Jeremy S. Abramson, MD, MMSc:
With relapsed/refractory CLL/small lymphocytic lymphoma (SLL), a major determinant of second- or later-line therapy is what therapy the patient received in the first-line setting. Prior to the approval of targeted therapies, most patients would have received first-line chemoimmunotherapy. Patients treated closer to present day will have received either venetoclax/obinutuzumab or a covalent BTK inhibitor first line. 

If a patient previously received prior chemoimmunotherapy, they are targeted inhibitor–naive; therefore, healthcare professionals (HCPs) should treat them as if they were previously untreated, considering such factors as time-limited vs continuous therapy, bleeding risk vs no bleeding risk, and ease of initial dosing. 

If a patient received prior covalent BTK inhibitor therapy, HCPs should ask why the patient discontinued that inhibitor. If the patient progressed on a covalent BTK inhibitor, HCPs should initiate something other than a covalent BTK inhibitor. If, however, the patient discontinued the covalent BTK inhibitor because of toxicity, but they were responding, then that patient could potentially be switched to a different covalent BTK inhibitor. For example, if the patient were on ibrutinib and discontinued due to toxicity, they could change to acalabrutinib or zanubrutinib. However, if a patient’s CLL progressed with a covalent BTK inhibitor, venetoclax plus obinutuzumab should be considered. 

If the patient received a prior covalent BTK inhibitor and progressed on that and also had received prior venetoclax, pirtobrutinib should be considered. 

For patients who received initial venetoclax/obinutuzumab therapy (time-limited therapy), second-line treatment is more complex. If the patient progressed during or shortly after this regimen, they should receive second-line therapy with a covalent BTK inhibitor. However, if the patient had a lengthy remission (eg, 6 years of remission after venetoclax plus obinutuzumab), then an HCP could consider initiating time-limited therapy again with venetoclax plus obinutuzumab at the time of progression. This should be a shared decision with the patient. 

Let’s now look at the data to help guide our selection of second- or later-line therapy. 

Jeremy S. Abramson, MD, MMSc:
I will begin by discussing 2 trials that compare ibrutinib with a next-generation covalent BTK inhibitor. The first, ELEVATE-RR, took patients with relapsed/refractory CLL and randomized them to either acalabrutinib 100 mg twice daily (n = 265) or ibrutinib 420 mg once daily (n = 268). Of importance, the patients had to have high-risk disease based on cytogenetic features (17p or 11q deletion).  After a median follow-up of 40.9 months, analysis showed that there was no difference (noninferiority) in median progression-free survival (PFS) in the 2 arms.¹ 

Jeremy S. Abramson, MD, MMSc:
However, there was a difference between ibrutinib and acalabrutinib: toxicity. Analysis with Kaplan-Meier curves showed that there were higher rates of short- and long-term toxicity with ibrutinib vs acalabrutinib. Specifically, ibrutinib was associated with higher rates of atrial fibrillation (HR for acalabrutinib:ibrutinib for patients without prior history of atrial fibrillation was 0.37 [95% CI: 0.20-0.67], HR with prior history of atrial fibrillation was 1.00 [95%: 0.34-2.95]), higher rates of hypertension (HR for patients without prior history of hypertension was 0.23 [95% CI: 0.11-0.48], HR for patients with prior history of hypertension was 0.46 [95%CI: 0.25-0.85), bleeding events (HR: 0.63 [95% CI: 0.49-0.82), diarrhea (HR: 0.61 [95% CI: 0.46-0.80]), and arthralgias (HR: 0.61 [95% CI: 0.41-0.90]).

Based on these data (similar efficacy with better tolerability favoring acalabrutinib), HCPs should favor acalabrutinib over ibrutinib when considering those 2 options.^1,2 

Jeremy S. Abramson, MD, MMSc:
Now we will discuss the data with zanubrutinib, another next-generation covalent BTK inhibitor. The ALPINE study randomized patients with relapsed/refractory CLL to zanubrutinib 160 mg PO twice daily or ibrutinib 420 mg PO once daily and continued, as with all of these trials, until progression or unacceptable toxicities. The ALPINE study was designed a little differently than the ELEVATE-RR trial, and did not enrich exclusively for high-risk patients.³

Jeremy S. Abramson, MD, MMSc:
The ALPINE trial met its endpoint of superior overall response rate (ORR) favoring zanubrutinib (86.2%) over ibrutinib (75.7%). Of importance, this trial also showed a better PFS for zanubrutinib over ibrutinib. At 3 years, 64.9% of patients on zanubrutinib remained progression free compared with 54.8% of patients on ibrutinib (HR: 0.68) This PFS difference was also preserved in the high-risk subset of patients with 17p deletions or TP53 mutations (HR: 0.77).⁴

