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LYMPHOMA

Long-term outcomes by bone marrow B-cell depletion from the R2W trial of bortezomib with cyclophosphamide and rituximab in Waldenstrőm macroglobulinaemia

Leukemia volume 38, pages 822–828 (2024)Cite this article

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Abstract

There remains a lack of consensus as to the most appropriate primary therapy in Waldenstrőm macroglobulinemia (WM). We evaluated a novel bortezomib-based combination and developed a sensitive WM-specific flow cytometry assay (limit of detection 0.004% of leucocytes) to assess bone marrow (BM) response. Sixty treatment-naïve WM patients were enroled into this phase II trial and randomised (2:1) to receive cyclophosphamide and rituximab with either bortezomib (BRC) or fludarabine (FCR). The primary objective was to assess the overall response rate (ORR) in eligible patients receiving BRC (N = 41). An ORR of 97.6% (95%CI:87.1–99.9) was observed; 27 (65.9%) patients remain alive without progression after 62.6 months median follow-up, with 2-, 3- and 5-year progression-free survival (PFS) rates of 92.7% (95%CI:79.0–97.6), 80.5% (95%CI:64.8–89.7) and 65.5% (95%CI:48.8–77.9). Persistent WM B-cells were demonstrable in 19/38 patients at the end of treatment (median 0.24%, range 0.02–11.2%). PFS was markedly longer in patients with BM B-cell depletion (<0.004%) compared to those who had persistent BM B-cells detectable at end of treatment (HR = 0.06, 95%CI:0.01–0.47, p < 0.001), and remained independently associated after adjusting for baseline risk stratification or investigator-assessed response. BRC is a tolerable, highly efficacious regimen for treatment-naïve WM patients. BM B-cell depletion is independently associated with patient outcomes.

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Fig. 1
Fig. 2: Outcomes for patients treated with BRC.
Fig. 3: Effect of bone marrow B-cell depletion on progression free survival.

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Data availability

Original data are available for this study upon reasonable request and review. Please contact Rebecca.auer@nhs.net.

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Acknowledgements

This study was supported by the grant C26303/A14139 to RA from Cancer Research UK and by Roche Products Ltd and Janssen-Cilag Ltd. The authors would like to thank Professor Malcolm Ranson (Christie Hospital NHS Trust), Dr Robert Glynne-Jones (Mount Vernon Hospital), Professor Peter Donnan (University of Dundee), Professor Claire Harrison (Guy’s and St Thomas’ NHS Foundation Trust), Professor David Miles (Mount Vernon Cancer Centre), Dr Paul Silcocks (University of Liverpool) and Dr Caroline Kelly (CR UK Clinical Trials Unit, Glasgow) for providing study oversight as the Independent Data Monitoring Committee (current and former members) as well as all of the patients and investigators who contributed to this study.

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Author notes

  1. These authors contributed equally: Ruth de Tute, Nicholas Counsell.

Authors and Affiliations

  1. St James’s University Hospital, Leeds, UK

    Ruth de Tute & Roger Owen

  2. CR UK and UCL Cancer Trials Centre, London, UK

    Nicholas Counsell, Laura Clifton-Hadley, Bilyana Popova, Paul Smith & Oliver Schofield

  3. University College London Hospital, London, UK

    Shirley D’Sa & William Townsend

  4. University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

    Guy Pratt

  5. Colchester General Hospital, Colchester, UK

    Gavin Campbell

  6. Oxford University Hospitals NHS Foundation Trust, Oxford, UK

    Lauren Campbell & Ross Sadler

  7. Barts Health NHS Trust, London, UK

    Rebecca Auer

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  1. Ruth de Tute
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Contributions

RdT was responsible for designing the laboratory flow cytometry assay, performing laboratory analyses, verifying and analysing data, interpreting results, making the figures and writing parts of the paper. NC was responsible for designing the trial, verifying and analysing data, interpreting results, making the figures and writing parts of the paper. LCH was responsible for designing the trial and contributed to writing the paper. SD’S was responsible for designing the trial and performing the research by treating patients and collecting their data. GP was responsible for designing the trial and performing the research by treating patients and collecting their data. GC was responsible for performing the research by treating patients and collecting their data. LC was responsible for performing laboratory analyses. RS was responsible for performing laboratory analyses and analysing the data. WT was responsible for designing the trial and helped with writing of the trial protocol. BP was responsible for designing the trial and helped with writing of the trial protocol. PS was responsible for designing the trial. OS was responsible for collecting the trial data. RO was responsible for responsible for designing the trial, performing the research by treating patients and collecting their data, interpreting results and writing parts of the paper. RA was responsible for designing the trial, performing the research by treating patients and collecting their data, interpreting results and writing the paper. As Chief Investigator of the trial she had overall responsibility for the trial and trial protocol. All authors had full access to all the data in the study, critically reviewed the manuscript and approved the content. All authors accept responsibility to submit for publication.

Corresponding author

Correspondence to Rebecca Auer.

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Competing interests

LC-H has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials. Funding has been awarded/used in the last 2 years from Millennium pharmaceutics inc., Bristol-Myers Squibb Pharmaceuticals Ltd., Amgen GmBbH., Celgene Ltd., Merck Sharp and Dohme Ltd., Janssen-Cilag Ltd and Pfizer Ltd., SD’S has received research funds from BeiGene and Janssen-Cilag Ltd. and has acted on an advisory board and received honoraria from BeiGene, Janssen-Cilag Ltd and Sanofi, WT has received honoraria and consultancy fees from Roche, Gilead and Celgene, GC has received educational grants from Novartis and Bristol-Myers Squibb, RO has received honoraria from AstraZeneca and Celgene and has acted on an advisory board and received honoraria from BeiGene and Janssen-Cilag Ltd, RA has received consultancy fees from BeiGene and Janssen-Cilag Ltd. Funding has been awarded to support a clinical trial from Janssen-Cilag Ltd. No other authors declared conflicts of interest.

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de Tute, R., Counsell, N., Clifton-Hadley, L. et al. Long-term outcomes by bone marrow B-cell depletion from the R2W trial of bortezomib with cyclophosphamide and rituximab in Waldenstrőm macroglobulinaemia. Leukemia 38, 822–828 (2024). https://doi.org/10.1038/s41375-024-02162-5

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