An increasing number of patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) now receive both a covalent Bruton tyrosine kinase (BTK) inhibitor and a BCL2 inhibitor such as venetoclax as standard-of-care therapy.¹ This approach is based in part on the improved survival seen in the phase III MURANO trial with the combination of venetoclax and rituximab compared to bendamustine plus rituximab.² This has resulted, however, in a significant proportion of “doubly exposed” patients developing resistance to these agents, with subsequent disease progression.^3,4 Nearly half of all patients who initially receive a covalent BTK inhibitor and venetoclax eventually relapse or have disease progression due to intolerance or development of resistance to these agents and are thus considered to be double refractory. Historically, outcomes have been poor for such patients, with a short progression-free survival and overall survival; median time to progression or death is typically less than 6 months.^4-6 Risk of relapse is particularly high for those with high-risk cytogenetic features such as del(17p), del(11q), or complex karyotype; TP53 aberrations; or unmutated immunoglobulin heavy chain variable (IGHV) genes.^1,7 According to Matthew S. Davids, MD, MMSc, of the Dana-Farber Cancer Institute, “This double-refractory population is growing and represents an important unmet need in the disease. These patients have very poor outcomes with the prior treatments that were used.”

This double-refractory population is growing and represents an important unmet need in the disease. These patients have very poor outcomes with the prior treatments that were used. Matthew S. Davids, MD, MMSc

Until recently, few effective treatments existed for patients with double-refractory CLL/SLL. Currently, however, two treatments are approved by the U.S. Food and Drug Administration (FDA) for patients with relapsed/refractory CLL/SLL following at least two lines of prior therapy including a BTK inhibitor and BCL2 inhibitor: the noncovalent BTK inhibitor pirtobrutinib and the CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (liso-cel).^8,9 As discussed below, both treatments are effective but have different mechanisms of action and toxicity profiles; other clinical and patient-specific factors, among others, should also be considered when selecting the most appropriate therapy in this setting. In addition to these approved therapies, other approaches under investigation for the treatment of double-refractory CLL/SLL include next-generation BTK and BCL2 inhibitors, BTK degraders such as proteolysis-targeting chimeras, phosphoinositide 3-kinase inhibitors, novel immunotherapeutics such as bispecfic T-cell engagers, and CAR natural killer (NK) cell therapy.^3,10-12

Pirtobrutinib for Double-Refractory CLL/SLL

Covalent BTK inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib bind covalently and irreversibly to the C481 residue of the BTK protein. Yet all covalent BTK inhibitors are susceptible to C481 resistance mutations, which can result in eventual disease progression. C481 mutations reduce BTK inhibitor binding affinity, contributing to resistance.³ Because all covalent BTK inhibitors share common resistance mechanisms, sequential use of another covalent BTK inhibitors is not recommended for patients who are already resistant to one inhibitor of this class. In contrast to covalent BTK inhibitors, noncovalent BTK inhibitors bind outside the C481 residue and therefore can be effective against such resistance mutations.¹³ Pirtobrutinib is a selective, noncovalent (and therefore reversible) BTK inhibitor that exhibits high selectivity for BTK (> 300 times more selective for BTK vs 98% of other kinases tested) and minimal off-target inhibition, with sustained occupancy of the BTK binding site.^14,15 Its high bioavailability (85.5% after a 200-mg dose) and prolonged half-life (~ 20 hours) result in prolonged BTK inhibition.^16,17 In preclinical studies, pirtobrutinib was shown to inhibit both wild-type and C481-mutant BTK, inhibiting BTK signaling and tumor growth in B-cell lymphoma cell lines and human tumor xenografts.¹⁸

In clinical trials, pirtobrutinib demonstrated efficacy in patients with relapsed/refractory CLL/SLL.¹³ The phase I/II BRUIN trial evaluated pirtobrutinib monotherapy (200 mg once daily) in patients with CLL/SLL who were previously treated with a covalent BTK inhibitor and a BCL2 inhibitor.¹⁹ Patients had received a median of five prior lines of therapy (range = 2–11). Among the 108 enrolled patients, the overall response rate was 72% (all partial responses). Median time to response was 3.7 months, and median duration of response was 12.2 months (95% confidence interval [CI] = 9.3–14.7).⁹ These results led to FDA accelerated approval of pirtobrutinib for the treatment of adult patients with CLL/SLL who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL2 inhibitor.⁹ The phase III randomized confirmatory trial intended to convert this approval to traditional approval is BRUIN CLL-321, which is comparing pirtobrutinib to investigator’s choice of rituximab combined with idelalisib or bendamustine; this trial has reached its target number of progression-free survival events and met its primary endpoint.²⁰ NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) include pirtobrutinib as a recommended treatment option for patients with relapsed/refractory CLL/SLL after prior BTK inhibitor– and venetoclax-based regimens.²¹ “In the double-refractory population,” noted Dr. Davids, “we have seen patients who have had  prolonged benefit from pirtobrutinib.”

