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Stem cell transplantation

Engraftment kinetics after transplantation of double unit cord blood grafts combined with haplo-identical CD34+ cells without antithymocyte globulin

Leukemia volume 35, pages 850–862 (2021)Cite this article

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Abstract

Double unit cord blood (dCB) transplantation (dCBT) is associated with high engraftment rates but delayed myeloid recovery. We investigated adding haplo-identical CD34+ cells to dCB grafts to facilitate early haplo-identical donor-derived neutrophil recovery (optimal bridging) prior to CB engraftment. Seventy-eight adults underwent myeloablation with cyclosporine-A/mycophenolate mofetil immunoprophylaxis (no antithymocyte globulin, ATG). CB units (median CD34+ dose 1.1 × 105/kg/unit) had a median 5/8 unit-recipient human leukocyte antigen (HLA)-match. Haplo-identical grafts had a median CD34+ dose of 5.2 × 106/kg. Of 77 evaluable patients, 75 had sustained CB engraftment that was mediated by a dominant unit and heralded by dominant unit-derived T cells. Optimal haplo-identical donor-derived myeloid bridging was observed in 34/77 (44%) patients (median recovery 12 days). Other engrafting patients had transient bridging with second nadir preceding CB engraftment (20/77 (26%), median first recovery 12 and second 26.5 days) or no bridge (21/77 (27%), median recovery 25 days). The 2 (3%) remaining patients had graft failure. Higher haplo-CD34+ dose and better dominant unit-haplo-CD34+ HLA-match significantly improved the likelihood of optimal bridging. Optimally bridged patients were discharged earlier (median 28 versus 36 days). ATG-free haplo-dCBT can speed neutrophil recovery but successful bridging is not guaranteed due to rapid haplo-identical graft rejection.

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Fig. 1: Pattern of whole blood chimerism in engrafting patients in the first year after haplo-dCBT (n = 75).
Fig. 2: Probability of neutrophil recovery after haplo-dCBT by engraftment group (Groups 1–3, n = 75).
Fig. 3: Chimerism patterns after haplo-dCBT in patients with an early myeloid bridge (Group 1, n = 34).
Fig. 4: Chimerism patterns after haplo-dCBT in patients with a transient myeloid bridge (Group 2, n = 20).
Fig. 5: Chimerism patterns after haplo-dCBT in patients with no myeloid bridge and sustained CB engraftment (Group 3, n = 21).

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Acknowledgements

This work was supported in part by the National Institutes of Health (NIH) Grant P01 CA23766 and NIH/NCI Cancer Center Support Grant P30 CA008748. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Authors and Affiliations

  1. Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Ioannis Politikos, Molly A. Maloy, Kristine A. Naputo, Josel D. Ruiz, Christopher M. Mazis, Parastoo B. Dahi, Sergio A. Giralt, Katherine C. Hsu, Ann A. Jakubowski, Esperanza B. Papadopoulos, Miguel A. Perales, Craig S. Sauter, Roni Tamari, Doris M. Ponce & Juliet N. Barker

  2. Department of Medicine, Weill Cornell Medical College, New York, NY, USA

    Ioannis Politikos, Parastoo B. Dahi, Sergio A. Giralt, Katherine C. Hsu, Ann A. Jakubowski, Esperanza B. Papadopoulos, Miguel A. Perales, Craig S. Sauter, Roni Tamari, Doris M. Ponce & Juliet N. Barker

  3. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Sean M. Devlin

  4. Diagnostic Molecular Pathology, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Maria E. Arcila

  5. Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Jonathan C. Barone & Scott T. Avecilla

  6. Stem Cell Transplantation and Cellular Therapies, MSK Kids, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Andromachi Scaradavou & Richard J. O’Reilly

  7. Department of Pediatrics, Weill Cornell Medical College, New York, NY, USA

    Andromachi Scaradavou & Richard J. O’Reilly

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Contributions

JNB and RJOR designed the clinical trial (NCT01682226). IP and JNB assembled and analyzed the data, and wrote the paper. SMD and IP performed the statistical analysis. MAM, KAN, JDR, and CMM maintained the patient database and procured data for the study. MEA, JCB, and STA were responsible for the whole blood and white cell subset chimerism assays. IP, PBD, SAG, AAJ, EBP, MAP, CSS, RT, DMP, and JNB provided patient care. IP, SMD, JCB, AS, STA, PBD, SAG, KCH, AAJ, EBP, MAP, CSS, RT, DMP, RJOR, and JNB interpreted the data, reviewed and edited the paper. All authors have approved the submitted version of the paper.

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Correspondence to Ioannis Politikos or Juliet N. Barker.

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IP has received research funding from Merck and serves on a Data and Safety Monitoring Board (DSMB) for ExCellThera. AS serves on a DSMB for ExcellThera and is the medical director of the New York Blood Center/National Cord Blood Program. STA has received honoraria from Abbott Laboratories. SAG has served as a consultant for Amgen, Actinium, Celgene, Johnson & Johnson, Jazz pharmaceutical, Takeda, Novartis, Kite, Spectrum Pharma and has received research funding from Amgen, Actinium, Celgene, Johnson & Johnson, Miltenyi, Takeda. MAP has received honoraria from Abbvie, Bellicum, Bristol-Myers Squibb, Incyte, Merck, Novartis, Nektar Therapeutics, and Takeda; serves on DSMBs for Servier and Medigene, and the scientific advisory boards of MolMed and NexImmune; and has received research support for clinical trials from Incyte, Kite (Gilead) and Miltenyi Biotec. CSS has served as a paid consultant on advisory boards for Juno Therapeutics, Sanofi-Genzyme, Spectrum Pharmaceuticals, Novartis, Genmab, Precision Biosciences, Kite, a Gilead Company, Celgene, Gamida Cell, Pfizer, and GSK, and has received research funding for clinical trials from Juno Therapeutics, Celgene, Precision Biosciences and Sanofi-Genzyme. RJOR receives royalties from Atara Biotherapeutics. JNB has received research funding from Angiocrine Bioscience, Gamida Cell, and Merck. The authors have no other relevant conflicts of interest to declare.

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Politikos, I., Devlin, S.M., Arcila, M.E. et al. Engraftment kinetics after transplantation of double unit cord blood grafts combined with haplo-identical CD34+ cells without antithymocyte globulin. Leukemia 35, 850–862 (2021). https://doi.org/10.1038/s41375-020-0922-x

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