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Chronic Lymphocytic Leukemia
Impaired nodal shrinkage and apoptosis define the independent adverse outcome
of NOTCH1 mutated patients under ibrutinib therapy in chronic lymphocytic leukemia
Giovanni Del Poeta,1 Annalisa Biagi,1 Luca Laurenti,2 Annalisa Chiarenza,3 Federico Pozzo,4 Idanna Innocenti,2 Massimiliano Postorino,1
Francesca Maria Rossi,4 Maria Ilaria Del Principe,1 Riccardo Bomben,4 Paolo de Fabritiis,1 Antonio Bruno,1 Maria Cantonetti,1
Francesco Di Raimondo,3 Antonella Zucchetto4 and Valter Gattei4
1Division of Hematology, Department of Biomedicine and Prevention, University Tor Vergata, Roma; 2Division of Hematology, Università Cattolica del Sacro Cuore, Roma; 3Division of Hematology, Ferrarotto Hospital, Catania and 4Clinical and Experimental Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano (PN), Italy.
ABSTRACT
The introduction of agents inhibiting the B-cell receptor-associated kinases such as ibrutinib has dramatically changed treatments algo- rithms of chronic lymphocytic leukemia (CLL) as well as the role of different adverse prognosticators. We evaluated the efficacy of ibrutinib as a single agent, in a real-life context, in 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 (NOTCH1 M) were correlated with a reduced redistribution lymphocytosis, calculated at 3 months on ibrutinib (P=0.022). Moreover, NOTCH1 M 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 M patients (P=0.00002 and P=0.001). Interestingly, NOTCH1 M plus a 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 a lower BAX/BCL-2 ratio, consistent with defective apoptosis, lower redistribution lymphocytosis and lower nodal shrinkage under ibrutinib treatment, this last paramter being responsible for partial responses, subsequent relapses, as well as shorter PFS and OS. Either new small molecule combination approaches or antibodies targeting NOTCH1 could be future therapeutic options for NOTCH1 M patients.
Introduction
Chronic lymphocytic leukemia (CLL) is the most frequent adult leukemia in Western countries and it is characterized by an extremely heterogeneous clinical course. New molecular aberrations with negative prognostic value in CLL, such as NOTCH1, MYD88, TP53 and SF3B1 gene mutations, were identified in the last decade mainly thanks to the advent of next-generation sequencing (NGS).1,2 In partic- ular NOTCH1 mutations (M) are found in 10-14% of patients at diagnosis with fre- quency increasing with disease progression and during transformation to Richter syndrome.3 Furthermore NOTCH1 M are associated with the presence of trisomy 12 and with high CD49d expression which are negative prognostic factors in CLL. NOTCH1 M are also associated with an increased activation of the NF-kB pathway, promoting tumour cell proliferation and survival.4 NOTCH1 M were shown to affect
Ferrata Storti Foundation
Haematologica 2021 Volume 106(9):2345-2353
Correspondence:
GIOVANNI DEL POETA
g.delpoeta@tin.it
Received: February 29, 2020. Accepted: July 20, 2020. Pre-published: July 30, 2020.
https://doi.org/10.3324/haematol.2020.251488 ©2021 Ferrata Storti Foundation
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