Jeremy S. Abramson, MD, MMSc:
Analysis of toxicity in the ALPINE trial showed substantially less atrial fibrillation or flutter with zanubrutinib over ibrutinib (6.7% vs 16.4%; P = .0001). Of note, there was no difference in hypertension between treatment groups.⁴

Jeremy S. Abramson, MD, MMSc:
Now, as with the frontline setting, we do have BCL-2 antagonists available for relapsed/refractory CLL/SLL. Use of venetoclax/rituximab is based on the MURANO trial, which included patients who relapsed exclusively after chemoimmunotherapy. Patients were randomized to receive either venetoclax plus rituximab (venetoclax dose ramp-up 20-400 mg PO QD for 5 weeks, then 400 mg PO QD for cycles 1-6 combined with rituximab 375 mg/m² on Day 1 of cycle 1, then 500 mg/m² Day 1 of cycles 2-6; then venetoclax monotherapy until PD, unacceptable toxicity, or maximum of 2 years from Day 1 of cycle 1; n = 194) or bendamustine 70 mg/m² on Days 1 and 2 of cycles 1 to 6 plus rituximab 375 mg/m² on Day 1 of cycle 1, then 500 mg/m² on Day 1 of cycles 2 to 6 (n = 195).⁵ 

Jeremy S. Abramson, MD, MMSc:
Venetoclax/rituximab was substantially superior to bendamustine/rituximab in terms of median PFS (53.6 months vs 17 months; P <.0001). Therefore, venetoclax/rituximab is another effective option in the relapsed/refractory setting for CLL/SLL.^6,7

Jeremy S. Abramson, MD, MMSc:
How should you treat patients who received venetoclax/obinutuzumab and then get a covalent BTK inhibitor, or vice versa, and then progress on both? We have some recently approved options available, including pirtobrutinib and lisocabtagene maraleucel.

Pirtobrutinib is a noncovalent BTK inhibitor. This agent has a different BTK binding domain than approved covalent BTK inhibitors and can overcome some BTK inhibitor resistance mutations that emerge after treatment with covalent BTK inhibitors. 

BRUIN was a phase I/II study of pirtobrutinib that included patients who had relapsed with a covalent BTK inhibitor and venetoclax. There was an ORR of 83.1% in patients with prior BTK inhibition but no prior BCL-2 inhibitor and an ORR of 79.7% in patients with both prior BTK inhibitor and BCL-2 inhibitor therapy. In patients with prior BTK inhibition, the median PFS was 19.4 months, and at 2 years, 38.6% of patients remained progression free with pirtobrutinib.⁸ 

Findings from this trial led to the accelerated FDA approval of pirtobrutinib for adults with CLL/SLL who received 2 or more prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.⁹ 

Jeremy S. Abramson, MD, MMSc:
HCPs now have another option that is specifically FDA approved in the post-BTK inhibitor, post-venetoclax setting: CAR T-cell therapy. Lisocabtagene maraleucel is an anti-CD19 CAR T-cell treatment that was studied in the TRANSCEND-CLL 004 trial, which included a very–high risk population of 70 patients who were largely refractory to BTK inhibitor therapy and were exposed to the BCL-2 inhibitor venetoclax.

This trial found that treatment with lisocabtagene maraleucel was associated with an ORR of 43% by International Workshop of CLL (iwCLL) criteria. However, these criteria are not effective at gauging response because if a patient has a lymph node of 1.6 cm, they are considered to have a PR and not a complete response (CR). The more effective way to gauge response is to use next-generation measurable residual disease (MRD) testing. In this study, 62% of patients with double refractory disease achieved undetectable MRD in the blood and 59% achieved undetectable MRD in the bone marrow when receiving lisocabtagene maraleucel.¹⁰

TRANSCEND-CLL 004 led to the FDA approval of lisocabtagene maraleucel as the first CAR T-cell therapy for patients with relapsed/refractory CLL/SLL who have received at least 2 prior lines of treatment, including a BTK inhibitor and a BCL-2 inhibitor.¹¹

Shuo Ma, MD, PhD:
Are you using or considering lisocabtagene maraleucel treatment in patients older than 75 years?

Jeremy S. Abramson, MD, MMSc:
Absolutely. There is no upper age limit, and we have treated patients far more than a decade older than 75 years. Instead, factors we think about when potentially initiating lisocabtagene maraleucel include fitness, organ function, and performance status.

