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

Y M Geurts; S I M Neppelenbroek; B M P Aleman; C P M Janus; A D G Krol; D J van Spronsen; W J Plattel; J M Roesink; K M S Verschueren; J M Zijlstra; H R Koene; M R Nijziel; E C Schimmel; E de Jongh; F Ong; L C J Te Boome; R S van Rijn; L H Böhmer; B D P Ta; H P J Visser; E F M Posthuma; Y M Bilgin; K Muller; D van Kampen; C So-Osman; J S P Vermaat; R J de Weijer; M J Kersten; F E van Leeuwen; M Schaapveld

doi:10.1016/j.esmoop.2024.102248

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

Y M Geurts, S I M Neppelenbroek, B M P Aleman, C P M Janus, A D G Krol, D J van Spronsen, W J Plattel, J M Roesink, K M S Verschueren, J M Zijlstra, H R Koene, M R Nijziel, E C Schimmel, E de Jongh, F Ong, L C J Te Boome, R S van Rijn, L H Böhmer, B D P Ta, H P J VisserE F M Posthuma, Y M Bilgin, K Muller, D van Kampen, C So-Osman, J S P Vermaat, R J de Weijer, M J Kersten, F E van Leeuwen, M Schaapveld^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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/m 2 cyclophosphamide/>300 mg/m 2 doxorubicin versus ≤2250 mg/m 2/≤150 mg/m 2, 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/m 2 cyclophosphamide/>300 mg/m 2 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.

Original language	English
Article number	102248
Journal	ESMO open
Volume	9
Issue number	2
DOIs	https://doi.org/10.1016/j.esmoop.2024.102248
Publication status	Published - Feb 2024

Keywords

alkylating agents
anthracyclines
diffuse large B-cell lymphoma
radiotherapy
subsequent neoplasms
survivorship

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Geurts, Y. M., Neppelenbroek, S. I. M., Aleman, B. M. P., Janus, C. P. M., Krol, A. D. G., van Spronsen, D. J., Plattel, W. J., Roesink, J. M., Verschueren, K. M. S., Zijlstra, J. M., Koene, H. R., Nijziel, M. R., Schimmel, E. C., de Jongh, E., Ong, F., Te Boome, L. C. J., van Rijn, R. S., Böhmer, L. H., Ta, B. D. P., ... Schaapveld, M. (2024). Treatment-specific risk of subsequent malignant neoplasms in five-year survivors of diffuse large B-cell lymphoma. ESMO open, 9(2), Article 102248. https://doi.org/10.1016/j.esmoop.2024.102248

@article{72c11d81bc6e49ec8e1b6249e9f0bea0,

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

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/m 2 cyclophosphamide/>300 mg/m 2 doxorubicin versus ≤2250 mg/m 2/≤150 mg/m 2, 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/m 2 cyclophosphamide/>300 mg/m 2 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",

author = "Geurts, {Y M} and Neppelenbroek, {S I M} and Aleman, {B M P} and Janus, {C P M} and Krol, {A D G} and {van Spronsen}, {D J} and Plattel, {W J} and Roesink, {J M} and Verschueren, {K M S} and Zijlstra, {J M} and Koene, {H R} and Nijziel, {M R} and Schimmel, {E C} and {de Jongh}, E and F Ong and {Te Boome}, {L C J} and {van Rijn}, {R S} and B{\"o}hmer, {L H} and Ta, {B D P} and Visser, {H P J} and Posthuma, {E F M} and Bilgin, {Y M} and K Muller and {van Kampen}, D and C So-Osman and Vermaat, {J S P} and {de Weijer}, {R J} and Kersten, {M J} and {van Leeuwen}, {F E} and M Schaapveld",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = feb,

doi = "10.1016/j.esmoop.2024.102248",

language = "English",

volume = "9",

number = "2",

}

Geurts, YM, Neppelenbroek, SIM, Aleman, BMP, Janus, CPM, Krol, ADG, van Spronsen, DJ, Plattel, WJ, Roesink, JM, Verschueren, KMS, Zijlstra, JM, Koene, HR, Nijziel, MR, Schimmel, EC, de Jongh, E, Ong, F, Te Boome, LCJ, van Rijn, RS, Böhmer, LH, Ta, BDP, Visser, HPJ, Posthuma, EFM, Bilgin, YM, Muller, K, van Kampen, D, So-Osman, C, Vermaat, JSP, de Weijer, RJ, Kersten, MJ, van Leeuwen, FE & Schaapveld, M 2024, 'Treatment-specific risk of subsequent malignant neoplasms in five-year survivors of diffuse large B-cell lymphoma', ESMO open, vol. 9, no. 2, 102248. https://doi.org/10.1016/j.esmoop.2024.102248

TY - JOUR

T1 - Treatment-specific risk of subsequent malignant neoplasms in five-year survivors of diffuse large B-cell lymphoma

AU - Geurts, Y M

AU - Neppelenbroek, S I M

AU - Aleman, B M P

AU - Janus, C P M

AU - Krol, A D G

AU - van Spronsen, D J

AU - Plattel, W J

AU - Roesink, J M

AU - Verschueren, K M S

AU - Zijlstra, J M

AU - Koene, H R

AU - Nijziel, M R

AU - Schimmel, E C

AU - de Jongh, E

AU - Ong, F

AU - Te Boome, L C J

AU - van Rijn, R S

AU - Böhmer, L H

AU - Ta, B D P

AU - Visser, H P J

AU - Posthuma, E F M

AU - Bilgin, Y M

AU - Muller, K

AU - van Kampen, D

AU - So-Osman, C

AU - Vermaat, J S P

AU - de Weijer, R J

AU - Kersten, M J

AU - van Leeuwen, F E

AU - Schaapveld, M

PY - 2024/2

Y1 - 2024/2

N2 - 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/m 2 cyclophosphamide/>300 mg/m 2 doxorubicin versus ≤2250 mg/m 2/≤150 mg/m 2, 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/m 2 cyclophosphamide/>300 mg/m 2 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.

AB - 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/m 2 cyclophosphamide/>300 mg/m 2 doxorubicin versus ≤2250 mg/m 2/≤150 mg/m 2, 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/m 2 cyclophosphamide/>300 mg/m 2 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.

KW - alkylating agents

KW - anthracyclines

KW - diffuse large B-cell lymphoma

KW - radiotherapy

KW - subsequent neoplasms

KW - survivorship

UR - http://www.scopus.com/inward/record.url?scp=85184806743&partnerID=8YFLogxK

U2 - 10.1016/j.esmoop.2024.102248

DO - 10.1016/j.esmoop.2024.102248

M3 - Article

C2 - 38350338

SN - 2059-7029

VL - 9

JO - ESMO open

JF - ESMO open

IS - 2

M1 - 102248

ER -

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

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