Advancements and Updates in Therapies for CLL - Episode 5
Developing Clinical Trials for Newly Diagnosed Disease
Key opinion leaders discuss trials focusing on patient populations with newly diagnosed chronic lymphocytic leukemia (CLL).
Alison Duffy, PharmD, BCOP: I'd love to hear your thoughts on other treatment options besides ibrutinib in a newly diagnosed setting and otherwise.
Cody Steeves, PharmD, BCOP: I agree with what you said about ibrutinib, as it should be considered in pretty much every patient with CLL [chronic lymphocytic leukemia] who walks through the door, but there are other options to consider. One of the other recent trials, the ELEVATE trial, got the approval going for acalabrutinib plus or minus obinutuzumab, CD20 inhibition. They had 3 arms, 1 acalabrutinib monotherapy, 1 acalabrutinib with obinutuzumab, and then the older agent, chlorambucil, with obinutuzumab as well, as the third arm.
The main data point there was progression-free survival [PFS], and after 28 months of follow-up they hadn't reached the median for either acalabrutinib arm for PFS, and did reach it in 22 months for the chlorambucil-obinutuzumab arm.
Regarding toxicities, neutropenia, infection, we're going to be seeing in chlorambucil and obinutuzumab a little bit more. Comparing the 2 acalabrutinib arms, when you added obinutuzumab you did see a significant amount more of neutropenia, and infection off the pneumonia, versus acalabrutinib alone. Headache or diarrhea, as would be expected, was higher in the acalabrutinib-containing arms, but grade 3 of those headache or diarrhea was also pretty rare, so that wasn't a huge issue.
What can be gleaned from this study is the acalabrutinib versus the acalabrutinib-obinutuzumab combination arm, and discuss whether we should be adding obinutuzumab, because the NCCN [National Comprehensive Cancer Network] guidelines will say it's plus or minus at this point for the first-line recommendation. They did see what they described as a likely trend toward progression-free survival with the combination therapy. They described that as at a 30-month period, 90% versus 82%, with 90% being the combination of acalabrutinib and obinutuzumab.
But again, more data are going to be needed to include this, as well as weighing out the toxicity risk for these treatments. Is it worth taking that extra risk of neutropenia, potential pneumonias, versus getting that extra relatively small benefit in progression-free survival at the 30-month interval?
Then the data, as you mentioned, as they mature, what are they going to look like at 54 months? Like we have now in the long RESONATE trial, 6, 7 years, because these are not patients who we expect to only follow for 3 or 4 years; we hope to follow them for 8 or 10, 15 years. So we do need these data to mature, but definitely it is a good sign that the acalabrutinib combination therapy was very effective.
Then in regard to venetoclax, and venetoclax has that recommended combination with obinutuzumab. It's not plus or minus on the recommended regimens, it is plus obinutuzumab based on the CLL14 trial, which compared again to chlorambucil plus obinutuzumab in previously untreated patients with CLL, many of whom had coexisting conditions.
The benefit of this study was it provided that first major first-line, fixed-duration study of oral chemotherapy, and they stopped the treatment at 12 months. Then their end point was PFS at 24 months, at which point the venetoclax combination arm had an 88% rate of PFS, versus 64% for the chlorambucil.
As we talked a little bit earlier, this benefit was still observed across that TP53 or 17p deletion population, as well as the IgHV [immunoglobulin heavy chain variable] unmutated population, which would be considered very unfavorable to receive that chemoimmunotherapy.
One of the interesting things in this study, as we talked about a few points ago, is the MRD [minimum residual disease]. The MRD was measured in this study, and at 24-month follow-up, it's really impossible to know what exactly that will mean, but it is noted that venetoclax and obinutuzumab had a much higher rate of negative MRD both in the peripheral blood and in the bone marrow.
So again, we need to see if this will lead to the discontinuations being permanent or being very sustainable, or how long that may be in venetoclax, because we only really know in FCR [fludarabine, cyclophosphamide, rituximab] what those data mean, because it has a lot more long-term follow-up.
It affects our treatment plan by providing yet another first-line option, and of course, this being the first and really the only of those 3 first-line options that is completely fixed duration that the NCCN recommends right now. It’s a great option for the aforementioned patient who doesn't want to commit to lifelong therapy and wants to be off the drug as soon as possible to have this option in our pocket as health care providers.
Alison Duffy, PharmD, BCOP: Yes, I agree with you regarding the role of those agents, and also the data. I think they are still maturing for both acalabrutinib and venetoclax, but are promising, and we definitely have some great results in the relapsed/refractory setting for venetoclax, especially, based on the MURANO trial. We'll see how things pan out in the first-line setting.