Abstract
We evaluated long-term outcome in 40 patients with MDS or AML, transplanted from related or unrelated donors following conditioning with targeted busulfan (Bu, over 4 days), fludarabine (Flu, 120 [n = 23] or 250 [n = 17] mg/m2) and thymoglobulin (THY). Compared to 95 patients conditioned with Bu/Cyclophosphamide (Cy) without THY, BuFluTHY-conditioned patients had lower rates of chronic graft-vs.-host disease (GVHD). Adjusted hazard ratios (HR) for BuFlu(120)THY and BuFlu(250)THY-conditioned patients were 1.60 (95% confidence interval (CI) 0.66–3.86) and 1.87 (0.68–5.11), respectively, for relapse; 0.77 (0.30–1.99) and 1.32 (0.54–3.23) for non-relapse mortality; 0.81 (0.42–1.57) and 1.38 (0.72–2.57) for overall mortality; and 0.78 (0.30–2.05) and 1.62 (0.63–4.41) for relapse or death (failure for relapse-free survival). At one year, 45% of BuFlu(120 or 250)THY-conditioned patients had mixed CD3+ chimerism compared to 0% with BuCy (p < 0.0001). None of 7 patients with long-term mixed chimerism had chronic GVHD; two relapsed, five remained stable mixed chimeras. THY is effective in reducing chronic GVHD, and long-term mixed T-cell chimerism can be compatible with relapse-free survival. However, Thy may also be associated with an increased risk of relapse and, dose-dependent, with non-relapse mortality.
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Acknowledgements
We thank our research nurses and data coordinators as well as laboratory technicians for their ongoing excellent work. We thank Helen Crawford for help with the manuscript and figure preparation. We acknowledge the support by Genzyme who provided thymoglobulin for the two investigational protocols.
Author contributions
PVO’D, JMcC, and HJD designed the protocols; HJD, ACY, BES, TG and JPC analyzed the data. ACY and HJD wrote the manuscript. JSMcC was responsible for the busulfan pharmacokinetics; MEDF provided long-term follow-up data; MLS scored the comorbidities; GS maintained the database; CMcF carried out the chimerism determinations; PJM, KD, and FRA provided critical comments. All authors read and approved the manuscript.
Funding
This work was supported by NIH CA018029 (HJD), NIH/NCI T32 CA009515 (ACY), the American Society of Hematology Research Training Award for Fellows (RTAF) (ACY), and The Miklos Kohary and Natalia Zimonyi Kohary Endowed Chair (HJD).
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Yeh, A.C., O’Donnell, P.V., Schoch, G. et al. Long-term survival with mixed chimerism in patients with AML and MDS transplanted after conditioning with targeted busulfan, fludarabine, and thymoglobulin. Bone Marrow Transplant 57, 198–206 (2022). https://doi.org/10.1038/s41409-021-01518-0
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DOI: https://doi.org/10.1038/s41409-021-01518-0