ASH 2013 - New Orleans, LA, US

Idelalisib and rituximab for previously treated chronic lymphocytic leukaemia (CLL)

Dr Richard Furman - New York Weill Cornell Medical Center, USA

The idelalisib, which previously was known as GS-1101, has shown very good efficacy and excellent tolerability in heavily pre-treated patients. Idelalisib really has been the first drug that went through phase I trials as one of these novel group of tyrosine kinase inhibitors, really was tried in patients who were very heavily treated. So the original phase I group of patients was far sicker than those patients that we’re seeing with some of these other trials. Now that we have experience with these drugs, the willingness to put not so heavily treated patients on them is leading to a population of patients who are not as refractory in having other comorbidities. Given its excellent tolerability and efficacy, the decision was really made to how best to get the drug approved and doing it in a population of patients who couldn’t get chemotherapy would allow us to take advantage of the excellent safety profile.

What was the focus of the methodology of this study?

The primary endpoint for this study was progression free survival, so patients were randomised to either receiving idelalisib plus rituximab or placebo plus rituximab and were followed until they demonstrated evidence of progressive disease. Patients were actually then allowed to cross over to an extension trial which allowed them all to get idelalisib, so everyone eventually had the opportunity to get the study drug. The primary endpoint was progression free survival but we did look at overall response rate by the modified IWCLL criteria, as well as lymph node reduction as an endpoint as well.

So the median progression free survival has not been reached for the idelalisib plus Rituxan arm whereas it was 5.5 months for the placebo plus rituximab arm. That being the primary endpoint and the hazard ratio being 0.15 really led to the study being unblinded. Additionally there was an overall survival benefit seen in the patients who received idelalisib plus Rituxan versus placebo plus Rituxan which really just demonstrated the importance of unblinding the study and getting everyone on to active treatment. The overall survival benefit teaches us a lot of the importance of controlling CLL actively and quickly; it also shows us how sick this population of patients were.

Were there any downsides to this treatment?

The safety profiles are actually comparable in both arms. It’s interesting to note that there was an increase in infusion reactions in the placebo treated patients compared to the idelalisib treated patients which is interesting and I surmise is likely due just to the fact that when you’re treating the patients with something that’s going to control the CLL the likelihood of infusion reactions becomes less. The toxicity signal in idelalisib was really exactly what we expected from earlier studies where we do see a small number of patients develop a transaminitis and this is usually asymptomatic and occurs between weeks eight and twelve and is always reversible. Four out of the six patients who had the transaminitis on the study were able to be successfully rechallenged and resumed on drug.

What kind of impact will idelalisib make on the treatment of CLL?

I think it’s going to make a tremendous impact upon the treatment of CLL patients. My hope is that these new tyrosine kinase inhibitors will enable us to treat people before they develop a lot of the problems that CLL patients develop and allow us to treat them in a manner that’s going to not create future problems, namely in terms of myelosuppression, marrow failure, secondary myeloid neoplasias. This would allow us to really extend the overall survival which is now 79 years to really unlimited. The important thing is that once this drug is approved that it really offers a great opportunity to patients who are considered medically unfit and unable to receive chemotherapy. Those data should be easily extrapolatable to patients who are medically fit and who really have a lot of reasons to not want chemotherapy.