Philadelphia-negative myeloproliferative neoplasms (MPNs) are a diverse group of diseases whose common feature is the presence of V617F mutation of the JAK2 gene. In the era of novel therapeutic strategies in MPNs, such as JAK-inhibitor therapy, there is a growing need for establishing high sensitive quantitative methods, which can be useful not only at diagnosis but also for monitoring therapeutic outcomes, such as minimal residual disease (MRD). In this study, we compared the qPCR and ddPCR methods and their clinical utility for diagnosis, prognostication, and treatment monitoring of MPNs with JAK2 V617F mutation in 63 MPN patients of which 6 were subjected to ruxolitinib treatment. We show a high conformance between the two methods (correlation coefficient r = 0.998 (p < 0.0001)). Our experiments revealed high analytical sensitivity for both tests, suggesting that they are capable of detecting the JAK2 V617F mutation at diagnosis of MPN with a limit of detection (LoD) of 0.12% for qPCR and 0.01% for ddPCR. The alterations of JAK2 V617F allele burden in patients treated with ruxolitinib were measured by both methods with equal accuracy. The results suggest an advantage of ddPCR in monitoring MRD because of allele burdens below the LoD of qPCR. Overall, the clinical utility of qPCR and ddPCR is very high, and both methods could be recommended for the routine detection of the V617F mutation at diagnosis, though ddPCR will probably supersede qPCR in the future due to cost-effectiveness.
Thus, no significant differences in the studied polymorphism frequencies were observed. It is then suggested that the studied polymorphisms, although probably good candidates in other tissue cancer types, might not be good predictive factors in breast cancer risk or development in Caucasians.
In our opinion, a detailed evaluation and appropriate interpretation of clinical and laboratory data in such a category of patients seem to be extremely important, especially when a decision about the TKI change due to therapy failure is considered.
In April 2017 midostaurin was approved by the US Food and Drug Administration for the treatment of patients with aggressive systemic mastocytosis (ASM). So far, very limited real world data on its efficacy is available. Thirteen patients aged from 48 to 79 years, who received midostaurin in the early access program, were included in the study. Midostaurin was used both in first (n = 5) and subsequent lines of treatment (n = 8). The median duration of exposure was 9 months. Most patients (77%, n = 10) had a clinical improvement already as soon as the second month of therapy. Objective response was noted in 4 (50%) of eight evaluated patients. Among responders, we observed a decrease in serum tryptase level (median 74.14%) and bone marrow infiltration by mast cells (median 50%) in the sixth month of treatment. In one case, in the 10th month of treatment, allogenic stem cell transplantation was performed, achieving complete remission. Five patients died, three due to progression of disease, one in the course of secondary acute myeloid leukemia and one due to reasons not related to mastocytosis. Treatment is ongoing in seven patients. We found that midostaurin therapy is beneficial to patients with ASM.
Recent data indicate that MIR142 is the most frequently mutated miRNA gene and one of the most frequently mutated noncoding elements in all cancers, with mutations occurring predominantly in blood cancers, especially diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. Functional analyses show that the MIR142 alterations have profound consequences for lympho- and myelopoiesis. Furthermore, one of the targets downregulated by miR-142-5p is CD274, which encodes PD-L1 that is elevated in many cancer types, including myeloproliferative neoplasms (MPNs). To extend knowledge about the occurrence of MIR142 mutations, we sequenced the gene in a large panel of MPNs [~ 700 samples, including polycythemia vera, essential thrombocythemia, primary myelofibrosis (PMF), and chronic myeloid leukemia], neoplasm types in which such mutations have never been tested, and in panels of acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL). We identified 3 mutations (one in a PMF sample and two others in one CLL sample), indicating that MIR142 mutations are rare in MPNs. In summary, mutations in MIR142 are rare in MPNs; however, in specific subtypes, such as PMF, their frequency may be comparable to that observed in CLL or AML.
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