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Acute myeloid leukemia

Clonal dominance is an adverse prognostic factor in acute myeloid leukemia treated with intensive chemotherapy

Leukemia volume 35, pages 712–723 (2021)Cite this article

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Abstract

Intra-tumor heterogeneity portends poor outcome in many cancers. In AML, a higher number of drivers worsens prognosis. The Shannon Index is a robust metric of clonal heterogeneity that accounts for the number of clones, but also their relative abundance. We show that a Shannon Index can be estimated from bulk sequencing, which is correlated (ρ = 0.76) with clonal diversity from single-colony genotyping. In a discovery cohort of 292 patients with sequencing of 43 genes, a higher number of drivers (HR = 1.18, P = 0.028) and a lower Shannon Index (HR = 0.68, P = 0.048), the latter reflecting clonal dominance, are independently associated with worse OS independently of European LeukemiaNet 2017 risk. These findings are validated in an independent cohort of 1184 patients with 111-gene sequencing (number of drivers HR = 1.16, P = 1 × 10−5, Shannon Index HR = 0.81, P = 0.007). By re-interrogating paired diagnosis/relapse exomes from 50 cytogenetically normal AMLs, we find clonal dominance at diagnosis to be correlated with the gain of a significantly higher number of mutations at relapse (P = 6 × 10−6), hence with clonal sweeping. Our results suggest that clonal dominance at diagnosis is associated with the presence of a leukemic phenotype allowing rapid expansion of new clones and driving relapse after chemotherapy.

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Fig. 1: Estimation of clonal dominance with Shannon Index from bulk targeted sequencing of AML samples.
Fig. 2: Prognostic impact of number of drivers and clonal diversity in the discovery cohort.
Fig. 3: Prognostic impact of clonal dominance in the validation cohort.
Fig. 4: Clonal evolution at relapse based on clonal dominance at diagnosis.

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Acknowledgements

We are indebted to the Institut de Recherche Saint-Louis Core Facility (Niclas Setterblad, Antonio Alberdi, Simon Tournier), Emilie Gaudas, Kelly Vanoukia, Esther Dubo, Kaddour Chabane, Carole Charlot and Christine Lespinasse for help with sequencing. RI is supported by grants from Association Laurette Fugain, Association Princesse Margot, Association pour la Recherche contre le Cancer, Fondation Leucémie Espoir, and Ligue Contre le Cancer.

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Authors and Affiliations

  1. Service Hématologie Adultes, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, F-75010, Paris, France

    Marco Cerrano, Loic Vasseur, Florence Rabian, Etienne Lengliné, Emmanuel Raffoux, Karine Celli-Lebras, Hervé Dombret & Raphael Itzykson

  2. Department of Molecular Biotechnology and Health Sciences, Division of Hematology, University of Turin, Turin, Italy

    Marco Cerrano

  3. Hematology Laboratory, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, University of Paris, Paris, France

    Matthieu Duchmann, Rathana Kim, Samuel Quentin, Marie Passet, Odile Maarek, Anna Raimbault, Jean Soulier & Emmanuelle Clappier

  4. Université de Paris, Génomes, Biologie Cellulaire et Thérapeutique U944, INSERM, CNRS, F-75010, Paris, France

    Matthieu Duchmann, Rathana Kim, Samuel Quentin, Justine Pasanisi, Marie Passet, Marie Sébert, Lionel Adès, Pierre Fenaux, Jean Soulier, Emmanuelle Clappier & Raphael Itzykson

  5. Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Hôpital Saint-Antoine, Hématologie Biologique, F-75012, Paris, France

    Pierre Hirsch & François Delhommeau

  6. Hospices Civils de Lyon, Lyon-Sud Hospital, Hematology Department, Pierre Bénite, France

    Xavier Thomas

  7. Senior Leukemia Unit, Department of Hematology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, University of Paris, Paris, France

    Ramy Rahmé, Marie Sébert, Lionel Adès & Pierre Fenaux

  8. Adolescent & Young Adult Leukemia Unit, Department of Hematology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, University of Paris, Paris, France

    Nathalie Dhédin & Nicolas Boissel

  9. EA3518, Saint-Louis Resarch Institute, University of Paris, Paris, France

    Nicolas Boissel & Hervé Dombret

  10. Hospices Civils de Lyon, Hôpital Lyon Sud, Service d’Hématologie Biologique, Pierre-Bénite, France

    Pierre Sujobert

  11. Cancer Research Center of Lyon, INSERM U1052 UMR CNRS 5286, Lyon, France

    Pierre Sujobert

  12. Equipe labellisée Ligue Contre le Cancer, Université de Lyon, Lyon, France

    Pierre Sujobert

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  1. Marco Cerrano
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Contributions

MC and RI designed the study, assembled and analyzed the data and drafted the paper. PS, EC and RI supervised the study. MD performed the bioinformatic analyses. RK, MP, SQ, JP, JS, EC, and PS performed genotyping of the discovery cohort. LV, XT, FR, RR, EL, ER, ND, MS, OM, AR, KCL, LA, PF, NB, and HD provided clinical data for the discovery cohort. PH and FD performed single-colony genotyping. All authors revised the paper and accepted its final version.

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Correspondence to Raphael Itzykson.

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Cerrano, M., Duchmann, M., Kim, R. et al. Clonal dominance is an adverse prognostic factor in acute myeloid leukemia treated with intensive chemotherapy. Leukemia 35, 712–723 (2021). https://doi.org/10.1038/s41375-020-0932-8

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