17p deletion strongly influences rituximab elimination in chronic lymphocytic leukemia
Abstract Chronic lymphocytic leukemia (CLL) is the most common type of leukemia and the anti-CD20 monoclonal antibody, rituximab, represents the therapeutic gold standard for more than 2 decades in this pathology, when used in combination with chemotherapy. However, some patients experience treatmen...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2019-01-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-019-0509-0 |
| _version_ | 1818538769516593152 |
|---|---|
| author | Cristina Bagacean Adrian Tempescul David Ternant Anne Banet Nathalie Douet-Guilbert Anne Bordron Boutahar Bendaoud Hussam Saad Mihnea Zdrenghea Christian Berthou Gilles Paintaud Yves Renaudineau |
| author_facet | Cristina Bagacean Adrian Tempescul David Ternant Anne Banet Nathalie Douet-Guilbert Anne Bordron Boutahar Bendaoud Hussam Saad Mihnea Zdrenghea Christian Berthou Gilles Paintaud Yves Renaudineau |
| author_sort | Cristina Bagacean |
| collection | DOAJ |
| description | Abstract Chronic lymphocytic leukemia (CLL) is the most common type of leukemia and the anti-CD20 monoclonal antibody, rituximab, represents the therapeutic gold standard for more than 2 decades in this pathology, when used in combination with chemotherapy. However, some patients experience treatment resistance or rapid relapses, and in particular, those harboring a 17p/TP53 deletion (del(17p)). This resistance could be explained by a chemo-resistance, but it could also result from the direct impact of del(17p) on the pharmacokinetics of rituximab, which represents the aim of the present study. Accordingly, 44 CLL patients were included in the study, and among them 9 presented a del(17p). Next, a total of 233 rituximab sera were selected for a pharmacokinetic study and analyzed in a two-compartment model showing important differences when del(17p) CLL patients were compared with non-del(17p) patients treated with rituximab and chemotherapy: (1) clearance of rituximab was faster; (2) central volume of rituximab distribution V1 (peripheral blood) was reduced while peripheral volume V2 (lymphoid organs and tissues) was increased; and (3) the rate of rituximab elimination (Kout) was faster. In contrast, the group with a better prognosis harboring isolated del(13q) presented a slower rate of elimination (Kout). Pharmacokinetic parameters were independent from the other factors tested such as age, sex, chemotherapy regimen (fludarabine/cyclophosphamide versus bendamustine), IGHV mutational status, and FCGR3A 158VF status. In conclusion, this study provides an additional argument to consider that del(17p) is effective not only to control chemoresistance but also monoclonal antibody activity, based on higher rituximab turnover. |
| first_indexed | 2024-12-11T21:33:15Z |
| format | Article |
| id | doaj.art-874ce61e568a46c38d593ea120b275c2 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-11T21:33:15Z |
| publishDate | 2019-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-874ce61e568a46c38d593ea120b275c22022-12-22T00:50:05ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-01-01711510.1186/s40425-019-0509-017p deletion strongly influences rituximab elimination in chronic lymphocytic leukemiaCristina Bagacean0Adrian Tempescul1David Ternant2Anne Banet3Nathalie Douet-Guilbert4Anne Bordron5Boutahar Bendaoud6Hussam Saad7Mihnea Zdrenghea8Christian Berthou9Gilles Paintaud10Yves Renaudineau11U1227 B Lymphocytes and Autoimmunity, University of Brest; INSERM; networks IC-CGO and REpiCGO from “Canceropole Grand Ouest”U1227 B Lymphocytes and Autoimmunity, University of Brest; INSERM; networks IC-CGO and REpiCGO from “Canceropole Grand Ouest”University of Tours, EA 7501 Innovation and Cell Targeting Group, CHRU de Tours, Laboratory of Pharmacology-ToxicologyDepartment of Hematology, Brest University Medical School HospitalLaboratory of Cytogenetics, Brest University Medical School HospitalU1227 B Lymphocytes and Autoimmunity, University of Brest; INSERM; networks IC-CGO and REpiCGO from “Canceropole Grand Ouest”Laboratory of Immunology and Immunotherapy, Brest University Medical School HospitalDepartment of Hematology, Brest University Medical School Hospital“Iuliu Hatieganu” University of Medicine and PharmacyU1227 B Lymphocytes and Autoimmunity, University of Brest; INSERM; networks IC-CGO and REpiCGO from “Canceropole Grand Ouest”University of Tours, EA 7501 Innovation and Cell Targeting