Avoidance of ATG improves outcomes in double-cord blood transplantation for hematological malignancies

Abstract Background Umbilical cord blood transplantation (CBT) is an alternative source of hematopoietic stem cells providing access to curative therapy for patients with hematological malignancies lacking an available human leukocyte antigen (HLA)-matched related or unrelated donor. The cell dose of CD34+ and total nucleated cells (TNC), as well as the degree of HLA disparities between the cord blood donor and recipient are known to affect engraftment and clinical outcome. Published CBT guidelines specify minimum CD34+ and TNC counts, HLA-matching, and storage volume thresholds, and recommend avoiding the use of anti-thymocyte globulin (ATG). Adherence to guidelines is associated with improved outcomes in single CBT. Here, we investigated the outcomes between double CBT (dCBT) that adhered to these guidelines versus those that did not. Methods This analysis included adult patients (age > 18 years) who received a dCBT for MDS, AML, or ALL between 1/2010, and 12/2021 reported to the Center for International Blood & Marrow Transplant Research (CIBMTR). Adherence to CBT guidelines was defined as: 1) a unit with a TNC > 1.5x107 cells/kg or CD34+ > 1.0x105cells/kg; 2) HLA matching ≥ 4/8; 3) product volume between 24.5-27.5ml (1 bag) or 48-52ml (2 bags). ATG use was modeled as a separate variable, as it is not a CB unit-specific parameter. The primary endpoint was overall survival (OS). Secondary endpoints were disease-free survival (DFS), primary disease relapse, treatment-related mortality (TRM), engraftment, acute and chronic graft-versus-host disease (GVHD), and GVHD-, relapse-free survival (GRFS). Univariable probabilities of OS, DFS, and GRFS were calculated using the Kaplan-Meier estimator. Cumulative incidences of relapse, TRM, engraftment, and GVHD were calculated using the cumulative incidence estimator to accommodate competing risks. Cox proportional hazards models were used to compare adherent (both cords adherent), semi adherent (one cord adherent and the other non-adherent), and non-adherent dCBT (both cords non-adherent). A significance level of p<0.01 was used to account for multiple testing. Results A total of 1,478 dCBT were included. 368 transplants were performed with two adherent units, 580 with one adherent unit, 263 with two non-adherent units, and 267 had missing data on HLA matching. There were no statistically significant differences in age, KPS, HCT-CI, disease state, or conditioning intensity between the groups. Overall, both cords were known to be adherent to: CD34 count (41%), TNC count (96%), HLA (67%) and volume (40%) criteria. 83% of transplants did not use ATG. In multivariable analysis with ATG as a separate characteristic from other unit characteristics, there was no significant association of adherence with outcomes. ATG use was associated with significantly higher TRM (HR=1.38, 1.08-1.77, p =0.0105) and lower but not statistically significant OS (HR 1.25, 1.02-1.52, p=0.029), DFS (HR 1.23, 1.00-1.51, p=0.049), aGVHD 2-4 (HR 0.68, 0.47-0.96, p=0.0308), aGVHD 3-4 (HR 0.74, 0.57-0.97, p=0.0273) with no significant reduction of cGVHD, increase in relapse, or change in engraftment compared to CBT without ATG. When adherence factors were separately analyzed and the model was adjusted for ATG use, adherence of CD34+ dose in both units was associated with significantly improved neutrophil recovery (hazard ratio, HR=1.37, 1.19-1.57, p<0.0001) and platelet engraftment (HR=1.26, 1.12-1.41, p=0.0001). Adherence of both units to volume thresholds was associated with improved platelet engraftment (HR=1.17, 1.04-1.31, p=0.0095). Conclusion This data suggests that adherence to guidelines, and in particular avoidance of ATG, can result in higher OS and DFS, less TRM, and faster engraftment among patients treated with dCBT for acute leukemias and MDS.