Hematologic cancers impact the normal production and function of blood cells. These cancers often begin in bone marrow, where stem cells develop into white blood cells, red blood cells, or platelets. Hematologic cancers such as myeloid and lymphoid neoplasms occur when there is an uncontrolled growth of abnormal cells which overtake the development of normal blood cells. An overabundance of abnormal cells interferes with the regular functions of normal cells (ACCC, 2022). Myeloid neoplasms occur when there is a proliferation of myeloid cells that have originated from a primitive stem cell (NCBI, 2023b). In contrast, lymphoid neoplasms are composed of a lymphocytic cell population which is usually malignant (clonal) by molecular genetic and/or immunophenotypic analysis (NCBI, 2023a).

For guidance on flow cytometry in hematopoietic neoplasms, please refer to CAM 120 -Flow Cytometry.

For guidance on minimal/measurable residual disease (MRD) in hematopoietic neoplasms, please refer to CAM 251 -Minimal Residual Disease.

Regulatory Status
On April 28, 2017 the FDA approved the LeukoStrat^® CDx FLT3 Mutation Assay as a “PCR-based, in vitro diagnostic test designed to detect internal tandem duplication (ITD) mutations and the tyrosine kinase domain mutations D835 and I836 in the FLT3 gene in genomic DNA extracted from mononuclear cells obtained from peripheral blood or bone marrow aspirates of patients diagnosed with acute myelogenous leukemia (AML). The LeukoStrat^® CDx FLT3 Mutation Assay is used as an aid in the selection of patients with AML for whom RYDAPT^® (midostaurin) treatment is being considered. The Leukostrat^® CDx FLT3 Mutation Assay is to be performed only at Laboratory for Personalized Molecular Medicine (LabPMM) LLC, a single site laboratory located at 6330 Nancy Ridge Dr., San Diego, CA 92121.”

On Aug. 1, 2017 the FDA approved the Abbott RealTime IDH2 as an “in vitro polymerase chain reaction (PCR) assay for the qualitative detection of single nucleotide variants (SNVs) coding nine IDH2 mutations (R140Q, R140L, R140G, R140W, R172K, R172M, R172G, R172S, and R172W) in DNA extracted from human blood (EDTA) or bone marrow (EDTA). Abbott RealTime IDH2 is for use with the Abbott m2000rt System. Abbott RealTime IDH2 is indicated as an aid in identifying acute myeloid leukemia (AML) patients with an isocitrate dehydrogenase-2 (IDH2) mutation for treatment with IDHIFA^® (enasidenib).”

Many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare & Medicaid Services (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). LDTs are not approved or cleared by the U.S. Food and Drug Administration; however, FDA clearance or approval is not currently required for clinical use.

Policy
Application of coverage criteria is dependent upon an individual’s benefit coverage at the time of the request.

