Incidence and Prognostic Impact of Gene Mutations in Older Patients with AML Treated in the ALFA-9801 Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1525-1525
Author(s):  
Aline Renneville ◽  
Sylvie Castaigne ◽  
Sylvie Chevret ◽  
Laura Llopis ◽  
Nathalie Philippe ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Older Patients ◽  
Gene Mutations ◽  
Significant Prognostic Factor ◽  
Prognostic Impact ◽  
Npm1 Mutation ◽  
Younger Patients ◽  
Mutational Status ◽  
Cebpa Mutations ◽  
The Impact

Abstract Introduction: The impact of gene mutations, i.e. poor-prognosis FLT3 internal tandem duplications (ITDs) and good-prognosis NPM1 or CEBPA mutations, has been welldocumented in several recent reports dealing with younger patients with acute myeloid leukemia (AML). As these mutations were associated with cytogenetically normal (CN) AML, most of these reports focused on CN-AML patients. Both FLT3-ITD and NPM1 mutations were also associated with higher WBC. The objective of the present study was to evaluate the incidence, correlations, and prognostic value of these mutations in older patients with the disease. Methods: The French ALFA group has screened a total of 583 patients, including 333 younger patients (15–50 years) treated in the ALFA-9802 trial and 250 older patients (50–70 years) treated in the ALFA-9801 trial. The older ALFA-9801 trial included 468 patients with previously untreated de novo AML and studied the role of idarubicin (IDA) as compared to high-dose daunorubicin (DNR) as well as interleukine-2 as a maintenance therapy (C. Pautas et al. ASH 2007, abstract #162). Comparison between the 250 patients tested for mutations in that trial and the 218 patients not tested showed no differences in age, sex ratio, FAB classification, bone marrow blasts percentage, randomization arm, and performance status at entry in the study. There was, however, a higher rate of patients with intermediate cytogenetics (p=.01) or increased WBC (p=.01) in the former subgroup. Results: Median age of the 250 patients tested was 60 years. Cytogenetics was studied in 232 patients (12 favorable, 174 intermediate, 46 unfavorable). One hundred twenty-two patients (49%) had CN-AML. CR rate was 67.5% and estimated 4-year OS was 26% (95% CI, 20–33). Incidences of FLT3-ITD, NPM1, and CEBPA mutations were 37/250 (15%), 64/249 (26%), and 20/249 (8%), respectively. These incidences were very similar than in the younger ALFA-9802 population [50/329 (15%), 76/321 (24%), and 24/316 (8%), respectively]. In these older AML patients, the correlation between increased WBC and FLT3-ITD (p<.001) or NPM1 mutation (p<.001) was still observed. Conversely, NPM1 mutations only (p<.001), but not FLT3-ITDs (p=.10) or CEBPA mutations (p=.99), were significantly associated with CN-AML. In the whole group of 249 patients with either normal or abnormal karyotype tested for all mutations, 46 were NPM1+/FLT3-ITDwt, 19 FLT3-ITD+/NPM1wt, 18 FLT3-ITD+/NPM1+, and 166 NPM1wt/FLT3-ITDwt. CR rate was 87%, 84%, 56%, and 75% and median OS was 20.5, 18.6, 6.0, and 14.6 months, respectively. In the 20 CEBPA+ patients, CR rate was 80% and median OS was 22.8 months. In the group of 122 CN-AML patients tested for all mutations, 36 were NPM1+/FLT3-ITDwt, 8 FLT3-ITD+/NPM1wt, 15 FLT3-ITD+/NPM1+, and 63 NPM1wt/FLT3- ITDwt. CR rate was 92%, 87.5%, 60%, and 78% and median OS was 20.5, 16.9, 7.0, and 16.8 months, respectively. In the 10 CEBPA+ patients, CR rate was 80% and median OS was not reached. In multivariate analysis including age, WBC, cytogenetics (favorable versus others), and gene mutational status (NPM1+ or CEBPA+ if FLT3-ITDwt versus others), a pejorative effect of age (p=.02) and WBC (p<.001), but a protective effect of mutational status (HR= 0.66, p=.05) and favorable cytogenetics (HR=0.43, p=.06) was observed in the whole patient population. Nevertheless, estimated 4-year OS was only 37% (95% CI, 23–50) in patients with a favorable mutational status. In those with CNAML and a favorable mutational status, estimated 4-year OS reached only 40% (95% CI, 23–56). In this subgroup of patients with CN-AML, WBC was the only significant prognostic factor identified in multivariate analysis (p<.001). Conclusion: This study conducted in a large cohort of patients aged 50 to 70 years and prospectively treated in the same trial showed that gene mutational status still affect the outcome of older patients with AML. Mutation incidences are in the same range than in younger patients. Nevertheless, their impact on OS appeared to be less marked than in younger patients, probably due to the worse general outcome observed in these older patients.

