scholarly journals A Comprehensive Clinical Next Generation Sequencing-Based Assay Can Impact Hematopathologic Diagnosis in a Significant Subset of Patients with Hematologic Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2984-2984
Author(s):  
Janine D. Pichardo ◽  
Julie T Feldstein ◽  
Maria Arcila ◽  
Connie Batlevi ◽  
Andrew D. Zelenetz ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Research Funding ◽  
Hematologic Malignancy ◽  
Hematologic Malignancies ◽  
Genomic Testing ◽  
Genomic Profiling ◽  
Pathologic Assessment ◽  
Somatic Alterations ◽  
The Impact ◽  
Generation Sequencing

Abstract High throughput genomic studies have identified novel recurrent somatic alterations with prognostic or therapeutic relevance in hematological malignancies. By contrast, few studies have investigated the impact on pathologic assessment, and clinicopathologic diagnosis. We therefore assessed the impact of a CLIA-certified CAP-accredited comprehensive clinical grade next-generation sequencing-based assay, FoundationOne Heme (FOH), on hematopathologic assessment of patients at our institution. The FOH assay targets 405 cancer-related genes and 31 frequently rearranged genes by DNA-capture and sequencing, and 265 frequently-rearranged genes by RNA-capture and sequencing. We prospectively tested 92 cases as part of routine clinical practice, including malignant lymphoid neoplasms (n=51) and suspected myeloid malignancies (n=41). (Table 1) The samples submitted included 30 blood, 38 bone marrow and 24 FFPE specimens. We were able to obtain genomic profiling data in90 of the 92 submitted cases (98%) including all FFPE specimens. A total of 282 genomic abnormalities (range 0-11, average 3.2 abnormalities/case) including substitutions, insertions/deletions and gene fusions were detected. There was excellent concordance between conventional cytogenetic or molecular genetic assays and FOH assay. Only 10 cases lacked any genomic abnormality. Six of these were morphologically normal bone marrows submitted to rule out myeloid neoplasia. Of the 4 remaining cases without recurrent somatic alterations, 2 cases were derived from myeloma patients where the sample analyzed had less than 20% plasma cells and 2 cases were from patients with myelodysplasia with likely low tumor content. In 84 cases with a diagnosis of hematologic malignancy, we identified genomic abnormalities with diagnostic relevance in 42 cases (50%). Most importantly, in 12 cases (14% of cohort), the presence of specific genomic alterations led to a change or refinement of the diagnosis. (Table 2) This included two cases in which a diagnosis of T-LGL was confirmed based on the presence of STAT3 mutations, three cases of lymphoma/myeloma in which a specific diagnosis was reached based on identification of pathogenic fusions/rearrangements, and 4 cases of MPN/MDS which could be confirmed based on the presence of known MPN/MDS disease alleles. In addition, we identified genomic alterations with prognostic relevance in 54 cases (64%), and with potential therapeutic impact in 64 cases (76%). Our data demonstrate that the FOH assay can be performed with a very high success rate (98%) in a routine clinical setting and that comprehensive genomic profiling can substantively impact pathologic assessment and diagnosis of a wide spectrum of hematologic malignancies. Genomic testing provided critical diagnostic information in half of the cases, in some instances refining or changing the conventional pathological diagnosis. These findings suggest that comprehensive targeted genomic testing has an important role to play not only in identifying prognostic and therapeutic targets but also in hematopathology diagnosis, and should be considered as a first line testing platform in hematologic malignancies. Table 1:Clinical characteristicsTotal number of casesN=92 Median age58 (18-82) SexMale58 (63%)Female34 (37%) Myeloid neoplasms33 (36%)AML14MDS11MPN6CMML1CML1 Lymphoid neoplasms51 (55%)DLBCL17B-ALL6TLPD6MCL5Myeloma5CLL3MZL3FL3BCL-NOS2CHL1 Normal marrow6 (7%) Sample failed2 (2%) Genomic abnormalities in hematologic malignancies80/84 (93%)Diagnostic42/84 (50%)Prognostic54/84 (64%)Potential therapeutic64/84 (76%) Table 2: Genomic changes which led to improved diagnosis and classification of the hematologic malignancy Case Diagnosis/Problem Genomic alteration Final/refined diagnosis 1 Neutropenia, T-LGL? STAT3 (N647I) T-LGL 2 Neutropenia, T-LGL? STAT3 (D661Y) T-LGL 3 T-LPD? JAK3 (M511I) T-PLL 4 T-LPD? TET2 (Q1523*), TP53 (R175G) PTCL, NOS 5 Transformed FL CIITA-DSCAML1 (Fusion) PMBL 6 CHL vs ALCL IGH-BCL2 (Rearrang.) DLBCL 7 BCL-NOS IGL-MYC (Rearrang.) BCL between DLBCL/BL 8 Myeloma IGH-MAF8 (Rearrang.) High risk myeloma 9 MDS? STK11 (F354L) RUNX1-MECOM (Fusion) MDS 10 MDS? MLL (ITD) MDS 11 MDS? KDM6A MDS 12 MPN MPL (R514_W515>KK) ET Disclosures Moskowitz: Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Research Funding; Merck: Research Funding. Horwitz:Research: Celgene, Millennium, Infinity, Kiowa-Kirin, Seattle Genetics, Spectrum•Consulting: Amgen, Bristol-Myers Squibb, Celgene, Jannsen, Millennium, seattle genetics: Consultancy, Honoraria, Research Funding. Stein:Janssen Pharmaceuticals: Consultancy. He:Foundation Medicine: Employment. Stephens:Foundation Medicine, Inc. : Employment, Equity Ownership. Miller:Foundation Medicine: Employment. Younes:Novartis: Research Funding; J & J: Research Funding; Curis: Research Funding; Bayer; Bristol Meyer Squibb; Celgene; Incyte; Janssen R & D; Sanofi; Seattle Genetics; Takeda Millenium: Honoraria. Dogan:Foundation Medicine: Consultancy.

