Abstract
The impact of ABO mismatch has been studied on various hematopoietic cell transplant (HCT) outcomes including neutrophil and platelet engraftment, pure red cell aplasia (PRCA), acute and chronic GVHD, non-relapse mortality (NRM) and overall survival (OS). Yet conflicting results have been reported. However, the impact of ABO mismatch on transplant outcomes with various graft types has not been carefully investigated. We analyzed the impact of various graft sources and type of ABO mismatch on transplant outcomes for 1502 patients who underwent HCT at the University of Minnesota, between 2000–2014: 312 receiving marrow (BM), 475 filgrastim-mobilized blood (PBSC), and 715 cord blood (UCB) grafts. Neutrophil engraftment by day 28 was marginally less frequent in the bidirectional ABO mismatched transplants receiving UCB while ABO matching had no influence on engraftment in the BM or PBSC cohorts. ABO mismatch led to no significant differences in platelet engraftment irrespective of stem cell source. We observed a modest, but not significantly lower incidence of grade II/IV acute GVHD in the bidirectional ABO mismatched transplants in the UCB and the PBSC cohorts, but not in the BM group. We found a higher incidence of chronic GVHD in the PBSC group, but it was not significantly lower in the minor ABO mismatched transplants. The incidence of chronic GVHD was similar in the major ABO mismatched transplants receiving BM. We found no significant difference in the overall survival (OS) and non-relapse mortality (NRM) between the ABO matched and the ABO mismatched transplants within each of the three graft source groups. Multivariable analysis adjusting for other relevant factors confirmed that ABO match status did not significantly influence the outcomes of either engraftment, acute or chronic GVHD or NRM. We conclude that ABO mismatch does not influence the outcomes of allogeneic HCT, regardless of stem cell source.
Keywords: ABO mismatched HCT, ABO incompatibility, transplant, graft source
INTRODUCTION
The impact of ABO mismatch (MM) has been studied on various transplant outcomes including neutrophil and platelet engraftment, pure red cell aplasia (PRCA), acute and chronic graft versus host disease (GVHD), non-relapse mortality (NRM) and overall survival (OS), yet conflicting results have been reported from various groups. Importantly, the influence of ABO MM on transplant outcomes considering various graft types and the type of ABO mismatch has not been carefully analyzed.
Although ABO blood group antigens are also expressed on lymphocytes and platelets, no clear influence of ABO MM on leukocyte and platelet recovery has been reported[1, 2]. Registry studies of the Japan Marrow Donor Program (JMDP; n=5549) and the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGMTC; n=1108) reported a correlation of slower neutrophil engraftment with major ABO MM. A study from the National Marrow Donor Program (NMDP; n=6978) observed no difference in engraftment influenced by ABO match [3,4,5]. A meta-analysis of 7 cohort studies evaluating platelet engraftment, and other studies showed a delay in platelet recovery for recipients of major ABO-incompatible grafts [3,6,7].
ABO minor MM is unique to allogeneic-HCT and solid organ transplantation and occurs when donors transfer anti-recipient ABO reactive B lymphocytes and antibodies. Because adoptive transfer of such passenger B lymphocytes into a host with abundant cognate antigen may lead to their further stimulation, this may induce hemolysis of recipient-derived erythroid cells in the peri-transplant period and has been linked to decreased OS [8,9,10,11]. ABO antigens are also widely expressed on vascular and lymphatic endothelium, peri-vascular connective tissues, and bile duct epithelium, so tissue targeting by adoptively transferred B cells may extend beyond red cells [12,13] and conceivably could influence GVHD.
Kimura et al. [3] reported a higher incidence of acute GVHD grade III–IV in both the major and minor ABO MM, but not with bi-directional ABO-incompatibility. Interestingly, the incidence of liver GVHD was higher in minor ABO-mismatched HCT. They hypothesized that bile duct epithelial cells expressing ABO blood group antigens may be injured by donor-derived isohemagglutinins, thereby augmenting the incidence and severity of liver GVHD. On the contrary Seebach et al. [14] observed severe acute GVHD (grade III–IV) of the liver limited to recipients of bi-directional ABO-incompatible grafts. Bacigalupo et al. [15] reported 174 patients receiving an HLA-identical allogeneic bone marrow (BM) HCT, and found minor ABO MM was associated with a significantly higher risk of severe acute GVHD, compared to ABO-matched or major ABO-mismatched pairs. Besides the ABO match, donors of group O, older recipients, rapid engraftment, and older donors were also associated with a higher risk of GVHD. The cumulative incidence of grade II GVHD was 39% for ABO-matched, 54% for major ABO-mismatched, and 82% for minor ABO-mismatched pairs.
ABO associated outcomes in 1,737 HCT patients at Stanford University reported inferior OS in minor MM HCT (median 2.1 vs 6.3 years; HR 1.56; 95%CI 1.19–2.05; p=0.001) in comparison with ABO matched grafts. ABO minor MM was associated with an increase in early NRM (18% vs 13%; HR 1.48, 95%CI 1.06–2.06; p=0.02)[16]. In a Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of 435 lymphoma patients receiving mobilized peripheral blood stem cell (PBSC) allografts, worse OS (HR 1.55; 95%CI 1.07 – 2.25; p=0.021) and increased NRM (HR 1.72; 95%CI 1.11 – 2.68; p=0.03) was observed in recipients of ABO minor MM grafts [17]. A second independent analysis of a CIBMTR dataset including 5,179 patients with AML and MDS showed a non-significant trend toward decreased OS in recipients of ABO minor MM grafts and also found ABO major MM associated with decreased OS (HR 1.19, 95% CI 1.08 – 1.31, p<0.001) and increased NRM (HR 1.23, 95%CI 1.08 – 1.4, p=0.002). ABO minor and major MM are risk factors for worse transplant outcomes, although the associated hazards vary substantially across different transplant populations [16].