Heterogeneity Of Patients With Cytogenetically Normal Acute Myeloid Leukemia (CN-AML) and Nucleophosmin-1 (NPM1) Gene Mutation: An Acute Leukemia French Association (ALFA) Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 831-831
Author(s):  
Pierre Peterlin ◽  
Aline Renneville ◽  
Raouf Ben Abdelali ◽  
Olivier Nibourel ◽  
Xavier Thomas ◽  
...  
Keyword(s):  
Older Patients ◽  
Missing Values ◽  
Conflicts Of Interest ◽  
Cox Model ◽  
Gene Mutations ◽  
Advanced Age ◽  
Multivariable Model ◽  
Npm1 Mutation ◽  
Younger Patients ◽  
Mutational Status

Abstract Background CN-AML with NPM1 mutation accounts for 25% of AML cases and is individualized as a provisional entity in the WHO classification. In this large AML subset, additional gene mutations could influence patient outcome, like it has been shown for bad-prognosis FLT3 internal tandem duplication (FLT3-ITD). We thus reviewed the characteristics and outcome of 409 patients with de novo NPM1-mutated CN-AML treated in sequential ALFA studies. Methods Patients were treated between 1990 and 2012 (median follow-up, 31 months) according to ALFA-9000 (#16), 9801 (#91), 9802 (#89), 9803 (#19) and 0701 (#84) published protocols or in the ongoing 0702 study (#110). In addition to NPM1, the following mutations were centrally assessed using standard-PCR methods and Sanger sequencing: FLT3-ITD, mutations of FLT3 tyrosine kinase domain (FLT3-TKD, i.e. FLT3D835/I836), IDH1R132, IDH2R140, IDH2R172, TET2 (exons 3-11), and DNMT3A (exons 8-9, 11-23). Primary endpoint was cumulative incidence of relapse (CIR) after censoring the 73 patients who received allogeneic stem cell transplantation (SCT) in first CR at SCT time. Analyses were performed with multiple imputations of missing values, followed by multivariable logistic regression or Cox model. Results Median age was 52 years (17-79). Median white blood cell count (WBC) was 23.5 x 109/L (0.8-377). Gene mutations are indicated in Table 1. Multivariable analyses showed that: 1) FLT3-ITD was associated with higher median WBC (60 versus 18 x 109/L, P<0.001) and less frequent FLT3-TKD, IDH1R132 and IDH2R140 mutations (P=0.003, 0.037 and <0.001, respectively); 2) IDH2R140 mutations were associated with higher median WBC (42 versus 24 x 109/L, P<0.001) and less frequent IDH1R132 and DNMT3AR882 mutations (P<0.001 and 0.001, respectively); 3) TET2 mutations were associated with higher median WBC (37 versus 22 x 109/L, P=0.003) and less frequent FLT3-ITD, FLT3-TKD, and IDH1R132 mutations (P=0.007, 0.028 and 0.022, respectively); and 4) non-R882 DNMT3A mutations, but not R882 mutations, were markedly associated with advanced age (22% in patients ≥ 50 years versus 9% in younger patients; P<0.001). Overall, 372 patients (91%) reached complete remission (CR). In multivariable models, advanced age and higher WBC negatively influenced CR achievement (P=0.044 and 0.037, respectively), but none of the additional mutations. In CR patients, 3-year CIR was 51% (45-58). In a first multivariable model not considering TET2 mutational status (analyzed in 232 patients only), advanced age was associated with a higher specific hazard of relapse (SHR) (P<0.001). At 3 years, CIR was 63% in patients ≥ 50 years versus 35% in younger patients. The other factors associated with a higher CIR were FLT3-ITD (SHR, 2.04 [1.35-3.09]; P=0.001) and non-R882 DNMT3A mutations (SHR, 1.94 [1.10-3.42]; P=0.023), while FLT3-TKD was associated with a lower CIR (SHR, 0.38 [0.16-0.94]; P=0.036). Conversely, WBC, IDH1/2 mutations and R882 DNMT3A mutations did not influence CIR. Advanced age, FLT3-ITD and non-R882 DNMT3A mutations were also identified as independent risk factors in a second multivariable model performed in the subset of patients tested for TET2 mutations. Here, TET2 mutations had no impact on CIR. Overall 3-year CIR estimates were 41%, 61%, 68% and 94% in the FLT3-ITD-/non-R882 DNMT3A-, FLT3-ITD+/non-R882 DNMT3A-, FLT3-ITD-/non-R882 DNMT3A+, and FLT3-ITD+/non-R882 DNMT3A+ subsets, respectively. Conclusions This study confirms the heterogeneity of patients with NPM1-mutated CN-AML, independently of the known poor prognosis of FLT3-ITD. Higher WBC was associated with FLT3-ITD, IDH2R140 and TET2 mutations, but did not represent per se an independent risk factor for relapse. Higher incidence of unfavorable non-R882 DNMT3A mutations in older patients may explain, at least in part, why older patients do worse than younger patients in this peculiar AML subset. A potential favorable prognostic role of FLT3-TKD mutations in these patients needs to be confirmed. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Fludarabine, High Dose Cytarabine and Idarubicin-Based Induction Is Highly Effective in Young AML Patients with Concomitant NPM1 and FLT3-ITD Mutation Irrespectively of FLT3-ITD Allelic Burden

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3828-3828
Author(s):  
Paola Minetto ◽  
Anna Candoni ◽  
Fabio Guolo ◽  
Marino Clavio ◽  
Maria Elena Zannier ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Leukemic Cells ◽  
High Dose ◽  
Prognostic Impact ◽  
Allogeneic Bone ◽  
Wild Type ◽  
Npm1 Mutation ◽  
Mutational Status ◽  
High Dose Cytarabine ◽  
Allelic Burden

