Response to Comments: DL40022 MolDX: Non-Next Generation Sequencing Tests for the Diagnosis of BCR-ABL Negative Myeloproliferative Neoplasms

The following comment was submitted to Palmetto GBA, CGS, WPS, and Noridian:
On behalf of the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP), we thank you for the opportunity to comment on draft Local Coverage Determination (LCD) entitled MolDX: Non-Next Generation Sequencing Tests for the Diagnosis of BCR-ABL Negative Myeloproliferative Neoplasms.

AMP is an international medical and professional association representing approximately 2,900 physicians, doctoral scientists, and medical laboratory scientists (technologists) who perform or are involved with laboratory testing based on knowledge derived from molecular biology, genetics, and genomics. Membership includes professionals from academic medicine, hospital-based and private clinical laboratories, the government and the in vitro diagnostics industry.

The College of American Pathologists (CAP) is the world’s largest organization of board-certified pathologists and the leading provider of laboratory accreditation and proficiency testing programs. The CAP serves patients, pathologists, and the public by fostering and advocating for excellence in the practice of pathology and laboratory medicine worldwide.

AMP and CAP members are highly involved in the development, validation, and interpretation of molecular diagnostic tests. As such, we are concerned that the requirements for testing to be covered under this policy do not accurately reflect the current landscape of Non-Next Generation Sequencing Tests for the diagnosis of BCR-ABL Negative Myeloproliferative Neoplasms.

Specifically, we are concerned that the Coverage Guidance, under Indications and Limitations of Coverage, includes the requirement that “[t]he test is comprised of one or more highly sensitive single- or multi- gene assays (i.e. quantitative polymerase chain reaction [PCR], digital droplet PCR [ddPCR]) that can accurately detect a minimum variant allele frequency (VAF) of <1% for JAK2 (and 1-3% for CALR and MPL when they are included in the testing).” Requiring tests to detect a minimum VAF of less than 1% for JAK2 is not clinically relevant when completing a diagnostic work-up of BCR-ABL negative myeloproliferative neoplasms (MPNs) since 1% commonly understood to be the positive threshold¹²³⁴. Our evaluation of current clinical practice indicates that the draft LCD may restrict patient access to tests performed by laboratories who have appropriately validated their tests to the scientifically supported threshold of one percent. Notably, within the coverage policy it states, “Patients with high suspicion of a BCR-ABL negative MPN who test negative by a non-NGS test for mutations in JAK2 (including the detection of JAK2 V617F at a VAF <1%), CALR, MPL and/or CSF3R may have a subsequent NGS panel performed for additional relevant mutations, as outlined in national or international consensus guidelines”. This denotes that a result of less than 1% for JAK2 as a negative result for the purposes of additional testing and thus further outlines that a VAF for JAK2 of less than 1% is typically of uncertain clinical significance the setting of initial diagnostic testing.

AMP completed a survey of their members to better understand how they will be impacted. A large majority of our membership that completes JAK2 testing validate their assays to a 1% VAF. Further, survey respondents noted that it would be too burdensome for laboratories to revalidate their testing to a less than 1% VAF to align with the requirements of the draft LCD which would likely force them to remove the test from their menu and limit testing options for patient care.

We acknowledge that NCCN guidelines recommend highly sensitive assays for the detection of JAK2 V617F. However, there is no clinical significance between JAK2 assays validated to 1% versus less than 1% and the clinical reasoning for this recommendation remains unclear. We are concerned that the recommendations made are not reflective of the current molecular testing landscape, which acknowledges that a positive JAK2 result is 1%^1-4. We would like to have a greater understanding behind the decision to base this coverage policy off of this NCCN guideline recommendation.

AMP and CAP recommend change the language to: “The test is comprised of one or more highly sensitive single- or multi- gene assays (i.e. quantitative polymerase chain reaction [PCR], digital droplet PCR [ddPCR]) that can accurately detect a minimum variant allele frequency (VAF) of 1% for JAK2 (and 1-3% for CALR and MPL when they are included in the testing)” in the draft LCD to reflect that there are many laboratories that complete accurate and clinically relevant JAK2 testing at VAF of 1%.

Thank you again for the opportunity to review and comment on this draft policy.
References were provided for review.