ABO MM in UCB recipients have not been well studied and thus we analyzed a large cohort with umbilical cord blood (UCB) grafts and report the impact of graft source and type of ABO mismatch on transplant outcomes.
MATERIALS AND METHODS
The study included 1502 patients who underwent HCT at the University of Minnesota between 2000–2014. Of the 1502 patients, 312 received BM, 475 PBSC, and 715 UCB grafts. Patients studied were receiving their first HCT for a malignant diagnosis. Patients with a non-malignant diagnosis were included only if they received BM and were older than 10 years of age (n=120). There were too few PBSC recipients with non-malignant disease to analyze, and non-malignant UCB recipients have been reported separately [19]. For double UCBT (n=532), the engrafting unit was considered to be the unit with > 70% donor chimerism at day 100 or day 21 (if day 100 chimerism was unavailable). HLA and ABO match was categorized according to the engrafting unit. If neither unit dominated, the worse HLA and ABO match was used (for ABO, bidirectional > major-mismatch > minor-mismatch > match). Plasma depletion of ABO minor mismatched and RBC depletion for major mismatch were used for adult donor grafts. The cryopreserved UCB grafts contained negligible amounts of plasma and no intact RBCs. After thawing, they were not washed or RBC depleted prior to infusion.
Hematologic endpoints were defined as follows: Engraftment: sustained absolute neutrophil count (ANC) >0.5 x 109/L for at least 3 days. RBC transfusion independence: absence of transfusion needs for at least 7 days with sustained hemoglobin level > 8 g/dl. Platelet recovery: platelet count > 20 x 109/L with no transfusion needs for at least 5–7 days. Patients who did not recover ANC or platelets before a second HCT were analyzed as graft failure and patients were censored at the day of second transplant (n=84) for other outcomes, since ABO status could differ if an alternate donor was used for the 2nd HCT.
Unadjusted outcome estimates and 95% confidence intervals were calculated using the Kaplan-Meier method [20] for OS and the cumulative incidence function [21] for all other outcomes, considering death as a competing risk for GVHD and engraftment and relapse as a competing risk for NRM.
The independence of ABO compatibility and overall outcomes were tested separately in each graft source cohort. Chi-square tests were used for neutrophil and platelet recovery, Cox regression [22] for OS, and Fine and Gray competing hazards regression [23] for GVHD and NRM. Acute and chronic GVHD analyses adjusted for recipient age quartile, HLA match status, donor-recipient sex combination and GVHD prophylaxis cyclosporine (CSA)/mycophenolate mofetil (MMF), CSA/methotrexate (MTX) or other). NRM analyses were adjusted for recipient age quartile, recipient CMV serostatus, and grade II–IV acute GVHD as a time-dependent variable. The BM subgroup analyses were also adjusted for diagnosis type (malignant or non-malignant) using stratified Cochran-Mantel-Haenszel tests instead of Chi-square tests for engraftment outcomes.
Outcomes and covariates were all pre-specified. All statistical tests are reported and there was no adjustment for multiple testing.
RESULTS
The patients’ characteristics based on graft source are shown in Table 1. We divided each of the groups based on ABO typing of patient and donor into 4 subcategories: ABO matched, major ABO mismatch, minor ABO mismatch and bidirectional mismatch and these sub-categories were then analyzed as specified.
Table 1.
Patient and transplant characteristics by Donor: Recipient ABO match and graft source
| A. Umbilical Cord Blood | ABO match status | ||||
|---|---|---|---|---|---|
| Variable | Category | Match (n=256) | Minor Mismatch (n=227) | Bidirectional Mismatch (n=66) | Major Mismatch (n=166) |
