Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial

Al‐Sawaf, Othman; Zhang, Can; Tandon, Maneesh; Sinha, Arijit; Fink, Anna Maria; Robrecht, Sandra; Samoylova, Olga; Liberati, Anna Marina; Pinilla‐Ibarz, Javier; Opat, Stephen; Sivcheva, Lylia; Dû, Katell Le; Fogliatto, Laura; Niemann, Carsten Utoft; Weinkove, Robert; Robinson, Sue; Kipps, Thomas J.; Tausch, Eugen; Schary, William; Ritgen, Matthias; Wendtner, Clemens; Kreuzer, Karl; Eichhorst, Barbara; Stilgenbauer, Stephan; Hallek, Michael; Fischer, Kirsten

doi:10.1016/s1470-2045(20)30443-5

Cited by 258 publications

(276 citation statements)

References 22 publications

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“…21 Subgroup analyses for IGHV-mutated disease also demonstrated a significant benefit for venetoclax plus obinutuzumab compared with chlorambucil plus obinutuzumab as well as for unmutated IGHV disease [mutated IGHV HR 0.33 (CI 0.16-0.70); unmutated IGHV disease HR 0.23 (CI 0.15-0.35)]. 43 So far, no difference in OS has been observed. Venetoclax plus obinutuzumab combination, if available, would be the preferred therapy in comparison with CIT for patients with comorbid conditions [I, A].…”

Section: Annals Of Oncologymentioning

confidence: 98%

Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

et al. 2021

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Section: Annals Of Oncologymentioning

confidence: 98%

Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

et al. 2021

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“…After a median follow-up of 39.6 months, patients in the venetoclax arm had a significantly longer PFS than patients in the chlorambucil arm. 58 How this compares to indefinite treatment regimens, and whether venetoclax can be administered to patients who relapse after end of treatment, are questions that need to be addressed in future studies (NCT04419519).…”

Section: Temporally Sequenced and Fixed-duration Therapiesmentioning

confidence: 99%

Overcoming resistance to targeted therapies in chronic lymphocytic leukemia

Skånland

Mato

2021

Blood Advances

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Insight into the critical role of B-cell receptor signaling for the pathogenesis of chronic lymphocytic leukemia (CLL) led to the development of targeted therapies directed at key regulators of cell survival. Agents targeting B-cell lymphoma-2 protein, Bruton’s tyrosine kinase (BTK), and phosphatidylinositol 3-kinase are approved for treatment of CLL, and have significantly improved the disease management. Nevertheless, acquired resistance to the targeted therapies is a challenge still to be resolved. The mechanisms underlying resistance are becoming clearer, and include secondary mutations within the drug target and activation of bypass pathways. This knowledge has allowed development of strategies to prevent and overcome treatment resistance. Approaches to prevent resistance include targeting bypass mechanisms by combination therapies, temporally sequencing of therapies, improved clinical trial designs, and real-time monitoring of patient response. A rational design of drug sequencing may secure effective treatment options at the relapsed setting. Next-generation inhibitors and bispecific antibodies have the potential to overcome resistance to the BTK inhibitor ibrutinib. Immunotherapy, including chimeric antigen receptor-modified T-cell therapy, is explored for relapsed CLL. Here, recent advances that have contributed to the understanding of resistance to targeted therapies in CLL are discussed. Strategies for managing resistance are reviewed, including translational, real-world, and clinical perspectives.

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“…With venetoclax, PFS and OS were superior to bendamustine plus rituximab in patients with relapsed/refractory CLL in the phase 3 MURANO trial (73). Results of the phase 3 CLL14 trial indicated that patients with treatment-naïve CLL receiving venetoclax plus obinutuzumab had a significantly longer PFS than did patients on chlorambucil plus obinutuzumab (HR, 0.31; 95% CI: 0.22-0.44; p < 0.0001) (74). Interim results from an ongoing phase 2 trial evaluating a timelimited combination of acalabrutinib, venetoclax, and obinutuzumab in treatment-naïve CLL (NCT03580928) showed a 100% response rate (75% PR; 25% CR) (75).…”

Section: Discussionmentioning

confidence: 98%

Acalabrutinib: A Selective Bruton Tyrosine Kinase Inhibitor for the Treatment of B-Cell Malignancies

Abbas

Wierda

2021

Front. Oncol.

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Bruton tyrosine kinase (BTK) is a validated target for treatment of B-cell malignancies, and oral inhibitors of BTK have emerged as a standard of care for these diseases. Acalabrutinib is a second generation, highly selective, potent, covalent BTK inhibitor that exhibits minimal off-target activity in in vitro assays, providing the potential to improve tolerability over the first-in-class BTK inhibitor, ibrutinib. Acalabrutinib was approved for the treatment of relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) in the US in 2017 and 2019, respectively. Acalabrutinib is also undergoing trials for other B-cell malignancies, both as monotherapy and in combinations. In this review, we discuss results from clinical trials evaluating the efficacy and safety of acalabrutinib in patients with CLL, MCL, and Waldenstrom’s macroglobulinemia. Recent phase 3 data showed that acalabrutinib improved progression-free survival (PFS) compared with rituximab plus idelalisib or rituximab plus bendamustine in patients with relapsed/refractory CLL, and acalabrutinib with or without obinutuzumab improved PFS compared with chlorambucil plus obinutuzumab in patients with treatment-naïve CLL. Overall, acalabrutinib had a tolerable safety profile, with most adverse events being grade 1/2 severity (most commonly headache and diarrhea) and a low rate of discontinuation due to adverse events.

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Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial

Cited by 258 publications

References 22 publications

Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Overcoming resistance to targeted therapies in chronic lymphocytic leukemia

Acalabrutinib: A Selective Bruton Tyrosine Kinase Inhibitor for the Treatment of B-Cell Malignancies

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