SF3B1 Mutations and Not TP53 Are Associated with Poor Outcomes in Patients with Del(5q) Myelodysplastic Syndromes (MDS)

Background: Genetic alterations are increasingly being recognized to play an important role in both diagnosis and prognosis of MDS. In general, SF3B1 mutated MDS is known to have favorable outcomes whereas those with mutated TP53 have dismal survivals. However, it is unclear if the impact of these mutations applies to all subtypes of MDS including del(5q), a unique entity that is known for its sensitivity to lenalidomide and better prognosis. A prior study suggests TP53 mutations are associated with worse outcomes in del(5q) MDS (Jadersten et al. 2011), but a more recent study did not find this association and instead they showed SF3B1 mutants (MT) conferred shorter survival compared to wild-type (WT) (Meggendorfer et al. 2017). Herein, we describe our experience of del(5q) MDS patients and assess the prognostic impact of somatic mutations in this population. Methods: We retrospectively reviewed our database of 132 patients with del(5q) MDS who were treated at the Moffitt Cancer Center from 2001 to 2019. Sixty-three patients had molecular data available for analysis. Fisher's exact test of independence was used to determine significance for categorical variables. Univariate and multivariate analyses were conducted using log-rank and Cox regression, respectively. Kaplan-Meier analysis with log-rank test was used to estimate survival outcomes. Results: A total of 132 patients (47M/85F) with a median age of 70 at diagnosis were included in this analysis (Table 1). The majority had isolated del(5q) (86.3%) and the remaining with del(5q) plus other aberration(s) but not meeting criteria as complex cytogenetics. Among patients who received lenalidomide (n=98), 50%, 42.9%, and 7.1% achieved hematologic improvement (HI) or better, no response (NR), and disease progression (DP)/death with a median overall survival (OS) of 93.2, 72.4, and 25.6 months from the time of diagnosis, respectively (p<0.0001) (Figure 1). The median OS of the entire cohort was 73.3 months (median follow-up of 131.3 months), and OS from the time patients stopped lenalidomide was only 26 months. Of the 63 patients with molecular data available, 23.8% were found to have TP53 mutations with a median variant allele frequency (VAF) of 20.4% and 10% SF3B1 MT (median VAF 38.9%). Other common mutations include TET2 (19%) and DNMT3A (17%) as shown in Figure 2. Interestingly, TP53 status did not impact OS (MT 86.4 vs. WT 73.3 months; p=0.72), but those with SF3B1 mutations had a significantly shorter median OS compared to WT (23.9 vs. 83.5 months; p=0.001) (Figure 3). When test for effects of multiple genes had on survival, no combinations were found to be predictive. Univariate analysis showed lenalidomide response significantly impacted OS (HI compared to NR: HR 0.19, 95% CI: 0.05-0.68, p=0.005). Multivariate regression confirmed lenalidomide response and SF3B1 status are independently associated with outcomes. Conclusions: SF3B1 mutations, typically correlate with favorable risk in MDS, are associated with significantly worse prognosis compared to WT in patients with del(5q) MDS. On the contrary, there was no significant difference in OS in patients with TP53 MT vs. TP53 WT. A substantial portion of patients benefited from lenalidomide; however, after lenalidomide failure survivals were limited. Despite the known overall associations between MDS and mutations such as SF3B1 and TP53, our data suggests the del(5q) subset behaves differently which adds to the heterogeneity of the disease. Further studies are needed to clarify the impact of treatments and somatic mutations on outcomes. Disclosures Sallman: Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy; Celgene, Jazz Pharma: Research Funding. Padron:Novartis: Honoraria; Incyte: Research Funding; Kura: Research Funding; BMS: Research Funding. Lancet:Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy. Komrokji:BMS: Honoraria, Speakers Bureau; Agios: Speakers Bureau; Abbvie: Honoraria; Incyte: Honoraria; Acceleron: Honoraria; Novartis: Honoraria; Jazz: Honoraria, Speakers Bureau; Geron: Honoraria.

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Minimal Residual Disease (MRD) Monitoring in NPM1 Mutated Acute Myeloid Leukemia (AML): Impact of Concurrent FLT3-ITD and DNMT3A Mutations on MRD Kinetics and Clinical Outcome

Blood ◽

10.1182/blood.v122.21.2555.2555 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2555-2555

Author(s):

Silke Kapp-Schwoerer ◽

Jan Krönke ◽

Andrea Corbacioglu ◽

Verena I. Gaidzik ◽

Peter Paschka ◽

...

Keyword(s):

