Matched unrelated donor hematopoietic stem cell transplantation

What every physician needs to know about matched unrelated donor hematopoietic stem cell transplantation

Matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) is a viable alternative for approximately 75% of patients who will not have an HLA (human leukocyte antigen)-identical sibling.

The first successful unrelated donor transplant was performed in 1973 in New York when a young boy with congenital immunodeficiency received multiple marrow transplants from a donor identified as a match through a blood bank in Denmark. Currently greater than 5,000 unrelated transplants are performed in the United States of America (USA) and more than 10,000 worldwide every year. Approximately half of all allogeneic transplants in the USA are performed from unrelated donors. Transplant outcomes from MUDs have improved over time and, with fully matched donors, outcomes are now comparable to matched sibling transplantation.

Unrelated donor transplants in the USA are coordinated by the National Marrow Donor Program, founded in 1986. Donor registries are networked with each other and cord blood banks worldwide.

What are the indications for MUD-HSCT?

Indications for MUD-HSCT are generally the same as for HLA-matched sibling transplantation. These include hematologic malignancies and marrow failure states.

A current list of allogeneic transplantation indications and timing for referral can be found in The National Marrow Donor Program’s ”Be The Match”‘ Donor Registry (see references).

The extent of donor mismatch will often influence the timing of a MUD transplant, particularly in patients with nonmalignant disease who cannot benefit from the compensatory increase in graft-versus-malignancy effect arising from the mismatch. Also, there is a greater risk of graft rejection in mismatched unrelated donor transplants for non-malignant indications such as severe aplastic anemia in which patients are often allo-immunized.

How is an unrelated donor identified? How is the graft obtained?

Volunteer unrelated donors are registered in large national registries
Information available includes age, gender, and partial or complete HLA typing
Contact information is concealed from the recipient’s transplant center
Finding a match

– The transplant center will enter details of the recipient HLA type and, often after several rounds of HLA testing, the best matched unrelated donor will be selected from the registry.

Donor testing and consenting

– The donor will be invited to the nearest donor center and, after testing and consenting, will undergo either a marrow harvest or G-CSF (granulocyte colony-stimulating factor) mobilized peripheral blood collection by apheresis.

Graft is couriered to the recipient’s transplant center, typically within 24 hours of collection, for a fresh infusion

What is the likelihood of finding a well matched unrelated donor?

This depends upon the recipients HLA genotype, haplotype, and the size and diversity of the donor registries
The NMDP (The National Marrow Donor Program)

– This provides access to 9 million volunteer unrelated donors, and to a further 16 million through international networks.

The two most important factors are the ethnic background of the recipient and the amount of time available
Unrelated donor search

– Should begin as soon as unrelated transplant is a consideration to provide adequate time to find a match.

Race/ethnicity

– Within the NMDP registry, the probability of identifying at least one antigen level–matched (HLA-A and -B) and potential allele level–matched (HLA-DRB1) donor depends upon race/ethnicity. Probabilities are as follows, white 88%, black 60%, Hispanic 81%, Asian/Pacific Islanders 78% and American Indians/Alaska Natives 82%.

Black patients were 2.83 times, Asian patients 2.05 times, and Hispanic patients 1.73 times more likely to have a less-matched HCT donor than Caucasian patients.

How is HLA typing performed for unrelated donor identification?

(See Table I)

DNA-based tissue typing

– DNA-based tissue typing offers improved resolution over traditional serologic typing (antigen level), which translates into reduced rejection, GVHD (graft-versus-host disease), and mortality.

Predicting the donor’s DRB1 type

– Most donors in the registry are partially matched at HLA A and B. The HapLogic algorithm in the NMDP utilizes extended HLA typing for haplotype analysis to predict the donor’s DRB1 type and narrow the list of potential unrelated donors.

Potential donors undergo full HLA typing
Matching at HLA A, B, C, and DRB1 loci are most critical to outcome

– Full HLA matching is defined as matching at the allele level (high resolution) at A, B, C, and DRB1. This would be considered an 8/8 (or 100%) match.

Isolated mismatch at DQB1 or DPB1 does not significantly impact overall survival

The number of potential HLA matches for a given HLA-type in the NMDP registry can be screened informally at no cost by accessing The National Marrow Donor Program’s ”Be The Match”‘ Donor Registry (see references).

Apart from HLA matching, are there other considerations in the selection of the donor?

Work-up of the donor

– Once the best matched donor is identified, a full work-up of the donor will include at a minimum, infectious disease markers, a physical exam, and counseling.

Donor age is the most important characteristic

Other factors include CMV (Cytomegalovirus) serology and KIR (killer immunoglobulin-like receptor) typing. However, KIR typing is rarely available in time to influence the selection of the donor and the role of donor CMV serology is undergoing reevaluation in the era of effective anti-CMV strategy.

Female donors who have never been pregnant are sometimes preferred, but this is controversial.

