Clinical and Molecular Features of Disseminated Pediatric Low Grade Glioma - A Systematic Review of Literature

INTRODUCTIONGliomas account for approximately 46% of all pediatric CNS tumors. There is growing awareness of pediatric low-grade gliomas (PLGG) that disseminate to distant parenchymal or leptomeningeal locations either at the time of initial diagnosis or upon disease surveillance. Disseminated PLGGs (dPLGGs) are associated with a poorer prognosis than non-disseminated PLGGs. To date there is no comprehensive report characterizing the genome profile of dPLGGs and their associated management. This systematic review aims to identify the pattern of genetic alterations and treatment outcomes described for dPLGG.METHODSA systematic review of the literature was performed to identify relevant articles. A quality and risk of bias assessment of articles was done using the GRADE framework and ROBINS-I tool, respectively.RESULTSFifty-two studies published from 1994 to 2020 were included in this review with 368 cases reported. There was sporadic reporting of genetic alterations. The most common genetic alteration observed among study subjects was 1p deletion (76%) and BRAF-KIAA1549 fusion (55%). BRAF p.V600E mutation was found in 7% of subjects. A higher proportion of cases demonstrated primary dissemination compared to secondary dissemination (65% vs 25%). First-line chemotherapy consisted primarily of an alkylation-based regimen and vinca alkaloids. Surgical intervention ranged from biopsy alone to surgical resection and CSF diversion, and depended largely upon tumor location and timing of dissemination. Overall, 73% of cases were alive at last follow-up (median, 40.2 months). All studies reviewed either ranked low or moderate for both quality and risk of bias assessments. CONCLUSIONWhile 1p deletion and BRAF-KIAA1549 fusion are the most commonly described molecular alterations in dPLGG, these tumors appear to express heterogeneous molecular and biological characteristics distinct from non-disseminated PLGGs. Additional studies on the molecular and biological features of these tumors are needed to better understand the pathogenesis of dPLGG and to inform the development of additional targeted regimens.

Chromosome Imbalances in Neuroblastoma—Recent Molecular Insight into Chromosome 1p-deletion, 2p-gain, and 11q-deletion Identifies New Friends and Foes for the Future

Neuroblastoma is the most common extracranial solid pediatric tumor, with around 15% childhood cancer-related mortality. High-risk neuroblastomas exhibit a range of genetic, morphological, and clinical heterogeneities, which add complexity to diagnosis and treatment with existing modalities. Identification of novel therapies is a high priority in high-risk neuroblastoma, and the combination of genetic analysis with increased mechanistic understanding—including identification of key signaling and developmental events—provides optimism for the future. This focused review highlights several recent findings concerning chromosomes 1p, 2p, and 11q, which link genetic aberrations with aberrant molecular signaling output. These novel molecular insights contribute important knowledge towards more effective treatment strategies for neuroblastoma.

Comparison of Next-Generation Sequencing and Fluorescence In Situ Hybridization for Detection of Segmental Chromosomal Aberrations in Neuroblastoma

The aim of this study was to compare next-generation sequencing (NGS) with the traditional fluorescence in situ hybridization (FISH) for detecting segmental chromosomal aberrations (SCAs) such as 1p deletion, 11q deletion and 17q gain, which are well-known predictive markers for adverse outcome in neuroblastoma. The tumor tissue obtained from 35 patients with neuroblastoma was tested by FISH and targeted NGS, which is specially designed to detect copy number alterations across the entire chromosomal region in addition to mutations in 353 cancer-related genes. All chromosomal copy number alterations were analyzed using the copy number variation plot derived from targeted NGS. FISH was performed to detect 1p deletion, 11q deletion and 17q gain. The copy numbers of 1p, 11q, and 17q obtained via NGS were correlated with those acquired via FISH. The SCAs determined by NGS were matched with those by FISH. Most 17q gain of mismatched cases detected by NGS alone showed a subsegmental gain of 17q. FISH revealed 11q deletion and 17q gain in a few tumor cells of two cases, which were not detected by NGS. NGS can be a sensitive complementary and alternative method to the conventional FISH for detecting SCAs.

Comparison of next-generation sequencing and FISH/IHC for molecular classification in glioma.

