Scholarly article on topic 'Impact of Donor-Recipient Major ABO Mismatch on Allogeneic Transplantation Outcome According to Stem Cell Source'

Impact of Donor-Recipient Major ABO Mismatch on Allogeneic Transplantation Outcome According to Stem Cell Source Academic research paper on "Clinical medicine"

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{"Acute graft-versus-host disease" / "Bone marrow" / "ABO incompatibility" / "Hematopoietic recovery" / "Transfusion needs"}

Abstract of research paper on Clinical medicine, author of scientific article — Nicolas Blin, Richard Traineau, Stéphanie Houssin, Régis Peffault de Latour, Anna Petropoulou, et al.

Major ABO incompatibility between donor and recipient is not considered a barrier to successful allogeneic hematopoietic stem cell transplantation (HSCT), even if it can be associated with several immunohematologic complications. Nevertheless, conflicting data still exist as to its influence on graft-versus-host disease (GVHD) incidence, relapse rate, and survival. To further investigate the relevance of ABO major mismatch on transplantation outcome, we retrospectively analyzed results from 414 patients with major or major/minor ABO-mismatched bone marrow (BM), peripheral blood (PB), and cord blood (CB) allogeneic HSCT. Transplantation outcome was assessed by comparison with results from a 395-patient ABO-compatible population with similar characteristics. Median time to red cell transfusion independence was significantly longer in ABO-incompatible BM recipients (median time, 63 days vs 41 days; P =.001), with faster disappearance of antidonor IgM hemagglutinins in unrelated recipients (median time, 36 days vs 44 days; P = .03) and in patients with grade ≥II acute GVHD (aGVHD) (median time, 35 days vs 59 days ; P = .001). In PB stem cell (PBSC) and CB transplantation, erythroid reconstitution was not significantly delayed, regardless of donor type or presence of aGVHD. A slight correlation between ABO incompatibility and GVHD incidence was found in PBSC recipients when considering grade ≥II aGVHD incidence (63% in ABO-matched HSCT vs 83% in ABO-mismatched HSCT; P = .055), but this was not confirmed in multivariate analysis. In patients with acute leukemia, multivariate analysis revealed an association between major ABO mismatch and decreased relapse rate with borderline statistical significance (hazard ratio, 0.65; P = .04). Major ABO incompatibility mainly, if not exclusively, affects red blood cell engraftment after BM transplantation. Somewhat surprisingly, the graft-versus-plasma cell effect seems to be confined to this stem cell source.

Academic research paper on topic "Impact of Donor-Recipient Major ABO Mismatch on Allogeneic Transplantation Outcome According to Stem Cell Source"

ASBMI

American Society for Blood and Marrow Transplantation

Impact of Donor-Recipient Major ABO Mismatch on Allogeneic Transplantation Outcome According

to Stem Cell Source

I 2 3 I

Nicolas Blin, Richard Traineau, Stephanie Houssin, Regis Peffault de Latour, Anna Petropoulou,1 Marie Robin,1 Jerome Larghero,4 Patricia Ribaud,1,5 Gerard Socie1,5,6

Major ABO incompatibility between donor and recipient is not considered a barrier to successful allogeneic hematopoietic stem cell transplantation (HSCT), even if it can be associated with several immunohemato-logic complications. Nevertheless, conflicting data still exist as to its influence on graft-versus-host disease (GVHD) incidence, relapse rate, and survival. To further investigate the relevance of ABO major mismatch on transplantation outcome, we retrospectively analyzed results from 414 patients with major or major/minor ABO-mismatched bone marrow (BM), peripheral blood (PB), and cord blood (CB) allogeneic HSCT. Transplantation outcome was assessed by comparison with results from a 395-patient ABO-compatible population with similar characteristics. Median time to red cell transfusion independence was significantly longer in ABO-incompatible BM recipients (median time, 63 days vs 41 days; P =.001), with faster disappearance of antidonor IgM hemagglutinins in unrelated recipients (median time, 36 days vs 44 days; P = .03) and in patients with grade $II acute GVHD (aGVHD) (median time, 35 days vs 59 days ; P = .001). In PB stem cell (PBSC) and CB transplantation, erythroid reconstitution was not significantly delayed, regardless of donor type or presence of aGVHD. A slight correlation between ABO incompatibility and GVHD incidence was found in PBSC recipients when considering grade $II aGVHD incidence (63% in ABO-matched HSCT vs 83% in ABO-mismatched HSCT; P = .055), but this was not confirmed in multivariate analysis. In patients with acute leukemia, multivariate analysis revealed an association between major ABO mismatch and decreased relapse rate with borderline statistical significance (hazard ratio, 0.65; P = .04). Major ABO incompatibility mainly, if not exclusively, affects red blood cell engraftment after BM transplantation. Somewhat surprisingly, the graft-versus-plasma cell effect seems to be confined to this stem cell source. Biol Blood Marrow Transplant 16: 1315-1323 (2010) © 2010 American Society for Blood and Marrow Transplantation

