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Next-Generation Sequencing for the Assessment of Measurable Residual Disease

Policy Number: MP-722

Latest Review Date: May 2019

Category: Laboratory

Policy Grade: B

DESCRIPTION OF PROCEDURE OR SERVICE

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. Clinical practice guidelines in a number of hematological malignancies recommend MRD testing and recognize MRD status as a reliable indicator of clinical outcome and response to therapy.

Disease

There are three main types of hematologic malignancies: lymphomas, leukemias, and myelomas. Lymphoma is the most common type of hematologic malignancy and is typically divided into two categories, Hodgkin lymphoma (also known as Hodgkin disease) and non-Hodgkin lymphoma (NHL). Lymphoma begins in lymph cells of the immune system, which originate in bone marrow and collect in lymph nodes and other tissues. The two types of lymph cells that develop into NHL are B lymphocytes (B cells), which mature in the bone marrow, and T lymphocytes (T cells), which mature in the thymus.

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. Leukemia may be acute or chronic, and affect either lymph or myeloid cells. The most common forms of leukemia are acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and chronic myeloid leukemia. There are a number of less common forms of leukemia. Multiple myeloma (MM), also called plasma myeloma, is a malignancy of plasma cells in the bone marrow.

Hodgkin Lymphoma

Hodgkin lymphoma is a relatively uncommon B-cell lymphoma. In 2017, the estimated number of new cases in the United States was approximately 8260 with 1070 estimated deaths. The disease has a bimodal distribution, with most patients diagnosed between the ages of 15 and 30 years, with a second peak in adults aged 55 years and older.

Non-Hodgkin Lymphoma

NHL includes a heterogeneous group of lymphoproliferative malignancies. In general, NHL can be divided into two prognostic groups: indolent and aggressive. Follicular lymphoma is the most common indolent NHL (70%-80% of cases), and often the terms indolent lymphoma and follicular lymphoma are used synonymously. Indolent NHL has a relatively good prognosis, with a median survival of 10 years; however, it is not curable in advanced clinical stages. Histologic transformation to higher grade lymphoma occurs in up to 70% of patients with low-grade lymphoma, and median survival with conventional chemotherapy is one year or less. Aggressive NHL has a shorter natural history; however, 30% to 60% of these patients can be cured with intensive combination chemotherapy regimens.

Acute Lymphoblastic Leukemia

Childhood ALL

ALL is the most common cancer diagnosed in children; it represents nearly 25% of cancers in children younger than 15 years. Remission of disease is now typically achieved with pediatric chemotherapy regimens in 98% of children with ALL, with up to 85% long-term survival rates. The prognosis after the first relapse is related to the length of the original remission. For example, the leukemia-free survival rate is 40% to 50% for children whose first remission was longer than three years compared with 10% to 15% for those who relapse less than three years after treatment.

Adult ALL

ALL accounts for 20% of acute leukemias in adults. Between 60% and 80% of adults with ALL can be expected to achieve a complete response after induction chemotherapy; however, only 35% to 40% can be expected to survive two years. “Poor prognosis” genetic abnormalities such as the Philadelphia chromosome (translocation of chromosomes nine and 22) are seen in 25% to 30% of adult ALL but infrequently in childhood ALL. Other adverse prognostic factors in adult ALL include age greater than 35 years, poor performance status, male sex, and leukocytosis count of greater than 30,000/μL (B-cell lineage) or greater than 100,000/μL (T-cell lineage) at presentation.

Chronic Lymphocytic Leukemia

CLL tends to present as asymptomatic enlargement of the lymph nodes and tends to be indolent, but can undergo transformation to a more aggressive form of the disease. The median age at diagnosis of CLL is approximately 72 years. Both low- and intermediate-risk CLL demonstrate relatively good prognoses, with a median survival of six to ten years; however, the median survival of high-risk CLL may only be two years. Although typically responsive to initial therapy, CLL is rarely cured by conventional therapy, and nearly all patients die of their disease.

