Prognostic Impact Of Molecular Mutations In 182 Patients With Myelodysplastic Syndromes

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2758-2758 ◽  
Author(s):  
Andrea Kuendgen ◽  
Jenny Seidler ◽  
Michael Lauseker ◽  
Torsten Haferlach ◽  
Susanne Schnittger ◽  
...  
Keyword(s):  
Research Funding ◽  
Somatic Mutations ◽  
Risk Group ◽  
Normal Karyotype ◽  
Diagnostic Procedures ◽  
Risk Groups ◽  
Employment Equity ◽  
Clinical Routine ◽  
Blast Count ◽  
Equity Ownership

Abstract Introduction Myelodysplastic syndromes (MDS) are heterogeneous regarding clinical characteristics, as well as prognosis and treatment approaches. Therapeutic decision making relies greatly on prognostic scoring systems. Recently, the gold-standard IPSS (International prognostic scoring system [Greenberg Blood 1997]) has been revised. The new IPSS-R still uses cell counts, marrow blast count, and karyotypic abnormalities to stratify patients (pts) into risk groups [Greenberg Blood 2012]. However, more than 50% of all MDS pts present with a normal karyotype and even in pts with identical chromosomal abnormalities outcome may vary. Somatic mutations are more common than cytogenetic abnormalities and can be identified in over 70% of pts including pts with normal karyotype [Bejar JCO 2012]. Therefore, the addition of such mutations to common prognostic markers might help to refine prognostication in MDS pts and improve therapeutic procedures by individualizing MDS treatment. Patients and Methods We analyzed 182 pts with different subtypes of MDS: RCUD, RARS, MDS-U, 5q- (n=28), RCMD +/-RS (n=85), RAEB 1 (n=16), RAEB 2 (n=25), MDS/MPD (n=24), AML <30% marrow blasts (n=4). Median age was 68 (16-87) years. Patients belonged to the following cytogenetic risk groups: 73% good, 13% intermediate, and 14% poor risk according to IPSS. In 29% of pts IPSS risk group was low, 43% intermediate 1, 21% intermediate 2, and 7% belonged to the high risk group. IPSS-R risk groups were very good 10%, good 32%, intermediate 29%, poor 13%, and very poor 16%. Various molecular assays were performed including sensitive next-generation sequencing for mutations in ASXL1, DNMT3A, EZH2, FLT3-ITD, IDH1, KRAS, MLL-PTD, NRAS, RUNX1, SF3B1, SFRS2, TET2, and TP53. Most of the data was collected prospectively within the clinical routine diagnostic procedures. During that time the marker panel was adjusted, when new analyses became available. Thus, not all markers are currently available for all pts (see table). To assess the impact of the biomarkers, Kaplan-Meier curves were estimated starting at the day of diagnosis. Results The most frequent mutation was TET2 (30.2%), followed by ASXL1 (25.4%), SF3B1 (22.9%), SFRS2 (22.2%), RUNX1 (20.4%), DNMT3A (13.7%), TP53 (9.9%), EZH2 (9.0%), NRAS (4.7%), MLL-PTD (3.8), IDH1 (3.5%), FLT3-ITD (3.3%), KRAS (2.8%), IDH2 (2.8%), and CBL (2.2%). Three pts with normal karyotype, who would have been classified as ICUS (idiopathic cytopenia of undetermined significance) due to only mild dysplasia, were reclassified as MDS-U as they exhibited typical somatic mutations (RUNX1 plus TET2; TET2, and DNMT3A). Median follow up was 3.8 years (95% confidence interval [CI] 3.1-4.5). During this time 74 pts died and 108 pts were censored at the last date they were known to be alive. Median survival was 4.9 years (95% CI 2.7-7.1). A significant influence on survival in univariate analysis could be demonstrated for TP53 (p<0.001), EZH2 (p=0.003), SF3B1 (p=0.016), ASXL1 (p=0.016), and RUNX1 (p=0.042) (see table). Other prognostic variables with significant impact regarding survival were age at diagnosis (p<0.001), Hb (p=0.001), platelet count (p=0.002), marrow blast count (p<0.001), FAB subgroup (p<0.001), IPSS (p<0.001), IPSS-R (p<0.001), and cytogenetic risk groups according to IPSS (p<0.001) as well as IPSS-R (p=0.001). Conclusion We could confirm mutations in TP53, EZH2, RUNX1, and ASXL1 to be predictors of poor overall survival, while SF3B1 mutations conferred a favorable prognosis in pts with MDS. Integrating mutation assessment into the clinical routine might improve diagnostic procedures as well as prognostication, and individualize treatment approaches. Further analyses are ongoing. Disclosures: Kuendgen: Celgene: Honoraria, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Gattermann:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Götze:Celgene Corp: Honoraria. Germing:Celgene: Honoraria, Research Funding.

Somatic Mutations in MDS Patients Are Associated with Clinical Features and Predict Prognosis Independent of the IPSS-R: Analysis of Combined Datasets from the International Working Group for Prognosis in MDS-Molecular Committee

