scholarly journals Clinical Utility of Hematopathologist-Triaged NGS Testing When Investigating Patients with Suspected MDS

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4675-4675
Author(s):  
Christina K Ferrone ◽  
Amy JM McNaughton ◽  
Iran Rashedi ◽  
Hubert Tsui ◽  
Michael J Rauh
Keyword(s):  
Allele Frequency ◽  
Conflicts Of Interest ◽  
Low Risk ◽  
Variant Allele ◽  
Low Grade ◽  
Variant Allele Frequency ◽  
Mutational Status ◽  
Morphological Criteria ◽  
Significant Difference

Abstract The recognition of MDS is challenging in early stages, where diagnosis may rely solely upon morphological criteria for dysplasia, a non-specific finding prone to inter-observer variation. Patients with equivocal bone marrow (BM) findings may be discharged from Hematology clinics and lost to follow up, or subjected to serial, invasive BM investigations and diagnostic delays. We therefore aimed to demonstrate the importance of hematopathologist-triaged, targeted NGS in identifying clonal cytopenias of undetermined significance (CCUS) in cases where MDS diagnostic criteria are not met based on morphology or cytogenetic analysis. We explored this using three REB-approved cohorts. Our first cohort was retrospective with BM samples ranging from 2010-14, involving cases that were previously suspicious for but non-MDS diagnostic. This included 70 patients from Sunnybrook (SHSC) and Kingston Health Sciences Centres (KHSC): 16 age-matched controls (8 negative lymphoma staging, 8 non-MDS cytopenias); 18 suspicious for MDS; 20 MDS; and 16 MDS/MPN. DNA was extracted and NGS was performed using our custom 48-gene Ion Torrent AmpliSeq myeloid panel (ThermoFisher). We identified suspected mutations in 2/16 (13%) controls (i.e. CHIP), 12/18 (67%) suspicious cases, 17/20 (85%) MDS cases, and 16/16 (100%) MDS/MPN cases. The mean and median number of mutations per suspicious patient (respectively 0.89 and 1; most commonly in SF3B1, TET2, RUNX1, and ASXL1) were lower than MDS (1.85 and 2; p=0.011) and MDS/MPN (3.13 and 3; p<0.0001). There was a significant difference in the average variant allele frequency (VAF) per patient (those with ≥1 mutation) between control and suspicious groups (p=0.022), however, there were no significant differences in the average VAF between suspicious, MDS, and MDS/MPN cases. Furthermore, of the 16 patients with BM suspicious for MDS, 7 went on to get MDS. 4 of these patients had at least 1 clinically relevant somatic variant, while 3 had none. Of those with at least 1 variant, 3 had IPSS-level cytopenias at the time, indicating that had their mutational status been known at the time of their assessment, they would have been diagnosed with the provisional CCUS entity (while the rest would be classified as CHIP). To supplement these findings, we are amassing a prospective cohort involving cases at SHSC where patients have either idiopathic cytopenias (ICUS), or confirmed MDS diagnoses with one or more previously non-diagnostic BM. To date, we have performed sequencing for 36 of these patients, including 23 ICUS and 13 diagnosed MDS cases. Of the ICUS cases, 10 (44%) had at least 1 variant (mean # variant/patient = 1, mean variant allele frequency (VAF) = 34.0%) consistent with CCUS, while 12/13 (92%) of MDS patients had at least 1 variant (mean # variants/patient = 2, mean VAF = 42.3%). These findings are consistent with CCUS being common in suspicious MDS cases, with similar clonal size but lesser mutational burden than diagnosed MDS. In addition to these preliminary findings, 15/36 patients have serial samples that we are currently processing for NGS (among other cases we are accruing to present at the ASH meeting). By exploring serial cases with molecular results pre- and post- MDS diagnosis, we aim to further elucidate which features of CCUS may predict progression to MDS. Finally, we assessed clonality in cases suspicious for myeloid malignancy in our existing prospective myeloid NGS cohort at KHSC (Ferrone et al, JMD 2021). In this cohort of 168 patients, when focusing on cytopenias yet to be diagnosed, 71 patients had suspected MDS, MPN, or MDS/MPN prior to NGS (completed using the Oncomine Myeloid Assay; ThermoFisher). 36/71 (51%) were found to have variants that indicate clonality. This facilitated diagnoses of either myeloid malignancies or pre-malignant states, with nine cases in total of ICUS resulting in the identification of variants that were non-diagnostic of MDS (mainly in TET2), but indicative of CHIP (n=2) or CCUS (n=7). Furthermore, for the limited number with available follow up data, we found no significant difference in survival between individuals with low-grade MDS (n=10) and CCUS (n=6) (p=0.457). This evidence is in keeping with recent findings that the clinical features of CCUS may be consistent with low-risk MDS, emphasizing the importance of closely monitoring these patients, and even the possibility of assessing and treating them similarly to those with low-risk MDS. Disclosures No relevant conflicts of interest to declare.

