Graft vs Host Reaction

Although the majority of patients with acute myeloid leukemia (AML) treated with intensive chemotherapy achieve a complete remission (CR), many are destined to relapse if treated with intensive chemotherapy alone. Allogeneic stem cell transplant (allo-SCT) represents a pivotally important treatment strategy in fit adults with AML because of its augmented anti-leukemic activity consequent upon dose intensification and the genesis of a potent graft-versus-leukemia effect. Increased donor availability coupled with the advent of reduced intensity conditioning (RIC) regimens has dramatically increased transplant access and consequently allo-SCT is now a key component of the treatment algorithm in both patients with AML in first CR (CR1) and advanced disease. Although transplant related mortality has fallen steadily over recent decades there has been no real progress in reducing the risk of disease relapse which remains the major cause of transplant failure and represents a major area of unmet need. A number of therapeutic approaches with the potential to reduce disease relapse, including advances in induction chemotherapy, the development of novel conditioning regimens and the emergence of the concept of post-transplant maintenance, are currently under development. Furthermore, the use of genetics and measurable residual disease technology in disease assessment has improved the identification of patients who are likely to benefit from an allo-SCT which now represents an increasingly personalized therapy. Future progress in optimizing transplant outcome will be dependent on the successful delivery by the international transplant community of randomized prospective clinical trials which permit examination of current and future transplant therapies with the same degree of rigor as is routinely adopted for non-transplant therapies.

Over the last decade, the development of multiple strategies to allow the safe transfer from the donor to the patient of high numbers of partially HLA-incompatible T cells has dramatically reduced the toxicities of haploidentical hematopoietic cell transplantation (haplo-HCT), but this was not accompanied by a similar positive impact on the incidence of post-transplantation relapse. In the present review, we will elaborate on how the unique interplay between HLA-mismatched immune system and malignancy that characterizes haplo-HCT may impact relapse biology, shaping the selection of disease variants that are resistant to the "graft-vs.-leukemia" effect. In particular, we will present current knowledge on genomic loss of HLA, a relapse modality first described in haplo-HCT and accounting for a significant proportion of relapses in this setting, and discuss other more recently identified mechanisms of post-transplantation immune evasion and relapse, including the transcriptional downregulation of HLA class II molecules and the enforcement of inhibitory checkpoints between T cells and leukemia. Ultimately, we will review the available treatment options for patients who relapse after haplo-HCT and discuss on how a deeper insight into relapse immunobiology might inform the rational and personalized selection of therapies to improve the largely unsatisfactory clinical outcome of relapsing patients.

Allogeneic stem cell transplantation (allo-SCT) is a curable method for the treatment of hematological malignancies. In the past two decades, the establishment of haploidentical transplant modalities make "everyone has a donor" become a reality. However, graft-versus-host disease (GVHD) and relapse remain the major two causes of death either in the human leukocyte antigen (HLA)-matched transplant or haploidentical transplant settings, both of which restrict the improvement of transplant outcomes. Preclinical mice model showed that both donor-derived T cells and natural killer (NK) cells play important role in the pathogenesis of GVHD and the effects of graft-versus-leukemia (GVL). Hence, understanding the immune mechanisms of GVHD and GVL would provide potential strategies for the control of leukemia relapse without aggravating GVHD. The purpose of the current review is to summarize the biology of GVHD and GVL responses in preclinical models and to discuss potential novel therapeutic strategies to reduce the relapse rate after allo-SCT. We will also review the approaches, including optimal donor selection and, conditioning regimens, donor lymphocyte infusion, BCR/ABL-specific CTL, and chimeric antigen receptor-modified T cells, which have been successfully used in the clinic to enhance and preserve anti-leukemia activity, especially GVL effects, without aggravating GVHD or alleviate GVHD.

Relapse of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) affects 40-50% of recipients and remains the leading cause of posttransplant mortality; median overall survival is approximately 5 months and 1-year survival is below 20%. Conventional salvage-chemotherapy, immunosuppression withdrawal, donor lymphocyte infusion (DLI), hypomethylating agents, targeted agents, and second transplantation-benefits a minority and has improved only incrementally over two decades. Relapse in this setting reflects leukemia that has survived an engrafted allogeneic immune system. Documented escape mechanisms include genomic loss of the mismatched human leukocyte antigen (HLA) haplotype, epigenetic downregulation of class II HLA molecules, checkpoint ligand upregulation, microenvironmental suppression, and clonal evolution-each calling for targeted redirection of the graft-versus-leukemia (GVL) response rather than further nonspecific cytotoxicity. We propose a GVL Failure Framework that organizes posttransplant relapse into three biologically defined categories of immune escape, aligns matched cellular therapies with each, and overlays a separate clinical transplant-eligibility axis that sets the therapeutic goal. Several cellular strategies have matured: autologous and donor-derived chimeric antigen receptor T (CAR-T) cells targeting CD33, CD123, C-type lectin-like molecule 1 (CLL-1)/CD371, and CD117; armored CAR-T products secreting interleukin-18; CD83-directed CAR-T cells targeting blasts and alloreactive T cells simultaneously; HLA-DRB1-directed CAR-T and chimeric antigen receptor natural killer (CAR-NK) cells exploiting donor-recipient mismatch for leukemia specificity; and off-the-shelf CAR-NK platforms reprogramming innate rather than adaptive allogeneic immunity. We integrate the mechanistic rationale and early clinical evidence for each approach, propose a four-pathway treatment algorithm built around relapse-clone HLA typing before DLI, and outline the gaps that must close before cellular therapy enters standard practice.