Key Points

  • There is a need to identify the best HLA haplotype-mismatched related donor.

  • Use of young, male, NIMA-mismatched donors results in the best survival after HLA haplotype-mismatched related donor transplants.

Abstract

The best donor for a related donor for a human leukocyte antigen (HLA) haplotype-mismatched transplant for hematological neoplasms is controversial. We studied outcomes in 1210 consecutive transplant recipients treated on a uniform protocol. Younger donors and male donors were associated with less nonrelapse mortality (NRM; hazard ratio [HR] = 0.30; 95% confidence interval [CI] = 0.01-0.39; P = .008 and HR = 0.65; 95% CI = 0.49-0.85; P = .002) and better survival (HR = 0.73; 95% CI = 0.54-0.97; P = .033 and HR = 0.73; 95% CI = 0.59-0.91; P = .005). Father donors were associated with less NRM (HR = 0.65; 95% CI = 0.45-0.95; P = .02), acute graft-versus-host disease (GVHD) (HR = 0.69; 95% CI = 0.55-0.86; P = .001), and better survival (HR = 0.66; 95% CI = 0.50-0.87; P = .003) compared with mother donors. Children donors were associated with less acute GVHD than sibling donors (HR = 0.57; 95% CI = 0.31-0.91; P = .01). Older sister donors were inferior to father donors with regard to NRM (HR = 1.87; 95% CI = 1.10-3.20; P = .02) and survival (HR = 1.59; 95% CI = 1.05-2.40; P = .03). Noninherited maternal antigen-mismatched sibling donors were associated with the lowest incidence of acute GVHD compared with parental donors and noninherited paternal antigen-mismatched sibling donors. Specific HLA disparities were not significantly correlated with transplant outcomes. Our data indicate which HLA haplotype-mismatched related donors are associated with the best transplant outcomes in persons with hematological neoplasms.

Introduction

Human leukocyte antigen (HLA) haplotype-mismatched transplants from related donors are increasing.1-3  Several approaches were used including ex-vivo T-cell depletion 4,5  granulocyte colony-stimulating factor,6  posttransplant cyclophosphamide 7,8  and pre- and posttransplant antithymocyte globulin (ATG).9  Kasamon et al8  reported degree of HLA disparity on the HLA-mismatched haplotype is not correlated with survival after nonmyeloablative transplants with posttransplant cyclophosphamide. Similarly, we found that number of HLA mismatches was not correlated with survival after T-cell–replete transplants. These data suggest variables other than HLA matching on the mismatched HLA haplotype should be studied to determine their impact on transplant outcomes.10,11  Donor age and gender correlate with outcomes after transplants from HLA-identical sibling donors and HLA-matched unrelated donor.12,13  Matching for noninherited maternal antigens (NIMAs) is reported to correlate with incidence of graft-versus-host disease (GVHD) after HLA-identical transplants.14-16  These data suggest the possible impact of donor-related variables correlated with transplant outcomes in the setting of related HLA haplotype-mismatched transplants.

We reported our approach to related HLA haplotype-mismatched T-cell–replete transplants in >1000 subjects during the last 10 years, an approach also used by others.10,11  During this interval, pretransplant conditioning regimen, graft type, and GVHD prophylaxis have not changed. Consequently, our dataset provides an opportunity to explore donor-related variables that might correlate with transplant outcomes.

Materials and methods

Eligibility

A total of 1256 consecutive subjects with hematological neoplasms receiving related HLA haplotype-mismatched transplants May 2002 through February 2013 at Peking University Institute of Hematology were considered. We excluded 32 subjects with cousin donors and 14 subjects who received porcine ATG. The remaining 1210 subjects were enrolled; 713 were previously reported.10  The Institutional Review Board of Peking University approved this study, and all subjects and donors gave written informed consent. This study was conducted in accordance with the Declaration of Helsinki.

Donor selection and HLA typing

A human leukocyte antigen (HLA)-matched sibling donor was the first choice for allotransplant. If an HLA-matched sibling donor was unavailable, subjects without a suitable, closely HLA-matched, unrelated donor (>8 of 10 matching HLA-A, B, C, DR, and DQ loci and >5 of 6 matching HLA-A, B, and DR loci or whose disease state left insufficient time for an unrelated donor search) were eligible for HLA haplotype-mismatched transplant. Family members were assessed for degree of HLA mismatch. HLA-A and HLA-B typing were performed by intermediate resolution DNA typing, whereas HLA-DRB1 typing was performed by high-resolution DNA techniques. Each subject received a graft from a family member sharing one HLA haplotype with the recipient but differed to a variable degree for the HLA-A, B, and DR antigens of the unshared HLA haplotype.

Transplants

Pretransplant conditioning was with cytarabine (4 g/m E+2 per day, days –10 to –9), busulfan (4 mg/kg per day, orally days –8 to –6 before January 2008 and 3.2 mg/kg per day, intravenously days –8 to –6 thereafter), cyclophosphamide (1.8 g/m E+2 per day, days –5 to –4), semustine (250 mg/mE+2, day –3), and rabbit ATG (thymoglobulin; Imtix Sangstat, Lyon, France, days –5 to –2). Before June 2008, subjects received 2.5 mg/kg per day, and thereafter subjects with advanced leukemia (defined below) received 1.5 mg/kg per day. Between December 2010 and May 2012, subjects with standard-risk leukemia (defined below) were randomized to receive 2.5 mg/kg per day or 1.5 mg/kg per day (study registered at www.chictr.org #ChiCTR-TRC-11001761). Overall, 158 subjects received an ATG total dose of 6 mg/kg and 1052 received 10 mg/kg. GVHD prophylaxis was with cyclosporine, mycophenolate mofetil, and short course methotrexate as described.10  Grafts were granulocyte-colony stimulating factor mobilized bone marrow and blood cells as described.10 

Definitions

Subjects with acute leukemia were categorized as standard-risk if they were in first or second complete remission.14  Subjects with lymphoma or multiple myeloma were categorized as standard risk if they were in first or second complete remission, partial remission, or had stable disease, as were subjects with chronic myeloid leukemia in first chronic phase and those with myelodysplastic syndrome with <20% bone marrow blasts.14  Other subjects were classified as high risk.

