Abstract
Background: Secondary solid cancer is one of the most important late complications among long-term survivors after allogeneic hematopoietic stem cell transplantation (HSCT). Although age at HSCT, total body irradiation (TBI) as part of the conditioning regimens and chronic graft-versus-host diseases (GVHD) have been already reported as risk factors for secondary solid cancers, the impact of stem cell source has not been fully evaluated.
Patients and Methods: We reviewed the medical records of Japanese adult patients who underwent allogeneic HSCT for the first time at the Toranomon Hospital between 1993 and 2015. Cumulative incidences of secondary solid cancers or GVHD were estimated, with death without developing secondary cancers or GVHD treated as a competing risk. The date of the first cancer in patients developing multiple metachronous secondary cancers was used in calculations of cumulative incidence. A step-wise multivariate approach was used to identify risk factors for secondary cancers. The variables considered were age at HSCT, sex, primary diseases, donor-type, conditioning regimens, TBI as part of the conditioning, grade II-IV acute GVHD and extensive chronic GVHD. Acute GVHD and chronic GVHD were considered as time-dependent covariates.
Results: A total of 1374 patients were included in the analysis, with the median age of 54 years (16-82). Approximately two-thirds (64%) of the patients were male and were diagnosed with Acute leukemia/Myelodysplastic syndrome, respectively. Eight-hundred twelve (59.1%) patients underwent unrelated cord blood transplantation (UCBT), 313 (22.8%) underwent unrelated bone marrow transplantation (UBMT) and the remaining 249 (18.1%) underwent transplantation from a related donor. Half of the patients received reduced-intensity conditioning, and about 60% had any dose of total body irradiation. Cumulative incidence of grade II-IV acute GVHD at day 100 and extensive chronic GVHD at 2 years were 47.7% and 22.4%, respectively.
Thirty-two patients developed secondary cancers at a median of 4.1 years (1.1months-14.8 years), four of who had two (2) or three (2) cancers in different organs. Overall, 38 cancers were identified. The most common sites of cancers were esophagus (9) and stomach (9), followed by oral (6), colon (3), skin (2), lung (2) and bladder (2). Cumulative incidence of secondary cancers at 5, 10, and 15 years after transplantation were 2.4%, 4.6%, and 10.8%, respectively. Compared with UBMT recipients, the risk of secondary cancers tended to be lower in transplant recipients from a related donor (HR 0.41, P=0.075) and was significantly lower in UCBT recipients (HR 0.45, P=0.035, Figure). Multivariate analysis revealed age ≥ 40 years (HR 9.3, P=0.027) and extensive chronic GVHD (HR 4.9, P<0.001) were identified as significant risk factors for secondary cancers.
We also compared the incidence and risk factors for secondary cancers between UCBT (671) and UBMT (217) recipients who aged ≥ 40 years and underwent transplantation after 2002, because UCBT was introduced in 2002 at our hospital and only one case of secondary cancer was identified in transplant recipients from a related donor thereafter. The median age of UCBT recipients was higher than that of UBMT recipients (60 years vs. 56 years, P<0.001). Cumulative incidence of secondary cancers was 9.6%, which was significantly lower after UCBT compared to UBMT (5.2% vs. 18.4%, P=0.014). Extensive chronic GVHD was identified as a significant risk factor for secondary cancers (HR 3.38, P=0.04). Cumulative incidence of extensive chronic GVHD at 2 years was significantly lower after UCBT than after UBMT (12.3% vs. 39.1%, P<0.001), and extensive chronic GVHD had no significant impact on the risk of secondary cancers after UCBT (HR 2.8, P=0.134), in contrast with a strong association between extensive chronic GVHD and the development of secondary cancers after UBMT (HR 5.6, P=0.025).
Conclusions: Endscopic screening is important as part of lifelong follow-up, especially for patients who are aged 40 and older or have extensive chronic GVHD. Despite the limitation of relatively shorter follow-up, the use of cord blood may have potential for reducing the risk of secondary solid cancers, probably because of lower frequency of extensive chronic GVHD.
No relevant conflicts of interest to declare.
