Utility of measurable residual disease for predicting treatment outcomes with BCR- and BCL2-Targeted therapies in patients with CLL

Abstract

Inhibitors targeting B-cell receptor (BCR) signaling pathway proteins and B-cell lymphoma-2 (BCL2) in chronic lymphocytic leukemia (CLL) are recommended in the first-line and relapsed/refractory disease settings. Measurable residual disease (MRD) is an important prognostic tool in patients treated with the BCL2-targeted agent, venetoclax. We explored the relationship between MRD status and progression-free (PFS)/overall survival (OS) in patients with CLL, following treatment with novel BCR- and BCL2-targeted agents. Compared with chemoimmunotherapy, higher rates of undetectable (u)MRD were achieved with BCL2-targeted therapies; achieving uMRD status was associated with longer PFS and OS than MRD-positivity. Continuous treatment with BCR-targeted agents did not achieve uMRD status in many patients, and outcomes were not correlated with uMRD status. Future clinical trials of targeted treatment combinations could be designed to demonstrate uMRD as a treatment objective, and allow a response-driven, personalized strategy to optimize treatment and improve OS outcomes.

Keywords:

• Lymphoid leukemia
• pharmacotherapeutics
• prognostication

Acknowledgments

Venetoclax is being developed in a collaboration between Genentech, Inc. and AbbVie. Third-party medical writing assistance, under the direction of the authors, was provided by Lynda McEvoy, PhD, and Rachel Dobb, PhD, of Ashfield MedComms, an Ashfield Health company, and was funded by F. Hoffmann-La Roche Ltd.

Author contributions

All authors were involved in interpreting the data and writing the manuscript. All authors approved the final version for submission.

Disclosure statement

WGW is employed by The University of Texas MD Anderson Cancer Center; and has received research funding from AbbVie and Genentech, Inc; and travel, accommodations, and expenses from AbbVie and Genentech, Inc. TJK owns stock in and patents/royalties from Oncternal Therapeutics Inc; has received research funding from Pharmacyclics, AbbVie, Breast Cancer Research Foundation, MD Anderson Cancer Center, Oncternal Therapeutics Inc, Specialized Center of Research (SCOR) – The Leukemia and Lymphoma Society (LLS), California Institute for Regenerative Medicine (CIRM), and the National Cancer Institute/NIH; and honoraria from Pharmacyclics, AbbVie, Genentech, Inc., F. Hoffmann-La Roche Ltd, Janssen, Gilead, National Cancer Institute/NIH, and Celgene. Cirmtuzumab was developed by TJK in the TJK laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the TJK laboratory. OA-S has received honoraria from F. Hoffmann-La Roche Ltd, Janssen, Gilead, AbbVie, AstraZeneca, BeiGene, and Adaptive; has participated in advisory boards and received personal fees from F. Hoffmann-La Roche Ltd, Janssen, Gilead, AbbVie, and AstraZeneca; and has received research funding from BeiGene, F. Hoffmann-La Roche Ltd, Janssen, and AbbVie. BC is employed by and owns equity in AbbVie. JMLB is employed by Genentech, Inc./F. Hoffmann-La Roche Ltd and owns equity in F. Hoffmann-La Roche Ltd. YM is employed by Genentech, Inc. and owns equity in F. Hoffmann-La Roche Ltd. YJ is employed by Genentech, Inc./F. Hoffmann-La Roche Ltd and owns equity in F. Hoffmann-La Roche Ltd. JFS has received consultancy fees from Celgene and F. Hoffmann-La Roche Ltd; research funding from AbbVie, Celgene, Janssen, and F. Hoffmann-La Roche Ltd; has participated in speakers bureau for AbbVie, Celgene, and F. Hoffmann-La Roche Ltd; has membership of an entity’s Board of Directors or has participated in advisory committees for, and received honoraria from, AbbVie, AstraZeneca, BMS, Gilead, Janssen, Mei Pharma, Morphosys, F. Hoffmann-La Roche Ltd, Sunesis, and Takeda.

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

Additional information

Funding

This comprehensive literature review was supported by F. Hoffmann-La Roche Ltd.