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Graft-versus-host disease prophylaxis shapes T cell biology and immune reconstitution after hematopoietic cell transplant.

Graft-versus-host disease prophylaxis shapes T cell biology and immune reconstitution after hematopoietic cell transplant. medRxiv : the preprint server for health sciences Siegel, S. J., DeWolf, S., Schmalz, J., Saber, W., Dong, J., Martens, M. J., Logan, B., Albanese, A., Iovino, L., Chen, E., Kaminski, J., Neuberg, D., Hebert, K., Keskula, P., Zavistaski, J., Steinberg, L., Schichter, I., Cagnin, L., Hernandez, V., Warren, M., Applegate, K., Bar, M., Chhabra, S., Choi, S. W., Clark, W., Das, S., Jenq, R., Jones, R. J., Levine, J. E., Murthy, H., Rashidi, A., Riches, M., Sandhu, K., Sung, A. D., Larkin, K., Al Malki, M. M., Gooptu, M., Elmariah, H., Alousi, A., Runaas, L., Shaffer, B., Rezvani, A., El Jurdi, N., Loren, A. W., Scheffey, D., Sanders, C., Hamadani, M., Dudakov, J., Bien, S., Robins, H., Horowitz, M., Bolaños-Meade, J., Holtan, S., Bhatt, A. S., Perales, M. A., Kean, L. S. 2025

Abstract

Successful hematopoietic cell transplant requires immunosuppression to prevent graft-versus-host disease (GVHD), a lethal, T-cell-mediated post-transplant complication. The phase 3 BMT CTN 1703 trial demonstrated superior GVHD-free/relapse-free survival for post-transplant cyclophosphamide (PT-Cy)-based GVHD prophylaxis versus tacrolimus/methotrexate (Tac/MTX), but did not improve overall survival. To compare T-cell biology between GVHD prophylaxis regimens, 324 patients were co-enrolled onto BMT CTN 1801 (NCT03959241). We quantified T-cell immune reconstitution using multi-modal analysis, including T-cell receptor (TCR) sequencing of 2,359 longitudinal samples (180,432,350 T-cells). Compared to Tac/MTX, PT-Cy was associated with an early, substantial reduction in TCR diversity that was sustained for 2 years. PT-Cy led to a T-cell reconstitution bottleneck, including reduced thymic output and virus-associated TCRs. Decreased D+14 TCR diversity predicted prevention of chronic GVHD, but also correlated with increased moderate-to-severe infections. This study reveals how distinct immunosuppression strategies have significant effects on the global immune repertoire, underpinning post-transplant clinical outcomes.

View details for DOI 10.1101/2025.02.25.25322901

View details for PubMedID 40061351

View details for PubMedCentralID PMC11888538