Statistics

Transplant outcomes considered were measured in terms of GVHD, nonrelapse mortality (NRM), relapse, progression-free survival (PFS), and survival with the major endpoints of NRM and survival. Cumulative incidences were estimated for engraftment, GVHD, NRM, and relapse to accommodate competing risks. Relapse was a competing risk for NRM, and death from any cause was a competing risk for engraftment, GVHD, and relapse. Probabilities of survival and PFS were estimated by the Kaplan-Meier method. Potential prognostic factors were evaluated in univariate analyses by the log-rank test, with a P value <.05 considered significant. Cox proportional hazards regression was used to identify risk factors associated with outcomes. Multivariate analyses were done for the entire cohort and predefined subgroups. The assumption of proportional hazards for each factor in the Cox model was tested. The test indicated that the proportionality assumptions hold. Variables considered in the multivariate models were donor sex (male vs female, except in the comparison between parental donors), donor age (continuous variable), HLA disparity (3/6 vs 4/6 vs 5/6 or 6/6), donor-recipient sex (match vs mismatch), donor-recipient blood type pair (match vs major mismatch vs minor mismatch), and donor-recipient relationship (father vs mother vs sibling vs children for the entire study population and separate comparison performed in subgroup analysis). Cytomegalovirus (CMV) serological state was not considered as a covariate, because only 1% of subjects were low risk (recipient [R]−, donor [D]−) for CMV reactivity. Killer immunoglobulin-like receptor matching was not analyzed because of too few data. The test indicated that the effect of donor-related factor on relapse is independent of disease type. The final multivariate models were built using a forward stepwise model selection approach with 5% significance level. Final models for each outcome were reported. The end point of the last follow-up for all of survivors was December 1, 2013. The median follow-up of survivors was 1299 days (range; 283-4241 days).

Results

Subjects and outcomes

Characteristics of the donors, recipients, and grafts are listed in Table 1. Parental donors account for 60% of the study population. The majority of patient/recipient pairs were cytomegalovirus serology+/+. The median time to granulocytes >0.5 × 10E+9/L was 13 days (range, 8-49 days) and was 16 days (range, 5-100 days) to platelets >25 × 10E+5/L. A total of 1199 (99%) of subjects had sustained bone marrow recovery. The 3-year cumulative incidences of NRM and relapse were 17% (95% confidence interval [CI] = 15% to 19%) and 17% (95% CI = 15% to 19%). The 100-day cumulative incidences of acute GVHD ≥grade 2 and grade 3 were 40% (95% CI = 37% to 42%) and 12% (95% CI = 10% to 14%), respectively. The 3-year cumulative incidences of total and extensive chronic GVHD were 50% (95% CI = 47% to 53%) and 21% (95% CI = 19% to 24%). The 3-year probabilities of PFS and survival were 67% (95% CI, = 63 −69%) and 70% (95% CI = 67% to 73%).