KEY WORDS: Acute graft-versus-host disease, Bone marrow, ABO incompatibility, Hematopoietic recovery, Transfusion needs

From the 'AP-HP, Saint Louis University Hospital, Hematology Department-Transplant Unit, 1 Avenue Claude Vellefaux, 75010 Paris, France; 2Saint Louis University Hospital, Transfusion Department, 1 Avenue Claude Vellefaux, 75010 Paris, France; 3Nantes University Hospital, Biostatistics Department,

1 Place Alexis Ricordeau, 44093 Nantes, France; 4AP-HP, Saint

Louis University Hospital, Cellular Engineering Unit, 1 Avenue

Claude Vellefaux, 75010 Paris, France; 5Denis Diderot Paris 7

University, Hayem Center, 1 Avenue Claude Vellefaux, 75010

Paris, France; and 6INSERM U728, University Institute of He-

matology, Denis Diderot Paris 7 University, Paris, France. Financial disclosure: See Acknowledgments, page 1322. Correspondence and reprint requests: Gerard Socié, Service d'Hématologie Greffe & Inserm U728, Hôpital Saint-Louis, 1 Ave Claude Vellefaux, 75010 Paris, France (e-mail: gerard. socie@sls.aphp.fr). Received December 1, 2009; accepted March 22, 2010 © 2010 American Society for Blood and Marrow Transplantation 1083-8791/$36.00 doi:10.1016/j.bbmt.2010.03.021

INTRODUCTION

In contrast to solid organ transplantation, allogeneic hematopoietic stem cell transplantation (HSCT) can be performed across the ABO blood group barrier [1]. ABO incompatibility between donor and recipient occurs in 30%-40% of patients undergoing HSCT, because ABO blood groups are inherited independently from human leukocyte antigens [2].

Three groups of ABO mismatch can be distinguished in HSCT: minor, major, and bidirectional ABO incompatibility. Minor ABO incompatibility (eg, from an type-O donor to a type-A, -B, or -AB recipient) is characterized by the ability of donor B lymphocytes to produce antirecipient isoagglutinins. In contrast, major ABO-incompatible HSCT (eg, from a type-A, -AB, or -B donor to an type-O recipient) is characterized by the presence of preformed antidonor isoagglutinins. In bidirectional ABO

incompatibility (eg, type-A donor to a type-B recipient), a combination of both major and minor ABO blood group barriers must be overcome.

Although ABO incompatibility between donor and recipient does not represent a barrier to successful HSCT, it is well established that major ABO incompatibility can lead to prolonged destruction of donor-derived erythrocytes, with pure red blood cell (RBC) aplasia and prolonged transfusion requirements [3], despite such techniques as plasma exchange and RBC depletion of the donor marrow [4,5]. Similarly, minor ABO incompatibility can result in an increased risk of delayed immune hemolysis [6,7], which occurs in approximately 10%-15% of cases [1].

Mielcarek et al. [8] reported that the degree of genetic disparity between donor and recipient, especially in unrelated graft recipients, and graft-versus-host disease (GVHD) can affect the rate of disappearance of antidonor isohemagglutinins, suggesting a graft-versus-plasma cell effect. More recently, Kimura et al. [9] reported specific effects of major and minor ABO incompatibility on transplantation-related mortality and incidence of acute GVHD (aGVHD) in recipients of bone marrow transplants (BMTs) from unrelated donors. However, conflicting data still exist about the influence of major ABO incompatibility on GVHD incidence [8,10], hematologic recovery [11], relapse rate [12,13], and survival [14-16], especially with the use of alternative donor sources, such as peripheral blood (PB) and cord blood (CB).

Allogeneic PB stem cell transplantation (PBSCT) has been increasingly preferred over BMT because of its more rapid hematologic recovery and potent graft-versus-tumor effect in hematologic malignancies [17,18]. However, to date, only a few studies have addressed the impact of major ABO mismatch on GVHD incidence and survival in PBSCT.

The aims of this single-center study were to (1) validate the impact of major ABO mismatch and genetic disparity on erythroid reconstitution in allogeneic BMT; (2) investigate the role of major ABO incompatibility on hematologic recovery, GVHD incidence, relapse rate, and overall survival (OS) in PBSCT; and (3) analyze these 4 parameters in CB transplantation (CBT).

MATERIALS AND METHODS

Patient Characteristics

The study included a total of 414 patients who underwent HSCT at Saint Louis University Hospital, Paris, between 1978 and 2005. Median follow-up was 76 months. Of the 414 patients, 226 underwent BMT, 138 underwent PBSCT, and 49 underwent CBT.

