In a study reported in JAMA Oncology, Ghosh et al found that a more intense reduced-intensity conditioning and nonmyeloablative conditioning (RIC-NMAC) regimen consisting of fludarabine plus melphalan at 140 mg/kg (Flu-Mel14) appears to be associated with poorer overall survival and higher non–relapse-related mortality compared with less intense regimens among patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for non-Hodgkin lymphoma.
As stated by the investigators, “[RIC-NMAC] regimens are frequently used in allogeneic HSCT for non-Hodgkin lymphoma. However, the optimal RIC-NMAC regimen in allogeneic HSCT for non-Hodgkin lymphoma is not known.”
Study Details
The study involved data from 1,823 adult patients in the Center for International Blood and Marrow Transplant Research registry who underwent allogeneic HSCT using matched related or unrelated donors between January 2008 and December 2016. Patients received one of four RIC-NMAC regimens:
- Fludarabine plus busulfan at a uniform dose of approximately 6.4 mg/kg (Flu-Bu, n = 458)
- Flu-Mel140 (n = 885)
- Fludarabine plus cyclophosphamide (Flu-Cy, n = 391)
- Flu-Cy with 2 Gy total-body irradiation (Flu-Cy-2GyTBI, n = 89).
Patients could have received in vivo T-cell depletion with antithymocyte globulin or alemtuzumab. The primary outcome measure of the analysis was overall survival.
Key Findings
The 4-year overall survival rates were 58% in the Flu-Bu cohort, 67% in the Flu-Cy-2GyTBI cohort, 49% in the Flu-Mel140 cohort, and 63% in the Flu-Cy cohort (overall P < .001). In multivariate analysis adjusting for age, Karnofsky performance score, HSCT comorbidity index, non-Hodgkin lymphoma subtype, remission status at HSCT, and use of antithymocyte globulin or alemtuzumab, the mortality risk with Flu-Mel140 was significantly higher than that associated with Flu-Bu (hazard ratio [HR] = 1.34, 95% confidence interval [CI] =1.13–1.59), Flu-Cy-2GyTBI (HR = 1.82, 95% CI = 1.23–2.69), and Flu-Cy (HR = 1.59, 95% CI = 1.29–1.95). No significant differences were observed among the Flu-Bu, Flu-Cy-2GyTBI, and Flu-Cy cohorts.
The 4-year cumulative incidence of nonrelapse mortality was 16% in the Flu-Bu cohort, 17% in the Flu-Cy-2GyTBI cohort, 26% in the Flu-Mel140 cohort, and 17% in the Flu-Cy cohort (overall P < .001). In multivariate analysis adjusted for the above factors, risk with Flu-Mel140 was significantly higher vs Flu-Bu (HR = 1.78, 95% CI = 1.37–2.31). Compared with Flu-Bu, the Flu-Cy and Flu-Cy-2GyTBI regimens were not associated with increased risk.
In analysis adjusting for donor type, graft-vs-host disease prophylaxis, and antithymocyte globulin or alemtuzumab use, the Flu-Mel140 regimen was associated with higher risk of chronic graft-vs-host disease than the Flu-Cy regimen (HR = 1.38, 95% CI = 1.15–1.65).
The investigators concluded, “The findings suggest that use of the more intense RIC-NMAC regimen, Flu-Mel140, may have a negative association with overall survival and may be associated with higher nonrelapse mortality. The Flu-Bu and Flu-Cy regimens with or without 2GyTBI regimens appeared to provide comparable overall survival.”
Mehdi Hamadani, MD, of the Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was supported by the National Cancer Institute; National Heart, Lung, and Blood Institute; and others. For full disclosures of the study authors, visit jamanetwork.com.
