Ibrutinib Maintenance after Chemoimmunotherapy Is Feasible and Results in Excellent Progression-Free and Overall Survival in Patients with Detectable MRD after Chemoimmunotherapy
Authors: Guedes Nayara Ribeiro , Da Fonseca Ana Rita , Carneiro Thiago Xavier , de Molla Vinicius Campos , Santucci Silva Rodrigo , Fortier Sérgio Costa , Figueiredo Vera Lucia de Piratininga , Ommati Larissa , Buccheri Valeria , Borba Oliveira Gislaine , Perobelli Leila Martins , Ferreira Fernando Sergio Blumm , Vescovi Matheus , Arrais-Rodrigues Celso 
Published: November 2019

Introduction
Given the variety of highly effective therapies available for chronic lymphocytic leukemia (CLL), a tailored treatment strategy is needed. Fixed-duration chemoimmunotherapy can produce sustained and deep responses. The presence of minimal residual disease (MRD) has been studied as an independent prognostic factor for long-term survival in patients with CLL. Multiple novel agents have been recently approved for previously untreated patients, including the BTK inhibitor, ibrutinib, but its effect on MRD is still unclear. We performed a prospective clinical trial to evaluate the efficacy of maintenance therapy with ibrutinib in patients with detectable MRD after first-line chemoimmunotherapy.
Patients and methods
In this phase 2 clinical trial, we assessed the efficacy and safety of ibrutinib 420 mg daily as maintenance therapy, until progression or unacceptable toxicity, after achieving complete remission (CR) or partial remission (PR) with chemoimmunotherapy in previously untreated 40 patients with CLL from 9 centers in Brazil. The median age was 60 years (range: 43-85 years). Twenty-nine patients (73%) had been treated with fludarabine and cyclophosphamide (FC) ± rituximab, 10 (25%) with chlorambucil ± rituximab, and one (2%) with bendamustine + rituximab. Responses definitions were based on the 2018 iwCLL guidelines. Twenty-five patients (63%) were in CR and 15 (37%) in PR before the start of maintenance. Patients with detectable MRD within 12 months after the end of the first line chemoimmunotherapy were included. Besides, three patients with undetectable MRD were also included in order to evaluate possible effects of ibrutinib on that group. Responses were assessed monthly during the first year and every three months thereafter. MRD was assessed by 8-color flow cytometry in the bone marrow and in the peripheral blood before and after one year of maintenance therapy, and in peripheral blood every 3 months thereafter. Primary end point was progression-free survival (PFS).
Results
Median follow-up time was 25 months (range: 12-46 months). Among the 40 patients included, two patients withdrew consent (one just after inclusion and one after 30 days), and one patient died 7 days after ibrutinib was started due to an unrelated cause (ruptured aortic aneurysm). Thirty-seven patients were treated with ibrutinib and prospectively followed. The median PFS and overall survival (OS) were not reached. PFS and OS at 2 years were 92% and 95%, respectively. Among the 15 patients who started maintenance in PR, 8 (53%) achieved CR (3 of which had incomplete hematologic recovery), and 7 had complete nodal response, but remained in PR due to persistent lymphocytosis. Among the 22 who entered maintenance in CR, all but one remained in CR: 1 patient presented ≥ 50% increase in his baseline lymphocyte count 40 months after maintenance was started, but remains on ibrutinib with no cytopenias or clinical indication to treatment change. Among the 34 patients who had detectable MRD, 9% had at least 1-log reduction after one year and 20% after 2 years. Besides, one patient achieved undetectable MRD so far, 30 months after ibrutinib was started. All 3 patients with undetectable MRD at baseline, remained undetectable. Sustained increases from baseline values in the hemoglobin and platelet levels were observed in 30 patients (81%). Adverse events of any grade that occurred during maintenance with ibrutinib included diarrhea (23%), nausea (10%), and fatigue (8%), but only 2 patients had grade 3 diarrhea, associated with the concomitant use of metformin that resolved after discontinuation. Atrial fibrillation occurred intermittently in 3 patients during maintenance. A total of 81% of patients remain on ibrutinib. Four patients discontinued the drug: one after 8 months to perform a stem cell transplant by the decision of the treating physician, one after 10 months due to adverse events (lymphomatoid granulomatosis), and 2 after 13 months due to logistic difficulties to remain on regular follow up.
Conclusions
Maintenance with ibrutinib for CLL patients achieving CR or PR after chemoimmunotherapy resulted in excellent PFS and OS, and sustained improvement in hematologic variables irrespectively of achieving undetectable MRD. Efficacy of this regimen compares well to other frontline chemo-free treatments offered to patients with CLL in the United States and Europe.

Disclosures
No relevant conflicts of interest to declare.