HSCT from Alternative Sources and Donors

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Chapter 130 HSCT from Alternative Sources and Donors

Two thirds of patients who need allogeneic hematopoietic stem cell transplantation (HSCT) do not have an available human leukocyte antigen (HLA)-identical sibling. Alternative donor sources of hematopoietic stem cells are being increasingly used and include matched unrelated donors (MUDs), unrelated umbilical cord blood (UCB), and HLA-haploidentical relatives. Each of these options has advantages and limitations, but rather than being considered competing alternatives, they should be regarded as complementary alternatives to be chosen after a careful evaluation of the relative risks and benefits in the individual patient. The choice of the donor will depend on various factors related to urgency of transplantation, center experience, and patient-, disease-, and transplant-related factors.

Unrelated Donor Transplants

One of the most widely used strategies for children who need an allograft and do not have an available HLA-identical sibling is to identify an unrelated HLA-matched donor in the registries. Worldwide international registries include more than 13 million HLA-typed volunteer donors. HLA-A, -B, -C, class I loci, and the DRB1 class II locus are the HLA loci that most influence outcome after HSCT from an unrelated volunteer. The roles played by other class II loci (DQB1, DP1 loci) on a patient’s outcome remain controversial.

Data on serologic typing of HLA class I A and B loci are available for all donors, and information on DRB1 typing is available for approximately one third of donors. While in the past serologic (low-resolution) typing was used for HLA-A and -B loci, currently the unrelated donors are selected using high-resolution (allelic) molecular typing of loci HLA-A, -B, -C, and DRB1. The chance of finding an HLA-matched donor depends on the frequency of the HLA phenotype, which is closely linked to the ethnic origin of the registry donors, with a range of 60-70% for white patients to <10% for persons of other ethnic groups (Hispanic, black, etc.).

Identifying a suitable unrelated donor is a complicated and lengthy process, with the median time from the start of search to transplantation being 4-5 mo. During this period, a patient with acute leukemia may relapse and require further therapy, accumulating organ toxicity that unfavorably affects outcome. Moreover, for a variety of reasons, a relevant proportion of donors (sometimes reaching 10-20%) are either no longer available or refuse donation. Despite these limitations, many thousands of matched unrelated donor transplants have been performed.

Initially, HLA polymorphism and the limitations of conventional (i.e., serological) HLA-typing techniques unfavorably affected the accuracy of matching, thus increasing rejection rates and the incidence of acute and chronic graft versus host disease (GVHD). Consequently, because the event-free survival of recipients of an unrelated donor allograft was worse than that observed when the donor was a compatible sibling transplant, there was no consensus on the use of unrelated donor transplants for nonmalignant diseases, such as thalassemia. DNA-based (i.e., high-resolution molecular) techniques for HLA typing have revealed an impressive number of new alleles within antigens that were previously defined by serology. Matching by high-resolution DNA typing reduces the risk of immune complications, namely graft rejection and GVHD, but also decreases the chance of finding a suitable donor. Nevertheless, the advent of both high-resolution molecular HLA class I and II loci-typing coupled with progress in the prophylaxis and treatment of GVHD has resulted in a reduction of transplantation-related mortality and improved outcomes. Indeed, outcomes from a fully matched unrelated volunteer donor are now similar to those of HSCT from an HLA-identical sibling, as indicated by results of unrelated donor transplantation in children with acute lymphoblastic leukemia (ALL) in the 2nd complete remission, juvenile myelomonocytic leukemia, or thalassemia (Fig. 130-1).

In patients with leukemia, a single locus disparity does not substantially affect the probability of event-free survival, as the increased risk of toxic death may be compensated by a reduction in the relapse rate. In contrast, in patients with non-malignant disorders, optimal results are obtained only when a donor matched at the allelic level with the recipient is selected. In general, a single HLA disparity in the donor/recipient pair, irrespective of whether antigenic or allelic, predicts a greater risk of nonleukemia mortality; multiple allelic disparities at different HLA loci have an additive detrimental effect and are associated with an even worse outcome. Ex vivo T-cell depletion of the graft has reduced the risk of acute GVHD but has not significantly affected patient outcomes.

The survival rates of unrelated donor HSCT include only patients who are transplanted and do not take into account patients for whom a donor is not found. For patients who urgently need a transplant, the time required to identify a suitable donor from a potential panel, establish eligibility, and harvest the cells may lead to relapse and failure to transplant. For patients who do not have a matched donor or who urgently need a transplant, attention has focused on unrelated cord blood and the HLA-haploidentical, mismatched family member.

Umbilical Cord Blood Transplants

UCB transplantation (UCBT) is a viable option for children who need allogeneic HSCT (Fig. 130-2). Several hundred children have been cured through transplantation with either related or unrelated UCB units. UCBT offers the advantages of absence of risks to donors, reduced risk of transmitting infections, and, for transplants from unrelated donors, immediate availability of cryopreserved cells, with the median time from start of search to transplantation being only 3-4 wk. In comparison to bone marrow transplantation (BMT), advantages of UCBT include lower incidence and severity of GVHD, easier procurement and prompter availability of cord blood cells, and potential to use donors that have HLA disparities with the recipient. Despite these advantages, UCBT patients may be exposed to an increased risk of early fatal complications, mainly due to a lower engraftment rate of donor hematopoiesis, delayed kinetics of neutrophil recovery, and lack of adoptive transfer of pathogen-specific memory T-cells. Transfer of donor-derived, memory T cells significantly contributes to early immunologic reconstitution of children after unmanipulated allogeneic bone marrow or peripheral blood stem cell transplantation.


Figure 130-2 Probability of leukemia-free survival after bone marrow (BM) and cord blood (CB) transplantation adjusted for disease status at transplantation. AG, antigen; MM, mismatched.

(From Eapen M, Rubinstein P, Zhang NJ, et al: Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study, Lancet 369:1947–1954, 2007.)

There is a strong inverse correlation between the number of nucleated cord blood cells infused per kg recipient body weight and the risk of dying from transplantation-related causes. In particular, engraftment is a major concern when the nucleated cells are <2.5 × 107/kg of recipient body weight. As a cord blood unit usually contains between 8 × 108 and 1.5 × 109 cells, it is not surprising that UCB transplantation has been less frequently employed for adolescents or adults with body weight >40 kg. Indeed, it can be estimated that only 20% of the UCB units available in the bank inventory could suffice for a 75 kg patient according to the recommended threshold cell dose (namely more than 2.5 × 107 total nucleated cells/kg recipient body weight before thawing the unit). In view of these findings, it is not surprising that efforts have been focused on approaches capable of increasing the number of UCB cells to be transplanted. Selection of the richest cord blood units, infusion of 2 units in the same recipient (i.e., double UCBT), and transplantation of ex vivo expanded progenitors have contributed to improving the results of UCBT, opening new scenarios for a wider application of the procedure. In particular, double UCBT is largely employed, as it significantly increases the engraftment rate when compared to single-unit UCBT. In the majority of double UCBT, the 2 UCB units are partially HLA-matched with the recipient and with each other. Sustained hematopoiesis after double UCBT is usually derived from a single donor.

Direct intrabone transplantation

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