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O. Moser et al.
for SMN after NHL compared to the normal population in patients diagnosed before the age of 18 years with signif- icantly higher risks for breast cancer and acute non-lym- phoid leukemia in a cohort of 1,150 patients treated between 1973 and 2002.2 Another SEER analysis in a cohort of 1,832 5-year survivors of childhood NHL under 15 years of age at initial diagnosis reported SIR of 3.3 for SMN.4 Focusing on 4,310 NHL survivors treated with chemotherapy only, the CCSS-group reported a lower SIR of 2.4 for SMN occurring ≥5 years from initial diagnosis without non-melanoma skin cancers.5 The evaluation of late outcomes in a cohort of 200 childhood NHL patients who had survived for ≥10-years in the St Jude Lifetime Cohort Study revealed SIR of 6.3 for SMN, with none occurring in individuals not irradiated.12 We observed a higher SIR of 19.8 (without basal-cell carcinoma), which is similar to the SIR after acute lymphoblastic leukemia reported by the GCCR.6 Different inclusion criteria of patients regarding the age at initial diagnosis, varying restriction of the latency period to SMN-development, exclusion or inclusion of some SMN types (e.g., lym- phoma), and possibly differences in the treatment regimen may influence variations in the SIR estimates. Younger age at initial diagnosis (<15 years), no restriction of latency period to SMN-development, inclusion of patients with known CPC, and inclusion of second lymphoid malignan- cies explain a higher SIR in our cohort of patients treated by contemporary NHL-protocols with prophylactic brain irradiation only in LBL-patients. We cannot exclude that variations of the estimated cancer incidence in the control population might interfere regarding the different SIR-esti- mates as well.
Identified risk factors for SMN development in the pub- lished studies were female sex,9 previous radiothera- py,1,2,8,9,12 and use of epipodophyllotoxins (for development of sAML/MDS).2,10 Cumulative incidence of SMN in our study was significantly higher in patients with LBL receiv- ing ALL-type therapy compared to patients with other NHL-entities receiving B-NHL-type therapy, mainly attributable to the high incidence of sAML/MDS and car- cinomas in LBL-patients. In contrast to Leung et al.10 and Inskip et al.2 we could not explain the occurrence of AML/MDS after LBL by excess use of epipodophyllotox- ins, as these were not part of the BFM-ALL-type treatment regimen. The anthracycline doses of 240 mg/m2 doxoru- bicin-equivalent received by most LBL-patients could be potentially associated with the induction of AML/MDS. However, only four of 21 observed AML showed MLL- rearrangements characteristic for topoisomerase-II inhibitors-induced AML.27,28 The majority of AML/MDS developed in patients with advanced stage T-LBL. An increased risk of AML was reported in pediatric patients after ALL with T-cell phenotype, too.29 Single reports on lineage switch in T-ALL relapsing as AML30 suggest a com- mon origin of precursor T and myeloid cells. Our analysis of NHL-patients supports the above observations towards a possible common underlying mechanism predisposing some patients with T-cell precursor neoplasm to the development of AML/MDS.
In an analysis of late outcomes after treatment in 570 children with B-NHL11 who survived ≥5 years from initial diagnosis, none of the 126 children treated with the con- temporary “Lymphome Malin de Burkitt (LMB) therapy” between 1987 and 1999 without radiotherapy developed SMN. Patients treated with non-LMB protocols, including
radiotherapy, had a SMN incidence rate of 2.2 per 1,000 person-years (5,871 total person-years).11 The inclusion of second lymphoid malignancies in our cohort which accounted for 37.8% of all SMN after B-NHL and the restriction of the reported SMN to ≥5-year survivors in the earlier study11 can explain the higher risk estimate for patients after B-NHL type therapy in our analysis of 3.9%.
The most frequent SMN after NHL in our as well as other analyses were solid tumors, the largest group con- sisting of carcinomas. Compared to the hematologic SMN, the cumulative incidence estimates for solid tumors do not show a plateau after 20 years which is in line with the observation of higher estimates in the CCSS studies with longer follow-up.
Several studies demonstrated a relationship between radiotherapy and solid SMN as exemplified by the occur- rence of CNS-tumors after radiotherapy for a primary CNS-malignancy or after cranial radiotherapy for ALL.31,32 The latter was also observed in our study. In contrast to the findings of others,1,2,8,9,12 radiotherapy was not associat- ed with development of SMN outside the CNS in our study. This can be explained by the omission of local radiotherapy early in the BFM-studies, and consecutively, very low numbers of patients exposed to radiotherapy outside the CNS in our cohort (38 of the 3,590 patients), precluding the detection of a significant impact on SMN- development in the radiation field outside the CNS.
Several patterns noticed in our cohort suggest the possi- ble existence of unknown familial cancer syndromes pre- disposing patients to NHL and solid neoplasia.33 Unlike previous reports1-10 we encountered an unusual high num- ber of gastrointestinal tract-carcinomas, most of them occured after T-LBL. Interestingly, SIR of 67.3 for develop- ment of SMN of digestive tract after childhood NHL was also reported by Erhardt et al.12 In three patients with gas- trointestinal tract-carcinomas in our cohort a constitution- al mismatch repair deficiency (CMMRD)34 was diagnosed (Table 4). Nine patients developed >2 malignancies, in six of them a CPC was diagnosed, suggesting the presence of more, as yet undiscovered CPC. An European Inter-Group for Childhood Non-Hodgkin Lymphoma survey and i- BFM-survey revealed a 10-year cumulative incidence of SMN of 24±5% among 151 children with CPC and NHL.35 An increased cancer risk (SIR 1.5) of siblings of patients with SMN after childhood cancer also support the theory of familial susceptibility for cancer development.3 Due to of the retrospective character of our study, a detailed fam- ily history of cancer burden can not be obtained or further genetic investigations cannot be easily performed. Further studies are needed to address this issue.
Skin cancer as SMN after childhood cancer has been mostly associated with radiotherapy.36 Among the nine basal-cell carcinomas and four melanomas in our cohort, however, only six had received radiotherapy. Astonishingly, four basal-cell carcinomas developed after ALCL (without radiotherapy), an association which has not been observed so far.
Unexpectedly, in our analysis the third most frequent SMN after a childhood NHL was another lymphoid malig- nancy (Online Supplementary Table S3). A high incidence of second lymphoid malignancy after NHL has not been reported so far.
Most of the second lymphoid malignancies (70%) occurred after mature B-NHL. Primary and secondary immune deficiencies, as well as defects of mismatch DNA-
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haematologica | 2021; 106(5)