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 907-907 ◽  
Author(s):  
Rafael Bejar ◽  
Elli Papaemmanuil ◽  
Torsten Haferlach ◽  
Guillermo Garcia-Manero ◽  
Jaroslaw P. Maciejewski ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Somatic Mutations ◽  
Prognostic Significance ◽  
Risk Groups ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background Somatic mutations identified in patients with myelodysplastic syndromes (MDS) are associated with disease features and carry prognostic information independent of the International Prognostic Scoring System (IPSS) and the revised IPSS (IPSS-R). Risk models that include mutation information have been proposed, but not widely adopted. In practice, there is no consensus on how to best combine clinical information with tumor sequencing data to predict prognosis. To accomplish this, we must define the relevant genes to consider and accurately measure their prognostic impact. Here we examine the relationship between mutations in MDS-associated genes and clinically relevant measures, including overall survival, in a large, multi-center analysis of MDS patient cohorts collected around the globe. Methods Data on 3392 MDS patients gathered by members of the International Working Group for Prognosis in MDS-Molecular Committee were combined under the aegis of the MDS Foundation. Patients gave informed consent for collection of their data and tumor samples at their respective institutions in accordance with the Declaration of Helsinki. Samples were examined for somatic mutations primarily by next generation sequencing. Categorical variables were compared using a chi-squared test, while continuous variables were compared using a Wilcoxon rank-sum test. Overall survival (OS) was calculated from the date of the sequenced sample to the date of death and was censored at transplant or the last known follow-up time. P-values are two-sided and considered significant at the <0.001 level to adjust for multiple comparisons. Results Survival data were available for 3200 patients with a median follow up of 3.7 years and included 1671 deaths. Median survival of the cohort was 2.88 years. The 27 genes sequenced in at least half of the cohort and mutated in > 1.5% of samples were included for analysis (Figure 1). Mutations in 12 genes were strongly associated with shorter OS in univariate analyses (p<0.001 for each gene): ASXL1, CBL, EZH2, IDH2, NF1, NRAS, PTPN11, RUNX1, SRSF2, STAG2, TP53, and U2AF1. Only mutations of SF3B1 were associated with a longer OS at this significance threshold. The large size of the cohort allowed for more precise estimates of survival in less frequently mutated genes. For example, mutations of IDH2 (present in 3.4% of cases, n=103) were associated with shorter OS (hazard ratio [HR] 1.61, 95% confidence interval [CI] 1.26-2.05; p=0.0001) whereas IDH1 mutations (present in 2.4% of cases, n=77) were only marginal (HR 1.29, CI: 0.97-1.72; p=0.082), demonstrating the distinct impact of mutations in these highly related genes. IPSS-R risk groups could be determined for 2173 patients and were strongly associated with OS. Adjusting the hazard ratio of death for IPSS-R risk groups identified several mutated genes with independent prognostic significance: TP53 (HR 2.37, CI 1.94-2.90), CBL (HR 1.57, CI 1.22-2.03), EZH2 (HR 1.55, CI 1.22-2.03), and RUNX1 (HR 1.50, CI 1.24-1.83). Mutations of U2AF1 (HR 1.29, CI 1.06-1.58) and ASXL1 (HR 1.21, CI 1.04-1.41) retained a more modest association with shorter OS. Adjustment for IPSS-R risk groups also moderated the favorable risk associated with mutations of SF3B1 (HR 0.83, CI 0.70-0.99). Patients without mutations in any of the 6 adverse genes above represented 58% of the fully sequenced cohort and had a longer median survival than patients with adverse mutations (4.8 years vs. 1.6 years respectively, p < 0.0001; Figure 2) even after correction for IPSS-R risk groups (adjusted HR 0.59, CI 0.51-0.67). Multivariable analysis of this dataset will examine the combined contribution of mutated genes to prognosis. A mutation score based on survival risk will be proposed and internally validated. The impact of somatic mutation in patients traditionally considered lower risk will be explored. Conclusions This large study definitively validates the prognostic value of mutations in several MDS-associated genes while clarifying the significance of other, less frequently mutated ones. Mutations in several genes retain their prognostic significance after adjustment for IPSS-R risk groups, indicating that these select abnormalities could refine the prediction of prognosis when incorporated into a clinical scoring system such as the IPSS-RM. The results of this analysis will serve as the template with which to build an integrated molecular risk model for MDS. Disclosures Bejar: Alexion: Other: ad hoc advisory board; Celgene: Consultancy, Honoraria; Genoptix Medical Laboratory: Consultancy, Honoraria, Patents & Royalties: MDS prognostic gene signature. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Fenaux:Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Shih:Novartis: Research Funding. Komrokji:Celgene: Consultancy, Research Funding; Incyte: Consultancy; Novartis: Research Funding, Speakers Bureau; Pharmacylics: Speakers Bureau. List:Celgene Corporation: Honoraria, Research Funding. Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Campbell:14M genomics: Other: Co-founder and consultant. Ebert:Celgene: Consultancy; Genoptix: Consultancy, Patents & Royalties; H3 Biomedicine: Consultancy.

scholarly journals p53 Mutant Independently Impacts Risk: Analysis of Deletion 5q, Lower-Risk Myelodysplastic Syndromes (MDS) Patients Treated with Lenalidomide (LEN) in the MDS-004 Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 414-414 ◽  
Author(s):  
Leonie Saft ◽  
Jack Shiansong Li ◽  
Peter L. Greenberg ◽  
Mikkael A. Sekeres ◽  
Guillermo F. Sanz ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Lower Risk ◽  
Research Funding ◽  
Risk Group ◽  
Risk Groups ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Very High

Abstract Introduction: Refined risk-classification of patients (pts) with MDS allows for improved treatment selection for individual pts. The Revised International Prognostic Scoring System (IPSS-R) has recently been validated as a prognostic tool in lower-risk MDS pts with deletion 5q [del(5q)], who were treated with LEN in the MDS-004 study (Sekeres et al. Blood Cancer J 2014; in press). P53 nuclear protein expression, as assessed by immunohistochemistry (IHC), predicted overall survival (OS) and risk of progression to acute myeloid leukemia (AML) in lower-risk MDS pts with del(5q) (Saft et al. Haematologica 2014;99:1041-9). This analysis evaluated the prognostic value of adding p53 IHC to IPSS-R to predict OS and AML progression in pts with lower-risk MDS with del(5q). Methods: In a subset of 85 pts from MDS-004 with bone marrow (BM) biopsies available, p53+ staining (≥ 1% IHC+++ BM cells) was visualized by IHC. Twenty-four pts had missing IPSS-R scores; 1 due to lack of baseline cytogenetic data and 23 because of missing exact BM blast percentage. Thus, 61 pts (42 initially treated with LEN and 19 with placebo) had IPSS-R and p53 IHC data available; 89% of pts in the placebo group crossed over to LEN 5 mg at Week 16. The IPSS-R Very Low and Very High risk groups with < 5 pts were combined with the Low and High risk groups, respectively. AML-free survival (AFS), OS, and time to AML progression within p53 IHC status (p53+ vs p53−), and IPSS-R risk groups were characterized by the Kaplan-Meier method with differences evaluated by the log-rank test. Results: Of 61 pts, 38% were p53+. There was a linear increasing trend in the proportion of pts with p53+ across IPSS-R risk groups from Very Low/Low, Intermediate to High/Very High (29%, 47% and 63%, respectively; Cochran-Armitage trend test P = 0.050). The 3 IPSS-R risk groups significantly predicted AFS and OS (log-rank P < 0.001 for both AFS and OS), but not time to AML progression (P = 0.335). Overall, AFS, OS, and time to AML progression differed significantly between p53+ versus p53− pts (23.9 vs 47.9 months for median AFS, P = 0.003; 27.0 vs 50.6 months for median OS, P = 0.005; and 44.3 months vs not reached [NR] for median time to AML progression,P = 0.003). In the IPSS-R Very Low/Low risk group (n = 38), AFS, OS, and time to AML progression were significantly worse in p53+ versus p53− pts (20.1 vs 63.1 months for median AFS, P = 0.011; 28.4 vs 76.8 months for median OS, P = 0.031; and 65.2 months vs NR for median time to AML progression, P = 0.014). Results for all IPSS-R risk groups in pts with p53 and IPSS-R data are presented in the Figure. The lack of significant differences between p53+ versus p53− pts in the Intermediate and High/Very High risk groups is likely due to the small sample size of these groups. Conclusions: In this exploratory subset analysis of lower-risk MDS pts with del(5q), p53 IHC status in the IPSS-R Very Low/Low risk group significantly impacted AFS, OS, and AML progression. These data support the addition of p53 mutational analysis to prognostic risk assessment which should help inform the selection of appropriate treatment for individual MDS pts with del(5q). These results need to be validated in a large sample set, which will be accomplished as part of the ongoing efforts to include prognostic molecular mutations in future updates of IPSS-R Figure 1 AFS (A), OS (B), and time to AML progression (C) in pts with p53 and IPSS-R data (N = 61) Figure 1. AFS (A), OS (B), and time to AML progression (C) in pts with p53 and IPSS-R data (N = 61) Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Shiansong Li: Celgene Corporation: Employment, Equity Ownership. Greenberg:Celgene: Research Funding; Onconova: Research Funding; GSK: Research Funding; Novartis: Research Funding; KaloBios: Research Funding. Sekeres:Amgen Corp.: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim Corp.: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Dreyfus:Novartis: Honoraria; Celgene: Honoraria. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene: Research Funding. Swern:Celgene: Employment, Equity Ownership. Sugrue:Celgene: Employment, Equity Ownership. Hellstrom-Lindberg:Celgene: Research Funding.

