Let’s begin our discussion with a case. An 80-year-old man is newly diagnosed with CLL and has hypertension, bulky disease, and renal insufficiency. His disease is characterized by unmutated IGHV and normal fluorescence in situ hybridization. He presents with bulky lymphadenopathy in both axillary lymph nodes and a large abdominal mass with significant chest lymphadenopathy. He has symptomatic anemia with a hemoglobin of 8.9 g/dL, a low platelet count of 90,000/μL, and a white blood cell count of 325,000/μL. He has long-term controlled hypertension and diabetes and has developed chronic renal insufficiency.  

The B‑cell receptor pathway has critical roles in growth, proliferation, and survival of normal and malignant B cells.¹ BTK is an essential enzyme in the B‑cell receptor signaling pathway. As such, BTK is an obvious target for inhibiting this pathway in malignant cells. Inhibiting BTK mitigates downstream signaling, thereby blocking growth, proliferation, adhesion, migration, and ultimately, overall B-cell survival. BTK inhibitors have been studied in and approved for treating multiple lymphomas and have indications for treating CLL, mantle cell lymphoma, marginal zone lymphoma, and Waldenström macroglobulinemia.^2-4

This slide summarizes the current regulatory status of various BTK inhibitors in the CLL setting.^2-7 Ibrutinib is a first-generation, irreversible, covalent BTK inhibitor and acalabrutinib is a second-generation, irreversible, covalent BTK inhibitor. In Europe and the United States, both ibrutinib and acalabrutinib have broad indications for treatment-naive and relapsed/refractory CLL.

Zanubrutinib, a second-generation, irreversible, covalent BTK inhibitor, has been studied in treatment-naive CLL in the SEQUOIA trial and in relapsed/refractory CLL in the ALPINE trial.^8,9 In Europe and the US, approval was recently granted for zanubrutinib as monotherapy for treatment-naive and relapsed/refractory CLL. In May 2023, zanubrutinib was also approved for use in China for treatment-naive adult patients with CLL.

Two third-generation, noncovalent, reversible BTK inhibitors are being investigated in CLL. Pirtobrutinib is a highly selective, noncovalent, reversible BTK inhibitor that has been studied in the phase I/II BRUIN study.¹⁰ Four phase III trials are also examining pirtobrutinib in patients with either treatment-naive or relapsed/refractory CLL.

Nemtabrutinib, another noncovalent, reversible BTK inhibitor, is being studied in various malignancies in a phase II basket study that is currently enrolling.¹¹

As shown in this kinome map, the irreversible, covalent BTK inhibitors ibrutinib, acalabrutinib, and zanubrutinib have variable kinase selectivity.¹² This variable selectivity influences the toxicity profiles associated with each of these agents.

Among the covalent BTK inhibitors, ibrutinib is the least selective and is consequently associated with the highest rates of off-target toxicities compared with acalabrutinib or zanubrutinib. 

The most recent European Society of Medical Oncology (ESMO) guidelines were released in 2020.¹³ These guidelines recommend that patients requiring therapy be categorized according to their TP53 and/or del(17p) status and immunoglobulin gene (IGHV) mutation status. Patients with disease characterized by unmutated IGHV, wild-type TP53, and no del(17p) are further categorized according to their fitness. Regardless of fitness status, BTK inhibitors—either ibrutinib (fit patients) or ibrutinib or acalabrutinib (unfit patients)—are recommended therapy options.

In patients with disease characterized by mutated IGHV, wild-type TP53, and without del(17p), either ibrutinib in fit patients or ibrutinib or acalabrutinib in unfit patients is the recommended therapy.

In patients with disease characterized by mutated TP53 or del(17p), therapy options include ibrutinib or acalabrutinib and other targeted therapies. 

As mentioned, zanubrutinib was approved in Europe as monotherapy for patients with CLL following the publication of the ESMO guidelines. In US guidelines, zanubrutinib is a preferred first-line therapy option for patients with CLL with or without del(17p) or a TP53 mutation.¹⁴

In several clinical trials, ibrutinib has demonstrated superiority to chemoimmunotherapy in treatment-naive patients.^15-19 These phase III trials collectively compared ibrutinib with or without an anti-CD20 antibody vs various chemoimmunotherapy regimens. The regimens included chlorambucil with or without the anti-CD20 antibody obinutuzumab; bendamustine with or without the anti-CD20 antibody rituximab; and fludarabine plus cyclophosphamide plus rixtuximab (FCR), which has traditionally been given to younger, fitter patients with good renal function. 

