54 results on '"Krämer, Alwin"'
Search Results
2. A phase 1 study of IDH305 in patients with IDH1 R132 -mutant acute myeloid leukemia or myelodysplastic syndrome.
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DiNardo CD, Hochhaus A, Frattini MG, Yee K, Zander T, Krämer A, Chen X, Ji Y, Parikh NS, Choi J, and Wei AH
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- Humans, Bayes Theorem, Isocitrate Dehydrogenase genetics, Enzyme Inhibitors, Leukemia, Myeloid, Acute genetics, Myelodysplastic Syndromes drug therapy
- Abstract
Purpose: Isocitrate dehydrogenase enzyme 1 (IDH1) mutations at 132nd amino acid residue (R132*) result in the cellular accumulation of the oncometabolite, 2-hydroxyglutarate (2-HG). IDH305 is an orally bioavailable, brain-penetrant, mutant-selective allosteric IDH1 inhibitor demonstrating target engagement in preclinical models. This first-in human study was designed to identify the recommended dose for expansion/maximum tolerated dose of IDH305 in patients with IDH1
R132 -mutant acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)., Methods: IDH305 was given at doses 75-750 mg twice daily in 41 patients with IDH1R132 -mutant AML/MDS. Dose escalation was designed using Bayesian hierarchical model with overdose control principle and relationship with dose-limiting toxicity., Results: IDH305 exhibited rapid absorption with mean T1/2 approximately 4-10 h across doses. Interpatient variability was moderate and exposure increased with dose in a less than dose proportional manner. Most patients (35/41) demonstrated target engagement with reduction in 2-HG concentration at all doses. Complete remission (CR) or CR with incomplete count recovery occurred in 10/37 (27%) patients with AML and 1/ 4 patients with MDS. Adverse events (AEs) suspected to be related to study drug were reported in 53.7% of patients: increased blood bilirubin (14.6%), nausea (14.6%), increased alanine aminotransferase and aspartate aminotransferase (12.2%, each); most frequent grade 3 or 4 AEs were differentiation syndrome and tumor lysis syndrome (n = 3; 7.3%, each). Hepatotoxicity was manageable with dose modification., Conclusion: Due to potentially narrow therapeutic window, the study was prematurely halted and recommended phase 2 dose could not be declared., Trial Registration: Clinicaltrials.gov identifier: NCT02381886., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2023
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3. Different treatment strategies versus a common standard arm (CSA) in patients with newly diagnosed AML over the age of 60 years: a randomized German inter-group study.
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Niederwieser D, Lang T, Krahl R, Heinicke T, Maschmeyer G, Al-Ali HK, Schwind S, Jentzsch M, Cross M, Kahl C, Wolf HH, Sayer H, Schulze A, Dreger P, Hegenbart U, Krämer A, Junghanss C, Mügge LO, Hähling D, Hirt C, Späth C, Peter N, Opitz B, Florschütz A, Reifenrath K, Zojer N, Scholl S, Pönisch W, Heyn S, Vucinic V, Hochhaus A, Aul C, Giagounidis A, Balleisen L, Oldenkott B, Staib P, Kiehl M, Schütte W, Naumann R, Eimermacher H, Dörken B, Sauerland C, Lengfelder E, Hiddemann W, Wörmann B, Müller-Tidow C, Serve H, Schliemann C, Hehlmann R, Berdel WE, Pfirrmann M, Krug U, and Hoffmann VS
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- Aged, Aged, 80 and over, Humans, Middle Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cytarabine therapeutic use, Daunorubicin adverse effects, Disease-Free Survival, Prognosis, Remission Induction, Leukemia, Myeloid, Acute drug therapy, Mitoxantrone adverse effects
- Abstract
A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA (n = 132) or to the study group arms (n = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60-87) years. CR/CRi status at 90 days was not significantly different between the CSA (54% (95%CI: 45-64)) and the study group arms (53% (95%CI: 47-60) and 59% (95%CI: 58-63)). The five-year event-free survival (EFS) probability (primary endpoint) was 6.2% (95%CI: 2.7-14.0) in the CSA, 7.6% (95%CI: 4.5-12.8) in study group A and 11.1% (95%CI: 9.0-13.7) in B. The 5-year OS was 17.2% (95%CI: 11.0-26.9), 17.0% (95%CI: 2.0-23.9), and 19.5% (95%CI: 16.7-22.8) in CSA, study group A and B, respectively. Neither study group differed significantly from the CSA regarding EFS, OS, or relapse-free survival. In multivariate analyses, allocation to the treatment strategy was not significantly associated with the time-to-event endpoints. The evaluation of more intensive treatment strategies did not show clinically relevant outcome differences when compared to CSA., (© 2023. The Author(s).)
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- 2023
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4. Impact of IDH1 and IDH2 mutational subgroups in AML patients after allogeneic stem cell transplantation.
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Kunadt D, Stasik S, Metzeler KH, Röllig C, Schliemann C, Greif PA, Spiekermann K, Rothenberg-Thurley M, Krug U, Braess J, Krämer A, Hochhaus A, Scholl S, Hilgendorf I, Brümmendorf TH, Jost E, Steffen B, Bug G, Einsele H, Görlich D, Sauerland C, Schäfer-Eckart K, Krause SW, Hänel M, Hanoun M, Kaufmann M, Wörmann B, Kramer M, Sockel K, Egger-Heidrich K, Herold T, Ehninger G, Burchert A, Platzbecker U, Berdel WE, Müller-Tidow C, Hiddemann W, Serve H, Stelljes M, Baldus CD, Neubauer A, Schetelig J, Thiede C, Bornhäuser M, Middeke JM, and Stölzel F
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- Humans, Mutation, Nucleophosmin, Prognosis, Hematopoietic Stem Cell Transplantation, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy
- Abstract
Background: The role of allogeneic hematopoietic cell transplantation (alloHCT) in acute myeloid leukemia (AML) with mutated IDH1/2 has not been defined. Therefore, we analyzed a large cohort of 3234 AML patients in first complete remission (CR1) undergoing alloHCT or conventional chemo-consolidation and investigated outcome in respect to IDH1/2 mutational subgroups (IDH1 R132C, R132H and IDH2 R140Q, R172K)., Methods: Genomic DNA was extracted from bone marrow or peripheral blood samples at diagnosis and analyzed for IDH mutations with denaturing high-performance liquid chromatography, Sanger sequencing and targeted myeloid panel next-generation sequencing, respectively. Statistical as-treated analyses were performed using R and standard statistical methods (Kruskal-Wallis test for continuous variables, Chi-square test for categorical variables, Cox regression for univariate and multivariable models), incorporating alloHCT as a time-dependent covariate., Results: Among 3234 patients achieving CR1, 7.8% harbored IDH1 mutations (36% R132C and 47% R132H) and 10.9% carried IDH2 mutations (77% R140Q and 19% R172K). 852 patients underwent alloHCT in CR1. Within the alloHCT group, 6.2% had an IDH1 mutation (43.4% R132C and 41.4% R132H) and 10% were characterized by an IDH2 mutation (71.8% R140Q and 24.7% R172K). Variants IDH1 R132C and IDH2 R172K showed a significant benefit from alloHCT for OS (p = .017 and p = .049) and RFS (HR = 0.42, p = .048 and p = .009) compared with chemotherapy only. AlloHCT in IDH2 R140Q mutated AML resulted in longer RFS (HR = 0.4, p = .002)., Conclusion: In this large as-treated analysis, we showed that alloHCT is able to overcome the negative prognostic impact of certain IDH mutational subclasses in first-line consolidation treatment and could pending prognostic validation, provide prognostic value for AML risk stratification and therapeutic decision making., (© 2022. The Author(s).)
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- 2022
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5. Molecular profiling and clinical implications of patients with acute myeloid leukemia and extramedullary manifestations.