Varying Importance of Prognostic Factors in Subgroups of Myelodysplastic Syndromes Defined by Blast Count, Cytogenetic Risk Group, or WHO Classification.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2776-2776
Author(s):  
Andrea Kuendgen ◽  
Corinna Strupp ◽  
Kathrin Nachtkamp ◽  
Barbara Hildebrandt ◽  
Rainer Haas ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
High Risk ◽  
Research Funding ◽  
Risk Group ◽  
Univariate Analysis ◽  
Risk Groups ◽  
High Risk Group ◽  
Intermediate Risk ◽  
Blast Count

Abstract Abstract 2776 Poster Board II-752 Introduction: We wondered whether prognostic factors have similar relevance in different subpopulations of MDS patients. Methods: Our analysis was based on patients with primary, untreated MDS, including 181 RA, 169 RARS, 649 RCMD, 322 RSCMD, 79 5q-syndromes, 290 RAEB I, 324 RAEB II, 266 CMML I, 64 CMML II, and 209 RAEB-T. The impact of prognostic variables in univariate analysis was compared in subpopulations of patients defined by medullary blast count, namely <5%, ≥5% (table), ≥10%, and ≥20% (not shown), as well as 3 subpopulations defined by the cytogenetic risk groups according to IPSS (table). Multivariate analysis of prognostic factors was performed for cytogenetically defined subgroups and WHO-subtypes. Results: Strong prognostic factors in all blast-defined subgroups were hemoglobin, transfusion dependency, increased WBC, age, and LDH. However, all variables became less important in patients with ≥20% blasts (RAEB-T) and increased WBC was rare. Platelet count and cytogenetic risk groups were relevant in patients with <5%, ≥5%, and ≥10% marrow blasts, but not in RAEB-T. Marrow fibrosis was important in patients with <5% or ≥5% blasts, but not ≥10%. Gender and ANC <1000/μl were significant only in patients with a normal blast count. Furthermore, we looked for the effect of the karyotypes, relevant for IPSS scoring (-Y, del5q, del20q, others, del7q/-7, complex), and found a comparable influence on survival, irrespective whether patients had < or ≥5% marrow blasts. In subpopulations defined by cytogenetic risk groups, several prognostic factors were highly significant in univariate analysis, if patients had a good risk karyotype. These included hemoglobin, sex, age, LDH, increased WBC, transfusion need, and blast count (cut-offs 5%, 10%, and 20%). In the intermediate risk group only LDH, platelets, WBC, and blasts were significant prognostic factors, while in the high risk group only platelets and blast count remained significant. Multivariate analysis was performed for the cytogenetic risk groups and for subgroups defined by WHO subtypes. The analysis considered blast count (</≥5%), hemoglobin, platelets, ANC, cytogenetic risk group, transfusion need, sex, and age. In the subgroup including RA, RARS, and 5q-syndrome, LDH, transfusion, and age in descending order were independent prognostic parameters. In the RCMD+RSCMD group, karyotype, age, transfusion, and platelets were relevant factors. In the RAEB I+II subgroup, the order was hemoglobin, karyotype, age, and platelets, while in CMML I+II only hemoglobin had independent influence. In RAEB-T none of the factors examined was of independent significance. Looking at cytogenetic risk groups, in the favorable group, several variables independently influenced survival, namely transfusion, blasts, age, sex, and LDH (in this order). Interestingly, in the intermediate and high risk group, only blast count and platelets retained a significant impact. Conclusion: Univariate analysis showed prognostic factors (except ANC) included in IPSS and WPSS are relevant in most subgroups defined by marrow blast percentage. However, they all lose their impact if the blast count exceeds 20%. Regarding cytogenetic risk groups, several prognostic factors lose their influence already in the intermediate risk group. This underscores the prognostic importance of MDS cytogenetics. Multivariate analysis showed MDS subpopulations defined by WHO types also differ with regard to prognostic factors. In particular, CMML and RAEB-T stand out against the other MDS types. Disclosures: Kuendgen: Celgene: Honoraria. Hildebrandt:Celgene: Research Funding. Gattermann:Novartis: Honoraria, Participation in Advisory Boards on deferasirox clinical trials. Germing:Novartis, Celgene: Honoraria, Research Funding.

Major Route Additional Chromosomal Aberrations (ACA) Precede Increase of Blasts in CML: An Analysis of the German CML-Studies III and IIIA

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1581-1581
Author(s):  
Christian T. Dietz ◽  
Alice Charlotte Fabarius ◽  
Michael Lauseker ◽  
Susanne Saussele ◽  
Lida Kalmanti ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Employment Equity ◽  
Advisory Committees ◽  
Score Study ◽  
Major Route ◽  
Blast Count ◽  
Travel Grant ◽  
Equity Ownership

