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Date Printed: April 22, 2018: 05:43 PM

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This medical policy (medical coverage guideline) is Copyright 2017, Blue Cross and Blue Shield of Florida (BCBSF). All Rights Reserved. You may not copy or use this document or disclose its contents without the express written permission of BCBSF. The medical codes referenced in this document may be proprietary and owned by others. BCBSF makes no claim of ownership of such codes. Our use of such codes in this document is for explanation and guidance and should not be construed as a license for their use by you. Before utilizing the codes, please be sure that to the extent required, you have secured any appropriate licenses for such use. Current Procedural Terminology (CPT) is copyright 2017 American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values, or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS restrictions apply to government use. CPT® is a trademark of the American Medical Association. The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

09-J2000-94

Original Effective Date: 03/15/18

Reviewed: 02/14/18

Revised: 00/00/00

Next Review: 07/10/19

Subject: Acalabrutinib (Calquence) Oral

THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION.

           
Dosage/ Administration Position Statement Billing/Coding Reimbursement Program Exceptions Definitions
           
Related Guidelines Other References Updates    
           

DESCRIPTION:

Acalabrutinib (Calquence) is an irreversible Bruton tyrosine kinase (BTK) inhibitor first approved by the U.S. Food and Drug Administration (FDA) in October 2017 for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. It was granted an accelerated approval based on overall response rate, and continued approval may be contingent upon verification of clinical benefit in confirmatory trials. Acalabrutinib is also being investigated for the treatment of various other B-cell malignancies. Prior to approval acalabrutinib was granted orphan designation by the FDA for the treatment of MCL in September 2015. Acalabrutinib also has orphan designations for the treatment of chronic lymphocytic leukemia (CLL) (May 2015) and the treatment of Waldenstrom macroglobulinemia (October 2015). Acalabrutinib is the second BTK inhibitor to be approved by the FDA. Ibrutinib (Imbruvica) was the first BTK inhibitor to be approved by the FDA in November 2013. Bruton tyrosine kinase is a signaling molecule early in the B-cell antigen receptor (BCR) signaling cascade, and the inhibition of BTK enzymatic activity leads to the inhibition of malignant B-cell proliferation and survival. Acalabrutinib is a “second generation” BTK inhibitor and was designed to be more potent and selective than ibrutinib. However, the clinical significance of these attributes is unknown.

Mantle cell lymphoma is a subtype of non-Hodgkin lymphoma (NHL) that accounts for about 6% of all NHL cases. MCL is thought to possess the worst characteristics of both indolent and aggressive NHL subtypes owing to the incurability of disease with conventional chemotherapies and a more aggressive disease course. Treatment of MCL is dependent on the extent of disease (clinical stage), if the disease is more aggressive or indolent, and if the patient is a candidate for stem cell transplantation. Most patients with aggressive disease will require combination induction chemotherapy with rituximab followed by rituximab maintenance therapy (for patients that achieved a complete response). Second-line agents are used when a complete response cannot be achieved with first-line induction or in patients with disease relapse. An allogenic stem cell transplant can be considered as second-line consolidation therapy. The National Comprehensive Cancer Network (NCCN) Guidelines for B-cell Lymphomas (Version 7.2017) list acalabrutinib as a second-line therapy for the treatment of relapsed or refractory MCL lymphoma (category 2A recommendation). Other category 2A second-line therapies listed by NCCN include: bendamustine ± rituximab, bortezomib ± rituximab, cladribine + rituximab, ibrutinib, lenalidomide ± rituximab, and venetoclax. No second-line therapy is currently given a category 1 recommendation. In addition, the NCCN Guidelines for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) (Version 3.2018) list acalabrutinib monotherapy as a Category 2A recommendation under “Other recommended regimens” for the treatment of relapsed/refractory CLL/SLL with or without del(17p)/TP53 mutation with an additional footnote of “Acalabrutinib should not be used for ibrutinib refractory CLL/SLL in patients with BTK C481S mutations. Patients with ibrutinib intolerance have been successfully treated with acalabrutinib without recurrence of these symptoms.”

The safety and efficacy of acalabrutinib leading to FDA approval for MCL was based upon Trial LY-004 titled “An Open-label, Phase 2 Study of ACP-196 in Subjects with Mantle Cell Lymphoma” (NCT02213926). The single-arm trial enrolled a total of 124 adults (≥18 years of age) with MCL who had received at least one prior therapy. The median age was 68 (range 42 to 90) years, 80% were male, and 74% were Caucasian. At baseline, 93% of patients had an ECOG performance status of 0 or 1. The median time since diagnosis was 46.3 months and the median number of prior treatments was 2 (range of 1 to 5), including 18% with prior stem cell transplant. Patients who received prior treatment with BTK inhibitors were excluded. The most common prior regimens were CHOP-based (52%) and ARA-C (34%). Acalabrutinib was administered orally at 100 mg twice daily until disease progression or unacceptable toxicity. Tumor response was assessed according to the Lugano Classification for Non-Hodgkin’s lymphoma. The major efficacy outcome was overall response rate (ORR). The independent review committee-assessed ORR was 80% (complete response rate of 40%). At a median follow-up of 15.2 months, the median time to best response was 1.9 months and the median duration of response was not reached (range, up to greater than 20 months). A temporary increase in lymphocyte counts occurred in 31.5% of patients. The median time to onset of lymphocytosis was 1.1 weeks and the median duration of lymphocytosis was 6.7 weeks.

