Concert Genetic Testing: Hematologic Conditions (non-cancerous) V1.2025 Date of Last Revision: 11/2024 CENTENE Corporation Revision log Coding Implications

CONCERT GENETIC TESTING: HEMATOLOGIC CONDITIONS (NON-CANCEROUS)

See Important Reminder at the end of this policy for important regulatory and legal information.

OVERVIEW

Genetic testing for hematologic (non-cancerous) conditions may be used to confirm a diagnosis in a patient who has signs and/or symptoms of a specific hematologic condition. Confirming the diagnosis may alter aspects of management and may eliminate the need for further diagnostic workup. This document addresses genetic testing for common hematologic (non-cancerous) conditions.

POLICY REFERENCE TABLE

Coding Implications

This clinical policy references Current Procedural Terminology (CPT®). CPT is a registered trademark of the American Medical Association. All CPT codes and descriptions are copyrighted 2023, American Medical Association. All rights reserved. CPT codes and CPT descriptions are from the current manuals and those included herein are not intended to be all-inclusive and are included for informational purposes only. Codes referenced in this clinical policy are for informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage. Providers should refer to the most up-to-date sources of professional coding guidance prior to the submission of claims for reimbursement of covered services.

The tests, associated laboratories, CPT codes, and ICD codes contained within this document serve only as examples to help users navigate claims and corresponding criteria; as such, they are not comprehensive and are not a guarantee of coverage or non-coverage. Please see the Concert Platform for a comprehensive list of registered tests.

OTHER RELATED POLICIES

This policy document provides criteria for Genetic Testing for Hematologic Conditions (Non-Cancerous). Please refer to:

• Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies for criteria related to exome and genome sequencing of solid tumors and hematologic malignancies.
• Genetic Testing: Prenatal and Preconception Carrier Screening for criteria related to carrier screening in the prenatal, preimplantation, and preconception setting.
• Genetic Testing: Prenatal Diagnosis (via amniocentesis, CVS, or PUBS) and Pregnancy Loss for coverage related to prenatal and pregnancy loss diagnostic genetic testing for tests intended to diagnose genetic conditions following amniocentesis, chorionic villus sampling or pregnancy loss.
• Genetic Testing: Multisystem Inherited Disorders, Intellectual Disability, and Developmental Delay for criteria related to diagnostic genetic testing for conditions affecting multiple organ systems.
• Genetic Testing: Metabolic, Endocrine, and Mitochondrial Disorders for criteria related to genetic testing for MTHFR.
• Genetic Testing: General Approach to Genetic and Molecular Testing for criteria related to genetic testing for non-cancerous hematologic disorders that are not specifically discussed in this or another non-general policy, including known familial variant testing.

back to top

CRITERIA

It is the policy of health plans affiliated with Centene Corporation® that the specific genetic testing noted below is medically necessary when meeting the related criteria:

back to top

HEMOGLOBINOPATHIES

back to top

HEMOPHILIA

GLUCOSE-6-PHOSPHATE DEHYDROGENASE (G6PD) DEFICIENCY

back to top

VON-WILLEBRAND DISEASE

back to top

back to top

DEFINITIONS

1. Close relatives include first, second, and third degree blood relatives on the same side of the family:

   a. First-degree relatives are parents, siblings, and children. b. Second-degree relatives are grandparents, aunts, uncles, nieces, nephews, grandchildren, and half siblings. c. Third-degree relatives are great grandparents, great aunts, great uncles, great grandchildren, and first cousins.

2. Nonsurgical transient risk factors include confinement to bed in the hospital with acute illness for at least 3 days, or a combination of minor transient risk factors such as admission of less than 3 days with acute illness or confinement to bed outside of hospital for at least 3 days, or leg injury associated with decreased mobility for at least 3 days.

back to top

BACKGROUND AND RATIONALE

Factor V Leiden (F5) and Prothrombin (F2) Variant Analysis for Inherited Thrombophilia

American Society of Hematology (ASH)

Evidence based guidelines published in 2023 provide recommendations for testing for thrombophilia, including hereditary and acquired types. These recommendations are helpful to guide anticoagulation treatment for patients with a personal or family history of venous thromboembolism (VTE).