Abstract During the course of chronic myeloid leukemia (CML) progression to blast crisis (BC) is thought to be caused by genetic instability such as cytogenetic aberrations in addition to the translocation t(9;22)(q34;q11). We have shown previously that major route ACA indicate an unfavorable outcome (Fabarius et al., Blood 2011). We now investigate whether there is a correlation in time between appearance of major route ACA and increase in blast count. Methods: Cytogenetic data and blast count in the peripheral blood were available from 1,290 CML patients recruited to the German CML-studies III (621 patients) and IIIa (669 patients) from January 1995 to January 2004. Treatments were interferon-alpha-based or related allogeneic stem cell transplantation (HSCT). Presence of ACA and major route ACA was considered as a time-dependent covariate. Multivariate proportional hazards models were estimated taking Euro CML score, study III vs. IIIa and stem cell transplantability into account. Cumulative incidences of blast increases were calculated starting at the date of the first ACA or major route ACA, respectively, regarding death as a competing risk. Patients were censored at the date of HSCT with an unrelated donor. Results: 1,287 patients were evaluable with median observation times of 13 and 12 years and a 10-year survival of 48% and 61% in CML studies III and IIIa, respectively. 258 patients progressed to BC with a cumulative 10-year incidence of 20%. 195 patients displayed ACA during the course of disease. 45 patients (15.7%) showed ACA already at diagnosis. 44 patients showed unbalanced minor route, 29 balanced minor route aberrations, 23 -Y. 109 patients showed major route aberrations including 10 with other prior ACA. In a multivariate analysis on 1,257 patients, patients with ACA had a hazard ratio (HR) for a blast increase of between 2.0-2.2 (p<0.001) for blast increases to ≥1%, ≥5%, ≥10%, ≥15%, ≥ 20% and ≥30% compared with patients without ACA (Table). When the same model was performed for major route ACA only at any time during disease, HRs of 2.2-2.7 (p<0.001) were found. For ACA without major route ACA HRs were 1.6-2.1 (p<0.001). In the multivariate analyses of major route ACA vs. no major route ACA a blast increase of 1-5% after diagnosis of major route ACA seems already indicative of progression. 5 years after the diagnosis of any ACA the cumulative incidence for a blast increase was 30% (95%- confidence interval (CI): 23-38%), of a major route ACA 40% (95%- CI: 28-49%). The 6-year probability of death without blast increase was 10%. 14 additional patients received an unrelated transplant of which 6 died. We conclude that ACA, particularly major route ACA, precede an increase of blasts. Major route ACA have to be considered as a prognostic indicator for disease progression at any time. Table 1. Blast increase to HR (univariate): ACA vs. no ACA HR(multivariate)*: ACA vs. no ACA HR (univariate): major route ACA vs. no major route ACA HR (multivariate)*: major route ACA vs. no major route ACA ≥30% 2.409 2.139 2.646 2.203 ≥20% 2.413 2.144 2.656 2.211 ≥15% 2.415 2.161 2.868 2.426 ≥10% 2.416 2.160 2.799 2.357 ≥5% 2.286 2.047 2.719 2.278 ≥1% 2.209 1.999 3.171 2.684 *adjusted to Euro-Score, study (III vs. IIIa) and transplantability Disclosures Saussele: ARIAD: Honoraria; BMS: Honoraria, Other: Travel grant, Research Funding; Pfizer: Honoraria, Other: Travel grant; Novartis Pharma: Honoraria, Other: Travel grant, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Scheid:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Baerlocher:Geron Corporation: Research Funding; Novartis: Research Funding. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Müller:BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Pfirrmann:BMS: Consultancy, Honoraria; Novartis Pharma: Consultancy, Honoraria. Baccarani:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hehlmann:BMS: Consultancy; Novartis Pharma: Research Funding.

scholarly journals Molecular Dissection of Del(5q): Distinction between Primary and Secondary Del(5q) and Pathogenetic Implications

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4221-4221
Author(s):  
Vera Adema ◽  
Laura Palomo ◽  
Cassandra M Kerr ◽  
Wencke Walter ◽  
Bartlomiej Przychodzen ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Somatic Mutations ◽  
Germ Line ◽  
Data Monitoring Committee ◽  
Allelic Exclusion ◽  
Employment Equity ◽  
Advisory Committees ◽  
Associated Lesions ◽  
Equity Ownership

Del(5q) is the most common cytogenetic (CG) alteration in myeloid neoplasia (MN), and solo defines the 5q- syndrome. Despite significant progress in understanding the disease mechanisms resulting from del(5q), the pathogenesis behind this lesion, in particular its effect on leukemogenesis, is still not clear. The absence of corresponding somatic LOH in the del(5q) region suggests that the haploinsufficiency (HI) resulting from the deletion might be the key pathogenic factor. However, none of the investigated HI genes located on del(5q) can explain the 5q related growth advantage/transformation. High molecular diversity including somatic mutations in the retained allele, additional CG abnormalities, epigenetic factors (loss/gain of silencing), and LOH for germ line (GL) protective alleles may preclude the identification of the pathogenically essential lesions. We revisit the genomics of del(5q) by taking advantage of a large cohort of patients with molecular (WES, WGS, RNAseq) and clinical annotation. We analyzed a total of 400 samples (388 patients) with del(5q) and 825 diploid patients with MN. Patients were subgrouped into isolated del(5q) (iso-del5q; 49%) and del(5q) with additional lesions referred to as compound del(5q) (comp-del5q). Availability of paired GL WES results allowed us to reconstruct clonal hierarchy using precise bioanalytic allelic exclusion methods. Studies have postulated that del(5q) is a founder event; we now demonstrate that 52% of iso-del5q patients did have a dominant del(5q) event, but in 56% of comp-del5q and 28% of iso-del5q, del(5q) was subclonal. Co-dominant del(5q) with somatic mutations were also found (iso-del5q: 20% vs. comp-del5q: 11%). When del(5q) was dominant, patients had fewer associated mutations, while cases with secondary del(5q) had a poor prognosis due to ancestral TP53 mutations (MT) and accumulation of chromosomal breaks. We then focused on the expression level: 405 genes on 5q were interrogated, 188 within q14q34 (CDR-1: 41; CDR-2: 55). We defined HI as expression <25th %tile of the diploid expression. CSNK1A1 was deleted in 90% and HI in 77% of del(5q), whereas RPS14 was deleted in 89% but HI in 39% of del(5q) cases. Applying a more stringent definition (<68% of diploid), the most consistently HI genes were SIL1 in 61%, H2AFY in 58%, and CTNNA1 in 49% of cases vs. <5% of diploid cases. By this criterion, RPS14, ACSL6 and TGFBI were also HI in 19%, 17% and 16% of diploid cases. Del(5q) HI genes showed an enrichment of 49x in β-catenin phosphorylation cascade genes (P<.0001), 25x in Wnt signaling (P=.001) and 5x in cell cycle genes (P<.0001). When the entire profile was examined, TP53 and apoptotic genes also showed enrichment in upregulation (both P<.0001). We also genotyped del(5q) and a control diploid cohort for somatic mutations. Within the 5q CDR APC, RAD50, and CSNK1A1 were most frequently mutated (all hemizygous), particularlly in iso-del5q. No canonical DDX41 frame shift mutations (GL) or somatic mutations occurred in its ATP binding domains were found. However, there were DDX41MT (n=2) that coincided with del(5q) and one patient coincided with the CDR. Del(5q) patients had a distinct mutational profile of co-associated lesions with a higher frequency of TP53MT (P<.0001) and a significantly lower frequency of SF3B1, ASXL1, TET2, JAK2, SETBP1, U2AF1 and SRSF2 mutations (all P<.01) than diploid patients. TP53MT were enriched in comp-del5q in cases that frequently also demonstrated -7/7q- and 17p-. CSNK1A1 and TP53 are the two most common mutations in del(5q) patients. CSNK1A1MT were co-mutated with TP53 in only 15% of patients and CSNK1A1 HI did not enrich for TP53MT. Expression of p21 (a TP53 activation marker) was up-regulated in del(5q) except for cases with biallelic TP53 inactivation. RPS14 was HI in a fraction of del(5q) patients. Patients with the RPS14 deleted locus were more likely that those with HI to have an increase in p21 expression (P<.0001) but only in patients with advanced disease. In sum, our analysis of a comprehensive compendium of del(5q) genomics revises previous assumptions (del(5q) is not a uniform founder lesion, and the heterogeneity HI of genes across patients), discovers new HI candidate genes and precisely describes molecular relationships (e.g., del(5q) with TP53) and generated a minimalistic expression signature of del(5q). Disclosures Walter: MLL Munich Leukemia Laboratory: Employment. Hutter:MLL Munich Leukemia Laboratory: Employment. Díez-Campelo:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nazha:Jazz Pharmacutical: Research Funding; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Incyte: Speakers Bureau; Tolero, Karyopharma: Honoraria; Abbvie: Consultancy; Daiichi Sankyo: Consultancy. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Maciejewski:Alexion: Consultancy; Novartis: Consultancy.

