Prognostic Impact of Clinical and Molecular Markers in Normal Karyotype AML-Results from the AMLCG 2000 Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3482-3482
Author(s):  
Friederike Schneider ◽  
Eva Hoster ◽  
Marietta Rottenkolber ◽  
Stephanie Schneider ◽  
Annika Dufour ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Risk Stratification ◽  
Multivariate Analyses ◽  
Normal Karyotype ◽  
Molecular Techniques ◽  
Prognostic Impact ◽  
Clinical Parameters ◽  
Single Mutation ◽  
Free Survival ◽  
Molecular Alterations

Abstract Background: Prognosis of AML is influenced by different clinical and molecular alterations. We performed a multivariate analysis including five molecular markers NPM1, FLT-ITD, CEBPA, FLT-TKD and MLL-PTD combined with clinical parameters at initial diagnosis to refine risk stratification. Patients and methods: Prognostic impact of clinical and molecular parameters in respect to OS, EFS, RFS and CR was assessed in 803 patients with normal karyotype included in the AMLCG (German AML Cooperative Group) 2000 trial until 01/2006. Patients were randomly assigned to treatment with TAD (thioguanine, conventional-dose AraC, daunorubicin) followed by HAM (high-dose AraC, mitoxantrone) or with the double-induction regimen consisting of two courses of HAM (quotation Buechner JCO 2006). Patient age ranged from 17 to 85 years (median: 60 yrs). 51% of patients were male, 49% female. 81% of patients had de novo AML. Performance status was normal or slightly impaired in the majority of patients (71% ECOG 0/1). Median blood counts at diagnosis were: Hb: 9.2 g/dl (4.2–16.4 g/dl); WBC: 16.0 G/l (0.1–798.2 G/l); platelets: 58 G/l (0.02–643 G/l), LDH: 410 U/l (8–14332 U/l) and bone marrow (BM) blasts: 80% (6–100%). Molecular markers’ mutation status and all mentioned clinical parameters were included in univariate analyses. In multivariate analyses only univariate significant parameters were used. Results: In 560 patients with all five molecular markers analyzed by routine molecular techniques at diagnosis the frequency of mutations were the following: 52.7% NPM1+, 29.3% FLT3-ITD+, 6.1% FLT3-TKD+, 7.5% MLL-PTD+ and 7.5% CEBPA+. The majority of analyzed patients (44.1%) showed one single mutation only. About one quarter of patients displayed either none (27.5%) or two (26.2%) mutations. A minority of 2.1% had 3 mutations, whereas the combination of four or all five molecular alterations was not found. The most frequent single mutation was NPM1 (28.4%), followed by FLT3-ITD (5.4%), CEBPA (4.8%), MLL-PTD (4.6%) and FLT3-TKD (0.9%). The combination of FLT3-ITD and NPM1 was detected in 18.8% of patients. Complete remission (CR) rate was 65.1%. Median overall survival (OS), event-free survival (EFS) and relapse-free survival (RFS) were 19.3, 7.7 and 17.2 months. Multivariate analyses identified the following parameters to have significant impact on prognosis. OS: NPM1, FLT3-ITD, WBC, age (p<0.0001 each) and CEBPA (p=0.003); EFS/RFS: NPM1, FLT3-ITD and age (p<0.0001 each / p<0.0001 each) and LDH (p=0.020 / p=0.040); CR: NPM1 and age (p=0.001 each). Conclusions: Our data show in a large cohort of 560 patients that at least one molecular marker can be identified in 72.5% of patients with NK-AML. The NPM1 mutation and age are the only parameters with an independent impact on all outcome parameters (OS, EFS, RFS, CR). These data provide the basis for a prognostic model in NK-AML that can be used for risk stratification and selection of patients that will benefit from allogeneic stem cell transplantation.

