MURANO trial: Sustained disease survival in CLL following venetoclax plus rituximab

Dr Arnon Kater - Cancer Center Amsterdam, Amsterdam, Netherlands

The MURANO trial is a phase III trial where a direct comparison was made between standard immunochemotherapy, bendamustine rituximab, or a fixed duration treatment, venetoclax rituximab, for patients with relapsed refractory CLL. The important thing here is it’s an industry-sponsored trial by Roche Genentech. This is most likely the first trial, first of all, that a fixed duration treatment with novel agent was tried and the second important thing is that it was the first trial where a novel targeted agent was directly compared to standard chemoimmunotherapy.

What did this analysis investigate?

With this five year analysis we looked into some different things than we have done before. Since it’s five years we have now a focus on long-term progression free survival and overall survival outcomes. We also have now an addition: we reported on off-therapy MRD candidates and MRD response rates to retreatment with VenR with now an overall median follow-up of 59 months.

What are the key results from this trial?

Patients who completed venetoclax monotherapy, so remember this is a therapy of fixed duration but still takes two years, so six months of combination venetoclax and rituximab and then 18 months of venetoclax monotherapy, so rituximab is given only in the first six cycles. What we now can say is that most patients who completed venetoclax monotherapy had an undetectable MRD at the end of treatment and MRD status continues to be a very robust predictor of outcomes.

We also have learned that patients in the VenR arm with undetectable MRD at the end of treatment had a 61.3% progression free survival rate at 36 months post end of treatment. Then an important thing is if you zoom into those patients with MRD undetectable levels, what happens to those patients afterwards and how long does it take until they convert and how long does it take until they get progressive disease? What we have learned from this study, from this update, is that the median time to MRD conversion is 19 months and median time to progressive disease from MRD conversion is an additional 25 months, of course for patients with undetectable MRD at the end of treatment.

Of those reported at this time point a significant proportion of patients, more than 30%, remained with undetectable MRD at this follow-up.

A third point is that we now looked into MRD kinetics, specifically MRD doubling rates, and what we found is that poor baseline characteristics are associated with a faster MRD doubling rate. What are those poor baseline characteristics? First of all that is harbouring TP53, del 17p aberrations. Second is if you have genomic complexity defined as three or more genetic aberrations, genomic aberrations I should say. And the third one is if you have an unmutated IGVH status.

The fourth conclusion is that if you re-treat patients with venetoclax rituximab after first treatment, so when we look now at the end of combination treatment too, that’s the data we have now of 60 patients, we can say that deep and durable initial response alongside favourable baseline characteristics predicts sensitivity to retreatment with venetoclax. And that is actually the main conclusion which we think supports the use of fixed duration of venetoclax rituximab in patients with relapsed/refractory CLL.

From a more biological stand of view what, for me, is very interesting is the fact that so far we actually don’t understand what happens after this MRD conversion and how long does it take. Some of the models say that the speed that MRD went down is exactly the same as the speed that it went up but actually we don’t know what factors are there. Is the therapy a factor here? Are the baseline characteristics a factor? So that’s what we looked into and there are two interesting things here. First is if you calculate the MRD growth rate we see that the doubling time of patients is actually higher for patients treated with VenR than with BR. So if you look to the doubling time in days it’s 72 days for VenR and 52 days for BR. So treatment itself actually dictates for the MRD doubling time. But also then we looked with patients that have been treated with VenR and we took patients that made it to the end of treatment. We also saw that specific baseline characteristics actually also define, maybe, the MRD doubling times. If you compare patients with abnormal or normal del 17p we see that it’s 45 days versus 86 days for patients with 17p deletion compared to those without; 62 versus 96 days in patients with complex genetics versus those without complex genetics and 60 versus 120 days in patients with IGVH unmutated disease compared to those with IGVH mutated disease.

So we think that this indicates, actually, that residual disease in patients with these poor risk factors could grow back faster than those patients without these risk factors.

How can these results impact the future treatment of CLL?

This study, again, shows what was already shown earlier that novel targeted agents can actually be more effective, at least as compared to bendamustine rituximab. It’s safe to give, it gives very good outcomes and retreatment seems to be possible, at least for patients with a good response after first VenR, which I think is very promising.

The second is that I think from this all novel targeted agents that we can choose a fixed duration is feasible. What’s very remarkable and clinically highly important is that it first takes 19 months for MRD conversion and then another 25 months for progression free survival. What we haven’t done yet here, because it’s a bit too early, but calculate from progression free survival until next treatment can also be a couple of months. So the time that you are actually off therapy is actually extremely prolonged, and remember that these are relapsed/refractory patients. So I think that’s extremely promising also for first line treatment that fixed duration treatment can really result in very long off-treatment periods of time.