CALQUENCE plus venetoclax demonstrated statistically significant and clinically meaningful improvement in progression-free survival vs. chemoimmunotherapy, with 77% of patients progression free at three years in AMPLIFY Phase III trial

AstraZeneca’s CALQUENCE^® (acalabrutinib) in combination with venetoclax has been approved in the US as the first all-oral, fixed-duration regimen for the treatment of adult patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

The approval by the US Food and Drug Administration (FDA) was based on positive results from the AMPLIFY Phase III trial, which were presented at the American Society of Hematology 2024 Annual Meeting and published in The New England Journal of Medicine.^1-2

CLL is the most common type of leukemia in adults.³ An estimated 18,500 people were treated for CLL in the 1st-line setting in the US in 2024.⁴

Jennifer Brown, MD, PhD, Director of the CLL Center of the Division of Hematologic Malignancies, Dana-Farber Cancer Institute, and the Worthington and Margaret Collette Professor of Medicine at Harvard Medical School, and principal investigator of the AMPLIFY trial, said: “The continuous regimens frequently used to treat chronic lymphocytic leukemia often come with side effects that may become burdensome to patients over time. The US approval of the CALQUENCE combination offers patients an all-oral, 14-month, fixed-duration treatment option that is highly effective and well-tolerated, and gives physicians greater flexibility to tailor treatment plans for individual patient needs and goals.”

Dave Fredrickson, Executive Vice President, Oncology Haematology Business Unit, AstraZeneca, said: “Today’s approval delivers the first all-oral, fixed-duration BTK inhibitor-based regimen in the US for the treatment of chronic lymphocytic leukemia. This CALQUENCE combination has the potential to meaningfully change 1st-line chronic lymphocytic leukemia treatment decisions and underscores our commitment to improving on the current standard of care for people living with blood cancers.”

Gwen Nichols, MD, Chief Medical Officer of Blood Cancer United, formerly The Leukemia & Lymphoma Society, said: “Managing an incurable blood cancer that progresses slowly can often feel indefinite and overwhelming. We welcome new treatment options that may ease the burden, restore a sense of control and offer renewed hope for those navigating life with chronic lymphocytic leukemia.”

Results from the AMPLIFY Phase III trial showed 77% of patients treated with CALQUENCE plus venetoclax were progression free at three years, versus 67% of patients treated with standard-of-care chemotherapy (investigator’s choice of fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab).² Median progression-free survival (PFS) was not reached versus 47.6 months for chemoimmunotherapy.² Further, CALQUENCE plus venetoclax reduced the risk of disease progression or death by 35% compared to chemoimmunotherapy (based on hazard ratio 0.65; 95% confidence interval 0.49-0.87; p=0.0038).²

CALQUENCE plus venetoclax is approved in the European Union, Canada, UK and several other countries, and regulatory applications for the regimen based on the AMPLIFY results are currently under review in additional countries.

The safety and tolerability of CALQUENCE was consistent with its known safety profile, and no new safety signals were identified.

INDICATIONS AND USAGE

CALQUENCE is a Bruton tyrosine kinase (BTK) inhibitor indicated:

• For the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE^® (acalabrutinib) tablets

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 29% of 2,055 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (18% of all patients, including pneumonia in 14%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 8% of all patients. Opportunistic infections in recipients of CALQUENCE have included, but are not limited to, hepatitis B virus reactivation, fungal pneumonia, Pneumocystis jirovecii 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 treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 4.7% of patients, with fatal hemorrhage occurring in 0.1% of 2,055 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 39% of patients.

Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 5% of patients taking CALQUENCE without antithrombotic agents and 3.2% 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 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Cytopenias

CALQUENCE can cause Grade 3 or 4 cytopenias. Grade 3 or 4 cytopenias included absolute neutrophil count decreased (28%), absolute lymphocyte count decreased (10%), hemoglobin decreased (9%), and platelets decreased (9%) in 1,758 patients treated with CALQUENCE alone and in combination with obinutuzumab or venetoclax; Grade 4 neutropenia developed in 14% 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 16% of 2,055 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 9% of patients, followed by other solid tumors in 8% (including melanoma, lung cancer, gastrointestinal cancers, and genitourinary cancers) and hematologic malignancies (1.1%). Fatal second primary malignancies occurred in 0.8% of patients. Monitor patients for the development of second cancers and advise protection from sun exposure.

