Recent Developments in Haploidentical Stem Cell Transplantation: Therapy and Complications

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Background

Allogeneic stem cell transplantation (Allo-SCT) remains an important therapy for hematological malignancies. In the past ten years, haploidentical SCT (haplo-SCT) has become available for nearly all patients. This treatment has a very low acquisition cost and does not require an extensive search, previously associated with stem cell therapies. A series of studies have demonstrated that treating patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia, and myelodysplastic syndrome using haplo-SCT could achieve comparable outcomes to those undergoing human leukocyte antigen (HLA)-matched sibling donor transplantation (MSDT). More recently, studies have shown that, for patients with high-risk AML in Complete Remission (CR) 1 or those with Hodgkin's lymphoma, a haploidentical allograft could achieve a lower cumulative incidence of relapse (CIR) and better survival that those receiving MSDT. This suggests that haploidentical donors might have a stronger graft-versus-leukemia (GVL) effect compared with that of HLA-identical donors, although most of these studies are single center and retrospective. Therefore, prospective, multi-center studies are needed to confirm the findings. Moreover, the mechanisms underlying the GVL effect of haplo-SCT should be explored further.

Unfortunately, relapse of the original disease remains a major cause of death after transplantation, although several strategies, such as donor lymphocyte infusion, interferon therapy, targeted drugs, hypomethylating agents, immune checkpoints, and chimeric antigen receptor (CAR)-expressing T cells, have been used in relapse prophylaxis and treatment. Thus, the underlying mechanism of leukemia relapse should be investigated. Previous studies have demonstrated the association of disease status, cytogenetic and molecular factors with clinical outcomes. Currently, minimal/measurable residual disease (MRD) determined by flow cytometry, quantitative real-time PCR, and next-generation sequencing after induction therapy, consolidation therapy, pre-transplantation and post-transplantation has been routinely used for prediction of leukemia relapse. On the other hand, rapid recovery of T cell and natural killer cells have been reported to be associated with decreased CIR after allografts. Therefore, advancing our understanding of the association of immune recovery profiles and kinetics of MRD would make it possible to develop more strategies for improving post-transplantation immunologic reconstitution and decrease CIR of patients with MRD following allo-SCT.

Other causes of death after allo-SCT, especially haploidentical allografts, include graft failure, acute and chronic graft-versus-host disease (GVHD), which could be hampered by T cell alloreactivity due to differences in one or more HLA loci on an unshared chromosome 6. As a result, elucidating the mechanisms for crossing HLA barriers in haplo-SCT modality is key to improving disease outcomes. In addition, infections, particularly cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation following haploidentical transplantation, minimize the improvement of clinical outcomes.

In this Research Topic, we welcome the submission of Original Research, Review articles and Clinical Trial studies that address, but are not limited to, the following sub-topics:

• Studies that investigate the detailed mechanisms of transplant immune tolerance or leukemia relapse
• Studies reviewing haplo SCT therapies
• Clinical Trials, and preclinical studies on novel strategies, including CAR-T cells
• MRD-directed intervention for leukemia recurrence as well as adoptive transfer of virus specific cytotoxic T cells for CMV and EBV infections, to improve survival and reduce transplant complications

Keywords: Haplo-SCT, transplantation, immunotherapy, CMV, EBV, hematological malignancies

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