Prognostic Implications of the IDH1 synonymous SNP rs11554137 In Pediatric and Adult AML: a Children's Oncology Group and Southwest Oncology Group Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2737-2737
Author(s):  
Phoenix A. Ho ◽  
Todd A. Alonzo ◽  
Kenneth J. Kopecky ◽  
Kristen L. Miller ◽  
Julia Kuhn ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Expression Profiling ◽  
Prognostic Significance ◽  
Normal Karyotype ◽  
Prognostic Impact ◽  
Wild Type ◽  
Bone Marrow Blast ◽  
Free Survival ◽  
Cytogenetic Abnormalities ◽  
Pediatric Aml

Abstract Abstract 2737 Synonymous SNPs may directly impact gene function through various translational or post-translational mechanisms. Further, such “silent” SNPs in the mutational hotspots of AML-associated genes have recently been reported to carry prognostic impact. We aimed to determine the prevalence, clinical associations, and prognostic significance of a known SNP in exon 4 of IDH1, near the location of the frequently-mutated R132 codon. Diagnostic marrow specimens from 253 pediatric AML patients (treated on the COG trial AAML03P1) and 274 adult AML patients (treated on SWOG trials S9031, S9333, or S9500) were analyzed for the presence of SNP rs11554137 via direct sequencing. In the pediatric cohort (median age 9.8 years), SNP rs11554137 was present in 27 of 253 (10.7%) patients. SNP+ pediatric patients did not differ significantly from wild-type patients in terms of sex, racial distribution (African American patients accounted for 23% of SNP+ patients vs. 14% of wild-type patients, P=0.24), bone marrow blast percentage, or age distribution, except in patients aged 0–2 years, who accounted for 44% of SNP+ patients vs. 23% of wild- type patients (P=0.013). Recurrent cytogenetic abnormalities occurred with similar frequencies in both the SNP+ and wild-type pediatric populations, as did FLT3/ITD, NPMc, and CEBPA mutations. Miscellaneous cytogenetic abnormalities accounted for 33% of SNP+ patients vs. 14% of wild-type patients, P=0.033. IDH1 SNP status had no prognostic impact on survival in the pediatric cohort, as SNP+ and wild-type patients had similar rates of five-year overall survival (OS, 76% vs. 63%, P=0.50), disease-free survival (DFS, 48% vs. 53%, P=0.97), and relapse rate (RR, 39% vs. 39%, P=0.94). In the adult cohort (median age 63 years), the IDH1 SNP was present in 30 of 274 (10.9%) patients. A slight female predominance for the SNP (63% vs. 37%, P=0.052) occurred among adult patients. The SNP was more prevalent in African American patients, who accounted for 30% of the SNP+ patients vs. 7% of wild-type patients, P=0.0046. SNP+ patients also had somewhat higher diagnostic bone marrow blast percentages (medians 80% vs. 70%, P=0.025). The normal karyotype subset accounted for similar proportions of SNP+ vs. wild-type patients (42% vs. 46%, P=0.83). Notably, SNP rs11554137 was not present in adult core-binding factor AML. Miscellaneous cytogenetic abnormalities were significantly more common in SNP+ patients (46% vs. 22%, P=0.022). SNP status was not significantly associated with FLT3/ITD status when all adult patients were considered (P=0.14). However, within the normal karyotype subset, FLT3/ITD was present in 90% of SNP+ patients vs. 59% of wild-type patients (P=0.0053). SNP+ patients had somewhat poorer 5 year OS (10% vs. 18%, hazard ratio [HR]=1.17) though this difference was not statistically significant (P=0.44). Among the 142 patients who achieved complete remission (CR), however, 5-year relapse-free survival (RFS) was significantly worse for SNP+ patients (0% vs. 25%, HR = 2.89, P=0.0014). Of the 14 SNP+ patients who achieved CR, 13 relapsed and the 14th patient died of sepsis in remission after 61 days. In multivariate analysis, after adjusting for the effects of age and cytogenetic group, SNP rs11554137 retained an independent prognostic effect (P=0.0062) regarding RFS. Notably, when FLT3/ITD status is included in multivariate analysis, SNP positivity loses independent prognostic significance (HR=1.72, P=0.18). Genome-wide expression profiling was performed on 134 pediatric AML specimens in whom IDH1 SNP status was known. By comparing SNP+ patients with wild-type patients, we derived a distinct gene-expression signature for patients with SNP rs11554137. Among the most upregulated probe sets in the SNP+ cohort were those representing PEX6 and NFYA, both of which interact with the TGF-beta/SMAD signaling network; the retinoid × receptor beta gene RXRB; and the FER gene, a tyrosine kinase critical to FLT3 signaling. The IDH1 SNP rs11554137 is present in approximately 11% of pediatric and adult AML patients, and gene expression profiling data suggests that leukemia in SNP+ patients may have unique biologic features. The SNP was an independent predictor of decreased RFS in adult AML in univariate analysis, but not in multivariate analysis when adjusting for FLT3/ITD status. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The FLT3ITD mRNA level has a high prognostic impact in NPM1 mutated, but not in NPM1 unmutated, AML with a normal karyotype

