Systemic mastocytosis (SM) is a highly heterogeneous disease with indolent and aggressive forms, with the mechanisms leading to malignant transformation still remaining to be elucidated. Here, we investigated the presence and frequency of genetic variants in 34 SM patients with multilineal KIT D816V mutations. Initial screening was performed by targeted sequencing of 410 genes in DNA extracted from purified bone marrow cells and hair from 12 patients with nonadvanced SM and 8 patients with advanced SM, followed by whole-genome sequencing (WGS) in 4 cases. Somatic mutations were further investigated in another 14 patients with advanced SM. Despite the fact that no common mutation other than KIT D816V was found in WGS analyses, targeted next-generation sequencing identified 67 nonsynonymous genetic variants involving 39 genes. Half of the mutations were somatic (mostly multilineal), whereas the other half were germline variants. The presence of ≥1 multilineal somatic mutation involving genes other than KIT D816V, ≥3 germline variants, and ≥1 multilineal mutation in the SRSF2, ASXL1, RUNX1, and/or EZH2 genes (S/A/R/E genes), in addition to skin lesions, splenomegaly, thrombocytopenia, low hemoglobin levels, and increased alkaline phosphatase and β2-microglobulin serum levels, were associated with a poorer patient outcome. However, the presence of ≥1 multilineal mutation, particularly involving S/A/R/E genes, was the only independent predictor for progression-free survival and overall survival in our cohort.
Indolent systemic mastocytosis (ISM) patients have a normal life expectancy, except in the 5% to 10% of cases that progress to more advanced SM (advSM), which has a significantly poorer outcome. Mutations in genes other than KIT frequently found in myeloid neoplasms have been associated with a poorer outcome among advSM, whereas limited information exists about their frequency and prognostic impact in ISM. We investigated the frequency and prognostic impact of variants in 18 genes, found to be altered in advSM, in 322 ISM patients (median follow-up, 5.7 years) divided into discovery (n = 200) and validation (n = 122) cohorts. Overall, 71 genetic variants were detected in 55 of 322 (17%) patients. Mutated ISM cases, particularly those carrying ASXL1, RUNX1, and/or DNMT3A (A/R/D) pathogenic variant allele frequencies (VAFs) ≥ 30%, exhibited significantly shortened (P < .001) progression-free survival (PFS) and overall survival (OS). Multivariate analysis showed that serum β2-microglobulin (sβ2M) levels > 2.5 µg/mL (hazard ratio [HR], 9.8; P = .001), together with a KIT D816V VAF ≥ 1% in bone marrow (BM) (HR, 10.1; P = .02) and pathogenic variants of A/R/D VAFs ≥ 30% (HR, 4.2; P = .02), were the best combination of independent predictors for PFS. In turn, A/R/D gene pathogenic VAF ≥ 30% was the only independent predictor for OS (HR, 51.8; P < .001). Based on these variables, 2 scoring systems were constructed for risk stratification of ISM at diagnosis with significantly different 10-year PFS (100%, 91%, 0% for scores of 0, 1, ≥2, respectively) and OS (100% and 50% for scores of 0 and 1) rates.
The presence of the KIT D816V mutation in PB of ISM patients is associated with (early) involvement of circulating CD34 HPC and multiple myeloid cell subpopulations, KIT-mutated PB CD34 HPC potentially contributing to early dissemination of the disease.
Despite recent therapeutic advances, systemic mastocytosis (SM) remains an incurable disease due to limited complete remission (CR) rates even after novel therapies. To date, no study has evaluated the expression on SM bone marrow mast cells (BMMC) of large panel of cell surface suitable for antibody-targeted therapy. In this study, we analyzed the expression profile of six cell-surface proteins for which antibody-based therapies are available, on BMMC from 166 SM patients vs. 40 controls. Overall, variable patterns of expression for the markers evaluated were observed among SM BMMC. Thus, CD22, CD30, and CD123, while expressed on BMMC from patients within every subtype of SM, showed highly variable patterns with a significant fraction of negative cases among advanced SM (aggressive SM (ASM), ASM with an associated clonal non-MC lineage disease (ASM-AHN) and MC leukemia (MCL)), 36%, 46%, and 39%, respectively. In turn, CD25 and FcεRI were found to be expressed in most cases (89% and 92%) in virtually all BMMC (median: 92% and 95%) from both indolent and advanced SM, but with lower/absent levels in a significant fraction of MC leukemia (MCL) and both in MCL and well-differentiated SM (WDSM) patients, respectively. In contrast, CD33 was the only marker expressed on all BMMC from every SM patient. Thus, CD33 emerges as the best potentially targetable cell-surface membrane marker in SM, particularly in advanced SM.
e15050 Background: Avian paramyxoviruses (APMVs) are negative-sense, single-stranded RNA viruses, of which best known is APMV-1, commonly referred to as Newcastle disease virus (NDV). NDV has been extensively studied as an oncolytic virus (OV) and has been shown to be a promising viral agent for human cancer therapy. We identified APMV-4 as a novel OV from the APMV family, with several advantages over NDV and other classes of OVs. APMV-4 is selective for cancer cells, it is not a human pathogen, there is no pre-existing immunity to this virus in humans, and it can be engineered to deliver various therapeutics. Here, we investigated anti-tumor properties of APMV-4 in mouse tumor models, and the role of Vascular Endothelial Growth Factor-C (VEGF-C), a key lymphangiogenesis factor, on therapeutic effects of AMPV-4. Methods: Anti-tumor effects of OVs were assessed using B16F10 melanoma and CT26.WT colon carcinoma in syngeneic mouse models. Tumor cells were injected intradermally into the flank, and treatment commenced when tumors reached ̃50mm3. Viruses were injected intratumorally (107 PFU) every two days, for a total of four treatments. For studies of VEGF-C, B16F10 cells were transfected with VEGF-C or with an empty vector. Tumor regression and long-term survival were assessed. Mice in complete remission were re-challenged with tumor cells on the opposite side. High-dimensional immunophenotyping using Aurora Spectral flow cytometry was performed on tumor samples collected 12 hr after the 2nd treatment with OVs. Results: Intratumoral administration of APMV-4 extended survival, promoted tumor elimination and conferred protection against re-challenge in murine colon carcinoma and melanoma tumor models, and was more effective than NDV strain LaSota. Expression of VEGF-C in B16F10 melanoma enhanced anti-tumor effects of APMV-4 or NDV, resulting in complete remission in 100% and 86% of mice, respectively (n = 7). Mice remained tumor-free during the 90-day observation period, and following re-challenge remained tumor-free for more than a year. Protection from tumor development upon re-challenge was observed in 71% and 83% of mice treated with APMV-4 or NDV, respectively. Results are representative of two experiments. VEGF-C expression in tumors induced lymphangiogenesis, which correlated with high T-cell densities. Analysis of tumor immune cell composition by flow cytometry revealed multiple unique T-cell and NK-cell subsets associated with complete remission. Conclusions: These studies identify APMV-4 as a novel oncolytic agent with great therapeutic potential and VEGF-C as potent enhancer of anti-tumor immunity. High anti-tumor efficacy of APMV-4/VEGF-C monotherapy, that in preclinical models leads to tumor eradication, indicates great therapeutic and vaccine potential of APMV-4 when combined with VEGF-C.
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