Key Clinical Data for Frontline Targeted Therapy in CLL

John C. Byrd, MD: We’re blessed to have 2 long-term studies with previously untreated CLL [chronic lymphocytic leukemia], including 1 that Dr Paul Barr just updated with a 7-year follow-up, the RESONATE-2 comparing ibrutinib to chlorambucil. These studies show a long sustainable readmission in patients with previously untreated CLL. As you get further in these trials, there’s less discontinuation for hypertension, AFib [atrial fibrillation], and other things, although it’s still there in a small number. What’s encouraging about the studies is that we’re not seeing really bad things happening to patients for the long term. There’s a considerable amount of safety, much better than we had in the past with chemotherapy-immunotherapy, and patients don’t appear to be relapsing at a high rate as we get out with further follow-up.

The real big question about all the up-front studies is the benefit of CD20 antibodies. There have been several studies: rituximab in addition to ibrutinib, and both…a study done…in relapse patients and up-front 17p patients. Neither study really showed an advantage to rituximab. There’s only 1 randomized study of obinutuzumab plus or minus a second-generation BTK [Bruton tyrosine kinase] inhibitor, and that was the ELEVATE TN treatment-naïve study. It demonstrated that obinutuzumab adds to progression-free survival [PFS] compared with when it’s added to acalabrutinib vs acalabrutinib. That wasn’t an intended analysis, and it was done post hoc. One has to take that into consideration, but we would expect this in part that acalabrutinib would go better with a CD20 antibody because it doesn’t inhibit antibody-directed cells of toxicity. If I’m going to give a CD20 antibody, I would do it with a second-generation BTK inhibitor, such as acalabrutinib.

Anna Schuh, MD, PhD: Acalabrutinib is a second-generation BTK inhibitor, and recent studies—the ELEVATE TN study and the 4-year follow-up—have compared with chlorambucil-obinutuzumab with or without the addition of obinutuzumab. Acalabrutinib is very well tolerated and has superior efficacy with respect to progression-free survival. The question is where it sits in the treatment algorithm. For me, when the ibrutinib results first came out, they were hugely impressive. Longer follow-up use of the drug in the real world with the patients who are frailer compared with the patients going into clinical trials has shown that the cardiac-risk factors are quite significant with ibrutinib. They’re still present with acalabrutinib, so the head-to-head comparison in patients with relapsed CLL and high-risk features has shown that there’s not a complete absence of atrial fibrillation and hypertension in patients with acalabrutinib, but clearly there’s a reduction compared with ibrutinib. These long-awaited data are significant because they’ll push people more toward prescribing acalabrutinib, particularly in frailer patients.

Paolo Ghia, MD, PhD: For a few months, we’ve had available venetoclax in frontline and, typically together with obinutuzumab, the CD20 antibody. The pivotal study that led to the approval is CLL14, which is a study designed by the German CLL study group. Though it was an international study, it randomized older and sick patients to a fixed-duration therapy with venetoclax plus obinutuzumab for 12 cycles or a chlorambucil plus obinutuzumab, which was considered a standard therapy for immunochemotherapy for the older patients.

The results are quite impressive for a fixed-duration treatment in the front line because we do see that 3 of 4 patients still respond after a median or 4-year follow-up. When we think that progression in CLL doesn’t mean a need of therapy, the time to next statement is even longer, with more than 80% still not needing therapy after more than 4 years. These data are quite reassuring at the population level. When we consider the subgroups based on genetic features, the situation tends to be a little different. For patients with mutated immunoglobulin genes, their responses are quite durable and stable, so of course we need longer follow-up to see if we can achieve that plateau or PFS that we observed with FCR [fludarabine, cyclophosphamide, rituximab] in the young population. That would be very reassuring because it implies that patients with mutated immunoglobulin genes can benefit from a fixed-duration therapy that doesn’t include immunotherapy.

When we speak about unmutated patients, the situation is a little different. These patients tend to progress a little earlier. Indeed, immediate progression-free survival has been reached, which is probably almost 4 years. That suggests that this patient may benefit a little less, but we also have to consider that this patient, when relapsing, might be re-treated with the same venetoclax-based treatment. This might prolong the overall PFS. We have the possibility to maintain the patient on the same treatment for a long time. A patient with TP53 aberration instead tends to progress much earlier. Here, the PFS has been reached, and there’s a statistically significant difference between the patient with and without the TP53 aberration, so maybe the fixed-duration treatment with this combinational drug isn’t yet the best treatment for this patient.

Of course, we have to see how many patients can be re-treated with venetoclax before making a firm conclusion. The same treatment has been also proven in another study. These are older patients who are better and sick patients who were fit to FCR [fludarabine, cyclophosphamide, rituximab], suggesting that the results were quite similar in terms of MRD [minimal residual disease] attainment. It’s reassuring to see that the data are reproducible in different studies, confirming that at least frail and sick older patients can really benefit and tolerate this treatment. There are probably a few doubts that the same will also be true in the young patients.

Transcript Edited for Clarity