Cardiac Arrhythmias

Fatal and serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. Grade 3 or 4 atrial fibrillation or flutter was reported in 2.2% of 2,055 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 7% of all patients. Grade 3 or higher ventricular arrhythmia events were reported in 0.5% of patients, including fatal cases in 0.3% of all patients. The risk of arrhythmias may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection. Monitor for symptoms of arrhythmia (eg, palpitations, dizziness, syncope, dyspnea) and manage as appropriate.

Hepatotoxicity, Including Drug-Induced Liver Injury

Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including CALQUENCE.

Evaluate bilirubin and transaminases at baseline and throughout treatment with CALQUENCE. For patients who develop abnormal liver tests after CALQUENCE, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold CALQUENCE. Upon confirmation of DILI, discontinue CALQUENCE.

ADVERSE REACTIONS

Chronic Lymphocytic Leukemia

In patients with previously untreated CLL in the AMPLIFY study who received CALQUENCE plus venetoclax (AV) (n=291), the most common adverse reactions (≥15%) of any grade were headache (35%), diarrhea (33%), musculoskeletal pain (25%), COVID-19 (21%), fatigue (18%), bruising (17%), rash (16%), and nausea (15%).

The most common laboratory abnormalities (≥15%) of any grade in patients with previously untreated CLL who received AV were neutrophils decreased (78%), glucose increased (74%), lymphocytes decreased (56%), platelets decreased (43%), hemoglobin decreased (35%), calcium decreased (30%), ALT increased (26%), urate increased (25%), LDH increased (24%), potassium increased (22%), AST increased (22%), ALP increased (20%), glucose decreased (20%), creatinine increased (19%), and sodium increased (15%). Grade 4 laboratory abnormalities in >15% of patients treated with AV include absolute neutrophil count decreased (15%).

Serious adverse reactions occurred in 25% of patients receiving AV. The most common serious adverse reactions (≥2%) were COVID-19 including COVID-19 pneumonia (9%), second primary malignancies (2.7%), and neutropenia (2.1%). Fatal adverse events occurred in 3.4% of patients. The most common fatal adverse events included COVID-19 and COVID-19 pneumonia.

Treatment discontinuation of CALQUENCE due to adverse reactions occurred in 8% of patients receiving AV. The most common adverse reaction (≥2%) leading to treatment discontinuation was COVID-19 pneumonia (2.1%). Dose reduction of CALQUENCE occurred in 6% of patients. Neutropenia was the only adverse reaction leading to dose reduction that occurred in ≥1% of patients.

DRUG INTERACTIONS

Strong CYP3A Inhibitors: Avoid co-administration of CALQUENCE with a strong CYP3A inhibitor. If these inhibitors will be used short-term, interrupt CALQUENCE. After discontinuation of strong CYP3A inhibitor for at least 24 hours, resume previous dosage of CALQUENCE.

Moderate CYP3A Inhibitors: Reduce the dosage of CALQUENCE to 100 mg once daily when co-administered with a moderate CYP3A inhibitor.

Strong CYP3A Inducers: Avoid co-administration of CALQUENCE with a strong CYP3A inducer. If co‑administration is unavoidable, increase the dosage of CALQUENCE to 200 mg approximately every 12 hours.

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 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 2 weeks after the last dose.

Of patients that received AV in AMPLIFY, 33% (97/291) were ≥65 years, and 4.5% (13/291) were ≥75 years of age. In patients ≥65 years and <65 years of age, the fatal adverse reactions were 5% and 2.6%, respectively.

Avoid use of CALQUENCE in patients with severe hepatic impairment (Child-Pugh class C). No dosage adjustment of CALQUENCE is recommended in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.

Please see full Prescribing Information, including Patient Information.

Notes

Chronic lymphocytic leukemia (CLL)

CLL is the most prevalent type of leukemia in adults, with an estimated 40,000 people being treated for CLL in the first line in the US, UK, France, Germany, Spain, Italy, Japan and China in 2024.⁴ Although some people with CLL may not experience any symptoms at diagnosis, others may experience symptoms, such as weakness, fatigue, weight loss, chills, fever, night sweats, swollen lymph nodes and abdominal pain.⁵ In CLL, there is an accumulation of abnormal lymphocytes within the blood, bone marrow and lymph nodes. As the number of abnormal cells increases, there is less room within the marrow for the production of normal white blood cells, red blood cells and platelets.³ This could result in infection, anemia and bleeding. B-cell receptor signaling through BTK is one of the essential growth pathways for CLL.