scholarly journals Only SF3B1 Mutation involving K700E (And Not Other Codons), Independently Predicts Overall Survival in Myelodysplastic Syndromes

2020 ◽  
Author(s):  
Rashmi Kanagal-Shamanna ◽  
Guillermo Montalban-Bravo ◽  
Koji Sasaki ◽  
Elias Jabbour ◽  
Carlos Bueso-Ramos ◽  
...  
Keyword(s):  
Overall Survival ◽  
Allele Frequency ◽  
Myelodysplastic Syndromes ◽  
Variant Allele ◽  
Low Grade ◽  
Variant Allele Frequency ◽  
Pathologic Features ◽  
Significant Difference ◽  
Ring Sideroblasts ◽  
Mutation Type

ABSTRACTBackgroundSF3B1 mutations (SF3B1mut) in myelodysplastic syndromes (MDS) frequently involve codon K700E and have a favorable prognosis. The prognostic effect of non-K700E SF3B1mut is uncertain.MethodsWe analyzed the clinical-pathologic features and outcomes of a single-institutional series of 94 SF3B1mut and 415 SF3B1wt newly diagnosed untreated MDS patients and explored the differences between K700E and non-K700E subgroups.FindingsNinety-four (19%) patients had SF3B1mut: median age, 74 years. Fifty-five (60%) patients carried K700E. Recurrent non-K700E mutations (39, 40%) included R625, H662 and K666. Compared to SF3B1mut K700E, non-K700E patients had a lower median ANC (1·8 vs. 2·4, p=0·005) and were frequently “high” R-IPSS (revised International Prognostic Scoring System) [7(19%) vs. 2(4%), p=0·031]. Non-K700E MDS frequently associated with RUNX1 (26% vs. 7%, p=0·012) and exclusively with BCOR, IDH2, and SRSF2 mutations. There was no significant difference in karyotype or SF3B1 variant allele frequency. Most (∼80%) were treated with hypomethylating agents. SF3B1mut had superior overall survival (OS) than SF3B1wt in all MDS categories [not-reached vs. 25·2 months, p=0·0003], low-grade MDS, and MDS with ring sideroblasts (MDS-RS). Compared to SF3B1wt, SF3B1mut K700E had superior outcomes in all MDS categories (25 months vs. not-reached, p=0·0001), low-grade MDS, and MDS-RS, but no significant difference was seen with non-K700E. By multivariate analysis, absence of SF3B1mut K700E (not non-K700E) independently associated with prognosis.InterpretationSF3B1mut MDS show distinct clinical and mutational profiles, with K700E showing a significantly better OS compared to non-K700E mutations and SF3B1wt. Our study highlights the importance of SF3B1 mutation type in MDS risk assessment.Data Sharing StatementThe datasets generated during and/or analyzed during the current study are not publicly available due to patient privacy concerns but are available from the corresponding author on reasonable request.Research in ContextEvidence before this studyWe designed this study based on the collective evidence from a systematic search of the literature for outcomes of patients MDS with SF3B1 mutations (SF3B1mut) from January 2013 to June 2020. Both the International Working Group for the Prognosis of MDS (IWG-PM) proposal and 2016 revisions to the World Health Organization (WHO) Classification of Myelodysplastic Syndromes recognize SF3B1mut MDS with <5% blasts (or ring sideroblasts >5% for WHO) as a distinct sub-category, in the absence of other unfavorable features. This was largely based on favorable prognostic outcomes, a distinct gene expression profile, and association with ring sideroblasts. However, the natural history of SF3B1mut MDS is heterogeneous. A high proportion of SF3B1 mutations occur within codon K700, leading to large-scale mRNA downregulation due to branch point recognition error, while the rest occur outside of this codon. The downstream functional effects of SF3B1 mutations outside of the K700 codon are unclear. The clinical course of SF3B1mut MDS patients likely depends on the type of SF3B1 mutation and other features such as variant allele frequency, concomitant gene mutations, and karyotype. Until now, the effects of the different types of SF3B1 mutations were largely unknown.Added value of this studyIn this study, we report distinctive clinicopathologic characteristics and outcomes of MDS patients with SF3B1 mutations segregated based on mutation type: K700E vs. non-K700E. We show that ∼40% of SF3B1 mutated MDS patients have non-K700E mutations. Non-K700E SF3B1mut MDS have distinct clinico-pathologic features, such as lower ANC and frequent association with mutations in RUNX1, BCOR, IDH2, and SRSF2. There was no significant difference in karyotype or SF3B1 variant allele frequency. Importantly, K700E SF3B1mut MDS had superior overall survival compared to SF3B1wt, in all MDS, low-grade MDS, and MDS with ring sideroblasts, but no significant difference was seen with non-K700E. By multivariate analysis, absence of SF3B1mut K700E, but not non-K700E, independently associated with prognosis.Implications of all the available evidenceTo the best of our knowledge, this is the first study to report these findings from a single-institutional series of MDS primarily treated with hypomethylating agents. Our study highlights the importance of determining the SF3B1 mutation type in MDS risk assessment. These findings are important in light of the recent FDA approval of luspatercept based on the results of the MEDALIST trial that suggested sustained hematological responses in SF3B1mut MDS patients.