Thank you for your comment.

The literature has supported that a JAK2 VAF < 1% may or may not be clinically relevant. However, in individuals undergoing a diagnostic evaluation for Myeloproliferative Neoplasms (higher pre-test probability), the likelihood is higher that such a VAF reflects a true (low) positive result. There are a number of publications that support this.

The International Consensus Classification (ICC) publications (Arber et al. 2022; Thiele et al. 2023) and the NCCN comment below (see comment #3) all support a recommended minimum VAF for JAK2 to be < 1%. However, the ICC publications also state that the required minimum VAF is 1%. We have revised the minimum VAF in criterion #3 of the LCD to be ≤1%.

The following comment was submitted to Palmetto GBA, CGS, WPS, and Noridian:

Labcorp appreciates the opportunity to comment on the following Draft Policy: MolDX: Non-Next Generation Sequencing Tests for the Diagnosis of BCR-ABL Negative Myeloproliferative Neoplasms and associated Billing and Coding Article. Labcorp is a global life-sciences company that brings diagnostic testing and drug development together. For over fifty years, we've developed some of the world's most advanced testing capabilities with one mission in mind: to help improve health and lives. Today, through our comprehensive clinical laboratories, we process more than 3 million patient specimens per week—and, in doing so, help medical professionals and patients make important health decisions. The insights we gain through testing then fuel our drug development practice, by identifying patterns and even individuals who might benefit from enrollment in specific drug trials. It's this combination that makes us unique.

Our comments are listed below for your consideration:

1) We believe that guidelines for testing should be methodology agnostic. The proposed policy is targeted for multi-gene non-next generation sequencing panels and outlines differences in recommendations for cascade vs. simultaneous testing based on methodology, with “single gene tests” requiring a sequential and reflexive approach, while a “panel (i.e. multiplex PC)” approach is presumably not bound by this restriction. Patients whose providers’ labs have “single gene tests” would have delayed diagnoses. Obtaining JAK2 V617F and exon 12 mutational status simultaneously in the workup of suspected PV has been recommended to avoid undue delay in the diagnostic process (1). Similarly, simultaneous analysis of JAK2 V617F, CALR, and MPL will both accelerate the diagnostic workup of ET and PMF, and relieve the burden to the laboratory to retain diagnostically viable specimens in a cascading order. Regarding methodology, next generation sequencing panels have undergone diverse evolution in recent years and cost-effective and rapid turn-around small NGS panels can enable simultaneous and high sensitivity testing of MPN driver genes (2).

2) Analytic threshold of 1% sensitivity for JAK2, CALR, and MPL mutations in diagnosis of MPN is suggested, but requires additional support. The presence of detectable JAK2 V617F varies per the sensitivity of the assay, and how to interpret low JAK2 V617F allele burden regarding MPN diagnosis remains unclear (1). JAK2 V617F have been detected in healthy individuals (2). The optimal assay performances for detection of CALR and MPL mutations in supporting clinical diagnoses require additional study.

References were provided for review.

Thank you for your comment.

1. Obtaining JAK2 V617F and exon 12 mutational status simultaneously in the evaluation of suspected PV is not precluded by this LCD, nor is the simultaneous interrogation of JAK2, CALR, and MPL. Further, this contractor maintains a separate LCD for the interrogation of these genes by NGS for the work-up of myeloid and suspected myeloid neoplasms. However, as noted in this LCD, given that the prevalence of JAK2 V617F is far greater than that of exon 12 mutations, an initial rapid diagnostic test for the former is a reasonable and necessary diagnostic approach for patients being evaluated for Polycythemia Vera. This approach need not result in a significant diagnostic delay, particularly if testing occurs by methods with rapid turnaround times, which is often the case with PCR testing.

2. Regarding the minimum VAF required for JAK2, please refer to Response 1 above.

The following comment was submitted to Palmetto GBA and Noridian:

The National Comprehensive Cancer Network^® (NCCN^®) appreciates the opportunity to comment on the Proposed Local Coverage Determination (LCD) - MolDX: Non-Next Generation Sequencing Tests for the Diagnosis of BCR-ABL Negative Myeloproliferative Neoplasms as it relates to NCCN’s mission of improving and facilitating, quality, effective, equitable, and accessible cancer care. NCCN will focus our comments on our guideline recommendations in relation to the proposed LCD as well as ways NCCN content can be used as a resource to inform coverage determinations, keep LCDs evergreen as the science evolves, and ensure Medicare beneficiaries have access to the highest standard of possible.

