Relapse

The impact of donor gender on outcome of allogeneic hematopoietic stem cell transplantation for multiple myeloma: reduced relapse risk in female to male transplants

Summary:

The impact of the donor gender on outcome in HLA-identical sibling donor hematopoietic stem cell transplantation for multiple myeloma was studied in a retrospective registry study of 1312 patients (476 male to male (M → M); 334 female to male (F → M); 258 male to female (M → F); 244 female to female (F → F) reported to the European Group for Blood and Marrow Transplantation (EBMT). The best overall survival (OS) from the time of transplantation was found in F → F (median 41 months) with no significant difference between other groups (median 25 months in M → M, 18 months in F → M, 19 months in M → F) despite a significantly higher nonrelapse mortality in F → M. This was due to a significantly lower relapse rate (REL) in F → M compared to all other groups. Before 1994, OS was poorer in F → M than in M → M, which improved to similarity from 1994 onwards (median 29 months in M → M and 25 months in F → M). The reduced REL contributed to this improvement in F → M indicting a gender-specific graft vs myeloma effect. Therefore, a female donor is as good as a male one for male patients, while for female patients gender disparity is a negative factor for outcome.

Main

Multiple myeloma is a disease characterized by a median overall survival (OS) of about 3 years with conventional chemotherapy and no cures.1, 2, 3, 4 Autologous transplantation has improved survival but cures are unlikely to occur.5, 6, 7 Allogeneic transplantation has been carried out since the early 1980s.8, 9, 10 This treatment modality has been hampered by high transplantation-related mortality,11, 12 but occasionally patients have been long-term survivors without signs of disease. Using myeloablative conditioning treatment, the relapse rate (REL) has proven to be lower than with autologous transplantation.11 Sustained molecular remissions are observed in approximately 30% of patients and predict for improved survival.13 Prognostic factor analyses have been performed repeatedly by the EBMT10, 12 and other groups, in particular the Seattle group.14, 15 Many of the factors of importance for outcome following allogeneic transplantation are the same as for autologous transplantation or conventional chemotherapy. Favorable prognostic factors are low age, low stage at diagnosis, low beta2-microglobulin at diagnosis, few treatment regimens before the transplant, and response to previous chemotherapy. It has been difficult to find specific procedural factors of importance for prognosis. Thus, no conditioning regimen has proved to be superior to the conventional total body irradiation (TBI)+cyclophosphamide treatment, and no graft-vs-host prevention method has proved to be superior to the classical combination of methotrexate and cyclosporin. A procedural factor that is specific to allogeneic transplants is the donor. It is well known that HLA compatibility is a favorable prognostic factor and a prerequisite for successful hematopoietic stem cell transplantation in most disorders.16 Also, in multiple myeloma, sibling donor transplants have a better outcome than transplants from unrelated donors,17 although only a few such transplants have been performed in myeloma and the results are therefore uncertain. Previous studies have indicated that the gender of the sibling donor is of importance, not only in transplantation of multiple myeloma patients12, 14 but also in other hematological disorders.18, 19, 20 In one study of myeloma patients, there was a tendency for better survival in female to female transplants than female to male transplants,12 and in another study a transplant from a male donor to a female patient was an adverse risk factor.14 Various reasons for the disparity in outcome have been discussed, and in some studies there has been an influence only on transplant-related mortality, while in others there has been a difference in REL. The recent findings of minor histocompatibility antigens encoded by genes on the Y chromosomes and their possible importance in a graft vs tumor effect20, 21, 22, 23, 24, 25 was an additional reason to perform the present study. We have now investigated 1312 patients reported to the EBMT on so-called MED-B forms (complete data set) transplanted with HLA-matched sibling donors in an attempt to delineate the importance of donor gender in transplantation of patients with multiple myeloma.

