Ibrutinib plus Obinutuzumab as Frontline Therapy for Chronic Lymphocytic Leukemia Is Associated with a Lower Rate of Infusion-Related Reactions and with Sustained Remissions after Ibrutinib Discontinuation: A Single-Arm, Open-Label, Phase 1b/2 Clinical Trial NCT0231576.

Januario E Castro,Jose V Forero,Carlos I Amaya-Chanaga,Alaina Heinen,Chaja Jacobs,Michael Y Choi,Eider F Moreno-Cortes,Thomas J Kipps,Juan Esteban Garcia-Robledo,Paula A Lengerke-Diaz,Juliana Velez Lujan,Colin Mccarthy,Estella M Matutes

doi:10.1155/2022/4450824

Abstract

Ibrutinib-based therapies are costly and require continuous administration. We hypothesized combining BTK inhibition with anti-CD20 monoclonal antibodies would yield deep remissions allowing discontinuation. We enrolled 32 therapy-naïve CLL patients to receive ibrutinib plus obinutuzumab, followed by single-agent ibrutinib. Patients could discontinue ibrutinib after 36 months with sustained complete response (CR). We evaluated treatment safety, efficacy, and outcomes after ibrutinib discontinuation. The overall response rate was 100%, 28% achieved a CR, and 12.5% achieved bone marrow undetectable minimal residual disease. At a three-year median follow-up, 91% remain in remission with 100% overall survival. Five patients in sustained CR stopped ibrutinib and have not progressed. Eight non-CR patients discontinued for other reasons, with only two progressing. The treatment was safe, with a lower IRR rate. All patients responded to treatment with longer time-to-progression after discontinuation of ibrutinib. Our data support the evaluation of ibrutinib discontinuation strategies in more extensive clinical trials (https://Clinicaltrials.gov Identifier https://clinicaltrials.gov/ct2/show/NCT02315768).

Highlights

Standard treatment for patients with chronic lymphocytic leukemia (CLL) includes the combination of monoclonal antibodies and targeted therapies with small molecule inhibitors. e phase 3 trial RESONATE-2 showed that single-agent ibrutinib, a first-in-class Bruton tyrosine kinase (BTK) inhibitor, is effective in previously untreated patients, including those that are older than 65 or considered unfit to receive chemotherapy. is was supported by a significant benefit in progression-free survival (PFS), and overall survival (OS) compared to chlorambucil [1]. e majority of patients treated with single-agent ibrutinib achieve an objective response with prolonged PFS that exceeds five years of duration [2, 3]
Randomized trials show that the addition of type II glycoengineered anti-CD20 monoclonal antibodies can increase the efficacy, complete response (CR) rates, and the duration of response when combined with different agents [4,5,6]
At a median follow-up of 35.5 months after starting treatment, thirteen patients (41%) discontinued ibrutinib. e median time to ibrutinib discontinuation was 35 months

Summary

Introduction

Standard treatment for patients with chronic lymphocytic leukemia (CLL) includes the combination of monoclonal antibodies (mAbs) and targeted therapies with small molecule inhibitors. e phase 3 trial RESONATE-2 showed that single-agent ibrutinib, a first-in-class Bruton tyrosine kinase (BTK) inhibitor, is effective in previously untreated patients, including those that are older than 65 or considered unfit to receive chemotherapy. is was supported by a significant benefit in progression-free survival (PFS), and overall survival (OS) compared to chlorambucil [1]. e majority of patients treated with single-agent ibrutinib achieve an objective response with prolonged PFS that exceeds five years of duration [2, 3]. Standard treatment for patients with chronic lymphocytic leukemia (CLL) includes the combination of monoclonal antibodies (mAbs) and targeted therapies with small molecule inhibitors. E phase 3 trial RESONATE-2 showed that single-agent ibrutinib, a first-in-class Bruton tyrosine kinase (BTK) inhibitor, is effective in previously untreated patients, including those that are older than 65 or considered unfit to receive chemotherapy. Randomized trials show that the addition of type II glycoengineered anti-CD20 monoclonal antibodies (e.g., obinutuzumab) can increase the efficacy, CR rates, and the duration of response when combined with different agents (chlorambucil, ibrutinib, and venetoclax) [4,5,6]. ® ibrutinib and obinutuzumab-Gazyva (IG-regimen) is safe and effective in previously untreated CLL patients older than 65 or considered unfit/unwilling to receive chemoimmunotherapy.

Methods

Results

Disclosure

Conflicts of Interest