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

Rathana Kim 1 Nicolas Boissel 2 Aurore Touzart 1 Thibaut Leguay 3 Florian Thonier 1 Xavier Thomas 4 Emmanuel Raffoux 5 Françoise Huguet 6 Patrick Villarese 1 Cécile Fourrage 7 Loïc Passini 1 Mathilde Hunault 8, 9 Stéphane Leprêtre 10 Patrice Chevallier 11, 12 Thorsten Braun 2, 13, 14 Véronique Lhéritier 15 Sylvain Chantepie 16 Sébastien Maury 17 Martine Escoffre 18 Emmanuelle Tavernier 19 Yves Chalandon 20, 21 Carlos Graux 22 Elizabeth Macintyre 1 Norbert Ifrah 9 Vahid Asnafi 1 Herve Dombret 5 Ludovic Lhermitte 1
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 TALL 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 TALL (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) TALL were slow-responders, with a high rate of M2/M3 day-8 marrow compared with IL7Rp non-mutated (IL7Rp WT) TALL (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.
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Submitted on : Thursday, April 23, 2020 - 10:05:47 AM
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Rathana Kim, Nicolas Boissel, Aurore Touzart, Thibaut Leguay, Florian Thonier, 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, Nature Publishing Group: Open Access Hybrid Model Option B, 2020, Epub ahead of print. ⟨10.1038/s41375-019-0685-4⟩. ⟨inserm-02551756⟩

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