scholarly journals Overall Survival in Older Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) with >30% Bone Marrow Blasts Treated with Azacitidine By Cytogenetic Risk Status: Results of the AZA-AML-001 Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 621-621 ◽  
Author(s):  
Hartmut Döhner ◽  
John F Seymour ◽  
Aleksandra Butrym ◽  
Agnieszka Wierzbowska ◽  
Dominik Selleslag ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Older Patients ◽  
Research Funding ◽  
Risk Groups ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Poor Risk ◽  
Equity Ownership

Abstract Background: Overall survival (OS) in older patients (pts) with AML and poor-risk cytogenetics is only ~2-3 months (mos) (Burnett, Cancer, 2007). Often these pts receive only palliative treatment (Tx) with best supportive care (BSC). Low-dose Ara-C (LDAC) provides no OS benefit in pts with poor cytogenetics (Döhner, Blood, 2010). Typically, intensive chemotherapy (IC) is either not suitable for older AML pts with poor cytogenetics or, when it is used, provides no OS benefit (Kantarjian, Blood, 2010). The phase 3, multicenter, randomized, open-label AZA-AML-001 trial showed azacitidine (AZA) Tx in older pts with newly diagnosed AML (>30% bone marrow [BM] blasts) prolonged median OS by ~4 mos vs conventional care regimens (CCR) (10.4 vs 6.5 mos; p=0.1009) and improved 1-year survival (46.5% vs 34.2%) (Dombret, EHA, 2014). Cytogenetic risk is a prognostic indicator in elderly AML and a frequent determinant of Tx approach and outcomes. Objective: To determine the effect of Tx with AZA vs CCR on OS and 1-year survival in AZA-AML-001 pt subgroups based on cytogenetic risk classification. Methods: Pts aged ≥65 years with newly diagnosed de novo or secondary AML who were ineligible for transplant, with intermediate- or poor-risk cytogenetics (pts with favorable cytogenetics were excluded from study), ECOG performance status 0-2, and WBC count ≤15x109/L, were eligible. Before randomization, each pt was preselected to receive 1 of 3 commonly used CCR for older pts with AML, per investigator choice: IC (standard 7+3 regimen), LDAC (20 mg SC BID x 10 days/28-day cycle), or BSC only. Pts were then randomized to AZA (75 mg/m2/day SC x 7 days/28-day cycle) or to CCR, in which case they received their preselected Tx. The primary endpoint was OS. Cytogenetic risk groups were assessed per NCCN criteria by central review: intermediate (INT; all cases), intermediate with normal karyotype (cytogenetic normal [CN]), and poor. Survival at 1 year was compared between Tx. Median OS for AZA vs CCR was calculated using Kaplan-Meier methods, hazard ratios (HR) and 95% confidence intervals (CI) were determined by unstratified Cox proportional hazards model, and p values by log-rank test. Results: In all, 488 pts were randomized, 241 to AZA and 247 to CCR. Cytogenetic risk was balanced between Tx groups: 315 pts had INT-risk cytogenetics (AZA n=155 [64%], CCR n=160 [65%]), including 218 who were CN (AZA n=113 [73%], CCR n=105 [66%]), and 170 pts had poor-risk cytogenetics (AZA n=85 [35%], CCR n=85 [34%]). Within each of the 3 cytogenetic risk subgroups, the distribution of pts receiving individual CCR was very consistent: ~18% of each cytogenetic risk subgroup received BSC, ~64% received LDAC, and ~18% received IC. Baseline characteristics were generally balanced among the AZA and CCR Tx arms and the 3 cytogenetic risk groups (Table). At baseline, proportionately more pts with poor-risk cytogenetics in the AZA group were aged ≥75 years (57.6% vs 47.1% with CCR) and more pts in the CCR group had AML with myelodysplastic changes (45.9% vs 37.6% with AZA). Median OS (95%CI) in poor-risk pts was significantly prolonged with AZA vs CCR: 6.4 mos (4.2, 8.1) vs 3.2 mos (2.2, 4.7), respectively; HR=0.68 (0.50, 0.94), p=0.019 (Figure). Median OS in INT-risk pts was 13.0 mos (11.2, 16.3) vs 10.1 mos (7.1, 13.3) with AZA vs CCR; HR=0.90 (0.70, 1.16), p=0.41. Median OS in the CN subgroup was 14.1 mos (12.6, 19.5) vs 10.0 mos (6.4, 13.3); HR=0.81 (0.59, 1.10), p=0.18. Estimated 1-year survival was higher with AZA vs CCR in all cytogenetic risk subgroups. Twice the proportion of AZA-treated pts in the poor-risk subgroup were alive at 1 year vs. CCR pts (30.9% vs 14.0%, respectively), a clinically meaningful difference of 16.9% (95%CI 4.4, 29.5). Similarly, in the CN subgroup, 60.7% vs 44.1% of pts were alive at 1 year in the AZA and CCR groups, a difference of 16.5% (3.2, 29.8). AZA effect on 1-year survival in the INT-risk subgroup was also favorable (55.2% vs 45.5% with CCR) (difference 9.7% [-1.4, 20.8]). Grade 3-4 hematologic adverse event rates with AZA were consistent with previous reports (Santini, Eur J Haematol, 2010), with no meaningful differences among all cytogenetic risk groups. Conclusions: Median OS in older pts with AML and poor-risk cytogenetics was meaningfully improved with AZA compared with the CCR currently used for AML, with those pts receiving AZA twice as likely to be alive at 1 year as those treated with CCR. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Döhner: Celgene: Consultancy. Off Label Use: Use of azacitidine in AML with blast count >30%. Seymour:Celgene: Consultancy, Honoraria, Speakers Bureau. Wierzbowska:Celgene: Honoraria, Speakers Bureau. Selleslag:Celgene: Consultancy, Research Funding, Speakers Bureau. Cavenagh:Celgene: Honoraria. Kumar:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Schuh:Celgene: Membership on an entity's Board of Directors or advisory committees. Candoni:Celgene: Consultancy, Speakers Bureau. Récher:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sandhu:Celgene: Honoraria. Bernal del Castillo:Celgene: Consultancy. Al-Ali:Celgene: Honoraria, Research Funding. Martinelli:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; ARIAD: Consultancy. Falantes:Celgene: Consultancy. Stone:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Minden:Celgene: Honoraria. McIntyre:Celgene: Employment. Songer:Celgene: Employment, Equity Ownership. Lucy:Celgene: Employment, Equity Ownership. Beach:Celgene: Employment, Equity Ownership. Dombret:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Whole-Exome Sequencing Revealed No Recurrent Mutations within the PI3K Pathway in Relapsed Chronic Lymphocytic Leukemia Patients Progressing Under Idelalisib Treatment

