Burger Reviews BTK Inhibitors and Beyond in Frontline CLL

Jan A. Burger, MD, PhD

During a virtual Case Based Peer Perspectives event, Jan A. Burger, MD, PhD, professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center in Houston, TX, discussed testing and the treatment options for chronic lymphocytic leukemia (CLL), based on the a case of 71-year-old female patient.

Targeted Oncology^TM: What testing would you order to confirm diagnosis if you saw this patient in the clinic?

BURGER: We need to establish the diagnosis by flow cytometry and then we would do, at a minimum, FISH cytogenetics and, ideally, the mutational status. Cytogenetics can change, but
mutational status usually doesn’t change. If that’s been established somewhere outside [of your clinic], then you don’t have to repeat that test.

It’s important to repeat cytogenetics if you talk about the relapse setting. But here, we’re treating in the frontline setting, and she was tested. She was found to be IGHV unmutated and [positive
for] del(11q). That, traditionally, has been regarded as a higher-risk disease status because these patients respond OK to standard chemotherapy, but they have short remissions and survival times with FCR [fludarabine, cyclophosphamide, and rituximab (Rituxan)], BR [bendamustine plus rituximab], and those kinds of regimens compared with low-risk patients, such as those [who are positive for] deletion 13q and have IGHV mutated disease.

In terms of these sequences, when you see a patient with lymphocytosis, you send for flow cytometry, and part of the flow cytometry panel can test for additional markers, CD38 and ZAP-70. We have it [at MD Anderson], but I’m not sure if there are any outside routine flow cytometry labs reporting CD38 positivity or negativity or ZAP-70. These markers used to be very popular 10
years or so ago when IGHV-mutation status was not so commonly done and was more complicated to get. Nowadays, there’s a shift with sending a sample directly for IGHV-mutation testing.

If you have that and the routine CLL FISH panel, then you have a good amount of information about your patient to say this is high-, low-, or an intermediate-risk disease. I think the main purpose for doing these is, first, to identify [patients with] high-risk disease who have a deletion 17p [del(17p)] or TP53 mutations. If it’s a young patient, you want to know that to [be able to] avoid chemotherapy. If it’s a young patient, [you may want to] send those patients for evaluation for stem cell transplant. For some patients, that is still something that eventually needs to be considered for those with del(17p).

What systemic therapy would you offer?

If you have treated with ibrutinib [Imbruvica] and you’re comfortable with that, I don’t think at this time there is a strong reason to change. In selected patients, it might be reasonable to try
switching them from one [agent] to the other. But right now, for this patient, consensus says a BTK [Bruton tyrosine kinase] inhibitor is a good treatment.

Both ibrutinib and acalabrutinib [Calquence] can be used as single agents or in combination with CD20 antibodies. We’ve done a clinical study with ibrutinib where patients were randomized to receive monotherapy versus a combination with rituximab, and the outcome was virtually identical—where patients had the exact same progression-free survival [PFS] with a single agent
versus the combination with a CD20 antibody.¹

CD20 antibodies with BTK inhibitors don’t seem to add benefit in terms of survival if you go with the long-term BTK inhibitor treatment and if you’re not planning to stop your treatment at
some point. What they do is they get patients into remission faster and you clear the disease faster if you add a CD20 antibody, but then you stop after 6 months. You continue your BTK
inhibitor, and patients do great 2, 3, and 4 years later. Then, you don’t see any effect in terms of longer-term PFS or overall survival [OS] from the addition of the CD20 antibody.

What data support the use of single-agent ibrutinib in patients with untreated CLL?

There are data from the RESONATE-2 study [NCT01722487], which randomized patients between ibrutinib and chlorambucil. This study was designed at the time when chlorambucil monotherapy was still the standard of care. Patients were randomized 1:1, and patients with del(17p) were excluded.²

What is nice about this study is that we have a long follow-up now.³ At the 5-year follow-up, you see this major difference in terms of PFS [HR, 0.146; 95% CI, 0.098-0.218]. There is also an
overall survival benefit [HR, 0.450; 95% CI, 0.266-0.761].

What [we saw was] that patients with del(11q) seemed to have a better PFS than those patients who lack del(11q) when they are treated with ibrutinib. Patients with del(11q) who are treated with chemotherapy do not do as well as those who lack this cytogenetic abnormality. The same is true here for [IGHV] mutational status.

