Dynamics of Red Blood Cell Hematopoiesis Following ABO-Incompatible Allogeneic Hematopoietic Stem Cell Transplantation

[Background] ABO-incompatibility is not thought to be a contraindication for allogeneic hematopoietic stem cell transplantation (allo-HSCT), although the clinical impacts are occasionally debated. Post-transplant pure red blood cell aplasia (p-PRCA) is a disorder of erythropoiesis during the post-transplant immune tolerance process and is a rare complication after ABO-incompatible allo-HSCT. Donor-derived erythropoiesis is clinically predicted by the recovery of reticulocyte number and transfusion independence. However, the dynamics of donor erythropoiesis are complex and are not fully investigated because donor and recipient-derived, and transfused red blood cells (RBCs) circulate after ABO-incompatible allo-HSCT.

[Method] Here, we analyzed the clinical courses of red blood cell engraftment and the dynamics of erythropoiesis after ABO-incompatible allo-HSCT. p-PRCA was defined as a case in which reticulocytes did not recover for more than 60 days despite neutrophil engraftment and platelet transfusion withdrawal. And the red blood cell-chimerism at several time points after ABO-incompatible allo-HSCT was monitored by flow cytometry analyses using anti-A/ B-IgM antibodies and patient-derived RBCs (ABO-FCM).

[Results] Of the 408 allogeneic transplants performed at our institute from 2013 to 2024, 210 cases were ABO-incompatible allo-HSCT (76 cases of major mismatch, 88 cases of minor mismatch, and 46 cases of bidirectional mismatch). Although there was no significant difference in neutrophil engraftment, reticulocyte recovery was statistically delayed in ABO-incompatible allo-HSCT cases (p < 0.001). p-PRCA were observed in 3.8% (8 cases) of cases in ABO incompatible HSCT (minor mismatch 0 case, major mismatch 5 cases, and bidirectional mismatch 3 cases, respectively). In the red blood cell chimerism analyses using ABO-FCM, circulating red blood cells were clearly divided into donor-derived, recipient-derived and transfused red blood cells in bidirectional mismatched case (e.g. A, B, and O type in donor and recipient-derived and transfused RBCs, respectively) whereas only donor-derived red blood cells can be detected in major mismatched cases (e.g. A, O, and O type in donor and recipient-derived and transfused RBCs, respectively). Of note, there were some cases in which donor-derived red blood cells were detected in circulating red blood cells significantly earlier than the day of reticulocyte recovery (more than 10 ‰), suggesting that ABO-FCM is more sensitive method for the detection of donor-derived red blood cells than reticulocyte recovery. Further, recipient-derived RBCs and those transfused early after transplantation were clearly detected by ABO-FCM 3-6 months after major/bidirectional mismatched allo-HSCT in the recipient who did not develop p-PRCA. In the cases of p-PRCA, ABO-FCM could monitor the recovery of donor-derived erythropoiesis during immunosuppressive therapy.

[Conclusion] In ABO incompatible-HSCT, donor erythropoiesis was statistically delayed compared with the cases of ABO compatible HSCT (p < 0.001). Chimeric state with donor-, recipient- and transfusion-derived RBCs was observed even in the patients who did not develop p-PRCA. ABO-FCM is a useful method for monitoring post-transplant red blood type and diagnosing as p-PRCA.

Obara:Asahi Kasei Pharma Corporation: Honoraria; Novartis: Honoraria; F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Swedish Orphan Biovitrum Japan Co., Ltd.: Honoraria; Sanofi K.K.: Honoraria; Novartis Pharma K.K.: Consultancy, Honoraria; Kyowa Kirin Co., Ltd.: Consultancy, Honoraria, Research Funding. Sakata-Yanagimoto:LSI Medience: Patents & Royalties; Chugai Pharma, Eisai, Meiji Seika, Janssen, AbbVie, Astellas, Kyowa Kirin, Takeda, Nippon Kayaku, MSD, Nippon Shinyaku: Speakers Bureau; Chugai Pharma, Eisai, Bristol Myers Squibb: Research Funding.