Weighing Fixed Duration Versus Continuous Therapy for CLL Q&A With Matthew S. Davids, MD, MMSc

Evolving ParadigmsRecent Advances in the Treatment of Chronic Lymphocytic Leukemia

Matthew S. Davids, MD, MMSc, discusses the rapid developments in the chronic lymphocytic leukemia treatment landscape.

Matthew S. Davids, MD, MMSc

Matthew S. Davids, MD, MMSc

TARGETED ONCOLOGYTM:Given the rapid developments in the chronic lymphocytic leukemia (CLL) treatment landscape, can you reflect on what you feel were the most important and significant therapeutic trends from the past year?

DAVIDS:There have been 2 major inflection points in the field over the last year, and one of them is the data that came out initially at the ASH [American Society of Hematology] annual meeting last year—and were subsequently published in the New England Journal of Medicine1,2—examining ibrutinib compared to current standards of care in younger and older patients. The whole field pivoted after ASH and subsequent publication of data toward more use of ibrutinib. The NCCN [National Comprehensive Cancer Network] guidelines were updated accordingly, and for a period of time, ibrutinib was the only novel agent-based approach recommended for all types of patients, all risk factors, etc.

That period was relatively short lived, as the second major inflection point in the past year was the FDA approval of venetoclax plus obinutuzumab. The combination was approved in May,3and at the ASCO [American Society of Clinical Oncology] meeting in June, we saw the data for the first time publicly. I moderated that session at ASCO and gave a discussion on the abstract to try to put it in context. In my opinion, this new regimen, venetoclax/obinutuzumab, is, in some ways, the best of both worlds: Like ibrutinib, it’s a novel agent-based approach, so you don’t have to deal with the adverse effects of chemoimmunotherapy. But like chemoimmunotherapy, venetoclax/obinutuzumab is designed as a time-limited treatment.

The data look strong for venetoclax/obinutuzumab so far: It was designed as a 1-year-long therapy, and about 1 year after patients completed therapy, 88% were still in remission. Although these data suggest that this is likely to be a durable benefit, I do caution that the follow-up was short, and it will be important to follow up on what happens in the next year. If a lot of patients begin to progress, the feasibility of a time-limited regimen becomes harder to justify. But what we’re seeing so far looks good, and the adverse effect profile is also manageable.

Compared with ibrutinib, venetoclax/obinutuzumab is certainly a more challenging regimen to start from a logistics perspective. First, you have to deal with the infusion component of obinutuzumab and the risk of infusion reactions. Then, the venetoclax dose ramp-up begins and takes 5 weeks, with laboratory monitoring for tumor lysis syndrome [TLS] required a couple of days each week. Therefore, you need to invest some time and energy up front to get patients started on this regimen. In comparison, ibrutinib is pretty easy to start; the monitoring is much less, but on the flip side, there is the need for long-term continuous therapy. I think there are some potential real advantages for a time-limited regimen. Since its approval, venetoclax/obinutuzumab has made its way into the NCCN guidelines, and it is certainly a good thing for patients to have different options to choose from.

TARGETED ONCOLOGYTM:What are the benefits of the combination approach of venetoclax/obinutuzumab?

DAVIDS:One of the elements about the CLL144 study that led to the approval venetoclax/obinutuzumab, [was] that [the] patient population was restricted [to only] those with significant medical comorbidities (CIRS [Cumulative Illness Rating Scale] score greater than 6), so the patients on in the study were generally older patients, along with some younger patients with significant medical issues. One question that arises is how applicable the data from CLL14 are outside of this comorbid population. In my practice, I get a lot of questions from younger patients who are fit regarding their candidacy for venetoclax/obinutuzumab. They like the idea of the time-limited therapy, and they think that’s really appealing, rather than the idea of being on long-term ibrutinib. Personally, I have been comfortable applying the data from the CLL14 study for my younger patients, and I have started some on venetoclax/obinutuzumab. But if you’re a true data purest, then you would say there should be some more data for that young, fit population before using the regimen more widely in such patients. This is similar to where we were with ibrutinib a couple of years ago, when we only had phase III data with chlorambucil as a comparator. In that situation, oncologists were also fairly comfortable using ibrutinib in younger patients.

