The Impact of the Absolute Lymphocyte Count before Anti-T-Lymphocyte Globulin (ATLG) Administration on Transplant Outcomes in Matched Unrelated Peripheral Blood Stem Cell Allogeneic Stem Cell Transplantation
Authors: Massoud Radwan , Ursi Margherita , Barbato Francesco , De Felice Francesco , Maffini Enrico , Roberto Marcello , Klyuchnikov Evgeny , Langebrake Claudia , Gagelmann Nico , Zeck Gabriele , Niederwieser Christian , Lück Catherina , Janson Dietlinde , Wolschke Christine , Ayuk Francis A. , Kroeger Nicolaus , Bonifazi Francesca 
Published: December 2024

Background:
Data on optimal ATLG dosing in MUD-PBSC-allo-SCT is limited. Conventional weight-based dosing may excessively deplete T-cells and lead to unfavorable outcomes. ALC-based dosing on ATLG administration day has been proposed as an alternative. We conducted a retrospective study at University Medical Center Hamburg-Eppendorf (UKE) and University Medical Center Bologna to investigate the impact of ALC and ATLG dose on transplant outcomes.
Methods:
We included 378 (UKE n=251, Bologna n=127) patients who underwent allo-SCT (years 2018-2023) with PBSCs from UD (97% HLA 10/10, 3% HLA 9/10) and received ATLG at a total dose of 30 mg/kg between days -4 and -1 in the UKE cohort and days -6 to -2 in the Bologna Cohort. Patients were categorized based on the median ALC 0.32Mrd/L (range 0-13.85) into the “low-ALC” group with (ALC ≤ 0.32Mrd/L) and the “high-ALC” group with measurable lymphocytes (ALC &gt; 0.32Mrd/L) on the first day of ATLG administration, allowing for a comparison of transplant outcomes between these groups.
Results:
Median follow-up was 12 months (range 1-56). Median days to neutrophil engraftment was 11 (range 6-21) in the low-ALC group and 13 (range 8-27) in the high-ALC group (p&lt;0.001).
In univariate analysis, no significant differences in 2-year NRM were observed between low-ALC (16% [95%CI: 11-22%]) and high-ALC groups (12% [95%CI: 8-17%]; p=0.24), whereas allo-SCT year (≤ 2020: 18% vs &gt;2020 10%, p=0.02), conditioning intensity (MAC 9% vs RIC 19%) p=0.005), disease status at transplant (CR: 10% vs not CR 18%, p=0.03) significantly affected NRM. In Multivariate analysis (MVA) only ALC (per 1 point increase HR 1.03 [95%CI: 1.0-1.1]; p=0.04) and conditioning intensity (RIC vs. MAC: HR 2 [95%CI: 1-3.8]; p=0.038) significantly impacted NRM.
There was a trend for higher cumulative incidence of relapse (CIR) at 2 years in the low-ALC group (21% [95%CI: 16-27%]) when compared to the high-ALC group (16% [95%CI: 11-21%]), p=0.09. On UVA only Patient age (≤66 years 22% vs &gt; 66 years 14%, p=0.02), TBI (No TBI 18% vs TBI 38%, p=0.003) affected CIR. On MVA only ALC (HR 0.98 [95%CI: 0.96-0.99]; p=0.013) TBI vs no TBI (HR 2.14 [95%CI: 1.3-3.5]; p=0.003) significantly affected CIR.
A trend toward decreased 2-year OS was noted in patients with low-ALC (62%) compared to those with high-ALC (74%) p=0.06. On UVA disease status at transplant (CR: 74% vs not CR 61% p=0.004) conditioning intensity (MAC: 75% vs RIC: 62% p=0.01) and Immunosuppression significantly impacted OS. MVA revealed lower OS for non-CR patients (HR 2.68 [95%CI 1.6-4.49], p=0.024) and improved OS for MDS (HR 0.34 [95%CI 0.18-0.64]) and PMF (HR 0.04 [95%CI 0.01-0.35]), compared to AML and TAC+MMF led to reduced OS versus CSA+MMF (HR 5.99 [95%CI 1.91-18.82], p=0.002)
PFS at 2 years was significantly lower in the low-ALC group (56%) compared to the high-ALC group (67%), p=0.038. Factors affecting PFS included ATLG dosing schedule (D-6 to -3: 70% vs D-4 to -1: 57% , p=0.02), patient age (≤66 years: 61% vs &gt;66 years: 63%, p=0.04), disease status (CR: 68% vs not CR: 55%, p=0.005), and conditioning intensity (MAC: 67% vs RIC: 57%, p=0.048). MVA showed that females had higher PFS than males (HR 0.66 [95%CI: 0.45-0.97], p=0.037), non-CR status lower PFS (HR 2.51 [95%CI: 1.58-3.98], p&lt;0.001), and MDS or PMF higher PFS over AML (HR 0.3 [95%CI: 0.17-0.55] and HR 0.08 [95%CI: 0.02-0.40], p&lt;0.001, p=0.002).
GRFS at 2 years was significantly lower in patients with low-ALC (31%) compared to those with high-ALC (48%) p=0.005). On UVA ATLG dosing-schedule (D-6 to -3: 52% vs D-4 to -1: 33%, p=0.001), donor CMV serology (negative: 47% vs positive: 33%, p=0.013), disease status (CR: 48% vs not CR: 28%, p=0.0002), and conditioning intensity (MAC: 44%vs RIC: 35%). Multivariate analysis showed non-CR status was associated with lower GRFS (HR 2.68 [95%CI: 1.6-4.49], p&lt;0.001), transplantation for MDS (HR 0.34 [95%CI: 0.18-0.64], p&lt;0.001) and PMF (HR 0.04 [95%CI: 0.01-0.35], p=0.003) higher GRFS compared to AML.
We observed no significant differences in the cumulative incidence of aGVHD grade III-IV (8% in bopth groups, p=0.87) and cGVHD moderate/severe between the groups (at 2 years low-ALC 22% [95%CI 16-28] vs high-ALC 16% [95%CI 11-22] p=0.16).
Conclusion:
Higher ALC at ATLG administration may improve transplant outcomes after allo-SCT. These findings suggest tailoring ATLG doses based on ALC and earlier administration could optimize allo-SCT outcomes.