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Acute lymphoblastic leukemia

Adult T-cell acute lymphoblastic leukemias with IL7R pathway mutations are slow-responders who do not benefit from allogeneic stem-cell transplantation

Leukemia volume 34, pages 1730–1740 (2020)Cite this article

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Abstract

The prognostic value of IL7-receptor pathway (IL7Rp) mutations in T-cell acute lymphoblastic leukemia (T-ALL) remains unclear. We performed a comprehensive study of 200 adult patients with T-ALL included in the GRAALL2003/2005 protocols to address the clinical significance of IL7Rp mutations. Next-generation sequencing of the IL7Rp (IL7R/JAK1/JAK3/STAT5B) revealed that IL7Rp mutations were frequent in adult T-ALL (28%) particularly in immature/early T-cell progenitor (ETP)-ALL. They were associated with mutations of NOTCH-pathway, PHF6, and PRC2 components but not with K/NRAS. IL7Rp mutated (IL7Rpmut) T-ALL were slow-responders, with a high rate of M2/M3 day-8 marrow compared with IL7Rp non-mutated (IL7RpWT) T-ALL (p = 0.002) and minimal residual disease positivity at 6-weeks (MRD1) (p = 0.008) but no difference in MRD2 positivity at 12-weeks. Despite this, no adverse prognosis was evidenced when censored for allogeneic hematopoietic stem cell transplantation (HSCT). In time-dependent analysis, HSCT did not benefit IL7Rpmut patients whereas it was of marked benefit to IL7RpWT cases. IL7Rp-mutations identify a subgroup of slow-responder T-ALLs which benefit from post-induction chemotherapy regimens but not from HSCT. Our data suggest that prior knowledge of the mutation status of IL7Rp may influence HSCT decision and help to guide therapy reduction.

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Fig. 1: IL7R signaling pathway genes mutational landscape in adult T-ALL enrolled in the GRAALL-2003 and -2005 protocols.
Fig. 2: Genetic profiles of adult IL7Rpmut T-ALL.
Fig. 3: Adult IL7Rpmut T-ALLs are not associated with poor prognosis.
Fig. 4: Adult high-risk IL7Rpmut T-ALL displayed favorable outcome treated by chemotherapy and did not benefit from HSCT.

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Acknowledgements

We thank all the participants in the GRAALL-2003 and GRAALL-2005 study groups for the collection and the provision of data and patient samples, and Véronique Lheritier for the collection of clinical data. We thank the Swiss State Secretariat for Education, Research and Innovation (SERI) Switzerland for support. We thank Force Hemato and Association pour la Recherche contre le Cancer (ARC) for support. We acknowledge Guillaume Andrieu, Emmanuelle Clappier, André Delannoy, and Philippe Rousselot for their support in editing the manuscript.

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Authors and Affiliations

  1. Université de Paris, Institut Necker-Enfants Malades, Institut National de Recherche Médicale U1151, Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France

    Rathana Kim, Aurore Touzart, Florian Thonier, Patrick Villarese, Loïc Passini, Elizabeth Macintyre, Vahid Asnafi & Ludovic Lhermitte

  2. Université de Paris, EA-3518, Institut de Recherche Saint-Louis, Hematology Adolescent and Young Adult Unit, Assistance Publique-Hôpitaux de Paris, Saint-Louis Hospital, Paris, France

    Nicolas Boissel

  3. Department of Hematology, CHU de Bordeaux, Hôpital du Haut-Levêque, Pessac, France

    Thibaut Leguay

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

    Xavier Thomas

  5. Université de Paris, Department of Hematology, Adult Hematology Unit, Assistance Publique-Hôpitaux de Paris, Saint-Louis Hospital, Paris, France

    Emmanuel Raffoux & Hervé Dombret

  6. Service d’Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France

    Françoise Huguet

  7. Plateforme Bioinformatique, Institut Imagine, Paris, France

    Cécile Fourrage

  8. Department of Hematology, CHU Angers, Angers, France

    Mathilde Hunault & Norbert Ifrah

  9. CRCINA, INSERM Université de Nantes, Université d’Angers, Angers, France

    Mathilde Hunault

  10. Inserm U1245 and Department of Hematology, Centre Henri Becquerel and Normandie Univ UNIROUEN, Rouen, France

    Stéphane Lepretre

  11. Department of Hematology, CHU, Nantes, France

    Patrice Chevallier

  12. INSERM UMR1232 & CNRS ERL6001 CRCINA IRS-UN, Nantes, France

    Patrice Chevallier

  13. Institut Universitaire d’Hématologie, Université Paris Diderot, Sorbonne Paris Cité, Paris Cancer Research Institute (PACRI), Paris, France

    Thorsten Braun

  14. Laboratoire de Transfert des Leucémies, EA3518, Université de Paris, Paris, France

    Thorsten Braun

  15. Département d’Hématologie, Assistance Publique - Hôpitaux de Paris, Hôpital Avicenne, Université Paris 13, Bobigny, France

    Thorsten Braun

  16. Group for Research on Adult Acute Lymphoblastic Leukemia, Coordination Office, Centre Hospitalier Lyon Sud, Pierre Bénite, France

    Véronique Lhéritier

  17. Institut d’Hématologie de Basse-Normandie, CHU, Caen, France

    Sylvain Chantepie

  18. Service d’Hématologie, Assistance Publique, Hôpitaux de Paris, Hôpital Henri Mondor, Créteil, France

    Sébastien Maury

  19. Service d’Hématologie Clinique, CHU, Hôpital Pontchaillou, Rennes, France

    Martine Escoffre

  20. Service d’Hématologie, Institut de Cancérologie Lucien Neuwirth, Saint Priest en Jarez, France

    Emmanuelle Tavernier

  21. Department of Oncology, Department of Medical Specialties, University Hospital and University of Geneva, Geneva, Switzerland

    Yves Chalandon

  22. Swiss Group for Clinical Cancer Research, Bern, Switzerland

    Yves Chalandon

  23. Université Catholique de Louvain, Service d’Hématologie, CHU UCL Namur—Godinne, Yvoir, Belgique

    Carlos Graux

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  1. Rathana Kim
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Conception and design: RK, LL, and NB. Collection and assembly of data: all authors. Data analysis and interpretation: RK, LL, NB, VL, HD, and VA. Manuscript writing: all authors.

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Correspondence to Ludovic Lhermitte.

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Kim, R., Boissel, N., Touzart, A. et al. Adult T-cell acute lymphoblastic leukemias with IL7R pathway mutations are slow-responders who do not benefit from allogeneic stem-cell transplantation. Leukemia 34, 1730–1740 (2020). https://doi.org/10.1038/s41375-019-0685-4

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