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Key Points

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  • 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.

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Diagnostic Criteria and Clinical Characteristics

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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 for over ...

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