Transfusion Practices in Myelodysplastic Syndromes: Preliminary Results of An Epidemiologic and Economical Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4336-4336
Author(s):  
Matthieu Filloux ◽  
Adrien Chauchet ◽  
Yvan Beaussant ◽  
Chrystelle Vidal ◽  
Franck Leroux ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Transfusion Requirement ◽  
Conflicts Of Interest ◽  
Age Groups ◽  
Iron Chelation ◽  
Low Risk ◽  
Economic Study ◽  
Transfusion Threshold ◽  
Significant Difference

Abstract Abstract 4336 Background Despite the improvements and promises of novel agents (demethylating and erythropoiesis stimulating agents), red blood cells (RBC) and platelets transfusion remains frequent and essential in the management of myelodysplastic syndromes (MDS). Reducing patients’ dependence to transfusion is a major outcome, linked with the disease prognosis, patients’ quality of life and economical issues. Few data in the literature have described transfusions practices and requirements in MDS patients. We report here an epidemiological study of the transfusion practices in our center and try to build an economical evaluation of direct transfusions costs. Design and Methods We conducted a retrospective, descriptive study including all new patients diagnosed with MDS in the department of haematology of Besan□ on between 2006 and 2009. Patients were classified as high risk (HR) MDS when IPSS was ≥ 1.5, and as low risk (LR) when IPSS was ≤ 1. We compared HR and LR groups and four categories of age (≤68; [68–76]; [76–83] and >83 years) according to transfusion data. The economic study compared direct costs of RBC transfusions and erythroipoiesis-stimulating agents for LR and HR patients, including the costs of hospital stays. Materials, transport, medical examinations, doctors’ and nurses’ wages and iron chelation were not considered in this analysis. T-test and χ2-test were used for comparisons. Results 205 patients were analysed, median age at diagnosis was 74.3 years (table 1), with a predominance of men (sex ratio 1.33). IPSS score was available for 75% of patients (n=154), 111 LR patients and 43 HR patients. Median follow-up was 32 months [10–57]. Twenty-three patients (11%) developed a secondary acute leukaemia and 11 (5%) received allogeneic stem cell transplantation. At diagnosis, hemoglobin (Hb) level was not significantly different between HR and LR patients. Platelets level was lower in the HR vs LR (109 vs. 178 G/L respectively, p<0.0001). 60.5% of patients (n=124/205) received labile blood products during the follow-up, more frequently RBC than platelets (87.5% vs. 12.5% respectively). The mean Hb threshold at transfusion was 8.1 g/dl without any significant difference between neither age groups nor IPSS; age did not influenced transfusion requirement (Table 2). In comparison to HR patients, LR patients were less transfused (55 vs. 79%, p<0.006, table 2), and had longer mean intervals between transfusions (32.5 vs. 16.9 days, p<0.001). Furthermore, a progressive shortening of transfusion intervals was observed for both groups along the time; this progression was faster for HR patients. The anti-erythrocyte immunization rates, excluding anti-RH or anti-Kell, was 6.7%. Economical analysis showed that annual costs of RBC transfusion were 11,409 euros in LR patients and 21,945 euros in HR patients versus 11,492 euros for EPO. Conclusion In our study, neither transfusion requirement nor transfusion threshold were correlated with age, whereas both were affected by IPSS. Furthermore, age did not appear to be a predictive factor concerning the transfusion dependence. Despite its limits, the economic study reveals that EPO and transfusion's annual costs are similar in low risk patients. Updated data will be presented on EPO and 5-azacytidine use in our cohort to assess their impact on transfusion practices. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Examination of the predicted prevalence of Gitelman syndrome by ethnicity based on genome databases

