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Multicenter Study
. 2024 Feb;9(2):102248.
doi: 10.1016/j.esmoop.2024.102248. Epub 2024 Feb 12.

Treatment-specific risk of subsequent malignant neoplasms in five-year survivors of diffuse large B-cell lymphoma

Y M Geurts  1 , S I M Neppelenbroek  1 , B M P Aleman  2 , C P M Janus  3 , A D G Krol  4 , D J van Spronsen  5 , W J Plattel  6 , J M Roesink  7 , K M S Verschueren  8 , J M Zijlstra  9 , H R Koene  10 , M R Nijziel  11 , E C Schimmel  12 , E de Jongh  13 , F Ong  14 , L C J Te Boome  15 , R S van Rijn  16 , L H Böhmer  17 , B D P Ta  18 , H P J Visser  19 , E F M Posthuma  20 , Y M Bilgin  21 , K Muller  22 , D van Kampen  23 , C So-Osman  24 , J S P Vermaat  25 , R J de Weijer  26 , M J Kersten  27 , F E van Leeuwen  1 , M Schaapveld  28
Affiliations
Multicenter Study

Treatment-specific risk of subsequent malignant neoplasms in five-year survivors of diffuse large B-cell lymphoma

Y M Geurts et al. ESMO Open. 2024 Feb.

Abstract

Background: The introduction of rituximab significantly improved the prognosis of diffuse large B-cell lymphoma (DLBCL), emphasizing the importance of evaluating the long-term consequences of exposure to radiotherapy, alkylating agents and anthracycline-containing (immuno)chemotherapy among DLBCL survivors.

Methods: Long-term risk of subsequent malignant neoplasms (SMNs) was examined in a multicenter cohort comprising 2373 5-year DLBCL survivors treated at ages 15-61 years in 1989-2012. Observed SMN numbers were compared with expected cancer incidence to estimate standardized incidence ratios (SIRs) and absolute excess risks (AERs/10 000 person-years). Treatment-specific risks were assessed using multivariable Cox regression.

Results: After a median follow-up of 13.8 years, 321 survivors developed one or more SMNs (SIR 1.5, 95% CI 1.3-1.8, AER 51.8). SIRs remained increased for at least 20 years after first-line treatment (SIR ≥20-year follow-up 1.5, 95% CI 1.0-2.2, AER 81.8) and were highest among patients ≤40 years at first DLBCL treatment (SIR 2.7, 95% CI 2.0-3.5). Lung (SIR 2.0, 95% CI 1.5-2.7, AER 13.4) and gastrointestinal cancers (SIR 1.5, 95% CI 1.2-2.0, AER 11.8) accounted for the largest excess risks. Treatment with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin versus ≤2250 mg/m2/≤150 mg/m2, respectively, was associated with increased solid SMN risk (hazard ratio 1.5, 95% CI 1.0-2.2). Survivors who received rituximab had a lower risk of subdiaphragmatic solid SMNs (hazard ratio 0.5, 95% CI 0.3-1.0) compared with survivors who did not receive rituximab.

Conclusion: Five-year DLBCL survivors have an increased risk of SMNs. Risks were higher for survivors ≤40 years at first treatment and survivors treated with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin, and may be lower for survivors treated in the rituximab era, emphasizing the need for studies with longer follow-up for rituximab-treated patients.

Keywords: alkylating agents; anthracyclines; diffuse large B-cell lymphoma; radiotherapy; subsequent neoplasms; survivorship.

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Conflict of interest statement

Disclosure MJK has received research support from Kite/Gilead and financial compensation for attending advisory boards and/or presentations from Roche, Kite/Gilead, Novartis, BMS/Celgene, Miltenyi Biotec, Takeda and Adicet Bio. All other authors have declared no conflicts of interest.

Figures

Figure 1
Figure 1
Cumulative incidence of any solid subsequent malignant neoplasm, with death as a competing risk. (A) Overall cumulative incidence of any solid SMN. (B) cumulative incidence of any solid SMN according to age at first DLBCL treatment. Solid lines represent the observed incidence in the cohort, dashed lines represent the expected incidence in the general population. In panel B, red lines represent survivors ≤40 years at first DLBCL treatment and blue lines represent survivors >40 years at first DLBCL treatment. DLBCL, diffuse large B cell lymphoma; SMN, subsequent malignant neoplasm.
Figure 2
Figure 2
Standardized incidence ratios and absolute excess risks of any solid subsequent malignant neoplasm after DLBCL treatment according to follow-up interval. (A) Standardized incidence ratios of any solid SMN according to follow-up interval. (B) Absolute excess risks of any solid SMN according to follow-up interval. Standardized incidence ratios of the observed and expected number of solid SMNs in the study population and their corresponding 95% confidence intervals (vertical lines) were calculated using exact Poisson probabilities of observed numbers. Absolute excess risk was calculated as the observed number of subsequent malignancies in the cohort minus the number expected and divided by the number of person-years (expressed per 10 000 person-years). DLBCL, diffuse large B cell lymphoma; n, number; SMN, subsequent malignant neoplasm.
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