High BAALC Expression in Cytogenetically Normal Acute Myeloid Leukemia Strongly Correlates with Adverse Markers Such As RUNX1mut, MLL-PTD and FLT3-ITD and Is Useful for Disease Monitoring

Abstract Abstract 1376 Introduction: BAALC expression is thoroughly explored in cytogenetically normal AML (CN-AML) and has been shown to be associated with an adverse outcome. Nevertheless, its prognostic importance in relation to other molecular markers and its relevance for detection of minimal residual disease (MRD) remains to be defined. The objective of this study was to evaluate the prognostic impact of BAALC expression on clinical outcome in the context of other relevant molecular prognosticators and to examine its utility as a marker for detection of MRD in CN-AML. Patients: BAALC mRNA expression was analyzed in a cohort of 332 patients with de novo CN-AML. The cohort was composed of 169 females (50.9%) and 163 males (49.1%). Age ranged from 18.3 to 64.8 years (median: 52.9). Data on other molecular markers was available in: FLT3-ITD: n=332, NPM1: n=332, RUNX1: n=330, CEBPA: n=332, MLL-PTD: n=332, ASXL1: n=330, FLT3-TKD: n=331, IDH1G105: n=229, IDH1R132: n=253, IDH2: n=232, NRAS: n=254, WT1 mut: n=247, TET2: n=74 and TP53: n=182. In addition, BAALC expression was assessed in 25 follow-up samples of 8 patients in comparison with an established MRD marker. Methods: To assess BAALC mRNA expression levels RQ-PCR was performed by the use of the Applied Biosystems 7500 Fast Real Time PCR System. BAALC expression was normalized against the expression of the control gene ABL1. The median ratio BAALC/ABL1 was used to separate low from high BAALC expressers. Expression data of diagnostic samples was correlated to clinical outcomes and to the presence of molecular mutations. BAALC expression ratios of follow-up samples were also correlated to the status of other molecular markers available in the same patients. Results: 1) Evaluation of prognostic relevance: Expression ratios of BAALC/ABL1 represented a continuum ranging from 0.001 to 80.199 (median: 0.321). In agreement with previous studies, patients with high BAALC expression had shorter overall survival (OS at 3 years: 51.4% vs 73.0%, p=0.046) and event free survival (EFS at 3 years: 38.5% vs 50.6%, p=0.021) as compared to low BAALC expressers. Though, associations of BAALC expression to other molecular markers were found. In high BAALC expressers, as compared to low BAALC expressers, the following mutations were more frequent: RUNX1 mut (32/164, 19.5% vs 2/166, 1.2%, p<0.001), MLL-PTD (22/166, 13.3% vs 5/166, 3.0%, p=0.001) and FLT3-ITDmut/wt ratio>0.5 (51/166, 30.7% vs 24/166, 14.5%, p=0.001), whereas NPM1 mut were less frequent (72/166, 43.3% vs 138/166, 83.1%, p<0.001). In univariable Cox regression analyses shorter OS and EFS was associated with higher age, higher WBC count, high BAALC expression and the presence of at least one of the established adverse markers RUNX1 mut, MLL-PTD, or FLT3-ITDmut/wt ratio>0.5 grouped together as one parameter (OS, p<0.001, <0.001, 0.0048, <0.001, respectively; EFS, p=0.002, <0.001, 0.022, <0.001, respectively). In multivariable models, BAALC expression had an independent impact on EFS (p=0.042) but not on OS. Further, Kaplan Meier analysis within the subgroup with adverse markers (RUNX1 mut, MLL-PTD, or FLT3-ITDmut/wt ratio>0.5, n=98) revealed no additional impact of BAALC expression on OS or EFS. Also within the prognostically favorable subgroup with NPM1 mut/FLT3-ITDmut/wt ratio<0.5 high BAALC expression had no impact on OS or EFS. 2) Validation as follow-up marker: To evaluate the impact of BAALC expression for disease monitoring during follow-up, the BAALC/ABL1 ratio of high BAALC expressers was compared to the %MLL-PTD/ABL1 or %RUNX1 mut levels in patients who had at least one of these aberrations in parallel. In total, 33 diagnostic and follow-up samples of 8 patients were analyzed. Comparison of BAALC/ABL1 ratios to mutational status of MLL-PTD and/or RUNX1 revealed a significant correlation (r=0.577, p<0.001). Additionally, in one case with paired samples at diagnosis and relapse, BAALC expression levels at diagnosis and at relapse were in the same range (BAALC/ABL1: 10.870 vs 17.600). Conclusion: 1) BAALC expression in CN-AML predicts an adverse clinical outcome, but is associated with other well established prognostic markers. Thus, in our study BAALC expression had no independent prognostic impact on OS when analyzed together with RUNX1, MLL-PTD, FLT3-ITD and NPM1. 2) Correlation of BAALC expression with MLL-PTD and RUNX1 during follow up indicates that BAALC expression is a potential target for MRD monitoring. Disclosures: Weber: MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Eder:MLL Munich Leukemia Laboratory: Employment. Dicker:MLL Munich Leukemia Laboratory: Employment. Jeromin:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Fasan:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership.

Download Full-text

Impact of the cardio-hepatic syndrome on outcomes after transcatheter mitral valve edge-to-edge repair

European Heart Journal ◽

10.1093/eurheartj/ehab724.2217 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

L Stolz ◽

M Orban ◽

N Karam ◽

E Lubos ◽

M Wild ◽

...

