Overall Survival in Male Patients With Advanced Hematological Disease (Mostly Acute Leukemia) Is Influenced by CYP1B1 C432G Polymorphism and Donor Sex in Allogeneic Stem Cell Transplantation

Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic key enzyme involved in estrogen metabolism, steroid synthesis, and pro-carcinogen activation. CYP1B1 is strongly overexpressed in multiple human malignancies and has been used as a target for cancer chemotherapy and immunotherapy. CYP1B1 is also overexpressed in acute lymphocytic leukemia, acute myeloid leukemia, lymphoma, and myeloma [1].

In allogeneic hematopoietic stem cell transplantation (HSCT), disease stage is an established risk factor for overall survival [2]. Our cohort of 118 male patients with advanced disease consisted of advanced forms and stages of AML (n = 47), ALL (n = 17), MDS (n = 12), myeloma (n = 10), CML (n = 9), NHL (n = 8), OMF (n = 6), CLL (n = 6), and CMML (n = 3).

In our recent paper of 382 patients who underwent allogeneic HSCT, we reported a lower overall survival (OS) in male patients with advanced disease (AD) associated with mutant CYP1B1 Leu432Val polymorphism (n = 118, p = 0.002): OS 44% ± 8% (CC) vs. 32% ± 6% (CG) vs. 6% ± 6% (GG). Multivariate analysis for OS in male patients with AD revealed CYP1B1 polymorphism as the only prognostic factor: RR 1.78, p = 0.001 [1].

We then tested whether donor sex played a role in the outcome of this subgroup of patients and found a surprising result. In our original study we investigated the outcome of male patients with advanced disease (n = 118) and results were stratified by donor sex: male (n = 93) versus female (n = 25). We did not find a major difference in this subgroup of patients by sex mismatch, see supplementary results [1].

An interesting and very different picture emerges when recipient CYP1B1 polymorphism (R SNP) data is included in the analysis and the results are stratified by donor sex. In the case of male patients with AD and male donors, the estimated 5-year OS was 47% (wildtype, wt) versus 21% (mutant, mut). Median OS was reached after 4.5 versus 1.2 years (Figure 1A), p = 0.002 (log-rank). For female donors the estimated 5-year OS was 30% (wt) versus 47% (mut) and median OS was reached after 0.6 versus 2.2 years (Figure 1B), not significant. While OS is similar in case of sex mismatch, the difference in OS between wt and mut SNP is biggest if the donor is male. Patients with wt SNP have significantly better results regarding OS with a male donor (n = 93), and worse with a female donor (n = 25). In patients with mut SNP both donor sexes perform poorly. The main finding of our recent analysis (mut R SNP does worse in male patients with advanced disease compared to wt R SNP) is especially true if the donor is male and less so when the donor is female (sex mismatch). There was no difference between mut and wt SNP in male patients with early disease irrespective of the donor sex.

FIGURE 1

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Overall survival estimate at 5 years in male patients with advanced disease (AD) by donor sex and CYP1B1 polymorphism. (A) Male patients with AD and male donors (n = 93): Patients with mutant recipient SNP had a lower overall survival than patients with wildtype recipient SNP (p = 0.002, log-rank). (B) Male patients with AD and female donors (n = 25) displaying no difference (p = 0.42). AD: Advanced disease; R SNP: Recipient SNP, here CYP1B1 C432G polymorphism: wt (CC) and mut (CG and GG); SCT: Stem cell transplantation.

The same holds true for non-relapse mortality (NRM) and relapse in male patients with AD, but not for severe acute graft-versus-host disease (saGvHD) (Table 1). A higher OS in wt R SNP correlates with a lower NRM and lower relapse rate in male patients with AD and a male donor. Female donors led to a higher rate of saGvHD in patients with mut R SNP (trend, p = 0.07). Chronic graft-versus-host disease (cGvHD, all stages) was seen in 20/29 (wt) patients and in 37/64 (mut) with male donors, and in 5/10 (wt) and in 8/15 (mut) with female donors (not significant). Of note, 92% of transplants were myeloablative, 54% of patients had acute leukemia, and median follow-up was 76 months.

TABLE 1. Outcome results stratified by R SNP and donor sex for male patients with advanced disease (n = 118).

	Male donor			Female donor
	wt (%)	mut (%)	p	wt (%)	mut (%)	p
OS—5 years	47 ± 9	21 ± 5	0.002	30 ± 14	47 ± 13	NS
OS—median (years)	4.5 ± 2.3	1.2 ± 0.4	0.002	0.6 ± 0.6	2.2 ± 4.2	NS
NRM—1 year	3 ± 3	27 ± 6	0.02	20 ± 13	27 ± 11	NS
Relapse—3 years	28 ± 8	42 ± 6	0.01	40 ± 16	40 ± 13	NS
saGvHD—100 day	20 ± 11	26 ± 7	NS	20 ± 18	52 ± 16	0.07

• Note: Data are shown as mean ± standard error.
• Abbreviations: CYP1B1 Leu432Val polymorphism: wt (wildtype gene CC), mut (mutant genes CG and GG); NRM: non-relapse mortality; NS: not significant; OS: overall survival; p: log-rank test; saGvHD: severe acute graft-versus-host disease.

The sex differences observed in this study comparing wt and mut SNP in recipients were striking [1]. So far, sex differences in outcome after allogeneic HSCT have not been reported with the exception of increased rates of acute and chronic GvHD for female donors and male recipients [3-6], and Kim et al. [6] who also found that male recipients had a worse outcome than female recipients independent of donor sex, which had an effect in itself on overall survival. We also observed a lower 5-year OS in male patients (48% ± 4%) versus female patients (58% ± 4%), p = 0.026 (log-rank, n = 382), which in our case was primarily associated with mut R SNP in male patients with AD (see Figure 1 and Table 4 in our original paper [1]). T cells of female donors specific for minor histocompatibility antigens encoded by genes on chromosome Y may contribute to GvHD, graft rejection, and graft-versus-leukemia effects in hematological malignancies [3, 5, 6].

Interestingly, mutated CYP1B1 was more common in male (62%) than in female patients (48%) p = 0.006, unlike in donors [1]. However, in contrast to the recipient group (which has hematological cancer—and has, therefore, also been exposed to anticancer drugs and radiation), there was no sex difference in distribution between wt and mut SNP within the donor group. It could therefore be postulated that men with mut SNP have a higher risk of hematological cancer, or are more likely to relapse post induction and consolidation therapy (and thus become transplant candidates more often) than men with wt SNP.

In conclusion, if confirmed in a prospective study or an independent cohort, this finding on CYP1B1 may have an impact on overall survival and the selection of donor sex in male patients with advanced hematological disease: that is, male donor “preference” can be neglected in patients with mut SNP (contrary to common practice in allogeneic HSCT) and special emphasis should be placed on selecting a male donor in patients with wt SNP.