Awan Compares BTK Inhibition and Other Treatments for a Patient With CLL

Farrukh Awan, MD

Associate Professor, Department of Internal Medicine

University of Texas Southwestern (UTSW) Medical Center

Member, UTSW Harold C. Simmons Comprehensive Cancer Center and William P. Clements Jr. University Hospital

Dallas, TX

Targeted Oncology^TM: What are the National Comprehensive Cancer Network (NCCN) guidelines for treating a patient with CLL?

AWAN: The final product that [came] out from the NCCN is very complicated, and there are a lot of things on the recommendations that we don’t necessarily agree with. A lot of that has to do with how the guidelines have evolved. There is also a lot of opinion and only a few things have a clear category 1 recommendation. A lot of the recommendations are in the gray area. The idea is that the NCCN guidelines have to be universally adaptable and usable. Therefore, as long as there are some data to support the utility of a certain regimen, it will stay on the guidelines; we don’t want to eliminate those options because these guidelines are used by insurance providers to justify coverage. There are other reasons for the many options listed in the guidelines, even though we would never use some of them in our regular practice.

Having said that, we should focus on the main regimens because that’s where there is very little discussion in the community. These are acalabrutinib [Calquence] plus obinutuzumab [Gazyva], ibrutinib [Imbruvica], and venetoclax [Venclexta] plus obinutuzumab.¹ These regimens can be used for [almost all] patients including those with low risk [or] high risk, young and old. There are also variations based on comorbid conditions, patient age, and other factors.

There are other guidelines, which some of you might use, that indicate a preference for 1 option. From my experience that would not be ibrutinib anymore. That’s interesting because the field is already evolving and ibrutinib has been the established front runner for a long time. But there’s a lot of debate. I’ll share some very interesting recent data and my personal concerns, as well as the positives and the negatives, in a transparent way.

The bottom line is that our 3 options [for treating CLL] are acalabrutinib with or without obinutuzumab, ibrutinib, and venetoclax/obinutuzumab. Having said that, around 20% to 30% of patients in this country are treated with bendamustine/rituximab [Rituxan], which is still a very commonly used regimen. Other options are single-agent rituximab for really old patients. I think those are still being used in a sizable number of patients despite the fact that we have some very good and effective nontoxic or relatively less toxic options.

I think there is consensus among most of us that those are the regimens we should stick to. If you look at the footnotes in the NCCN criteria, they summarize the discussion points.

…It’s nice to focus on and read those footnotes to understand how the decisions on what to include were made because we all try to justify our opinions and that’s sometimes interesting to read. For example, recently there was a debate about what to say regarding the BTK [Bruton tyrosine kinase] inhibitors acalabrutinib and ibrutinib and proton pump inhibitors, and whether we should recommend one over the other. There were a lot of arguments back and forth and finally it was all summarized in the footnote. The footnote elaborates on what we suggest and what to consider when selecting a specific agent as that could make a huge difference.

What are the data behind using acalabrutinib plus obinutuzumab for patients with CLL?

The Elevate CLL TN study [NCT02475681] compared acalabrutinib vs acalabrutinib plus obinutuzumab.² The thought was the addition of a newer CD20 antibody might be better than rituximab. The study also had a standard [obinutuzumab/chlorambucil] control arm for patients younger than 65 years who had a lot of comorbid conditions or patients older than 65 years—basically patients who would historically not be considered candidates for chemotherapy.

The updated 4-year results are very interesting. It is obvious that the acalabrutinib-containing arms are significantly better than the comparative chlorambucil/ obinutuzumab arm. I don’t think anybody was surprised by that. What I found surprising was that, at 4 years out, the median PFS [progression-free survival] was 87% vs 78% with acalabrutinib alone.²

So the additional obinutuzumab is improving PFS by 9%. That’s not trivial. It’s definitely encouraging to see that if these patients are followed for long enough, they might have a better outcome. Therefore there is some evidence that the additional CD20 antibody might improve our lives, as this is the best result that we have seen so far. The trial was not designed to study this difference so we cannot comment on it too much because that was not one of the primary end points. But that is a very provocative finding and when we saw the 3-year outcomes, it was beginning to separate, and now at 4 years, it’s definitely more separated and the obinutuzumab-containing arm is doing well. So that’s why this is an important study.