Clinical Outcome ◽

Research Funding ◽

Residual Disease ◽

Prognostic Impact ◽

Mutation Status ◽

Free Survival ◽

Transcript Levels ◽

Additional Information ◽

Significant Difference ◽

The Impact

Abstract Introduction In a recent update on MRD monitoring in 407 NPM1 mutated (NPM1mut) AML patients (pts) we could confirm the results from our previous study showing that achievement of RQ-PCR negativity after double induction (DI), after completion of therapy (CT) as well as during the follow-up period (FUP) is significantly associated with a lower cumulative incidence of relapse (CIR) and superior overall survival (OS) [Döhner K, Annals of Hematol; 2013;Suppl.1,92:S39]. In addition, in pts with concurrent FLT3-ITD (FLT3-ITDmut) or DNMT3A (DNMT3Amut) mutations, we also showed that the median NPM1mut transcript levels after each treatment cycle were significantly higher. Aim To evaluate the impact of concurrent FLT3-ITD and DNMT3Amut on MRD kinetics and clinical outcome in NPM1mutAML pts. Methods For this analysis we included all pts enrolled on one of two AMLSG treatment trials [AMLHD98A (NCT00146120) n=46; AMLSG 07-04 (NCT00151242) n=199] for whom the FLT3-ITD and DNMT3A mutation status at the time of diagnosis was determined. MRD levels (ratio NPM1mut/ABL1 transcripts x 104) were detected by NPM1mut specific RQ-PCR using TaqMan technology; the sensitivity of the assays was 10-5 - 10-6. DNMT3A and FLT3-ITD mutation status was assessed by standard PCR-based methods Results In total, 1588 samples [bone marrow n=1564; peripheral blood n=24] from 245 NPM1mut pts were analyzed [at diagnosis, n= 240; during therapy, n= 807; during FUP, n= 541]. FLT3-ITD and DNMT3A mutation status was available in 245/245 (FLT3-ITDmut n=94) and in 234/245 (DNMT3Amut n= 122) pts, respectively. Pre-treatment NPM1mut transcript levels did not correlate with clinical characteristics, DNMT3A or FLT3-ITD mutation status and had no impact on event-free survival, relapse-free survival and OS. Multivariable analyses stratified for FLT3-ITD mutation status after DI and CT revealed RQ-PCR negativity as a significant factor for longer remission duration (hazard ratio (HR) 15.15 and 8.95, respectively) and better OS (HR 6.13 and 4.27, respectively); DNMT3A mutation status had no significant impact in these models. Subgroup analyses showed that the proportion of pts achieving RQ-PCR negativity after DI, after CT and during FUP was significantly lower in DNMT3Amut compared to the DNMT3A wildtype pts (8.6% vs 33.3%, p=<0.001; 36,3% vs 61.9%, p=0.009; 33% vs 51%, p=0.04, respectively) whereas for FLT3-ITDmut pts this effect was only significant after DI (8.3% vs 25%, p=0.022). Based on these findings we further investigated the impact of RQ-PCR negativity in the context of concurrent FLT3-ITD and DNMT3A mutations. After DI, there was no significant difference in CIR and OS for RQ-PCR negative pts with respect to FLT3-ITD or DNMT3A mutation status. After CT, RQ-PCR negative pts with DNMT3Amut had a significantly higher CIR compared to DNMT3A wildtype pts (34% vs 8% at 4 years; p=0.007). This adverse prognostic impact was consistently seen during the FUP (CIR 21% vs 3% at 4 years; p=0.01); there was no difference in CIR rates between pts with and without FLT3-ITD mutations. Conclusions We demonstrate a significant correlation between the DNMT3A mutation status and the achievement of RQ-PCR negativity at all clinically relevant time points i.e. after DI, and CT, and during FUP while this strong correlation was not observed for FLT3-ITDmut. Within the NPM1mut RQ-PCR negative group the presence of DNMT3Amut allows the identification of pts at high risk of relapse. Based on our findings DNMT3A mutation status should be determined in NPM1mut pts to further refine MRD monitoring. The establishment of DNMT3Amut specific MRD assays might provide additional information on MRD status in these pts. Disclosures: Schlegelberger: Celgene: Consultancy. Lübbert:Johnson and Johnson: Advisory Board Other. Kindler:Novartis: Membership on an entity’s Board of Directors or advisory committees. Germing:Celgene: Honoraria, Research Funding. Schlenk:Novartis: Research Funding; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Chugai: Research Funding; Ambit: Honoraria; Celgene: Honoraria, Research Funding.

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Evolutionary Action Score of Missense TP53 Mutations Can Predict Outcome in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-119095 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1820-1820

Author(s):

Rashmi Kanagal-Shamanna ◽

Koji Sasaki ◽

Guillermo Montalban Bravo ◽

Christopher B. Benton ◽

Elias J. Jabbour ◽

...

Keyword(s):

