Prioritizing Unrelated Donor Characteristics in Allogeneic Transplants How Do Age, HLA Disparity Affect Survival?

The number of adults registered as unrelated donors for hematopoietic stem cell transplantation has topped 24 million worldwide, and that number is still increasing. Given the large number of unrelated-donor transplantations, it is important to understand which donor characteristics are associated with better survival in patients with hematologic malignancies.

“While there is agreement that donor–recipient HLA-match is an important criterion and that HLA-matching should consider allele-level HLA-match, strategies vary when prioritizing among comparably HLA-matched potential donors,” Craig Kollman, PhD, from the Jaeb Center for Health Research in Tampa, Florida, and colleagues wrote in a study recently published in Blood. “With increasing numbers of transplantations being performed with grafts from adult unrelated donors, it is critical to identify donor characteristics associated with survival after transplantation after adjusting for relevant patient, disease, and transplantation characteristics.”

Dr. Kollman and co-authors analyzed the following donor characteristics on survival, hematopoietic recovery, and graft-versus-host disease (GVHD) in donors and recipients with allele-level HLA typing at HLA-A, -B, -C, and -DBR1:

  • Age
  • Sex
  • Parity
  • Cytomegalovirus serostatus
  • HLA-match
  • ABO blood group match

Data were collected from the Center for International Blood and Marrow Transplant Research, a network of more than 450 transplant centers worldwide, including information on patient, disease, and transplantation characteristics. Patients who had previously received autologous or allogeneic transplantation, had ex vivo T-cell depletion, or CD34-selected grafts were excluded from the study.

Patients included in the study had the following cancers: acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, and myelodysplastic syndromes.

The researchers analyzed two independent data sets:

  • A training cohort for transplant from 1988 to 2006 (n=6,349)
  • A validation cohort for transplant from 2007 to 2011 (n=4,690)

Characteristics of the training cohort are seen in TABLE 1. In the 1988 to 2006 cohort, the median age of donors was 35 years (range, 18-61 years), and male donors accounted for 62 percent of transplantations. Fifty-nine percent of donor–recipient pairs were 8/8 HLA-matched and 43 percent were ABO blood–matched. Notably, older donors were more likely to be mismatched to their recipients, be cytomegalovirus-seropositive, and donate grafts with lower cell dose compared with younger donors (p<0.001 for all).

In the 2007 to 2011 cohort, most of the donors (55%) were 18 to 32 years of age. Overall, patient, disease, and donor characteristics were similar to the original cohort.

Dr. Kollman and investigators analyzed the following donor-related variables:

  • Donor age: 18-32 years vs. 33-50 years vs. ≥50 years
  • Donor–recipient sex match
  • Donor parity: Male vs. nulliparous female vs. parous female
  • Donor–recipient race match
  • Donor–recipient cytomegalovirus serostatus: donor-negative/recipient-negative vs. donor-positive/recipient-negative vs. donor-negative/recipient-positive vs. donor-positive/recipient-positive
  • ABO blood match: Match versus minor mismatch versus major mismatch
  • Donor–recipient HLA match: 8/8 vs. 7/8 vs. 6/8 vs. 5/8 or lower

For the 1988 to 2006 cohort, the risk of mortality was higher when donors were older than 32 years of age, mismatched for ABO blood group, or mismatched at one or more HLA-loci (p<0.001). The findings were similar in the 2007 to 2011 cohort.

“A similar trend was observed when comparing donors older than 50 years to donors aged 33 to 50 years (hazard ratio [HR] = 1.15; 95% CI 1.02-1.29; p=0.02),” the authors reported. While other donor characteristics were not associated with mortality, several patient, disease, and transplant characteristics were associated with higher mortality (TABLE 2).

In the validation cohort, donor age acted as a continuous variable for overall survival; for each 10-year increment in donor age, there was a 5.5-percent increase in mortality risk. After adjustment for recipient age, disease, disease status, performance score, and recipient cytomegalovirus serostatus, donor–recipient HLA-match was the only donor factor associated with mortality.