Across the trials, ibrutinib was associated with improved PFS compared with chemoimmunotherapy. In some trials, ibrutinib was also associated with improved OS.

E1912 was a randomized phase III trial comparing ibrutinib plus rituximab vs FCR for 529 treatment-naive patients aged 70 years or younger without del(17p) disease.¹⁸ Ibrutinib was associated with a significantly higher 5-year PFS rate compared with FCR (78% vs 51%; P <.0001). The PFS benefit associated with ibrutinib was consistent regardless of IGHV status. Ibrutinib was also associated with higher OS rates compared with FCR (95% vs 89%).

The A041202/ALLIANCE trial was a randomized phase III trial comparing ibrutinib with or without rituximab vs bendamustine plus rituximab (BR) in 524 treatment-naive older patients (aged 65 years or older).¹⁹

PFS was significantly improved with ibrutinib and ibrutinib plus rituximab compared with BR (HR: 0.39 and 0.38, respectively; P <.001 for both comparisons). The trial also demonstrated that adding rituximab to ibrutinib monotherapy does not convey a benefit in the frontline setting.

The ELEVATE-TN trial was a randomized phase III study of the second-generation BTK inhibitor acalabrutinib plus obinutuzumab, acalabrutinib monotherapy, or chlorambucil plus obinutuzumab for treatment-naive patients with CLL who were aged 65 years or older or younger than 65 years with comorbidities that would exclude them from receiving fludarabine-based therapy.²⁰

At 5 years of follow-up, there was a clear PFS benefit with acalabrutinib vs chemoimmunotherapy (median PFS not reached in either acalabrutinib arm vs 27.8 months with chlorambucil plus obinutuzumab).

There are a few other key points from this study. First, at the longer follow-up, addition of the anti-CD20 antibody provided more durable disease control, as demonstrated by a 12% difference in median 5-year PFS rates between the acalabrutinib plus obinutuzumab group and the acalabrutinib monotherapy group (84% vs 72%). Overall, acalabrutinib-based therapy was associated with durable disease control, and after 5 years of acalabrutinib therapy, more than 70% of patients were still alive and in remission.

Second, in the small subgroup of patients with mutated TP53 and/or del(17p) disease, the addition of obinutuzumab did not appear to provide any clear benefit. At 5 years of follow-up, median PFS was not reached in either the acalabrutinib plus obinutuzumab group or the acalabrutinib monotherapy group and the median 5-year PFS rate was 71% in both groups.

Trials with BTK inhibitors and other therapies have examined treatment of patients with CLL characterized by TP53 mutation and/or del(17p).

CLL14 was a randomized phase III study comparing a combination of the BCL-2 inhibitor venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab for patients with treatment-naive CLL. In this trial, among the small subgroup of patients with mutated TP53 and/or del(17p) CLL, the median PFS was reached at approximately 4 years.²¹

Data from the mutated TP53 and/or del(17p) CLL subgroup of the ELEVATE-TN trial demonstrated that PFS at 4 years was approximately 75% to 80%, meaning that PFS was not at all close to reaching the median.²² These and other data with BTK inhibitors suggest that continuous BTK inhibition may potentially provide a more durable disease response compared with other targeted therapies such as venetoclax.

SEQUOIA is an ongoing, randomized, multicohort phase III trial.⁸ Cohort 1 of the trial compares zanubrutinib monotherapy with BR in patients with treatment-naive CLL who are aged 65 years or older or younger than 65 years with comorbidities that make them ineligible for FCR. Results from the initial readout for cohort 1 demonstrated a >15% difference in the 2-year PFS rates between zanubrutinib and BR (85.5% vs 69.5%).

Extended follow-up data from SEQUOIA will be presented at EHA 2023.

There is no obvious best initial therapy for CLL. Treatment decisions should be individually tailored and based on multiple factors. Patient preference and comorbidities should both factor heavily into the final treatment decision. Toxicity profiles and resources available for delivering certain therapies are also important considerations.

Note that concomitant administration of acalabrutinib capsules with proton pump inhibitors reduces acalabrutinib exposure and is currently not recommended.² In the United States, a new tablet formulation of acalabrutinib that can be taken with gastric acid–reducing agents has been approved based on results of the ELEVATE-PLUS studies, which showed that the capsule and tablet formulations are bioequivalent.²³

Each of the targeted inhibitors provides high efficacy and, in many cases, long‑term disease control. However, there are specific patient populations in which continuous BTK inhibition may be more beneficial than shorter, fixed‑duration therapy with therapies such as venetoclax plus obinutuzumab. Conversely, there are some lower-risk patients who may benefit from fixed-duration therapy.