Blood ◽  
2012 ◽  
Vol 119 (19) ◽  
pp. 4383-4386 ◽  
Author(s):  
Friederike Schneider ◽  
Eva Hoster ◽  
Michael Unterhalt ◽  
Stephanie Schneider ◽  
Annika Dufour ◽  
...  
Keyword(s):  
Cox Regression ◽  
Mrna Level ◽  
Normal Karyotype ◽  
Hazard Ratio ◽  
Independent Effect ◽  
Prognostic Impact ◽  
Internal Tandem Duplication ◽  
Npm1 Mutation ◽  
Free Survival ◽  
The Impact

Abstract The impact of a FLT3-internal tandem duplication (FLT3ITD) on prognosis of patients with acute myeloid leukemia (AML) is dependent on the ratio of mutated to wild-type allele. In 648 normal karyotype (NK) AML patients, we found a significant independent effect of the quantitative FLT3ITD mRNA level—measured as (FLT3ITD/wtFLT3)/(FLT3ITD/wtFLT3 + 1)—on outcome. Moreover, this effect was clearly seen in 329 patients with a mutated NPM1 gene (NPM1+), but not in 319 patients without a NPM1 mutation (wtNPM1). In a multivariate Cox regression model, the quantitative FLT3ITD mRNA level showed an independent prognostic impact on overall survival (OS) and relapse-free survival (RFS) only in the NPM1+ subgroup (OS: hazard ratio, 5.9; [95% confidence interval [CI]: 3.1-11.2]; RFS: hazard ratio, 7.5 [95% CI: 3.4-16.5]). The FLT3ITD mRNA level contributes to relapse risk stratification and might help to guide postremission therapy in NPM1-mutated AML.

Implications of NRAS mutations in AML: a study of 2502 patients

Blood ◽  
2006 ◽  
Vol 107 (10) ◽  
pp. 3847-3853 ◽  
Author(s):  
Ulrike Bacher ◽  
Torsten Haferlach ◽  
Claudia Schoch ◽  
Wolfgang Kern ◽  
Susanne Schnittger
Keyword(s):  
Molecular Markers ◽  
Hot Spots ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Prognostic Impact ◽  
Event Free Survival ◽  
Free Survival ◽  
Total Cohort ◽  
History Of ◽  
Disease Free

We analyzed 2502 patients with acute myeloid leukemia at diagnosis for NRAS mutations around the hot spots at codons 12, 13, and 61 and correlated the results to cytomorphology, cytogenetics, other molecular markers, and prognostic relevance of these mutations. Two hundred fifty-seven (10.3%) of 2502 patients had NRAS mutations (NRASmut). Most mutations (112 of 257; 43.6%) were found at codon 12, mostly resulting in changes from glycine to asparagine. The history of AML did not differ significantly in association with NRAS mutations. The subgroups with inv(16)/t(16;16) and inv(3)/t(3;3) showed a significantly higher frequency of NRASmut (50 of 133, 37.6% [P < .001], and 11 of 41, 26.8% [P = .004], respectively) than the total cohort. In addition, in these 2 subgroups, mutations of codon 61 were significantly overrepresented (both P < .001). In contrast, NRAS mutations were significantly underrepresented in t(15;17) (2 of 102; 2%; P = .005) in the subgroup with MLL/11q23 rearrangements (3 of 77; 3.9%; P = .061) and in the complex aberrant karyotype (4 of 258; 1.6%; P < .001). Overall, we did not find a significant prognostic impact of NRASmut for overall survival, event-free survival, and disease-free survival. However, there was a trend to better survival in most subgroups, especially when other molecular markers (FLT3-LM, MLL-PTD, and NPM) were taken into account.

Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML)

Blood ◽  
2006 ◽  
Vol 107 (10) ◽  
pp. 4011-4020 ◽  
Author(s):  
Christian Thiede ◽  
Sina Koch ◽  
Eva Creutzig ◽  
Christine Steudel ◽  
Thomas Illmer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Normal Karyotype ◽  
Clinical Impact ◽  
Prognostic Impact ◽  
Npm1 Mutation ◽  
Free Survival ◽  
High Bone ◽  
Acute Myeloid

Mutations of the nucleophosmin (NPM1) gene have recently been described in patients with acute myeloid leukemia (AML). To clarify the prevalence as well as the clinical impact of this mutation, we investigated 1485 patients with AML for NPM1 exon 12 mutations using fragment analysis. A 4 bp insert was detected in 408 of 1485 patients (27.5%). Sequence analysis revealed known mutations (type A, B, and D) as well as 13 novel alterations in 229 analyzed cases. NPM1 mutations were most prevalent in patients with normal karyotype (NK) (324 of 709; 45.7%) compared with 58 of 686 with karyotype abnormalities (8.5%; P < .001) and were significantly associated with several clinical parameters (high bone marrow [BM] blasts, high white blood cell [WBC] and platelet counts, female sex). NPM1 alterations were associated with FLT3-ITD mutations, even if restricted to patients with NK (NPM1-mut/FLT3-ITD: 43.8%; versus NPM1-wt/FLT3-ITD: 19.9%; P < .001). The analysis of the clinical impact in 4 groups (NPM1 and FLT3-ITD single mutants, double mutants, and wild-type [wt] for both) revealed that patients having only an NPM1 mutation had a significantly better overall and disease-free survival and a lower cumulative incidence of relapse. In conclusion, NPM1 mutations represent a common genetic abnormality in adult AML. If not associated with FLT3-ITD mutations, mutant NPM1 appears to identify patients with improved response toward treatment.

Impact of FISH and Cytogenetics On Overall and Event Free Survival in Myeloma: An IMWG Analysis of 9,897 Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 743-743 ◽  
Author(s):  
Herve Avet-Loiseau ◽  
Brian G M Durie ◽  
Jeff Haessler ◽  
John Crowley ◽  
Antje Hoering ◽  
...  
Keyword(s):  
Multivariate Analyses ◽  
Conflicts Of Interest ◽  
Negative Impact ◽  
Stage I ◽  
Stage Iii ◽  
Prognostic Impact ◽  
Predictive Capability ◽  
Free Survival ◽  
Molecular Changes ◽  
Molecular Features

Abstract Abstract 743 Background There has been considerable recent focus upon the molecular classification of myeloma. However, the prognostic impact of molecular changes has mostly been assessed from small and/or incomplete studies from single institutions or groups. There has been no large scale analysis of molecular features linked to ISS stage. Methods In order to clarify the overall impact of molecular changes we undertook a collective analysis of 9,897 patients through the International Myeloma Working Group (IMWG). Within this population 2,295 patients had presence of cytogenetic abnormalities (Any CA); 1,713 hypodiploidy; 1,673 hyperdiploidy; 2,309 cytogenetic deletion 13; 3,226 deletion 13 by FISH; 1,573 FISH t(4;14); 1,486 FISH del p17; 1, 683 FISH t(11:14); and 366 FISH t(4;16). Enrolled patients had complete clinical and treatment details available including baseline standard prognostic factors, ISS stage, as well as both progression free survival (PFS) and overall survival (OS) information. Data came from 14 sites: 3 from the US and the remainder from Europe, Asia, and Latin America as for the ISS staging system analyses. Univariate and multivariate analyses were performed. Results Each of the known adverse molecular features had a negative impact upon both PFS and OS (p=002 - <0.0001). Among the deleterious FISH abnormalities the t(4;14) abnormality was the most highly correlated with poorer outcomes by PFS: 4 year estimate: 32% vs. 60% (p<0.0001). The t(4;14) abnormality combined with ISS Stage also significantly enhanced predictive capability: ISS Stage I without t(4;14) OS 81% @ 4 years; ISS Stage III with t(4;14) OS 22% @ 4 years (P<0.0001) [Figure 1]. The best outcomes were for ISS Stage I in the presence of t(11;14): OS 89% @ 4 years. Absence of any one adverse feature correlated with 80-81% OS @ 4 years for Stage I. Presence of any one adverse feature had a more variable impact and correlated with 22%-40% OS at 4 years for Stage III. In univariate correlations the most predictive correlations with OS were presence of Any CA, t(4;14), 17p-, hypodiploidy, cytogenetic 13q- with R2 values of 6.9%, 4.5%, 4.1% and 3.8% respectively. In multivariate analyses, ISS stage provided the best predictions: R2 values = 13.3%. The added contributions from molecular features were: t(4;14) 3.8%; cytogenetic 13q- 2.9%; Any CA 2.3%; and 17p- 1.0%. The maximum total R2 for OS was 22%. Conclusions This large multicenter analysis confirms the correlations between abnormal molecular findings and outcomes. Combinations with ISS Stage provide the best predictive capability. Presence of Any CA, t(4;14), 17p-, hypodiploidy and cytogenetic 13q- contribute to poorer outcomes by ISS stage. The presence of hyperdiploidy and/or t(11;14) contribute to better outcomes. There is thus validation of prior molecular studies related to prognosis utilizing this large IMWG database. Disclosures: No relevant conflicts of interest to declare.