1. For the initial diagnosis and profiling of hematopoietic neoplasms, the following testing is considered MEDICALLY NECESSARY:
   1. Bone marrow cytogenetics and/or fluorescent in situ hybridization (FISH) of bone marrow samples.
   2. Multigene panel testing.
2. For the differential diagnosis of chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL) or for optimal risk stratification and treatment planning for individuals diagnosed with B-cell ALL (B-ALL), one time qualitative or quantitative RT-PCR testing on blood or bone marrow for identification of the BCR-ABL1 fusion gene transcript type, including determination of transcript size (e.g., p190 vs. p210), is considered MEDICALLY NECESSARY.
3. For individuals diagnosed with acute lymphoblastic leukemia (ALL) or pediatric ALL (PEDALL) who are under surveillance, the following tests is considered MEDICALLY NECESSARY  once every 3 to 6 months for at least 5 years:
   1. Bone marrow cytogenetics.
   2. Bone marrow FISH.
   3. Multigene panel testing.
4. For all individuals with Philadelphia chromosome positive ALL (Ph+ ALL), BCR-ABL1 transcript-specific quantification is considered MEDICALLY NECESSARYat the following frequency:
   1. Once per month for individuals who have detectable levels of BCR-ABL1 transcript.
   2. Once every three months for individuals who have undetectable levels of BCR-ABL1 transcript.
5. For individuals diagnosed with acute myeloid leukemia (AML) who had cytogenetic abnormalities at diagnosis, cytogenetic or FISH testing is considered MEDICALLY NECESSARY at the following time points:
   1. Fourteen to twenty-one days after the start of therapy to document hypoplasia.
      1. When hypoplasia is documented, repeat analysis seven to fourteen days later to clarify persistence of leukemia.
      2. When hypoplasia is not documented, repeat analysis at the time of hematologic recovery to document remission.
   2. By 42 days post-treatment with either standard-dose or high-dose cytarabine induction for poor-risk AML, regardless of the degree of hematologic recovery.
6. For individuals with AML who have experienced relapsed/refractory disease after the completion of post-remission therapy, multigene panel testing is considered MEDICALLY NECESSARY.
7. For optimal risk stratification and treatment planning for individuals diagnosed with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), one time testing with any of the following tests (when not already performed during initial diagnosis) is considered MEDICALLY NECESSARY:
   1. FISH to detect +12; del(11q); del(13q); del(17p).
   2. TP53 mutation testing.
   3. CpG-stimulated metaphase karyotype for complex karyotype.
   4. Immunoglobulin heavy chain variable region gene (IGHV) mutation testing.
8. For individuals diagnosed with chronic myeloid leukemia (CML), quantitative reverse transcription polymerase chain reaction (qPCR) testing for the BCR-ABL1 fusion gene transcript is considered MEDICALLY NECESSARY at the following frequency:
   1. To establish baseline levels at diagnosis.
   2. For individuals undergoing TKI therapy:
      1. Every 3 months after initiation of therapy until major molecular response (MMR) (BCR-ABL1 (IS) < 1% (>0.1%-1%)) has been achieved.
      2. Every 3 months for 2 years and every 36 months thereafter.
      3. If there is a 1-log increase in BCR-ABL1 transcript levels with MMR, repeat in 1 – 3 months.
9. For individuals diagnosed with CML who are pursuing or who are actively undergoing TKI therapy, bone marrow cytogenetics is considered MEDICALLY NECESSARY at the following time points:
   1. To establish cytogenetic changes.
   2. When there is a failure to reach response milestones.
   3. When there is any sign of loss of hematologic response.
   4. When there is any sign of loss of complete cytogenetic response (CCyR) or its molecular response correlate, defined as an increase in BCR-ABL1 transcript to >1%.
10. Evaluation of BCR-ABL kinase domain point mutations in patients with CML is considered MEDICALLY NECESSARY at the following time points:
    1. When the individual has chronic phase CML.
    2. When there is failure to reach response milestones.
    3. When there is any sign of loss of hematologic response.
    4. When there is any sign of loss of CCyR or its molecular response correlate, defined as an increase in BCR-ABL1 transcript to 1%.
    5. When there is a 1-log increase in BCR-ABL1 transcript levels and a loss of MMR.
    6. When the disease progresses to accelerated or blast phase.
11. For individuals with CML who are undergoing treatment discontinuation with TKI therapy and who remain in MMR after discontinuation of therapy, qPCR on blood or bone marrow for the BCR-ABL1 fusion gene transcription is considered MEDICALLY NECESSARY at the following frequency:
    1. Every month for the first 6 months following discontinuation.
    2. Once every two months in months 7-12 following discontinuation.
    3. Once every three months beginning 12 months following discontinuation of therapy, as long as the individual remains in MMR.
12. For individuals with CML, the use of FISH to monitor response to TKI therapy is considered NOT MEDICALLY NECESSARY.
13. Simultaneous testing of both bone marrow and blood for monitoring purposes is considered NOT MEDICALLY NECESSARY.

The following does not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of an individual’s illness.

14. For the diagnosis or prognosis of individuals with confirmed acute leukemia, global/gene specific methylation, microRNA (miRNA) expression, or gene expression analysis is considered NOT MEDICALLY NECESSARY.
15. For diagnosis or prognosis of myeloid or lymphoid neoplasms, all other testing not addressed above is considered NOT MEDICALLY NECESSARY.

NOTES:

Note: For 2 or more gene tests being run on the same platform, please refer to CAM 235 Reimbursement Policy.

Table of Terminology