Among the ABO-mismatch population, patients received a major (n = 337; 81%) or major/minor

(n = 77; 19%) ABO-mismatched allogeneic transplant from a matched related donor (MRD; n = 136; 33%) or a matched unrelated donor (MUD; n = 278; 67%). Myeloablative (MA) conditioning regimens included fractioned total body irradiation (TBI) + cyclophosphamide (n = 166; 40%) and busulfan + cyclophosphamide (n = 168; 41%). Nonmyeloablative (NMA) regimens were all fludarabine-based, either with (n = 20; 5%) or without (n = 60; 14%) 2 Gy TBI. HSCT was performed for both malignant (n = 296; 71%) and nonmalignant (n = 118; 29%) he-matologic diseases, and GVHD prophylaxis was based mainly on standard regimen with cyclosporine A (CsA) + methotrexate (n = 312; 75%) after MA conditioning and with cyclosporine A (CsA) + mycophenolate mo-fetil (MMF; n = 73 [18%]) after NMA conditioning. Details regarding indications for HSCT, GVHD prophylaxis, GVHD incidence, and other patient and transplant characteristics are given in Table 1.

Transplantation outcomes were compared with those from a 395-patient ABO-compatible population with similar characteristics with respect to period of transplantation, stem cell source, conditioning regimen, GVHD prophylaxis, and donor type (Table 2).

Hemagglutinin Titer Monitoring and Transfusion Policy

As described previously [8,19], posttransplantation anti-A and anti-B isohemagglutinin IgG and IgM titers were followed weekly from day +4 post-HSCT for each patient. For patients with an anti-A and/or anti-B titer >1:128 during pretransplantation assessment, IgG and IgM were evaluated twice weekly after transplantation until achievement of titers below 1:16, then weekly until their complete disappearance. Hemagglutinin titer quantification was followed until it was undetectable for 2 consecutive weeks, except in patients with persistent RBC transfusion requirements.

All transfused packed RBCs and platelets were separated from plasma and irradiated at a dose of 30 Gy to prevent the risk of acute transfusion-induced GVHD. Whatever the period of transplant was, all patients received recipient- or type-O RBCs as long as isoagglu-tinins directed against the donor blood group remained measurable. At that point, RBC transfusions were switched to donor type.

Statistical Analysis

OS within ABO compatibility groups for all stem cell source and donor type was estimated by the Kaplan-Meier method [20]. For survival analysis, follow-up time was censored at the date of last contact for surviving patients, and the log-rank test was used to test the significance of differences [21], adjusting for potential confounding variables (age, disease status,

Biol Blood Marrow Transplant 16:1315-1323, 2010 ABO Incompatibility and Allogeneic Transplantation Outcome 1317

Table 1. ABO-Mismatched Transplantations: Patients and Table 2. Characteristics of ABO-Matched and ABO-

Transplant Characteristics Mismatched Populations

Parameter MRD MUD P Parameter ABO Mismatch ABO Match P

Total, n (%) 136 (33) 278 67) NA Total, n (%) 414(51) 395 (49) NA

Sex, % male 58 54 .68 Sex, % male 55 54 .42

Age, years, median (range) 26.2 (3-55) 24.3 (0.6-66) .75 Age, years, median range) 25.3 (0.6-66) 28.6 (3-60) .35

Hematologic diagnosis, n (%) Hematologic diagnosis, n %)

AML 30 (22) 57 (2l) .65 AML 87(12) 83 (10) .39

ALL 24(18) 52 19) .76 ALL 76 (9) 74 (9) .46

MDS 9(7) l8 (6) .60 MDS 27 (3) 27 (3) .50

CML 31 (23) 53 19) .32 CML 84(10) 84 (10) .30

SAA 14(10) 3l 11) .40 SAA 45 (6) 45 (6) .42

PNH 3 (2) 3 (l) .86 PNH 6 (l) 5 (l) .41

Hodgkin lymphoma 2(1) 4 (l) .90 Hodgkin 6 (l) 8 (l) .45

NHL 5 (4) ll (4) .76 NHL l6 (2) l4 (2) .42

Fanconi anemia 11 (8) 26 (9) .67 Fanconi anemia 37(5) 34(4) .50

Sickle cell anemia/thalassemia 3 (2) 7 (3) .80 Sickle cell anemia/thalassemia l0 (l) l0 (l) .41

Miscellaneous 4(3) l6 (6) .26 Miscellaneous 20 (2) ll (l) .21

Stem cell source, n (%) Stem cell source, n %)

BM 72 (53) l54 (55) .43 BM 226 (27) 2l3 (26) .25

PBSC 56(41) 82 (29) .05 PBSC 138(17) 135(17) .37

CB (simple) 8 (6) 34 12) .l6 CB simple) 42 (5) 4l (5) .l8

CB (double) 0 (0) 7 (3) .65 CB double) 7 (l) 6 (l) .30

BM + CB 0 (0) l (l) .90 BM + CB l (l) 0 (0) .45

Conditioning regimen, n (%) Conditioning regimen, n %)

TBI/Cy 52 (38) 114 (4l) .35 TBI/Cy 166 (21) l63 (20) .45

Bu/Cy 58 (43) 110 (40) .42 Bu/Cy l68 (20) 154 (19) .29

Other TBI-containing regimens 7(5) l3 (4) .60 Other TBI-containing regimens 20 (2) 20 (2) .50

