Interrelation of 5q-Deletions and Mutations of TP53 in Patients with Myelodysplastic Syndromes and Complex Aberrations

Introduction: Cytogenetic changes occur in 50% of patients (pts) with Myelodysplastic Syndromes (MDS). Complex aberrations (cA, = 3 or more) are associated with a very poor outcome. In about 50% of the cases with cA aberrations of the TP53 locus are detectable. Those pts show an even worse outcome with a significantly shortened median overall survival (OS) compared to pts with wildtype TP53 (wtTP53). One of the most common cytogenetic aberrations in MDS is an interstitial deletion of the long arm of chromosome 5 (5q). As an isolated aberration, it is associated with a rather favorable prognosis. As part of a cA, 5q deletions however are assumed to even worsen the prognosis further. We wanted to find out in which prevalence 5q deletions and TP53 changes appear together and how those two factors in combination or not influence the OS of pts with MDS and cA. Methods: 218 pts with MDS or sAML and cA were identified and extensively characterized. 126 of them were diagnosed with MDS, 89 with sAML and 3 with CMML. Cytogenetic analysis by chromosome banding (CBA) and fluorescence in situ hybridization (FISH) of the TP53 locus on 17p as well as sequencing of TP53 either by Sanger or by Next Generation Sequencing was available for all pts. Multicolour FISH (mFISH) was available for 146 pts, SNP array analysis for 42 pts. The median number of cytogenetic aberrations was 8 (range 3-50). At the time of first diagnosis with cA the median age was 72 (range: 29-95). Median OS of the entire cohort was 10.7 months (95% CI: 8.0-16.4). Results: In 146 of 218 pts we found alterations of TP53: a single hit mutation in 32 pts, a single deletion in 22 pts, a combined mutation and deletion in 67 pts and more than 1 mutation in 25 pts. The OS of those 146 pts was 6.6 months compared to 22 months of the pts with wtTP53 (p-value <0.0001). In 161 of 218 pts we found deletions of 5q (del(5q)). The median OS of those pts was significantly shorter than those of pts without del(5q) (8.4 vs. 20 months, p-value 0.001). 130 of 218 pts both had a del(5q) and an alteration of TP53, 31 pts only had a del(5q) and wtTP53 and 16 pts showed different types of TP53 alterations without del(5q). The median OS of pts with TP53 multi hit status as defined by Bernard (Bernard et al., Nature Medicine 2020) was 6.6 months, 5.3 months in pts with single hit TP53 mutations and a del(5q) and 21.6 months in pts, with wtTP53 and del(5q) (p-value = 0.0025, figure 1). Conclusion: Mutations and/or deletions of TP53 show a strong association with del(5q). Both were frequent in our cohort of 218 pts with MDS and cA. There also was a large intersection of 130 pts with both del(5q) and TP53 alteration. The combination of both changes seems to further worsen the already poor prognosis of pts with MDS and cA. Our observation that those two factors appear together frequently supports the hypothesis that the presence of del(5q) may promote the acquisition of cA. This is in accordance with Hsu´s hypothesis that in small clones with a mono-allelic TP53 mutation a del(5q) may favor the loss of heterozygosity of TP53 which could in a next step lead to a higher complexity of cytogenetic aberrations (Hsu et al, 2019). It is remarkable that the presence of del(5q) in combination with a single hit status of TP53 confers the same bad prognosis compared to multi hit TP53 status (figure 1).We will continue analyzing pts with MDS and cA to examine the influence of different TP53 and 5q alterations on the prognosis, the disease progression and median OS of those pts with cA. Figure 1 Disclosures Platzbecker: Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria.

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Comprehensive Genomic Analysis Provides Further Evidence That Iron Overload Can Induce Genetic Instability in Myelodysplastic Syndromes

Blood ◽

10.1182/blood.v126.23.2842.2842 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2842-2842 ◽

Cited By ~ 6

Author(s):

Gina Westhofen ◽

Christina Ganster ◽

Fabian Beier ◽

Tienush Rassaf ◽

Haifa Kathrin Al-Ali ◽

...

Keyword(s):