The panel provided conditional recommendations for thrombophilia testing in the following scenarios:

• patients with VTE associated with nonsurgical major transient or hormonal risk factors;
• patients with cerebral or splanchnic venous thrombosis, in settings where anticoagulation would otherwise be discontinued;
• individuals with a family history (first or second degree relative) of VTE when considering thromboprophylaxis for minor provoking risk factors and for guidance to avoid COCs/hormone replacement therapy;
• pregnant women with a family history (first or second degree relative) of high-risk thrombophilia types;
• patients with cancer receiving systemic therapy at low or intermediate risk of thrombosis and with a family history (first or second degree relative) of VTE.

The panel also strongly recommends against thrombophilia testing in the general population before starting combined oral contraceptives. (p. 7101)

American College of Obstetricians and Gynecologists (ACOG)

ACOG also published Practice Bulletin 197 (2018) on Inherited Thrombophilias in Pregnancy which states that “...screening for inherited thrombophilias is not recommended for women with a history of fetal loss or adverse pregnancy outcomes including abruption, preeclampsia, or fetal growth restriction because there is insufficient clinical evidence that antepartum prophylaxis with unfractionated heparin or low-molecular-weight-heparin prevents recurrence in these patients, and a causal association has not been established.” (p. e23)

HBA1/HBA2 and/or HBB Variant Analysis

GeneReviews is an expert-authored review of current literature on a genetic disease, and goes through a rigorous editing and peer review process before being published online.

The recommended hemoglobinopathy evaluation testing for Alpha-Thalassemia, Beta-Thalassemia, and Sickle Cell Disease is as follows:

GeneReviews: Alpha-Thalassemia

Hemoglobin Bart hydrops fetalis (Hb Bart) syndrome, which is caused by deletion or inactivation of all four alpha globin genes, exhibits the following hematologic findings: severe macrocytic hypochromic anemia (in the absence of ABO or Rh blood group incompatibility), reticulocytosis (may be >60%), and peripheral blood smear with large, hypochromic red cells, severe anisopoikilocytosis, and numerous nucleated red cells. In addition, hemoglobin analysis will typically display decreased amounts or complete absence of hemoglobin A and increased amounts of Hb Bart.

Hemoglobin H disease (HbH disease), which is caused by deletion or inactivation of three alpha globin genes, exhibits the following hematologic findings: mild-to-moderate (rarely severe) microcytic hypochromic anemia, moderate reticulocytosis (3%-6%). Peripheral blood smear with anisopoikilocytosis, and very rarely nucleated red blood cells. Red blood cell supravital stain showing HbH inclusions (β4 tetramers) in 5%-80% of erythrocytes following incubation of fresh blood smears with 1% brilliant cresyl blue for one to three hours. In addition, hemoglobin analysis will typically display the presence of 0.8%-40% HbH and 60%-90% hemoglobin A.

GeneReviews: Beta-Thalassemia

Beta-Thalassemia typically displays the following hematologic findings: microcytic hypochromic anemia, absence of iron deficiency, anisopoikilocytosis with nucleated red blood cells on peripheral blood smear, and decreased or complete absence of hemoglobin A (HbA) and increased hemoglobin A2 (HbA2) and often hemoglobin F (HbF) on hemoglobin analysis.

GeneReviews: Sickle Cell Disease

Laboratory features of sickle cell disease include: normocytic anemia; sickle cells, nucleated red blood cells, target cells, and other abnormal red blood cells on peripheral blood smear; Howell-Jolly bodies indicate hyposplenism; presence of hemoglobin (HbS) on a high-performance liquid chromatography [HPLC], isoelectric focusing, cellulose acetate electrophoresis, citrate agar electrophoresis) with an absence or diminished amount of HbA.

