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Extended Phase 3 Results From RESONATE-2
Introduction
Chronic lymphocytic leukemia (CLL) is the most com- mon leukemia in Western countries and is increasing in prevalence with the prolonged survival observed with introduction of novel combinations and targeted treat- ments such as ibrutinib.1 With a median age at diagnosis of 71 years,1 management of this predominately older population is controversial given that frequent comorbidi- ties often preclude aggressive therapy. Randomized stud- ies have provided disparate results in older compared with younger patients.2,3 Less intensive approaches, such as chlorambucil, provide limited response durability. While the addition of anti-CD20 antibodies has improved out- comes achieved with single-agent chlorambucil, adminis- tration of these intravenous agents has associated toxicity, and response durations remain limited.4
The first-in-class, oral, once-daily, Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib targets signaling via the B-cell receptor cascade, critical to survival of malignant lymphocytes.5-9 Ibrutinib demonstrated tolerability, a high rate of objective responses, and prolongation of progres- sion-free survival and overall survival in patients with relapsed/refractory CLL.10 Early-phase studies demonstrat- ed responses of up to 84% in previously untreated patients, with complete response (CR) rates of up to 23% and up to 3 years of median follow up.11,12 This small cohort suggested that single-agent ibrutinib might provide durable efficacy in first-line treatment of patients with CLL while avoiding toxicity inherent to cytotoxic or other infused regimens.
RESONATE-2 was an international phase 3 study designed to definitively evaluate first-line ibrutinib treat- ment in older patients who often had baseline frailties against a standard chemotherapeutic agent, chlorambu- cil.13 Primary results demonstrated an 84% reduction in the risk of death at a median follow up of 18 months for ibrutinib compared with chlorambucil. Based on these findings, ibrutinib received approval in the United States, Europe, and other regions for the first-line treatment of patients with CLL, and allows for treatment without chemotherapy.14,15 A detailed analysis of overall survival (OS) with longer follow up and adjustment for the impact of treatment crossover was previously reported.16 A sepa- rate data cut was subsequently performed after this detailed OS analysis to evaluate additional outcomes after long-term follow up. Herein, we present the extended analysis of additional outcomes from RESONATE-2 including quality-of-life (QOL) measures that may help guide appropriate use of ibrutinib for previously untreated patients.
Methods
Study design and population
Eligible patients for RESONATE-2 (PCYC-1115/1116; clinicaltri- als.gov identifier 01722487/01724346) had previously untreated CLL or SLL with active disease and were ≥65 years. Patients ≤70 years of age must have had a comorbidity that precluded treatment with fludarabine-cyclophosphamide-rituximab. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status ≤2, absolute neutrophil count ≥1000 cells/mm3, platelet count ≥50,000/mm3, and adequate liver and kidney function. Those with del(17p) CLL were excluded.
This study was conducted according to principles of the Declaration of Helsinki and the International Conference on Harmonisation Guidelines for Good Clinical Practice and approved by the institutional review boards of participating insti- tutions. All patients provided written informed consent.
Patients were randomly assigned in a 1:1 ratio to treatment with oral ibrutinib, 420 mg once daily until disease progression or chlo- rambucil, 0.5 mg/kg (increased up to 0.8 mg/kg based on tolerabil- ity) on days 1 and 15 of a 28-day cycle for 12 cycles. Patients from the chlorambucil treatment arm with independent review com- mittee (IRC)-confirmed disease progression were eligible to cross over to second-line treatment with ibrutinib at the investigator’s discretion.
End points and assessments
End points included progression-free survival (PFS, defined as time from randomization to progression or death, whichever occurs earlier), overall survival (OS), overall response rate (ORR), improvement in hematologic variables, patient-reported health- related QOL, and safety. Disease progression and response was determined by investigator. QOL was assessed using the Functional Assessment of Chronic Illness Therapy (FACIT)- Fatigue questionnaires. Safety assessments included adverse events (AEs) and laboratory parameters. Non-hematologic AEs were graded using Common Terminology Criteria for Adverse Events, v4.03. Hematologic AEs were graded using International Workshop on CLL criteria.17
Statistical analyses
PFS and OS were analyzed using Kaplan-Meier estimates and a 2-sided log-rank test stratified by the randomization factors. Sensitivity analyses were performed to adjust for the impact of crossover on OS as previously described.16 ORR was analyzed with the Cochran-Mantel-Haenszel c2 test, stratified by the ran- domization factors. QOL analyses were based on the proportion of patients with clinically meaningful changes in scores from base- line (≥3 points for FACIT-Fatigue). Additional QOL analyses used time-dependent mixed-models repeated measures analysis.
Results
Patients
There were 269 patients randomly assigned to ibrutinib (n=136) or chlorambucil (n=133) monotherapy in the RES- ONATE-2 study (Online Supplementary Figure S1).13 Patient characteristics were well balanced across treatment arms, as previously reported (Table 1).13 The median patient age was 73 years on the ibrutinib arm and 72 years on the chlorambucil arm. In the ibrutinib treatment arm, of those evaluated, 22% (29/130) had del(11q), and 48% (58/121) had unmutated IGHV. Patients initiated ibrutinib treat- ment for active disease per iwCLL criteria, most common- ly manifesting as marrow failure (progressive anemia or thrombocytopenia [40%]), progressive or symptomatic lymphadenopathy (40%) or splenomegaly (26%), with many patients having more than one indication for treat- ment including disease symptoms such as fatigue or night sweats (Table 1). Although 32% of patients had substan- tial fatigue when entering study, only 5% were started on CLL treatment solely for fatigue that was considered to have interfered with work or usual activities. With a medi- an follow up for this extended analysis of 29 months (maximum, 36 months), 107 patients (79%) remain on first-line ibrutinib.
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