Because many of these agents are approved for treating relapsed/refractory CLL, questions regarding therapy sequencing will continue to emerge as the agents are used in the frontline setting.

The choice of therapy for relapsed/refractory CLL is dependent on which of 2 key regimens—BTK inhibitors with or without an anti-CD20 monoclonal antibody or venetoclax plus obinutuzumab—the patient received as frontline therapy. Depending on which frontline therapy the patient received, how durable their response was, whether and what kind of toxicities they experienced, and whether they have any obvious resistance to the therapy, the patient will be directed to a different therapy path for relapsed/refractory disease. Other considerations when choosing a relapsed/refractory treatment path include patient preference, therapy goals, AEs prior to therapy, and comorbidities.

Acalabrutinib, venetoclax plus rituximab, and zanubrutinib are preferred options for all patients, regardless of age or comorbidities.¹⁴ Thus, the distinction of age and comorbidities is relatively inconsequential in the relapsed/refractory CLL setting. 

It should be noted that acalabrutinib, venetoclax plus rituximab, and zanubrutinib are active in mutated TP53 and/or del(17p) CLL and, therefore, are considered as preferred options in this setting.

As discussed previously, choice of therapy for relapsed/refractory CLL depends on factors including frontline therapy and response/AEs, age, comorbidities (such as cardiac status or renal dysfunction), and the patient’s current disease status.

Examples of questions that should be addressed before selecting a second-line or subsequent therapy include the following.

• Has the patient acquired a new TP53 mutation?
• Does the patient have bulky disease on imaging and/or impaired renal function that may make venetoclax‑based therapy more challenging? 
• Does the patient have undefined cytopenias that require further investigation? In other words, does the patient have immune cytopenias or is the patient at risk of secondary myelodysplasia?

There are also practical aspects to consider, including infrastructure available for treatment delivery, the patients’ social support and financial situation, whether the treatment requires hospitalization, how frequently the patient needs monitoring, and whether the patient has COVID-19. 

Let’s now turn to safety considerations with BTK inhibitors in managing CLL. 

BTK inhibitors are associated with several class-specific AEs. Cardiac AEs can be associated with BTK inhibitors; these include atrial fibrillation and a rare risk of ventricular arrhythmia.

Other AEs include myalgia, arthralgia, and occasionally rash or skin issues. Diarrhea is a common AE that occurs early in treatment but tends to improve with time. Similarly, cytopenias are common early in treatment but usually improve with time. By contrast, the risk of hypertension, which is particularly problematic with ibrutinib, can increase over time. 

Subsequent therapy choice depends on the issues encountered during previous therapy. BTK inhibitor discontinuation can occur for toxicity (as we will discuss below). Patients who tolerate covalent BTK inhibitors and remain on continuous covalent BTK inhibitor therapy may acquire mutations at cysteine 481 in the BTK binding pocket that convert the cysteine to serine (C481S mutations).^24-26 Of importance, these mutations confer resistance not only to the patient’s current BTK inhibitor therapy, but to all covalent BTK inhibitors.

Another issue that we are starting to see is so-called double-refractory relapsed/refractory CLL.²⁷ Double-refractory relapsed/refractory CLL refers to patients who have developed resistance to both covalent BTK inhibitors and BCL-2 inhibitors. Data in patients with double-refractory disease have shown poor survival outcomes and limited time on subsequent therapy, with the median time to discontinuation of a subsequent line of therapy being approximately 5 months. Clearly, new drug development for addressing the double-refractory population is needed. 

Data from the United States illustrate the issue of discontinuation with ibrutinib.²⁵ In a retrospective analysis of more than 600 patients treated with ibrutinib in clinical trials or commercially, 42% discontinued this drug. Among both treatment-naive patients and those with relapsed/refractory CLL, most discontinuations (>50%) were due to toxicities. Discontinuation due to toxicity was considerably more common than discontinuation due to CLL disease progression or transformation. 

