A pooled analysis of cardiovascular (CV) safety data from 762 patients treated with CALQUENCE® (acalabrutinib) monotherapy for chronic lymphocytic leukemia (CLL), the most common type of adult leukemia, across four clinical trials showed a low incidence of cardiac adverse events (AEs) leading to discontinuation.1,2 This data was presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition on 7 December 2020.

The analysis included patients with previously untreated and relapsed or refractory CLL treated with CALQUENCE alone from the ELEVATE TN and ASCEND Phase III trials, as well as the 15-H-0016 Phase II trial and ACE-CL-001 Phase I/II trial. In the analysis, 129 patients (17%) reported a cardiac AE of any grade at a median follow up of 25.9 months, and seven patients (0.9%) discontinued treatment due to cardiac AEs.1

Jennifer Brown, MD, PhD, Director of the CLL Center of the Division of Hematologic Malignancies, Dana-Farber Cancer Institute, and principal investigator, said: “Cardiac adverse events have emerged as an important consideration for treating chronic lymphocytic leukemia patients with Bruton’s tyrosine kinase inhibitors, as cardiovascular complications have become a frequent reason for discontinuation. The data presented in this study suggests a low risk of cardiac adverse events with acalabrutinib that is similar to those in a general population of untreated patients with chronic lymphocytic leukemia, giving clinicians further reassurance when prescribing this therapy.”

José Baselga, Executive Vice President, Oncology R&D, said: “These combined results across four of our clinical trials reinforce the cardiovascular safety profile of CALQUENCE for the treatment of chronic lymphocytic leukemia. With CALQUENCE, we aim to selectively target Bruton’s tyrosine kinase to help improve safety and long-term adherence while maintaining outstanding efficacy.”

Median exposure to CALQUENCE was 24.9 months. Cardiac events that occurred in 2% or more of patients included atrial fibrillation (4%), atrial fibrillation/flutter (5%), palpitations (3%) and tachycardia (2%). The incidence of atrial fibrillation was similar to that in a general, previously untreated CLL patient population (6%).1,3

Grade 3 or higher cardiac AEs occurred in 37 patients (4%) treated with CALQUENCE monotherapy, of which 25% were reported during the first six months of treatment. Grade 3 or higher cardiac AEs of interest included atrial fibrillation (1.3%), complete atrioventricular (AV) block (0.3%), acute coronary syndrome (0.1%), atrial flutter (0.1%), second degree AV block (0.1%) and ventricular fibrillation (0.1%). Two patients experienced Grade 5 AEs (one with congestive heart failure and one with heart attack).1

Overall, 91% of patients with cardiac AEs versus 79% patients without cardiac AEs had one or more CV risk factors before receiving CALQUENCE. The most prevalent CV risk factors (greater than or equal to 20% of patients) among those who experienced cardiac AEs were hypertension (67%), hyperlipidemia (29%) and arrhythmias (22%).1

AstraZeneca is exploring additional trials in CLL, including the ELEVATE-RR Phase III trial (ACE-CL-006) evaluating CALQUENCE versus ibrutinib in patients with previously treated high-risk CLL. Data is anticipated in 2021.

INDICATION AND USAGE

CALQUENCE is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE® (acalabrutinib) capsules

Serious and Opportunistic Infections

Fatal and serious infections, including opportunistic infections, have occurred in patients with hematologic malignancies treated with CALQUENCE.

Serious or Grade 3 or higher infections (bacterial, viral, or fungal) occurred in 19% of 1029 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (11% of all patients, including pneumonia in 6%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 1.9% of all patients. Opportunistic infections in recipients of CALQUENCE have included, but are not limited to, hepatitis B virus reactivation, fungal pneumonia, Pneumocystis jiroveci pneumonia, Epstein-Barr virus reactivation, cytomegalovirus, and progressive multifocal leukoencephalopathy (PML). Consider prophylaxis in patients who are at increased risk for opportunistic infections. Monitor patients for signs and symptoms of infection and treat promptly.

