gene mutational status and / gene expression as clinical outcome predictors in CLL patients in remission following treatment with oral fludarabine plus cyclophosphamide

Karim Maloum (1) , Catherine Settegrana (1) , Elise Chapiro (1) , Bruno Cazin (2) , Stéphane Leprêtre (3) , Alain Delmer (4) , Michel M. Leporrier (5) , Brigitte Dreyfus (6) , Olivier Tournilhac (7) , Beatrice Mahe (8) , Florence Nguyen-Khac (1) , Claude Lesty (1) , Frederic Davi (1) , Hélène Merle-Béral (1)

1 CHU Pitié-Salpêtrière [AP-HP]
2 SMS - Service des Maladies du Sang [CHU Lille]
3 CLCC Henri Becquerel - Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen
4 URCA - Université de Reims Champagne-Ardenne
5 Laboratoire d'Hématologie Biologique [CHU Caen]
6 Service d'Hématologie Clinique
7 Service d’Hématologie Biologique [CHU Clermont-Ferrand]
8 Service Hématologie Clinique

Several prognostic factors can predict the rapid progression in chronic lymphocytic leukaemia (CLL), including mutational status, cytogenetic abnormalities and, more recently, / expression. In contrast, few studies have been devoted to the influence of these factors on clinical outcome in responding patients after therapy. We here propose to analyse the impact of gene status, and gene expression on disease-free survival (DFS) and overall survival (OS) in 41 stage B or C CLL patients in remission after oral fludarabine plus cyclophosphamide. The median follow-up was of 64 (16–74) months. Sequencing of showed mutated (M) genes in 16 of 41 cases and unmutated (UM) in 25 cases. Analysis of and expression in 35 of 41 cases showed overexpression of in 17 cases (14 M and three UM) and in 18 cases (all UM). Patients expressing UM and had shorter DFS and OS when compared to patients expressing M and/or . Furthermore, blood minimal residual disease (MRD) evaluation using four-colour flow cytometry was performed in 33 out the 41 patients. We showed that patients who achieved phenotypic remission displayed longer DFS than those with MRD. Our results support the use of and gene expression associated to mutational status for predicting the clinical outcome of patients treated by oral fludarabine + cyclophosphamide and could be considered for treatment strategies.

Mots clés: CLL; Oral fludarabine; Cyclophosphamide; Mutational status

Karim Maloum, Catherine Settegrana, Elise Chapiro, Bruno Cazin, Stéphane Leprêtre, et al.. gene mutational status and / gene expression as clinical outcome predictors in CLL patients in remission following treatment with oral fludarabine plus cyclophosphamide. Annals of Hematology, 2009, 88 (12), pp.1215-1221. ⟨10.1007/s00277-009-0742-6⟩. ⟨hal-00535053⟩