Acalabrutinib may be an option for patients with CLL who discontinue ibrutinib due to toxicity. This is supported by data from 2 phase II studies, including the open-label phase II ACE-CL-208 trial, which examined the efficacy and safety of acalabrutinib following ibrutinib discontinuation.²⁸ Data from this study showed that patients who received acalabrutinib after discontinuing ibrutinib due to intolerance typically experienced a considerably lower recurrence of the initial toxicity that resulted in ibrutinib discontinuation. 

Like the data with acalabrutinib, data from a trial with zanubrutinib show that this may be an effective option in patients who have discontinued BTK inhibitor therapy due to toxicity.²⁹ Among the 60 patients in the trial—most of whom had previously received ibrutinib therapy—the recurrence and severity of subsequent toxicity while receiving zanubrutinib were minimal compared with the initial toxicity that resulted in discontinuation. The data show that toxicity recurrence was uncommon and that the grade of recurrence was also generally lower than the grade experienced with the previous BTK inhibitor therapy. 

The ELEVATE-RR and ALPINE trials are head-to-head trials comparing acalabrutinib and ibrutinib for patients with previously treated CLL.

ELEVATE‑RR was a randomized phase III noninferiority trial comparing acalabrutinib with ibrutinib in 533 patients with relapsed/refractory CLL characterized by del(17p) or del(11q).³⁰ Patients with significant cardiovascular disease or previousexposure to a targeted inhibitor were excluded. Results from the primary endpoint, median PFS, revealed a PFS of 38.4 months (HR: 1.00) in both groups, which established noninferiority.

The trial also had numerous superiority‑based secondary endpoints that were performed in a hierarchical fashion and that demonstrated that the acalabrutinib toxicity profile was superior to ibrutinib. 

In the ELEVATE-RR trial, ibrutinib was associated with significantly higher rates of several AEs—both any-grade and grade ≥3. Compared with acalabrutinib, ibrutinib was associated with significantly higher rates of any-grade atrial fibrillation (9.4% vs 16.0%), hypertension (9.4% vs 23.2%), and pneumonitis (2.6% vs 6.5%). Compared with acalabrutinib, ibrutinib was also associated with significantly higher rates of grade ≥3 hypertension (4.1% vs 9.1%).

Ventricular arrhythmias can occur with ibrutinib. An association with second-generation BTK inhibitors is less well established. A small cohort study of 290 patients has suggested that acalabrutinib may be associated with ventricular arrhythmias. However, this has not been demonstrated in a large, pooled analysis from the phase I, II, and III clinical trials of acalabrutinib and validation of the cohort data set is still necessary before the association of ventricular arrhythmias with acalabrutinib can be confirmed.³¹

ALPINE was a randomized phase III trial comparing zanubrutinib with ibrutinib in 652 patients with relapsed/refractory CLL.⁹ Patients who had ≥1 previous therapies and had not had previous BTK inhibitor therapy were eligible for the study.

In this study, zanubrutinib significantly improved PFS vs ibrutinib (HR: 0.65; 95% CI: 0.49-0.86; P = .002; median follow-up: 29.6 months). Overall response rate also was significantly improved with zanubrutinib vs ibrutinib (86% vs 76%; P = .007).

AEs leading to treatment discontinuation occurred numerically more frequently with ibrutinib (22%) vs zanubrutinib (15%), and the incidence of atrial fibrillation/flutter was significantly decreased (zanubrutinib: 5.2%; ibrutinib: 13.3%; P = .0004). However, rates of other toxicities such as hypertension, infections, and cytopenias were similar between treatment groups.

Notably, an assessment of health-related quality of life with zanubrutinib vs ibrutinib in ALPINE will be presented at EHA 2023.

Now, let’s return to our case question from earlier in the activity. An 80-year-old man is newly diagnosed with CLL and has hypertension, bulky disease, and renal insufficiency. His disease is characterized by unmutated IGHV and normal fluorescence in situ hybridization. He presents with bulky lymphadenopathy in both axillary lymph nodes and a large abdominal mass with significant chest lymphadenopathy. He has symptomatic anemia with a hemoglobin of 8.9 g/dL, a low platelet count of 90,000/μL, and a white blood cell count of 325,000/μL. He has long-term controlled hypertension and diabetes and has developed chronic renal insufficiency. 

Let’s now move on to a discussion of AE management with BTK inhibitors. Because atrial fibrillation is a common AE associated with BTK inhibitors, managing atrial fibrillation in patients receiving BTK inhibitors is a critical part of the overall management of CLL.

