Treatment Options for Frontline CLL Merit In-depth Patient Discussions

Erlene Seymour, MD

During a Targeted Oncology Case Based Peer Perspective event, Erlene Seymour, MD, assistant professor, Clinical Hematology-Oncology, Wayne State University, Karmanos Cancer Institute, reviewed the front-line treatment options for chronic lymphocytic leukemia (CLL).

Targeted Oncology™: What type of molecular testing should be ordered for a patient such as this?

SEYMOUR: I usually order a translocation test and a flow cytometry. The results of the flow cytometry [can help] rule out mantle cell lymphoma. I will order that test if the patient is curious about their prognostication.

I find that some patients aren’t, but for patients who are definitely wanting to know a little more about their prognosis, you can get the testing for that. There’s even a CLL-IPI [International Prognostic Index for Chronic Lymphocytic Leukemia] that requires various testing, including TP53 status, which is not always easy to get. That fine-tunes prognostication that we usually do within trials. It’s not as mainstream. It’s fair to get those [tests] at the beginning if your patient is curious about prognosis.

What are your thoughts on the ELEVATE CLL TN study (NCT02475681)?

The one comment I have is that the 2 arms that had those combinations, acalabrutinib and acalabrutinib plus obinutuzumab [Gazyva], weren’t powered to find a difference between those 2 arms.1 It’s trending, it’s looking better, but we don’t know definitively.

The ELEVATE CLL TN study helped get acalabrutinib [approved] for frontline therapy. This was a randomized phase 3 study looking at acalabrutinib plus obinutuzumab plus acalabrutinib monotherapy versus obinutuzumab plus chlorambucil. And this was in patients older than 65 years but also less than 65 years with coexisting conditions. The patient in our case had a few coexisting conditions.

The PFS [progression-free survival] for patients in the acalabrutinib arms outperformed the control, which was obinutuzumab/chlorambucil, by a significant difference. It appears that there may be a difference between the 2 acalabrutinib arms, but it was not powered in the study to find a difference between [them]. It looks as if it’s trending that way, but it’s not quite powered to tell you whether there’s an absolute difference between those 2 arms.

If you look at PFS by subgroup, no matter the age of the patient, whether it’s less than 65 years with comorbidities or greater than 65 years, it favors the acalabrutinib combination over obinutuzumab or monotherapy.

For [patients with] unmutated IGVH status, as well as del(11q), [PFS] favors acalabrutinib versus obinutuzumab and chlorambucil.

How would you characterize the response rates in ELEVATE?

The response rate is pretty similar to what you see with ibrutinib [Imbruvica]. You’re not going to see a lot of CRs [complete responses]. All the BTKs [Bruton tyrosine kinases] will demonstrate mostly partial responses but very durable responses. This is why patients can be on this [agent] for a very long period but don’t necessarily get a complete response. We see that with acalabrutinib [also]. We do see a bit deeper responses when you add obinutuzumab, so that’s why you see a little higher percentage in the CRs.

Did ELEVATE CLL TN demonstrate any safety challenges for these patients?

In terms of the safety in trials evaluating acalabrutinib, we’re seeing less atrial fibrillation and less bleeding [compared with ibrutinib]. This is a more specific BTK inhibitor. There was one study that looked at patients who took ibrutinib and then switched to acalabrutinib, and we could see a decrease in the grade of those toxicities when patients switched. These studies hint at perhaps less toxicity. To get that [definitive] answer, [we need] to do a head-to-head study between acalabrutinib and ibrutinib, and that is ongoing. Atrial fibrillation is about 3%, and hypertension is about 7%, which is a lot less than what we had seen with the cooperative studies. Infections are still quite common, and there is little risk of second primary malignancies.¹

How often are you using acalabrutinib in the frontline setting?

I’m not one that uses it almost every time. I definitely think in the situations where I’ve used it, a patient has a toxicity that I’m trying to not make worse.