Prognostic Factors ◽

Splice Site ◽

Research Funding ◽

Tp53 Mutation ◽

Univariate Analysis ◽

Complex Karyotype ◽

Coding Region ◽

Tp53 Mutations ◽

Genetics Research ◽

The Impact

Abstract Introduction Gene mutations carry a significant prognostic value and influence the management of MDS and AML. However, until now, data on the impact of the type and functional effects of mutations on outcome, especially in genes lacking a hotspot such as TP53, are limited. TP53 mutation (TP53mut) is an independent predictor of poor outcome in MDS/AML. Majority of TP53mut are missense, few are nonsense, frameshift and splice-site. These occur across the entire coding region, and result in either loss-of-function, gain-of-function (GOF) or exert dominant negative effect on wild-type allele. Until now, there is limited data on the impact of the different types of TP53mut on the outcome in MDS/AML. There are several quantitative predictors to assess the molecular effect of TP53mut. Evolutional Action (EA) scoring system quantifies the deleterious effect of missense TP53mut based on the location of AA residue involved by the mutation and the effect of the AA change. Within head and neck cancer, this scoring system has identified a subset of mutations that have an adverse outcome. In this study, we assessed the impact of different parameters of TP53mut and the utility of EA score in well-characterized MDS and AML cohorts. Methods A total of 593 MDS, 139 CMML and 808 AML patients were selected for analysis. Coding region of TP53 was assessed by NGS for mutations by targeted amplicon-based NGS panel. Gain-of-function (GOF) mutations were defined as R172H, R175H, R270H, G245S, R248W, G248Q or R273H. Overall survival (OS) was calculated from the time of diagnosis to death or last follow-up. Event-free survival (EFS) was calculated from the time from therapy to progression/death. Various parameters of TP53mut, including the number, VAF, location, functional effect were correlated to outcome. In patients with missense TP53mut, EA score was correlated to outcome. Results Among a total of 732 MDS/CMML patients, 208 TP53 mutations were identified in 159 (21.7%) patients [99 men; 60 women; median age of 68 years (range, 18-98)]. The median VAF of TP53 mutations was 36.7% (range, 1.0-93.6). These included 164 missense, 21 frameshift, 17 nonsense and 6 splice-site mutations. Majority (n=149, 94%) involved DNA-binding domain (DBD). Twenty-four (15%) patients had a GOF type mutation. The median EA score was 76.7 (range, 16.6-97.7). The median OS was 33 months (12 months in TP53mut, 112 months in TP5wt; p<0.001). The presence of complex karyotype (CK) with TP53mut showed worse OS compared to TP53mut alone (median 22 months vs. 12 months; p=0.010). The presence of deletion 17p did not affect OS in TP53 mutated patients (del17p + TP53mut, 14 months versus TP53mut alone, 12 months; p=0.789). By univariate analysis, the prognostic factors for OS and EFS included the presence and VAF of TP53mut; in addition, EA score was prognostic for EFS (p=0.04). Using statistical approach, a mathematical EA score of >87.4 could predict a significantly worse EFS in MDS/CMML (p=0.01). Among 808 AML patients, 197 TP53 mutations were identified in 161 (~20%) patients [90 men, 71 women; median age of 70 years (range, 20-90)]. The median VAF of TP53 mutations was 42.7% (range, 1.2-94.4). These included 171 missense, 13 frameshift, 6 nonsense and 7 splice-site mutations. Majority (n=151, 77%) involved DBD. Twenty-six (16%) were of GOF type. The median EA score was 78.5 (range, 4.2-97.6). 139 TP53 mutated patients had a complex karyotype. The median OS was 16 months (6 month, TP53mut; 20 months, TP53wt; p< 0.001). Patients with >1 TP53mut showed worse OS than patients with one mutation (7 months, single; 7 months, multiple; p=0.006). The presence of CK with TP53mut showed worse OS compared to TP53mut alone (median 5 months vs. 11 months; p=0.002). The presence of deletion 17p did not affect OS in TP53mut patients (del17p + TP53mut, 5 months versus TP53mut alone 7 months; p=0.136). By univariate analysis, the presence, number (2 vs. 1) and VAF of TP53 mutation(s) were prognostic factors for OS, EFS and LFS. GOF type mutation was prognostic for EFS but showed a trend for OS and LFS. EA score and site of mutation did not influence the outcome in AML. In AML, EA score of >57.7 could predict a significantly worse OS (EA score <57.7, 5 months versus >57.7, 9 months; p=0.02). Conclusion The presence, number and VAF of TP53 mutation(s) are associated with worse outcome in AML and MDS. EA score can be helpful to further stratify MDS and AML patients with missense mutations. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Kadia:Abbvie: Consultancy; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Takeda: Consultancy; Celgene: Research Funding; Abbvie: Consultancy; Novartis: Consultancy; Celgene: Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding. Ravandi:Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Orsenix: Honoraria; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Xencor: Research Funding; Jazz: Honoraria; Jazz: Honoraria; Xencor: Research Funding.

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Monitoring of Minimal Residual Disease (MRD) of DNMT3A Mutations (DNMT3Amut) in Acute Myeloid Leukemia (AML): A Study of the AML Study Group (AMLSG)

Blood ◽

10.1182/blood.v126.23.226.226 ◽

2015 ◽

Vol 126 (23) ◽

pp. 226-226 ◽

Cited By ~ 2

Author(s):

Verena I. Gaidzik ◽

Daniela Weber ◽

Peter Paschka ◽

Anna Kaumanns ◽

Stefan Krieger ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Continuous Variable ◽

