Acalabrutinib is an oral inhibitor of Bruton’s tyrosine kinase that is used in the therapy of B cell malignancies including refractory mantle cell lymphoma and chronic lymphocytic leukemia. Acalabrutinib has been associated with mild-to-moderate serum enzyme elevations during therapy but has not been linked to instances of idiosyncratic acute liver injury, although it has been associated with cases of reactivation of hepatitis B which can be severe and even fatal.
Acalabrutinib is an orally available inhibitor of Bruton’s tyrosine kinase (BTK) with potential antineoplastic activity. Upon administration, acalabrutinib inhibits the activity of BTK and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents both B-cell activation and BTK-mediated activation of downstream survival pathways. This leads to an inhibition of the growth of malignant B cells that overexpress BTK. BTK, a member of the src-related BTK/Tec family of cytoplasmic tyrosine kinases, is overexpressed in B-cell malignancies; it plays an important role in B lymphocyte development, activation, signaling, proliferation, and survival.
Acalabrutinib is a member of the class of imidazopyrazines that is imidazo[1,5-a]pyrazine substituted by 4-(pyridine-2-ylcarbamoyl)phenyl, (2S)-1-(but-2-ynoyl)pyrrolidines-2-yl, and amino groups at positions 1, 3 and 8, respectively. It is an irreversible second-generation Bruton’s tyrosine kinase (BTK) inhibitor that is approved by the FDA for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. It has a role as an EC 18.104.22.168 (non-specific protein-tyrosine kinase) inhibitor, an antineoplastic agent, and an apoptosis inducer. It is a secondary carboxamide, a member of benzamides, a member of pyridines, an aromatic amine, a pyrrolidinecarboxamide, an imidazopyridine, a none, and a tertiary carboxamide.
Mechanism of Action
Mantle Cell Lymphoma (MCL) is a rare yet aggressive type of B-cell non-Hodgkin lymphoma (NHL) with a poor prognosis. Subsequently, relapse is common in MCL patients and ultimately represents disease progression. Lymphoma occurs when immune system lymphocytes grow and multiply uncontrollably. Such cancerous lymphocytes may travel to many parts of the body, including the lymph nodes, spleen, bone marrow, blood, and other organs where they can multiply and form a mass(es) called a tumor. One of the main kinds of lymphocytes that can develop into cancerous lymphomas is the body’s own B-lymphocytes (B-cells). Bruton Tyrosine Kinase (BTK) is a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways. Such BTK signaling causes the activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. Acalabrutinib is a small-molecule inhibitor of BTK. Both acalabrutinib and its active metabolite, ACP-5862, act to form a covalent bond with a cysteine residue (Cys481) in the BTK active site, leading to the inhibition of BTK enzymatic activity. As a result, acalabrutinib inhibits BTK-mediated activation of downstream signaling proteins CD86 and CD69, which ultimately inhibits malignant B-cell proliferation and survival Whereas ibrutinib is typically recognized as the first-in-class BTK inhibitor, acalabrutinib is considered a second generation BTK inhibitor primarily because it demonstrates higher selectivity and inhibition of the targeted activity of BTK while having a much greater IC50 or otherwise virtually no inhibition on the kinase activities of ITK, EGFR, ERBB2, ERBB4, JAK3, BLK, FGR, FYN, HCK, LCK, LYN, SRC, and YES1. In effect, acalabrutinib was rationally designed to be more potent and selective than ibrutinib, all the while demonstrating fewer adverse effects – in theory – because of the drug’s minimized off-target effects.
- Acalabrutinib is currently indicated for the treatment of adult patients with Mantle Cell Lymphoma (MCL) who have received at least one prior therapy. It has also been recently approved for chronic lymphocytic leukemia and small lymphocytic lymphoma.
- Calquence as monotherapy or in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukemia (CLL).
- Calquence as monotherapy is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.
- Acalabrutinib is an oral inhibitor of Bruton’s tyrosine kinase that is used in the therapy of B cell malignancies including refractory mantle cell lymphoma and chronic lymphocytic leukemia.
- Acalabrutinib is approved to treat Chronic lymphocytic leukemia or small lymphocytic lymphoma in adults. Mantle cell lymphoma in adults who have received at least one other type of treatment.
- Chronic Lymphocytic Leukemia (CLL)
- Mantle Cell Lymphoma (MCL)
- Small Lymphocytic Lymphoma
Use in Cancer
Acalabrutinib is approved to treat:
- Chronic lymphocytic leukemia or small lymphocytic lymphoma in adults.
- Mantle cell lymphoma in adults who have received at least one other type of treatment.¹
¹This use is approved under FDA’s Accelerated Approval Program. As a condition of approval, a confirmatory trial(s) must show that acalabrutinib provides a clinical benefit in these patients.