Assessing cardiovascular risk factors before initiating BTK inhibitor therapy is essential in managing atrial fibrillation.³² Assessments may include ECGs, echocardiograms, and cardio-oncology consultations.

In patients who develop new‑onset atrial fibrillation, risk–benefit assessments for both cardiovascular risk and thromboembolic risk are necessary. 

Assessing the patient’s atrial fibrillation stroke risk with the CHAD2DS‑VAS score should be considered, and oral anticoagulation therapies should be considered for patients at higher risk for stroke.

β-blockers and digoxin are typically used for controlling heart rate in patients with atrial fibrillation. β-blockers and digoxin are preferred over CYP3A4 inhibitors (eg, verapamil and diltiazem) or P‑glycoprotein substrates (eg, amiodarone), both of which can interact directly with BTK inhibitors. 

Anticoagulation strategies generally include a novel oral anticoagulant such as apixaban. When used concomitantly with BTK inhibitors, apixaban doses are typically reduced to 2.5 mg twice daily to avoid toxicities resulting from a potential interaction with the antiplatelet effect of the BTK inhibitors. In patients requiring oral anticoagulation, it is also important to avoid vitamin K antagonists because they have not been part of most of the BTK inhibitor clinical trials and also because, in the earliest studies with BTK inhibitors, they were associated with concerning bleeding events. 

Hypertension is a concern with BTK inhibitors, particularly in patients who receive continuous ibrutinib therapy over several years. Hypertension prevalence increases over time. Clinical trial data suggest that after 3 years of therapy, 1 in 5 patients will have hypertension. In one analysis, 80% of patients exhibited a 10 mm Hg increase from baseline and more than 10% of patients experienced an increase of 50 mm Hg.³³ Consequently, before initiating BTK inhibitor therapy, it is important to be aware of the patient’s current oral antihypertensive regimen and to decide the best strategies for monitoring the patient and for initiating additional therapies to control incident hypertension before it becomes an issue.³² Clearly, a successful hypertension management strategy will require close communication with the patient’s primary care provider.

Bleeding is a common AE associated with BTK inhibitors.^32,34 Most bleeding events are minor and self-limiting and do not require therapy interruption or reduction. Most bruising and bleeding events are grade 1/2, often involve the forearms and lower limbs, and tend not to be severe. Grade 1/2 bleeding or bruising occur in 40% to 50% of patients receiving ibrutinib, acalabrutinib, or zanubrutinib.

Major bleeding events are uncommon, occurring in approximately 2% to 5% of patients. These events are typically grade ≥3 and require hospitalization or transfusion.

The mechanism underlying BTK inhibitor–associated bleeding is thought to involve inhibition of BTK and other related TEC family proteins, which are important in platelet aggregation.

Minor bruising is not typically associated with major hemorrhage risk and does not require therapy interruption.³²

If patients require minor surgical procedures, protocols typically require temporary BTK inhibitor therapy interruption for 3 days before and after the procedure. For major surgical procedures, protocols typically require therapy interruption for 7 days before and after the procedure. It is important to ensure that patients are informed of the therapy interruption requirement.

For minor bleeding events, if therapy does need to be interrupted, events typically resolve quickly after interrupting treatment and resolve within 2 or 3 days.

For severe bleeding, BTK inhibitor therapy must be discontinued. Platelet transfusion can be used to assist in stopping bleeding. It is also important to investigate other reasons that make the patient susceptible to bruising or bleeding. The investigation might include assessing coagulation status and identifying medications that can increase the patient’s bleeding risk, including vitamin E or fish oil or oral antiplatelets or anticoagulants.

Infection and diarrhea with associated with BTK inhibitor treatment are relatively common.^5,6,32,34 Infection rates among patients receiving a BTK inhibitor may be more than 50%. Pneumonia is the most common infection, with grade ≥3 pneumonia occurring in approximately 12% of patients.

Opportunistic infections reported with BTK inhibitors include aspergillosis and pneumocystitis pneumonia (PCP), caused by Aspergillus species and Pneumocystis jirovecii, respectively. These infections are particularly common in patients who have received multiple lines of previous therapy before receiving a BTK inhibitor and who therefore may already be highly immunocompromised. In these patients, it is particularly important to be vigilant and monitor for infection.

PCP prophylaxis should be considered in patients at higher risk of infection or in those who have a history of infection. 

In patients who present with a severe infection, it is important to consider temporarily discontinuing the BTK inhibitor until a definitive diagnosis is made and then to restart that BTK inhibitor once patients have clinically improved.

