PREVIOUSLY UNTREATED CLL

NCCN CLINICAL PRACTICE GUIDELINES IN ONCOLOGY (NCCN GUIDELINES®)

THE NCCN GUIDELINES® RECOMMEND ACALABRUTINIB (CALQUENCE®) AS A CATEGORY 1 PREFERRED TREATMENT OPTION FOR CLL*1

*CLL without 17p deletion/TP53 mutation and second-line and subsequent therapy for CLL with and without 17p deletion/TP53 mutation.1

Category 1 Preferred NCCN Recommendation

Category 2A, preferred NCCN recommendation:

Acalabrutinib (CALQUENCE) ± obinutuzumab is a preferred regimen for previously untreated CLL with 17p deletion/TP53 mutation.1

National Comprehensive Cancer Network® (NCCN®) Categories of Evidence and Consensus1

  • Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate
  • Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate
  • Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate
  • Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate

NCCN Categories of Preference1

  • Preferred intervention: Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability
  • Other recommended intervention: Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes
  • Useful in certain circumstances: Other interventions that may be used for selected patient populations (defined with recommendation)

All recommendations are considered appropriate.

PREVIOUSLY UNTREATED CLL

Previously Untreated CLL
Previously Untreated CLL

SECOND-LINE AND SUBSEQUENT THERAPY

Second-Line and Subsequent Therapy Second Line and Subsequent Therapy

To learn more about the NCCN Guidelines for CLL/SLL, please visit NCCN.org.

All recommendations are Category 2A unless otherwise indicated.1

NCCN makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. To view the most recent and complete version of the guidelines, go online to NCCN.org.1

Data from the CLL10 study confirm the superiority of FCR over BR in younger patients. For patients >65 years, the outcome was similar for both regimens with less myelosuppression and infection for BR. FCR was associated with improved PFS (with a plateau in PFS beyond 10-year follow-up) in patients with mutated IGHV without 17p deletion/TP53 mutation (Thompson P, et al. Blood. 2016;127:303-309).1

§Not recommended for CLL with del(11q). Outcomes for CLL with del(11q) are better with chemoimmunotherapy containing an alkylating agent.

||Acalabrutinib has not been shown to be effective for ibrutinib-refractory CLL with BTK C481S mutations. Patients with ibrutinib intolerance have been successfully treated with acalabrutinib without recurrence of symptoms.1

Not recommended for frail patients.

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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 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.

INDICATION AND USAGE

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

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Reference: 1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.

References: 1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019. 2. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial [published correction appears in Lancet. 2020;395(10238):1694]. Lancet. 2020;395(10232):1278‐1291. 3. Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE TN: phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil (Clb) in patients (pts) with treatment-naive chronic lymphocytic leukemia (CLL). Abstract for American Society of Hematology Annual Meeting; December 7-10, 2019; Orlando, FL. 4. Ghia P, Pluta A, Wach M, et al. ASCEND: Phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. Published online ahead of print, May 27, 2020. doi:10.1200/JCO.19.03355.

References: 1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019. 2. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial [published correction appears in Lancet. 2020;395(10238):1694]. Lancet. 2020;395(10232):1278‐1291. 3. Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE TN: phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil (Clb) in patients (pts) with treatment-naive chronic lymphocytic leukemia (CLL). Abstract for American Society of Hematology Annual Meeting; December 7-10, 2019; Orlando, FL. 4. Data on File, REF-64711. AstraZeneca Pharmaceuticals LP. 5. Ghia P, Pluta A, Wach M, et al. ASCEND: Phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. Published online ahead of print, May 27, 2020. doi:10.1200/JCO.19.03355.

References: 1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019. 2. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial [published correction appears in Lancet. 2020;395(10238):1694]. Lancet. 2020;395(10232):1278‐1291. 3. Data on File, REF-64711. AstraZeneca Pharmaceuticals LP. 4. Ghia P, Pluta A, Wach M, et al. ASCEND: Phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. Published online ahead of print, May 27, 2020. doi:10.1200/JCO.19.03355.

Reference: 1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.

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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.