scholarly journals The Impact of Clonal Hematopoiesis of Indeterminate Potential on Survival in Patients with Newly Diagnosed Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4359-4359
Author(s):  
Koji Sasaki ◽  
Rashmi Kanagal-Shamanna ◽  
Guillermo Montalban-Bravo ◽  
Rita Assi ◽  
Kiran Naqvi ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Next Generation ◽  
Risk Of Death ◽  
Genetics Research ◽  
The Impact ◽  
Generation Sequencing

Abstract Introduction: Clearance of detected somatic mutations at complete response by next-generation sequencing is a prognostic marker for survival in patients with acute myeloid leukemia (AML). However, the impact of allelic burden and persistence of clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations on survival remains unclear. The aim of this study is to evaluate the prognostic impact of allelic burden of CHIP mutations at diagnosis, and their persistence within 6 months of therapy. Methods: From February 1, 2012 to May 26, 2016, we reviewed 562 patients with newly diagnosed AML. Next-generation sequencing was performed on the bone marrow samples to detect the presence of CHIP-associated mutations defined as DNMT3A, TET2, ASXL1, JAK2 and TP53. Overall survival (OS) was defined as time period from the diagnosis of AML to the date of last follow-up or death. Univariate (UVA) and multivariate Cox proportional hazard regression (MVA) were performed to identify prognostic factors for OS with p value cutoff of 0.020 for the selection of variables for MVA. Landmark analysis at 6 months was performed for the evaluation of the impact of clearance of CHIP, FLT3-ITD, FLT3D835, and NPM1 mutations. Results: We identified 378 patients (74%) with AML with CHIP mutations; 134 patients (26%) with AML without CHIP mutations. The overall median follow-up of 23 months (range, 0.1-49.0). The median age at diagnosis was 70 years (range, 17-92) and 66 years (range, 20-87) in CHIP AML and non-CHIP AML, respectively (p =0.001). Of 371 patients and 127 patients evaluable for cytogenetic in CHIP AML and non-CHIP AML, 124 (33%) and 25 patients (20%) had complex karyotype, respectively (p= 0.004). Of 378 patients with CHIP AML, 183 patients (48%) had TET2 mutations; 113 (30%), TP53; 110 (29%), ASXL1; 109 (29%), DNMT3A; JAK2, 46 (12%). Of 378 patients, single CHIP mutations was observed in 225 patients (60%); double, 33 (9%); triple, 28 (7%); quadruple, 1 (0%). Concurrent FLT3-ITD mutations was detected in 47 patients (13%) and 12 patients (9%) in CHIP AML and non-CHIP AML, respectively (p= 0.287); FLT3-D835, 22 (6%) and 8 (6%), respectively (p= 0.932); NPM1 mutations, 62 (17%) and 13 (10%), respectively (p= 0.057). Of 183 patients with TET2-mutated AML, the median TET2 variant allele frequency (VAF) was 42.9% (range, 2.26-95.32); of 113 with TP53-mutated AML, the median TP53 VAF, 45.9% (range, 1.15-93.74); of 109 with ASXL1-mutated AML, the median ASXL1 VAF