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Clinical and Translational Research

Who Is the Best Hematopoietic Stem-Cell Donor for a Male Patient With Acute Leukemia?

Ringdén, Olle1,15; Labopin, Myriam2; Solders, Martin1; Beelen, Dietrich3; Arnold, Renate4; Ehninger, Gerhard5; Milpied, Noel6; Niederwieser, Dietger7; Hamladji, Rose-Marie8; Kyrcz-Krzemien, Slawomira9; Ganser, Arnold10; Socié, Gerard11; Stelljes, Matthias12; Volin, Liisa13; Craddock, Charles14; Mohty, Mohamad2 for the Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation

Author Information
doi: 10.1097/TP.0000000000000102

Abstract

Using a female donor for a male recipient in allogeneic hematopoietic stem-cell transplantation (HSCT) is reported to be associated with an increased risk of acute graft-versus-host disease (GVHD) (1–4). It has been suggested that human minor histocompatibility antigens encoded by the Y chromosome contribute to the alloreactivity of female donor cells in a male recipient (5–7). Minor histocompatibility antigens have been found to elicit T-cell responses from female donors. A female donor for a male recipient also results in worse overall survival and leukemia-free survival (LFS) compared with other sex combinations (8–11).

Unrelated donors are being used increasingly in HSCT (12–16). With the use of genomic typing, outcome after unrelated donor transplantation is improved compared with serologic typing (14, 16–19) and similar to that using human leukocyte antigen (HLA)–identical sibling donors (20–23). Thus, a well-matched unrelated donor may be superior to an HLA-identical sibling donor, making it possible to select a young donor with the possibility to achieve a high cell dose, factors which are of importance for outcome after HSCT (4, 24).

A Centre for International Blood and Marrow Transplant Research study found that the graft-versus-leukemia (GVL) effect in using well-matched unrelated donors was the same as in using HLA-identical sibling donors (25). Female donors also contribute to the GVL effect in male recipients (26). The purpose of this analysis was to identify the optimal donor for a male recipient with acute leukemia.

RESULTS

Engraftment and GVHD

Engraftment was seen in 98% of the patients with acute myeloid leukemia (AML), for both the sibling group and the matched unrelated donor (MUD) group. In patients with acute lymphoblastic leukemia (ALL), engraftment occurred in 97% in both groups. Acute GVHD of grades II to IV was more common in the MUD group (27%) than in the female sibling donor group (24%) of patients with AML (P=0.05). Grade III to IV acute GVHD was seen in 10% of the patients with AML, both in the sibling group and in the MUD group (P=0.87).

In the multivariate analysis, the factors of importance for acute GVHD of grades II to IV in the AML group included the donor (MUD group vs. sibling group, P<0.001), interval diagnosis to transplantation greater than the median (P=0.001), no antithymocyte globulin (ATG) given (P=0.005), myeloablative conditioning (MAC) (P=0.03), and active disease (P=0.01) (Table 2).

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TABLE 2:
Multivariate analysis of factors of importance for acute GVHD of grades II to IV, chronic GVHD, and NRM

In patients with ALL, the proportion with acute GVHD of grades II to IV was 36% in the MUD group and 31% in the sibling group (P=0.04). In patients with ALL, grade III to IV acute GVHD was seen in 11% of the patients in the sibling group and in 13% of those in the MUD group (P=0.34).

In the multivariate analysis of the ALL group, acute GVHD of grades II to IV was associated with being in the MUD group (P<0.001) and with no ATG during conditioning (P<0.001) (Table 2).

In the AML cohort, the mean±SE cumulative incidence of chronic GVHD at 2 years was 50%±1% in the sibling group and 38%±2% in the MUD group (P<0.001) (Fig. 1A).