Other non-TBI-containing 19 (14) 4l 15) .45 Other non-TBI-containing 60 (7) 58 (7) .35

regimens regimens

Myeloablative 110 (81) 226 8l) .90 Myeloablative 336 (41) 32l (40) .32

Nonmyeloablative 26 (19) 52 19) .85 Nonmyeloablative 78(10) 74 (9) .41

GVHD prophylaxis, n (%) GVHD prophylaxis, n %)

CsA-MTX 100 (74) 2l2 76) .65 CsA-MTX 3l2 (38) 302 (37) .28

CsA alone 6(4) l0 4) .80 CsA alone l6 (2) l0 (l) .25

CsA-MMF 23(17) 50 18) .65 CsA-MMF 73 (9) 72 (9) .30

MMF-corticosteroids 3 (2) 4 l) .87 MMF-corticosteroids 7 (l) 7 (l) .43

MTX alone 4(3) 2 l) .80 MTX alone 6 (l) 4(1) .26

aGVHD, n (%) Donor type

Grade 0-I 66 (49) 44 16) .01 MRD 136 (17) 146 (18) .28

Grade II-IV 70(51) 234 84) .01 MUD 278 (34) 249 (32) .25

ABO incompatibility, n (%) Period of transplantation

Major mismatch 108 (79) 229 82) .26 1978-1985 32(4) 28 (3) .29

Major/minor mismatch 28 (2l) 49 18) .40 1985-1995 141 (17) 140(17) .42

Hemagglutinin type, n (%) 1995-2005 241 (30) 227 (28) .38

Anti-A 89 (65) l85 67) .41 aGVHD, n (%)

Anti-B 44 (32) 86 31) .50 Grade 0-I 110(14) 144(17) .l6

Anti-A + anti-B 3(2) 7 2) .90 Grade II-IV 304 (38) 251 (3l) .06

AML indicates acute myelogenous leukemia; ALL, acute lymphoblastic leukemia; MDS, myelodysplastic syndrome; CML, chronic myelogenous leukemia; SAA, severe aplastic anemia; PNH, paroxysmal nocturnal hemoglobinuria; NHL, non-Hodgkin lymphoma; Cy, cyclophosphamide; Bu, busulfan; CsA, cyclosporine A; MTX, methotrexate.

AML indicates acute myelogenous leukemia; ALL, acute lymphoblastic leukemia; MDS, myelodysplastic syndrome; CML, chronic myelogenous leukemia; SAA, severe aplastic anemia; PNH, paroxysmal nocturnal hemoglobinuria; NHL, non-Hodgkin's lymphoma; Cy, cyclophosphamide; Bu, busulfan; CsA, cyclosporine A; MTX, methotrexate; MRD, matched related donor; MUD, matched unrelated donor; BM, bone marrow; CB, cord blood.

HLA match, GVHD prophylaxis and incidence, sex mismatch, and year of transplantation). Incidences of aGVHD, relapse rate, and attainment of hemagglutinin titer endpoint were calculated using cumulative incidence estimates [21].

Hematologic endpoints were defined as follows:

• Engraftment: sustained absolute neutrophil count (ANC) $0.5 109/L for at least 5 days with no use of granulocyte colony-stimulating factor

• RBC transfusion independence: absence of transfusion needs for at least 7 days with sustained hemoglobin level $8 g/dL

• Platelet recovery: platelet count $ 20 109/L with no transfusion needs for at least 72 hours

Univariate analysis was performed using C and Mann-Whitney U tests, whereas multivariate analysis was done using Cox proportional hazard regression models [22], with assessment of age, disease status at time of transplantation, donor type, stem cell source, and ABO major mismatch on 3-year overall survival, incidence of aGVHD and chronic GVHD (cGVHD), and relapse rate. All reported P values are 2-sided, and P < .05 is considered to indicate statistical significance.

RESULTS

Impact of ABO Major Incompatibility on Erythroid Reconstitution in BMT Recipients

To validate the relevance of our 2 populations (ABO-mismatched and control ABO-matched), we first selected patients undergoing BMT and determined the impact of ABO incompatibility on erythroid reconstitution based on RBC transfusion requirements. As shown in Table 2, the 2 populations appeared to have similar characteristics, especially in terms ofstem cell source, conditioning regimen, donor type, period of transplantation, and GVHD incidence (P > .05 for each parameter).

In ABO-incompatible marrow recipients, median time to RBC transfusion independence was significantly longer (median time, 63 days vs 41 days; P = .001) (Figure 1). This difference appears to be independent of the amount of cells infused during transplantation, with a median number of CD341 cells of 2.4 106/kg in ABO-mismatched patients and 2.6 106/ kg in control ABO-matched patients (P = .28).