was 34.5% (range, 1.17-58.62); of 109 with DNMT3A-mutated AML, the median DNMT3A VAF was 41.8% (range, 1.02-91.66); of 46 with JAK2-mutated AML, the median JAK2 VAF was 54.4% (range, 1.49-98.52). Overall, the median OS was 12 months and 11 months in CHIP AML and non-CHIP AML, respectively (p= 0.564); 16 months and 5 months in TET2-mutated AML and non-TET2-mutated AML, respectively (p <0.001); 4 months and 13 months in TP53-mutated and non-TP53-mutated AML, respectively (p< 0.001); 17 months and 11 months in DNMT3A-mutated and non-DNMT3A-mutated AML, respectively (p= 0.072); 16 months and 11 months in ASXL1-mutated AML and non-ASXL1-mutated AML, respectively (p= 0.067); 11 months and 12 months in JAK2-murated and non-JAK2-mutated AML, respectively (p= 0.123). The presence and number of CHIP mutations were not a prognostic factor for OS by univariate analysis (p=0.565; hazard ratio [HR], 0.929; 95% confidence interval [CI], 0.722-1.194: p= 0.408; hazard ratio, 1.058; 95% confidence interval, 0.926-1.208, respectively). MVA Cox regression identified age (p< 0.001; HR, 1.036; 95% CI, 1.024-1.048), TP53 VAF (p= 0.007; HR, 1.009; 95% CI, 1.002-1.016), NPM1 VAF (p=0.006; HR, 0.980; 95% CI, 0.967-0.994), and complex karyotype (p<0.001; HR, 1.869; 95% CI, 1.332-2.622) as independent prognostic factors for OS. Of 33 patients with CHIP AML who were evaluated for the clearance of VAF by next generation sequencing , landmark analysis at 6 months showed median OS of not reached and 20.3 months in patients with and without CHIP-mutation clearance, respectively (p=0.310). Conclusion: The VAF of TP53 and NPM1 mutations by next generation sequencing can further stratify patients with newly diagnosed AML. Approximately, each increment of TP53 and NPM1 VAF by 1% is independently associated with 1% higher risk of death, and 2% lower risk of death, respectively. The presence of CHIP mutations except TP53 does not affect outcome. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Short:Takeda Oncology: Consultancy. Ravandi:Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Sunesis: Honoraria; Xencor: Research Funding; Jazz: Honoraria; Seattle Genetics: Research Funding; Abbvie: Research Funding; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria; Abbvie: Research Funding; Jazz: Honoraria; Xencor: Research Funding; Orsenix: Honoraria; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria. Kadia:BMS: Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Celgene: Research Funding. DiNardo:Karyopharm: Honoraria; Agios: Consultancy; Celgene: Honoraria; Medimmune: Honoraria; Bayer: Honoraria; Abbvie: Honoraria. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding.

scholarly journals Proficiency Testing of Standardized Samples Shows High Interlaboratory Agreement for Clinical Next-Generation Sequencing–Based Hematologic Malignancy Assays With Survey Material–Specific Differences in Variant Frequencies