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FIGURE 1:
Time to and cumulative incidence of chronic graft-versus-host disease in male patients who received grafts from HLA-identical female donors (solid line) or a matched unrelated male donor (dotted line). A, patients with AML. The difference was not statistically significant in the multivariate analysis (HR, 0.91; 95% CI, 0.77–1.06; P=0.25). B, patients with ALL. The difference was not statistically significant in the multivariate analysis (HR, 0.84; 95% CI, 0.66–1.07; P=0.17). C, NRM in patients with AML was similar in the two groups in the multivariate analysis (HR, 1.17; 95% CI, 0.95–1.44; P=0.13). D, in patients with ALL, there was a nonsignificant trend for an increased NRM in the multivariate analysis using an MUD (HR, 1.22; 95% CI, 0.90–1.65; P=0.18).

In the multivariate analysis for risk factors for chronic GVHD in patients with AML, there was no significant difference between the sibling group and the MUD group (P=0.25) (Table 2). Factors significant for chronic GVHD included second complete remission (CR2), active disease, no ATG given, and peripheral blood stem cells (PBSCs).

In the ALL group, the mean±SE cumulative incidence of chronic GVHD was 53%±2% in the sibling group and 37%±2% in the MUD group (P<0.001) (Fig. 1B).

In patients with ALL, factors associated with chronic GVHD included PBSCs, no ATG treatment, and a trend for active disease (Table 2).

Nonrelapse Mortality

Nonrelapse mortality (NRM) was similar in male patients with AML receiving grafts from female HLA-identical siblings (20%±1% at 2 years) and in those with grafts from male unrelated donors (21%±1% at 2 years) (P=0.22) (Fig. 1C). In the multivariate analysis, risk factors for NRM in patients with AML included older age (P<0.001), no ATG given, active disease rather than first complete remission (CR1), PBSCs, and MAC (Table 2).

In patients with ALL, mean±SE NRM at 2 years was 21%±2% in the HLA-identical sibling group and 25%±2% in the MUD group (P=0.12) (Fig. 1D). Risk factors for NRM in patients with ALL included interval diagnosis to transplantation greater than the median, cytomegalovirus (CMV)–seropositive recipient, and older age (Table 2).

Relapse

The mean±SE cumulative incidence of relapse in patients with AML was 29%±1% in the sibling group and 33%±1% in the MUD group (P=0.04) (Fig. 2A). However, this was not significant in the multivariate analysis (P=0.43) (Table 3). Factors of importance for probability of relapse in patients with AML included active disease, poor cytogenetics, interval diagnosis to transplantation greater than the median, ATG, and reduced-intensity conditioning (RIC).

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TABLE 3:
Multivariate analysis of factors of importance for relapse, survival, and LFS
F2-16
FIGURE 2:
Time to and cumulative incidence of relapse in male patients who received grafts from HLA-identical female donors (solid line) or a matched unrelated male donor (dotted line). A, in patients with AML, there was no significant difference in the multivariate analysis between the two groups (HR, 0.93; 95% CI, 0.79–1.10; P=0.43). B, among patients with ALL, those with an MUD showed a significantly lower risk of relapse in the multivariate analysis (HR, 0.75; 95% CI, 0.57–0.99; P=0.05). C, LFS in patients with AML did not differ significantly in the multivariate analysis between the two groups (HR, 1.05; 95% CI, 0.92–1.19; P=0.44). D, among patients with ALL, there was no statistically significant difference in the multivariate analysis between the two groups (HR, 0.90; 95% CI, 0.74–1.10; P=0.31).

In patients with ALL, the mean±SE 2-year probability of relapse was 33%±2% in the sibling group and 29%±2% in the MUD group (P=0.07) (Fig. 2B). In the multivariate analysis, patients in the MUD group experienced significantly fewer relapses (P=0.05) (Table 3). Other significant factors included active disease, CR2, RIC, and Ph-positive ALL.

Overall Survival and LFS

Mean±SE 2-year overall survival in patients with AML was 57%±1% in the sibling group and 52%±2% in the MUD group (P=0.004). However, in the multivariate analysis, there was no significant difference between the groups (P=0.26). Factors of importance for poor survival were active disease (Table 3), poor cytogenetics, CR2, interval diagnosis to HSCT greater than the median, age greater than the median, and year of transplantation.