Group, CHRU de Tours, Laboratory of Pharmacology-ToxicologyLaboratory of Immunology and Immunotherapy, Brest University Medical School HospitalAbstract Chronic lymphocytic leukemia (CLL) is the most common type of leukemia and the anti-CD20 monoclonal antibody, rituximab, represents the therapeutic gold standard for more than 2 decades in this pathology, when used in combination with chemotherapy. However, some patients experience treatment resistance or rapid relapses, and in particular, those harboring a 17p/TP53 deletion (del(17p)). This resistance could be explained by a chemo-resistance, but it could also result from the direct impact of del(17p) on the pharmacokinetics of rituximab, which represents the aim of the present study. Accordingly, 44 CLL patients were included in the study, and among them 9 presented a del(17p). Next, a total of 233 rituximab sera were selected for a pharmacokinetic study and analyzed in a two-compartment model showing important differences when del(17p) CLL patients were compared with non-del(17p) patients treated with rituximab and chemotherapy: (1) clearance of rituximab was faster; (2) central volume of rituximab distribution V1 (peripheral blood) was reduced while peripheral volume V2 (lymphoid organs and tissues) was increased; and (3) the rate of rituximab elimination (Kout) was faster. In contrast, the group with a better prognosis harboring isolated del(13q) presented a slower rate of elimination (Kout). Pharmacokinetic parameters were independent from the other factors tested such as age, sex, chemotherapy regimen (fludarabine/cyclophosphamide versus bendamustine), IGHV mutational status, and FCGR3A 158VF status. In conclusion, this study provides an additional argument to consider that del(17p) is effective not only to control chemoresistance but also monoclonal antibody activity, based on higher rituximab turnover.http://link.springer.com/article/10.1186/s40425-019-0509-0Chronic lymphocytic leukemiaAnti-CD20 monoclonal antibodyRituximabPharmacokineticsClearance17p deletion |
| spellingShingle | Cristina Bagacean Adrian Tempescul David Ternant Anne Banet Nathalie Douet-Guilbert Anne Bordron Boutahar Bendaoud Hussam Saad Mihnea Zdrenghea Christian Berthou Gilles Paintaud Yves Renaudineau 17p deletion strongly influences rituximab elimination in chronic lymphocytic leukemia Journal for ImmunoTherapy of Cancer Chronic lymphocytic leukemia Anti-CD20 monoclonal antibody Rituximab Pharmacokinetics Clearance 17p deletion |
| title | 17p deletion strongly influences rituximab elimination in chronic lymphocytic leukemia |
| title_full | 17p deletion strongly influences rituximab elimination in chronic lymphocytic leukemia |
| title_fullStr | 17p deletion strongly influences rituximab elimination in chronic lymphocytic leukemia |
| title_full_unstemmed | 17p deletion strongly influences rituximab elimination in chronic lymphocytic leukemia |
| title_short | 17p deletion strongly influences rituximab elimination in chronic lymphocytic leukemia |
| title_sort | 17p deletion strongly influences rituximab elimination in chronic lymphocytic leukemia |
| topic | Chronic lymphocytic leukemia Anti-CD20 monoclonal antibody Rituximab Pharmacokinetics Clearance 17p deletion |
| url | http://link.springer.com/article/10.1186/s40425-019-0509-0 |
| work_keys_str_mv | AT cristinabagacean 17pdeletionstronglyinfluencesrituximabeliminationinchroniclymphocyticleukemia AT adriantempescul 17pdeletionstronglyinfluencesrituximabeliminationinchroniclymphocyticleukemia AT davidternant 17pdeletionstronglyinfluencesrituximabeliminationinchroniclymphocyticleukemia AT annebanet 17pdeletionstronglyinfluencesrituximabeliminationinchroniclymphocyticleukemia AT nathaliedouetguilbert 17pdeletionstronglyinfluencesrituximabeliminationinchroniclymphocyticleukemia AT annebordron 17pdeletionstronglyinfluencesrituximabeliminationinchroniclymphocyticleukemia AT boutaharbendaoud 17pdeletionstronglyinfluencesrituximabeliminationinchroniclymphocyticleukemia AT hussamsaad 17pdeletionstronglyinfluencesrituximabeliminationinchroniclymphocyticleukemia AT mihneazdrenghea 17pdeletionstronglyinfluencesrituximabeliminationinchroniclymphocyticleukemia AT christianberthou 17pdeletionstronglyinfluencesrituximabeliminationinchroniclymphocyticleukemia AT gillespaintaud 17pdeletionstronglyinfluencesrituximabeliminationinchroniclymphocyticleukemia AT yvesrenaudineau 17pdeletionstronglyinfluencesrituximabeliminationinchroniclymphocyticleukemia |