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Three driver mutations (JAK2, CALR and MPL) comprise one of the major diagnostic criteria for Philadelphia negative (Ph-) myeloproliferative neoplasms (MPN) in the current World Health Organisation (WHO) classification. Although driver mutations were previously thought to be mutually exclusive, recent reports have demonstrated their uncommon co-existence. The impact of single driver mutations on phenotype and prognosis has been established, though the clinical implication of coexisting driver mutations remains unclear. With more sensitive and cost-effective next generation sequencing (NGS) applications for patients with blood cancers, novel mutations are being discovered that have important clinical and prognostic significance. Herein, we report a case of three stages of molecular and clinical evolution of a MPN from polycythemia vera (PV) to post-PV myelofibrosis (MF), and then to accelerated phase MF. We found the acquisition of new mutations and copy number changes using an NGS panel that correlated with changes in clinical features; the late acquisition of a new MPL p.Y591D mutation in addition to baseline JAK2 p.V617F and ASXL1 p.R1415Ter mutations resulted in accelerated disease with severe leukocytosis. Our case is of a 73-year-old woman who was diagnosed with JAK2 p.V617F mutant PV in 2008. The initial diagnosis of PV was made based on WHO criteria, including a positive test for the JAK2 p.V617F mutation and a low serum erythropoietin (EPO) level (2 IU/mL); a bone marrow biopsy was not performed. Initial treatment included hydroxycarbamide, aspirin and intermittent venesections. Retrospective molecular assessment using a custom designed AmpliSeq panel run on an Illumina MiniSeq analyser showed heterozygosity for the JAK2 p.V617F mutation (variant allele frequency [VAF]=0.51) and a heterozygous single nucleotide variant (SNV) in the ASXL1 gene, leading to a nonsense amino acid change, p.R1415Ter (VAF=0.43) (Table 1). This variant has been reported as a pathogenic mutation in the Catalogue of Somatic Mutations in Cancer (COSMIC) database (v90). Six years after diagnosis, the patient developed new fatigue, night sweats and splenomegaly. Full blood examination (FBE) showed anemia (hemoglobin 9.1g/dL), leucocytosis (white cell count [WCC] 17x10/L) (Figure 1) and thrombocytosis (platelets 661x10/L) (Figure 2, blue arrow). There was also new monocytosis, basophilia and eosinophila in the blood (Figure 1, blue arrow). The blood smear showed leucoerythroblastosis with prominent teardrop poikilocytes. The lactate dehydrogenase was 1049 U/L (reference range: 125-255 U/L). A bone marrow biopsy demonstrated a markedly hypercellular and fibrotic marrow with increased granulocytic proliferation and abnormal megakaryocyte clustering, consistent with post-PV MF. Molecular analysis of DNA extracted from the trephine detected the same two sequence variants; i.e., (i) a JAK2 p.V617F missense mutation with a VAF of 0.82 suggesting uniparental disomy (UPD) in a fraction of the cells of the malignant clone, and (ii) the same ASXL1 mutation at the same VAF of 0.45 (Table 1) (Figure 3). No other variants were detected in the coding regions of 86 genes that includes most variants documented to be associated with progression of PV to MF. 8 Hydroxycarbamide was changed to ruxolitinib 15 mg twice daily (Figure 2) with improvement in constitutional symptoms and reduction in spleen size. The FBE remained stable with a mild anemia (hemoglobin 9.5-11 g/dL), moderate leucocytosis white cell count (WCC) 2535x10/L) and mild thrombocytopenia (platelets 75125x10/L). Four years after commencing ruxolinitib, there was sudden progression into an accelerated phase of disease with marked leucocytosis (WCC 115x10/L) (Figure 1, red arrow) and splenomegaly. The hemoglobin and platelet values (Figure 2) remained stable. A blood smear showed prominence of myelocytes and basophils. A repeat bone marrow trephine was fibrotic with increased abnormal megakaryocytes, but not markedly different from the bone marrow performed four years earlier. A BCR-ABL1 fusion transcript was not detected by quantitative real-time PCR. Molecular analysis on the peripheral blood using the same NGS panel now detected three sequence variants: (i) the same JAK2 p.V617F missense mutation with a VAF=0.97, consistent with a selective advantage for the clone with UPD, (ii) the same ASXL1 nonsense mutation with a VAF=0.48, and (iii) a new SNV in the MPL gene, leading to a p.Y591D amino acid change (Table 1 and Figure 3). This is not one of the common p.W515L/K/A gain of function mutations in MPL, but has been reported to be pathogenic. This new MPL variant was present at a VAF =0.96, so we performed concurrent peripheral blood cytogenetic testing, with no abnormalities found. In particular, monosomy 1, a common cytogenetic abnormality in MPL-driven MPN, was not present, so we conclude that there must be UPD

Clinical acceleration of JAK2 p.V617F driven myeloproliferative disease due to a new uncommon homozygous MPL p.Y591D mutation