Iron Overload ◽

Myelodysplastic Syndromes ◽

Genetic Instability ◽

Research Funding ◽

Snp Array ◽

Iron Chelation ◽

Genomic Analysis ◽

Array Analysis ◽

Γh2ax Foci ◽

Snp Array Analysis

Abstract Introduction: Experimental and clinical data have shown that iron overload (IO) has the potential to accelerate progression of myelodysplastic syndromes (MDS) towards secondary leukemia and coincides with a lower survival rate. While genetic instability is understood as a common driver of MDS progression, the mechanisms involved have not yet been fully explored, albeit that oxidative stress is considered to be a main factor for IO related genetic instability. We aimed to investigate the influence of IO, measured by serum ferritin (SF) as a suitable surrogate parameter, on the stability of the genome of MDS patients (pts). Patients/Methods: 60 pts with proven MDS were included, cut-off for elevated SF being 275 µg/l. 29 pts had normal SF levels (median 61 µg/l [range 8-256 µg/l]), 31 pts had elevated SF levels (median 1,246 µg/l [283-6,907]); 1 out of 8 patients with SF > 1,005 µg/l tested positive for labile plasma iron (LPI). Pts were investigated for possible correlations of IO with distinct manifestations of genetic instability as shown by TP53 mutations, chromosome banding analysis, and molecular karyotyping (SNP array analysis). DNA double-strand breaks were quantified by γH2AX immunostaining on enriched CD34+ peripheral blood cells (PB). In addition, telomere length (TL) in PB granulocytes and lymphocytes was analyzed using flow-FISH, PB of 104 healthy donors being used for age-adaption. Plasma nitric oxide metabolites (nitrite, nitrate, nitroso species) are pending but will be screened for a possible correlation with SF. Results: Parameters for genomic stability were determined in the group of pts with elevated SF levels and the group of pts with normal SF levels. Through SNP array analysis, pts with increased SF levels were found to have significantly bigger total genomic aberrations (TGA) size than the subgroup with normal SF levels (median 87.5 Mbp TGA [range 0-229] vs. 0 Mbp TGA [0-155]; p = 0.005; Fig. 1). Likewise, telomere analysis showed significant more age-adapted TL shortening in granulocytes, representing the myeloid compartment, in the subgroup with increased SF levels (mean -1.81 kb) compared to patients with normal SF (0,64 kb, p = 0.003; Fig. 2). No significant TL shortening in lymphocytes of pts with normal SF was observed compared to pts with elevated SF. When only pts with marrow blasts <10% were considered, the subgroup with increased SF levels exhibited higher numbers of γH2AX-foci per CD34+ cell (median 5.7 γH2AX foci [range 2.1-8.6] vs. 1.6 γH2AX foci [0.5-3.5]; p = 0.008; Fig. 3). Elevated SF levels had no impact on the number, or type of chromosome abnormalities. Sanger sequencing identified only one patient with a TP53 mutation (SF = 1,246 µg/l); a search for smaller TP53-mutated clones by ultra-deep-sequencing is under way. Conclusion: In this MDS cohort, higher SF levels were significantly associated with bigger TGA size, premature granulocyte TL shortening, and increased numbers of γH2AX foci in CD34+ cells. These results further support the assumption that IO might be causally related to genetic instability in pts with MDS. Furthermore, our data suggest that SF levels not only above 1,000 µg/l, but also between upper limit of normal value but below 1,000 µg/L adversely affect genetic stability. Additionally, our results imply that the biological relevance of LPI for IO in MDS might be overestimated and is in need of reevaluation. Therefore, iron chelation might be relevant for pts with MDS at lower SF levels than previously thought. Whether investigation of the level of genetic instability by comprehensive genomic analysis as indicated above may be beneficial for the therapeutic decision regarding the timing of iron chelation therapy in individual pts with MDS remains to be explored. Disclosures Al-Ali: Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Brümmendorf:Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: Patent on the use of imatinib and hypusination inhibitors, Research Funding. Gattermann:Novartis: Honoraria, Research Funding.

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Sleep Disturbance Among Patients with Myelodysplastic Syndromes and Acute Leukemia

Blood ◽

10.1182/blood-2019-125147 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4786-4786

Author(s):

Marlise Luskin ◽

Eric Zhou ◽

Zilu Zhang ◽

Daniel J. DeAngelo ◽

Richard Stone ◽

...

Keyword(s):