The PCYC-1102-CA study [NCT01105247] opened around 2010, and we now have 7 to 8 years of follow-up. If you use a BTK inhibitor in the frontline setting, you can expect that most patients are going to do well for an extended period of time. At 5, 6, and 7 years or longer, 70% to 80% of patients are still in remission and have not died.⁴

Another randomized study that created some waves [is the E1912 study (NCT02048813)]. We’ve been big proponents of FCR, which was the comparator arm [of this trial] versus ibrutinib. Patients receive either 6 cycles FCR or continuous ibrutinib [with rituximab] for the first 6 cycles.⁵

That study showed that compared with FCR, there was a significant increase in PFS [HR, 0.39; 95% CI, 0.26-0.57; P <.0001] but also in OS benefit from the BTK inhibitor–containing regimen
[HR, 0.34; 95% CI, 0.15-0.79; P = .009].

Would you say ibrutinib is the standard of care for treatment of CLL in the frontline setting?

Ibrutinib monotherapy, I would say, is the standard of care, but ibrutinib plus rituximab can be used. Some of you use it and, based on the data we just saw, the FDA has now officially
approved it.⁶ It doesn’t mean you must use rituximab.

What other ibrutinib combinations are available?

The ALLIANCE trial [NCT01886872] had a single-agent ibrutinib arm versus ibrutinib plus rituximab versus bendamustine plus rituximab.⁷ When you have patients randomized to receive ibrutinib/rituximab versus ibrutinib as a single agent, the [Kaplan-Meier survival] curves are basically identical, and that’s what we got as well in a slightly diff erent patient population, mostly
relapsed patients. In terms of PFS, rituximab doesn’t seem to add very much when you go with continuous ibrutinib treatment. You see the difference for bendamustine/rituximab, with which
patients have significantly shorter PFS.

I think the theme is the same over and over again with these randomized studies. With the new targeted agents, such as the BTK inhibitors and venetoclax [Venclexta], we see the same
pattern. The new agents are doing better than our traditional chemoimmunotherapy.

ILLUMINATE [NCT02264574] is the study comparing ibrutinib/obinutuzumab [Gazyva] with another chemoimmunotherapy regimen, which has been somewhat popular for older populations, more frail patients for whom you don’t want to use FCR or BR. You traditionally use chlorambucil alone and then more recently…it’s combined with CD20 antibodies. The patients were randomized to either [ibrutinib/obinutuzumab] versus chlorambucil/obinutuzumab treatment.⁸

The results show a major PFS benefits for patients on the BTK inhibitor [HR, 0.23; 95% CI, 0.15-0.37; P < .0001]. There was a big difference for genetically high-risk patients [HR, 0.15; P <
.0001] or patients who had bulky disease.

What other BTK inhibitors would you consider here?

Now we’re going to the second-generation BTK inhibitor, acalabrutinib [Calquence], which is somewhat more selective and doesn’t inhibit some other kinases that ibrutinib does. It’s a new
BTK inhibitor with not as much long-term follow-up data available.

[In the phase 3 ELEVATE TN trial (NCT02475681)], you have 3 arms: single-agent acalabrutinib, acalabrutinib combined with obinutuzumab, and the comparator arm of chlorambucil/obinutuzumab. 9 If you give that to treatment-naïve patients, those receiving BTK inhibitor alone or with the CD20 antibody do well. It’s debatable if the PFS difference is significant, but clearly, the BTK inhibitor–treated patients do much better than those receiving
chlorambucil plus obinutuzumab.

[If you look at the] subgroups of patients benefitting from the BTK inhibitor treatment versus obinutuzumab/chlorambucil, it basically shows that all subgroups have benefit. Some may be a
little more than others...but I think particularly patients that we traditionally called high risk are the ones who benefit the most from new agents. There’s less difference if you go into the lowrisk
patient populations.

Are there data supporting the use of a BCL2 inhibition?

The other frontline option involves venetoclax, and that’s coming from this CLL14 trial [NCT02242942]. Patients were receiving venetoclax/obinutuzumab or chlorambucil/obinutuzumab, and this is a finite treatment for 12 months. These are patients who were older and who have some comorbidities. Deletion(17p) was not excluded.¹⁰

There is a major difference in PFS favoring the new targeted agent venetoclax. Now it’s approved for the frontline treatment of selected patients,11 but you can also see in comparison to the
BTK inhibitors [that] the follow-up is relatively short of 3 years.

