Part 2: BTK Inhibitor Options for Frontline CLL


During a live virtual event, Sameer A. Parikh, MBBS, discussed with participating physicians frontline treatment options of BTK inhibitors in patients with chronic lymphocytic leukemia.

Sameer A. Parikh, MBBS

Assistant Professor of Medicine and Oncology

Mayo Clinic

Rochester, MN

Sameer A. Parikh, MBBS

Assistant Professor of Medicine and Oncology

Mayo Clinic

Rochester, MN

During a live virtual event, Sameer A. Parikh, MBBS, discussed with participating physicians frontline treatment options of Bruton’s tyrosine kinase (BTK) inhibitors in patients with chronic lymphocytic leukemia (CLL).

Editor’s Note: This article is based on an earlier event. As such, more recent updates to the chronic lymphocytic leukemia landscape may not be reflected.

Targeted OncologyTM: Which clinical trial data led to the approval of ibrutinib across different settings?

PARIKH: The phase 3 trial called RESONATE-2 [NCT01722487] looked at treatment-naive patients with CLL who were older and had a lot of comorbidities that may have precluded standard chemoimmunotherapy. These patients were randomized 1:1 to either ibrutinib [Imbruvica] as a single agent or chlorambucil as a single agent. Importantly, this trial excluded patients with del(17p). The median age was typical for patients with CLL at 72 years, and about three-quarters of these were older than 70 years. Chlorambucil was given for up to 12 cycles, so about a year, whereas ibrutinib was administered indefinitely. There was crossover allowed for patients who had progression of disease on chlorambucil.1

There’s no doubt in anyone’s mind that if you’re comparing an agent like ibrutinib to single-agent chlorambucil, ibrutinib does better. With a median follow-up of 18.4 months, roughly 70% of patients are progression free [HR, 0.16; 95% CI, 0.09-0.28; P < .001]. This is incredible given that in the past, these patients didn’t have such long progression-free survival [PFS], even with the use of FCR [fludarabine, cyclophosphamide, and rituximab (Rituxan)] or BR [bendamustine/rituximab], particularly when patients had high-risk features. It’s important to remember that this trial excluded patients with del(17p), so those patients are not [included in these data].

This patient had del(11q) by FISH [fluorescence in situ hybridization]. For patients with ibrutinib who have del(11q), although there was not a statistically significant P value [versus those treated with chlorambucil], patients with del(11q) do well with ibrutinib. This has been shown in many other analyses where patients with del(11q) performed the best compared with no FISH abnormalities.

For the vast majority of these studies, we are interested in looking at how ibrutinib performs. Chlorambucil is not going to have a good response, so I’m not surprised to see those responses with del(11q) status. With IGHV mutation status, the use of ibrutinib and other BTK inhibitors appears to [produce] no significant differences in the PFS, which indicates that it is a prognostic marker for time to first therapy. Once patients start treatment with a BTK inhibitor, it doesn’t matter what the IGHV mutational status is. You could have unmutated status and despite that, the patient is likely to do well.

The phase 3 study Alliance protocol [NCT01886872] randomized older patients greater than 65 years of age, similar to the RESONATE-3 study [NCT01578707], with an ECOG performance status of 0 to 2 with standard inclusion criteria. This study randomized patients to either single-agent ibrutinib, ibrutinib plus rituximab, or BR. This comparator arm of BR is what we are all used to thinking about as a comparator, because a lot of us generally reserve the use of chlorambucil to patients who are older. Even BR can sometimes become a problem, so this is a more realistic sort of comparison arm.2

The patients got BR for 6 cycles versus ibrutinib administered indefinitely versus ibrutinib and rituximab; the rituximab was given for 6 cycles. In contrast to the earlier studies where patients with del(17p) were excluded, they allowed patients with del(17p). That’s a poor-risk marker, so we need to remember that as we interpret these data. Now, the primary end point for this study was a PFS analysis, and if patients progressed on BR, they were allowed to cross over to single-agent ibrutinib.

