Chronic lymphocytic leukemia

Prognostic value of high-sensitivity measurable residual disease assessment after front-line chemoimmunotherapy in chronic lymphocytic leukemia

Abstract

Measurable residual disease (MRD) status is widely adopted in clinical trials in patients with chronic lymphocytic leukemia (CLL). Findings from FILO group trials (CLL2007FMP, CLL2007SA, CLL2010FMP) enabled investigation of the prognostic value of high-sensitivity (0.7 × 10−5) MRD assessment using flow cytometry, in blood (N = 401) and bone marrow (N = 339), after fludarabine, cyclophosphamide, and rituximab (FCR)-based chemoimmunotherapy in a homogeneous population with long follow-up (median 49.5 months). Addition of low-level positive MRD < 0.01% to MRD ≥ 0.01% increased the proportion of cases with positive MRD in blood by 39% and in bone marrow by 27%. Compared to low-level positive MRD < 0.01%, undetectable MRD was associated with significantly longer progression-free survival (PFS) when using blood (72.2 versus 42.7 months; hazard ratio 0.40, p = 0.0003), but not when using bone marrow. Upon further stratification, positive blood MRD at any level, compared to undetectable blood MRD, was associated with shorter PFS irrespective of clinical complete or partial remission, and a lower 5-year PFS rate irrespective of IGHV-mutated or -unmutated status (all p < 0.05). In conclusion, high-sensitivity (0.0007%) MRD assessment in blood yielded additional prognostic information beyond the current standard sensitivity (0.01%). Our approach provides a model for future determination of the optimal MRD investigative strategy for any regimen.

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Fig. 1: Study flowchart and analysis populations.
Fig. 2: Event free survival according to classical MRD status.
Fig. 3: Event free survival according to sensitive MRD status.
Fig. 4: Prognostic value of sensitive MRD subsets.
Fig. 5: Prognostic value of combined clinical response and sensitive MRD status.
Fig. 6: Prognostic value of combined IGHV mutational status and sensitive MRD status.

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Acknowledgements

We thank Cath Carsberg, Ph.D. for medical writing assistance in the preparation of this paper; Roche kindly provided funding for this assistance.

French Innovative Leukemia Organization (FILO)

Sylvie Cailleres24, Gandhi Damaj25, Bruno Royer25, Martine Gardembas26, Mamoun Dib26, Matgorzata Truchan-Graczyk26, Mathilde Hunault26, Charles Foussard26, Bernadette Corront27, Anne Parry27, Frédérique Orsini-Piocelle27, Sébastien Trouillier28, Bohiane Slama29, Gérard Lepeu29, Hacene Zerazhi29, Olivier Boulat29, Ahmed Azzedine29, Carla Araujo30, Anne Banos30, Frédéric Bauduer30, Jean-Luc Dutel31, Kamel Ghomari31, Eric Deconinck32, Annie Brion32, Jacqueline Vuillier32, Alain Saad33, Abderrazak EL Yamani34, Philippe Rodon34, Pierre Soubeyran35, Gabriel Etienne35, Marie-Sarah Dilhuydy36, Krimo Bouabdallah36, Thibaut Leguay36, Bachra Chouffi37, Bertrand Pollet37, Abdallah Maakaroun38, Gaëlle Guillerm39, Christian Berthou39, Nathalie Cheron40, Marc André41, Jean Pierre Vilque42, Christophe Fruchart42, Laurent Voillat43, Gian Matteo Pica44, Sélim Corm45, Jean-Michel Micléa46, Bertrand Souleau47, Cécile Molucon-Chabrot48, Benoit De Renzis48, Olivier Tournilhac48, Jacques-Olivier Bay48, Carine Chaleteix48, Romain Guieze48, Joel Fleury49, Cristina Precupanu50, Selwa Bouledroua51, Stéphanie Haiat51, Charlotte Petitdidier51, Jehan Dupuis52, Karim Belhadj52, Olivier Casasnovas53, Jean-Noel Bastie53, Emmanuelle Ferrant53, Dany Gholam54, Lysiane Molina55, Frédéric Garban55, Mourad Tiab56, Hervé Maisonneuve56, Bruno Villemagne56, Dominique Jacomy57, Caroline Besson58, Gérard Tertian58, Kamel Laribi59, Pierre Morel60, Bruno Cazin61, Stéphane Moreau62, Liliane Reminieras62, Marie-José Rapp62, Philippe Moreau63, Catherine Sebban64, Anne-Sophie Michallet64, Gilles Salles65, Florence Broussais65, Thérèse Aurran-Schleinitz66, Diane Coso66, Wajed Abarah67, Claire Kulekci68, Véronique Dorvaux69, Philippe Carassou69, Isabelle Guibaud69, Bernard Christian70, Carlos Graux71, Jean-François Rossi72, Philippe Quittet72, Guillaume Cartron72, Alain Dubois73, Jean-Claude Eisenmann74, Bernard Drénou74, Nadine Morineau75, Béatrice Mahé76, Jean-Michel Karsenti77, Eric Jourdan78, Eric Legouffe79, Magda Alexis-Vigier80, Jean-Michel Boulet80, Malek Aoudjhane81, Catherine Thiéblemont82, Anna Lisa Andreoli82, Florence Cymbalista83, Vincent Lévy83, François Dreyfus84, Véronique Leblond85, Sylvain Choquet85, Karim Maloum85, Hélène Merle-Béral85, Anne Vekhoff81, Didier Decaudin86, Philippe Brault86, Richard Delarue87, Maud Janvier88, Carole Soussain88, Xavier Vallantin89, Laurence Sanhes89, Brigitte Dreyfus90, Cécile Tomowiak90, Riad Benramdane91, Hugo Gonzalez91, Anne Blaise-Brenna92, Brigitte Kolb92, Alain Delmer92, Charles Dauriac93, Roch Houot93, Martine Escoffre-Barbe93, Thierry Lamy93, Sophie De Guibert93, Marc Bernard93, Bernard Grosbois94, Oana Brehar95, Stéphane Leprêtre95, Patrick Morice96, Denis Guyotat97, Jérome Jaubert97, Christelle Portois97, Luc-Matthieu Fornecker98, Raoul Herbrecht98, Karin Bilger98, Shanti Ame98, Loic Ysebaert99, Caroline Dartigeas100, Pierre Feugier101, Pascal Godmer102, Henry Jardel102

