Secondary Cancer after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Tanaka Yosuke , Kurosawa Saiko , Tajima Kinuko , Inamoto Yoshihiro , Ito Reiko , Tanaka Takashi , Inoue Yoshitaka , Ozawa Takayuki , Kawajiri Akihisa , Onishi Akio , Okinaka Keiji , Fuji Shigeo , Kim Sung-Won , Tanosaki Ryuji , Yamashita Takuya , Fukuda Takahiro 
Published: October 2019

Abstract

Introduction
Secondary cancer is one of the life-threatening late complications among long-term survivors after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several studies have reported that survivors of allo-HSCT had a 2-3-fold increased risk of developing new malignancies compared to the general population, although results were inconsistent among the studies in types, incidence, and risk factors of secondary cancers. We conducted a retrospective single-center study, in order to assess the incidence, risks, and risk factors of developing secondary cancers.
Methods
We retrospectively evaluated data on patients who received a first allo-HSCT for hematological disorders between 1982 and 2012. Cumulative incidences of secondary cancers were estimated, with death without developing secondary cancers treated as a competing risk. Standardized incidence ratios (SIRs) of secondary cancers were calculated using the incident rate in the general population. Multivariate analyses were used to identify risk factors of developing secondary cancers. Variables considered in multivariate analyses were patient age at HSCT (<50, 50 or older), patient gender (male, female), donor type (related, unrelated bone marrow, or unrelated cord blood), disease type (acute leukemia, malignant lymphoma/adult T-cell leukemia, chronic myelogenous leukemia [CML]/myeloproliferative disease [MPD], or others), conditioning regimens (myeloablative with total body irradiation [TBI], myeloablative without TBI, or reduced intensity), graft-versus-host disease (GVHD) prophylaxis (cyclosporine-based or tacrolimus-based), and the presence or absence of chronic GVHD. Kaplan-Meier method was used to calculate survival probability among patients who developed secondary cancers.
Results
A total of 1060 patients were included in the analysis, with the median age of 46 years (1-69) and the median follow-up of 4.2 years. 60% of patients were males. 43% of patients had peripheral blood transplantation from a related donor, 22% had bone marrow transplantation from a related donor, 31% had bone marrow transplantation from an unrelated donor, and the remaining 4% had others including cord blood transplantation or haplo-identical transplantation. Approximately half (49%) of the patients received reduced-intensity conditioning, and in those who received myeloablative regimens, two-thirds had total body irradiation (>10Gy). Overall, 42 secondary cancers were identified: the sites of cancers with >2 patients were esophagus (8), stomach (5), colon (4), oral (4), lung (4) and breast (3). The cumulative incidence rate of developing any secondary cancers at 5, 10, and 15 years after allo-HSCT were 2.5% (95% CI 1.6-3.8%), 5.9% (95% CI 4.1-8.3%), and 8.5% (95% CI 5.6-12.1%), respectively. Allo-HSCT recipients had a 3.4-fold higher risk of developing cancers compared with the general population. SIR was particularly higher for the oral (SIR = 15.3) and esophagus (SIR = 23.4). The development of oral or esophageal cancer was detected at ≥3 years after allo-HSCT. Multivariate analysis showed that patient age ≥50 years, CML/MPD, and chronic GVHD were associated with onset of secondary cancers. As for the site of chronic GVHD, patients who developed oral or intestinal GVHD had a higher incidence of secondary cancers compared with those who did not. The overall survival rate was 62% at 3 years after the diagnosis of a secondary cancer. In 18 of the 42 patients who developed secondary cancers, cancers were diagnosed by routine medical checkups or follow-up screenings at outpatient clinic.
Conclusions
Recipients of allo-HSCT have a significantly higher risk of developing secondary cancers than the general population. SIRs were especially higher in oral and esophageal cancers. Lifelong screening is important for patients who have risk factors such as older age and oral or intestinal chronic GVHD.

Disclosures
No relevant conflicts of interest to declare.