Acute Myeloid Leukemia

AML, also called acute nonlymphocytic leukemia, refers to a set of leukemias that arise from a myeloid precursor in the bone marrow. Clinical signs and symptoms are associated with neutropenia, thrombocytopenia, and anemia. The incidence of AML increases with age, with a median of 67 years. Molecular studies have identified a number of genetic abnormalities that can be used to guide prognosis and management of AML. Cytogenetically normal AML is the largest defined subgroup of AML, comprising approximately 45% of all AML cases. Despite the absence of cytogenetic abnormalities, these cases often have genetic variants that affect outcomes.

Chronic Myeloid Leukemia

Chronic myeloid leukemia accounts for about 15% of newly diagnosed cases of leukemia in adults and occurs in one to two cases per 100,000 adults. The natural history of the disease consists of an initial (indolent) chronic phase, lasting a median of three years, which typically transforms into an accelerated phase, followed by a “blast crisis,” which is usually the terminal event. Most patients present in chronic phase, often with nonspecific symptoms secondary to anemia and splenomegaly. Conventional-dose chemotherapy regimens used for chronic phase disease can induce multiple remissions and delay the onset of blast crisis to a median of four to six years. However, successive remissions are invariably shorter and more difficult to achieve than their predecessors.

Multiple Myeloma

MM represents approximately 10% of all hematologic cancers. It is treatable but rarely curable. Treatment is usually reserved for patients with symptomatic disease (usually progressive myeloma), whereas asymptomatic patients are observed because there is little evidence that early treatment of asymptomatic MM prolongs survival compared with therapy delivered at the time of symptoms or end-organ damage. In some patients, an intermediate asymptomatic but the more advanced premalignant stage is recognized and referred to as smoldering MM. The overall risk of disease progression from smoldering to symptomatic MM is 10% per year for the first five years, approximately 3% per year for the next five years, and 1% for the next ten years.

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 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).

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 (e.g., initial diagnosis or relapse) to identify dominant or “trackable” B- or T-cell 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 Table 1, NGS can detect clonal cells with greater sensitivity than either flow cytometry or PCR. Information obtained from this testing is recommended to be used to decide on whether and when to pursue additional treatment. According to FDA cleared indications and guidelines, it is anticipated that an episode of testing will typically require a baseline assay and three follow-up assays.

Table 1. Sensitivity of Methods for Detecting Minimal Residual Disease

Technique

Sensitivity

Blasts per 100,000 Nucleated Cells

Microscopy (complete response)

50,000

Multiparameter flow cytometry

10-4

10

Next-generation flow cytometry

10-5

1.0

Polymerase chain reaction

10-5

1.0

Quantitative next-generation sequencing

10-5

1.0

Next-generation sequencing

10-6

0.1

POLICY

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.

KEY POINTS

This evidence review was created in October 2018 with a search of literature performed through May 28, 2019.

Next Generation Sequencing to Detect Measurable Residual Disease

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Clinical Context and Test Purpose

The purpose of next-generation sequencing (NGS) to detect measurable residual disease (MRD) in patients who have been treated for hematologic cancers and achieved a complete response after induction therapy is to inform a decision regarding subsequent treatment.

The question addressed in this evidence review is: Does the use of NGS testing for MRD improve the net health outcome in patients with hematologic cancers?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest is patients who have been treated for hematologic cancers and exhibit complete morphologic remission.

Interventions

The test being considered is NGS (e.g., clonoSEQ®). This test is proposed as an adjunct to existing methods of assessing MRD with complete blood count and cell morphology, and as an alternative to flow cytometry or polymerase chain reaction (PCR).

Comparators

The following tests are currently being used to detect MRD: flow cytometry and PCR. The reference standard is clinical (hematologic) relapse.

Outcomes

The general outcomes of interest are remission and relapse in the short term and survival at longer follow-up.

Beneficial outcomes of a true-positive test result would be intensification or continuation of an effective treatment leading to a reduction in relapse and improvement in overall survival (OS). The beneficial outcome of a true-negative test is the avoidance of unnecessary treatment and reduction of adverse events.

