Thursday, July 3, 2025

MolDx Finalized LCD July 3: Non-NGS Tests for BCR-ABL Negative Neoplasms

 MolDx finalizes a draft LCD offered last year; the final LCD is in comment period July 3-August 16, 2025.

MolDX: Non-Next Generation Sequencing Tests for the Diagnosis of BCR-ABL Negative Myeloproliferative Neoplasms.  L39919 (Palmetto, Final).

Note that this is to complement another LCD, "NGS LDTs for Myloid Malignancies," L38047.

I've clipped the full MolDx rules of coverage below.  Ahead of that, I clip a Chat GPT simplification.  You can use the simplification as an entry point for your reading, but only use the Full LCD Rules verbatim, for actual cases and claims.

I haven't done a redline comparing draft to final, but from the Comments article A60223 there are selective acknowledgements of corrections madein the final.  There were, however, quite a few comments.  Find A60223 here.   Find an AI discussion of A60223, below, after the cut/paste LCD sections.

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Simplified Version - Chat GPT - For Curiousity Only.  See Full Intricate MolDx Rules at Bottom.

Here's a concise AI summary of the Medicare MolDx coverage criteria for non-NGS molecular testing of BCR-ABL-negative myeloproliferative neoplasms (MPNs) from the LCD:

Coverage Summary: Simplified, Non-Official: Non-NGS Molecular Testing for Suspected BCR-ABL-Negative MPNs

Covered MPNs:
Classical MPNs (PV, ET, PMF) and select non-classical types (e.g., CNL, CEL-NOS).
Myelodysplastic/Myeloproliferative neoplasms are excluded.

General Requirements (All Must Be Met):

  1. Patient is being evaluated for BCR-ABL-negative MPN per WHO or ICC criteria.

  2. BCR-ABL testing must precede molecular testing (except in PV suspicion).

  3. Test methods (e.g., qPCR, ddPCR) must detect mutations with high sensitivity (VAF ≤1% for JAK2; ≤3% for CALR/MPL).

  4. For single-gene tests, a reflexive stepwise approach is required and must stop once a diagnosis is reached:

    • Step 1: BCR-ABL

    • Step 2: JAK2 V617F

    • Step 3: If JAK2 V617F-negative or <1% VAF:

      • JAK2 exon 12 (if PV suspected)

      • CALR and MPL (if ET/PMF suspected)

  5. For multiplex PCR panels, must include genes needed for accurate diagnosis of the suspected MPN:

    • Always include JAK2 (V617F and exon 12), CALR, MPL.

    • For CNL: CSF3R required (after excluding classical MPNs).

    • If blast-phase PMF is suspected: test must include AML-associated genes, likely requiring NGS (see LCD L38047).

  6. If initial non-NGS testing is negative (including low VAF results), NGS panel may be used to detect additional, non-duplicative mutations (per guidelines).

Analytical & Clinical Standards:
7. All analytes must have published peer-reviewed evidence of clinical validity.
8. Test must be used in a population and setting consistent with its validated intended use.
9. Test must pass technical assessment (TA) confirming AV, CV, and CU.
10. Tests similar to existing covered ones must show equal or superior performance.
11. Covered for diagnosis only, not for monitoring or MRD.

Note:
NGS-based testing for MPNs is not covered under this LCD. It must meet criteria outlined in LCD L38047.

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FULL OFFICIAL MOLDX RULES FOLLOW NOW:

MolDx writes, and I quote,

This policy provides limited coverage for multi-gene non-next generation sequencing (NGS) panel testing and limited coverage for single-gene testing for the diagnostic workup of patients with suspected BCR-ABL negative myeloproliferative neoplasms (MPNs).

Classical BCR-ABL negative MPNs include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF), and non-classical BCR-ABL negative MPNs include Chronic Neutrophilic Leukemia (CNL) and Chronic Eosinophilic Leukemia, Not Otherwise Specified (CEL, NOS), among other rare entities.

