What are the criteria and steps for identifying the optimal HLA-matched donor for a bone‑marrow transplant, including related, unrelated, haploidentical, and cord‑blood options, and how should ABO compatibility and infection screening be addressed?

Bone Marrow Matching: Optimal Donor Selection Criteria

For unrelated donor bone marrow transplantation, prioritize an 8/8 HLA-matched donor (HLA-A, -B, -C, -DRB1 at high resolution) with younger donor age, and when an 8/8 match is unavailable, haploidentical, cord blood, and 7/8 mismatched unrelated donors are all viable alternatives without a definitive hierarchy—selection depends on disease urgency, patient age, and center experience. 1

HLA Typing Requirements

For Adult Donors and Patients

• Mandatory high-resolution DNA-based typing for HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DPB1 1
• Additional loci (HLA-DQB1, HLA-DRB3/4/5, HLA-DQA1, HLA-DPA1) do not substantially impact survival in isolation but assist in search strategy and avoiding graft failure in HLA-sensitized patients 1

For Cord Blood Units

• High-resolution DNA-based typing for HLA-A, HLA-B, HLA-C, and HLA-DRB1 1
• Confirmatory typing programs also include DQB1 and DPB1 1

Donor Selection Algorithm

Step 1: HLA-Matched Related Donor (MSD)

• First choice when available 2
• Provides highest overall survival even in the posttransplant cyclophosphamide era 3

Step 2: When MSD Unavailable—Assess Urgency

For Non-Urgent Cases (>8 weeks available):

• Search for 8/8 HLA-matched unrelated donor (MUD) 2
• If multiple 8/8 matches exist, apply secondary criteria (see below)

For Urgent Cases (<8 weeks):

• Proceed directly to haploidentical donor (Haplo-SCT) 2
• Haploidentical transplants show similar outcomes to MSD and MUD for AML, ALL, MDS, and SAA 2

Step 3: If 8/8 Match Unavailable—Alternative Donors

All three options are viable without definitive hierarchy 1:

• 7/8 mismatched unrelated donor
• Haploidentical related donor
• Cord blood

Selection factors:

• Disease risk: High-risk/refractory disease favors haploidentical (lower relapse rates) 2
• Patient age: Younger patients tolerate alternative donors better
• Center experience: Choose the platform your center has most experience with 1

Secondary Selection Criteria (When Multiple Equivalent Donors Available)

For 8/8 Matched Donors (in order of priority):

1. Donor age: Select younger donors 1

   • Younger donor age consistently impacts overall survival across all studies 4

2. HLA-DPB1 permissive mismatching: Select matched or permissive DPB1 mismatch over nonpermissive 1

3. Minimize HLA-DRB3/4/5 and HLA-DQB1 mismatches 1

4. Avoid donor-specific antibodies (DSA): Avoid mismatches of allotypes targeted by patient's DSAs, including DQA1 and DPA1 1

For 7/8 Mismatched Donors:

1. Prefer HLA-C03:03 vs C03:04 mismatch if present 1

   • No other preference for which locus to mismatch (HLA-A/B/C/DRB1 equally tolerated) 1

2. Select younger donors 1

3. Vector of mismatch: Select donor with single allele mismatched at patient's homozygous locus if applicable 1

4. Avoid DSAs 1

For Haploidentical Donors (When Multiple Candidates):

Based on analysis of 1,210 consecutive cases 2:

• Younger donors (HR=0.30 for NRM, p=0.008)
• Male donors over female (HR=0.65 for NRM, p=0.002)
• Father donors preferred over mother donors (HR=0.65 for NRM, HR=0.66 for OS)
• Child donors have lower aGVHD than sibling donors (HR=0.57, p=0.01)
• Avoid older sister donors (inferior to father donors: HR=1.87 for NRM)

ABO Compatibility

ABO incompatibility is NOT a contraindication to transplantation 5. However:

• ABO major mismatch is a risk factor for transplant-related mortality 5
• When selecting between otherwise equivalent donors, prefer ABO-matched donors 5
• The impact of ABO matching on outcomes remains debatable and is a lower priority than HLA matching and donor age 4

Infection Screening

While the provided evidence does not detail specific infection screening protocols, standard practice requires:

• CMV serostatus matching: CMV-negative donor preferred for CMV-negative recipients 4
• This is particularly important, though more research is needed in the letermovir prophylaxis era 4
• All donors undergo standard infectious disease screening per regulatory requirements

Critical Pitfalls to Avoid

1. Delaying transplant for futile searches: Rapid assessment of search success likelihood is essential—avoid prolonged searches for perfect matches in high-risk disease 1

2. Ignoring donor-specific antibodies: Always screen for DSAs and avoid mismatches at targeted allotypes to prevent graft failure 1

3. Assuming 6/8 or less matching is acceptable: Multiple mismatches significantly worsen survival under conventional HCT practices 1

4. Overlooking haploidentical options: With modern GVHD prophylaxis, haploidentical donors provide outcomes comparable to matched donors and are immediately available 2, 3

5. Prioritizing ABO over HLA: Never compromise HLA matching for ABO compatibility 5