Acute Leukemia ◽

Sleep Quality ◽

Sleep Disturbance ◽

Myelodysplastic Syndromes ◽

Research Funding ◽

Poor Sleep ◽

Poor Sleep Quality ◽

Entire Cohort ◽

Obstructive Sleep ◽

Leukemia Data

BACKGROUND: Most patients with myelodysplastic syndromes (MDS) describe difficulty sleeping (Luskin et al Br J Haem 2017) and sleep disturbance is a likely contributor to the fatigue experienced by patients with MDS and acute leukemia. Data are sparse regarding the sleep of this patient population as formally assessed with sleep-focused survey instruments. METHODS: We surveyed consecutive adult patients with MDS, AML or ALL at the Dana-Farber Leukemia clinic. With permission from the treating oncologist, patients with a physician-assessed life expectancy ≥ 12 weeks were mailed a questionnaire packet assessing insomnia symptom severity (Insomnia Severity Index; ISI), sleep quality (Pittsburgh Sleep Quality Index; PSQI), obstructive sleep apnea risk (STOP-Bang), and depressive symptoms (Patient Health Questionnaire-9; PHQ-9). Respondents underwent concomitant medical record review. RESULTS: Of 332 eligible patients contacted, 158 (47.6%) responded. Responders were 56% male with a median age of 67 years. Overall, 42% of patients reported insomnia symptoms (ISI ≥10) with the prevalence of such symptoms similar among patients with MDS and acute leukemia (48% vs 38%, p=0.23). OSA risk was high (58%), particularly in patients with MDS (67% vs 52% p=0.10). Those with high OSA risk were more likely to have clinical insomnia as defined by ISI ≥10 (OR 2.6, p=0.01). Depression was uncommon: only 7% had PHQ-measured moderately severe or severe depression. Median sleep duration for the entire cohort was 6.9 hours (range 3-12) indicating that over half of respondents slept less than the 7 hours per night recommended by the National Sleep Foundation for healthy adults. Poor sleep quality (PSQI "Bad Sleep") was seen in 79% of the overall cohort. CONCLUSION: When measured with validated tools, disturbed sleep is common among patients with MDS and acute leukemia. OSA risk is also prevalent but does not likely explain all of the poor sleep quality seen. These data suggest that strategies are needed to improve both quantity and quality of sleep in this population. Table Disclosures DeAngelo: Abbvie: Research Funding; GlycoMimetics: Research Funding; Blueprint: Consultancy, Research Funding; Amgen: Consultancy; Celgene: Consultancy; Shire: Consultancy; Incyte: Consultancy; Novartis: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Jazz Pharmaceuticals Inc: Consultancy; Pfizer: Consultancy. Garcia:Abbvie: Research Funding; Genentech: Research Funding. Winer:Jazz Pharmaceuticals, Pfizer: Consultancy. Steensma:Aprea: Research Funding; Arrowhead: Equity Ownership; Pfizer: Consultancy; H3 Biosciences: Other: Research funding to institution, not investigator.; Astex: Consultancy; Onconova: Consultancy; Stemline: Consultancy; Summer Road: Consultancy.

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Interdependency Between TP53 Mutations, Cytogenetics, Genetic Instability and Prognosis in MDS and Secondary AML

Blood ◽

10.1182/blood.v128.22.2001.2001 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2001-2001 ◽

Cited By ~ 1

Author(s):

Roxana Schaab ◽

Christina Ganster ◽

Sascha Dierks ◽

Katayoon Shirneshan ◽

Marc Talló Parra ◽

...

Keyword(s):

Research Funding ◽

Tp53 Mutation ◽

Median Number ◽

Prognostic Impact ◽

Mutation Status ◽

Tp53 Mutations ◽

Entire Cohort ◽

Genomic Imbalances ◽

Cytogenetic Aberrations ◽

Pharmaceutical Industries

Abstract Introduction: Alterations of TP53 (cytogenetic 17p13.1 deletions and molecular TP53 mutations) were reported to be frequent in pts with myelodysplastic syndromes (MDS) and complex abnormalities (≥3 clonal cytogenetic aberrations, CA) that represent around 15% of all MDS cases. It was suggested that pts with MDS and complex abnormalities may be further prognostically subdivided by the molecular TP53 mutation status (Bejar et al, ASH, 2014, abstract #532). In this study we investigated the frequency of different types of TP53 alterations, their cytogenetic profile and their clinical impact in the adverse cytogenetic MDS subgroup of complex abnormalities. We performed comprehensive cytogenetic and molecular genetic analysis focusing as well on the extent of cytogenetic instability. Methods: We included 105 pts (57 m/48 f; median 71 yrs, range, 47-95 yrs) with MDS (n=86) and sAML after MDS (n=19) with complex abnormalities in our study. A total of 56/89 (62.9%) pts had received azacitidine. Survival was censored at allogeneic stem cell transplantation (26/83; 31.3%). Pts were characterized by chromosome banding analysis, interphasefluorescence in situ hybridization (FISH) with a panel including a 17p13/TP53-covering probe, multicolor FISH (mFISH), Sanger sequencing of TP53 and SNP-array analysis (SNP-A). The extent of genetic imbalances was objectified by counting the number of CA, the number of cytogenetic fusions as shown by mFISH and the size of total genomic aberrations (TGA) measured by SNP-A in megabases (Mb). Results: A molecular TP53 mutation was found in 46/105 (43.8%) pts; a cytogenetic TP53 deletion in 38/105 (36.2%) pts. TP53 was not affected by a molecular mutation or a cytogenetic deletion in 44/105 (42.2%) pts, 23/105 (21.9%) pts were affected by combined TP53 alterations (molecular mutation and cytogenetic deletion), 23/105 (21.9%) pts by a molecular mutation only and 15/105 (14.3%) pts by a cytogenetic deletion only. The median number of CA was 6 (range, 3-41) in the entire cohort. Median overall survival for the entire cohort was 17 months. The degree of genomic imbalances was higher in pts with any TP53 alteration (molecular mutation and/or cytogenetic deletion) as compared to those without: The median number of CA was 8 (range, 3-41) vs. 4 (3-20) (P<0.001), the median number of fusions was 5 (0-13) vs. 2 (0-9) (P<0.001), and the median TGA size was 327 (97-511) vs. 105 (64-226) Mb (P<0.001). The extent of genomic imbalances was higher in pts with a TP53 deletion only compared to pts with a TP53 mutation only: The median number of CA was 10 (range, 4-21) vs. 8 (3-25) (P=0.093; n.s.); the median number of fusions was 7 (2-13) vs. 3 (0-10) (P=0.031). By univariate analysis, presence of ≥5 CA as compared to 3-4 CA increased the hazard ratio (HR) to 3.34 (P=0.017). When we limited the analysis to the subgroup of pts without evidence of a molecular TP53 mutation, presence of a cytogenetic TP53 deletion resulted in a HR of 5.67 (P=0.029). When the analysis was restricted to pts without a TP53 deletion, presence of a molecular TP53 mutation did not significantly change the HR (1.58, P=0.448; n.s.). Multivariate analysis that considered molecular TP53 mutation status, cytogenetic TP53 deletion status, the number of CA and treatment with azacitidine identified presence of a cytogenetic TP53 deletion as the most significant prognostic marker for OS (HR 15.1, P=0.010). HR was increased for pts with ≥5 CA compared to pts with 3-4 CA (HR 5.9, P=0.012). The molecular TP53 mutation status showed no significant impact on HR in our cohort. Conclusion: Presence of a cytogenetic TP53 deletion and a higher number of cytogenetic aberrations (≥5) showed a negative prognostic impact even within the unfavorable cytogenetic subgroup of MDS with complex abnormalities. In contrast, we found no strong prognostic impact for a molecular TP53 mutation in our cohort of MDS with complex abnormalities. The lower impact of TP53 mutations compared to TP53 deletions might be due to the lower degree of cytogenetic imbalances in pts with TP53 mutations only compared to pts with TP53 deletions only. However, molecular as well as cytogenetic TP53 aberrations were associated with a greater extent of chromosomal imbalances and displayed clear interdependencies. Our data suggest that TP53 alterations (molecular mutations and/or cytogenetic deletions) may not have an independent prognostic impact in the MDS subgroup with complex abnormalities. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Platzbecker: Amgen: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Kroeger:Novartis: Honoraria, Research Funding.

