Would Bone Marrow be Associated with Superior Outcomes Compared with Peripheral Blood for Male Recipients with Female Donors in HLA-Matched Related Transplantation?
Authors: Nakasone Hideki , Kawamura Koji , Yakushijin Kimikazu , Shinohara Akihito , Kanamori Heiwa , Ohashi Kazuteru , Fukuda Takahiro , Uchida Naoyuki , Nakamae Hirohisa , Kanda Junya , Ichinohe Tatsuo , Atsuta Yoshiko , Inamoto Yoshihiro , Seo Sachiko , Kimura Fumihiko , Ogata Masao 
Published: October 2019

Abstract
【Background】
Sex-mismatched hematopoietic cell transplant (HCT), especially male recipients with female donors (FtoM) HCT, is known to be associated with an increased risk of graft-versus-host disease (GVHD) and non-relapse mortality (NRM). In addition, the usage of G-CSF-mobilized peripheral blood (PB) is known to be associated with an increased risk of chronic GVHD compared with bone marrow (BM). Therefore, an issue would be raised whether PB usage in FtoM HCT might deteriorate allo-responses, resulting in fatal complications. Thus, we hypothesized that BM could contribute to better outcomes than PB in FtoM HCT, through reducing NRM.
【Patients & Methods】
Using Japanese transplant registry database, we analyzed 864 patients (FtoM n=241, MtoF n=199, sex-matched n=424) with standard-risk diseases who received HCT from an HLA-matched related donor since 2013. A median of their age was 44 years (range: 16-72), and their diseases were AML in 400, ALL in 209, lymphomas in 139, and MDS/MPD in 116. The median follow-up duration of survivors was 609 days (range: 2-1332 days). The impact of PB vs. BM on transplant outcomes was separately assessed in FtoM, MtoF, and sex-matched HCT. In multivariate analyses, the Cox hazard model was performed, and the hazard ratio (HR) of PB usage was adjusted for age of patient and donor, sero-status of cytomegalovirus, conditioning types, diseases, GVHD prophylaxis, HCT-comorbidity index (HCT-CI), performance status, and the usage of total body irradiation. This study was approved by institutional review board of Jichi Medical University.
【Results】
The patient characteristics were not so different in age of patient and donor, diseases, conditioning regimens, and HCT-CI between the groups with PB and BM among FtoM, MtoF, and sex-matched HCT, respectively.
Overall survival (OS) at 2 years post HCT was significantly lower in patients with PB than those with BM in FtoM HCT [73% (95%CI: 60-82%) vs. 60% (95%CI: 51-68%), P=0.049], while no differences were observed in MtoF or sex-matched HCT (Figure 1). Multivariate analyses actually confirmed the adverse impact of PB in FtoM HCT alone [HR for OS 2.01 (95%CI: 1.07-3.76, P=0.03)], but not significantly in MtoF HCT [HR 1.80 (95%CI: 0.76-4.21, P-0.18] nor in sex-matched HCT [HR 0.88 (95%CI: 0.55-1.41, P=0.60].
NRM at 2 years post HCT was significantly higher in patients with PB than those with BM in FtoM HCT [23% (95%CI: 16-30%) vs. 11% (95%CI: 5-21%), P=0.04], while no significant impact of donor source was observed in the other HCT types (Figure 2). Multivariate analyses also confirmed the adverse impact of PB in FtoM HCT alone [HR 3.79 (95%CI: 1.31-11.0, P=0.014)].
The cumulative incidence of chronic GVHD was significantly associated with the PB groups in both FtoM [HR 2.02 (95%CI: 1.22-3.35), P=<0.01] and MtoF HCTs [HR 2.40 (95%CI: 1.24-4.61), P<0.01], but not significantly in sex-matched HCT [HR 1.45 (95% CI: 0.97-2.16), P=0.07].
Their relapse incidence was not different according to PB vs. BM in all HCTtypes.
Causes of death differed by sources in FtoM HCT (P=0.048). Of the 80 deaths in FtoM HCT, GVHD-related (21% vs. 0%) and organ failure (26% vs. 18%) was more frequently observed in the PB group compared with the BM group.
【Conclusion】
In conclusion, the usage of PB in FtoM HCT was associated with an increased risk of non-relapse mortality even in the early phase, resulting in inferior survival. GVHD-related death or fatal adverse complications were frequently observed in the PB group of FtoM HCT. On the other hand, the usage of PB did not seem to affect the incidence of fatal complications in MtoF and sex-matched HCT. Therefore, when we have to select female donors for male patients, BM would better be selected to improve their outcomes.

Disclosures
Nakasone: Phizer: Honoraria; Novartis: Honoraria; Kyowa Hakko Kirin: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Ichinohe:Janssen Pharmaceutical K.K.: Honoraria; Otsuka Pharmaceutical Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Mundipharma: Honoraria; Novartis.: Honoraria; JCR Pharmaceuticals: Honoraria; Celgene: Honoraria; Zenyaku Kogyo Co.: Research Funding; Takeda Pharmaceutical Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; Bristol-Myers Squibb: Honoraria; Alexion Pharmaceuticals: Honoraria; Taiho Pharmaceutical Co.: Research Funding; Astellas Pharma: Research Funding; Chugai Pharmaceutical Co.: Research Funding; CSL Behring: Research Funding; Eisai Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Pfizer: Research Funding; MSD: Research Funding; Nippon Shinyaku Co.: Research Funding.