There is a PFS advantage to the ibrutinib-containing arms compared with BR (HR, 0.39; 95% CI, 0.26-0.58; 1-sided P < .001). The other thing it points out is that there appears to be no significant difference between ibrutinib and ibrutinib/rituximab (HR, 1.00; 95% CI, 0.62-1.62; 1-sided P = .49). This trial suggests that the addition of rituximab to ibrutinib as a single agent is not needed for all patients.

The few exceptions where I would consider adding rituximab to [ibrutinib for] my patients include when I need a rapid response to treatment. When you start with single-agent ibrutinib, there is lymphocytosis, and the patient’s blood [counts] take a while to get better. If I need a rapid response because their white [blood cell] count started off with 400,000/mm3 and it’s getting up to 600,000/mm3 or 700,000/mm3, that makes me a bit nervous, and I might consider adding rituximab for that group of patients.

Can you further discuss these trial results?

The other group of patients for whom I would consider adding an anti-CD20 agent is those who have extramedullary or skin involvement or who have a glomerulonephritis. I want to get on top of the creatinine number that may have gone up because of CLL. There are small subsets of patients for whom I will typically consider the addition of an anti-CD20 agent. Otherwise, based on studies like this, I would generally use single-agent [ibrutinib] in my practice.

With respect to overall survival [OS], there wasn’t a significant improvement between BR and ibrutinib-containing regimens. If you wanted to, you could argue that you could get started with BR for your patient and then give ibrutinib down the road on first relapse because there isn’t an OS benefit. But again, because of the favorable adverse effect [AE] profile, a lot of people have moved over to ibrutinib as their frontline treatment regimen.

The complete response rate with ibrutinib and ibrutinib/rituximab is in single digits. This is the complete opposite of what we’ve always learned, which is that the deeper responses trans-late to longer PFS and better patient [outcomes]. But in the case of ibrutinib, it is completely the other way around, where despite minimal response, patients continue to do well for years. You will see that the MRD [minimal residual disease]–negativity rates at 9 months in the bone marrow are small—1% and 4% [with ibrutinib and ibrutinib/rituximab, respectively]—which is one of the reasons we have to continue with a BTK inhibitor for the long term. We cannot stop treatment, unlike with venetoclax, which can induce deep MRD-negative remissions.

The third study I’d like to discuss is the ECOG E1912 study [NCT02048813].3 It’s a phase 3 study with a 2:1 randomization to either ibrutinib/rituximab or FCR. This randomization was conducted in younger individuals who were less than 70 years of age. This [can be thought of as] a companion study to Alliance [NCT01886872]; that study allowed only older patients, but this allowed younger patients with the comparator treatment arm of FCR. The primary end point was PFS. This study excluded patients with del(17p) because it was thought that these patients would not respond well to FCR.

The PFS for all patients was far superior with ibrutinib/rituximab compared with FCR, with a P value that was highly statistically significant and a hazard ratio of 0.39 [0.26-0.57; P < .0001]. This was consistent across the IGHV mutation status, particularly among the unmutated IGHV subgroup of patients, where there is a significant benefit to the use of ibrutinib compared with FCR. Interestingly, this trial also showed an OS benefit at an early time point, at 3 years, in favor of ibrutinib/rituximab compared with FCR.

This trial established that ibrutinib is a superior agent in the treatment of frontline CLL in the absence of del(17p). If they included patients with del(17p) here, the FCR group would have responded even worse, and we would have likely seen even more PFS benefit. The other thing that this trial established is that you could safely combine ibrutinib and rituximab, as was shown in the Alliance study. But if you’re a purist and you want to apply evidence-based medicine in a young patient who would otherwise be a candidate for FCR, you could argue that using the ibrutinib plus rituximab regimen as in this protocol wouldn’t be wrong, because it is supported by literature.

This trial led to the approval of the combination of ibrutinib and rituximab for the frontline management of CLL.4 It’s important to remember that this was done in a way that patients would start off with ibrutinib for a month as a single agent and rituximab was added at month 2 for a total of 6 months. Doing that has significantly reduced the infusion reactions that can happen with anti-CD20 monoclonal antibody therapy.

Should clinicians be aware of any other trials of ibrutinib combinations?