Patients who have IGHV mutations do well regardless of treatment and they have a fairly good outcome with chlorambucil and obinutuzumab. Even in those patients, the acalabrutinib arms looked better. Obviously, for IGHV unmutated, more aggressive [disease], the acalabrutinib arms were significantly better and there was a dramatic difference.² One thing we have seen consistently is that the IGHV mutation status does not matter for treatment with a CD20 antibody or for that matter with acalabrutinib alone. Both of those regimens are doing well.

As expected, most responses are PRs [partial responses].² There is a slightly higher complete remission rate with the addition of obinutuzumab, as expected. The additional obinutuzumab also increases the undetectable MRD [minimal residual disease] rates, and the deeper the remission, the longer it lasts. But there’s also a lot of debate about what level of MRD you need. I think the MRD story needs a little more work. But that’s definitely one of the surrogates we have and, in this study, the MRD undetectability level was 10−4. That’s what we would call a medium MRD. It’s very difficult to demonstrate a survival advantage with a lot of the newer CLL agents as there will be a lot of crossover and people will go from one arm to the other. So survival is pretty good for our patients [and] that’s encouraging.

What was the toxicity profile in Elevate CLL TN?

A lot of the debate is focused on the safety. The most common problem that we see with any CLL trial is pneumonia.² Infusion reactions are very minimal and are not a big problem as they can be managed fairly easily with premedication. In fact, starting acalabrutinib or a BTK inhibitor a few days before obinutuzumab results in 0 reactions. If you start the obinutuzumab on the same day as the acalabrutinib or ibrutinib, you will have a few more problems, but even 3 days makes a huge difference. Febrile neutropenia and tumor lysis are not a problem.

It was encouraging that the AFib, bleeding, and hypertension rates were fairly low; however, they were not 0. The big question raised was whether the 7% incidence of AFib was a real effect from the drug or just background. But in the control arm the AFib rates were very low, indicating that there was some drug effect. But it was encouraging that it was only around 7%. The hypertension rate was higher than [that in] the control group but not dramatically. Bleeding was definitely a problem, including major bleeding, although at a very low incidence.

We are used to seeing 5% to 10% major bleeds and up to 30% minor bleeds. Here the minor bleeds were around 30% but the rate of major bleeds was fortunately very low. That’s excellent. The big problem that all serial patients deal with is infection. Neutropenias are common especially in the first cycle and with the addition of obinutuzumab. Another problem with acalabrutinib is headaches, which respond very nicely to caffeine. So this is what we saw with the Elevate CLL TN study. It clearly showed improvement in outcomes with acalabrutinib and a possible trend toward better outcomes by the addition of obinutuzumab.

How has ibrutinib plus rituximab been studied for patients with CLL?

The ECOG-E1912 trial [NCT02048813] was a very important large cooperative US study comparing ibrutinib plus rituximab to FCR [fludarabine, cyclophosphamide, and rituximab] with 2:1 randomization.³ The study was designed for young patients who were eligible for chemotherapy.

There was a clear statistically significant improvement in survival within 3 years.⁴ These results should settle the debate of whether FCR or ibrutinib is better, even for the purists who want to see a survival advantage, which is very difficult to demonstrate in patients with CLL. Ibrutinib was clearly better.

The debate remains regarding which regimen is better depending on the IGHV-mutation status. In patients [with] IGHV mutations, the cases are so low at 3 years that there was no significant statistical difference. But it was getting close to being significant—88% at 3 years with IGHV-mutated [disease] and ibrutinib vs 82% [with FCR].³ So the curves are beginning to separate in favor of ibrutinib. On the unmutated side, there is no question that ibrutinib is better and we feel that after 4 or 5 years of follow-up, the mutated patients will also be better in terms of PFS. The bottom line [is that] survival is also getting better for all patients and this is why everyone has moved on from FCR.

What is the evidence for the use of venetoclax for patients with CLL?

The CLL14 trial [NCT02242942] is a German study with patients who have comorbid conditions that were not ordinarily considered candidates for chemoimmunotherapy.⁵ Patients were assessed using the Cumulative Illness Rating [Scale], which assesses the comorbid burden but is a cumbersome tool to use. It assigns a point to almost everything, such as having eyeglasses, and therefore it is easy to get a score of 5 or 6. CLL14 was a fairly simple trial comparing venetoclax with obinutuzumab vs obinutuzumab plus chlorambucil.

