scholarly journals Differential impact of IDH1/2 mutational subclasses on outcome in adult AML: Results from a large multicenter study

2021 ◽  
Author(s):  
Jan Moritz Middeke ◽  
Klaus H. Metzeler ◽  
Christoph Röllig ◽  
Michael Kramer ◽  
Jan-Niklas Eckardt ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Risk Groups ◽  
Newly Diagnosed ◽  
Blood Cell Count ◽  
Differential Impact ◽  
Distinct Entity ◽  
Isocitrate Dehydrogenase 1 ◽  
Mutation Pattern ◽  
Idh1 Mutations ◽  
Idh1 And Idh2 Genes

Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are amongst the most frequent alterations in acute myeloid leukemia (AML) and can be found in ~20% of patients at diagnosis. Among 4930 patients (median age 56 years, interquartile range 45-66) with newly diagnosed, intensively treated AML, we have identified IDH1 mutations (mIDH1) in 423 (8.6%) and IDH2 mutations (mIDH2) in 575 (11.7%) patients. Overall, there were no differences in response rates or survival for patients with mIDH1 or mIDH2 compared to patients without mutated IDH1/2. However, distinct clinical and co-mutational phenotypes of the most common subtypes of IDH1/2 mutations could be associated with differences in outcome. IDH1-R132C was associated with significantly increased age, lower white blood cell count (WBC), less frequent co-mutation of NPM1 and FLT3-ITD as well as lower rate of complete remissions and a trend for reduced overall survival (OS) compared to other mIDH1 variants and wtIDH1/2. In our analysis, IDH2-R172K was associated with significantly lower WBC, more karyotype abnormalities, and less frequent co-mutations of NPM1 and/or FLT3-ITD. Among patients within the ELN2017 intermediate- and adverse-risk groups, RFS and OS were significantly better for patients with IDH2-R172K compared to wtIDH, providing evidence that AML with IDH2-R172K could be a distinct entity with a specific co-mutation pattern and favorable outcome. In summary, the presented data from a large cohort of IDH1/2 mutant AML patients indicate novel and clinically relevant findings for the most common IDH-mutation subtypes.

scholarly journals Isocitrate dehydrogenase 1 and 2 mutations, 2‐hydroxyglutarate levels, and response to standard chemotherapy for patients with newly diagnosed acute myeloid leukemia

Cancer ◽  
2018 ◽  
Vol 125 (4) ◽  
pp. 541-549 ◽  
Author(s):  
Andrew M. Brunner ◽  
Donna S. Neuberg ◽  
Seth A. Wander ◽  
Hossein Sadrzadeh ◽  
Karen K. Ballen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Isocitrate Dehydrogenase ◽  
Myeloid Leukemia ◽  
Newly Diagnosed ◽  
Standard Chemotherapy ◽  
Isocitrate Dehydrogenase 1 ◽  
Acute Myeloid

scholarly journals Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia

2021 ◽  
Vol 39 (1) ◽  
pp. 57-65
Author(s):  
Courtney D. DiNardo ◽  
Anthony S. Stein ◽  
Eytan M. Stein ◽  
Amir T. Fathi ◽  
Olga Frankfurt ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Adverse Events ◽  
Isocitrate Dehydrogenase ◽  
Myeloid Leukemia ◽  
Qt Prolongation ◽  
Newly Diagnosed ◽  
Isocitrate Dehydrogenase 1 ◽  
Grade 3 ◽  
Acute Myeloid

PURPOSE Ivosidenib is an oral inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, approved for treatment of IDH1-mutant (m IDH1) acute myeloid leukemia (AML). Preclinical work suggested that addition of azacitidine to ivosidenib enhances mIDH1 inhibition–related differentiation and apoptosis. PATIENTS AND METHODS This was an open-label, multicenter, phase Ib trial comprising dose-finding and expansion stages to evaluate safety and efficacy of combining oral ivosidenib 500 mg once daily continuously with subcutaneous azacitidine 75 mg/m2 on days 1-7 in 28-day cycles in patients with newly diagnosed m IDH1 AML ineligible for intensive induction chemotherapy (ClinicalTrials.gov identifier: NCT02677922 ). RESULTS Twenty-three patients received ivosidenib plus azacitidine (median age, 76 years; range, 61-88 years). Treatment-related grade ≥ 3 adverse events occurring in > 10% of patients were neutropenia (22%), anemia (13%), thrombocytopenia (13%), and electrocardiogram QT prolongation (13%). Adverse events of special interest included all-grade IDH differentiation syndrome (17%), all-grade electrocardiogram QT prolongation (26%), and grade ≥ 3 leukocytosis (9%). Median treatment duration was 15.1 months (range, 0.3-32.2 months); 10 patients remained on treatment as of February 19, 2019. The overall response rate was 78.3% (18/23 patients; 95% CI, 56.3% to 92.5%), and the complete remission rate was 60.9% (14/23 patients; 95% CI, 38.5% to 80.3%). With median follow-up of 16 months, median duration of response in responders had not been reached. The 12-month survival estimate was 82.0% (95% CI, 58.8% to 92.8%). m IDH1 clearance in bone marrow mononuclear cells by BEAMing (beads, emulsion, amplification, magnetics) digital polymerase chain reaction was seen in 10/14 patients (71.4%) achieving complete remission. CONCLUSION Ivosidenib plus azacitidine was well tolerated, with an expected safety profile consistent with monotherapy with each agent. Responses were deep and durable, with most complete responders achieving m IDH1 mutation clearance.