Patients and methods

The study population comprised 1312 patients reported from 186 centers to the EBMT registry from 1983 to 2001. In total, there were 502 female and 810 male patients. Patients who had received a transplant from an HLA-matched sibling donor and in whom data had been reported on MED-B forms (complete data set) were included. The patient characteristics of the four groups male donor-male patient (M → M), female donor–male patient (F → M), male donor–female patient (M → F), and female donor–female patient (F → F), are shown in Table 1. A prerequisite for including a patient in the study was the knowledge of the gender of both patient and donor and the outcome of the transplant. As can be seen in Table 1, the proportion of patients in the different known prognostic subgroups for male and female subjects, respectively, was similar. Most important was a similar distribution of patients who had received only one line of pretreatment before transplant as opposed to two or more, and of patients who were in a complete remission (CR) as opposed to being in only partial remission, not responding or in progression. Also, the distribution of procedural factors, that is, source of graft, conditioning regimen and graft-vs-host prevention, was relatively similar between the groups. The median follow-up was 36 months, with no significant difference among the four groups. CR after transplantation was defined for the purpose of this study as the disappearance of abnormal immunoglobulins from serum or light chain from the urine using either conventional electrophoresis or immunofixation, as well as disappearance of apparent myeloma cells from the marrow, as previously described.10, 12, 26

Table 1 Patient characteristics

Statistical analysis

In the EBMT Myeloma registry we found, for the period between 1983 and 2001, 1419 patients treated with allogeneic hematopoietic stem cell transplantation from HLA-identical siblings for whom basic information was available. Among these only 3% had missing information on donor gender, and therefore we were able to select 1376 potential patients for the study. Since the information regarding the main prognostic factors was not complete in all patients, it was decided to select cases with complete information on the interval diagnosis-transplant and the use of total body irradiation (TBI), since this reduced the population by less than 5%, and to consider the level ‘missing’ as a further category for the other variables (the treatment of missing values is illustrated below). Therefore, the final number of cases included in the study was 1312.

Differences in the distributions of the risk factors in different groups were evaluated by a chi-square test on the appropriate cross tabulations for the discrete variables, and by a Mann–Whitney test for the continuous variables. Survival probabilities for OS and relapse-free survival (RFS) were estimated according to the Kaplan–Meier product limit method and differences among groups were tested by the Log-Rank test. The analysis of REL and nonrelapse mortality (NRM) as competing risks was carried out estimating the cumulative incidence curves by the proper estimator, and testing the differences using the Gray test.27

The CR rate was also estimated in a framework of competing risks, the competing event being death without CR. This explains why in previous studies where the competing risks situation was ignored and the cumulative incidence was estimated as the One-Minus-Survival probability obtained from the Kaplan–Meier curve, higher CR rates were reported for the same kind of patients: in fact, the latter method overestimates the cumulative incidence.28, 29 Moreover, due to the structure of the Med-B forms it was not possible to distinguish between cases where CR was achieved but the information was missing and cases where CR was never achieved (in particular, when CR was achieved beyond the first 100 days); therefore, all missing cases were considered as ‘no CR’, which means that the estimated rate is the minimum rate observed in the population, but the real rate could be higher.

The effect on the hazard of each of the four major outcomes (OS, RFS, REL, and NRM) of gender combination was estimated via multivariate Cox models to adjust for the main prognostic factors known from the literature (see below). The results are reported in Table 2 as Hazard ratios (HR) with respect to a reference category (indicated in the tables by HR=1) with 95% confidence interval (CI) and P-values.

Table 2 Effect of gender combination (donor → recipient) (multivariate analysis)

For each variable with missing values, it was verified that the outcomes of the ‘missing’ group were statistically equivalent to the outcomes of the ‘known’ group (all the other levels considered as a unique one), indicating that there was no hidden pattern of risk factors in the missing group. As a consequence, including the latter as one of the categories of the variable allowed the estimation of the adjusted effect of gender combination without problems in the interpretation and with the advantage of keeping all cases in the analysis.