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Eckardt JN, Stölzel F, Kunadt D, Röllig C, Stasik S, Wagenführ L, Jöhrens K, Kuithan F, Krämer A, Scholl S, Hochhaus A, Crysandt M, Brümmendorf TH, Naumann R, Steffen B, Kunzmann V, Einsele H, Schaich M, Burchert A, Neubauer A, Schäfer-Eckart K, Schliemann C, Krause SW, Herbst R, Hänel M, Hanoun M, Kaiser U, Kaufmann M, Rácil Z, Mayer J, Kroschinsky F, Berdel WE, Ehninger G, Serve H, Müller-Tidow C, Platzbecker U, Baldus CD, Schetelig J, Bornhäuser M, Thiede C, and Middeke JM
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- Humans, Mutation, Nucleophosmin, Prognosis, Retrospective Studies, fms-Like Tyrosine Kinase 3 genetics, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy
- Abstract
Background: Extramedullary manifestations (EM) are rare in acute myeloid leukemia (AML) and their impact on clinical outcomes is controversially discussed., Methods: We retrospectively analyzed a large multi-center cohort of 1583 newly diagnosed AML patients, of whom 225 (14.21%) had EM., Results: AML patients with EM presented with significantly higher counts of white blood cells (p < 0.0001), peripheral blood blasts (p < 0.0001), bone marrow blasts (p = 0.019), and LDH (p < 0.0001). Regarding molecular genetics, EM AML was associated with mutations of NPM1 (OR: 1.66, p < 0.001), FLT3-ITD (OR: 1.72, p < 0.001) and PTPN11 (OR: 2.46, p < 0.001). With regard to clinical outcomes, EM AML patients were less likely to achieve complete remissions (OR: 0.62, p = 0.004), and had a higher early death rate (OR: 2.23, p = 0.003). Multivariable analysis revealed EM as an independent risk factor for reduced overall survival (hazard ratio [HR]: 1.43, p < 0.001), however, for patients who received allogeneic hematopoietic cell transplantation (HCT) survival did not differ. For patients bearing EM AML, multivariable analysis unveiled mutated TP53 and IKZF1 as independent risk factors for reduced event-free (HR: 4.45, p < 0.001, and HR: 2.05, p = 0.044, respectively) and overall survival (HR: 2.48, p = 0.026, and HR: 2.63, p = 0.008, respectively)., Conclusion: Our analysis represents one of the largest cohorts of EM AML and establishes key molecular markers linked to EM, providing new evidence that EM is associated with adverse risk in AML and may warrant allogeneic HCT in eligible patients with EM., (© 2022. The Author(s).)
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- 2022
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6. Differential impact of IDH1/2 mutational subclasses on outcome in adult AML: results from a large multicenter study.
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Middeke JM, Metzeler KH, Röllig C, Krämer M, Eckardt JN, Stasik S, Greif PA, Spiekermann K, Rothenberg-Thurley M, Krug U, Braess J, Krämer A, Hochhaus A, Brümmendorf TH, Naumann R, Steffen B, Einsele H, Schaich M, Burchert A, Neubauer A, Görlich D, Sauerland C, Schäfer-Eckart K, Schliemann C, Krause SW, Hänel M, Frickhofen N, Noppeney R, Kaiser U, Kaufmann M, Kunadt D, Wörmann B, Sockel K, von Bonin M, Herold T, Müller-Tidow C, Platzbecker U, Berdel WE, Serve H, Baldus CD, Ehninger G, Schetelig J, Hiddemann W, Bornhäuser M, Stölzel F, and Thiede C
- Subjects
- Humans, Mutation, Nucleophosmin, Phenotype, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute drug therapy
- Abstract
Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are among 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 identified IDH1 mutations in 423 (8.6%) and IDH2 mutations in 575 (11.7%). Overall, there were no differences in response rates or survival for patients with mutations in IDH1 or IDH2 compared with patients without mutated IDH1/2. However, distinct clinical and comutational phenotypes of the most common subtypes of IDH1/2 mutations could be associated with differences in outcome. IDH1-R132C was associated with increased age, lower white blood cell (WBC) count, less frequent comutation of NPM1 and FLT3 internal tandem mutation (ITD) as well as with lower rate of complete remission and a trend toward reduced overall survival (OS) compared with other IDH1 mutation variants and wild-type (WT) IDH1/2. In our analysis, IDH2-R172K was associated with significantly lower WBC count, more karyotype abnormalities, and less frequent comutations of NPM1 and/or FLT3-ITD. Among patients within the European LeukemiaNet 2017 intermediate- and adverse-risk groups, relapse-free survival and OS were significantly better for those with IDH2-R172K compared with WT IDH, providing evidence that AML with IDH2-R172K could be a distinct entity with a specific comutation pattern and favorable outcome. In summary, the presented data from a large cohort of patients with IDH1/2 mutated AML indicate novel and clinically relevant findings for the most common IDH mutation subtypes., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2022
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7. CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome.
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Taube F, Georgi JA, Kramer M, Stasik S, Middeke JM, Röllig C, Krug U, Krämer A, Scholl S, Hochhaus A, Brümmendorf TH, Naumann R, Petzold A, Mulet-Lazaro R, Valk PJM, Steffen B, Einsele H, Schaich M, Burchert A, Neubauer A, Schäfer-Eckart K, Schliemann C, Krause SW, Hänel M, Noppeney R, Kaiser U, Baldus CD, Kaufmann M, Herold S, Stölzel F, Sockel K, von Bonin M, Müller-Tidow C, Platzbecker U, Berdel WE, Serve H, Ehninger G, Bornhäuser M, Schetelig J, and Thiede C
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- Adult, Aged, Basic-Leucine Zipper Transcription Factors metabolism, CCAAT-Enhancer-Binding Proteins metabolism, Female, Humans, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute metabolism, Male, Middle Aged, Prognosis, Protein Binding, Retrospective Studies, Survival Analysis, CCAAT-Enhancer-Binding Proteins genetics, Leukemia, Myeloid, Acute genetics, Mutation
- Abstract
Biallelic mutations of the CEBPA gene (CEBPAbi) define a distinct entity associated with favorable prognosis; however, the role of monoallelic mutations (CEBPAsm) is poorly understood. We retrospectively analyzed 4708 adults with acute myeloid leukemia (AML) who had been recruited into the Study Alliance Leukemia trials, to investigate the prognostic impact of CEBPAsm. CEBPA mutations were identified in 240 patients (5.1%): 131 CEBPAbi and 109 CEBPAsm (60 affecting the N-terminal transactivation domains [CEBPAsmTAD] and 49 the C-terminal DNA-binding or basic leucine zipper region [CEBPAsmbZIP]). Interestingly, patients carrying CEBPAbi or CEBPAsmbZIP shared several clinical factors: they were significantly younger (median, 46 and 50 years, respectively) and had higher white blood cell (WBC) counts at diagnosis (median, 23.7 × 109/L and 35.7 × 109/L) than patients with CEBPAsmTAD (median age, 63 years, median WBC 13.1 × 109/L; P < .001). Co-mutations were similar in both groups: GATA2 mutations (35.1% CEBPAbi; 36.7% CEBPAsmbZIP vs 6.7% CEBPAsmTAD; P < .001) or NPM1 mutations (3.1% CEBPAbi; 8.2% CEBPAsmbZIP vs 38.3% CEBPAsmTAD; P < .001). CEBPAbi and CEBPAsmbZIP, but not CEBPAsmTAD were associated with significantly improved overall (OS; median 103 and 63 vs 13 months) and event-free survival (EFS; median, 20.7 and 17.1 months vs 5.7 months), in univariate and multivariable analyses. Additional analyses revealed that the clinical and molecular features as well as the favorable survival were confined to patients with in-frame mutations in bZIP (CEBPAbZIP-inf). When patients were classified according to CEBPAbZIP-inf and CEBPAother (including CEBPAsmTAD and non-CEBPAbZIP-inf), only patients bearing CEBPAbZIP-inf showed superior complete remission rates and the longest median OS and EFS, arguing for a previously undefined prognostic role of this type of mutation., (© 2022 by The American Society of Hematology.)
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- 2022
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8. The RUNX1 database (RUNX1db): establishment of an expert curated RUNX1 registry and genomics database as a public resource for familial platelet disorder with myeloid malignancy.
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Homan CC, King-Smith SL, Lawrence DM, Arts P, Feng J, Andrews J, Armstrong M, Ha T, Dobbins J, Drazer MW, Yu K, Bödör C, Cantor A, Cazzola M, Degelman E, DiNardo CD, Duployez N, Favier R, Fröhling S, Fitzgibbon J, Klco JM, Krämer A, Kurokawa M, Lee J, Malcovati L, Morgan NV, Natsoulis G, Owen C, Patel KP, Preudhomme C, Raslova H, Rienhoff H, Ripperger T, Schulte R, Tawana K, Velloso E, Yan B, Liu P, Godley LA, Schreiber AW, Hahn CN, Scott HS, and Brown AL
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- Core Binding Factor Alpha 2 Subunit genetics, Genomics, Humans, Registries, Blood Platelet Disorders genetics, Blood Platelet Disorders pathology, Leukemia, Myeloid, Acute, Neoplasms
- Published
- 2021
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9. Impact of PTPN11 mutations on clinical outcome analyzed in 1529 patients with acute myeloid leukemia.
