This is a phase III trial and it was designed to answer two main questions – one is is the BTK inhibitor ibrutinib better than standard of care, bendamustine plus rituximab, for older patients with chronic lymphocytic leukaemia. The second question is is the addition of rituximab, can that improve efficacy over single agent ibrutinib alone. The reason we designed this trial for older patients with CLL is because we know that if we design an all-comers trial the studies tend to under-represent our older patient population which makes up the majority of patients with CLL. So we really wanted this to be a practice changing trial that would be relevant to the patients who actually have CLL.
What did you do?
We enrolled 547 patients at 219 sites across the United States and Canada and then we randomised them one to one to one after stratifying based on Rai stage and the presence or absence of 17p or 11q deletion. They were randomised to either bendamustine plus rituximab, ibrutinib given as a single agent daily until disease progression or ibrutinib given in combination with rituximab where the rituximab was given for six cycles and then the ibrutinib continued indefinitely.
What did you find?
At a median follow-up of 38 months we do have a significantly improved progression free survival for patients treated on either of the ibrutinib arms compared with bendamustine plus rituximab. The median progression free survival for bendamustine plus rituximab is 43 months and has not yet been reached for patients on either of the ibrutinib containing arms. At two years our progression free survival was 74% in the bendamustine plus rituximab arm compared with 87% in the ibrutinib arm and 88% in the ibrutinib plus rituximab arm.
Adverse effects?
In order to look at adverse events in this study, since the drugs were given for such disparate periods of time, we chose to look at all of the adverse events, first of all regardless of attribution, then throughout the entire observation period until a crossover for the patients on bendamustine plus rituximab. What we found is that hematologic toxicities are more frequent with bendamustine plus rituximab and that’s specifically neutropenia and thrombocytopenia. Non-hematologic toxicities overall are slightly more common on the ibrutinib containing arms than bendamustine plus rituximab. When we looked at toxicities that are unique to ibrutinib we found a very low rate of bleeding and it wasn’t different among the arms. The rate of infection was not different among the arms. The rate of atrial fibrillation was slightly more common in the ibrutinib containing arms; the rate of hypertension was more common in the ibrutinib containing arms.
Did you look at the overall survival?
Overall survival, while a secondary endpoint of the study, is one that we did not think that we would actually be able to show a difference, that’s mainly due to the crossover design. So patients who were enrolled on bendamustine plus rituximab at the time of disease progression could cross over to single agent ibrutinib. So everybody on the study actually got ibrutinib if they wanted to. We also, right now at least, have a fairly short follow-up for a front line CLL study looking at overall survival just because patients tend to, luckily, live for a very long period of time.
What is the potential impact of this research?
Ibrutinib is already FDA approved for front line therapy and has been since 2016 and it’s fairly widely used in clinical practice. This really changes the conversation that doctors have with their patients in terms of before we could say ibrutinib has this advantage versus chlorambucil, it is very effective in the front line setting, and now we can really say ibrutinib is more effective than our standard chemo-immunotherapy for this disease.
