A kinase inhibitor indicated for the treatment of adults with mantle cell lymphoma who have received at least one prior therapy.
A next generation Bruton’s tyrosine kinase inhibitor.
It is a covalent inhibitor that binds to C481.
Acalabrutinib specifically binds covalently to BTK, thus inhibiting its activity.
It binds to very few kinases other than BTK and therefore has fewer off target effects then Ibrutinib.
Acalabrutinib approved as initial or subsequent therapy for adults with chronic lymphocytic leukemia or small lymphocytic lymphoma.
Acalabrutinib is being developed for the treatment of multiple B-cell blood cancers including CLL, mantle cell lymphoma (MCL), diffuse large B-cell lymphoma, Waldenstrom’s macroglobulinaemia, follicular lymphoma, and other hematologic malignancies.
The interim analyses of 2 phase 3 randomized clinical trials (ELEVATE-TN and ASCEND) compared acalabrutinib with other standard therapies for chronic lymphocytic leukemia indicated progression-free survival was longer with acalabrutinib treatment than with other standard therapies.
A Bruton tyrosine kinase (BTK) inhibitor.
A irreversible BTK inhibitor.
It is a more selective BTK inhibitor than ibrutinib.
The phase 3 ELEVATE-RR trial demonstrated that compared to with ibrutinib (Imbruvica), acalabrutinib (Calquence) met the study’s primary end point of demonstrating non-inferior progression-free survival (PFS) for adults with previously treated, high-risk chronic lymphocytic leukemia (CLL).
Acalabrutinib in CLL had benefit in progressive free survival with patients with a generic features, such as TP53 aberrations, deletions of 17p, or an mutated immunoglobulin heavy chain variable gene.
BTK a major component of B-cell receptor signaling and downstream survival.
Irreversibly binds to be BTK, inhibiting aberrant B-cell receptor signaling and malignant B-cell proliferation, adhesion and survival
Approved on the basis of a phase II ACE-LY-004 trial, in which 81% of patients responded, and 72% of patients who responded maintained response for 12 months.
Adverse events include: headache, diarrhea, arthralgias, bruising, nausea, hypertension, infections, and fatigue.
Serious hemorrhagic events, including fatal events, have occurred.
Overall, bleeding events, including bruising and petechiae of any grade, occurred in approximately 50% of patients with hematological malignancies.
About 3% developed grade 3 hemorrhage or worse.
Only 7% discontinued the drug and only 3% required a dose reduction.
It may further increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies, and patients should be monitored for signs of bleeding.
Consider the benefit-risk of withholding the drug for 3 to 7 days pre- and post-surgery, depending upon the type of surgery and the risk of bleeding.
Associated with a lower rate of hemorrhage and atrial fibrillation than with ibrutinib
Pooled data suggest the drug is associated with atrial fibrillation in 4.4% of cases.
Serious infections of bacterial, viral, or fungal type, including fatal events and opportunistic infections, have occurred.
Infections due to hepatitis B virus (HBV) reactivation and progressive multifocal leukoencephalopathy (PML) have occurred.
Prophylaxis in patients who are at increased risk for opportunistic infections is a consideration.
Lymphocytosis occurred in 315 ofpatients.
Monitoring with complete blood counts monthly during treatment is required as pancytopenia can occur.
Second primary malignancies, including non-skin carcinomas, have occurred in 11% of patients with hematologic malignancies.
The most common associated cancer, 7%, is skin cancer.
Atrial Fibrillation and Flutter occur in 3% of patients.
The most common adverse reactions (20%) of any grade were anemia, thrombocytopenia, headache (39%), neutropenia, diarrhea (31%), fatigue (28%), myalgia (21%), bruising (21%), URI, headache and musculoskeletal pain.
Associated with headaches.
The most common Grade 3 non-hematological adverse reaction was diarrhea (3.2%).
Dosage reductions or discontinuation due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively.
Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients.
Avoid co-administration with a strong CYP3A inhibitor, and if a a strong CYP3A inhibitor is to be used short-term, interruption of the drug is indicated.
When is co-administered with a moderate CYP3A inhibitor, reducing dose to 100 mg once daily.
Strong CYP3A Inducers: avoid co-administration with a strong CYP3A inducer.
If a strong CYP3A inducer cannot be avoided, increasing the dose to 200 mg twice daily is indicated.
If treatment with a gastric acid reducing agent is required, consider using an H2-receptor antagonist or an antacid.
It should be taken 2 hours before taking an H2-receptor antagonist.
Separate dosing with an antacid by at least 2 hours.
Avoid co-administration with proton pump inhibitors.
Acalabrutinib 100 mg capsules BID.
A Bruton tyrosine kinase (BTK) inhibitor indicated for the treatment of adult patients with mantle cell lymphoma who have received at least one prior therapy.
Has a demonstrated an overall response rate of 80%.
In a Phase 2 clinical trial of 124 patients with relapsed/refractory MCL, overall response rate 81%, complete response rate was 49%, with median duration of response not reached at a median follow-up of 15.2 months.
As a single agent or in combination with obinutuzumab has a significant improved progression free survival compared with Obintuzumab plus chlorambucil in treatment naïve patients with CLL- ELEVATE-TN trial.
The most common adverse reactions are: anemia, thrombocytopenia, headache, neutropenia, diarrhea, fatigue, myalgia, and bruising.
Most patients completed therapy at the recommended dose; adverse events caused dose reduction in 1.6% of patients and discontinuation in 6.5% of patients.
One 100-mg capsule is taken orally approximately every 12 hours, until disease progression or unacceptable toxicity.
Serious hemorrhagic events, including fatal events, have occurred.
Grade 3 or higher bleeding events, including gastrointestinal, intracranial, and epistaxis, have been reported in 2% of patients.
Overall, bleeding events, including bruising and petechiae of any grade, occurred in approximately 50% of patients with hematological malignancies.
May further increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies, and patients should be monitored for signs of bleeding.
Consider withholding the drug for 3 to 7 days pre- and post-surgery, depending upon the type of surgery and the risk of bleeding.
Serious infections, including fatal events and opportunistic infections, have occurred in the combined safety, with Grade 3 or higher infections occurring in 18% of these patients.
The most frequently reported Grade 3 or 4 infection was pneumonia.
Infections due to hepatitis B virus (HBV) reactivation and progressive multifocal leukoencephalopathy (PML) have occurred.
In patients with hematologic malignancies, patients experience Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (11%), and thrombocytopenia (8%).
Complete blood counts are monitored monthly during treatment.
Second primary malignancies, including non-skin carcinomas, have occurred in 11% of patients with hematologic malignancies.
The most frequent second primary malignancy was skin cancer, reported in 7% of patients.
Patients should be protected from sun exposure.
Atrial fibrillation and atrial flutter of any grade occurred in 3% of patients, and Grade 3 in 1% of patients.
Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients.
Avoid co-administration with a strong CYP3A inhibitor.
When co-administered with a moderate CYP3A inhibitor, reduce dose to 100 mg once daily.
Avoid co-administration with a strong CYP3A inducer.
If a strong CYP3A inducer cannot be avoided, increase the dose to 200 mg twice daily.
If treatment with a gastric acid reducing agent is required, using an H2-receptor antagonist or an antacid is preferred.
Avoid co-administration with proton pump inhibitors, due to the long-lasting effect of proton pump inhibitors.
Daily dose is two 100 mg capsules.