Mutation Analysis in 276 Cases of Newly Diagnosed Acute Myeloid Leukemia By Next Generation Sequencing: Association with Established Prognostic Variables and MRC Risk Groups

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1392-1392
Author(s):  
Parsa Hodjat ◽  
Kankana Ghosh ◽  
Priyanka Priyanka ◽  
Beenu Thakral ◽  
Keyur P. Patel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Next Generation Sequencing ◽  
Mutation Analysis ◽  
Myeloid Leukemia ◽  
Risk Groups ◽  
Newly Diagnosed ◽  
Generation Sequencing ◽  
Acute Myeloid ◽  
Who 2008

Abstract INTRODUCTION Acute myeloid leukemia (AML) is known to have numerous genomic aberrations that predict response to treatment and overall survival. We aimed to assess various mutations in newly diagnosed AML cases by next generation sequencing (NGS) and their association with various well-established clinicopathologic parameters and Medical Research Council (MRC) risk groups. MATERIALS AND METHODS We performed molecular studies on DNA extracted from bone marrow aspirate specimens in 276 newly diagnosed treatment na•ve AML patients presenting at a single referral institution from 08/2013 to 03/2015 as part of routine clinical work up in a CLIA certified molecular diagnostics laboratory. Cases met criteria for AML per WHO 2008 criteria. The entire coding sequences of 28 genes (ABL1, ASXL1, BRAF, DNMT3A, EGFR, EZH2, FLT3, GATA1, GATA2, HRAS, IDH1, IDH2, IKZF2, JAK2, KIT, KRAS, MDM2, MLL, MPL, MYD88, NOTCH1, NPM1, NRAS, PTPN11, RUNX1, TET2, TP53, WT1) were sequenced using a NGS-based custom-designed assay using TruSeq chemistry on Illumina MiSeq platform. FLT3 internal tandem duplications (ITD) and codon 835/836 point mutation were detected by PCR followed by capillary electrophoresis. CEBPA mutation analysis was performed on 262 patients by PCR followed by Sanger sequencing. Cases were categorized as favorable, intermediate and adverse groups as per revised MRC cytogenetic risk group classification. RESULTS Median age was 67 years. Patients included 167 (60.5%) males and 109 (39.5%) females. 38 (14%) and 6 (2%) patients had prior diagnosis of myelodysplastic syndrome and myeloproliferative neoplasms respectively. Hematologic parameters are as follows [median (range)]: Hb 8.7 g/dL (2.8-13.9), platelets 50.5 K/μ L (1-1109), WBC 5.4 K/μ L (0.4-620.4), ANC 0.9 K/μ L (0-145.7), AMC 0.3 K/μ L (0-98.1). Bone marrow (BM) blast % [median (range)] was 45.5% (5-96). LDH was 733 IU/dL (225-13156). Of 275 patients with cytogenetic analysis performed, 98 (35.64%) had diploid karyotype, 75 (27.27%) had one, 38 (13.82%) had two, 8 (2.91%) had three, 56 (20.36%) had > three abnormalities, 75 (27.27%) had monosomies and 62 (22.55%) had trisomies. Of 34 cases classified as AML with recurrent cytogenetic abnormalities per WHO 2008, 10 (3.64%) had t(8;21), 13 (4.73%) had inv(16), 1 (0.36%) had t(15;17), 3 (1.09%) had inv (3), 4 (1.45%) had t(9;11)(p22;q23) and 3 (1.09%) had t(6;9)(p23;q34). MRC risk categorization of the cases was as follows: favorable 24 (8.72%), intermediate 161 (58.55%) and adverse 90 (32.73%). Mutations identified by NGS are as detailed in Table 1. Of 56 patients with FLT3 mutations detected by PCR, the breakdown is as follows: FLT3 ITD (39, 14.13%), FLT3 D835 (16, 5.80%), FLT3, ITD + D835 (1, 0.36%). Of 262 patients assessed, CEBPA mutation was detected in 26 (9.92%). Thirty one (11.23%) cases had no mutations detected in the genes analyzed by NGS or PCR, 93 (33.70%) had mutations in one, 80 (28.98%) in two, 42 (15.22%) in three and 30 (10.87%) in > three genes. We found positive associations between mutated genes and various parameters as detailed in Table 2. CONCLUSIONS: AML is a heterogeneous group of myeloid neoplasms at the genetic level. Multiple genetic mutations in a large subset of cases likely indicate clonal evolution. A subset of mutations has significant association with well-established clinico-pathologic parameters like WBC. With longer follow-up, we could use this data to refine prognostic models for AML. Table 1. Genes Number of Cases Percentage of Cases FLT3 61 22.10 NPM1 48 17.39 NRAS 48 17.39 DNMT3A 47 17.03 TP53 45 16.30 IDH2 40 14.49 IDH1 33 11.96 TET2 32 11.59 ASXL1 30 10.87 RUNX1 30 10.87 PTPN11 13 4.71 KRAS 11 3.99 KIT 8 2.90 WT1 8 2.90 GATA2 7 2.54 EZH2 6 2.17 JAK2 4 1.45 MPL 2 0.72 ABL1 1 0.36 EGFR 1 0.36 GATA1 1 0.36 IKZF2 1 0.36 MDM2 1 0.36 MLL 1 0.36 MYD88 1 0.36 NOTCH1 1 0.36 Table 1. Mutated genes p value Hb NRAS, NPM1 <0.05, <0.04 Platelets TP53, IDH2 <0.03, <0.02 WBC FLT3, NRAS, TP53 <0.05, <0.05, <0.05 AMC NRAS, NPM1, TP53 <0.001, <0.02, <0.02 ABC FLT3 NPM1 <0.049, <0.02 PB blast % FLT3, NPM1, TP53, CEBPA <0.000, <0.002, <0.005, <0.000 BM blast % FLT3, NRAS, NPM1, TP53, IDH1, CEBPA >0.000, <0.0000, <0.014, <0.004, <0.002, <0.012 AMC: absolute monocyte count, ABC: absolute basophil count, PB: peripheral blood, BM: bone marrow Disclosures No relevant conflicts of interest to declare.