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2770-2770 ◽  
Author(s):  
Paolo Ghia ◽  
Viktor Ljungström ◽  
Eugen Tausch ◽  
Andreas Agathangelidis ◽  
Annika Scheffold ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Research Funding ◽  
Somatic Mutations ◽  
Lymphocytic Leukemia ◽  
Employment Equity ◽  
Phase 3 ◽  
Whole Exome ◽  
Equity Ownership

Abstract Introduction: Idelalisib (IDELA) is an ATP-competitive, reversible, and selective small molecule inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3Kδ) approved for the treatment, in combination with rituximab, of patients with relapsed chronic lymphocytic leukemia (CLL). In the relapsed CLL randomized, controlled trials, IDELA + rituximab showed high response rates with improved progression-free and overall survival as compared with placebo + rituximab. While IDELA therapy has significant efficacy, disease progression after response occurs, indicating that escape mechanisms may develop. However, the molecular basis for relapse or progressive disease (PD) in CLL patients treated with IDELA has not yet been characterized. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from 13 CLL patients enrolled in the phase 3 studies; NCT01539512 (study 116; IDELA + rituximab vs placebo + rituximab), 116 extension study NCT01539291 (study 117) and NCT01659021 (study 119; IDELA + ofatumumab). Sample selection criteria included treatment period of at least 180 days (range: 243-703 days), achieving at least partial nodal response followed by PD, PD did not occur within a drug interruption window, PD was not associated with Richter's transformation, and PBMC samples were available from both baseline and time of PD. Whole-exome sequencing (WES) was conducted on the matched samples from 13 subjects fitting the above criteria. In 6/13 cases, DNA was available from CD19+/CD5+ enriched tumor cells, and neutrophils or T-lymphocytes served as a source of germline DNA. These 6 patients were considered as a discovery set for mutational analysis. Established bioinformatics tools were used for detection of somatic mutations and for the comparison of baseline and PD samples. Results: Baseline clinical patient profiles indicated that 12 of 13 patients with PD had unmutated IGHV genes and 8 patients carried TP53 aberrations (ie, 17p deletion and/or TP53 mutation). WES resulted in a mean read depth of 106X within the targeted coding region across samples. In the discovery set, on average 25 somatic mutations (range: 4-44) at baseline and 32 mutations (range: 15-81) at progression were identified. By comparing baseline and PD samples, we identified 88 PD-associated mutations. These specific mutations were tested for in a complete set of 13 patient samples; however, no recurrent progression-associated mutations were identified in more than 1 patient. In particular, no progression-associated mutations were identified in the PI3K signaling pathway or in any other related pathway. Conclusion: Across 3 phase 3 studies in relapsed CLL, WES on 13 samples from patients with PD while on IDELA treatment were evaluated. This analysis detected no relapse-associated mutations in common across this patient set; in particular, no mutations were identified in the drug-binding site (ie, "gateway mutation") or in any other related signaling pathway. Based on these results, we conclude there is no common mutational mechanism of IDELA resistance in this patient group. Disclosures Ghia: Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria, Research Funding; Adaptive: Consultancy; Abbvie: Consultancy, Honoraria. Tausch:Gilead: Other: Travel support, Speakers Bureau; Celgene: Other: Travel support; Amgen: Other: Travel support. Owen:Roche: Honoraria, Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Honoraria; Lundbeck: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria; Gilead: Honoraria, Research Funding. Barrientos:Gilead: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy, Research Funding. Munugalavadla:Gilead Sciences: Employment, Equity Ownership. Degenhardt:Gilead Sciences: Employment, Equity Ownership. Kim:Gilead Sciences: Employment, Equity Ownership. Dubowy:Gilead Sciences: Employment, Equity Ownership. Dreiling:Gilead Sciences: Employment, Equity Ownership. Rosenquist:Gilead Sciences: Speakers Bureau. Stilgenbauer:Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding.

Possible Biomarkers To Predict Response In Patients With Myelodysplastic Syndromes (MDS) Or Acute Myeloid Leukemia (AML) Treated With 5-Azacitidine

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2757-2757 ◽  
Author(s):  
Andrea Kuendgen ◽  
Catharina Müller-Thomas ◽  
Petra Urbaniak ◽  
Michael Lauseker ◽  
Torsten Haferlach ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Research Funding ◽  
Response Rate ◽  
Normal Karyotype ◽  
Allogeneic Transplantation ◽  
Chromosome 7 ◽  
P Value ◽  
Complex Karyotype ◽  
Employment Equity ◽  
Equity Ownership