Keyword(s):

Liver Function ◽

Cox Regression ◽

Cox Model ◽

Hepatic Function ◽

Gamma Glutamyl Transferase ◽

Prognostic Impact ◽

Laboratory Parameters ◽

Glutamyl Transferase ◽

The Impact

Abstract Background The prognostic value of impaired liver function in the presence of moderate-to-severe and severe mitral regurgitation (MR), also called cardio-hepatic syndrome (CHS), for outcomes in patients undergoing transcatheter edge-to-edge repair (TEER) has not been studied yet. Purpose In this work, we aimed at identifying the prognostic impact of the CHS on two-year all-cause mortality in patients undergoing TEER compared to established risk factors. Furthermore, we evaluated the change in hepatic function after TEER. Methods Hepatic function was assessed by laboratory parameters of liver function (bilirubin, gamma glutamyl transferase [GGT], alkaline phosphatase [AP], aspartate and alanine aminotransferase [AST and ALT]). We defined CHS as elevation of at least two out of three laboratory parameters of hepatic cholestasis (bilirubin, GGT, AP). The impact of CHS on two-year mortality was evaluated using a proportional hazards Cox model. The change in hepatic function after TEER was evaluated by repeat laboratory testing at follow-up. Results We included 1083 patients who underwent TEER for highly symptomatic primary or secondary MR at four high volume academic European centers between 2008 and 2019. In 66.4% of patients, we observed elevated levels of either bilirubin, GGT or AP. CHS was present in 23% of patients and showed strong association with a reduced two-year survival (52.9% vs. 87.0% in patients without CHS, p<0.01). In a multivariate Cox regression model, CHS was identified as a strong and independent predictor of increased two-year mortality (hazard ratio 1.49, p=0.03). In patients with successful MR reduction ≤2+ (90.7% of patients), parameters of hepatic function significantly improved from baseline to follow-up (−0.2 mg/dl for bilirubin; −21 U/l for GGT, respectively, p<0.01), while they did not in case of residual postprocedural MR >2+. Conclusions CHS can be observed in up to 25% of patients undergoing TEER and is associated with impaired two-year survival rates. Successful TEER is associated with decreased levels of hepatic enzymes at follow-up evaluation. FUNDunding Acknowledgement Type of funding sources: None. Cardio-hepatic syndrome TEER

Download Full-text

Characterization and Prognostic Impact of Multiple Productive IGHV Rearrangements in CLL

Blood ◽

10.1182/blood.v128.22.3207.3207 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3207-3207

Author(s):

Sabine Jeromin ◽

Claudia Haferlach ◽

Frank Dicker ◽

Manja Meggendorfer ◽

Torsten Haferlach ◽

...

Keyword(s):

Prognostic Factors ◽

Lymphocytic Leukemia ◽

Prognostic Impact ◽

Employment Equity ◽

Mutational Status ◽

Treatment Naïve ◽

Trisomy 12 ◽

Equity Ownership ◽

The Impact

Abstract Background: In chronic lymphocytic leukemia (CLL) one of the strongest prognostic factors is IGHV mutational status. Infrequently, patients present not only with a single IGHV rearrangement but with multiple productive rearrangements. In about 2% of all CLL patients analyzed on cDNA level multiple rearrangements display the same mutational status and are categorized accordingly following ERIC recommendations. In another 1% rearrangements with discordant IGHV mutational status are detected and preclude a definite risk assignment. Only limited data exist on these rare subgroups. Aim: To characterize treatment-naive CLL patients with multiple productive IGHV rearrangements and determine the impact on prognosis. Patients and Methods: Out of 8,016 treatment-naive CLL patients between 2005 and 2015 and with data on IGHV mutational status we identified 204 (3%) with multiple productive rearrangements. IGHV mutational status was analyzed on cDNA and in all cases according to ERIC recommendations. IGHV mutated status (M) was defined by sequence identity <98% and unmutated status (U) by ≥98%. Chromosome banding analysis was available in 102 cases and interphase FISH with probes for 17p13, 13q14, 11q22 and centromeric region of chromosome 12 in 191. Male:female ratio was 3:1 and median age 68 years (range: 38-89). Additionally, data on SF3B1 and TP53 mutations was present in all cases. Follow-up data on time to first treatment (TTT) and overall survival (OS) was available in 105 cases with a median follow-up of 4 years. For statistical comparison we used a cohort of 1,262 untreated CLL patients with single IGHV rearrangement (median age: 67 years; range: 30-91, median follow-up: 6 years). Results: Out of 204 patients with multiple, productive rearrangements 199 (98%) presented with two and 5 patients (2%) with three IGHV rearrangements. Concordant IGHV mutated status (MM) was present in 120 cases (59%), whereas concordant unmutated status (UU) was seen in 34 patients (17%). In 50 cases (25%) a mixed IGHV status (UM) was detected. We analyzed frequencies of complex karyotype by CBA, biclonality according to immunophenotype (concurrent kappa restricted and lambda restricted subpopulations) and/or CBA, TP53 disruption (TP53mut and/or del(17p)), SF3B1mut, del(11q), trisomy 12, and del(13q). Overall, a higher frequency of biclonality was detected in patients with multiple vs. single IGHV rearrangements (16% vs. 1%, p<0.001). However, association to neither MM, UU nor UM existed. MM presented with molecular and cytogenetic characteristics similar to M. Correspondingly, UU showed similar frequencies of mutations and aberrations to U, except for higher frequency of trisomy 12 in UU vs. U (42% vs. 19%, p=0.003). Interestingly, UM presented with characteristics similar to U and UU. UM was associated with TP53 disruption vs. M (16% vs. 5%, p=0.003) and vs. MM (5%, p=0.035) as well as with SF3B1mut vs. M (16% vs. 5%, p=0.008). Furthermore, UM cases showed high frequency of del(11q) vs. M (29% vs. 3%, p<0.001) and vs. MM (1%, p<0.001) and less frequently del(13q) sole vs. M (41% vs. 60%, p=0.011) and MM (41% vs. 69%, p=0.001). No significantly differences in TTT were observed between MM and M (median: 13 vs. 14 years) and between UU and U (6 vs. 4 years), respectively. However, the difference between MM vs. UU (p=0.022) and M vs. U (p<0.001) was significant. The UM subgroup presented with a TTT (median: 4 years) similar to U and UU, whereas it was significantly shorter vs. M (p=0.003) and MM (p=0.006), respectively. A similar picture emerged for survival. 5-year OS of MM was not different vs. M (94% vs. 90%) but vs. U (78%, p=0.001). The statistical analysis of OS in UU was hampered by low case numbers. UM presented again with similar 5-year OS vs. U (81% vs. 78%, n.s.) and significantly worse OS vs. M (90%, p=0.049) and vs. MM (94%, p=0.014). Conclusions: (1) Patients with multiple productive IGHV rearrangements and concordant IGHV status show similar prognosis and characteristics to patients with single rearrangement with the respective IGHV status. (2) Cases with mixed IGHV status show similar prognosis to patients with IGHV unmutated status and accordingly are characterized by high frequencies of adverse prognostic factors like TP53 disruption, SF3B1mut, and del(11q), whereas del(13q) sole is less frequent. Disclosures Jeromin: MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Dicker:Munich Leukemia Laboratory: Employment. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Download Full-text

