Anti-Thymocyte Globulin Exposure in CD34+T Cell Depleted Allogeneic Hematopoietic Cell Transplantation

Background: Traditional weight-based dosing results in variable rabbit anti-thymocyte-globulin (rATG) clearance that can delay CD4+Tcell immune reconstitution (CD4+IR) leading to higher mortality. Methods: In a retrospective, pharmacokinetic (PK)/pharmacodynamic analysis of patients undergoing their first CD34+ T-cell depleted (TCD) Allogeneic Hematopoietic Cell Transplantation (HCT) after myeloablative conditioning with rATG, we estimated post-HCT rATG exposure as area-under-the-curve (AUC;AU*d/L) using a validated population-PK model. We related rATG exposure to non-relapse mortality (NRM), CD4+IR (CD4+≥50/µL at two consecutive measures within 100 days after HCT), overall survival, relapse, and acute-graft versus host disease (GVHD) to define an optimal rATG-exposure. Cox-proportional hazard models, and multi-state competing risk models were used.  Results: 554 patients were included (age 0.1-73 years). Median post-HCT rATG exposure was 47AU*d/L (range 0–101). Low post–HCT AUC ( 55AU*d/L and 30-55AU*d/L groups, respectively, compared to <30AU*d/L group. Post-HCT rATG exposure ≥55AU*d/L was associated with higher risk of acute GVHD (HR 2.28,95%CI 1.01-5.16).  Conclusions: High post-HCT rATG-exposure is associated with higher NRM secondary to poor CD4+IR after TCD-HCT. Using personalized PK-directed rATG dosing to achieve optimal exposure may improve survival after HCT. Funding Information: MSK authors acknowledge the support of the NCI Cancer Center Support Grant P30 CA008748. Declaration of Interests: Madhavi Lakkaraja, MD, MPH, Audrey Mauguen, PhD, Christina Cho, MD, Sean Devlin, PhD, Scott T Avecilla, MD PhD, Farid Boulad, MD, Maria I. Cancio, MD, Ann A. Jakubowski, MD PhD, , Andrew L. Kung, MD, PhD, Esperanza B. Papadopoulos, MD, Ichelle Roessel, Josel D Ruiz, MPH, Brian C. Shaffer, MD, Gunjan Shah, MD, Barbara Spitzer, MD, Roni Tamari, MD : No Disclosures Michael Scordo, MD - Research support: Angiocrine Bioscience, Inc.; Omeros Corporation. Consultancy: Angiocrine Bioscience, Inc.; Omeros Corporation; McKinsey & Company. Ad-hoc advisory board: Kite – A Gilead Company. One-time speaking commitment: i3Health (CME). Kevin J. Curran, MD- Consultancy: Mesoblast, Consultancy and Research funding: Novartis, Research funding: Celgene. Nancy A. Kernan, MD - Equity in Amgen, Johnson and Johnson, Pfizer and Merck. Richard J O'Reilly, MD - Consultancy, Patents & Royalties: EBV-specific T-cell bank and Research Funding : Atara Biotherapeutics Susan Prockop, MD – Support for the conduct of clinical trials, Atara Biotherapeutics, Jasper Pharmaceuticals, AlloVir. Advisory Boards - Mesoblast, Neovii. S.E.P. is an inventor of intellectual property licensed to Atara Biotherapeutics by MSKCC; S.E.P. assigned all rights to MSKCC and has no financial interest in Atara Biotherapeutics. Andromachi Scaradavou, MD - Membership on an entity's Board of Directors or advisory committees: Excellthera Sergio A. Giralt, MD- Consultancy, Honoraria and Research funding : Celgene, Novartis, Consultancy and Research funding: Amgen, Actinuum, Miltenyi, Consultancy and Honoraria: Jazz, Omeros, Research funding: Takeda, Consultancy: Kite Miguel-Angel Perales, MD- Dr. Perales reports honoraria from Abbvie, Astellas, Bristol-Myers Squibb, Celgene, Equilium, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Novartis, Nektar Therapeutics, Omeros, Takeda, and VectivBio AG, Vor Biopharma. He serves on DSMBs for Cidara Therapeutics, Medigene, Sellas Life Sciences, and Servier, and the scientific advisory board of NexImmune. He has ownership interests in NexImmune and Omeros. He has received research support for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, and Novartis. He serves in a volunteer capacity as a member of the Board of Directors of the American Society for Transplantation and Cellular Therapy (ASTCT) and Be The Match (National Marrow Donor Program, NMDP), as well as on the CIBMTR Cellular Immunotherapy Data Resource (CIDR) Executive Committee. Jaap Jan Boelens, MD, PhD -Consultancy: Race Oncology, Omeros, Avrobio, Takeda, Advanced Clinical, Bluerock. Ethics Approval Statement: The study protocol was approved by the institutional review board at Memorial Sloan Kettering Cancer Center (MSKCC).