Myelodysplastic/Myeloproliferative neoplasms are considered a separate class outside the scope of this LCD.

Testing myeloid and suspected neoplasms by NGS is covered by a separate LCD, MolDX: Next-Generation Sequencing Lab-Developed Tests for Myeloid Malignancies and Suspected Myeloid Malignancies (L38047).

ALL of the following criteria must be met:

1. The patient is being evaluated for a BCR-ABL-negative MPN according to national or international consensus diagnostic criteria (i.e., World Health Organization (WHO); International Consensus Classification (ICC)).

2. Testing follows the assessment of BCR-ABL (this is required unless the patient is only suspected of having PV).

3. 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).

4. 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 required for subsequent management of the patient or as further described below.

  • When testing for the classical BCR-ABL-negative MPNs (PV, ET, or PMF) using single gene tests, reflex testing to the next gene will be considered reasonable and necessary according to the following sequence of tests for known driver mutations:
  • BCR-ABL negative test results, progress to ii.
  • Note: For the rare patient with high clinical suspicion of PV despite a positive BCR-ABL result, testing for a mutation in JAK2 mutation may still be performed.
  • JAK2 V617F negative test results (this includes JAK2 V617F positive at <1% VAF), progress to iii or iv.
  • JAK2, exon 12 (required when PV is suspected)
  • Calreticulin (CALR) and Thrombopoietin Receptor (MPL) driver mutations (required when ET or PMF is suspected)
  • Note: testing for CALR/MPL does NOT require a negative JAK2 exon 12, just a negative JAK2 V617F result.

5. If testing is performed using a panel (i.e., multiplex PCR) the panel must include at least the minimum necessary genes and gene alterations that would be reasonably expected by the test to achieve a diagnosis according to national or international consensus guidelines, given the specific MPN subtype suspected. For example:

  • Molecular testing for mutations in JAK2 (including V617F and exon 12), CALR and MPL genes is considered medically necessary for the identification of the classical MPNs.
  • However, if the accelerated/blast phase of PMF is suspected at diagnosis, molecular testing should also include acute myeloid leukemia (AML)- associated mutations and would likely require the performance of a NGS panel; in this case, a panel that does not include the AML-associated mutations does not meet the minimum necessary gene requirements.
  • Additional MPN-associated genes must also be included as appropriate for the identification of other non-classical BCR-ABL-negative MPNs. For example, when CNL is suspected, testing for the colony stimulating factor 3 receptor (CSF3R) is required. Note also that testing for CNL requires the exclusion of the classical BCR-ABL-negative MPNs.

6. 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. The additional testing by NGS must comprise non-duplicative genetic alterations.

7. Clinical validity (CV) of analytes measured must be established through a study published in the peer-reviewed literature for the intended use of the test in the intended population.

8. The test is being used (a) in a patient who is part of the population in which the test was analytically validated and (b) according to the intended use of the test.

9. The test satisfactorily completes a technical assessment (TA) that will evaluate and confirm that analytical validity (AV), clinical validity (CV), and clinical utility (CU) have been demonstrated.

10. Tests utilizing a similar methodology or evaluating a similar molecular analyte to a test for which there is a generally accepted testing standard or for which existing coverage exists must demonstrate equivalent or superior test performance (i.e., sensitivity and/or specificity) when used for the same indication in the intended-use population.

11. Testing is performed for diagnosis and not as a test of cure or for monitoring minimal residual disease (MRD).

NOTE: Testing by NGS falls outside the scope of this LCD but must fulfill the criteria outlined in LCD L38047, MolDX: Next-Generation Sequencing Lab-Developed Tests for Myeloid Malignancies and Suspected Myeloid Malignancies.

[End full MolDx rules]

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And you've been waiting for - an AI summary of the Q&A document.

