Ibrutinib has shown promising activity in patients with relapsed and/or refractory chronic lymphocytic leukaemia (CLL) as well as in those deemed unfit to receive other agents. “No study has previously compared first-line ibrutinib with the gold standard therapy (fludarabine, cyclophosphamide and rituximab (FCR)) in patients ≤70 years of age,” explains Tait Shanafelt, lead investigator of a study that has now shown improved outcomes with ibrutinib in this patient population.

In the E1912 trial, 354 patients were randomly assigned to receive ibrutinib plus rituximab and 175 patients to FCR. At 33.6 months of follow up, both progression-free survival (PFS) and overall survival (OS) were better with ibrutinib plus rituximab: 3-year PFS 89.4% versus 72.9% (HR 0.35 (95% CI 0.22–0.56); P < 0.001) and 3-year OS 98.8% versus 91.5% (HR 0.17 (95% CI 0.05–0.54); P < 0.001). “Surprisingly, this advantage was apparent at the first interim analysis, resulting in the data safety monitoring board recommending immediate release of the results because they were deemed practice-changing,” highlights Shanafelt.

this advantage was apparent at the first interim analysis … recommending immediate release of the results

Subgroup analyses of 3-year PFS results revealed that ibrutinib plus rituximab is superior to FCR in patients with non-mutated IGHV (90.7% versus 62.5%; HR 0.26 (95% CI 0.14–0.50)) but not in those with mutated IGHV (87.7% versus 88.0%; HR 0.44 (95% CI 0.14–1.36)), although this could change with further follow-up.

The overall response rate was higher with ibrutinib plus rituximab: 95.8% versus 81.1%. However, the complete response and minimal residual disease negativity rates were lower in the ibrutinib plus rituximab group: 17.2% versus 30.3%, and 8.3% versus 59.2%, respectively, suggesting that, whereas ibrutinib extends survival, FCR results in deeper responses.

The incidence of grade ≥3 adverse events (AEs) was similar in both groups — 80.1% with ibrutinib plus rituximab versus 79.7% with FCR — but the toxicity profiles were different for each regimen: the ibrutinib regimen was associated with lower incidence of neutropenia and infectious complications and a higher incidence of hypertension and haemorrhagic AEs.

These results indicate that ibrutinib should be considered a new standard-of-care first-line treatment for patients with CLL ≤70 years of age, although whether it needs to be combined with rituximab remains unclear. “Future trials are evaluating whether combining ibrutinib with other novel targeted treatments can lead to deeper remissions, eliminating the need for patients to take therapy indefinitely”, mentions Shanafelt.