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Azacitidine Plus Lenalidomide for Untreated AML Patients Ineligible for Conventional Chemotherapy

Blood ◽

10.1182/blood.v120.21.3575.3575 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3575-3575

Author(s):

Daniel A Pollyea ◽

James L. Zehnder ◽

Steven Coutre ◽

Jason Gotlib ◽

Leonel Gallegos ◽

...

Keyword(s):

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Treatment Options ◽

Single Agent ◽

Early Death ◽

Clinical Activity ◽

P Value ◽

Related Factors ◽

Equal Distribution ◽

Entire Cohort

Abstract Abstract 3575 There are limited treatment options for older patients with acute myeloid leukemia (AML) and prognosis has remained poor, thereby warranting development of novel therapeutic strategies. The optimal treatment for these patients requires the consideration of multiple factors, such as patient and disease-related factors that can help to determine the appropriate therapy. Previous studies have shown that both azacitidine and lenalidomide have single-agent activity in patients older than 60 years with untreated AML and have non-overlapping mechanisms of action that may complement each other. We evaluated the efficacy and safety of the combination of azacitidine plus lenalidomide as front-line therapy for untreated, older AML patients. In this phase 2 study, patients 60 years of age or older with untreated AML received azacitidine 75mg/m2 for 7 days followed by escalating doses of lenalidomide daily for 21 day on 42-day cycles. Patients received continued therapy until disease progression, an unacceptable adverse event, or completion of 12 cycles. Forty-one AML patients (median age, 74 years) were enrolled with equal distribution according to ELN risk. Overall response rate (ORR) was 41% (CR/CRi rate was 29%). The median time to CR/CRi was 12 weeks, and duration of CR/CRi was 28 weeks (range, 4- >104 weeks). The median OS was 20 weeks (range, 1–121+) for the entire cohort and 69 weeks (range, 10–121+) for responders (Figure 1A; responders had better OS compared to non-responders (69 vs. 15 weeks, p-value <0.01). Baseline characteristics, such as age at diagnosis, baseline WBC count, bone marrow blast percentage or ELN risk classification, or molecular markers were not predictive of responses. Overall survival was similar according to ELN classification. Therapy-related AML and high hematopoietic cell transplantation comorbidity index were the only negative predictors of response. Early death was noted in 14% of patients. Grades ≥ 3 toxicities were uncommon and most adverse events were gastrointestinal, fatigue and myelosupression. Sequential combination of azacitidine plus lenalidomide has evidence of clinical activity as initial therapy for older AML patients, and further study of this combination in AML and MDS is warranted. This study is registered at www.clinicaltrials.gov as # NCT00890929. Disclosures: Gotlib: Celgene: Research Funding. Liedtke:Celgene: Research Funding. Medeiros:Celgene: Consultancy, Research Funding. Off Label Use: Treatment of AML.

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Clustering of Prognostically Important Cytogenetic Aberrations in Multiple Myeloma with Translocation t(11;14)) (q13;q32)

Blood ◽

10.1182/blood.v120.21.3961.3961 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3961-3961

Author(s):

Luba Trakhtenbrot ◽

Anfisa Stanevsky ◽

Ilya Novikov ◽

Merav Leiba ◽

Arnon Nagler ◽

...