POSITION STATEMENT:

Comparative Effectiveness

The FDA has deemed the drug(s) or biological product(s) in this coverage policy to be appropriate for self-administration or administration by a caregiver (i.e., not a healthcare professional). Therefore, coverage (i.e., administration) in a provider-administered setting such as an outpatient hospital, ambulatory surgical suite, physician office, or emergency facility is not considered medically necessary.

Initiation of acalabrutinib (Calquence) meets the definition of medical necessity when ALL of the following criteria are met (“1”, “2”, “3”, “4”, “5”, and “6”):

1. Member has a confirmed diagnosis of any of the following (“a”, “b”, or “c”):

a. Relapsed or refractory mantle cell lymphoma (MCL)

b. Relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)

c. Relapsed or refractory Waldenstrom macroglobulinemia - laboratory documentation of the member’s baseline (i.e., within 60 days prior to initiating treatment with acalabrutinib) serum IgM level must be submitted

2. The member has received at least ONE prior therapy for the treatment of their disease

3. The member has NOT previously had refractory disease (i.e., disease progression on treatment or progression within 60 days after the last dose of a given therapy) during treatment with ibrutinib (Imbruvica)*

4. Acalabrutinib will be used as monotherapy

5. Acalabrutinib will NOT be taken concurrently with a proton pump inhibitor (PPI)

6. The dosage of acalabrutinib does not exceed 100 mg twice daily

*An exception is permitted if the member is negative for the BTK C481S mutation the DNA sequencing results confirming absence of the mutation must be submitted

Approval duration: 6 months

Continuation of acalabrutinib (Calquence) meets the definition of medical necessity when ALL of the following criteria are met (“1”, “2”, “3”, “4”, and “5”):

1. The member has been previously approved by Florida Blue or another health plan in the past 2 years for the treatment of MCL, Waldenstrom macroglobulinemia, or CLL/SLL, OR the member has previously met all initiation criteria

2. The member has not had disease progression during treatment with acalabrutinib

3. Acalabrutinib is being used as monotherapy

4. Acalabrutinib is NOT being taken concurrently with a PPI

5. The dosage of acalabrutinib does not exceed 100 mg twice daily

Approval duration: 12 months

DOSAGE/ADMINISTRATION:

THIS INFORMATION IS PROVIDED FOR INFORMATIONAL PURPOSES ONLY AND SHOULD NOT BE USED AS A SOURCE FOR MAKING PRESCRIBING OR OTHER MEDICAL DETERMINATIONS. PROVIDERS SHOULD REFER TO THE MANUFACTURER’S FULL PRESCRIBING INFORMATION FOR DOSAGE GUIDELINES AND OTHER INFORMATION RELATED TO THIS MEDICATION BEFORE MAKING ANY CLINICAL DECISIONS REGARDING ITS USAGE.

FDA-approved

• 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.

• The recommended dose is 100 mg taken orally approximately every twelve hours until disease progression or unacceptable toxicity. Advise patients not to break, open, or chew capsules. Avoid concomitant use with proton pump inhibitors.

Dose Adjustments

• Renal impairment: no dosage adjustment is needed in patients with mild or moderate renal impairment (eGFR ≥30 mL/min/1.73m2). Data is not available in patients with severe renal impairment or renal impairment requiring dialysis.

• Hepatic impairment: no dosage adjustment is needed in patients with mild or moderate hepatic impairment (Child-Pugh A and B). Data is not available in patients with severe hepatic impairment (Child-Pugh C).

• Dose Modifications for Grade 3 or greater non-hematologic toxicities, Grade 3 thrombocytopenia with bleeding, Grade 4 thrombocytopenia, or Grade 4 neutropenia lasting longer than 7 days:

o First and Second Occurrence: Interrupt treatment. Once toxicity has resolved to Grade 1 or baseline level, treatment may be resumed at 100 mg twice daily.

o Third Occurrence: Interrupt treatment. Once toxicity has resolved to Grade 1 or baseline level, treatment may be resumed at 100 mg daily.

o Fourth Occurrence: Discontinue treatment

• Dose Modifications for Use with CYP3A Inhibitors or Inducers:

o Strong CYP3A inhibitor: Avoid concomitant use. If these inhibitors will be used short-term (such as anti-infectives for up to seven days), interrupt acalabrutinib treatment.

o Moderate CYP3A inhibitor: 100 mg once daily

o Strong CYP3A inducer: Avoid concomitant use. If these inducers cannot be avoided, increase the acalabrutinib dose to 200 mg twice daily

Drug Availability

• 100 mg capsules in a 60-count bottle

PRECAUTIONS:

Boxed Warning

• None

Contraindications

• None

Precautions/Warnings

• Hemorrhage: Serious hemorrhagic events, including fatal events, have occurred. Monitor for bleeding and manage appropriately.

