Efficacy of Front-Line Ibrutinib and Rituximab Combination and the Impact of Treatment Discontinuation in Unfit Patients with Chronic Lymphocytic Leukemia: Results of the Gimema LLC1114 Study.

Francesca Romana Mauro,Mauro Nanni,Roberto Marasca,Pier Luigi Zinzani,Gian Matteo Rigolin,Francesca Paoloni,Antonino Neri,Daniela Gottardi,Gerardo Musuraca,Luca Laurenti,Annalia Molinari,Annalisa Chiarenza,Lorella Orsucci,Ilaria Del Giudice,Daniela Pietrasanta,Marzia Varettoni,Paola Fazi,Antonio Cuneo,Adalberto Ibatici,Donato Mannina,Gianluigi Reda,Valeria Ruocco,Nicola Di Renzo,Irene Della Starza,Monia Marchetti,Anna Guarini,Marta Coscia,Fiorella Ilariucci,Alfonso Piciocchi,Caterina Stelitano,Anna Marina Liberati,Roberta Murru,Robin Foà,Stefano Molica,Massimo Gentile,Alessandro Gozzetti,Monica Tani,Paolo Sportoletti,Sara Raponi,Livio Trentin,Francesca Re,Gianluca Gaïdano ,Maria De De Stefania Propris

doi:10.3390/cancers14010207

Abstract

Simple SummaryThis prospective, multicenter study aimed to investigate the efficacy and safety of a front-line treatment with the ibrutinib and rituximab combination in 146 unfit patients with chronic lymphocytic leukemia (CLL). We observed an OR, CR, and 48-month PFS rates of 87%, 22.6%, and 77%, respectively. Responses with undetectable MRD were observed in 6.2% of all patients and 27% of CR patients. TP53 disruption and B-symptoms revealed a significant and independent impact on PFS. The 48-month cumulative treatment discontinuation rate due to adverse events in this patient population was 29.1%. It was significantly higher in male patients, in patients aged ≥70 years, and in those managed at centers that enrolled less than five patients. In conclusion, the ibrutinib and rituximab combination was an effective front-line treatment for unfit patients with CLL. However, a high rate of treatment discontinuations due to adverse events was observed in this unfit population.The GIMEMA group investigated the efficacy, safety, and rates of discontinuations of the ibrutinib and rituximab regimen in previously untreated and unfit patients with chronic lymphocytic leukemia (CLL). Treatment consisted of ibrutinib, 420 mg daily, and until disease progression, and rituximab (375 mg/sqm, given weekly on week 1–4 of month 1 and day 1 of months 2–6). This study included 146 patients with a median age of 73 years, with IGHV unmutated in 56.9% and TP53 disrupted in 22.2%. The OR, CR, and 48-month PFS rates were 87%, 22.6%, and 77%, respectively. Responses with undetectable MRD were observed in 6.2% of all patients and 27% of CR patients. TP53 disruption (HR 2.47; p = 0.03) and B-symptoms (HR 2.91; p = 0.02) showed a significant and independent impact on PFS. The 48-month cumulative rates of treatment discontinuations due to disease progression (DP) or adverse events (AEs) were 5.6% and 29.1%, respectively. AEs leading more frequently to treatment discontinuation were atrial fibrillation in 8% of patients, infections in 8%, and non-skin cancers in 6%. Discontinuation rates due to AEs were higher in male patients (HR: 0.46; p = 0.05), patients aged ≥70 years (HR 5.43, p = 0.0017), and were managed at centers that enrolled <5 patients (HR 5.1, p = 0.04). Patients who discontinued ibrutinib due to an AE showed a 24-month next treatment-free survival rate of 63%. In conclusion, ibrutinib and rituximab combination was an effective front-line treatment with sustained disease control in more than half of unfit patients with CLL. Careful monitoring is recommended to prevent and manage AEs in this patient population.

Highlights

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the adult population
One hundred and fifty-nine chronic lymphocytic leukemia (CLL) patients were enrolled in this study
One hundred and forty-six patients with a median follow-up of 49.1 months (IQR, 39.4–54) represent the intentionto-treat population assessed for treatment response and safety

Summary

Introduction

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the adult population. Relevant advances in the understanding of the biologic mechanisms associated with the proliferation and survival of CLL cells have led to the clinical use of ibrutinib, a small molecule that inhibits the Bruton tyrosine kinase (BTK). Ibrutinib has been proven to be highly effective, regardless of age, prior treatment, and high-risk biologic features of the leukemic cell [2,3]. The excellent therapeutic activity of this agent has revolutionized the treatment approach of CLL, and today, ibrutinib is a standard of care for CLL patients of all ages, both in the relapsed/refractory and in front-line settings. Despite the excellent response rates and prolonged responses, treatment discontinuation, mainly due to adverse events (AE), is a relevant problem limiting the effectiveness of this agent [8,9,10]

Methods

Results

Conclusion