TARGETED ONCOLOGYTM:Can you discuss the factors you consider when you are talking with a patient and potentially suggesting a combination regimen like venetoclax/obinutuzumab?

DAVIDS:Specific to the venetoclax/obinutuzumab combina- tion, one thing I think about is that starting obinutuzumab in a patient with a high disease burden can sometimes be challenging, because it’s common for patients to get infusion reactions. We see [that] about 20% to 30% of patients have some kind of infusion reaction, so it is important to prepare patients for that possibility. Then, having some expertise on the nursing end, to be able to know when to stop the infusion and how to adjust the rate, and so forth.

One of the interesting things is that in the CLL14 study, there were 3 cases of tumor lysis syndrome, all of which occurred after the obinutuzumab, so before the patients even received venetoclax, and that was kind of something that wasn’t on our radar as much with that drug. Fortunately, these were laboratory changes only; they weren’t actually cases of clinical TLS. But I think it is important for oncologists to be aware that patients with a large disease burden [who are] starting obinutuzumab are at risk.

Interestingly, because the obinutuzumab was so effective in cytoreducing the patients in the CLL14 study, the tumor bulk was a lot lower when patients started the venetoclax. Thus, their risk was generally lower for TLS than we saw in previous studies, where venetoclax was given as monotherapy. But patients do still need to be monitored closely. There’s always the option with venetoclax to admit patients to the hospital, so in some practices, that’s a necessary step to be able to do the necessary tumor-lysis monitoring. Even if you’re doing the monitoring in the outpatient setting, it does require some back and forth on the part of the patient to ensure they can safely start the drug.

With ibrutinib, starting is much simpler. Patients can begin taking the drug at home, and then we may bring them back a week or two later to check their labs and see how they are tolerating it. If things are going well, we see them a month or so later, and then every 3 months after that, so it’s a fairly convenient schedule. When I’m meeting with a patient and going through the pros and cons of both regimens, I spend a lot more time on ibrutinib talking about all of the different adverse effects and a lot less time talking about the logistics; whereas with venetoclax/obinutuzumab, I spend more time talking about logistics and not as much time talking about adverse effects, because there are not as many to describe.

TARGETED ONCOLOGYTM:With added interest in combinations like venetoclax/obinutuzumab, what is the value of a monotherapy in the treatment of CLL, particularly with ibrutinib?

DAVIDS:I think that monotherapy for novel agents will continue to play an important role in CLL going forward, because it can be a convenient and effective option for many patients—for example, if I have an older patient who finds it hard to get back and forth to the center, or has trouble tolerating IV [intravenous] fluids. There are a number of scenarios like this in which putting someone on a single novel agent is simple and straightforward, and they can do well for many years, especially if they’re tolerating it well. Patients can do very well long term on ibrutinib, and some of the recently published long-term ibrutinib data reinforce that.

TARGETED ONCOLOGYTM:When it comes to weighing risks and benefits, what factors do you consider? To what extent does the duration of investigation matter?

DAVIDS:One of the most important aspects to consider is efficacy, and particularly durability of response. What happens for a patient who has received 1 year of venetoclax/obinutuzumab, goes off therapy for a period of time, and then relapses? What happens when we then treat them again with venetoclax? Do they go back into remission or not? Increasingly, a variable we’re going to be looking at is actually time to next class of drug. For example, someone might get venetoclax/obinutuzumab for a year, go into remission for 2 years, get venetoclax/obinutuzumab again for a year, go into remission for a year, and get venetoclax/obinutuzumab again, and [go into] remission for 6 months. That patient may eventually move on to ibrutinib, but they benefitted for 4 or 5 years from the venetoclax/obinutuzumab regimen used intermittently. If, on the other hand, patients receiving venetoclax/obinutuzumab relapse, and they don’t respond well to the same regimen a year or two later, that’s a little more troublesome, and that is going to limit the benefits [of] time-limited therapies.

Sometimes patients are hesitant to stop a therapy, knowing that their CLL probably is not cured. But one of the things we’ve noticed emerging with novel agent mono- therapy is resistance. From a scientific perspective, there’s a hope that by giving time-limited combination approaches, rather than continuous novel agent monotherapy, we might be able to reduce the development of resistance. Finally, even if you’re giving a couple of drugs—which could be more expensive in the short term—if you’re doing it over a shorter period of time, it might actually be less expensive for the healthcare system compared [with] many years of continuous novel agent therapy.

