TLI and ATG conditioning with low risk of graft-versus-host disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from related and unrelated donors

Abstract

A hematopoietic cell transplantation regimen was adapted from a preclinical model that used reduced-intensity conditioning (RIC) and protected against graft-versus-host disease (GVHD) by skewing residual host T-cell subsets to favor regulatory natural killer T cells. One hundred eleven patients with lymphoid (64) and myeloid (47) malignancies received RIC using total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) followed by the infusion of granulocyte colony-stimulating factor-mobilized grafts. Included were 34 patients at least 60 years of age, 32 patients at high risk of lymphoma relapse after disease recurrence following prior autologous transplantation, and 51 patients at high risk of developing GVHD due to lack of a fully human leukocyte antigen (HLA)-matched related donor. Durable chimerism was achieved in 97% of patients. Cumulative probabilities of acute GVHD (grades II-IV) were 2 and 10% of patients receiving related and unrelated donor grafts. Nonrelapse mortality (NRM) at 1 year was less than 4%. Cumulative incidence of chronic GVHD was 27%. The 36-month probability of overall and event-free survival was 60% and 40%, respectively. Disease status at start of conditioning and the level of chimerism achieved after transplantation significantly impacted clinical outcome. The high incidence of sustained remission among patients with active disease at time of transplantation suggests retained graft-versus-tumor reactions. Active trial registration currently at clinicaltrials.gov under IDs of NCT00185640 and NCT00186615.

Figures

Figure 1

Effect of TLI + ATG on circulating T-cell subsets. Absolute T-cell subset population size pre-TLI (x-axis) and immediately post-TLI (y-axis) with plotted linear regression (solid lines, constrained through 0,0) for CD3, CD4, CD8, and NKT-cell subsets. Dashed line representative of a population with no change (y = x) in population size between pre-TLI and immediately post-TLI (A). Boxplot of fold decrease in CD3, CD4, CD8, and NKT-cell populations (median, thick line; quartiles, box; range, whiskers; outliers, circle; B).

Figure 2

NRM. Cumulative incidence of NRM, with 95% CIs, among patients who received matched-related donor (A) and matched-unrelated donor (B) grafts with competing risks of relapse.

Figure 3

GVHD. Cumulative incidence of acute GVHD with 95% CIs, among patients who received matched-related donor (A) and matched-unrelated donor (B) grafts. Cumulative incidence of chronic GVHD with 95% CIs, among patients who received matched-related donor (C) and matched-unrelated donor (D) grafts. Cumulative incidence of acute and chronic GVHD were calculated with competing risks including relapse, death, and primary graft failure.

Figure 4

Effect of disease status at transplant on OS and EFS. Kaplan-Meier OS (A) and EFS (B) curve estimates among patients with NHL stratified by disease status at time of transplantation (first CR, PR, or SD and PD). Kaplan-Meier OS (C) and EFS (D) curve estimates among patients with de novo AML stratified by disease status at time of transplantation (first CR, second CR, or beyond second remission including persistent disease). Corresponding 36-month OS or EFS noted. The OS curve for patients with de novo AML falls below the EFS at 19.5 months as an artifact of censoring of 2 subjects between the times of another subject's relapse and death.

Figure 5

Effect of chimerism on OS and EFS. Kaplan-Meier OS (A) and EFS (B) curve estimates among patients with NHL enrolled with CR or PR stratified by chimerism (complete or mixed chimerism, no graft failures occurred). Kaplan-Meier OS (C) and EFS (D) curve estimates among patients with de novo AML enrolled with disease control, CR1 or CR2 stratified by chimerism (complete, mixed, or primary graft failure). Corresponding 36-month OS or EFS noted.