174: Transplantation Genetics and Genomics: Alloreactivity After Hematopoietic Stem Cell Transplantation

Key Points

• Disease summary:

  • Hematopoietic stem cell transplantation (HSCT) is a curative therapy for a number of malignant and nonmalignant conditions including leukemia, bone marrow failure, severe immunodeficiencies, and other disorders involving the hematopoietic system such as thalassemia and sickle cell anemia.

  • The HSCT procedure involves multiple phases including a preparative regimen consisting of cytotoxic and immune-depleting agents followed by infusion of a hematopoietic graft. Recovery of neutrophils and platelets typically occurs within 2 to 4 weeks but full immunologic recovery can take months to more than a year.

  • Graft sources currently being used include bone marrow, peripheral blood stem cells collected via an apheresis procedure, and cryopreserved umbilical cord blood.

  • Graft-versus-host disease (GVHD) represents one of the major causes of morbidity and mortality after allogeneic HSCT. However, donor-versus-recipient alloreactivity can also contribute to the curative potential of HSCT via the graft- versus-leukemia (GVL) reaction.

  • Degree of donor and recipient matching at the human leukocyte antigens (HLA) system encoded on chromosome 6 has a significant impact on transplant outcomes including the risk of GVHD and relapse of malignancy.

  • GHVD can occur even when donor and recipient are fully HLA-matched as in the matched sibling donor setting illustrating the importance of other non-HLA minor histocompatibility antigens (miHAs) such as those encoded on the Y chromosome.

  • Donor killer immunoglobulin-like receptor genotype encoded on chromosome 19 can also influence the potency of the GVL effect and the risk of leukemia relapse.

  • Polymorphisms in other genes such as those encoding cytokines, cytokine receptors, and innate immune response genes among others can also influence transplant outcomes.

• Genome-wide associations:

  • The application of genome-wide association study (GWAS) to HSCT is relatively recent. Two studies have demonstrated that these approaches can be used to identify single-nucleotide polymorphisms (SNPs) that modulate outcomes following HSCT. Future studies will be needed to validate these findings in larger populations.

• Pharmacogenomics:

  • Patients are frequently on multiple medications during HSCT including agents with substantial toxicity. Metabolism and clearance of many of these agents can be affected by pharmacogenomic variants (Table 174-1). Many of the medications used in HSCT are dose adjusted to achieve a target range.

Diagnostic Criteria and Clinical Characteristics

Primary factors affecting outcome after HSCT are GVHD, infection, organ toxicity, and relapse or recurrence of the underlying disease for which the HSCT is being performed. GVHD is a disorder arising from immunologic targeting of recipient tissues by donor cells. Due to better supportive care resulting in lower mortality from preparative regimen-related toxicity or infection, GVHD and relapse have become the primary causes of poor outcome. However, despite GVHD-associated morbidity and mortality, it is well established that donor immune reactivity against leukemia (the GVL effect) improves survival. Therefore, a major focus of HSCT research has sought to separate the harmful effects of GVHD from the beneficial effects of GVL at the molecular level. Genomics has played a role in this and other aspects of HSCT ...