For instance, I think there was one time a BTK [inhibitor] made more sense than venetoclax [Venclexta], and they had a bleeding issue. So perhaps acalabrutinib was better, so we tried it. And another patient had an autoimmune arthritis, so this patient had issues with chronic joint pain. That’s something I see commonly with chronic ibrutinib and BTKs. This has also been reported to be perhaps less in acalabrutinib, so that was an instance. I’ll be completely honest—I don’t use it almost every time, but I do think [as time passes that] we’re going to see different toxicity profiles of these BTK inhibitors, which is similar to what we see with the TKIs in chronic myeloid leukemia.

What organizations can help with patient assistance?

Sometimes if you’ve got a good specialty pharmacy or a financial counselor who knows how to access or apply for a foundation grant, that seems to be the best [way to find assistance]. But it’s a complicated process. There’s also something called FundFinder, through the PAN Foundation. They’re a very good foundation grant organization, but it is complicated to try to find grants for patients.

What evidence supports the use of ibrutinib in the front line?

I would look to the RESONATE-2 [NCT01722487] trial evaluating first-line ibrutinib for CLL.² This was a randomized trial that looked at ibrutinib versus chlorambucil in patients who were treatment naїve and over 65 years with comorbidities that may preclude them from getting FCR [fludarabine, cyclophosphamide, and rituximab]. Investigators reported a significantly better PFS for ibrutinib versus chlorambucil, a treatment that we hardly use anymore [median PFS, not reached vs 18.9 months; HR, 0.16; P < .001].

We can see that even by these high-risk features, del(11q) and IGVH unmutated status, that we do improve with the BTKs, which we see also with acalabrutinib.

A more important study that came out just a couple of years ago was a cooperative study that looked at ibrutinib plus rituximab versus FCR [ECOG-E1912; NCT02048813].³ This was 1 of 2 cooperative studies. There was an additional study that looked at ibrutinib versus ibrutinib plus rituximab versus bendamustine and rituximab in older patients. This is the younger patient trial that was run by ECOG. This compared ibrutinib plus rituximab and FCR.

How were PFS and overall survival (OS) affected by IGVH mutation status?

If you look at the risk [based on IGVH status], PFS in patients with the mutation treated with FCR versus ibrutinib showed no difference. And if you remember the data when we looked at FCR and the follow-up data from the older studies, it’s a long PFS, almost longer than 10 to 12 years.

For those patients, I think that it is still a reasonable option. Obviously, it has to be somebody who can tolerate FCR, who is young, and who you wouldn’t be uncomfortable giving it to. But it’s not something that you should consider in that older patient population. However, unmutated status is quite common, and we tend to have older patients. And so for unmutated patients, I’m not thinking about chemoimmunotherapy, given these data.

Would you consider adding rituximab to ibrutinib for patients with CLL? What data support your decision to do so or not?

The Alliance data [NCT01886872] looked at patients were randomized to receive ibrutinib versus ibrutinib/rituximab versus BR [bendamustine plus rituximab].4 In that study, ibrutinib versus ibrutinib/rituximab had no difference in PFS. Based on that study, I typically don’t add rituximab to ibrutinib. When [Ted D. Shanafelt, MD] presented this study at ASH [American Society of Hematology Annual Meeting] in 2018, his late-breaking abstract, he commented that because we do know there was no difference in the Alliance study, he’s quite comfortable not using rituximab with ibrutinib.

The only clinical scenario [in which I would use that combination] would be if for whatever reason you need a faster response. I haven’t had that. I haven’t been in that situation just yet because ibrutinib actually does tend to respond fast in patients, at least within a week or so, and that may be the clinical scenario in which I would consider it, if you wanted to achieve a faster response. But that would probably be the only time. Otherwise, I usually use [ibrutinib] by itself.

What data do we have to support venetoclax?

We can look to the CLL14 trial [NCT02242942], which came out last year.⁵ This trial involved obinutuzumab given first followed by venetoclax, and this is time-limited therapy. This was a randomized study comparing obinutuzumab/venetoclax versus obinutuzumab plus chlorambucil, and treatment is complete after a year.

