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

• Published in: Leukemia Vol. 34; no. 7; pp. 1730 - 1740
• Main Authors: Kim, Rathana, Boissel, Nicolas, Touzart, Aurore, Leguay, Thibaut, Thonier, Florian, Thomas, Xavier, Raffoux, Emmanuel, Huguet, Françoise, Villarese, Patrick, Fourrage, Cécile, Passini, Loïc, Hunault, Mathilde, Lepretre, Stéphane, Chevallier, Patrice, Braun, Thorsten, Lhéritier, Véronique, Chantepie, Sylvain, Maury, Sébastien, Escoffre, Martine, Tavernier, Emmanuelle, Chalandon, Yves, Graux, Carlos, Macintyre, Elizabeth, Ifrah, Norbert, Asnafi, Vahid, Dombret, Hervé, Lhermitte, Ludovic
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2020; Nature Publishing Group; Springer Nature
• Subjects: 45/23; 631/208/2489/68; 692/308/575; Acute lymphoblastic leukemia; Adolescent; Adult; Analysis; Biomarkers, Tumor - genetics; Cancer; Cancer Research; Chemotherapy; Critical Care Medicine; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Genetic aspects; Hematology; Hematopoietic Stem Cell Transplantation - mortality; Hematopoietic stem cells; Humans; Intensive; Interleukin 7; Interleukin 7 receptors; Internal Medicine; Janus kinase; Leukemia; Life Sciences; Lymphatic leukemia; Lymphocytes T; Male; Medical research; Medicine; Medicine & Public Health; Medicine, Experimental; Middle Aged; Minimal residual disease; Mutation; Neoplasm, Residual - genetics; Neoplasm, Residual - pathology; Neoplasm, Residual - therapy; Next-generation sequencing; Oncology; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - therapy; Prognosis; Receptors, Interleukin-7 - genetics; Stem cell transplantation; Stem cells; Subgroups; Survival Rate; T cells; Time dependent analysis; Transplantation; Transplantation, Homologous; Young Adult; France
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-019-0685-4

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 (IL7Rp mut ) T-ALL were slow-responders, with a high rate of M2/M3 day-8 marrow compared with IL7Rp non-mutated (IL7Rp WT ) 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 IL7Rp mut patients whereas it was of marked benefit to IL7Rp WT 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.