Background: The presence of FLT3 "internal tandem duplication" (FLT3-ITD) mutation is associated with poor prognosis in acute myeloid leukemia (AML). However, the concomitant presence of NPM1 mutation (NPM1-mut) partially overcomes the negative prognostic impact of FLT3-ITD, which is also modulated by FLT3-ITD/wild-type allelic ratio. NPM1 and FLT3 mutational status assessment is strongly recommended for risk stratificationat diagnosis by the last European Leukemia Net (ELN) guidelines. Aims: To investigate the efficacy of an intensive fludarabine-containing induction regimen (FLAI) for fit, de novo AML patients according to NPM1 and FLT3-ITD mutational status. Methods: One-hundred and sixteen consecutive AML patients, treated in 3 Hematology Italian centers from January 2008 to January 2018, were included in this analysis. Twenty five patients showed isolated FLT3-ITD, 39 concomitant FLT3-ITD and NPM1-mutation and 52 isolated NPM-1-mutation.Median age was 52 yrs (range: 18-65 years). All patients received fludarabine, high dose cytarabine-based induction (fludarabine 30 mg/sqm and ARA-C 2g/sqm ondays 1 to 5 plus idarubicin 10 mg/sqm on days 1-3-5). For patients achieving CR fludarabine was omitted on II induction course and idarubicin dose was increased to 12 mg/sqm. Before2017 patients with isolated FLT3-ITD mutation were scheduled to receive allogeneic bone marrow transplantation (BMT) in first complete remission regardless of allelic burden whereas after 2017 only patients with high allelic burden received BMT in 1st CR. Minimal residual disease was evaluated on marrow samples using multicolor flow-cytometry (MFC)or NPM1 expression levels. Negative MFC-MRD wasdefined by the presence of less than 25 clustered leukemic cells/105 total events (threshold of 0.025% residual leukemic cells, Minetto et. al, BJH 2019). NPM1mutation (NPM1-A, B and D) was measured using Muta Quant Kit Ipsogen from Qiagen. FLT3-ITD allelic burden was available in31/64 of FLT3-ITD patients. Results: Overall 60-days mortality was 4%. After two induction cycles, 101 patients achieved CR (87%). Thirty-three/101 (33%) CR patients underwent BMT in first CR. After a median follow up of 61 months, 3-year overall survival (OS) was 56.8% (median not reached). In univariate analysis OS duration was favorably affected by age <55 yrs (p<0.05), MRD-negative status after induction (both MFC and NPM1 based MRD) (p<0.001) and wild-type FLT3(p<0.05). However, in multivariate analysis only MRD status significantly affected OS (p<0.003). The probability of achieving a molecular MRD negative CR after first cycle among NPM1-mut patients was similar between patients with or without concomitant FLT3-ITD mutation (61% and 66%, respectively, p=n.s.). Interestingly, in younger patients (< 55yrs) OS was comparable in case of isolated NPM1 mutation or concomitant NPM1/FLT3-ITD mutation (3-year OS 68.4% and 62.3%, respectively, p= n.s, Figure 1), regardless of FLT3-ITD allelic burden.Patients with isolated FLT3-ITD mutation had a significantly worse prognosis (3-year OS 34.4%, p<0.05). Again, multivariate analysis showed that persistence of MRD (by any method, p <0.05) was the strongest predictor of outcome. Moreover, performing BMT infirst CR did not impact OS neither in univariate or multivariate analysis. Conclusion: Despite the potential bias due to the retrospective nature of the analysis, our data indicate that intensive fludarabine-high dose cytarabine-based induction exerts a strong anti-leukemic efficacy in younger AML patients carrying NPM1 mutation irrespectively of FLT3 mutational status.Thus, the synergism of fludarabine and cytarabine seems to affect the intrinsic chemosensitivity of NPM1-mut leukemic cells, overcoming the negative impact of FLT3-ITD. Moreover, our data suggest the strong prognostic impact on survival of MRD clearance and question the role of BMT in I CR in this setting of patients. Figure 1 Disclosures Candoni: Gilead: Honoraria, Speakers Bureau; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Merck SD: Honoraria, Speakers Bureau. Bocchia:Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria.

Prognostic Impact of Genetic Characterization in the GIMEMA LAM99P Study for Newly Diagnosed Adult AML. Relevance of Combined Analysis of Conventional Karyotyping, FLT3 and NPM Mutational Status.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 226-226
Author(s):  
G. Saglio ◽  
Francesco Lo Coco ◽  
A. Cuneo ◽  
F. Pane ◽  
G. Rege Cambrin ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
High Risk ◽  
Genetic Characterization ◽  
High Risk Group ◽  
Low Risk ◽  
Prognostic Impact ◽  
Intermediate Risk ◽  
Mutational Status ◽  
Molecular Studies ◽  
The Impact

