Hematopoietic Stem Cell Transplantation for Childhood Leukemias

Ingrid Kuehnle

C. Philip Steuber

Hematopoietic stem cell transplantation (HSCT or SCT) is the process of replacing or substituting a patient’s diseased, defective, or damaged bone marrow elements with healthy donor stem cells. A basic requirement is that the host’s defect be correctable by hematopoietic stem cell-derived cells. Potential sources of hematopoietic stem cells have increased in recent years and, in addition to bone marrow, cytokine-mobilized peripheral blood and umbilical cord blood increasingly are being used. In malignancies, stem cell transplants permit the intensification of therapy and add the additional graft-versus-malignancy effect provided by an allogeneic graft.

With improvements in histocompatibility testing, donor availability, immunosuppressive therapies, and supportive care since the 1980s, hematopoietic stem cell transplants between related and unrelated individuals (allogeneic) are increasingly the therapy chosen for a variety of malignant and nonmalignant conditions. Most stem cell transplants have been performed for patients with leukemia, although the list of indications for stem cell transplant is growing. It is being used increasingly in the treatment of hematopoietic diseases such as sickle cell anemia and beta-thalassemia major, immunodeficiencies, and metabolic storage diseases.

The first marrow transplants for leukemia were syngeneic or allogeneic and were given to patients with advanced refractory disease to rescue them from myeloablative therapies. The few successes (5% to 10%) observed at that time outnumbered those seen with other therapies and led investigators to explore the indications for and optimal applications of the transplant procedure.

Although HSCT is indicated unequivocally for diseases for which no other curative therapy exists, such as severe combined immunodeficiency, the value of transplant for many malignant diseases remains controversial. Current guidelines for considering hematopoietic stem cell transplantation for childhood leukemia include the diagnoses found in Box 303.1.

Although conceptually simple, the stem cell transplant process and sequelae are complex. Histocompatibility-matched donor and recipient pairs are needed, appropriate effective
preparative programs are required, and the extensive capabilities must be available to support a lengthy period of marrow aplasia, immunosuppression, and graft-versus-host disease (GVHD) after transplantation.

DONOR SELECTION

Initially, allogeneic hematopoietic stem cell donors were full siblings who inherited the same genes determining class I (HLA A and B), and class II (HLA DR, DP, and DQ) antigens. Historically however, only 30% to 40% of patients have an HLA-genotype matched-sibling donor available. Recent progress in graft manipulation, immunosuppressive strategies, and post-transplant supportive therapies has shown improved results using mismatched family members such as parents (i.e., haploidentical), and HLA-matched or partially matched unrelated donors. For pediatric patients with acute leukemias, the outcome after an unrelated matched donor stem cell transplant is approaching that after a matched-sibling donor transplant.

In comparison to HLA-identical sibling donor transplants, stem cell transplants from matched/mismatched unrelated or mismatched related donors increase the risk of posttransplant complications, particularly GVHD. GVHD is caused by immunocompetent donor T cells transferred to the patient with the donor stem cell infusion. To reduce the incidence and severity of GVHD under HLA-disparate conditions, methods are used to purge the donor stem cells of immunocompetent T cells. Reduction of donor T cells can be achieved using either in vivo or in vitro T cell-depleting antibodies or by targeted selection of CD34⁺ hematopoietic stem cells. These methods are effective in reducing the GVHD-related problems, but the incidence of graft rejection, infectious complications, and recurrent leukemia increases. These observations underscore the contribution of immunocompetent donor T cells to engraftment and to disease control.

Since it was established in 1986, the National Marrow Donor Program (NMDP) has facilitated more than 15,000 unrelated transplants and now has an ethnically diverse database with 5 million potential stem cell donors and more than 25,000 umbilical cord blood units. The probability of identifying a suitably matched donor through the NMDP is currently 80%.

Only gold members can continue reading. Log In or Register to continue