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Oxaliplatin before autologous transplantation in combination with high-dose cytarabine and rituximab provides longer disease control than cisplatin or carboplatin in patients with mantle-cell lymphoma: results from the LyMA prospective trial

Bone Marrow Transplantation volume 56, pages 1700–1709 (2021)Cite this article

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Abstract

LyMA trial has demonstrated the benefit of rituximab maintenance after autologous stem cell transplantation (ASCT) in previously untreated mantle-cell lymphoma patients (MCL). Induction consisted of four courses of R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and platinum derivative). The platinum derivative (PD) choice was free: R-DHA-cisplatin, R-DHA-carboplatin, or R-DHA-oxaliplatin. We investigated the prognostic impact of each PD. PFS and OS calculated from inclusion and investigated in an intention-to-treat (ITT) (= 298) and per-protocol analyses (PP) (n = 227). R-DHACis, R-DHACa, or R-DHAOx were used at first cycle in 184, 76, and 38 patients, respectively. Overall, 71 patients (59 in the R-DHACis) required a change in PD, mainly because of PD toxicity. In ITT-analysis, PFS in the R-DHACis and R-DHACa groups were similar (4-year PFS of 65%), while R-DHAOx had a better PFS (4-year PFS of 65% versus 86.5%, respectively, HR = 0.44, p = 0.02). The 4-year OS was 92% for R-DHAOx versus 75.9% for R-DHACis/DHACa (HR = 0.37, p = 0.03). Similar results were yielded in the PP analysis. Low MIPI and R-DHAOx were independent favorable prognostic markers for both PFS (HR = 0.44, p = 0.035) and OS (HR = 0.36, p = 0.045). In vitro and in silico analyses confirmed that oxaliplatin has an anti-MCL cytotoxic effect that differs from that of other PD. R-DHAOx before ASCT provides better outcome in transplantation eligible young MCL patients.

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Fig. 1: Consort diagram of platinum derivative usage.
Fig. 2: Kaplan–Meier estimates of progression free survival (PFS) and overall survival (OS).
Fig. 3: Linear regression analysis of growth index 50 (extracted from CellMinerCDB, n = 50 cell lines with complete data for four PDs, GI50 values are centered and scaled).
Fig. 4: Platinum derivative-induced cell death measured by annexin V staining in five MCL cell lines (REC, Mino, MAVER, GRANTA, and NTS3).

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Funding

Roche SAS supplied rituximab and funded the trial. Amgen provided complementary financial support.

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Authors and Affiliations

  1. Department of Clinical Hematology, Nantes University Hospital, Nantes, France

    Benoit Tessoulin & Steven Le Gouill

  2. CRCINA, INSERM, CNRS, Angers University, Nantes University, Nantes, France

    Benoit Tessoulin, David Chiron & Steven Le Gouill

  3. Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Hemato-Oncology, Paris, France

    Catherine Thieblemont

  4. Sorbonne Paris Cité, Diderot University, Paris, France

    Catherine Thieblemont

  5. Department of Clinical Hematology, Purpan University Hospital, Toulouse, France

    Lucie Oberic

  6. Department of Clinical Hematology, Bordeaux University Hospital, Bordeaux, France

    Kamal Bouadballah

  7. Department of Clinical Hematology, Tours University Hospital, Tours, France

    Emmanuel Gyan

  8. Inserm UMR 1415, Tours University, Tours, France

    Emmanuel Gyan

  9. Department of Clinical Hematology, Amiens University Hospital, Amiens, France

    Gandhi Damaj

  10. Department of Clinical Hematology, Caen University Hospital, Caens, France

    Gandhi Damaj

  11. Department of Hematology, Institut Gustave Roussy, Villejuif, France

    Vincent Ribrag

  12. Department of Clinical Hematology, Grenoble University Hospital, Grenoble, France

    Rémy Gressin

  13. Department of Clinical Hematology, Nancy University Hospital, INSERM 1256, Nancy, France

    Pierre Feugier

  14. Service d’Hématologie Clinique, Centre Hospitalier Universitaire Dijon, INSERM UMR1231, Dijon, France

    Olivier Casasnovas

  15. Department of Hematology, Centre Hospitalier d’Avignon, Avignon, France

    Hacène Zerazhi

  16. Unité Hémopathies Lymphoïdes, AP-HP Hôpital Henri Mondor, Créteil, France

    François Lemonnier

  17. Department of Clinical Hematology, Vendée Hospital Center, La Roche sur Yon, France

    Hervé Maisonneuve

  18. Department of Biostatistics, LYSARC, Lyon, France

    Clementine Joubert

  19. Cliniques Universitaires Saint-Luc, Université de Louvain, Brussels, Belgium

    Eric Van Den Neste

  20. Department of Clinical Hematology, MICA Research Unit, Rennes University Hospital, Rennes, France

    Thierry Lamy

  21. Department of Hematology, Centre Henri Becquerel, University Rouen, INSERM U1245, Rouen, France

    Hervé Tilly

  22. Department of Pathology, Nantes University Hospital, Nantes, France

    Anne Moreau

  23. Hôpital Necker, Institut Imagine, Assistance Publique-Hôpitaux de Paris, University Paris Descartes, Paris, France

    Olivier Hermine

Authors
  1. Benoit Tessoulin
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  2. David Chiron
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  3. Catherine Thieblemont
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  4. Lucie Oberic
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  7. Gandhi Damaj
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  8. Vincent Ribrag
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  13. François Lemonnier
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  14. Hervé Maisonneuve
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  15. Clementine Joubert
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  18. Hervé Tilly
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  19. Anne Moreau
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  20. Olivier Hermine
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  21. Steven Le Gouill
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Contributions

BT and SLG analyzed the data and wrote the article. DC performed the in vitro analyses. CT, LO, KB, EG, GD, VR, RG, PF, OC, HZ, FL, HM, EVDN, TL, HT, and OH provided data. AM performed central reviewing of histological specimen. CJ performed the statistical analysis.

Corresponding author

Correspondence to Steven Le Gouill.

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The authors declare that they have no conflict of interest.

Ethics

The LyMa study was performed according to the Declaration of Helsinki and approved by an ethics committee (CPP Ouest 1–11 March, 2008), ClinicalTrials.gov (NCT00921414). Patients signed informed consent.

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Tessoulin, B., Chiron, D., Thieblemont, C. et al. Oxaliplatin before autologous transplantation in combination with high-dose cytarabine and rituximab provides longer disease control than cisplatin or carboplatin in patients with mantle-cell lymphoma: results from the LyMA prospective trial. Bone Marrow Transplant 56, 1700–1709 (2021). https://doi.org/10.1038/s41409-020-01198-2

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