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RL has received honoraria or speaker’s fee from ABBVIE, ROCHE, JANSSEN; has consulting or advisory role for ABBVIE; has to disclose funding for travel, accommodations, or expenses from ABBVIE and JANSSEN. AD has received honoraria or speaker’s fee from ABBVIE. LB has received honoraria or speaker’s fee from ABBVIE. MLG-T has received honoraria or speaker’s fee from ABBVIE and JANSSEN. MCB has received honoraria or speaker’s fee from BMS, JANSSEN; has to disclose funding for travel, accommodations, or expenses from CHUGAI. CD has received honoraria or speaker’s fee from ROCHE, JANSSEN; has to disclose funding for travel, accommodations, or expenses from ROCHE, GILEAD, ABBVIE. EVDN has consulting or advisory role for ROCHE, MUNDIPHARMA. PF has received honoraria or speaker’s fee from ROCHE, JANSSEN, GILEAD, ABBVIE; has consulting or advisory role for ROCHE, JANSSEN, GILEAD, ABBVIE; has received research funding from ROCHE, JANSSEN, GILEAD; has to disclose funding for travel, accommodations, or expenses from ROCHE, JANSSEN, GILEAD, ABBVIE. GC has received honoraria or speaker’s fee from SANOFI, ROCHE, JANSSEN, GILEAD; has consulting or advisory role for CELGENE, ROCHE. V Leblond has received honoraria or speaker’s fee from ROCHE, ABBVIE, AMGEN, GILEAD, JANSSEN; has consulting or advisory role for ROCHE, ABBVIE, GILEAD, JANSSEN; has to disclose funding for travel, accommodations, or expenses from ROCHE, ABBVIE. V Lévy has consulting or advisory role for ABBVIE, JANSSEN, ROCHE, OCTAPHARMA; has to disclose funding for travel, accommodations, or expenses from ABBVIE, JANSSEN, GILEAD. FC has received honoraria or speaker’s fee from JANSSEN, GILEAD, ABBVIE, SUNESIS; has consulting or advisory role for ABBVIE; has received research funding from SUNESIS (institution); has to disclose funding for travel, accommodations, or expenses from ROCHE, ABBVIE, GILEAD. MB, LC, BC, A Debliquis, BD, M-CJ, EL, A-CL, MT, CQ, NR, CA, SK, RD, SV, VR, and SL declare no potential competing interests that relate to this report.

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Letestu, R., Dahmani, A., Boubaya, M. et al. Prognostic value of high-sensitivity measurable residual disease assessment after front-line chemoimmunotherapy in chronic lymphocytic leukemia. Leukemia (2020). https://doi.org/10.1038/s41375-020-01009-z

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