Table 1

Characteristics of subjects and donors

Characteristics All patients (n = 1210) 
Transplant year  
 2002-2005 112 
 2006-2010 676 
 2011-2013 422 
Subject gender (male) 770 (64%) 
Median patient age, range, y 25 (2-67) 
 <20 450 (37%) 
 20-40 577 (48%) 
 >40 183 (15%) 
CMV serology  
 Low risk (R–, D–) 12 (1%) 
 Intermediate risk (R−, D+) 169 (14%) 
 High risk (R+) 1029 (85%) 
Disease state  
 Standard risk 884 (73%) 
 High risk 336 (27%) 
Disease type  
 Acute myeloid leukemia 475 (39%) 
 Acute lymphoblastic leukemia 461 (38%) 
 Chronic myeloid leukemia 163 (14%) 
 Myelodysplastic syndrome 75 (6%) 
 Other hematologic malignancy 36 (3%) 
Donor sex, male 686 (57%) 
Median donor age, range, y 41 (8-65) 
 <30 241 (20%) 
 30-45 591 (49%) 
 >45 378 (31%) 
Matched HLA loci at A, B, DR  
 3/6 678 (56%) 
 4/6 407 (34%) 
 5/6 122 (10%) 
 6/6 3 (0.2%) 
Individual HLA locus mismatch  
 Mismatch at HLA-A 867 (72%) 
 Mismatch at HLA-B 1051 (87%) 
 Mismatch at HLA-DR 1016 (84%) 
Donor-recipient gender  
 Male-male 442 (37%) 
 Male-female 244 (20%) 
 Female-male 331 (27%) 
 Female-female 193 (16%) 
Donor-recipient blood type  
 Match 686 (57%) 
 Minor mismatch 265 (22%) 
 Major mismatch 190 (16%) 
 Minor + major 69 (6%) 
Donor-recipient relation  
 Father-child 412 (34%) 
 Mother-child 301 (25%) 
 Sibling-sibling 386 (32%) 
 Child-parent 111 (9%) 
Dose of ATG, mg/kg  
 10 1052 (87%) 
 6 158 (13%) 
Median mononuclear cells, range, 108/kg 7.80 (2.20-18.21) 
Median CD34+ cells, range, 106/kg 2.30 (0.27-55.27) 
Median CD3+, median, range, 108/kg 1.53 (0.10-8.29) 
Subjects alive until last follow-up, N 855 
Median follow-up time in survivors, range, d posttransplant 1299 (283-4241) 
Characteristics All patients (n = 1210) 
Transplant year  
 2002-2005 112 
 2006-2010 676 
 2011-2013 422 
Subject gender (male) 770 (64%) 
Median patient age, range, y 25 (2-67) 
 <20 450 (37%) 
 20-40 577 (48%) 
 >40 183 (15%) 
CMV serology  
 Low risk (R–, D–) 12 (1%) 
 Intermediate risk (R−, D+) 169 (14%) 
 High risk (R+) 1029 (85%) 
Disease state  
 Standard risk 884 (73%) 
 High risk 336 (27%) 
Disease type  
 Acute myeloid leukemia 475 (39%) 
 Acute lymphoblastic leukemia 461 (38%) 
 Chronic myeloid leukemia 163 (14%) 
 Myelodysplastic syndrome 75 (6%) 
 Other hematologic malignancy 36 (3%) 
Donor sex, male 686 (57%) 
Median donor age, range, y 41 (8-65) 
 <30 241 (20%) 
 30-45 591 (49%) 
 >45 378 (31%) 
Matched HLA loci at A, B, DR  
 3/6 678 (56%) 
 4/6 407 (34%) 
 5/6 122 (10%) 
 6/6 3 (0.2%) 
Individual HLA locus mismatch  
 Mismatch at HLA-A 867 (72%) 
 Mismatch at HLA-B 1051 (87%) 
 Mismatch at HLA-DR 1016 (84%) 
Donor-recipient gender  
 Male-male 442 (37%) 
 Male-female 244 (20%) 
 Female-male 331 (27%) 
 Female-female 193 (16%) 
Donor-recipient blood type  
 Match 686 (57%) 
 Minor mismatch 265 (22%) 
 Major mismatch 190 (16%) 
 Minor + major 69 (6%) 
Donor-recipient relation  
 Father-child 412 (34%) 
 Mother-child 301 (25%) 
 Sibling-sibling 386 (32%) 
 Child-parent 111 (9%) 
Dose of ATG, mg/kg  
 10 1052 (87%) 
 6 158 (13%) 
Median mononuclear cells, range, 108/kg 7.80 (2.20-18.21) 
Median CD34+ cells, range, 106/kg 2.30 (0.27-55.27) 
Median CD3+, median, range, 108/kg 1.53 (0.10-8.29) 
Subjects alive until last follow-up, N 855 
Median follow-up time in survivors, range, d posttransplant 1299 (283-4241) 

Impact of HLA matching

Overall degree and specific HLA matching or mismatching were not significantly correlated with cumulative incidences of NRM, acute or chronic GVHD, or survival (Table 2).