Hemorrhage

Fatal and serious hemorrhagic events have occurred in patients with hematologic malignancies treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 3.0% of patients, with fatal hemorrhage occurring in 0.1% of 1029 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 22% of patients.

Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 2.7% of patients taking CALQUENCE without antithrombotic agents and 3.6% of patients taking CALQUENCE with antithrombotic agents. Consider the risks and benefits of antithrombotic agents when co-administered with CALQUENCE. Monitor patients for signs of bleeding.

Consider the benefit-risk of withholding CALQUENCE for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (8%), thrombocytopenia (7%), and lymphopenia (7%), developed in patients with hematologic malignancies treated with CALQUENCE. Grade 4 neutropenia developed in 12% of patients. Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted.

Second Primary Malignancies

Second primary malignancies, including skin cancers and other solid tumors, occurred in 12% of 1029 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was skin cancer, reported in 6% of patients. Monitor patients for skin cancers and advise protection from sun exposure.

Atrial Fibrillation and Flutter

Grade 3 atrial fibrillation or flutter occurred in 1.1% of 1029 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 4.1% of all patients. The risk may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection. Monitor for symptoms of arrhythmia (e.g., palpitations, dizziness, syncope, dyspnea) and manage as appropriate.

ADVERSE REACTIONS

The most common adverse reactions (≥ 30%) of any grade in patients with CLL were anemia,* neutropenia,* thrombocytopenia,* headache, upper respiratory tract infection, and diarrhea.

*Treatment-emergent decreases (all grades) of hemoglobin, platelets, and neutrophils were based on laboratory measurements and adverse reactions.

In patients with previously untreated CLL exposed to CALQUENCE, fatal adverse reactions that occurred in the absence of disease progression and with onset within 30 days of the last study treatment were reported in 2% for each treatment arm, most often from infection. Serious adverse reactions were reported in 39% of patients in the CALQUENCE plus obinutuzumab arm and 32% in the CALQUENCE monotherapy arm, most often due to events of pneumonia (7% and 2.8%, respectively).

Adverse reactions led to CALQUENCE dose reduction in 7% and 4% of patients in the CALQUENCE plus obinutuzumab arm (N=178) and CALQUENCE monotherapy arm (N=179), respectively. Adverse events led to discontinuation in 11% and 10% of patients, respectively. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 3.9% and 2.8% of patients in the CALQUENCE combination arm and monotherapy arm, respectively.

In patients with relapsed/refractory CLL exposed to CALQUENCE, serious adverse reactions occurred in 29% of patients. Serious adverse reactions in > 5% of patients who received CALQUENCE included lower respiratory tract infection (6%). Fatal adverse reactions within 30 days of the last dose of CALQUENCE occurred in 2.6% of patients, including from second primary malignancies and infection.

Adverse reactions led to CALQUENCE dose reduction in 3.9% of patients (N=154), dose interruptions in 34% of patients, most often due to respiratory tract infections followed by neutropenia, and discontinuation in 10% of patients, most frequently due to second primary malignancies followed by infection. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 1.3% of patients who received CALQUENCE.

DRUG INTERACTIONS

Strong CYP3A Inhibitors: Avoid co-administration with a strong CYP3A inhibitor. If a strong CYP3A inhibitor will be used short-term, interrupt CALQUENCE.

Moderate CYP3A Inhibitors: When CALQUENCE is co-administered with a moderate CYP3A inhibitor, reduce CALQUENCE 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, increase the CALQUENCE dose to 200 mg approximately every 12 hours.

Gastric Acid Reducing Agents: If treatment with a gastric acid reducing agent is required, consider using an H2-receptor antagonist or an antacid. Take CALQUENCE 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. Due to the long-lasting effect of proton pump inhibitors, separation of doses may not eliminate the interaction with CALQUENCE.

SPECIFIC POPULATIONS

Based on findings in animals, CALQUENCE may cause fetal harm and dystocia when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. Advise pregnant women of the potential risk to a fetus.

