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Second malignancy after childhood NHL
repair mechanisms bear susceptibility for development of NHL.37 In our study six patients with second lymphoid malignancy had a known CPC. For the remaining 14 patients either as yet unknown susceptibilities for develop- ment of lymphoma, or defects of immune surveillance might be responsible.
Following a large cohort of children with NHL enrolled in consecutive clinical studies with uniform treatment backbones is a strength of our study. The combined fol- low-up of patients by the NHL-BFM study group as well as the GCCR ensured a high probability to collect most of the SMN after NHL in childhood. Furthermore, all reports were medically validated. Careful analysis of second lym- phoid tumors after NHL including comparison of tumor material from first and second tumors enabled us to distin- guish second lymphoid malignancies from relapses. However, we cannot exclude an under-reporting of second lymphoid malignancies in cases of assumed relapses with similar histology and insufficient tumor material for molecular comparison. With a median follow-up time of 9.4 years (maximum 36 years) it is likely that we captured most of the hematologic SMN, but did not capture all sec- ond solid tumors. Despite the significant higher risk of SMN for patients with known CPC, it is also likely that we underestimated the frequency of CPC among children suf- fering from NHL, since CPC were not systematically screened for.
Genetic predisposition and immune suppression are important risk factors for the development of SMN in line with previously administered chemotherapy and/or radio- therapy. Therefore efforts should be made to identify indi- viduals with CPC. The inclusion of basic immunological examinations and using standardized questionnaires38 about the personal and family history of the patients should be discussed for all children with NHL in order to provide a better basis for long-term patient care. Our study underscores the importance to continue to pay high atten- tion on patient follow-up beyond the pediatric age. Patients and caregivers of survivors of childhood NHL should be aware of the specific risk factors for the develop- ment of SMN, and should be highly alert to early signs and symptoms of possible malignancy, such as carcinoma of the gastrointestinal tract or CNS tumor, in order to allow timely diagnosis. Also directed screening for SMN might be appropriate with the goal to improve the prognosis for the treatment of the second malignancy. In cases of late recurring lymphoid malignancies, the possibility of a SMN as opposed to relapse of the primary lymphoma should be
considered with potential implications for the application of diagnostic tools (e.g., molecular genetics and clonality analysis) and treatment decisions.
In conclusion, our analysis revealed an increased risk for SMN after successful treatment of childhood NHL. The cumulative incidence of SMN was significantly higher in LBL-patients compared to the other subtypes of NHL. The diagnosis of LBL was an independent risk factor for the development of AML/MDS. Patients with known CPC had a significantly higher risk for the development of SMN than patients without known CPC. Solid malignancies were the most frequent SMN followed by AML/MDS and second lymphoid malignancy.
Disclosures
MS has received honoraria from prIME Oncology, is part of the speakers’ bureau of Baxalta, has received research funding from Sigma Tau, Baxter and Medac; TK has a consulting and adviso- ry role at Novartis; AA has received honoraria from Jazz Pharmaceuticals and has a consulting and advisory role at Jazz Pharmaceuticals; MZ, OM, UM, WK, IO, GM, FN, CS, UK, AR, BB and WW have no conflicts of interest to declare.
Contributions
AR, BB, WW and OM designed the study; AR, BB, FN, GM, and WW were trial coordinators. IO, and WK did laboratory tests; AA, AR, BB, FN, GM, MS, OM, TK, UK, and WW recruited patients for the BFM-trials coordinators; UM, MZ and CS estab- lished the dataset; MZ performed statistical analysis; AR, BB, MZ, WW, and OM analyzed data; BB, WW, and OM wrote the paper; OM had full access to all the data in the study and had final responsibility for the decision to submit for publication; all authors reviewed the draft of the paper submitted for publication.
Acknowledgments
We acknowledge the contribution of past and present coordina- tors and medical records technicians of the BFM study group for helping to establish this dataset. We thank all the clinicians who entered patients into the subsequent NHL-BFM trials and the children and families who agreed to take part.
Funding
This study was supported by the Forschungshilfe Station Peiper (Research Support Peiper), Germany, and the Deutsche Kinderkrebsstiftung (German Childhood Cancer Foundation) for the NHL-BFM Registry 2012 (DKS 2014.11 A/B), and the St. Anna Kinderkrebsforschung (Children’s Cancer Research Institute), Austria.
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