EHA 2025 | Ask the Expert: Barbara Eichhorst answers your CLL questions at EHA 2025

Hello everyone, my name is Barbara Eichhorst. I’m a hematologist and consultant at the University Hospital of Cologne in Germany, and I welcome you here from the EHA 2025 from the wonderful city of Milan, and we are recording this here for the Ask the Expert session. 

So one of the questions which was submitted is considering the progression-free survival benefit of adding Ibrutinib to Venetoclax-Obinutuzumab within the CLL13 GAIA trial, would you consider using this triple combination in first-line treatment of patients with CLL or specific subgroups? Thank you very much for that question. Arnon Kater from Amsterdam UMC presented the data here yesterday. And indeed, there is a 12% difference by adding Ibrutinib now after more than five years’ observation time in comparison to Venetoclax-Obinutuzumab only. However, the reason why I still wouldn’t use it in clinical practice is that on the first hand we don’t see a difference in the overall survival, and we also see on the other hand more toxicities, we see more infections with a triple combination, more cardiac comorbidities, and also when we look at quality of life, we see at least that during the treatment, patients’ health-related quality of life is improving only when patients finish the triple treatment. 

I think a subgroup which may benefit from that but they were excluded from the GAIA trial are patients with TP53 abberation, deletion 17p. We did a Phase II trial on those patients also showing promising results. I think this may be justified in this group of patients to use the regimen. Otherwise, even in patients with unmutated IGHV status, that’s where we saw most of the benefit of the triplet treatment. Considering that many of them still have a very good prognosis, I would still not use it from the beginning. The only subgroup which may benefit are patients with high complex karyotype where we have seen that the triplet is working here very effectively, and even patients with Venetoclax-Obinutuzumab do have a shorter PFS when they have five or more chromosomal aberrations. 

So the next question is coming from Dr Wang from the Mayo Clinic, and he says he’s curious to know thoughts on the acalabrutinib-venetoclax or acalabrutinib-venetoclax-obinutuzumab frontline CLL therapies when to use these regimens as opposed to Venetoclax Obinutuzumab or BTKi continuous treatment. Very excellent question, difficult to answer because we are waiting here for study results for the comparison of continuous BTKi versus a double oral therapy. We are waiting for the results from the CLL17 trial comparing venetoclax-ibrutinib versus ibrutinib. We will have the results at the end of the year, and for VG, Venetoclax-Obinutuzumab, versus AV and the Magic study from the Dana-Farber Cancer Institute and fully recruited fast, and also here we are waiting for the results. 

But obviously, the advantage of the acalabrutinib-venetoclax is it’s much more convenient for the patients than CD20 antibody infusions. On the other hand, when we have young patients who wish to have very long-lasting remissions, MRD rates with acalabrutinib plus venetoclax were relatively low, particularly low in comparison to venetoclax-obinutuzumab and seem to be, if you would like to do a cross-trial comparison, also a little bit lower than ibrutinib-venetoclax. Therefore, though in the AMPLIFY study evaluating Acalabrutinib Venetoclax, more fit patients were included, but I personally would consider acalabrutinib-venetoclax more in an unfit elderly patient population for whom it is not so convenient to come for the obinutuzumab infusions frequently to the clinic. 

With respect to the triple combination, the AVO combination certainly due to the relatively high rate of COVID deaths in the treatment arm, but the study recruited during the pandemic, most of the patients, 90% were not vaccinated before, but still this shows that obviously there’s a severe immunosuppression with the AVO regimen. On the other hand, we do really see a high efficacy with the triplet regimen, and for example, patients with TP53 abberation, although they were excluded from this trial, could be candidates for using this triplet combination. We are currently investigating that in the CLL16 trial. 

The next question is from Dr Kerry Rogers from Ohio State. She’s asking with two fixed-duration options now available for frontline CLL, Venetoclax plus obinutuzumab or BTK inhibitor-Venetoclax, how do you decide between those two treatment options? Which patient groups do you favor for one over the other? 

So when we look at the two subgroups of patients with mutated and unmutated IGHV status, we do see that in particular patients with a mutated IGHV status have very long progression in the CLL14 trial for the LLE patients, after six years, 75% of the patients are still without a relapse. And also now in the GAIA CLL13 trial, after five years, 80% of the patients in this subgroup are without a relapse. Therefore, I personally think, again, doing cross-trial comparisons since we do not have the head-to-head comparison, and that these patients in particular benefit from the CD20 antibody plus venetoclax. 

For the unmutated patients, I think it really depends. It’s hard to tell. It could be that patients with lymphadenopathy benefit more from the combination of the BTK inhibitor plus BCL2 inhibitor, for example. And I would discuss that with the patients in the absence yet of data from the head-to-head comparison, how convenient it is for the patient to come to the clinic having the controls and then finally also considering the immunosuppressive effect of the CD20 antibody in case the patient had a history of several infections, severe infections, I would consider this patient rather for the double oral combination than administering a CD20 antibody. 

The next question also from Kerry Rogers is while the data is still developing, what second line options do you think will be best after initial therapy with BTK inhibitor-venetoclax combination. Yeah, that’s a very difficult but important question because that’s of course what patients are asking for. So from the CAPTIVATE trial here at the EHA study, we have now with a new update and data being presented on 36 patients receiving relapse treatment, around 24 of them receiving a continuous treatment with ibrutinib and 12 or so again with a combination of ibrutinib plus venetoclax, the response was quite good in those patients. So in two of those patients now BCL2 mutation which has not yet been reported, which is not yet known that this is really resulting in resistance. So obviously that’s a big disadvantage on the double oral combinations that we have a lack of data here for the relapse treatment options and how effectively patients respond. However, at least for venetoclax obinutuzumab, we don’t see BCL2 mutations in the relapse situation, at least at the last data cutoff already a few years ago. In general, I would suggest we will not see many patients becoming refractory with this time-limited treatment, but certainly this is a risk we have to inform patients about. 

Then another question is, which patients do you think are best treated with continuous BTKi monotherapy. According, for example, to the ESMO guidelines, this would still be the first treatment of preference for patients with TP53 mutation or deletion 17p, since it seems that progression-free survival rate, when we compare those across the clinical trials, is still better with continuous treatment with BTK inhibitors. That is the one group. The other one which may be considered are patients of older age for whom it is really difficult to come frequently to the physician’s office that they may benefit for example from continuous treatment with the second generation of BTK inhibitors for having good disease control but do not necessarily achieve undetectable MRD rates. 

Thank you very much for listening to Ask the Expert and warm regards here from Milan.

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