Acalabrutinib is also being studied in the treatment of other types of cancer.
- Safety and efficacy have not been established in patients younger than 18 years.
- a bad infection
- an increased risk of bleeding
- decreased blood platelets
- low levels of a type of white blood cell called neutrophils
- atrial fibrillation
- a patient who is producing milk and breastfeeding
- Anticoagulant therapy, bleeding, dental work, intracranial bleeding, surgery.
- Anemia, neutropenia, thrombocytopenia.
- Fungal infection, hepatitis B exacerbation, infection, progressive multifocal leukoencephalopathy, viral infection.
- New primary malignancy, sunlight (UV) exposure.
Strengths: 100 mg
- 100 mg orally every 12 hours
- Start treatment at cycle 1 (each cycle is 28 days) when use concomitantly with obinutuzumab.
- Start obinutuzumab at Cycle 2 for a total of 6 cycles and refer to the obinutuzumab prescribing information for recommended dosing; administer this drug prior to obinutuzumab when given on the same day.
- Treatment should be continued until the disease progresses or has unacceptable toxicity.
- As monotherapy for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy
- As monotherapy or in combination with obinutuzumab for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)
RECOMMENDED DOSE ADJUSTMENTS FOR ADVERSE REACTIONS:
Grade 3 or greater nonhematologic toxicities, Grade 3 thrombocytopenia with bleeding, Grade 4 thrombocytopenia, or Grade 4 neutropenia lasting longer than 7 days:
- First and second occurrence: Temporarily interrupt this drug; when toxicity has resolved to Grade 1 or baseline, this drug may be resumed at 100 mg orally 2 times a day
- Third occurrence: Temporarily interrupt this drug; when toxicity has resolved to Grade 1 or baseline, this drug may be resumed at 100 mg orally once daily
- Fourth occurrence: Discontinue this drug
CONCOMITANT USE WITH CYP450 3A INDUCERS OR INHIBITORS:
- Strong CYP450 3A inhibitor: Avoid concomitant use; if the inhibitor will be used short-term (e.g., anti-infectives for up to 7 days), interrupt this drug
- Moderate CYP450 3A inhibitor: 100 mg orally once daily
- Strong CYP450 3A inducer: Avoid concomitant use. If these inducers cannot be avoided, increase the dose to 200 mg approximately every 12 hours
CONCOMITANT USE WITH GASTRIC ACID-REDUCING AGENTS:
- Proton pump inhibitors: Avoid concomitant use
- H2 receptor antagonist: Administer this drug 2 hours before or 10 hours after taking an H2-receptor antagonist
- Antacid: Separate dosing by at least 2 hours
The Most Common
- abdominal pain
- light bruising or small red or purple spots on skin
- joint or muscle pain
- extreme tiredness
- fever, sore throat, chills, or other signs of infection
- cough, shortness of breath, chest pain when you breathe or cough, fever
- fast or irregular heartbeat, palpitations, feeling lightheaded or dizzy, fainting, shortness of breath, chest pain
- unusual or severe bleeding or bruising
- blood in your stools or black, tarry stools; pink or brown urine; vomiting blood or coffee-ground vomit; coughing up blood
- feeling dizzy, weak, or confused; changes in speech; a headache that lasts a long time
- arm, leg, and back pain
- decreased appetite
- mouth sores
- skin rash or redness
- stomach pain or cramps
- tingling, pain, or numbness in the hands, legs, or feet
- trouble sleeping
- unsteadiness, causing falls
- watery eyes
- unusual bleeding (nose, mouth, vagina, or rectum), or any bleeding that will not stop;
- heart rhythm problems–chest pain, shortness of breath, pounding heartbeats or fluttering in your chest, feeling light-headed;
- signs of a serious brain infection–any change in your mental state, decreased vision, weakness on one side of your body, or problems with walking (may start gradually and get worse quickly).
