Genetic Testing for Cystic Fibrosis Form

Description

Cystic fibrosis (CF) is an inherited disorder that causes severe damage to the lungs, pancreas and sweat glands. CF is the result of mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. It is characterized by the production of abnormally viscous mucus produced by the affected glands bringing about infections, inflammation, respiratory failure and other complications.

The diagnosis of CF is a multistage process. For infants, it involves newborn screening (NBS) (eg, immunoreactive trypsinogen [IRT] and/or genetic testing), sweat chloride testing and additional genetic testing, when appropriate. Genetic testing is utilized for additional indications aiding in the diagnosis of an individual with signs and symptoms of the disease and carrier screening for reproductive decision-making.

Genetic Testing for Cystic Fibrosis

Effective Date: 08/24/2023

Revision Date: 08/24/2023

Review Date: 08/24/2023

Policy Number: HUM-0526-015

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

CFTR gene mutation panels analyze multiple CF pathogenic variants (mutations) simultaneously. The CF standard panel, which had been the testing of choice, included only 23 of the most common mutations based on the population in the United States; however, with the advancement of technology, laboratories now incorporate the 23 variants plus numerous additional genes.

Complete (or full) CFTR gene analysis by sequencing utilizes next-generation sequencing (next-gen sequencing, NGS) to provide a comprehensive scan of the CFTR gene and should not be used for routine screening testing. One application of the technology is to detect the presence of CFTR mutations to determine who may benefit from treatment with CFTR modulators. These prescription drugs include:

• Kalydeco (ivacaftor) is indicated for an individual 1 month of age or older who have one of the following mutations in the CFTR gene:
  • 2789+5G→A, 3272‐26A→G, 3849+10kbC→T, 3945L, 5977F, 711+3A→G, A1067T, A455E, D110E, D110H, D1152H, D1270N, D579G, E193K, E56K, E831X, F1052V, F1074L, G1069R, G1244E, G1349D, G178R, G551D, G551S, K1060T, L206W, P67L, R1070Q, R1070W, R117C, R117H, R347H, R352Q, R74W, S1251N, S1255P, S549N, S549R, S945L or S977F
• Orkambi (lumacaftor/ivacaftor) has been US Food & Drug Administration (FDA) approved for an individual 1 year of age or older who are homozygous for the F508del mutation in the CFTR gene
• Symdeko (tezacaftor-ivacaftor) is prescribed for an individual 6 years of age or older who have one of the following mutations in the CFTR gene:
  • Homozygous F508del, A1067T, A455E, D110E, D110H, D1152H, D1270N, D579G, E193K, E56K, E831X, F1052V, F1074L, K1060T, L206W, P67L, R1070W, R117C, R347H, R352Q, R74W, S945L, S977F, 2789+5G-->A, 3272-26A-->G, 3849+10kbC-->T, 711+3A-->G
• Trikafta (elexacaftor-tezacaftor-ivacaftor) is used for an individual 2 years of age or older who have at least one F508del mutation in the CFTR gene

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. For information regarding Kalydeco, Orkambi, Symdeko or Trikafta, please refer to Kalydeco (ivacaftor), Orkambi (lumacaftor/ivacaftor), Symdeko (tezacaftor-ivacaftor) or Trikafta (elexacaftor-tezacaftor-ivacaftor) Pharmacy Coverage Policies.

CFTR deletion/duplication testing may be initiated by the laboratory as a reflex test following CFTR gene sequencing. This type of testing has been proposed for CF to identify the absence (deletion) of a segment of DNA and/or the presence of an extra segment (duplication) of DNA in a coding region.

Reflex testing for the 5T allele may be initiated by the laboratory, known as reflex testing, when the R117H mutation has been detected on CFTR genetic testing. This type of testing is not recommended for routine screening.

Single site CF genetic testing analyzes specific CFTR pathogenic variants that have been detected in an affected (diagnosed) blood relative.

For information about genetic testing for cystic fibrosis related to conditions not addressed in this policy, please see the following:

• Description of Procedure: Array comparative genomic hybridization
• Corresponding Medical Coverage Policy: Comparative Genomic
• Prenatal diagnosis to identify a fetus with CF
• Prenatal Invasive Diagnostic

For information regarding genetic testing for the following, please refer to Genetic Testing Medical Coverage Policy:

• DNA banking or preservation
• General population screening
• Individual 17 years of age or younger for adult-onset conditions
• Interpretation and reporting for molecular pathology procedure
• Polygenic risk score (PRS) and single nucleotide polymorphisms (SNPs)
• Repeat germline or somatic genetic testing
• Retrieved archival tissue

Humana recognizes that the field of genetic testing is rapidly changing and that other tests may become available.