Abstract Introduction Azacitidine (aza) was the first drug to demonstrate a survival benefit for MDS patients (pts) in a randomized trial [Fenaux, Lancet Oncol 2009]. However, only about half of the pts respond and even after achieving complete remission (CR) and with sustained treatment, pts usually relapse. To date, limited data is available on prognostic factors influencing response. Therefore, until now we have analyzed 71 pts with MDS or AML, treated with at least 3 cycles of aza, to identify prognostic indicators that might help to improve treatment decisions. Patients and Methods 71 cases were included and characterized by cytogenetics and various molecular assays including sensitive next-generation sequencing for mutations in ASXL1, DNMT3A, EZH2, FLT3-LM, IDH1, IDH2, KRAS, MLL-PTD, NRAS, RUNX1, SF3B1, SRSF2, TET2, and TP53. Median age was 71 (50-84) years. 38 pts had MDS (8 RAEB I, 26 RAEB II, 4 RCMD), 28 had AML (6 dysplastic, 16 sAML/MDS, and 6 tAML/MDS), and 5 pts had MDS/MPD. The IPSS [Greenberg, Blood 1997] was low in one, intermediate (int) 1 in 4, int 2 in 26, and high in 14 pts. Regarding cytogenetic risk groups we found 39 low, 11 int and 20 high risk pts according to IPSS and 49 int vs 21 high risk pts according to AML criteria [Grimwade, Blood 2010]. Median time from diagnosis to treatment was 122 days (0-2348). With a median follow up of 1091 days from start of treatment median survival was 530 days (95% CI 412-874). Pts received a median number of 6 cycles (3-43). 12 pts have received allogeneic transplantation after aza treatment and were censored at that date. To assess the impact of biomarkers, Kaplan-Meier curves and Cox models were estimated from the first day of treatment. Variables were considered for multivariate analysis if the univariate p value was <0.1. Results Regarding cytogenetics, 47% of pts exhibited a normal karyotype, 17% had chromosome 7 abnormalities, 13% of karyotypes included del5q, 13% +8, 7% del20q, and 13% were complex. All except one case showed molecular aberrations. The most frequently mutated gene was ASXL1 (42%), followed by RUNX1 (38%), SRSF2 (38%), TET2 (30%), TP53 (18%), DNMT3A (16%), IDH2 (13%), NRAS (13%), EZH2 (12%), SF3B1 (11%), IDH1 (9%), FLT3-ITD (8%), MLL-PTD (7%), and KRAS (6%). Responses were observed in 33 pts (46%; 4 CR, 3 marrow CR with hematological improvement, 8 partial remission, and 18 HI). When cytogenetic abnormalities were examined, responses were seen in 45% of pts with normal karyotype, in 50% of pts with chromosome 7 aberrations, in 33% with del5q, in 67% with +8, in 56% with complex karyotype, and in all 5 cases with del20q (p=0.02). Regarding molecular abnormalities response rate was highest in pts with mutations in NRAS (67%) and IDH2 (63%), followed by RUNX1 (56%), ASXL1 (54%), SF3B1 (43%), TP53 (42%), SRSF2 (36%), TET2 (30%), DNMT3A (30%), MLL-PTD (25%), KRAS (25%), FLT3-ITD (20%), IDH1 (17%), and EZH2 (13%). However none of these mutations had a significant impact on response rate, possibly due to limited statistical power. The only p-value <0.1 was seen for EZH2 (p=0.08). Finally we analyzed the influence of prognostic markers on survival in aza treated pts. In univariate analysis potential candidate variables were: TP53 (p=<0.01, HR: 3.63), cytogenetic group according to AML (p=0.02, HR 2.02) or IPSS (p=0.07, HR (high-low) 1.92, (int-low) 0.86), complex karyotype (p<0.01, HR: 3.17), age [yrs] (p=0.01, HR: 1.08), Hb [g/dl] (p=0.078, HR: 0.836), time to start of aza [yrs] (p=0.01, HR: 0.753), MLL-PTD (p=0.07, HR: 2.87), and AML vs MDS (p=0.01, HR: 2.13). In multivariate analysis TP53 retained a significant influence on survival (HR: 4.99 [CI: 2.20-11.31], p<0.01), accompanied by age (HR:1.10 [CI: 1.03-1.16], p<0.01), Hb (HR: 0.69 [CI: 0.52-0.93], p=0.01), AML vs. MDS (HR: 2.42 [CI: 1.21-4.84], p=0.01), and time to start of aza (HR: 0.70 [CI: 0.52-0.94], p=0.02). TP53 mutations negatively influenced survival, although response rates were comparable to other pts. Response duration was often short. However, pts might still benefit from aza treatment, if combination therapy (e.g. lenalidomide in del5q and TP53 positive pts) or allogeneic transplantation consolidate and prolong treatment results Conclusion After the analysis of 71 pts, TP53 mutations represent the only somatic mutations with a significant negative impact on survival in aza treated pts. The small group of pts with del20q might have higher response rates. The analysis of further pts is ongoing. Disclosures: Kuendgen: Celgene: Honoraria, Research Funding. Off Label Use: Azacitidine in AML >30% marrow blasts. Lauseker:Celgene: Honoraria. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Alpermann:MLL Munich Leukemia Laboratory: Employment. Albuquerque:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Gattermann:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Germing:Celgene: Honoraria, Research Funding. Götze:Celgene Corp: Honoraria.

scholarly journals Long-Term Follow-up Identifies Double Hit and Key Mutations As Impacting Progression Free and Overall Survival in Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 110-110 ◽  
Author(s):  
Cody Ashby ◽  
Eileen Boyle ◽  
Ruslana G. Tytarenko ◽  
Hongwei Wang ◽  
Adam Rosenthal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Copy Number ◽  
Research Funding ◽  
Risk Groups ◽  
Employment Equity ◽  
Risk Status ◽  
Equity Ownership ◽  
Double Hit ◽  
Mutation Braf

Abstract Introduction: The study of multiple myeloma (MM) genomics has identified many abnormalities that are associated with poor progression free survival (PFS) and overall survival (OS). Copy number abnormalities have been extensively studied in many datasets with long follow-up, however, the prognostic impact of mutations have not been extensively studied and available datasets have generally had a relatively short follow-up of 22-25 months, with one dataset being up to 5.4 years. These analyses have identified a range of mutations that are associated with prognosis, making it important to extend these observations in larger studies with robust diagnostic technologies. Methods: Samples from newly diagnosed MM patients enrolled in Total Therapy trials (n=199) were sequenced on a targeted panel consisting of 140 genes and additional regions of interest for copy number, as well as tiling of the Ig and MYC loci for detection of translocations. Samples were sequenced to a median depth of 452x using 2x75 bp paired end reads. Reads were aligned to hg19 and mutations called using Strelka and filtered with fpfilter. Translocations were called by Manta, and copy number determined by read depth ratio and loss of heterozygosity comparison with a patient matched non-tumor sample. Additional copy number data were generated by ultra-low pass whole genome sequencing (median 0.5x). Events in <2% of patients were not considered for further analysis. Risk groups including international staging system (ISS), revised-ISS, IMWG risk groups, and Double Hit MM (biallelic TP53 or amp1q with ISS III) were defined. Results: The median follow-up for this dataset was 8 years, with a median PFS of 6 years and OS of 11 years. The median age was 60.6 years and risk groups were comparable to other studies with 29.1% of patients with ISS III and 20% with high IMWG risk status. In a univariate analysis the markers with highest hazard ratios (HR) for PFS were Double Hit (9%, HR 5.2; 95% CI 2.79-9.76), abnormal BIRC3 (5%, 2.89; 1.32-6.32), ISS III (29%, 2.88; 1.65-5.02), mutation BRAF (11%, 2.26; 1.3-3.93), mutation LRP1B (6%, 2.23; 1.39-3.58), mutation DIS3 (9%, 2.2; 1.22-3.97), bi-allelic inactivation CYLD (10%, 2.04; 1.01-4.10), and high IMWG risk (20%, 2.01; 1.29-3.13). For OS the markers with highest HR were ISS III (5.21; 2.46-11.07), mutation KMT2C (3%, 4.4; 1.37-14.14), t(14;16) (4%, 3.83; 1.38-10.62), mutation EGR1 (4%, 3.58; 1.28-10.00), Double Hit (3.24; 1.65-6.40), mutation BRAF (2.89; 1.57-5.33), mutation LRP1B (2.49; 1.19-5.24), rearrangements surrounding MYC (46%, 2.49; 1.50-4.11), and high IMWG risk (2.11; 1.26-3.53). In a multivariate analysis for PFS Double Hit (HR 4.37, 95% CI 2.31-8.26), loss of BIRC2/3 (5%, 3.95; 1.69-9.21); mutation LRP1B (3.21; 1.53-6.72), mutation DIS3 (2.44; 1.31-4.53), ISS III (2.29; 1.22-4.32), mutation BRAF (2.28; 1.24-4.18) contributed to the model. For OS, ISS III (3.15;1.40-7.06); 1q21 amp (6%, 2.988; 1.01-8.86); mutation LRP1B (2.90; 1.33-6.35), Double Hit (2.51; 1.05-6.01), deletion CDKN1B (10%, 2.44; 1.15-5.16), and mutation BRAF (2.25; 1.13-4.48) contributed to the model. Conclusion: We confirm the clinical relevance of Double Hit risk status that constitutes 9% of patients; median PFS of 2 vs. 7 years (P<0.0001), and OS 3 vs. 13 years (P=0.0003). With long follow-up and deep sequencing additional mutated genes associated with adverse outcome were identified including BRAF (11%), DIS3 (9%), LRP1B (6%) and KMT2C (3%). Further, inactivation of NF-κB regulators (CYLD, BIRC2/3) were associated with poor PFS or OS. Patients with a BRAF mutation had a median PFS of 2 vs. 7 years (P=0.003), and OS of 6 vs 13 years (P=0.0004), indicating a potential useful intervention for BRAF inhibitors. Disclosures Ortiz: Celgene Corporation: Employment, Equity Ownership. Flynt:Celgene Corporation: Employment, Equity Ownership. Barlogie:Celgene: Consultancy, Research Funding; European School of Haematology- International Conference on Multiple Myeloma: Other: travel stipend; International Workshop on Waldenström's Macroglobulinemia: Other: travel stipend; Myeloma Health, LLC: Patents & Royalties: : Co-inventor of patents and patent applications related to use of GEP in cancer medicine licensed to Myeloma Health, LLC; Dana Farber Cancer Institute: Other: travel stipend; ComtecMed- World Congress on Controversies in Hematology: Other: travel stipend; Millenium: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Other: travel stipend. Thakurta:Celgene Corporation: Employment, Equity Ownership. Morgan:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Research Funding.