- memory loss
- new cancers (skin or other)
- rapid, pounding heartbeat
- signs of anemia (low red blood cells; e.g., dizziness, pale skin, unusual tiredness or weakness, shortness of breath)
- signs of clotting problems (e.g., unusual nosebleeds, bruising, blood in urine, coughing blood, bleeding gums, cuts that don’t stop bleeding)
- signs of infection (symptoms may include fever or chills, severe diarrhea, shortness of breath, prolonged dizziness, headache, stiff neck, weight loss, or listlessness)
- symptoms of irregular heartbeat (e.g., chest pain, dizziness, confusion, rapid, pounding heartbeat, shortness of breath)
- symptoms of low blood pressure (e.g., fainting, dizziness, lightheadedness, blurred vision, nausea)
- symptoms of pneumonia (e.g., cough with or without mucus, fever, chills, difficult and painful breathing, shortness of breath when climbing stairs)
- signs of bleeding in the stomach (e.g., bloody, black, or tarry stools, spitting up of blood, vomiting blood or material that looks like coffee grounds)
There may be an interaction between acalabrutinib and any of the following:
- antacids (e.g., aluminum hydroxide, calcium carbonate, magnesium hydroxide)
- anticancer medications (e.g., cladribine, irinotecan)
- anticoagulants (e.g. apixaban, dabigatran, edoxaban, rivaroxaban, warfarin)
- “azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
- calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
- grapefruit juice
- H2 antagonists (e.g., famotidine, ranitidine)
- HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs; e.g., efavirenz, etravirine, nevirapine)
- HIV protease inhibitors (e.g., atazanavir, indinavir, ritonavir, saquinavir)
- macrolide antibiotics (e.g., clarithromycin, erythromycin)
- protein kinase inhibitors (e.g., crizotinib, dabrafenib, idelalisib, imatinib, palbociclib,)
- proton pump inhibitors (e.g., lansoprazole, omeprazole)
- St. John’s wort
Pregnancy And Lactation
US FDA pregnancy category Not Assigned
This medication should not be used during pregnancy. If you become pregnant while taking this medication, contact your doctor immediately.
No information is available on the clinical use of acalabrutinib during breastfeeding. Because acalabrutinib is over 97% bound to plasma proteins, and the half-life of the drug and metabolite are less than 7 hours, the amount in milk is likely to be low. However, the protein binding of the active metabolite is not known and the manufacturer recommends that breastfeeding be discontinued during acalabrutinib therapy and for at least 2 weeks after the final dose.
How should this medicine be used?
Acalabrutinib comes as a capsule to take by mouth. It is usually taken with or without food every 12 hours (twice a day) for as long as your doctor recommends that you receive treatment. Take acalabrutinib at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take acalabrutinib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.
Swallow the capsules whole with a glass of water; do not open, chew, or break them.
Your doctor may temporarily or permanently stop your treatment or decrease your dose of acalabrutinib depending on the side effects that you experience. Be sure to talk to your doctor about how you are feeling during your treatment. Do not stop taking acalabrutinib without talking to your doctor. Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.
What special precautions should I follow?
Before taking acalabrutinib,
- tell your doctor and pharmacist if you are allergic to acalabrutinib, any other medications, or any of the ingredients in acalabrutinib capsules. Ask your pharmacist or check the Patient’s Information for a list of the ingredients.
- tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention anticoagulant medications (‘blood thinners) such as warfarin (Coumadin); antiplatelet medications (‘blood thinners) such as aspirin, cilostazol, clopidogrel (Plavix), dipyridamole (Persantine, in Aggrenox), prasugrel (Effient), ticagrelor (Brilinta), and felodipine; diltiazem (Cardizem, Cartia, Diltzac, others); erythromycin (E.E.S., Eryc, Erythrocin, others); fluconazole (Diflucan); itraconazole (Onmel, Sporanox); proton pump inhibitors such as dexlansoprazole (Dexilant), esomeprazole (Nexium, in Vimovo), lansoprazole (Prevacid, in Prevpac), omeprazole (Prilosec, in Yosprala, Zegerid), pantoprazole (Protonix), and rabeprazole (Aciphex); and rifampin (Rifadin, Rimactane, in Rifater, Rifamate). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with acalabrutinib, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
- if you are taking cimetidine (Tagamet), famotidine (Pepcid, in Duexis), nizatidine (Axid), or ranitidine (Zantac) take acalabrutinib at least 2 hours before taking these medications.
- if you are taking antacids (Maalox, Mylanta, Tums, others) take acalabrutinib at least 2 hours before or after taking these medications.
- tell your doctor if you have an infection or have had surgery recently, or if you have or have ever had liver disease including hepatitis B, problems with your heart rhythm, or bleeding problems.
- tell your doctor if you are pregnant or plan to become pregnant. You should not become pregnant while you are taking acalabrutinib. You should not start taking acalabrutinib until a pregnancy test has shown that you are not pregnant and you should use birth control to prevent pregnancy during your treatment and for at least 1 week after your final dose. Acalabrutinib may harm your unborn baby. If you become pregnant while taking acalabrutinib, call your doctor immediately.
- tell your doctor if you are breastfeeding. Your doctor may tell you not to breastfeed during your treatment and for 2 weeks after your final dose.
- if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking acalabrutinib. Your doctor may tell you to stop taking acalabrutinib for a period of time before and after the surgery or procedure.
- plan to avoid unnecessary or prolonged exposure to sunlight and to wear protective clothing, sunglasses, and sunscreen. Acalabrutinib may make your skin sensitive to the dangerous effects of sunlight and may increase your risk of developing skin cancer.