Coombs Considers Role of BTK Inhibitors in CLL and Treatment Selection

Catherine Coombs, MD

Associate Professor

Division of Hematology/Oncology

UCI School of Medicine

Irvine, CA

CASE SUMMARY

• A man aged 65 years who was diagnosed with chronic lymphocytic leukemia (CLL) in 2019 presented to his oncologist at routine follow-up.
• Medical history: type 2 diabetes controlled with insulin
• Patient received previous treatments with: First line: acalabrutinib (Calquence) monotherapy Achieved good clinical response over 3 years but later progressed on therapy
• Second line: venetoclax (Venclexta) plus rituximab (Rituxan) Completed 24-month treatment regimen
• Was in treatment-free interval for 6 months
• Due to disease progression, his hemoglobin has dropped over the past 3 months and is currently at 10 g/dL.
• At follow-up, the patient is now aged 70 years and does not report any symptoms.
• ECOG performance status: 0

Peers & Perspectives in Oncology: Please discuss the available treatments for patients with CLL.

COOMBS: We have so many effective therapies that it is often difficult to choose. Bruton tyrosine kinase [BTK] inhibitors are the mainstay in CLL, with ibrutinib [Imbruvica] being the first approved, followed by acalabrutinib, zanubrutinib [Brukinsa], and pirtobrutinib [Jaypirca], which is the most recent approval.1 However, the approval for pirtobrutinib is the most restrictive FDA approval. It is an accelerated approval [for use] in the third line after having received both a covalent BTK and a BCL2 inhibitor.

We also have the BCL2 inhibitor therapeutic class. The only FDA-approved option in this category is venetoclax, and this is often paired with a monoclonal antibody. The ones that are used most frequently are obinutuzumab [Gazyva] and rituximab. Chemotherapy, technically speaking, is still an option. Most clinicians use chemotherapy less and less, if at all. In my case, not because it does not work but because of the potential for long-term toxicity. Chemotherapy could be considered for either young or extremely fit patients, those with an IGHV mutation, or for those with a TP53 mutation. I do not recommend using chemotherapy, but it is not wrong and is still listed as a potential option for a small subset of patients in the NCCN guidelines.²

With all these options, what factors should be considered when choosing therapy for a specific patient with CLL?

First, patient factors such as age, performance status, and comorbidities play a role in choosing therapy. Next, disease factors, including the genetic features of the CLL, should be considered—such as the presence of del(17p), TP53 mutation, complex karyotype, or unmutated IGHV. These have less favorable responses, especially to chemotherapy, but also to some of our newer therapies, such as venetoclax.

You always want to consider the risk of the regimen, the potential benefit, how interested the patient is in a time-limited therapy. This often helps me steer patients either toward venetoclax-based therapy or away from it. You also want to consider their access to the center for the necessary appointments and ramp-up [doses]. Patient preference is still hugely important. We do not have head-to-head data on some of our most effective therapies, so there is not a single right answer for any one patient. Their preference is hugely important.

In relapse, you need to consider what the response was to the therapy the patient had before and why they stopped it. Making a distinction in the BTK inhibitor class is important, considering whether the patient had intolerance to their first-line BTK inhibitor or actual progression. This is because it will change what the future options may be.

What is the rationale for genetic testing in the CLL population?

There are NCCN-recommended prognostic tests that one should consider for all patients with CLL, and I evaluate these in any patient who needs therapy.² The reason these are important is that even though our new therapies work well, there is a differential response, especially with the time-limited venetoclax/obinutuzumab regimen for patients who have unfavorable-risk disease. This includes those with unmutated IGHV CLL and those with a deletion in 17p or a TP53 mutation.

These aspects do not completely take the venetoclax/obinutuzumab regimen off the table, but they require a more nuanced discussion with this patient. Every patient who has high-risk features should understand expectations on efficacy of the venetoclax/obinutuzumab regimen vs another, such as the use of a continuous BTK inhibitor.

I also test for karyotype, though it could be skipped to limit testing. However, testing for a complex karyotype is important because it provides independent prognostic value as an adverse marker.

The β₂-microglobulin is a cheaper test. I order it for all my patients who are newly diagnosed. There is an argument not to do this; however, the reason I do, as well as all these other tests, is because I am enthusiastic about an ongoing clinical trial looking at early intervention in patients with higher-risk CLL.³ I am generally keen to know which patients are higher risk because then I can talk to them about this trial. Regardless of the trial, the other advantage of sending prognostic tests at first diagnosis is that for those who are higher risk, I would watch more closely vs those who are very low risk.

Q:Can you explain the recent updates to the NCCN guidelines for treating CLL, particularly regarding relapse therapies?

