New Strategies in Myeloproliferative Neoplasms: The Evolving Genetic and Therapeutic Landscape

Patel, Ami B.; Vellore, Nadeem A.; Deininger, Michael W.

doi:10.1158/1078-0432.ccr-15-0905

Cited by 13 publications

(11 citation statements)

References 128 publications

(121 reference statements)

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“…In recent years, targeted NGS panels have been used in oncology for early detection of tumor, risk stratification and prognosis, disease monitoring, and targeted therapy . Mutational analysis for patients with unexplained cytopenia is becoming common practice, especially in large academic medical centers .…”

Section: Introductionmentioning

confidence: 99%

The diagnostic utility of targeted gene panel sequencing in discriminating etiologies of cytopenia

et al. 2019

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The diagnostic utility of somatic mutations in the context of cytopenias is unclear: clonal hematopoiesis can be found in healthy individuals, patients with aplastic anemia (AA), clonal cytopenia of undetermined significance (CCUS) and myelodysplastic syndrome (MDS). We examined a cohort of 207 well-characterized cytopenic patients with a 640-gene next generation sequencing (NGS) panel and compared its diagnostic utility with a "virtual" 41 gene panel. The TET2, SF3B1, ASXL1, and TP53 were the most commonly mutated genes (frequency > 10%). Mutations in the 640-gene panel show high sensitivity (98.3%) but low specificity (47.6%) for diagnosis of MDS. Notably, mutations of splicing factors and genes in the RAS pathway are relatively specific to MDS. Furthermore, high variant allele frequency (VAF) predicts MDS: when the VAF is set at 20%, the positive predictive value (PPV) for MDS is 95.9%, with a specificity of 95.3%. The presence of two or more somatic mutations with ≥10% VAF showed a PPV of 95.2%. While the "virtual" 41-gene panel showed a mild decrease in sensitivity (95.7% vs 98.3%), 100% specificity was observed when either VAF was set at ≥20% (100% vs 95.3%), or two or more somatic mutations had VAFs ≥ 10%. Our study shows targeted gene panel sequencing improves the diagnostic approach and accuracy for unexplained cytopenia, with its high sensitivity and high PPV for MDS when applying VAF cutoffs. Furthermore, a 41-gene panel was shown to have at least comparable performance characteristics to the large 640-gene panel.

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Section: Introductionmentioning

confidence: 99%

The diagnostic utility of targeted gene panel sequencing in discriminating etiologies of cytopenia

et al. 2019

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“…Other phase I trial (NCT02436135) investigated the combination of RUX with idelalisib, a PI3K delta inhibitor, as therapy for intermediate to high-risk PMF, post-PV MF, or post-ET MF with progressive or relapsed disease [127].…”

Section: Pcd Resistance In Myeloid Proliferation Exploited In Single mentioning

confidence: 99%

“…Due to the preclinically proved synergic effects of PI3K/AKT/mTOR inhibitors and JAK inhibitors, several clinical studies were initiated: PI3K inhibitor TGR-1202 in combination with RUX (NCT02493530), PI3K inhibitor buparlisib with RUX (NCT01730248), PI3K inhibitor INCB050465 and RUX (NCT02718300), and selective PI3Kδ inhibitor TGR-1202 and RUX (NCT02493530). Preliminary results of buparlisib and RUX phase 1b study indicated that this drug association was well tolerated, and ≥ 50% reduction in splenomegaly was observed in 70% of JAK-inhibitor naive patients and 54% of patients who did not previously respond to JAK2 inhibitor monotherapy [97,127].…”

Section: Pcd Resistance In Myeloid Proliferation Exploited In Single mentioning

confidence: 99%

Programmed Cell Death Deregulation in BCR-ABL1-Negative Myeloproliferative Neoplasms

Diaconu¹,

Gurban²,

Mambet³

et al. 2020

Programmed Cell Death

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BCR-ABL1-negative myeloproliferative neoplasms are classically represented by primary myelofibrosis, polycythemia vera, and essential thrombocythemia. These entities are stem cell-derived clonal disorders characterized by hematopoietic progenitor autonomy or hypersensitivity to cytokines, most of them presenting mutations in Janus kinase 2 (JAK2), calreticulin (CALR), or myeloproliferative leukemia virus oncogene (MPL). Deregulation of pro-and antiapoptotic genes is also claimed as an important mechanism involved in cell resistance to cell death and accumulation of myeloid cells in myeloproliferative neoplasms. Apoptosis, as one of the best-characterized types of programmed cell death, has a clear role in hematopoiesis control. However, the exact pathways affected in BCR-ABL1-negative myeloproliferative neoplasms have not yet been fully clarified. This chapter will explore the modifications affecting programmed cell death pathways involved in myeloid proliferation and how these alterations might be exploited in single or combined targeted therapeutic strategies.

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“…25 Treatment reduces splenomegaly, itch and fatigue and improves survival but the newer agents now in phase 3 trials, such as momelotinib and pacritinib, may offer similar efficacy with a lower risk of myelosuppression (though they may have other adverse effects such as, in the case of momelotinib, peripheral neuropathy). 26 …”

Section: Myeloproliferative Disordersmentioning

confidence: 99%

Janus kinase inhibitors for autoimmune disorders

Chaplin¹

2017

Prescriber

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New Strategies in Myeloproliferative Neoplasms: The Evolving Genetic and Therapeutic Landscape

Cited by 13 publications

References 128 publications

The diagnostic utility of targeted gene panel sequencing in discriminating etiologies of cytopenia

The diagnostic utility of targeted gene panel sequencing in discriminating etiologies of cytopenia

Programmed Cell Death Deregulation in BCR-ABL1-Negative Myeloproliferative Neoplasms

Janus kinase inhibitors for autoimmune disorders

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