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Stasik S, Eckardt JN, Kramer M, Röllig C, Krämer A, Scholl S, Hochhaus A, Crysandt M, Brümmendorf TH, Naumann R, Steffen B, Kunzmann V, Einsele H, Schaich M, Burchert A, Neubauer A, Schäfer-Eckart K, Schliemann C, Krause S, Herbst R, Hänel M, Frickhofen N, Noppeney R, Kaiser U, Baldus CD, Kaufmann M, Rácil Z, Platzbecker U, Berdel WE, Mayer J, Serve H, Müller-Tidow C, Ehninger G, Bornhäuser M, Schetelig J, Middeke JM, and Thiede C
- Subjects
- Humans, Mutation, Nucleophosmin, Phosphoprotein Phosphatases, Prognosis, Protein Tyrosine Phosphatase, Non-Receptor Type 11 genetics, Remission Induction, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics
- Abstract
The tyrosine-protein phosphatase nonreceptor type 11 (PTPN11) is an important regulator of RAS signaling and frequently affected by mutations in patients with acute myeloid leukemia (AML). Despite the relevance for leukemogenesis and as a potential therapeutic target, the prognostic role is controversial. To investigate the prognostic impact of PTPN11 mutations, we analyzed 1529 adult AML patients using next-generation sequencing. PTPN11 mutations were detected in 106 of 1529 (6.93%) patients (median VAF: 24%) in dominant (36%) and subclonal (64%) configuration. Patients with PTPN11 mutations were associated with concomitant mutations in NPM1 (63%), DNMT3A (37%), and NRAS (21%) and had a higher rate of European LeukemiaNet (ELN) favorable cytogenetics (57.8% vs 39.1%; P < .001) and higher white blood cell counts (P = .007) compared with PTPN11 wild-type patients. In a multivariable analysis, PTPN11 mutations were independently associated with poor overall survival (hazard ratio [HR]: 1.75; P < .001), relapse-free survival (HR: 1.52; P = .013), and a lower rate of complete remission (odds ratio: 0.46; P = .008). Importantly, the deleterious effect of PTPN11 mutations was confined predominantly to the ELN favorable-risk group and patients with subclonal PTPN11 mutations (HR: 2.28; P < .001) but not found with dominant PTPN11 mutations (HR: 1.07; P = .775), presumably because of significant differences within the rate and spectrum of associated comutations. In conclusion, our data suggest an overall poor prognostic impact of PTPN11 mutations in AML, which is significantly modified by the underlying cytogenetics and the clonal context in which they occur., (© 2021 by The American Society of Hematology.)
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- 2021
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10. Sorafenib or placebo in patients with newly diagnosed acute myeloid leukaemia: long-term follow-up of the randomized controlled SORAML trial.
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Röllig C, Serve H, Noppeney R, Hanoun M, Krug U, Baldus CD, Brandts CH, Kunzmann V, Einsele H, Krämer A, Müller-Tidow C, Schäfer-Eckart K, Neubauer A, Burchert A, Giagounidis A, Krause SW, Mackensen A, Aulitzky W, Herbst R, Hänel M, Frickhofen N, Kullmer J, Kaiser U, Kiani A, Link H, Geer T, Reichle A, Junghanß C, Repp R, Meinhardt A, Dürk H, Klut IM, Bornhäuser M, Schaich M, Parmentier S, Görner M, Thiede C, von Bonin M, Platzbecker U, Schetelig J, Kramer M, Berdel WE, and Ehninger G
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- Adolescent, Adult, Double-Blind Method, Female, Follow-Up Studies, Humans, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Neoplasm Recurrence, Local pathology, Prognosis, Survival Rate, Young Adult, Antineoplastic Agents therapeutic use, Leukemia, Myeloid, Acute drug therapy, Neoplasm Recurrence, Local drug therapy, Sorafenib therapeutic use
- Abstract
Early results of the randomized placebo-controlled SORAML trial showed that, in patients with newly diagnosed acute myeloid leukaemia (AML), sorafenib led to a significant improvement in event-free (EFS) and relapse-free survival (RFS). In order to describe second-line treatments and their implications on overall survival (OS), we performed a study after a median follow-up time of 78 months. Newly diagnosed fit AML patients aged ≤60 years received sorafenib (n = 134) or placebo (n = 133) in addition to standard chemotherapy and as maintenance treatment. The 5-year EFS was 41 versus 27% (HR 0.68; p = 0.011) and 5-year RFS was 53 versus 36% (HR 0.64; p = 0.035). Allogeneic stem cell transplantation (allo SCT) was performed in 88% of the relapsed patients. Four years after salvage allo SCT, the cumulative incidence of relapse was 54 versus 35%, and OS was 32 versus 50%. The 5-year OS from randomization in all study patients was 61 versus 53% (HR 0.82; p = 0.282). In conclusion, the addition of sorafenib to chemotherapy led to a significant prolongation of EFS and RFS. Although the OS benefit did not reach statistical significance, these results confirm the antileukaemic activity of sorafenib., (© 2021. The Author(s).)
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- 2021
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11. The JmjC-domain protein NO66/RIOX-1 affects the balance between proliferation and maturation in acute myeloid leukemia.
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Yu W, Lutz C, Krämer A, and Schmidt-Zachmann MS
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- Cell Line, Tumor, Gene Expression Regulation, Leukemic genetics, Humans, Leukemia, Myeloid, Acute pathology, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Protein Domains genetics, Cell Proliferation genetics, Dioxygenases genetics, Histone Demethylases genetics, Leukemia, Myeloid, Acute genetics, Neoplasm Proteins genetics
- Abstract
As epigenetic regulators are frequently dysregulated in acute myeloid leukemia (AML) we determined expression levels of the JmjC-protein NO66 in AML cell lines and sub fractions of healthy human hematopoietic cells. NO66 is absent in the AML cell lines KG1/KG1a which consist of cells with the immature CD34
+ /CD38- phenotype and is regarded as a "stem cell-like" model system. Similarly, NO66 is not detectable in CD34+ /CD38- cells purified from healthy donors but is clearly expressed in the more committed CD34+ /CD38+ cell population. Loss of NO66 expression in KG1/KG1a cells is due to hyper-methylation of its promoter and is released by DNA-methyltransferase inhibitors. In KG1a cells stably expressing exogenous wild type (KG1a66wt) or enzymatically inactive mutant (KG1a66mut) NO66, respectively, the wild type protein inhibited proliferation and rDNA transcription. Gene expression profiling revealed that the expression of NO66 induces a transcriptional program enriched for genes with roles in proliferation and maturation (e.g.EPDR1, FCER1A, CD247, MYCN, SNORD13). Genes important for the maintenance of stem cell properties are downregulated (e.g. SIRPA, Lin28B, JAML). Our results indicate that NO66 induces lineage commitment towards myeloid progenitor cell fate and suggest that NO66 contributes to loss of stem cell properties., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
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12. Concentration-QTc analysis of quizartinib in patients with relapsed/refractory acute myeloid leukemia.
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Kang D, Ludwig E, Jaworowicz D, Huang H, Fiedler-Kelly J, Cortes J, Ganguly S, Khaled S, Krämer A, Levis M, Martinelli G, Perl A, Russell N, Abutarif M, Choi Y, and Yin O
- Subjects
- Adult, Aged, Aged, 80 and over, Benzothiazoles therapeutic use, Cytochrome P-450 CYP3A Inhibitors pharmacology, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Phenylurea Compounds therapeutic use, Benzothiazoles pharmacology, Electrocardiography drug effects, Leukemia, Myeloid, Acute drug therapy, Phenylurea Compounds pharmacology
- Abstract
Purpose: This analysis evaluated the relationship between concentrations of quizartinib and its active metabolite AC886 and QT interval corrected using Fridericia's formula (QTcF) in patients with relapsed/refractory acute myeloid leukemia (AML) treated in the phase 3 QuANTUM-R study (NCT02039726)., Methods: The analysis dataset included 226 patients with AML. Quizartinib dihydrochloride was administered as daily doses of 20, 30, and 60 mg. Nonlinear mixed-effects modeling was performed using observed quizartinib and AC886 concentrations and time-matched mean electrocardiogram measurements., Results: Observed QTcF increased with quizartinib and AC886 concentrations; the relationship was best described by a nonlinear maximum effect (E
max ) model. The predicted mean increase in QTcF at the maximum concentration of quizartinib and AC886 associated with 60 mg/day was 21.1 ms (90% CI, 18.3-23.6 ms). Age, body weight, sex, race, baseline QTcF, QT-prolonging drug use, hypomagnesemia, and hypocalcemia were not significant predictors of QTcF. Hypokalemia (serum potassium < 3.5 mmol/L) was a statistically significant covariate affecting baseline QTcF, but no differences in ∆QTcF (change in QTcF from baseline) were predicted between patients with versus without hypokalemia at the same quizartinib concentration. The use of concomitant QT-prolonging drugs did not increase QTcF further., Conclusion: QTcF increase was dependent on quizartinib and AC886 concentrations, but patient factors, including sex and age, did not affect the concentration-QTcF relationship. Because concomitant strong cytochrome P450 3A (CYP3A) inhibitor use significantly increases quizartinib concentration, these results support the clinical recommendation of quizartinib dose reduction in patients concurrently receiving a strong CYP3A inhibitor., Clinical Trial Registration: NCT02039726 (registered January 20, 2014).- Published
- 2021
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13. Clinical Outcomes in Patients with FLT3-ITD-Mutated Relapsed/Refractory Acute Myelogenous Leukemia Undergoing Hematopoietic Stem Cell Transplantation after Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial.