Table 2

Univariate analysis of donor-related characteristics on transplant outcomes

Risk factors 100-d GVHD ≥grade 2
 
Chronic GVHD
 
Relapse
 
NRM
 
Survival
 
3-y estimated cumulative incidence or probability, % (95% CI)* 
Extent of HLA match      
 3/6 41 (38-44) 51 (47-55) 16 (13-19) 18 (15-21) 70 (67-73) 
 4-6/6 38 (34-42) 51 (47-55) 18 (15-21) 16 (13-19) 70 (66-74) 
P .23 .84 .27 .38 .74 
HLA locus mismatch      
 Match at A 42 (36-48) 54 (48-60) 20 (15-25) 14 (10-18) 70 (65-75) 
 Mismatch at A 40 (37-43) 50 (46-54) 14 (11-17) 19 (16-22) 70 (67-73) 
P .57 .37 .01 .07 .76 
 Match at B 33 (26-40) 43 (35-51) 18 (12-24) 17 (11-23) 70 (62-78) 
 Mismatch at B 42 (39-45) 52 (49-55) 15 (13-17) 17 (15-19) 69 (66-72) 
P .09 .06 .27 .74 .83 
 Match at DR 37 (30-44) 57 (49-65) 16 (10-22) 17 (11-23) 69 (63-75) 
 DR mismatch 42 (39-45) 50 (47-53) 15 (13-17) 18 (16-20) 70 (67-73) 
P .31 .07 .80 .74 .80 
Donor sex      
 Male 37 (34-40) 47 (43-51) 15 (12-18) 14 (12-16) 73 (70-76) 
 Female 44 (40-48) 54 (50-58) 16 (13-19) 20 (17-23) 66 (62-70) 
P .007 .02 .83 .005 .01 
Donor age†      
Continuous (HR) 1.01 (1.00-1.02) 0.99 (0.99-1.01) 1.00 (0.99-1.01) 1.01 (0.99-1.02) 1.01 (0.99-1.02) 
P .001 .69 .49 .21 .09 
 <30 27 (22-32) 47 (41-53) 15 (11-19) 13 (9-17) 76 (71-81) 
 ≥30 43 (40-46) 51 (48-54) 17 (15-19) 18 (16-20) 69 (66-72) 
P <.0001 .42 .52 .04 .04 
 <30 27 (22-32) 47 (41-53) 15 (11-19) 13 (9-17) 76 (71-81) 
 30-45 45 (41-49) 52 (48-56) 17 (14-20) 17 (15-19) 71 (66-76) 
P <.0001 .26 .69 .09 .13 
 30-45 45 (41-49) 52 (48-56) 17 (14-20) 17 (15-19) 71 (66-76) 
 >45 41 (36-46) 49 (44-54) 17 (13-21) 18 (14-22) 67 (62-72) 
P .21 .28 .86 .71 .52 
Sex matching      
 Matched 40 (37-43) 50 (46-54) 17 (14-20) 14 (11-17) 72 (68-76) 
 Mismatched 40 (36-44) 51 (47-55) 16 (13-19) 19 (15-23) 68 (64-72) 
P .84 .92 .57 .03 .14 
Relationship      
 Paternal donor 40 (36-44) 48 (44-52) 18 (14-22) 13 (10-16) 74 (70-78) 
 Maternal donor 52 (47-57) 57 (52-62) 16 (12-20) 21 (16-26) 64 (59-69) 
 Sibling donor 36 (32-40) 50 (45-55) 16 (12-20) 16 (12-20) 72 (69-75) 
 Offspring donor 22 (15-29) 44 (36-52) 15 (9-21) 20 (14-26) 68 (60-76) 
  P <.0001 .07 .80 .02 .04 
 Paternal donor 40 (36-44) 48 (44-52) 18 (14-22) 13 (10-16) 74 (70-78) 
 Maternal donor 52 (47-57) 57 (52-62) 16 (12-20) 21 (16-26) 64 (59-69) 
  P .001 .02 .81 .001 .007 
 Sibling donor 36 (32-40) 50 (45-55) 16 (12-20) 16 (12-20) 72 (69-75) 
 Offspring donor 22 (15-29) 44 (36-52) 15 (9-21) 20 (14-26) 68 (60-76) 
  P .008 .37 .80 .38 .38 
 Paternal donor 40 (36-44) 48 (44-52) 18 (14-22) 13 (10-16) 74 (70-78) 
 Sibling donor 36 (32-40) 50 (45-55) 16 (12-20) 16 (12-20) 72 (69-75) 
  P .25 .57 .33 .23 .57 
Risk factors 100-d GVHD ≥grade 2
 
Chronic GVHD
 
Relapse
 
NRM
 
Survival
 
3-y estimated cumulative incidence or probability, % (95% CI)* 
Extent of HLA match      
 3/6 41 (38-44) 51 (47-55) 16 (13-19) 18 (15-21) 70 (67-73) 
 4-6/6 38 (34-42) 51 (47-55) 18 (15-21) 16 (13-19) 70 (66-74) 
P .23 .84 .27 .38 .74 
HLA locus mismatch      
 Match at A 42 (36-48) 54 (48-60) 20 (15-25) 14 (10-18) 70 (65-75) 
 Mismatch at A 40 (37-43) 50 (46-54) 14 (11-17) 19 (16-22) 70 (67-73) 
P .57 .37 .01 .07 .76 
 Match at B 33 (26-40) 43 (35-51) 18 (12-24) 17 (11-23) 70 (62-78) 
 Mismatch at B 42 (39-45) 52 (49-55) 15 (13-17) 17 (15-19) 69 (66-72) 
P .09 .06 .27 .74 .83 
 Match at DR 37 (30-44) 57 (49-65) 16 (10-22) 17 (11-23) 69 (63-75) 
 DR mismatch 42 (39-45) 50 (47-53) 15 (13-17) 18 (16-20) 70 (67-73) 
P .31 .07 .80 .74 .80 
Donor sex      
 Male 37 (34-40) 47 (43-51) 15 (12-18) 14 (12-16) 73 (70-76) 
 Female 44 (40-48) 54 (50-58) 16 (13-19) 20 (17-23) 66 (62-70) 
P .007 .02 .83 .005 .01 
Donor age†      
Continuous (HR) 1.01 (1.00-1.02) 0.99 (0.99-1.01) 1.00 (0.99-1.01) 1.01 (0.99-1.02) 1.01 (0.99-1.02) 
P .001 .69 .49 .21 .09 
 <30 27 (22-32) 47 (41-53) 15 (11-19) 13 (9-17) 76 (71-81) 
 ≥30 43 (40-46) 51 (48-54) 17 (15-19) 18 (16-20) 69 (66-72) 
P <.0001 .42 .52 .04 .04 
 <30 27 (22-32) 47 (41-53) 15 (11-19) 13 (9-17) 76 (71-81) 
 30-45 45 (41-49) 52 (48-56) 17 (14-20) 17 (15-19) 71 (66-76) 
P <.0001 .26 .69 .09 .13 
 30-45 45 (41-49) 52 (48-56) 17 (14-20) 17 (15-19) 71 (66-76) 
 >45 41 (36-46) 49 (44-54) 17 (13-21) 18 (14-22) 67 (62-72) 
P .21 .28 .86 .71 .52 
Sex matching      
 Matched 40 (37-43) 50 (46-54) 17 (14-20) 14 (11-17) 72 (68-76) 
 Mismatched 40 (36-44) 51 (47-55) 16 (13-19) 19 (15-23) 68 (64-72) 
P .84 .92 .57 .03 .14 
Relationship      
 Paternal donor 40 (36-44) 48 (44-52) 18 (14-22) 13 (10-16) 74 (70-78) 
 Maternal donor 52 (47-57) 57 (52-62) 16 (12-20) 21 (16-26) 64 (59-69) 
 Sibling donor 36 (32-40) 50 (45-55) 16 (12-20) 16 (12-20) 72 (69-75) 
 Offspring donor 22 (15-29) 44 (36-52) 15 (9-21) 20 (14-26) 68 (60-76) 
  P <.0001 .07 .80 .02 .04 
 Paternal donor 40 (36-44) 48 (44-52) 18 (14-22) 13 (10-16) 74 (70-78) 
 Maternal donor 52 (47-57) 57 (52-62) 16 (12-20) 21 (16-26) 64 (59-69) 
  P .001 .02 .81 .001 .007 
 Sibling donor 36 (32-40) 50 (45-55) 16 (12-20) 16 (12-20) 72 (69-75) 
 Offspring donor 22 (15-29) 44 (36-52) 15 (9-21) 20 (14-26) 68 (60-76) 
  P .008 .37 .80 .38 .38 
 Paternal donor 40 (36-44) 48 (44-52) 18 (14-22) 13 (10-16) 74 (70-78) 
 Sibling donor 36 (32-40) 50 (45-55) 16 (12-20) 16 (12-20) 72 (69-75) 
  P .25 .57 .33 .23 .57 
*