Clinical value of event-free survival (EFS) in acute myeloid leukemia (AML).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e18513-e18513
Author(s):  
Abhishek Maiti ◽  
Hagop M. Kantarjian ◽  
Vinita Popat ◽  
Carlos Blanco ◽  
Miguel Velasquez ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Blood Product ◽  
Risk Groups ◽  
Care Utilization ◽  
Newly Diagnosed ◽  
Inclusion Criteria ◽  
Event Free Survival ◽  
Imaging Studies ◽  
Clinical Value ◽  
Free Survival

e18513 Background: EFS is not considered a robust end-point for AML trials. We hypothesized that rather than a surrogate for overall survival (OS), improvement in EFS may be valuable due to patients (pts) staying in remission and thus decreasing health care utilization (HCU). Methods: In this retrospective study we identified AML pts treated on frontline therapy trials at our institute from 2003-2013 with EFS ≥2 months (mo) and OS of 12-36 mo. We captured the amount of HCU from diagnosis till death, including number of clinic and emergency room (ER) visits, hospitalizations, consultations, blood product transfusions, invasive procedures, laboratory and imaging studies. Linear regression and product-moment correlation were used to determine the relation between these parameters and EFS. Results: Among 337 pts meeting inclusion criteria, the median age was 65 years, 30% had adverse risk AML, 47% received intensive chemotherapy (IC) and 27% received hypomethylating agents (HMA). The median EFS was 10.8 mo. Increasing EFS led to statistically significant decline in HCU for all patients regardless of OS and the correlations were stronger for pts achieving a complete remission (CR, Table). These observations held true across European LeukemiaNet risk groups, younger and older pts, and those receiving IC, HMA, and non-IC, with or without other agents. Conclusions: In newly diagnosed AML, improvement in EFS is correlated with decrease in all HCU irrespective of OS duration. [Table: see text]

scholarly journals High EVI1 Expression Predict Adverse Outcome in Children with Acute Myeloid Leukemia: A Multicenter, Nonrandomized Clinical Study in China

