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CHRONIC LYMPHOCYTIC LEUKEMIA

Is unmeasurable residual disease (uMRD) the best surrogate endpoint for clinical trials, regulatory approvals and therapy decisions in chronic lymphocytic leukaemia (CLL)?

Leukemia volume 36, pages 2743–2747 (2022)Cite this article

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Survival is widely considered the most important endpoint in cancer clinical trials. However, in some cancers such as chronic lymphocytic leukaemia (CLL) observing a survival endpoint requires long follow-up which may be impractical for clinical decision-making and regulatory drug approvals. Consequently, several recent clinical trials and approvals in CLL used surrogate endpoints such as progression-free survival (PFS). However, considerable data in diverse cancers indicate PFS is an unreliable survival surrogate [1, 2]. Another potential surrogate, quality-of-life (QoL), also correlates imperfectly with survival in cancers with relatively long survivals such as CLL [3,4,5,6,7,8,9].

Recently, achieving a negative measurable residual disease (MRD)-test determined by several technologies such as multi-parameter flow cytometry (MPFC), polymerase chain reaction (PCR) or next-generation sequencing (NGS) has been used as a surrogate primary endpoint for clinical trials and regulatory approvals. For example, MRD-test data from clinical trials was accepted by the Europeans Medicines Agency (EMA) but not the US Food and Drug Administration (FDA) for approval of blinatumomab in acute lymphoblastic leukaemia (ALL) [10]. Data supporting use of results of MRD-testing for clinical decision-making and/or regulatory drug approvals in acute myeloid leukaemia (AML) and plasma cell myeloma (PCM) are controversial and not yet accepted by regulatory agencies [11, 12]. But what about using results of MRD-testing as an primary endpoint of clinical trials and regulatory approvals in CLL?

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Acknowledgements

RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme and the Ministry of Science and Technology of China (84000-51200002).

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Authors and Affiliations

  1. Peking University Peoples Hospital, Peking University Institute of Hematology, Beijing, China

    Shenmiao Yang

  2. Mayo Clinic, Department of Medicine, Division of Hematology, Rochester, MN, USA

    Neil E. Kay

  3. Mayo Clinic, Department of Laboratory Medicine and Pathology, Division of Hematopathology, Rochester, MN, USA

    Min Shi & Curtis A. Hanson

  4. Haematology Research Centre, Department of Immunology and Inflammation, Imperial College of Science, Technology and Medicine, London, UK

    Robert Peter Gale

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SY and RPG conceived the typescript. All authors contributed to developing the typescript, approved the final iteration and agreed to submit for publication.

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NEK, Advisory Board for: AbbVie, Astra Zeneca, Beigene, Behring, Cytomx Therapy, Dava Oncology, Janssen, Juno Therapeutics, Oncotracker, Pharmacyclics and Targeted Oncology. DSMC (Data Safety Monitoring Committee) for: Agios Pharm, AstraZeneca, BMS –Celgene, Cytomx Therapeutics, Dren Bio Janssen, Morpho-sys, Rigel. Research funding from: AbbVie, Acerta Pharma, Bristol Meyer Squib, Celgene, Genentech, MEI Pharma, Pharmacyclics, Sunesis, TG Therapeutics, Tolero Pharmaceuticals. RPG, consultant to NexImmune Inc, Nanexa Pharma, Ascentage Pharma Group, Antengene Biotech LLC, Medical Director, FFF Enterprises Inc.; Partner, AZAC Inc.; Board of Directors, Russian Foundation for Cancer Research Support; and Scientific Advisory Board: StemRad Ltd.

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Yang, S., Kay, N.E., Shi, M. et al. Is unmeasurable residual disease (uMRD) the best surrogate endpoint for clinical trials, regulatory approvals and therapy decisions in chronic lymphocytic leukaemia (CLL)?. Leukemia 36, 2743–2747 (2022). https://doi.org/10.1038/s41375-022-01699-7

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