Donor and cord blood unit selection guidelines

Guidelines for selection of unrelated donors and cord blood units for hematopoietic cell transplantation (HCT)

Multiple patient and donor factors can impact transplant outcomes. Guidelines summarizing current evidence-based research provide a foundation for the search and selection of unrelated adult donors and umbilical cord blood units (CBU) for transplantation.

The degree of human leukocyte antigen (HLA) matching between the transplant recipient and the hematopoietic cell graft has a significant impact on the outcomes of unrelated donor hematopoietic cell transplantation (HCT). [1] In addition, research supports younger donor age as the second most impactful consideration in donor source selection.

Donor and Cord Blood Selection Guidelines

Access the evidence-based guidelines

These guidelines were developed and published in September 2019, and are continually reviewed for updates, jointly by the National Marrow Donor Program® (NMDP) the CIBMTR® (Center for International Blood and Marrow Transplant Research®), and the NMDP^SM Histocompatibility Advisory Group.

Access the on-demand webinar

Jason Dehn, MPH, Director, Laboratory Services, NMDP, and Bronwen Shaw, MD, PhD, Scientific Director, CIBMTR, summarize current guidelines for unrelated adult donor and CBU selection, and provide supporting evidence for the recommendations.

Access the Donor Selection course in the HLA & Search Strategy Interactive Learning Series

Complete this interactive course to learn how to apply the guidelines to donor selection.

The following charts summarize the HLA-, donor age, and cell-dose-related factors to be considered in the selection of unrelated donors and umbilical cord blood units, however reading the entire manuscript is encouraged for context. [1]

Table 1. Unrelated donor selection guidelines

	Multiple HLA-A, -B, -C, - DRB1 (8/8) HLA matched unrelated donors available	8/8 match unavailable; multiple 7/8 unrelated donors available
1. Resolution of typing HLA-A,-B,-C,-DRB1	High-resolution, matches for antigen recognition domains	High-resolution matches for antigen recognition domains for 7 matched alleles; Select HLA-C03:03 versus C03:04 mismatch, if present; No other preference for mismatched loci (HLA-A/B/C/DRB1) or other allele combinations
2.Donor age	Select donors of younger age	Select donors of younger age
3. Permissive mismatching HLA-DPB1	Select matched/permissive DPB1 mismatch based on the algorithm developed by Crivello et al^68,70 (https://www.ebi.ac.uk/ipd/imgt/hla/dpb_v2.html)	Select matched/permissive DPB1 mismatch based on the algorithm developed by Crivello et al^68,70(https://www.ebi.ac.uk/ipd/imgt/hla/dpb_v2.html)
4. Matching HLA- DRB3/4/5 and -DQB1	Minimize mismatches	Minimize mismatches
5. Vector of mismatch	N/A	Select donor with single allele mismatched at patient's homozygous locus (HLA-A/B/C/DRB1), if applicable
6. Donor-specific antibody (DSA) in patient	Avoid mismatches of allotypes targeted by DSA, including DQA1 and DPA1	Avoid mismatches of allotypes targeted by DSA, including DQA1 and DPA1
7. Transplant center practice may differ in additional considerations to use in the selection among multiple donors equivalent for the characteristics above

When an 8/8 donor is not an available option, 7/8 matched unrelated donors, related haploidentical donors and umbilical cord blood represent additional options for which patient- and provider-level factors are used in graft selection.

Cord Blood Unit Selection Guidelines

The cord blood unit selection guidelines were developed by the American Society of Transplantation and Cellular Therapy (ASTCT) Cord Blood Special Interest Group.

Table 2. Unrelated cord blood unit selection guidelines

Bank Practices	Guidelines
Attached segment identity testing	Mandatory
Use of RBC-replete units^a,b	Not Recommended
Cryovolume^c	Should be considered, especially if the unit is to be diluted post thaw
Year of cryopreservation	More recent units may be linked to optimal banking practices depending on the bank
Bank location	Domestic or international units fulfilling selection criteria
Bank accreditation and/or licensure	Should be considered
HLA Match	Guidelines
Resolution of HLA-typing	Minimum of 8 high-resolution (HLA-A,-B,-C,-DRB1) for both patient & CBU
Donor-recipient HLA-match	≥4/6 HLA-A,-B antigen, -DRB1 high-resolution (Traditional Match) & ≥4/8 high-resolution match (Some centers investigating use of 4/6 & 3/8 units if adequate dose)
Unit-unit HLA-match for double unit CBT	Not required
Avoidance of units against which recipient has DSA^d	Conflicting results in hematological malignancies; Avoid if non-malignant diagnosis
Cryopreserved Cell Dose^f,g,h	Guidelines
Single unit CBT: Minimum dose/kg	TNC ≥2.5 x 10⁷/kg & CD34⁺ cells ≥1.5 x 10⁵/kg (Some centers recommend higher CD34⁺ dose as minimum)
Double unit CBT: Minimum dose/kg/unit	TNC ≥ 1.5 x 10⁷/kg for each unit & CD34⁺ cells ≥1.0 x 10⁵/kg for each unit (Some centers recommend higher CD34⁺ doses for each unit as minimum)

Republished with permission of American Society of Hematology, from Blood, HLA Typing and Matching, Optimal Timing of Transplant vs. Match, Dehn J, et al. 134(12), 2019]; permission conveyed through Copyright Clearance Center, Inc.