In patients with ALL, mean±SE 2-year overall survival was 52%±2% in the sibling group and 51%±2% in the MUD group (P=0.45). In the multivariate analysis, there was no significant difference in the overall survival between the sibling and the MUD groups (P=0.85) (Table 3). Factors associated with poor survival in the multivariate analysis were active disease, CR2, interval diagnosis to HSCT greater than the median, RIC, CMV-seropositive recipient, and age greater than the median.

Mean±SE 2-year LFS in patients with AML was 51%±1% in the sibling group and 46%±2% in the MUD group (P=0.003) (Fig. 2C). In the multivariate analysis, there was no significant difference between the two groups (P=0.44) (Table 3). Factors associated with poor LFS in patients with AML included active disease, poor cytogenetics, interval diagnosis to transplantation greater than the median, more recent year of transplantation, age greater than the median, and CR2.

In the ALL group, the mean±SE 2-year probability of LFS was 45%±2% in the HLA-identical sibling donor group and 46%±2% in the MUD group (P=0.85) (Fig. 2D). In the multivariate analysis for LFS in patients with ALL, there was no significant difference between the sibling group and the MUD group (P=0.31) (Table 3). Factors significantly associated with better LFS were CR1, MAC rather than RIC, interval diagnosis to HSCT greater than the median, CMV-seronegative recipient, and treatment with ATG.

With the use of a CMV-seronegative MUD (n=104) for a CMV-seronegative recipient, the mean±SE 2-year LFS was 45%±4%, which was similar to that when using a female CMV-seropositive donor (n=214), being 47%±6% (P=0.2) (for AML, P=0.18; for ALL, P=0.92).

In the setting of a male patient older than 50 years with an older female sibling donor (≥50 years of age, n=885), mean±SE 2-year LFS was 42%±2%. This was similar to the situation using an MUD (≤35 years of age, n=195), where the mean±SE 2-year survival was 39%±4% (AML, P=0.33; ALL, P=0.32).

When we combined a young CMV-seropositive male MUD (≤35 years of age) with a CMV-seronegative male patient (n=49), the mean±SE 2-year LFS was 50%±8%. This was not significantly different from the mean±SE 2-year survival of 47%±4% using an older (≥50 years of age) CMV-seropositive female donor (n=234; P=0.68; AML, P=0.99; ALL, P=0.37).

DISCUSSION

The main problem in using a female donor for a male recipient in HSCT has been the increased risk of acute GVHD (1, 3). This has contributed to a worse survival (8–11). Parity was also of importance, but unfortunately, this was not collected in the European Group for Blood and Marrow Transplantation (EBMT) database. This study found that unrelated male donor transplantation to male recipients resulted in significantly more acute GVHD of grades II to IV than when using a female sibling donor (Table 2). This was seen despite the fact that the MUD patients were more often treated with ATG, which has been shown to reduce the risk of acute GVHD in MUD patients to an extent similar to that seen in HLA-identical sibling donors without ATG (21, 27, 28). Among the factors that were of significant importance in the multivariate analysis for acute GVHD were ATG treatment in both groups and MAC rather than RIC (Table 2). It has previously been reported that RIC is associated with a reduced probability of acute GVHD (29).

In the univariate analysis, the cumulative incidence of chronic GVHD was increased in the sibling group, but this was not significant in the multivariate analysis (Fig. 1, Table 2). It may have been expected that chronic GVHD is also increased in the MUD group because there is a correlation between acute and chronic GVHDs (2, 30). Antithymocyte globulin—which was preferentially used in the MUD group—reduced the risk of chronic GVHD (Table 2) (27). Another significant reason for chronic GVHD was the use of PBSCs, which is in line with previous studies (31, 32).

Nonrelapse mortality was not significantly different in the MUD and sibling groups, despite the increased risk of acute GVHD in the MUD group (Fig. 1C, D).