• Infections: Serious infections (bacterial, viral or fungal), including fatal events and opportunistic infections have occurred. In the combined safety database, Grade 3 or higher infections occurred in 18% of these patients. Consider prophylaxis in patients who are at increased risk for opportunistic infections. Monitor patients for signs and symptoms of infection and treat as needed

• Cytopenias: In the combined safety database, patients treated with acalabrutinib 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: In the combined safety database, second primary malignancies, including non-skin carcinomas, have occurred in 11% of patients. The most frequent second primary malignancy was skin cancer, reported in 7% of patients. Advise patients to use sun protection.

• Atrial Fibrillation and Flutter: Monitor for atrial fibrillation and atrial flutter and manage as appropriate.

• Pregnancy: Based on findings in animals, acalabrutinib may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus.

• Lactation: Acalabrutinib and its active metabolite were present in the milk of lactating rats. Advise women not to breastfeed while taking acalabrutinib and for at least 2 weeks after the final dose.

• Drug Interactions:

o CYP3A Inhibitors: Avoid co-administration with strong CYP3A inhibitors. Dose adjustments may be recommended.

o CYP3A Inducers: Avoid co-administration with strong CYP3A inducers. Dose adjustments may be recommended

o Gastric Acid Reducing Agents: Avoid co-administration with proton pump inhibitors (PPIs). Stagger dosing with H2-receptor antagonists (2 hours before) and antacids (2 hours before or after).

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding

J8999

Prescription drug, oral, chemotherapeutic, Not Otherwise Specified

ICD-10 Diagnoses Codes That Support Medical Necessity

C83.00 – C83.09

Small cell B-cell lymphoma

C83.10 – C83.19

Mantle cell lymphoma

C88.00

Waldenström’s macroglobulinemia

C91.10 – C91.12

Chronic lymphocytic leukemia of B-cell type

REIMBURSEMENT INFORMATION:

Refer to section entitled POSITION STATEMENT.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Part D: BCBSF has delegated to Prime Therapeutics authority to make coverage determinations for the Medicare Part D services referenced in this guideline.

Medicare Advantage: No National Coverage Determination (NCD) and/or Local Coverage Determination (LCD) were found at the time of guideline creation.

DEFINITIONS:

None

RELATED GUIDELINES:

Ibrutinib (Imbruvica), 09-J2000-09

OTHER:

None

REFERENCES:

  1. 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 Nov;363(2):240-252. Epub 2017 Sep.
  2. Byrd JC, Harrington B, O'Brien S, et al. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jan 28;374(4):323-32. Epub 2015 Dec 7.
  3. Calquence (acalabrutinib capsules) [package insert], AstraZeneca Pharmaceuticals; Wilmington, DE. October 2017.
  4. Clinical Pharmacology [Internet]. Tampa (FL): Gold Standard, Inc.; 2018 [cited 2018 Jan 25]. Available from: http://www.clinicalpharmacology.com/.
  5. DRUGDEX System [Internet]. Greenwood Village (CO): Thomson Micromedex; Updated periodically [cited 2018 Jan 25]. Available from: http://www.thomsonhc.com/.
  6. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines). B-cell Lymphomas (Version 7.2017) [cited 2018 Jan 25]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf
  7. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines). B-cell Lymphomas (Version 3.2018) [cited 2018 Feb 13]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf
  8. NCCN Drugs & Biologics Compendium [Internet]. Fort Washington (PA): National Comprehensive Cancer Network; 2018 [cited 2018 Jan 25]. Available from: http://www.nccn.org/professionals/drug_compendium/content/contents.asp.
  9. Orphan Drug Designations and Approval [Internet]. Silver Spring (MD): US Food and Drug Administration; 2018 [cited 2018 Jan 25]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm/.
  10. Patel V, Balakrishnan K, Bibikova E, et al. Comparison of Acalabrutinib, A Selective Bruton Tyrosine Kinase Inhibitor, with Ibrutinib in Chronic Lymphocytic Leukemia Cells. Clin Cancer Res. 2017 Jul 15;23(14):3734-3743. Epub 2016 Dec 29.
  11. 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. 2017 Dec 11. pii: S0140-6736(17)33108-2. [Epub ahead of print].
  12. Wu J, Zhang M, and Liu D. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol 2016;9:21.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 02/14/18.

GUIDELINE UPDATE INFORMATION:

03/15/18

New Medical Coverage Guideline.

Date Printed: April 22, 2018: 05:43 PM