 30 had the best outcomes,” Dr. Kröger said. “However, patients who had clearance by day 100 had better outcomes than those who have not, and patients who cleared by day 180 were better than those who never clear.”
The researchers also found a difference in chimerism and mutation clearance at day 30, with mutation clearance appearing to outperform the traditional assessment. Full chimerism occurred in 144 patients, but only about half (54%) had mutation clearance. In contrast, 17 patients with mixed chimerism had full mutation clearance.
The cumulative incidence of relapse at one year was 6% (95% CI 2-10) among patients who had mutation clearance by day 30 compared with 21% (95% CI 15-27) for those without clearance by day 30.
“The difference in survival was more than 20% between those who cleared and those who did not,” Dr. Kröger said. Disease-free survival and overall survival at six years was 61% and 74%, respectively, for patients who had mutation clearance by 30 days, compared with 41% and 60% for those who did not have mutation clearance.
Mutation clearance by day 30 was independently associated with post-transplant outcomes (hazard ratio = 0.36; 95% CI 0.21-0.61) and appeared to be more important than the type of driver mutation.
The study was limited by the fact that the patient cohort was primarily German citizens and primarily included non-Hispanic white patients, which “may not fully capture the diversity of the broader population of patients with MF, including groups such as Black or Hispanic patients.” The patient group also included a limited number of patients with MPL or TP53 mutations.
A next step for researchers is to look at what can be done clinically for those patients who underwent transplant but did not have mutation clearance by day 30.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Gagelmann N, Quarder M, Badbaran A, et al. Clearance of driver mutations after transplantation for myelofibrosis. N Engl J Med. 2025;392(2):150-160.
Perspectives
Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative therapy for patients with MF. Despite the advances made in alloHCT, disease relapse remains a significant issue, occurring in up to 30% of cases. Many retrospective studies have identified factors that predict survival following transplant for MF, examining conditioning regimens, donor type, and recipient characteristics.1 However, our understanding of the post-transplant events and outcomes is less clear. Although several studies have evaluated this in small groups of patients,2,3 the study by Gagelmann et al. systematically evaluated a large number of patients with rigorous methods.4
This study provides important insight into the impact of persistence of measurable residual disease and chimerism. It demonstrated that persistence of one of the driver mutations, such as JAK2, CALR, and MPL, at days 30, 100, and 180 increases the risk for relapse. Detection of the driver mutation outweighs donor chimerism in its ability to predict relapse and remains significant when accounting for other pretransplant variables that are associated with outcome. As expected, the presence of the mutation is an indicator of a higher risk of relapse. However, its ability to outperform chimerism and maintain significance when taking into account pretransplant variables is notable.
There are limitations to this study. The variant allele frequency (VAF) of these mutations was not reported. Although the study notes that a decrease in the VAF by 50% or greater in patients whose baseline VAF was greater than 20% is a good marker of relapse risk, the VAF in patients who were “positive” was not reported. It is unclear whether there is a threshold at which the VAF is more significant. Additionally, in the patients who had other high-risk mutations (38%), clearance of these mutations was not assessed.
Despite these questions, these data provide critical benchmarks to design post-transplant interventions to prevent relapse. Interventions, such as more rapid tapering of immunosuppression and administration of donor lymphocyte infusions,2 may be considered. If we can identify a population that has a high risk of relapse, we can justify the risks to these approaches and enhance our ability to detect a benefit.
Jeanne Palmer, MD
Professor of Medicine
Division of Hematology/Oncology
Mayo Clinic
Phoenix, AZ
References
- Palmer J. Are transplant indications changing for myelofibrosis? Hematology Am Soc Hematol Educ Program. 2023;2023(1):676-681.
- Gagelmann N, Wolschke C, Badbaran A, et al. Donor lymphocyte infusion and molecular monitoring for relapsed myelofibrosis after hematopoietic cell transplantation. Hemasphere. 2023;7(7):e921.
- Wolschke C, Badbaran A, Zabelina T, et al. Impact of molecular residual disease post allografting in myelofibrosis patients. Bone Marrow Transplant. 2017;52(11):1526-1529.
- Gagelmann N, Quarder M, Badbaran A, et al. Clearance of driver mutations after transplantation for myelofibrosis. N Engl J Med. 2025;392(2):150-160.
