Fixed-Duration versus Continuous Treatment for Chronic Lymphocytic Leukemia

Author(s): Othman Al-Sawaf, M.D., Ph.D.¹; Janina Stumpf, M.D.¹; Can Zhang, Ph.D.¹; Florian Simon, M.D.¹; Francesc Bosch, M.D., Ph.D.²; Emadoldin Feyzi, M.D.³; Paolo Ghia, M.D., Ph.D.^4,5; Michael Gregor, M.D.⁶; Arnon P. Kater, M.D., Ph.D.⁷; Vesa Lindström, M.D.⁸; Mattias Mattsson, M.D.⁹; Carsten U. Niemann, M.D., Ph.D.^10,11; Philipp B. Staber, M.D., Ph.D.^12,13; Tamar Tadmor, M.D.^14,15; Patrick Thornton, M.D.¹⁶; Clemens-Martin Wendtner, M.D., Ph.D.¹⁷; Ann Janssens, M.D.¹⁸; Thomas Noesslinger, M.D.¹⁹; Jan-Paul Bohn, M.D., Ph.D.²⁰; Caspar da Cunha-Bang, M.D., Ph.D.¹⁰; Christian B. Poulsen, M.D.²¹; Juha Ranti, M.D.²²; Thomas Illmer, M.D.²³; Bjoern Schoettker, M.D.²⁴; Sebastian Böttcher, M.D.²⁵; Tobias Gaska, M.D.²⁶; Elisabeth Vandenberghe, M.D.²⁷; Ruth Clifford, M.D., Ph.D.²⁸; Ohad Benjamini, M.D.²⁹; Anna Maria Frustaci, M.D.³⁰; Lydia Scarfò, M.D.^4,5; Paolo Sportoletti, M.D.³¹; John Schreurs, M.D.³²; Mark-David Levin, M.D.³³; Hanneke van der Straaten, M.D.³⁴; Marjolein van der Klift, M.D.³⁵; Hoa Tran, M.D.³⁶; Javier de la Serna, M.D.³⁷; Javier Loscertales, M.D.³⁸; Oscar Lindblad, M.D.³⁹; Anna Bergendahl Sandstedt, M.D.⁴⁰; Jeroen Goede, M.D.⁴¹; Michael Baumann, M.D.⁴²; Anna Maria Fink, M.D.¹; Kirsten Fischer, M.D.¹; Matthias Ritgen, M.D.⁴³; Karl-Anton Kreuzer, M.D.¹; Christof Schneider, M.D.⁴⁴; Eugen Tausch, M.D.⁴⁴; Stephan Stilgenbauer, M.D.⁴⁴; Sandra Robrecht, Ph.D.¹; Barbara Eichhorst, M.D.¹; Michael Hallek, M.D.¹; the CLL17 Trial Investigators*;

Source: DOI: 10.1056/NEJMoa2515458

Dr. Anjan Patel's Thoughts

CLL17 shows that fixed‑duration venetoclax–obinutuzumab or venetoclax–ibrutinib is noninferior to continuous ibrutinib upfront, with 3‑year PFS ≈80% across all arms. The big difference is depth of response, undetectable MRD was 73% with venetoclax–obinutuzumab, 47% with venetoclax–ibrutinib, and 0% with ibrutinib. Toxicities tracked with mechanism (more cytopenias/infusion reactions with ven‑obinutuzumab, more cardiac events with ibrutinib). Overall, this strongly supports time‑limited therapy as a frontline standard for many chronic lymphocytic leukemia (CLL) patients.

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 3 years). Secondary end points included minimal residual disease (MRD), response, overall survival, and safety. Research Summary Fixed-Duration versus Continuous Treatment for Chronic Lymphocytic Leukemia

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 Affiliations

¹Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany; ²Department of Hematology, University Hospital Vall d’Hebron, Vall d’Hebron Institute of Oncology (VHIO), Barcelona; ³St. Olavs University Hospital, Department of Hematology, Trondheim, Norway; ⁴School of Medicine, Università Vita Salute San Raffaele, Milan; ⁵Comprehensive Cancer Center, IRCCS Ospedale San Raffaele, Milan; ⁶Cantonal Hospital of Lucerne, Lucerne, Switzerland; ⁷Department of Hematology, Cancer Center Amsterdam, Hemato-Oncology Foundation for Adults Netherlands (HOVON), Amsterdam University Medical Centers, University of Amsterdam, Amsterdam; ⁸Department of Hematology, Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki; ⁹Uppsala University Hospital, Uppsala, Sweden; ¹⁰Rigshospitalet, Copenhagen University Hospital, Copenhagen; ¹¹Danish Cancer Institute, Copenhagen; ¹²Medical University Vienna, Vienna, Austria; ¹³Saarland University Medical School, Saarland, Germany; ¹⁴Bnai Zion Medical Center, Technion, Haifa, Israel; ¹⁵Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel; ¹⁶Cancer Clinical Trials and Research Unit, Cancer Trials Ireland, Beaumont Hospital, Dublin; ¹⁷Ludwig-Maximilians University (LMU), Medical Clinic III, Munich, Germany; ¹⁸Universitaire Ziekenhuizen Leuven, Leuven, Belgium; ¹⁹Hanusch Krankenhaus, Vienna; ²⁰Medical University of Innsbruck, Department of Hematology and Oncology, Innsbruck, Austria; ²¹Zealand University Hospital, Roskilde, Denmark; ²²Turku University Hospital, Turku, Finland; ²³Berufsausüebungsgemeinschaft, Gokos, Dresden, Germany; ²⁴Hämatologisch-Onkologische Schwerpunktpraxis, Wuerzburg, Germany; ²⁵Clinic III (Hematology, Oncology, and Palliative Medicine), Rostock University Medical Center, Rostock, Germany; ²⁶Bruederkrankenhaus Paderborn, Paderborn, Germany; ²⁷Trinity St. James Cancer Institute, Dublin; ²⁸University Hospital Limerick, Limerick, Ireland; ²⁹Chaim Sheba Medical Center, Ramat Gan, Israel; ³⁰ASST Grande Ospedale Metropolitano Niguarda, Milan; ³¹Department of Medicine and Surgery, Institute of Hematology and Center for Hemato-Oncology Research (CREO), University of Perugia, Santa Maria della Misericordia Hospital, Perugia, Italy; ³²Martini Ziekenhuis, Groningen, the Netherlands; ³³Albert Schweitzer Ziekenhuis, Dordrecht, the Netherlands; ³⁴Ziekenhuis St Jansdal, Harderwijk, the Netherlands; ³⁵Amphia Ziekenhuis, Breda, the Netherlands; ³⁶Akershus University Hospital, Oslo; ³⁷Hospital Universitario 12 de Octubre, Madrid; ³⁸Hospital Universitario La Princesa, Madrid; ³⁹Skane University Hospital, Lund, Sweden; ⁴⁰University Hospital Linköping, Linköping, Sweden; ⁴¹KS Winterthur, Winterthur, Switzerland; ⁴²HOCH Health Ostschweiz, Kantonsspital St. Gallen, St. Gallen, Switzerland; ⁴³Universitaetsklinikum Schleswig-Holstein, Medizinische Klinik II, Kiel, Germany; ⁴⁴Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany

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