Acalabrutinib (a-cal-a-broo-ti-nib), which is marketed under the tradename of Calquence® in the U.S. and Canada, is a second-generation small molecule inhibitor of Bruton’s tyrosine kinase (BTK). Upon oral administration, acalabrutinib binds to and irreversibly inhibits the activity of BTK which prevents both B-cell activation and B-cell-mediated signaling. This action leads to an inhibition of the growth of malignant B cells that overexpress BTK. BTK is required for B-cell signaling, plays a key role in B-cell maturation, and is overexpressed in a number of B-cell malignancies, including CLL/SLL. The expression of BTK in tumor cells is associated with increased proliferation and survival. As a second-generation BTK inhibitor, acalabrutinib was designed to maximize the effect on BTK and minimize off-target activity on TEC (Tec Protein Tyrosine Kinase), EGFR (epidermal growth factor receptor), and ITK (interleukin-2-inducible T-cell kinase). The first generation BTK inhibitor, ibrutinib (Imbruvica®), lacks this specificity which results in a higher incidence of adverse effects. In addition to CLL/SLL, acalabrutinib is approved for Mantle Cell Lymphoma (MCL). The National Cancer Center Network (NCCN) Guidelines list acalabrutinib with or without obinituzumab as first line therapy for CLL/SLL as well as appropriate for use in relapsed or refractory (R/R) CLL.
Calquence® is supplied as a 100mg capsule with the standard dose of 1 capsule by mouth twice a day (as close to every 12 hours as possible). Your medical team may adjust the dose downward depending upon such factors as adverse side effects or if you have known liver failure. At present, there is no recommended dosage adjustment for renal failure patients however the use of acalabrutinib in End Stage Renal Disease and dialysis has not been studied.
Many patients become alarmed when first starting acalabrutinib or ibrutinib because the first lab tests after starting this medication often show a dramatic rise in the White Blood Cell (WBC) count. This is, in fact, a sign that the medication is working as lymphocytes in the bone marrow and lymph nodes are driven into the circulating blood where they can be affected by the drug. Your provider may start you on the anti-gout medication allopurinol when you start acalabrutinib because there is a possibility that the drug may cause a phenomenon known as Tumor Lysis Syndrome (TLS). In TLS the malignant cells rupture and, in doing so, release large quantities of uric acid. Gout is the manifestation of increased uric acid levels and the allopurinol enhances the excretion of uric acid both in gout and TLS. It should be noted that the incidence of TLS is less with Calquence® compared to Imbruvica®.
When taking acalabrutinib it is important to take it at approximately the same times each day with a full glass of water and you should maintain good hydration throughout the day. It is important to swallow the capsules whole and not open, break of chew the capsules. Calquence® can be taken without regards to meals but, there should be taken either 2 hours before or after any antacids or any of the H-2 Receptor blockers such as Pepcid® (famotidine), Zantac® (ranitidine) or Tagamet® (cimetidine) that are used to reduce stomach acidity. Because the other group of stomach reducing medications known as the Proton Pump Inhibitors (PPI) remain in the bloodstream longer they should be avoided altogether. PPI drugs include omeprazole (Prilosec®/Zegerid®), esomeprazole (Nexium®), lansoprazole (Prevacid®), dexlanzoprazole (Dexilant®), pantoprazole (Protonix®), rabeprazole (AciPhex®) and esomeprazole/naproxen (Vivimo®). The reason for these precautions is that these medications significantly reduce the effectiveness of acalabrutinib.
Acalabrutinib has a mild anti-coagulant effect essentially equivalent to 325mg of aspirin. It is important that you provide a complete list of medications that includes any nutritional supplements or over-the-counter medications to your provider. Your provider or the clinical pharmacist assigned to your clinic will review your medication history and make recommendations on items to reduce or eliminate. Some common medications to avoid without provider approval are, aspirin or Non-Steroidal Anti-Inflammatory agents such as ibuprofen, naproxen, or diclofenac; anti-platelet agents. In addition, several herbal products can enhance the anti-coagulant properties of acalabrutinib including Omega-3 Fatty Acids (Fish-Oil), Flaxseed Oil, Vitamin E, and Curcumin. Of course, if you are on any anticoagulant or antiplatelet therapy your medical team may need to adjust or eliminate your current therapy.
In addition to the acid reduction medication precautions, there are numerous drug-to-drug interactions to consider as well. I will only discuss the most significant.
Many HIV and antifungal drugs inhibit the enzyme that metabolizes acalabrutinib and result in increased blood levels and side effects. The HIV drugs can be recognized because they end in “Vir” and the antifungals end in “Zole”. In addition, the antibiotics clarithromycin and telithromycin and the antidepressant nefazodone have the same effect.
On the opposite side are drugs that induce the enzyme that metabolizes acalabrutinib and reduces the blood levels and may render the drug sub-therapeutic. These include the anti-seizure medications phenytoin, carbamazepine and phenobarbital, the anti-tubercular agents, rifampin, rifabuten and rifapentin, the steroid dexamethasone and the herbal product St. John’s Wort.
Your provider will evaluate the risks of these interactions and decide to either adjust therapy or potentially switch to similar agents for the same purpose that do not interact with acalabrutinib. I must caution that the listing I have provided is only a small group of the most significant restricted medications. This is why you must discuss all current and contemplated new medications with all your medical team including your primary care provider.
There are some serious food interactions to consider as well. Grapefruit, grapefruit juice and Seville oranges inhibit the enzyme that metabolizes acalabrutinib and the drug levels increase, risking worsening of potential side effects. Seville oranges are often used to make orange marmalade and should be avoided.
The list of POTENTIAL side-effects is long. Some are merely a nuisance and tend to be transient and others are more severe and require medical intervention. Seek immediate medical attention for:
- Serious infections, which can occur during treatment as well as a result of compromised immune system function associated with CLL/SLL.
- Any signs of an allergic reaction such as rash, hives, tightness in the chest or throat, trouble breathing or talking, swelling of the mouth tongue or throat.
- Signs of bleeding internally such as throwing up what looks like coffee grounds, blood in the urine (pink or brown) or black, red or tarry stools. Additional signs include coughing up blood or blood clots, dizziness, weakness, confusion, changes in speech, headaches that last a long time, unexpected severe bleeding or bruising.
- Heart rhythm problems (atrial fibrillation or atrial flutter) which manifests as fast or irregular heartbeat, dizziness, feeling faint, chest discomfort or shortness of breath.
Acalabrutinib is a breakthrough in the treatment of CLL. It is generally a safe medication, but all medications have risks. By educating yourself and listening to your body you will likely benefit from this drug and be able to identify potential problems and risks in your treatment.
Thomas Henry is a Registered Pharmacist and CLL Patient. He serves as Clinical Pharmacy Advisor to Lumere, a healthcare technology company that helps healthcare systems reduce spending on medications and medical devices. In addition, he is President and Senior Consultant for Burlington Consulting Associates a company that provide consulting services to health-systems nationwide. He has a forty year career in pharmacy and has served as Chief Pharmacy Officer at two Top-15 Comprehensive Cancer Centers, Moffitt (Tampa, FL) and Roswell Park, (Buffalo, NY).