NCCN Background

As an alliance of 33 leading academic cancer centers in the United States that treat hundreds of thousands of patients with cancer annually, NCCN^® is a developer of authoritative information regarding cancer prevention, screening, diagnosis, treatment, and supportive care that is widely used by clinical professionals and payers alike. The NCCN Clinical Practice Guidelines in Oncology^® (NCCN Guidelines^®) are a comprehensive set of guidelines detailing the sequential management decisions and interventions that currently apply to 97 percent of cancers affecting patients in the United States.

NCCN Guidelines^® and Library of Compendia products help ensure access to appropriate care, clinical decision-making, and assessment of quality improvement initiatives. The NCCN Drugs & Biologics Compendium (NCCN Compendium^®) has been recognized by CMS and clinical professionals in the commercial payer setting since 2008 as an evidence-based reference for establishment of coverage policy and coverage decisions regarding off-label use of anticancer and cancer-related medications. NCCN was recognized by CMS in 2016 and renewed in 2021 as a qualified Provider Led Entity (PLE) for the Medicare Appropriate Use Criteria (AUC) Program for the development of AUC and the establishment of policy and decision-making for diagnostic imaging in patients with cancer.

NCCN Guidelines

NCCN develops authoritative information regarding cancer prevention, screening, diagnosis, treatment, and supportive care that is widely used by clinical professionals and payers alike. The NCCN Guidelines are a comprehensive set of 88 guidelines detailing the sequential management decisions and interventions across 228 algorithms that currently apply to 97 percent of cancers affecting patients in the United States. More than 1900 panel members participate in Guideline development. In 2023, there were over 15 million downloads of the Guidelines across web-based and mobile applications. NCCN Guidelines are developed by multidisciplinary expert panels from NCCN Member Institutions in an evidence-based process integrated with expert consensus. The NCCN Guidelines are updated at least annually, but quite often are updated more frequently, with 210 total version updates across all guidelines in 2023.

The NCCN Guidelines are considered the standard for clinical care and policy in oncology in the United States. The Guidelines are the most thorough and most frequently updated clinical practice guidelines in any area of medicine, are the most frequently referenced clinical practice guideline in oncology, and are widely available free of charge for non-commercial use. Our Guidelines are also available through a multitude of health information technology vendors, used by payers representing more than 85% of covered lives in the United States, and form the basis for insurance coverage policy and quality evaluation.

NCCN imposes strict policies to shield the guidelines development processes from external influences. The “firewall” surrounding the NCCN Guidelines processes includes: financial support policies; panel participation and communication policies; guidelines disclosure policies; and policies regarding relationships to NCCN’s other business development activities. The guidelines development is supported exclusively by the Member Institutions’ dues and does not accept any form of industry or other external financial support for the guidelines development program.

Proposed LCD Comments

NCCN thanks MolDX for referencing NCCN content and considering our guidelines within the analysis of evidence. NCCN believes the proposed LCD is largely aligned with current NCCN Guidelines recommendations. NCCN is pleased to provide this respectful feedback regarding the interpretation of our content within the proposed LCD and also respectfully requests the following edits to ensure the accuracy of the information. Specifically:

• Under criteria 4 of the Indications and Limitations of Coverage section, the Proposed LCD states “If testing is performed using single gene tests, a sequential and reflexive approach is expected. Once a positive result is obtained and the appropriate diagnosis is established, further testing should stop unless otherwise indicated and as further described below.” NCCN notes that within the NCCN Guidelines^®, once an MPN diagnosis is strongly suspected or is confirmed, multigene NGS is recommended for mutational prognostication. NCCN is concerned that the LCD as proposed would limit the ability of clinicians to identify additional medically necessary information regarding mutations that can inform prognosis.
• Within the Special Considerations Regarding Testing for Gene Alterations in BCR-ABL Negative MPN section, the proposed LCD states “NCCN guidelines endorse either the single-gene PCR reflex testing approach or the initial multigene approach for the molecular diagnosis of BCR-ABL negative MPNs. For the single-gene approach, guidelines recommend that molecular testing of blood or bone marrow for JAK2 V617F be performed; if negative, it is important to test for CALR and MPL mutations (for patients with suspected ET and PMF) and JAK2 exon 12 mutations (for patients with suspected PV).⁵” Please note the NCCN Guidelines list MF, not PMF, and MF is broader, comprising of both Prefibrotic and Overt myelofibrosis as well as Primary or Secondary (post-ET and post-PV) MF.
• Within the Special Considerations Regarding Testing for Gene Alterations in BCR-ABL Negative MPN section, the proposed LCD cites to NCCN Guidelines for the following statement: “Finding a JAK2 V617F VAF of <1% should also prompt the search for coexisting canonical CALR and MPL mutations” We believe this interpretation is incorrect. The Guidelines state that it is recommended to use highly sensitive assays for JAK2 V617F (sensitivity level <1%) and CALR and MPL (sensitivity level 1% to 3%). In negative cases, the Guidelines recommend to consider searching for noncanonical JAK2 and MPL mutations for PMF early/prefibrotic stage, PMF overt fibrotic stage, and ET; and to consider searching for noncanonical or atypical JAK2 mutations for PV. Please note that as written, this statement is not included within the NCCN Guideline referenced. The statements NCCN provided above are attributed to Arber DA, et al. Blood 2022 and to Thiele J, et al. Am J Hematol 2023. NCCN respectfully suggests amending the statement and requests the removal of this citation for this statement. The original source should be cited directly.
• Within the Special Considerations Regarding Testing for Gene Alterations in BCR-ABL Negative MPN section, the proposed LCD states “For PV and ET, such high-risk individuals include those age >60 years and those with a history of thrombotic event(s).” NCCN respectfully notes that for Polycythemia Vera (PV), NCCN Guidelines include this as ≥ 60 years and/or prior history of thrombosis. Additionally, for Essential Thrombocythemia (ET), high-risk includes history of thrombosis at any age or those age >60 years with a JAK2 NCCN respectfully requests the addition of these clarifications.
• NCCN notes that the NCCN Clinical Practice Guidelines for Myeloproliferative Neoplasms^® version 2.2023 are cited within the proposed LCD. The current NCCN Guidelines for Myeloproliferative Neoplasms^® are Version 2.2024. NCCN respectfully requests use of the most recent version of the NCCN Guidelines. Notable updates within the NCCN Guidelines for Myeloproliferative Neoplasms^® Version 2.2024 include the removal of the tables for PV and ET. Additionally, the table for Primary Myelofibrosis (PMF) was updated. NCCN requests updates to Table 1 to account for new information within the most recent version of the NCCN Guidelines.

NCCN notes that our most pressing concern is criteria number four under Indications and Limitations of Coverage which would significantly limit the utility of testing if implemented as currently worded. NCCN requests the removal of this language to allow for testing to inform prognosis in addition to diagnosis. NCCN notes that the remainder of the LCD appears to largely align with NCCN recommendations and supports the remainder of the LCD. NCCN thanks MolDX for its consideration of these requested language updates.

Guideline Adherence as a Tool to Improve Outcomes, Reduce Costs, and Keep Coverage Evergreen

Numerous independent studies have found adherence to NCCN Guidelines improves care delivery and outcomes for patients with cancer. Improved health outcomes proven through concordance with NCCN Guidelines include: improved rates of survival for colon cancer, ovarian cancer, gastric cancer, nasopharyngeal cancer, and pancreatic cancer; decreased locoregional recurrence of melanoma; and improved pain control.^1,2,3,4,5,6