Impact of Donor Type on Transfusion Needs and Antidonor Hemagglutinin Disappearance Kinetics in the ABO-Mismatched Population

To confirm the role of donor type in erythroid recovery after BMT, we evaluated RBC transfusion needs after MRD and MUD HSCT in both ABO-matched and ABO-major mismatched patients. In the MRD population, the mean number of RBC packs transfused was significantly greater in the ABO-mismatched population than in the ABO-matched population (13 vs 6; P = .01), but this difference did not reach statistical significance in the MUD population (12 vs 14; P = .22). These results are given in Table 3.

We then evaluated the role of genetic disparity on erythroid reconstitution in the same population; 154

Days after transplant

Figure 1. Probability of RBC transfusion independence according to time after transplantation in ABO-matched and major ABO-mismatched BMT recipients.

patients in the ABO-major mismatched group received a transplant from a MUD, compared with 72 from an MRD. For the 2 groups, we determined the number of days posttransplantation required to reach undetect-able antidonor IgM hemagglutinins. The disappearance of antidonor IgM hemagglutinins was significantly faster in MUD recipients (median time, 36 days vs 44 days; P = .03) (Figure 2).

We also analyzed the correlation between the degree of HLA matching and RBC engraftment in this MUD population. Among the 154 patients receiving ABO-major mismatched BM from an MUD donor, 35 were antigen-matched and 119 were allele-matched. Among the 119 patients with allele-matched BMT, the majority (n = 87; 73%) received a 10/10 matched transplant, whereas 20 (17%) received a 9/10 matched transplant and 12 (10%) received a 8/10 matched transplant. When considering the delay after transplantation in reaching undetect-able antidonor IgM hemagglutinins in those subgroups, we found a trend of shorter time for antigen-matched transplants compared with allele-matched transplants, but the difference did not attain statistical significance (32 days vs 36 days; P = .07). Comparing the 3 different populations according to degree of HLA allele matching (ie, 10/10, 9/10, and 8/10) revealed no significant difference, because of the small size of the corresponding subgroups (data not shown).

We investigated the effect of antithymocyte globulin (ATG) administration as part of the conditioning regimen. Among the 154 patients in the MUD group, 102 (66%) received ATG, and 52 (34%) did not. The median time to disappearance of antidonor IgM hem-agglutinins was not significantly influenced by the use of ATG (34 days vs 37 days; P = .16).

Impact of Allogeneic Effect on Hemagglutinin Titer Clearance

After confirming the impact of donor type on the kinetic of antidonor IgM disappearance and RBC transfusion requirements, we verified the role of the allogeneic effect on the speed of clearance of hemagglutinin titers in the MUD group. For that purpose, in both the MRD and MUD groups, we compared the median time to reach undetectable antidonor IgM according to aGVHD occurrence. In the MRD group, this time was significantly shorter in patients with grade II-IV aGVHD than in those with grade 0-I aGVHD (57 vs 78 days; P = .001; relative risk [RR] = 1.92). In the MUD group, no significant difference was seen between these 2 groups (46 days vs 59 days; P = .06; RR = 1.21).

We also investigated the impact of grade II-IV aGVHD on the kinetics of transfusion independence (Figures 3 and 4). In the MRD group, the median time to RBC transfusion independence was

Table 3. Median Number of RBC Packs Transfused among ABO-Mismatched BM Recipients with MRDs and MUDs

Stem Cell Source Donor Type ABO Compatibility n RBC Packs Transfused, Median (Range) Univariate RR P value 95% CI

BM MRD ABO match 78 6 (0-26) 1.0 NA NA

ABO mismatch 72 13 (2-92) 1.86 0.01 1.54-2.10

MUD ABO match 135 14(0-44) 1.0 NA NA

ABO mismatch 154 12(4-32) 0.95 0.22 0.80-1.05

BM indicates bone marrow; MRD, matched related donor; MUD, matched unrelated donor.

significantly shorter in patients with grade II-IV aGVHD compared with those with grade 0-I aGVHD (42 days vs 80 days; P = .001). Of the MRD recipients with grade II-IV aGVHD (n = 70), only 7 patients (10%) died before day +100 posttransplantation. When those patients were excluded from the analysis, the difference in median time to RBC transfusion independence remained significant between the 2 groups (45 days vs 80 days; P = .002). Fourteen patients presented with additional causes of anemia (9 with severe bleeding, 3 with drug-induced acute hemolysis, and 2 with severe fungal infection), and were excluded from the analysis.

In the MUD group, there was no significant difference between patients with grade 0-I aGVHD and those with grade II-IV aGVHD (35 days vs 60 days; P = .08).

Our evaluation of ABO-major mismatch on ery-throid and hematopoietic reconstitution in both PBSCT and CBT revealed no significant impact using these cell sources. These results are summarized in the Supplemental Material.

in which significant difference has been observed (Table 4).

Among BM recipients, overall incidence of grade $2 aGVHD was similar in ABO-matched and ABO-mismatched transplants (72% [n = 154] and 76% [n = 172]; P = .19). No difference was observed between the MRD and MUD groups with ABO-mismatched transplants (data not shown).