As the effect of donor age in the haploidentical transplant had not been established, univariate analysis treated the donor age in different ways: (1) as continuous variable; (2) as a categorical variable to derive the optimal donor selection algorithm, the dichotomous variable of 30 y old was used as reported by Ash RC et al18  for non-HLA identical related donor transplant. Furthermore, we consider a fine group for donor age, such as <30, 30-45, >45 (as reported by Richa EM et al30  for HLA identical related donor transplant), there is no difference between the 30-45 and >45 groups in terms of NRM, whereas there is marginal difference between <30 and 30-45 regarding NRM. Therefore, we used 30 years as a cutoff point for age.

Cumulative incidences were estimated for GVHD, NRM, and relapse to accommodate the competing risks. Relapse was a competing risk for NRM, and death from any cause was a competing risk for GVHD and relapse. Probabilities of survival were estimated by the Kaplan-Meier method using the log-rank test.

Impact of donor age and gender

Younger donors were associated with a lower cumulative incidence of acute GVHD than older donors (Table 2). This association persisted when we considered donor age < or ≥30 years (Table 2). In multivariate analyses, in both models treating donor age as a continuous variable and a binary variable, respectively, donors <30 years old and male donors were independently significantly associated with less NRM and better survival than older or female donors (Table 3; Figure 1). Mother donors were also associated with a higher cumulative incidence of acute GVHD than other pairings in multivariate analyses (Table 3). To determine whether the higher cumulative incidences of acute GVHD associated with older and female donors resulted solely from use of mother donors, we conducted a separate analysis in which mother donors were excluded. In these 909 transplants, we found no significant correlation between donor gender and cumulative incidence of acute GVHD (P = .84). In contrast, donor age <30 years remained significantly associated with less acute GVHD compared with donors ≥30 years with an adjusted hazard ratio (HR) = 0.60 (P < .001).

Table 3

Significant factors in multivariate analysis of acute GVHD, NRM, and overall survival