High WT1 Expression Has An Independent Positive Influence On CR Rate and EFS in Non M3 AML Patients Treated with Chemotherapy.

Blood ◽

10.1182/blood.v114.22.4675.4675 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4675-4675

Author(s):

Nicoletta Colombo ◽

Raffaella Grasso ◽

Maurizio Miglino ◽

Marino Clavio ◽

Gianmatteo Pica ◽

...

Keyword(s):

Regression Model ◽

Prognostic Value ◽

Cox Regression ◽

Conflicts Of Interest ◽

Categorical Variables ◽

P Value ◽

Prognostic Impact ◽

Chi Square Analysis ◽

The Impact

Abstract Abstract 4675 The prognostic value of WT1 expression at diagnosis is still controversial. It has been retrospectively evaluated in 99 consecutive non pretreated non M3 AML patients who had undergone a complete prognostic work up at diagnosis and had received intensive chemotherapy. Biological markers were evaluated on fresh marrow samples collected at diagnosis. WT1 expression was evaluated using TaqMan Gene Expression Assays as described. All patients received induction therapy with combination of fludarabine, Ara-C and anthracycline ± low dose gemtuzumab ozogamicin (n. 59) or with a conventional combination of Ara-C and anthracycline (n. 40) A conventional post-induction chemotherapy including intermediate dosage Ara-C was administered to all responding patients. Univariate comparisons between patients in CR vs non CR were performed using chi-square analysis or Fisher's exact test for categorical variables and t-test for continuous variables. P values < 0.05 were considered statistically significant. Analyses were performed using SPSS. The prognostic impact of WT1 expression was evaluated using quartiles as cut off point and selecting the one with the lowest p value. The event free survival and OS were calculated using the Kaplan Meier method. Non CR after the first induction course, relapse and death due to any cause were considered events. OS and EFS duration were calculated from start of treatment. The impact of multiple predictor variables was assessed by multivariate analyses according to the Cox regression model for OS and EFS while for the evaluation of RC was used the Logistic regression model. Median age of patients was 59 years (range 17-81). Cytogenetic alterations were prognostically favorable in 3 patients and belonged to the intermediate prognostic group in 77 patients (normal karyotype in 75 patients and +8 in two). Nineteen patients had a poor prognosis cytogenetics. For statistical analyses we considered two karyotipic groups: unfavorable (19 patients) and not unfavorable (80 patients). CRs were 60/99 (60%), of which 40 in 51 patients aged 60 or less (78%) and 20 in 48 older than 60 years (41%). Twenty-six patients relapsed, 54 are alive, 45 have died, with a median follow up of 360 days (range 20-2300). In Table 1 are reported clinical indicators of outcome being patients grouped according to the percentile of WT1 expression with the lowest p value (75th). Statystical analysis showed that all WT1 quartiles were balanced for other prognostic factors, such as cytogenetics, BAALC expression, FLT3 and NPMA and B mutations, age, blast count and therapy. The lack of consense on the role of WT1 level at diagnosis in the prognostic stratification indicate that further clinical studies are required. The clear correlation between the level of WT1 transcript and the tumor burden explains why WT1 is used in the follow up of leukemic patients as universal marker of residual disease, also in patients with specific chimeric products. On the contrary, the biological explanation of the prognostic impact of WT1 transcript level at diagnosis remains uncertain. Over the years WT1 gene has been considered as an oncogene or a tumor suppressor gene. In our experience the protective influence of high WT1 expression cannot be explained with an association with good prognosis biological features (such as mut NPM and / or low BAALC). The positive prognostic value of high WT1 expression might be implicated either with WT1 antioncogenic function, or with the stimulating effect of WT1 oncogene on leukemic cellular cycle, possibly associated with an enhanced response to chemotherapy.Table 1WT1 <= 2400 N./N.pts (%)WT1 > 2400 N./N.pts (%)p univ,p multiv.*RR (95% CI)CR (all karyotypes)41/ 75 (54)19/24 (82)0,0260.063.364 (0.927-12.202)CR (int/good karyot.)36/59 (61)19/210.010,0276.649 (1.240-35.645)CR (denovo AML int kar)31/45 (69)14/15 (98)0.020,03412.557 (1.218-129.446)CR (denovo, N.K.)26/40 (65)15/16 (94)0.0250.0413.430 (1.111-162.318)EFS at 24 months (all karyotypes)8%6%0.0020.050.486 (0.235-1.007)EFS at 24 months (int / good karyot.)9%64%0.0010.0230.360 (0.150-0.866)EFS at 24 months (de novo, N.K.)5%70%0.0010.0070.227 (0.077-0.671)OS (all karyot)15%55%0,110,660.837 (0.371-1.890)OS (int/good kar.)18%63%0,050,180.507 (0.186-1.381)Table 1 legend: * for multivariate analysis age, karyotype, FLT3, NPM mutation, BAALC expression, denovo/secondary disease were considered. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