2020 ◽  
Vol 144 (8) ◽  
pp. 959-966 ◽  
Author(s):  
Alissa Keegan ◽  
Julia A. Bridge ◽  
Neal I. Lindeman ◽  
Thomas A. Long ◽  
Jason D. Merker ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Proficiency Testing ◽  
Hematologic Malignancy ◽  
False Negative ◽  
False Negative Rate ◽  
Hematologic Malignancies ◽  
Variant Allele ◽  
Next Generation ◽  
Single Nucleotide Variants ◽  
Generation Sequencing

Context.— As laboratories increasingly turn from single-analyte testing in hematologic malignancies to next-generation sequencing–based panel testing, there is a corresponding need for proficiency testing to ensure adequate performance of these next-generation sequencing assays for optimal patient care. Objective.— To report the performance of laboratories on proficiency testing from the first 4 College of American Pathologists Next-Generation Sequencing Hematologic Malignancy surveys. Design.— College of American Pathologists proficiency testing results for 36 different engineered variants and/or allele fractions as well as a sample with no pathogenic variants were analyzed for accuracy and associated assay performance characteristics. Results.— The overall sensitivity observed for all variants was 93.5% (2190 of 2341) with 99.8% specificity (22 800 of 22 840). The false-negative rate was 6.5% (151 of 2341), and the largest single cause of these errors was difficulty in identifying variants in the sequence of CEBPA that is rich in cytosines and guanines. False-positive results (0.18%; 40 of 22 840) were most likely the result of preanalytic or postanalytic errors. Interestingly, the variant allele fractions were almost uniformly lower than the engineered fraction (as measured by digital polymerase chain reaction). Extensive troubleshooting identified a multifactorial cause for the low variant allele fractions, a result of an interaction between the linearized nature of the plasmid and the Illumina TruSeq chemistry. Conclusions.— Laboratories demonstrated an overall accuracy of 99.2% (24 990 of 25 181) with 99.8% specificity and 93.5% sensitivity when examining 36 clinically relevant somatic single-nucleotide variants with a variant allele fraction of 10% or greater. The data also highlight an issue with artificial linearized plasmids as survey material for next-generation sequencing.

scholarly journals Next Generation Sequencing (NGS) Identifies an Association Between NPM1 Mutation and Leukemia Cutis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2341-2341
Author(s):  
Marlise R. Luskin ◽  
Campbell L. Stewart ◽  
Jennifer JD Morrissette ◽  
David Lieberman ◽  
David J. Margolis ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Hematologic Malignancy ◽  
World Health ◽  
Next Generation ◽  
Npm1 Mutation ◽  
Histologic Subtype ◽  
Leukemia Cutis ◽  
Next Generation Sequencing Ngs ◽  
The Impact ◽  
Generation Sequencing