ABC Proteins Activity Remains An Independent Prognostic Factor In 206 AML When Compared to Other Molecular Markers, FLT3, NPM1, CEBPα, and BAALC

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1698-1698
Author(s):  
Pierre Hirsch ◽  
Ruoping Tang ◽  
Christophe Marzac ◽  
Jean-Yves Perrot ◽  
Fanny Fava ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Conflicts Of Interest ◽  
Normal Karyotype ◽  
Functional Assay ◽  
Prognosis Factor ◽  
Prognosis Factors ◽  
Abc Proteins ◽  
Npm1 Mutation ◽  
Molecular Alterations ◽  
Mutational Status

Abstract Abstract 1698 Background: Many clinical and biological features are commonly used in order to predict the probability of response to standard treatment in adult acute myeloid leukaemia (AML). Although cytogenetic analysis provides the major information for prognosis, many molecular alterations like FLT3/ITD, mutations of NPM1, mutations of CEBPα, or BAALC over expression have been described these last years, in order to guide therapeutic choices, especially in patients with normal karyotype. In the other hand, prognostic implications of ABC proteins' expression and functionality, like ABCB1 (Pgp) and others, have been known for years but relationships between ABC proteins and those molecular markers haven't been fully studied. Material and methods: In this retrospective study, we explore the relationships between ABC proteins and these molecular markers, and evaluate whether ABC proteins' activity is an independent prognosis factor in 206 AML, homogenously treated in EORTC protocols. ABC proteins' activity has been assessed with JC1 functional test performed at the time of diagnosis, and all patients were screened from frozen bone marrow or peripheral blood samples for FLT3/ITD, NPM1 mutations, CEBPα mutations, and expression of BAALC. 206 patients aged from 16 to 81 years and treated either in EORTC AML 10, AML 12 or AML 13 from 1996 to 2008 have been included, with a median follow up time for alive patients of five years. Results: In the whole population, 42 patients (20%) showed a high ABC functional assay (JC1+). High ABC activity was associated with NPM1 wild type (p=0.03) and higher BAALC expression (p=0.007). FLT3-ITD was detected in only 2 patients with high ABC functional assay. There was no relationship between high ABC functionality and CEBPα mutational status. In multivariate analysis including age, leukocyte count, cytogenetic, existence of a pre leukemic phase, NPM1, FLT3/ITD, CEBPα and BAALC status and JC1 assay, high ABC proteins' activity was an independent prognosis factor for OS in the whole population (p=0.03). Others independent prognosis factors for OS were age (p=0.0004), cytogenetic (p=0,045), FLT3/ITD (p=0.0096), and NPM1 mutation (p= 0.07). When interesting to normal cytogenetic population (112 patients), high ABC proteins' activity was an independent prognosis factor for DFS (p=0.0107) and OS (p=0.0038). Age (p=0.0012), and FLT3/ITD (p=0.0173) were the only other prognosis factors for OS. In patients with normal cytogenetic, and both NPM1 WT and no FLT3/ITD, only age (p=0.0008) and high ABC proteins' activity (p=0.004) were independent prognosis factors for OS. Conclusion: ABC proteins' activity remains an independent prognosis factor in adult AML, when compared to these molecular factors. Because of its relatively high frequency (around 20 % of patients), and the easiness to perform this test, we think JC1 probe should be used in every AML patients in order to refine the treatment strategy at the time of diagnosis. Disclosures: No relevant conflicts of interest to declare.