Abstract Between 1998 and 2002, 509 patients with AML (median age 46 yrs, range 15–60) were enrolled in the multicenter LAM99P study of the Italian GIMEMA group. To better evaluate the clinical impact of genetic characterization, all patients received a uniform protocol and diagnostic samples were centralised for cytogenetic and molecular studies. Therapy consisted of HU pre-treatment (2g/m2 for 5 days) followed by induction with DNR (50 mg/m2 d 1, 3, 5), cytarabine (100 mg/m2 d 1–10) and etoposide (100 mg/m2 d 1–5) and consolidation with cytarabine (500 mg/m2/q12 hrs d 1–6) and DNR (50 mg/m2 d 4–6). After consolidation, eligible patients with an identical HLA donor were to receive allogeneic SCT and the remaining peripheral blood autologous SCT. Cytogenetic and molecular genetic characterization (including analysis of major fusion genes, FLT3 and NPM status) was available in 397 (78%) patients. Compared to previous GIMEMA studies, the possibility to collect samples during the 5d of HU pretreatment considerably improved genetic characterization and in particular centralised karyotyping by overcoming the problem of sampling and shipment over the w-end. After induction, 269/397 (68%) patients achieved CR. For induction response, conventional K identified 3 distinct risk groups as follows: low risk (inv. 16 and t8;21), intermediate (normal K and other anomalies not comprised in the high risk group) and high risk (t3;3, inv.3, t9;22, 11q23, 5/7 abnormalities complex K,) with CR rates of 92%, 67% and 39%, respectively (P<.0001). NPM mutations were significantly associated with older age, higher WBC, normal K and FLT3-ITD. CR rates in NPM+ (mutated) vs. NPM- (wildtype) groups were 76% vs. 60% for the whole population and 81% vs, 61% for patients in the normal K group (P<.001 for both comparisons). Multivariate analysis for CR indicated that low risk K and NPM+ were independent factors favorably affecting CR achievement while FLT3 status had no significant impact on CR. The analysis of prognostic factors for DFS and OS was carried out in 269 patients in CR (median follow-up of 39 mos.) and multivariate analysis performed after adjusting for unfavorable factors (WBC count). Multivariate analysis of variables influencing OS showed the following: low vs intermediate K, P=.0005; high vs intermediate K, P<.0001; FLT3+ vs. FLT3−, P=.06. Multivariate analysis for DFS showed: low risk vs. intermediate risk K, p=.01; high risk vs. intermediate risk K, p= .03; FLT3+ vs. FLT3-, p=.0002. NPM status did not significantly influence DFS in either the whole population or in the normal K group. In particular, there was no difference in the DFS rates among patients NPM+ and NPM- in the normal K/FLT3- group while in the normal K/FLT3+ group there was a trend (p=.06) for lower relapse rate for NPM+ patients as compared to NPM- ones. These results highlight the relevance of combining cytogenetic and molecular studies in the diagnostic work up of AML and confirm the impact of karyotype on all outcome estimates as well as of FLT3 status on DFS. As to NPM mutations, these appear a favorable predictor of CR achievement. Further investigations in large clinical trials are needed to assess the prognostic value of NPM mutations on outcome in AML with normal karyotype.

Mutational Status of IgVH Genes in B-Cell Chronic Lymphocytic Leukemia (B-CLL) and Prognosis: Percent Mutations or Evaluation of Antigen-Driven Selection?

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2106-2106
Author(s):  
Valter Gattei ◽  
Michele Dal ◽  
Antonella Zucchetto ◽  
Dania Benedetti ◽  
Eva Zaina ◽  
...  
Keyword(s):  
Scientific Literature ◽  
Patient Survival ◽  
Gene Mutations ◽  
Affinity Maturation ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Rt Pcr ◽  
Mutational Status ◽  
Definition Of ◽  
The Impact

Abstract Quantitative evaluation of IgVH genes mutations is widely considered a reliable prognosticator in B-CLL. Conversely, conflicting results have been reported regarding the prognostic impact of IgVH gene mutations when evidence of Ag-driven selection is investigated. To address this issue, the mutational status of IgVH genes was analysed in peripheral blood samples of 147 B-CLL patients, all with survivals, by a strategy of RT-PCR and cloning; B-CLL specific IgVH transcripts were analysed for both % mutation and Ag-driven selection by applying a multinomial statistical model evaluating the excess/scarcity of replacement/silent mutations in FR/CDR sequences of IgVH genes. Maximally selected log-rank statistics, applied for IgVH gene % mutations, estimated the most appropriate cutoffs capable to separate B-CLL patients into two subgroups with different survival; this approach identified an absolute peak at 0.2% IgVH mutations and two relative peaks at about 2% and 4% IgVH mutations. We therefore tested the impact of Ag-driven selection on B-CLL patient survival in the context of the cutoffs of 0.2, 2 and 4% IgVH mutations. For each cutoff, B-CLL cases were identified as mutated (M) or unmutated (UM) if the % IgVH mutations were above or below the chosen cutoff, respectively; M B-CLLs with evidence of Ag selection were named significantly mutated (sM), while cases lacking such an evidence were reported as not-sM (nsM). 1) 0.2% IgVH cutoff - The 133 B-CLLs with >0.2% mutations had longer survivals as compared to 14 cases with <0.2% mutations (p=2.6x10-5); regarding the prognostic impact of Ag selection within the 133 M B-CLLs, 78 sM B-CLL patients had longer survivals than the 55 nsM B-CLLs (p=2.7x10-2). This latter group maintained a better prognosis as compared to UM B-CLLs (p=8.8x10-3); 2) 2% IgVH cutoff - Using the standard cutoff, 99 M B-CLL cases, displaying >2% mutations, had longer survivals as compared to 48 UM cases with <2% mutations (p=1.4x10-4); again, within the M B-CLL group, 65 sM B-CLL patients had longer survivals than 34 nsM B-CLLs (p=1.4x10-2); nsM and UM B-CLL patients had similar survivals (p = 0.1); 3) 4% IgVH cutoff - According to this cutoff, 75 B-CLLs were M B-CLLs, while 72 cases were UM B-CLLs. Only percent of IgVH mutations split B-CLLs into two subgroups with different survivals (p=4.9x10-4); sM and nsM B-CLLs with >4% mutations had similar survivals; 4) sM vs. nsM (all cases) - In the absence of any cutoff, the 78 patients with sM B-CLLs had longer survival as compared to the 69 affected by nsM B-CLLs (p=9.6x10-4). By taking together this data, it appears that the use of % IgVH mutations remains the gold-standard for the definition of prognosis in B-CLL; however, at least when the canonical 2% cutoff is applied, a certain caution should be used by predicting patient survival in the absence of information regarding the affinity maturation of B-CLL clones. The expression by B-CLL cells of IgVH segments with evidence of affinity maturation seems to lose its positive prognostic impact when a cutoff is set at 4% IgVH mutations. In addition to its obvious clinical impact, these observations provide a putative explanation of the apparent discrepancies found in the scientific literature about this matter.