ERG Overexpression Is Highly Associated With ERG Gene Amplifications In Patients With Myeloid Malignancies

Blood ◽

10.1182/blood.v122.21.3744.3744 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3744-3744

Author(s):

Simone Weber ◽

Claudia Haferlach ◽

Louisa Noel ◽

Tamara Alpermann ◽

Wolfgang Kern ◽

...

Keyword(s):

Molecular Markers ◽

Mrna Expression ◽

De Novo ◽

Chromosome 21 ◽

Adverse Impact ◽

Employment Equity ◽

Expression Levels ◽

Myeloid Malignancies ◽

Copy Numbers ◽

Equity Ownership

Abstract Background The proto-oncogene ERG is located on chromosome 21q22 and overexpression of ERG was shown to have an adverse impact on outcome in cytogenetically normal AML (CN-AML). Acquired gain of chromosome 21 (+21) is a recurrent cytogenetic abnormality in AML, however, the pathogenetic impact remains elusive. Data indicate that +21 could be the underlying mechanism for altered expression of genes located in the respective regions, such as ERG, which might contribute to the pathogenesis in myeloid malignancies with +21. Aims 1) To investigate a possible relationship between ERG copy numbers and variations in ERG mRNA expression levels in patients (pts) with myeloid malignancies. 2) Analysis of ERG expression in CN-AML to reveal a possible association between ERG overexpression and other relevant molecular markers and to ascertain the prognostic impact of ERGin context of these markers. Methods ERG mRNA expression and ERG copy numbers were analyzed using a hydrolysis probe based real-time PCR assay. 1) To address ERG expression in relation to +21 the following cohorts were analyzed: 62 AML pts with a complex karyotype including +21 (CK+21); 44 AML pts with a non-complex aberrant karyotype including +21 (AK+21); 19 pts with various myeloid malignancies (10 de novo AML, 3 MDS, 1 s-AML, 2 t-AML, 1 MDS/AML, 1 t-MDS, 1 MDS/MPN) all of them showing ERG amplification by interphase FISH and array CGH (ERG-Amp). In addition, 32 CK-AML and 330 CN-AML pts without +21 or ERGamplification were analyzed. Results were expressed as mean values±SEM. Expression levels/DNA copy numbers were compared by t-test. 2)ERG expression was assessed in a cohort of 330 patients (<65 years) with de novo CN-AML. Female/male ratio was 169/161. To distinguish low from high ERG expressers the median %ERG/ABL1 level was used. BAALC expression levels were analyzed accordingly. Expression levels were correlated with clinical outcome and with the presence of mutations (mut) in ASXL1 (n=330), CEBPA (n=330), DNMT3A (n=261), FLT3-TKD (n=330), IDH1R132 (n=328), IDH2R140 (n=328), IDH2R172 (n=328), NPM1 (n=330), NRAS (n=330), RUNX1 (n=329), TET2 (n=166), WT1 (n=329) and FLT3-ITD (n=330), and with MLL-PTD (n=330) and BAALCexpression (n=328). Results 1) Analysis of pts with +21 or ERG-Amp revealed significantly higher expression levels of ERG in pts with +21 (AK+21 and CK+21 combined, 331 ± 28) and ERG-Amp (606 ± 127) as compared to pts with CN-AML (229 ± 10; p=0.001, p=0.008, respectively) or CK-AML (177 ± 36; p=0.001, p=0.004, respectively). Mean ERG expression was even higher in pts with ERG-Amp (606 ± 127) as compared to pts with +21 (331 ± 28, p=0.047). Quantification of ERG copy numbers on DNA level showed good correlation to ERG mRNA expression, with abundantly higher ERG DNA amount in +21 (3.25 ±0.14) and moreover in ERG-Amp (9.21 ±1.05) as compared to CN-AML and CK-AML (combined: 2.20 ± 0.05; p<0.001 and p<0.001, respectively). 2) In CN-AML, %ERG/ABL1 levels ranged from 0.078 to 1,016.027 (median: 188.904). High ERG expression was associated with lower age (mean: 48.7 vs. 52.4 years, p=0.002), higher white blood cell (WBC) count (mean: 64.8 vs. 44.4 x 109/L, p=0.019), FLT3-ITDmut/wt ratio≥0.5 (51/165, 30.9% vs. 24/165, 14.5%, p=0.001), IDH2R172mut (6/164, 3.7% vs. 0/164, 0.0%, p=0.030) and high BAALC expression (104/164, 63.4% vs. 59/164, 36.0%, p<0.001), as compared to low ERG expression. In contrast, NPM1mut (91/165, 55.2% vs. 118/165, 71.5%, p=0.003), IDH1R132mut (10/165, 6.1% vs. 29/163, 17.8%, p=0.001) and TET2mut (10/76, 13.2% vs. 22/90, 24.4%, p=0.077) were less frequent in high ERG expressers. Survival analysis revealed inferior overall survival (OS at 3 years: 52.2% vs. 68.7%, p=0.021) and event free survival (EFS at 3 years: 34.6% vs. 43.1%, p=0.052) for high ERG expressers as compared to low ERG expressers. In a multivariate analysis adjusted for age, WBC, BAALC expression, FLT3-ITDmut/wt ratio≥0.5, MLL-PTD and WT1mut, high ERG expression revealed a trend towards an adverse impact on OS (p=0.069), while no impact on EFS was observed. Conclusions 1) Gain of chromosome 21 and especially amplification of chromosomal band 21q22 is a mechanism for ERG overexpression. This might indicate ERG as an important factor contributing to the pathogenesis and progression of myeloid malignancies with gain of chromosome 21. 2) In CN-AML, ERG overexpression is associated to several molecular markers and has a negative impact on OS and EFS. Disclosures: Weber: MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Noel:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Download Full-text