Abstract Background:Leukemia cutis (LC) occurs in 10-30% of AML cases and may be a marker of poor prognosis. However, outside of monocytic AML (FAB M4/M5), no clinical or genetic predictors of LC are known. Recently, a number of somatic molecular mutations have been described in AML. Using amplicon-based next-generation sequencing (NGS) of a panel of recurrent, hematologic malignancy-associated mutations, we sought to determine potential molecular markers associated with the development of LC. Methods: A cohort of non-M3 AML patients treated at the University of Pennsylvania was identified in which NGS had been performed on either leukemic blasts obtained during clinical care or from the institutional tissue bank.Average read depth for 33 hematologic malignancy-associated genes was approximately 3000X, minimal depth was 250x, and reporting frequency cutoff for variants was 5%. Mutations were reported as pathogenic or variants of uncertain significance (VUS, further sub-classified internally as likely disease associated, VUS, or likely benign) based on the University’s Center for Personalized Diagnostics (CPD) review of publically available data; only pathogenic or likely disease-associated mutations were included in this analysis. A database maintained by dermatopathology was reviewed to identify cases of leukemia cutis at any time during the disease course. Independent dermatopathology review was obtained for indeterminate cases. Association between presence of each of the 3 most common molecular mutations (FLT3-ITD, DNMT3A, and NPM1) and development of LC was assessed by logistic regression, with adjustment for FAB M4/M5, as appropriate. The association between presence of a molecular mutation in different functional classes (tumor suppressors, activated signaling, chromatin modifiers, transcription factors, splicing machinery) and the development of LC was also assessed. Results:279 adult patients with AML with known molecular genotype were identified. Molecular profile was determined from AML diagnosis in (243, 88%) with the remainder undergoing assessment after prior therapy (relapsed or refractory). 56% were male with median age of 60 years (range 18-87) and median WBC count at diagnosis of 22 K/uL (range 0.4 -388 K/uL; 17% ≥100K/uL). The majority of patients had intermediate cytogenetic risk (12% favorable, 59% intermediate, 23% unfavorable, 6% unknown) and 41% of patients had FAB M4/M5 AML (9% unknown). The three most common mutations were NPM1 (29%), DNMT3A (25%), and FLT3-ITD (23%). NPM1mutations were enriched in patients with FAB M4/M5 AML (41% vs 23%, p=0.003). Leukemia cutis was present in 26 (9%) of patients. NPM1 mutant status was present in 14 of 26 cases of leukemia cutis (OR 3.17, 95% CI 1.40-7.20, p=0.006). No association was detected for LC and the presence of mutant FLT3-ITD (OR 1.27, p=0.613), mutant DNMT3A (OR 1.7, p=0.224), or a mutation in any functional class of AML mutations (all p-values NS). The impact of NPM1 mutant status remained significant after adjustment for association with M4/M5 AML (OR 3.91, p=0.005). As the histologic subtype of AML might modify the association between NPM1 mutations and leukemia cutis, we next examined the impact of NPM1 mutant status on patients with FAB M4/M5 AML and non-M4/M5 AML. Among patients with M4/M5 AML, 10/12 (80%) patients with LC were NPM1 mutant compared to 32/91 (35%) without LC suggesting that the presence of mutated NPM1 was significantly associated with the development of LC (OR 9.22, p=0.006). Among patients with non-M4/M5 AML, 3/9 (33%) of patients with leukemia cutis were NPM1 mutant compared to 32/142 (22.5%) without LC indicating no association in the non-M4/M5 subgroup (OR 1.72, p=0.461). Interestingly, M4/M5 AML was not associated with LC in the NPM1 WT cohort (OR 0.65, p=0.6). Conclusion: Using NGS, we identify a novel association between NPM1 mutation status and the presence of leukemia cutis, particularly within monocytic AML. Confirmation of these observations in a larger dataset is planned. Our data suggest potential cellular effects of NPM1 mutation affecting homing of leukemic blasts to skin and support the World Health Organization’s provisional classification of NPM1-mutated AML as a distinct biologic entity. Disclosures No relevant conflicts of interest to declare.

scholarly journals Next-Generation Sequencing Reveals High Concordance of Recurrent Somatic Alterations Between Primary Tumor and Metastases From Patients With Non–Small-Cell Lung Cancer

2013 ◽  
Vol 31 (17) ◽  
pp. 2167-2172 ◽  
Author(s):  
Stéphane Vignot ◽  
Garrett M. Frampton ◽  
Jean-Charles Soria ◽  
Roman Yelensky ◽  
Frédéric Commo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Next Generation Sequencing ◽  
Small Cell Lung Cancer ◽  
Primary Tumor ◽  
Small Cell ◽  
Genomic Profiling ◽  
Small Cell Lung ◽  
Somatic Alterations ◽  
High Concordance ◽  
Generation Sequencing