Donor group/outcome HR (95% CI) P 
All donors (n = 1210)    
 Acute GVHD grade 2-4    
  Model 1*    
   Patient-donor relation   .001† 
    Child-parent 111 1.0  
    Father-child 412 1.92 (1.26-2.93) .002 
    Mother-child 301 2.79 (1.82-4.26) .001 
    Sibling-sibling 386 1.74 (1.13-2.67) .01 
  Model 2‡    
   Patient-donor relation    
    Child-parent 111 1.0  
    Father-child 412 1.39 (0.82-2.33) .21 
    Mother-child 301 2.00 (1.19-3.37) .009 
    Sibling-sibling 386 1.39 (0.86-2.25) .16 
   Donor age, <30 vs >30 241 vs 969 0.69 (0.49-0.97) .03 
 NRM    
  Model 1*   .004 
   Donor sex, male vs female 686 vs 524 0.66 (0.50-0.87)  
  Model 2‡   .008 
   Donor age, <30 vs >30 241 vs 969 0.30 (0.01-0.39)  
   Donor sex, male vs female 686 vs 524 0.65 (0.49-0.85)  
 Overall survival    
  Model 1*   .005 
   Donor sex, male vs female 686 vs 524 0.74 (0.58-0.91)  
  Model 2‡    
   Donor age, <30 vs >30 241 vs 969 0.73 (0.54-0.97) .03 
   Donor sex, male vs female 686 vs 524 0.73 (0.59-0.91) .005 
Parental donors, n = 713 (model 1*)    
 Acute GVHD, grade 2-4    
  Paternal vs maternal donor 412 vs 301 0.65 (0.45-0.95) .02 
 NRM    
  Paternal vs maternal donor    
  Sex match vs mismatch 394 vs 319 0.66 (0.45-0.97) .03 
 Overall survival    
  Paternal vs maternal donor 412 vs 301 0.66 (0.50-0.87) .003 
Offspring or sibling donors, n = 497 (model 1*)    
 Acute GVHD, grade 2-4    
  Sibling vs offspring 386 vs 111 1.74 (1.13-2.66) .01 
 NRM    
  Donor age  1.07 (1.03-1.11) .001 
 Overall survival    
 Donor age  1.05 (1.01-1.08) .004 
Paternal or sibling donors, n = 798 (model 1*)    
 NRM    
  Donor age  1.03 (1.01-1.06) .002 
  Donor sex, male vs female 612 vs 186 0.53 (0.34-0.82) .005 
 Overall survival    
  Donor age  1.03 (1.00-1.06) .03 
NIMA/NIPA sibling model, n = 53 (model 1*)    
 Acute GVHD, grade 2-4    
  NIMA vs NIPA mismatch 27 vs 26 0.32 (0.11-0.91) .03 
 Overall survival    
  Donor age  1.07 (1.00-1.16) .04 
 NIMA/IPA model, n = 89 (model 1*)    
 Acute GVHD, grade 2-4    
  NIMA mismatch vs IPA 34 vs 55 0.21 (0.07-0.61) .004 
  Donor age  0.95 (0.91-1.00) .05 
Sibling-parent model, n = 238 (model 1*)    
 Acute GVHD, grade 2-4    
  NIMA mismatched sibling 27 1.0 — 
  NIPA mismatched sibling 26 2.92 (1.06-8.47) .04 
  Paternal donor 130 3.86 (1.21-12.2) .02 
  Maternal donor 55 3.03 (1.00-9.12) .04 
  Donor age  0.97 (0.94-0.99) .03 
Donor group/outcome HR (95% CI) P 
All donors (n = 1210)    
 Acute GVHD grade 2-4    
  Model 1*    
   Patient-donor relation   .001† 
    Child-parent 111 1.0  
    Father-child 412 1.92 (1.26-2.93) .002 
    Mother-child 301 2.79 (1.82-4.26) .001 
    Sibling-sibling 386 1.74 (1.13-2.67) .01 
  Model 2‡    
   Patient-donor relation    
    Child-parent 111 1.0  
    Father-child 412 1.39 (0.82-2.33) .21 
    Mother-child 301 2.00 (1.19-3.37) .009 
    Sibling-sibling 386 1.39 (0.86-2.25) .16 
   Donor age, <30 vs >30 241 vs 969 0.69 (0.49-0.97) .03 
 NRM    
  Model 1*   .004 
   Donor sex, male vs female 686 vs 524 0.66 (0.50-0.87)  
  Model 2‡   .008 
   Donor age, <30 vs >30 241 vs 969 0.30 (0.01-0.39)  
   Donor sex, male vs female 686 vs 524 0.65 (0.49-0.85)  
 Overall survival    
  Model 1*   .005 
   Donor sex, male vs female 686 vs 524 0.74 (0.58-0.91)  
  Model 2‡    
   Donor age, <30 vs >30 241 vs 969 0.73 (0.54-0.97) .03 
   Donor sex, male vs female 686 vs 524 0.73 (0.59-0.91) .005 
Parental donors, n = 713 (model 1*)    
 Acute GVHD, grade 2-4    
  Paternal vs maternal donor 412 vs 301 0.65 (0.45-0.95) .02 
 NRM    
  Paternal vs maternal donor    
  Sex match vs mismatch 394 vs 319 0.66 (0.45-0.97) .03 
 Overall survival    
  Paternal vs maternal donor 412 vs 301 0.66 (0.50-0.87) .003 
Offspring or sibling donors, n = 497 (model 1*)    
 Acute GVHD, grade 2-4    
  Sibling vs offspring 386 vs 111 1.74 (1.13-2.66) .01 
 NRM    
  Donor age  1.07 (1.03-1.11) .001 
 Overall survival    
 Donor age  1.05 (1.01-1.08) .004 
Paternal or sibling donors, n = 798 (model 1*)    
 NRM    
  Donor age  1.03 (1.01-1.06) .002 
  Donor sex, male vs female 612 vs 186 0.53 (0.34-0.82) .005 
 Overall survival    
  Donor age  1.03 (1.00-1.06) .03 
NIMA/NIPA sibling model, n = 53 (model 1*)    
 Acute GVHD, grade 2-4    
  NIMA vs NIPA mismatch 27 vs 26 0.32 (0.11-0.91) .03 
 Overall survival    
  Donor age  1.07 (1.00-1.16) .04 
 NIMA/IPA model, n = 89 (model 1*)    
 Acute GVHD, grade 2-4    
  NIMA mismatch vs IPA 34 vs 55 0.21 (0.07-0.61) .004 
  Donor age  0.95 (0.91-1.00) .05 
Sibling-parent model, n = 238 (model 1*)    
 Acute GVHD, grade 2-4    
  NIMA mismatched sibling 27 1.0 — 
  NIPA mismatched sibling 26 2.92 (1.06-8.47) .04 
  Paternal donor 130 3.86 (1.21-12.2) .02 
  Maternal donor 55 3.03 (1.00-9.12) .04 
  Donor age  0.97 (0.94-0.99) .03 
*

Model 1: donor age was treated as continuous variable.

Three degrees of freedom test.

Model 2: donor age was treated as dichotomous variable.

Figure 1

Cumulative incidences of NRM and acute GVHD and probability of survival. By donor age (A-C) and gender (D-F).

Figure 1

Cumulative incidences of NRM and acute GVHD and probability of survival. By donor age (A-C) and gender (D-F).

Impact of family relationships

Family relationship was also significantly correlated with transplant outcomes. Because many families have only 1 child, the most common comparisons we could analyze were grafts from father vs mother, child vs sibling, and of sibling vs parent.