Farrukh Awan, MD:
Yes, I do not think there is an age limit, as far as we are concerned at our center, for CAR T‑cell therapy. In that vein, Dr Ma, if a patient is double refractory to a covalent BTK inhibitor and venetoclax, do you try the noncovalent BTK inhibitor or is there a scenario in which you can skip and go straight to CAR T-cell therapy?

Shou Ma, MD, PhD:
That’s a tough question. If a patient really cannot receive CAR T-cell therapy, of course there is an easy answer of using pirtobrutinib. But if a patient were able to get either pirtobrutinib or lisocabtagene maraleucel, I would look at their tumor burden. If their tumor burden is relatively low, I might go straight into CAR T-cell therapy, especially for a younger patient, because sometimes with CAR T-cell therapy you can have long‑lasting remission. There were some patients who have had remission lasting for over 10 years and we do not know if there is a potential chance of cure for those patients. But if a patient has a high tumor burden, then my feeling is that the chance for them to get a complete and sustainable response might be lower with CAR T-cell therapy, so I would initiate pirtobrutinib first.

Shuo Ma, MD, PhD:
Ibrutinib, acalabrutinib, and zanubrutinib are all considered covalent BTK inhibitors. They have made a huge difference in patients with CLL, and most patients tolerate these agents well and respond well with years of disease control. However, with time, many patients will start to develop resistance. Here we have a study pooling 4 prospective studies with ibrutinib: after 5 years of treatment in the frontline setting, 41% of patients discontinued ibrutinib, and in the relapsed/refractory setting, 54% of patients discontinued ibrutinib. The most common reason for discontinuation was adverse events. In addition, 19% of those patients at 4 years had CLL progression. 

The most common reason for CLL progression on covalent BTK inhibitor therapy is the emergence of resistance mutations. In a study assessing acquired resistance to ibrutinib in patients with progressive CLL, BTK mutations occurred in 56% of patients and, less commonly, PLCG2 mutations in 8%; 16% of patients had both BTK and PLCG2 mutations. Among those mutations, the BTK C481 mutation is the most common.^12-19

Shuo Ma, MD, PhD:
Why is this BTK mutation so significant? BTK inhibitors work by binding to the BTK enzyme and blocking ATP binding and the catalytic activity of BTK. All of the covalent BTK inhibitors bind to BTK through 1 amino acid—C481—through a covalent bond; therefore, binding is irreversible.

Shuo Ma, MD, PhD:
If a patient acquires a mutation in the C481 amino acid, then the covalent BTK inhibitors are no longer able to bind to BTK and are no longer able to work. Those patients will develop disease progression and resistance to covalent BTK inhibitors.^18,20

Shuo Ma, MD, PhD:
In contrast, pirtobrutinib binds to BTK not through covalent binding, but instead to a pocket through reversible noncovalent binding. This noncovalent binding is not dependent on 1 amino acid; it is to the pocket. As such, pirtobrutinib can still bind to the mutant BTK C481 enzyme.^18,20

Shuo Ma, MD, PhD:
As Dr Abramson mentioned, BRUIN was a phase I/II study assessing pirtobrutinib for patients with relapsed/refractory CLL with at least 2 prior lines of therapy, one of those including a covalent BTK inhibitor. The ORR was 83.1% for patients with prior BTK inhibitor but no BCL-2 inhibitor and 79.7% for patients with both prior BTK and BCL-2 inhibition, and most of those responses are PRs.⁸ The PFS was 19.6 months in patients who had a median of 3 prior lines of therapy. If the patients had a median of 5 lines of prior therapy, the PFS was a little bit shorter, approximately 16.8 months. So pirtobrutinib does work for most patients, although the PFS is still relatively limited because this is a really heavily pretreated patient population.²¹

Shuo Ma, MD, PhD:
Here is a forest plot looking at a subgroup analysis on what patients’ prior therapies were, the reason for their BTK discontinuation, and whether or not they carry the C481 mutation. With pirtobrutinib there was almost no difference in ORR regardless of which subgroup we’re looking at. Pirtobrutinib demonstrated efficacy regardless if patients had the BTK C481 mutation or were wild-type, regardless of the prior BTK discontinued, the reason for discontinuation, and also regardless of prior exposure to other classes of agents.²²

Shuo Ma, MD, PhD:
There are a number of ongoing phase III clinical trials trying to compare noncovalent BTK inhibitors vs ibrutinib or in combination with other treatments compared with other standard of care treatments.

Shuo Ma, MD, PhD:
Even though the ORR with pirtobrutinib was over 80% in BRUIN, the response did not last for very long. There is apparently also resistance that can develop to the noncovalent BTK inhibitors. What are those mechanisms of resistance? 