^a RBC-replete units have been associated with life-threatening infusion reactions. Washing is difficult due to the lack of a clear interface after centrifugation; washing also risks cell loss. Therefore, RBC-replete units should be used with caution. They should only be considered in the absence of RBC-depleted CB units meeting acceptable criteria.

^b Incorporation of nucleated red cell content in unit selection is not recommended at this time.

^c Some expert centers prefer to use an RBC-depleted unit that has a post-cryopreservation volume of ∼25 mL/bag. If a unit was divided into 2 bags for storage, then each bag should contain ∼25 mL.

^d Regarding the significance of HLA antibodies, DSAs must be considered on a case-by-case basis based on diagnosis and prior immunosuppressive therapy that determine rejection risk, the intensity of planned conditioning, and the number, titer, specificity, and complement fixation of DSAs. DSA targeted units should be avoided in nonmalignant diagnoses. In patients with malignancies, avoid if possible, but use caution if avoidance of units against which the patient has antibodies compromises the selected CB unit dose and HLA match.

^f For single- vs double-unit CB transplant, if no adequate single-unit graft is available, then a double-unit graft is recommended. Clinical trials investigating the addition of other cellular products to a single-unit graft can also be considered.

^g For prioritization of cell dose vs HLA match (applies to single- and double-unit transplants), cell dose frequently needs to take priority over HLA match for adult and larger pediatric patients. HLA-match can take priority in children or smaller adults or those with common HLA typing who have multiple units with high cell dose. Optimizing HLA-match is very important in CB transplant for nonmalignant diagnoses. In children with nonmalignant diagnoses, higher cell doses ( ≥5 × 10⁷/kg) should be selected. Further data are required as to how to balance cell dose against HLA match. A current guidance for consideration is as follows: if high doses (eg, TNC ≥3 × 10⁷/kg and CD34⁺ ≥2 × 10⁵/kg), consider optimizing high-resolution HLA match over cell dose; if lower TNC and CD34⁺ doses, optimize dose first and high-resolution HLA match second; and if units have similar cell doses, optimize high-resolution HLA match.

^h Reporting of unit viability testing is not fully standardized. Flow-based assays of CD34⁺ cell viability on a segment can be informative but have not been validated in multiple banks/centers. The NMDP will facilitate discussion between centers and the bank if questions concerning viability testing arise.[JP1]

Best practices in cord blood selection from 6 experienced US transplant centers is available as a practical how-to guide for cord blood unit selection and was published by Barker et al. on behalf of the ASTCT and the NMDP. [2]

Timing for Patient and Family HLA Typing

If allogeneic transplant is an option, high-resolution HLA typing of the patient and potential family donors should be completed early after diagnosis. If no matches are found, a preliminary search of the NMDP Registry^® should be done.

This is especially important in acute diseases such as acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) due to the possibility that patients may experience rapid disease progression and will therefore need to proceed to transplant quickly.

The referral timing guidelines developed jointly by the NMDP and the American Society for Transplantation and Cellular Therapy (ASTCT) recommend that adult and pediatric patients with AML,Â adults with myelodysplastic syndromes and adolescent and adults with ALL be HLA tissue typed at high-resolution HLA at diagnosis [5].

Optimal Timing of Transplant vs. Match

Results of a study of 8,003 unrelated donor transplants demonstrated a significant interaction between 8/ 8 HLA match and disease stage at the time of transplant on outcomes.[6]

For patients with an 8/8 HLA-matched donor, 2,528 patients transplanted in an early disease state had a 71% (95% CI 69-73) 1-year survival rate while 1,444 patients transplanted in advanced disease incurred a 41% (95% CI 39-44) overall survival rate at 1 year
Patients with intermediate-stage disease had a 40% greater risk of mortality than patients with early-stage disease
At 3- and 5-years post-transplant, 8/8 HLA-matched patients with early-stage disease experienced survival rates of more than twice the rates of 8/8 HLA-matched patients with advanced disease: 56% vs. 27%, and 50% vs. 22%, respectively (p <0.001).

This study confirmed the results of an earlier study by Lee et al. where researchers concluded that an early referral is perhaps the single most important step that can affect survival. [7]

References

1. Dehn J, Spellman S, Hurley CK, et al. Selection of unrelated donors and cord blood units for hematopoietic cell transplantation: guidelines from NMDP/CIBMTR. Blood. 2019 Open Access

2. Barker JN, Kurtzberg J, Ballen K, et al. Optimal Practices in Unrelated Donor Cord Blood Transplantation for Hematologic Malignancies. Bio Blood Marrow Transplant. 2017; 23(6):882-896. Access

3. The National Marrow Donor Program/ NMDP 24^th Edition Standards and Glossary. January 1, 2018.

4. Eapen M, Klein JP, Ruggeri A, et al. Impact of allele-level HLA matching on outcomes after myeloablative single unit umbilical cord blood transplantation for hematologic malignancy. Blood. 2014; 123(1): 133-140. Access

5. NMDP and ASBMT Recommended Timing for Transplant Consultation. Download (PDF)

6. Pidala J, Lee SJ, Ahn KW, et al. Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation. Blood. 2014; 124(16): 2596-2606. Access

7. Lee S, Klein J, Haagenson M, et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood. 2007; 110(13): 4576-4583. Access