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Here is a focused summary of the MolDx revisions made in response to public comments on LCD A60223:

✅ MolDx Revisions to LCD A60223 [AI]

  1. JAK2 Variant Allele Frequency (VAF) Threshold Updated

    • Revised minimum sensitivity requirement from “<1%” to “≤1%” for JAK2 testing, acknowledging the standard practice and literature support.

  2. Clarified Allowance for Simultaneous Testing

    • Confirmed that simultaneous testing (e.g., JAK2 V617F and exon 12, or JAK2/CALR/MPL) is permitted and not restricted to reflex-only workflows.

  3. Revised Reflex Testing Language (Criterion #4)

    • Clarified that further testing may proceed if required for patient management, not only until initial diagnosis is established.

  4. Updated Terminology for Myelofibrosis

    • Replaced "PMF" with “MF” to reflect NCCN's broader category (including primary and secondary MF).

  5. Corrected Misattributed NCCN Citations

    • Removed one citation incorrectly attributed to NCCN and re-attributed it to its original sources (Arber et al., Thiele et al.).

  6. Added Clarifications for High-Risk Patients

    • Clarified high-risk definitions for PV and ET in alignment with current NCCN guidelines.

  7. Updated Guideline References

    • Cited the most recent NCCN Guidelines (Version 1.2025) and deleted outdated Table 1, instead referring to NCCN and other authoritative sources.

These revisions reflect MolDx's responsiveness to clinical practice realities, stakeholder feedback, and evolving guidelines.

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Here's a concise summary of the MolDx response to public comments on the draft LCD A60223 for non-NGS testing of BCR-ABL-negative myeloproliferative neoplasms (MPNs):

🔍 Main Stakeholder Concerns & MolDx Responses A60223

1. JAK2 Sensitivity Threshold (<1% VAF)

  • Concern (AMP, CAP, Labcorp): Requiring detection below 1% variant allele frequency (VAF) for JAK2 is unrealistic and unsupported. Most labs validate to a 1% VAF.

  • Response: MolDx revised the policy to accept a VAF of ≤1% for JAK2, aligning with the International Consensus Classification (ICC) and alleviating lab concerns.

2. Reflex Testing Requirements

  • Concern (Labcorp, NCCN): Mandating sequential (reflexive) single-gene testing delays diagnosis. Simultaneous testing (e.g., JAK2 V617F + exon 12) is often faster and more efficient.

  • Response: MolDx clarified that simultaneous testing is allowed, especially when clinically appropriate (e.g., high suspicion of PV), and that PCR testing is usually fast.

3. Use of Prognostic Panels (e.g., NGS) After Diagnosis

  • Concern (NCCN): Once diagnosis is confirmed, guidelines recommend further molecular testing for prognostication. Current LCD wording would prevent this.

  • Response: MolDx clarified that further testing is covered if it informs subsequent patient management, not just for prognosis alone. Criterion #4 was revised accordingly.

4. Guideline Alignment & Citation Accuracy

  • Concern (NCCN): Requested updates for:

    • Language (e.g., use “MF” instead of “PMF”)

    • VAF interpretation clarity

    • Up-to-date guideline references (Version 1.2025)

  • Response: MolDx accepted all suggestions, updating citations, removing outdated Table 1, and clarifying terminology and source attributions.

5. Supportive Comment

  • Concern (Independent Commenter): Expressed general support for the policy and the importance of accurate molecular testing in MPN diagnosis.

  • Response: Thanked the commenter and acknowledged their support.

✅ Key Policy Clarifications & Changes

  • JAK2 VAF threshold updated to ≤1%

  • Simultaneous testing (e.g., JAK2 + CALR/MPL) is allowed where appropriate

  • Further testing post-diagnosis is covered if clinically actionable

  • NCCN language and citations updated for accuracy and alignment

This summary should assist labs and clinicians in understanding the intent and flexibility of the LCD, as well as reassure stakeholders that practical clinical realities and guideline alignment were taken into account in finalizing the policy.