Coverage Determination

Any state mandates for genetic testing for CF take precedence over this medical coverage policy.

Please refer to the member’s applicable pharmacy benefit to determine benefit availability and the terms and conditions of coverage for medication for the treatment of CF.

Genetic testing may be excluded by certificate. Please consult the member’s individual certificate regarding Plan coverage.

Apply General Criteria for Genetic and Pharmacogenomics Tests when disease or gene-specific criteria are not available on a medical coverage policy. For information regarding general criteria for genetic tests, please refer to Genetic Testing Medical Coverage Policy.

CFTR Gene Mutation Panel Testing

Humana members may be eligible under the Plan for CFTR gene mutation panel testing for CF when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• For reproductive decision-making regardless of personal or family history or ethnicity; OR
• Individual to be tested diagnosed with bronchiectasis, idiopathic chronic or recurrent acute pancreatitis

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Humana members may be eligible under the Plan for complete CFTR gene analysis by sequencing and/or deletion/duplication analysis when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• Individual to be tested diagnosed with congenital absence of vas deferens (CAVD); OR
• Individual to be tested diagnosed with CF or exhibits signs/symptoms of CF and CFTR gene mutation panel is negative; OR
• Individual to be tested is diagnosed with CF and is under consideration for treatment with the following CFTR modulators:
  • Kalydeco (ivacaftor)
  • Orkambi (lumacaftor-ivacaftor)
  • Symdeko (tezacaftor-ivacaftor)
  • Trikafta (elexacaftor-tezacaftor-ivacaftor); OR
• Infant with positive NBS by serum IRT:
  • Inconclusive CFTR gene mutation panel testing; AND
  • Sweat chloride test is abnormal (at least 60 mmol/L), intermediate (30-59 mmol/L), inconclusive or cannot be performed (e.g., infant is too young to produce adequate volumes of sweat)
  *Testing strategy: If only one or no pathogenic variant is found by sequencing analysis, proceed to deletion/duplication analysis. Refer to Coverage Limitations section when deletion/duplication information is obtained as part of the sequencing procedure but submitted as an independent analysis.

Reflex CF Genetic Testing

Humana members may be eligible under the Plan for reflex CF genetic testing for 5T allele when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• CFTR gene analysis has detected the R117H mutation

Single Site CF Genetic Testing

Humana members may be eligible under the Plan for single site CF genetic testing when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• Individual to be tested has a first- or second-degree relative with a known CFTR pathogenic variant(s). Testing Strategy: Test appropriate affected family member first for familial mutations with CFTR gene mutation panel testing for CF unless unavailable for testing (e.g., deceased, declines genetic testing or unable to contact) or incomplete previous CF genetic testing

Note: The criteria for genetic testing for CF are not consistent with the Medicare National Coverage Policy, and therefore may not be applicable to Medicare members. Refer to the CMS website for additional information.

Coverage Limitations

Humana members may NOT be eligible under the Plan for genetic testing for CF for any indication or test other than those listed above including, but may not limited to, the following:

• Carrier screening in an individual who is not of reproductive age; OR
• Complete CFTR gene sequencing or 5T allele genotyping for routine carrier screening; OR
• Parental carrier screening when an affected child has a positive CF newborn screening (NBS) result

These are considered experimental/investigational as they are not identified as widely used and generally accepted for any other proposed uses as reported in nationally recognized peer-reviewed medical literature published in the English language.

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Humana members may NOT be eligible under the Plan for genetic testing for CF for any of the following:

• Deletion/duplication information is obtained as part of the sequencing procedure but submitted as an independent analysis
• Individual to be tested has an affected first-, second- or third-degree relative with a negative genetic testing result for the associated condition; OR
• Individual to be tested is unaffected and an affected first-, second- or third-degree relative who is available for genetic testing; OR
• KFV detection analysis using either of the following methods:
  1. Multigene panel that includes the KFV; OR
  2. Sequencing, deletion/duplication analysis or large genomic rearrangement analysis (conducted individually, as comprehensive testing or sequentially) without KFV results of a first, second- or third-degree relative

These are considered not medically necessary as defined in the member’s individual certificate. Please refer to the member’s individual certificate for the specific definition.

