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Chronic lymphocytic leukemia

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

Leukemia volume 35, pages 1597–1609 (2021)Cite this article

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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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  1. Laboratoire d’Hématologie, APHP CHU Avicenne, Bobigny, France

    Rémi Letestu, Abdelmalek Dahmani & Florence Cymbalista

  2. URC, APHP CHU Avicenne, Bobigny, France

    Marouane Boubaya

  3. Laboratoire d’Hématologie, Hospices Civils de Lyon/Groupement Hospitalier Sud, Lyon, France

    Lucile Baseggio

  4. Laboratoire d’Hématologie, CHU Saint Etienne, Saint Etienne, France

    Lydia Campos & Carmen Aanei

  5. Laboratoire d’Hématologie, CHU UCL Namur, Yvoir, Belgium

    Bernard Chatelain

  6. Laboratoire d’Hématologie, GHRMSA, Mulhouse, France

    Agathe Debliquis & Bernard Drénou

  7. Laboratoire d’Immunologie, CHU Grenoble-Alpes, Grenoble-Alpes, France

    Marie-Christine Jacob

  8. Laboratoire d’Hématologie, CHR Orléans, Orléans, France

    Eric Legac

  9. Laboratoire d’Hématologie, APHP CHU Pitié-Salpêtrière, Paris, France

    Magali Le Garff-Tavernier & Claire Quiney

  10. Laboratoire d’Hématologie, IPC, Marseille, France

    Anne-Catherine Lhoumeau

  11. Laboratoire d’Hématologie, CHU Nantes, Nantes, France

    Nelly Robillard & Marie-Christine Béné

  12. Laboratoire d’Immunologie, CHU L’Archet, Nice, France

    Michel Ticchioni

  13. URC, CHU Saint-Louis, Paris, France

    Sandrine Katsahian

  14. CHU Tours, Tours, France

    Roselyne Delepine

  15. CLCC, Rouen, France

    Sandrine Vaudaux

  16. CHU Montpellier, Montpellier, France

    Valérie Rouillé

  17. Hématologie Clinique, CHU Tours, Tours, France

    Caroline Dartigeas

  18. Hématologie Clinique, UCLouvain, Louvain, Belgium

    Eric Van Den Neste

  19. Hématologie Clinique, CLCC, Rouen, France

    Stéphane Leprêtre

  20. Hématologie Clinique, CHU Nancy, Nancy, France

    Pierre Feugier

  21. Hématologie Clinique, CHU Montpellier, Montpellier, France

    Guillaume Cartron

  22. Hématologie clinique, APHP CHU Pitié-Salpêtrière, Sorbonne Université Paris, Paris, France

    Véronique Leblond

  23. URC/CRC, APHP CHU Avicenne, Bobigny, France

    Vincent Lévy

  24. CH Aix-en-Provence, Hématologie, Aix-en-Provence, France

    Sylvie Cailleres

  25. Hôpital Sud, Maladies du Sang, Amiens, France

    Gandhi Damaj & Bruno Royer

  26. CHU Angers, Maladies du Sang, Angers, France

    Martine Gardembas, Mamoun Dib, Matgorzata Truchan-Graczyk, Mathilde Hunault & Charles Foussard

  27. CH Annecy Genevois, Service Hématologie, Pringy, France

    Bernadette Corront, Anne Parry & Frédérique Orsini-Piocelle

  28. CH Henri Mondor, Service de Médecine Interne, Aurillac, France

    Sébastien Trouillier

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    Bohiane Slama, Gérard Lepeu, Hacene Zerazhi, Olivier Boulat & Ahmed Azzedine

  30. CH de la Côte Basque, Hématologie, Bayonne, France

    Carla Araujo, Anne Banos & Frédéric Bauduer

  31. CH Beauvais, Hématologie, Beauvais, France

    Jean-Luc Dutel & Kamel Ghomari

  32. Hôpital Minjoz, Hématologie, Besançon, France

    Eric Deconinck, Annie Brion & Jacqueline Vuillier

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    Alain Saad

  34. CH Blois, Unité d’Hématologie, BLOIS, France

    Abderrazak EL Yamani & Philippe Rodon

  35. Institut Bergonié, Hématologie, Bordeaux, France

    Pierre Soubeyran & Gabriel Etienne

  36. Hôpital Haut Lévêque, Maladies du Sang, Pessac, France

    Marie-Sarah Dilhuydy, Krimo Bouabdallah & Thibaut Leguay

  37. CH Docteur Duchenne, Boulogne-sur-Mer, France

    Bachra Chouffi & Bertrand Pollet

  38. CH Jacques Coeur, Hématologie Clinique, Bourges, France

    Abdallah Maakaroun

  39. CHRU Augustin Morvan, Institut de Cancérologie et d’Hématologie, Brest, France

    Gaëlle Guillerm & Christian Berthou

  40. Centre Médical de Bligny, Oncologie-Hématologie, Briis-sous-Forges, France

    Nathalie Cheron

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    Marc André

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    Jean Pierre Vilque & Christophe Fruchart

