Cumulative Incidence of Subsequent Malignancy after Allo-HCT with Myeloablative Chemotherapy Plus Low-Dose Total Body Irradiation Versus Myeloablative Chemotherapy Alone.

Abstract

<h3>Introduction</h3> Total body irradiation (TBI) has been described as a major risk factor for the development of subsequent malignancies (SMs) after allogeneic hematopoietic cell transplant (allo-HCT). However, a recent study found that lower doses (< 450cGy) of TBI used with non-myeloablative conditioning conferred no more risk than that attributed to treatment with myeloablative chemotherapy alone. It is not clear whether addition of low dose TBI to myeloablative chemotherapy protocols increases risk of SM. At our centre, in approximately 2004, 400 cGy TBI was added to our standard myeloablative fludarabine/busulfan regimen. We hypothesized that no significant difference in the cumulative incidence of SMs would be observed between the cohort of patients who received myeloablative chemotherapy (no TBI group) versus those who received the same plus 400cGy of TBI in 2 fractions (TBI group). <h3>Methods</h3> We identified 676 sequentially treated 1-year survivors who received a first allo-HCT between 1999 and 2014 from a provincial database. All patients but one (aplastic anemia) received HCT for hematological malignancies. The cumulative incidence of SMs in the TBI group (N=424) & no TBI group (N=252) were compared using a multivariate competing risk regression model. Death without SM was treated as a competing risk. Covariates included age at HCT, sex, moderate-severe cGVHD & stem cell source. Squamous and basal cell carcinomas of the skin, post-transplant lymphoproliferative disease, and relapse of primary malignancy were excluded. <h3>Results</h3> Median age at HCT was 47 (IQR 36-56). A total of 47 patients developed 54 SMs at a median of 5.7 years post HCT (IQR 1.2-12.9 years). At a median follow-up for surviving patients of 8.1 years (range 1.1-19.8 years), the cumulative incidence of SM was 7.0% (95% CI: 5.3-9.1%). Sites of malignancy were: gastrointestinal (N=11), genitourinary/gynecologic (N=10), lung (N=9), skin (N=7), prostate (N=5), breast (N=4), thyroid (N=3), oropharyngeal (N=3) and hematologic (N=2). TBI was not associated with increased risk of SMs when compared to the chemotherapy-alone regimen (figure 1, sHR 0.68, 95% CI 0.39-1.19, p=0.18), while older age at HCT (sHR 1.07, 95% CI 1.04-1.1, p<0.001) and a history of moderate-severe cGVHD (sHR 1.76, 95% CI 0.99-3.14, p=0.056) were. <h3>Conclusion</h3> Low dose TBI added to myeloablative chemotherapy does not appear to be associated with an increased risk of SMs when compared to myeloablative chemotherapy alone. These data may inform patient counselling and cancer screening practices for allo-HCT recipients that have been treated with myeloablative chemotherapy plus low dose TBI protocols.