For each outcome, the candidate adjustment variables were: age, previous autologous transplantation, stage at diagnosis, time interval between diagnosis and transplant, response to chemotherapy, status at transplantation, source of stem cells, beta2-microglobulin levels, type of myeloma, TBI, T-cell depletion, reduced-intensity conditioning regimen (RIC), and calendar year (as a linear effect). The number of treatment lines before transplantation was not included as a candidate variable, firstly because it correlated significantly with the time interval from diagnosis to transplant and secondly since the information was lacking in 39% of the patients. The selection of the adjustment variables was carried out applying a backward procedure (except for the calendar year which was included regardless of the significance of its effect to represent possible unmeasured sources of heterogeneity correlated to it). No interaction between donor–recipient gender combination and any other variable was significant. For each model, the proportionality of the hazards was assessed, and the models for RFS and REL were stratified with respect to response status at transplant to avoid violation of this assumption of the Cox model.

In order to focus on the outcomes of patients transplanted before/after 1994, we considered a follow-up truncated at 2 years (a time period equal to the shorter median follow-up among the four donor–recipient groups for patients transplanted from 1994 onwards). Owing to the restriction of the follow-up period, the analysis of RELs would not have been informative, and therefore it was not performed. We also analyzed the occurrence of acute graft versus host disease (aGVHD) with respect to the calendar period.

The donor gender impact on REL, NRM, and OS in patients that had received the transplant from 1994 onwards was also analyzed separately, without restriction of follow-up.

The statistical analyses were performed using SPSS version 10.0.7 (2000), except the estimation of the cumulative incidence and the Gray test which were performed using R 1.6.2 (2003) and the software ‘cmprsk’ by T Gray, version 2 1-2 (2000).

Results

Engraftment

Engraftment was evaluable for 97% of the population. The engraftment frequency was similar in all groups, that is, 92.4, 91.3, 90.3, and 93.0%, respectively, in M → M, F → M, M → F, and F → F (comparison among male patients: P=0.8; comparison among female patients: P=0.5). Although there was a small tendency for a higher rejection rate in M → F than in F → F in evaluable patients (6.8 vs 5.0%), this difference was not statistically significant. Also, the time to engraftment did not differ significantly between the groups (P=0.6). The median time to neutrophils 0.5 × 106/l was 16 days and the median time to platelets 50 × 106/l was 31 days.

Response to transplantation

There was no significant difference between the groups in the estimated minimum CR rates at 2 years, which were 40, 42, 38, and 42% for F → M, M → M, M → F, and F → F, respectively. The P-value for the global effect of donor gender was 0.92 (F → M vs M → M: P=0.63; M → F vs F → F: P=0.80). As illustrated in the statistical section, the method applied for the estimation of CR rate produces only minimum estimates, which therefore were lower than CR rates reported previously.26

Survival and NRM

Male patients had a poor survival irrespective of whether the donor was male or female (Figure 1). However, there was no significant difference in OS between F → M and M → M, neither in the univariate (P=0.20) nor the multivariate analyses (P=0.12) (Table 2). Still, F → M had a much higher NRM than M → M (P<0.01) (Figure 2, Table 2).

Figure 1
figure1

Kaplan–Meier curves for OS. Better OS in female subjects with a female donor (F → F) than in female subjects with a male donor (M → F) (P<0.01) while there is no significant difference between male subjects with a female (F → M) or a male (M → M) donor.

Figure 2
figure2

Cumulative incidence of NRM. Higher NRM in male patients with a female donor (F → M) as compared to male patients with a male donor (M → M) (P<0.01) and in female subjects with a male donor (M → F) as compared to female subjects with a female donor (F → F) (P<0.01).

The survival for F → F was significantly better than for M → F (P<0.01). The combination was superior to all other donor–patient combinations (Figure 1). The reason for the difference was a lower NRM in F → F as compared to M → F (P<0.01) (Table 2, Figure 2). Owing to the previously reported improvement in survival in patients transplanted from 1994,26 an analysis of the donor influence on patients transplanted before and from 1994 was made (Figure 3a and b, Table 3). For comparability this required restriction of the follow-up period to the first 2 years after transplant (see Statistical analysis). Before 1994, the OS was significantly poorer in F → M than in M → M but similar in both groups from 1994 and onwards (Figure 3a). NRM was significantly reduced during the later time period, but comparatively more in F → M than in M → M, partly explaining the similar OS in F → M and M → M from 1994 (both combinations significantly improved as compared to the time period before 1994 as previously shown26).

