Risks and Benefits of Sex-Mismatched Hematopoietic Cell Transplantation Differ By Conditioning Strategy

Background:

Sex-mismatched hematopoietic cell transplantation (HCT) is associated with increased graft-versus-host disease (GVHD) and inferior survival for almost every conditioning regimen studied to date. The increased risk is clearest for male recipients with female donors (F->M). We hypothesized that total lymphoid irradiation with anti-thymocyte globulin (TLI-ATG) could reduce adverse effects of sex-mismatched transplant without reducing graft-versus leukemia (GVL) effect.

Patients and methods:

We reviewed 1041 adult recipients between 2006 and 2013 at Stanford and Karolinska University Hospitals, and assessed impacts of sex-mismatch within each conditioning: TLI-ATG, other reduced-intensity conditioning (RIC) and myeloablative conditioning (MAC). 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:

Within the TLI-ATG group, F->M transplant did not associate with an increased incidence of acute or chronic GVHD nor an increase in non-relapse mortality (NRM). For the MAC group, F->M transplant was associated with increased chronic GVHD (HR 1.83, P<0.01) and NRM (HR 1.84, P=0.022). For the RIC group F->M transplant was associated with increased acute GVHD (HR 1.96, P<0.01) but there was no association with NRM. Within the TLI-ATG group, sex-mismatched transplant was significantly associated with reduced relapse (HR 0.64 in F->M and 0.59 in M->F, P<0.01 in each), while no impact of sex-mismatch on relapse was observed in the MAC or RIC groups (Fig 1). Finally, in the TLI-ATG group, sex-mismatched transplant was significantly associated with superior OS (HR 0.69 in F->M, P=0.037; HR 0.61 in M->F, P=0.014), while F->M transplant was significantly associated with inferior OS in the MAC group (HR 1.59, P=0.018) and no improvement in OS in the RIC group (HR 1.31, P=0.36) (Fig 2).

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. 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-antibodies 3m post-HCT was significantly associated with reduced relapse in F->M HCT with TLI-ATG [HR 0.29, P=0.039].

Conclusion:

We conclude that the benefits and risks of sex-mismatch differ according to conditioning intensity/strategy, and is the first reported evidence that sex-mismatched transplant might preferably be selected in TLI-ATG, while avoided in MAC transplantation.