In the double-refractory population, we have seen patients who have had prolonged benefit from pirtobrutinib. Matthew S. Davids, MD, MMSc

Continuous BTK inhibitor therapy may lead to cardiovascular toxicities and increase the likelihood of developing resistance to such agents, with subsequent disease progression. In contrast, clinical trials of fixed-duration venetoclax combined with an anti-CD20 monoclonal antibody have shown the potential benefits of time-limited therapy in this setting.²² Similarly, in a cohort of patients in the BRUIN study, fixed-duration pirtobrutinib and venetoclax (PV) or pirtobrutinib, venetoclax, and rituximab (PVR) was evaluated for efficacy and safety in patients with previously treated CLL/SLL, including those who had received a covalent BTK inhibitor.²³ The ongoing phase III BRUIN CLL-322 trial is comparing fixed-duration pirtobrutinib combined with venetoclax/rituximab to venetoclax/rituximab alone in patients with relapsed/refractory CLL/SLL, including those previously treated with a covalent BTK inhibitor.¹³

Lisocabtagene Maraleucel

Liso-cel is an autologous, CD19-directed, 4-1BB costimulated CAR T-cell product, administered at equal target doses of CD8- and CD4-positive CAR-positive T cells. It was previously found to be effective in the treatment of relapsed/refractory lymphomas.^24,25 In the phase I/II TRANSCEND CLL 004 trial, liso-cel demonstrated activity in patients with relapsed/refractory CLL/SLL.^25,26 Liso-cel was administered to patients who had received at least two prior lines of therapy including a BTK inhibitor (median of five lines of prior therapy [range = 2–12]). Nearly all patients were either refractory or intolerant to a BCL2 inhibitor. Liso-cel was administered as a single infusion at one of two dose levels (50 × 10⁶ or 100 × 10⁶ CAR-positive T cells). In the primary analysis, for the 65 patients treated with liso-cel and evaluable for efficacy, the overall response rate was 45%, with a 20% complete response rate. Median time to first response was 1.1 month, and median duration of response was 35.3 months (95% CI = 12.4–not reached). In patients who achieved a complete response, the minimal residual disease (MRD) negativity rate was 100% in peripheral blood and 92.3% in bone marrow.^8,26 These data demonstrate the rapid, deep, and durable responses achieved with liso-cel in heavily pretreated patients with relapsed/refractory CLL/SLL who experience BTK inhibitor progression and venetoclax failure. Results of the TRANSCEND CLL 004 trial led to FDA accelerated approval of liso-cel for treatment of adult patients with relapsed/refractory CLL/SLL who have received at least two prior lines of therapy, including a BTK inhibitor and BCL2 inhibitor.⁸ The NCCN Guidelines® include liso-cel as a recommended treatment option for patients with relapsed/refractory CLL/SLL after prior BTK inhibitor– and venetoclax-based regimens.²¹

It is not yet clear why more patients do not respond to this CAR T-cell therapy. “It seems like to achieve truly a durable response with liso-cel, you do need a complete response,” said Dr. Davids. “What's making patients resistant and why we can't get complete responses in more patients is still not clear.” Mazyar Shadman, MD, MPH, of the Fred Hutchinson Cancer Center, emphasized that the timing of such treatment is key to maximize responses. “If you're considering liso-cel, the most critical point in taking care of a patient in this setting is to take them to CAR T-cell therapy while their disease is still under control.”

If you're considering liso-cel, the most critical point in taking care of a patient in this setting is to take them to CAR T-cell therapy while their disease is still under control. Mazyar Shadman, MD, MPH

To further optimize use of liso-cel and other CAR T-cell therapies for patients with relapsed/refractory CLL/SLL, ongoing studies are exploring various combination regimens, novel targets, and allogeneic “off-the-shelf” CARs.²⁷ For example, the combination of liso-cel and ibrutinib will be assessed in a separate phase I cohort of the TRANSCEND CLL 004 trial since ibrutinib may help restore T-cell function and enhance responses. Other potential approaches include CAR agents targeting CD20 to prevent CD19 antigen escape, and CAR therapy based on NK cells.²⁷