With venetoclax, you get more complete remissions and some of these remissions are MRD [minimal residual disease] negative. As long as these differences are not translating into a survival benefit, those are just numbers.

Would you recommend venetoclax after the first line?

I don’t think there’s a reason to make that change [from BTK inhibitors] because venetoclax has its own issues in terms of how it’s used and adverse effects [AEs]. For that question…maybe [we ask [is] venetoclax better in terms of outcome than a BTK inhibitor?

It’s difficult to be better than the BTK inhibitor in the frontline CLL setting, and you need a very long follow-up to show any differences if there are any.

A substantial number of patients [treated with venetoclax] receive MRD-negative remissions with this combination. MRD negativity doesn’t mean patients are cured. There is drop off in PFS, so MRD negativity doesn’t mean those patients will survive and never need treatment again. Most likely, those patients eventually will lose MRD and eventually have disease progression and need treatment again. I think for those studies based on frontline venetoclax for 12 months, we just have to stay tuned and wait for what the long-term outcome is going to be.

What are the AEs of venetoclax?

You see more AEs that are reminiscent of chemotherapy days, where patients get more cytopenia. It’s well established that venetoclax is myelosuppressive. Certainly, neutropenia can be seen, and less frequently, thrombocytopenia and anemia. If you treat a patient with venetoclax with or without a CD20 antibody, then you have to prepare for some patients having issues
with neutropenia and some who cannot be fully dose-escalated because of those cytopenias.

If the patient was younger, would you treat differently?

My answer would be no. I don’t see any difference. This patient was 71 years old. We wouldn’t use chemoimmunotherapy.

Somebody voted no. I think that’s interesting because it’s something I’m interested in [finding out about]. I’m wondering if we have to accept treating patients with BTK inhibitors…for very long periods or if we can maybe try it at least as an alternative treatment just for a certain period of time until we have the best response. Then, some patients maybe stop. I think that’s interesting for a clinical trial.

Outside of clinical trials, I’m not so sure. We have no data. But if you have a low-risk patient and you want to stop after 2 years and just see what happens, you need to tell the patient we don’t
know what’s going to happen and you have to watch that patient more closely. If it’s a patient with del(17p), a high-risk patient who was very symptomatic, I wouldn’t do that. But in low-risk patients, I think it’s an interesting question and not totally unreasonable.

Over time, we will find new solutions. Everybody’s working on transitioning BTK inhibitors…to limited-duration treatments for many reasons. It’s not the optimal situation to have patients on
kinase inhibitors for 5, 10, or 20 years. Right now, it’s a long-term treatment until we have better treatments.

_References:

_{1. Burger JA, Sivina M, Jain N, et al. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood. 2019;133(10):1011-1019. doi:10.1182/blood-2018-10-879429}

_{2. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437. doi:10.1056/NEJMoa1509388}

_{3. Burger JA, Barr PM, Robak T, et al. Long-term effi cacy and safety of fi rst-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798. doi:10.1038/s41375-019-0602-x}

_{4. Byrd JC, Furman RR, Coutre SE, et al. Ibrutinib treatment for fi rst-line and relapsed/ refractory chronic lymphocytic leukemia: fi nal analysis of the pivotal phase Ib/II PCYC- 1102 study. Clin Cancer Res. Published online March 24, 2020. doi:10.1158/1078-0432.CCR-19-2856}

_{5. Shanafelt TD, Wang XV, 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}

_{6. FDA approves ibrutinib plus rituximab for chronic lymphocytic leukemia. News release. FDA. April 21, 2020. Accessed July 27, 2020. https://bit.ly/3jV1hGW}

<sub>7. 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

8. Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in fi rst-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(1):43-56. Published correction appears in Lancet Oncol. 2019;20(1):e10.
doi:10.1016/S1470-2045(18)30788-5</sub>

_{9. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive 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. doi:10.1016/S0140-6736(20)30262-2}

_{10. 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}

_{11. FDA approves venetoclax for CLL and SLL. News release. FDA. May 15, 2019.Accessed July 27, 2020. https://bit.ly/3jLnEOU}