Higher Total Body Irradiation Dose Intensity in Fludarabine/TBI-Based Reduced-Intensity Conditioning Regimen Is Associated with Inferior Survival in Non-Hodgkin Lymphoma Patients Undergoing Allogeneic Transplantation

Disease relapse is the most common cause of therapy failure in patients with non-Hodgkin lymphoma (NHL) undergoing reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (allo-HCT). It is not known whether or not increasing total body irradiation (TBI) dose from 2 to 4 Gy in a RIC platform can provide improved disease control without increasing nonrelapse mortality (NRM). Using the Center for International Blood & Marrow Transplant Research (CIBMTR) database, we evaluated the outcomes of patients with NHL receiving RIC allo-HCT with either fludarabine (Flu)/2-Gy TBI versus Flu/4-Gy TBI. In the CIBMTR registry, 413 adult patients with NHL underwent a first allo-HCT using either a matched related or unrelated donor between 2008 and 2017, using a RIC regimen with either Flu/2-Gy TBI (n = 349) or Flu/4-Gy TBI (n = 64). The primary endpoint was overall survival (OS). Secondary endpoints included acute (a) and chronic (c) graft-versus-host disease (GVHD), NRM, relapse/progression, and progression-free survival (PFS). At baseline, the Flu/2-Gy TBI cohort had significantly fewer patients with Karnofsky performance status ≥90 and significantly more patients had a higher HCT-comorbidity index. On multivariate analysis, the 2 conditioning cohorts were not significantly different in terms of risk of grade 3 to 4 aGVHD or cGVHD. Compared to Flu/2-Gy TBI, the Flu/4-Gy TBI conditioning was associated with a significantly higher risk of NRM (hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.11 to 2.89; P = .02) and inferior OS (HR, 1.51; 95% CI, 1.03 to 2.23, P = .03). No significant differences were seen in the risk of relapse/progression (HR, 0.78; 95% CI, 0.47 to 1.29, P = .33) or PFS (HR, 1.09; 95% CI, 0.78 to 1.54, P = .61) between the 2 regimens. Comparing Flu/2-Gy TBI versus Flu/4-Gy TBI cohorts, the 5-year adjusted outcomes were NRM (28% versus 47%; P = .005), relapse/progression (35% versus 29%; P = .28), PFS (37% versus 24%; P = .03), and OS (51% versus 31%; P = .001), respectively. Relapse was the most common cause of death in both cohorts. In patients with NHL undergoing Flu/TB I-based conditioning, augmenting TBI dose from 2 to 4 Gy is associated with higher NRM and inferior OS, without any significant benefit in terms of disease control. The optimal dose is 2-Gy in the RIC Flu/TBI platform for lymphomas.