Prognostic Impact ◽

Advisory Committees ◽

Clinical Endpoints ◽

Clonal Hematopoiesis ◽

Significant Difference ◽

The Impact

Abstract Background: The DNA methyltransferase 3A (DNMT3A) is one of the most frequent mutated genes in AML with a hot spot mutation at codon R882 in 80% of the DNMT3Amut cases. In most of the studies DNMT3Amut predicts for poor overall (OS) and relapse-free survival (RFS). Recently, DNMT3Amut have been associated with age-related clonal hematopoiesis, and they have been identified in early preleukemic stem cells. These findings suggest that DNMT3Amut represents an early event in leukemogenesis and may be part of the leukemia founder clone in most AMLs harboring a DNMT3Amut. We thought to address the question whether MRD monitoring in DNMT3Amut patients (pts) can be used for prognostic classification and risk stratification in these pts. Aims: We monitored MRD for the most common DNMT3Amut (DNMT3Amut -R882H, n=126 and -R882C, n=55) in a large cohort of adult AML pts entered on three AMLSG treatment trials [AML HD98A (n=14; NCT00146120), AMLSG 07-04 (n=86; NCT00151242), AMLSG 09-09 (n=81; NCT00893399)]. Methods: DNMT3Amut MRD monitoring was performed using a cDNA-based RQ-PCR-assay by TaqMan technology with a sensitivity between 10-3 and 10-4. MRD levels are reported as normalized values of DNMT3Amut transcripts per 104ABL1 transcripts (DNMT3Amut/104ABL1). Results: In total, 1,494 samples [bone marrow (BM), n=798; peripheral blood (PB), n=696] from 181 DNMT3Amut pts were analysed [diagnosis, n=287; during therapy, n=840; follow-up, n=367]. Median age of the patients was 50 years (range, 22 to 78); median BM DNMT3Amut transcript level (TL) at the time of diagnosis was 12690 (range, 1396-54280). There was no significant association of TL with presenting clinical characteristics, such as age, white blood cell count, platelet count, BM and PB blasts, lactate dehydrogenase, or with mutations in NPM1, FLT3 [ITD and TKD], CEBPA and cytogenetics. DNMT3Amut TL as log 10 transformed continuous variable and stratified by study did not impact OS (p=0.29), RFS (p=0.17) and EFS (p=0.28). Comparing TL after double induction (DI) did not show a significant difference between 13 patients without complete remission (CR) and 117 in CR (12983 and 12595, respectively; p=0.52). In Cox regression analyses, BM DNMT3Amut TL as log 10 transformed continuous variable during therapy did not impact the clinical endpoints death and relapse. In general, DNMT3Amut TL during therapy (after induction I, induction II, consolidation I and II) were significantly higher in BM than in PB (p=0.01; p=0.05; p=0.004; p=0.008, respectively). We observed the greatest TL reduction (one log) after induction I, whereas subsequent cycles of therapy did not significantly influence TL. To evaluate the impact of DNMT3Amut MRD monitoring with regard to the clinical endpoints OS, cumulative incidence of relapse (CIR) and remission duration (RD) after DI and after end of therapy (ET) we used different statistical approaches; all survival analyses were stratified by study. After DI and ET, only 8/90 and 4/88 BM samples became MRD negative. At these two time-points MRD positivity did not significantly impact OS (p=0.99; p=0.74), CIR (p=0.73; p=0.15) and RD (p=0.83; p=0.16). Next, we investigated the MRD DNMT3Amut log10-reduction (compared to levels at diagnosis) after DI and ET using the median as a cut-off. Again, we could not detect a significant correlation for pts with a higher TL reduction compared with pts with a lower TL reduction for OS and RD after DI and ET (p=0.83; p=0.30; p=0.04; p=0.21, respectively). Lastly, we evaluated the BM DNMT3Amut TL as 4 increasing equally sized intervals according to the quartiles of the distribution. There was no prognostic impact after DI on OS and RD (p=0.53; p=0.89) and ET (p=0.76; p=0.53). When combining PB and BM samples for the analyses we could not find significant changes in the results. Conclusion: In our study most pts had persistent DNMT3Amut TL with only a minority achieving MRD negativity, a finding that supports the presence of persistent clonal hematopoiesis in hematologic remission. Using different explorative approaches, DNMT3Amut TL did not impact clinical outcome neither during therapy nor during follow-up. Disclosures Horst: Gilead: Honoraria, Research Funding; Pfizer: Research Funding; MSD: Research Funding; Boehringer Ingleheim: Research Funding; Amgen: Honoraria, Research Funding. Schlenk:Arog: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees.

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Prognostic Impact of Germinal Center (GC)/ Activated B-Cell (ABC) Classification Analysed by Immunochemistry, FISH Analysis and GEP, In Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL): The Bio-CORAL Study

Blood ◽

10.1182/blood.v116.21.993.993 ◽

2010 ◽

Vol 116 (21) ◽

pp. 993-993 ◽

Cited By ~ 3

Author(s):

Catherine Thieblemont ◽

Josette Briere ◽

Nicolas Mounier ◽

Hans-Ullrich Voelker ◽

Wendy Cuccini ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Prognostic Value ◽

Univariate Analysis ◽

B Cell Lymphoma ◽

High Dose ◽

Fish Analysis ◽

Prognostic Impact ◽

Matched Pairs ◽

Significant Difference

Abstract Abstract 993 Purpose: Cell of origin (COO) has a major prognostic impact in DLBCL. However this impact has never been analysed in the context of relapsed/refractory DLBCL. The purpose of this study was to evaluate the prognostic value of COO immunohistochemical markers and BCL2, BCL6 and c-MYC translocations in a well-defined cohort of patients included in the CORAL trial1. Methods: Enrolled patients had CD20+ DLBCL in first relapse or refractory after upfront therapy. Treatment was randomized to either R-ICE (rituximab, ifosfamide, etoposide, carboplatin) or R-DHAP (rituximab, dexamethasone, aracytine, cisplatin). Responding patients had high-dose chemotherapy and ASCT. Paraffin-embedded tumor samples of 249 patients were analysed by immunochemistry for CD10/MME, BCL6, MUM1/IRF4, FOXP1, BCL2 expression and for BCL2, BCL6 and c-MYC breakpoints by FISH, and were categorized according to different COO algorythms2-5. Primary biopsy at diagnosis and relapse biopsy were available for 189 and 147 patients respectively, including 87 matched pairs. Results: With a median follow-up at 27 months, there was no significant difference between R-ICE and R-DHAP for 2-year progression-free survival (PFS) (56.7%+/−5% vs 60%+/−5%, p=0.24) or overall survival (OS) (46%+/−5% vs 60%+/−5%, p=0.24). We confirmed that early relapse, prior rituximab exposure and secondary aaIPI had adverse prognostic value. In univariate analysis, absence of bcl6 expression, non-GC phenotype2, ABC phenotype4, at diagnosis were associated with an unfavourable PFS (p=0.038, p=0.0044, p=0.044, respectively), whereas only non-GC phenotype2 was associated to a worse OS (p=0.027). At relapse, expression of Foxp1 and bcl2, c-MYC breakpoint, ABC phenotype4, immunoFISH index5 was associated with an unfavourable PFS (p=0.02, p=0.027, p=0.03, p=0.032, p=0.02, respectively), and c-MYC breakpoint was associated with a worse OS (p=0.01). Tumor immunophenotype and FISH analysis at diagnosis and at relapse were statistically concordant in matched pairs (Wilcoxon's test between 0.42 and 1). In the whole group, only c-MYC breakpoint present in 13% of the patients was correlated with worse PFS (p= 0.02) and OS (p =0.04). Statistical interaction were found between GC/non-GC classification2 and the treatment R-ICE vs R-DHAP. Patients with GC B-cell like DLBCL subtype treated with R-DHAP have a better 2-year PFS (64% +/−7%) than those with GC B-cell like DLBCL treated with R-ICE (42% +/−7%), and the patients with ABC B-cell like DLBCL treated either with R-DHAP (35%+/−7%) or R-ICE (45%+/−7%) (p= 0.04). In multivariate analysis, only GC/non-GC phenotype2 interaction with the treatment, FOXP1 expression, prior rituximab exposure, secondary aaIIPI, time to relapse were statistically significant. Preliminary results of gene expression profiling seem to confirm these data and are currently under validation. Conclusion: COO remains a major factor in relapsed patients with a better response to R-DHAP salvage chemotherapy in GC-B DLBCL, underlying the importance of molecular DLBCL subtyping. Treatment of ABC subtype is still unsatisfactory. Disclosures: Schmitz: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gisselbrecht:Roche: Research Funding.

