EHA 2021 | IMPROVE: 33-month follow-up of MRD-driven therapy in CLL

At this EHA meeting, we are presenting the updated results of our IMPROVE study. Basically, we enrolled in the study patients with relapsed/refractory CLL, and they receive treatment with venetoclax single-agent first, and then, based on the minimal residual disease status, treatment could be intensified with the addition of ibrutinib, aiming at obtaining undetectable minimal residual disease and discontinuing both treatments.

In the first analysis of the study, we documented that actually about 45% of patients were able to obtain undetectable minimal residual disease, both in the peripheral blood and in the bone marrow with venetoclax alone. Then when we added ibrutinib, even for just a few months, more than 80% of the patients who started ibrutinib but with detectable minimal residual disease became MRD-negative, let’s say, showed undetectable MRD, and therefore stopped both treatments. And we have now a medium follow-up of about 33 months. Last update by April 30th, 2021.

And we have only seven patients who progressed. Only two of them actually require treatment for CLL. And these two patients were re-treated with venetoclax. Treatment is currently ongoing. So, we do not have yet the information on the response. Still, what’s worth underscoring is that 10 of these, of an initial cohort of 38 patients, are now in undetectable, minimal residual disease status, and are only follow-up over time. And five of them reached these important results with venetoclax only and are now continuing to be followed to understand when and if a clinical relapse requiring treatment occurs.

Treatment was in general very well-tolerated, meaning that in our experience, we did not encounter any clinical or laboratory TLS. That was an initial warning with the venetoclax treatment even if patients started with venetoclax first. So, there was no de-bulking strategy with the BTK inhibitor. The BTK inhibitor was added afterward based on the minimal residual disease status. In general, very few adverse events were reported and most of them were grade one or two. So, meaning that they were mostly very mild.

So, we are looking forward to proceed with the follow-up of patients enrolled into the study. Basically, to understand how they respond to retreatment with venetoclax once, and again, if they relapse. And the second very interesting point of course is to understand the dynamics of patients who never get minimal residual disease status, undetectable minimal residual disease status. And what happened at clonal level in those who, after obtaining undetectable minimal residual disease relapse with need for treatment.