Blood cancers

Ibrutinib-rituximab superior to chemo-immunotherapy in CLL

A combination of ibrutinib and rituximab is more effective and less toxic than standard immunochemotherapy in first line treatment of chronic lymphocytic leukaemia (CLL), a phase 3 trial has shown.

Ibrutinib–rituximab treatment was superior to fludarabine–cyclophosphamide–rituximab with respect to progression-free survival (PFS) and overall survival (OS) in a prospective randomised controlled trial involving 529 people with newly diagnosed CLL, according to US study findings published in NEJM.

In the multicentre study led by haematologists at Stanford Medicine, 354 patients were randomised   to receive six courses of ibrutinib and rituximab, followed by ibrutinib until their disease progressed, and 175 to receive six courses of standard chemotherapy consisting of fludarabine, cyclophosphamide and rituximab.

At a median follow-up of 33.6 months, progression-free survival favoured ibrutinib–rituximab over chemoimmunotherapy (89.4% vs. 72.9% at 3 years; hazard ratio for progression or death, 0.35).

Overall survival also favoured ibrutinib–rituximab over chemoimmunotherapy (98.8% vs. 91.5% at 3 years; hazard ratio for death, 0.17).

Rates of adverse events of grade 3 or higher were similar in both groups (80.1% vs 79.7%) ] but infectious complications of grade 3 or higher were less common with ibrutinib–rituximab than with chemoimmunotherapy (10.5% vs 20.3%).

In particular, the risk of atrial fibrillation of any grade was 7.4% in the ibrutinib–rituximab group, which was consistent with the results of previous trials of ibrutinib-based therapy, the study authors noted.

Subgroup analysis showed greater efficacy of ibrutinib–rituximab in high-risk patients without immunoglobulin heavy-chain variable region (IGHV) mutation, where there was a better PFS than chemoimmunotherapy (90.7% vs. 62.5% at 3 years; hazard ratio for progression or death, 0.26). PFS rates were similar in patients with IGHV mutation (87.7% vs 88.0%).

The study investigators said the survival advantages seen with ibrutinib–rituximab exceeded the prespecified thresholds for superiority at the time of the first interim analysis. However they conceded that the benefits of combining rituximab with ibrutinib were unclear. Another trial, Alliance 041202,  had found no differences in PFS or OS between the ibrutinib-alone group and the ibrutinib–rituximab, they noted

They also cautioned that the benefits in overall survival were based on a limited number of events, and therefore longer term follow-up was needed for this outcome as well as for myelodysplastic syndrome or acute myeloid leukemia, second cancers, and infectious complications. Long term therapy may also may increase the risk of clonal selection leading to drug resistance, they noted.

Nevertheless, study lead investigator Professor Tait Shanafelt, said the trial results showed the rituximab-ibrutinib combaintion that specifically target B cells may help patients avoid the toxic effects of traditional chemotherapy.

“We’ve found that this combination of targeted treatments is both more effective and less toxic than the previous standard of care for these patients. It seems likely that, in the future, most patients will be able to forego chemotherapy altogether.”

“This is one of those situations we don’t often have in oncology,” said Professor Shanafelt.

“The new treatment is both more effective and better tolerated. This represents a paradigm shift in how these patients should be treated. We can now relegate chemotherapy to a fallback plan rather than a first-line course of action.”

The study was funded by the National Cancer Institute and Pharmacyclics.

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