The trial results showed that venetoclax plus obinutuzumab does better in terms of PFS compared with chlorambucil and obinutuzumab, even as long as a 40-month follow-up. And we see similar results in terms of IGVH mutation status. We do have better results with the combination with venetoclax compared with obinutuzumab and chlorambucil, as well as for patients who have TP53-mutated status.

What was this combination’s effect on minimal residual disease (MRD)?

In the trial, we do see more patients getting undetectable MRD. It is a much deeper response observed with venetoclax plus obinutuzumab compared with chlorambucil plus obinutuzumab. There was a difference both in peripheral blood and bone marrow.

MRD status, in particular, favors venetoclax in studies. Investigators look at the clinical outcomes by MRD. MRD does predict a better PFS, particularly when you have undetected versus any MRD.

Venetoclax plus obinutuzumab does have some grade 3 or 4 AEs [adverse effects], particularly cytopenias, as well as infections and some neutropenia, but mostly cytopenias. And these can be, at least from my experience, adjusted by adjusting the dose at the beginning, but otherwise [no AEs] stand out as being severe.

When would you use obinutuzumab in a patient such as this one?

I would say it’s not wrong to, especially if you wanted to get a deeper response at the beginning for whatever reason. Say the patient is symptomatic because of hydronephrosis, and you just wanted a faster response; it wouldn’t be wrong to consider it. But it does do pretty well as monotherapy too.

Does high-risk genetic status at diagnosis matter at progression?

For me, it does and it doesn’t. For me, this is why I do like to know whether I have patients who have del(17p) at the beginning [of treatment]. I’ll typically check this before treatment, but the advantage is if someone has progressed through ibrutinib and they’re getting on venetoclax, it may be a person who is going to progress through that as well. So you have to think about the next step, particularly in the patients with del(17p). So the next step could be trial, CAR [chimeric antigen receptor] T-cell therapy, and transplant. But usually those are the patients who are high risk to fail 2 novel therapies, so it is actually good for me to know whether they are at high risk.

Could you summarize treatment options in the frontline setting?

If it’s a CLL or SLL [small lymphocytic leukemia] stage II to IV, the guidelines have not changed. Even though we have lots of fancy new, novel therapies, we’re still treating when there’s indication to treat. So if there’s no indication, we observe, but if there’s an indication—for example, if the patient is 17p or TP53 mutated—[we treat].

Remember, there’s a percentage of patients with del(17p) who don’t have a TP53 mutation and vice versa. If you suspect you have an aggressive presentation, send for the TP53 testing. It’s rare, but it does happen.

For those patients, BTKs, ibrutinib, venetoclax plus obinutuzumab, or acalabrutinib with or without obinutuzumab is appropriate. And we’re not thinking about chemoimmunotherapy because historically, and even now, you don’t have as good clinical outcomes with that.

For fit elderly patients, who are a lot of our patients, because this is CLL, these are also good options because these drugs are relatively well tolerated, but they do have differences in terms of toxicities and also chronic versus time-limited therapy.

This is a good discussion to have with your patients in terms of what kind of therapy they want to be treated with because they do have several options. For young, fit patients, you have those options. For patients who are IGVH mutated, I would consider FCR because you still have data showing a very long PFS. And it may be a very long time before they get next therapy.

BR is [almost obsolete]. However, I did notice in the New England Journal of Medicine Alliance study that it’s in the supplemental material. But most patients who are older do tolerate ibrutinib pretty well. I’ve been in situations where if it’s a very aggressive presenting CLL and they’re impatient and you just want to do something quick, then I’m using it because it’s a lot easier to give in patients and you just want a quick response. It’s not completely off the table, I think, but I think there are a lot of options here, particularly if it’s well covered for your patient.

_References:

_{1. 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}

_{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. 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}

_{4. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib alone or in combination with rituximab produces superior progression free survival (PFS) compared with bendamustine plus rituximab in untreated older patients with chronic lymphocytic leukemia\ (CLL): results of Alliance North American Intergroup study A041202. Blood. 2018;132 (suppl 1):6. doi:10.1182/blood-2018-99-116653}

_{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/NEJMoa181528}