Immunopathogenic mechanisms and modulatory approaches to graft-versus-host disease prevention in acute myeloid leukaemia

The application of allogeneic haematopoietic stem cell transplantation (HSCT) in human was first reported in 1957 after nurine studies revealed that allogeneic immune cells could exert powerful anti-leukemic effects, i.e., graft-versus-leukaemia (GvL) [1,2]. Since then, major discoveries in human immune system and leukaemia biology have greatly improved transplant outcomes and molded the modern-day practice of HSCT [3,4]. To date, HSCT remains the only potentially curative treatment for eligible patients with acute myeloid leukaemia (AML) that harbors adverse clinical, cytogenetic or molecular risk factors [5,6]. AML is the most common indication for HSCT in the US and worldwide [7,8]. Still, post-transplant relapse occurs in 15–60% of patients and carries a dismal prognosis [9]. To prevent relapse, it is crucial to maintain or enhance GvL early after HSCT.

Graft-versus-host disease (GvHD) is a unique side effect of HSCT. In GvHD, the donor immune system elicits an immune response towards the allogeneic donor tissue, causing a myriad of symptoms such as acute rash, diarrhea, and liver injury weeks to months post-HSCT (acute GvHD, aGvHD), and/or chronic malabsorption, sclerotic skin, sicca, and obstructive lung disease months to years later (chronic GvHD, cGvHD) [2,[10], [11], [12]]. Even with declining incidence and better treatment, GvHD remains the leading cause of non-relapse mortality (NRM) post-HSCT [[13], [14], [15], [16], [17], [18], [19]]. Although both GvL and GvHD are dependent on sustained immune reconstitution of the donor immune system, the presence of GvHD does not always translate into stronger GvL and reduced relapse incidence (RI), suggesting differences in the immune responses which could be targeted to GvL without inducing GvHD, or reducing GvHD without dampening GvL [20,21]. The immune responses that are implicated in GvL and GvHD are yet to be fully elucidated. Here we summarize the key components of GvL/GvHD immune responses and the mechanisms of action of selected GvHD prophylactic therapy and relapse-prevention/treatment regimens with a focus on AML.

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