Regarding NCCN guidelines and highlighting relapse CLL therapies, the preferred regimens are now acalabrutinib or zanubrutinib, if using a BTK inhibitor.² Acalabrutinib can be with or without obinutuzumab, and zanubrutinib is always as a single agent. These are preferred over ibrutinib because the studies with relapse show better safety.⁴ The other frontline therapy option is venetoclax with obinutuzumab.

In the second or subsequent line, the preferred regimens are also similar, including acalabrutinib or zanubrutinib. If a patient received a particular treatment as part of their first-line therapy and then progressed, it is generally not advisable to repeat that same treatment in the second line. However, if the patient was intolerant to the first-line treatment rather than experiencing progression, it may be reasonable to consider the same treatment again in the second line, depending on the situation. Venetoclax is also listed as a second-line treatment, and it represents a recent change to the NCCN guidelines that preferred venetoclax with obinutuzumab. I thought this was an interesting choice by the NCCN.

The FDA-approved regimen is the venetoclax/rituximab regimen, but most of us have slowly been trying to use obinutuzumab, even in the relapse setting. This choice is based on an extrapolation from a frontline trial where venetoclax with obinutuzumab was shown to be quite superior to venetoclax with rituximab.⁵ One could logically conclude that this approach should also apply in a relapse setting, which is why the guidelines have been updated to reflect this change. However, rituximab is still considered a reasonable option. There is also the option of venetoclax as a continuous monotherapy; however, I tend to do this less frequently. I apply it occasionally to certain patients [for whom] I am trying to adopt a “less is more” approach.

Over the past year or two, the NCCN guidelines have updated their recom-mendations for patients who have failed both covalent BTK inhibitors and venetoclax. The preferred treatment options for these patients now include lisocabtagene maraleucel [Breyanzi, liso-cel], a chimeric antigen receptor [CAR] T-cell therapy, or pirtobrutinib, a noncovalent BTK inhibitor.

Pirtobrutinib is the safer option. We do not have comparative data, but pirtobrutinib also has a higher degree of efficacy if your goal for efficacy is overall response rate and progression-free survival. I would not rule out liso-cel for patients who are young and interested in the chance for a longer-term remission. The results from the liso-cel study were a little disappointing, in my opinion. Thus, I do not favor this therapy for the average patient.⁶

There are other recommended regimens in the third line and beyond…. However, I almost never use any of these anymore because pirtobrutinib works quite well, and it is rare that patients progress into the third line. I do not see third-line patients often, and most patients are doing well on first- and second-line treatment.

Please discuss the design of the BRUIN trial (NCT03740529) evaluating pirtobrutinib.

Almost 800 patients are enrolled in this huge phase 1/2 trial.⁷ Regarding the CLL and small lymphocytic lymphoma patient population, which was around 300, most patients had a prior BTK inhibitor. When you exclude patients who did not have a prior BTK inhibitor, 252 patients remain to evaluate the efficacy of this drug.

The study evaluated a patient population that was heavily pretreated. When you consider the median number of prior therapies, 47% had 4 prior lines or more, a quarter of patients had 3, and about a quarter had 2 prior lines of therapy. Everyone had a prior BTK inhibitor, and about 40% had prior venetoclax. Almost every patient had prior chemotherapy and an anti-CD20 therapy. [Fewer] patients had prior CAR T-cell therapy or allogeneic stem cell transplant, and about 20% had previously received a PI3K inhibitor.

Importantly, when reviewing the reasons for discontinuing the prior BTK inhibitor, about three-fourths of patients had progressed, and one-fourth were intolerant. A recently published paper focused on the intolerant population and found that both groups responded well to treatment.⁸ Regarding BTK mutations, 40% of patients had a mutation, which some have commented seems low. However, this is likely due to the study’s methodology, which only detected clones at 5% or greater. Some mutations may be present in the lymph nodes but not detectable in the blood due to compartmental effects. This patient population also had very high-risk biology, with about half having a 17p deletion, TP53 mutation, or both.

What were the efficacy and toxicity seen in this trial?

The response rates are similar across several key clinical factors, including the presence of 17p deletion, known resistance mutations, and prior therapies. These response rates hover around 70%. Interestingly, responses tend to deepen over time. With longer follow-up, the proportion of responders increases. For example, after an early follow-up period, about half of patients may show a partial remission, but after more months of treatment, this number rises to around 70% to 75%. Most responses are partial remissions, which is consistent with the outcomes seen with other covalent BTK inhibitors.

One of the great aspects of pirtobrutinib is its very good safety profile. The atrial fibrillation rate was just under 4%, as they did allow patients with atrial fibrillation in the study. Considering the distinction between treatment-emergent and treatment-related events, the treatment-related problems are more likely to be de novo, meaning they are truly caused by the treatment itself. There is some objectivity in whether an investigator reports something as treatment related vs treatment emergent.