| Age (Years) | Mean (SD) | 36 (21) | 36 (22) | 38 (21) | 36 (22) |
| Range | 0–72 | 0–71 | 0–70 | 0–73 | |
| Gender | Male | 150 (59%) | 133 (59%) | 38 (58%) | 101 (61%) |
| Female | 106 (41%) | 94 (41%) | 28 (42%) | 65 (39%) | |
| Conditioning Intensity | Myeloablative | 146 (57%) | 125 (55%) | 31 (47%) | 89 (54%) |
| Non-Myeloablative | 110 (43%) | 102 (45%) | 35 (53%) | 77 (46%) | |
| HLA match | 4/6 | 102 (40%) | 88 (39%) | 27 (41%) | 74 (45%) |
| 5/6 | 116 (45%) | 99 (44%) | 35 (53%) | 68 (41%) | |
| 6/6 | 38 (15%) | 40 (18%) | 4 (6%) | 24 (14%) | |
| TNC dose(10^8/kg) | Mean (SD) | 0.5 (0.4) | 0.5 (0.5) | 0.5 (0.4) | 0.5 (0.4) |
| Range | 0.2 – 3.7 | 0.1 – 4.9 | 0.2 – 2.2 | 0.1 – 2.8 | |
| CD34 dose(10^5/kg) | Mean (SD) | 1.7 (5.1) | 1.1 (2.6) | 1.3 (4.2) | 1.0 (2.1) |
| Range | 0.1 – 40.5 | 0.1 – 27.5 | 0.1 – 29.6 | 0.1 – 21.4 | |
| Number of units | Single UCB | 69 (27%) | 63 (28%) | 12 (18%) | 39 (23%) |
| Double UCB | 187 (73%) | 164 (72%) | 54 (82%) | 127 (77%) | |
| Transplant Year | 2000–2004 | 69 (27%) | 64 (28%) | 19 (29%) | 43 (26%) |
| 2005–2009 | 101 (39%) | 92 (41%) | 26 (39%) | 68 (41%) | |
| 2010–2014 | 86 (34%) | 71 (31%) | 21 (32%) | 55 (33%) | |
| Disease Type | Malignant | 256 (100%) | 227 (100%) | 66 (100%) | 166 (100%) |
| Disease Category | ALL | 85 (33%) | 55 (24%) | 17 (26%) | 44 (27%) |
| AML | 97 (38%) | 108 (48%) | 28 (42%) | 64 (39%) | |
| CML | 7 (3%) | 3 (1%) | 4 (6%) | 6 (4%) | |
| Other Leukemia | 8 (3%) | 8 (4%) | 4 (6%) | 12 (7%) | |
| MDS | 22 (9%) | 20 (9%) | 7 (11%) | 19 (11%) | |
| NHL | 29 (11%) | 22 (10%) | 2 (3%) | 14 (8%) | |
| Hodgkins | 4 (2%) | 1 (0%) | 1 (2%) | 1 (1%) | |
| Myeloproliferative DZ | 3 (1%) | 3 (1%) | 2 (3%) | 4 (2%) | |
| Other Malignancy | 1 (0%) | 7 (3%) | 1 (2%) | 2 (1%) | |
| Karnofsky Score | 100 | 117 (46%) | 99 (44%) | 29 (44%) | 74 (45%) |
| ≤ 90 | 130 (51%) | 123 (54%) | 36 (55%) | 90 (54%) | |
| Missing | 9 (4%) | 5 (2%) | 1 (2%) | 2 (1%) | |
| Donor relation | Unrelated | 251 (98%) | 226 (100%) | 66 (100%) | 165 (99%) |
| Sibling | 5 (2%) | 1 (0%) | 1 (1%) | ||
| CMV Serostatus | R+ | 146 (57%) | 134 (59%) | 36 (55%) | 101 (61%) |
| R−/D− | 110 (43%) | 93 (41%) | 30 (45%) | 65 (39%) | |
| B. PBSC | ABO match status | ||||
|---|---|---|---|---|---|
| Variable | Category | Match (n=296) | Minor Mismatch (n=73) | Bidirectional Mismatch (n=19) | Major Mismatch (n=87) |
| Age (Years) | Mean (SD) | 49 (13) | 47 (14) | 52 (14) | 49 (13) |
| Range | 0 – 73 | 12 – 71 | 22 – 74 | 10 – 74 | |
| Gender | Male | 183 (62%) | 53 (73%) | 13 (68%) | 52 (60%) |
| Female | 113 (38%) | 20 (27%) | 6 (32%) | 35 (40%) | |
| Conditioning Intensity | Myeloablative | 144 (49%) | 42 (58%) | 4 (21%) | 52 (60%) |
| Non-Myeloablative | 152 (51%) | 31 (42%) | 15 (79%) | 35 (40%) | |
| HLA match | 4/6 | 1 (1%) | 1 (5%) | ||
| 5/6 | 22 (7%) | 6 (8%) | 2 (11%) | 10 (11%) | |
| 6/6 | 274 (93%) | 66 (90%) | 16 (84%) | 77 (89%) | |
| TNC dose(10^8/kg) | Mean (SD) | 9.1 (4.1) | 9.9 (4.7) | 10.2 (5.4) | 8.7 (4.5) |
| Range | 0.0 – 27.2 | 1.8 – 31.6 | 0.1 – 19.8 | 0.0 – 31.3 | |
| CD34 dose(10^6/kg) | Mean (SD) | 6.3 (2.8) | 6.3 (2.2) | 7.2 (2.5) | 6.3 (3.3) |
| Range | 0.0 – 18.2 | 1.1 – 14.7 | 3.5 – 12.4 | 0.5 – 21.8 | |
| Transplant Year | 2000–2004 | 112 (38%) | 24 (33%) | 3 (16%) | 30 (34%) |
| 2005–2009 | 100 (34%) | 25 (34%) | 5 (26%) | 31 (36%) | |
| 2010–2014 | 84 (28%) | 24 (33%) | 11 (58%) | 26 (30%) | |
| Disease Type | Malignant | 296 (100%) | 73 (100%) | 19 (100%) | 87 (100%) |
| Disease Category | ALL | 36 (12%) | 7 (10%) | 15 (17%) | |
| AML | 109 (37%) | 24 (33%) | 6 (32%) | 32 (37%) | |
| CML | 10 (3%) | 6 (8%) | 2 (2%) | ||
| Other Leukemia | 21 (7%) | 4 (5%) | 1 (5%) | 4 (5%) | |
| MDS | 34 (11%) | 15 (21%) | 6 (32%) | 9 (10%) | |
| NHL | 55 (19%) | 10 (14%) | 3 (16%) | 18 (21%) | |