The Effect of Number of Metaphases Studied and Abnormal Metaphase Percentage On Cytogenetic Risk Stratification in Primary Myelofibrosis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1742-1742
Author(s):  
Shaina A Rozell ◽  
Biruk Mengistu ◽  
Naseema Gangat ◽  
Curtis A. Hanson ◽  
Ryan A Knudson ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Conflicts Of Interest ◽  
International System ◽  
Normal Karyotype ◽  
Primary Myelofibrosis ◽  
Consecutive Series ◽  
Prognostic Impact ◽  
Abnormal Karyotype ◽  
Very High

Abstract Abstract 1742 Background Karyotype is one of the most potent and reproducible risk factors for both overall (OS) and leukemia-free (LFS) survival in primary myelofibrosis (PMF) (Blood 2011;118:4595). It is currently not clear if the number of metaphases studied or the abnormal metaphase percentage alters this prognostic impact. Methods: An updated Mayo Clinic database of karyotypically- and DIPSS-plus-annotated patients with PMF was used to identify a consecutive series of patients and their cytogenetic information obtained at time of referral was centrally re-reviewed. Cytogenetic results were interpreted and reported according to the International System for Human Cytogenetic Nomenclature; abnormal karyotype was defined by the presence of at least 2 metaphases with structural abnormalities or monosomy or 3 metaphases with polysomy, regardless of number of metaphases examined. For this particular study, the presence of less than 20 evaluable metaphases did not disqualify patients. “Very high risk” karyotype included monosomal karyotype, inv(3) or i(17q) abnormalities (Blood 2011;118:4595). “unfavorable” karyotype included complex or any sole or two abnormalities that included +8, −7/7q-, -5/5q-, inv(3), i(17q), 12p-, or 11q23 rearrangement (Blood 2011;118:4595). All other cytogenetic abnormalities were considered “favorable” Results: A total of 590 patients (median age 65 years; range 19–89 years) including 424 (72%) males. The DIPSS-plus (JCO 2011;29:392) risk distribution was 40% high, 39% intermediate-2, 12% intermediate-1 and 9% low. Cytogenetic findings included 17 (3%) very high risk, 69 (12%) unfavorable, 165 (28%) favorable and 339 (57%) normal karyotypes. The number of bone marrow metaphases studied to report these cytogenetic findings were ≥20 in 468 (79%) patients, 11 to 19 in 71 (12%) patients and ≤10 in 51 (9%) patients; the proportion of cases studied with ≥20 metaphases were 53% for very high risk, 74% for unfavorable, 83% for favorable and 80% for normal karyotype (p=0.006). Among patients with abnormal karyotype, the abnormal metaphase percentage was ≥75% in 148 (59%) patients, 50 to 74% in 36 (15%) patients, 26 to 49% in 27 (11%) patients and ≤25% in 38 (15%) patients; the proportion of patients with ≥75% was 59% for very high risk, 67% for unfavorable and 56% for favorable karyotypes (p=0.70). As expected, OS was significantly different among very high risk, unfavorable, favorable and normal karyotype patients with respective median survivals of 8, 23, 41 and 57 months (p<0.0001). The number of metaphases studied (p=0.62) or the abnormal metaphase percentage (p=0.12), by themselves, did not affect survival. Similarly, the survival difference among the aforementioned cytogenetic risk groups was equally apparent when patients with ≥20 metaphases studied (n=468; P<0.0001) and those with <20 metaphases studied (n=122; p<0.0001) were separately analyzed. Analysis of patients with very high risk or unfavorable karyotype (n=86) revealed no significant effect of abnormal metaphase percentage on survival (Figure; p=0.80). A similar scenario was demonstrated for patients with favorable karyotype (Figure; p=0.24). Conclusions: Neither the number of metaphases examined nor the abnormal metaphase percentage appear to influence the currently recognized cytogenetic risk stratification in PMF. The current study has implications for both clinical practice and clinical research involving cytogenetic prognostication in hematological malignancies. Disclosures: No relevant conflicts of interest to declare.

Prognostic Impact of MLL Partial Tandem Duplication in Acute Myeloid Leukemia of Intermediate Cytogenetic Risk: A Subgroup Analysis of Cetlam Protocol 2003 & 2012

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2514-2514
Author(s):  
Marta Pratcorona ◽  
Ana Garrido ◽  
Salut Brunet ◽  
Jordi Esteve ◽  
María Camino Estivill ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Risk Groups ◽  
Complete Response ◽  
Prognostic Impact ◽  
Free Survival ◽  
Molecular Alterations ◽  
Tandem Duplications ◽  
Acute Myeloid