Purpose Characterization of the genomic changes that drive an individual patient's disease is critical in management of many cancers. In patients with non–small-cell lung cancer (NSCLC), obtaining tumor samples of sufficient size for genomic profiling on recurrence is often challenging. We undertook this study to compare genomic alterations identified in archived primary tumors from patients with NSCLC with those identified in metachronous or synchronous metastases. Patients and Methods Primary and matched metastatic tumor pairs from 15 patients were analyzed by using a targeted next-generation sequencing assay in a Clinical Laboratory Improvement Amendments laboratory. Genomic libraries were captured for 3,230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to high coverage. Results Among 30 tumors, 311 genomic alterations were identified of which 63 were known recurrent (32 in primary tumor, 31 in metastasis) and 248 were nonrecurrent (likely passenger). TP53 mutations were the most frequently observed recurrent alterations (12 patients). Tumors harbored two or more (maximum four) recurrent alterations in 10 patients. Comparative analysis of recurrent alterations between primary tumor and matched metastasis revealed a concordance rate of 94% compared with 63% for likely passenger alterations. Conclusion This high concordance suggests that for the purposes of genomic profiling, use of archived primary tumor can identify the key recurrent somatic alterations present in matched NSCLC metastases and may provide much of the relevant genomic information required to guide treatment on recurrence.

scholarly journals Incidental findings from cancer next generation sequencing panels

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Nika Maani ◽  
Karen Panabaker ◽  
Jeanna M. McCuaig ◽  
Kathleen Buckley ◽  
Kara Semotiuk ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Incidental Findings ◽  
Complete Blood Count ◽  
Hematologic Malignancy ◽  
Retrospective Chart Review ◽  
Hematologic Malignancies ◽  
Next Generation ◽  
Inclusion Criteria ◽  
Pathogenic Variants ◽  
Generation Sequencing

AbstractNext-generation sequencing (NGS) technologies have facilitated multi-gene panel (MGP) testing to detect germline DNA variants in hereditary cancer patients. This sensitive technique can uncover unexpected, non-germline incidental findings indicative of mosaicism, clonal hematopoiesis (CH), or hematologic malignancies. A retrospective chart review was conducted to identify cases of incidental findings from NGS-MGP testing. Inclusion criteria included: 1) multiple pathogenic variants in the same patient; 2) pathogenic variants at a low allele fraction; and/or 3) the presence of pathogenic variants not consistent with family history. Secondary tissue analysis, complete blood count (CBC) and medical record review were conducted to further delineate the etiology of the pathogenic variants. Of 6060 NGS-MGP tests, 24 cases fulfilling our inclusion criteria were identified. Pathogenic variants were detected in TP53, ATM, CHEK2, BRCA1 and APC. 18/24 (75.0%) patients were classified as CH, 3/24 (12.5%) as mosaic, 2/24 (8.3%) related to a hematologic malignancy, and 1/24 (4.2%) as true germline. We describe a case-specific workflow to identify and interpret the nature of incidental findings on NGS-MGP. This workflow will provide oncology and genetic clinics a practical guide for the management and counselling of patients with unexpected NGS-MGP findings.

scholarly journals Next-Generation Sequencing of DDX41 in Myeloid Neoplasms Leads to Increased Detection of Germline Alterations

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2667-2667
Author(s):  
Sarah Bannon ◽  
Mark Routbort ◽  
Guillermo Garcia-Manero ◽  
Naval G. Daver ◽  
Betul Oran ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Next Generation Sequencing ◽  
Research Funding ◽  
Hematologic Malignancies ◽  
Germline Mutations ◽  
Myeloid Neoplasm ◽  
Myeloid Neoplasms ◽  
History Of ◽  
Related Donor ◽  
Generation Sequencing