Keyword(s):

Multiple Myeloma ◽

Cluster Analysis ◽

Odds Ratio ◽

Strong Association ◽

P Value ◽

Kappa Statistics ◽

Exact Tests ◽

Cytogenetic Aberrations ◽

Number Of Patients ◽

1Q Gain

Abstract Abstract 3961 The prognostic value of the translocation t(11;14)(q13;q32) in patients (pts) with Multiple Myeloma (MM) is not fully resolved. Using FISH, t(11;14) can be identified in 15–20% of patients with MM and in 15–30% of cases with MGUS. The clustering of prognostically established cytogenetic aberrations (CAs), namely gains of 1q and deletions of 13q,17p, 1p, 16q, as well as deletions of IGH segments, was analyzed by combined morphology and FISH techniques in 94 MM and 8 MGUS pts carrying the t(11;14)(q13;q32) translocation. We used commercially available LSI CCND1, LSI IGH/CCND1, LSI IGH, LSI IGH/MAF and LSI 13 (RB1) probes (Vysis, Downers, Grove, IL)and p53 deletion and CKS1B/CDKN2C amplification/deletion probes (Cytocell Ltd., Cambridge, UK). CAs were not found in MGUS patients and in 37/94 MM patients (39.4%). In 57 MM patients one to five CAs were found: one in 14, two in 21, three in 13, four in 5 and five in 4 patients. The association between different CAs within the group with t(11;14) translocation were studied using the kappa statistics, Odds Ratio and Fisher exact tests. We did cluster analysis of the binary variables (presence/absence) of each of CAs using median linkage with Yule measure of similarity. The Yule measure Y for two aberrations is defined as (ad-bc)/(ad+bc), where “a” is the number of patients with both aberrations, “d” is the number of patients with no one of the two aberrations, and “b” and “c” are the numbers of persons with only one of the aberrations. All calculations were done with STATA 12 SE software. A strong association was found between four CAs: del(13q), del (IGH), del(17p) and del(16q). A high correlation was also found between 1q gain and 1p loss, while correlation of these CAs with the other four CAs was not detected (Tab.1). Cluster analysis led to the identification of a cluster including del(13q), del (IGH), del(17p) and del(16q), while 1p loss and 1q gain were identified as a separate cluster. The apparently close connection between CAs from the same cluster raises the question whether these aberrations occur concurrently as the result of a single oncogenic event. It is possible to suggest that in the oncogenesis of MM with t(11;14) the formation of these clusters is not related and results from different oncogenic events. In conclusion we were able to demonstrate the strong association between del(13q), del (IGH), del(17p) in MM with translocation t(11;14) using a combination of morphology and FISH analyses, that was overlooked in previous investigations. The study of association between CAs additional to t(11;14) in MM patients is important for evaluating the prognostic significance of the combination of CAs and can provide insights into the biology of MM. Table 1. Chi-square exact tests and odds ratio (OR) test for the analysis of coexistence of different CAs Number in pairs* Fisher' P-value CA #1 CA#2 −/− +/− −/+ +/+ Kappa/p-value OR(95%CI) del(13q) del (IGH) 58 7 2 35 0.8145 (<0.0001) 145 (28.5–737.5) <0.001 del(13q) del(17p) 59 35 1 7 0.1797/0.0028 11.8 (1.39–99.95) 0.008 del(13q) loss 1p 55 40 5 2 −0.0408/0.7587 0.55 (0.102–2.98) 0.697 del(13q) gain 1q 51 29 9 13 0.1718/0.0269 2.54 (0.87–7.56) 0.085 del(13q) del(16q) 55 26 5 16 0.3218/0.0879 6.77 (2.04–25.7) <0.001 del (IGH) del(17p) 63 31 2 6 0.1581/0.0088 6.1 (1.16–31.97) 0.025 del (IGH) loss 1p 62 33 3 4 0.0751/0.1170 2.5 (0.53–11.87) 0.252 del (IGH) gain 1q 55 25 10 12 0.1868/0.0221 2.64 (0.9–7.75) 0.078 del (IGH) del(16q) 60 21 5 16 0.392/<0.0001 9.14 (2.7–35.1) <0.001 del(17p) loss 1p 87 8 7 0 −0.079/0.7881 – 1.0 del(17p) gain 1q 76 4 18 4 0.1713/0.0208 4.22 (0.7–24.57) 0.064 del(17p) del(16q) 76 5 18 3 0.1053/0.1083 2.53 (0.36–14.31) 0.356 loss 1p gain 1q 78 2 17 5 0.2687/0.0004 11.47 (1.65–125.5) 0.005 loss 1p del(16q) 76 5 19 2 0.0445/0.2942 1.6 (0.14–10.68) 0.631 gain 1q del(16q) 67 13 14 8 0.2045/0.0194 2.95 (0.87–9.40) 0.070 * Absence(−)/Presence(+) of CA#1/CA#2. Disclosures: Nagler: medac, germany: Research Funding.

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ACE-536 Increases Hemoglobin and Reduces Transfusion Burden in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS): Preliminary Results from a Phase 2 Study

Blood ◽

10.1182/blood.v124.21.411.411 ◽

2014 ◽

Vol 124 (21) ◽

pp. 411-411 ◽

Cited By ~ 10

Author(s):

Uwe Platzbecker ◽

Ulrich Germing ◽

Aristoteles Giagounidis ◽

Katharina Goetze ◽

Philipp Kiewe ◽

...