Dr. Kollman and colleagues also analyzed hematologic recovery associated with donor–recipient variables, finding that the likelihood of neutrophil recovery was lower after transplantation of allografts from female donors and from donors mismatched at two or more HLA-loci (odds ratio [OR] = 1.26; 95% CI 1.06-1.51; p=0.007). For degree of HLA-match, likelihood of recovery was lower after 6/8 (OR=0.72; 95% CI 0.55-0.93; p=0.01) and 5/8 (OR=0.55; 95% CI 0.40-0.74; p<0.001), but not 7/8 HLA-matched transplants (OR=0.85; 95% CI 0.69-1.04; p=0.11), compared with 8/8 HLA-matched transplants.

The risk of grade 2-4 GVHD was higher in older donors, though this rate was only significantly different between donors aged 18-32 and those ≥33 years (p=0.01), not between donors ≥50 years and 33-50 years.

“Our analyses support [that] donor parity, rather than the traditional donor–recipient sex match combination, is associated with greater incidence of chronic GVHD, non-relapse mortality, and relapse,” they added. “However, any benefit from lower relapse risks associated with transplantation of grafts from female parous donor was negated by higher non-relapse mortality.”

The current analyses revealed that sex, parity, and cytomegalovirus serostatus were not associated with survival.

“Patients receiving transplants from younger HLA-matched donors had the best survival rates after adjusting for patient, disease, and transplant characteristics,” the authors concluded. “Older donor transplantations were also associated with higher non-relapse mortality, but donor age was not associated with relapse.”

Given the results of the current analyses, Dr. Kollman and co-authors suggest that including donor age in the adult unrelated donor selection algorithm would optimize survival. However, “optimizing donor selection by blood ABO matching must be studied further before definitive recommendations can be offered.”


Reference

Kollman C, Spellman SR, Zhang M, et al. The effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy. Blood. 2015 November 2. [Epub ahead of print]

TABLE 1. Characteristics of Patients, Their Donors, and Transplantation
18-32 33-50 >50
Training cohort, 1988-2006
Donor-recipient HLA-match
8/8 matched 1,443 (64%) 2,066 (57%) 224 (51%)
7/8 matched 487 (22%) 960 (26%) 137 (31%)
6/8 matched 216 (10%) 421 (12%) 50 (11%)
5/8 matched or lower 114 (5%) 204 (6%) 27 (6%)
Donor-recipient ABO match
Matched 946 (42%) 1529 (42%) 180 (41%)
Minor mismatch 591 (26%) 885 (24%) 115 (26%)
Major mismatch 697 (31%) 1,157 (32%) 137 (31%)
Not reported 26 (1%) 80 (2%) 6 (1%)
Donor-recipient cytomegalovirus serostatus
Donor and recipient negative 771 (34%) 1,080 (30%) 114 (26%)
Donor negative, recipient positive 788 (35%) 1,187 (33%) 101 (23%)
Donor and recipient positive 412 (18%) 747 (20%) 128 (29%)
Donor positive, recipient positive 246 (11%) 550 (15%) 82 (19%)
Not reported 43 (2%) 87 (2%) 13 (3%)
Donor status at transplantation
1st complete remission/chronic phase 913 (40%) 1,527 (42%) 183 (42%)
2nd complete remission/chronic/accelerated phase 665 (29%) 1,088 (30%) 123 (28%)
Relapse/blast phase/refractory anemia excess blasts 682 (30%) 1,036 (28%) 132 (30%)


TABLE 2. Factors Associated with Overall Mortality
Hazard Ratio(95% CI) p Value
Recipient age <0.001
<18 years 1.00
18-45 years 1.42 (1.29-1.57) <0.001
>45 years 1.83 (1.64- 2.05) <0.001
Recipient cytomegalovirus serostatus <0.001
Seronegative 1.00
Seropositive 1.24 (1.15- 1.34) <0.001
Performance score <0.001
90 – 100 1.00
<90 1.27 (1.19-1.37) <0.001
Disease <0.001
Acute leukemia 1.00
Chronic myeloid leukemia 0.86 (0.78-0.94) 0.001
Myelodysplastic syndrome 0.79 (0.70-0.88) <0.001
Disease status at transplantation <0.001
1st complete remission/chronic phase 1.00
2nd complete remission/chronic/accelerated phase 1.29 (1.19-1.39) <0.001
Relapse/blast phase/refractory anemia excess blasts 2.10 (1.93-2.27) <0.001
Transplant period <0.001
2004-2006 1.00
1988-2003 1.22 (1.12-1.33) <0.001

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