NCCN Guidelines® recommend acalabrutinib (CALQUENCE) as a second-line therapy option for MCL (Category 2A).

NCCN Guidelines® B-cell Lymphomas (Version 4.2018–May 15, 2018)1

Suggested treatment regimens for second-line therapy for mantle cell lymphoma (MCL)*†1

SHORT RESPONSE DURATION TO PRIOR CHEMOIMMUNOTHERAPY (< EXPECTED MEDIAN PFS)

  • Preferred regimens (in alphabetical order)

    • Acalabrutinib‡§
    • Ibrutinib|| ± rituximab
    • Lenalidomide ± rituximab
    • Venetoclax
  • Other recommended regimen

    • Ibrutinib, lenalidomide, rituximab (category 2B)

Consider prophylaxis for tumor lysis system (See NHODG-B) See monoclonal antibody and viral reactivation (NHODG-B)

EXTENDED RESPONSE DURATION TO PRIOR CHEMOIMMUNOTHERAPY (> EXPECTED MEDIAN PFS)

  • Preferred regimens (in alphabetical order)

    • Bendamustine ± rituximab (if not previously given)
    • Bortezomib ± rituximab
  • Other recommended regimens (in alphabetical order by category)

    • Small molecule inhibitors as above
    • Bendamustine, bortezomib and rituximab (category 2B)
    • R-CHOP (if not previously given) (category 2B)
    • VR-CAP (if not previously given) (category 2B)
    • PEP-C (prednisone, etoposide, procarbazine, cyclophosphamide) ± rituximab (category 3)
    • See second-line therapy for DLBCL (BCEL-C2 of 4) without regard to transplantability
  • Second-line consolidation

    • Allogeneic hematopoietic cell transplant (nonmyeloablative or myeloablative)

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® Recommendations) for B-Cell Lymphomas V.4.2018. © 2018 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® Recommendations and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines Recommendations, go online to NCCN.org. The NCCN Guidelines Recommendations are a work in progress that may be redefined as often as new significant data become available.

*All recommendations in the B-cell lymphoma guidelines are category 2A unless otherwise noted. Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Rituximab and hyaluronidase human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion. This substitution cannot be made for rituximab used in combination with ibritumomab tiuxetan.

The Phase 2 ACE-LY-004 study excluded patients treated with BTK or BCL-2 inhibitors and concomitant warfarin or equivalent vitamin K antagonists.

§Special considerations for the use of the small-molecule inhibitor, acalabrutinib, include the following:

  • Dosage: The recommended dose of acalabrutinib is 100 mg PO approximately every 12 hours
  • Grade ≥3 bleeding events were observed in 2% of patients on acalabrutinib. The mechanism is not well understood. Acalabrutinib may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. The Phase 2 ACE-LY-004 study excluded patients on concomitant warfarin or equivalent vitamin K antagonists. Patient should be monitored for signs of bleeding. Consider the benefit-risk of withholding acalabrutinib for 3-7 days pre- and post-surgery depending on the type of surgery and risk of bleeding
  • Atrial fibrillation and flutter of any grade were reported in 3% of patients and atrial fibrillation Grade 3 was reported in 1% of patients. Monitor for atrial fibrillation and flutter, and manage as appropriate
  • Co-administration with CYP3A inhibitors and inducers
    • Avoid concomitant use of strong CYP3A inhibitors or inducers
    • For strong CYP3A inhibitors used short-term, interrupt acalabrutinib during the duration of inhibitor use
    • For concomitant use with a moderate CYP3A inhibitor, reduce acalabrutinib dose to 100 mg once daily
    • If concomitant use with a strong CYP3A inducer cannot be avoided, increase acalabrutinib dose to 200 mg twice daily

||For special considerations concerning ibrutinib, please see pages NHODG-E 2 of 3 and 3 of 3. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

ACALABRUTINIB IS RECOMMENDED AS A SECOND-LINE THERAPY OPTION FOR MCL (CATEGORY 2A)‡1

 

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Important Safety Information

Hemorrhage

Serious hemorrhagic events, including fatal events, have occurred in the combined safety database of 612 patients with hematologic malignancies treated with CALQUENCE monotherapy. Grade 3 or higher bleeding events, including gastrointestinal, intracranial, and epistaxis, have been reported in 2% of patients. Overall, bleeding events, including bruising and petechiae of any grade, occurred in approximately 50% of patients with hematological malignancies.

The mechanism for the bleeding events is not well understood.

CALQUENCE may further increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies, and patients should be monitored 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.

Infection

Serious infections (bacterial, viral, or fungal), including fatal events and opportunistic infections, have occurred in the combined safety database of 612 patients with hematologic malignancies treated with CALQUENCE monotherapy. Grade 3 or higher infections occurred in 18% of these patients. The most frequently reported Grade 3 or 4 infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation and progressive multifocal leukoencephalopathy (PML) have occurred.

Monitor patients for signs and symptoms of infection and treat as medically appropriate. Consider prophylaxis in patients who are at increased risk for opportunistic infections.