A Study on the Prognosis of Patients Relapsing after Autologous Stem Cell Transplantation (auto-SCT) for Follicular Lymphoma (FL): The Impact of Remission Duration.

Blood ◽

10.1182/blood.v108.11.3064.3064 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3064-3064

Author(s):

Julia Stumm ◽

Jens Dreyhaupt ◽

Martin Kornacker ◽

Manfred Hensel ◽

Michael Kneba ◽

...

Keyword(s):

Cox Regression ◽

Treatment Time ◽

Salvage Treatment ◽

Prognostic Impact ◽

Post Transplant ◽

Kaplan Meier ◽

Cox Analysis ◽

Time To Relapse ◽

The Impact

Abstract Although auto-SCT has been in use for treatment of advanced FL since many years, little is known about the course of those who relapse after this procedure. Because these patients may be candidates for aggressive salvage approaches, we sought to study the outcome of patients with FL relapsing after auto-SCT with particular focus on factors predicting for survival. Methods: Relapse cases were identified retrospectively from 244 patients autografted for FL between August 1990 and November 2002 in 3 institutions. Overall survival after relapse (OS) was calculated according to Kaplan-Meier and analyzed for the prognostic impact of pre-relapse variables as well as of post-relapse salvage treatment by univariate log rank comparisons and Cox regression analyses. Results: With a median follow-up of 88 (5–186) months post auto-SCT, 104 relapses occurred, corresponding to a 10-year relapse probability of 0.47 (95%CI 0.4–0.53). Median age of relapsed patients was 48 (22–65) years. FLIPI score at diagnosis was low in 18%, intermediate in 58%, and high in 24%. In 51%, auto-SCT had been given as part of first-line treatment, and 45% had been in complete remission at auto-SCT. Myeloablation included total body irradiation (TBI) in 57% of the cases. Median time from auto-SCT to relapse was 19 (2–128) months, with only 2 relapses occurring later than 6 years post transplant. Transformed FL was present in 14% of those 87 patients who had relapse histology available. Rituximab-containing salvage therapy was given to 50% of the patients after relapse. With 45 (1–139) months of follow-up, median OS after relapse was 100 months. Log rank comparisons identified auto-SCT as part of salvage treatment, time to relapse <12 months, and salvage without rituximab as factors adversely influencing OS, while all other variables listed above had no impact. Cox analysis considering sex, age, salvage auto-SCT, TBI, time to relapse, and rituximab salvage confirmed a possible adverse impact of time to relapse <12 months (hazard ratio 2.58 (95%CI 0.99–6.82); p 0.055) but none of the other covariates on OS. Conclusions: The prognosis of patients relapsing after auto-SCT for FL is surprisingly good. However, those whose disease recurs within the first post-transplant year tend to have a dismal outcome and might benefit from experimental salvage approaches, such as allogeneic SCT.

Download Full-text

In Chronic Lymphocytic Leukemia the Gain of the Short Arm of Chromosome 2 Is Highly Associated with an Unmutated IGHV status, 11q/ATM Deletion, SF3B1 Mutation and a Complex Karyotype

Blood ◽

10.1182/blood.v128.22.4379.4379 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4379-4379

Author(s):

Claudia Haferlach ◽

Sabine Jeromin ◽

Anna Stengel ◽

Manja Meggendorfer ◽

Melanie Zenger ◽

...

