The role of haploidentical stem cell transplantation in the management of children with haematological disorders

Abstract

The broader application of stem cell transplantation (SCT) for paediatric diseases has been limited by a lack of human leucocyte antigen (HLA)-matched donors. Virtually all children, however have at least one haploidentical parent who could serve as a donor. Such a donor is immediately available and the considerable costs of additional HLA typing, registry and banking expenditures that are necessary to procure an unrelated donor, could be reduced. Recent technological advances appear to have overcome the historical problems of graft rejection and severe graft versus host disease in the haploidentical setting, and in the latest studies the overall survival for children undergoing haploidentical SCT for leukaemia is now comparable with that following unrelated donor bone marrow or cord blood transplantation. Posttransplant infectious complications and leukaemia relapse remain the most important barriers yet to overcome, and new directions in the use of adoptive cellular immunity appear to be promising in this respect. Haploidentical SCT is now a viable option for those children who do not have an HLA compatible sibling or fully matched unrelated donor. The relative merits of a haploidentical family donor versus mismatched unrelated bone marrow or cord blood donation needs to be assessed in prospective, randomized clinical trials.

Graft dysfunction and delayed immune reconstitution following haploidentical peripheral blood hematopoietic stem cell transplantation

“…Delayed recovery of adaptive immunity results from the degree of HLA disparity, the low numbers of T cells infused in the graft, and the use of ATG, which may inhibit T-cell expansion. 12 Pediatric studies show that the median time to normal T and B cell numbers and proliferative responses was 7-8 months and our patients have similar reconstitution profiles. 8 Initial T-cell recovery is of oligoclonal memory T cells as a result of expansion of peripheral T cells from the graft.…”

“…Although it is generally reported that the problems of engraftment have been overcome in haplo-identical PBSCT, all centers undertaking this procedure have occasional patients with a dysfunctional graft. [11][12][13] However, even though some failures may be explained by differences in immune suppression given pre-transplant and lower doses of CD34 þ cells infused, 14,15 there is no doubt that not all patients receiving mega doses of CD34 þ cells are guaranteed engraftment. 16 Our relatively high levels of graft dysfunction cannot be explained by either low numbers of CD34 þ cells infused nor insufficient pre-transplant immune suppression.…”

“…Later, at approximately 6 months, naı¨ve T cells are recognizable presumably resulting from donor precursor cells emigrating from the thymus. 12 In the pediatric setting, immune recovery may be more rapid than in adults haplo-identical PBSCT for underlying hematological malignancies. The DFS is 41% with a follow-up of 1.5-6 years.…”

Haploidentical SCT in children: an update and future perspectives

“…Interestingly, higher numbers of infectious deaths are reported in adults 44 than in children, probably reflecting an impaired thymic function in older patients. 45 In haplo-SCT with CD34 þ selected stem cells, infections with adenovirus (ADV), CMV and Aspergillus remained a significant cause of mortality in children within the first 6 months post transplant. Incidences of CMV reactivation between 14 and 29% have been reported, leading to lethal infections in 0-8%.…”

Purified donor NK-lymphocyte infusion to consolidate engraftment after haploidentical stem cell transplantation

“…[1][2][3][4] Nearly all patients have a haploidentical donor within the family and, in contrast, to an unrelated donor search, the haploidentical family donor is rapidly available. The role of natural killer (NK)-cell alloreactivity in haploidentical HSCT 5 to promote engraftment and graft-versus-leukemia (GvL) effects is increasingly recognized.…”