Next-Generation Sequencing for the Assessment of Measurable Residual Disease

POLICY NUMBER

A.2.04.147

DESCRIPTION

Measurable residual disease (MRD), also known as minimal residual disease, refers to residual clonal cells in blood or bone marrow following treatment for hematologic malignancies. MRD is typically assessed by flow cytometry or polymerase chain reaction, which can detect one clonal cell in 100,000 cells. It is proposed that next-generation sequencing (NGS), which can detect one residual clonal sequence out of 1,000,000 cells, will improve health outcomes in patients who have been treated for hematologic malignancies such as acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), and mantle cell lymphoma (MCL).

Disease

There are three main types of hematologic malignancies: lymphomas, leukemias, and myelomas. Lymphoma begins in lymph cells of the immune system, which originate in the bone marrow and collect in lymph nodes and other tissues. Leukemia is caused by the overproduction of abnormal white blood cells in the bone marrow, which leads to a decrease in the production of red blood cells and plasma cells. The most common forms of leukemia are acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, and chronic myeloid leukemia. Multiple myeloma (MM), also called plasma myeloma, is a malignancy of plasma cells in the bone marrow. This policy will address B-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, diffuse large B-cell lymphoma, and mantle cell lymphoma. As B-Cell acute lymphoblastic leukemia and B-Cell lymphoblastic lymphoma are generally considered clinically indistinct, reference to B-Cell acute lymphoblastic leukemia is intended to encompass both entities.

Treatment

Treatment depends on the type of malignancy and may include surgery, radiotherapy, chemotherapy, targeted therapy, plasmapheresis, biologic therapy, or hematopoietic cell transplant. Treatment of acute leukemias can lead to complete remission. Multiple myeloma and the chronic leukemias are treatable, but generally incurable. Outcomes of lymphoma vary by subtype, and some forms are curable.

Measurable Residual Disease

Relapse is believed to be due to residual clonal cells that remain following "complete response” after induction therapy, but are below the limits of detection using conventional morphologic assessment. Residual clonal cells that can be detected in the bone marrow or blood are referred to as measurable residual disease (MRD), also known as minimal residual disease. MRD assessment is typically performed by flow cytometry or polymerase chain reaction (PCR) with primers for common variants. Flow cytometry or next generation flow cytometry evaluates blasts based on the expression of characteristic antigens, while PCR assesses specific chimeric fusion gene transcripts, gene variants, and overexpressed genes. PCR is sensitive for specific targets, but clonal evolution may occur between diagnosis, treatment, remission, and relapse that can affect the detection of MRD. Next-generation sequencing (NGS) has 10- to 100-fold greater sensitivity for detecting clonal cells, depending on the amount of DNA in the sample (see the table below) and does not require patient-specific primers. For both PCR and NGS a baseline sample at the time of high disease load is needed to identify tumor-specific sequences. MRD with NGS is frequently used as a surrogate measure of treatment efficacy in drug development.

It is proposed that by using a highly sensitive and sequential MRD surveillance strategy, one could expect better outcomes when therapy is guided by molecular markers rather than hematologic relapse. However, some patients may have hematologic relapse despite no MRD, while others do not relapse despite residual mutation-bearing cells. Age-related clonal hematopoiesis, characterized by somatic variants in leukemia-associated genes with no associated hematologic disease, further complicates the assessment of MRD. One available test (clonoSEQ) uses both PCR and NGS to detect clonal DNA in blood and bone marrow. ClonoSEQ Clonality (ID) PCR assessment is performed when there is a high disease load (eg, initial diagnosis or relapse) to identify dominant or “trackable” sequences associated with the malignant clone. NGS is then used to monitor the presence and level of the associated sequences in follow-up samples. As shown in the table below, NGS can detect clonal cells with greater sensitivity than either flow cytometry or PCR, although next-generation flow techniques have reached a detection limit of 1 in 10^-5 cells, which is equal to PCR and approaches the limit of detection of NGS (see the table below).

Sensitivity of Methods for Detecting Measurable Residual Disease

The clonoSEQ® Minimal Residual Disease Test is offered by Adaptive Biotechnologies. ClonoSEQ® was previously marketed as ClonoSIGHT™ (Sequenta), which was acquired by Adaptive Biotechnologies in 2015. ClonoSIGHT™ was a commercialized version of the LymphoSIGHT platform by Sequenta for clinical use in MRD detection in lymphoid cancers. In September 2018, ClonoSEQ received marketing clearance from the U.S. Food and Drug Administration (FDA) through the de novo classification process to detect MRD in patients with acute lymphoblastic leukemia or multiple myeloma. In 2020, clonoSEQ received marketing clearance from the FDA to detect MRD in patients with chronic lymphocytic leukemia. ClonoSEQ is available for use in other lymphoid cancers, such as diffuse large B-cell lymphoma (DLBCL), as a CLIA-validated laboratory developed test (LDT).

