Overall Survival in Male Patients With Advanced Hematological Disease (Mostly Acute Leukemia) Is Influenced by <scp><i>CYP1B1</i> C432G</scp> Polymorphism and Donor Sex in Allogeneic Stem Cell Transplantation
Authors: Norbert Stute, Michael Koldehoff
Journal: American Journal of Hematology (2024)

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. 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. 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. N.S. was responsible for the analysis of data, interpretation of results, and literature research. He performed the statistical analyses, created tables and figures, and wrote the manuscript. M.K. was responsible for the design of the study and conduct of the research. He obtained funds, designed the lab protocol, supervised experiments, and extracted and collected both clinical and lab data. He also revised and edited the manuscript. Both authors approved the final version of the manuscript. We thank Christiane Schary, Melanie Kroll, Silke Gottwald, and Ines Riepenhoff (all Essen, Germany) for their excellent technical assistance with PCR analyses. We also wish to thank patients and donors who participated in this study, as well as our colleagues, and the entire medical team at the BMT Center in Essen, especially Prof. Dr. Ahmet H. Elmaagacli. The EBMT statistics course in Leiden 2018 was very beneficial for implementing R. As a native English speaker Rachael Mellor assisted with grammar. This study was conducted in accordance with the amended Declaration of Helsinki. All aspects of this study were approved by the Institutional Review Board on Medical Ethics at the University Hospital of Essen (BO 06-3057), and all patients and donors gave their written informed consent. The authors declare no conflicts of interest. The data supporting the findings of this study are available upon reasonable request from the corresponding author.