Guideline adherent care has also been shown to decrease costs to both the payer and the patient. A study by United, eviCore, and NCCN entitled “Transforming Prior Authorization to Decision Support” demonstrated mandatory adherence to NCCN Guidelines and NCCN Compendium^® using a real-time Clinical Decision Support Mechanism by United Healthcare significantly reduced total and episodic costs of care by 20% compared to trend while also reducing denials and increasing access to guideline-concordant care.⁷ A 2019 study "Guideline Discordance and Patient Cost Responsibility in Medicare Beneficiaries With Metastatic Breast Cancer" by Williams, et.al found median cost for metastatic breast cancer patients receiving guideline-discordant treatment was $7,421 versus $5,171 for those receiving guideline-concordant care.⁸ This study found an additional $1,841 in out-of-pocket cost savings for patients receiving guideline concordant care versus patients who received care that did not adhere to guidelines. These cost savings have also been found in studies evaluating the Medicare population. At the 2022 ASCO annual conference, CVS Health also presented two abstracts looking at total costs of care beginning with the first treatment and for the subsequent 180 days for breast and colon cancer patients in relation to adherence to NCCN Guidelines.^9,10 In both studies, there was a significant reduction in total cost of care with concordance with NCCN Guidelines. In the colon cancer study, this was most prominent and significant in the Medicare population. In the breast cancer study, significant reductions were observed across both commercially insured and Medicare patients, with the greatest reductions again seen in the Medicare population.

NCCN is grateful when our content can be used to advance evergreen coverage and would welcome the opportunity to work together to advance Medicare beneficiary access to optimal cancer care. NCCN would welcome the opportunity to discuss this further should any additional questions arise. NCCN also recommends referring to the NCCN Biomarkers Compendium^® as it contains information designed to support decision-making around the use of biomarker testing in patients with cancer and is updated in conjunction with the NCCN Guidelines on a continual basis.

NCCN again appreciates the opportunity to comment on the Proposed Local Coverage Determination MolDX: Non-Next Generation Sequencing Tests for the Diagnosis of BCR-ABL Negative Myeloproliferative Neoplasms. NCCN is happy to serve as a resource and looks forward to working together to ensure Medicare beneficiary access to high-quality cancer care.

References were provided for review.

Thank you for your comment and for your support of this policy.

We respond to the NCCN Proposed LCD Comments bullets, in the order submitted –

1. Regarding LCD criterion #4, the NCCN recommendation of multigene NGS for mutational prognostication: We note that this LCD is limited to the diagnostic evaluation of BCR-ABL-negative MPNs and not tests for mutational prognostication. We also refer you to the Social Security Act 1862 (a) (1) (A) which states that:

   “Notwithstanding any other provision of this title, no payment may be made under part A or part B for any expenses incurred for items or services— (1)(A) which, except for items and services described in a succeeding subparagraph, are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.” Social Security Act §1862

   Tests performed solely for the purpose of prognostication are not covered by this contractor, in accordance with the above. However, testing that impacts the subsequent management of a patient may be a covered service, according to the criteria outlined in the LCD. To further clarify this, we have revised LCD criterion #4 to state “Once a positive result is obtained and the appropriate diagnosis is established, further testing should stop unless required for subsequent management of the patient or as further described below.”

2. To more accurately reflect the statement in the guidelines, we changed “PMF” to “MF” in the relevant Special Considerations Regarding Testing for Gene Alterations in BCR-ABL Negative MPN section of the LCD.

3. In the Special Considerations Regarding Testing for Gene Alterations in BCR-ABL Negative MPN section of the LCD, we modified the statement regarding the search for noncanonical mutations in triple-negative cases and cases with a JAK2 V617F VAF of <1%. We also removed the NCCN citation and attributed the statement to its original source.

4. In the Special Considerations Regarding Testing for Gene Alterations in BCR-ABL Negative MPN section of the LCD, we added clarifications regarding individuals at high-risk for PV and ET.

5. The most current NCCN Guidelines for Myeloproliferative Neoplasms are cited (Version 1.2025).

6. We deleted Table 1 completely, given the many changes made in the recent versions of the NCCN guidelines. For more information regarding the gene alterations associated with prognostic implications, we have referred the readers to the most current NCCN guidelines as well as to Vannucchi et al., 2022.

The following comment was submitted to WPS:

Nothing else to add, but since I did comment on Proposed LCD-MolDX: Non-Next Generation Sequencing Tests for the Diagnosis of BCR-ABL Negative Myeloproliferative Neoplasms. I wanted to put it in writing. I agree with the policy and these individual tests are important in the diagnoses of these rare neoplasms and to distinguish them from inflammatory or other non-neoplastic diseases.

Thank you for your comment and for your support of this policy.