Ibrutinib add-on to obinutuzumab sustains PFS benefit in CLL/SLL

Adding ibrutinib to obinutuzumab in the first-line setting sustains progression-free survival (PFS) benefit in patients with chronic lymphocytic leukaemia (CLL)/small lymphocytic leukaemia (SLL), including patients with high-risk genomic features, according to the final analysis of the iLLUMINATE* trial.

“With this extended follow-up, as has been observed consistently across several large, randomized phase III studies of ibrutinib in previously untreated and relapsed/refractory patients with CLL/SLL, highly durable PFS … [has] been confirmed [in the overall population and] even in patients with high-risk disease characteristics,” said the researchers.

This phase III, multicentre, open-label trial involved 229 patients with untreated CLL/SLL (median age 71 years; 80 percent aged ≥65 years) who were recruited from 71 sites in Australia, New Zealand, Canada, Israel, Turkey, Russia, the European Union, and the US. The majority of the patients had high-risk genomic features, such as del(17p), TP53 mutation, del(11q), or unmutated IGHV**. Participants were randomized to receive oral ibrutinib 420 mg once daily (n=113) or chlorambucil 0.5 mg/kg of body weight on days 1 and 15 of each 28-day cycle for six cycles (n=116) in addition to intravenous obinutuzumab*** for up to six cycles. [Haematologica 2022;doi:10.3324/haematol.2021.279012]

In this final analysis, the significant PFS benefit was sustained in the ibrutinib plus obinutuzumab arm compared with the chlorambucil plus obinutuzumab arm at a median follow-up of 45 months (median not reached vs 22 months; hazard ratio [HR], 0.25; p<0.0001), showing a 75 percent reduction in the risk of disease progression or death.

Of the 148 patients with high-risk disease features, those treated with ibrutinib plus obinutuzumab achieved a consistent PFS benefit compared with chlorambucil plus obinutuzumab (HR, 0.17; p<0.0001). This further confirms the earlier observations from the primary analysis of the iLLUMINATE trial, and “importantly, the benefit in PFS was observed regardless of high-risk features,” noted the researchers.

A higher estimated 42-month PFS rate was observed among patients on ibrutinib plus obinutuzumab than those on chlorambucil plus obinutuzumab in both the overall population (74.0 percent vs 33.0 percent) and high-risk population (70.0 percent vs 12.0 percent).

A higher percentage of patients treated with ibrutinib plus obinutuzumab compared with chlorambucil plus obinutuzumab also achieved undetectable minimal residual disease in peripheral blood or bone marrow (38.0 percent vs 25.0 percent; p=0.033), a finding particularly noticeable in the high-risk population (65.0 percent vs 27.0 percent).

Neutropenia (36.0 percent vs 46.0 percent), thrombocytopenia (19.0 percent vs 10 percent), and pneumonia (8.0 percent vs 3.0 percent) were the most common grade ≥3 adverse events (AEs) reported in the ibrutinib plus obinutuzumab vs chlorambucil plus obinutuzumab arms. Fourteen deaths occurred in the ibrutinib plus obinutuzumab arm compared with three in the chlorambucil plus obinutuzumab arm.

“Most patients had improvement or resolution of AEs following dose reduction, suggesting that many AEs are managed effectively by dose modification, allowing patients to stay on therapy and continue to maintain disease control,” said the researchers.

“In conclusion, ibrutinib plus obinutuzumab remains an effective chemotherapy-free regimen for patients with CLL/SLL that provides sustained efficacy and significantly reduces the risk of disease progression or death compared with chlorambucil plus obinutuzumab, including in patients with high-risk genomic features,” the researchers said. 

“In line with the results of the iLLUMINATE trial, other phase III studies have also reported the superiority of ibrutinib-based regimens compared with chemoimmunotherapy in the first-line treatment of CLL,” they added.

*iLLUMINATE: A multicenter study of ibrutinib in combination with obinutuzumab versus chlorambucil in combination with obinutuzumab in patients with treatment naïve chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)

**IGHV: Immunoglobulin heavy-chain variable region gene

***100, 900, and 1,000 mg on days 1, 2, and 8 and 15 of cycle one, respectively, and followed by 1,000 mg on day 1 of each subsequent 28-day cycle