Viprakasit V, Ekwattanakit S. Clinical classification, screening and diagnosis for thalassemia

Viprakasit and Ekwattanakit (2018) published a clinical classification, screening and diagnosis for thalassemia article that states:

Concert Genetic Testing: Hematologic Conditions (non-cancerous)
V1.2025
Date of Last Revision: 11/2024

“In general, these mutation analyses would be critical for the confirmation of thalassemia diagnoses in only a few selected cases for whom the basic hematology and Hb analysis described could not provide a conclusive diagnosis. However, these molecular analyses would be indispensable in a program for the prevention and control of thalassemia syndromes because the mutation data would be required for genetic counseling, genetic risk calculation in the offspring, and prenatal and preimplantation genetic diagnosis. In addition, DNA analysis could help in predicting the clinical severity and guiding clinical management; milder b-globin mutations (b1-thal) usually are associated with milder phenotypes, as has been shown in HbE/b-thalassemia.” (p. 207)

Factor VIII (F8) and Factor IX (F9) Variant Analysis for Hemophilia A and B

GeneReviews is an expert-authored review of current literature on a genetic disease, and goes through a rigorous editing and peer review process before being published online. The recommended hemoglobinopathy evaluation testing for Hemophilia A and Hemophilia B is as follows:

GeneReviews: Hemophilia A and Hemophilia B

Individuals with Hemophilia A (factor VIII deficiency) or Hemophilia B (factor IX deficiency) can exhibit the following clinical symptoms:

• Hemarthrosis, especially with mild or no antecedent trauma
• Deep-muscle hematomas
• Intracranial bleeding in the absence of major trauma
• Neonatal cephalohematoma or intracranial bleeding
• Prolonged oozing or renewed bleeding after initial bleeding stops following tooth extractions, mouth injury, or circumcision
• Prolonged or delayed bleeding or poor wound healing following surgery or trauma
• Unexplained GI bleeding or hematuria
• Heavy menstrual bleeding, especially with onset at menarche
• Prolonged nosebleeds, especially recurrent and bilateral
• Excessive bruising, especially with firm, subcutaneous hematomas

The following are laboratory findings in individuals with Hemophilia A or Hemophilia B:

• Normal platelet count
• Prolonged activated partial thromboplastin time (aPTT) (Note: in mild hemophilia B, aPTT may be normal or mildly prolonged)
• Normal prothrombin time (PT)

11

Concert Genetic Testing: Hematologic Conditions (non-cancerous)
V1.2025
Date of Last Revision: 11/2024

G6PD Variant Analysis

American Academy of Family Physicians

Frank (2005) published guidelines in American Family Physician for evaluating individuals for G6PD deficiency, including specific laboratory tests which notably do not include genetic testing:
“The diagnosis of G6PD deficiency is made by a quantitative spectrophotometric analysis or, more commonly, by a rapid fluorescent spot test detecting the generation of NADPH from NADP. The test is positive if the blood spot fails to fluoresce under ultraviolet light.” (p. 1278)

UpToDate: Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency

Per this summary of G6PD diagnosis and management, the tests commonly used are semi-quantitative screening tests, some of which are done at the point-of-care. Positive screening tests should be followed up with a quantitative test that reports G6PD enzyme activity per gram of hemoglobin. If initial results are negative, testing should be repeated three months following resolution of the hemolytic episode. Confirmatory testing using molecular methods (DNA) is available; however, it is not used routinely and is not useful for those of African or Mediterranean ancestry.

