Woyach Highlights Progress and Next Steps in CLL Paradigm

Partner | Cancer Centers | <b>The Ohio State University</b>

Jennifer A. Woyach, MD, discusses the evolving treatment paradigm and sequencing challenges in chronic lymphocytic leukemia.

Jennifer A. Woyach, MD

With therapeutic additions to the treatment paradigm of chronic lymphocytic leukemia (CLL), it is now a question of which regimen to give patients in the frontline setting, explained Jennifer A. Woyach, MD.

“In the frontline setting, our new options for targeted therapy include ibrutinib (Imbruvica), acalabrutinib (Calquence), and venetoclax (Venclexta) plus obinutuzumab (Gazyva). We have 3 great targeted therapy options. One of the difficulties right now is that we have such great options. [Which patient] do we choose for which agent?” said Woyach.

Acalabrutinib was the most recent BTK inhibitor to be approved in the CLL pipeline. The agent was approved based on data from the phase III ELEVATE-TN trial, which examined acalabrutinib alone versus acalabrutinib/obinutuzumab versus obinutuzumab/chlorambucil in treatment-naïve patients with CLL. At a median follow-up of 28.3 months, the combination of acalabrutinib plus obinutuzumab resulted in a 90% reduction in the risk of disease progression or death versus obinutuzumab/chlorambucil (HR, 0.10; 95% CI, 0.06-0.17; P <.0001).1 Acalabrutinib monotherapy also showed a significant benefit in progression-free survival (PFS; HR, 0.20; 95% CI, 0.13-0.30; P <.0001).

Researchers are also exploring combination strategies with BTK inhibitors, such as ibrutinib plus the BCL-2 inhibitor venetoclax in the CAPTIVATE study in the first-line setting. Results showed that 75% of patients achieved undetectable minimal residual disease (uMRD) in the peripheral blood at some point after baseline and 72% achieved uMRD in the bone marrow.2 With the attainment of MRD negativity, it is now a question of whether patients can stop treatment without CLL progression.

In an interview during the 2019 OncLive® State of the Science Summit™ on Hematologic Malignancies, Woyach, an associate professor at The Ohio State University Comprehensive Cancer Center—James, discussed the evolving treatment paradigm and sequencing challenges in CLL.

OncLive: Could you discuss some recent advances in frontline CLL?

Woyach: The trial that led to the FDA approval [of ibrutinib] in the frontline setting was the RESONATE-2 trial, which was ibrutinib versus chlorambucil in previously untreated patients who were aged 65 years of age and older. As you might imagine, ibrutinib [performed] significantly better than chlorambucil. We now have data out to 5 years with [ibrutinib] in this setting for that trial. About 70% of the patients are still in remission, which is fantastic.

Two studies—Alliance AO41202 and ECOG-ACRIN E1912—compared ibrutinib or ibrutinib regimens with standard chemoimmunotherapy. The ECOG-ACRIN E1912 trial compared ibrutinib plus rituximab (Rituxan) with fludarabine, cyclophosphamide, and rituximab (FCR). In that study, there was a significant advantage in both PFS and overall survival with ibrutinib/rituximab versus FCR. That was just updated at the 2019 ASH Annual Meeting. Interestingly, we're seeing not too much of a difference in the very good, genomic-risk patients, including those who have IGHV-mutated disease. The 2 treatments are fairly similar at this follow-up, although most of that is because those patients do very well; no one has relapsed on either arm.

The other study, Alliance AO41202, was performed in older patients. Here, we compared bendamustine plus rituximab, versus ibrutinib alone, versus ibrutinib/rituximab. Just like all of these other studies, ibrutinib or ibrutinib/rituximab was better than bendamustine plus rituximab. One of the other important takeaways from this study is that ibrutinib/rituximab was no better than ibrutinib alone. At least in the case of rituximab, adding an antibody is not helpful.

We also have the iLLUMINATE study, which looked at ibrutinib/obinutuzumab versus chlorambucil/obinutuzumab. Ibrutinib plus obinutuzumab was superior [to the chlorambucil arm]. Unfortunately, we are comparing “apples to oranges” with 2 completely different trials, but it doesn't seem like ibrutinib/obinutuzumab is significantly better than ibrutinib alone; however, we don't know that for sure.

More recently, the CLL14 study compared venetoclax plus obinutuzumab to chlorambucil plus obinutuzumab. That was just updated at the 2019 ASH Annual Meeting, and now we have 1 year of fixed-duration therapy plus 2 years of follow-up showing that venetoclax/obinutuzumab is significantly better than chlorambucil/obinutuzumab. It seems like patients who have TP53 abnormalities, such as TP53 mutation or 17p deletion, don't do quite as well with venetoclax/obinutuzumab, probably because of the fixed duration of treatment. Additionally, it seems like patients with IGHV-mutated disease have fantastic PFS with the available follow-up.

The most recent study is the ELEVATE-TN study, which led to the approval of acalabrutinib. That study was chlorambucil/obinutuzumab versus acalabrutinib alone versus acalabrutinib plus obinutuzumab. Acalabrutinib and acalabrutinib/obinutuzumab had significantly improved PFS with about a 90% 2-year PFS rate. Interestingly, it looks like there is a trend towards obinutuzumab adding some benefit to acalabrutinib, which is predicted from preclinical studies. Additionally, obinutuzumab is a better antibody than rituximab. Those data probably need to mature a bit more before we really know who benefits much from the addition of the antibody.