Safety

Awareness, prevention, and effective management of treatment-related adverse events are critical for maintaining and maximizing pirtobrutinib and liso-cel efficacy while minimizing their impact on patient quality of life. In the pirtobrutinib BRUIN trial, the most common (≥ 20%) all-grade adverse events, excluding laboratory events, were fatigue (36%), bruising (36%), cough (33%), musculoskeletal pain (32%), COVID-19 (28%), diarrhea (26%), pneumonia (27%), abdominal pain (25%), dyspnea (22%), hemorrhage (22%), edema (21%), nausea (21%), pyrexia (20%), and headache (20%).⁹ In a safety analysis of patients with CLL/SLL enrolled in the BRUIN trial, dose reductions due to adverse events occurred in 3.6% of patients and permanent discontinuation in 9%.⁹ Pirtobrutinib prescribing information indicates that serious and fatal infections and hemorrhage have occurred, as well as cytopenias (including grade ≥ 3) and hepatotoxicity, including drug-induced liver injury. The prescribing information also report atrial fibrillation or flutter in 3.2% of patients and second primary malignancies in 9% of patients in the full safety population of patients with B-cell malignancies treated with pirtobrutinib.⁹ Pirtobrutinib has a well-studied safety profile. According to Dr. Shadman, “Pirtobrutinib is very specific for BTK and doesn't have a lot of off-target activity for other enzymes, which is associated with fewer side effects, and we see that in the BRUIN clinical trial.”

Pirtobrutinib is very specific for BTK and doesn't have a lot of off-target activity for other enzymes. Mazyar Shadman, MD, MPH

In the liso-cel TRANSCEND CLL 004 trial, the most common (≥ 20%) nonlaboratory adverse events (any grade) were cytokine-release syndrome (83%), encephalopathy (44%), musculoskeletal pain (42%), fatigue (40%), nausea (35%), edema (30%), diarrhea (30%), headache (28%), dyspnea (27%), fever (27%), decreased appetite (27%), constipation (24%), tremor (24%), infection with pathogen unspecified (23%), rash (23%), dizziness (21%), tachycardia (21%), cough (20%), and delirium (20%).⁸ Liso-cel prescribing information notes the risk of infection due to neutropenia and of secondary T-cell malignancies, so careful monitoring during and following CAR T-cell therapy is necessary.⁸ Liso-cel is only available through a Risk Evaluation and Mitigation Strategies (REMS) program due to risk for cytokine-release syndrome (54% of patients; grade ≥ 3, 4%) and neurologic toxicities (31% of patients; grade ≥ 3, 10%).⁸

Clinicians prescribing these therapies should be familiar with the respective prescribing information and with guidelines on the management of toxicities associated with BTK inhibitors as well as CAR T-cell therapies such as liso-cel.^28-31

Considerations in Selection of Therapy for Double-Refractory CLL/SLL

Selection of pirtobrutinib or liso-cel therapy for double-refractory CLL/SLL should be individualized based on the patient’s condition (eg, age, fitness, comorbidities/frailty, tolerance for toxicities) and balance between the potential efficacy and toxicity of each treatment. Other clinical factors that can impact choice of therapy are disease burden, time needed for CAR T-cell therapy referral and manufacturing, and provider knowledge gaps regarding efficacy, patient selection criteria, and adverse event profiles and management.³² Patient-specific factors that may influence decision-making include patient caregiver and social support, transportation to appointments or transplant center, method of administration, and financial burden/insurance coverage.³²

Pirtobrutinib may be appropriate for patients who prefer to take a daily oral agent until progression rather than undergo infusional therapy. It may also be an option for patients who cannot wait for CAR T-cell production due to disease progression, do not wish to undergo lymphodepletion and CAR T-cell therapy, or do not meet standard liso-cel patient selection criteria. Maintaining adherence to oral BTK inhibitors can be challenging for certain individuals, such as older patients and those with comorbidities.⁷ Further study is needed to assess the prevalence and clinical relevance of pirtobrutinib resistance mechanisms.

Liso-cel may be suitable for patients who prefer a limited-duration, potentially curative treatment rather than continuous BTK inhibitor therapy. Compared to pirtobrutinib, liso-cel therapy is associated with greater “upfront” logistical requirements and support system needs, and its significantly higher cost must be weighed against the cost of extended BTK inhibitor treatment. As with other CAR T-cell therapies, patients must be fit enough to undergo lymphodepletion. Some patients may experience disease progression during the liso-cel manufacturing timeframe despite use of interim bridging therapy for disease control.³²

Provider-directed education and clear communication can help patients better understand these complex therapies and aid in the decision-making process, thereby enhancing patient satisfaction and engagement.³³ Awareness of prescribing information recommendations regarding dosing and adverse event management can help clinicians maximize efficacy of the selected therapy, lower treatment-related toxicities, and maintain patient quality of life.