Subsequent Cancers in Patients Affected with Moderate or Severe Chronic Graft-versus-Host Disease

Abstract

Subsequent cancer (SC) is a significant cause of morbidity and mortality in long-term survivors after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Chronic graft-versus-host disease (cGVHD) and treatment-related immunosuppression have been recognized as risk factors for SC. This study sought to investigate the incidence and risk factors for SC in patients with established cGVHD, assessed separately for onset of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)-categorized into nonmelanoma skin cancer (NMSC)-and all cancers other than NMSC. Two hundred and four patients were enrolled in the prospective cross-sectional cGVHD Natural History Study and underwent comprehensive clinical evaluation. Patients were followed-up with an annual survey. The cumulative incidences of NMSC and cancers other than NMSC with competing risks were estimated separately, and transplantation- and cGVHD-related factors were assessed for association with outcomes using Gray's test and multivariable Cox models. The time period for all analyses began at 2 years postevaluation to restrict analyses to patients presumed to not have had SC present at evaluation. Nineteen patients were diagnosed with NMSC and 19 were diagnosed with cancers other than NMSC, with 10-year cumulative incidences of 15.5% (95% confidence interval, 9.0% to 27.6%) and 13.8% (95% CI, 8.2% to 20.8%), respectively. Age at transplantation (hazard ratio [HR], 1.94; 95% CI, 1.23 to 3.06) and higher C-reactive protein level at evaluation (HR, 9.49; 95% CI, 1.26 to 71.58) were jointly associated with NMSC, and gastrointestinal cGVHD at evaluation (HR, 0.26; 95% CI, 0.09 to 0.78) was associated with reduced risk of NMSC. T cell depletion at transplantation (HR, 3.09; 95% CI, 1.17 to 8.20), lymphoma as an indication for transplantation (HR, 3.96; 95% CI, 1.56 to 10.05), and oral cGVHD severity at evaluation (HR, 4.36; 95% CI, 1.52 to 12.46) were jointly associated with cancers other than NMSC. This study estimates the incidence of SC in a population of allo-HSCT recipients with severe cGVHD and identifies correlations with the subsequent development of SC. These factors seem to differ between NMSC and cancers other than NMSC. Further longitudinal investigations accounting for dynamic and cumulative processes are needed to improve our understanding and management of SC.

Keywords: Allogeneic hematopoietic stem cell transplantation; Chronic geaft-versus-host disease; Late effects; Subsequent cancer.

Figure 1:

A Cumulative incidence of NMSC competing with death, relapse, or cancers other than NMSC; B Cumulative incidence of NMSC competing with death, relapse, or cancers other than NMSC stratified by age at transplant (Q1: 25, Q2: 43, Q3: 51); C Cumulative incidence of NMSC competing with death, relapse, or cancers other than NMSC stratified by C-reactive protein at evaluation (Q1: 0.55 mg/L)–p-value adjusted for multiple implicit comparisons conducted following combining groups; D Cumulative incidence of NMSC competing with death, relapse, or cancers other than NMSC stratified by gastrointestinal cGVHD at evaluation. Notes: Cumulative incidence estimates in panel A are with respect to initiation of follow-up at two years post-evaluation; Vertical axes have different scales. Abbreviations: CRP–C-reactive protein, GI – gastrointestinal, Qrt–Quartile

Figure 2:

A Cumulative incidence of cancers other than NMSC competing with death or relapse; B Cumulative incidence of cancers other than NMSC competing with death or relapse stratified by receipt of T-cell depletion at transplant; C Cumulative incidence of cancers other than NMSC competing with death or relapse stratified by transplant indication; D Cumulative incidence of cancers other than NMSC competing with death or relapse stratified by NIH oral score at evaluation. Note: cumulative incidence estimates in panel A are with respect to initiation of follow-up at two years post-evaluation. Notes: Cumulative incidence estimates in panel A are with respect to initiation of follow-up at two years post-evaluation; Vertical axes have different scales.