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NOTCH1, SF3B1 and TP53 Mutations in Fludarabine-Refractory CLL Patients Treated with Alemtuzumab: Results From the CLL2H Trial of the Gcllsg

Blood ◽

10.1182/blood.v120.21.710.710 ◽

2012 ◽

Vol 120 (21) ◽

pp. 710-710 ◽

Cited By ~ 1

Author(s):

Andrea Schnaiter ◽

Marianna Rossi ◽

Peter Paschka ◽

Mario Cazzola ◽

Konstanze Döhner ◽

...

Keyword(s):

Thymidine Kinase ◽

Research Funding ◽

Performance Status ◽

Prognostic Impact ◽

Wild Type ◽

Ecog Performance Status ◽

Tp53 Mutations ◽

Significant Difference ◽

Trisomy 12 ◽

11Q Deletion

Abstract Abstract 710 Genetic alterations play a major role in stratifying prognostic risk groups in chronic lymphocytic leukemia (CLL). Recently, next generation sequencing strategies revealed novel recurrent mutations in genes such as NOTCH1 and SF3B1 in CLL. Correlations have been reported for SF3B1 mutations (SF3B1mut) with deletion 11q and for NOTCH1 mutations (NOTCH1mut) with trisomy 12. Both mutations have been associated with unmutated IGHV, refractory disease and inferior outcome in heterogeneous cohorts outside clinical trials. We assessed the incidence and prognostic impact of NOTCH1, SF3B1 and TP53 mutations in the CLL2H trial of the GCLLSG, a multicenter phase II trial of subcutaneous alemtuzumab (3 × 30mg/week, max. 12 weeks, n=103, NCT00274976) for fludarabine-refractory CLL patients. Genetic studies were performed in the central reference laboratory of the GCLLSG on 97/103 (94%) trial patients based on availability of DNA. NOTCH1 was analyzed by Sanger sequencing of a PCR fragment from the PEST domain (exon 34, chr9:139,390,619–139,391,290), while SF3B1 (exons 13–16) and TP53 (exons 2–11) were analyzed by DHPLC (WAVE® 3500HT, Transgenomic Inc.) followed by sequencing of aberrant fragments. NOTCH1 mut were found in 13/97 (13.4%), SF3B1mut in 17/97 (17.5%), and TP53mut in 37/99 (37.4%) cases. Two different types of NOTCH1mut (c.7541_7542delCT, n=11; c.7444delC, n=2) and 13 different point mutations of SF3B1 were identified. All SF3B1mut were heterozygous missense mutations resulting into 11 different amino acid changes in exons 14, 15 and 16. Of note, in none of the 97 cases concurrent NOTCH1mut and SF3B1mut was found. IGHV was unmutated in 71/90 (79%) cases overall, in 100% of NOTCH1mut (p=.062) and in 60.0% of SF3B1mut (p=.078). Moreover, SF3B1mut was associated with 11q deletion (p=.042), but we observed no significant correlation of NOTCH1mut with trisomy 12 (p=.321). TP53 mut was found together with NOTCH1mut in 3/12 (25%, p=.349) and with SF3B1mut in 7/17 (41%, p=1.000) cases. The overall response rates (ORR) among the 97 cases was 34% (3% CR and 31% PR). After a median follow-up time of 33.9 months, the median progression-free survival (PFS) was 7.7 months, and the median overall survival (OS) was 18.3 months. The ORR was not significantly different when comparing the groups with or without mutations (50.0% vs. 34.2% for NOTCH1, p=.341 and 41.2% vs. 35.1 % for SF3B1, p=.781, respectively). PFS in NOTCH1mut cases was significantly superior as compared to wild type cases (median 15.47 months vs. 6.74 months, p=.025, see Figure) but there was no significant difference in OS (median not reached vs. 18.3 months, p=.181). For SF3B1mut, we found no significant difference between mutated and wild type cases in PFS (median 4.76 vs. 7.72, p=.974) and OS (median 29.0 vs. 17.1, p=.243). Multivariate analysis of PFS and OS was performed including age, ECOG performance status, WBC, thymidine kinase, β2-microglobulin, IGHV status, 11q deletion, 17p deletion, NOTCH1mut, SF3B1mut and TP53mut as potential factors. Regarding PFS, ECOG performance status > 1 (HR 2.080, p=.057), increased thymidine kinase (cont.) (HR 1.479, p=.007) and elevated β2-microglobulin (cont.) (HR 1.188, p=.0003) emerged as independent unfavorable prognostic factors, whereas NOTCH1mut (HR 0.375, p=.049) was a favorable marker. Regarding OS, none of the gene mutations showed significant prognostic impact, whereas age at increments of 10 years (HR 1.035, p=.024), ECOG performance status > 1 (HR 2.575, p=.017) and increased thymidine kinase (HR 1.568, p=.002) were identified as independent unfavorable factors. In summary, our analysis performed in a multicenter trial of fludarabine-refractory CLL patients showed NOTCH1mut in 13.4%, SF3B1mut in 17.5% and TP53mut in 37.4% cases, with NOTCH1mut and SF3B1mut being mutually exclusive. As compared to non-refractory CLL cohorts, the incidence of NOTCH1mut and SF3B1mut do not appear to be increased which is in contrast to TP53mut. NOTCH1mut was found as a favorable prognostic marker for PFS, but none of the mutations impacted OS in this trial. Figure: Figure:. Disclosures: Hallek: Roche: Consultancy, Honoraria, Research Funding. Stilgenbauer:Genzyme: Consultancy, Honoraria, Research Funding.

