6 Best Ibrutinib Alternatives

Ibrutinib is an innovative new therapy used mostly for B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström's macroglobulinemia. While many patients have been successfully treated with ibrutinib, this treatment may be limited due to side effects, drug interactions, and patient-specific issues. This blog will show the possible alternatives to ibrutinib, providing options for those looking for a different therapy.

 

Challenges and Side Effects

Although ibrutinib is widely used, it has potential limitations. Common side effects include:

• Bleeding complications: ibrutinib affects platelet function, which may result in an increased bleeding risk for patients.

• Cardiac issues: Patients have noted some degree of arrhythmia, such as atrial fibrillation. 

• Infections: Patients may have immunosuppressed or impaired immunologic response, meaning an increased risk of infections. 

• Gastrointestinal complaints: Nausea, diarrhea, and other gastrointestinal complaints are common. 

All the complications, the cost of treatment, and the potential for drug interactions may limit the use of ibrutinib. It is important to consider alternative therapies.

 

Best Ibrutinib Alternatives

There are many alternatives to ibrutinib for the treatment of patients with B-cell malignancies, depending on the type of B-cell malignancy, disease progression, and individual patient factors. Several alternatives are outlined below and some of the most commonly known as alternatives to ibrutinib:

 

Acalbrutinib

Acalbrutinib (a close relative to ibrutinib, as it is an alternative BTK inhibitor) is designed to inhibit BTK with fewer off-target effects. Reducing off-target effects theoretically should lower the related risk of issues like bleeding and cardiac problems, leading to a lower incidence of these side effects. Acalbrutinib is specifically beneficial for patients intolerant to the side effects of ibrutinib. Acalbrutinib has demonstrated significant efficacy in the treatment of:

• Chronic lymphocytic leukemia (CLL)

• Mantle cell lymphoma (MCL)

• Waldenström macroglobulinemia

Evidence indicates that acalbrutinib may have a better safety profile, especially with cardiovascular and bleeding complications, but once again, indications are aligned with having similar use patterns to ibrutinib based on efficacy and safety signals.

 

Idelalisib

Idelalisib is a drug that inhibits phosphoinositide 3-kinase (PI3K) delta and works by inhibition of the PI3K pathway, which is important in B-cell survival and proliferation. Inhibiting this pathway inhibits CLL and other cancers involving B cells, such as follicular lymphoma. 

Idelalisib is mostly used in combination or as an adjunct to other drugs, the most common being rituximab, to improve efficacy. Idelalisib, similar to ibrutinib, can be taken orally, and this is preferred by patients who do not want to receive injections (or IV) for their treatments. Idelalisib does have side effects such as liver toxicity and diarrhea that must be managed by health professionals.

 

Venetoclax

Venetoclax is an inhibitor of B-cell lymphoma-2 (BCL-2), which restores the normal apoptotic process, causing the cancer cells to die. Venetoclax is particularly well established in treating CLL and small lymphocytic lymphoma (SLL), and can be used in combination with rituximab to produce a more potent therapy. Venetoclax works using a completely different mechanism of action than BTK inhibitors like ibrutinib, and will help in patients failed or are intolerant of ibrutinib. 

Venetoclax has been evaluated in the first line and in relapsed/refractory settings. The results have been impressive in patients with specific genetic mutations (i.e., those having 17p deletions). Patients receiving venetoclax may experience side effects, such as low blood counts, nausea, and diarrhea, but it is very well tolerated generally well-tolerated.

 

Rituximab (with or without chemotherapy)

Rituximab is a monoclonal antibody that binds to the CD20 antigen on B cells. It is often used with chemotherapy as a treatment of B-cell malignancies like CLL, non-Hodgkin's lymphoma, and MCL. The goal of rituximab is to deplete B cells, abnormal and normal, by activating the immune system. 

Rituximab can be considered an optimal option for patients who cannot tolerate oral therapies, such as ibrutinib or venetoclax, particularly when combined with other chemotherapy drugs. While rituximab can cause infusion reactions and infections in some patients, these adverse events are usually tolerable.

 

Chemotherapy Regimens

Chemotherapy has been a treatment modality for various B-cell malignancies for many years, and combination chemotherapy regimens like FCR (fludarabine, cyclophosphamide, and rituximab) and BR (bendamustine and rituximab) are frequently used as treatment for CLL and lymphoma. While chemotherapy is still an effective treatment option for many patients, it can place a significant burden on the body, sometimes resulting in myelosuppression, hair loss, or increased risk of infection. 

Chemotherapy should also be considered for patients not eligible for targeted therapies due to comorbidities, drug interactions, or those treated previously have inadequate response.

 

Generic Alternatives to Ibrutinib 

Zanubrutinib (Brukinsa)

Zanubrutinib is a second-generation BTK inhibitor that has proved to be superior to ibrutinib in clinical studies, with a higher efficacy and better safety profile. It achieved a higher overall response rate and a lower rate of atrial fibrillation and bleeding. Zanubrutinib is approved for the treatment of CLL/SLL and MCL. It is an option for patients who are refractory or intolerant to ibrutinib.

 

Pirtobrutinib (Jaypirca)

Pirtobrutinib is a non-covalent BTK inhibitor that reversibly binds to BTK. As a result, the drug remains active against C481S mutated BTK, which is a mutation that confers resistance to the covalent BTK inhibitors, such as ibrutinib. Clinical evidence has established that pirtobrutinib is noninferior to ibrutinib on overall response rate, and has a different safety profile. It is indicated in patients with relapsed or refractory CLL/SLL and MCL who have received at least two prior lines of therapy.

 

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Considerations When Choosing an Alternative

When deciding on an alternative to ibrutinib, the following aspects need to be considered:

• Disease Type and Stage: The type of B-cell malignancy and its stage will drive the course of the therapy.

• Side Effects: The patient’s ability to tolerate the likely side effects will have an important bearing on the treatment decision.

• Comorbidities: Patients with other medical issues (like heart disease and liver disease) may desire alternative therapies that have fewer complications.

• Prior Treatments: The patient’s experience with prior therapies, including ibrutinib, may help identify the safest next line of therapy.

It is important for patients to have a meaningful and honest discussion with their healthcare provider so that the best treatment course is determined based on their individual needs.

 

Final Words

Ibrutinib is an effective treatment for B-cell malignancies; however, it is not appropriate for all patients due to side effects, cost, and possible drug interactions. Luckily, there are many alternatives, including acalbrutinib, idelalisib, venetoclax, rituximab, and chemotherapy. All these alternatives are potential treatment options for patients who cannot tolerate or do not respond to ibrutinib. Each treatment option has its pros and cons, and it is important to tailor treatment to the particular patient to maximize the outcome.

If you or a loved one is considering alternatives to ibrutinib, it is important to discuss with an oncologist which alternative treatment could be best for you as a patient, given your particular medical circumstances.

By knowing the alternatives, patients and providers can make the best decisions possible with respect to managing patients with B-cell malignancies, and improving outcomes and quality of life.