Fixed-Duration versus Continuous Treatment for Chronic Lymphocytic Leukemia

Othman Al-Sawaf; Janina Stumpf; Can Zhang; Florian Simon; Francesc Bosch; Emadoldin Feyzi; Paolo Ghia; Michael Gregor; Arnon P Kater; Vesa Lindström; Mattias Mattsson; Carsten U Niemann; Philipp B Staber; Tamar Tadmor; Patrick Thornton; Clemens-Martin Wendtner; Ann Janssens; Thomas Noesslinger; Jan-Paul Bohn; Caspar da Cunha-Bang; Christian B Poulsen; Juha Ranti; Thomas Illmer; Bjoern Schoettker; Sebastian Böttcher; Tobias Gaska; Elisabeth Vandenberghe; Ruth Clifford; Ohad Benjamini; Anna Maria Frustaci; Lydia Scarfò; Paolo Sportoletti; John Schreurs; Mark-David Levin; Hanneke van der Straaten; Marjolein van der Klift; Hoa Tran; Javier de la Serna; Javier Loscertales; Oscar Lindblad; Anna Bergendahl Sandstedt; Jeroen Goede; Michael Baumann; Anna Maria Fink; Kirsten Fischer; Matthias Ritgen; Karl-Anton Kreuzer; Christof Schneider; Eugen Tausch; Stephan Stilgenbauer; Sandra Robrecht; Barbara Eichhorst; Michael Hallek; CLL17 Trial Investigators

doi:10.1056/NEJMoa2515458

Fixed-Duration versus Continuous Treatment for Chronic Lymphocytic Leukemia

Othman Al-Sawaf^*, Janina Stumpf, Can Zhang, Florian Simon, Francesc Bosch, Emadoldin Feyzi, Paolo Ghia, Michael Gregor, Arnon P Kater, Vesa Lindström, Mattias Mattsson, Carsten U Niemann, Philipp B Staber, Tamar Tadmor, Patrick Thornton, Clemens-Martin Wendtner, Ann Janssens, Thomas Noesslinger, Jan-Paul Bohn, Caspar da Cunha-BangChristian B Poulsen, Juha Ranti, Thomas Illmer, Bjoern Schoettker, Sebastian Böttcher, Tobias Gaska, Elisabeth Vandenberghe, Ruth Clifford, Ohad Benjamini, Anna Maria Frustaci, Lydia Scarfò, Paolo Sportoletti, John Schreurs, Mark-David Levin, Hanneke van der Straaten, Marjolein van der Klift, Hoa Tran, Javier de la Serna, Javier Loscertales, Oscar Lindblad, Anna Bergendahl Sandstedt, Jeroen Goede, Michael Baumann, Anna Maria Fink, Kirsten Fischer, Matthias Ritgen, Karl-Anton Kreuzer, Christof Schneider, Eugen Tausch, Stephan Stilgenbauer, Sandra Robrecht, Barbara Eichhorst, Michael Hallek, CLL17 Trial Investigators

^*Corresponding author af dette arbejde

Afdeling for Blodsygdomme CKO

Abstract

BACKGROUND: Treatment of chronic lymphocytic leukemia (CLL) currently consists of two main approaches - continuous therapy with Bruton's tyrosine kinase inhibitors and fixed-duration regimens combining venetoclax with either CD20 antibodies or Bruton's tyrosine kinase inhibitors. Comparisons of these two therapeutic approaches are lacking.

METHODS: We conducted an investigator-initiated, phase 3, randomized trial involving patients with previously untreated CLL. Patients were randomly assigned to receive continuous ibrutinib or fixed-duration venetoclax-obinutuzumab or venetoclax-ibrutinib. The primary end point was investigator-assessed progression-free survival (noninferiority margin for the hazard ratio, 1.608, corresponding to a noninferiority margin of 8 percentage points at 3 years). Secondary end points included minimal residual disease (MRD), response, overall survival, and safety.

RESULTS: A total of 909 patients were assigned to venetoclax-obinutuzumab (303 patients), venetoclax-ibrutinib (305 patients), or ibrutinib (301 patients). The median follow-up was 34.2 months. In this prespecified interim analysis, 3-year progression-free survival was 81.1% in the venetoclax-obinutuzumab group, 79.4% in the venetoclax-ibrutinib group, and 81.0% in the ibrutinib group (hazard ratio for venetoclax-obinutuzumab vs. ibrutinib, 0.87 [98.3% confidence interval {CI}, 0.54 to 1.41]; hazard ratio for venetoclax-ibrutinib vs. ibrutinib, 0.84 [98.0% CI, 0.53 to 1.32]); the results for each comparison met the criterion for noninferiority. After the end of treatment, MRD in peripheral blood was undetectable in 73.3% of the patients in the venetoclax-obinutuzumab group, 47.2% in the venetoclax-ibrutinib group, and 0% in the ibrutinib group. Three-year overall survival was 91.5%, 96.0%, and 95.7%, respectively. The most common adverse events were infections, gastrointestinal disorders, and cytopenias.