Harmful outcomes of a false-positive test include an increase or continuation of unnecessary treatment resulting in treatment-related harms. Harmful outcomes of a false-negative test include a reduction in necessary treatment that would delay treatment, with a potential impact in progression-free survival (PFS) and OS.

Direct harms of the test are repeated bone marrow biopsy, although this test can also be performed in blood and would, therefore, reduce direct harms of the invasive test.

Timing

Relapse of acute hematologic malignancies may be measured in months and chronic hematologic malignancies measured in years. Changes in survival from acute hematologic malignancies would be observable at two years, while chronic hematologic malignancies would typically be observable by ten years.

Setting

Evaluation of MRD would be in an outpatient care setting by a hematologic oncologist.

Study Selection Criteria

For the evaluation of clinical validity of the clonoSEQ® test, studies that met the following eligibility criteria were considered:

  • Included a suitable reference standard (relapse or OS or PFS)
  • Patient/sample clinical characteristics were described
  • Patient/sample selection criteria were described.

Studies were excluded from the evaluation of the clinical validity of the test because they did not use the marketed or earlier version of the test, did not include information needed to calculate performance characteristics, did not use an appropriate reference standard or reference standard was unclear, did not adequately describe the patient characteristics, or did not adequately describe patient selection criteria.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Diagnostic Accuracy for Hematologic or Clinical Relapse

Characteristics and results of the diagnostic accuracy studies evaluating NGS for MRD are summarized in Tables 2 and 3. Kurtz et al (2015) reported a sensitivity of 31% and specificity of 100% to predict clinical relapse, with an MRD threshold of 10-6. A malignant clonal sequence was identified in 83% of patients.

Table 2. Characteristics of Diagnostic Accuracy Studies Assessing NGS for MRD

Study

Study Population

Design

Reference Standard

Threshold for Positive Index Test

Median Follow-Up, mo

Test Version

Kurtz et al (2015)

Adult B-cell lymphoma

Prospective

Clinical relapse

MRD at 10-6

34

LymphoSIGHT

MRD: measurable residual disease; NGS: next-generation sequencing

Table 3. Results of Diagnostic Accuracy Studies Assessing NGS for MRD

Study

N

% With an Identified Clonal Sequence

Clinical Validity (95% Confidence Interval), %

Sens

Spec

PPV

NPV

Kurtz et al (2015)

75

83

31

100

MRD: measurable residual disease; NGS: next-generation sequencing; NPV: negative predictive value; PPV: positive predictive value; Sens: sensitivity; Spec: specificity.

The purpose of the gaps tables (see Tables 4 and 5) is to display notable gaps identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement.

Table 4. Relevance Gaps

Study

Population

Intervention

Comparator

Outcomes

Duration of Follow-Up

Kurtz et al (2015)

A chain of evidence of decisions that would be affected by the test have not been explicated

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
 

Table 5. Study Design and Conduct Gaps

Study

Selection

Blinding

Delivery of Test

Selective Reporting

Data Completeness

Statistical

Kurtz et al (2015)

Study inclusion based in part on availability of sufficient blood samples with only 8 of 140 patients from 1 of the sites included

Confidence intervals and/or p values not reported

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
 

Prognosis

Tables 6 and 7 describe studies that have evaluated prognosis based on MRD detected by either flow cytometry or NGS, or for studies that have evaluated prognosis based on the level of MRD from 10-3 to 10-6. Outcome measures of these studies varied, which complicates analysis, but overall, higher levels of MRD are associated with worse prognosis. In the study by Wood et al (2018), higher levels of sensitivity were associated with a decrease in specificity, and the maximal hazard ratio was obtained at 10-4.