Father vs mother donors.

Mother donors were associated with more NRM and acute GVHD and worse survival than father donors in multivariate analyses (Table 3; Figure 2). This adverse impact of mother donors on acute GVHD persisted regardless of whether the recipient was a son (HR = 1.34; 95% CI = 1.07-1.34; P = .03) or a daughter (HR = 1.59; 95% CI = 1.20-2.10; P = .001). In contrast, maternal donors were associated with more NRM and worse survival when the recipient was a son17  (HR = 2.04; 95% CI = 1.37-3.03; P = .001 and HR = 1.49; 95% CI = 1.09-2.03; P = .01, respectively), but not when the recipient was a daughter. Donor age was not associated with any outcome in this subset analysis. These data favor the use of father donors over mother donors, especially when the recipient is a son.

Figure 2

Impact of family relationships. Cumulative incidences of NRM (A), acute GVHD (B), and probability of survival (C) between parental donors.

Figure 2

Impact of family relationships. Cumulative incidences of NRM (A), acute GVHD (B), and probability of survival (C) between parental donors.

Child vs sibling donors.

We also considered outcomes after child vs sibling donors in multivariate analysis, as this situation is obviously confounded by donor age and gender. Offspring donors were associated with less acute GVHD ≥ grade-2 compared with sibling donors (Table 3). In contrast, donor age rather than child vs sibling was more important in the context of NRM and survival (Table 3). Donor gender was not significantly associated with any outcome in this subset analysis.

Young brothers vs old sisters or fathers.

For many young adults without children, donor choice is between a sibling or a parent. Because we showed better outcomes with fathers vs mother, the critical choice is between a sibling or father donor. In our preliminary analyses, there was no significant difference in outcomes between sibling and father donors (Table 2), and these cohorts were combined in further analyses where father donors comprised >50% of the combined cohort. We next considered whether donor age and/or gender or gender matching were associated with transplant outcomes. Younger donors were associated with less NRM and better survival, whereas female donors (siblings only) were associated with more NRM in multivariate analysis (Table 3). To determine the relative import of donor age and sex on transplant outcomes, we created 4 subsets. Sibling donors <30 years were associated with less acute GVHD ≥grade 2 compared with sibling donors ≥30 years (HR = 0.68; 95% CI = 0.46-0.99; P = .05) or father donors < or ≥30 years (HR = 0.68; 95% CI = 0.48-0.98; P = .04). In contrast, outcomes of transplants from brothers ≥30 years were not significantly different than father donors (data not shown). Sister donors ≥30 years, especially when the recipient was a brother, were associated with more NRM (HR = 1.87; 95% CI = 1.10-3.20; P = .02) and worse survival (HR = 1.59; 95% CI = 1.05-2.40; P = .03) compared with father donors.

Effects of NIMAs.

The impact of NIMA disparities was studied in 264 subjects who had informative donor, recipient, and parent HLA-typing data. Subjects were divided into 3 subsets: (1) mother to offspring grafts with GvH reaction against inherited father HLA antigens (IPA); (2) offspring to mother grafts with GvH reaction against the NIMAs of offspring; and (3) sibling to sibling grafts, where the siblings are NIMA mismatched but share inherited father HLA antigens. Four models were created to study the NIMA effect as described.15  Estimates of event frequencies were calculated at 1.5 years because of briefer follow-up (except acute GVHD at 100 days).

In the sibling-only model (N = 53), NIMA-mismatched sibling donors (N = 27) had less acute GVHD ≥grade 2 (19% vs 46%; P = .02) and a trend toward lower cumulative incidence of relapse (7% vs 23%; P = .11) compared with NIPA-mismatched sibling donors (N = 26) (Table 3). Next, in the NIMA/IPA model (N = 89), the subset was divided into a NIMA-targeted subset (N = 34), which included NIMA-mismatched sibling grafts (N = 27) and child to mother grafts (N = 7) and an IPA-targeted subset referred to maternal donors (N = 55). Here, NIMA-mismatched donors and younger donors had less acute GVHD ≥grade 2 (Table 3). Then, in the sibling and parent combined model (N = 238), mother donors (N = 55) and father donors (N = 130) were associated with more acute GVHD ≥grade 2 compared with NIMA-mismatched sibling donors (N = 27; P = .04 and P = .02), but there was no significant difference when compared with NIPA-mismatched sibling donors (P = .93 and P = .58) (Table 3; Figure 3). Finally, the sibling-offspring combined model (N = 79) was divided into subsets including a NIMA-targeted subset (N = 34), which included NIMA-mismatched siblings grafts (N = 27), and offspring to mother grafts (N = 7) and a NIPA-targeted subset (N = 45), which included NIPA-mismatched siblings grafts (N = 26) and offspring to father grafts (N = 19). The NIMA-targeted subset had slightly less acute GVHD ≥grade 2 (23% vs 42%; P = .06). There were no differences in other outcomes, including NRM, chronic GVHD, and survival among any of the above-mentioned subsets regarding NIMA.

Figure 3

NIMA subsets. Cumulative incidences of NRM (A), acute GVHD (B), and probability of survival (C) by NIMA subset.

Figure 3

NIMA subsets. Cumulative incidences of NRM (A), acute GVHD (B), and probability of survival (C) by NIMA subset.