Abstract Introduction: Germline predispositions to hematologic malignancies were historically thought to be rare; however growing awareness has raised clinical challenges regarding how to identify, test, and manage these patients. Germline mutations in the gene DDX41 predispose to moderately increased lifetime risks of MDS and AML with a later age of onset. Optimal clinical care of these patients relies on identifying germline mutations and innovative strategies are needed to improve clinical detection. Methods: 1,262 individuals with myeloid malignancies underwent next-generation sequencing (NGS)-based molecular sequencing of DDX41. Individuals identified to have ≥1 DDX41 alterations present at >40% variant allele frequency (VAF) in the bone marrow were flagged for potential referral to genetic counseling (GC). All individuals referred for GC underwent standard genetic counseling evaluation and were offered DDX41 germline analysis on cultured skin fibroblasts. Results: Of 1,262 individuals, 32 (2.5%) were identified to have ≥1 somatic DDX41 mutation(s). Fourteen (44%) were referred for GC and germline confirmation testing. Eleven patients were male (78.5%) and 13/14 (93%) were Caucasian. Average age at diagnosis of myeloid neoplasm was 65 years (range 53-77 years). Fifty-seven percent (8/14) individuals were diagnosed with AML, 6/14 presented with MDS, including therapy-related MDS. 12/14 patients had diploid cytogenetics at presentation. A second somatic DDX41 mutation (biallelic) was identified in 10/14 (71%). There were no other significantly recurrent concomitant somatic mutations. Thirteen patients underwent germline evaluation and 12/13 (92%) were confirmed to have a germline DDX41 mutation. Six individuals underwent hematopoietic stem cell transplantation (SCT); five from a matched related donor, and in four cases, the related donor was negative for the familial DDX41 mutation. Six patients (43%) reported antecedent cytopenias: five with leukopenia and one with anemia. Five patients had a prior history of malignancy: three with prostate cancer, one with Non-Hodgkin's lymphoma and melanoma, and one with MGUS. 13/14 (93%) patients reported a family history of cancer, six (43%) of which included hematologic malignancies and/or cytopenias. From the 12 DDX41 germline-positive patients, 11 unaffected relatives underwent genetic testing. Four (36%) tested positive for the familial DDX41 mutation and seven (64%) tested negative. Conclusions: The detection of somatic DDX41 mutations at near-heterozygous frequencies on NGS panel testing is highly suggestive of a germline mutation and germline testing is strongly recommended. Our data validates existing reports in DDX41 germline patients including primarily high grade myeloid neoplasms, diploid cytogenetics, and later age at diagnosis. Interestingly nearly half of our patients had antecedent cytopenias, most often leukopenia. NGS screening for DDX41 mutations through multi-disciplinary collaboration is a useful and feasible tool to screen unselected myeloid neoplasm patients for high likelihood of germline DDX41 mutations enabling timely and appropriate care of these patients. Disclosures Daver: Novartis: Consultancy; Incyte: Research Funding; Pfizer: Consultancy; ImmunoGen: Consultancy; Pfizer: Research Funding; Sunesis: Consultancy; Alexion: Consultancy; Novartis: Research Funding; Sunesis: Research Funding; Kiromic: Research Funding; Karyopharm: Research Funding; ARIAD: Research Funding; Daiichi-Sankyo: Research Funding; BMS: Research Funding; Incyte: Consultancy; Otsuka: Consultancy; Karyopharm: Consultancy. Oran:AROG pharmaceuticals: Research Funding; Celgene: Consultancy, Research Funding; ASTEX: Research Funding. Kadia:Abbvie: Consultancy; Abbvie: Consultancy; Jazz: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Research Funding; Celgene: Research Funding; BMS: Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Novartis: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy. DiNardo:Karyopharm: Honoraria; Celgene: Honoraria; Bayer: Honoraria; Abbvie: Honoraria; Medimmune: Honoraria; Agios: Consultancy.

scholarly journals Outcomes of COVID-19 Infection in Patients with Hematologic Malignancies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-21
Author(s):  
Elizabeth Behrens ◽  
Anne Timmermann ◽  
Alexander Yerkan ◽  
Deborah A. Katz ◽  
Agne Paner ◽  
...  
Keyword(s):  
At Risk ◽  
Research Funding ◽  
Hematologic Malignancy ◽  
Hematologic Malignancies ◽  
Mortality Rates ◽  
Small Sample ◽  
Close Monitoring ◽  
Publicly Traded ◽  
Risk Population ◽  
The Impact