We assessed the incidence of aGVHD in the group of PBSC recipients similarly. Analysis performed after exclusion of patients with major/minor mismatch (n = 77) showed a tendency toward higher aGVHD incidence in ABO-mismatched transplants (83%, vs 63% in ABO-matched; P = .05). This borderline statistically significant difference was observed in both transplants from MRDs (46% vs 62%; P = .05) and those from MUDs (68% vs 83%; P = .04). No difference in GVHD prophylaxis or conditioning regimen was observed in those 2 groups (Tables 1 and 2).

In CBT recipients, analysis of transplants from both the MRD and MUD groups did not appear to be feasible, because of the small number of patients.

Correlation between ABO Incompatibility and GVHD Incidence

The probability of aGVHD was compared between the ABO-matched and ABO-mismatched transplants for the 3 different stem cell sources. A separate analysis was performed after exclusion of patients with bidirectional ABO incompatibility in subgroups

Days after transplant

Figure 2. Probability of anti-donor IgM disappearance according to time after transplantation in ABO-mismatched transplants with MRDs and MUDs.

Impact of ABO Major Incompatibility on Relapse Rate

The risk of relapse was evaluated after selection of patients undergoing HSCT for a malignant hemato-logic disease. Hematologic malignancies represented 74% (n = 292) of ABO-matched transplants and 71% (n = 296) of ABO-mismatched transplants (Tables 1 and 2).

Figure 3. Probability of transfusion independence posttransplantation among ABO-mismatched BMT recipients (MRDs) according to GVHD occurrence.

Bone marrow, matched unrelated donor

I I I I I

0 20 40 60 E0 100

Days after transplant

Figure 4. Probability of transfusion independence posttransplantation among ABO-mismatched BMT recipients (MUDs) according to GVHD occurrence.

Among BMT recipients, the relapse rate was 38% (n = 58) in ABO-matched transplants and 34% (n = 53) in ABO-mismatched transplants (P = .065). Analysis of the MRD and MUD groups for both ABO-matched and ABO-mismatched transplants demonstrated no significant difference in relapse risk (40% vs 43% in the MRD group [P = .11] and 33% vs 36% in the MUD group [P = .08]).

In both the PBSCT and CBT recipients, the relapse rate did not appear to be different in ABO-matched and ABO-mismatched transplants. Only a borderline statistical significance was observed in the PBSCT group, with a relapse rate of 41% (n = 45) in the ABO-matched group and 35% (n = 37) in the ABO-mismatched group (P = .055).

OS was analyzed by comparing ABO-matched and ABO-mismatched transplants for BMT, PBSCT, and CBT recipients only in patients treated for hemato-logic malignancies. The median follow-up time for surviving patients was 76 months for MRDs (range, 26-245 months) and 68 months for MUDs (range, 21-228 months).

OS according to stem cell source is summarized in Table 5. In BMT recipients, there was no significant difference in overall survival at 5 years between the MRD group (51% vs 49%; P = .18) and the MUD

group (38% vs 33%; P = .08). In PBSCT recipients, similar nonsignificant trends were found (MRD and MUD overall survival of 42 vs 46 months [P = .08] and 30 vs 38 months [P = .055] according to ABO match, respectively). Among CBT recipients, median overall survival was 20 months (n = 30) for ABO-matched transplants and 21 months (n = 35) for ABO-mismatched transplants (P = .06). Subgroup analysis in MRDs and MUDs could not be performed because of the small number of patients in this population.

Multivariate Analysis

We used Cox proportional hazard regression models to assess the impact of different transplantation parameters on 3-year OS, aGVHD and cGVHD incidence, and relapse rate. Among the parameters tested, we considered age, disease type, and status at time of transplantation, donor type, stem cell source, conditioning regimen, GVHD prophylaxis, ABO major mismatch, and hemagglutinin subtype. For OS and relapse risk, we considered grade $II aGVHD and cGVHD as time-dependent covariates. Moreover, relapse risk assessment in this multivariate analysis considered only patients with acute myelogenous or lymphoblastic leukemia, given the high heterogeneity of hematologic malignancies included in the study.

When considering 3-year OS, no impact of ABO major mismatch or hemagglutinin subtype on survival was identified (hazard ratio [HR], 1.07 [P = .45] and 0.97 [P = .35], respectively). Similarly, ABO mismatch did not significantly influence the aGVHD rate (odds ratio [OR], 1.24; P = .09). The sole parameter influenced by donor/recipient ABO mismatch was 3-year relapse risk (OR, 0.65; P = .04). This parameter also was influenced by cGVHD (OR, 0.55; P = .035). The results of multivariate analysis are summarized in Table 6.