Table 6. Characteristics of Prognostic Studies Assessing NGS for MRD

Study

Study Population

Design

Source

Reference Standard

Threshold for PIT

FU, y

Test Version

Wood et al (2018)

Pediatric B-ALL

Nonconcurrent from banked samples

Bone marrow

Event-free survival

MRD at 10-4 and 10-5

5

ImmunoSEQ

Pulsipher et al (2015)

Pediatric ALL

Nonconcurrent from banked samples

Pre- and post- HCT bone marrow

Time to relapse following HCT

FC at 10-3 NGS at 10-5

ImmunoSEQ

Martinez-Lopez et al (2014)

Multiple myeloma

Retrospective

Bone marrow

Time to progression

MRD at 10-3 and 10-5

LymphoSIGHT

ALL: acute lymphoblastic leukemia; FC: flow cytometry; FU: follow-up; HCT: hematopoietic cell transplantation; MRD: measurable residual disease; NGS: next-generation sequencing; PIT: positive index test.

Table 7. Results of Prognostic Studies Assessing NGS for MRD

Study

N

% With a Trackable Sequence

MRD Threshold

Results

TTP, mo

5-Year EFS, %

Relapse Rate at 2 Years, %

Hazard Ratio

p

Wood et al (2018)

607

95.4

<10-4

98.1

Maximal at 10-4

Pulsipher et al (2015)

40

Pre-HCT FC negative

16

Pre-HCT FC negative

0

Martinez-Lopez et al (2014)

133

91

>10-3

27

10-3 to 10-5

48

<10-5

80

TTP=3.97

<0.001

EFS: event-free survival; FC: flow cytometry; HCT: hematopoietic cell transplantation; MRD: measurable residual disease; NGS: next-generation sequencing; NPV: negative predictive value; NR: not reported; PPV: positive predictive value; TTP: time to progression.

Gaps in relevance and design and conduct are shown in Tables 8 and 9.

Table 8. Relevance Gaps

Study

Population

Intervention

Comparator

Outcomes

Duration of FU

Wood et al (2018)

Used ImmunoSEQ rather than OncoSEQ

Study does not elucidate how health outcomes would be improved by the prognostic information

Duration of FU insufficient to evaluate overall survival

Pulsipher et al (2015)

Used ImmunoSEQ rather than OncoSEQ

Study does not elucidate how health outcomes would be improved by the prognostic information

Martinez-Lopez et al (2014)

Study does not elucidate how health outcomes would be improved by the prognostic information

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. FU: follow-up.
 

Table 9. Study Design and Conduct Gaps

Study

Selection

Blinding

Delivery of Test

Selective Reporting

Data Completeness

Statistical

Wood et al (2018)

Blinding not described

Martinez-Lopez et al (2014)

Blinding not described

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
 

Section Summary: Clinically Valid

The performance characteristics of NGS at 10-6 to detect relapse are not well defined. One prospective study was identified and it evaluated the diagnostic accuracy of NGS. In this study, a clonal sequence could be identified in only 83% of the samples, which can be compared with the 100% identification of clonal cells by flow cytometry. At a detection limit of 10-6, NGS had 31% sensitivity and 100% specificity to detect clinical relapse. Several prognostic studies have reported on the association between MRD at various sensitivities and relapse prediction. The percentage of cases in which a clonal sequence could be identified ranged from 91% to 95.4%. The timing of the test and the outcome measures of these studies were variable, which complicates analysis, but overall, higher levels of MRD were associated with worse prognosis. One study, however, found that the maximal hazard ratio was obtained at a sensitivity of 10-4, the same as flow cytometry and that higher levels of sensitivity were associated with a decrease in specificity. Thus, the clinical validity of NGS to detect MRD is uncertain in all other situations aside from ALL.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

No RCTs assessing the clinical utility of NGS to detect malignant clonal sequences were identified.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

The evidence is insufficient to demonstrate clinical validity, and it is not known whether management changes based on the increase in sensitivity with NGS to detect malignant clonal sequences would improve health outcomes.

Section Summary: Clinically Useful

The evidence is insufficient to determine the test performance of NGS for detecting MRD, and no chain of evidence can be constructed to establish clinical utility in hematologic malignancies, in all situations aside from ALL. Direct evidence from RCTs are needed to evaluate whether patient outcomes are improved by changes in postinduction care (e.g., continuing therapy, escalating to hematopoietic cell transplantation, avoiding unnecessary adverse events) following NGS detection of MRD at 10-6 compared with the established methods of flow cytometry or PCR at 10-5.