Keyword(s):

Bone Marrow ◽

Adverse Events ◽

Myelodysplastic Syndromes ◽

Preliminary Data ◽

Research Funding ◽

Nature Medicine ◽

Phase 2 ◽

Employment Equity ◽

Volunteer Study ◽

Equity Ownership

Abstract Introduction. ACE-536, a recombinant fusion protein containing modified activin receptor type IIB and IgG Fc, is being developed for the treatment of anemias due to ineffective erythropoiesis, such as myelodysplastic syndromes (MDS). Patients with MDS often have elevated levels of erythropoietin (EPO) and may be non-responsive or refractory to erythropoiesis-stimulating agents (ESAs). MDS patients have also been shown to have increased serum GDF11 levels (Suragani R et al., Nature Medicine 2014) and increased Smad 2/3 signaling in the bone marrow (Zhou L et al., Blood 2008). ACE-536 binds to ligands in the TGF-ß superfamily, including GDF11, inhibits Smad 2/3 signaling, and promotes late-stage erythroid differentiation via a mechanism distinct from ESAs. RAP-536 (murine version of ACE-536) reduced Smad 2 signaling, increased hemoglobin (Hb) levels and decreased bone marrow erythroid hyperplasia in a mouse model of MDS (Suragani R et al., Nature Medicine 2014). In a healthy volunteer study, ACE-536 was well-tolerated and increased Hb levels (Attie K et al., Am J Hematol 2014). Aims. This is an ongoing, phase 2, multicenter, open-label, dose-finding study to evaluate the effects of ACE-536 on anemia in patients with Low or Int-1 risk MDS who have either high transfusion burden (HTB, defined as ≥4 units RBCs/8 weeks prior to baseline) or low transfusion burden (LTB, defined as <4 units RBCs/8 weeks prior to baseline). Study outcomes include erythroid response (either Hb increase in LTB patients or reduced transfusion burden in HTB patients), safety, tolerability, PK, and PD biomarkers. Methods.Inclusion criteria included Low or Int-1 risk MDS, age ≥ 18 yr, anemia (defined as either being HTB patient or having baseline Hb < 10.0 g/dL in LTB patient), EPO >500 U/L or nonresponsive/refractory to ESAs, no prior azacitidine or decitabine, and no current treatment with ESA, G-CSF, GM-CSF, or lenalidomide. In the dose escalation phase, ACE-536 was administered by subcutaneous (SC) injection once every 3 weeks in 7 sequential cohorts (n=3-6) at dose levels of 0.125, 0.25, 0.5, 0.75, 1.0, 1.33 and 1.75 mg/kg for up to 5 doses with a 3-month follow-up. An expansion cohort (n=30) is planned, and all patients completing this study may enroll in a 12-month extension study. Results. Preliminary data were available for 26 patients (7 LTB/19 HTB) as of 18 Jul 2014. Median age was 71 yr (range: 27-88 yr), 50% were female, 54% had prior EPO therapy and 15% had prior lenalidomide. 69% were WHO subtype RCMD, and the remaining patients were del(5q), RARS, or RAEB-1. Mean (SD) baseline Hgb for the LTB patients (n=7) was 9.1 (0.4) g/dL. Mean (SD) units RBC transfused in the 8 weeks prior to treatment was 0.9 (1.1) units for the LTB patients and 6.3 (2.4) units for the HTB patients. Two of the 7 LTB patients had an increase in mean Hb ≥1.5 g/dL over 8 weeks compared to baseline. Mean maximum Hb increase in the LTB patients was 0.8, 1.0, 2.2, and 2.7 g/dL in the 0.125 (n=1), 0.25 (n=1), 0.75 (n=3), and 1.75 (n=2) mg/kg dose groups, respectively. Six of the 7 LTB patients achieved RBC transfusion independence (RBC-TI) for ≥8 weeks during the study. Six of the 19 HTB patients had a ≥4 unit or ≥50% reduction in RBC units transfused over an 8-week interval during the treatment period compared to the 8 weeks prior to treatment; five of these 6 patients achieved RBC-TI ≥ 8 weeks during the study (range 71-152 days). Increases in neutrophil count following study drug administration were observed in some patients. ACE-536 was generally well tolerated. No related serious adverse events have been reported to date. The most frequent adverse events regardless of causality were: diarrhea (n=4, grade 1/2), bone pain, fatigue, muscle spasms, myalgia, and nasopharyngitis (n=3 each, grade 1/2). Conclusions. Based on preliminary data in Low or Int-1 MDS patients, ACE-536 administered SC every 3 weeks for up to 5 doses increased Hb levels or decreased transfusion requirement, with a favorable safety profile. These data strongly support further evaluation of longer-term treatment with ACE-536 in patients with MDS. Disclosures Platzbecker: Celgene: Honoraria, Research Funding. Germing:Celgene: Honoraria, Research Funding. Goetze:Celgene Corp: Honoraria; Novartis Pharma: Honoraria. Radsak:Celgene: Research Funding. Hankin:Acceleron Pharma: Employment, Equity Ownership. Wilson:Acceleron Pharma: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership. Attie:Acceleron Pharma: Employment, Equity Ownership.