DISCUSSION

The aim of this single-center retrospective study was to evaluate in a large cohort of patients the impact of donor/recipient major ABO mismatch on GVHD incidence, OS, and relapse risk according to stem cell

Table 4. Grade $11 aGVHD Incidence in ABO-Matched and -Mismatched Transplants According to Stem Cell Source

Grade $II

Stem Cell Source ABO Compatibility n aGVHD, n (%) Univariate RR P Value 95% CI

BM ABO match 213 154 (72) 1.0 NA NA

ABO mismatch 226 172 (76) 1.15 .19 1.08-1.28

PBSCs ABO match 135 85(63) 1.0 NA NA

ABO mismatch 138 113 (82) 2.10 .01 1.8-3.1

CB ABO match 47 12 (26) 1.0 NA NA

ABO mismatch 50 19(38) 1.21 .15 1.12-1.40

aGVHD indicates acute graft-versus-host disease; BM, bone marrow; PBSCs, peripheral blood stem cells; CB, cord blood.

Table 5. Median Overall Survival in ABO-Matched and ABO' Mismatched Transplants According to Stem Cell Source

Stem ABO Hematologic Median Overall

Cell Source Compatibility Malignancies, n (%) Survival, Months P

BM ABO match 153 (72) 38 NA

ABO mismatch 156 (69) 41 .07

PBSCs ABO match 109 (8i) 34 NA

ABO mismatch 105 (76) 39 .055

CB ABO match 30 (64) 20 NA

ABO mismatch 35 (70) 21 .35

All cohort ABO match 292 (74) 34 NA

ABO mismatch 296 (7l) 37 .06

BM indicates bone marrow; PBSCs, peripheral blood stem cells; CB, cord blood.

source. All patients were treated in a single center and received homogeneous management in terms of conditioning regimen, indications for transplantation, GVHD prophylaxis, immunohematologic monitoring, and transfusion policies. Moreover, PBSCT and CBT recipients were included in the study, so that our series represents, to the best of our knowledge, one of the largest to date on the impact of major ABO mismatch in patients undergoing allogeneic HSCT.

To evaluate the relevance of our population selection, we first assessed the impact of ABO mismatch on erythroid reconstitution in BMT recipients. As described previously [8], we found a significantly longer time to transfusion independence in the ABO-mismatch population. The level of genetic disparity between donor and recipient also appeared to have an impact on both antidonor IgM hemagglutinin disappearance and RBC pack transfusion needs with faster disappearance of antidonor IgM hemagglutinins in MUD recipients and MRD recipients with grade $II aGVHD.

The median time to reach undetectable antidonor IgM tends to be shorter in MUD recipients with grade II-IV aGVHD compared with those with grade 0-I aGVHD, but the difference does not reach statistical significance, as reported previously [8]. The lack of

Table 6. Multivariate Analysis of Factors Influencing Survival, aGVHD, and Relapse Risk

Parameter HR 95% CI P

3-year overall Age >35 2.56 1.95-3.35 .01

survival

No CR at transplantation 2.75 2.10-3.75 .005

Grade $II aGVHD 2.25 1.85-3.05 .008

aGVHD Age >35 2.18 1.65-2.75 .02

incidence

Unrelated donor 3.24 2.65-4.15 .001

Peripheral blood 1.78 1.25-2.95 .03

Relapse risk Donor/recipient ABO mismatch 0.65 0.58-0.72 .04

cGVHD 0.55 0.43-0.72 .035

aGVHD indicates acute graft-versus-host disease; cGVHD, chronic graft-versus-host disease; CR, complete remission.

correlation in this group was not related to a lack of power because of small sample size. We also investigated whether the higher mortality rate in MUD recipients with grade $II aGVHD could account for this lack of difference. The mortality rate before day + 100 after MUD HSCT was 14% (n = 33) in patients with grade $II aGVHD, compared with 6% (n = 1) in those without grade $II aGVHD. Excluding these patients with early death did not change the results in term of transfusion needs or antidonor IgM hemagglu-tinin clearance.

The hypothesis of a potential impact of early death rate in MRD patients with grade II-IV aGVHD on results has been verified. In 70 patients with grade II-IV aGVHD, only 10% (n = 7) died before day +100, compared with 6% (n = 4) of those with grade <II aGVHD. After excluding those patients with early death, the difference in median time to RBC transfusion independence remained significant between the 2 groups (45 days vs 80 days; P = .002).

When evaluating the impact of aGVHD on anti-donor hemagglutinin titer clearance, we assessed the impact of conditioning regimen, particularly the use of ATG. ATG is known to target B cells and plasma cells through a complement-independent apoptosis mechanism [23,24]. ATG was given as GVHD prophylaxis in 102 of 154 patients receiving a MUD transplant with ABO-mismatched BM (66%). A similar median time to disappearance was found in patients who received ATG and those who did not receive ATG, suggesting that the role of an allogeneic effect against host plasma cells is independent of ATG use.

We also identified a direct correlation between antidonor IgM hemagglutinin clearance and RBC transfusion needs in this ABO-mismatched population receiving MRD transplants by excluding from the analysis all patients with confounding causes of severe anemia. Median time to RBC transfusion independence was confirmed to be shorter in MRD recipients with grade II-IV aGVHD, with this difference independent of all associated conditions. These results are consistent with those of previous studies [1,3,8,25] and give another argument to the hypothesis of a graft-versus-plasma cell effect in BMT recipients.