NGS to Inform Treatment of B-Cell Acute Lymphoblastic Leukemia

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, two domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Clinical Context and Test Purpose

The purpose NGS to detect MRD in patients who are in remission for B-cell acute lymphoblastic leukemia (B-ALL) is to provide a treatment option that is an alternative to or an improvement on existing therapies.

In 2018, blinatumomab received approval from the Food and Drug Administration for the treatment of MRD positive B-cell precursor ALL in first or second complete remission with MRD positivity of 0.1% or greater (10-3 or 1 in 1000 cells).

The question addressed in this evidence review is: Does the use of NGS testing for MRD improve the net health outcome in patients with B-ALL who are being considered for treatment with blinatumomab?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest is patients who have been treated for B-ALL and exhibit complete morphologic remission.

Interventions

The test being considered is NGS (e.g., liter). This test is proposed as an adjunct to existing methods of assessing MRD with complete blood count and cell morphology, and as an alternative to flow cytometry or PCR.

Comparators

The following tests are currently being used to inform treatment decisions for those with B-ALL in remission: flow cytometry and PCR. The reference standard is clinical (hematologic) relapse.

Outcomes

The general outcomes of interest are remission and relapse in the short term and survival at longer follow-up.

Beneficial outcomes of a true-positive test result would be the administration of an effective treatment leading to a reduction in relapse and improvement in OS. The beneficial outcome of a true-negative test is the avoidance of unnecessary treatment and reduction of adverse events.

Harmful outcomes of a false-positive test are unnecessary treatment resulting in treatment-related harms. Harmful outcomes of a false-negative test are a reduction in necessary treatment that would delay treatment, with a potential impact in PFS and OS.

Direct harms of the test are repeated bone marrow biopsy, although this test can also be performed in blood and would, therefore, reduce direct harms of the invasive test.

Timing

Relapse of B-ALL may be measured in months. Changes in survival from B-ALL would be observable at two years.

Setting

Evaluation of MRD would be in an outpatient care setting by a hematologic oncologist.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
  • To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
  • Studies with duplicative or overlapping populations were excluded.

Clinical Studies

MRD is considered important for the evaluation of treatment in the management of patient with hematological malignancies. The clonoSEQ® assay is a PCR and NGS test that is used to identify specific sequences originating in lymphoid malignant B-cells in patient in order to quantify MRD over time. The assay is used to determine MRD in lymphoid malignancies to assess response to treatment and predict clinical outcomes.

Section Summary: NGS to Inform Treatment of B-Cell Acute Lymphoblastic Leukemia

The evidence is insufficient to determine the utility of using NGS to inform a decision to treat B-ALL patients in remission with blinatumomab. The practice of assessing the burden of disease, determining response to therapy and monitoring on-going disease status is certainly fundamental to patient management and has been done for many years using a variety of tools and methods. In recent years, the availability of molecular assays, such as the clonoSEQ® test, has been offered for the detection of MRD.

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 Table 10).

Table 10. Recommendations on Assessing Measurable Residual Disease

Guideline

Version

Recommendation

Acute lymphoblastic leukemia

2.2019

Collectively, studies show the high prognostic value of MRD in assessing risk for relapse in patients with ALL, and the role of MRD monitoring in identifying subgroups of patients who may benefit from further intensified therapies or alternative treatment strategies.

Chronic lymphocytic leukemia

1.2019

Response assessment involves both physical examination and evaluation of blood parameters. MRD-negative status in peripheral blood correlates with better PFS. Therapy is not guided by MRD status.

Hairy cell leukemia

2.2019

An immunohistochemical assessment of the percentage of MRD will enable patients to be separated into those with CR with or without evidence of MRD.

Multiple myeloma

1.2019

Treatment for progressive disease based on MRD with NGF or NGS on bone marrow at a minimum sensitivity of 10-5

  1. acute lymphoblastic leukemia, CR: complete response; FC: flow cytometry; MRD: measurable residual disease; NGF: next-generation flow cytometry; NGS: next-generation sequencing; PFS: progression-free survival; RQ-PCR: real-time quantitative polymerase chain reaction.

