Delivering Long-Term Results for Blood Cancer Patients

John M. Pagel, MD, PhD

During these unprecedented times where we as a nation are considering our health and wellbeing to better understand the impacts of COVID-19, the scientific community has been finding new, innovative ways to connect with each other. One of these ways is through virtual medical congresses where recently thousands of oncologists and medical professionals tuned into the American Society of Clinical Oncology (ASCO) and European Hematology Association (EHA) annual meetings to share insights, advancements and science for those living with cancer.

As a hematologist, I’ve had the privilege to work with and treat patients with the most common type of leukemia in adults, chronic lymphocytic leukemia (CLL).¹ This disease is estimated to affect more than 20,000 new patients in the United States (US) this year alone, and we anticipate the number of people living with CLL to grow as improved treatments become available and patients live longer with the disease.^2,3,4

It’s with this in mind, I’m encouraged and energized by the tremendous scientific advances discussed over the past several weeks that allow us, as healthcare professionals, to focus on finding the right treatment for our patients, while also ensuring that treatment enables our patients to live well, for a long time.

Data from the ACE-CL-001 study presented at both medical meetings evaluating the safety and efficacy of the Bruton Tyrosine Kinase (BTK) inhibitor, acalabrutinib, demonstrated a sustained safety profile for previously untreated CLL patients after more than four years follow-up.^5,6 Additionally, in the pivotal Phase III ASCEND trial for relapsed or refractory CLL evaluating the efficacy and safety of acalabrutinib alone versus investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab, 82% (95% confidence interval [CI]: 75.0, 87.3) of patients treated with acalabrutinib remained progression free at 18 months compared to 48% (95% CI: 39.6, 55.8) for comparator groups.^7,8 Initial study analysis showed an estimated 88% (95% CI: 81.0, 92.0) of patients remained progression free at 12 months for acalabrutinib versus 68% (95% CI, 59.0, 75.0) for the comparators.⁹ Both data sets showed no new safety signals, and this safety profile was further validated in the presentation of the ISS-9 pooled analysis of more than 1,000 patients who received acalabrutinib.^{5,6,7,8,10,11}

These results confirm the safety profile of acalabrutinib for the treatment of CLL over prolonged periods of time, suggesting that patients can continue to use acalabrutinib long-term.^{5,6,7,8,10,11} 

The care of CLL patients must continue to focus on the management of drug-induced side effects. Clearly one of our responsibilities remains to recognize the chronic nature of the disease and to be cognizant of side effects that can have a major impact on a patient’s quality of life.

While we have made great progress in developing and delivering new CLL treatment options, we must also look at how we can involve our patients so they feel in control of their care as well. In my career, I’ve learned that shared decision-making between the physician, patient and their loved ones – plus connecting patients with resources so they are empowered to advocate for themselves – is essential in making the right treatment decisions.

I’m inspired by the evolution of the CLL treatment landscape. We have come a long way in the past decade, and I think our data at ASCO and EHA are a testament to that progress. By truly understanding patients and their needs, I am confident we will continue to make scientific advancements and help patients faced with blood cancer.

CALQUENCE^® (acalabrutinib), a next-generation selective inhibitor of BTK, was approved in 2019 by the US Food and Drug Administration for the treatment of adult patients with CLL or small lymphocytic lymphoma (SLL).^12,13

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), dosage 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 agastric acid reducing agent is required, consider using an H2-receptor antagonistor 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.

References

1. American Cancer Society. What is Chronic Lymphocytic Leukemia. Available online. Accessed June 2020.
2. American Cancer Society. Key Statistics for Chronic Lymphocytic Leukemia. Available online. Accessed June 2020.
3. 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.
4. Jain N, et al. Prevalence and Economic Burden of Chronic Lymphocytic Leukemia (CLL) in the Era of Oral Targeted Therapies. Blood. 2015;126:871.
5. Byrd JC, et al. Acalabrutinib in Treatment-Naïve Chronic Lymphocytic Leukemia: Mature Results From Phase 2 Study Demonstrating Durable Remissions and Long-Term Tolerability. Abstract S163 presented at the Virtual Edition of the 15th European Hematology Association (EHA) Annual Meeting. Available online. Accessed June 2020.
6. Byrd JC, et al. Acalabrutinib in Treatment-Naïve Chronic Lymphocytic Leukemia: Mature Results from Phase 2 Study Demonstrating Durable Remissions and Long-Term Tolerability. Abstract 8024 at the American Society of Clinical Oncology ASCO20 Virtual Session. Available online. Accessed June 2020.
7. Ghia P, et al. Acalabrutinib (Acala) vs Idelalisib plus Rituximab (IdR) or Bendamustine plus Rituximab (BR) in Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL): ASCEND Final Results. Abstract S159 presented at the Virtual Edition of the 15th European Hematology Association (EHA) Annual Meeting. Available online. Accessed June 2020.
8. Ghia P, et al. Acalabrutinib vs Idelalisib plus Rituximab (IdR) or Bendamustine Plus Rituximab (BR) in Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL): ASCEND Final Results. Poster presentation at the American Society of Clinical Oncology ASCO20 Virtual Session. Available online. Accessed July 2020.
9. Ghia P, et al. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia [published online ahead of print, 2020 May 27]. J Clin Oncol. 2020; JCO1903355. doi:10.1200/JCO.19.03355.
10. Furman RR, et al. Safety of Acalabrutinib (Acala) Monotherapy in Hematologic Malignancies: Pooled Analysis from Clinical Trials. Abstract EP698 at the Virtual Edition of the European Hematology Association 25th EHA Annual Congress. Available online. Accessed June 2020.
11. Furman RR, et al. Safety of Acalabrutinib Monotherapy in Mature B Cell Malignancies: Pooled Analysis from Clinical Trials. Abstract 8064 at the American Society of Clinical Oncology ASCO20 Virtual Session. Available online. Accessed June 2020.
12. CALQUENCE^®(acalabrutinib) [prescribing information]. Wilmington, DE; AstraZeneca Pharmaceuticals LP; 2019.
13. Wu J, Zhang M & Liu D. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol. 2016;9.21.

CALQUENCE is a registered trademark of the AstraZeneca group of companies.
©2020 AstraZeneca. All rights reserved.