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 37-38
Author(s):  
Yongzhi Zheng ◽  
Jian Li ◽  
Xiaoqin Feng ◽  
Chunfu Li ◽  
Mincui Zheng ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Hazard Function ◽  
Adverse Outcome ◽  
Proportional Hazard ◽  
Newly Diagnosed ◽  
Blood Cell Count ◽  
Chi Square ◽  
Cox Proportional Hazard ◽  
Chi Square Test ◽  
Pediatric Aml

Backgroud and purpose In clinical studies in adult acute myeloid leukemia (AML), high ecotropic virus integration-1 (EVI1) gene expression has shown to be an independent prognostic factor. However, the predictive value of high EVI1 expression (EVI1+) in children with AML is little known. The purpose of this study was to investigate frequency and prognostic significance of high EVI1 expression in children with AML. Patients and methods Total of 403 newly diagnosed childhood AML patients from 7 centers of south of China from November 2014 to May 2020 were included in the study. A diagnostic assay detecting multiple EVI1 splice variants was developed to determine the relative EVI1 expression by single real-time quantitative polymerase chain reaction in the 403 newly diagnosed pediatirc patients with AML younger than 14 years. Patients were treated with C-HUANAN-AML15 protocol. In the C-HUANAN-AML15 protocol, tandem 2 courses of FLAG-IDA regimen, or sequential DAE(3+5+10) and DAE(3+5+8) were applied as induction chemotherapy. One course of Homoharringtonine (substitution of Amsacrine in MRC-AML 15 protocol)/ Cytarabine/ Etoposide and one course of Mitoxantrone/ Cytarabine in consolidation chemotherapy were uniform in both groups. 75 patients selected hematopoietic stem cell transplantation (HSCT) in first CR. The median follow-up period was 20 (0.8 to 67.7) months up to July 2020. The similarity of clinical data was analyzed by the chi square test and COX proportional hazard function model. Complete remission (CR) rates, event-free survival (EFS) and overall survival (OS) were compared by Log-Rank chi square test. Results EVI1+ was found in 36/403 (8.9%) of children with de novo AML. The clinical features of the patients with EVI1+(n=36) compared with EVI1-(n=367) AML were summarized in Table 1. No significant differences in sex, white blood cell count, and age were noted between EVI1+and EVI1- AML. When studying the relationship between EVI1+ and conventional classification criteria such as morphology (FAB classification) and cytogenetic data, EVI1+ was predominantly found in FAB M7, t(9;11) and other t(v;11q23), as well as complex karyotype, but mutually exclusive with t(8;21), inv(16)/t(16;16), CEBPA, NPM1 or C-KIT mutations. Furthermore, EVI1+ was significantly associated with unfavoralbe cytogenetic risk. Twenty-five patients (22 cases in the EVI1-group and 3 cases in the EVI1+ group) who gave up treatment or transferred to other hospital when treatment was not completed were excluded, and the remaining 378 AML children with standard treatment were included in the survival analysis. Univariate analysis showed that initial white blood cell count (≥50×109/L), RUNX1-RUNX1T1 fusion gene, FLT3-ITD mutation and EVI1+ affected 5-year EFS (P=0.000, 0.001, 0.016, 0.011). Multivariate prognostic analysis with COX proportional hazard function model for EFS identified EVI1+ as an independent prognosis factor (HR0.531, 95%CI 0.298-0.945, P=0.032). Patients with EVI1+ AML (n=12) who received HSCT in first CR had better 5-year EFS, but the difference was not statistically significant (46.103% vs. 56.250%, P=0.33). Conclusion It could be concluded that EVI1+ can be found in ~10% of pediatric AML in China. It is predominantly found in intermediate to unfavorable cytogenetic subtypes and predicts adverse outcome. EVI1 screening at diagnosis should be included in risk stratification of pediatric AML. Whether pediatric patients with EVI1+ AML can benefit from HSCT in first CR needs further reasearch. Disclosures No relevant conflicts of interest to declare.