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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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Violence and depression among pregnant women in Egypt

BMC Pregnancy and Childbirth ◽

10.1186/s12884-021-03932-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Hanan M. Ghoneim ◽

Mohamed Elprince ◽

Tamer Yehia M. Ali ◽

Waleed F. Gharieb ◽

Amal A. Ahmed

Keyword(s):

Intimate Partner Violence ◽

Sexual Violence ◽

Partner Violence ◽

Strong Association ◽

Depression Scale ◽

Intimate Partner ◽

University Hospital ◽

P Value ◽

Significant Difference ◽

History Of

Abstract Background Depression is a serious mental health disorder that might affect women in the childbearing period. Incidences increase during pregnancy as well as after delivery. Its association with intimate partner violence (defined as physical, sexual, or psychological harm by a current or former partner) has been reported in many countries. Data about this sensitive issue are lacking in Egypt. The aim of the study was to determine the relation between intimate partner violence and depression during pregnancy. Methods This was a case control study conducted at the outpatient clinics in Suez Canal University hospital, from January 2019 to March 2020. The study included two groups, the study group included women exposed to violence during the current pregnancy and a control one included women with no history of violence. Both groups were recruited according to the predetermined inclusion criteria (women aged 18-45 years, continuous marital relationship, no history of depression in current or previous pregnancies, and singleton pregnancy). Women were asked to complete the Arabic validated NorVold Domestic Abuse Questionnaire (measuring four types of abuse: emotional, physical, sexual, and violence in the health care system, the last one being excluded). Depression was evaluated using the Arabic validated form of the Edinburgh Postnatal Depression Scale (comprises 10 questions that represent patients’ feelings in the last 7 days). The main outcome measure was to assess the association between intimate partner violence and depression. Results We recruited 158 women in each group. Both groups were matched in their demographic characters. Although emotional violence was reported prominently among women exposed to IPV 87.9% (139/158), it was not significantly reported in depressed women (P value 0.084). Physical and sexual violence were significantly reported among depressed women (P value 0.022 and 0.001, respectively). There was a significant difference between women exposed to violence and those who were not exposed to violence in the total depression scores (13.63 ± 5.47 and 10.65 ± 5.44, respectively with a p value < 0.001). Emotional (p value < 0.001) and sexual violence (mild and severe with p value of 0.026 and 0.002 respectively) had significant roles as risk factors for depression during pregnancy in single regression and after control of other confounders. Conclusion There was a strong association between intimate partner violence and depression during pregnancy.

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Abstract TP20: Longer Procedural Times Are Independently Associated with Symptomatic Intracranial Hemorrhage in Large Vessels Occlusion Stroke Patients Undergoing Thrombectomy

Stroke ◽

10.1161/str.44.suppl_1.atp20 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Omar Kass-Hout ◽

Tareq Kass-Hout ◽

Michael R. Frankel ◽

Fadi Nahab ◽

Samir R. Belagaje ◽

...

Keyword(s):

Functional Outcomes ◽

Infarct Volume ◽

P Value ◽

Procedure Time ◽

Entire Cohort ◽

Radiographic Outcomes ◽

Academic Center ◽

Procedural Time ◽

Symptomatic Intracranial Hemorrhage

Background and Purpose: Time to reperfusion is an essential factor in determination of outcomes in (AIS). We sought to establish the effect of the procedural time on the clinical and radiographic outcomes of AIS patients undergoing intra-arterial therapy. Methods: Retrospective review of a prospectively collected database of endovascularly treated large vessel AIS in a large academic center. Data from all consecutive patients who underwent mechanical thrombectomy from September 2010 to July 2012 were analyzed. The variable of interest was procedural time (defined as time from groin puncture to end of procedure). Outcome measures included the rates of symptomatic intracebral hemorrhage (sICH, defined as any parenchymal hematoma e.g. PH-1/PH-2), final infarct volume, 90-day mortality, and independent functional outcomes (modified Rankin Scale, mRS 0-2) at 90 days. Results: The entire cohort included 242 patients with a mean age of 65.5+/- 14.2 and median baseline NIHSS 20. Of the patients 49.38% were females. The median ASPECTS score was 8. The mean procedure time was significantly shorter in patients with good outcome (86.73 vs. 73.13 respectively, P-value: 0.0228). However, after controlling for ASPECTS score, type of retrieval device, TICI score, volume of infarct, interval from symptoms onset to puncture, and co-morbidities, this association did not prove to be significant (P-value = 0.7101). Patients with SICH had significantly higher mean procedure time than patients without SICH (79.65 vs. 104.5 respectively; P-value: 0.0319) which remained significant when controlling to the previous factors (OR = 0.974 with a 95 % CI of (0.957, 0.991). There was no correlation between the volume of infarction and the procedure time (r = 0.10996, P-value: 0.0984). There was no association between procedure time and 90-day mortality (77.8 vs. 88.2 minutes in survivals vs. deaths respectively; P-value: 0.0958). Conclusion: Our data support an association between the risk of SICH and a longer procedure time while no definite association between procedural times and the final infarction volume or long-term functional outcomes was found after adjustment for multiple imbalances.

