Risks and Benefits of Sex-Mismatched Hematopoietic Cell Transplantation Differ By Conditioning Intensity
Authors: Nakasone Hideki , Remberger Mats , Tian Lu , Brodin Petter , Sahaf Bita , Wu Fang , Lowsky Robert , Mattsson Jonas , Negrin Robert S. , Miklos David B. , Meyer Everett 
Published: November 2019

Abstract
Backgrounds:
Sex-mismatched hematopoietic cell transplant (HCT), especially HCT of male recipients with female donors (F->M) is known to be associated with a higher incidence of graft-versus-host disease (GVHD) and inferior survival. Total lymphoid irradiation with anti-thymocyte globulin (TLI-ATG) has been reported to reduce GVHD incidences and non-relapse mortality (NRM). We hypothesized that TLI-ATG could reduce adverse effects of sex-mismatched HCT without reducing graft-versus leukemia/lymphoma (GVL) effect.
Methods:
We reviewed clinical charts of 1041 adult recipients who received peripheral blood stem cell transplant between 2006 and 2013 at Stanford University (n=749) and Karolinska University Hospital (n=292). Primary diseases included acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), lymphoma, chronic lymphocytic leukemia (CLL) and others. Our study excluded indications for which TLI-ATG is not used such as acute lymphoblastic leukemia. Haplo-identical HCT and recipients who received GVHD prophylaxis other than cyclosporine and tacrolimus were also excluded. Impacts of sex-mismatch on clinical outcomes were separately assessed in TLI-ATG (n=437), reduced-intensity conditioning (RIC, n=266), and myeloablative conditioning (MAC, n=345). We also measured allo-antibodies (HY-Ab) against 5 HY-antigens encoded on the Y-chromosome (DBY, UTY, ZFY, EIF1AY, and RPS4Y) at 3 months (3m) post F->M HCT in the Stanford cohort.
Results:
F->M HCT was significantly associated with an increased risk of acute GVHD grade 2-4 in the RIC group (HR 1.96, P<0.01) and an increased risk of chronic GVHD in the MAC group (HR 1.83, P<0.01), while no impact of sex-mismatch on GVHD was observed in the TLI-ATG group.
F->M HCT was also associated with an increased risk of NRM only in the MAC group (HR 1.84, P=0.022), while there was no difference in the TLI-ATG or RIC group.
In the TLI-ATG group, relapse incidences of sex-mismatched HCT at 2 years post-HCT (40% in F->M HCT and 33 % in M->F HCT) were significantly lower than that of sex-matched HCT (52%, P<0.01, Fig1). Multivariate analyses revealed that sex-mismatch was significantly associated with reduced relapse in the TLI-ATG group (HR 0.64 in F->M and 0.59 in M->F, P<0.01 in each), while no difference was observed in the RIC or MAC group. The GVL benefit of sex-mismatch in TLI-ATG was observed in AML and lymphoma patients other than CLL. In MDS and CLL patients, the GVL benefit by sex-mismatch was not observed.
We found that the overall survival (OS) of sex-mismatch recipients (69% in F->M and 70% in M->F HCT at 2 years post-HCT) was higher than that of sex-matched HCT (56%, P<0.01, Fig 1) in the TLI-ATG group. In contrast, for MAC recipients, OS of F->M HCT (49%) was significantly inferior to those of sex-matched HCT (60%) and M->F HCT (58%, P=0.01). Multivariate analyses confirmed that sex-mismatch was significantly associated with superior OS in the TLI-ATG group (HR 0.69 in F->M, P=0.037; HR 0.61 in M->F, P=0.014), while F->M HCT was significantly associated with inferior OS in the MAC group (HR 1.59, P=0.018).
In the TLI-ATG group, the benefit of sex-mismatched HCT on OS seems due to the reduced relapse rate. We previously reported HY-Ab response post-HCT was associated with chronic GVHD as a representative of allo-Ab response (Nakasone et al. ASH 2013). We then hypothesized that HY-Ab response 3m post-HCT could predict reduced relapse in F->M HCT with TLI-ATG. Excluding patients with MDS and CLL because of the absence of GVL benefit by sex-mismatch in TLI-ATG (above), relapse incidence at 2 years post-HCT was higher in the recipients who had no HY-Ab response at 3m post-HCT vs. those who did (49% vs. 26%, P=0.037, Fig 2). Multivariate analysis corroberated that the detection of HY-Ab 3m post-HCT was significantly associated with reduced relapse in F->M HCT with TLI-ATG (HR 0.29, P=0.039). On the other hand, in the MAC group, HY-Ab 3m post-HCT was not significantly associated with reduced relapse.
Conclusion:
Benefits and risks of sex-mismatch differ according to conditioning intensity. Recipients of TLI-ATG conditioning preferentially benefit from sex-mismatched HCT with significantly reduced relapse rates and improved OS. HY-Ab 3m post-HCT as a representative of allo-Ab demonstrated the association with reduced relapse in the TLI-ATG group. We believe that sex-mismatched HCT should be selected in TLI-ATG, while F->M HCT should be avoided in MAC.
Figure 1 Figure 1.
Figure 2 Figure 2.

Disclosures
No relevant conflicts of interest to declare.