Discussion

Our data confirm degree of HLA disparity on the HLA-mismatched haplotype is not significantly correlated with transplant outcomes among recipients of T-cell–replete–related HLA haplotype-mismatched transplants.10,11  Whether this is so in all transplant settings requires further study but seems so.8,19 

In contrast to the lack of impact of HLA disparity on transplant outcomes, we found that older donors were associated with more acute GVHD and that donors >30 years were associated with more NRM and worse survival. Similar findings operate in other transplant settings.12,13,18  The adverse impact of older donors operates in all subset analyses except the subset of parental donors (Table 3). This effect likely contributes to the lower NRM and better survival of younger sibling donors than parent donors. Why older donors are associated with worse transplant outcomes is uncertain but may reflect age-associated declines in hematopoiesis and immunity.20,21  However, it is important to recall we report statistically significant associations, which may but need not imply causality.

Donor gender was also significantly associated with transplant outcomes. Transplants from male donors had less NRM, less acute GVHD ≥grade 2, and better survival. This benefit was lost when mother donors were excluded. Similar associations of gender and transplant outcomes are reported in some but not all other transplant settings, especially transplants from parous mother.8,12,13,16  Some data suggest this effect may reflect immunity to minor histocompatibility antigen encoded genes on the Y chromosome.22,23  Unfortunately, we have insufficient data on donor parity to explore this further.

Family relationship was also an independent predictor of transplant outcomes. Similar but inconsistent relationships are reported by others.24-26  Mother donors were associated with more acute GVHD ≥grade 2 compared with father donors similar to some14  but not other studies.15,16  The reason for this disparity is uncertain but may reflect differences in several variables, including the pretransplant conditioning, graft composition, posttransplant immune suppression, and others. In the Perugia report,16  patients who received transplants from mothers had a more favorable risk profile regarding disease state at transplantation, although mother remained a better donor after adjustment in multivariable analysis. Controversial effects of natural killer cell alloreactivity between the European and American study and our study were reviewed in detail by our group.27,28 

In the sibling-only model and the sibling-parent combined model, our data, consistent with other studies, suggest a tolerance-inducing NIMA effect.29  However, we found no significant impact of NIMA mismatch on NRM, chronic GVHD, relapse, or survival. In a more detailed subset analysis, we found older NIMA-mismatched sibling donors were associated with less acute GVHD ≥grade 2 compared with younger NIPA-mismatched sibling donors. However, there were few subjects in each subset, and the difference was not statistically significant. We also found NIMA-mismatched sibling donors had less acute GVHD ≥grade 2 than father donors even after adjusting for age and gender. In contrast, this NIPA effect did not counterbalance the impacts of donor age and gender discussed above (data not shown). These conclusions should be interpreted cautiously, because of the few subjects in each subset. In the sibling-offspring combined model, the NIMA-targeted subset had a less acute GVHD ≥grade 2 compared with the NIPA-targeted subset. Again, the number of subjects in each cohort was small and analyses were confounded by the shared HLA haplotypes.15  Furthermore, the immune system of the child is more naive than that of the mother. Other factors may also operate. We were unable to critically analyze child to mother transplants or determine whether donor age or gender are more important than the NIMA effect because of a small sample size.

The strength of our study is the large sample size and relative consistency of transplant variables. Nevertheless, we were unable to analyze some potentially important variables such as CMV serological state and killer immunoglobulin-like receptor disparity.

In conclusion, selection of the best donor in the setting of related HLA haplotype-mismatched T-cell–replete transplants needs to consider donor age, gender, family relationship, NIMA effect, and other variables. Our data suggest choosing young, male, NIMA-mismatched donors is reasonable. Transplants from older mothers and NIPA-mismatched donors should probably be avoided (Table 4). Comparisons of different approaches in the setting of related HLA haplotype-mismatched transplant should probably be adjusted for the variables we identified, which are associated with transplant outcomes.

Table 4

Proposed algorithm for donor selection in haploidentical hematopoietic stem cell transplantation (based on GVHD and NRM)

Selection order Donor source 
Most preferred Child, NIMA-mismatched 
2nd choice Younger brother, NIMA-mismatched 
3rd choice Older sister, NIMA-mismatched or Father 
4th choice Older sibling, NIPA-mismatched 
The last choice Mother 
Selection order Donor source 
Most preferred Child, NIMA-mismatched 
2nd choice Younger brother, NIMA-mismatched 
3rd choice Older sister, NIMA-mismatched or Father 
4th choice Older sibling, NIPA-mismatched 
The last choice Mother 

There is an Inside Blood Commentary on this article in this issue.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

Acknowledgments

Professors Robert Peter Gale (Imperial College London), Mei-Jie Zhang (Medical College of Wisconsin), and Nelson Chao (Duke University) kindly reviewed the typescript.

This work was partly supported by grants from Collaborative Innovation Center of Hematology China, the Key Program of National Natural Science Foundation of China (81230013), and Beijing Municipal Science and Technology Commission (nos. Z121107002812033 and Z121107002612035).

Authorship

Contribution: X.-J.H. designed the study; Y.W. and Y.-J.C. collected data; Y.W., Y.-J.C. and X.-J.H. analyzed the data and wrote the typescript; and all authors contributed to interpretation of the data, preparing the typescript, and approved the final version.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Xiao-Jun Huang, Peking University People’s Hospital, Peking University Institute of Hematology, No 11 Xizhimen South St, Beijing, 100044, China; e-mail: xjhrm@medmail.com.cn.

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Author notes

Y.W. and Y.-J.C. contributed equally to this study.