Abstract Background Cytogenetics at diagnosis is the most important prognostic factor in acute myeloid leukemia (AML). Of note, intermediate cytogenetic risk group (IR-AML) is a very heterogeneous subset including normal karyotypes and all the cytogenetic abnormalities not included in the favorable or the adverse groups. Molecular alterations affecting NPM1, FLT3 and CEBPA show a prognostic impact in IR-AML. MLL partial tandem duplications (MLL-PTD) have also been described in this group of AML, but their prognostic impact have not been well established. Aim To analyze the prognostic relevance of MLL-PTD in the subset of patients diagnosed with IR-AML since 2003, and included in the CETLAM protocols LMA-2003 and LMA-2012. Methods Between 2003 and 2004 MLL-PTD were analyzed by Southern Blot (enzymes employed BglII, EcoRI, BamHI). Since 2004, a long PCR strategy was used to identify this abnormality. Results NPM1 mutations (NPM1mut), FLT3 internal tandem duplications (FLT3-ITD) and MLL-PTD were available for 893 patients. No MLL-PTD was found among 111 and 161 patients of the good and poor cytogenetic risk groups, respectively. The IR-AML group included 621 patients, and 37 carried a MLL-PTD (6%), thus only this cytogenetic group of patients was analyzed. NPM1mut were found in a 41% of patients and none of them had a concomitant MLL-PTD (p<0.001). FLT3-ITD were found in a 31% of patients, and 14 patients had also an MLL-PTD. No correlation between MLL-PTD and age, leukocyte count, and percentage of blasts in bone marrow was found. There was a significant association with gender: men were more frequently mutated than women (29 vs 8; p=0.001). Regarding outcome of IR-AML, leukemia-free survival (LFS) was significantly higher for patients without MLL-PTD (5-year LFS 44±3% vs 18±8%; p<0.001), and overall survival (OS) was also better for this subgroup of patients (5-year OS 42±2% vs 20±7%; p=0.004). There were no differences in the complete response rate, but patients with MLL-PTD had a higher risk of relapse (cumulative incidence at 5 years 39 vs 74%, p=0.000151). Among patients with MLL-PTD, no differences were observed depending on the concurrence of FLT3-ITD. When only patients with NPM1 wild-type were considered, MLL-PTD maintained a significantly poor prognostic impact (36±3% vs 21±7%; p=0.009). Conclusions MLL-PTD is a genetic alteration found in a 6% of IR-AML. Patients with this abnormality have a worse LFS and OS than the rest of patients of the IR-AML group. Based on these results, patients with MLL-PTD should be considered as patients with poor cytogenetic risk AML for treatment allocation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Molecular diagnostics helps to identify distinct subgroups of spinal astrocytomas

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Annamaria Biczok ◽  
Felix L. Strübing ◽  
Julia M. Eder ◽  
Rupert Egensperger ◽  
Oliver Schnell ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Molecular Markers ◽  
Prognostic Significance ◽  
The Elderly ◽  
Molecular Profile ◽  
Diffuse Astrocytoma ◽  
Molecular Alterations ◽  
High Grade Astrocytoma ◽  
Dismal Prognosis ◽  
Few Data

AbstractPrimary spinal cord astrocytomas are rare, hence few data exist about the prognostic significance of molecular markers. Here we analyze a panel of molecular alterations in association with the clinical course. Histology and genome sequencing was performed in 26 spinal astrocytomas operated upon between 2000 and 2020. Next-generation DNA/RNA sequencing (NGS) and methylome analysis were performed to determine molecular alterations. Histology and NGS allowed the distinction of 5 tumor subgroups: glioblastoma IDH wildtype (GBM); diffuse midline glioma H3 K27M mutated (DMG-H3); high-grade astrocytoma with piloid features (HAP); diffuse astrocytoma IDH mutated (DA), diffuse leptomeningeal glioneural tumors (DGLN) and pilocytic astrocytoma (PA). Within all tumor entities GBM (median OS: 5.5 months), DMG-H3 (median OS: 13 months) and HAP (median OS: 8 months) showed a fatal prognosis. DMG-H3 tend to emerge in adolescence whereas GBM and HAP develop in the elderly. HAP are characterized by CDKN2A/B deletion and ATRX mutation. 50% of PA tumors carried a mutation in the PIK3CA gene which is seemingly associated with better outcome (median OS: PIK3CA mutated 107.5 vs 45.5 months in wildtype PA). This exploratory molecular profiling of spinal cord astrocytomas allows to identify distinct subgroups by combining molecular markers and histomorphology. DMG-H3 tend to develop in adolescence with a similar dismal prognosis like GBM and HAP in the elderly. We here describe spinal HAP with a distinct molecular profile for the first time.

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