e14021 Background: The updated 2016 edition of the WHO Classification of CNS tumors indicates that IDH1 R132H, H3 K27M mutations, and co-deletion of 1p19q are strong stratification and prognostic markers glioma. FISH/IHC, as the commonly detected methods, present specific false-negative rates in the actual condition. Methods: In our study, IDH1 R132H status of 158 cases was assessed by IHC and NGS, and H3 K27M statuses of 83 patients were evaluated by IHC and NGS. 22 positive cases of 1p/19q co-deletion, all confirmed by FISH, were assessed by NGS. Results: For IDH1 R132H, 2 cases were IHC negative and were positive as confirmed by NGS. Another 10 patients with weakly IHC positive results were negative in NGS. Combined with histologic hallmarks, 6 cases of these samples could be diagnosed as glioblastoma, IDH wildtype; 1 case with POLE could be diagnosed as giant cell glioblastoma; 3 cases with BRAF V600E mutation, BRAF fusion, and ATRX mutation, respectively, could be diagnosed as pilocytic astrocytoma. Towards H3 K27M, 3 cases with IHC weakly positive were negative in NGS. Among these samples, 2 cases were diagnosed as glioblastoma, IDH wildtype by molecular and histologic hallmarks, and 1 case was medulloblastoma, SHH. Using NGS, IDH1 R132H /H3 K27M statues can be distinctly distinguished in which that is unknown by IHC. The results of NGS and FISH showed a 90.9%(20/22) consistent rate for the 1p19q co-deletion. 1 case was 1p deletion and intact 19q by FISH while 1p19q co-deletion by NGS because of the 19p deletion. 1 case was 1p19q co-deletion by FISH but 1p19q wildtype by NGS, diagnosed as glioblastoma, IDH wildtype with chr7+/10-. Conclusions: In our study, the agreement between NGS results and clinical pathology diagnosis was approximately 100%. NGS may act as the primary technology of molecular classification in glioma in the future.

Outcomes of Myeloma Patients with Deletion 1p Receiving Lenalidomide, Bortezomib, and Dexamethasone (RVD) Therapy

Introduction: Previous studies indicated that 1p deletion (del 1p) in multiple myeloma patients has a negative effect on overall survival (OS) and progression free survival (PFS). However, majority of studies were conducted before the introduction of current first line therapy of Lenalidomide, Bortezomib and Dexamethasone (RVD). Our study investigated the association between del 1p and clinical outcomes in patients with MM treated with RVD. Methods: Single-center, retrospective analysis of an IRB approved myeloma database of 1000 newly diagnosed multiple myeloma patients treated with RVD induction therapy per Richardson et al (Blood 2010), planned stem cell transplant and risk adapted maintenance (Nooka et al, Leukemia, 2014). 1p deletion status was determined by FISH. The primary outcomes were response to RVD, response to ASCT, progression free survival (PFS), and overall survival (OS). Treatment responses were evaluated as per IMWG Uniform Response Criteria. Results: We identified 1000 multiple myeloma patients who started RVD treatment from July 2005 to August 2016. Among these, 83 patients (8.3 %) were found to have 1p deletion on FISH. The remaining 917 patients formed the control group. Median age at diagnosis, sex and race were similar between groups. Patients with del 1p were more likely to have IgA isotype compared to controls (28.1% vs 19.7%, P=0.054). There was no significant difference between groups in baseline hemoglobin, calcium, platelet count, creatinine and albumin levels. Baseline LDH levels were more likely to be high in the del 1p group (P=0.009). 49.6% of del 1p patients had high risk status (t(4:14), t(14:16), 17p deletion) vs 26.6% in the control group (p<0.0001). There was no significant difference in the best response to induction therapy between groups, with an achievement of a VGPR or better in 62.8% vs 69.3% in the del 1p and control groups respectively (p=0.148). However, the del 1p group had lower best response after transplant, with a VGPR or better in 67.1% vs 89.2% respectively (P<0.001). Univariate regression analysis also showed a significant association of del 1p with decreased PFS (HR 1.782, P=0.002), which stayed significant after adjusting for disease stage, high risk FISH and maintenance (HR 2.265, p<0.001). There was no statistical decrease in OS in the del 1p population. Conclusion: This analysis demonstrated that the del 1p continues to be associated with adverse outcomes in the era of uniform induction therapy with RVD, transplant and risk-adapted maintenance. There was no significant difference in response to induction treatment, however, del 1p was a significant independent adverse prognostic factor for best response and PFS after ASCT. The lack of decrease in OS may be due to the routine use of risk adapted maintenance. Disclosures Heffner: Genentech: Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Research Funding; ADC Therapeutics: Research Funding. Hofmeister:Bristol-Myers Squibb: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy. Lonial:Amgen: Research Funding. Nooka:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kaufman:Roche: Consultancy; Abbvie: Consultancy; Karyopharm: Other: data monitoring committee; Janssen: Consultancy; BMS: Consultancy.