How do you determine what frontline regimen to give patients?

It depends on the patient and what is really important to them. We have the discussion for patients who are very high risk, meaning those with TP53 mutations or 17p deletions. The data with the BTK inhibitor look a little bit stronger compared with that fixed duration of venetoclax/obinutuzumab. I'm still trying to steer those patients towards the BTK inhibitor; however, it's not wrong to [give] venetoclax/obinutuzumab to those patients, either.

Regarding the side effect profile, ibrutinib has more robust safety and efficacy data. You know what you're getting with ibrutinib; however, there are more toxicities that have come out with a longer duration of follow-up, including atrial fibrillation in about 10% to 15% of patients—and in generally older patients—hypertension that is also likely more common in older patients and a small risk of bleeding. Additionally, there are those common but annoying adverse events (AEs), such as arthralgia, myalgia, diarrhea, bruising, and gastrointestinal AEs.

With acalabrutinib, you likely have fewer side AEs, including less atrial fibrillation, perhaps less hypertension, and probably the same risk of bleeding. These are less annoying AEs, but patients have to take [acalabrutinib] twice daily.

Then, you have venetoclax/obinutuzumab as a fixed duration, but it is more labor and time intensive in the beginning because you have the venetoclax ramp up and obinutuzumab. Both agents can be time consuming.

What research is being done regarding combinations with BTK inhibitors?

One exciting thing that has been presented at the last couple of ASH Annual Meetings has been the results of those combination studies. One study looked at combining venetoclax with the BTK inhibitor [ibrutinib] to see if you can both capitalize on the efficacy of the 2 agents, and then potentially get patients into such deep remissions that they can come off therapy. At the 2019 ASH Annual Meeting, we had the follow-up of The University of Texas MD Anderson Cancer Center study in both the frontline and relapsed/refractory settings, in which the majority of patients are getting MRD-negative responses. There are a lot of complete responses with fairly limited follow-up off treatment. Most patients are still in remission.

We have seen the same thing on our institutional study at The Ohio State University of venetoclax and ibrutinib plus obinutuzumab. With a little bit longer follow-up, even a couple years off drug, very few patients are relapsing. We also saw the first follow-up from the CAPTIVATE study. We have seen some follow-up from the CLARITY study, which was in patients with relapsed/refractory [disease] and showed that the combination of ibrutinib plus venetoclax has very good efficacy. The data we have [of ibrutinib plus venetoclax] so far show that patients can safely discontinue treatment.

What emerging treatments are being explored in the relapsed/refractory setting?

It depends on what they were treated with in the frontline setting. Patients who are on the continuous BTK inhibitor can then receive venetoclax with quite a bit of efficacy, which has been done in the clinical setting. We also have a few different reversible BTK inhibitors in development for patients who relapse on covalent BTK inhibitors, such as ibrutinib, acalabrutinib, and zanubrutinib (Brukinsa). A few of those reversible molecules [were presented] at the 2019 ASH Annual Meeting and showed very interesting efficacy; these included ARQ 531 and LOXO-305. There are a couple of other molecules, such as vecabrutinib (SNS-062). The dose levels are increasing [with vecabrutinib] but [there have been cases of] stable diseases and other signs of efficacy [with that agent].

For patients who receive venetoclax up front, we don't have as much data on that sequence of venetoclax with or without a monoclonal antibody and then going to a BTK inhibitor. There were [data] presented by Anthony Mato, MD, of Memorial Sloan Kettering Cancer Center, [which showed that] a lot of patients who are treated with venetoclax can then successfully transition to a BTK inhibitor, which are very exciting data.

The same thing was seen in a limited number of patients on the MURANO study. Data showed that patients who went on to that study of venetoclax plus rituximab, then relapsed, then they could either go back on venetoclax/rituximab, which showed some efficacy, or go on BTK inhibitors, which looked like it was pretty effective as well. If patients are on venetoclax/obinutuzumab and have a fairly long remission duration, you could potentially use that same regimen or venetoclax/rituximab next.

What is the status of CAR T-cell therapy in the treatment of CLL?

The CAR T cells have not been as effective in CLL as they have in some of the other cancers. The more recent data we are getting with the newer-generation CAR T cells, in some cases combined with ibrutinib pretreatment and sometimes posttreatment, are showing a lot more efficacy. That's also an exciting option for patients on trial.


  1. Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE TN: phase 3 study of acalabrutinib combined with obinutuzumab (o) or alone vs o plus chlorambucil (clb) in patients (pts) with treatment-naive chronic lymphocytic leukemia (CLL). Blood. 2019;134(suppl_1):31. doi: 10.1182/blood-2019-128404.
  2. Tam CS, Siddiqi T, Allan JN, et al. Ibrutinib (ibr) plus venetoclax (ven) for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): results from the MRD cohort of the phase 2 CAPTIVATE study. Blood. 2019;134(suppl_1):35. doi: 10.1182/blood-2019-121424.