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS

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

APPROVED BY GOVERNING BODIES

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.

BENEFIT APPLICATION

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.

CURRENT CODING

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:

81599

Unlisted multianalyte assay with algorithmic analysis

81479

Unlisted molecular pathology procedure

REFERENCES

  1. Adaptive Biotechnology announces medicare coverage of the ClonoSeq assay for MRD: Jan 18, 2019, available at https://www.adaptivebiotech.com/adaptive-biotechnologies-announces-medicare-coverage-of-the-clonoseq-assay-for-mrd-testing-in-patients-with-multiple-myeloma-and-acute-lymphoblastic-leukemia-at-multiple-timepoints-throughout-treatmen/
  2. Adaptive Biotechnologies, Company Information, available at http://adaptivebiotech.com/about-us/our-story/
  3. Adaptive Biotechnologies. clonoSEQ Technical Information. https://www.adaptivebiotech.com. Accessed 12/17/2018
  4. Clinical Data, clonoSEQ Test, available at https://www.adaptivebiotech.com/clonoseq/clinical-data
  5. ClonoSEQ Assay: Adaptive Biotechnologies Presentation submitted to Kentmere Healthcare, Aug, 20, 2018.
  6. ClonoSEQ Assay, FDA approval, news release, available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm622004.htm
  7. 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.
  8. Intelligen Myeloid test, Labcorp, available at https://www.labcorp.com/test-menu/39806/intelligen%C2%AE-myeloid
  9. 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.
  10. LeukoVantage Test, Quest Diagnostics, available at http://newsroom.questdiagnostics.com/2015-05-04-Quest-Diagnostics-Announces-LeukoVantage-Advancing-Precision-Medicine-for-Hematologic-Malignancies
  11. 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.
  12. Medicare Covers Adaptive Biotechnologies’ ClonoSeq Assay, Jan 18, 2019, available at https://www.genomeweb.com/sequencing/medicare-covers-adaptive-biotechnologies-clonoseq-assay#.XGLXBmzsbIU
  13. National Comprehensive Care Network. NCCN Clinical Practice Guidelines in Oncology: Acute Lymphoblastic Leukemia. Version 2.2019. www.nccn.org/professionals/physician_gls /pdf/all.pdf.
  14. National Comprehensive Care Network. NCCN Clinical Practice Guidelines in Oncology: Chronic lymphocytic leukemia. Version 1.2019. www.nccn.org/ professionals/physician_gls/pdf/cll.pdf.
  15. National Comprehensive Care Network. NCCN Clinical Practice Guidelines in Oncology: Hairy Cell Leukemia. Version 2.2019. www.nccn.org/professionals /physician_gls/pdf/hairy_cell.pdf.
  16. National Comprehensive Care Network. NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma. Version 1.2019. www.nccn.org/professionals/ physician_gls/pdf/myeloma.pdf.
  17. Overview of ClonoSEQ test, Adaptive Technologies, available at https://www.adaptivebiotech.com/clonoseq/clonoseq-assay
  18. Overview of MRD, Adaptive Technologies, available at https://www.adaptivebiotech.com/clonoseq/the-importance-of-mrd
  19. Patient Test Report: ClonoSEQ assay, available at https://www.adaptivebiotech.com/clonoseq/clonoseq-report
  20. 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.
  21. Test Details, ClonoSEQ assay, available at https://www.adaptivebiotech.com/clonoseq/how-clonoseq-works
  22. 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.
  23. Treatment of Multiple Myeloma: ASCO and CCO Joint Clinical Practice Guideline, http://ascopubs.org/doi/full/10.1200/JCO.18.02096
  24. U.S. Food and Drug Administration. Prescribing information for BLINCYTO. 2018; www.accessdata.fda.gov/drugsatfda_docs/label/2018/125557s013lbl.pdf.
  25. 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.

POLICY HISTORY

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


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.