Impact of Anti-CD20 Antibodies on the Incidence of Secondary Cancers in Patients Treated for Chronic Lymphocytic Leukemia
Authors: Guidez Stéphanie , Demarquette Hélène , Nudel Morgane , Le Grand Charline , Boyle Eileen , Herbaux Charles , Facon Thierry , Cazin Bruno , Morschhauser Franck 
Published: October 2019

Abstract
Background:
An increased incidence of second primary malignancies (SPM) is described in chronic lymphocytic leukemia (CLL). Current hypothesis to explain this phenomenon mainly relies on immunosuppression conferred by both CLL itself and CLL treatment. The imputability of fludarabine has been long recognized but the risk associated with monoclonal antibodies, especially rituximab recently shown to improve overall survival in CLL when combined with fludarabine and cyclophosphamide (FC), remains unknown.
Materials and methods:
We conducted a retrospective study of the incidence of secondary cancers in 1255 CLL patients diagnosed since 1980 in the University Hospital of Lille to better characterize the possible risk of SPM associated with rituximab
Results:
Of 1255 patients, 651 (52%) received therapy including rituximab (38%), FC (26.7%), F alone (22.4%), chlorambucil (27.5%), alemtuzumab (15.5%) and bendamustine (9.3%). Rituximab was given either in combination with FC (27.5%), other chemotherapy (2.6%) or as a single-agent (3.5%). There was no significant difference in terms of age (58 versus 62 years), gender, Binet stage, cytogenetic abnormalities and number of regimen received between patients treated with or without rituximab. Median follow-up was 6 years for all patients (range 2-23), 4.8 years (range, 2-8) since initiation of therapy for patients treated without rituximab and 3.6 years (range, 0.2-11) for patients who received rituximab. Median overall survival (OS) was 18 years for patients treated with R-chemotherapy versus 11 years for patients treated with chemotherapy alone (p<0,001). Of 1255 patients, 21.5% were diagnosed with SPM. The incidence of SPM was 17.1% in patients who did not receive treatment compared to 10% in those treated. Among treated patients, the incidence of SPM was significantly higher (19% v 2%) in patients who received rituximab (p <0.001). SPM incidence was increased after R-FC (24.4%), FC (10.5%) compared to other regimen (p<0,001) (table1). Most frequent SPM were skin (25%)-and urologic cancers (23%). Median onset of SPM was 5 years (range, 2-20) without rituximab and 2 years (range, 1-7) with rituximab.
Table 1. Incidence of SPM p Treatment, %- Purine analogs- FC- RFC- Chlorambucil- Bendamustine- Alemtuzumab- CorticothŽrapie - 1,9 10,5* 24,4* 4,9 0 3,5 0 <0,001
Conclusion:
In this large single center retrospective study, we found an earlier and significantly increased incidence of SPM, mainly skin cancers, in CLL patients treated with R-chemotherapy compared to those given chemotherapy alone. It remains to be determined whether this increased SPM incidence is a due to a direct toxicity of rituximab or merely a collateral consequence of improved OS observed after rituximab.

Disclosures
Facon: Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees. Cazin:ROCHE: Consultancy; MUNDIPHARMA: Honoraria, Research Funding; NOVARTIS: Honoraria; GILEAD,: Honoraria. Morschhauser:Genentech Inc./Roche: Other: Advisory boards.