Figure 3
figure3

(a) Male patients: for the OS in the first 2 years, the female donor is associated with a higher mortality only for patients transplanted before 1994 (95% CI: 1.03–2.17) and not for patients transplanted from 1994 (95% CI for HR: 0.8–1.4). (b) Female patients: for the OS in the first 2 years the female donor is superior to the male donor for patients transplanted after 1993 (95% CI for HR: 0.5–0.9).

Table 3 Effect of gender combination (donor → recipient) before and since 1994 (multivariate analysis)

In female patients NRM was lower in F → F as compared to M → F in patients transplanted from 1994 but on an improved level as compared to transplants before 1994. The difference in OS between F → F and M → F was also similar to the difference before 1994 but on an improved level, F → F still being superior to M → F (Figure 3b).

GVHD

As seen in Table 4, severe aGVHD grades III–IV tended to be more frequent in M → F (14.3%) as compared to F → F (9.3%) (P=0.096). This tendency was even more pronounced in transplants performed since 1994 (M → F 16.1% vs F → F 9.2%; P=0.06). Although the incidence of severe aGVHD in female subjects tended to be higher with a male donor, GVHD was not reported to be the primary cause of death more frequently than in female subjects with a female donor (Table 5).

Table 4 Acute GVHD
Table 5 Causes of death

In male patients, there was no significant difference (P=0.447) in severe aGVHD between those who received the graft from a male (14.4%) as compared to a female donor (16.4%) nor was aGVHD reported to be the primary cause of death more frequently in F → M (22.8%) than in M → M (16.7%) (P=0.152). The same lack of difference in aGVHD between the two groups F → M and M → M was seen in transplants performed after 1993 (data not shown).

The frequency of chronic GVHD (cGVHD) is seen in Table 6. While for female patients there was no association between donor gender and the incidence or severity of cGVHD (P=0.986), male patients had significantly (P=0.006) more cGVHD with a female donor (limited 23 % and extensive 33%) than with a male donor (limited 17%, extensive 22%).

Table 6 Chronic GVHD

REL and RFS

The REL is seen in Figure 4. The REL was significantly lower in F → M as compared to M → M (univariate analysis: P=0.002; multivariate: P=0.02) (Table 2). This corroborates the observation that relapse as a cause of death was more frequent in M → M (47.1%) as compared to F → M (29.0%).

Figure 4
figure4

Cumulative incidence of relapse. Significantly lower incidence of relapse in male subjects with a female donor (F → M) than in male subjects with a male donor (M → M) (P=0.02), but no difference in female subjects with a male (M → F) or a female (F → F) donor (P=0.19).

The lower REL compensated for the higher NRM in F → M, thus OS and RFS were similar in M → M and F → M (see above) (Figures 1 and 5 and Table 2). However as seen in Figure 3a, in patients transplanted before 1994, there was a significant difference in OS to the disadvantage of F → M due to the higher NRM as compared to M → M, in contrast to the finding in F → M during the later time period when NRM and OS were similar in F → M and M → M (Table 3). Although the REL for these two periods could not be compared beyond 2 years from transplant (see statistical methods), it was noted that it was 28% in M → M and 20% in F → M at this time. Also, a separate comparison of the relapse risk in F → M and M → M in patients transplanted from 1994 and onwards, disregarding the comparison between time periods, showed that F → M had a lower relapse risk (HR: 0.64, 95% CI: 0.46–0.90, P=0.009).

Figure 5
figure5

Kaplan–Meier curves for RFS. Significantly better RFS in female subjects with a female donor (F → F) than in female subjects with a male donor (M → F) (P<0.01), but no difference between male subjects with a female (F → M) or a male donor (M → M) (P=0.41).

In female subjects, there was no significant difference in REL (univariate analysis: P=0.824; multivariate analysis: P=0.19), and no difference in relapse as a cause of death due to the donor gender (47.9% of M → F and 51.5% of F → F, P=0.549) . This was also true for the REL in the separate analysis in transplants performed after 1993 (HR: 0.73, 95% CI: 0.50–1.08, P=0.119). Thus, the REL did not seem to have an impact on the advantageous OS (Figure 1) and RFS (Figure 5) seen in F → F as compared to M → F, either in transplants performed before or from 1994 (data not shown). These differences were due to differences in NRM.

