ASH 2024 | Ibrutinib plus venetoclax followed by MRD-guided ibrutinib plus obinutuzumab in first line CLL

So that’s a large story. It starts with that venetoclax is very often used in treatment of CLL patients. And all kinds of combinations are given to these patients, like venetoclax and obinutuzumab, or venetoclax and ibrutinib. In trials now also venetoclax, ibrutinib and obinutuzumab are given. The combination of venetoclax and obinutuzumab is sometimes hampered by remaining enlarged lymph nodes. And the combination of venetoclax and ibrutinib shows more often higher MRD values. And the combination of venetoclax, ibrutinib and obinutuzumab has the highest amount of toxicity. So that’s why we looked into this problem. And in 2018 there were a couple of presentations here at ASH, which showed that the CD20 expression on CLL cells go down after you start with ibrutinib, and it has the lowest point after six months. But after one year it’s at baseline level again. And another talk here from Andy Rawstron showed that if you start with obinutuzumab, which inhibits CD20. At the start of ibrutinib you have a very low number of MRD negative patients, but if you wait for one more year, then the CD20 expression is up again and obinutuzumab works much better and the number of patients with MRD negativity is higher. So that’s why we designed the HOVON 158 study in which the patients got IV treatment, ibrutinib and venetoclax treatment for one year as is normally done and normally the treatment is stopped then. But we looked into the patients after one year and if they didn’t have a complete remission, so the remaining enlarged lymph nodes or enlarged spleen, or they didn’t have a negative MRD value, then we gave them an intensification treatment with obinutuzumab in combination with ibrutinib. And looking into this, we expected that about 40% of patients wouldn’t have complete remission and MRD negativity. Finally, in our trial, it wasn’t 40%, but it was 65% of patients who still had some lymph nodes or enlarged spleen, or they exhibited not undetectable MRD values. So these patients got ibrutinib intensification in combination with the obinutuzumab. And after six cycles, 60% of patients got into complete remission and had no MRD values left anymore. So we think this is a successful trial because we expected about 45% of patients to be in complete remission and have a negative MRD value, but it was 65. And if you look at the progression-free survival curves, they are excellent. And maybe this way of MRD-guided treatment with IV can be advantageous for CLL patients on the long term, in which they wouldn’t get their illness back on the short term or on the long term. Of course, it’s also important to look at the side effects. And because you also can give ibrutinib, venetoclax and obinutuzumab at the same time, but it’s hampered at the increased toxicity. So we looked at the side effects and we saw the normal side effects of IV treatment like bleeding, atrial fibrillation and infections and gastrointestinal problems. And if you look at the intensification treatments, there were only some grade 2 or grade 3 toxicities. And it was apparent that no infusion-related problems were seen, which is normally about 30 or 40 percent. Probably due to the low number of CLL cells or the co-medication of ibrutinib. So without causing much extra toxicity, this is a successful treatment for our CLL patients.

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