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Integrated Analysis of Global DNA Methylation and Transcription Reveals a Leukemia Subtype with Extreme Hypermethylation Associated with Silencing of Regulators of Differentiation

Blood ◽

10.1182/blood-2018-99-118521 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2608-2608

Author(s):

Claudia Gebhard ◽

Roger Mulet-Lazaro ◽

Lucia Schwarzfischer ◽

Dagmar Glatz ◽

Margit Nuetzel ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Promoter Methylation ◽

Research Funding ◽

Promoter Hypermethylation ◽

Ctcf Binding ◽

P Value ◽

Global Dna Methylation ◽

Employment Equity ◽

Equity Ownership

Abstract Acute myeloid leukemia (AML) represents a highly heterogeneous myeloid stem cell disorder classified based on various genetic defects. Besides genetic alterations, epigenetic changes are recognized as an additional mechanism contributing to leukemogenesis, but insight into the latter process remains minor. Using a combination of Methyl-CpG-Immunoprecipitation (MCIp-chip) and MALDI-TOF analysis of bisulfite-treated DNA in a cohort of 196 AML patients we previously demonstrated that (cyto)genetically defined AML subtypes, including CBFB-MYH11, AML-ETO, NPM1-mut, CEBPA-mut or IDH1/2-mut subtypes, express specific DNA-methylation profiles (Gebhard et al, Leukemia, 2018). A fraction of AML patients (5/196) displayed a unique abnormal hypermethylation profile that was completely distinct from any other AML subtype. These patients present immature leukemia (FAB M0, M1) with various chromosomal aberrations but very few mutations (e.g. no IDH1/2, KRAS, DNMT3A) that might explain the CpG island methylator phenotype (CIMP) phenotype. The CIMP patients showed high resemblance with a recently reported CEBPA methylated subgroup (Wouters et al, 2007 and Figueroa et al, 2009), which we confirmed by MCIp-chip and MALDI-TOF analysis. To explore the whole range of epigenetic alterations in the CIMP-AML patients we performed in-depth global DNA methylation and gene expression analyses (MCIp-seq and RNA-seq) in 45 AML and 12 CIMP patients from both studies. Principle component analysis and t-distributed stochastic neighbor embedding (t-SNE) revealed that CIMP patients express a unique DNA-methylation and gene-expression signature that separated them from all other AMLs. We could discriminate promoter methylation from non-promoter methylation by selecting MCIp-seq peaks within 3kb around TSS. Promoter hypermethylation was highly associated with repression of genes (PCC = -0.053, p-value = 0.00075). Hypermethylation of non-promoter regions was more strongly associated with upregulation of genes (PCC = 0.046, p-value = 4.613e-06). Interestingly, differentially methylated regions also showed a positive association with myeloid lineage CTCF binding sites (27% vs 18% expected, p-value < 2.2e-16 in a chi-square test of independence). Methylation of CTCF sites causes loss of CTCF binding, which has been reported to disrupt boundaries between so-called topologically associated domains (TADs), allowing enhancers located in a particular TAD to become accessible to genes in adjacent TADs and affect their transcription. Whether this is the case is under investigation. In this study we particularly focused on the role of hypermethylation of promoters in CIMP-AMLs. Promoters of many transcriptional regulators that are involved in the differentiation of myeloid lineages of which several are frequently mutated in AML were hypermethylated and repressed, including CEBPA, CEBPD, IRF8, GATA2, KLF4, MITF or MAFB. Notably, HMGA2, a critical regulator of myeloid progenitor expansion, exhibited the largest degree of CIMP promoter hypermethylation compared to the other AMLs, accompanied by a reduction in gene expression. Moreover, multiple members of the HOXB family and KLF1 (erythroid differentiation) were methylated and repressed as well. In addition, these patients frequently showed hypermethylation of many chromatin factors (e.g. LMNA, CHD7 or TET2). Hypermethylation of the TET2 promoter could result in a loss of maintenance DNA demethylation and therefore successive hypermethylation at CpG islands. We carried out regulome-capture-bisulfite sequencing on CIMP-AMLs compared to other AML samples and normal blood cell controls and confirmed methylation of the same transcription and chromatin factor promoters. We conclude that these leukemias represent very primitive HSCPs which are blocked in differentiation into multiple hematopoietic lineages, due to the absence of regulators of these lineages. Although the underlying cause for the extreme hypermethylation signature is still subject to ongoing studies, the consequence of promoter hypermethylation is silencing of key lineage regulators causing the differentiation arrest in these cells. We argue that these patients may particularly benefit from therapies that revert DNA methylation. Disclosures Ehninger: Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; GEMoaB Monoclonals GmbH: Employment, Equity Ownership; Bayer: Research Funding. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding.

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