EHA 2015

Targeted combination therapy with potential to eliminate relapsed chronic lymphocytic leukaemia

Dr Andrew Roberts - Royal Melbourne Hospital, Melbourne, Australia

You’ve been looking at the use of a new agent, adding it to standard therapy in patients who are relapsed or refractory with chronic lymphocytic leukaemia. Why were you looking at this particular new agent and what was the outlook? It has been difficult to add to standard therapy up to now, hasn’t it?

The new agent that we’ve done the trial with is a drug called venetoclax, formerly known as ABT-199. It’s a targeted drug, an oral medication taken daily. The target is the protein BCL-2 and BCL-2, as people will know, is crucial for the survival of many blood cells but particularly for the survival of chronic lymphocytic leukaemia cells. So the hypothesis was that if we added venetoclax in combination with rituximab that we would get more efficacy than we would see with venetoclax alone or rituximab alone in people with relapsed chronic lymphocytic leukaemia.

So could you describe the study to me?

It’s a phase IB study. It was a dose finding study between 200mg/day and 600mg/day of venetoclax but each dose level was active in combination with rituximab and so for the presentation here at EHA we’ve combined all 49 patients for the efficacy analysis.

And what happened?

49 patients with relapsed or refractory CLL entered the trial. 41 out of 49 achieved an objective response. Impressively, 20 out of the 49 achieved a complete remission and even more impressively 13 people achieved minimal residual disease negative complete remission.

Now how much of that was due to the rituximab and how much to the venetoclax?

Rituximab typically has a response rate of about 20%, no-one getting complete remissions. Venetoclax on its own achieves a complete remission rate around the 20% range and an overall response rate in the high 70%. So most of the activity relates to the venetoclax but comparing between single arm trials it looks to be that there’s additive effect of rituximab to the venetoclax, particularly in terms of the depth of response we’re getting.

Were there any added toxicities?

We saw no added toxicities when we added the two agents together. Of course we saw the toxicities we saw with them as single agents.

What do you make of these findings then?

I think this is an important first step towards working out how best to use a BCL-2 inhibitor like venetoclax. This provides strong evidence that you can combine it with another targeted agent such as rituximab. The depth and durability of the responses suggest that this may be a step for providing very good long-term outcomes for people who currently have poor outcomes.

Indeed, some of your patients didn’t have to continue with treatment.

Six patients who achieved complete remission actually interrupted therapy and remained on study. The median follow-up on those patients is about 1½ years; to date five of the six patients remain in complete remission. Only one patient has had an asymptomatic indolent progression and that is at the two year mark off medication.

What are you doing about the tumour lysis syndrome because the drug is so effective it can cause a problem?

Early on in the clinical development of venetoclax we had problems with tumour lysis. Typically that was associated with using a dose of 50mg or higher as the first dose given to patients with disease. We’ve learned that if you start with 20mg and build up in a weekly ramp up schedule to the target dose of 400mg the tumour lysis is not a major clinical issue.

Clearly a phase IB, we can’t read too much into this yet but you have got a marked efficacy signal. What do you think could become of this clinically?

The importance of this will be determined by a currently ongoing randomised phase III study that compares bendamustine plus rituximab in standard regimen versus venetoclax and rituximab using a regimen very similar to the one that we’ve done with this phase IB study. I think that will put things in perspective, it may allow us to have a chemotherapy-free regimen as an alternative to chemotherapy containing regimens.

So what do you advise cancer doctors to take home from the findings so far?

Look for a clinical trial to enrol your patients in in this difficult disease group of patients. And look to see the results of the randomised trials with venetoclax and look to see venetoclax being combined with other non-chemotherapy agents in the future as we look to find a way to cure CLL.