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Receptor tyrosine kinase gene amplification is predictive of intraoperative seizures during glioma resection with functional mapping

Journal of Neurosurgery ◽

10.3171/2018.12.jns182700 ◽

2020 ◽

Vol 132 (4) ◽

pp. 1017-1023 ◽

Cited By ~ 2

Author(s):

Bryan D. Choi ◽

Daniel K. Lee ◽

Jimmy C. Yang ◽

Caroline M. Ayinon ◽

Christine K. Lee ◽

...

Keyword(s):

Tyrosine Kinases ◽

Univariate Analysis ◽

Tumor Resection ◽

Tumor Grade ◽

Molecular Data ◽

Genetic Alterations ◽

Functional Mapping ◽

Chi Square ◽

Kinase Gene ◽

Glioma Resection

OBJECTIVEIntraoperative seizures during craniotomy with functional mapping is a common complication that impedes optimal tumor resection and results in significant morbidity. The relationship between genetic mutations in gliomas and the incidence of intraoperative seizures has not been well characterized. Here, the authors performed a retrospective study of patients treated at their institution over the last 12 years to determine whether molecular data can be used to predict the incidence of this complication.METHODSThe authors queried their institutional database for patients with brain tumors who underwent resection with intraoperative functional mapping between 2005 and 2017. Basic clinicopathological characteristics, including the status of the following genes, were recorded: IDH1/2, PIK3CA, BRAF, KRAS, AKT1, EGFR, PDGFRA, MET, MGMT, and 1p/19q. Relationships between gene alterations and intraoperative seizures were evaluated using chi-square and two-sample t-test univariate analysis. When considering multiple predictive factors, a logistic multivariate approach was taken.RESULTSOverall, 416 patients met criteria for inclusion; of these patients, 98 (24%) experienced an intraoperative seizure. Patients with a history of preoperative seizure and those treated with antiepileptic drugs prior to surgery were less likely to have intraoperative seizures (history: OR 0.61 [95% CI 0.38–0.96], chi-square = 4.65, p = 0.03; AED load: OR 0.46 [95% CI 0.26–0.80], chi-square = 7.64, p = 0.01). In a univariate analysis of genetic markers, amplification of genes encoding receptor tyrosine kinases (RTKs) was specifically identified as a positive predictor of seizures (OR 5.47 [95% CI 1.22–24.47], chi-square = 5.98, p = 0.01). In multivariate analyses considering RTK status, AED use, and either 2007 WHO tumor grade or modern 2016 WHO tumor groups, the authors found that amplification of the RTK proto-oncogene, MET, was most predictive of intraoperative seizure (p < 0.05).CONCLUSIONSThis study describes a previously unreported association between genetic alterations in RTKs and the occurrence of intraoperative seizures during glioma resection with functional mapping. Future models estimating intraoperative seizure risk may be enhanced by inclusion of genetic criteria.

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288. Follow-Up Blood Cultures in Gram-Negative Bacteremia: How Do They Impact Outcomes

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.331 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S144-S144

Author(s):

Azza Elamin ◽

Faisal Khan ◽

Ali Abunayla ◽

Rajasekhar Jagarlamudi ◽

aditee Dash

Keyword(s):

Clinical Outcomes ◽

Antibiotic Treatment ◽

Readmission Rate ◽

Blood Cultures ◽

Categorical Variables ◽

Gram Negative ◽

Number Of Patients ◽

Significant Difference ◽

The Impact

Abstract Background As opposed to Staphylococcus. aureus bacteremia, there are no guidelines to recommend repeating blood cultures in Gram-negative bacilli bacteremia (GNB). Several studies have questioned the utility of follow-up blood cultures (FUBCs) in GNB, but the impact of this practice on clinical outcomes is not fully understood. Our aim was to study the practice of obtaining FUBCs in GNB at our institution and to assess it’s impact on clinical outcomes. Methods We conducted a retrospective, single-center study of adult patients, ≥ 18 years of age admitted with GNB between January 2017 and December 2018. We aimed to compare clinical outcomes in those with and without FUBCs. Data collected included demographics, comorbidities, presumed source of bacteremia and need for intensive care unit (ICU) admission. Presence of fever, hypotension /shock and white blood cell (WBC) count on the day of FUBC was recorded. The primary objective was to compare 30-day mortality between the two groups. Secondary objectives were to compare differences in 30-day readmission rate, hospital length of stay (LOS) and duration of antibiotic treatment. Mean and standard deviation were used for continuous variables, frequency and proportion were used for categorical variables. P-value < 0.05 was defined as statistically significant. Results 482 patients were included, and of these, 321 (67%) had FUBCs. 96% of FUBCs were negative and 2.8% had persistent bacteremia. There was no significant difference in 30-day mortality between those with and without FUBCs (2.9% and 2.7% respectively), or in 30-day readmission rate (21.4% and 23.4% respectively). In patients with FUBCs compared to those without FUBCs, hospital LOS was longer (7 days vs 5 days, P < 0.001), and mean duration of antibiotic treatment was longer (14 days vs 11 days, P < 0.001). A higher number of patients with FUBCs needed ICU care compared to those without FUBCs (41.4% and 25.5% respectively, P < 0.001) Microbiology of index blood culture in those with and without FUBCs Outcomes in those with and without FUBCs FUBCs characteristics Conclusion Obtaining FUBCs in GNB had no impact on 30-day mortality or 30-day readmission rate. It was associated with longer LOS and antibiotic duration. Our findings suggest that FUBCs in GNB are low yield and may not be recommended in all patients. Prospective studies are needed to further examine the utility of this practice in GNB. Disclosures All Authors: No reported disclosures

