Higher Total Body Irradiation (TBI) Dose-Intensity in Fludarabine (Flu)/TBI-Based Reduced-Intensity Conditioning (RIC) Regimen Is Associated with Inferior Survival in Non-Hodgkin Lymphoma (NHL) Patients Undergoing Allogeneic Hematopoietic Cell Transplantation (alloHCT).

Abstract

<h3>Introduction</h3> Disease relapse is the most common cause of therapy failure in NHL patients undergoing RIC alloHCT. Whether increasing TBI dose from 2Gy to 4Gy in RIC-platform can provide improved disease control without increasing non-relapse mortality (NRM) is not known. Using the CIBMTR database we evaluated the outcomes of NHL patients receiving RIC alloHCT with either Flu/2Gy TBI vs. Flu/4Gy TBI. <h3>Methods</h3> In the CIBMTR registry, 413 adult NHL patients underwent a first alloHCT using either a matched related or unrelated donor between 2008-2017, utilizing a RIC regimen with either Flu/2Gy TBI (n=349) or Flu/4Gy TBI (n=64). Graft-versus-host disease (GVHD) prophylaxis was calcineurin inhibitor-based. The primary endpoint was overall survival (OS). Secondary endpoints included acute (a) and chronic (c) GVHD, NRM, relapse/progression and progression-free survival (PFS). Probabilities of OS and PFS were calculated using the Kaplan-Meier estimator. Multivariable regression analysis was performed for GVHD, relapse/progression, NRM, PFS, and OS. Covariates with a p<0.05 were considered significant. <h3>Results</h3> Baseline characteristics are shown in Figure 1. The Flu/2Gy TBI cohort had significantly fewer patients with KPS ≥90 and significantly more patients with HCT-CI ≥3. On multivariate analysis (Figure 2), the two conditioning cohorts were not significantly different in terms of risk of grade 3-4 aGVHD or cGVHD. Compared to Flu/2Gy TBI, the Flu/4Gy TBI conditioning was associated with a significantly higher risk of NRM (HR 1.79, 95%CI=1.11-2.89, p=0.02), and inferior OS (HR 1.51, 95%CI=1.03-2.23, p=0.03). No significant differences were seen in the risk of relapse/progression (HR 0.78, 95%CI=0.47-1.29, p=0.33) or PFS (HR 1.09, 95%CI=0.78-1.54, p=0.61) between the two regimens. Comparing Flu/2Gy TBI vs. Flu/4Gy TBI cohorts the 5-year adjusted outcomes were; NRM (28% vs. 47%; p=0.005), relapse/progression (35% vs. 29%; p=0.28), PFS (37% vs. 24%; p=0.03) and OS (51% vs. 31%; p=0.001), respectively (Figure 3). Rate of graft failure at day100 in similar order was 0.6% vs. 1.6% (p = 0.54), respectively. Relapse was the most common cause of death in both cohorts. <h3>Conclusions</h3> In NHL patients undergoing Flu/TBI-based conditioning, augmenting TBI dose from 2Gy to 4Gy is associated with higher NRM and inferior OS, without any significant benefit in terms of disease control. 2Gy is optimal dose in the RIC Flu/TBI platform for lymphomas.