CD49d Prevails over the Novel Recurrent Mutations As Independent Prognosticator of Overall Survival in Chronic Lymphocytic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1706-1706
Author(s):  
Michele Dal Bo ◽  
Pietro Bulian ◽  
Riccardo Bomben ◽  
Antonella Zucchetto ◽  
Francesca Rossi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Gene Mutations ◽  
Normal Karyotype ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
The Novel ◽  
Analysis Model ◽  
Mutational Status ◽  
Notch1 Mutations

Abstract Background. CD49d, the alpha-chain of the integrin heterodimer VLA-4, has been identified among the strongest predictors of overall survival (OS) in chronic lymphocytic leukemia (CLL), along with IGHV mutational status and deletion of the 17p (17p-) chromosome involving TP53 (Bulian et al, JCO, 2014). In addition to TP53, the clinical relevance of NOTCH1, SF3B1 and BIRC3 gene mutations has been recently emphasized. Aim. To test the relevance of CD49d in molecular subgroups of CLL defined by NOTCH1, SF3B1 and BIRC3 gene mutations. Methods. The study was based on a cohort of 778 unselected CLL (422 untreated and 356 treated cases) all characterized for CD49d expression (CD49dhigh, ≥30% positive cells by flow cytometry in 229 cases), IGHV mutational status (unmutated, UM, in 262 cases), karyotype abnormalities according to the hierarchical stratification (13q- in 308 cases, +12 in 103 cases, 11q- in 64 cases), tested at diagnosis, along with mutations/deletions (hereinafter, disruption) of TP53 (disrupted in 84 cases, including 58 cases with 17p-), BIRC3 (disrupted in 59 cases), and mutationsof NOTCH1 (mutated in 81 cases), SF3B1 (mutated in 54 cases)tested at diagnosis in 65% of cases, in all cases before therapy. Chromosome abnormalities by FISH were defined by using a 5% cut-off; IGHV, TP53, BIRC3, NOTCH1 and SF3B1 mutations were investigated by Sanger sequencing. Median follow-up of patients was 80 months with 173 deaths. Results. i) association with CD49d: a CD49dhigh phenotype associated with age ≥65 years (p=0.0001), Rai stage I or higher (p>0.0001), UM IGHV status (p>0.0001), absence of 13q- (p=0.0001), presence of +12 (p<0.0001), presence of NOTCH1 mutations (p<0.0001). ii) CD49d prognostic impact: in univariate analysis, the following covariates had a significant impact on OS: age ≥65 years (hazard ratio/confidence interval (HR/CI)= 3.98/2.77-5.73; p<0.0001), Rai stage I or higher (HR/CI=1.81/1.33-2.46; p=0.0002), high CD49d expression (HR/CI=2.62/1.94-3.54; p<0.0001), UM IGHV status (HR/CI=3.03/2.24-4.10; p<0.0001), presence of 13q- (HR/CI=0.52/0.37-0.71; p=0.0001), +12 (HR/CI=1.59/1.08-2.33; p=0.0183), 11q- (HR/CI=2.16/1.42-3.30; p=0.0004), NOTCH1 mutations (HR/CI=2.66/1.82-3.88; p<0.0001), SF3B1 mutations (HR/CI=1.99/1.24-3.20; p=0.0048), BIRC3 disruption (HR/CI=2.41/1.58-3.68; p<0.0001), TP53 disruption (HR/CI=3.23/2.28-4.57; p<0.0001). In a multivariate analysis model including all these variables, high CD49d expression (HR/CI=1.76/1.28-2.42; p=0.0006), UM IGHV status (HR/CI=2.21/1.58-3.09; p<0.0001), presence of 11q- (HR/CI=2.11/1.35-3.31; p=0.0011), TP53 disruption (HR/CI=2.93/2.04-4.22; p<0.0001), and NOTCH1 mutations (HR/CI=1.76/1.16-2.67; p=0.0082) emerged as independent prognosticators, along with age ≥65 years (HR/CI=3.73/2.58-5.39; p<0.0001). iii) CD49d prognostic impact using the integrated hierarchical mutational/cytogenetic model: by integrating gene mutations and cytogenetic aberrations according to Rossi et al (Blood, 2013), a multivariate analysis model was applied with the following covariates: age, CD49d, IGHV status, TP53/BIRC3 disruption, NOTCH1 mutations/SF3B1 mutations/11q-, normal karyotype/+12, 13q-. Again, CD49dhigh phenotype (HR/CI=1.88/1.38-2.54; p=0.0001), UM IGHV status (HR/CI=2.16/1.54-3.01; p<0.0001), presence of NOTCH1 mutations/SF3B1 mutations/11q- (HR/CI=1.62/1.11-2.38; p=0.0139), and of TP53/BIRC3 disruption (HR/CI=2.67/1.92-3.70; p<0.0001) retained their independent prognostic impact, along with age ≥65 years (HR/CI=3.58/2.28-5.17; p<0.0001). Notably, CD49dhigh CLL patients experienced shorter OS than the CD49dlow cases in the context of each mutational/cytogenetic group (TP53/BIRC3 disruption, p=0.0064; NOTCH1 mutations/SF3B1 mutations/11q-, p=0.05; normal karyotype/+12, p=0.0153; 13q-, p=0.0126; see Figure). Conclusion. CD49d was confirmed as independent negative OS prognosticator in CLL also when the novel recurrent alterations of NOTCH1, BIRC3, and SF3B1 genes were considered. In this setting, TP53 disruption and NOTCH1 mutations remained independent OS prognosticators, allegedly for their physiopathological roles in CLL cell immuno-chemoresistance. Figure 1. Figure 1. Disclosures Gaidano: Morphosys, Roche, Novartis, GlaxoSmith Kline, Amgen, Janssen, Karyopharm: Honoraria, Other: Advisory boards; Celgene: Research Funding.