CONCLUSIONS: In patients with previously untreated CLL, fixed-duration treatment with venetoclax-obinutuzumab or venetoclax-ibrutinib was noninferior to continuous ibrutinib with regard to investigator-assessed progression-free survival. (Funded by the University of Cologne and others; CLL17 ClinicalTrials.gov number, NCT04608318; EudraCT number, 2019-003854-99.).

Originalsprog	Engelsk
Tidsskrift	The New England journal of medicine
ISSN	0028-4793
DOI	https://doi.org/10.1056/NEJMoa2515458
Status	E-pub ahead of print - 6 dec. 2025

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10.1056/NEJMoa2515458

Citationsformater

Al-Sawaf, O., Stumpf, J., Zhang, C., Simon, F., Bosch, F., Feyzi, E., Ghia, P., Gregor, M., Kater, A. P., Lindström, V., Mattsson, M., Niemann, C. U., Staber, P. B., Tadmor, T., Thornton, P., Wendtner, C.-M., Janssens, A., Noesslinger, T., Bohn, J.-P., ... CLL17 Trial Investigators (2025). Fixed-Duration versus Continuous Treatment for Chronic Lymphocytic Leukemia. The New England journal of medicine. Advance online publication. https://doi.org/10.1056/NEJMoa2515458

Al-Sawaf, O, Stumpf, J, Zhang, C, Simon, F, Bosch, F, Feyzi, E, Ghia, P, Gregor, M, Kater, AP, Lindström, V, Mattsson, M, Niemann, CU, Staber, PB, Tadmor, T, Thornton, P, Wendtner, C-M, Janssens, A, Noesslinger, T, Bohn, J-P, da Cunha-Bang, C, Poulsen, CB, Ranti, J, Illmer, T, Schoettker, B, Böttcher, S, Gaska, T, Vandenberghe, E, Clifford, R, Benjamini, O, Frustaci, AM, Scarfò, L, Sportoletti, P, Schreurs, J, Levin, M-D, van der Straaten, H, van der Klift, M, Tran, H, de la Serna, J, Loscertales, J, Lindblad, O, Bergendahl Sandstedt, A, Goede, J, Baumann, M, Fink, AM, Fischer, K, Ritgen, M, Kreuzer, K-A, Schneider, C, Tausch, E, Stilgenbauer, S, Robrecht, S, Eichhorst, B, Hallek, M & CLL17 Trial Investigators 2025, 'Fixed-Duration versus Continuous Treatment for Chronic Lymphocytic Leukemia', The New England journal of medicine. https://doi.org/10.1056/NEJMoa2515458

@article{f1966c407975467db2ca3cc4189cc051,

title = "Fixed-Duration versus Continuous Treatment for Chronic Lymphocytic Leukemia",

abstract = "BACKGROUND: Treatment of chronic lymphocytic leukemia (CLL) currently consists of two main approaches - continuous therapy with Bruton's tyrosine kinase inhibitors and fixed-duration regimens combining venetoclax with either CD20 antibodies or Bruton's tyrosine kinase inhibitors. Comparisons of these two therapeutic approaches are lacking.METHODS: We conducted an investigator-initiated, phase 3, randomized trial involving patients with previously untreated CLL. Patients were randomly assigned to receive continuous ibrutinib or fixed-duration venetoclax-obinutuzumab or venetoclax-ibrutinib. The primary end point was investigator-assessed progression-free survival (noninferiority margin for the hazard ratio, 1.608, corresponding to a noninferiority margin of 8 percentage points at 3 years). Secondary end points included minimal residual disease (MRD), response, overall survival, and safety.RESULTS: A total of 909 patients were assigned to venetoclax-obinutuzumab (303 patients), venetoclax-ibrutinib (305 patients), or ibrutinib (301 patients). The median follow-up was 34.2 months. In this prespecified interim analysis, 3-year progression-free survival was 81.1% in the venetoclax-obinutuzumab group, 79.4% in the venetoclax-ibrutinib group, and 81.0% in the ibrutinib group (hazard ratio for venetoclax-obinutuzumab vs. ibrutinib, 0.87 [98.3% confidence interval {CI}, 0.54 to 1.41]; hazard ratio for venetoclax-ibrutinib vs. ibrutinib, 0.84 [98.0% CI, 0.53 to 1.32]); the results for each comparison met the criterion for noninferiority. After the end of treatment, MRD in peripheral blood was undetectable in 73.3% of the patients in the venetoclax-obinutuzumab group, 47.2% in the venetoclax-ibrutinib group, and 0% in the ibrutinib group. Three-year overall survival was 91.5%, 96.0%, and 95.7%, respectively. The most common adverse events were infections, gastrointestinal disorders, and cytopenias.CONCLUSIONS: In patients with previously untreated CLL, fixed-duration treatment with venetoclax-obinutuzumab or venetoclax-ibrutinib was noninferior to continuous ibrutinib with regard to investigator-assessed progression-free survival. (Funded by the University of Cologne and others; CLL17 ClinicalTrials.gov number, NCT04608318; EudraCT number, 2019-003854-99.).",