But, when considering erythroid reconstitution in PBSCT and CBT recipients, we found any impact of major ABO incompatibility, regardless of hemaggluti-nin type and number of nucleated cells in the transplant. The majority of PBSCT recipients received nonmyeloablative conditioning, and more than half of the patients (70/138) experienced prolonged ery-throid reconstitution with this type of conditioning, in agreement with some [26-28], but not all [29], reports. The lack of impact of ABO mismatch in those transplants might result from the immunosuppressive treatment based on association of CsA with MMF,

because MMF has the ability to suppress B cell antibody production, and thus might possibly prevent pure red cell aplasia after low-dose conditioning [30]. Most of the CBT recipients (84%; 42/50) received standard conditioning with GVHD prophylaxis based mainly on CsA-MMF. The reasons for the absence of major ABO- mismatch impact on erythroid recovery in this population are unclear, but our results should be interpreted with caution because of the sample size-limited statistical power of the analysis. Thus, somewhat surprisingly, the graft-versus-plasma cell effect seems to be confined to BMT either directly or indirectly through aGVHD.

Our study revealed 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 previous studies that reported no impact of major ABO mismatch on engraftment [27,31].

In particular, we identified 5 patients (4 BMT recipients and 1 PBSCT recipient) with pure RBC aplasia and very prolonged RBC transfusion needs (time to transfusion independence ranging from day +245 to day +545 posttransplantation), with one patient still dependent on packed RBC transfusion at time of follow-up (25 months). All patients underwent HSCT after removal of ABO-incompatible RBCs following current methods for erythrocyte depletion in donor/recipient major ABO-incompatible allogeneic HSCT [4,5]. Two patients became transfusion-independent after rituximab infusion, confirming the use of this anti-CD20 monoclonal antibody in this situation [32,33]. One patient recovered from pure RBC aplasia after plasmapheresis, and another did so after high-dose dexamethasone, as described previously [34,35]. The only patient with persistent RBC transfusion needs failed to respond to the aforementioned treatments followed by 3 doses of donor lymphocyte infusion, with no occurrence of aGVHD. She received 2 units of packed RBCs every other week, and had a reticulocyte count <10 109/L at day +750 posttransplantation.

In this study, ABO incompatibility did not significantly impair survival or aGVHD rates. As expected, cGVHD represented the major parameter associated with reduced relapse risk in multivariate analysis (HR, 0.55; P = .035). The association of ABO incompatibility and decreased relapse rate should be interpreted with extreme caution, however (HR, 0.65; P = .04). Note that this statistical significance has been identified only in patients with acute leukemia after exclusion of other malignancies. Indeed, comparison between acute leukemias, CML, MDS, and lymphomas does not appear to be feasible because of the high heterogeneity in relapse risk stratification at the time of transplantation. When focusing only on BMT recipients for relapse rate in patients with acute

leukemia, no effect was found in ABO-mismatched transplants compared with ABO-matched transplants (36% vs 39%; P = .12). Moreover, during our relatively long study period, new risk factors have emerged (eg, flt3 ITD in AML and major role of cytogenetic classification in MDS and myeloma) that could not be included in these retrospective analyses.

Finally, we specifically explored correlation between cGVHD incidence and major ABO incompatibility, because little data are available on this subject. The only risk factor identified in multivariate analysis for cGVHD was PBSCT, with no effect of major ABO mismatch (HR, 1.04; P = .35; data not shown). This absence of correlation between chronic GVHD and major ABO mismatch might be linked to "donor-directed" instead of "host-directed" allogeneic activity in this situation, with cGVHD requiring sustained alloreactivity against minor histocompatibility antigens, which is more likely to occur in minor ABO-mismatched transplants.

In summary, in our experience, major ABO incompatibility leads mainly to delayed RBC recovery after BMT, but not after PBSCT or CBT. Major ABO mismatch does not seem to have a significant effect on other major outcomes after allogeneic HSCT, such as aGVHD and cGVHD incidence, relapse rate, and OS regardless of the stem cell source. Therefore, whenever feasible, major ABO-mismatched donors should be avoided in BMT recipients, to prevent delayed erythroid recovery with prolonged RBC transfusion needs and impaired quality of life.

ACKNOWLEDGMENTS

The authors thank Catherine Chadelat, data manager, Saint Louis Transplant Department for extracting information from adult and pediatric database. They also thank all of the members of the immunohe-matology laboratory at Saint Louis Hospital Transfusion Center for their helpful discussions and standardized methods for hemagglutinin level interpretation.

Fiwawcia/ dijc/osMre: The authors have no conflicts of interest to disclose.

SUPPLEMENTARY DATA

Supplementary data associated with this article can be found, in the online version, at doi:10.1016/ j.bbmt.2010.03.021

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