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Ganguly S, Cortes JE, Krämer A, Levis MJ, Martinelli G, Perl AE, Russell NH, Arunachalam M, Santos CD, Gammon G, Lesegretain A, Mires DE, Pham H, Wang Y, and Khaled SK
- Subjects
- Benzothiazoles, Humans, Phenylurea Compounds, fms-Like Tyrosine Kinase 3 genetics, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute drug therapy
- Abstract
Despite the substantial clinical activity of fms-related tyrosine kinase 3 (FLT3) inhibitors in relapsed or refractory (R/R) FLT3-ITD‒positive acute myelogenous leukemia (AML), durable remissions and prolonged survival in this population require allogeneic hematopoietic stem cell transplantation (allo-HSCT). Quizartinib, a once-daily oral, highly potent, and selective FLT3 inhibitor, significantly prolonged overall survival (OS) and improved clinical benefit compared with salvage chemotherapy (median OS, 6.2 months versus 4.7 months; hazard ratio [HR], .76; 95% confidence interval [CI], .58 to .98; P = .018; composite complete remission [CRc] rate, 48% versus 27%; median duration of CRc, 2.8 months versus 1.2 months; mortality rate, .8% versus 14% by day 30, 7% versus 24% by day 60) in patients with R/R FLT3-ITD AML in the phase 3 QuANTUM-R trial. In this post hoc analysis, we described the characteristics of and clinical outcomes in patients who underwent on-study HSCT in QuANTUM-R at the investigator's discretion and institutional practices. Of 367 randomized patients, 78 (32%) in the quizartinib arm and 14 (11%) in the salvage chemotherapy arm underwent on-study allo-HSCT without any intervening therapy for AML after quizartinib or study-specified salvage chemotherapy. Pooled data of patients from both treatment arms showed a longer median overall survival (OS) in transplant recipients versus those treated without allo-HSCT (12.2 months versus 4.4 months; HR, .315; 95% CI, .233 to .427). Pooled data also showed a longer median OS in patients with a last recorded response of CRc before allo-HSCT versus patients without a CRc (20.1 months versus 8.8 months; HR, .506; 95% CI, .296 to .864). By treatment arm, the median OS was 25.1 months with quizartinib and 20.1 months with salvage chemotherapy in patients with a last recorded response of CRc before allo-HSCT. Forty-eight patients in the quizartinib arm continued quizartinib treatment after allo-HSCT. In the 31 patients with a last recorded response of CRc before allo-HSCT who continued quizartinib after allo-HSCT, the median OS was 27.1 months. Continuation of quizartinib after allo-HSCT was tolerable, and no new safety signals were identified. These results suggest that post-transplantation survival following salvage chemotherapy and quizartinib treatment are similar. However, quizartinib response occurs more frequently than with salvage chemotherapy, potentially allowing more patients to undergo transplantation and achieve durable clinical benefit. In addition, post-transplant quizartinib was found to be tolerable and may be associated with prolonged survival in some patients, highlighting its potential value in the management of patients with FLT3-ITD R/R AML., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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14. Population Pharmacokinetic Analysis of Quizartinib in Healthy Volunteers and Patients With Relapsed/Refractory Acute Myeloid Leukemia.
- Author
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Kang D, Ludwig E, Jaworowicz D, Huang H, Fiedler-Kelly J, Cortes J, Ganguly S, Khaled S, Krämer A, Levis M, Martinelli G, Perl A, Russell N, Abutarif M, Choi Y, Mendell J, and Yin O
- Subjects
- Administration, Oral, Adolescent, Adult, Aged, Aged, 80 and over, Area Under Curve, Benzothiazoles administration & dosage, Benzothiazoles metabolism, Body Surface Area, Clinical Trials as Topic, Cytochrome P-450 CYP3A Inhibitors administration & dosage, Cytochrome P-450 CYP3A Inhibitors pharmacology, Drug Interactions, Female, Healthy Volunteers, Humans, Male, Middle Aged, Phenylurea Compounds administration & dosage, Phenylurea Compounds metabolism, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors metabolism, Young Adult, fms-Like Tyrosine Kinase 3 antagonists & inhibitors, Benzothiazoles pharmacokinetics, Leukemia, Myeloid, Acute drug therapy, Phenylurea Compounds pharmacokinetics, Protein Kinase Inhibitors pharmacokinetics
- Abstract
Quizartinib is an FMS-like tyrosine kinase 3 (FLT3) inhibitor that has shown robust clinical activity in patients with FLT3-internal tandem duplication-mutated relapsed/refractory acute myeloid leukemia (AML). This analysis evaluated the population pharmacokinetics (PK) of quizartinib and its active metabolite, AC886, in a pooled analysis of data from 649 healthy volunteers or patients with AML from 8 clinical trials including the phase 3 QuANTUM-R study. Quizartinib was given as a single dose or multiple once-daily doses of 20, 30, 60, or 90 mg. Nonlinear mixed-effects modeling was performed using observed concentrations of quizartinib and AC886. Strong CYP3A inhibitor use resulted in an 82% increase in the area under the curve (AUC) and a 72% increase in the maximum concentration (C
max ) of quizartinib. Albumin level, age, and body surface area were statistically significant covariates on quizartinib PK. However, their individual effects on quizartinib AUC and Cmax were <20%. For AC886, strong CYP3A inhibitor use, body surface area and black/African American race were significant covariates. Except for strong CYP3A inhibitor use, the effects on the overall exposure (AUC of quizartinib + AC886) were <20%. The population PK model provided an adequate description of the observed concentrations of quizartinib and AC886 in both healthy volunteers and patients with AML. Only concomitant use of strong CYP3A inhibitors had a clinically meaningful effect on quizartinib PK exposure., (© 2020 Daiichi Sankyo, Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)- Published
- 2020
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15. Safety and efficacy of BAY1436032 in IDH1-mutant AML: phase I study results.
- Author
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Heuser M, Palmisiano N, Mantzaris I, Mims A, DiNardo C, Silverman LR, Wang ES, Fiedler W, Baldus C, Schwind S, Pardee T, Perl AE, Cai C, Kaulfuss S, Lagkadinou E, Rentzsch C, Wagner M, Wilkinson G, Wu B, Jeffers M, Genvresse I, and Krämer A
- Subjects
- Adult, Aged, Aniline Compounds administration & dosage, Aniline Compounds adverse effects, Aniline Compounds pharmacokinetics, Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Benzimidazoles administration & dosage, Benzimidazoles adverse effects, Benzimidazoles pharmacokinetics, Bone Marrow pathology, DNA Mutational Analysis, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors adverse effects, Enzyme Inhibitors pharmacokinetics, Female, Humans, Isocitrate Dehydrogenase metabolism, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Prognosis, Survival Analysis, Treatment Outcome, Aniline Compounds therapeutic use, Antineoplastic Agents therapeutic use, Benzimidazoles therapeutic use, Enzyme Inhibitors therapeutic use, Isocitrate Dehydrogenase antagonists & inhibitors, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Molecular Targeted Therapy, Mutation
- Abstract
The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4 doses ranging from 300 to 1500 mg twice-daily. BAY1436032 exhibited a relatively short half-life and apparent non-linear pharmacokinetics after continuous dosing. Most subjects experienced only partial target inhibition as indicated by plasma R-2HG levels. BAY1436032 was safe and a maximum tolerated dose was not identified. The median treatment duration for all subjects was 3.0 months (0.49-8.5). The overall response rate was 15% (4/27; 1 CRp, 1 PR, 2 MLFS), with responding subjects experiencing a median treatment duration of 6.0 months (3.9-8.5) and robust R-2HG decreases. Thirty percent (8/27) achieved SD, with a median treatment duration of 5.5 months (3.1-7.0). Degree of R-2HG inhibition and clinical benefit did not correlate with dose. Although BAY1436032 was safe and modestly effective as monotherapy, the low overall response rate and incomplete target inhibition achieved at even the highest dose tested do not support further clinical development of this investigational agent in AML.