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AB0132 THE STUDY OF SUBCLINICAL SYNOVITIS DETECTED BY ULTRASONOGRAPHY AND MRI IN RA PATIENTS AFTER REACHING CLINICAL REMISSION ON PATIENT’S SUBJECTIVE SYMPTOMS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2830 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1094.2-1094

Author(s):

M. Nawata ◽

K. Someya ◽

T. Aritomi ◽

M. Funada ◽

K. Nakamura ◽

...

Keyword(s):

Clinical Remission ◽

Research Funding ◽

Morning Stiffness ◽

Univariate Analysis ◽

P Value ◽

Research Support ◽

Residual Symptoms ◽

Logistic Analysis ◽

Significant Difference ◽

Multivariate Logistic Analysis

Background:The goal of treatment in rheumatoid arthritis (RA) is to achieve remission. There is the patient with residual symptoms in the Japanese RA patient who achieved clinical remission. There are not many studies to examine the relation between everyday life, social activity and evaluation of disease activities using high-sensitivity image examinations (musculoskeletal ultrasound (MSKUS) and MRI).Objectives:To examine the relationship between subjective residual symptoms and imaging examinations in RA patients who have achieved clinical remission.Methods:30 RA patients who achieved SDAI remission during RA treatment. Age, sex, disease duration, physical findings, serological markers, disease activity, HAQ, EQ-5D-5L, FACIT-F, Patient Reported Outcomes (PROs), EGA and medications were evaluated. 44 joints were assessed by MSKUS with gray scale (GS) and power doppler (PD) and contrast-enhanced bilateral joint MRI scoring with OMERACT-RAMRIS scoring.Results:1. The mean SDAI of the 30 RA patients was 1.3. 2.In the analysis of the presence or absence of subjective residual symptoms that led to remission of SDAI (Table 1).Table 1.Subjective residual symptoms/presence (N=17)Subjective residual symptoms/absence (N=13)Univariate analysisp valueMultivariate logistic analysisp valueTJC0.0±0.00.3±0.50.0173HAQ0.4±0.40.05±0.10.00950.00181EQ5D-5L0.8±0.10.9±0.00.0001FACIT-F14.5±9.84.6±4.30.0233Morning stiffness (min)256.5±564.80.0±0.00.0210Pain (VAS) (mm)9.2±9.50.9±1.50.00440.0455PGA (mm)7.7±9.00.5±1.10.0013(1). In the univariate analysis, the number of tender joints, HAQ, EQ-5D-5L, FACIT-F, morning stiffness, and pain VAS were extracted with significant differences.(2). In multivariate logistic analysis, HAQ and pain VAS were extracted as independent factors with significant differences. 3.In univariate analysis of the association between HAQ and pain VAS extracted in multivariate logistic analysis and imaging examinations (MSKUS/MRI), MRI-synovitis was extracted with a significant difference in HAQ.Conclusion:1. It was suggested that Pain VAS and HAQ due to RA could be identified in patients reaching SDAI remission. 2. In patients reaching SDAI remission, Pain VAS ≤10 or HAQ ≤0.5 suggested that subjective residual symptoms may be eliminated. 3. HAQ ≤ 0.5 suggests that synovitis is less likely to be detected on MRI. 4. In patients who have reached SDAI remission, little residual inflammation was observed on US, suggesting that induction of remission is important not only to prevent joint destruction, but also to improve and maintain long-term QoL.Disclosure of Interests:MASAO NAWATA Grant/research support from: I have received research funding from Eli Lilly Japan K.K., Kazuki Someya: None declared, Takafumi Aritomi: None declared, Masashi funada: None declared, Katsumi Nakamura: None declared, SAITO KAZUYOSHI Grant/research support from: I have received research funding from Eli Lilly Japan K.K., Yoshiya Tanaka Speakers bureau: I have received speaking fees from Abbvie, Daiichi-Sankyo, Chugai, Takeda, Mitsubishi-Tanabe, Bristol-Myers, Astellas, Eisai, Janssen, Pfizer, Asahi-kasei, Eli Lilly, GlaxoSmithKline, UCB, Teijin, MSD, and Santen, Consultant of: I have received consulting fees from Abbvie, Daiichi-Sankyo, Chugai, Takeda, Mitsubishi-Tanabe, Bristol-Myers, Astellas, Eisai, Janssen, Pfizer, Asahi-kasei, Eli Lilly, GlaxoSmithKline, UCB, Teijin, MSD, and Santen, Grant/research support from: I have received research grants from Mitsubishi-Tanabe, Takeda, Chugai, Astellas, Eisai, Taisho-Toyama, Kyowa-Kirin, Abbvie, and Bristol-Myers

