Fludarabine and 2-Gy TBI is superior to 2 Gy TBI as conditioning for HLA-matched related hematopoietic cell transplantation: a phase III randomized trial

Abstract

The risks and benefits of adding fludarabine to a 2-Gy total body irradiation (TBI) nonmyeloablative regimen are unknown. For this reason, we conducted a prospective randomized trial comparing 2-Gy TBI alone, or in combination with 90 mg/m(2) fludarabine (FLU/TBI), before transplantation of peripheral blood stem cells from HLA-matched related donors. Eighty-five patients with hematological malignancies were randomized to be conditioned with TBI alone (n = 44) or FLU/TBI (n = 41). All patients had initial engraftment. Two graft rejections were observed, both in the TBI group. Infection rates, nonrelapse mortality, and graft-versus-host disease (GVHD) were similar between groups. Three-year overall survival was lower in the TBI group (54% versus 65%; hazard ratio [HR], .57; P = .09), with higher incidences of relapse/progression (55% versus 40%; HR, .55; P = .06), relapse-related mortality (37% versus 28%; HR, .53; P = .09), and a lower progression-free survival (36% versus 53%; HR, .56; P = .05). Median donor T cell chimerism levels were significantly lower in the TBI group at days 28 (61% versus 90%; P < .0001) and 84 (68% versus 92%; P < .0001), as was NK cell chimerism on day 28 (75% versus 96%; P = .0005). In conclusion, this randomized trial demonstrates the importance of fludarabine in augmenting the graft-versus-tumor effect by ensuring prompt and durable high-level donor engraftment early after transplantation.

Keywords: Fludarabine/low dose total body irradiation; HLA-matched related hematopoietic cell transplantation randomized trial; Nonmyeloablative conditioning.

Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Donor granulocyte and T-cell chimerism

Percent donor granulocyte (A) and T-cell chimerism (B) in patients conditioned with 2 Gy total body irradiation only (TBI, n=44) or in combination with 90 mg/m2 fludarabine (FLU/TBI, n=41). Horizontal lines represent medians and dots, the individual data points. P-values are two-tailed.

Figure 2. Immune reconstitution

Mean absolute numbers of natural killer (NK) cells, CD4+, naïve CD4+, and memory/effector CD4+ cells at days 28 (TBI n=16, FLU/TBI n=7) and 90 (TBI n=8, FLU/TBI n=13) post-transplant in patients conditioned with 2 Gy total body irradiation only (TBI) or in combination with 90 mg/m2 fludarabine (FLU/TBI). Bars represent standard error of the mean. P-values are two-tailed.

Figure 3. Graft-versus-host disease

Cumulative incidences of grade II-IV acute (A) and chronic (B) GVHD among patients conditioned with 2 Gy total body irradiation only (TBI) or in combination with 90 mg/m2 fludarabine (FLU/TBI).

Figure 4. Non-relapse mortality

Cumulative incidence of non-relapse mortality among patients conditioned with 2 Gy total body irradiation only (TBI) or in combination with 90 mg/m2 fludarabine (FLU/TBI).

Figure 5. Relapse or progression incidence and relapse related mortality

Cumulative incidences of relapse or progression (A) and relapse related mortality among patients conditioned with 2 Gy total body irradiation only (TBI) or in combination with 90 mg/m2 fludarabine (FLU/TBI).

Figure 6. Progression free survival and overall survival

Cumulative incidences of progression free survival (A) and overall survival (B) among patients conditioned with 2 Gy total body irradiation only (TBI) or in combination with 90 mg/m2 fludarabine (FLU/TBI).