Background

Additional information about CF may be found from the following websites:

• American College of Obstetricians and Gynecologists
• Cystic Fibrosis Foundation
• Genetics Home Reference
• National Library of Medicine
• American Lung Association

Alternatives to genetic testing for CF include, but may not be limited to, the following:

• Sweat chloride testing

Physician consultation is advised to make an informed decision based on an individual’s health needs.

Humana may offer a disease management program for this condition. The member may call the number on his/her identification card to ask about our programs to help manage his/her care.

Any CPT, HCPCS or ICD codes listed on this medical coverage policy are for informational purposes only. Do not rely on the accuracy and inclusion of specific codes. Inclusion of a code does not guarantee coverage and or reimbursement for a service or procedure.

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

References

1. American College of Medical Genetics and Genomics (ACMG). ACMG Technical Standard. CFTR variant testing: a technical standard of the American College of Medical Genetics and Genomics (ACMG). https://www.acmg.net. Published August 2020. Accessed July 17, 2023.
2. American College of Obstetricians and Gynecologists (ACOG). Committee Opinion. Carrier screening for genetic conditions. https://www.acog.org. Published October 2005. Updated 2020. Accessed July 13, 2023.
3. American College of Obstetricians and Gynecologists (ACOG). Committee Opinion. Carrier screening in the age of genomic medicine. https://www.acog.org. Published March 2017. Updated 2020. Accessed July 13, 2023.
4. American Urological Association (AUA). Diagnosis and treatment of infertility in men: AUA/ASRM guideline. https://www.auanet.org. Published July 2020. Accessed July 17, 2023.
5. American Urological Association (AUA). The evaluation of the azoospermic male: best practice statement. https://www.auanet.org. Published July 22, 2011. Accessed July 17, 2023.
6. ClinicalKey. Clinical Overview. Cystic fibrosis. https://www.clinicalkey.com. Updated January 13, 2023. Accessed July 13, 2023.
7. Clinical Pharmacogenetics Implementation Consortium (CPIC). Guidelines for Ivacaftor therapy in the context of CFTR genotype. https://www.cpic.com. Published June 2014. Updated May 2019. Accessed July 19, 2023.
8. Genetic Testing for Cystic Fibrosis Effective Date: 08/24/2023 Revision Date: 08/24/2023 Review Date: 08/24/2023 Policy Number: HUM-0526-015 Page: 10 of 13
9. Cystic Fibrosis Foundation (CFF). Diagnosis of cystic fibrosis: consensus guidelines from the Cystic Fibrosis Foundation. https://www.cff.org. Published February 2017. Accessed July 19, 2023.
10. ECRI Institute. ECRIgene Genetic Test Hotline Response. Full gene CFTR sequencing versus targeted variant testing for cystic fibrosis carrier screening. https://www.ecri.org. Published March 2020. Accessed July 10, 2023.
11. Hayes, Inc. Genetic Test Evaluation (GTE) Report (ARCHIVED). Cystic fibrosis transmembrane regulator (CFTR) testing for cystic fibrosis. https://evidence.hayesinc.com. Published May 30, 2013. Updated May 13, 2015. Accessed July 10, 2023.
12. Hayes, Inc. Medical Technology Directory (ARCHIVED). Genetic carrier testing for cystic fibrosis. https://evidence.hayesinc.com. Published June 7, 2004. Updated August 1, 2008. Accessed July 10, 2023.
13. MCG Health. Cystic fibrosis - CFTR gene and mutation panel. 27th edition. https://www.mcg.com. Accessed July 12, 2023.
14. National Center for Biotechnology Information (NCBI). Genetic Testing Registry (GTR). Cystic fibrosis. https://www.ncbi.nlm.nih.gov/gtr. Published March 26, 2001. Updated March 9, 2023. Accessed July 19, 2023.
15. National Society of Genetic Counselors (NSGC). Professional Issues. Molecular testing for cystic fibrosis carrier status practice guidelines: recommendations of the National Society of Genetic Counselors. https://www.nsgc.org. Published February 2014. Updated 2018. Accessed July 19, 2023.
16. UpToDate, Inc. Approach to the male with infertility. https://www.uptodate.com. Updated June 2023. Accessed July 10, 2023.
17. UpToDate, Inc. Clinical manifestations and diagnosis of bronchiectasis in adults. https://www.uptodate.com. Updated June 2023.

