Impact of Pretransplant HTLV-1 Seropositivity on Hematopoietic Stem Cell Transplantation for the Diseases Other Than ATLL- an Analysis on Behalf of JSHCT Complication Working Group-
Authors: Nakano Nobuaki , Nakasone Hideki , Fuji Shigeo , Shinohara Akihito , Suzuki Ritsuro , Utsunomiya Atae , Eto Tetsuya , Sawayama Yasushi , Nakachi Sawako , Uchida Naoyuki , Fukuda Takahiro , Kanda Junya , Atsuta Yoshiko , Ogata Masao 
Published: October 2019

Abstract
Background
Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus which is known as the cause of adult T-cell leukemia/lymphoma (ATLL). Some reports indicated that HTLV-1 carriers were immunologically compromised host. Although there were several reports about the survival impact of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for ATLL, no large study concerning HSCT for the HTLV-1 carrier with the diseases other than ATLL has been reported. Japan is one of endemic countries of HTLV-1, and the prevalence of HTLV-1 infection was reported to be almost 1% of Japanese population. On behalf of the Japan Society for Hematopoietic Cell Transplantation (JSHCT) Complication Working Group, we here report the impact of HTLV-1 serological status on survival in those with HSCT for the diseases other than ATLL by using the Transplant Registry Unified Management Program (TRUMP) which is the nationwide survey database of the Japanese Data Center for Hematopoietic Cell Transplantation.
Patients and Method
There were 25840 patients (24400 adult and 1440 child), who had the information about the pretransplant serological status of HTLV-1, received their first HSCT between Jan 2007 and Dec 2015 in TRUMP database. We analyzed an overall survival (OS) and non-relapse mortality (NRM) after HSCT in relation to HTLV-1 serological status using Kaplan-Meir method, Gray's test. A Gray test for NRM calculated considering with disease related death as the competing risk. In multivariate analyses using Cox proportional hazard model for OS and Fine-Gray proportional hazards models for competing risk of NRM. And a p-value of less than 0.05 was considered as statistically significant. A statistical analysis was performed with 'EZR'.
Results
Median age of HTLV-1 carrier and non-carrier in adult patients were 57 years (17-76) and 53 years (16-88) and in pediatric patients were 11 years (0-15) and 8 years (0-15), respectively. The number of HTLV-1 carrier/non-carrier in adult patients in each disease were 80/7511 in AML, 133/6673 in malignant lymphoma, 34/3265 in plasma cell neoplasm, 30/2885 in ALL, 31/2178 in MDS, 8/446 in CML, 5/539 in aplastic anemia, and 11/570 in others, respectively. The number of HTLV-1 carrier/non-carrier in pediatric patients in each disease were 3/684 in ALL, 6/394 in AML, 2/170 in MDS, 2/76 in congenital metabolic disease, and 3/100 in others. The number of HTLV-1 carrier/non-carrier in adult patients who received allo-HSCT or auto-HSCT were 237/15777 and 95/8920, and in pediatric patients who received allo-HSCT was 16/1424, respectively. No HTLV-1 carrier child recipients who recieved auto-HSCT were identified in TRUMP database. There were no significant differences about stem cell sources, disease risk, and HCT-CI score before HSCT between HTLV-1 carriers and non-carriers. The OS rates at 3yr after allo-HSCT in adult and pediatric HTLV-1 carrier vs non-carrier were 40.7% vs. 50.2% (P=0.003) and 49.1% vs. 67.1% (P=0.318), and NRM rates at 1yr after allo-HSCT were 46.9% vs 23.6% (P=0.001) and 18.8% vs 11.7% (P=0.05), respectively. In multivariate analyses in terms of OS and NRM, HTLV-1 carrier was a significant prognostic factor in adult patients (HR 1.23, 95% CI 1.03-1.47, P‹0.001 for OS, and HR 1.27, 95% CI 1.05-1.61, P‹0.001 for NRM) and in pediatric patients (no statistical significance was seen on OS, and HR 2.58, 95% CI 1.17-5.70, P‹0.001 for NRM). The incidence of non-infectious NRM, such as pulmonary complications (IPS/DAH, ARDS), acute and chronic GVHD, MOF, and VOD/SOS was significantly higher in adult HTLV-1 carriers who received allo-HSCT when compared with that in HTLV-1 non-carriers. On the other hand, Infectious NRM was significantly higher incidence in child HTLV-1 carrier. With respect to disease related death, there were no differences between HTLV-1 carrier and non-carrier both in adult and pediatric patients. Among the adult patients who received auto-HSCT, there was no statistically significant difference in terms of OS, NRM, and disease related death between HTLV-1 carrier and non-carrier.
Conclusion
This is the first large study showing the survival impact of HTLV-1 serological status in patients with diseases other than ATLL who received HSCT. It demonstrated that HTLV-1 antibody-positivity was the poor prognostic factor in terms of OS and NRM after allo-HSCT in adult patients and NRM after allo-HSCT in pediatric patients.

Disclosures
Nakasone: Phizer: Honoraria; Novartis: Honoraria; Kyowa Hakko Kirin: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Suzuki:Kyowa-Hakko Kirin: Honoraria; Chugai Pharmaceutical: Honoraria; Mochida Pharmaceutical: Honoraria; Novartis: Honoraria; Shionogi: Honoraria; Takeda Pharmaceuticals: Honoraria; Meiji Seika Pharma: Honoraria; MSD: Research Funding; Ohtsuka: Honoraria; Sawai Pharmaceutical: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Gilead Sciences: Consultancy; MundiPharma: Consultancy; Jazz Pharmaceuticals: Consultancy.