| Hodgkins | 6 (2%) | 1 (1%) | 1 (5%) | ||
| Myeloproliferative Dz | 4 (1%) | 1 (1%) | 4 (5%) | ||
| Other Malignancy | 21 (7%) | 5 (7%) | 2 (11%) | 3 (3%) | |
| Karnofsky Score | 100 | 93 (31%) | 23 (32%) | 10 (53%) | 20 (23%) |
| ≤ 90 | 195 (66%) | 49 (67%) | 9 (47%) | 64 (74%) | |
| Missing | 8 (3%) | 1 (1%) | 3 (3%) | ||
| Donor relation | Unrelated | 10 (3%) | 8 (11%) | 1 (5%) | 3 (3%) |
| Sibling | 274 (93%) | 65 (89%) | 16 (84%) | 79 (91%) | |
| Other related | 12 (4%) | 2 (11%) | 5 (6%) | ||
| CMV Serostatus | R+ | 163 (55%) | 41 (56%) | 10 (53%) | 52 (60%) |
| R−/D− | 94 (32%) | 22 (30%) | 7 (37%) | 31 (36%) | |
| R−/D+ | 39 (13%) | 10 (14%) | 2 (11%) | 4 (5%) | |
| C. Bone Marrow | ABO match status | ||||
|---|---|---|---|---|---|
| Variable | Category | Match (n=152) | Minor Mismatch (n=72) | Bidirectional Mismatch (n=17) | Major Mismatch (n=71) |
| Age (Years) | Mean (SD) | 22 (18) | 25 (17) | 21 (17) | 22 (15) |
| Range | 0 – 75 | 1 – 67 | 1 – 54 | 1 – 58 | |
| Gender | Male | 86 (57%) | 41 (57%) | 7 (41%) | 47 (66%) |
| Female | 66 (43%) | 31 (43%) | 10 (59%) | 24 (34%) | |
| Conditioning Intensity | Myeloablative | 113 (74%) | 54 (75%) | 13 (76%) | 55 (77%) |
| Non-Myeloablative | 39 (26%) | 18 (25%) | 4 (24%) | 16 (23%) | |
| HLA match | 5/6 | 27 (18%) | 11 (15%) | 1 (6%) | 16 (23%) |
| 6/6 | 125 (82%) | 61 (85%) | 16 (94%) | 55 (77%) | |
| TNC dose(10^8/kg) | Mean (SD) | 2.8 (4.3) | 2.6 (1.7) | 1.8 (1.1) | 2.5 (2.6) |
| Range | 0.0 – 50.9 | 0.0 – 11.1 | 0.0 – 3.6 | 0.0 – 18.9 | |
| CD34 dose(10^6/kg) | Mean (SD) | 3.7 (7.1) | 3.1 (2.0) | 3.1 (2.9) | 3.2 (2.7) |
| Range | 0.5 – 86.6 | 0.4 – 9.9 | 0.8 – 13.1 | 0.6 – 14.3 | |
| Transplant Year | 2000–2004 | 61 (40%) | 31 (43%) | 12 (71%) | 25 (35%) |
| 2005–2009 | 37 (24%) | 17 (24%) | 2 (12%) | 22 (31%) | |
| 2010–2014 | 54 (36%) | 24 (33%) | 3 (18%) | 24 (34%) | |
| Disease Type | Malignant | 96 (63%) | 48 (67%) | 12 (71%) | 36 (51%) |
| Non-malignant | 56 (37%) | 24 (33%) | 5 (29%) | 35 (49%) | |
| Disease Category | AA or FA | 38 (25%) | 19 (26%) | 5 (29%) | 26 (37%) |
| Hemaglobinopathy | 3 (2%) | 2 (3%) | |||
| Immune Deficiency | 1 (1%) | 2 (3%) | |||
| Storage Disorder | 12 (8%) | 5 (7%) | 4 (6%) | ||
| EB | 2 (1%) | 1 (1%) | |||
| ALL | 31 (20%) | 7 (10%) | 2 (12%) | 7 (10%) | |
| AML | 23 (15%) | 11 (15%) | 1 (6%) | 6 (8%) | |
| CML | 19 (13%) | 12 (17%) | 2 (12%) | 9 (13%) | |
| Other Leukemia | 6 (4%) | 10 (14%) | 2 (12%) | 4 (6%) | |
| MDS | 8 (5%) | 5 (7%) | 2 (12%) | 2 (3%) | |
| NHL | 4 (3%) | 1 (1%) | 2 (12%) | 7 (10%) | |
| Myeloproliferative Dz | 3 (2%) | ||||
| Other Malignancy | 2 (1%) | 2 (3%) | 1 (6%) | 1 (1%) | |
| Karnofsky Score | 100 | 86 (57%) | 35 (49%) | 10 (59%) | 41 (58%) |
| ≤ 90 | 62 (41%) | 36 (50%) | 7 (41%) | 29 (41%) | |
| Missing | 4 (3%) | 1 (1%) | 1 (1%) | ||
| Donor relation | Unrelated | 71 (47%) | 46 (64%) | 11 (65%) | 49 (69%) |
| Sibling | 75 (49%) | 18 (25%) | 6 (35%) | 22 (31%) | |
| Other related | 6 (4%) | 5 (15%) | |||
| CMV Serostatus | R+ | 83 (54%) | 32 (44%) | 7 (41%) | 39 (55%) |
| R−/D− | 50 (33%) | 24 (33%) | 7 (41%) | 22 (31%) | |
| R−/D+ | 19 (13%) | 16 (22%) | 3 (18%) | 10 (14%) | |
ABO INCOMPATIBILTY AND ENGRAFTMENT
Neutrophil and platelet engraftment were compared between the ABO matched and ABO mismatched transplants for each of the 3 different stem cell sources (Table 2). We observed that neutrophil engraftment by day 28 was less frequent in the bidirectional ABO mismatched transplants, but only in the UCB group. There were no significant differences based on ABO matching observed in the other graft source groups. There were no significant differences in platelet engraftment associated with ABO status using any stem cell source. In double unit UCB transplants, ABO matching did not predict which unit would predominate for long term engraftment (data not shown).