Vaccinations for COVID-19 and pneumococcus and other encapsulated organisms should be considered as part of a broader management strategy for CLL in general, including in patients receiving BTK inhibitor therapy. Patients with CLL should also receive an annual influenza vaccine.

As mentioned, diarrhea is a common AE that occurs with BTK inhibitors. It is generally mild and typically occurs early in treatment. It can often be managed with basic supportive care including ensuring patients are well hydrated, using antimotility agents, and, occasionally, switching ibrutinib dosing, particularly to the evening. Grade ≥3 diarrhea is relatively uncommon. When it does occur, it is important to exclude other infective causes. In ADDITION, BTK inhibitor therapy may need to be temporarily interrupted.

Fatigue, arthralgias, and myalgias are some of the more challenging symptoms that patients receiving BTK inhibitor therapy can experience.³² Fatigue is relatively common, occurring in approximately one third of patients. It is difficult to clearly associate fatigue with BTK inhibitor therapy and it is important exclude all other causes of fatigue before considering therapy interruption or dose reduction. Early in BTK inhibitor therapy, it is important to avoid therapy interruptions or dose reductions for fatigue because there is a risk of CLL flaring when the patient goes off treatment, which may potentially worsen the fatigue.

Arthralgia and myalgia can also occur in up to one third of patients receiving BTK inhibitors. In real‑world studies, arthralgia commonly has been associated with ibrutinib dose reductions. As with fatigue, it is important to exclude other causes of arthralgia. Most arthralgia events are grade 1/2 and observation or simple supportive care are sufficient to allow patients to continue with their normal lives. On occasion, patients may require a dose reduction. A therapy interruption followed by rechallenge with the BTK inhibitor at a lower dose may also be necessary.

Short courses of steroids and anti‑inflammatory drugs can also be considered for treating arthralgia and myalgia. However, caution must be exercised when administering concomitant nonsteroidal anti-inflammatory drugs and BTK inhibitor therapy because there is an increased risk of bleeding when the agents are taken together.

Cytopenias, skin manifestations, and headache may also occur with BTK inhibitor therapy.^5,6,32

Treatment‑emergent flares of autoimmune cytopenias can generally be managed with steroids and, on occasion, the addition of an anti-CD20 antibody. Most patients can continue BTK inhibitor therapy unless there is a particular concern about bruising or bleeding with a very low platelet count. 

Although treating skin manifestations can be challenging, they are often responsive to local corticosteroids. On occasiona, therapy interruptions may need to be considered. It is also important to obtain a dermatologic consultation to consider all other differential diagnoses. In some patients, biotin supplementation and nail oil application may be effective in addressing textural changes in the hair and skin.

Headaches are one of the most common early AEs with acalabrutinib, occurring in about one-third of patients. Headaches tend to occur in the first 1 or 2 weeks of treatment and are often transient. It is important that patients understand that the headaches are highly likely to resolve and can be treated with basic analgesia. Caffeine may also be effective in some patients.

Given that the severity of many BTK inhibitor–related AEs will likely decrease over time, it is generally important to encourage patients to continue therapy with supportive care for AEs rather than interrupting therapy or reducing the dose.³² Ideally, dose reductions and therapy interruptions should be avoided during the first 6 months of therapy. During this period, active disease is still present and there is a risk that the disease will flare with dose reductions or therapy interruption. However, if patients have particularly severe AEs and dose reductions are required, it is unlikely that short dose interruptions will result in the emergence of drug‑resistant clones. In addition, data do not suggest that dose interruptions compromise long‑term survival outcomes. 

This slide summarizes some of the guidance for dose reductions and therapy interruptions for managing nonhematologic AEs associated with ibrutinib, acalabrutinib, and zanubrutinib.^5-7 Note that no dose reductions or interruptions are recommended for grade 1/2 nonhematologic AEs.

Dose reductions and therapy interruptions are reserved for patients with grade 3/4 nonhematologic AEs. Dosing should be held initially and then restarted at the standard dose. However, if the AE recurs, then dose reduction can be considered.

If the AE repeatedly recurs with grade 3/4 severity despite dose reduction, further dose reduction and eventual discontinuation should be considered. 

Let’s return to a question from earlier in the activity.

Let’s discuss a few more cases that illustrate management strategies for patients with CLL.