In patients with AML, the probability of relapse was the same in the MUD and sibling groups, but in patients with ALL, the MUD patients demonstrated a lower risk of relapse despite the fact that a GVL effect has been reported when using a female donor and a male recipient (26) and despite our previous finding that the GVL effect was the same using well-matched unrelated donors and HLA-identical sibling donors (25) (Fig. 2A, B). This study did not support a GVL effect using a female donor for a male recipient. The reason for the reduced risk of relapse in the MUD group with ALL may have been the increased probability of acute GVHD in this group. A Centre for International Blood and Marrow Transplant Research study showed that in patients with ALL, acute GVHD was important to reduce the risk of relapse (33). However, most studies have shown that chronic GVHD is more important for the GVL effect than acute GVHD (Table 3) (34). Thus, there was no difference in relapse in patients with AML, in whom the probability of chronic GVHD was the same in the sibling and in the MUD groups. High relapse probability was associated with poor cytogenetics, active disease, RIC, and ATG and, in patients with ALL, greater than the median time from diagnosis to HSCT (Table 3), in accordance with previous reports (29, 35). The increased risk of relapse after ATG was seen in a matched-pair analysis (28), but it was not seen in a prospective randomized study (27).

There was no significant difference in survival and LFS between the sibling and MUD groups (Fig. 2C, D; Table 3). Despite the possibility of selecting a young and CMV-seronegative donor, a male MUD was not superior to an older CMV-seropositive HLA-identical female sibling donor for a male CMV-seronegative patient. This was seen despite the fact that MUD transplantations in general have an outcome similar to that of HLA-identical sibling HSCT (20–23). Because it is cheaper and easier to plan, a female sibling donor should be preferred to searching for an unrelated male donor for male recipients with acute leukemia. For survival and LFS, other factors were significantly more important, such as age, year of transplantation, poor cytogenetics, and CR status (Table 3). In patients with ALL, the RIC patients demonstrated a significantly worse survival and LFS compared with the MAC patients (Table 3). Such a difference was not seen in patients with AML. These findings are in accordance with previous reports (29, 34, 36).

Because of the limitations of using retrospective registry analyses, the data in this study must be interpreted with some caution, although more than 4,000 patients were included. The multivariate analysis may have adjusted for many obvious disease and biologic factors. Still, there may have been factors of importance that we were not able to take into account. For example, there is an obvious selection bias that better fitted patients with AML (CR1, better cytogenetics) were selected for a transplantation with an HLA-identical sibling donor than for an MUD. There are some obvious differences between the two groups, such as more patients in CR1 in the sibling AML cohort and also fewer patients with poor cytogenetics (Table 1). Because of the possibility to select among several donors, there are more CMV-seronegative donor-recipient pairs among the MUDs. In patients with AML, there is also a shorter follow-up because in more recent years, it is easier to find a well-matched donor because of the increased number of volunteer donors. Therefore, more MUD transplantations are performed in more recent years. The worse outcome in more recent years may be caused by the fact that patients with good cytogenetics are now more rarely selected for HSCT.

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TABLE 1:
Characteristics of adult male patients with AML and with ALL who received grafts from an HLA-identical female donor (the sibling group) or a male HLA-matched unrelated donor (the MUD group)

To conclude, male patients with acute leukemia who received grafts from male unrelated donors demonstrated a higher risk of acute GVHD compared with the recipients of grafts from female HLA-identical sibling donors. Overall survival and LFS were similar between the two groups. Thus, a female sibling donor should be preferred.

MATERIALS AND METHODS

Data Collection and Patient Selection

The study included first HSCTs performed between 2004 and 2011 and reported to the EBMT. The EBMT is a group of 605 HSCT centers that report all consecutive transplantations to a common registry. This retrospective study involved 4,670 adult male patients (≥18 years of age) with acute leukemia who received a hematopoietic stem-cell transplant from a female HLA-identical sibling donor (n=2,656) or a hematopoietic stem-cell transplant from an MUD (n=2,014). The recipients and donors were identified by serologic or genomic tissue typing for HLA class I and by genomic typing for HLA class II. The MUDs were identical for 8/8 antigens, that is, HLA-A, HLA-B, HLA-C, and HLA-DRB1. This study was approved by the institutional review board and the ethics committee of Karolinska Institutet.