Table 2.
Outcomes by graft source
| Umbilical Cord Blood | ABO match status | ||||
|---|---|---|---|---|---|
| Outcome | Match (n=256) | Minor Mismatch (n=227) | Bidirectional Mismatch (n=66) | Major Mismatch (n=166) | P-value |
| ANC > 500 by day 28 (95% CI) | 80% (75– 85) | 80% (75– 85) | 68% (57– 70) | 73% (67– 70) | 0.08 |
| Platelets >20K by day 35 (95% CI) | 14% (10– 18) | 15% (10– 19) | 17% (7– 26) | 11% (6– 16) | 0.62 |
| Platelets >50K by day 45 (95% CI) | 26% (20– 31) | 27% (21– 33) | 18% (9– 28) | 24% (17– 31) | 0.53 |
| Grade II–IV Acute GVHD (95% CI) | 50% (44– 57) | 49% (42– 56) | 36% (24– 49) | 45% (37– 53) | 0.10 |
| Chronic GVHD by day 365 (95% CI) | 18% (13– 24) | 20% (15– 26) | 12% (3– 22) | 19% (13– 26) | 0.59 |
| NRM by day 180 (95% CI) | 21% (16– 26) | 19% (13– 24) | 22% (12– 33) | 19% (13– 26) | 0.86 |
| Overall survival at day 365 (95% CI) | 61% (55– 67) | 66% (59– 72) | 55% (42– 67) | 58% (50– 66) | 0.29 |
| Peripheral Blood | ABO match status | ||||
|---|---|---|---|---|---|
| Outcome | Match (n=296) | Minor Mismatch (n=73) | Bidirectional Mismatch (n=19) | Major Mismatch (n=87) | P-value |
| ANC >500 by day 28 (95% CI) | 97% (95– 99) | 95% (89– 99) | 95% (81– 99) | 95% (91– 99) | 0.83 |
| Platelets >20K by day 35 (95% CI) | 79% (74– 84) | 75% (65– 86) | 89% (73– 99) | 74% (64– 83) | 0.40 |
| Platelets >50K by day 45 (95% CI) | 73% (68– 78) | 70% (59– 81) | 63% (40– 86) | 75% (65– 84) | 0.72 |
| Grade II–IV Acute GVHD (95% CI) | 45% (39– 51) | 48% (36– 60) | 28% (6– 50) | 40% (30– 51) | 0.74 |
| Chronic GVHD by day 365 (95% CI) | 46% (40– 52) | 32% (21– 44) | 53% (28– 77) | 41% (29– 52) | 0.08 |
| NRM by day 180 (95% CI) | 16% (11– 20) | 21% (11– 30) | 5% (1– 16) | 18% (10– 27) | 0.55 |
| Overall survival at day 365 (95% CI) | 61% (55– 67) | 58% (45– 68) | 63% (38– 80) | 61% (50– 70) | 0.92 |
| Marrow | ABO match status | ||||
|---|---|---|---|---|---|
| Outcome | Match (n=152) | Minor Mismatch (n=72) | Bidirectional Mismatch (n=17) | Major Mismatch (n=71) | P-value |
| ANC > 500 by day 28 (95% CI) | 95% (91– 98) | 97% (93– 99) | 88% (70– 99) | 93% (87– 99) | 0.43 |
| Platelets >20K by day 35 (95% CI) | 59% (51– 67) | 64% (52– 75) | 53% (27– 78) | 49% (37– 61) | 0.43 |
| Platelets >50K by day 45 (95% CI) | 59% (51– 67) | 65% (54– 77) | 65% (40– 90) | 54% (42– 65) | 0.51 |
| Grade II–IV Acute GVHD (95% CI) | 25% (18– 32) | 36% (25– 48) | 35% (11– 59) | 28% (17– 38) | 0.60 |
| Chronic GVHD by day 365 (95% CI) | 16% (10– 22) | 14% (5– 23) | 20% (1– 42) | 26% (14– 38) | 0.07 |
| NRM by day 180 (95% CI) | 17% (11– 23) | 14% (6– 22) | 12% (1– 28) | 16% (7– 25) | 0.66 |
| Overall survival at day 365 (95% CI) | 74% (66– 80) | 71% (59– 80) | 82% (54– 94) | 69% (57– 79) | 0.64 |
Other parameters of engraftment were also examined, but no impact of ABO mismatch was observed. Secondary graft failure was uncommon (<5% in all 3 graft types) and was similar in each of the ABO matching groups. The median donor chimerism at day 100 post HCT was 100% in all subgroups. Incomplete donor engraftment in the absence of graft failure was uncommon and did not differ in the ABO mismatched cohorts in any of the graft type subgroups (data not shown).
ABO INCOMPATIBILTY AND GVHD
The incidence of both acute and chronic GVHD was compared between the ABO matched and ABO mismatched transplants for the 3 different graft sources (Table 2, Figure 1). We noted a slight, but not significantly lower incidence of grade II–IV acute GVHD in the bidirectional ABO mismatched HCT in the UCB and the PBSC cohorts, but not in the BM group. As expected we found a higher incidence of chronic GVHD in the PBSC group and it was slightly, but not significantly lower in the minor ABO mismatched transplants. Similarly, the incidence of chronic GVHD was slightly, but not significantly higher in the major ABO mismatched transplants receiving BM grafts.
Fig 1. GVHD and survival by Graft source and ABO match.