Pretreatment Cytogenetic Abnormalities Are Predictive of Induction Success, Cumulative Incidence of Relapse and Overall Survival in Patients >60 Years of Age with Newly Diagnosed Acute Myeloid Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3293-3293
Author(s):  
Richard F. Schlenk ◽  
Sabine Kayser ◽  
Martina Morhardt ◽  
Konstanze Döhner ◽  
Hartmut Döhner ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Normal Karyotype ◽  
Risk Groups ◽  
High Risk Group ◽  
Newly Diagnosed ◽  
Balanced Translocations ◽  
Acute Myeloid

Abstract Purpose: Karyotype at diagnosis provides the most important prognostic information in younger adults with acute myeloid leukemia (AML). However, there are few data available looking in particular at patients (pts.) above 60 years of age. We prospectively analyzed 361 elderly pts. with newly diagnosed AML. All pts. were treated within the AMLHD98B treatment trial and received intensive induction and consolidation therapy. Pts. exhibiting a t(15;17) received an age-adjusted AIDA-regimen. Median follow-up time was 48 months. The median age was 67 years (range 60–85 years). Results: 160 pts. had a normal karyotype (44%); 48 pts. (13%) exhibited the balanced translocations t(8;21) (n=12), inv(16) (n=14), t(15;17) (n=11), or t(11q23) (n=11); in the absence of these balanced translocations, 73 pts. exhibited a single aberration, 179 pts. two aberrations, and 61 pts. a complex karyotype (≥3 aberrations; including 44 pts. with 5 or more aberrations). Analyses were normalized to the complete remission (CR) rate (52%), cumulative incidence of relapse (CIR) (77%) and overall survival (OS) (13%) after 4 years of pts. with normal karyotype. Pts. exhibiting a t(15;17) showed a significantly better CIR (29%) and OS (55%), whereas pts. with the other balanced translocations [t(8;21), inv(16)/t(16;16) and t(11q23)] did not differ from pts. with normal karyotype. The limited backward selected Cox-model for OS [t(15;17) excluded] revealed two risk groups: standard-risk [normal karyotype, t(8;21), inv(16), t(11q23), +8 and +11 in absence of a complex karyoytpe] and high-risk [all other aberrations]. The CR rates were 56% and 18%, and the OS-rates after 4 years for the standard- (n=223) and the high-risk group (n=127) were 15% and 0%, respectively. The MRC risk classification system for patients &gt;55 years applied to our patients revealed CR- and OS-rates after 4 years of 73% and 19%, 47% and 12%, as well as 7% and 0% for the low (n=26), intermediate (n=282) and high risk groups (n=44), respectively [t(15;17) excluded]. In conclusion, our risk classification system identified a large high-risk group (36%) of elderly patients with AML who did not benefit from intensive chemotherapy.

scholarly journals Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia

Blood ◽  
2020 ◽  
Vol 135 (7) ◽  
pp. 463-471 ◽  
Author(s):  
Gail J. Roboz ◽  
Courtney D. DiNardo ◽  
Eytan M. Stein ◽  
Stéphane de Botton ◽  
Alice S. Mims ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
Hematologic Malignancies ◽  
Idh1 Mutation ◽  
Newly Diagnosed ◽  
Isocitrate Dehydrogenase 1 ◽  
Hematologic Disorder ◽  
Transfusion Independence ◽  
Acute Myeloid

Abstract Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase 1 (IDH1; mIDH1) enzyme. From a phase 1 study of 258 patients with IDH1-mutant hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received 500 mg ivosidenib daily. Median age was 76.5 years, 26 patients (76%) had secondary AML, and 16 (47%) had received ≥1 hypomethylating agent for an antecedent hematologic disorder. The most common all-grade adverse events were diarrhea (n = 18; 53%), fatigue (n = 16; 47%), nausea (n = 13; 38%), and decreased appetite (n = 12; 35%). Differentiation syndrome was reported in 6 patients (18%) (grade ≥3 in 3 [9%]) and did not require treatment discontinuation. Complete remission (CR) plus CR with partial hematologic recovery (CRh) rate was 42.4% (95% confidence interval [CI], 25.5% to 60.8%); CR 30.3% (95% CI, 15.6% to 48.7%). Median durations of CR+CRh and CR were not reached, with 95% CI lower bounds of 4.6 and 4.2 months, respectively; 61.5% and 77.8% of patients remained in remission at 1 year. With median follow-up of 23.5 months (range, 0.6-40.9 months), median overall survival was 12.6 months (95% CI, 4.5-25.7). Of 21 transfusion-dependent patients (63.6%) at baseline, 9 (42.9%) became transfusion independent. IDH1 mutation clearance was seen in 9/14 patients achieving CR+CRh (5/10 CR; 4/4 CRh). Ivosidenib monotherapy was well-tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML. This trial was registered at www.clinicaltrials.gov as #NCT02074839.

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