ASH 2015

Idelalisib combination therapy in relapsed or treatment-resistant CLL better than standard regimen

Dr Andrew Zelenetz - Memorial Sloan Kettering Cancer Center, New York, USA

You’ve been looking at patients with refractory or relapsing chronic lymphocytic leukaemia and you’ve been using this agent idelalisib. What were you trying to do and what was the basis, what was the reason, the issue, you were investigating here?

The problem is that though we have increasing treatment options relapse in CLL still is inevitable. We’re not curing patients with CLL so patients end up with relapse and often refractory disease, disease that’s not responding to conventional treatment anymore. So we wanted to ask the question whether addition of idelalisib to a standard of care regimen for the relapsed refractory CLL patient, that is bendamustine rituximab, would improve outcome.

Now this drug is targeting an inhibitor of PI3 kinase delta. What does that mean and why is it important potentially?

The PI3 kinase pathway is actually important in many cell types, it’s not just important in CLL and lymphoma. It is a critical pathway for regulating cell growth and survival. There are multiple isoforms, alpha, beta, gamma and delta and they have different tissue distributions. The delta is actually useful for us as haematological oncology doctors because it targets white blood cells. We don’t see the targeting of some of the other tissues and therefore we get less toxicity. So the delta targeting allows us to deliver much more effective dosing and really inhibit the PI3 kinase.

You looked at 416 patients, a very substantial number of patients, what did you find?

We compared 209 patients who received bendamustine rituximab plus a placebo versus 207 patients who received bendamustine rituximab with the idelalisib. The primary endpoint was progression free survival and what we found is that the progression free survival for the patients receiving bendamustine and rituximab and the placebo was 11.1 months, completely in line with what we expect. But when we added idelalisib we added 12 months to progression free survival, going up to 23.1 months, representing a 67% reduction in the risk of progression or death.

And this was such a big effect that at interim analysis the study was halted early.

Yes, the study had a planned interim analysis when two-thirds of the events had occurred and that occurred in October and in mid-October the independent safety data monitoring committee met and actually recommended immediate discontinuation and publication of the information because of the overwhelming benefit in favour of the experimental arm.

So I can’t resist asking you about response rates and complete responses and, of course, the possibility of overall survival being increased.

The overall response rate was 67% which was about a 20% improvement over the bendamustine rituximab arm. The complete response rate was higher but it was actually quite low. The overall complete response rate was only 2%. Now I know that part of the problem is that we use a very stringent definition of complete response and in CLL to abide by this stringent definition of complete response it requires a repeat bone marrow biopsy. 24 patients in the idela arm met the criteria for a complete response but only 5 of them had a bone marrow biopsy. Those five were all negative but the other ones couldn’t be called a complete response because they didn’t have a repeat bone marrow. In the bendamustine rituximab arm there were only 8 patients who met the criteria to be called a complete response if they had a bone marrow but none of them had a bone marrow either.

And overall survival?

Overall survival was significantly improved. In both arms the median hasn’t been reached but there was a 45% reduction in the risk of death in the experimental arm.

Toxicities?

Toxicities were greater with the addition of idelalisib but in a way that we expected. We saw more transaminitis, well that’s a known toxicity of idelalisib, it’s manageable. There were more respiratory problems, pneumonitis is a known complication of idelalisib. Whether all of these increased respiratory symptoms were infection or drug toxicity we’re not sure and we also saw some more rash and diarrhoea. Those are all idelalisib side effects. The thing that we saw more of, we saw more febrile neutropenia and it was a significant increase in febrile neutropenia; there were no deaths from febrile neutropenia. The rate of sepsis was actually similar between the two arms. One of the interesting side effects of idelalisib is pyrexia and because we’re combining idelalisib with chemotherapy the chemotherapy is causing neutropenia and if the drug is causing pyrexia those are automatically going to be assumed to be febrile neutropenia. So we see more episodes of low blood counts and fever but they are not turning out to be serious life threatening infections.

Right, so there’s something to cope with there but manageable, you think?

The increased side effects are very manageable.

What are the clinical implications coming out of this, then?

So the clinical implication is pretty straightforward. For patients in whom the physician is thinking bendamustine and rituximab is the right thing to do then addition of a small molecule PI3 kinase delta inhibitor, idelalisib, will provide meaningful improvement over the standard of care.

A short take-home for doctors?

That we’re in a great era and this is not only a take-home for doctors, it’s also for patients. We’re in a great era in CLL, we have lots of drugs. Our challenge today is how to figure out how to combine them to really completely change the natural history of this disease and we’re only going to do that with our colleagues in the community putting patients on clinical trials and the patients being willing to participate in them.