What are the disadvantages of MUD transplantation?

Firstly, volunteer donor identification, selection, and collection may impose delays
Secondly, the choice of the stem cell source, marrow, or peripheral blood, is often dictated by the donor
Thirdly, the logistic issues involved

– International shipments of a graft will sometimes result in the graft reaching the transplant center at the limits of viability. This precludes cryopreservation or extensive ex vivo graft manipulation.

What are the options to MUD and when are they appropriate?

Alternative donor transplant options have shown a surge in recent years. The biggest disadvantage with MUD transplants is the time to identify a donor. In urgent cases, alternative options include umbilical cord blood transplantation (UCBT) and mismatched related, including haploidentical transplants.

UCBT

– UCBT retains strong anti-malignancy effects, and permits a greater degree of mismatch than a MUD. However, attention must be paid to CD34+ dose.

Mismatched related

– Mismatched related, including haploidentical transplants may have utility in the setting of MDS/AML (myelodysplastic syndromes/acute myeloid leukemia), particularly with KIR mismatch in the GVH (graft-versus-host) direction.

What is the optimum stem cell source for a MUD transplant?

Bone marrow harvest and G-CSF mobilized peripheral blood stem cell transplantation are the two options to collect stem cells from MUDs. The choice is often determined by donor preference.

Adults

– The optimum stem cell source for adults is undefined and a randomized phase III trial (CTN 0201) comparing G-CSF mobilized PBSC (peripheral blood stem cells) to marrow has shown that overall survival is similar, but there is reduced chronic GVHD and also greater graft rejection in recipients of marrow grafts, compared to peripheral blood. An interesting secondary outcome of this study will be the donor experience between marrow harvest, versus G-CSF mobilized PBSC collection.

Children

– In the pediatric population, unmanipulated peripheral blood stem cell grafts from unrelated donors have been associated with higher rates of GVHD without improved survival, compared to marrow grafts.

When should one initiate the search for the unrelated donor?

Timing is critical and a search for a possible match should begin as early as possible in the course of the disease. A longer lead time allows identification of the best possible match. Urgent searches can be completed in 21 days, but it may take considerably longer to obtain the graft.

Transplant outcomes depend not only on the extent of match but also on the disease stage; transplanting earlier in the course of the disease is often superior to obtaining the best match.

What can be done to mitigate increased GVHD from HLA-mismatch?

Consider ex vivo T cell depletion
Consider in vivo T cell depletion (ATG [anti-thymocyte globulin], campath, or post transplant cyclophosphamide)
Consider marrow as an unmanipulated graft source, over peripheral blood stem cells
Consider umbilical cord blood transplantation, which can permit a greater degree of mismatch

How much does a MUD transplant cost?

Donor recruitment and typing

– It costs about $100 to add a donor to the NMDP, this cost is often covered by sponsors of donor recruitment drives.

The cost of donor search

– Preliminary registry search is free, but in-depth searches requiring full HLA typing of multiple potential unrelated donors can cost several thousand dollars. This is often covered in the USA by grants to the transplant center.

Transplant center charges

Typically exceed $500,000, but are charged to the patient’s financial plan.

What do interested individuals need to know if they wish to become a volunteer donor?

National registries

– In the USA, the National Marrow Donor Program also known as the “Be The Match” Registry runs frequent drives to recruit donors. Other countries have their own national registries.

Minority and mixed race donors

– Since diversity is critical, there is a great need for representation of minority and mixed race donors.

– Donors are eligible to donate at age 18 and remain registered till age 61. Beyond the age of 60, the risk to the donor and the recipient are increased.

Preliminary HLA typing

– This is now performed on a buccal swab and does not require a blood draw.

The likelihood of being asked to donate

– The likelihood of a registered donor being asked to donate is about 1 in 500. The donor will be contacted for additional blood work, physical examination, and counseling.

Common exclusions

– These are diseases transmissible by blood, hematological disorders, severe autoimmune disorders, history of malignancy, chemical dependency, pregnancy, or physical contraindications to the method of collection.

Logistics of donation

– The donation process is entirely voluntary and is conducted at the donor center closest to the donor. The choice belongs to the donor to either undergo a bone marrow harvest under general anaesthesia, or G-CSF mobilization and peripheral blood stem cell apheresis.

Confidentiality

– The process is confidential and, for the first year of the transplant, neither the donor nor the recipient can know each other’s identity. At the end of the year, with mutual consent from the transplant center, donor and recipient, contact may be permitted.

Why are outcomes improving in MUD transplantation?

Improved HLA-matching

– Higher resolution DNA-based typing replacing serologic typing.

– Improved matching criteria, knowledge of which HLA loci are important to outcomes, permissive versus non-permissive matches.

Improved timing

– Patients transplanted earlier in the course of their disease have better outcomes regardless of the degree of HLA match.

– Since referral at an earlier disease stage is a controllable factor, early referrals are improving survival.