Pregnancy testing is recommended for females of reproductive potential prior to initiating CALQUENCE therapy. Advise female patients of reproductive potential to use effective contraception during treatment with CALQUENCE and for at least 1 week following the last dose of CALQUENCE.

It is not known if CALQUENCE is present in human milk. Advise lactating women not to breastfeed while taking CALQUENCE and for at least 2 weeks after the final dose.
Avoid administration of CALQUENCE in patients with severe hepatic impairment. Dose modifications are not required for patients with mild or moderate hepatic impairment.

Please see full Prescribing Information, including Patient Information.

Chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults, with an estimated 105,000 new cases globally in 2016 and 21,040 new cases in the US in 2020, and the number of people living with CLL is expected to grow with improved treatment as patients live longer with the disease.2,4,5,6 In CLL, too many blood stem cells in the bone marrow become abnormal lymphocytes and these abnormal cells have difficulty fighting infections. As the number of abnormal cells grows, there is less room for healthy white blood cells, red blood cells, and platelets. This could result in anemia, infection, and bleeding.4 B-cell receptor signaling through Bruton’s tyrosine kinase (BTK) is one of the essential growth pathways for CLL.

CALQUENCE
CALQUENCE (acalabrutinib) is a next-generation, selective inhibitor of BTK. CALQUENCE binds covalently to BTK, thereby inhibiting its activity.7,8 In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.7

CALQUENCE is approved for the treatment of CLL and SLL in the US and is approved for CLL in the EU and several other countries worldwide. CALQUENCE is also approved for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy in the US and several other countries.

As part of an extensive clinical development program, AstraZeneca and Acerta Pharma are currently evaluating CALQUENCE in more than 20 company-sponsored clinical trials. CALQUENCE is being developed for the treatment of multiple B-cell blood cancers including CLL, MCL, diffuse large B-cell lymphoma, Waldenström’s macroglobulinemia, follicular lymphoma, and other hematologic malignancies.

AstraZeneca in hematology
Leveraging its strength in oncology, AstraZeneca has established hematology as one of four key oncology disease areas of focus. The Company’s hematology franchise includes two medicines approved by the US Food and Drug Administration and a robust global development program for a broad portfolio of potential blood cancer treatments. Acerta Pharma serves as AstraZeneca’s hematology research and development arm. AstraZeneca partners with like-minded science-led companies to advance the discovery and development of therapies to address unmet need.

AstraZeneca in oncology
AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients' lives and the Company's future. With seven new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers.

By harnessing the power of six scientific platforms - Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response, Antibody Drug Conjugates, Epigenetics, and Cell Therapies - and by championing the development of personalized combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.

References
1. Brown J, et al. Pooled Analysis of Cardiovascular Events From Clinical Trials Evaluating Acalabrutinib Monotherapy in Patients with Chronic Lymphocytic Leukemia (CLL). Abstract #3146 at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition.
2. American Cancer Society. What is Chronic Lymphocytic Leukemia. Available at: https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/what-is-cll.html.
3. Shanafelt TD, et al. Atrial Fibrillation in Patients with Chronic Lymphocytic Leukemia (CLL). Leuk Lymphoma. 2017;58(7):1630-1639.
4. National Cancer Institute. Chronic Lymphocytic Leukemia Treatment (PDQ®)–Patient Version. Available at: https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq.
5. Global Burden of Disease Cancer Collaboration. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2016. JAMA Oncol. 2018;4(11):1553-1568.
6. Jain N, et al. Prevalence and Economic Burden of Chronic Lymphocytic Leukemia (CLL) in the Era of Oral Targeted Therapies. Blood. 2015;126:871.
7. CALQUENCE (acalabrutinib) [prescribing information]. Wilmington, DE; AstraZeneca Pharmaceuticals LP; 2019.
8. Wu J, Zhang M & Liu D. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol. 2016;9(21).

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