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LYMPHOMA

Immune priming with avelumab and rituximab prior to R-CHOP in diffuse large B-cell lymphoma: the phase II AvR-CHOP study

Leukemia volume 37, pages 1092–1102 (2023)Cite this article

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Abstract

Immune evasion, due to abnormal expression of programmed-death ligands 1 and 2 (PD-L1/PD-L2), predicts poor outcomes with chemoimmunotherapy in diffuse large B-cell lymphoma (DLBCL). Immune checkpoint inhibition (ICI) has limited efficacy at relapse but may sensitise relapsed lymphoma to subsequent chemotherapy. ICI delivery to immunologically intact patients may thus be the optimal use of this therapy. In the phase II AvR-CHOP study, 28 patients with treatment-naive stage II–IV DLBCL received sequential avelumab and rituximab priming (“AvRp;” avelumab 10 mg/kg and rituximab 375 mg/m2 2-weekly for 2 cycles), R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone for 6 cycles) and avelumab consolidation (10 mg/kg 2-weekly for 6 cycles). Grade 3/4 immune-related adverse events occurred in 11%, meeting the primary endpoint of a grade ≥3 irAE rate of <30%. R-CHOP delivery was not compromised but one patient ceased avelumab. Overall response rates (ORR) after AvRp and R-CHOP were 57% (18% CR) and 89% (all CR). High ORR to AvRp was observed in primary mediastinal B-cell lymphoma (67%; 4/6) and molecularly-defined EBV-positive DLBCL (100%; 3/3). Progression during AvRp was associated with chemorefractory disease. Two-year failure-free and overall survival were 82% and 89%. An immune priming strategy with AvRp, R-CHOP and avelumab consolidation shows acceptable toxicity with encouraging efficacy.

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Fig. 1: Patient disposition.
Fig. 2: Outcomes of patients treated with AvR-CHOP.
Fig. 3: PET-CT characteristics after 2 cycles of AvR priming.
Fig. 4: PET-CT characteristics after 2 cycles of AvR priming.
Fig. 5: Gene expression profiling.

Data availability

Requests for non-identifiable data for valid academic reasons as judged by the trial management group will be granted, with appropriate data sharing agreement, and should be addressed to the chief investigator (EAH). The study protocol is included as a data supplement available with the online version of this article.

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Acknowledgements

This work was financially supported by Merck Healthcare Pty. Ltd., Macquarie Park, Australia, an affiliate of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945), as part of an alliance between the healthcare business of Merck KGaA, Darmstadt, Germany, and Pfizer. Funding for biomarker analysis provided by Scott Canning Tour de Cure grant (EAH) and the Wilson Centre for Lymphoma Genomics. Dr Catherine Oakman, Western Health, provided intellectual input and logistical support. KM is a DMedSci candidate at the University of Melbourne. This work is submitted in partial fulfillment of the requirement for the DMedSci and is supported by a Research Training Program Scholarship.

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Authors and Affiliations

  1. Olivia Newton John Cancer Research Institute at Austin Health, Heidelberg, VIC, Australia

    Kate Manos, Sze-Ting Lee, Charmaine Smith, Tineke Fancourt, Joanne Hawking, Wendi Lin, Andrew M. Scott, Andrew Grigg, Chun Yew Fong & Eliza A. Hawkes

  2. Ballarat Regional Integrated Cancer Centre, Ballarat Central, VIC, Australia

    Geoffrey Chong

  3. Princess Alexandra Hospital, Woolloongabba, QLD, Australia

    Colm Keane & Melinda Burgess

  4. Melbourne Medical School, University of Melbourne, Parkville, VIC, Australia

    Leonid Churilov

  5. Eastern Health, Box Hill, VIC, Australia

    Joseph McKendrick

  6. Western Health, Footscray, VIC, Australia

    William Renwick

  7. Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia

    Piers Blombery & Niles Elizabeth Nelson

  8. Fiona Stanley Hospital, Murdoch, WA, Australia

    Allison Barraclough

  9. Townsville University Hospital, Douglas, QLD, Australia

    Joel Wight

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Contributions

Contributions: EAH, GC, LC, CK, PB, CF, AS, STL designed the study; EAH, KM, GC, STL, JM, WR, JH, AB, JW, AG conducted the study; EAH, KM, GC, JM, WR, JH, AB, JW, AG recruited and followed-up with patients; EAH, KM, GC, JM, WR, JH, AB, JW, AG, CS, WL were responsible for data collection; EAH, KM, CK, STL, CS, LC, PB, MB, NN, TF, AS were responsible for data analysis; EAH, KM, GC, CK, PB, NN were involved in the interpretation of data. All authors reviewed and approved the final manuscript.

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Correspondence to Eliza A. Hawkes.

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Competing interests

KM has received travel expenses from Bristol Myers Squibb. GC has acted as a consultant/advisor for Bristol Myers Squibb Foundation (paid to institution) and received research funding from AstraZeneca, Bayer, Bristol-Myers Squibb, Hutchison MediPharma, Isofol Medical, Merck Serono, Pharmacyclics, Regeneron, SERVIER (all paid to institution). CK has received honoraria from Roche, Beigene, Karyopharm Therapeutics. WR has received research funding from GSK, Janssen, MorphoSys and Incyte (all paid to institution). AS has acted as a consultant for Imagion; received research funding from Telix, Curis, ITM, Adalta, Fusion, Astra Zeneca, EMD Serono, Cyclotek, AVID/Lilly and Merck (all paid to institution); and holds patents relating to antibodies to EGFR, HER2, PDGF-CC, FN-14, GM-CSF and EPhA3. AB has acted as a speaker for Roche and as a consultant/advisor for Gilead. JW has received honoraria and travel subsidies from Abbvie and Janssen; and is on the advisory board for Abbive and Alexion. CF has received honoraria from Abbvie, Amgen, Bristol-Myers Squibb, Novartis and Pfizer; has acted as a consultant/advisor for Abbvie, Amgen, Astellas Pharma, Bristol-Myers Squibb, Novartis and Pfizer; and has received research funding from Amgen and Astellas Pharma. EAH has received research funding Bristol Myers Squibb/Celgene, Merck KgA, Astra Zeneca, and F. Hoffmann-La Roche (all paid to institution); has acted as a consultant/advisor for F. Hoffmann-La Roche, Antigene, Bristol Myers Squibb, Astra Zeneca, Novartis, Merck Sharpe Dohme, Specialised therapeutics and Gilead; has acted as a speaker for Roche, Astra Zeneca, Janssen, and Regeneron. The remaining authors declare no competing financial interests.

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Manos, K., Chong, G., Keane, C. et al. Immune priming with avelumab and rituximab prior to R-CHOP in diffuse large B-cell lymphoma: the phase II AvR-CHOP study. Leukemia 37, 1092–1102 (2023). https://doi.org/10.1038/s41375-023-01863-7

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