Title: Validation of immune biomarkers predictive of clinical outcome after HLA-haploidentical hematopoietic
stem cell transplantation for acute leukemia.


Project Coordinator:
Attilio BONDANZA (Italy) IRCCS Ospedale San Raffaele Experimental Hematology and Bone Marrow Transplantation Unit, Milan


Project Partners:
Sven OLEK (Germany) Epiontis Gmbh, Berlin
Antoine TOUBERT (France) Hopital Saint Louis, UMRS940, Paris Cedex
Andrea VELARDI (Italy) Ospedale Santa Maria della Misericordia (Azienda Ospedaliera, Regione Umbria), Dipartimento di Medicina Clinica e Sperimentale, Perugia

Project Abstract:
Hematopoietic stem cell transplantation from a full HLA-haplotype mismatched family donor (haplo- HSCT) is a ready and widely available form of adoptive immunotherapy for high-risk leukemia. The procedure is however complex and, at the current-state-of-the-art, the final outcome is rather unpredictable. In this project, through a collaborative effort between 2 major clinical EU centers performing haplo-HSCT and 2 research partners (one academic, one SME), we aim at validating a restricted number of pre-specified immune biomarkers, identified in previous exploratory studies, for the purpose of predicting transplant outcome. Once validated, these biomarkers will be crucial for personalizing haplo-HSCT, thus maximizing its efficacy and reducing its toxicity.

Publishable Summary:
Hematopoietic stem cell transplantation from a full HLA-haplotype mismatched family donor (haplo-HSCT) is a ready and widely available form of adoptive immunotherapy for high-risk leukemia. The procedure is however complex and, at the current-state-of-the-art, the final outcome is rather unpredictable. In this Project, through a collaborative effort between two major clinical EU clinical Centers performing haplo-HSCT and two research partners (one academic, one by SME), we aimed at validating a restricted number of pre-specified immune biomarkers, identified in previous exploratory studies, for the purpose of predicting transplant outcome. In particular, the Consortium evaluated the clinical role of differential lymphocyte counts measured by flow cytometry (T-cell, B-cell, NK-cell counts and counts of specific T-cell subsets), of NK-cell alloreactivity, of the T-cell receptor excision circles (sjTRECs) by qPCR and of the T-cell specific de-methylated region (TSDR) of the Foxp3 gene by qPCR. One of the major achievements was that the early recovery of CD8+ T-cell counts, rather than other lymphocyte subpopulations, was an independent factor predicting a better overall survival and a lower rate of non-relapse mortality. The Consortium further characterized T-cell reconstitution and found that the Treg counts, evaluated either by flow cytometry or epigenetic tests, and the sjTREC levels are associated with the severity of GVHD, one of the major determinants of clinical outcome after HSCT. Additionally, CMV-specific T-cell counts proved to be a predictor of infection rates. Among NK cell-related biomarkers, the donor-versus-recipient NK-cell alloreactivity evaluated by genetic tests was associated with markedly reduced NRM and with significantly better event-free survival. As well as previously identified biomarkers, additional promising immune ones were proposed, i.e. CD34+lin- CD24+CD10- lymphocyte progenitor counts, the quantification of k-deleting recombination excision circles (KRECs) by qPCR for the analysis of B-cell reconstitution and the epigenetic measuring of immune cell counts (CD3, CD4, CD8 T cells, B cells, NK cells, monocytes and neutrophils). To sum up, the biomarkers validated in the HAPLO-IMMUNE Project represent a crucial step in the personalization of haplo-HSCT, that can lead to a higher efficacy and a lower toxicity of this procedure.

 

(Project funded under JTC 2011)