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    Laurent Voillat

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    Gian Matteo Pica

  45. CH Chambery, Hématologie-Oncologie, Chambery, France

    Sélim Corm

  46. CH Louis Pasteur, Hématologie Clinique, Chartres, France

    Jean-Michel Micléa

  47. Hôpital Percy, Hématologie, Clamart, France

    Bertrand Souleau

  48. CHU Estaing, Hématologie Clinique et Thérapie Cellulaire, Clermont Ferrand, France

    Cécile Molucon-Chabrot, Benoit De Renzis, Olivier Tournilhac, Jacques-Olivier Bay, Carine Chaleteix & Romain Guieze

  49. Pôle Santé République, Oncologie Médicale, Clermont Ferrand, France

    Joel Fleury

  50. HCC, Oncologie Hématologie, Colmar, France

    Cristina Precupanu

  51. Hôpital Sud Francilien, Hématologie, Corbeil Essonnes, France

    Selwa Bouledroua, Stéphanie Haiat & Charlotte Petitdidier

  52. CHU Henri Mondor, Hématologie Clinique, Créteil, France

    Jehan Dupuis & Karim Belhadj

  53. CHU-Hôpital Enfants, Hématologie Clinique, Dijon, France

    Olivier Casasnovas, Jean-Noel Bastie & Emmanuelle Ferrant

  54. CH Draguignan, Cancérologie, Draguignan, France

    Dany Gholam

  55. CH Michallon, Hématologie Clinique, Grenoble, France

    Lysiane Molina & Frédéric Garban

  56. CHD, Médecine Interne-Hématologie, La Roche-sur-Yon, France

    Mourad Tiab, Hervé Maisonneuve & Bruno Villemagne

  57. CH Laval, Médecine-Hématologie, Laval, France

    Dominique Jacomy

  58. CHU Bicêtre APHP, Hématologie, Le Kremin-Bicêtre, France

    Caroline Besson & Gérard Tertian

  59. CH du Mans, Médecine Interne Onco-Hématologie, Le Mans, France

    Kamel Laribi

  60. CH Lens, Hématologie, Lens, France

    Pierre Morel

  61. CHRU Huriez, Hématologie, Lille, France

    Bruno Cazin

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    Philippe Moreau

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    Thérèse Aurran-Schleinitz & Diane Coso

  67. CH Meaux, Service d’Hématologie, Meaux, France

    Wajed Abarah

  68. Centre M. Jacquet, Hématologie, Melun, France

    Claire Kulekci

  69. Hôpital de Mercy, Service d’Hématologie, Metz, France

    Véronique Dorvaux, Philippe Carassou & Isabelle Guibaud

  70. Hôpital Notre Dame De Bon Secours, Service Hématologie, Metz, France

    Bernard Christian

  71. CHU UCL Namur, Mont-Godinne, Yvoir, Belgium

    Carlos Graux

  72. CHU St Eloi, Service Hématologie, Montpellier, France

    Jean-François Rossi, Philippe Quittet & Guillaume Cartron

  73. Clinique Beau Soleil, Service de Médecine Interne, Montpellier, France

    Alain Dubois

  74. CH E. Muller, Département d’Hématologie, Mulhouse, France

    Jean-Claude Eisenmann & Bernard Drénou

  75. Hôpital Privé Du Confluent, Hématologie, Nantes, France

    Nadine Morineau

  76. CHU Hôtel Dieu, Hématologie Clinique, Nantes, France

    Béatrice Mahé

  77. CHU Archet, Hématologie Clinique, Nice, France

    Jean-Michel Karsenti

  78. CHU Caremeau, Unité Onco-Hématologie, Nimes, France

    Eric Jourdan

  79. Clinique Valdegour, Hématologie, Nîmes, France

    Eric Legouffe

  80. Hôpital de La Source, Oncologie médicale, Orleans, France

    Magda Alexis-Vigier & Jean-Michel Boulet

  81. CHU Saint Antoine APHP, Maladies du Sang et de Thérapie Cellulaire, Paris, France

    Malek Aoudjhane & Anne Vekhoff

  82. CHU Saint Louis APHP, Hématologie, Paris, France

    Catherine Thiéblemont & Anna Lisa Andreoli

  83. CHU Avicenne APHP, Hématologie Biologique, Bobigny, France

    Florence Cymbalista & Vincent Lévy

  84. CHU Cochin APHP, Unité d’Hématologie, Paris, France

    François Dreyfus

  85. CHU La Pitié Salpêtrière APHP, Hématologie, Paris, France

    Véronique Leblond, Sylvain Choquet, Karim Maloum & Hélène Merle-Béral

  86. Institut Curie, Hématologie, Paris, France

    Didier Decaudin & Philippe Brault

  87. CHU Necker-Enfants Malades APHP, Hématologie, Paris, France

    Richard Delarue

  88. Centre René Huguenin, Hématologie, Saint Cloud, France

    Maud Janvier & Carole Soussain

  89. CHG Saint Jean, Hématologie, Perpignan, France

    Xavier Vallantin & Laurence Sanhes

  90. CHU Jean Bernard, Hématologie et Oncologie Médicale, Poitiers, France

    Brigitte Dreyfus & Cécile Tomowiak

  91. CH René Dubos, Onco-hématologie, Pontoise, France

    Riad Benramdane & Hugo Gonzalez

  92. CHU Robert Debré, Hématologie Clinique, Reims, France

    Anne Blaise-Brenna, Brigitte Kolb & Alain Delmer

  93. CHU Pontchaillou, Hématologie Clinique, Rennes, France

    Charles Dauriac, Roch Houot, Martine Escoffre-Barbe, Thierry Lamy, Sophie De Guibert & Marc Bernard