scholarly journals Clinical Characteristics and Outcome in IDH1/2 Mutant AML Patients - Analysis of 3898 Newly Diagnosed Patients with Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1461-1461 ◽  
Author(s):  
Jan Moritz Middeke ◽  
Christoph Rollig ◽  
Michael Kramer ◽  
Alwin Kramer ◽  
Tilman Bochtler ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Normal Karyotype ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Acute Myeloid

Abstract Purpose Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are one of the most frequent alterations in acute myeloid leukemia (AML) and can be found in ~20% of patients at diagnosis. Several IDH inhibitors are currently in late stage clinical development with Enasidenib, an IDH2 inhibitor, being recently approved by the FDA. Previous analyses have reported differential impact on response to chemotherapy and outcome, depending on the IDH-mutation type, co-occurring mutations and cytogenetic abnormalities, as well as the variant allele frequency (VAF) of IDH mutations. In order to better understand its prognostic role, we analyzed newly diagnosed AML patients enrolled in prospective trials of the Study Alliance Leukemia (SAL) to investigate the impact of IDH1/2 mutations on outcome. Patients and Methods All AML patients consecutively enrolled into intensive AML treatment protocols of the SAL or into the SAL registry were included in this analysis. Next-generation sequencing (NGS) on an Illumina MiSeq-system was performed to detect IDH1/2 mutations using pre-treatment samples. Overall survival (OS) and response to therapy were analyzed for all patients with intensive treatment and according to the mutational status. Results Overall, samples of 3898 patients were analyzed. The median follow-up was 91 months (95% CI 87.2 - 93.9). Patients' characteristics are shown in Tbl.1. Three-hundred twenty-nine patients (8.4%) had IDH1 mutations and 423 (11%) had IDH2 mutations; both mutations were found in 12 pts, so the overall mutation rate in IDH1 and 2 was 19% (740/3898 patients). Of the IDH1 variants, the most common ones were the R132C found in 143 patients (43%) and R132H in 137 patients (42%). For IDH2, 324 patients had the R140Q (77%) and 80 patients the R172K (19%) variant. According to the two main variants of the more common IDH2 mutations, as reported before, the IDH2 R172K was mutually exclusive with NPM1 and/or FLT3-ITD mutations. Overall, there was a trend for increased OS for patients with IDH2 R172K (26 vs. 15 months) as compared to those with R140Q. Considering only patients with a normal karyotype and no NPM1/FLT3-ITD mutation, these patients (n=27) had a highly significant better OS than patients with IDH2 R140Q (46.3 vs. 13.1 months, p=.012), supporting the findings published by Papaemmanuil et al. (NEJM 2016). In IDH1-mutated patients, we observed statistically significant differences in baseline characteristics between the two most common mutation types, IDH1 R132C and R132H. Patients carrying the R132C mutation were older (62 vs. 55 years, p=.001), had lower WBC (3.6 vs. 21 Gpt/L, p≤.001) and were less likely to have a normal karyotype (43% vs. 66%, p=.002), NPM1 (23% vs. 66%, p=<.001), and FLT3-ITD mutations (8% vs. 27%, p<.001) than those with the R132H variant. In univariate testing, the CR rate was also statistically significant lower in patients with IDH1 R132C (53% vs. 72%, p≤.001), with a median OS of 12.9 months compared to 17.4 months for patients with R132H variant (p=.08). In multivariate analysis including age, WBC, NPM1 and FLT3 status, and ELN risk, the CR rate was significantly lower in patients with the IDH1 R132C variant (p=.038). The median IDH VAF was 38% (range, 0.1 - 58) with no difference according to the different types of mutation. Patients with a VAF > 30% had a significantly higher BM blast count (73% vs 40% for VAF≤5%) and WBC (21.2 Gpt/L vs. 3.7 Gpt/L) at baseline, but there was no clear impact on CR rate or OS found in multivariate analysis. Conclusion In this large cohort of AML patients with IDH1/2 mutations, we found significant and so far not reported differences for one of the two most prominent mutations types of IDH1. The R132C variant was associated with increased age, lower WBC, and lower NPM1 and/or FLT3 co-mutation rate. Further, these patients had lower CR rates and a trend for shorter OS. For IDH2 we were able to reproduce findings on co-mutations and showed a favorable outcome for intensively treated patients with a normal karyotype and no NPM1/FLT3-ITD mutation and the IDH2 R172K variant, providing additional evidence for classification as a separate AML entity. Disclosures Middeke: Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees. Rollig:Bayer: Research Funding; Janssen: Research Funding. Kramer:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Daiichi Sankyo: Consultancy. Scholl:Alexion: Other: Travel support; Abbivie: Other: Travel support; Novartis: Other: Travel support; Deutsche Krebshilfe: Research Funding; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; MDS: Other: Travel support; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Hochhaus:Incyte: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Brümmendorf:Takeda: Consultancy; Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Novartis: Consultancy, Research Funding. Burchert:Novartis: Research Funding; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Bayer: Research Funding. Krause:Novartis: Research Funding. Hänel:Amgen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Takeda: Honoraria. Platzbecker:Celgene: Research Funding. Mayer:Johnson & Johnson: Research Funding; Roche: Research Funding; Eisai: Research Funding; Affimed: Research Funding; Novartis: Research Funding. Serve:Bayer: Research Funding. Ehninger:Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; Bayer: Research Funding; GEMoaB Monoclonals GmbH: Employment, Equity Ownership. Schetelig:Gilead: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria; Janssen: Consultancy, Honoraria; Roche: Honoraria; Sanofi: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding. Stoelzel:Neovii: Speakers Bureau.

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