ID1 Expression Correlates with CEBPA Mutational Status and Is Not An Independent Risk Factor in Cytogenetically Normal AML,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3554-3554
Author(s):  
Katharina Wagner ◽  
Frederik Damm ◽  
Michael A Morgan ◽  
Felicitas Thol ◽  
Haiyang Yun ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Prognostic Factor ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
High Expression ◽  
Prognostic Impact ◽  
Mutational Status ◽  
Negative Prognostic Factor ◽  
Cebpa Mutations

Abstract Abstract 3554 Background: Acute myeloid leukemia with normal karyotype (CN-AML) is a heterogenous disease. During the last years, mutations in several genes (e.g. NPM1, FLT3, CEBPA, WT1, IDH1, IDH2) have been identified which are involved in the pathogenesis of AML and affect the prognosis of these patients. Moreover, deregulated expression of genes such as MN1, BAALC, ERG and WT1 was demonstrated to be predictive of outcome in CN-AML. Recently, high expression of the ID1 gene was described as a negative prognostic factor in AML (Tang et al. Blood 2009, 114:2993–3000). Aims: We have shown that C/EBPα, a transcription factor encoded by the CEBPA gene, binds to a regulatory element in the promoter region of the ID1 gene and regulates ID1 expression in leukemic cells (Wagner et al. Proc Natl Acad Sci USA 2006, 103:6338–6343). Therefore, we wanted to analyze the prognostic impact of ID1 expression in CN-AML in the context of other molecular markers, in particular CEBPA mutations. Methods: ID1 expression was quantified normalized to ABL by real time RT-PCR in 269 patients (age 16–60 years) with CN-AML treated with intensive double induction and consolidation therapy within the AMLSG 295 and 0199 trials (NCT00209833). The patients were also analyzed for mutations in the genes NPM1, FLT3, CEBPA, WT1, IDH1 and IDH2. Median follow up was 79 months. Results: Expression of ID1 varied over a 3-log range. High expression of ID1 (ID1high, defined as > median expression level) was significantly associated with the presence of a FLT3 -ITD or an IDH2 mutation and WT1 wildtype. Moreover, ID1 expression was closely associated with CEBPA mutational status. Altogether, 41 patients (15%) harboured a CEBPA mutation (24 monoallelic and 17 biallelic mutations). ID1 expression in the CEBPA wildtype patients was significantly higher than in patients with monoallelic CEBPA mutations and these patients had a significantly higher ID1 expression compared to patients with biallelic CEBPA mutations (p = 0.001). ID1high patients had a trend to a lower complete remission (CR) rate (74% vs. 84%; p = 0.07), but in multivariate analysis only blast clearance on day 15 after induction 1, age and WT1 SNP rs16754 were independent predictors for the achievement of CR. In univariate analysis, ID1high patients had an inferior overall survival (OS) compared to patients with low expression (median OS 29 vs. 78 months, 5 year OS 39% vs. 53%, p = 0.026). ID1high status was an independent negative prognostic factor in multivariate analysis when analyzed together with NPM1, FLT3 -ITD, WT1, IDH1, IDH2, extramedullary disease and platelet counts (HR 1.51; 95% CI 1.06–2.19). However, when also CEBPA mutational status was entered into the model, ID1 expression lost its prognostic impact and the only independent prognostic factors were age, platelets, CEBPA mutations, NPM1 /FLT3 -ITD risk group and WT1 SNP rs16754. Likewise, ID1high patients had a trend to an inferior relapse-free survival (RFS; HR 1.36, 95% CI 0.96–1.93, p = 0.086) in univariate analysis. However, in multivariate analysis including CEBPA mutational status, ID1 expression had no impact on RFS and the only prognostic factors for RFS were NPM1 and CEBPA mutations and WT1 SNP rs16754. In CEBPA wildtype patients, ID1 expression had no impact on CR-rate, OS or RFS in univariate or multivariate analysis. Conclusions: CEBPA mutations seem to deregulate ID1 expression in CN-AML. Therefore, ID1 expression is not an independent prognostic factor in CN-AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The prognostic impact of FLT3-ITD and NPM1 mutation in adult AML is age-dependent in the population-based setting

