Ex Vivo T Cell-Depleted and In Vivo T Cell-Depleted Allogeneic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia in First Complete Remission Resulted in Similar Overall Survival Survival: On Behalf of the ALWP of the EBMT and the MSKCC

Background. Myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well-established therapy for adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) with intermediate or high-risk cytogenetics. However regimen-related toxicities, in particular graft-versus-host disease (GVHD) have limited its widespread use. Therefore several strategies have been developed to deplete T cells in order to prevent GVHD. In vivo T-cell depletion (TCD) using antithymocyte globulin (ATG) with an unmanipulated graft is widely used in some centers in Europe, while other centers have develop an effective platform based on ex-vivo TCD CD34 selected (CD34+) graft. The aim of the current study was to compare these two strategies for GVHD prevention.

Patients and methods. This retrospective analysis assessed the outcome of all consecutives patients over 18 years at time of transplant with an AML in CR1 with intermediate or high risk cytogenetics who received an in-vivo or ex-vivo T cell depleted myeloablative allo-HSCT using busulfan or total body irradiation based conditioning regimen between 2005 and 2011 and reported to the EBMT ALWP registry centers or at Memorial Sloan Kettering Cancer Center (MSK), respectively. Patients treated in EBMT centers received in vivo TCD with either thymoglobuline or grafalon ATG. In addition, all patients in the ATG group received GVHD prophylaxis consisting of a calcineurin inhibitor in combination with another drug. Patients treated at MSK received an ex-vivo TCD graft (CD34+). TCD was performed by immunomagnetic CD34+ cell selection of peripheral blood grafts. No additional GVHD prophylaxis was administered in those patients. Main transplant outcomes including refined GVHD-free/relapse-free survival (GRFS) were evaluated.

Results. A total of 525 patients were included (363 ATG, 162 CD34+) with a median age of 46 (19-77) and 58 (range, 20-73) years, respectively (p<0.001). The ATG cohort had more unrelated donors (67.5% vs. 54.9%, p=0.006). Median follow-up was significantly longer in the CD34+ cohort [58.0 (range, 6-139.0), vs. 24.5, 51.9-131.0) months, p<0.001], therefore all patients were censored at 2 years for comparison between groups. There were no additional differences between cohorts including donor/recipient gender, CMV status and cytogenetic risk. The CD34+ cohort had less relapse (21.6% vs. 30%, p=0.03), grade II-IV aGVHD (11.3% vs. 21.2%, p=0.006), III-IV aGVHD (1.3% vs. 6.2%, p=0.01), cGVHD (2.5% vs. 27.6%, p<0.0001) and extensive cGVHD (0.6% vs. 11.3%, p=0<0.0001) and a higher GRFS (61% vs. 47%, p=0.0007) while there was no difference regarding OS (67.6% vs. 56.4%, p=0.31), LFS (61% vs. 57.9%, p=0.29) and NRM (17.4%, vs 12.1%, p=0.16). In multivariate analysis, the cumulative incidence of grade II-IV aGVHD and chronic GVHD were higher in the ATG cohort [HR 2.0 (95% CI 1.1-3.7), p=0.02 and HR 15.1 (95% CI 5.3-42.2), p<0.0001]. There were no statistical differences between both approach in terms of relapse, NRM, OS, and LFS. Parameters associated with a lower GRFS were ATG group, adverse cytogenetic and use of an unrelated donor [HR 1.7 (95% CI 1.2-2.5) p=0.001; HR 1,7 (95% CI 1.3-2.2) p=0.0002 and HR 1.5 (95% CI 1.1-2.0) p=0.01]. Cytogenetic status (high risk versus intermediate risk) also has a significant impact on relapse incidence [HR 2.1 (95% CI 1.4-3.0), p<0.0001] and LFS [HR 1.7 (95% CI 1.2-2.3) p=0.0006]. Finally there was significantly more death related to infection in the CD34 group (16/52, vs. 19/112, p=0.04).

Conclusion. The cumulative incidence of acute (total and severe) and chronic GVHD were higher after allo-HSCT with ATG, leading to a lower GRFS in those patients. In contrast, enhance immunosuppression in the CD34+ group lead to a higher incidence of infectious related death. Overall NRM, OS and LFS are similar after ex-vivo CD34 selected and in-vivo ATG TCD allo-HSCT from related/unrelated donors in patients with AML in CR1 and intermediate/high-risk cytogenetic. Both approaches are associated with a good disease control and a high OS, and should be compared in a prospective randomized trial.