Keyword(s):

Multivariate Analysis ◽

Cox Regression ◽

Prognostic Impact ◽

Chromosome 2 ◽

Complex Karyotype ◽

Employment Equity ◽

Cox Regression Analysis ◽

Tp53 Mutations ◽

Equity Ownership

Abstract Background: CLL is characterized by a distinct pattern of translocations, genomic gains and losses and molecular mutations. The most frequent abnormalities such as trisomy 12 and deletions of 6q, 11q, 13q and 17p have been intensively studied. However, data on less frequent recurrent abnormalities such as the partial gain of the short arm of chromosome 2 is lacking. Aims: a) Determine the frequency of 2p gain in CLL, b) Characterize the size and the commonly gained region, c) Analyze the spectrum of additional cytogenetic abnormalities and molecular mutations, and d) Evaluate the prognostic impact. Patients and Methods: Chromosome banding analysis (CBA) revealed a gain of 2p in 113 out of 5564 (2%) CLL cases. In 72 cases with sufficient material genomic array analysis (SurePrint G3 ISCA CGH+SNP Microarray, Agilent, Waldbronn, Germany) and determination of the mutation status of TP53, SF3B1 and IGHV were performed. Results:76% of patients with gain of 2p were male. The median WBC count was 33,700/µL (range: 5,900 - 228,000). Median age was 66 years (range: 29 - 87). The gain of 2p always encompassed the 2p telomere (2pter) while the centromeric border of the 2p gain varied between 2p21 and the centromere of chromosome 2 (2p10) (genomic positions 45,859,076 to 92,297,003). The gain of 2p was the sole chromosomal abnormality in only 8/72 cases (11%) and was accompanied by one, two or more than two additional aberrations in 10, 20, and 34 cases. In total 209 chromosome abnormalities were observed in addition to the 2p gain (median per patient: 2, range: 0-16). Of these only 21 were balanced while 188 were unbalanced abnormalities leading to gain or loss of chromosomal material. Gain of 2p was most frequently accompanied by deletions in 13q (total: 74%, homozygous: 11%), 11q (56%), 18p (18%), and 6q (13%) and gains of 8q (11%). 17p deletions were present in 6% of cases. In 49 cases (68%) the gain of 2p was present in the main clone while it was present in a subclone only in 23 cases (32%). The gain of 2p material was due to a duplication in the short arm of chromosome 2 in 10 cases, while a gain of an isochromosome 2p was present in 3 cases. In the remaining cases material of the short arm of chromosome 2p was attached to a variety of different partner chromosomes. The most frequent acceptor chromosome was chromosome 18 (n=13; 18%). In two cases (2%) 2 IGH rearrangements were observed of which one was mutated and the other unmutated. The IGHV status was unmutated (IGHV-U) in 66 (92%) and mutated in only 4 cases (6%). Three of these 4 cases with mutated IGHV showed only a low mutation rate (sequence homology to germline 97-97.9%). Stereotyped B-cell receptors were present in 14 cases (19%). SF3B1 mutations were observed in 21 cases (29%) with a median mutation load (ML) of 39% (range: 10-51%). TP53 mutations were detected in 8 (11%) cases (median ML: 60%, range: 13-100%). In 2 patients with a TP53 mutation a TP53 deletion was present and in 3 cases a copy neutral loss of heterozygosity (CN-LOH) of 17p was detected leading to TP53 wild-type loss in these 5 cases. TP53 mutations were less frequent in cases harboring the gain of 2p as the sole abnormality (3% vs 21%, p=0.02) The prognostic impact of 2p gain was evaluated in an unselected cohort of 1381 CLL cases with available follow up data (median follow up: 5.1 years) including 22 cases with 2p gain. The frequency of IGHV-Ustatus, SF3B1 mutations and 11q/ATM deletions was significantly higher in CLL with 2p gain compared to cases without (for all p<0.05). In univariate Cox regression analysis gain of 2p was significantly associated with shorter overall survival (OS) (relative risk (RR): 2.1; p=0.05). 5 year OS was 69% in CLL with 2p gain compared to 85% in cases without 2p gain (p=0.05). However, in multivariate analysis only IGHV-U, mutations in SF3B1 and TP53 and TP53/17p deletion were independently associated with shorter OS, while gain of 2p and 11q/ATM deletion were not. 2p gain was associated with shorter time to treatment (TTT) (RR: 2.0; p=0.02). In multivariate analysis only IGHV-U, SF3B1 mutation and 11q/ATM and TP53/17p deletion were independently associated with shorter TTT, while gain of 2p and TP53 mutations were not. Conclusions:CLL with gain of 2p is highly associated with an unmutated IGHV status (92%), a high frequency of 11q/ATM deletion (56%), 13q deletion (74%), SF3B1 mutation (29%) and a complex karyotype (47%). Data suggest that gain of 2p is a later event in CLL pathogenesis and might be a marker of progression. Disclosures Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Jeromin:MLL Munich Leukemia Laboratory: Employment. Stengel:MLL Munich Leukemia Laboratory: Employment. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Zenger:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Download Full-text

The impact of statin therapy after surgical or endovascular treatment of cerebral aneurysms

Journal of Neurosurgery ◽

10.3171/2019.3.jns183500 ◽

2020 ◽

Vol 133 (1) ◽

pp. 182-189

Author(s):

