Front-line ibrutinib therapy results in a lower rate of disease progression or death than the current standard-of-care chemoimmunotherapy with bendamustine and rituximab in older patients with chronic lymphocytic leukemia (CLL). Adding rituximab to ibrutinib did not improve outcomes compared with ibrutinib alone, reported Jennifer A. Woyach, MD, Associate Professor, Ohio State University Comprehensive Cancer Center, Columbus, at ASH 2018.
Data from the international phase 3 clinical trial (Alliance A041202) of patients aged ≥65 years with newly diagnosed CLL demonstrated a 2-year estimate of progression-free survival (PFS) of 87% in patients randomized to ibrutinib alone and 88% in those randomized to ibrutinib plus rituximab versus 74% in patients in the bendamustine plus rituximab arm.
After a median follow-up of 38 months, the median PFS was 43 months in the bendamustine plus rituximab arm and had not been reached in the 2 ibrutinibcontaining arms. No difference has yet emerged in overall survival (OS), which may be the result of crossover from the chemoimmunotherapy arm to an ibrutinib-containing regimen, as well as the short follow-up period, said Dr Woyach.
“At the time the study was designed, bendamustine-rituximab was widely used in the community based on excellent data in the phase 2 setting,” she said. “During this time, the BTK [Bruton’s tyrosine kinase] inhibitor ibrutinib was just entering the clinic. Despite now widespread use in the front-line following its FDA approval for this indication in 2016, the efficacy of ibrutinib versus standard chemoimmunotherapy had not previously been investigated.”
Ibrutinib, with or without rituximab, was compared with bendamustinerituximab in 547 patients (median age, 71 years) with treatment-naïve, intermediate- or high-risk CLL. Overall, 54% of patients had high-risk disease, and 25% had high-risk cytogenetics—deletion (del)17p or del11q. Study participants were stratified according to disease risk (high or intermediate) and cytogenetics, and were randomized in a 1:1:1 ratio to 3 arms: arm A, bendamustine plus rituximab administered in six 28-day cycles (N = 183); arm B, oral ibrutinib (N = 182); and arm C, ibrutinib plus rituximab on days 1, 8, 15, and 22 of cycle 2, and on day 1 of cycles 3 to 6 (N = 182). Patients received treatment until disease progression or until unacceptable toxicity; patients randomized to arm A could cross over to arm B if their disease progressed.
Of the 547 patients, 96% were available for the primary PFS analysis. The 2-year PFS values translated to a lower risk of disease progression or death in the 2 ibrutinib-containing arms (hazard ratio, 0.39 for arm A vs arm B; 0.38 for arm A vs arm C; P <.001 for both). The median OS has not been reached in any arm. The 2-year OS estimates for bendamustine plus rituximab, ibrutinib alone, and ibrutinib plus rituximab are 95%, 90%, and 94%, respectively.
Grade ≥3 hematologic adverse events were more common in the chemoimmunotherapy group (61%) than in the ibrutinib-alone (41%) or ibrutinib plus rituximab group (38%). Overall, 40% of the bendamustine plus rituximab arm had grade ≥3 neutropenia compared with 15% to 21% of the ibrutinib-containing arms. Grade ≥3 nonhematologic adverse events were more common in the ibrutinib-containing arms (74%) versus the chemoimmunotherapy arm (63%). Grade ≥3 hypertension was 29% in the ibrutinib-alone arm and 34% in the ibrutinib plus rituximab arm versus 15% in the bendamustine plus rituximab arm (P <.001). Atrial fibrillation was reported in up to 17% of patients who received ibrutinib.
Clinical Implications
“This really does indicate that ibrutinib as front-line therapy, which many clinicians have been doing, is a very reasonable practice,” commented David P. Steensma, MD, Institute Physician, Hematologic Oncology Treatment Center, Dana-Farber Cancer Institute, Boston.
Ongoing clinical trials are investigating more specific second-generation BTK inhibitors, with potentially better safety profiles, as well as novel combination therapies, such as venetoclax (Venclexta) plus ibrutinib, with or without obinutuzumab (Gazyva), that do not include chemotherapy. By using these new combinations “we try to intensify therapy earlier on, to try to get deeper remissions and therefore stop therapy,” Dr Woyach said. Limiting the duration of therapy may also be important to explore, she noted.