Impaired nodal shrinkage and apoptosis define the independent adverse outcome of NOTCH1 mutated patients under ibrutinib therapy in chronic lymphocytic leukaemia
Open Access
- 30 July 2020
- journal article
- research article
- Published by Ferrata Storti Foundation (Haematologica) in Haematologica
- Vol. 106 (9), 2345-2353
- https://doi.org/10.3324/haematol.2020.251488
Abstract
The introduction of agents inhibiting the BCR-associated kinases such as ibrutinib has dramatically changed treatments algorithms of chronic lymphocytic leukaemia (CLL) as well as the role of different adverse prognosticators. We evaluated the efficacy of ibrutinib as single agent, in a real-life context, on 180 patients with CLL mostly pre-treated, recruited from three independent cohorts from Italy. Patients received 420 mg oral ibrutinib once daily until progression or occurrence of unacceptable side effects. Seventy-three patients discontinued ibrutinib for progression or for adverse events. NOTCH1 mutations (M) were correlated with a reduced redistribution lymphocytosis, calculated at 3 months on ibrutinib (p=0.022). Moreover, NOTCH1 mutated patients showed inferior nodal response at 6 months on ibrutinib compared to NOTCH1 wild type patients (p<0.0001). Significant shorter progression free survival (PFS) and overall survival (OS) were observed in NOTCH1 mutated patients (p=0.00002 and p=0.001). Interestingly, NOTCH1 M plus lower bax/bcl-2 ratio identified a CLL subset showing the worst PFS and OS (p=0.0002 and p=0.005). In multivariate analysis of PFS and OS, NOTCH1 M were confirmed an independent prognosticator (p=0.00006 and p=0.0039). In conclusion, NOTCH1 M are strongly associated with lower bax/bcl-2 ratio, consistent with a defective apoptosis, lower redistribution lymphocytosis and lower nodal shrinkage under ibrutinib treatment, this last responsible for partial responses, subsequent relapses, shorter PFS and OS. The therapeutic options for NOTCH1 mutated patients could be represented by either new small molecules combination approaches or from antibodies targeting NOTCH1.This publication has 45 references indexed in Scilit:
- The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trialBlood, 2013
- Trisomy 12 CLLs progress through NOTCH1 mutationsLeukemia, 2012
- Different distribution of NOTCH1 mutations in chronic lymphocytic leukemia with isolated trisomy 12 or associated with other chromosomal alterationsGenes, Chromosomes and Cancer, 2012
- Integrative Genomics Viewer (IGV): high-performance genomics data visualization and explorationBriefings in Bioinformatics, 2012
- Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemiaBlood, 2012
- Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activationThe Journal of Experimental Medicine, 2011
- Therapeutic antibody targeting of individual Notch receptorsNature, 2010
- Mutational status of IgVH genes in B-cell chronic lymphocytic leukemia and prognosis: percent mutations or antigen-driven selection?Leukemia, 2005
- Chronic Lymphocytic LeukemiaThe New England Journal of Medicine, 2005
- Analysis of IgVH gene mutations in B cell chronic lymphocytic leukaemia according to antigen-driven selection identifies subgroups with different prognosis and usage of the canonical somatic hypermutation machineryBritish Journal of Haematology, 2004