- Published
- 2020
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16. Does time from diagnosis to treatment affect the prognosis of patients with newly diagnosed acute myeloid leukemia?
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Röllig C, Kramer M, Schliemann C, Mikesch JH, Steffen B, Krämer A, Noppeney R, Schäfer-Eckart K, Krause SW, Hänel M, Herbst R, Kunzmann V, Einsele H, Jost E, Brümmendorf TH, Scholl S, Hochhaus A, Neubauer A, Sohlbach K, Fransecky L, Kaufmann M, Niemann D, Schaich M, Frickhofen N, Kiani A, Heits F, Krümpelmann U, Kaiser U, Kullmer J, Wass M, Stölzel F, von Bonin M, Middeke JM, Thiede C, Schetelig J, Berdel WE, Ehninger G, Baldus CD, Müller-Tidow C, Platzbecker U, Serve H, and Bornhäuser M
- Subjects
- Aged, Female, Follow-Up Studies, Germany epidemiology, Humans, Leukemia, Myeloid, Acute epidemiology, Male, Middle Aged, Prognosis, Registries, Retrospective Studies, Survival Analysis, Treatment Outcome, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute therapy, Time-to-Treatment statistics & numerical data
- Abstract
In fit patients with newly diagnosed acute myeloid leukemia (AML), immediate treatment start is recommended due to the poor prognosis of untreated acute leukemia. We explored the relationship between time from diagnosis to treatment start (TDT) and prognosis in a large real-world data set from the German Study Alliance Leukemia-Acute Myeloid Leukemia (SAL-AML) registry. All registered non-acute promyelocytic leukemia patients with intensive induction treatment and a minimum 12 months of follow-up were selected (n = 2263). We analyzed influence of TDT on remission, early death, and overall survival (OS) in univariable analyses for each day of treatment delay, in groups of 0 to 5, 6 to 10, 11 to 15, and >15 days of TDT, adjusted for influence of established prognostic variables on outcomes. Median TDT was 3 days (interquartile range, 2-7). Unadjusted 2-year OS rates, stratified by TDT of 0 to 5, 6 to 10, 11 to 15, and >15 days, were 51%, 48%, 44%, and 50% (P = .211). In multivariable Cox regression analysis accounting for established prognostic variables, the TDT hazard ratio as a continuous variable was 1.00 (P = .617). In OS analyses, separately stratified for age ≤60 and >60 years and for high vs lower initial white blood cell count, no significant differences between TDT groups were observed. Our study suggests that TDT is not related to survival. As stratification in intensive first-line AML treatment evolves, TDT data suggest that it may be a feasible approach to wait for genetic and other laboratory test results so that clinically stable patients are assigned the best available treatment option. This trial was registered at www.clinicaltrials.gov as #NCT03188874., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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17. The clinical mutatome of core binding factor leukemia.
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Opatz S, Bamopoulos SA, Metzeler KH, Herold T, Ksienzyk B, Bräundl K, Tschuri S, Vosberg S, Konstandin NP, Wang C, Hartmann L, Graf A, Krebs S, Blum H, Schneider S, Thiede C, Middeke JM, Stölzel F, Röllig C, Schetelig J, Ehninger G, Krämer A, Braess J, Görlich D, Sauerland MC, Berdel WE, Wörmann BJ, Hiddemann W, Spiekermann K, Bohlander SK, and Greif PA
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Mutation, Young Adult, Core Binding Factors genetics, Leukemia, Myeloid, Acute genetics
- Abstract
The fusion genes CBFB/MYH11 and RUNX1/RUNX1T1 block differentiation through disruption of the core binding factor (CBF) complex and are found in 10-15% of adult de novo acute myeloid leukemia (AML) cases. This AML subtype is associated with a favorable prognosis; however, nearly half of CBF-rearranged patients cannot be cured with chemotherapy. This divergent outcome might be due to additional mutations, whose spectrum and prognostic relevance remains hardly defined. Here, we identify nonsilent mutations, which may collaborate with CBF-rearrangements during leukemogenesis by targeted sequencing of 129 genes in 292 adult CBF leukemia patients, and thus provide a comprehensive overview of the mutational spectrum ('mutatome') in CBF leukemia. Thereby, we detected fundamental differences between CBFB/MYH11- and RUNX1/RUNX1T1-rearranged patients with ASXL2, JAK2, JAK3, RAD21, TET2, and ZBTB7A being strongly correlated with the latter subgroup. We found prognostic relevance of mutations in genes previously known to be AML-associated such as KIT, SMC1A, and DHX15 and identified novel, recurrent mutations in NFE2 (3%), MN1 (4%), HERC1 (3%), and ZFHX4 (5%). Furthermore, age >60 years, nonprimary AML and loss of the Y-chromosomes are important predictors of survival. These findings are important for refinement of treatment stratification and development of targeted therapy approaches in CBF leukemia.
- Published
- 2020
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18. EZH2 mutations and impact on clinical outcome: an analysis in 1,604 patients with newly diagnosed acute myeloid leukemia.
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Stasik S, Middeke JM, Kramer M, Röllig C, Krämer A, Scholl S, Hochhaus A, Crysandt M, Brümmendorf TH, Naumann R, Steffen B, Kunzmann V, Einsele H, Schaich M, Burchert A, Neubauer A, Schäfer-Eckart K, Schliemann C, Krause S, Herbst R, Hänel M, Frickhofen N, Noppeney R, Kaiser U, Baldus CD, Kaufmann M, Rácil Z, Platzbecker U, Berdel WE, Mayer J, Serve H, Müller-Tidow C, Ehninger G, Bornhäuser M, Schetelig J, and Thiede C
- Subjects
- Enhancer of Zeste Homolog 2 Protein genetics, Humans, Mutation, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics
- Published
- 2020
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19. RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML.
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Brown AL, Arts P, Carmichael CL, Babic M, Dobbins J, Chong CE, Schreiber AW, Feng J, Phillips K, Wang PPS, Ha T, Homan CC, King-Smith SL, Rawlings L, Vakulin C, Dubowsky A, Burdett J, Moore S, McKavanagh G, Henry D, Wells A, Mercorella B, Nicola M, Suttle J, Wilkins E, Li XC, Michaud J, Brautigan P, Cannon P, Altree M, Jaensch L, Fine M, Butcher C, D'Andrea RJ, Lewis ID, Hiwase DK, Papaemmanuil E, Horwitz MS, Natsoulis G, Rienhoff HY, Patton N, Mapp S, Susman R, Morgan S, Cooney J, Currie M, Popat U, Bochtler T, Izraeli S, Bradstock K, Godley LA, Krämer A, Fröhling S, Wei AH, Forsyth C, Mar Fan H, Poplawski NK, Hahn CN, and Scott HS
- Subjects
- Epigenesis, Genetic, Germ Cells, Humans, Mutation, Pedigree, Phenotype, Core Binding Factor Alpha 2 Subunit genetics, Leukemia, Myeloid, Acute genetics
- Abstract
First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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20. Allogeneic hematopoietic cell transplantation improves outcome of adults with t(6;9) acute myeloid leukemia: results from an international collaborative study.
- Author
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Kayser S, Hills RK, Luskin MR, Brunner AM, Terré C, Westermann J, Menghrajani K, Shaw C, Baer MR, Elliott MA, Perl AE, Ráčil Z, Mayer J, Zak P, Szotkowski T, de Botton S, Grimwade D, Mayer K, Walter RB, Krämer A, Burnett AK, Ho AD, Platzbecker U, Thiede C, Ehninger G, Stone RM, Röllig C, Tallman MS, Estey EH, Müller-Tidow C, Russell NH, Schlenk RF, and Levis MJ
- Subjects
- Adult, Cytarabine, Disease-Free Survival, Humans, Middle Aged, Remission Induction, Retrospective Studies, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute therapy
- Abstract
Acute myeloid leukemia (AML) with t(6;9)(p22;q34) is a distinct entity accounting for 1-2% of AML cases. A substantial proportion of these patients have a concomitant FLT3 -ITD. While outcomes are dismal with intensive chemotherapy, limited evidence suggests allogeneic hematopoietic cell transplantation (allo-HCT) may improve survival if performed early during first complete remission. We report on a cohort of 178 patients with t(6;9)(p22;q34) within an international, multicenter collaboration. Median age was 46 years (range: 16-76), AML was de novo in 88%, FLT3 -ITD was present in 62%, and additional cytogenetic abnormalities in 21%. Complete remission was achieved in 81% (n=144), including 14 patients who received high-dose cytarabine after initial induction failure. With a median follow up of 5.43 years, estimated overall survival at five years was 38% (95%CI: 31-47%). Allo-HCT was performed in 117 (66%) patients, including 89 in first complete remission. Allo-HCT in first complete remission was associated with higher 5-year relapse-free and overall survival as compared to consolidation chemotherapy: 45% (95%CI: 35-59%) and 53% (95%CI: 42-66%) versus 7% (95%CI: 3-19%) and 23% (95%CI: 13-38%), respectively. For patients undergoing allo-HCT, there was no difference in overall survival rates at five years according to whether it was performed in first [53% (95%CI: 42-66%)], or second [58% (95%CI: 31-100%); n=10] complete remission or with active disease/relapse [54% (95%CI: 34-84%); n=18] ( P =0.67). Neither FLT3 -ITD nor additional chromosomal abnormalities impacted survival. In conclusion, outcomes of t(6;9)(p22;q34) AML are poor with chemotherapy, and can be substantially improved with allo-HCT., (Copyright© 2020 Ferrata Storti Foundation.)