CKS1B/CDKN2C Copy Number Ratio : A New Predictor of Survival in Transplant- and Non Transplant-Eligible Multiple Myeloma Patients

BACKGROUND Current molecular risk stratification of multiple myeloma (MM), based on the presence of t(4 ;14) and 17p deletion, cannot fully explain treatment outcome heterogeneity, as other features also predict prognosis. About 30% of genetic events map to chromosome 1 : most upregulated genes to 1q and most downregulated ones to 1p. CKS1B gains on 1q21 and CDKN2C loss on 1p32, both favoring cell cycle progression, portended impaired outcome in many but not all studies. Based on their recurrence and considering their functional convergence, we hypothesized CKS1B/CDKN2C copy number ratio to be a risk factor fitter than each aberration alone. METHODS This single-center retrospective study, enrolled 104 newly diagnosed adult patients aged ≥18 years, 48 transplant-eligible and 56 not. All patients were routinely tested for CKS1B and CDKN2C and treated according to consensus guidelines. Data were collected from 2012 to May 31, 2018. For each subject, we calculated a FISH-based ratio by CKS1B on CDKN2C copy number : it was equal to 1 with no change in copy number and >1 in case of CKS1B gains, CDKN2C loss or both. In patients with CDKN2C biallelic loss, the ratio was not equal to 0, but to CKS1B copy number, as functional consequence should prevail over arithmetic result. We, then, analyzed separately the impact of CKS1B gains, CDKN2C loss and CKS1B/CDKN2C ratio on PFS and OS. RESULTS In the transplant subgroup, the median follow-up was 22.9 (1.4-71.9) months. By FISH analysis, 15 patients had variable gains of CKS1B, 6 monoallelic and 1 biallelic CDKN2C loss ; CKS1B/CNKN2C copy number ratio was ≥1.5 in 17, ≥2 in 9 and ≥3 in 2. ROC curves evaluating the relevance of the ratio were statistically significant for PFS (p=0.008) and OS (p=0.049). Median PFS from diagnosis, overall and for patients with CKS1B gains, CDKN2C loss and ratio ≥1.5 was 21.6 (1.4-68.4), 24.8 (vs 41.5 with no CKS1B gains), 28.7 (vs 37.7 with no 1p deletion) and 25 (vs 42 with normal ratio) months, respectively. By Kaplan-Meier log-rank analyses, PFS was significantly impaired by CKS1B gains (p=0.014) and ratio ≥1.5 (p=0.007), but not by CDKN2C loss (p=0.339). Median OS from diagnosis, overall and for patients with CKS1B gains, CDKN2C loss and ratio ≥1.5 was 22.9 (1.4-71.9), 24.2 (vs 64.2 with no CKS1B gains), 44.9 (vs 54.8 with no 1p deletion) and 32 (vs 64 with normal ratio) months, respectively. By Kaplan-Meier log-rank analyses, OS was also significantly impaired by CKS1B gains (p=0.001) and ratio ≥1.5 (p=0.004), but not CDKN2C loss (p=0.339). In multivariate analyses, parameters negatively influencing PFS were age >65 years (p=0.005), CKS1B gains (p=0.001), ratio ≥1.5 (p=0.006) and ISS3 status (p=0.019) ; factors unfavorably affecting OS were age >65 years (p=0.044), ratio ≥1.5 (p=0.049) and non secretory status (p=0.018), but not CKS1B gains (p=0.174). In the non transplant subgroup, the median follow-up was 26.4 (0.2-87.3) months. By FISH analysis 30 patients had variable gains of CKS1B and 10 hemizygous loss of CDKN2C ; CKS1B/CDKN2C ratio was ≥1.5 in 34, ≥2 in 21 and ≥3 in 7. ROC curves evaluating the relevance of the ratio showed only a trend toward statistical significance for PFS (p=0.065), but not for OS (p=0.137). Median PFS from diagnosis, overall and for patients with CKS1B gains, CDKN2C loss, ratio ≥2 and ≥3 was 17.5 (0.2-79.9), 20.9 (vs 26.7 with no CKS1B gains), 15.9 (vs 24.9 with no CDKN2C loss), 16.6 (vs 26.9 for ratio <2) and 11.1 (vs 25.6 for ratio <3) months, respectively. In Kaplan-Meier log-rank analyses, PFS was significantly impaired by ratio ≥3 (p=0.000), but not by CKS1B gains (p=0.204) or CDKN2C loss (p=0.273). Median OS from diagnosis, overall and for patients with CKS1B gains, CDKN2C loss, ratio ≥2 and ≥3 was 26.4 (0.2-87.3), 34 (vs 40 with no CKS1B gains), 24 (vs 43.6 with no 1p loss), 31.2 (vs 44.6 with ratio <2) and 13 (vs 45.2 with ratio <3) months, respectively. By Kaplan-Meier log-rank analyses, OS was also negatively affected by ratio ≥3 (p<0.0001), but not by CKS1B gains (p=0.476) or CDKN2C loss (p=0.207). In multivariate analyses, factors negatively impacting PFS were platelet count <150 G/L (p=0.020) and ratio ≥3 (p=0.031) ; parameters unfavorably affecting OS were bone marrow plasma cells ≥60% (p=0.018) and ratio ≥3 (p=0.026). CONCLUSIONS Even with few patients, these results provide proof of the concept of CKS1B/CDKN2C ratio as an outcome predictor. Of note, the ratio indicated worse post-transplant PFS and OS in patients over 65 years. Disclosures No relevant conflicts of interest to declare.