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Next-Generation Sequencing for the Assessment of Measurable Residual Disease

Policy Number: MP-722

ARCHIVED – Refer to AIM Genetic Testing Guidelines effective 3/1/20

Latest Review Date: May 2019

Category: Laboratory

Policy Grade: B


For dates of service June 1, 2019 and after:

Next-generation sequencing for measureable residual disease using the clonoSEQ® assay may be considered medically necessary to assess response to treatment and predict clinical outcomes in acute lymphoblastic leukemia (ALL).

Next-generation sequencing for measureable residual disease is considered not medically necessary and investigational for all other indications, including but not limited to multiple myeloma (MM).

For dates of service prior to May 31, 2019:

Next-generation sequencing for measurable residual disease is considered not medically necessary and investigational.


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.


There are 3 main types of hematologic malignancies: lymphomas, leukemias, and myelomas. Lymphoma begins in lymph cells of the immune system, which originate in 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 production of red blood cells and plasma cells. The most common forms of leukemia are acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). Multiple myeloma (MM), also called plasma myeloma, is a malignancy of plasma cells in the bone marrow.


Treatment depends on the type of malignancy and may include surgery, radiotherapy, chemotherapy, targeted therapy, plasmapheresis, biologic therapy, or hematopoietic cell transplant. Treatment of the acute leukemias can lead to complete remission. MM and the chronic leukemias are treatable but generally incurable. Patients are typically followed by complete blood count and morphologic assessment of bone marrow. Complete hematologic response is defined as a bone marrow blast (immature cells) composition of less than 5% and hematologic recovery (normal neutrophil and platelet count) without the need for red blood cell transfusions.

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 blood or bone marrow 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 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 (see Table 1) 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 and is transitioning from “bench-to-bedside” for clinical use.

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 relapse 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. There is currently no consensus on which method provides clinically meaningful assessment of MRD. A 2018 international consensus paper recommended that flow cytometry presents a high enough sensitivity to be used in routine clinical practice, but for a more sensitive result and if MRD eradication is the goal for the selected patient, then allele-specific PCR should be used. It is notable that next-generation flow techniques have reached a detection limit of one in 10-5 cells, which is equal to PCR and approaches the limit of detection of NGS (see Table 1).

Table 1. Sensitivity of Methods for Detecting Minimal Residual Disease



Blasts per 100,000 Nucleated Cells

Microscopy (complete response)



Multiparameter flow cytometry



Next-generation flow cytometry



Polymerase chain reaction



Quantitative next-generation sequencing



Next-generation sequencing




This most recent search of literature was performed through October 16, 2019.

Summary of Evidence

Studies show the high prognostic value of MRD is assessing risk for relapse in patient with ALL, and the role of MRD monitoring in identifying subgroups of patient who may benefit from further intensified therapies or alternative treatment strategies. For individuals with acute lymphoblastic leukemia (ALL) who have completed initial induction therapy or following bone marrow transplantation to guide subsequent therapy, the evidence is sufficient to determine the effects of NGS for determining MRD using the clonoSEQ® assay on health outcomes.

MRD has limited usefulness outside of clinical trials in multiple myeloma (MM) based on the joint American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO) guideline on treatment of MM.  There is insufficient evidence to make modifications to maintenance therapy based on depth of response, including MRD status. Continuous therapy should be offered over fixed-duration therapy when initiating an immunomodulatory drug or Pl- based regimen, independent of MRD status. There is insufficient evidence to support change in type and length of therapy based on depth of response as measured by conventional standard International Myeloma Working Group (IMWG) approaches or MRD. Treatment of relapsed MM may be continued until disease progression. The evidence is not sufficient to determine the effects of the technology on health outcomes.

For individuals who have achieved a complete response and are being evaluated for MRD who receive NGS for MRD in all other situations aside from ALL, the evidence is insufficient to determine the clinical validity of NGS for assessing MRD, and no chain of evidence can be constructed to establish clinical utility in hematologic malignancies. NGS can identify more blast cells with an identified clonal sequence by a factor of ten. However, the clinical utility of this increase in the detection of clonal sequences is uncertain in all other situations aside from ALL. Direct evidence from randomized controlled trials is needed to evaluate whether patient outcomes are improved by changes in postinduction care (e.g., continuing therapy, escalating to hematopoietic cell transplant, avoiding unnecessary therapy) following NGS detection of MRD at 10-6 compared with the established methods of flow cytometry or polymerase chain reaction (at 10-5) in all other situations aside from ALL. The evidence is insufficient to determine the effects of the technology on health outcomes in all other situations aside from ALL.

Practice Guideline and Position Statement

The National Comprehensive Cancer Network has published guidelines of relevance to this review (see the below table).

Table. Recommendations on Assessing Measurable Residual Disease




Acute lymphoblastic leukemia


Risk stratification after treatment induction by MRD positivity. MRD in ALL refers to the presence of leukemic cells below the threshold of detection by conventional morphologic methods. The most frequently employed methods for MRD assessment are FC, RQ-PCR, and NGS. The concordance rate between these methods is generally high.

FC: flow cytometry; MRD: measurable residual disease; NGS: next-generation sequencing; RQ-PCR: real-time quantitative polymerase chain reaction.

