Prognostic Impact of Graft-Versus-Host Disease on Allogeneic Transplantation for CMML Focusing on Conditioning Intensity

Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is only a therapeutic option to provide a curative outcome for chronic myelomonocytic leukemia (CMML). We have previously demonstrated that the development of graft-versus-host disease (GVHD) correlated with better survival, in which the most of patients received myeloablative conditioning (MAC) regimen (1987-2010). Due to the increased utilization of reduced-intensity conditioning (RIC) regimen for CMML, we updated the database (2001-2020) and conducted a nationwide retrospective study to evaluate whether acute (aGVHD) and chronic GVHD (cGVHD) improve outcomes in CMML patients with special emphasis on the effects of the conditioning intensity.

Methods

This study included patients (i) who were diagnosed as de novo CMML, (ii) who were 16 years or older at HSCT, and (iii) who received their first allo-HSCT between 2001 and 2020, from the Transplant Registry Unified Management Program of the Japan Society for Hematopoietic Cell Transplantation. Semi-landmark plots were used to illustrate the effects of GVHD on survival using the median days of the occurrence of GVHD. Cox proportional hazards regression models were used to evaluate variables potentially affecting overall survival (OS). Fine and Gray proportional hazards models were used to evaluate variables potentially affecting cumulative incidences of relapse (CIR), non-relapse mortality (NRM), and GVHD, using cumulative incidence curves to accommodate competing events. In the hazard models, the onset date of aGVHD or cGVHD was treated as a time-dependent covariate.

Results

In a total of 314 patients, 174 and 140 patients received MAC (MAC group) and RIC regimens (RIC group), respectively. The median age in the MAC group (53 years, range 16-71) was younger than that in the RIC group (60 years, range 26-75) (P<0.001). The 3-year OS rate was 47.7% and 35.2%; the 3-year CIR was 30.4% and 32.7% the 3-year NRM was 30.3% and 40.5%; the incidence of aGVHD at day 100 was 58.4% and 47.8%; and the 3-year incidence of cGVHD was 47.8% and 39.3% in the MAC and RIC groups, respectively. No significant difference in these outcomes was observed between both groups.

In the MAC group, the semi-landmark analysis showed that the development of any grade aGVHD has no impact on OS and CIR. The development of limited cGVHD correlated with better OS (P=0.022), and that of extensive cGVHD correlated with lower CIR than the absence of cGVHD (P=0.034). In the multivariate analysis, the development of any grade aGVHD was not associated with OS. The development of limited cGVHD correlated with better OS (Hazard ratio (HR) [95% confidential interval], 0.34 [0.14-0.81]; P=0.015), and that of extensive cGVHD correlated with better OS (HR, 0.44 [0.21-0.91]; P=0.026) and lower CIR (HR, 0.28 [0.08-0.94]; P=0.040) when compared to the absence of cGVHD.

In the RIC group, the semi-landmark analysis revealed that the development of grade I-II aGVHD showed better OS (P=0.003) and lower CIR (P=0.033) than the absence of aGVHD. The development of any severity cGVHD did not have any impact on OS, CIR, and NRM. In the multivariate analysis, the development of grade I-II aGVHD was associated with better OS (HR, 0.39 [0.20-0.76]; P=0.005) and lower CIR (HR, 0.30 [0.13-0.70]; P=0.006) than the absence of aGVHD, and that of extensive cGVHD correlated with better OS (HR, 0.44 [0.20-0.96]; P=0.039) than the absence of cGVHD.

Conclusion

In the regard to the improved OS and CIR, the development of extensive cGVHD confers a beneficial impact in the MAC group, while the development of grade I-II aGVHD showed an advantage in the RIC group. These results suggested a difference between type of GVHD and survival benefit with conditioning intensity in CMML patients.

Miyazaki:Eizai: Honoraria; Daiichi-Sankyo: Honoraria; Takeda: Honoraria; Janssen Pharmaceutical: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Otsuka Pharmaceutical: Honoraria; AbbVie: Honoraria; Kyowa-Kirin: Honoraria; Sumitomo Pharma: Honoraria; Chugai: Honoraria. Uchida:Takeda Pharmaceutical Co.: Honoraria; Astellas Pharma Inc.: Consultancy; Nippon Shinyaku Co.: Honoraria; Novartis Pharma Co.: Honoraria; Takeda Pharmaceutical Co.: Consultancy; Chugai Pharmaceutical Co.: Honoraria; Chugai Pharmaceutical Co.: Research Funding; Fuji Pharma Co.: Research Funding; Sumitomo Pharma Co.: Research Funding; JCR Pharmaceuticals Co.: Research Funding; CSL Behring: Honoraria; MSD (Merck & Co. Inc.): Honoraria; Asahi Kasei Pharma Co.: Honoraria; Astellas Pharma Inc.: Honoraria; AstraZeneca: Honoraria; AbbVie GK: Honoraria; Otsuka Pharmaceutical Co.: Honoraria; Kyowa Kirin Co.: Honoraria; Nippon Boehringer Ingelheim Co.: Research Funding; SymBio Pharmaceuticals: Honoraria; Daiichi Sankyo Co.: Honoraria. Yoshimitsu:Chugai Pharmaceutical: Honoraria; Nippon Kayaku Co., Ltd.: Honoraria; Ono Pharmaceutical: Honoraria; Takeda: Honoraria; PharmaEssentia Corp.: Honoraria; Kissei: Honoraria; Daiichi Sankyo: Honoraria; Genmab: Honoraria; Meiji Seika Pharma Co., Ltd: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb Company: Honoraria; Asteras: Honoraria; Novartis: Honoraria. Kanda:Asahi-kasei, MSD, Novartis, Pfizer, Sanofi, Chugai, Astellas, Kyowa-Kirin: Honoraria; Chugai, Kyowa-kirin, Asahi-kasei, Otsuka: Research Funding. Atsuta:Otsuka Pharmaceutical Co., Ltd: Speakers Bureau; CHUGAI PHARMACEUTICAL CO., LTD.: Speakers Bureau; Novartis Pharma KK: Speakers Bureau; Meiji Seika Pharma Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; JCR Pharmaceuticals Co., Ltd.: Consultancy.