Abstract
Genomic loss of the mismatched human leukocyte antigen (HLA) is a recently described mechanism of leukemia immune escape and relapse after allogeneic hematopoietic stem cell transplantation (HSCT). Here we first evaluated its incidence, risk factors and outcome in 233 consecutive transplants from partially HLA-mismatched related and unrelated donors (MMRD and MMUD, respectively). We documented 84 relapses, 23 of which with HLA loss. All the HLA loss relapses occurred after MMRD HSCT, and 20/23 in patients with acute myeloid leukemia. Upon MMRD HSCT, HLA loss variants accounted for 33% of the relapses (23/69), occurring later than their ‘classical’ counterparts (median: 307 vs 88 days, P<0.0001). Active disease at HSCT increased the risk of HLA loss (hazard ratio (HR): 10.16; confidence interval (CI): 2.65–38.92; P=0.001), whereas older patient ages had a protective role (HR: 0.16; CI: 0.05–0.46; P=0.001). A weaker association with HLA loss was observed for graft T-cell dose and occurrence of chronic graft-versus-host disease. Outcome after ‘classical’ and HLA loss relapses was similarly poor, and second transplantation from a different donor appeared to provide a slight advantage for survival. In conclusion, HLA loss is a frequent mechanism of evasion from T-cell alloreactivity and relapse in patients with myeloid malignancies transplanted from MMRDs, warranting routine screening in this transplantation setting.
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Acknowledgements
This work was supported by the Italian Ministry of Health, by the Italian Ministry of University and Research, by the Cariplo Foundation, by the Associazione Italiana per la Ricerca sul Cancro (Investigator Grant to KF and Start-Up Grant to LV), by the Conquer Cancer Foundation and by the European Commission. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Author Contributions
LaC, RC, KF, FC and LV designed the study. LaC, RC and AS performed the statistical analysis. CT, BM, FS, LoC, EZ, KF and LV performed the experiments and analyzed the data for the immunogenetic studies. LaC, RG, MTLS, AA, MGC, SM, MM, CC, MB, JP, FC and LV contributed to patient clinical care and data collection. ClB and ChB provided scientific advice and supervision. LaC, FC and LV wrote the manuscript. All authors have approved the final version of the manuscript.
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Professor Claudio Bordignon is an employee of MolMed SpA, Milano, Italy. Dr Chiara Bonini is a scientific consultant of MolMed SpA, Milano, Italy. The remaining authors declare no conflict of interest.
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Crucitti, L., Crocchiolo, R., Toffalori, C. et al. Incidence, risk factors and clinical outcome of leukemia relapses with loss of the mismatched HLA after partially incompatible hematopoietic stem cell transplantation. Leukemia 29, 1143–1152 (2015). https://doi.org/10.1038/leu.2014.314
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DOI: https://doi.org/10.1038/leu.2014.314
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