The coronavirus disease 2019 (COVID-19) outbreak, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic on March 11, 2020. This novel virus can cause a rapid progression from cough to acute respiratory distress syndrome and death. Cancer patients infected with COVID-19 were reported to have a 39% incidence of severe events, including admission to intensive care unit (ICU), mechanical ventilation, or death. Patients with hematologic malignancies, especially those undergoing treatment, are a particularly at-risk population due to disease-related impairment of the immune system and chemotherapy-induced neutropenia. The goal of this study is to analyze outcomes of COVID-19 infected patients with hematologic malignancies in order to better understand the impact of SARS-CoV-2 on this vulnerable population. Methods We performed a retrospective analysis on 26 COVID-19 positive patients with hematologic malignancies identified at our center. On July 22, 2020, there were 264 COVID-19 positive patients with hematologic malignancies (including our center's 26 patients) reported to the American Society of Hematology Research Collaborative COVID-19 Registry (ASH RC), a global public reference tool. We extracted our patient's data from each category reported to the ASH RC and compared hospitalization, ICU admissions, and mortality rates between our cohort and the remaining 238 cases. Chi-square test was used for analyses. We also performed a subgroup analysis comparing demographics; type and status of hematologic malignancy, as well as COVID-19 directed treatments between our center's patients and the patients reported to the ASH RC. Results Between March and June 2020, a total of 1265 COVID-19 positive patients were hospitalized at our institution. A significantly higher percentage of COVID-19 patients with hematologic malignancies were hospitalized at our institution compared to the ASH RC (61.5% versus 35.3%, P=. 009). There was no difference in ICU admission rate at our center compared to the ASH RC (23.1% versus 30.2%, P=.45). Significantly less COVID-19 directed therapies were administered at our center compared to the ASH RC (46.2% versus 66.4%, P=.041). Our patients received: 7.7% Remdesivir, 11.5% Tocilizumab, 15.4% hydroxychloroquine, 11.5% azithromycin, 0% convalescent plasma, compared to the ASH RC: 1.7% Remdesivir, 5.5% Tocilizumab, 30.3% hydroxychloroquine, 25.6% azithromycin, 4.6% convalescent plasma. Lastly, our institution had a significantly decreased mortality rate compared to the ASH RC (11.5% versus 29.8%, P=.049). Demographics as well as type and status of hematologic malignancy comparing the two cohorts are shown in Table 1. Conclusions In our comparative analysis, we found that our center's patients were hospitalized significantly more than the ASH RC cohort yet had lower mortality rates. These differences were seen despite similar distribution of malignancy types between the two groups. It should be noted that more patients in our cohort were in remission and none presented at initial cancer diagnosis at the time of infection, which may have contributed to better outcomes. The difference in mortality rates may also be attributed to variance in provider experience, higher percentage of patients &gt;80 years of age reported to the ASH RC, and closer patient monitoring at our center due to a higher hospitalization rate. Differences in ICU admissions were not significant, suggesting a similar rate of severe COVID-19 infection between the two cohorts. Our demographics reflect the urban population we serve with more African Americans and Hispanics compared to the ASH RC. The greater number of COVID-19 directed therapies in the ASH RC cohort compared to ours is likely attributed to the use of convalescent plasma, which was not commonly used as COVID-19 directed treatment at our institution. Limitations of our study include a restricted time frame, small sample size, and the possibility of incomplete datasets within the ASH RC, as stated on the registry's website. In conclusion, we recommend close monitoring and a lower threshold for hospitalizing patients with hematologic malignancies in the setting of COVID-19 infection; however, additional prospective studies are needed to confirm our findings, and further investigate the complications and outcomes of SARS-CoV-2 on this at-risk population. Disclosures Ustun: Kadmon: Honoraria. Shammo:Celgene: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Onconova: Research Funding; Incyte: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy; Regeneron: Consultancy; Novartis: Consultancy; Agios: Consultancy; Sanofi: Speakers Bureau; Abbive: Current equity holder in publicly-traded company; Baxter: Current equity holder in publicly-traded company; Takeda: Current equity holder in publicly-traded company; Alexion: Consultancy, Research Funding, Speakers Bureau.

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