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Total body irradiation (TBI) is used as a preparative regimen for hematopoietic stem cell transplantation (HSCT) and is highly efficacious but with an elevated risk of serious toxicity which are poorly understood. This analysis provides the largest cohort investigation of long-term complications and toxicity risk factors.

A total of 513 consecutive patients who were treated with total body irradiation (TBI) for HSCT were analyzed from 2008 to 2018. TBI was based on national and international guidelines (DGMP and ILROG) and applied in in bidaily 2Gy fractions. Patients were followed with serial clinical and imaging exams. Timepoint of toxicity (CTCAE version 5) was differentiated in acute (during primary hospitalization for HSCT), subacute (≤100 days following HSCT) and late (>100 days following HSCT).

Patients were in median 49.6 years old, in 62% male and underwent in 56% primary therapy (vs. relapse therapy in 44%). Median follow up was 48 months (range: 6 days to 13.6 years) in the overall cohort and of 70 months (range 369 days to 13.6 years) in the subcohort with at least one year of follow-up (n=369 patients). Acute leukemias (40%) and aggressive lymphomas (18%) were the most frequent indications for HSCT. Donors were matched related (27%) or unrelated (50%) in most cases. The most common total TBI dose was 8Gy (54%, dose range 2-12Gy). Five-year OS and EFS was 53% and 50%, respectively, and was depending on previous relapse before HSCT, previous irradiation, TBI dose and immunosuppression regimen. EFS stratified by TBI dose is shown in figure 1. Acute and subacute toxicity was dominated by gastrointestinal complications (65 and 51% of patients, respectively) while late toxicity was dominated by pulmonary complications (27% of patients) which led to death in 6% of all patients (mainly pulmonary infections in the setting of immunosuppression). Multiple independent risk factors were found that influenced organ-specific toxicity rates and timepoint of toxicity: Male sex, age, Karnofsky index, pre-exiting diseases of organ systems, diagnosis, previous irradiation, and TBI total dose. Secondary malignancies were observed in 6% of patients (1.2% hematologic and 4.8% solid malignancies, respectively) and influenced by previous irradiation and TBI dose. Hematologic or solid secondary malignancies were characteristically observed during the first two years or continuously during the follow-up period. For solid secondary malignancies, one-year and five-year secondary malignancy-free survival was 82% and 33%, respectively. For hematooncologic secondary malignancies, one-year and five-year secondary malignancy-free survival was 40% and 20%, respectively.

These data demonstrate robust efficacy and toxicity outcomes of HSCT including TBI. While gastrointestinal side effects dominate the acute and subacute phase, pulmonary sequelae are the most frequent and lethal complication in the late phase. Multiple risk factors were identified.