Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL
Romain Guièze
(1)
,
Pauline Robbe
(2)
,
Ruth Clifford
(2)
,
Sophie De Guibert
,
Bruno Pereira
(3)
,
Adele Timbs
(4, 2)
,
Marie-Sarah Dilhuydy
(5)
,
Maite Cabes
(2)
,
Loic Ysebaert
(6)
,
Adam Burns
(2)
,
Florence Nguyen-Khac
(7, 8)
,
Frédéric Davi
(7, 8)
,
Lauren Veronese
(9, 10)
,
Patricia Combes
(10, 9)
,
Magali Le Garff-Tavernier
(8)
,
Véronique Leblond
(8)
,
Hélène Merle-Béral
(7, 8)
,
Reem Alsolami
(2)
,
Angela Hamblin
(2)
,
Joanne Mason
(2)
,
Andrew Pettitt
,
Peter Hillmen
(11)
,
Jenny Taylor
(2)
,
Samantha J. L. Knight
(2)
,
Olivier Tournilhac
(12, 1)
,
Anna Schuh
(4, 2)
1
EA7283, CIC501
2 University of Oxford
3 Service Biostatistiques, Télématiques, Traitement de l’image [CHU Clermont-Ferrand]
4 National Haemoglobinopathy Reference Laboratory, Molecular Haematology, Haemophilia Centre, Churchill Hospital
5 Service des maladies du sang
6 Service Hématologie - IUCT-Oncopole [CHU Toulouse]
7 CRC - Centre de Recherche des Cordeliers
8 CHU Pitié-Salpêtrière [AP-HP]
9 ERTICa - Equipe de recherche sur les traitements individualisés des cancers
10 Thérapie ciblée combinatoire en onco-hématologie
11 Department of Hematology
12 Service Thérapie Cellulaire et Hématologie Clinique [CHU Clermont-Ferrand]
2 University of Oxford
3 Service Biostatistiques, Télématiques, Traitement de l’image [CHU Clermont-Ferrand]
4 National Haemoglobinopathy Reference Laboratory, Molecular Haematology, Haemophilia Centre, Churchill Hospital
5 Service des maladies du sang
6 Service Hématologie - IUCT-Oncopole [CHU Toulouse]
7 CRC - Centre de Recherche des Cordeliers
8 CHU Pitié-Salpêtrière [AP-HP]
9 ERTICa - Equipe de recherche sur les traitements individualisés des cancers
10 Thérapie ciblée combinatoire en onco-hématologie
11 Department of Hematology
12 Service Thérapie Cellulaire et Hématologie Clinique [CHU Clermont-Ferrand]
Sophie De Guibert
- Fonction : Auteur
Bruno Pereira
- Fonction : Auteur
- PersonId : 949620
- IdHAL : bruno-pereira
- ORCID : 0000-0003-3778-7161
- IdRef : 181458675
Adele Timbs
- Fonction : Auteur
- PersonId : 885412
Loic Ysebaert
- Fonction : Auteur
- PersonId : 1054891
- ORCID : 0000-0001-8478-5623
- IdRef : 06931151X
Andrew Pettitt
- Fonction : Auteur
Olivier Tournilhac
- Fonction : Auteur
- PersonId : 760569
- ORCID : 0000-0002-9438-621X
Anna Schuh
- Fonction : Auteur
- PersonId : 885413
Résumé
Although TP53, NOTCH1, and SF3B1 mutations may impair prognosis of patients with chronic lymphocytic leukemia (CLL) receiving frontline therapy, the impact of these mutations or any other, alone or in combination, remains unclear at relapse. The genome of 114 relapsed/refractory patients included in prospective trials was screened using targeted next-generation sequencing of the TP53, SF3B1, ATM, NOTCH1, XPO1, SAMHD1, MED12, BIRC3, and MYD88 genes. We performed clustering according to both number and combinations of recurrent gene mutations. The number of genes affected by mutation was ≥2, 1, and 0 in 43 (38%), 49 (43%), and 22 (19%) respectively. Recurrent combinations of ≥2 mutations of TP53, SF3B1, and ATM were found in 22 (19%) patients. This multiple-hit profile was associated with a median progression-free survival of 12 months compared with 22.5 months in the remaining patients (P = .003). Concurrent gene mutations are frequent in patients with relapsed/refractory CLL and are associated with worse outcome