Chronic lymphocytic leukemia (CLL) is a malignant disorder of mature B cells. Conventional chemoimmunotherapy is commonly used to treat CLL patients; however, a lot of targeted therapies have been introduced in the management of CLL due to a better understanding of the molecular mechanisms that govern CLL cells’ survival. These targeted therapies can be broadly classified into several classes such as SYK inhibitors, PI3K inhibitors, BCL-2 inhibitors, BTK inhibitors, and others. Among these classes of therapeutic agents, BTK and BCL-2 inhibitors are the most commonly used and well-studied agents.
Targets in CLL treatment include Bruton’s tyrosine kinase (BTK), a crucial component involved in B-cell receptor signaling, and B-cell lymphoma 2 (BCL-2), a potent anti-apoptotic protein. Their mechanistic differentiation, including that related to Jaypirca versus Brukinsa, is crucial for discharging appropriate therapeutic options for individual patients.
B-Cell Receptor Signaling in CLL
BCR signaling in CLL is an essential pathway in the normal development of B-cells, including proliferation, migration, and survival of mature B cells. Importantly, CLL cells are dependent on BCR signaling for their survival and their expansion within the tumor mass. As such, this pathway is a target for therapeutic intervention. Moreover, the dependence on BCR signaling of CLL cells constitutes a rationale for the development of targeted drugs.
The BCR needs to be constantly activated for CLL cells’ survival, and the downstream signaling involves a number of proteins, including BTK. Inhibiting BTK disrupts signaling for CLL cells’ survival and affects interactions with the tumor microenvironment.
CLL cells require BCR signaling for their survival and proliferation. Inhibiting key molecules involved in BCR signaling, such as BTK, can block critical survival pathways, leading to the death of the leukemic cells. Additionally, these agents can also inhibit key interactions between the malignant cells and their tumor microenvironment.
BTK as a Therapeutic Target
BTK, or Bruton’s tyrosine kinase, is a cytoplasmic tyrosine kinase that acts downstream of the B-cell receptor. Inhibiting the enzyme function of BTK in CLL leads to anti-tumor activity and also has profound effects on CLL cells and their interaction with the microenvironment of tumor cells and stroma.
Inhibitors of BTK can be categorized broadly into covalent (irreversible) inhibitors of BTK such as Zanubrutinib and non-covalent (reversible) inhibitors of BTK such as Pirtobrutinib. Covalent BTK inhibitors react with cysteine residues within the active site of BTK and form a permanent bond to that BTK protein. Non-covalent (or reversible) inhibitors of BTK bind BTK in a reversible fashion and allow BTK to return to its pre-inhibitor conformation between drug administrations.
Different mechanisms of BTK inhibition have been developed to treat CLL patients. Since alterations in the BTK protein may influence the activity of the compounds mentioned, they represent additional treatment options that should be evaluated by healthcare professionals, especially in heavily pre-treated patients with CLL.
Brukinsa: Covalent BTK Inhibition
Brukinsa, also known as zanubrutinib, is a covalent BTK inhibitor by design. This medication forms covalent bonds with cysteine residues within the active sites of BTK and related proteins, resulting in long-term inhibition of BTK-mediated signaling.
Brukinsa (zanubrutinib) is a covalent BTK inhibitor that binds to the enzyme’s active site via covalent attachment to a cysteine residue to produce sustained inhibition of BTK signaling. By inhibiting BTK, zanubrutinib blocks key downstream signaling events that drive the proliferation, adhesion, and survival of the malignant B-cells in CLL. Importantly, Brukinsa is a BTK inhibitor that has demonstrated selective BTK inhibition in clinical and preclinical studies with minimal activity towards other kinases.
Molecular changes occurring in the BTK binding site area affect covalent inhibitors more than others and thus may confer resistance. There are BTK C481 residue mutations described to confer resistance to covalent BTK inhibitors.
Jaypirca: Non-Covalent BTK Inhibition
Jaypirca (pirtobrutinib) is a highly selective, non-covalent BTK inhibitor. Unlike Brukinsa, Jaypirca does not covalently bind BTK. Instead, Jaypirca may inhibit both wild-type BTK and BTK mutations in a reversible manner. Treatment with this agent provides an alternative method of targeting BCR signaling in CLL patients who have been previously treated with covalent BTK inhibitors and have relapsed due to the development of resistance.
This drug’s ability to inhibit BTK with C481 mutations makes it useful as a treatment after a patient has relapsed on a covalent BTK inhibitor due to the emergence of C481 mutations in the BTK gene. However, it is not indicated for use after relapse on a non-covalent BTK inhibitor such as Jaypirca.
Non-covalent methods to inhibit BCR signaling by targeting BTK in previously treated CLL patients with covalent BTK inhibitor-resistant disease are also becoming available. Here, these new therapeutic approaches for CLL treatment and their clinical application to treatment decision-making can be considered in the context of currently approved indications.