Here are some patients who developed resistance and progressed on pirtobrutinib. With NGS on these patients, there are other mutations that are not on the C481 site.²³ 

Shuo Ma, MD, PhD:
All those mutations seen with pirtobrutinib are found in the tyrosine kinase catalytic domain, but they are different from the C481 site. When noncovalent BTK inhibitors and covalent BTK inhibitors were tested against those mutations, resistance was observed across multiple different inhibitors.²³ 

Shuo Ma, MD, PhD:
So how do those mutations impact the function of the BTK inhibitor? All of those mutations are able to block the binding of even noncovalent BTK inhibitors to the BTK enzyme. Some of these mutants interestingly make the kinase activity inactive. It sounds a bit counterintuitive as to why an inactivating mutation would confer resistance to BTKi treatment. It.turns out that even when those mutants impair BTK catalytic activity, the protein can still transmit signals through other enzymes in alternative pathways such as HCK. In this case, the BTK protein serves as a scaffold, not relying on its kinase activity.²⁴ 

Shuo Ma, MD, PhD:
So how do you overcome resistance due to kinase-impaired BTK mutations? How about getting rid of the protein altogether? 

This is where the BTK degrader could be potentially useful.  This is a very interesting new class of treatment under investigation. It is a small molecule that binds on one end to the target protein, in this case the BTK protein. On the other end, it binds to the E3 ubiquitin ligase complex, bringing the target protein BTK to the ubiquitin complex to allow ubiquitination of the BTK protein, which will lead to protease degradation. Thus, you are getting rid of the BTK protein regardless of whether it has kinase activity. 

There is a clinical trial that was reported with the BTK degrader NX‑2127 in relapsed/refractory B‑cell malignancies that had been treated with at least 2 prior lines of therapy, at least 1 of those including a BTK inhibitor. In this study, regardless of what kind of a BTK mutant was present, all were able to be degraded by the  BTK degrader. As a result, most patients were able to have a reduction in tumor burden. 

There are also a few other BTK degraders currently under study, including NX‑5948, ABBV‑101, and BGB‑16673.²⁴

Shuo Ma, MD, PhD:
There also has been progress with BCL-2 inhibition. Sonrotoclax, a novel BCL-2 inhibitor, is highly selective for BCL-2 and has a significantly lower IC₅₀ compared with venetoclax the in vitro setting.²⁵ 

Shuo Ma, MD, PhD:
There is a large ongoing phase I/II study with sonrotoclax in CLL and other non‑Hodgkin lymphomas testing monotherapy and various combinations.

Data from the sonrotoclax plus zanubrutinib cohort of this trial were reported at the 2023 American Society of Hematology meeting. Two dose levels were tested, with the 320 mg once daily dose the recommended phase II dose. Patients started treatment with zanubrutinib with a lead-in of 2 to 3 months and then added sonrotoclax with slow dose ramp-up to mitigate the tumor lysis risk; patients continued on treatment until progression or unacceptable toxicity.

The ORR with this combination was 100%. The CR rate was 42% with twice-daily dosing and 33% with once-daily dosing. At 24 weeks, 78% of patients were able to achieve an undetectable MRD. At 48 weeks, 100% of patients who were receiving the 320 mg once daily dose achieved an undetectable MRD. There is an upcoming phase III study comparing this combination, sonrotoclax plus zanubrutinib, with standard of care venetoclax plus obinutuzumab for frontline treatment of CLL.²⁶

Shuo Ma, MD, PhD:
Bispecific antibodies are antibodies that bind on one end to the CD20 B‑cell marker and on the other end to the CD3 T‑cell marker. As such, these antibodies can bring T‑cells to the malignant B‑cells and allow effective cellular immunity against lymphoma cells. There are multiple bispecific antibodies currently approved for relapsed/refractory diffuse large B-cell lymphoma and follicular lymphoma. These are not currently approved for CLL but are being studied in this disease.²⁷ 

Shuo Ma, MD, PhD:
For example, epcoritamab is being studied in the EPCORE CLL‑1 study, which includes patients with CLL as well as patients with Richter transformation. Based on the initial dose-escalation phase, there is no dose-limiting toxicity. The maximum tolerated dose was not reached and the recommended phase II dose was identified.  This trial is ongoing for CLL.^28,29 

Shuo Ma, MD, PhD:
This cohort reported response in patients with Richter transformation. Treatment for Richter transformation represents a major challenge and unmet medical need. Epcoritamab does appear to show promising activity in these patients with an ORR of 60% and CR of 50%.  Some of the patients have response ongoing beyond 3 years. Hopefully more mature data will be upcoming with this very interesting and promising treatment.²⁹