Shown are the incidence of Acute GVHD grade II–IV and Survival for the ABO matching groups within each of the 3 graft types analyzed. There are no significant differences in either GVHD (p=0.10, 0.74, 0.60 for UCB, PBSC, BM, per the multivariate analysis Table 3A), or Survival (p=0.29, 0.92, 0.64, respectively).
SURVIVAL AND NON-RELAPSE MORTALITY
As shown in Table 2 (Figure 1), there were no significant differences in both OS and NRM between the ABO matched and the ABO mismatched transplants—and this was seen in all three graft source groups.
MULTIVARIATE ANALYSIS
Multivariable analysis adjusting for other relevant factors confirmed that ABO match status did not significantly influence the outcomes of either acute or chronic GVHD or NRM (Table 3). This was confirmed in separate multivariable models for each of the graft source cohorts. GVHD prophylaxis and HLA matching influenced acute GVHD risks in UCB recipients while HCT for non-malignant disease was associated with less frequent acute and chronic GVHD in those receiving BM grafts. Older age influenced NRM in UCB and in the oldest cohort (age 55–75 years) of BM recipients. No other factors demonstrated independently significant effects on these outcomes.
Table 3.
Multivariable Analysis; ABO mismatch and graft source
| A. Acute GVHD – Grade II–IV | |||||
|---|---|---|---|---|---|
| Acute GVHD: Umbilical Cord Blood | |||||
| Factor | Category | Hazard Ratio | Lower 95% CL | Upper 95% CL | P-value |
| ABO match | match | 1.00 | 0.10 | ||
| bidirectional mm | 0.59 | 0.37 | 0.92 | ||
| major mm | 0.82 | 0.61 | 1.09 | ||
| minor mm | 0.95 | 0.73 | 1.23 | ||
| GVHD prophylaxis | CSA/MMF | 1.00 | < 0.01 | ||
| Other | 0.49 | 0.35 | 0.68 | ||
| Donor:recipient sex | male to male | 1.00 | 0.06 | ||
| female to female | 0.70 | 0.51 | 0.96 | ||
| female to male | 0.83 | 0.63 | 1.10 | ||
| male to female | 0.69 | 0.51 | 0.94 | ||
| HLA match | 6/6 | 1.00 | 0.01 | ||
| 5/6 | 1.70 | 1.18 | 2.45 | ||
| 4/6 | 1.70 | 1.17 | 2.48 | ||
| Acute GVHD: PBSC | |||||
|---|---|---|---|---|---|
| Factor | Category | Hazard Ratio | Lower 95% CL | Upper 95% CL | P-value |
| ABO match | match | 1.00 | 0.74 | ||
| bidirectional mm | 0.70 | 0.26 | 1.85 | ||
| major mm | 0.90 | 0.61 | 1.31 | ||
| minor mm | 1.11 | 0.76 | 1.62 | ||
| GVHD prophylaxis | CSA/MMF | 1.00 | 0.09 | ||
| CSA/MTX | 1.08 | 0.82 | 1.43 | ||
| Other | 0.50 | 0.25 | 0.99 | ||
| Donor:recipient sex match | male to male | 1.00 | 0.87 | ||
| female to female | 1.05 | 0.72 | 1.54 | ||
| female to male | 0.91 | 0.63 | 1.30 | ||
| male to female | 0.92 | 0.62 | 1.37 | ||
| HLA match | 6/6 | 1.00 | 0.30 | ||
| 5/6 | 0.72 | 0.38 | 1.35 | ||
| Acute GVHD: Bone Marrow | |||||
|---|---|---|---|---|---|
| Factor | Category | Hazard Ratio | Lower 95% CL | Upper 95% CL | P-value |
| ABO match | match | 1.00 | 0.60 | ||
| bidirectional mm | 1.46 | 0.62 | 3.40 | ||
| major mm | 1.28 | 0.72 | 2.27 | ||
| minor mm | 1.36 | 0.81 | 2.29 | ||
| GVHD prophylaxis | CSA/MMF | 1.00 | 0.47 | ||
| CSA/MTX | 0.71 | 0.41 | 1.23 | ||
| Other | 0.80 | 0.43 | 1.50 | ||
| Donor:recipient sex match | male to male | 1.00 | 0.26 | ||
| female to female | 0.49 | 0.23 | 1.05 | ||
| female to male | 0.97 | 0.54 | 1.73 | ||
| male to female | 1.07 | 0.62 | 1.85 | ||
| HLA match | 6/6 | 1.00 | 0.53 | ||
| 5/6 | 0.81 | 0.43 | 1.55 | ||
| Diagnosis | malignant | 1.00 | < 0.01 | ||
| non-malignant | 0.34 | 0.19 | 0.60 | ||
| B. Chronic GVHD | |||||
|---|---|---|---|---|---|
| Chronic GVHD : Umbilical Cord Blood | |||||
| Factor | Category | Hazard Ratio | Lower 95% CL | Upper 95% CL | P-value |
| ABO match | match | 1.00 | 0.59 | ||
| bidirectional mm | 0.62 | 0.26 | 1.47 | ||
| major mm | 1.05 | 0.64 | 1.72 | ||
| minor mm | 1.14 | 0.74 | 1.75 | ||
| GVHD prophylaxis | CSA/MMF | 1.00 | 0.10 | ||
| Other | 0.60 | 0.33 | 1.10 | ||
| Donor:recipient sex match | male to male | 1.00 | 0.41 | ||
| female to female | 0.64 | 0.36 | 1.13 | ||
| female to male | 0.79 | 0.50 | 1.25 | ||
| male to female | 0.75 | 0.45 | 1.25 | ||
