Back Back
Managing CLL/SLL and MCL with BTKis
Current and Novel Approaches to the Management of Patients With CLL/SLL and MCL Using BTK Inhibitors

Released: May 25, 2023

Beth Faiman
Beth Faiman, PhD, MSN, APN-BC, AOCN, BMTCN, FAAN, FAPO
Activity Information

Activity

Progress
1
Course Completed
Continue
Key Takeaways
  • The B-cell receptor pathway is key to the progression and survival of chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma, and its targeting using BTK inhibitors is highly effective.
  • In patients with newly diagnosed CLL/SLL with del(17p) and/or TP53 mutation, a second-generation BTK inhibitor with or without an anti-CD20 monoclonal antibody is highly recommended.
  • A BCL-2 inhibitor may be preferred in patients with interest in pursuing limited duration therapy, but should be avoided in patients with renal disfunction or bulky disease that may put the patient at risk for tumor lysis syndrome.

B-cell lymphomas account for approximately 85% of non-Hodkin lymphomas (NHLs) in the United States. Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) are among the 10 most common types of B-cell lymphomas.

MCL is a fast-growing (aggressive) dystinct subtype of B-cell NHL. MCL accounts for approximately 5% to 8% of NHLs, or about 400 patients each year. MCL is often diagnosed in later stage and most cases involves the gastrointestinal tract. MCL can be associated with excess cyclin D1 and higher than normal levels of lactate dehydrogenase (LDH) and beta-2 macroglobulin (B2M) proteins. It is most commonly diagnosed in elderly men with a median age at diagnosis of 65 years. 

Clinical presentation of MCL can be highly variable, but most patients will present with common symptoms including lymph node swelling or lymphadenopathy. A smaller subset of patients may present with increased white blood counts or a mildly enlarged spleen. 

Chromosomal rearrangement t(11;14), t(q13;q32) and TP53 gene abnormalities can occur in MCL and are often associated with more phenotype and a poor prognosis.

The B-cell receptor (BCR) pathway plays a key role in the growth, proliferation, and survival of normal and malignant B-cells. BTK is an essential enzyme in the BCR signaling pathway and its inhibition can lead to downstream mitigation of cell growth, proliferation, adhesion, migration, and survival of malignant B-cells.

Optimal care of patients with leukemias (CLL/SLL) and lymphomas (MCL) begins with an accurate diagnosis. Patients suspected of having any type of blood malignancy get tested for abnormalities in the blood, initially with complete blood count (CBC) and laboratory chemistries. Abnormalities in the CBC can be the first indicator that there is a problem with the blood or lymphactic system. CLL/SLL often arise from neoplastic cells in the bone marrow, whereas MCL arises from secondary lymphoid tissue (eg, tonsils, lymph nodes, and spleen). 

Current Data for BTK inhibitors in MCL
In the phase III PCYC-1104, the BTK inhibitor ibrutinib was shown to have efficacy in patients with relapsed/refractory MCL who previously received 1 to 5 lines of therapy, and who had adequate organ function (N = 111). This trial included patients who had prior and no prior bortezomib exposure. Patients received ibrutinib at 560 milligrams once daily, and could continue on this treatment until unacceptable toxicity or disease progression. The median progression-free survival (PFS) of patients receiving ibrutinib was 13.0 months, and median overall survival was 22.5 months. The most common adverse events (AEs) with ibrutinib include infection (78%), bleeding and bruising (50%), and cardiac (11%), with atrial fibrillation being of interest. Recently, the second-generation BTK inhibitors zanubrutinib and acalabrutinib have become available and have demonstrated a more favorable safety profile with equivalent efficacy. The manufacturer for ibrutinib has recently removed its indication for use in patients with previously treated MCL.