TARGETED ONCOLOGYTM:Could you talk about the ibrutinib plus venetoclax combination that is under investigation? Specifically, what might a combination like this offer patients, and how could it impact the overall treatment spectrum?

DAVIDS:In the laboratory setting, we and others found this combination had great potential to be synergistic, and now we’re seeing this play out in CLL clinical trials. Based on findings from the CLARITY trial and the MD Anderson [Cancer Center] study recently published in the Journal of Clinical Oncology and New England Journal of Medicine,5,6respectively, we are seeing unprecedented survival curves, with almost no progression so far, with a couple years of follow-up. We will see over time how things play out with longer follow-up, but certainly the initial results look very promising.

It’s obviously expensive to put these 2 drugs together, so having a minimal residual disease (MRD)—guided, time-limited approach is going to be important. We now have several effective regimens in CLL, so one question is going to be where this one fits in with the others. I think that for the highest-risk patients—those with TP53 aberrancy, like 17p deletion, for example—that is a group where using the 2 drugs at the same time might make the most sense, because we know that such patients less commonly have a durable response to ibrutinib or venetoclax when given as monotherapy.

TARGETED ONCOLOGYTM:Could you offer your thoughts on how acalabrutinib, which was recently granted fast-track designation by the FDA, might fit into the treatment market?

DAVIDS:If we are giving continuous therapies, we need to be mindful of toxicities, because patients will be on these drugs for many years. The early trial data for acalabrutinib, along with my own anecdotal clinical experience with some patients I have treated outside of a clinical trial setting with acalabrutinib, show that this drug is generally well tolerated. We’ve seen somewhat lower rates of significant adverse effects compared with ibrutinib when we look across studies, particularly rates of more serious atrial fibrillation, other cardiac arrhythmias, or major bleeding events, and also less in the way of rash and hypertension.

I anticipate that acalabrutinib will get a label in CLL fairly soon. At the 2019 ASH meeting, we will see data from the ELEVATE-[TN] treatment-naïve study, which has demonstrated a PFS benefit with acalabrutinib with or without obinutuzumab over chlorambucil with obinutuzumab. We are also excited to eventually see the results of [the] ELEVATE-RR study, which is directly comparing ibrutinib with acalabrutinib head to head, so that should be an informative study. It’s designed as a noninferiority study around a PFS primary end point. It is likely that acalabrutinib is noninferior to ibrutinib from a PFS perspective, but we are also interested in the safety comparison between the 2 arms. If it looks like, in a randomized setting, that acalabrutinib is better tolerated and comparably efficacious to ibrutinib, that would strongly support using acalabrutinib going for- ward as the preferred BTK [Bruton tyrosine kinase] inhibitor in CLL, not just with monotherapy, but also for patients who are receiving combination approaches.


  1. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmuno- therapy for chronic lymphocytic leukemia.N Engl J Med. 2019;381(5):432-443. doi: 10.1056/NEJMoa1817073.
  2. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL.N Engl J Med. 2018;379(26):2517-2528. doi: 10.1056/NEJMoa1812836.
  3. FDA approves chemotherapy-free regimen, venetoclax plus obinutuzumab, as first-line treatment for CLL/SLL. The ASCO Post website. ascopost.com/issues/ may-25-2019/fda-approves-chemotherapy-free-regimen-venetoclax-plus-obinutu- zumab-as-first-line-treatment-for-cllsll/. Published May 25, 2019. Accessed October 21, 2019.
  4. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions.N Engl J Med;380(23):2225-2236. doi: 10.1056/NEJMoa1815281.
  5. Hillmen P, Rawstron AC, Brock K, et al. Ibrutinib plus venetoclax in relapsed/ refractory chronic lymphocytic leukemia: the CLARITY study.J Clin Oncol. 2019;37(30):2722-2729. doi: 10.1200/JCO.19.00894.
  6. Jain N, Keating M, Thompson P, et al. Ibrutinib and Venetoclax for First-Line Treatment of CLL.N Engl J Med. 2019;380(22):2095-2103. doi: 10.1056/NEJ- Moa1900574.
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