VWF Variant Analysis

Centers for Disease Control and Prevention (CDC)

Guidelines for diagnosis and management of von Willebrand disease (VWD) were developed by the CDC for practicing primary care and specialist clinicians - including family physicians, internists, obstetrician-gynecologists, pediatricians, and nurse-practitioners - as well as hematologists and laboratory medicine specialists, which included recommendations for laboratory tests to aid in the diagnosis of VWD, which notably do not include genetic testing.

back to top

12

Concert Genetic Testing: Hematologic Conditions (non-cancerous)
V1.2025
Date of Last Revision: 11/2024

Important Reminder
This clinical policy has been developed by appropriately experienced and licensed health care professionals based on a review and consideration of currently available generally accepted standards of medical practice; peer-reviewed medical literature; government agency/program

14

Concert Genetic Testing: Hematologic Conditions (non-cancerous)
V1.2025
Date of Last Revision: 11/2024

approval status; evidence-based guidelines and positions of leading national health professional organizations; views of physicians practicing in relevant clinical areas affected by this clinical policy; and other available clinical information. The Health Plan makes no representations and accepts no liability with respect to the content of any external information used or relied upon in developing this clinical policy. This clinical policy is consistent with standards of medical practice current at the time that this clinical policy was approved. “Health Plan” means a health plan that has adopted this clinical policy and that is operated or administered, in whole or in part, by Centene Management Company, LLC, or any of such health plan’s affiliates, as applicable.

The purpose of this clinical policy is to provide a guide to medical necessity, which is a component of the guidelines used to assist in making coverage decisions and administering benefits. It does not constitute a contract or guarantee regarding payment or results. Coverage decisions and the administration of benefits are subject to all terms, conditions, exclusions, and limitations of the coverage documents (e.g., evidence of coverage, certificate of coverage, policy, contract of insurance, etc.), as well as to state and federal requirements and applicable Health Plan-level administrative policies and procedures.

This clinical policy is effective as of the date determined by the Health Plan. The date of posting may not be the effective date of this clinical policy. This clinical policy may be subject to applicable legal and regulatory requirements relating to provider notification. If there is a discrepancy between the effective date of this clinical policy and any applicable legal or regulatory requirement, the requirements of law and regulation shall govern. The Health Plan retains the right to change, amend or withdraw this clinical policy, and additional clinical policies may be developed and adopted as needed, at any time.

This clinical policy does not constitute medical advice, medical treatment, or medical care. It is not intended to dictate to providers how to practice medicine. Providers are expected to exercise professional medical judgment in providing the most appropriate care and are solely responsible for the medical advice and treatment of member/enrollees. This clinical policy is not intended to recommend treatment for member/enrollees. Member/enrollees should consult with their treating physician in connection with diagnosis and treatment decisions.

Providers referred to in this clinical policy are independent contractors who exercise independent judgment and over whom the Health Plan has no control or right of control. Providers are not agents or employees of the Health Plan.

This clinical policy is the property of the Health Plan. Unauthorized copying, use, and distribution of this clinical policy or any information contained herein are strictly prohibited. Providers, member/enrollees, and their representatives are bound to the terms and conditions expressed herein through the terms of their contracts. Where no such contract exists, providers,

15

Concert Genetic Testing: Hematologic Conditions (non-cancerous)
V1.2025
Date of Last Revision: 11/2024

member/enrollees and their representatives agree to be bound by such terms and conditions by providing services to member/enrollees and/or submitting claims for payment for such services.

Note: For Medicaid member/enrollees, when state Medicaid coverage provisions conflict with the coverage provisions in this clinical policy, state Medicaid coverage provisions take precedence. Please refer to the state Medicaid manual for any coverage provisions pertaining to this clinical policy.

Note: For Medicare member/enrollees, to ensure consistency with the Medicare National Coverage Determinations (NCD) and Local Coverage Determinations (LCD), all applicable NCDs and LCDs and Medicare Coverage Articles should be reviewed prior to applying the criteria set forth in this clinical policy. Refer to the CMS website at http://www.cms.gov for additional information.

©2018 Centene Corporation. All rights reserved. All materials are exclusively owned by Centene Corporation and are protected by United States copyright law and international copyright law. No part of this publication may be reproduced, copied, modified, distributed, displayed, stored in a retrieval system, transmitted in any form or by any means, or otherwise published without the prior written permission of Centene Corporation. You may not alter or remove any trademark, copyright or other notice contained herein. Centene® and Centene Corporation® are registered trademarks exclusively owned by Centene Corporation.

back to top

16