Impaired nodal shrinkage and apoptosis define the independent adverse outcome of NOTCH1 mutated patients under ibrutinib therapy in chronic lymphocytic leukaemia

Luca Laurenti, Idanna Innocenti, Maria Francesca Rossi, Giovanni Del Poeta, Annalisa Biagi, Annalisa Chiarenza, Federico Pozzo, Massimiliano Postorino, Maria Ilaria Del Principe, Riccardo Bomben, Paolo de Fabritiis, Antonio Bruno, Maria Cantonetti, Francesco Di Raimondo, Antonella Zucchetto, Valter Gattei

Risultato della ricerca: Contributo in rivistaArticolo in rivista

Abstract

The introduction of agents inhibiting the B-cell receptor-associated kinases such as ibrutinib has dramatically changed treatments algorithms 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.
Lingua originaleEnglish
pagine (da-a)2345-2353-2353
RivistaHaematologica
Volume106
DOI
Stato di pubblicazionePubblicato - 2021

Keywords

  • chronic lymphocytic leukaemia

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