  94. Hôpital Sud, Médecine Interne, Rennes, France

    Bernard Grosbois

  95. CLCC H. Becquerel, Hématologie, Rouen, France

    Oana Brehar & Stéphane Leprêtre

  96. Hôpital Yves Le Foll, Hématologie, Saint Brieuc, France

    Patrick Morice

  97. Institut Cancerologie de La Loire (ICL), Hématologie, Saint Priest-en-Jarez, France

    Denis Guyotat, Jérome Jaubert & Christelle Portois

  98. CHU Hautepierre, Hématologie-Oncologie, Strasbourg, France

    Luc-Matthieu Fornecker, Raoul Herbrecht, Karin Bilger & Shanti Ame

  99. CHU Purpan, Hématologie Adulte, Toulouse, France

    Loic Ysebaert

  100. CHU Bretonneau, Oncologie Médicale-Thérapie Cellulaire, Tours, France

    Caroline Dartigeas

  101. CHU Brabois,Hématologie - Médecine Interne, Vandoeuvre-les-Nancy, France

    Pierre Feugier

  102. CH Bretagne Atlantique, Médecine Interne, Vannes, France

    Pascal Godmer & Henry Jardel

Authors
  1. Rémi Letestu
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  2. Abdelmalek Dahmani
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  3. Marouane Boubaya
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  4. Lucile Baseggio
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  5. Lydia Campos
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  6. Bernard Chatelain
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  7. Agathe Debliquis
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  8. Bernard Drénou
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  9. Marie-Christine Jacob
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  10. Eric Legac
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  11. Magali Le Garff-Tavernier
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  12. Anne-Catherine Lhoumeau
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  13. Claire Quiney
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  14. Nelly Robillard
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  15. Michel Ticchioni
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  21. Marie-Christine Béné
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  22. Caroline Dartigeas
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  23. Eric Van Den Neste
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  24. Stéphane Leprêtre
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  27. Véronique Leblond
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  28. Vincent Lévy
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  29. Florence Cymbalista
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Consortia

on behalf of the French Innovative Leukemia Organization (FILO)

  • Sylvie Cailleres
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  • , Martine Gardembas
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  • , Véronique Dorvaux
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  • , Isabelle Guibaud
  • , Bernard Christian
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  • , Jean-François Rossi
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  • , Guillaume Cartron
  • , Alain Dubois
  • , Jean-Claude Eisenmann
  • , Bernard Drénou
  • , Nadine Morineau
  • , Béatrice Mahé
  • , Jean-Michel Karsenti
  • , Eric Jourdan
  • , Eric Legouffe
  • , Magda Alexis-Vigier
  • , Jean-Michel Boulet
  • , Malek Aoudjhane
  • , Catherine Thiéblemont
  • , Anna Lisa Andreoli
  • , Florence Cymbalista
  • , Vincent Lévy
  • , François Dreyfus
  • , Véronique Leblond
  • , Sylvain Choquet
  • , Karim Maloum
  • , Hélène Merle-Béral
  • , Anne Vekhoff
  • , Didier Decaudin
  • , Philippe Brault
  • , Richard Delarue
  • , Maud Janvier
  • , Carole Soussain
  • , Xavier Vallantin
  • , Laurence Sanhes
  • , Brigitte Dreyfus
  • , Cécile Tomowiak
  • , Riad Benramdane
  • , Hugo Gonzalez
  • , Anne Blaise-Brenna
  • , Brigitte Kolb
  • , Alain Delmer
  • , Charles Dauriac
  • , Roch Houot
  • , Martine Escoffre-Barbe
  • , Thierry Lamy
  • , Sophie De Guibert
  • , Marc Bernard
  • , Bernard Grosbois
  • , Oana Brehar
  • , Stéphane Leprêtre
  • , Patrick Morice
  • , Denis Guyotat
  • , Jérome Jaubert
  • , Christelle Portois
  • , Luc-Matthieu Fornecker
  • , Raoul Herbrecht
  • , Karin Bilger
  • , Shanti Ame
  • , Loic Ysebaert
  • , Caroline Dartigeas
  • , Pierre Feugier
  • , Pascal Godmer
  •  & Henry Jardel

Corresponding authors

Correspondence to Rémi Letestu or Florence Cymbalista.

Ethics declarations

Conflict of interest

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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Members of the French Innovative Leukemia Organization (FILO) are listed below Acknowledgements.

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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 35, 1597–1609 (2021). https://doi.org/10.1038/s41375-020-01009-z

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