Influence Of Acute and Chronic Graft-Versus-Host Disease On Outcome After Allogeneic Hematopoietic Stem Cell Transplantation For Chronic Myelomonocytic Leukemia
Authors: Itonaga Hidehiro , Iwanaga Masako , Aoki Kazunari , Aoki Jun , Ishiyama Ken , Kobayashi Takeshi , Sakura Toru , Fukuda Takahiro , Yujiri Toshiaki , Hirokawa Makoto , Morishima Yasuo , Nagamura-Inoue Tokiko , Atsuta Yoshiko , Ishikawa Takayuki , Miyazaki Yasushi 
Published: October 2019

Abstract

Introduction
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a therapeutic option for chronic myelomonocytic leukemia (CMML), with the possibility that the graft-versus-CMML (GvL) effect has an important role for survival after allo-HSCT. In a clinical situation, GvL effect was assumed to closely correlate with graft-versus-host disease (GVHD). This study aimed to evaluate the influence of acute and chronic GVHD on long-term outcomes for patients with CMML that were treated with allo-HSCT.

Patients and Methods
Data were obtained from the Transplant Registry Unified Management Program, which includes three data sources of the Japan Society for Hematopoietic Cell Transplantation, the Japan Marrow Donor Program, and the Japan Cord Blood Bank Network. There was a total of 177 records of CMML patients who were 16 years of age or older and had received allo-HSCT between January 1, 1987 and December 31, 2010. Of those, 141 patients had received allo-HSCT without in-vivo or ex-vivo T-cell depletion, and survived with neutrophil engraftment, which were subjects for this analysis. The probability of overall survival (OS) was estimated by Kaplan-Meier method. Disease-associated mortality was estimated with the use of cumulative incidence curves to accommodate the competing events. Semi-landmark plots were used to illustrate the effects of GVHD on OS and cumulative incidence of disease-associated mortality using the median days of the occurrence of GVHD. Univariate and multivariate Cox proportional hazards regression models were used to evaluate variables potentially affecting OS. Fine and Gray proportional hazards models were used to evaluate variables potentially affecting disease-associated mortality. In these hazard models, the occurrence of GVHD was treated as time-varying covariate.

Result
The median age of recipients was 49 years old. There were 68 transplants from HLA-matched related donor, 10 from HLA-mismatched related donor, 53 from unrelated bone marrow donor, and 10 using unrelated cord blood. One hundred one and 40 patients received myeloabrative and reduced intensity conditioning, respectively. Median survival times after allo-HSCT was 2.8 years. Estimated OS and cumulative disease-associated mortality at 3 years after allo-HSCT were 47.3% (95% confidential interval, 38.5-55.7) and 18.2% (12.2-25.1), respectively. Acute GVHD of grades 1 and 2-4 occurred in 25 and 62 patients, respectively. The median onset of acute GVHD of any grade after allo-HSCT was 22 days (range, 6-80). The analysis using semi-landmark plots revealed that the development of grade 1 acute GVHD was significantly associated with a better OS (p=0.015) and a lower disease-associated mortality (p=0.012) compared with the absence of acute GVHD. However, in multivariate analysis, the emergence of grade 1 acute GVHD was not associated with OS (Hazard ratio (HR) [95% confidential interval], 2.12 [0.69-6.51]; P=0.189) and disease-associated mortality (HR, 1.71 [0.60-4.86]; p=0.31). With a median day of chronic GVHD occurrence after allo-HSCT of 138 (range, 57-669), limited and extensive chronic GVHDs occurred in 17 and 39 patients, respectively. The analysis using semi-landmark plots revealed that the development of limited chronic GVHD related to better OS (p<0.001) and lower disease-associated mortality (p<0.001) compared with the absence and extensive chronic GVHD. In multivariate analysis, OS tended to be better for patients with limited chronic GVHD than the absence of chronic GVHD (HR, 3.86 [0.83-17.9]; P=0.085), while the absence of chronic GVHD possibly affected with the higher disease-associated mortality compared with the emergence of limited chronic GVHD, with a borderline statistical significance (HR, 3.92 [0.91-16.9]; P=0.067).

Conclusion
Our results showed the efficacy of allo-HSCT for patients with CMML and suggested an important role of GvL linked to chronic GVHD on the better outcome of the patients after receiving allo-HSCT.

Disclosures:
Fukuda: the Japanese Ministry of Health, Labour, and Welfare: Research Funding.