- Published
- 2020
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21. TP53 deficiency permits chromosome abnormalities and karyotype heterogeneity in acute myeloid leukemia.
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Cazzola A, Schlegel C, Jansen I, Bochtler T, Jauch A, and Krämer A
- Subjects
- Aneuploidy, CRISPR-Cas Systems, Cell Line, Tumor, Cell Proliferation, DNA Damage, Gene Deletion, Humans, In Situ Hybridization, Fluorescence, Karyotyping, Leukemia, Myeloid, Acute diagnosis, Mutation, Prognosis, Chromosome Aberrations, Leukemia, Myeloid, Acute genetics, Tumor Suppressor Protein p53 genetics
- Abstract
Abnormal karyotypes are common in cancer cells and frequently observed in acute myeloid leukemia (AML), in which complex karyotype aberrations are associated with poor prognosis. How exactly abnormal karyotypes arise and are propagated in AML is unclear. TP53 mutations and deletions are frequent in complex karyotype AML, suggesting a role of TP53 alterations in the development of chromosome abnormalities. Here, we generated isogenic TP53-knockout versions of the euploid AML cell line EEB to investigate the impact of TP53 on karyotype stability. We show that chromosome abnormalities spontaneously arise in TP53-deficient cells. Numerical aneuploidy could, to some extent, be propagated in a TP53-proficient setting, indicating that it does not necessarily trigger TP53 activation. In contrast, tolerance to structural chromosome aberrations was almost entirely restricted to TP53-knockout clones, all of which were able to continue proliferation in the presence of damaged DNA. Mechanistically, as a source of chromosome aberrations, limited numerical but not structural chromosomal instability was tolerated by TP53-wildtype cells. In contrast, structural instability was found only in TP53-knockout cells. Together, in myeloid cells TP53 loss allows for the development of complex karyotype aberrations and karyotype heterogeneity by perpetuation of chromosome segregation errors.
- Published
- 2019
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22. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial.
- Author
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Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, and Levis MJ
- Subjects
- Adult, Aged, Benzothiazoles pharmacology, Female, Humans, Leukemia, Myeloid, Acute genetics, Male, Middle Aged, Neoplasm Recurrence, Local genetics, Phenylurea Compounds pharmacology, Survival Rate, Tandem Repeat Sequences, fms-Like Tyrosine Kinase 3 antagonists & inhibitors, fms-Like Tyrosine Kinase 3 genetics, Benzothiazoles therapeutic use, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute mortality, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local mortality, Phenylurea Compounds therapeutic use, Salvage Therapy
- Abstract
Background: Patients with relapsed or refractory FLT3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukaemia have a poor prognosis, including high frequency of relapse, poorer response to salvage therapy, and shorter overall survival than those with FLT3 wild-type disease. We aimed to assess whether single-agent quizartinib, an oral, highly potent and selective type II FLT3 inhibitor, improves overall survival versus salvage chemotherapy., Methods: QuANTUM-R is a randomised, controlled, phase 3 trial done at 152 hospitals and cancer centres in 19 countries. Eligible patients aged 18 years or older with ECOG performance status 0-2 with relapsed or refractory (duration of first composite complete remission ≤6 months) FLT3-ITD acute myeloid leukaemia after standard therapy with or without allogeneic haemopoietic stem-cell transplantation were randomly assigned (2:1; permuted block size of 6; stratified by response to previous therapy and choice of chemotherapy via a phone-based and web-based interactive response system) to quizartinib (60 mg [30 mg lead-in] orally once daily) or investigator's choice of preselected chemotherapy: subcutaneous low-dose cytarabine (subcutaneous injection of cytarabine 20 mg twice daily on days 1-10 of 28-day cycles); intravenous infusions of mitoxantrone (8 mg/m
2 per day), etoposide (100 mg/m2 per day), and cytarabine (1000 mg/m2 per day on days 1-5 of up to two 28-day cycles); or intravenous granulocyte colony-stimulating factor (300 μg/m2 per day or 5 μg/kg per day subcutaneously on days 1-5), fludarabine (intravenous infusion 30 mg/m2 per day on days 2-6), cytarabine (intravenous infusion 2000 mg/m2 per day on days 2-6), and idarubicin (intravenous infusion 10 mg/m2 per day on days 2-4 in up to two 28-day cycles). Patients proceeding to haemopoietic stem-cell transplantation after quizartinib could resume quizartinib after haemopoietic stem-cell transplantation. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02039726, and follow-up is ongoing., Findings: Between May 7, 2014, and Sept 13, 2017, 367 patients were enrolled, of whom 245 were randomly allocated to quizartinib and 122 to chemotherapy. Four patients in the quizartinib group and 28 in the chemotherapy group were not treated. Median follow-up was 23·5 months (IQR 15·4-32·3). Overall survival was longer for quizartinib than for chemotherapy (hazard ratio 0·76 [95% CI 0·58-0·98; p=0·02]). Median overall survival was 6·2 months (5·3-7·2) in the quizartinib group and 4·7 months (4·0-5·5) in the chemotherapy group. The most common non-haematological grade 3-5 treatment-emergent adverse events (within ≤30 days of last dose or >30 days if suspected to be a treatment-related event) for quizartinib (241 patients) and chemotherapy (94 patients) were sepsis or septic shock (46 patients [19%] for quizartinib vs 18 [19%] for chemotherapy), pneumonia (29 [12%] vs eight [9%]), and hypokalaemia (28 [12%] vs eight [9%]). The most frequent treatment-related serious adverse events were febrile neutropenia (18 patients [7%]), sepsis or septic shock (11 [5%]), QT prolongation (five [2%]), and nausea (five [2%]) in the quizartinib group, and febrile neutropenia (five [5%]), sepsis or septic shock (four [4%]), pneumonia (two [2%]), and pyrexia (two [2%]) in the chemotherapy group. Grade 3 QT prolongation in the quizartinib group was uncommon (eight [3%] by central reading, ten [4%] by investigator report); no grade 4 events occurred. There were 80 (33%) treatment-emergent deaths in the quizartinib group (31 [13%] of which were due to adverse events) and 16 (17%) in the chemotherapy group (nine [10%] of which were due to adverse events)., Interpretation: Treatment with quizartinib had a survival benefit versus salvage chemotherapy and had a manageable safety profile in patients with rapidly proliferative disease and very poor prognosis. Quizartinib could be considered a new standard of care. Given that there are only a few available treatment options, this study highlights the value of targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor., Funding: Daiichi Sankyo., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2019
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23. Safety and efficacy of vismodegib in relapsed/refractory acute myeloid leukaemia: results of a phase Ib trial.
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Bixby D, Noppeney R, Lin TL, Cortes J, Krauter J, Yee K, Medeiros BC, Krämer A, Assouline S, Fiedler W, Dimier N, Simmons BP, Riehl T, and Colburn D
- Subjects
- Adult, Aged, Aged, 80 and over, Anilides adverse effects, Female, Humans, Male, Middle Aged, Pyridines adverse effects, Anilides administration & dosage, Leukemia, Myeloid, Acute drug therapy, Pyridines administration & dosage
- Published
- 2019
- Full Text
- View/download PDF
24. A phase I trial investigating the Aurora B kinase inhibitor BI 811283 in combination with cytarabine in patients with acute myeloid leukaemia.