author = "Othman Al-Sawaf and Janina Stumpf and Can Zhang and Florian Simon and Francesc Bosch and Emadoldin Feyzi and Paolo Ghia and Michael Gregor and Kater, {Arnon P} and Vesa Lindstr{\"o}m and Mattias Mattsson and Niemann, {Carsten U} and Staber, {Philipp B} and Tamar Tadmor and Patrick Thornton and Clemens-Martin Wendtner and Ann Janssens and Thomas Noesslinger and Jan-Paul Bohn and {da Cunha-Bang}, Caspar and Poulsen, {Christian B} and Juha Ranti and Thomas Illmer and Bjoern Schoettker and Sebastian B{\"o}ttcher and Tobias Gaska and Elisabeth Vandenberghe and Ruth Clifford and Ohad Benjamini and Frustaci, {Anna Maria} and Lydia Scarf{\`o} and Paolo Sportoletti and John Schreurs and Mark-David Levin and {van der Straaten}, Hanneke and {van der Klift}, Marjolein and Hoa Tran and {de la Serna}, Javier and Javier Loscertales and Oscar Lindblad and {Bergendahl Sandstedt}, Anna and Jeroen Goede and Michael Baumann and Fink, {Anna Maria} and Kirsten Fischer and Matthias Ritgen and Karl-Anton Kreuzer and Christof Schneider and Eugen Tausch and Stephan Stilgenbauer and Sandra Robrecht and Barbara Eichhorst and Michael Hallek and {CLL17 Trial Investigators}",

note = "Copyright {\textcopyright} 2025 Massachusetts Medical Society.",

year = "2025",

month = dec,

day = "6",

doi = "10.1056/NEJMoa2515458",

language = "English",

journal = "The New England journal of medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

