Principles and practice of pediatric hematopoietic cell transplantation

1

Describe the types of transplant and their indications.

2

What is human leukocyte antigen typing, and how is it used for allogeneic hematopoietic stem cell transplantation?

Human leukocyte antigen (HLA) typing has had a tremendous impact on allogeneic hematopoietic stem cell transplantation (alloHCT) outcomes. HLA genes are part of the major histocompatibility complex, responsible for alloreactivity because of minor and major HLA mismatch between patient and donor. HLA genes are located on chromosome 6, and HLA antigens are divided into two groups. Class I consists of HLA-A, HLA-B, and HLA-C and Class II includes HLA-DP, HLA-DQ, and HLA-DRBI.

HLA typing can be performed on blood samples or buccal swabs. The current standard is to perform matching by analyzing DNA at the allelic level, which is more precise than antigen typing. Over the decades, the level of matching for unrelated donors has evolved from matching at 8 alleles (HLA-A, HLA-B, HLA-C, and HLA-DRBI) to 10 alleles (HLA-A, HLA-B, HLA-C, HLA-DQ, and HLA-DRBI). When several 10 out of 10 (10/10) HLA-matched donors are available, typing can be extended to 12 alleles (to include HLA-DPB1). A better match is associated with better outcomes because of lower risk of graft versus host disease (GVHD) and graft rejection.

For sibling and haploidentical donors, HLA typing should be performed at 10 HLA alleles. In the past, siblings were typed at 6 alleles (HLA-A, HLA-B, and HLA-DRBI). Occasionally, however, 6 out of 6 HLA-matched siblings may not be a 10/10 match.

For unrelated umbilical cord blood (CB) transplants, HLA typing has also evolved. In the past, antigen typing was performed for HLA-A, HLA-B, and allelic typing for HLA-DRB1; however, CB is now typed at the allelic level for all 6 loci.

3

What are the different types of donors considered for alloHCT?

AlloHCT donors can be broadly divided into two groups: HLA-matched sibling donors (MSD) and alternate donors. Alternate donors can be further subdivided into mismatched family donors (50%–90% HLA matched) or unrelated donors, which include adult unrelated donors and unrelated umbilical CB (HLA matched [100% matching] or mismatched [70%–90% match]).

The use of an MSD is the gold standard and is associated with best overall outcomes because of lower risk of acute GVHD. Conversely, a MSD is associated with higher incidence of leukemia relapse, likely because of lower alloreactivity provided by donor immune system. When an HLA-matched sibling is unavailable, a 10/10 HLA-matched unrelated donor (MUD) is preferred. If 10/10 MUD is also unavailable, depending on a center’s experience, haploidentical or unrelated umbilical cord can be chosen as donor for alloHCT.

4

What types of hematopoietic cell sources can be used for alloHCT?

Hematopoietic cells can be obtained from the bone marrow (BM), peripheral blood (PBSC), or umbilical CB. BM harvests from related and unrelated donors are performed under general anesthesia. The most common side effect is procedural pain, which typically resolves in 1 to 2 weeks. Some centers use granulocyte colony-stimulating factor (G-CSF) mobilization to increase the number of CD34 ⁺ cells in the BM, especially when the donor’s weight is lower than the recipient’s weight.

For PBSC donation, G-CSF is administered to the donors for 4 to 5 days. Most donors require temporary placement of a double lumen catheter (i.e., in the internal jugular vein) for an apheresis procedure. The procedure takes approximately 4 to 6 hours to complete and may require a second day of apheresis.

In pediatrics, BM is the preferred stem cell source for alloHCT because it is associated with a lower incidence of chronic graft versus host disease (cGVHD). This is particularly true for patients with nonmalignant diseases when GVHD is not beneficial for cure. For patients with pre-alloHCT comorbidities, especially infectious concerns, PBSC is used because neutrophil recovery is much faster.