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Research
The transplantation of allogeneic hematopoietic stem cells (HSCs) (i.e., cells from a healthy matched donor) is a well-established treatment for children with high-risk acute myeloid leukemia (AML) or very-high-risk acute lymphoblastic leukemia (ALL). Patients with persistent minimal residual disease and those who suffer a relapse of disease while on therapy are also candidates for transplantation. However, transplant procedures are not always successful, and many patients cannot receive a transplant because no matched donor is available.
Wing H. Leung, MD, PhD (Bone Marrow Transplantation & Cellular Therapy), and colleagues recently evaluated the outcomes of 190 patients with AML or very-high-risk ALL who underwent allogeneic HSC transplantation after receiving intensive multiagent chemotherapy during one of two treatment eras (1991–2002 or 2002–2008). In the journal Blood1, Dr. Leung’s team reported that the 5-year overall survival rate of patients who received transplants during the most recent treatment era was 70%, which was more than double the 31% rate observed in those who received transplants a decade earlier.
Improvement in the 5-year overall survival rate was most remarkable (from 19% to 88%) in patients who received an human leukocyte antigen (HLA)-haploidentical graft from a parent. The incidence of death related to organ dysfunction decreased from 27% to less than 8%, and that associated with infection was reduced from 16% to less than 4% in the recent treatment era. Similarly, the probability of death related to graft-versus-host disease (GVHD), a serious complication of bone marrow transplantation (BMT), in the recent treatment era was only half of that seen during the earlier era.
Contradicting the widely held belief that high-risk leukemias are incurable, findings from this study led Dr. Leung’s team to conclude that all children with very-high-risk ALL or high-risk AML should be considered candidates for BMT early on in their anticancer treatment, regardless of whether an HLA-identical sibling donor is available.
This improvement in patient outcome is attributed to progress made by the St. Jude Transplant Program in cellular therapy approaches and the donor-selection process. Before transplantation, blood samples from potential donors are examined in Dr. Leung’s lab, and the genes that regulate natural killer (NK) cells, a specialized type of white blood cells, are assessed.
The investigators found that to select the optimal donor, it is essential that donor NK cells be typed for their killer cell immunoglobulin-like receptor (KIR) gene family to minimize the risk of leukemia relapse, infection, and graft rejection after transplantation. Molecular determinants of some KIR genes have already been identified. These findings led to the development of single nucleotide polymorphism assays that enable high-resolution functional typing of NK cells from a large number of potential donors within 24 hours of obtaining blood samples, allowing patients to receive a life-saving transplantation procedure with minimal delay.
1Leung W, Campana D, Yang J, Pei D, Coustan-Smith E, Gan K, Rubnitz JE, Sandlund JT, Ribeiro RC, Srinivasan A, Hartford C, Triplett BM, Dallas M, Pillai A, Handgretinger R, Laver JH, Pui CH. High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia. Blood Jul 14;118(2):223-30, 2011. Epub 2011 May 25. PubMed PMID: 21613256; PubMed Central PMCID: PMC3138677. Abstract | Full Text
Photo: Illustration of an NK cell destroying a leukemic cell.
Art work by Joshua Stokes, Biomedical Communications.
