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Genetic and genomic testing are of increasing importance in the diagnosis and management of patients with hematologic neoplasms. Nevertheless, due to the variety of available genetic targets and limited evidence base, the appropriate use of these diagnostic tools in a clinical setting can be challenging. The British Society for Haematology (BSH) has addressed this issue via the creation of a Good Practice Paper, which has been published by Cross et al.1, to provide a consensus or a consistent approach on the use of genetic and genomic tests in patients with myeloproliferative neoplasms (MPN), myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN), myeloid/lymphoid neoplasms with eosinophilia and rearrangements of PDGFRA, PDGFRB or FGFR1, or with PCM1-JAK2, and mastocytosis. Here, we summarize the recommendations for BCR-ABL1-negative MPN; the guidance on genetic testing in atypical MPN subtypes is summarized separately here.
Good-Practice Papers aim to recommend good practice in areas where the evidence is limited but a degree of consensus or uniformity may improve patient care. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature is used to indicate the quality of evidence (summarized in Table 1) and the strength of a recommendation: in Grade 1 (strong) clinicians are certain that benefits do, or do not, outweigh risks and burdens; in Grade 2 (weak) clinicians believe that benefits and risks and burdens are finely balanced, or appreciable uncertainty exists about the magnitude of benefits and risks.
Table 1. The quality of evidence*
(A) High |
Further research is very unlikely to change confidence in the estimate of effect |
(B) Moderate |
Further research is likely to have a significant impact on confidence and may change the recommendation in the estimate of effect and may change the estimate |
(C) Low |
Further research is very likely to have an important impact on confidence in the estimate of effect, and is likely to change the estimate |
(D) Very Low |
Any estimate of effect is very uncertain |
*Adapted from the BSH Guidelines Committee2 |
A PubMed search was performed from January 2018 to September 2020 for the terms: (myeloproliferative OR polycythemia OR thrombocythemia OR myelofibrosis OR eosinophilia OR mastocytosis OR neutrophilia OR myelomonocytic OR eosinophilic CEL OR CNL OR CMML OR JMML) AND (mutation OR variant) AND (diagnosis or prognosis). The search returned a total of 135 relevant papers.
Molecular screening for MPN driver mutations (JAK2, CALR, and MPL) is highly likely to identify a mutation in almost all patients with polycythemia vera (PV), and 85–90% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). Assessment for these drivers is performed on peripheral blood DNA.
Table 2. Targets in suspected MPN*
Presentation |
Variant |
Frequency |
---|---|---|
Erythrocytosis |
JAK2 V617F |
96–97% PV |
JAK2 exon 12 mutations |
~3% PV |
|
Thrombocytosis |
JAK2 V617F |
50–60% ET |
CALR exon 9 mutation |
25–30% ET |
|
MPL exon 10 mutation |
3–11% ET |
|
BCR–ABL1 fusion |
To exclude CML |
|
Suspected PMF |
JAK2 V617F |
50–60% PMF |
CALR exon 9 mutation |
15–35% PMF |
|
MPL exon 10 mutation |
6–9% PMF |
|
Suspected CML |
BCR-ABL1 fusion |
100% CML |
CML, chronic myeloid leukemia; ET, essential thrombocythemia; MPN, myeloproliferative neoplasms; PMF, primary myelofibrosis; PV, polycythemia vera. |
Additional driver mutations are shown to have an impact on prognosis, the risk of disease progression and implications for treatment response in MPN, read more here.
Frequencies of additional somatic driver variants are often higher in PMF or secondary MF and/or blast phase of other MPN or MDS/MPN. The minimum requirement for genes to be assessed for MPN in the National Genomic Test Directories3 include KRAS, NRAS, TP53, JAK2, CALR, MPL, ASXL1, CBL, CHEK2, CSF3R, CUX1, DNMT3A, EZH2, IDH1, IDH2, IKZF1, KIT, NFE2, SF3B1, SH2B3, SRSF2, TET2, U2AF1, HRAS, RUNX1, SETBP1, and ZRSR2 (multi-panel NGS).3 It is preferable to run these panels on bone marrow (BM) if available, but peripheral blood is also acceptable. Due to high cost and the potential to identify incidental clonal hematopoiesis, it is not considered appropriate to use panels in all MPN patients; however, these screenings may be useful in specific situations.
Erythrocytosis: Patients with unexplained erythrocytosis and without JAK2 V617F may be considered for a BM biopsy and JAK2 exon 12 mutation; most patients are diagnosed with idiopathic erythrocytosis if there is no secondary cause. In patients JAK2-unmutated PV, testing may be considered; however, there is no evidence to guide this approach.
Thrombocytosis or suspected PMF: Screening for additional mutations in patients with triple-negative ET and PMF may be useful in diagnosing a clonal disorder depending on age, clinical presentation, and gene panel content. Testing is recommended in patients with BM histology and clinical features consistent with PMF using myeloid gene panels combined with conventional karyotyping (or single nucleotide polymorphism assay). In patients with triple-negative ET, some patients may harbour a non-canonical mutation in JAK2 or MPL, or in another driver gene; testing for a clonal marker may be advisable for younger patients (<60 years old) with BM histology typical of ET (or MPN-unclassifiable or suspected prefibrotic MF) where confirmation of a clonal disorder may inform on disease progression with a broad panel with non-canonical variants in JAK2 and MPL and a range of other driver genes. Another case may be patients with significant thrombocytosis (>600 × 109/L) where no reactive cause has been identified, and cytoreduction would be helpful for a clonal disorder, such as unexplained thrombotic events, especially in younger patients. In triple-negative patients with thrombocytosis, screening for driver mutations may be considered at intervals (e.g., 5 years) if thrombocytosis is persistent. BM histology is still very important to confirm an MPN diagnosis in these patients.
Figure 1 summarizes the recommended guidelines in patients with suspected MPN who test negative for driver mutations.
Figure 1. Flow of genetic testing in case of suspected ET/PV/PMF with a negative result for driver mutations*
BM, bone marrow; CML, chronic myeloid leukemia; ET, essential thrombocythemia; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasms; PMF, primary myelofibrosis; PV, polycythemia vera; SNP, single nucleotide polymorphism.
*Adapted from Cross et al.1
In patients with known clonal disorders with JAK2, CALR, or MPL mutations, myeloid gene panels can provide supplementary information on diagnosis and prognosis at presentation or suspected transformation with a potential to inform treatment decisions for targeted therapy in the future. These panels may also be useful to diagnose other disorders associated with JAK2 V617F, including MDS/MPN. They also represent a valuable tool for evaluating prognosis when deciding on a patient’s suitability for allogenic stem cell transplantation.
In patients with blast-phase MPN, myeloid panel testing is recommended for prognostic risk stratification, or this information would allow patients to enter a clinical trial. Repeated testing at the chronic phase is rarely helpful.
Myeloid gene panel testing is recommended:
Current research in patients receiving pegylated interferon-alpha and ruxolitinib has not yet confirmed that a particular level of molecular response is associated with a more favourable vascular or transformation risk; therefore, molecular response is not considered a treatment target. As such, there is no evidence to recommend routine quantitative monitoring of clonal burden:
Genetic and genomic testing provide novel insights in the diagnosis and management of hematologic disorders and have an impact on clinical practice. Considering cost-effectiveness and clinically appropriateness, it is vital to assess its utility on a case-by-case basis rather than adopting an untargeted approach.
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