Clinical data and practice guidelines have evolved at a rapid pace for this heterogeneous group of disorders. To date, conventional approaches to mutation profiling have involved complex, sequentially cascaded testing algorithms that are resource intensive and often inefficient. With the advent of next generation sequencing (NGS), multiplex targeted gene panels now provide a practical solution for comprehensive mutation analysis in routine clinical practice.
MPLN NGS panel content is based on NCCN and updated WHO practice guidelines. Oncogenic driver mutations significantly impact prognosis and management in MPNs, and mutations may also serve as diagnostically useful markers of clonality. For example, the differential diagnosis of chronic eosinophilic leukemia, not otherwise specified (CEL, NOS) and idiopathic hypereosinophilic syndrome is known to be especially challenging, as the former generally requires identification of clonal cytogenetic abnormalities that are only rarely detected. In a recent study involving the nation’s leading cancer centers, the diagnosis of CEL, NOS was initially missed in ~1/3 of patients, however utilization of NGS mutation data resulted in accurate reclassification of these cases. NGS panel testing also informs prognostic risk stratification in PMF, where survival has been reported to broadly range from 3.2 - 17.7 years, depending on mutation subtype. Further information can be found below in additional resources.
MPLN NGS panel content is based on NCCN and 2016 updated WHO practice guidelines.
The MPN Core Panel
JAK2 (V617F and Exon 12), CALR (type 1 and type 2 mutations), MPL, p.W515 mutations
Has prognostic utility in PMF. Cases of PMF and CALR-mutant PMF presenting with “triple negative” JAK2 V617F, CALR and MPL are associated with inferior overall survival when compared to patients with JAK2 and/or CALR or MPL. Additionally triple-negative mutation status in essential thrombocytothemia (ET) is favorable and predicts lower incidence of vascular events.
Click here to view Kaplan-Meier analysis of survival of PMF patients stratified according to their driver mutation or a clinical-molecular prognostic model that includes IPSS variables and driver mutation. Rumi E, Cazzola M 2017. Diagnosis, risk stratfication, and response evaluation in classical myeloproliferative neoplasms. Blood. 129:680-692)
Myeloid Extended Panel
JAK2 (V617F and Exon 12), CALR, MPL, ASXL1, CBL, CSF3R, ETV6/TEL, EZH2, IDH1, IDH2, KIT, KRAS, NRAS, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53
In the absence of mutations in JAK2, CALR, or MPL, extended NGS Panel analysis can be targeted to assess for the other most frequently accompanying mutations in MPNs to help establish clonality (ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1). (Rumi E, Cazzola M 2017. Diagnosis, risk stratfication, and response evaluation in classical myeloproliferative neoplasms. Blood. 129:680-692)
Oncogenic mutations in IDH are predictive of therapeutic responses to oral IDH inhibitors, currently in clinical trials.
SF3B1 mutations are highly recurrent in cases of MDS-RARS and MDS-RARS-T. Mutations in this gene essentially exclude secondary reactive causes of ring sideroblast accumulation in bone marrow (e.g. EtOH, vitamin/mineral deficiency, other secondary reactive etiologies.
Mutation data refines prognostication in IPSS-R lower risk MDS cases. The presence of mutations in ASXL1, EZH2, ETV6/TEL, RUNX1, and/or TP53 have been reported to represent significant indicators of adverse clinical prognosis and reduced overall survival in IPSS-R very low, low, and intermediate risk disease
Click here to view Survival curves comparing patients with one or more mutations in TP53, EZH2, RUNX1, ASXL1, or ETV6 James A. Kennedy and Benjamin L. Ebert. 2017. Clinical Implications of Genetic Mutations in Myelodysplastic SyndromeJournal of Clinical Oncology 35(9): 968-974