Reductions in non-relapse (transplant-related) mortality

– Tailoring of conditioning regimen intensity based on patient age, performance, and disease.

– Customization of GVHD prophylaxis based on the extent of mismatch.

– General improvements in supportive care.

What features of the presentation will guide me toward possible causes and next treatment steps:

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What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

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What conditions can underlie matched unrelated donor hematopoietic stem cell transplantation:

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When do you need to get more aggressive tests:

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What imaging studies (if any) will be helpful?

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What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

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What other therapies are helpful for reducing complications?

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What should you tell the patient and the family about prognosis?

What should you tell the patient and the family about prognosis with respect to MUD transplant?

The overall prognosis with transplantation for a high-resolution (allele level) fully HLA matched at HLA A, B, C, and DRB1 graft [8/8] from a young unrelated donor is excellent and generally considered equivalent to that of a HLA-identical sibling.

If an 8/8 allele-matched donor is not available, then single mismatches at HLA-B or HLA-C appear to be better tolerated than single HLA-A or -DRB1 mismatches. Each additional mismatch is associated with a 9% to 10% absolute reduction in overall survival.

In multivariable analysis, a 6/8 matched transplantation in earlier stage malignant disease produces superior survival to 8/8 matched transplantation late in the course of disease. This emphasizes the danger in delaying transplant in efforts to find a perfect match.

HLA mismatch is more detrimental in patients with severe aplastic anemia and other nonmalignant conditions, who cannot benefit from the compensatory increase in graft-versus-malignancy effect arising from the mismatch. Also, there is a greater risk of graft rejection in mismatched unrelated donor transplants for non-malignant indications in which patients are often allo-immunized.

“What if” scenarios.

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Pathophysiology

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What other clinical manifestations may help me to diagnose matched unrelated donor hematopoietic stem cell transplantation?

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What other additional laboratory studies may be ordered?

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What’s the evidence?

[A current list of allogeneic transplantation indications and timing for referral.]

[Screen the number of potential HLA matches for a given HLA-type in the NMDP registry informally at no cost.]

Anasetti, C, Logan, BR, Lee, SJ. “Peripheral-blood stem cells versus bone marrow from unrelated donors”. NEngl J Med. vol. 367. 2012. pp. 1487-1496. [Randomized controlled trial to define the optimum stem cell source for matched unrelated donor transplantation in adults, comparing G-CSF mobilized PBSC to marrow. Marrow grafts are similar to PBSC in overall survival, but have greater graft rejection balanced by reduced chronic GVHD.]

[This single center analysis of 433 consecutive 6/6 HLA matched unrelated donor transplants versus 187 matched related donor transplants found superior progression free survival in the MUD cohort.]

[In allogeneic transplantation for secondary MDS, including those with transformation to AML, matched related donor transplants (n= 135) had greater relapse and inferior relapse-free survival, compared to unrelated donor transplants (n=122).]

[Race and ethnicity determine the probability of finding an acceptable match in the NMDP registry. Within the NMDP adult donor registry, the probability of identifying at least 1 antigen level–matched (HLA-A and -B) and potential allele level–matched (HLA-DRB1) matched donor depends upon race/ethnicity. Probabilities are as follows, white 88%, black 60%, Hispanics 81%, Asian/Pacific Islanders 78%, and American Indians/Alaska Natives 82%.]

[Race is the greater barrier to finding an acceptable match in the NMDP registry. Black patients were 2.83 times, Asian patients 2.05 times, and Hispanic patients 1.73 times more likely to have a less-matched HCT donor than Caucasian patients.]

[Current NMDP matching guidelines.]

[An excellent overview of HLA matching and donor selection.]

Kollman, C, Howe, CWS, Anasetti, C. “Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age”. Blood. vol. 98. 2001. pp. 2043-2051. [This retrospective analysis of 6,978 unrelated bone marrow transplantations found that younger donors reduced GVHD and improved survival.]

[Multicenter concurrent phase II trials show impressive results for double umbilical cord blood transplantation and for HLA-mismatched related bone marrow (haploidentical). These are excellent alternatives to MUD transplantation with impressive outcomes and are rapidly growing in utilization.]

[This cautionary retrospective study suggests that, in contrast to HLA-matched sibling donors, MUD transplants, using PBSC rather than marrow as the graft source, have higher rates of GVHD without improving overall survival.]

[This study analyzes NMDP data between 1988 to 2003 for 3,857 transplantations with high-resolution typing information. Best outcomes were noted with matching for HLA-A, -B, -C, and -DRB1 (8/8 match). A single locus mismatch worsened survival and mismatching at two or more loci compounded the risk. Interestingly, disease stage was as critical as the degree of mismatch. It might be superior to transplant a patient with aggressive disease early with a mismatched donor, than to delay transplant in order to find a better matched donor.]

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Matched unrelated donor hematopoietic stem cell transplantation