Chemoimmunotherapy with chlorambucil plus obinutuzumab or bendamustine plus rituximab is standard frontline treatment for older patients with chronic lymphocytic leukemia (CLL). However, chemoimmunotherapy is associated with toxic effects, and the risk increases with age. For patients with CLL, frontline ibrutinib monotherapy is widely used in clinical practice. The benefit of this Bruton’s tyrosine kinase (BTK) inhibitor versus standard chemoimmunotherapy remains a critical consideration, which led researchers to conduct a head-to-head phase 3 study to evaluate the efficacy of ibrutinib, either alone or in combination with rituximab, relative to chemoimmunotherapy (Woyach JA, et al. N Engl J Med. 2018;379:2517-2528).
The Alliance North American Intergroup Study A041202 included treatment-naïve, intermediate- or high-risk patients with CLL aged ≥65 years. A total of 547 patients were randomized 1:1:1 to ibrutinib monotherapy, ibrutinib plus rituximab, or to bendamustine plus rituximab. Bendamustine was given at 90 mg/m2 on days 1 and 2 of each 28-day cycle plus rituximab at 375 mg/m2 on day 0 of cycle 1, then 500 mg/m2 on day 1 of cycles 2 to 6. Ibrutinib was given at 420 mg daily. In the ibrutinib combination arm, rituximab was given at 375 mg/m2 weekly for 4 weeks starting on day 1 of cycle 2, and then on day 1 of cycles 3 to 6. Patients received treatment until disease progression or unacceptable toxicity; at disease progression, patients in the bendamustine group were allowed to cross over to the ibrutinib monotherapy group. The primary end point was progression-free survival (PFS), and the secondary end point was overall survival.
The addition of rituximab to ibrutinib had no additional PFS benefit. At 2 years, the PFS rates were 74% with bendamustine plus rituximab compared with 87% with single-agent ibrutinib and 88% with ibrutinib plus rituximab. The researchers observed no significant difference between the ibrutinib plus rituximab group and the ibrutinib monotherapy group with regard to PFS (P = .49).
“Improvement in overall survival is the ultimate goal of new therapies, and in this analysis, there was no significant difference among the three treatment groups with regard to overall survival, although the follow-up period was short for this disease,” noted the researchers.
Grade ≥3 hematologic adverse events were higher in the bendamustine group (61%) compared with the ibrutinib or ibrutinib plus rituximab groups (41% and 39%, respectively). However, grade ≥3 nonhematologic adverse events were more prevalent in the ibrutinib treatment arms (74% for both) compared with the bendamustine treatment arm (63%).
“The results of this analysis show the efficacy of treatment with continuous ibrutinib among patients with untreated CLL, but the results also raise the issue of whether indefinite therapy with a BTK inhibitor is needed,” the researchers noted, adding that 2 upcoming studies in this patient population may help address this issue.