U.S. Preventive Services Task Force Recommendations

Not applicable.


Next Generation Sequencing, NGS, Measurable Residual Disease, MRD, residual clonal sequence, flow cytometry, polymerase chain reaction, hematologic malignancies, lymphoma, leukemia, myeloma, LymphoSIGHT, ClonoSEQ, Sequenta, ClonoSight, ImmunoSEQ, ALL, MM, acute lymphoblastic leukemia, multiple myeloma, minimal 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 Food and Drug Administration through the de novo classification process to detect MRD in patients with ALL or multiple myeloma.


Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.


CPT Codes:

There is no specific code for next generation sequencing for measurable residual disease monitoring. ClonoSEQ® Minimal Residual Disease Test would probably be billed with the unlisted codes below:


Unlisted multianalyte assay with algorithmic analysis


Unlisted molecular pathology procedure


  1. Bal S, Weaver A, Cornell RF et al. Challenges and opportunities in the assessment of measurable residual disease in multiple myeloma. Br. J. Haematol., 2019 Aug 1.
  2. Berry DA, Zhou S, Higley H et al. Association of Minimal Residual Disease With Clinical Outcome in Pediatric and Adult Acute Lymphoblastic Leukemia: A Meta-analysis. JAMA Oncol, 2017 May 12; 3(7).
  3. Food and Drug Administration. FDA authorizes first next generation sequencing-based test to detect very low levels of remaining cancer cells in patients with acute lymphoblastic leukemia or multiple myeloma. Accessed 12/17/18.
  4. Kumar S, Paiva B, Anderson KC et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol., 2016 Aug 12; 17(8).
  5. Kurtz DM, Green MR, Bratman SV, et al. Noninvasive monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput sequencing. Blood. Jun 11 2015; 125(24):3679-3687.
  6. Larson RA. Post-remission therapy for Philadelphia chromosome negative acute lymphoblastic leukemia in adults. UpToDate. Accessed September 6, 2019.
  7. Larson RA. Treatment of relapsed or refractory acute lymphoblastic leukemia in adults. UpToDate. Accessed September 6, 2019.
  8. LeukoVantage Test, Quest Diagnostics, available at
  9. Martinez-Lopez J, Lahuerta JJ, Pepin F, et al. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. Blood. May 15 2014; 123(20):3073-3079.
  10. National Comprehensive Care Network. NCCN Clinical Practice Guidelines in Oncology: Acute Lymphoblastic Leukemia. Version 2.2019. Accessed September 4, 2019.
  11. National Comprehensive Care Network. NCCN Clinical Practice Guidelines in Oncology: Chronic lymphocytic leukemia. Version 1.2019. Accessed September 27, 2018.
  12. National Comprehensive Care Network. NCCN Clinical Practice Guidelines in Oncology: Hairy Cell Leukemia. Version 2.2019. Accessed September 27, 2018.
  13. National Comprehensive Care Network. NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma. Version 3.2019. Accessed August 29, 2019.
  14. Perrot A, Lauwers-Cances V, Corre J et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood, 2018 Sep 27; 132(23).
  15. Pulsipher MA, Carlson C, Langholz B, et al. IgH-V(D)J NGS-MRD measurement pre- and early post-allotransplant defines very low- and very high-risk ALL patients. Blood. May 28 2015; 125(22):3501-3508.
  16. Rajkumar SV. Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis, UpToDate. Accessed September 6, 2019.
  17. Stock W and Estrov Z Clinical use of measurable residual disease detection in acute lymphoblastic leukemia. UpToDate. Accessed September 6, 2019.
  18. Stock W and Estrov Z Detection of measurable residual disease in acute lymphoblastic leukemia. UpToDate. Accessed September 6, 2019.
  19. Tomuleasa C, Selicean C, Cismas S, et al. Minimal residual disease in chronic lymphocytic leukemia: A consensus paper that presents the clinical impact of the presently available laboratory approaches. Crit Rev Clin Lab Sci. Aug 2018; 55(5):329-345.
  20. U.S. Food and Drug Administration. Evaluation of automatic class II designation for clonoSEQ Assay; Decision summary Accessed September 6, 2019.
  21. U.S. Food and Drug Administration. Prescribing information for BLINCYTO. 2018; Accessed October 5, 2018.
  22. Wood B, Wu D, Crossley B, et al. Measurable residual disease detection by high-throughput sequencing improves risk stratification for pediatric B-ALL. Blood. Mar 22 2018; 131(12):1350-1359.


Medical Policy Panel, October 2018

Medical Policy Group, October 2018 (9): Policy created with literature review through August 6, 2018. Considered investigational

Medical Policy Administration Committee, December 2018

Available for comment November 19, 2018 through January 3, 2019

Medical Policy Group, May 2019 (9): Updates to Description, Key Points, and References. Added key words: ALL, MM, acute lymphoblastic leukemia, multiple myeloma, minimal residual disease. Policy statement updated to include coverage for clonoSEQ® for ALL.

Medical Policy Administration Committee, June 2019.

Available for comment June 1, 2019 through July 15, 2019

Medical Policy Panel, November 2019

Medical Policy Group, November 2019 (9): 2019 Updates to Description, Key Points, and References. No change to policy statement.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.