Our second case is a younger patient who is treatment naive with a high‑risk genetic profile. Initially, this 57-year-old man with CLL was followed with observation rather than receiving therapy. He was found to have disease characterized by del(17p). In addition, the patient was found to be negative for t(11;14) and had unmutated IGHV and a complex karyotype. 

After 18 months of observation, the patient’s lymphadenopathy progressed and he developed neck pain and splenomegaly. His blood counts included a lymphocyte count of 61,000/μL, hemoglobin of 11.4 g/dL, and a platelet count of 105,000/μL. The patient was not interested in clinical trials.

Given the data with venetoclax and the BTK inhibitors that we’ve discussed in this presentation, the preferred frontline treatment options for this patient’s demographic—the younger patient with high‑risk disease—would be zanubrutinib monotherapy or ibrutinib or acalabrutinib with or without obinutuzumab.

The third case is a patient with relapsed/refractory CLL who has difficult-to-control hypertension while receiving an ibrutinib regimen. This 73-year-old year man had CLL characterized by del(17p) that had progressed after 4 years on a regimen of venetoclax plus obinutuzumab. The patient had a history of hypertension and dyslipidemia and his medications included atorvastatin 40 mg once daily and lisinopril 40 mg once daily. He was otherwise reasonably fit with an Eastern Cooperative Oncology Group performance status of 1.

He received frontline ibrutinib, generally responded well to therapy, and tolerated the treatment well for the first year. However, after 12 months, he developed hypertension that was difficult to control despite being treated with multiple agents.

In this situation, there are 2 reasonable therapeutic approaches. The first is to switch the patient to acalabrutinib. From phase II studies, we know that acalabrutinib is associated with a low probability of recurrent hypertension and the patient seemed to have had no other toxicities related to his BTK inhibitor regimen. Recall that in ALPINE, zanubrutinib was associated with a similar rate of hypertension vs ibrutinib. The second approach is to switch to a fixed-duration venetoclax-based regimen such as venetoclax plus rituximab. Frontline venetoclax‑based therapy was well tolerated by the patient and provided a 4-year remission. Retreatment with a venetoclax-based therapy can be considered in patients like this one.

The final case is a patient with atrial fibrillation after starting a BTK inhibitor. A 75-year-old woman presented with Binet stage C CLL characterized by unmutated IGHV and mutated TP53. At diagnosis, she had an enlarged spleen (17 cm) but no enlarged lymph nodes and blood work that included hemoglobin of 80 g/dL, white blood cell count of 140,000/μL, and a platelet count of 75,000/μL. She was initiated on frontline ibrutinib monotherapy, which she tolerated well for 9 months. However, after 9 months of therapy, she was admitted with breathlessness, dizziness, and fatigue and a blood panel that included hemoglobin 110 g/dL, white blood cell count of 20,000/μL, and a platelet count of 170,000/μL. Her ECG revealed atrial fibrillation with a ventricular rate of 160, which was classified as grade 3 atrial fibrillation, resulting in hospitalization. 

In this situation, the strategy is to optimize atrial management, assess thromboembolic risk, and consider oral anticoagulation while simultaneously assessing the patient’s bleeding risk. Given that the patient was hospitalized, consulting with cardio-oncology is important when making a treatment decision. Options in this situation include switching the patient to venetoclax plus rituximab as a second-line regimen or switching to a second-generation BTK inhibitor that is associated with low frequency of atrial fibrillation. In this instance, either zanubrutinib or acalabrutinib may be appropriate. 

Now we will discuss emerging BTK inhibitor strategies. As we have seen, covalent BTK inhibitors are all highly effective and highly active in treating CLL. However, data from head‑to‑head trials suggest that acalabrutinib and zanubrutinib are associated with at least comparable efficacy compared with ibrutinib but demonstrate a significant relative risk reduction vs ibrutinib regarding specific cardiovascular toxicities.

Current investigations are addressing whether BTK inhibition can be optimized further.

Pirtobrutinib, which was previously known as LOXO‑305, is a noncovalent BTK inhibitor and has been studied in BRUIN, a open-label phase I/II trial of 773 patients with various B-cell malignancies, including CLL and non-Hodgkin lymphoma.¹⁰ Patients with CLL were generally otherwise fit and had had previous treatment, including a BTK inhibitor. Phase I of the trial examined pirtobrutinib doses ranging from 25-300 mg once daily and included a dose-escalation cohort and an expansion cohort. Phase II examined the recommended dose of 200 mg once daily.