Venetoclax was better than obinutuzumab [in terms of PFS].^5,6 As for the IGHV-mutation status, patients with unmutated IGHV were a little bit worse [off] with the venetoclax compared with patients with mutated IGHV. Now, we know that that’s a characteristic of the disease, but comparing the 2 treatment arms there’s a clear difference between venetoclax and obinutuzumab for both mutated and unmutated patients; the venetoclax arm is better than the chlorambucil/obinutuzumab arm.

Probably the most important results from this study were the differences between patients with or without del(17p) or TP53 mutations. Patients without these markers do very well, but those with these markers do poorly and don’t seem to plateau despite being on venetoclax and regardless of MRD status. Venetoclax has an obvious advantage that is well known: It gets patients into a nice deep remission.

But if you stop therapy after 12 months, these patients have a pretty poor outcome, almost as bad as patients who didn’t get venetoclax. So this is one group of patients that we have to be very careful about. There are different ways to manage these patients. Most of us in the CLL community are not stopping therapy for these patients because patients relapse very quickly after they stop the venetoclax at 12 months.

Did MRD play a role in the CLL14 data?

The MRD data clearly show that venetoclax produces a deep remission in the bone marrow and the peripheral blood. Having said that, what we don’t talk about is that there is a group of patients on venetoclax in a MRD-negative state (10−6) despite the fact that they continue on venetoclax. So they have disease progression at the molecular level despite being on venetoclax. That doesn’t happen in a lot of patients; it happens in only a small percentage. But the fact is that MRD negativity even at the 10−6 level is not this magical cut-off that guarantees a full remission.

Now, why does that happen? We don’t know. Why [do] the patients with MRD-negative disease, despite having TP53, relapse? And why do they have inferior outcomes? There aren’t answers for that and this is an area of active research. So while it is good to get into deep remission and stop therapy after 12 months, ultimately what is important is the longevity of the patient.

Can you control the disease over 10 or 15 years and can you achieve that with venetoclax? Maybe you’ll have to do venetoclax after 4 or 5 years. The goal is that a 61-year-old patient could live an average of 20 more years at least, with 80 years being the average life expectancy. If you want your patient to live 20 years, how will you get to that 20-year mark? There is no right or wrong answer, so you can either do venetoclax and then venetoclax again and then venetoclax again, maybe 2 or 3 times to get to 20 years. Or maybe you can continue with the pill once or twice a day and they might get to the same end point. That is the debate.

The 4-year PFS rate with venetoclax and obinutuzumab was 74%, with acalabrutinib it was 79%, [and] with acalabrutinib and obinutuzumab it was 89%. Now it gets interesting. I know we shouldn’t compare one trial [with] another but remember, these trials had very similar populations and this is a 15% difference. That is provocative and that’s the big question and I don’t know the answer to that.

Tumor lysis syndrome [was] a big issue—it’s what made venetoclax famous early on—but frankly, it’s been a while since we saw tumor lysis with venetoclax. It just doesn’t happen that much if you prime the patients well. The way I do it is that I do the CD20 antibody first. I debulk the patients and after 2 months, I can easily do the escalation as an outpatient [procedure] without having to admit the patient for tumor lysis monitoring.

My biggest challenge with using venetoclax in the frontline or in the relapse setting is not tumor lysis; it’s cytopenias. When you do day 1, 2, 8, and 15 of obinutuzumab, if you do venetoclax concurrently, you will invariably have to stop one or the other because of cytopenias, primarily neutropenia or thrombocytopenia. That’s also what we saw in the study, that the neutropenia and thrombocytopenia were the most common issues.⁵ So what I typically do as I get the patient through the first cycle…is make sure that their white [blood cell] count has declined and that their lymph nodes are resolved, and then we can start venetoclax as an outpatient.

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 2.2022. Accessed January 21, 2022. https://bit.ly/3rXORmz}

_{2. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naïve chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291. Published correction appears in Lancet. 2020;395(10238):1694.}

_{3. Shanafelt TD, Wang V, Kay NE, et al. Ibrutinib and rituximab provides superior clinical outcome compared to FCR in younger patients with chronic lymphocytic leukemia (CLL): extended follow-up from the E1912 trial. Blood. 2019;134(suppl 1):33. doi:10.1182/blood-2019-126824}

_{4. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432-443. doi:10.1056/NEJMoa1817073}

_{5. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236. doi:10.1056/NEJMoa1815281}

_{6. Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21(9):1188-1200. doi:10.1016/S1470-2045(20)30443-5}