Twenty-five percent chance a given sibling will be HLA-matched at A, B, and DR loci

Preferred stem cell source over other donor sources

Associated with lower rates of acute and chronic GVHD

More rapid and less expensive donor workup and stem cell procurement

Improved clinical outcomes

Despite improvements in outcomes (TRM, relapse-free, and OS) of URD transplants, MRD are still favored in patients > 50 years of age:

Higher risk of relapse of malignancy (AML, CML > ALL) if donor is an identical twin (syngeneic).

Only 30 % of patients who require an allogeneic HSCT will have an HLA-MRD.

Large number of donors are needed in registries due to the large diversity in the HLA system (> 5500 class I alleles and > 1600 class II alleles resulting in millions of HLA combinations).

Certain racial and ethnic groups (e.g., African Americans are more polymorphic than Caucasians at HLA loci) have a large number of specific haplotypes and have more difficulty in finding suitable donors.

Identification of a suitable MUD can take 2–6 months.

The longer search times make MUD HSCT less feasible for high-risk leukemias. Donor searches should be started early in the treatment course of these diseases.

Each HLA antigen or allele mismatch is associated with approximately a 10 % decrease in 5-year post-transplant survival. In a large retrospective study of 3857 myeloablative BM transplants done between 1988 and 2003 in the USA, a single mismatch detected by low- or high-resolution DNA testing at HLA-A, -B, -C, or DRB1 (7/8 match) was associated with higher mortality, lower 1-year OS 43 versus 52 %, lower DFS, increased TRM, and acute GVHD. Single mismatches at HLA-B and -C were better tolerated than mismatches at HLA-A or DRB1. Mismatching at two or more loci increased the risks while mismatches at HLA-DP or DQ and other donor characteristics did not affect survival.

Retrospective analysis of 1933 unrelated donor–recipient pairs that received PBSC HSCT between 1999 and 2006 showed that an 8/8 match was associated with better 1-year survival than a 7/8 match (56 % vs. 47 %). Mismatch at HLA-C antigen correlated with decreased leukemia-free survival (LFS) and increased risk of mortality, TRM, and grade 3-4 acute GVHD.

Other donor factors such as age, sex, parity, cytomegalovirus (CMV) status, ABO matching may have weak effects on outcome.

Haploidentical donors

Related haploidentical donors are matched at three of six loci (HLA-A, -B, -DR) sharing one chromosome 6 with the recipient.

Multiple individuals in a family including parents, siblings, and even children can potentially serve as the donor.

Increased donor availability in racial and ethnic groups.

Intensive GVHD prophylaxis is necessary. In one international study, ATG, cyclosporin, methotrexate , mycophenolate, and anti-CD25 antibody were utilized. Cumulative incidence of grade 2-4 acute GVHD was 24 % (5 % grade 3-4) and extensive chronic GVHD was 6 % at 2 years. OS was estimated at 45 % at 3 years.

Immunosuppression with post-transplant cyclophosphamide is emerging as a standard haploidentical GVHD prophylactic strategy with acceptable outcomes.

The BMT-CTN conducted two parallel phase II trials for patients without HLA-matched donors. Reduced intensity conditioning (RIC) with post-­transplant cyclophosphamide was used, followed by either double UCB (BMT-CTN 0602; see Sect. 4.b.11) or haploidentical BM (BMT-CTN 0603). The 1-year OS and progression-free survival (PFS) were 62 and 48 %, respectively, 100-day incidence of acute grade 2-4 GVHD 32 %, 1-year incidence of NRM 7 % and relapse 45 % after haploidentical transplant. A prospective phase III trial comparing double UCB and haploidentical transplantation is underway (BMT-CTN 1101).

Mismatch of maternal antigens is better tolerated than mismatch of paternal antigens. Leukemia patients, who received myeloablative conditioning followed by T-cell depleted haploidentical maternal grafts, had superior 5-year event-free survival (EFS) than those who received paternal grafts (50.6 vs. 11.1 %; P < 0.001). Improved survival was the result of lower relapse rates and TRM. The protective effect was seen in both female and male recipients.

Demand for UCB HSCT has increased rapidly due to lack of suitable HLA-matched donors, particularly in ethnic groups, time limitations due to aggressive disease, and the potential lower incidence of GVHD.

Advantages include expanded donor pool, ease of product procurement, lack of donor attrition, donor safety, and decreased incidence of GVHD.

Major disadvantages include delayed engraftment , prolonged defects in immune reconstitution , increased risk of graft failure, no opportunity for additional donations, and increased risk of infection.

In children with malignancy, HSCT with UCB units matched for 4/6, 5/6, or 6/6 HLA haplotypes produces results that are equal to an 8/8 HLA-matched BM HSCT.

Potential UCB units should be selected on the basis of greatest HLA-match that contains an adequate TNC count. Acceptable UCB units should contain ≥ 3 × 10⁷nucleated cells/kg and also, preferentially ≥ 2 × 10⁵ CD34 + cells/kg. In patients transplanted for nonmalignant disease, the risk of rejection is higher and a cutoff of ≥ 3.5 × 10⁷ TNC/kg is recommended.

In a large retrospective study of adults transplanted for acute leukemia, LFS after UCB HSCT was comparable to 8/8 and 7/8 allele-matched URD PBSC or BM HSCT:

HLA-C matching appears to improve outcomes. In a retrospective analysis of 803 patients with leukemia or myelodysplastic syndrome (MDS), who underwent an unrelated UCB HSCT, patients matched for HLA-A, -B, and -DRB1, but mismatched for HLA-C and had higher TRM than those matched for HLA-C (HR 3.97).

Priority should be given to unidirectional mismatches in the GVHD direction; avoid mismatches in the host-versus-graft direction: