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Novel Treatment Approaches in Chronic Lymphocytic Leukemia
What were some of the novel treatment approaches in chronic lymphocytic leukemia [CLL] that you saw discussed during the recent American Society of Hematology [ASH] meeting?
There were a number of novel approaches to treat CLL that were reported at ASH. I think of them as being in 3 main categories: large, phase 3, practice-changing trials; smaller studies that are combining novel drugs together; and studies presenting on longer follow-up of previously reported phase 3 studies.
To summarize that first category, I’d say the 2 most important abstracts that we saw presented were the Alliance trial for frontline treatment of older CLL patients, which was a randomized phase 3 trial comparing ibrutinib to ibrutinib with rituximab and comparing that to the standard of care of bendamustine and rituximab — this study looked favorable for the ibrutinib-containing regimens with respect to PFS [progression-free survival], although there was no overall survival [OS] benefit.1
The second one was for younger CLL patients who needed frontline treatment, and this was the ECOG 1912 study, which compared ibrutinib with rituximab [IR] to the standard FCR [fludarabine, cyclophosphamide, and rituximab]. This study showed both a PFS and OS benefit for the IR arm of the study.2
In the category of smaller novel agent studies, 1 important emerging combination approach is ibrutinib with venetoclax. A couple of abstracts to highlight from that group are the work of Dr Nitin Jain and colleagues from the MD Anderson Cancer Institute, which showed impressive data for frontline treatment with ibrutinib and venetoclax, particularly with regard to depth of response, including MRD [minimal residual disease] undetectability.3
The other abtract to highlight here is the update of the CLARITY study from the UK group, presented by Dr. Peter Hillmen and colleagues, which looked at a similar regimen of ibrutinib with venetoclax, but in relapsed CLL patients.4 Even in this more hard to treat population, this approach again led to very high rates of complete remission and MRD undetectability in the bone marrow.
We also saw data from Dr Kerry Rogers and the Ohio State group with the same combination of ibrutinib with venetoclax, but also with a third drug added, the obinutuzumab anti-CD20 antibody, and these data also looked promising, although it remains uncertain how much, if anything, an antibody is adding to the efficacy of the novel agent doublet.5
In the third category: An important update of a previously published phase 3 study was the MURANO study, which is a randomized phase 3 trial of venetoclax with rituximab compared with the standard bendamustine and rituximab in relapsed/refractory CLL patients.6 In this update, we saw an additional year of follow-up on patients compared with the original report. The reason why this extra year of follow-up is so important is that the regimen is designed as a time-limited course of 2 years — and we got to see the results for patients who are now all off therapy, for a median of about 10 months off treatment. So far it looks promising, in that the majority of patients are still off therapy and in remission. This raises the prospect of time-limited novel agent therapy in CLL, which I think would be a real major development, since previously novel agents have been developed as continuous therapies in this disease.
So to me, those were the biggest takeaways and highlights of the ASH meeting for CLL.
It sounds like the last example you mentioned might change the standard of care. Were there other presentations that you mentioned that will also probably change the current standard of care?
Yes, I think the first 2 presentations that I mentioned, the larger cooperative group studies, both have practice-changing implications. The Alliance study shows that, particularly for patients with unmutated IGHV, that ibrutinib should be considered as a new standard of care for that group.1
So far, based on the lack of overall survival benefit, one could still consider using bendamustine and rituximab for CLL patients with mutated IGHV who are older and need initial therapy. Ibrutinib is also a reasonable option for those patients — although was not without its toxicities, so patient selection will be important. The Alliance study is also important because it reinforces the fact that rituximab doesn’t add much to the ibrutinib. So, if patients are getting an ibrutinib-based regimen, it really should generally be ibrutinib monotherapy.
From that ECOG study, for patients with unmutated IGHV, the data suggest that these younger patients should be started on ibrutinib as opposed to FCR. For patients with mutated IGHV, FCR remains an important option, as compared with all the other therapies being discussed, it remains the only 1 proven to have the potential for truly durable complete remissions of 10 years or longer.
And then, as the MURANO study continues to mature, it is beginning to provide a robust dataset for the efficacy of venetoclax with rituximab for patients who relapse with CLL after chemoimmunotherapy.6 Many hematologists have been using ibrutinib as their first choice in the relapsed setting setting, but I think the MURANO study shows us that there may be some advantages of the venetoclax/rituximab regimen, whereby patients can respond nicely to a time-limited regimen. This appears to allow for remission for some time off of drug, which I think is a potential advantage over ibrutinib, which is given as a continuous therapy.
Were there any surprising findings from any of the sessions that you really didn’t expect to see?
I would say the most surprising finding was from the ECOG 1912 study, which demonstrated an overall survival benefit for patients who received ibrutinib with rituximab compared with those patients who received FCR.2 For a frontline CLL trial in younger patients, it’s quite early to observe an overall survival benefit. Since we only saw a brief presentation on this, we are going to need to see some of the details of that study when it’s finally published to figure out why there were more deaths in the FCR arm. In the presentation, it seemed like it was mainly due to progression of CLL rather than toxicities. One of the potential limitations of that study is, as far as I understand, they did not do screening for TP53 mutation status for eligibility. We know that those patients with a TP53 mutation would do poorly with FCR, and it’s possible that the overall survival difference is really due to the fact that patients who should not have received FCR due to a TP53 mutation were getting that treatment. These are the types of details we’ll need to look for once the final publication comes out.
In the context of residual disease, do you think a cure for CLL would ever be possible?
I do think that cure is still a worthy goal to pursue for CLL, because, particularly for our younger patients, they may have a long life ahead of them, and developing a time-limited regimen with curative potential, particularly for patients in their 50s or 60s (or even younger), I think is important.
Fortunately, we already have 1 regimen with curative potential — FCR. But this is a therapy that we can only safely use for our youngest and fittest patients with mutated IGHV and lower-risk cytogenetics. So I think as we develop novel agent combinations it’s certainly possible that, if we can get patients into deep-enough remissions, that there may be curative potential with regimens like that. But it’s too early to know that based on the limited follow-up of data that we have so far.
I think it’s also important to mention that for older, frailer CLL patients, we don’t necessarily need to be developing these complicated combination strategies for long-term remissions, because for these older patients, in their late 70s or into their 80s, it may be better to put them on a single novel agent like ibrutinib or venetoclax, for example, and they may do well for several years. If they progress, they can switch to another novel agent monotherapy and get a few more years of response. And so, for that older, frailer population, I think the goal is less about cure and more about disease control with well-tolerated and convenient novel agents.
What were you disappointed with at ASH, and in the future, what do you look forward to in terms of data that are slated to be presented at future meetings?
One of the more disappointing things to me about the meeting was that I was hoping to see data from the CLL14 study, which is an important ongoing randomized phase 3 trial in Europe that is comparing venetoclax and obinutuzumab to a standard of care, chlorambucil and obinutuzumab, in the frontline older CLL population. This dataset is potentially practice-changing and label-enabling for venetoclax in the frontline setting, which may change how we approach our frontline treatment algorithms in this disease.
That answers both of your questions, actually, because we didn’t see the CLL14 dataset at this meeting, it’s likely that [it] will be one of the most heavily anticipated datasets to be presented at a future meeting. I’m certainly excited to see those results as soon as they’re available.
1. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib alone or in combination with Rituximab produces superior progression free survival (PFS) compared with bendamustine plus Rituximab in untreated older patients with chronic lymphocytic leukemia (CLL): results of Alliance North American Intergroup Study A041202. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 6.
2. Shanafelt TD, Wang V, Kay NE, et al. A randomized phase 3 study of ibrutinib (PCI-32765)-based therapy vs. standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOG-ACRIN cancer research group (E1912). Oral presentation at: 2018 American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, California. Abstract LBA-4.
3. Jain N, Keating MJ, Thompson PA, et al. Combined ibrutinib and venetoclax in patients with treatment-naive high-risk chronic lymphocytic leukemia (CLL). Oral presentation at: 2018 American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, California. Abstract 186.
4.Hillmen P, Rawstron A, Brock K, at al. Ibrutinib plus venetoclax in relapsed/refractory CLL: results of the Bloodwise TAP Clarity study. Oral presentation at: 2018 American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, California. Abstract 182.
5.Rogers KA, Huang Y, Ruppert AS, et al. Phase 2 study of combination obinutuzumab, ibrutinib, and venetoclax in treatment-naive and relapsed/refractory chronic lymphocytic leukemia. Oral presentation at: 2018 American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, California. Abstract 693.
6. Seymour JF, Kipps TJ, Eichhorst B, et al. MURANO trial establishes feasibility of time-limited venetoclax-rituximab (VenR) combination therapy in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Oral presentation at: 2018 American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, California. Abstract 184.