Tae-Jin Song ◽

Seung-Hun Oh ◽

Jinkwon Kim

Keyword(s):

Statin Therapy ◽

Coil Embolization ◽

Primary Outcome ◽

Cox Regression ◽

Cerebral Aneurysms ◽

Time Dependent ◽

Lipid Lowering ◽

Surgical Clipping ◽

The Impact

OBJECTIVECerebral aneurysms represent the most common cause of spontaneous subarachnoid hemorrhage. Statins are lipid-lowering agents that may expert multiple pleiotropic vascular protective effects. The authors hypothesized that statin therapy after coil embolization or surgical clipping of cerebral aneurysms might improve clinical outcomes.METHODSThis was a retrospective cohort study using the National Health Insurance Service–National Sample Cohort Database in Korea. Patients who underwent coil embolization or surgical clipping for cerebral aneurysm between 2002 and 2013 were included. Based on prescription claims, the authors calculated the proportion of days covered (PDC) by statins during follow-up as a marker of statin therapy. The primary outcome was a composite of the development of stroke, myocardial infarction, and all-cause death. Multivariate time-dependent Cox regression analyses were performed.RESULTSA total of 1381 patients who underwent coil embolization (n = 542) or surgical clipping (n = 839) of cerebral aneurysms were included in this study. During the mean (± SD) follow-up period of 3.83 ± 3.35 years, 335 (24.3%) patients experienced the primary outcome. Adjustments were performed for sex, age (as a continuous variable), treatment modality, aneurysm rupture status (ruptured or unruptured aneurysm), hypertension, diabetes mellitus, household income level, and prior history of ischemic stroke or intracerebral hemorrhage as time-independent variables and statin therapy during follow-up as a time-dependent variable. Consistent statin therapy (PDC > 80%) was significantly associated with a lower risk of the primary outcome (adjusted hazard ratio 0.34, 95% CI 0.14–0.85).CONCLUSIONSConsistent statin therapy was significantly associated with better prognosis after coil embolization or surgical clipping of cerebral aneurysms.

Download Full-text

POS0941 IN SPONDYLOARTHRITIS PATIENTS THE PRESENCE OF COMORBIDITIES IS AN INDEPENDENT PREDICTOR OF INSUFFICIENT RESPONSE TO THERAPY WITH BIOLOGIC AGENTS AND TREATMENT DISCONTINUATION

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.4222 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 733.2-734

Author(s):

I. Flouri ◽

N. Kougkas ◽

N. Avgustidis ◽

A. Repa ◽

A. Eskitzis ◽

...

Keyword(s):

Clinical Practice ◽

Disease Duration ◽

Cox Regression ◽

Independent Predictor ◽

Response To Therapy ◽

Treatment Discontinuation ◽

Randomized Controlled Studies ◽

Insufficient Response ◽

The Impact

Background:Long-term observational studies of patients under biologic disease-modifying anti-rheumatic drug (bDMARD) therapies in routine clinical practice can provide us with important data regarding patients with comorbidities, who are usually excluded from randomized controlled studies.Objectives:To study the impact of comorbidities in the outcome (response and persistence to therapy) of patients with spondyloarthritis (SpA) receiving bDMARDs in real-world clinical practice.Methods:Prospective study of all patients who start a bDMARD in a tertiary centre University Hospital after their consent. All patient comorbidities [among a list of approximately 100 pre-specified major comorbidities] are registered by treating physicians at baseline and during follow-up.Comorbidities were studied as total Comorbidities Count (CC) and rheumatic disease comorbidity index (RDCI). Statistical analyses were performed using logistic and Cox regression models, adjusting for the potential confounding of age, sex, disease duration, diagnosis (axial vs. peripheral SpA), number of previous conventional synthetic and biologic DMARDs, year of therapy start, and co-administered methotrexate and corticosteroids (yes/no). Analyses of response to therapy also included baseline BASDAI or ASDAS indices as confounding variables.Results:A total of 603 biologic treatments (1st: 298, 2nd: 157, ≥3rd: 148) were analyzed. Half (51%) of the patients were female, 413 patients had axial SpA (AxSpA) and 190 peripheral SpA (perSpA). At baseline, median (IQR) age: 48 (38-57) years, disease duration: 11 (4-19) years, CC: 2 (1-4) and RDCI: 1 (0-2). Both comorbidity indices were significantly higher in perSpA compared to AxSpA (p<0.001).At 6 months of therapy, 31% of patients with AxSpA achieved BASDAI50 and 39% had ASDAS-ESR < 2.1. Higher CC was an independent predictor of insufficient response according to BASDAI50 [OR (95%) = 0.70 (0.52-0.94), p=0.019] and higher RDCI was predicting failure to achieve ASDAS-ESR < 2.1 [OR (95%) = 0.59 (0.37-0.94), p=0.027]. Other independent predictors of non-response were age, longer disease duration and (for ASDAS-ESR<2.1) higher baseline disease activity.During 1405 patient-years of follow-up, 349 (58%) treatments were discontinued. The adjusted hazard ratio for bDMARD discontinuation within the first 2 years of treatment due to insufficient response was doubled in patients with CC ≥2 versus those with CC ≤1 [HR = 2.27 (1.14-4.53), p=0.020] or with RDCI ≥1 (vs. RDCI = 0) [HR = 2.23 (1.22-4.07), p=0.009]. Comorbidities’ indices were not significant predictors of treatment discontinuations due to adverse events.Conclusion:The presence of comorbidities in patients with SpA is an independent predictor for insufficient 6-month response to bDMARDs and resultant treatment discontinuation due to failure.Acknowledgements:This research is co-financed by Greece and the European Union (European Social Fund- ESF) through the Operational Programme «Human Resources Development, Education and Lifelong Learning» in the context of the project “Reinforcement of Postdoctoral Researchers - 2nd Cycle” (MIS-5033021), implemented by the State Scholarships Foundation (ΙΚΥ).Disclosure of Interests:None declared