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Atsushi Kondo ◽  
China Nagano ◽  
Shinya Ishiko ◽  
Takashi Omori ◽  
Yuya Aoto ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Carrier Frequency ◽  
Japanese Population ◽  
Autosomal Recessive ◽  
Disease Prevalence ◽  
Gitelman Syndrome ◽  
Variant Allele ◽  
Variant Allele Frequency ◽  
Genome Databases ◽  
Heterozygous Carriers

AbstractGitelman syndrome is an autosomal recessive inherited salt-losing tubulopathy. It has a prevalence of around 1 in 40,000 people, and heterozygous carriers are estimated at approximately 1%, although the exact prevalence is unknown. We estimated the predicted prevalence of Gitelman syndrome based on multiple genome databases, HGVD and jMorp for the Japanese population and gnomAD for other ethnicities, and included all 274 pathogenic missense or nonsense variants registered in HGMD Professional. The frequencies of all these alleles were summed to calculate the total variant allele frequency in SLC12A3. The carrier frequency and the disease prevalence were assumed to be twice and the square of the total allele frequency, respectively, according to the Hardy–Weinberg principle. In the Japanese population, the total carrier frequencies were 0.0948 (9.5%) and 0.0868 (8.7%) and the calculated prevalence was 0.00225 (2.3 in 1000 people) and 0.00188 (1.9 in 1000 people) in HGVD and jMorp, respectively. Other ethnicities showed a prevalence varying from 0.000012 to 0.00083. These findings indicate that the prevalence of Gitelman syndrome in the Japanese population is higher than expected and that some other ethnicities also have a higher prevalence than has previously been considered.

Abstract 569: Correlation of variant allele frequency and mean tumor molecules with tumor burden in patients with solid tumors

2021 ◽  
Author(s):  
Antony Tin ◽  
Vasily Aushev ◽  
Ekaterina Kalashnikova ◽  
Raheleh Salari ◽  
Svetalana Shchegrova ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Allele Frequency ◽  
Tumor Burden ◽  
Variant Allele ◽  
Variant Allele Frequency

scholarly journals Variant allele frequency enrichment analysis in vitro reveals sonic hedgehog pathway to impede sustained temozolomide response in GBM

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Nidhan K. Biswas ◽  
Vikas Chandra ◽  
Neeta Sarkar-Roy ◽  
Tapojyoti Das ◽  
Rabindra N. Bhattacharya ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Sonic Hedgehog ◽  
Enrichment Analysis ◽  
Hedgehog Pathway ◽  
Variant Allele ◽  
Sonic Hedgehog Pathway ◽  
Variant Allele Frequency

scholarly journals Warshaw Technique in Laparoscopic Spleen-Preserving Distal Pancreatectomy: Surgical Strategy and Late Outcomes of Splenic Preservation

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Lei Wang ◽  
Dong Wu ◽  
Yu-gang Cheng ◽  
Jian-wei Xu ◽  
Hai-bo Chu ◽  
...  
Keyword(s):  
Distal Pancreatectomy ◽  
Splenic Abscess ◽  
Healthy Population ◽  
Low Grade ◽  
Efficient Treatment ◽  
Spleen Preserving ◽  
Significant Difference ◽  
Splenic Vessels

Laparoscopic spleen-preserving distal pancreatectomy (LSPDP) can be accomplished with either the preservation or the resection of splenic vessels; the latter is also known as Warshaw technique. Our study is designed to investigate the operation selection strategy when proceeding LSPDP and to evaluate the long-term outcomes of patients undergoing Warshaw surgery. The medical records and follow-up data of patients who underwent LSPDP in Qilu Hospital, Shandong University, were reviewed retrospectively. A total of thirty-five patients were involved in this study, including 17 cases of patients who were treated with Warshaw procedure (WT) while the other 18 cases had splenic vessels preserved (SVP). Compared with the SVP group, the operative time and intraoperative blood loss in WT group were improved significantly. The incidence of early postoperative splenic infarction was higher in WT group. However, there was no report of splenic abscess or second operation. Follow-up data confirmed that there was no significant difference in spleen phagocytosis and immune function compared with normal healthy population. Our study confirms that LSPDP-Warshaw procedure is a safe and efficient treatment for the benign or low grade malignant tumors in distal pancreas in selected patients. The long-term spleen function is normal after Warshaw procedure. Preoperative assessment and intraoperative exploration are recommended for the selection of operation approaches.

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