Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease
Copyright © 2023 Massachusetts Medical Society..
BACKGROUND: The combination of ibrutinib and venetoclax has been shown to improve outcomes in patients with chronic lymphocytic leukemia (CLL) as compared with chemoimmunotherapy. Whether ibrutinib-venetoclax and personalization of treatment duration according to measurable residual disease (MRD) is more effective than fludarabine-cyclophosphamide-rituximab (FCR) is unclear.
METHODS: In this phase 3, multicenter, randomized, controlled, open-label platform trial involving patients with untreated CLL, we compared ibrutinib-venetoclax and ibrutinib monotherapy with FCR. In the ibrutinib-venetoclax group, after 2 months of ibrutinib, venetoclax was added for up to 6 years of therapy. The duration of ibrutinib-venetoclax therapy was defined by MRD assessed in peripheral blood and bone marrow and was double the time taken to achieve undetectable MRD. The primary end point was progression-free survival in the ibrutinib-venetoclax group as compared with the FCR group, results that are reported here. Key secondary end points were overall survival, response, MRD, and safety.
RESULTS: A total of 523 patients were randomly assigned to the ibrutinib-venetoclax group or the FCR group. At a median of 43.7 months, disease progression or death had occurred in 12 patients in the ibrutinib-venetoclax group and 75 patients in the FCR group (hazard ratio, 0.13; 95% confidence interval [CI], 0.07 to 0.24; P<0.001). Death occurred in 9 patients in the ibrutinib-venetoclax group and 25 patients in the FCR group (hazard ratio, 0.31; 95% CI, 0.15 to 0.67). At 3 years, 58.0% of the patients in the ibrutinib-venetoclax group had stopped therapy owing to undetectable MRD. After 5 years of ibrutinib-venetoclax therapy, 65.9% of the patients had undetectable MRD in the bone marrow and 92.7% had undetectable MRD in the peripheral blood. The risk of infection was similar in the ibrutinib-venetoclax group and the FCR group. The percentage of patients with cardiac serious adverse events was higher in the ibrutinib-venetoclax group than in the FCR group (10.7% vs. 0.4%).
CONCLUSIONS: MRD-directed ibrutinib-venetoclax improved progression-free survival as compared with FCR, and results for overall survival also favored ibrutinib-venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN Registry number, ISRCTN01844152; EudraCT number, 2013-001944-76.).
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2024 |
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Erschienen: |
2024 |
Enthalten in: |
Zur Gesamtaufnahme - volume:390 |
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Enthalten in: |
The New England journal of medicine - 390(2024), 4 vom: 25. Jan., Seite 326-337 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Munir, Talha [VerfasserIn] |
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Links: |
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Anmerkungen: |
Date Completed 29.01.2024 Date Revised 20.03.2024 published: Print-Electronic ISRCTN: ISRCTN01844152 EudraCT: 2013-001944-76 Citation Status MEDLINE |
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doi: |
10.1056/NEJMoa2310063 |
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funding: |
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Förderinstitution / Projekttitel: |
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520 | |a Copyright © 2023 Massachusetts Medical Society. | ||
520 | |a BACKGROUND: The combination of ibrutinib and venetoclax has been shown to improve outcomes in patients with chronic lymphocytic leukemia (CLL) as compared with chemoimmunotherapy. Whether ibrutinib-venetoclax and personalization of treatment duration according to measurable residual disease (MRD) is more effective than fludarabine-cyclophosphamide-rituximab (FCR) is unclear | ||
520 | |a METHODS: In this phase 3, multicenter, randomized, controlled, open-label platform trial involving patients with untreated CLL, we compared ibrutinib-venetoclax and ibrutinib monotherapy with FCR. In the ibrutinib-venetoclax group, after 2 months of ibrutinib, venetoclax was added for up to 6 years of therapy. The duration of ibrutinib-venetoclax therapy was defined by MRD assessed in peripheral blood and bone marrow and was double the time taken to achieve undetectable MRD. The primary end point was progression-free survival in the ibrutinib-venetoclax group as compared with the FCR group, results that are reported here. Key secondary end points were overall survival, response, MRD, and safety | ||
520 | |a RESULTS: A total of 523 patients were randomly assigned to the ibrutinib-venetoclax group or the FCR group. At a median of 43.7 months, disease progression or death had occurred in 12 patients in the ibrutinib-venetoclax group and 75 patients in the FCR group (hazard ratio, 0.13; 95% confidence interval [CI], 0.07 to 0.24; P<0.001). Death occurred in 9 patients in the ibrutinib-venetoclax group and 25 patients in the FCR group (hazard ratio, 0.31; 95% CI, 0.15 to 0.67). At 3 years, 58.0% of the patients in the ibrutinib-venetoclax group had stopped therapy owing to undetectable MRD. After 5 years of ibrutinib-venetoclax therapy, 65.9% of the patients had undetectable MRD in the bone marrow and 92.7% had undetectable MRD in the peripheral blood. The risk of infection was similar in the ibrutinib-venetoclax group and the FCR group. The percentage of patients with cardiac serious adverse events was higher in the ibrutinib-venetoclax group than in the FCR group (10.7% vs. 0.4%) | ||
520 | |a CONCLUSIONS: MRD-directed ibrutinib-venetoclax improved progression-free survival as compared with FCR, and results for overall survival also favored ibrutinib-venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN Registry number, ISRCTN01844152; EudraCT number, 2013-001944-76.) | ||
650 | 4 | |a Clinical Trial, Phase III | |
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650 | 7 | |a Vidarabine |2 NLM | |
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700 | 1 | |a Cwynarski, Kate |e verfasserin |4 aut | |
700 | 1 | |a Pettitt, Andrew |e verfasserin |4 aut | |
700 | 1 | |a Paneesha, Shankara |e verfasserin |4 aut | |
700 | 1 | |a Fox, Christopher P |e verfasserin |4 aut | |
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700 | 1 | |a Forconi, Francesco |e verfasserin |4 aut | |
700 | 1 | |a Elmusharaf, Nagah |e verfasserin |4 aut | |
700 | 1 | |a Kennedy, Ben |e verfasserin |4 aut | |
700 | 1 | |a Gribben, John |e verfasserin |4 aut | |
700 | 1 | |a Pemberton, Nicholas |e verfasserin |4 aut | |
700 | 1 | |a Sheehy, Oonagh |e verfasserin |4 aut | |
700 | 1 | |a Preston, Gavin |e verfasserin |4 aut | |
700 | 1 | |a Schuh, Anna |e verfasserin |4 aut | |
700 | 1 | |a Walewska, Renata |e verfasserin |4 aut | |
700 | 1 | |a Duley, Lelia |e verfasserin |4 aut | |
700 | 1 | |a Howard, Dena |e verfasserin |4 aut | |
700 | 1 | |a Hockaday, Anna |e verfasserin |4 aut | |
700 | 1 | |a Jackson, Sharon |e verfasserin |4 aut | |
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700 | 1 | |a Dalal, Surita |e verfasserin |4 aut | |
700 | 1 | |a de Tute, Ruth |e verfasserin |4 aut | |
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700 | 1 | |a Patten, Piers E M |e verfasserin |4 aut | |
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700 | 0 | |a National Cancer Research Institute Chronic Lymphocytic Leukemia Subgroup |e verfasserin |4 aut | |
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