- Author
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Döhner H, Müller-Tidow C, Lübbert M, Fiedler W, Krämer A, Westermann J, Bug G, Schlenk RF, Krug U, Goeldner RG, Hilbert J, Taube T, and Ottmann OG
- Subjects
- Aged, Aged, 80 and over, Aurora Kinase B metabolism, Cytarabine administration & dosage, Cytarabine adverse effects, Cytarabine pharmacokinetics, Female, Humans, Male, Middle Aged, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors pharmacokinetics, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Aurora Kinase B antagonists & inhibitors, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute enzymology, Neoplasm Proteins antagonists & inhibitors
- Published
- 2019
- Full Text
- View/download PDF
25. SMC3 protein levels impact on karyotype and outcome in acute myeloid leukemia.
- Author
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Kraft B, Lombard J, Kirsch M, Wuchter P, Bugert P, Hielscher T, Blank N, and Krämer A
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Female, Humans, Karyotype, Karyotyping, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Prognosis, Young Adult, Cell Cycle Proteins metabolism, Chondroitin Sulfate Proteoglycans metabolism, Chromosomal Proteins, Non-Histone metabolism, Leukemia, Myeloid, Acute metabolism
- Published
- 2019
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- View/download PDF
26. Phase I dose-escalation trial investigating volasertib as monotherapy or in combination with cytarabine in patients with relapsed/refractory acute myeloid leukaemia.
- Author
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Ottmann OG, Müller-Tidow C, Krämer A, Schlenk RF, Lübbert M, Bug G, Krug U, Bochtler T, Voss F, Taube T, Liu D, Garin-Chesa P, and Döhner H
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Female, Humans, Male, Maximum Tolerated Dose, Middle Aged, Pteridines administration & dosage, Salvage Therapy methods, Cytarabine therapeutic use, Leukemia, Myeloid, Acute drug therapy, Pteridines therapeutic use
- Published
- 2019
- Full Text
- View/download PDF
27. Hematological Malignancies in Adults With a Family Predisposition.
- Author
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Bochtler T, Haag GM, Schott S, Kloor M, Krämer A, and Müller-Tidow C
- Subjects
- CCAAT-Enhancer-Binding Proteins, Core Binding Factor Alpha 2 Subunit, Fibroblasts pathology, Genetic Counseling methods, Germany epidemiology, Hematologic Neoplasms diagnosis, Hematologic Neoplasms epidemiology, Hematologic Neoplasms therapy, Humans, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute epidemiology, Mutation, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes epidemiology, Prospective Studies, Retrospective Studies, Genetic Predisposition to Disease genetics, Germ-Line Mutation genetics, Hematologic Neoplasms genetics, Leukemia, Myeloid, Acute genetics, Myelodysplastic Syndromes genetics
- Abstract
Background: Some hematological malignancies arise in persons with a hereditary predisposition. The hereditary nature of these diseases often goes unrecognized, particularly when symptoms begin in adulthood., Methods: This review is based on pertinent publications retrieved by a selective search in PubMed., Results: Many rare germline mutations have been identified that lead to acute leukemia and myelodysplastic syndromes. They differ from one another with respect to their penetrance, the age of onset of disease, and the clinical manifestations. In view of this heterogeneity, no uniform recommendations have yet been formulated for their diagnosis and treatment. The most common types of hematological malig- nancy with a hereditary predisposition are traceable to an underlying disturbance of DNA damage response and repair mechanisms and to mutations of hematological transcription factors. With regard to the selection of patients for testing, the con- sensus is that cytogenetic and molecular-genetic findings that are suspect for a hereditary predisposition, such as CEBPA and RUNX1 mutations, call for further investigation, as do any clinical features that are typical of tumor syndromes, or a positive family history. The knowledge that a hereditary predisposition may be present is highly stressful for patients; testing should only be carried out after the patient has received genetic counseling. The confirmation of a germline mutation always requires a comparison with healthy tissue. A fibroblast culture is recom- mended as the gold standard for this purpose., Conclusion: The detection of a hereditary predisposition to hematological neoplasia is often relevant to treatment and follow-up care: for example, it may motivate early allogeneic stem-cell transplantation. Counseling, predictive testing, and follow-up care are available to the patients' relatives as well.
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- 2018
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28. Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial.
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Platzbecker U, Middeke JM, Sockel K, Herbst R, Wolf D, Baldus CD, Oelschlägel U, Mütherig A, Fransecky L, Noppeney R, Bug G, Götze KS, Krämer A, Bochtler T, Stelljes M, Groth C, Schubert A, Mende M, Stölzel F, Borkmann C, Kubasch AS, von Bonin M, Serve H, Hänel M, Dührsen U, Schetelig J, Röllig C, Kramer M, Ehninger G, Bornhäuser M, and Thiede C
- Subjects
- Aged, Antimetabolites, Antineoplastic adverse effects, Azacitidine adverse effects, Biomarkers, Tumor genetics, Biomarkers, Tumor immunology, Drug Administration Schedule, Female, Germany, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute immunology, Male, Middle Aged, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes immunology, Neoplasm, Residual, Nucleophosmin, Progression-Free Survival, Prospective Studies, Recurrence, Risk Assessment, Risk Factors, Time Factors, Antimetabolites, Antineoplastic administration & dosage, Azacitidine administration & dosage, Leukemia, Myeloid, Acute drug therapy, Myelodysplastic Syndromes drug therapy
- Abstract
Background: Monitoring of measurable residual disease (MRD) in patients with advanced myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) who achieve a morphological complete remission can predict haematological relapse. In this prospective study, we aimed to determine whether MRD-guided pre-emptive treatment with azacitidine could prevent relapse in these patients., Methods: The relapse prevention with azacitidine (RELAZA2) study is an open-label, multicentre, phase 2 trial done at nine university health centres in Germany. Patients aged 18 years or older with advanced MDS or AML, who had achieved a complete remission after conventional chemotherapy or allogeneic haemopoietic stem-cell transplantation, were prospectively screened for MRD during 24 months from baseline by either quantitative PCR for mutant NPM1, leukaemia-specific fusion genes (DEK-NUP214, RUNX1-RUNX1T1, CBFb-MYH11), or analysis of donor-chimaerism in flow cytometry-sorted CD34-positive cells in patients who received allogeneic haemopoietic stem-cell transplantation. MRD-positive patients in confirmed complete remission received azacitidine 75 mg/m
2 per day subcutaneously on days 1-7 of a 29-day cycle for 24 cycles. After six cycles, MRD status was reassessed and patients with major responses (MRD negativity) were eligible for a treatment de-escalation. The primary endpoint was the proportion of patients who were relapse-free and alive 6 months after the start of pre-emptive treatment. Analyses were done per protocol. This trial is registered with ClincialTrials.gov, number NCT01462578, and finished recruitment on Aug 21, 2018., Findings: Between Oct 10, 2011, and Aug 20, 2015, we screened 198 patients with advanced MDS (n=26) or AML (n=172), of whom 60 (30%) developed MRD during the 24-month screening period and 53 (88%) were eligible to start study treatment. 6 months after initiation of azacitidine, 31 (58%, 95% CI 44-72) of 53 patients were relapse-free and alive (p<0·0001; one-sided binomial test for null hypothesis pexp ≤0·3). With a median follow-up of 13 months (IQR 8·5-22·8) after the start of MRD-guided treatment, relapse-free survival at 12 months was 46% (95% CI 32-59) in the 53 patients who were MRD-positive and received azacitidine. In MRD-negative patients, 12-month relapse-free survival was 88% (95% CI 82-94; hazard ratio 6·6 [95% CI 3·7-11·8], p<0·0001). The most common (grade 3-4) adverse event was neutropenia, occurring in 45 (85%) of 53 patients. One patient with neutropenia died because of an infection considered possibly related to study treatment., Interpretation: Pre-emptive therapy with azacitidine can prevent or substantially delay haematological relapse in MRD-positive patients with MDS or AML who are at high risk of relapse. Our study also suggests that continuous MRD negativity during regular MRD monitoring might be prognostic for patient outcomes., Funding: Celgene Pharma, José Carreras Leukaemia Foundation, National Center for Tumor Diseases (NCT), and German Cancer Consortium (DKTK) Foundation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)- Published
- 2018
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29. JAM-C Expression as a Biomarker to Predict Outcome of Patients with Acute Myeloid Leukemia-Letter.
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von Bonin M, Moll K, Kramer M, Oelschlägel U, Wermke M, Röllig C, Thiede C, Ehninger G, Krämer A, Müller-Tidow C, Mitroulis I, and Bornhäuser M
- Subjects
- Biomarkers, Humans, Prognosis, Leukemia, Myeloid, Acute, src-Family Kinases
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- 2018
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30. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial.
