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. 2024 Apr;26(4):351-359.
doi: 10.1016/j.jcyt.2024.01.004. Epub 2024 Feb 12.

Impact of rabbit anti-thymocyte globulin (ATG) exposure on outcomes after ex vivo T-cell-depleted hematopoietic cell transplantation in pediatric and young adult patients

Madhavi Lakkaraja  1 , Audrey Mauguen  2 , Farid Boulad  3 , Maria I Cancio  4 , Kevin J Curran  4 , Andrew C Harris  4 , Nancy A Kernan  3 , Elizabeth Klein  3 , Andrew L Kung  3 , Joseph Oved  4 , Susan Prockop  5 , Andromachi Scaradavou  4 , Barbara Spitzer  4 , Richard J O'Reilly  4 , Jaap Jan Boelens  6
Affiliations

Impact of rabbit anti-thymocyte globulin (ATG) exposure on outcomes after ex vivo T-cell-depleted hematopoietic cell transplantation in pediatric and young adult patients

Madhavi Lakkaraja et al. Cytotherapy. 2024 Apr.

Abstract

Background aims: Traditional weight-based dosing of rabbit anti-thymocyte globulin (rATG) used in allogeneic hematopoietic cell transplantation (HCT) to prevent graft-versus-host disease (GVHD) and graft rejection leads to variable exposures. High exposures induce delayed CD4+immune reconstitution (CD4+IR) and greater mortality. We sought to determine the impact of rATG exposure in children and young adults receiving various types of EX-VIVO T-cell-depleted (EX-VIVO-TCD) HCT.

Methods: Patients receiving their first EX-VIVO-TCD HCT (CliniMACS CD34+, Isolex or soybean lectin agglutination), with removal of residual T cells by E-rosette depletion (E-) between 2008 and 2018 at Memorial Sloan Kettering Cancer Center were retrospectively analyzed. rATG exposure post-HCT was estimated (AU*d/L) using a validated population pharmacokinetic model. Previously defined rATG-exposures, <30, 30-55, ≥55 AU*d/L, were related with outcomes of interest. Cox proportional hazard and cause-specific models were used for analyses.

Results: In total, 180 patients (median age 11 years; range 0.1-44 years) were included, malignant 124 (69%) and nonmalignant 56 (31%). Median post-HCT rATG exposure was 32 (0-104) AU*d/L. Exposure <30 AU*d/L was associated with a 3-fold greater probability of CD4+IR (P < 0.001); 2- to 4-fold lower risk of death (P = 0.002); and 3- to 4-fold lower risk of non-relapse mortality (NRM) (P = 0.02). Cumulative incidence of NRM was 8-fold lower in patients who attained CD4+IR compared with those who did not (P < 0.0001). There was no relation between rATG exposure and aGVHD (P = 0.33) or relapse (P = 0.23). Effect of rATG exposure on outcomes was similar in three EX-VIVO-TCD methods.

Conclusions: Individualizing rATG dosing to target a low rATG exposure post-HCT while maintaining total cumulative exposure may better predict CD4+IR, reduce NRM and increase overall survival, independent of the EX-VIVO-TCD method.

Keywords: T-cell depletion; adolescent and young adult; hematopoietic stem cell transplant; individualized dosing; pediatric; rabbit anti-thymocyte globulin.

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Conflict of interest statement

Declaration of competing interest KJC: research support: Novartis, Celgene, Cellectis, Atara Bio; consultant: Novartis, Atara Bio. SEP: support for the conduct of clinical trials: AlloVir, Jasper Therapeutics, Atara Biotherapeutics; consultation (last 24 months) CellEvolve, ADMA, Regeneron; intellectual property related to the use of third-party VSTs licensed to Atara Biotherapeutics with all rights assigned to Memorial Sloan Kettering Cancer Center. RJO: royalties following licensure of EBV-specific T-cell bank by Atara Biotherapeutics, research support and consultant fees from Atara Biotherapeutics. JJB: consulting Sobi, Bluebird Bio, Avrobio, BlueRock, SmartImmune, Sanofi, Omeros, Advanced Clinical (DMC Chair). All other authors have no commercial, proprietary or financial interest in the products or companies described in this article.

Figures

Figure 1.
Figure 1.
Outcomes by EX-VIVO-TCD. A, NRM and TCD. B, CD4+IR and TCD. C,OS and TCD. There was no correlation between types of TCD and NRM, CD4+ immune reconstitution defined as CD4+>= 50 x 2 within 100 days and OS. rATG: rabbit anti-thymocyte globulin, OS: Overall survival, NRM: Non-relapse mortality, CD4+ IR: CD4+ Immune Reconstitution defined as CD4+ levels twice above 50/μL at two consecutive measures within 100 days
Figure 2.
Figure 2.
Post-HCT rATG exposure in different types of EX-VIVO TCD and its effect on NRM, CD4+IR, OS. A, NRM based on levels of rATG exposure. B, CD4+IR based on levels of rATG exposure. C, NRM and CD4+IR. D, CD4+IR by rATG exposure. E, NRM by rATG exposure. F, OS based on levels of rATG exposure. Post-HCT rATG exposure < 30 AU*d/L is associated with lower NRM driven by faster CD4+IR and thus higher OS. Patients who reconstitute CD4+IR early have lower NRM. rATG: rabbit anti-thymocyte globulin, NRM: Non-relapse mortality, CD4+ IR: CD4+ Immune Reconstitution defined as CD4+ levels twice above 50/μL at two consecutive measures within 100 days.
Figure 3.
Figure 3.
Cause of Death by Post-HCT rATG exposure and GVHD and rATG exposure. A, Post-HCT rATG <30AU*d/L. B, Post-HCT rATG 30-55AU*d/L. C, Post-HCT >55AU*d/L. D, aGVHD and rATG exposure. rATG: rabbit anti-thymocyte globulin, HCT: Hematopoietic Cell Transplantation, POD: Progression of disease, GVHD: Graft versus Host Disease
Figure 4.
Figure 4.
Infection by Post-HCT rATG exposure. A, Post-HCT rATG exposure and cumulative incidence of all infections. B, Post-HCT rATG exposure and cumulative incidence of adenovirus infection. C, Post-HCT rATG exposure and cumulative incidence of EBV infection. D, Post-HCT rATG exposure and cumulative incidence of CMV infection. Post-HCT rATG exposure of < 30 was associated with an overall lower rate of infections. rATG: rabbit anti-thymocyte globulin, HCT: Hematopoietic Cell Transplantation
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