There were 247 patients with CLL within the primary efficacy population of the BRUIN trial. At baseline, patients had received a median of 3 previous lines of systemic therapy and all had received a previous BTK inhibitor. In addition, 88% had previously received an anti-CD20 antibody, 79% had received chemotherapy, and 41% had received a BCL-2 inhibitor. Seventy-seven percent of patients discontinued due to progressive disease and 25% discontinued due to toxicity or another cause. Among the patients tested, 38% had a BTK C481 mutation. In general, this was a high‑risk cohort with 39% having a TP53 mutation and 29% having del(17p) disease.

At a median follow-up of 19.4 months, the median PFS was 19.6 months in patients with a median of 3 previous lines of therapy and 16.8 months in heavily pretreated patients with a median of 5 previous lines of therapy, including a covalent BTK inhibitor and a BCL-2 inhibitor.

In a subgroup analysis comparing patients with or without a C481 mutation, pirtobrutinib conveyed a durable benefit regardless of C481 mutation status.

In the BRUIN trial, among the 773 patients with various B-cell malignancies in the safety population, any-grade atrial fibrillation occurred in 2.8% of patients and any-grade hypertension occurred in 9.2% of patients. The main grade 3/4 AE was neutropenia, which was generally manageable with granulocyte colony-stimulating factor support. Only 2.6% of patients discontinued pirtobrutinib due to treatment‑related AEs. 

Nemtabrutinib is another reversible noncovalent BTK inhibitor that has demonstrable activity in patients with a C481 mutation. Nemtabrutinib is being examined in a phase I/II dose escalation trial in patients with various relapsed/refractory B-cell malignancies.¹¹ Early data from 57 patients with CLL demonstrated a median PFS of 26.3 months.

Patients who develop resistance to a covalent BTK inhibitor most frequently have a BTK C481S mutation, which alters the cysteine-binding covalent binding pocket of BTK.

Recent data have suggested that there are also a range of BTK inhibitor–related resistance mutations outside of the C481 mutation.³⁵ Some of these may confer resistance to pirtobrutinib in patients who are receiving pirtobrutinib after having initially developed resistance to a covalent BTK inhibitor. In other words, these mutations may confer resistance to both pirtobrutinib and covalent BTK inhibitors. We await additional evidence supporting this analysis.

We are also awaiting data from patients who have covalent BTK inhibitor–naive CLL who are receiving a noncovalent BTK inhibitor as their initial BTK inhibitor therapy, as the mechanisms of resistance in these circumstances have not yet been formally assessed.

There are several ongoing phase III trials investigating pirtobrutinib in CLL. In patients with previous covalent BTK inhibitor therapy, pirtobrutinib is being compared with investigator’s choice of a combination of BR or a combination of the PI3K inhibitor idelalisib plus rituximab. In the CLL-322 trial of patients with relapsed/refractory CLL with or without previouscovalent BTK inhibitor exposure, a combination of venetoclax plus rituximab plus pirtobrutinib is being compared with a venetoclax plus rituximab regimen.

Two studies in treatment-naive patients include a trial comparing pirtobrutinib with BR and a head‑to‑head study comparing pirtobrutinib with ibrutinib.

Here are the key takeaways from this activity.

• BTK inhibitors target a major vulnerability of CLL, providing a highly effective treatment option in treatment-naive patients and in those with relapsed/refractory CLL.
• In several randomized studies in treatment-naive patients, continuous BTK inhibitor monotherapy has demonstrated superiority compared with chemoimmunotherapy.
• Cardiovascular toxicity remains a key covalent BTK inhibitor–related toxicity and is an important consideration when planning therapy with covalent BTK inhibitors.
• Second-generation BTK inhibitors have a better safety profile than ibrutinib and are at least as efficacious. These agents can be valuable in patients who have had previous ibrutinib intolerance that has resulted in discontinuation.
• Critical factors to consider when deciding on an optimal therapeutic approach for a given patient include the patient’s clinical history, patient preference, treatment goals, and the patient’s social situation.
• Patients with problematic cardiac issues—particularly arrhythmias and poorly controlled hypertension—may receive the most benefit from switching to alternative treatment modalities such as a BCL-2 inhibitor–based regimen, which is typically not associated with cardiac adverse events.
• Given the impressive efficacy data supporting the use of BTK inhibitors for the treatment of CLL, managing associated toxicities is critically important as these agents are likely to remain a cornerstone of therapy for CLL in the future.