Discussion

This study clearly demonstrates that transplantation of a male patient with a graft from a female donor involves a graft vs myeloma effect. This donor gender-specific effect has not been seen in previous studies of myeloma transplants, probably because of lack of detectable advantageous effect on OS, masked by increased transplant-related mortality, and inadequate follow-up. Before 1994, there was even a highly significantly poorer OS in F → M than in M → M due to this higher NRM hiding the impact of a reduced REL. However with the decrease in this mortality after 1993, unmasking the reduced REL, the OS was improved and became similar in M → M and F → M.

The lower REL in F → M corroborates with more cGVHD in these patients compared to M → M. An association between graft vs myeloma and GVHD has previously been reported.13, 30, 31, 32

Recent studies in chronic myelocytic leukemia and acute leukemia have shown a similar gender-dependent effect, that is, lower REL and higher transplant-related mortality in female to male as compared to male to male transplants and this was assumed to be due to the presence of female donor T cells that are specific for recipient minor histocompatibility antigens (H-Y) encoded by Y chromosome genes.24, 33 H-Y antigens have been shown to be present in a variety of male cells and anti H-Y peptide-specific cytotoxic T cells as well as H-Y-directed antibodies have been identified in male patients who received marrow from female donors.25 Women may be sensitized to men during pregnancy34, 35 and therefore some female patients may have cytotoxic T cells directed against male antigens before the donation. An association between GVHD and presence of cytotoxic T cells was found in a woman who rejected bone marrow from a male donor.20, 21, 22, 23 Thus it seems reasonable to conclude that H-Y antigens are responsible both for eliciting a stronger graft vs myeloma effect in male patients with a female donor than with a male donor, and the concomitant higher GVHD related mortality in this donor–patient combination. By decreasing overall transplant-related mortality with improved methods of preventing transplant-related complications during the years from 1994, it has been possible to unmask the lower REL, translating into a significantly better survival in this group as compared to the earlier time period.

The present study confirms previous observation in multiple myeloma that the combination female recipient–female donor has the best outcome. No advantageous impact of gender disparity could be seen on REL, RFS, or OS in female subjects. Thus, there seem to be no minor histocompatibility antigens in female subjects eliciting a clinically detectable antimyeloma response from male T cells. However, it is interesting to note that 6.6% of the female subjects rejected male grafts, but only 4.9% of the female grafts. Although not significant, this tendency for more rejections of male grafts in female subjects corroborates with an importance of male H-Y antigens, perhaps inducing an immune response in some female subjects. However, there is no obvious explanation for the significantly lower NRM in female to female transplants as compared to male to female ones. Female to female transplants have the best OS of all four combinations.

Multiple myeloma appears to be a good model to explore the possible advantageous effect of H-Y as well as other minor histocompatibility antigens. Donor lymphocyte transfusions in relapsed patients may induce up to 30% CRs.36 Improving the specificity of donor lymphocytes by sorting or utilizing differences in minor histocompatibility antigens in other ways may prove to be beneficial. With more effective prevention and treatment of transplant-related complications, the effect of a donor gender mismatch in male patients could be further explored. The present study has only utilized sibling donor transplants in order to prove the principle. It may well be possible that similar effects could be explored in unrelated transplants. From the practical point of view, it may be more realistic to select for gender-specific minor histocompatibility antigens in the unrelated donor pool, now containing more than 8 million HLA-typed donors.37 Within a family it is rare to find two major histocompatibility antigen compatible donors with opposing gender. With further improvement in NRM it may well be advantageous to choose a female instead of a male donor for a male patients, in contrast to what has been thought until now. Presently, there seems to be no reason to preferentially choose a male donor.

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Acknowledgements

This study was supported by grants from the Swedish Cancer Fund and the Cancer Society in Stockholm. This work is based on data reported to the EBMT registry by EBMT centers , which is greatly acknowledged.

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Correspondence to G Gahrton.

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Keywords

  • multiple myeloma
  • allogeneic stem cell transplantation

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