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BTKi in CLL/SLL and MCL
BTK Inhibitors in CLL/SLL and MCL: The Latest Guidance and Evidence for the Clinic

Released: December 14, 2023

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Key Takeaways
  • For patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with or without del(17p)/TP53 mutations experiencing first relapse after venetoclax-based therapy or chemoimmunotherapy, the Bruton’s tyrosine kinase inhibitors (BTKi) acalabrutinib and zanubrutinib are preferred treatments.
  • In patients with CLL/SLL who relapsed after ≥2 systemic therapies, including previous BTKi–based regimens and a BCL2-inhibitor, third-generation BTKi pirtobrutinib is now available.
  • A second-generation BTKi may be considered as second-line treatment for patients with mantle cell lymphoma and disease progression after initial chemotherapy; closely monitor for bruising and bleeding with the use of both covalent and noncovalent BTKi because of potential for severe bleeding.

Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and mantle cell lymphoma (MCL) are associated with oncogenic activation of Bruton’s tyrosine kinase (BTK) for which clinical trials using BTK inhibitors (BTKi) have shown improved patient outcomes and prolonged survival.

Indications for Covalent BTKi in CLL/SLL and Relapsed/Refractory (R/R) MCL
FDA-approved BTKi are available for both CLL/SLL and MCL. Ibrutinib, a first-generation BTKi, is approved for CLL/SLL at a dose of 420 mg daily. Acalabrutinib is a more selective, second-generation BTKi that is approved for use in both CLL/SLL and MCL. Acalabrutinib is dosed at 100 mg twice daily (every 12 hours) in both CLL/SLL and MCL. Zanubrutinib is another second-generation BTKi indicated for both CLL/SLL and MCL with twice daily (160 mg) or once daily (320 mg) dosing schedules.

When considering treatment for patients with newly diagnosed CLL, factors including the del(17p)/TP53 status, IGHV mutation status, patient fitness, comedications, and patient preference should be incorporated into the decision. Patient comorbidities are also important for decisions involving BTKi treatment choice including history of cardiac arrhythmias, hypertension, susceptibility to infections, platelet clotting function, and anticoagulation comedication. High-grade bleeding is a concern with all BTKi.

Evidence for BTKi in CLL/SLL
Extended follow-up has shown durable disease control with all 3 covalent BTKi. The phase II NHLBI of ibrutinib as first-line therapy in patients with CLL with del(17p) showed a 6-year overall survival (OS) of 79%. The phase III ELEVATE-TN trial 5-year update of acalabrutinib ±obinutuzumab in patients with del(17p) and/or mutated TP53 CLL showed a consistent progression-free survival (PFS) benefit with addition of acalabrutinib. The phase III SEQUOIA trial of zanubrutinib in a similar population showed a 24-month PFS of 88.9%.

Two key studies of BTKi in previously treated CLL/SLL are ELEVATE-RR and ALPINE. The phase III ELEVATE-RR trial compared acalabrutinib vs ibrutinib in previously treated CLL. This is an interesting study because a head-to-head BTKi comparison is rare. The ELEVATE-RR study showed no statistical difference in the hazard ratio for PFS between groups (HR: 1.00); however, in the safety analysis according to age and prior lines of therapy, patients in the ibrutinib arm had higher incidence of atrial fibrillation and hypertension when compared to acalabrutinib.

The phase III ALPINE study assessed zanubrutinib vs ibrutinib for previously treated CLL and found a 24-month PFS benefit with zanubrutinib vs ibrutinib (79.5% vs 67.3; HR: 0.65; 2-sided P = .0024). Analyses of the del(17p) or the TP53 populations also showed improved PFS at 24 months with zanubrutinib vs ibrutinib. (77.6% vs 55.7; HR: 0.52; 2-sided P = .0024).

Based on these data, single-agent acalabrutinib or zanubrutinib are the preferred BTKi after first CLL/SLL relapse with or without del(17p)/TP53 mutations after venetoclax-based therapy or chemoimmunotherapy.

Acquired BTKi Resistance in R/R CLL/SLL and MCL
Despite the progress with first- and second-generation BTKi, patients with R/R CLL/SLL or MCL can experience disease relapse. Ibrutinib, acalabrutinib, and zanubrutinib are all covalent BTKi, and unfortunately, BTK may acquire resistance mutations which block covalent BTKi binding and reduce BTKi efficacy. Mutations in BTK protein can occur at the cysteine 481 (or BTKC481) and often take the form of a cysteine to serine substitution mutations (or BTKC481S) following treatment with a covalent BTKi. It is important to note that most BTK mutations are C481S mutations, but others may affect the tyrosine kinase catalytic domain.

The phase I/II BRUIN study evaluated pirtobrutinib, a third-generation, noncovalent, reversible BTKi in patients with R/R CLL and R/R MCL. The results from that study in the R/R MCL cohort show that pirtobrutinib yields an ORR of 56.7% (CR: 18%) despite previous treatment with a distinct BTKi. The safety profile with pirtobrutinib (in all treated patients, including CLL) is manageable, with infections (17.6%) and neutropenia (19.7%) being the most common grade 3 treatment-emergent adverse events. Pirtobrutinib received FDA approval in January 2023 for the treatment of adults with R/R MCL after at least 2 previous lines of therapy including a BTKi. Pirtobrutinib is dosed at 200 mg once daily in patients with MCL. Other noncovalent BTKi that are in development and not yet FDA approved include nemtabrutinib, vecabrutinib, and fenebrutinib—with nemtabrutinib being farthest in development to date. The investigational, noncovalent BTKi, nemtabrutinib has also demonstrated remarkable and durable responses (ORR: 56%) in a single arm phase I/II trial in patients with BTK C481S-mutated CLL.

Current clinical practice guidelines recommend the second-generation BTKi acalabrutinib or zanubrutinib as second-line treatment, and the third-generation noncovalent BTKi pirtobrutinib for patients with MCL who progress after initial chemotherapy or with C481S-mutated BTK. Ibrutinib is no longer recommended as treatment in MCL. On December 1, 2023, the third-generation BTKi pirtobrutinib received FDA approval for adults with CLL/SLL who have received at least 2 previous lines of therapy, including a BTKi and a BCL-2 inhibitor.

Identifying, Mitigating, and Managing Adverse Events With BTKi
In practice, it is important to recognize the safety signals associated with the different BTKi and learn to mitigate and manage potential adverse events. BTKi should be held for grade 3 neutropenia with infection or fever, or grade 4 cytopenia. Prophylaxis should be considered in patients at an increased risk for opportunistic infections. For cardiac arrhythmias, the incidence of atrial fibrillation is highest with ibrutinib, with 11% in MCL and 5% in CLL, with lower rates reported for acalabrutinib (0% in MCL and 3% in CLL), and zanubrutinib (2% in all evaluable patients). Closely monitor patients for bruising and bleeding with all BTKi because of the potentially serious or life-threatening bleeding, particularly for any patient requiring anticoagulation with warfarin, or other oral anticoagulants.

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