AMPLIFY

AMPLIFY is a randomized, global, multi-center, open-label Phase III trial evaluating the efficacy and safety of CALQUENCE in combination with venetoclax, with or without obinutuzumab, compared to investigator's choice of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) in adult patients with previously untreated CLL without del(17p) or TP53 mutation.⁶ Patients were randomized 1:1:1 to receive either CALQUENCE plus venetoclax, or CALQUENCE plus venetoclax with obinutuzumab for a fixed duration, or standard-of-care chemoimmunotherapy.⁶ Both the CALQUENCE containing arms were administered for a fixed duration of 14 cycles (each 28 days), and the standard-of-care chemoimmunotherapy was administered for 6 cycles.⁶

The primary endpoint is PFS in the CALQUENCE and venetoclax arm as assessed by an Independent Review Committee, and PFS is a key secondary endpoint in the CALQUENCE plus venetoclax with obinutuzumab arm.⁷ Other key secondary endpoints include overall survival (OS) and undetectable measurable residual disease.⁶ The trial includes 27 countries across North and South America, Europe, Asia and Oceania.⁶

The AMPLIFY trial enrolled patients from 2019 to 2021, continuing through the COVID-19 pandemic.⁶

CALQUENCE

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

CALQUENCE is approved for the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) in the US, Japan and China, and approved for CLL in Europe and many other countries. CALQUENCE is also approved as a fixed-duration treatment for the treatment of adult patients with previously untreated CLL in combination with venetoclax in the US, and in combination with venetoclax, with or without obinutuzumab, in Europe, Canada, the U.K. and several other countries. CALQUENCE is also approved for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL) in the US, Europe, Japan and other countries. It is also approved for the treatment of adult patients with MCL who have received at least one prior therapy in China and several other countries.

As part of an extensive clinical development program, CALQUENCE is currently being evaluated as a single treatment and in combination with standard-of-care chemoimmunotherapy for patients with multiple B-cell blood cancers, including CLL, MCL and diffuse large B-cell lymphoma.

AstraZeneca in hematology

AstraZeneca is pushing the boundaries of science to redefine care in hematology. Our goal is to help transform the lives of patients living with malignant, rare and other related hematologic diseases through innovative medicines and approaches that are shaped by insights from patients, caregivers and physicians.

In addition to our marketed products, we are spearheading the development of novel therapies designed to target underlying drivers of disease across multiple scientific platforms. Our acquisitions of Alexion, with expertise in rare, non-malignant blood disorders, and Gracell Biotechnologies Inc., pioneers of autologous cell therapies, expand our hematology pipeline and enable us to reach more patients with high unmet needs through the end-to-end discovery, development and delivery of novel therapies.

AstraZeneca in oncology

AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

AstraZeneca

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References

1. Brown, J et al. Fixed-duration acalabrutinib plus venetoclax with or without obinutuzumab versus chemoimmunotherapy for first-line treatment of chronic lymphocytic leukemia: interim analysis of the multicenter, open-label, randomized, Phase 3 AMPLIFY Trial. Presented at ASH 2024. Abstract 1009. 2024.
2. Brown J, et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. NEJM. 2025;392:748-762.
3. National Cancer Institute. Chronic lymphocytic leukemia treatment (PDQ^®)-Patient version. Available at: https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq. Accessed December 2025.
4. AstraZeneca 2024. Full Year and Q4 2024 Financial Results Epidemiology Spreadsheet. Available at: https://www.astrazeneca.com/investor-relations.html. Accessed December 2025.
5. American Cancer Society. Signs and Symptoms of Chronic Lymphocytic Leukemia. Available at: https://www.cancer.org/cancer/types/chronic-lymphocytic-leukemia/detection-diagnosis-staging/signs-symptoms.html. Accessed December 2025.
6. ClinicalTrials.gov. Study of Acalabrutinib (ACP-196) in Combination With Venetoclax (ABT-199), With and Without Obinutuzumab (GA101) Versus Chemoimmunotherapy for Previously Untreated CLL (AMPLIFY). Available at: https://clinicaltrials.gov/study/NCT03836261. Accessed December 2025.
7. Wu J, et al. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol. 2016;9(21).

US-109173 Last Updated 2/26

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