Cytopenias

In the combined safety database of 612 patients with hematologic malignancies, patients treated with CALQUENCE monotherapy experienced Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (11%) and thrombocytopenia (8%), based on laboratory measurements. Monitor complete blood counts monthly during treatment.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinomas, have occurred in 11% of patients with hematologic malignancies treated with CALQUENCE monotherapy in the combined safety database of 612 patients. The most frequent second primary malignancy was skin cancer, reported in 7% of patients. Advise protection from sun exposure.

Atrial Fibrillation and Flutter

In the combined safety database of 612 patients with hematologic malignancies treated with CALQUENCE monotherapy, atrial fibrillation and atrial flutter of any grade occurred in 3% of patients, and Grade 3 in 1% of patients. Monitor for atrial fibrillation and atrial flutter and manage as appropriate.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) of any grade were anemia,* thrombocytopenia,* headache (39%), neutropenia,* diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%).

*Treatment-emergent decreases (all grades) of hemoglobin (46%), platelets (44%), and neutrophils (36%) were based on laboratory measurements and adverse reactions.

The most common Grade ≥ 3 non-hematological adverse reaction (reported in at least 2% of patients) was diarrhea (3.2%).

Dosage reductions or discontinuations due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively.

Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients.

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 twice daily.

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

There is insufficient clinical data on CALQUENCE use in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Advise women of the potential risk to a fetus.

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.

Indication and Usage

CALQUENCE is a Bruton tyrosine kinase (BTK) inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Please see complete Prescribing Information including Patient Information.

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Reference:

  1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.

References:

  1. Dreyling M, Aurer I, Cortelazzo S, et al. Treatment for patients with relapsed/refractory mantle cell lymphoma: European-based recommendations. Leuk Lymphoma. 2018;59(8):1814-1828.
  2. Sandoval-Sus JD, Sotomayor EM, Shah BD. Mantle cell lymphoma: contemporary diagnostic and treatment perspectives in the age of personalized medicine. Hematol Oncol Stem Cell Ther. 2017;10(3):99-115.
  3. Shah BD, Martin P, Sotomayor EM. Mantle cell lymphoma: a clinically heterogeneous disease in need of tailored approaches. Cancer Control. 2012;19(3):227-235.
  4. Parrott M, Rule S, Kelleher M, Wilson J. A systemic review of treatments of relapsed/refractory mantle cell lymphoma. Clin Lymphoma Myeloma Leuk. 2018;18(1):13-25.
  5. Cohen JB, Zain JM, Kahl BS. Current approaches to mantle cell lymphoma: diagnosis, prognosis, and therapies. Am Soc Clin Oncol Educ Book. 2017;37:512-525.
  6. Cheah CY, Seymour JF, Wang ML. Mantle cell lymphoma. J Clin Oncol. 2016;34:1256-1269.
  7. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659-667.
  8. Dreyling M, Ferrero S; on behalf of European Mantle Cell Lymphoma Network. The role of targeted treatment in mantle cell lymphoma: is transplant dead or alive? Haematologica. 2016;101(2):104-114.
  9. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas V.4.2018. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed May 17, 2018. To view the most recent and complete version of the guideline, go online to NCCN.org.
  10. Pal Singh S, Dammeijer F, Hendriks RW. Role of Bruton’s tyrosine kinase in B cells and malignancies. Mol Cancer. 2018;17(1):57.
  11. Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): A covalent bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J Pharmacol Exp Ther. 2017;363(2):240-252.
  12. Barf T, Kaptein A. Irreversible protein kinase inhibitors: balancing the benefits and risks. J Med Chem. 2012;55(14):6243-6262.
  13. Paweletz CP, Andersen JN, Pollock R, et al. Identification of direct target engagement biomarkers for kinase-targeted therapeutics. PLoS One. 2011;6(10):e26459.
  14. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.

Reference:

  1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas V.4.2018. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed May 17, 2018. To view the most recent and complete version of the guideline, go online to NCCN.org.

References:

  1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.
  2. Hendriks RW, Yuvaraj S, Kil LP. Targeting Bruton’s tyrosine kinase in B cell malignancies. Nat Rev Cancer. 2014;14(4):219-232.
  3. Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): A covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J Pharmacol Exp Ther. 2017;363(2):240-252.

References:

  1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.
  2. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659-667.
  3. Data on File, REF-33702, AstraZeneca Pharmaceuticals LP.

References:

  1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.
  2. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659-667.
  3. Data on File, REF-43179. AstraZeneca Pharmaceuticals LP.

References:

  1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.
  2. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659-667.
  3. Data on File, REF-43179. AstraZeneca Pharmaceuticals LP.
  4. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano Classification. J Clin Oncol. 2014;32:3059-3068.
  5. Data on File, REF-18540. AstraZeneca Pharmaceuticals LP.

References:

  1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.
  2. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659-667.
  3. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano Classification. J Clin Oncol. 2014;32:3059-3068.
  4. Data on File, REF-43179. AstraZeneca Pharmaceuticals LP.

References:

  1. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659-667.
  2. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.
  3. Data on File, REF-43179, AstraZeneca Pharmaceuticals LP.

Reference:

  1. CALQUENCE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.