Treatment-related adverse events [AEs] are low at 1.3%. Interestingly, bleeding is also lower than expected. Most covalent BTK inhibitors are associated with about 5% of grade 3 or higher bleeding events, but here it is around 2%. Other AEs are generally minimal. About one-third of patients report fatigue, though it is not clearly related to treatment. Diarrhea can occur, but the most common AE is neutropenia. I want to highlight this, as it affects about 20% to 30% of patients, whether it is classified as treatment-related or simply treatment-emergent—meaning it occurs during treatment, regardless of whether it is directly caused by the drug.

The median PFS for pirtobrutinib is 19.4 months, which is quite good. This is with a mature follow-up of 27.5 months. This was presented at the American Society of Hematology Annual Meeting in December 2023.⁹ In the presentation, investigators showed that there was a near-universal reduction of lymph node size for most patients treated. Patients were evaluated for over 2 years; the response rate is 81.6%. There were a few complete responses observed, but most of the responses are partial responses, as one has grown to expect with the BTK classes.

In the trial, investigators stratified patients by whether they had prior venetoclax.⁷ For patients who were naive to a BCL2 inhibitor, response rates were high at 83%. Those who received a prior BCL2 inhibitor had similarly high responses of 79%. The PFS was a bit shorter for patients with prior venetoclax, about 16 months, compared with 23 months for those who did not receive prior venetoclax. Keep in mind that these are heavily pretreated patients. The cohort with prior BCL2 inhibitor therapy had a median of 5 prior treatments, compared with 3 prior treatments in the cohort without prior BCL2 inhibitor exposure.

An aspect that I am keeping my radar on is the resistance mechanism to the covalent drugs. The most common mechanism of resistance is the C481 mutations. Pirto-brutinib is a bit different. It is quite active in patients with a C481 mutation, but it can lead to its own resistance.

In patients who experience progression on pirtobrutinib, there are several different acquired mutations. The most common is the T474 mutation. They call that the gatekeeper mutation because it impairs the binding of all the drugs that inhibit BTK. The second most common is the L528W mutation, which is often associated with resistance to covalent BTK inhibitors and is sometimes referred to as a “kinase-dead” mutation due to its impact on the enzyme’s function in the presence of these inhibitors. When patients develop this mutation, it disrupts the kinase function of BTK, yet downstream signaling still occurs. This suggests that, in addition to its role as a kinase, BTK may also function as a biochemical scaffold, supporting downstream signaling autonomously in the presence of this mutation.

_REFERENCES

_{1. Fares A, Carracedo Uribe C, Martinez D, Rehman T, Silva Rondon C, Sandoval-Sus J. Bruton’s tyrosine kinase inhibitors: recent updates. Int J Mol Sci. 2024;25(4):2208. doi:10.3390/ijms25042208}

_{2. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/ small lymphocytic lymphoma, version 1.2025. Accessed December 16, 2024. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf}

_{3. Hoechstetter MA, Wendtner CM. Clinical trials in early-stage CLL: what has been learned and what’s next? Leuk Lymphoma. 2024:1-11. doi:10.1080/10428194.2024.2422839}

_{4. Tam CS, Thompson PA. BTK inhibitors in CLL: second-generation drugs and beyond. Blood Adv. 2024;8(9):2300-2309. doi:10.1182/bloodadvances.2023012221}

_{5. Molica S. Venetoclax: a real game changer in treatment of chronic lymphocytic leukemia. Int J Hematol Oncol. 2020;9(4):IJH31. doi:10.2217/ijh-2020-0010}

_{6. Siddiqi T, Maloney DG, Kenderian SS, et al. Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Lancet. 2023;402(10402):641-654. doi:10.1016/S0140-6736(23)01052-8}

_{7. Mato AR, Woyach JA, Brown JR, et al. Pirtobrutinib after a covalent BTK Inhibitor in chronic lymphocytic leukemia. N Engl J Med. 2023;389(1):33-44. doi:10.1056/NEJMoa2300696}

_{8. Shah NN, Wang M, Roeker LE, et al. Pirtobrutinib monotherapy in Bruton tyrosine kinase inhibitor–intolerant patients with B-cell malignancies: results of the phase I/II BRUIN trial. Haematologica. Published online October 3, 2024. doi:10.3324/haematol.2024.285754}

_{9. Sharman J, Munir T, Grosicki S, et al. BRUIN CLL-321: randomized phase III trial of pirtobrutinib versus idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) in BTK inhibitor pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at: 66th American Society of Hematology Annual Meeting and Exposition; December 7-10, 2024; San Diego, CA. Accessed December 16, 2024. https:// ash.confex.com/ash/2024/webprogram/Paper198147.html}