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Molecular determinants of outcomes in relapsed or refractory mantle cell lymphoma treated with ibrutinib or temsirolimus in the MCL3001 (RAY) trial

Leukemia volume 36, pages 2479–2487 (2022)Cite this article

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Abstract

Mantle cell lymphoma (MCL) is a rare, incurable lymphoma subtype characterized by heterogeneous outcomes. To better understand the clinical behavior and response to treatment, predictive biomarkers are needed. Using residual archived material from patients enrolled in the MCL3001 (RAY) study, we performed detailed analyses of gene expression and targeted genetic sequencing. This phase III clinical trial randomized patients with relapsed or refractory MCL to treatment with either ibrutinib or temsirolimus. We confirmed the prognostic capability of the gene expression proliferation assay MCL35 in this cohort treated with novel agents; it outperformed the simplified MCL International Prognostic Index in discriminating patients with different outcomes. Regardless of treatment arm, our data demonstrated that this assay captures the risk conferred by known biological factors, including increased MYC expression, blastoid morphology, aberrations of TP53, and truncated CCND1 3′ untranslated region. We showed the negative impact of BIRC3 mutations/deletions on outcomes in this cohort and identified that deletion of chromosome 8p23.3 also negatively impacts survival. Restricted to patients with deletions/alterations in TP53, ibrutinib appeared to abrogate the deleterious impact on outcome. These data illustrate the potential to perform a molecular analysis of predictive biomarkers on routine patient samples that can meaningfully inform clinical practice.

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Fig. 1: MCL35 assay heat map for all patients (N = 134).
Fig. 2: Survival by MCL35 risk groups.
Fig. 3: IRC-assessed PFS across each MCL35 risk group stratified by treatment (temsirolimus vs. ibrutinib).
Fig. 4: Frequency of mutations observed in sequenced cohorta.
Fig. 5: Influence of mutations on survival.

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Data availability

The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. Requests for access to data from select studies can be submitted through the Yale Open Data Access (YODA) Project site at yoda.yale.edu. Raw data files are available under controlled access in the European Genome-phenome Archive, under accession numbers EGAD00001008975.

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Acknowledgements

This study was funded by Janssen Research & Development, LLC. The authors would like to thank Dr Simon Rule’s contributions to the study and all the patients who were included in this analysis. Writing assistance was provided by Min Yu, MD, and Ian Phillips, PhD, of Parexel, and was funded by Janssen Research & Development, LLC.

Funding

This trial was sponsored by Janssen Research & Development, LLC.

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Author notes

  1. Ciara L. Freeman

    Present address: Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Centre and Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

  2. These authors contributed equally: Ryan D. Morin, David W. Scott, Georg Lenz.

Authors and Affiliations

  1. Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada

    Ciara L. Freeman, Aixiang Jiang, Merrill Boyle & David W. Scott

  2. Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada

    Prasath Pararajalingam & Ryan D. Morin

  3. Medical Department A for Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany

    Ling Jin, Wendan Xu, Michael Grau, Myroslav Zapukhlyak & Georg Lenz

  4. Oncology Translational Research, Janssen Research & Development, San Diego, CA, USA

    Sriram Balasubramanian

  5. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada

    Aixiang Jiang

  6. Oncology Translational Research, Janssen Research & Development, Spring House, PA, USA

    Brendan Hodkinson & Michael Schaffer

  7. Clinical Oncology, Janssen Research & Development, Raritan, NJ, USA

    Christopher Enny & Sanjay Deshpande

  8. Clinical Biostats, Janssen Research & Development, Raritan, NJ, USA

    Steven Sun

  9. Clinical Oncology, Janssen Research & Development, Leiden, The Netherlands

    Jessica Vermeulen

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Contributions

CLF, PP, LJ, SB, AJ, WX, MG, MZ, MB, BH, MS, CE, SD, SS, JV, RDM, DWS, and GL conceived and/or designed the work that led to the submission, performed experiments, acquired data, technical support, and/or played an important role in interpreting the results; drafted or revised the manuscript; approved the final version; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Ciara L. Freeman.

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Competing interests

CLF received honoraria from Seattle Genetics, Incyte, Janssen, Amgen, Celgene, AbbVie, and Sanofi and research funding from Janssen, Roche, and Teva. SB, BH, MS, CE, SD, SS, and JV are employees of Janssen Research & Development; SB, MS, CE, SD, SS, and JV also have equity ownership with the company. DWS has patents, one of which is licensed to NanoString Technologies, has served as a consultant for AstraZeneca, AbbVie, and Celgene, and received research funding from NanoString Technologies, Janssen, Celgene, and Roche. GL received research funding from Agios, Aquinox, Janssen, MorphoSys, Celgene, Roche, AstraZeneca, Gilead, Bayer, Novartis, and Verastem, and honoraria from Janssen, Celgene, Roche, AstraZeneca, Gilead, Bayer, Novartis, Bristol Myers Squibb, and Hexal, and has served on advisory boards for Janssen, Celgene, Roche, AstraZeneca, Gilead, Bayer, Novartis, Bristol Myers Squibb, Hexal, AbbVie, Genmab, MorphoSys, NanoString, and Takeda. PP, LJ, AJ, WX, MG, MZ, MB, and RDM have no conflicts of interest to disclose.

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Freeman, C.L., Pararajalingam, P., Jin, L. et al. Molecular determinants of outcomes in relapsed or refractory mantle cell lymphoma treated with ibrutinib or temsirolimus in the MCL3001 (RAY) trial. Leukemia 36, 2479–2487 (2022). https://doi.org/10.1038/s41375-022-01658-2

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