Evaluating the Impact of Absolute Lymphocyte Count on Outcomes in ATG Containing Haploidentical HSCT for Acute Myeloid Leukemia

Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely performed as a treatment for acute myeloid leukemia (AML). In HSCT, graft-versus-host disease (GVHD) remains a critical issue associated with mortality, and several drugs are used in conditioning as prophylaxis. Anti-thymocyte globulin (ATG) has been widely used for GVHD prophylaxis, but recent data have led to a decline in the use of ATG, suggesting the superior efficacy of alternative prophylaxis such as post-transplant cyclophosphamide. Nevertheless, there is still no consensus on the optimal timing and dosage of ATG administration, and identifying a more optimal method of administration could potentially reaffirm the value of ATG in HSCT.

Recent studies have suggested that absolute lymphocyte count (ALC) may serve as a significant indicator of outcomes in ATG-based HSCT regimens, particularly in unrelated donor or pediatric transplants, as ALC may influence the metabolism of ATG. However, no studies have evaluated the impact of ALC at the time of ATG administration on outcomes in haploidentical HSCT, particularly in adult AML patients. Based on this background, we retrospectively analyzed our single-center experience with ATG-containing haploidentical HSCT to investigate the relationship between ALC at the time of ATG administration and HSCT outcomes.

Methods: This study analyzed adult AML patients who achieved remission after chemotherapy and underwent haploidentical HSCT at a single institution between 2010 and 2023. Patients received a homogenous conditioning regimen 5 days of Fludarabine 30mg/BSA plus 2 days of Busulfan 3.2mg/kg and fractionated total body irradiation of 800cGY. ATG was administered from day-4 to day-1, 1.25mg/kg per day. Methotrexate 5mg/BSA for 4 days was administered after stem cell infusion. The graft source was peripheral blood stem cells with non-ex vivo T-cell depletion. We evaluated the absolute dose of ATG infused, ALC and weight on the day of ATG administration, the CD3 cell dose infused, and their association with overall survival (OS), relapse-free survival (RFS), GVHD-relapse-free survival (GRFS), cumulative incidence of relapse, and non-relapse mortality (NRM). We also assessed the cumulative incidence of acute GVHD (grade≥2) and chronic GVHD (moderate or severe), considering death as a competing risk.

Results: Firstly, we attempted to create a Cox model to predict OS using the aforementioned variables. In our data, there was no significant likelihood ratio (LR) difference between the model using ALC alone and models including other variables, and the ALC single-variable model showed the lowest Akaike Information Criterion (AIC). Additionally, when comparing the linear relationship model between ALC and hazard with non-linear relationship models using spline methods, splining with 4 knots model showed the lowest AIC. Based on these results, we confirmed that among the various indicators related to ATG administration, only ALC was significant, and we decided to compare the HSCT outcomes based on three groups according to ALC count (<0.02 x 10^9/L, 0.02~0.05 x 10^9/L, >0.05 x 10^9/L)

Despite the overall baseline similarities, there were significant differences in OS between the groups, especially in the high ALC group (median OS in lower, medium, higher ALC group: Not reached vs. Not reached vs. 2.1 years. p-value= 0.013). RFS, and GRFS showed similar trends. The cumulative incidence analysis showed no statistical significance across all outcomes; interestingly, the highest ALC group showed highest cumulative incidence of relapse. The incidence chronic GVHD tended to be higher in high ALC groups.

Conclusion: In our regimen, where ATG is administered close to the time of stem cell infusion, the post-HSCT exposure to ATG may not be significantly different, even when dosed per kilogram, since ATG dose does not show any significance in HSCT outcomes. We observed that the prognosis varied significantly according to the ALC at the time of ATG administration, with the high ALC group showing worse outcomes. The reason for this needs to be investigated. It is necessary to determine what differences in outcomes occur when the ATG dose is adjusted in the high ALC group. Further studies are needed to determine the optimal ATG regimen and dose in haploidentical HSCT for adult AML.

Park:ImpriMed, Inc.: Consultancy, Current holder of stock options in a privately-held company. Kim:AbbVie, AIMS Bioscience, AML-Hub, Astellas, BMS & Celgene, Boryung Pharm Co., Daiichi Sankyo, Janssen, Handok, LG Chem, Novartis, Pfizer, SL VaxiGen, VigenCell, Aston Bioscience, Ingenium, Amgen, Sanofi Genzyme, Takeda, Meiji Pharm Co. and GreenCross Phar: Consultancy; AbbVie, Astellas, BMS, Handok, Novartis, AML-Hub, Jazz Pharmaceuticals and Takeda: Honoraria, Speakers Bureau; BL&H: Research Funding; BMS & Celgene, Novartis, APLC, AbbVie, Astellas, Janssen, Handok, Pfizer, Sanofi Genzyme, AML-Hub, Daiichi Sankyo and APBMT: Membership on an entity's Board of Directors or advisory committees.