Patient Characteristics

The patients were divided into those with AML and those with ALL. The characteristics of the patients who received a hematopoietic stem-cell transplant from a female HLA-identical sibling donor (sibling group) or from a male MUD (MUD group) are shown in Table 1. Of the patients with AML, the male patients who received grafts from HLA-identical female donors were generally younger (P<0.001), underwent transplantation earlier (P<0.001), were more likely to have poor cytogenetics (P=0.003), were more often in CR1 (P<0.001), were less often treated with ATG (P<0.001), were more likely to be CMV seropositive (P=0.001), and were more likely to have a donor who was CMV seropositive (P<0.001). In the ALL cohort, the sibling group differed from the MUD group such that HSCT was performed earlier (P<0.001), ATG was less commonly used (P<0.001), and CMV seropositivity in recipient and donor was more common (P<0.001, Table 1).

Prophylaxis for GVHD

Graft-versus-host disease prophylaxis consisted of cyclosporine A (CsA) alone, CsA combined with four doses of methotrexate, or CsA combined with mycophenolate mofetil. In the sibling group, CsA plus methotrexate was more commonly used, both in patients with AML and in patients with ALL (P<0.001) (Table 1). Cyclosporine A plus mycophenolate mofetil was more common in the MUD group.

Conditioning Regimen

Myeloablative conditioning was given to most patients in the sibling group and also in the MUD group, both in patients with AML and in patients with ALL (Table 1). Myeloablative conditioning was defined as an established conditioning regimen that results in pancytopenia if HSCT was not performed. The most common conditioning regimen was cyclophosphamide (120 mg/kg) combined with fractionated total-body irradiation. Busulfan (16 mg/kg, orally) or intravenously administered Busulvex combined with cyclophosphamide (120 mg/kg) was preferentially used in patients with AML. Reduced-intensity conditioning was defined as the use of Fludarabine (Flu) associated with fewer than 6 Gy (low dose) total-body irradiation, or Busulfan (≤8 mg/kg), or other nonmyeloablative drugs. Reduced-intensity conditioning was more commonly used in the MUD group than in the sibling group (P<0.001) (Table 1).

Definition of Outcomes

Acute GVHD was graded from 0 to IV (37). Chronic GVHD was defined as being present or absent (38). Nonrelapse mortality was defined as all causes of death, except leukemia.

Statistical Analysis

Cumulative incidence curves were used in a competing-risks setting, with death being treated as a competing event to calculate probability of chronic GVHD (39, 40). They were also used for relapse mortality and NRM because death and relapse were competing events. Comparisons between cumulative incidence curves were performed using the Gray test. Probability of survival and LFS was calculated using the Kaplan-Meier estimate, and the log-rank test was used for univariate comparisons. Patient-related, disease-related, and transplant-related variables of the groups were compared using the chi-square statistic for categorical variables and the Mann-Whitney U test for continuous variables. The variables considered were age of the recipient, disease characteristics, French-American-British classification, cytogenetics, white blood cell count at the time of diagnosis, time from diagnosis to HSCT greater than the median of 177 days for AML and 198 days for ALL, age of the donor, conditioning (MAC vs. RIC), source of stem cells (bone marrow vs. PBSCs), ATG, GVHD prophylaxis, and CMV status of the recipient and donor. Factors that differed significantly between the sibling group and the MUD group with P values less than 0.05 and all factors known to influence outcome were included in the final models. For all prognostic analyses, continuous variables were categorized, and the median was used as a cutoff point.

Associations of patient and graft characteristics with outcomes were evaluated in the multivariate analysis, using logistic regression for acute GVHD and Cox proportional hazards model or a Fine-Gray model for competing events. All tests were two sided. The type 1 error rate was fixed at 0.05 for determination of factors associated with time to event outcomes. Statistical analyses were performed with SPSS 19 (SPSS, Inc., Chicago, IL) and R 2.13.2 (R Development Core Team, Vienna, Austria) software packages.

ACKNOWLEDGMENT

The authors thank all the EBMT centers for submitting data to the Acute Leukaemia Working Party (ALWP, Table S1, SDC,https://links.lww.com/TP/A968). The authors also thank Inger Holmstrom for preparing this article.

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Keywords:

Acute leukemia; Stem-cell transplantation; GVHD; Female donor to male recipient

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