2020 ◽  
Vol 4 (6) ◽  
pp. 1094-1101 ◽  
Author(s):  
Gunnar Juliusson ◽  
Martin Jädersten ◽  
Stefan Deneberg ◽  
Sören Lehmann ◽  
Lars Möllgård ◽  
...  
Keyword(s):  
Clinical Relevance ◽  
Older Patients ◽  
Strong Dependence ◽  
Population Based ◽  
Prognostic Impact ◽  
Prognostic Information ◽  
Npm1 Mutation ◽  
Younger Patients ◽  
Prognostic Effect ◽  
Choice Of Treatment

Abstract In acute myeloid leukemia (AML) FLT3 internal tandem duplication (ITD) and nucleophosmin 1 (NPM1) mutations provide prognostic information with clinical relevance through choice of treatment, but the effect of age and sex on these molecular markers has not been evaluated. The Swedish AML Registry contains data on FLT3-ITD and NPM1 mutations dating to 2007, and 1570 adult patients younger than 75 years, excluding acute promyelocytic leukemia, had molecular results reported. Females more often had FLT3ITD and/or NPM1mut (FLT3ITD: female, 29%; male, 22% [P = .0015]; NPM1mut: female, 36%; male, 27% [P = .0001]), and more males were double negative (female, 53%; male, 64%; P &lt; .0001). Patients with FLT3ITD were younger than those without (59 vs 62 years; P = .023), in contrast to patients with NPM1mut (62 vs 60 years; P = .059). Interestingly, their prognostic effect had a strong dependence on age: FLT3ITD indicated poor survival in younger patients (&lt;60 years; P = .00003), but had no effect in older patients (60-74 years; P = .5), whereas NPM1mut indicated better survival in older patients (P = .00002), but not in younger patients (P = .95). In FLT3ITD/NPM1mut patients, the survival was less dependent on age than in the other molecular subsets. These findings are likely to have clinical relevance for risk grouping, study design, and choice of therapy.

Incidence and Prognostic Impact of SNPs Regulating PU.1 Gene Expression in AML

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2949-2949
Author(s):  
Nicolas Boissel ◽  
Olivier Nibourel ◽  
Jean-Baptiste Micol ◽  
Nathalie Philippe ◽  
M. Crepin ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
De Novo ◽  
Regulatory Element ◽  
Gene Mutations ◽  
Normal Karyotype ◽  
Prognostic Impact ◽  
Healthy Controls ◽  
Complex Karyotype ◽  
Mutational Status ◽  
The Impact

Abstract Background/Aim: The transcription factor PU.1 is crucial for hematopoiesis. The transcriptional control of PU.1 gene is mediated by a distal upstream regulatory element (URE). Mice lacking URE have a decreased PU.1 expression and develop AML. In human, 2 SNPs reported in the URE of PU.1 reduce PU.1 expression in myeloid progenitors and have been reported frequently associated with complex karyotype in AML patients (Steidl, JCI, 2007). The aim of this study was to investigate the frequency of PU.1/URE SNPs in different cytogenetical and molecular AML subgroups and to evaluate their prognosis impact. Methods: Patients with de novo AML homogeneously treated in the ALFA9802 protocol (15-50y, non PML) were screened by pyro-sequencing for both SNP1 and SNP2 status (+/+,+/− and −/−). Samples were available for 260 AML patients, also characterized for FLT3dup, FLT3d835, NPMm, CEBPAm and WT1m gene mutations. The SNP profile in AML patients was compared to 207 healthy controls. Results: SNP1(+) allele was detected at the same frequency in AML patients than in healthy controls (SNP1: 43% vs 43%, p=NS by the Pearson’s test).SNP2(+) allele was less frequent in AML patients (13% vs 18% p=.05). No difference was observed between cytogenetical subgroups (low-, int- and high- risk) or according to gene mutational status. In this cohort, SNPs allele frequencies were similar in patients with complex karyotype (&gt;=5abn.). Homozygous SNP1(+/+) and SNP2(+/+) profiles were found in 53 (20.3%) and 6 (2.3%) AML patients respectively. Considering SNP+ patients presenting SNP1(+/+) or SNP2(+/+) genotype, a trend for a lower risk of relapse (5y-RR: 35% vs 52%, p=0.10) and a better EFS (5y-EFS: 54% vs 37%, p=.08) was observed in the global population. Considering patients with normal karyotype AML (NK-AML, n=106), SNP+ was predictive of a better outcome (5y-OS: 77% vs 44%;p=.03). This difference was due to a better CR rate (100% vs 77%, p=.2) but also to a lower relapse rate (5y-RR: 27% vs 52%,p=.11) with a global significant impact on EFS (5y-EFS: 70% vs 37%, p=.02). In patients with NK-AML, the other prognosis factors for OS were the WBC (p=.01), the NPMm+/FLT3dup- status (p=.03). In multivariate analysis considering WBC, FLT3dup, NPMm and SNP+ as covariates, factors influencing OS were NPMm (p=.03), WBC (p=.04) and SNP+ (p=.05; HR=.36[.13-.99]). Among the 66 patients with NPMm, no relapse was observed in SNP+ patients (5y-EFS: 80% vs 40%, p=.03). In patients with FLT3dup (n=36), a mutation reported to downregulate PU.1 expression, no effect of SNP was observed (5y-EFS: 33% vs 20%, p=.40). Conclusion: In young adults with AML, PU.1/URE SNP2 allele is less frequent than in healthy donors. Furthermore, a homozygous genotype leading to PU.1 downregulation is found to be associated with a favorable outcome in patients with normal karyotype. These paradoxical effects of constitutive PU.1 downregulation in human deserve further functional and clinical studies to compare the impact of constitutional- versus oncogenicrelated modulation of PU.1 expression in AML.