}

TY - JOUR

T1 - Fixed-Duration versus Continuous Treatment for Chronic Lymphocytic Leukemia

AU - Al-Sawaf, Othman

AU - Stumpf, Janina

AU - Zhang, Can

AU - Simon, Florian

AU - Bosch, Francesc

AU - Feyzi, Emadoldin

AU - Ghia, Paolo

AU - Gregor, Michael

AU - Kater, Arnon P

AU - Lindström, Vesa

AU - Mattsson, Mattias

AU - Niemann, Carsten U

AU - Staber, Philipp B

AU - Tadmor, Tamar

AU - Thornton, Patrick

AU - Wendtner, Clemens-Martin

AU - Janssens, Ann

AU - Noesslinger, Thomas

AU - Bohn, Jan-Paul

AU - da Cunha-Bang, Caspar

AU - Poulsen, Christian B

AU - Ranti, Juha

AU - Illmer, Thomas

AU - Schoettker, Bjoern

AU - Böttcher, Sebastian

AU - Gaska, Tobias

AU - Vandenberghe, Elisabeth

AU - Clifford, Ruth

AU - Benjamini, Ohad

AU - Frustaci, Anna Maria

AU - Scarfò, Lydia

AU - Sportoletti, Paolo

AU - Schreurs, John

AU - Levin, Mark-David

AU - van der Straaten, Hanneke

AU - van der Klift, Marjolein

AU - Tran, Hoa

AU - de la Serna, Javier

AU - Loscertales, Javier

AU - Lindblad, Oscar

AU - Bergendahl Sandstedt, Anna

AU - Goede, Jeroen

AU - Baumann, Michael

AU - Fink, Anna Maria

AU - Fischer, Kirsten

AU - Ritgen, Matthias

AU - Kreuzer, Karl-Anton

AU - Schneider, Christof

AU - Tausch, Eugen

AU - Stilgenbauer, Stephan

AU - Robrecht, Sandra

AU - Eichhorst, Barbara

AU - Hallek, Michael

AU - CLL17 Trial Investigators

PY - 2025/12/6

Y1 - 2025/12/6

N2 - BACKGROUND: Treatment of chronic lymphocytic leukemia (CLL) currently consists of two main approaches - continuous therapy with Bruton's tyrosine kinase inhibitors and fixed-duration regimens combining venetoclax with either CD20 antibodies or Bruton's tyrosine kinase inhibitors. Comparisons of these two therapeutic approaches are lacking.METHODS: We conducted an investigator-initiated, phase 3, randomized trial involving patients with previously untreated CLL. Patients were randomly assigned to receive continuous ibrutinib or fixed-duration venetoclax-obinutuzumab or venetoclax-ibrutinib. The primary end point was investigator-assessed progression-free survival (noninferiority margin for the hazard ratio, 1.608, corresponding to a noninferiority margin of 8 percentage points at 3 years). Secondary end points included minimal residual disease (MRD), response, overall survival, and safety.RESULTS: A total of 909 patients were assigned to venetoclax-obinutuzumab (303 patients), venetoclax-ibrutinib (305 patients), or ibrutinib (301 patients). The median follow-up was 34.2 months. In this prespecified interim analysis, 3-year progression-free survival was 81.1% in the venetoclax-obinutuzumab group, 79.4% in the venetoclax-ibrutinib group, and 81.0% in the ibrutinib group (hazard ratio for venetoclax-obinutuzumab vs. ibrutinib, 0.87 [98.3% confidence interval {CI}, 0.54 to 1.41]; hazard ratio for venetoclax-ibrutinib vs. ibrutinib, 0.84 [98.0% CI, 0.53 to 1.32]); the results for each comparison met the criterion for noninferiority. After the end of treatment, MRD in peripheral blood was undetectable in 73.3% of the patients in the venetoclax-obinutuzumab group, 47.2% in the venetoclax-ibrutinib group, and 0% in the ibrutinib group. Three-year overall survival was 91.5%, 96.0%, and 95.7%, respectively. The most common adverse events were infections, gastrointestinal disorders, and cytopenias.CONCLUSIONS: In patients with previously untreated CLL, fixed-duration treatment with venetoclax-obinutuzumab or venetoclax-ibrutinib was noninferior to continuous ibrutinib with regard to investigator-assessed progression-free survival. (Funded by the University of Cologne and others; CLL17 ClinicalTrials.gov number, NCT04608318; EudraCT number, 2019-003854-99.).

AB - BACKGROUND: Treatment of chronic lymphocytic leukemia (CLL) currently consists of two main approaches - continuous therapy with Bruton's tyrosine kinase inhibitors and fixed-duration regimens combining venetoclax with either CD20 antibodies or Bruton's tyrosine kinase inhibitors. Comparisons of these two therapeutic approaches are lacking.METHODS: We conducted an investigator-initiated, phase 3, randomized trial involving patients with previously untreated CLL. Patients were randomly assigned to receive continuous ibrutinib or fixed-duration venetoclax-obinutuzumab or venetoclax-ibrutinib. The primary end point was investigator-assessed progression-free survival (noninferiority margin for the hazard ratio, 1.608, corresponding to a noninferiority margin of 8 percentage points at 3 years). Secondary end points included minimal residual disease (MRD), response, overall survival, and safety.RESULTS: A total of 909 patients were assigned to venetoclax-obinutuzumab (303 patients), venetoclax-ibrutinib (305 patients), or ibrutinib (301 patients). The median follow-up was 34.2 months. In this prespecified interim analysis, 3-year progression-free survival was 81.1% in the venetoclax-obinutuzumab group, 79.4% in the venetoclax-ibrutinib group, and 81.0% in the ibrutinib group (hazard ratio for venetoclax-obinutuzumab vs. ibrutinib, 0.87 [98.3% confidence interval {CI}, 0.54 to 1.41]; hazard ratio for venetoclax-ibrutinib vs. ibrutinib, 0.84 [98.0% CI, 0.53 to 1.32]); the results for each comparison met the criterion for noninferiority. After the end of treatment, MRD in peripheral blood was undetectable in 73.3% of the patients in the venetoclax-obinutuzumab group, 47.2% in the venetoclax-ibrutinib group, and 0% in the ibrutinib group. Three-year overall survival was 91.5%, 96.0%, and 95.7%, respectively. The most common adverse events were infections, gastrointestinal disorders, and cytopenias.CONCLUSIONS: In patients with previously untreated CLL, fixed-duration treatment with venetoclax-obinutuzumab or venetoclax-ibrutinib was noninferior to continuous ibrutinib with regard to investigator-assessed progression-free survival. (Funded by the University of Cologne and others; CLL17 ClinicalTrials.gov number, NCT04608318; EudraCT number, 2019-003854-99.).

U2 - 10.1056/NEJMoa2515458

DO - 10.1056/NEJMoa2515458

M3 - Journal article

C2 - 41358601

SN - 0028-4793

JO - The New England journal of medicine

JF - The New England journal of medicine

ER -

Fixed-Duration versus Continuous Treatment for Chronic Lymphocytic Leukemia

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