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A Survey of Marine Coastal Litters around Zhoushan Island, China and Their Impacts

Journal of Marine Science and Engineering ◽

10.3390/jmse9020183 ◽

2021 ◽

Vol 9 (2) ◽

pp. 183

Author(s):

Xuehua Ma ◽

Yi Zhou ◽

Luyi Yang ◽

Jianfeng Tong

Keyword(s):

Rapid Development ◽

Univariate Analysis ◽

Local Environment ◽

Marine Litter ◽

Social Ecological ◽

The Social ◽

Significant Difference ◽

Valuable Method ◽

Beach Litter ◽

The Impact

Rapid development of the economy increased marine litter around Zhoushan Island. Social-ecological scenario studies can help to develop strategies to adapt to such change. To investigate the present situation of marine litter pollution, a stratified random sampling (StRS) method was applied to survey the distribution of marine coastal litters around Zhoushan Island. A univariate analysis of variance was conducted to access the amount of litter in different landforms that include mudflats, artificial and rocky beaches. In addition, two questionnaires were designed for local fishermen and tourists to provide social scenarios. The results showed that the distribution of litter in different landforms was significantly different, while the distribution of litter in different sampling points had no significant difference. The StRS survey showed to be a valuable method for giving a relative overview of beach litter around Zhoushan Island with less effort in a future survey. The questionnaire feedbacks helped to understand the source of marine litter and showed the impact on the local environment and economy. Based on the social-ecological scenarios, governance recommendations were provided in this paper.

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POS1189 THE IMPACT OF TELEMEDICINE AND COVID-19 ON A TERTIARY RHEUMATOLOGY SERVICE: A RETROSPECTIVE AUDIT

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.1497 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 876-877

Author(s):

W. Zhu ◽

T. De Silva ◽

L. Eades ◽

S. Morton ◽

S. Ayoub ◽

...

Keyword(s):

Immunosuppressive Therapy ◽

Univariate Analysis ◽

Diagnostic Delay ◽

Cohort Differences ◽

Phone Calls ◽

Retrospective Audit ◽

Common Diagnosis ◽

Significant Difference ◽

The Impact

Background:Telemedicine was widely utilised to complement face-to-face (F2F) care in 2020 during the COVID-19 pandemic, but the impact of this on patient care is poorly understood.Objectives:To investigate the impact of telemedicine during COVID-19 on outpatient rheumatology services.Methods:We retrospectively audited patient electronic medical records from rheumatology outpatient clinics in an urban tertiary rheumatology centre between April-May 2020 (telemedicine cohort) and April-May 2019 (comparator cohort). Differences in age, sex, primary diagnosis, medications, and proportion of new/review appointments were assessed using Mann-Whitney U and Chi-square tests. Univariate analysis was used to estimate associations between telemedicine usage and the ability to assign a diagnosis in patients without a prior rheumatological diagnosis, the frequency of changes to immunosuppression, subsequent F2F review, planned admissions or procedures, follow-up phone calls, and time to next appointment.Results:3,040 outpatient appointments were audited: 1,443 from 2019 and 1,597 from 2020. There was no statistically significant difference in the age, sex, proportion of new/review appointments, or frequency of immunosuppression use between the cohorts. Inflammatory arthritis (IA) was a more common diagnosis in the 2020 cohort (35.1% vs 31%, p=0.024). 96.7% (n=1,444) of patients seen in the 2020 cohort were reviewed via telemedicine. In patients without an existing rheumatological diagnosis, the odds of making a diagnosis at the appointment were significantly lower in 2020 (28.6% vs 57.4%; OR 0.30 [95% CI 0.16-0.53]; p<0.001). Clinicians were also less likely to change immunosuppressive therapy in 2020 (22.6% vs 27.4%; OR 0.78 [95% CI 0.65-0.92]; p=0.004). This was mostly driven by less de-escalation in therapy (10% vs 12.6%; OR 0.75 [95% CI 0.59-0.95]; p=0.019) as there was no statistically significant difference in the escalation or switching of immunosuppressive therapies. There was no significant difference in frequency of follow-up phone calls, however, patients seen in 2020 required earlier follow-up appointments (p<0.001). There was also no difference in unplanned rheumatological presentations but significantly fewer planned admissions and procedures in 2020 (1% vs 2.6%, p=0.002). Appointment non-attendance reduced in 2020 to 6.5% from 10.9% in 2019 (OR 0.57 [95% CI 0.44-0.74]; p<0.001), however the odds of discharging a patient from care were significantly lower in 2020 (3.9% vs 6%; OR 0.64 [95% CI 0.46-0.89]; p=0.008), although there was no significance when patients who failed to attend were excluded. Amongst patients seen via telemedicine in 2020, a subsequent F2F appointment was required in 9.4%. The predictors of needing a F2F review were being a new patient (OR 6.28 [95% CI 4.10-9.64]; p<0.001), not having a prior rheumatological diagnosis (OR 18.43 [95% CI: 2.35-144.63]; p=0.006), or having a diagnosis of IA (OR 2.85 [95% CI: 1.40-5.80]; p=0.004) or connective tissue disease (OR 3.22 [95% CI: 1.11-9.32]; p=0.031).Conclusion:Most patients in the 2020 cohort were seen via telemedicine. Telemedicine use during the COVID-19 pandemic was associated with reduced clinic non-attendance, but with diagnostic delay, reduced likelihood of changing existing immunosuppressive therapy, earlier requirement for review, and lower likelihood of discharge. While the effects of telemedicine cannot be differentiated from changes in practice related to other aspects of the pandemic, they suggest that telemedicine may have a negative impact on the timeliness of management of rheumatology patients.Disclosure of Interests:None declared.

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