Related medical policies – 

• Hematopoietic Cell Transplantation for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

• Hematopoietic Cell Transplantation for Plasma Cell Dyscrasias, Including Multiple Myeloma and POEMS Syndrome

• Hematopoietic Cell Transplantation for Non-Hodgkin Lymphomas

• Hematopoietic Cell Transplantation for Acute Myeloid Leukemia

• Hematopoietic Cell Transplantation for Hodgkin Lymphoma

• Hematopoietic Cell Transplantation for Chronic Myeloid Leukemia

• Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia

POLICY

Next-generation sequencing (eg clonoSEQ) to detect measurable residual disease at a threshold of 10^-4 as an alternative test in individuals with acute lymphoblastic leukemia may be considered medically necessary.

Next-generation sequencing (eg clonoSEQ) to detect measurable residual disease at a threshold of less than 10^-4 in individuals with acute lymphoblastic leukemia is considered investigational.

Next-generation sequencing (eg clonoSEQ) to detect measurable residual disease at a threshold of 10^-4 as an alternative test in individuals with chronic lymphocytic leukemia may be considered medically necessary.

Next-generation sequencing (eg clonoSEQ) to detect measurable residual disease at a threshold of less than 10^-4 in individuals with chronic lymphocytic leukemia is considered investigational.

Next-generation sequencing (eg clonoSEQ) to detect measurable residual disease at a threshold of 10^-5 as an alternative test in individuals with multiple myeloma may be considered medically necessary.

Next-generation sequencing (eg clonoSEQ) to detect measurable residual disease at a threshold of less than 10^-5 in individuals with multiple myeloma is considered investigational.

Next-generation sequencing (eg clonoSEQ) to detect measurable residual disease in individuals with diffuse large B-cell lymphoma is considered investigational.

Next-generation sequencing (eg clonoSEQ) to detect measurable residual disease in individuals with mantle cell lymphoma is considered investigational.

Next-generation sequencing to detect measurable residual disease is considered investigational in all other situations.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

1. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

2. appropriate with regard to standards of good medical practice; and

3. not solely for the convenience of the Member, his or her Provider; and

4. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

08/01/2019: New policy added. Approved by Medical Policy Advisory Committee.

01/01/2022: Policy revised to focus on the three indications: acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM). Added policy statements that next-generation sequencing (NGS) to detect measurable residual disease (MRD) at a threshold of 10^-4 as an alternative test in patients with ALL or CLL may be considered medically necessary. Added policy statements that NGS to detect MRD at a threshold of less than 10^-4 in patients with ALL or CLL is considered investigational. Added statement that NGS to detect MRD at a threshold of 10^-5 as an alternative test in patients with MM may be considered medically necessary. Added statement that NGS to detect MRD at a threshold of less than 10^-5 in patients with MM is considered investigational. Revised statement to state that next-generation sequencing to detect MRD is considered investigational in all other situations. Policy Guidelines updated to define medically necessary. Code Reference section updated to change the investigational codes table to medically necessary and add ICD-10 diagnosis codes C90.00 - C90.02, C91.00 - C91.02, and C91.10 - C91.12.

02/04/2022: Policy reviewed; no changes.

03/28/2022: Code Reference section updated to add new 04/01/2022 CPT codes 0306U and 0307U as investigational.

03/30/2023: Code Reference section updated to add new CPT code 0364U as investigational, effective 04/01/2023.

06/01/2023: Policy description updated to include diffuse large B-cell lymphoma and mantle cell lymphoma. Added investigational policy statements for diffuse large B-cell lymphoma and mantle cell lymphoma. Code Reference section updated to add CPT codes 0171U and 0340U as investigational.

01/09/2024: Policy description updated. Policy statements updated to clarify that next generation sequencing to detect measurable residual disease in individuals with diffuse large B-cell lymphoma and mantle cell lymphoma is considered investigational at any sensitivity threshold.

10/01/2024: Code Reference section updated to add new ICD-10 diagnosis codes C81.7A and C88.91.

02/06/2025: Policy description updated regarding tests. Policy statements unchanged.

07/18/2025: Code Reference section updated to add new CPT codes 0560U and 0561U. Effective 07/01/2025.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.147

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Codes

Investigational Codes

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