Hematologic Diseases

Detects  mutations in key genes recurrently mutated in acute myeloid leukemia (AML). DNA sequence of targeted regions of the ASXL1, BCOR, CEBPA, CSF3R, DNMT3A, EZH2, IDH1, IDH2, KIT, KRAS, NPM1, NRAS, PHF6, PTPN11, RAD21, RUNX1, SF3B1, SRSF2, STAG2, TET2, TP53, U2AF1, WT1, and ZRSR2 genes is determined using next-generation sequencing (NGS) technology.

disease state indication(s)
Acute myeloid leukemia (AML)

clinical use
Acute myeloid leukemia (AML) has traditionally been classified into 3 distinct categories defined by the ability to document an antecedent myelodysplastic syndrome or myeloproliferative neoplasm (secondary AML, s-AML), prior exposure to leukemogenic therapies (therapy-related AML, t-AML), or the absence of both (de novo AML). Disease classification, thus, can be difficult in practice and depends on the availability of prior clinical information rather than objective and reproducible criteria at the time of diagnosis. Recent studies on the genomic landscape of AML, however, have generated a catalogue of leukemia-associated genes that is increasingly comprehensive and clinically informative in regards to disease classification, risk assessment, and treatment selection [1-4].

In one study, genomic analysis was able to define 3 distinct genetic ontogenies for AML defined by the presence of (1) secondary-type mutations, (2) TP53 mutations, or (3) de novo-type or pan-AML mutations [2]. The presence of a mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 was >95% specific for the diagnosis of s-AML. In t-AML and elderly de novo AML populations, these alterations defined a distinct genetic subtype that shared clinicopathologic properties with clinically confirmed s-AML and highlighted a subset of patients with worse clinical outcomes, including lower complete remission rate, more frequent re-induction, and decreased event-free survival. AML with TP53 mutations was shown to have highly distinctive characteristics, including marked karyotype complexity with multiple monosomies, a paucity of driver co-mutations, and very short survival. De novo-type AML as defined by CBF rearrangement, MLL/11q23 rearrangement, and NPM1 mutation may have improved chemosensitivity and better than expected clinical outcomes.

In another more comprehensive study, genomic analysis was able to define 11 distinct genomic subgroups for AML. These include currently defined AML genomic subgroups described in the World Health Organization classification as well as 3 other genomic categories: (1) AML with mutations in genes encoding chromatin, RNA-splicing regulators, or both; (2) AML with TP53 mutations, chromosomal aneuploidies, or both; and provisionally, (3) AML with IDH2R172. Patients with spliceosome and TP53–aneuploidy AML had poor outcomes, with the various class-defining mutations contributing independently and additively to the outcome. In addition to class-defining lesions, other co-occurring driver mutations also had a substantial effect on overall survival.

1. The Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013;368: 2059-2074.
2. Lindsley RC, et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 2015;125(9):1367-76.
3. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. N Engl J Med 2016;374(23):2209-21.
4. Arber D, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-405.

methodology/product platform
Capture-based, next-generation sequencing (NGS)

specimen type and requirements
Peripheral blood: 2-3 mL in EDTA (purple-top) tube.
Bone marrow: 2-3 mL in EDTA (purple-top) tube.
Note: Use refrigerated cold pack for transport. Make sure cold pack is not in direct contact with specimen.

turnaround time
Global: 10-12 days

cpt code(s)
81450 (x1)

medicare moldx cpt code
Not applicable

regulatory classification
Laboratory developed test (LDT)

ordering option