| HLA match | 6/6 | 1.00 | 0.10 | ||
| 5/6 | 1.24 | 0.67 | 2.31 | ||
| 4/6 | 1.73 | 0.95 | 3.15 | ||
| Chronic GVHD: PBSC | |||||
|---|---|---|---|---|---|
| Factor | Category | Hazard Ratio | Lower 95% CL | Upper 95% CL | P-value |
| ABO match | match | 1.00 | 0.08 | ||
| bidirectional mm | 1.35 | 0.74 | 2.47 | ||
| major mm | 0.85 | 0.58 | 1.27 | ||
| minor mm | 0.59 | 0.38 | 0.94 | ||
| GVHD prophylaxis | CSA/MMF | 1.00 | 0.08 | ||
| CSA/MTX | 1.00 | 0.74 | 1.35 | ||
| Other | 0.42 | 0.20 | 0.90 | ||
| Donor:recipient sex match | male to male | 1.00 | 0.15 | ||
| female to female | 1.11 | 0.72 | 1.71 | ||
| female to male | 1.46 | 1.02 | 2.08 | ||
| male to female | 1.00 | 0.64 | 1.57 | ||
| HLA match | 6/6 | 1.00 | 0.34 | ||
| 5/6 | 0.71 | 0.35 | 1.44 | ||
| Chronic GVHD: Bone Marrow | |||||
|---|---|---|---|---|---|
| Factor | Category | Hazard Ratio | Lower 95% CL | Upper 95% CL | P-value |
| ABO match | match | 1.00 | 0.07 | ||
| bidirectional mm | 1.11 | 0.37 | 3.32 | ||
| major mm | 2.21 | 1.10 | 4.45 | ||
| minor mm | 0.80 | 0.35 | 1.84 | ||
| GVHD prophylaxis | CSA/MMF | 1.00 | 0.81 | ||
| CSA/MTX | 0.89 | 0.43 | 1.85 | ||
| Other | 1.14 | 0.49 | 2.64 | ||
| Diagnosis | malignant | 1.00 | < 0.01 | ||
| non-malignant | 0.29 | 0.13 | 0.62 | ||
| C. Non-Relapse Mortality | |||||
|---|---|---|---|---|---|
| NRM: Umbilical Cord Blood | |||||
| Factor | Category | Hazard Ratio | Lower 95% CL | Upper 95% CL | P-value |
| ABO match | match | 1.00 | 0.86 | ||
| bidirectional mm | 1.00 | 0.54 | 1.84 | ||
| major mm | 0.89 | 0.56 | 1.41 | ||
| minor mm | 0.85 | 0.56 | 1.27 | ||
| Recipient CMV | positive | 1.00 | 0.11 | ||
| negative | 0.75 | 0.53 | 1.06 | ||
| Age | 0–17 | 1.00 | < 0.01 | ||
| 18–39 | 2.41 | 1.52 | 3.81 | ||
| 40–54 | 1.04 | 0.62 | 1.73 | ||
| 55–75 | 0.85 | 0.50 | 1.43 | ||
| Acute GVHD Grade II–IV | 0.81 | 0.56 | 1.18 | 0.28 | |
| NRM: PBSC | |||||
|---|---|---|---|---|---|
| Factor | Category | Hazard Ratio | Lower 95% CL | Upper 95% CL | P-value |
| ABO match | match | 1.00 | 0.55 | ||
| bidirectional mm | 0.36 | 0.05 | 2.62 | ||
| major mm | 1.13 | 0.62 | 2.04 | ||
| minor mm | 1.31 | 0.74 | 2.33 | ||
| Recipient CMV | positive | 1.00 | 0.44 | ||
| negative | 0.83 | 0.53 | 1.32 | ||
| Age | 0–17 | 1.00 | 0.23 | ||
| 18–39 | 0.38 | 0.08 | 1.89 | ||
| 40–54 | 0.82 | 0.18 | 3.69 | ||
| 55–75 | 0.74 | 0.17 | 3.31 | ||
| Acute GVHD Grade II–IV | 2.80 | 1.69 | 4.64 | < 0.01 | |
| NRM: Bone Marrow | |||||
|---|---|---|---|---|---|
| Factor | Category | Hazard Ratio | Lower 95% CL | Upper 95% CL | P-value |
| ABO match | match | 1.00 | 0.66 | ||
| bidirectional mm | 0.65 | 0.13 | 3.25 | ||
| major mm | 0.74 | 0.35 | 1.55 | ||
| minor mm | 0.63 | 0.29 | 1.37 | ||
| Recipient CMV | positive | 1.00 | 0.58 | ||
| negative | 0.85 | 0.47 | 1.53 | ||
| Age | 0–17 | 1.00 | 0.05 | ||
| 18–39 | 1.89 | 0.95 | 3.77 | ||
| 40–54 | 2.75 | 0.99 | 7.65 | ||
| 55–75 | 3.27 | 1.27 | 8.41 | ||
| Acute GVHD Grade II–IV | 2.93 | 1.46 | 5.88 | < 0.01 | |
| Diagnosis | malignant | 1.00 | 0.06 | ||
| non-malignant | 1.99 | 0.98 | 4.02 | ||
DISCUSSION
We evaluated the impact of ABO mismatch on the outcome of HCT from various graft sources and recognized only limited impact of ABO mismatch on the major outcomes of HCT. In addition to the largest single institution and registry reports [1–5] noted in the Introduction, plus other sizeable reports include Blin et al reporting on 414 patients, most studies did not examine the types of ABO mismatch in their analysis [18]. Based upon the variation in findings within these previous reports, we hypothesized that we might observe differences in GVHD and overall survival rates based on the type of ABO mismatch. A largely pediatric series of UCB HCT for non-malignant diseases from our institution observed no influence of ABO match on HCT outcomes or RBC transfusion needs, but did not examine other graft sources as a comparison. [19]. Thus, conclusions from the previous literature are quite inconsistent.