Download Full-text

Concomitant tricuspid regurgitation severity and its secondary reduction determine long-term prognosis after transcatheter mitral valve edge-to-edge repair

Clinical Research in Cardiology ◽

10.1007/s00392-020-01798-4 ◽

2021 ◽

Author(s):

Martin Geyer ◽

Karsten Keller ◽

Kevin Bachmann ◽

Sonja Born ◽

Alexander R. Tamm ◽

...

Keyword(s):

Tricuspid Regurgitation ◽

Survival Data ◽

Common Finding ◽

Prognostic Impact ◽

Term Survival ◽

Long Term Prognosis ◽

The Impact ◽

Symptomatic Benefit

Abstract Background Concomitant tricuspid regurgitation (TR) is a common finding in mitral regurgitation (MR). Transcatheter repair (TMVR) is a favorable treatment option in patients at elevated surgical risk. To date, evidence on long-term prognosis and the prognostic impact of TR after TMVR is limited. Methods Long-term survival data of patients undergoing isolated edge-to-edge repair from June 2010 to March 2018 (combinations with other forms of TMVR or tricuspid valve therapy excluded) were analyzed in a retrospective monocentric study. TR severity was categorized and the impact of TR on survival was analysed. Results Overall, 606 patients [46.5% female, 56.4% functional MR (FMR)] were enrolled in this study. TR at baseline was categorized severe/medium/mild/no or trace in 23.2/34.3/36.3/6.3% of the cases. At 30-day follow-up, improvement of at least one TR-grade was documented in 34.9%. Severe TR at baseline was identified as predictor of 1-year survival [65.2% vs. 77.0%, p = 0.030; HR for death 1.68 (95% CI 1.12–2.54), p = 0.013] and in FMR-patients also regarding long-term prognosis [adjusted HR for long-term mortality 1.57 (95% CI 1.00–2.45), p = 0.049]. Missing post-interventional reduction of TR severity was predictive for poor prognosis, especially in the FMR-subgroup [1-year survival: 92.9% vs. 78.3%, p = 0.025; HR for death at 1-year follow-up 3.31 (95% CI 1.15–9.58), p = 0.027]. While BNP levels decreased in both subgroups, TR reduction was associated with improved symptomatic benefit (NYHA-class-reduction 78.6 vs. 65.9%, p = 0.021). Conclusion In this large study, both, severe TR at baseline as well as missing secondary reduction were predictive for impaired long-term prognosis, especially in patients with FMR etiology. TR reduction was associated with increased symptomatic benefit. Graphic abstract

Download Full-text

H3K27M-mutant Diffuse Midline Gliomas should be Further Molecularly Stratified: An Integrated Analysis of 669 Patients

10.21203/rs.3.rs-949930/v1 ◽

2021 ◽

Author(s):

Huy Gia Vuong ◽

Hieu Trong Le ◽

Tam N.M. Ngo ◽

Kar-Ming Fung ◽

James D. Battiste ◽

...

Keyword(s):

Cox Regression ◽

Fatal Outcome ◽

Extent Of Resection ◽

Tumor Location ◽

Genetic Alterations ◽

Integrated Analysis ◽

Prognostic Impact ◽

Kaplan Meier ◽

Hazard Ratios ◽

The Impact

Abstract Introduction: H3K27M-mutated diffuse midline gliomas (H3-DMGs) are aggressive tumors with a fatal outcome. This study integrating individual patient data (IPD) from published studies aimed to investigate the prognostic impact of different genetic alterations on survival of these patients.Methods: We accessed PubMed and Web of Science to search for relevant articles. Studies were included if they have available data of follow-up and additional molecular investigation of H3-DMGs. For survival analysis, Kaplan-Meier analysis and Cox regression models were utilized, and corresponding hazard ratios (HR) and 95% confidence intervals (CI) were computed to analyze the impact of genetic events on overall survival (OS).Result: We included 30 studies with 669 H3-DMGs. TP53 mutations were the most common second alteration among these neoplasms. In univariate Cox regression model, TP53 mutation was an indicator of shortened survival (HR = 1.446; 95% CI = 1.143-1.829) whereas ACVR1 (HR = 0.712; 95% CI = 0.518-0.976) and FGFR1 mutations (HR = 0.408; 95% CI = 0.208-0.799) conferred prolonged survival. In addition, ATRX loss was also associated with a better OS (HR = 0.620; 95% CI = 0.386-0.996). Adjusted for age, gender, tumor location, and the extent of resection, the presence of TP53 mutations, the absence of ACVR1 or FGFR1 mutations remained significantly poor prognostic factors.Conclusions: We outlined the prognostic importance of additional genetic alterations in H3-DMGs and recommended that these neoplasms should be further molecularly segregated. It could help neuro-oncologists better evaluate the risk stratification of patients and consider pertinent treatments.

Download Full-text