What is the mechanism of action of Ibrutinib (Imbruvica)?

From the Guidelines

Ibrutinib is recommended as a first-line treatment for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), particularly for those with del(17p) or other high-risk features, due to its ability to induce durable responses and improve overall survival, as demonstrated in recent studies 1.

Key Points

• Ibrutinib is an oral medication that works by blocking Bruton's tyrosine kinase (BTK), an enzyme that helps abnormal B cells survive and multiply.
• The typical dosage is 420 mg (three 140 mg capsules) taken once daily for CLL/SLL, though dosing may vary by condition.
• Common side effects include diarrhea, fatigue, muscle pain, bruising, and increased risk of bleeding.
• Patients should take ibrutinib at approximately the same time each day with water, and missed doses should be taken as soon as possible on the same day.
• Important precautions include avoiding grapefruit products and certain medications that may interact with ibrutinib.
• Regular blood tests are necessary to monitor for side effects, and patients should immediately report unusual bleeding, fever, or signs of infection to their healthcare provider.

Efficacy and Safety

• A phase III randomized study (RESONATE) demonstrated that ibrutinib significantly improved overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) compared with ofatumumab in patients with relapsed/refractory CLL/SLL 1.
• The final analysis of this study (up to 6-year follow-up) confirmed that ibrutinib significantly improved ORR, PFS, and OS compared with ofatumumab, with a median PFS of 44 months and an estimated 5-year PFS rate of 40% 1.
• Grade 3 atrial fibrillation and hypertension occurred in 9% and 6% of patients, respectively, and the incidence of most grade 3 adverse events decreased with follow-up 1.

Special Considerations

• Ibrutinib can cause early mobilization of lymphocytes into the blood, which should not be mistaken for progressive disease, and therapy should be continued unless there are clinical consequences such as leukostasis 1.
• Slow or incomplete resolution of lymphocytosis does not appear to impact outcome as measured by PFS, and patients should be monitored regularly for side effects and response to treatment 1.

From the FDA Drug Label

3)]. Patients with cGVHD Avoid use of IMBRUVICA in patients with total bilirubin level > 3 x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome). Reduce recommended dose when administering IMBRUVICA to patients with total bilirubin level > 1.5 to 3 x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome) [see Dosage and Administration (2.4)]. 12. 1 Mechanism of Action Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK). 12. 3 Pharmacokinetics Ibrutinib exposure increases with doses up to 840 mg (2 times the maximum approved recommended dosage) in patients with B-cell malignancies.

Ibrutinib Mechanism and Use: Ibrutinib is a kinase inhibitor that works by inhibiting Bruton’s tyrosine kinase (BTK), a signaling molecule involved in B-cell antigen receptor and cytokine receptor pathways. It is used to treat certain B-cell malignancies.

• Key Points:
  • Ibrutinib is contraindicated in patients with total bilirubin level > 3 x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome).
  • The recommended dose should be reduced in patients with total bilirubin level > 1.5 to 3 x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome) 2.

From the Research

Ibrutinib Mechanism and Efficacy

• Ibrutinib is a first-in-class oral inhibitor of Bruton tyrosine kinase (BTK) approved for treatment of relapsed chronic lymphocytic leukemia (CLL) 3, 4.
• It blocks downstream signaling of the B-cell receptor, disrupting stromal microenvironment interactions and B-cell cytokine signaling 3.
• BTK inhibition has been shown to be effective in relapsed or refractory CLL, with a high overall response rate observed in clinical trials 3, 4.

Clinical Trials and Outcomes

• A Phase III study evaluated ibrutinib versus ofatumumab in relapsed or refractory CLL, with a primary endpoint of progression-free survival (PFS) 3.
• Ibrutinib-treated individuals achieved a partial response or partial response with lymphocytosis in 63% of cases, as determined by independent assessments 3.
• Overall, ibrutinib reduced the rate of mortality by 57% 3.
• In patients with mantle cell lymphoma (MCL), ibrutinib induced a high overall response rate in a phase II study 4.

Safety and Tolerability

• Ibrutinib has been shown to have an acceptable tolerability profile, with <10% of patients discontinuing treatment due to adverse events 4.
• Major hemorrhage was reported in 2 (1%) patients treated with ibrutinib, and a total of 8 (4%) patients discontinued treatment due to toxicity or adverse reactions 3.
• Ibrutinib is well tolerated, with manageable, low-grade toxicities compared to traditional cytotoxic agents 5.

Indications and Approvals

• Ibrutinib is indicated for the treatment of patients with relapsed/refractory MCL or CLL, and for the treatment of patients with CLL and a chromosome 17 deletion (del 17p) or TP53 mutation 4.
• It has been approved in the USA for the treatment of MCL in previously treated patients, and applications have been filed in the EU seeking regulatory approval in this indication 6.
• Ibrutinib has also been granted accelerated approval for patients with CLL who have received at least one prior therapy 7.