ABO blood group antigens are also expressed on lymphocytes and platelets. However no clear influence of ABO mismatch with regard to leukocyte and platelet recovery has been found [1, 2]. Registry studies of the Japan Marrow Donor Program (JMDP; >5000 patients) and the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGMTC; >1000 patients) found a correlation of slower neutrophil engraftment with major ABO mismatch. However the National Marrow Donor Program (NMDP; >6000 patients) study noted no difference in engraftment with respect to ABO match [3, 4, 5]. In terms of platelet engraftment a meta-analysis of 7 cohort studies, the report for the JMDP, and other studies showed a delay in recovery for recipients of major ABO-incompatible grafts [3, 6, 7]. Our study identified no impact of major ABO incompatibility on neutrophil or platelet recovery regardless of donor type, conditioning regimen, and stem cell source. These results are consistent with other previous studies that reported no influence of major ABO mismatch on engraftment [18,19]. The conclusions remain modestly discordant in the reported literature.
Kimura et al. [3] reported a higher incidence of acute GVHD grade III–IV in both the major and minor ABO mismatch, but not in the bi-directional ABO-incompatible group. A study by Seebach et al. [14] observed severe acute GVHD (grade III–IV) of the liver limited to recipients of bi-directional ABO-incompatible grafts. In a study of 174 patients by Bacigalupo et al. [15], minor ABO mismatch was associated with a significantly higher risk of severe acute GVHD when compared with ABO-matched and major ABO-mismatched pairs. Ludajic et al. [27] observed that a minor ABO-mismatch represents a significant risk factor for acute GVHD (grade II–IV) with an estimated risk increase of almost 3-fold, and even 4-fold for severe acute GVHD (grade III–IV). Gutiérrez-Aguirre et al. [28] analyzed a cohort of patients exclusively receiving RIC and found the highest rate of acute GVHD in minor ABO-mismatched transplant recipients (25%) compared with ABO-identical (20.5%) and major ABO-mismatched cases (15.4%). Other publications observe no influence of ABO mismatch on the incidence of clinically significant acute GVHD [6, 29]. We found that ABO incompatibility did not significantly modify risks of acute GVHD. We found a lower incidence of grade II/IV acute GVHD in the bidirectional ABO mismatched transplants among the cord blood (36% vs. 45–50%) and the PBSC group (28% vs 40–48%), but not in the BM group (35% vs. 25–36%). However we found a higher incidence of chronic GVHD in the major ABO mismatched group among the BM graft recipients, yet a lower incidence in the minor ABO mismatched among PBSC recipients. There were no differences in GVHD based upon ABO disparities observed in the cord blood transplant cohort.
Kimura et al. [3] observed a shorter overall survival for patients receiving a major ABO-mismatched graft compared to minor or bi-directional ABO-mismatched transplantation, whereas Michallet et al. [5] observed a lower survival rate for minor ABO-mismatched versus ABO-matched cases. Benjamin et al. [30] revealed a significantly decreased survival in ABO-mismatched BM graft recipients in the first 100 days after transplantation. Multivariate analyses showed that the effect was significant for both minor and major ABO mismatches only in patients with acute myelogenous leukemia and myelodysplastic syndrome. Stussi et al. [25] showed a lower overall survival only for bi-directional ABO mismatched cases. In contrast, Mehta et al. [31] found that ABO mismatch was associated with superior OS and DFS as did Erker et al. [32] for patients receiving minor and bi-directional ABO-mismatched grafts. In adjusted multivariate analysis we observed that ABO incompatibility did not significantly impair OS.
Two registry studies found a higher risk for NRM in the RIC cohort, one of those also for major ABO-mismatched cases if myeloablative conditioning was applied [3, 5], whereas some cohort studies observed an increased risk for patients after minor, major or bi-directional ABO-mismatched transplants [28,33]
In a study on 89 adult patients Kim et al observed that time to neutrophil, platelet, and red blood cell engraftment, transfusion requirements, incidence of acute or chronic GVHD, relapse, and survival were not influenced by ABO incompatibility after allogeneic PBSCT from HLA-matched sibling donors [24]. However Stussi et al in a 2 center study on 562 patients concluded that ABO incompatibility represents a risk factor not only for post-transplant hemolysis, but also for survival and the incidence of mild GVHD after allogeneic SCT [25]. Data on 153 patients reported by Goldman et al do not support a significant role for ABO donor-recipient matching in allogeneic stem cell transplantation [26].
We conclude that there is no clear data consensus on ABO mismatch. Our data clearly indicates that ABO mismatching does not influence the outcomes of allogeneic HCT including engraftment, acute GVHD, chronic GVHD, OS and NRM, regardless of stem cell source. We suggest therefore, that whenever feasible, ABO mismatched donors should be avoided in BMT recipients in order to prevent hemolysis or delayed erythroid recovery, but we also conclude that there are few consistently recognized deleterious consequences of donor: recipient ABO mismatch using BM, PBSC or UCB HCT.
Acknowledgments
Supported in part by grants from the NCI, the American Society of Hematology and the University of Minnesota
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