Impact of KRAS mutational status on outcomes in patients with pancreatic cancer (PDAC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4142-4142
Author(s):  
Lucy Xiaolu Ma ◽  
Gun Ho Jang ◽  
Amy Zhang ◽  
Robert Edward Denroche ◽  
Anna Dodd ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Advanced Disease ◽  
Cox Proportional Hazards ◽  
Prognostic Impact ◽  
First Line ◽  
Kras Mutations ◽  
Kaplan Meier ◽  
Mutational Status ◽  
Translational Research Program ◽  
The Impact

4142 Background: KRAS mutations (m) (KRASm) are present in over 90% of pancreatic adenocarcinomas (PDAC) with a predominance of G12 substitutions. KRAS wildtype (WT) PDAC relies on alternate oncogenic drivers, and the prognostic impact of these remains unknown. We evaluated alterations in WT PDAC and explored the impact of specific KRASm and WT status on survival. Methods: WGS and RNAseq were performed on 570 patients (pts) ascertained through our translational research program from 2012-2021, of which 443 were included for overall survival (OS) analyses. This included 176 pts with resected and 267 pts with advanced PDAC enrolled on the COMPASS trial (NCT02750657). The latter cohort underwent biopsies prior to treatment with first line gemcitabine-nab-paclitaxel or mFOLFIRINOX as per physician choice. The Kaplan-Meier and Cox proportional hazards methods were used to estimate OS. Results: KRAS WT PDAC (n = 52) represented 9% of pts, and these cases trended to be younger than pts with KRASm (median age 61 vs 65 years p = 0.1). In resected cases, the most common alterations in WT PDAC (n = 23) included GNASm (n = 6) and BRAFm/fusions (n = 5). In advanced WT PDAC (n = 27), alterations in BRAF (n = 11) and ERBB2/3/4 (n = 6) were most prevalent. Oncogenic fusions (NTRK, NRG1, BRAF/RAF, ROS1, others) were identified in 9 pts. The BRAF in-frame deletion p.486_491del represented the most common single variant in WT PDAC, with organoid profiling revealing sensitivity to both 3rd generation BRAF inhibitors and MEK inhibition. In resected PDAC, multivariable analyses documented higher stage (p = 0.043), lack of adjuvant chemotherapy (p < 0.001), and the KRAS G12D variant (p = 0.004) as poor prognostic variables. In advanced disease, neither WT PDAC nor KRAS specific alleles had an impact on prognosis (median OS WT = 8.5 mths, G12D = 8.2, G12V = 10.0, G12R = 12.0, others = 9.2, p = 0.73); the basal-like RNA subtype conferred inferior OS (p < 0.001). A targeted therapeutic approach following first line chemotherapy was undertaken in 10% of pts with advanced PDAC: MMRd (n = 1), homologous recombination deficiency (HRD) (n = 19), KRASG12C (n = 1), CDK4/6 amplification (n = 3), ERBB family alterations (n = 2), BRAF variants (n = 2). OS in this group was superior (14.7 vs 8.8 mths, p = 0.04), mainly driven by HRD-PDAC where KRASm were present in 89%. Conclusions: In our dataset, KRAS G12D is associated with inferior OS in resected PDAC, however KRAS mutational status was not prognostic in advanced disease. This suggests that improved OS in the WT PDAC population can only be achieved if there is accelerated access to targeted drugs for pts.

The impact of a time target on older patients attending the emergency department

2010 ◽  
Vol 27 (Suppl 1) ◽  
pp. A2.1-A2
Author(s):  
Sue Mason
Keyword(s):  
Emergency Department ◽  
Older Patients ◽  
Age Groups ◽  
Unintended Consequences ◽  
Older Patient ◽  
Younger Patients ◽  
Patient Level ◽  
Level Data ◽  
Younger Age ◽  
The Impact

IntroductionThe 4 h emergency standard for English acute trusts was introduced in 2003 and became full established by 2008 at 98% for all Emergency Department (ED) patients to be seen and discharged. This study examined the impact of the target for older patients attending departments.MethodsRoutine patient level data was received from 15 English EDs representing 774 095 individual patient attendances during May and June for 2003 to 2006. The data were used to determine the distribution of the total time spent in the EDs. Attendances were compared for older patients (65 years and above) with younger age groups.ResultsA total of 145 596 attendances were for patients aged 65+ years (18.9%). Across each year analysed, these older patients have a significantly longer median total time in the ED than those younger than 65 years (162 min vs 103 min, p<0.001). In addition, older patients are significantly more likely to leave the emergency department in the last 20 min prior to 4 h (12.4% vs 5.2% in those <65 years, p<0.001). This proportion is growing year on year in both the admitted and discharged categories of patients. Finally, older patients are significantly more likely to breach the 4-h than their younger counterparts (16.6% vs 6.3%, p<0.001).ConclusionsThere are some unintended consequences of introducing the 4 h target in UK emergency departments. While the target has reduced overall time in departments, the older patient appears to be disadvantaged relative to younger patients. Older patients are more likely to be ‘rushed through’ to other unmonitored areas of the hospital just prior to the target or to breach the target altogether. This finding calls in to question the benefits that the target is conveying for individual patients, and especially the most vulnerable in society.

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