17. UpToDate, Inc. Clinical manifestations and diagnosis of chronic and acute recurrent pancreatitis in children. https://www.uptodate.com. Updated June 2023. Accessed July 10, 2023.
18. UpToDate, Inc. Cystic fibrosis: carrier screening. https://www.uptodate.com. Updated June 2023. Accessed July 10, 2023.
19. UpToDate, Inc. Cystic fibrosis: clinical manifestations and diagnosis. https://www.uptodate.com. Updated June 2023. Accessed July 10, 2023.
20. UpToDate, Inc. Cystic fibrosis: overview of the treatment of lung disease. https://www.uptodate.com. Updated June 2023. Accessed July 10, 2023.
21. UpToDate, Inc. Cystic fibrosis: treatment with CFTR modulators. https://www.uptodate.com. Updated June 2023. Accessed July 10, 2023.
22. US Food & Drug Administration (FDA). 510(k) summary: Illumina MiSeqDx Cystic Fibrosis 139-Variant Assay. https://www.fda.gov. Published November 19, 2013. Accessed July 12, 2023.
23. US Food & Drug Administration (FDA). 510(k) summary: Illumina MiSeqDx Cystic Fibrosis Clinical Sequencing Assay. https://www.fda.gov. Published November 19, 2013. Accessed July 12, 2023.
24. US Food & Drug Administration (FDA). 510(k) summary: InPlex CF Molecular Test. https://www.fda.gov. Published March 13, 2008. Accessed July 12, 2023.
25. US Food & Drug Administration (FDA). 510(k) summary: xTAG Cystic Fibrosis 39 Kit v2. https://www.fda.gov. Published September 1, 2009. Accessed July 12, 2023.
26. US Food & Drug Administration (FDA). 510(k) summary: xTAG Cystic Fibrosis (CFTR) 60 Kit v2. https://www.fda.gov. Published December 15, 2016. Accessed July 12, 2023.

Genetic Testing for Cystic Fibrosis Effective Date: 08/24/2023 Revision Date: 08/24/2023 Review Date: 08/24/2023 Policy Number: HUM-0526-015 Page: 11 of 13

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

27. US Food & Drug Administration (FDA). Full prescribing information: Kalydeco (ivacaftor). https://www.fda.gov. Published 2012. Updated May 2023. Accessed July 12, 2023.
28. US Food & Drug Administration (FDA). Full prescribing information: Orkambi (lumacaftor/ivacaftor). https://www.fda.gov. Published 2015. Updated September 2022. Accessed July 12, 2023.
29. US Food & Drug Administration (FDA). Full prescribing information: Symdeko (tezacaftor-ivacaftor). https://www.fda.gov. Published 2018. Updated December 2020. Accessed July 12, 2023.
30. US Food & Drug Administration (FDA). Full prescribing information: Trikafta (elexacaftor-tezacaftor-ivacaftor). https://www.fda.gov. Published 2019. Updated April 2023. Accessed July 12, 2023.
31. Wainwright CE, Elborn JS, Ramsey BW et al. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for phe508del CFTR. N Engl J Med. 2015;373(3):220-231. https://www.nejm.org. Accessed July 12, 2023.

Genetic Testing for Cystic Fibrosis Effective Date: 08/24/2023 Revision Date: 08/24/2023 Review Date: 08/24/2023 Policy Number: HUM-0526-015 Page: 13 of 13

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version.

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Appendix A

Pre- and Post-Test Genetic Counseling Criteria

Pre- and post-test genetic counseling performed by any of the following qualified medical professionals:

• Genetic counselor who is board-certified or board-eligible by the American Board of Medical Genetics and Genomics (ABMGG) or American Board of Genetic Counseling, Inc (ABGC) and is not employed by a commercial genetic testing laboratory; OR
• Genetic clinical nurse (GCN) or advanced practice nurse in genetics (APNG) who is credentialed by the Genetic Nursing Credentialing Commission (GNCC) or the American of Nurses Credentialing Center (ANCC) and is not employed by a commercial genetic testing laboratory; OR
• Medical geneticist who is board-certified or board-eligible by ABMGG; OR
• Treating physician who has evaluated the individual to be tested and has completed a family history of three generations

Appendix B

Family Relationships