Jaypirca vs Brukinsa: Mechanistic Differences
In this review, the major difference between Jaypirca and Brukinsa is that Brukinsa is a covalent (irreversible) BTK inhibitor, while Jaypirca is a non-covalent (reversible) BTK inhibitor.
The design of these drugs to form covalent or non-covalent interactions with BTK and other substrates and their subsequent actions as irreversible or reversible inhibitors are critical in determining how the drugs may function in the context of several acquired BTK mutations.
Just because both Zanubrutinib (Brukinsa) and Pirtobrutinib (Jaypirca) inhibit BTK does not mean they are interchangeable. Their selectivity and covalency or non-covalency have created different development pathways. The approval status of each drug, its indication(s), and its use after prior BTK inhibition are all factors that the treating physician must consider.
BCL-2 Inhibition in CLL
Secondly, CLL cells are often dependent on BCL-2 mediated survival pathways. The BCL-2 protein is an anti-apoptotic protein that inhibits apoptosis or programmed cell death. There are several members of the BCL-2 family, and many of them are anti-apoptotic (inhibiting cell death), whereas a few of them are pro-apoptotic (promoting cell death).
In CLL, anti-apoptotic BCL-2 proteins (in particular BCL-2, BCL-xL and BCL-w) protect tumor cells from programmed cell death (apoptosis). In a large fraction of cases, BCL-2 is involved in the pathogenesis of CLL and is even expressed at higher levels in malignant cells compared to normal B cells. Venetoclax specifically inhibits BCL-2 (but not the related anti-apoptotic BCL-2 family members BCL-xL and BCL-w), thereby reactivating apoptosis in cancer cells which reliant on BCL-2 for their survival.
As noted above, BTK and BCL-2 inhibition of B cell malignancies act through distinct biological mechanisms. Thus, combinations and treatment sequences of these therapeutic classes are of increasing interest.
Anti-CD20 Monoclonal Antibodies
The use of CD20 targeted therapy represents another major mechanism of targeted therapy in the management of CLL. CD20 is a cell surface protein found on B cells, and treatment with anti-CD20 monoclonal antibodies induces an immune-mediated cell death of the targeted cells.
Anti-CD20 monoclonal antibodies, including rituximab, in combination with other agents like chemo or targeted therapies, are used in the management of CLL and other lymphoid malignancies. The approach to treatment with anti-CD20 monoclonal antibodies is distinct from both BTK and BCL-2 inhibitors given that the former targets an external B-cell antigen (i.e., CD20), compared to the intracellular, signaling, or anti-apoptotic proteins that are targeted by the latter.
Mechanisms of Treatment Resistance
While targeted therapies have many advantages, such as increased efficacy and reduced side effect profiles, resistance can develop. This is particularly true for BTK inhibitors that form covalent interactions with the enzyme. Such covalent BTK inhibitors may be impaired by certain BTK mutations, especially those affecting the C481 site of the kinase. Changes in downstream signaling molecules can also impede the function of these targeted therapies.
Non-covalent inhibitors like Jaypirca (pirtobrutinib) may be affected by different resistance-associated BTK mutations to the treatment. The same also holds for venetoclax and other BCL-2 inhibitors. There are various molecular changes in leukemic cells leading to a reduced dependence on the anti-apoptotic protein BCL-2 or even to a reduced sensitivity to the respective inhibition. This is increasingly important to consider in the treatment of CLL and for the identification of subsequent therapy for patients who have relapsed on previous therapy.
Translating Mechanism Into Clinical Decisions
The mechanism of action of a treatment provides only part of the information needed to make treatment decisions; the indication for the treatment, the patient’s history, the molecular characteristics of the patient’s CLL, the patient’s comorbidities, the medications that the patient is taking concomitantly, the toxicities of the treatment, and the patient’s preferences for treatment are also important considerations in the management of the patient with CLL.
This approach to CLL therapy will continue to grow, focusing on a variety of targeted therapies to deliver the most effective sequence of treatment to manage CLL resistant to prior therapies.
Key Takeaways
Targeted therapies are among the treatment approaches used to manage CLL. As with many other malignancies, there are different ways to inhibit BTK and its downstream pathways, including covalent and non-covalent inhibitors of BCR signaling, as well as BCL-2 inhibition to cause apoptosis and anti-CD20 antibodies to destroy B-cells.
Differences in the mechanism of action between treatment approaches for CLL can facilitate the selection of the appropriate agent or regimen for a particular patient. Understanding the mechanism of action and causes of resistance to treatments can enable healthcare professionals in treatment selection.
Disclaimer: The information provided in this article is intended for educational purposes only and should not be interpreted as medical advice, a clinical guideline, or a recommendation for any specific treatment.