A study called ILLUMINATE [NCT02264574] looked at the combination of ibrutinib and obinutuzumab [Gazyva] compared with chlorambucil and obinutuzumab.5 This study would have been ideal if there was a single-agent ibrutinib arm here, because that would have answered the question of whether obinutuzumab adds anything to single-agent ibrutinib. Unfortunately, there isn’t a trial like that similar to the ibrutinib versus ibrutinib plus rituximab question.

Patients who got the combination of ibrutinib/obinutuzumab did well, and a median PFS was not reached versus a median PFS of about 19.0 months for chlorambucil and obinutuzumab, which is not surprising [HR, 0.23; 95% CI, 0.15-0.37; P < .001].

The other thing you learn from [these data] is that if you compare this chlorambucil-plus-obinutuzumab [Kaplan-Meier] curve with the chlorambucil single-agent arm of RESONATE-3, you will know that patients do much better with the addition of obinutuzumab. About 35% of these patients achieved MRD negativity. But unfortunately, this trial wasn’t designed where you would stop treatment based on MRD negativity, so patients can choose ibrutinib regardless of whatever the MRD status was. It’s interesting to note that a quarter of the patients treated with chlorambucil got the MRD-negative status, which is perhaps why they had a longer PFS.

What other BTK inhibitors could be administered to this patient?

Now we shift gears from ibrutinib and talk about the ELEVATE CLL TN study [NCT02475681], which is with acalabrutinib [Calquence] [in the control arm]. Again, this is a similar design to the Alliance study, where they had ibrutinib plus rituximab, but instead, they have acalabrutinib and obinutuzumab compared with acalabrutinib alone or chlorambucil and obinutuzumab.6

The primary end point of this study was to assess the PFS difference between single-agent acalabrutinib and the combination of chlorambucil and obinutuzumab. They had close to 535 patients who were randomized equally among the 3 arms. Patients with del(17p) were allowed in this study. Crossover was allowed from chlorambucil/obinutuzumab to the acalabrutinib single-agent arm if there was progression. The median age of these patients was 70 years.

It’s no surprise here that the acalabrutinib-containing arms did better compared with chlorambucil and obinutuzumab. There was a statistically significant P value [for the comparison of both]. Although they did not power the study to compare acalabrutinib as a single agent versus acalabrutinib and obinutuzumab, it appears that the addition of obinutuzumab may be slightly better compared with acalabrutinib alone. They can’t make a formal P value comparison because that wasn’t a part of their plan. This could be an argument that if you wanted to use an anti-CD20 monoclonal antibody therapy, you could consider the addition of obinutuzumab to acalabrutinib.

The forest plot shows that by subgroup analysis, [factors] including age, patient’s sex, Rai stage, ECOG performance status, and bulky disease all favor the acalabrutinib-containing regimens compared with chlorambucil and obinutuzumab. The vast majority are in favor of acalabrutinib-containing regimens.

Given the short follow-up at 28 months, there doesn’t appear to be any significant difference between these 3 regimens with respect to OS.

In terms of safety, what are the differences between these drugs?

Events of clinical interest that are becoming important with BTK inhibitors include atrial fibrillation. About 3.5% of patients get any sort of atrial fibrillation with the use of acalabrutinib-containing regimens, whereas it was almost nonexistent in the comparator arm with chlorambucil and obinutuzumab.

Similarly, hypertension has now been recognized as an important AE of BTK inhibitors, and it is important to pay attention to this. With all of us being busy and not paying attention to the vital signs of these patients, this can creep up on us. This is similar to other TKIs [tyrosine kinase inhibitors] used, for example, in the metastatic renal cell carcinoma setting where hypertension can become a marker of disease activity; it can happen in this group of patients, as well. Infections and second primary malignancies are all becoming an important issue as these patients live longer and experience many of these AEs.

As you go through the algorithm in your mind of what you’re going to choose for these patients, it’s important to keep in context or in mind what your patient may already have when you begin some of these treatments. There is no question that these drugs are extremely efficacious, but we are slowly beginning to realize many of the AEs that can occur also need a lot of attention.


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

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. 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. FDA approves ibrutinib plus rituximab for chronic lymphocytic leukemia. FDA. Updated April 21, 2020. Accessed August 26, 2020.

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

6. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2

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