Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL

被引：85

作者：

Guieze, Romain ^{[1
,2
]}

Robbe, Pauline ^{[3
]}

Clifford, Ruth ^{[3
]}

de Guibert, Sophie ^{[4
]}

Pereira, Bruno ^{[5
]}

Timbs, Adele ^{[3
]}

Dilhuydy, Marie-Sarah ^{[6
]}

Cabes, Maite ^{[3
]}

Ysebaert, Loic ^{[7
]}

Burns, Adam ^{[3
]}

Nguyen-Khac, Florence ^{[8
]}

Davi, Frederic ^{[8
]}

Veronese, Lauren ^{[9
,10
]}

Combes, Patricia ^{[9
,10
]}

Le Garff-Tavernier, Magali ^{[8
]}

Leblond, Veronique ^{[11
]}

Merle-Beral, Helene ^{[8
]}

Alsolami, Reem ^{[3
]}

Hamblin, Angela ^{[3
]}

Mason, Joanne ^{[3
]}

Pettitt, Andrew ^{[12
]}

Hillmen, Peter ^{[13
]}

Taylor, Jenny ^{[14
]}

Knight, Samantha J. L. ^{[14
]}

Tournilhac, Olivier ^{[1
,2
]}

Schuh, Anna ^{[3
]}

机构：

[1] CHU Clermont Ferrand, Serv Hematol, Clin Adulte & Therapie Cellulaire, Clermont Ferrand, France

[2] Univ Auvergne, Ctr Invest Clin CIC 501, Equipe Accueil EA 7283, Canc Resistance Exploring & Targeting CREAT, Clermont Ferrand, France

[3] Univ Oxford, Oxford Mol Diagnost Ctr, Oxford, England

[4] CHU Rennes, Serv Hematol Clin, Rennes, France

[5] CHU Clermont Ferrand, Dept Biostat, Clermont Ferrand, France

[6] CHU Bordeaux, Serv Hematol, Clin & Therapie Cellulaire, Bordeaux, France

[7] CHU Toulouse, Serv Hematol, Toulouse, France

[8] AP HP La Pitie Salpetriere, Serv Hematol Biol, Paris, France

[9] CHU Clermont Ferrand, Lab Cytogenet, Clermont Ferrand, France

[10] Univ Auvergne, ERTICA, EA4677, Clermont Ferrand, France

[11] AP HP La Pitie Salpetriere, Serv Hematol Clin, Paris, France

[12] Royal Liverpool & Broadgreen Univ Hosp Natl Hlth, Liverpool, Merseyside, England

[13] St James Univ Hosp, Dept Hematol Oncol, Leeds LS9 7TF, W Yorkshire, England

[14] Univ Oxford, Wellcome Trust Ctr Human Genet, Biomed Res Ctr, Oxford Natl Inst Hlth Res NIHR, Oxford, England

来源：

BLOOD | 2015年 / 126卷 / 18期

基金：

英国惠康基金;

关键词：

CHRONIC LYMPHOCYTIC-LEUKEMIA; GENOMIC ABERRATIONS; SF3B1; MUTATIONS; NOTCH1; TP53; FLUDARABINE; PROGRESSION; INACTIVATION; EXPRESSION; EVOLUTION;

D O I：

10.1182/blood-2015-05-647578

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 andcombinations of recurrentgene 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.

引用

页码：2110 / 2117

页数：8

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