Acalabrutinib was also shown to have activity in relapsed/refractory MCL. In the phase II ACE-LY-004, acalabrutinib was shown to yield 81% response (40% complete responses in patients with R/R MCL who had good performance status, no cardiovascular disease, and no previous BTK inhibitor) (N = 124). Patients received acalabrutinib 100 mg twice daily until disease progression. The 12-month PFS and overall survival were 67% and 87%, respectively. The AEs of interest of infection (53%), bleeding and bruising (31%), and cardiac (8%) were similar to ibrutinib, but no atrial fibrillation was reported. Of importance, headaches are more common with acalabrutinib but they can be transient and typically get better a few months from starting the drug. Bleeding risk also is a concern, and we should educate patients about managing side effects and to avoid drugs like aspirin for headaches, which may actually increase the risk for bleeding episodes.

Zanubrutinib was shown to have efficacy in relapsed/refractory MCL. The phase II BGB-3111-206 evaluated zanubrutinib in patients with MCL who had 1 or more previous therapies, good performance status, no cardiovascular disease, and no previous BTK inhibitor (N = 86). Patients could receive zanubrutinib at 160 mg twice daily for up to 3 years, until disease progression, or unacceptable toxicity. In this study, patients receiving zanubrutinib achieved an overall response rate of 81% (15% complete response). The 12-month and 15-month PFS were 74% and 72%, respectively.

The safety profile of zanubrutinib is similar to other BTK inhibitors, with infections (34.9%), bleeding and bruising (26%), and hypertension (15%) being the most common AEs of interest. Of note, patients on acalabrutinib did not experience atrial fibrillation/flutter in the BGB-3111-206 trial.

The phase I/II BRUIN trial evaluated the third-generation BTK inhibitor pirtobrutinib in patients with relapsed/refractory MCL who were previously treated with BTK inhibitor and discontinued treatment because of toxicity or disease progression, as well as BTK inhibitor naive disease (N = 101). In this study, patients received pirtobrutinib 200 mg once daily. The overall response rate in this group of patients was encouraging at 51%, with half of them being complete responses. The safety profile for zanubrutinib is similar to that of other BTK inhibitors, yet hypertension and atrial fibrillation/flutter are notably lower.

Current Data for BTK inhibitors in CLL/SLL
A second-generation BTK inhibitor with or without an anti-CD20 monoclonal antibody was found to be superior to fludarabine, cyclophosphamide, and rituximab in patients with newly diagnosed CLL/SLL and del(17p)/TP53 mutation. Fludarabine, cyclophosphamide, and rituximab is no longer a recomended treatment in this setting. Other options include ibrutinib with or without venetoclax, obinutuzumab, or single-agent zanubrutinib.

As a drug class, BTK inhibitors are associated with a similar safety profile in CLL/SLL as in MCL. Most common AEs include cardiac, bleeding/bruising, and infections but the incidence of each of these tends to vary depending on which BTK inhibitor is used. Whereas the rates of neutropenia are equivalent among BTK inhibitors (12%-29%), headaches are more common with acalabrutinib (25%), atrial fibrilation/flutter more frequent with ibrutinib (11%) and the lowest with pirtobrutinib, hypertension more common with zanubrutinib (15%), and any grade bleeding more common with pirtobrutinib (14%).

Selecting a BTK inhibitor vs BCL-2 Inhibitor in CLL/SLL
Treatment with a BTK inhibitor is usually quite easy. It is an oral treatment and can be given indefinitely. We don't need to worry about tumor lysis syndrome (TLS), bulky disease status, or potential preventative hospitalization. However, BTK inhibitors can be associated with cardiac risk depending on which one you select and some patients may not want to be on indefinite therapy.

The BCL2 inhibitor, venetoclax, on the other hand, can be given for a fixed duration but is slightly more challenging to administer. Many centers continue to apply the “ramp-up” dosing of venetoclax to prevent TLS. Some centers have gotten away from preventive hospitalization altogether, particularly if the patient is deemed to be low risk for TLS. However, venetoclax should be avoided in patients with renal dysfunction (eg, CrCl <80 mL/min) and or high tumor burden with splenomegaly because of the potential risk for development of tumor lysis syndrome.

Your Thoughts?
What are your most pressing questions about the use of BTK inhibitors for the management of patients with CLL/SLL or MCL? Join the conversation by answering the poll and posting a comment below.

Continue

Poll

1.

How often do you review the latest clinical trial data supporting the use of novel BTK inhibitors with your patients with CLL/SLL or MCL?

Submit