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CHRONIC LYMPHOCYTIC LEUKEMIA

Venetoclax consolidation in high-risk CLL treated with ibrutinib for ≥1 year achieves a high rate of undetectable MRD

Leukemia volume 37, pages 1444–1453 (2023)Cite this article

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Abstract

Patients receiving ibrutinib for CLL rarely achieve undetectable measurable residual disease (U-MRD), necessitating indefinite therapy, with cumulative risks of treatment discontinuation due to progression or adverse events. This study added venetoclax to ibrutinib for up to 2 years, in patients who had received ibrutinib for ≥12 months (mo) and had ≥1 high risk feature (TP53 mutation and/or deletion, ATM deletion, complex karyotype or persistently elevated β2-microglobulin). The primary endpoint was U-MRD with 10–4 sensitivity (U-MRD4) in bone marrow (BM) at 12mo. Forty-five patients were treated. On intention-to-treat analysis, 23/42 (55%) patients improved their response to CR (2 pts were in MRD + CR at venetoclax initiation). U-MRD4 at 12mo was 57%. 32/45 (71%) had U-MRD at the completion of venetoclax: 22/32 stopped ibrutinib; 10 continued ibrutinib. At a median of 41 months from venetoclax initiation, 5/45 patients have progressed; none have died from CLL or Richter Transformation. In 32 patients with BM U-MRD4, peripheral blood (PB) MRD4 was analyzed every 6 months; 10/32 have had PB MRD re-emergence at a median of 13 months post-venetoclax. In summary, the addition of venetoclax in patients treated with ≥12mo of ibrutinib achieved high rate of BM U-MRD4 and may achieve durable treatment-free remission.

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Fig. 1
Fig. 2: Treatment Response, PFS and OS.
Fig. 3
Fig. 4
Fig. 5: MRD-free survival from time of cessation of venetoclax.

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Acknowledgements

We would like to thank our fantastic research nurses, Yan Wang, CJ Wei and Ana Ayala for their tireless work in running this study.

Funding

This study was conducted by M.D. Anderson Cancer Center as a investigator-initiated study. Funding and study drug were provided by AbbVie. M.D. Anderson Cancer Center is also supported by NCI Support Grant P30 CA016672. The design of the study, acquisition and interpretation of data and writing of the study was performed entirely by the authors. AbbVie had no role in the conduct or analysis of the study or the writing of the paper.

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Authors and Affiliations

  1. Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    Philip A. Thompson, Michael J. Keating, Alessandra Ferrajoli, Nitin Jain, Tapan M. Kadia, Prithviraj Bose, Naveen Pemmaraju, Nicholas J. Short & William G. Wierda

  2. Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    Christine B. Peterson

  3. Department of Body Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    Naveen Garg

  4. Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    Sa A. Wang & Jeffrey L. Jorgensen

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Contributions

PAT designed and wrote the study, provided clinical care to patients, analyzed data and wrote the paper; MJK, AF, NJ, YW, CW, AA, TMK, PB, NP, and NJS provided clinical care to patients and revised the work critically for important intellectual content; SW and JLJ performed flow cytometry and revised the work critically for important intellectual content; CBP provided the statistical design for the stud and revised the work critically for important intellectual content; NG evaluated imaging studies and revised the work critically for important intellectual content; WGW provided important intellectual input into study design, provided clinical care to patients and revised the work critically for important intellectual content; all authors reviewed the final version and approved it for publication.

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Correspondence to William G. Wierda.

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Competing interests

PT: Research support from AbbVie, Pharmacyclics, Lilly and Adaptive Biotechnologies; Advisory board/honoraria from Janssen, AbbVie, Adaptive Biotechnologies, Beigene, Lilly, Genentech. AF: Research support from Beigene and AstraZeneca; Advisory board/honoraria from Janssen, Beigene and AstraZeneca. NJ: Research support from Pharmacyclics, AbbVie, Genentech, AstraZeneca, BMS, Pfizer, Servier, ADC Therapeutics, Cellectis, Adaptive Biotechnologies, Incyte, Precision Biosciences, Aprea Therapeutics, Fate Therapeutics, Kite/Gilead, Mingsight, Takeda, Medisix, Loxo Oncology, Novalgen, Dialectic Therapeutics, Newave, TransThera Sciences, Novartis; Consulting/Honoraria from Pharmacyclics, Janssen, AbbVie, Genentech, AstraZeneca, BMS, Adaptive Biotechnologies, Kite/Gilead, Precision Biosciences, Beigene, Cellectis, TG Therapeutics, MEI Pharma, Ipsen, CareDX. TMK: Consulting: AbbVie, Agios, Daiichi Sankyo, Genetech, Genzyme, Jazz Pharmaceuticals, Liverum, Novartis, Pfizer, PinotBio, Pulmotect, Sanofi-Aventis, Servier; Research support: AbbVie, Amgen, Ascentage, Astellas, Astex, AstraZeneca, BMS, Celgene, Cellnkos, Cyclacel, Delta-Fly Pharmac, Genetech, Genfleet, Glycomimetics, Iterion, Janssen, Jazz, Pfizer, Pulmotect, Regeneron, SELLAS Life Sciences; Speaker’s Bureau: Biologicx, Cure, Hikma Pharmaceuticals. PB: Honoraria: Incyte, BMS, CTI, Sierra, GSK, Morphosys, Blueprint, Cogent, Novartis, Abbvie, Karyopharm, Pharma Essentia; Research support: Incyte, BMS, CTI, Kartos, Morphosys, Blueprint, Cogent, Ionis, Astellas, Pfizer, NS Pharma and Promedior. NP: Board of Directors/Management: Dan’s House of Hope; Consulting: Protagonist Therapeutics, Cimeio Therapeutics AG, Immunogen, Pacylex Pharmaceuticals, MoreHealth, Cellectis, Stemline; Scientific/Advisory Committee Member: Incyte; Speaker/Preceptorship: Medscape, Intellisphere, LLC; Research Support: US Department of Defense (DOD). NJS: Consulting fees from Pfizer Inc., Jazz Pharmaceuticals, and Sanofi; Research funding from Takeda Oncology, Astellas Pharma Inc., Xencor and Stemline Therapeutics; honoraria from Novartis, Amgen, Astellas Pharma Inc., Sanofi and BeiGene. WGW: Research Support: GSK/Novartis, Abbvie, Genentech, Pharmacyclics LLC, AstraZeneca/Acerta Pharma, Gilead Sciences, Bristol Myers Squibb (Juno & Celgene), KITE Pharma, Sunesis, Miragen, Oncternal Therapeutics, Inc., Cyclacel, Loxo Oncology, Inc./Lilly, Janssen, Xencor.

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Thompson, P.A., Keating, M.J., Ferrajoli, A. et al. Venetoclax consolidation in high-risk CLL treated with ibrutinib for ≥1 year achieves a high rate of undetectable MRD. Leukemia 37, 1444–1453 (2023). https://doi.org/10.1038/s41375-023-01901-4

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