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Cortes J, Perl AE, Döhner H, Kantarjian H, Martinelli G, Kovacsovics T, Rousselot P, Steffen B, Dombret H, Estey E, Strickland S, Altman JK, Baldus CD, Burnett A, Krämer A, Russell N, Shah NP, Smith CC, Wang ES, Ifrah N, Gammon G, Trone D, Lazzaretto D, and Levis M
- Subjects
- Administration, Oral, Adult, Aged, Canada, Disease-Free Survival, Dose-Response Relationship, Drug, Drug Administration Schedule, Europe, Female, Humans, Internationality, Leukemia, Myeloid, Acute mortality, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Recurrence, Local diagnosis, Neoplasm Recurrence, Local mortality, Prognosis, Survival Rate, Treatment Outcome, United States, Young Adult, fms-Like Tyrosine Kinase 3 administration & dosage, Benzothiazoles therapeutic use, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy, Neoplasm Recurrence, Local drug therapy, Phenylurea Compounds therapeutic use, fms-Like Tyrosine Kinase 3 antagonists & inhibitors
- Abstract
Background: Old age and FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations in patients with acute myeloid leukaemia are associated with early relapse and poor survival. Quizartinib is an oral, highly potent, and selective next-generation FLT3 inhibitor with clinical antileukaemic activity in relapsed or refractory acute myeloid leukaemia. We aimed to assess the efficacy and safety of single-agent quizartinib in patients with relapsed or refractory acute myeloid leukaemia., Methods: We did an open-label, multicentre, single-arm, phase 2 trial at 76 hospitals and cancer centres in the USA, Europe, and Canada. We enrolled patients with morphologically documented primary acute myeloid leukaemia or acute myeloid leukaemia secondary to myelodysplastic syndromes and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 into two predefined, independent cohorts: patients who were aged 60 years or older with relapsed or refractory acute myeloid leukaemia within 1 year after first-line therapy (cohort 1), and those who were 18 years or older with relapsed or refractory disease following salvage chemotherapy or haemopoietic stem cell transplantation (cohort 2). Patients with an FLT3-ITD allelic frequency of more than 10% were considered as FLT3-ITD positive, whereas all other patients were considered as FLT3-ITD negative. Patients received quizartinib once daily as an oral solution; the initial 17 patients received 200 mg per day but the QTcF interval was prolonged for more than 60 ms above baseline in some of these patients. Subsequently, doses were amended for all patients to 135 mg per day for men and 90 mg per day for women. The co-primary endpoints were the proportion of patients who achieved a composite complete remission (defined as complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete haematological recovery) and the proportion of patients who achieved a complete remission. Efficacy and safety analyses included all patients who received at least one dose of quizartinib (ie, the intention-to-treat population). Patients with a locally assessed post-treatment bone marrow aspirate or biopsy were included in efficacy analyses by response; all other patients were considered to have an unknown response. This study is registered with ClinicalTrials.gov, number NCT00989261, and with the European Clinical Trials Database, EudraCT 2009-013093-41, and is completed., Findings: Between Nov 19, 2009, and Oct 31, 2011, a total of 333 patients were enrolled (157 in cohort 1 and 176 in cohort 2). In cohort 1, 63 (56%) of 112 FLT3-ITD-positive patients and 16 (36%) of 44 FLT3-ITD-negative patients achieved composite complete remission, with three (3%) FLT3-ITD-positive patients and two (5%) FLT3-ITD-negative patients achieving complete remission. In cohort 2, 62 (46%) of 136 FLT3-ITD-positive patients achieved composite complete remission with five (4%) achieving complete remission, whereas 12 (30%) of 40 FLT3-ITD-negative patients achieved composite complete remission with one (3%) achieving complete remission. Across both cohorts (ie, the intention-to-treat population of 333 patients), grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients were febrile neutropenia (76 [23%] of 333), anaemia (75 [23%]), thrombocytopenia (39 [12%]), QT interval corrected using Fridericia's formula (QTcF) prolongation (33 [10%]), neutropenia (31 [9%]), leucopenia (22 [7%]), decreased platelet count (20 [6%]), and pneumonia (17 [5%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (126 [38%] of 333; 76 treatment related), acute myeloid leukaemia progression (73 [22%]), pneumonia (40 [12%]; 14 treatment related), QTcF prolongation (33 [10%]; 32 treatment related), sepsis (25 [8%]; eight treatment related), and pyrexia (18 [5%]; nine treatment related). Notable serious adverse events occurring in less than 5% of patients were torsades de pointes (one [<1%]) and hepatic failure (two [1%]). In total, 125 (38%) of 333 patients died within the study treatment period, including the 30-day follow-up. 18 (5%) patients died because of an adverse event considered by the investigator to be treatment related (ten [6%] of 157 patients in cohort 1 and eight [5%] of 176 in cohort 2., Interpretation: Single-agent quizartinib was shown to be highly active and generally well tolerated in patients with relapsed or refractory acute myeloid leukaemia, particularly those with FLT3-ITD mutations. These findings confirm that targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor is a promising clinical strategy to help improve clinical outcomes in patients with very few options. Phase 3 studies (NCT02039726; NCT02668653) will examine quizartinib at lower starting doses., Funding: Ambit Biosciences/Daiichi Sankyo., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
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- 2018
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31. Prediction of acute myeloid leukaemia risk in healthy individuals.
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Abelson S, Collord G, Ng SWK, Weissbrod O, Mendelson Cohen N, Niemeyer E, Barda N, Zuzarte PC, Heisler L, Sundaravadanam Y, Luben R, Hayat S, Wang TT, Zhao Z, Cirlan I, Pugh TJ, Soave D, Ng K, Latimer C, Hardy C, Raine K, Jones D, Hoult D, Britten A, McPherson JD, Johansson M, Mbabaali F, Eagles J, Miller JK, Pasternack D, Timms L, Krzyzanowski P, Awadalla P, Costa R, Segal E, Bratman SV, Beer P, Behjati S, Martincorena I, Wang JCY, Bowles KM, Quirós JR, Karakatsani A, La Vecchia C, Trichopoulou A, Salamanca-Fernández E, Huerta JM, Barricarte A, Travis RC, Tumino R, Masala G, Boeing H, Panico S, Kaaks R, Krämer A, Sieri S, Riboli E, Vineis P, Foll M, McKay J, Polidoro S, Sala N, Khaw KT, Vermeulen R, Campbell PJ, Papaemmanuil E, Minden MD, Tanay A, Balicer RD, Wareham NJ, Gerstung M, Dick JE, Brennan P, Vassiliou GS, and Shlush LI
- Subjects
- Adult, Age Factors, Aged, Disease Progression, Electronic Health Records, Female, Humans, Leukemia, Myeloid, Acute epidemiology, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Models, Genetic, Mutagenesis, Prevalence, Risk Assessment, Genetic Predisposition to Disease, Health, Leukemia, Myeloid, Acute genetics, Mutation
- Abstract
The incidence of acute myeloid leukaemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 65. Most cases arise without any detectable early symptoms and patients usually present with the acute complications of bone marrow failure
1 . The onset of such de novo AML cases is typically preceded by the accumulation of somatic mutations in preleukaemic haematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion2,3 . However, recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal haematopoiesis (ARCH)4-8 . Here we use deep sequencing to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign ARCH. We analysed peripheral blood cells from 95 individuals that were obtained on average 6.3 years before AML diagnosis (pre-AML group), together with 414 unselected age- and gender-matched individuals (control group). Pre-AML cases were distinct from controls and had more mutations per sample, higher variant allele frequencies, indicating greater clonal expansion, and showed enrichment of mutations in specific genes. Genetic parameters were used to derive a model that accurately predicted AML-free survival; this model was validated in an independent cohort of 29 pre-AML cases and 262 controls. Because AML is rare, we also developed an AML predictive model using a large electronic health record database that identified individuals at greater risk. Collectively our findings provide proof-of-concept that it is possible to discriminate ARCH from pre-AML many years before malignant transformation. This could in future enable earlier detection and monitoring, and may help to inform intervention.- Published
- 2018
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32. Enasidenib.
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Krämer A and Bochtler T
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- Animals, Humans, Mice, Mutation, Aminopyridines pharmacology, Antineoplastic Agents pharmacology, Isocitrate Dehydrogenase antagonists & inhibitors, Leukemia, Myeloid, Acute drug therapy, Triazines pharmacology
- Abstract
Enasidenib is an orally available, selective, potent, small molecule inhibitor of mutant isocitrate dehydrogenase 2 (IDH2). Neomorphic mutations in IDH2 are frequently found in both hematologic malignancies and solid tumors and lead to the production of the oncometabolite (R)-2-hydroxyglutarate. Increased levels of (R)-2-hydroxyglutarate cause histone and DNA hypermethylation associated with blocked differentiation and tumorigenesis. In PDX mice transplanted with human IDH2-mutant acute myeloid leukemia cells, enasidenib treatment led to normalization of (R)-2-hydroxyglutarate serum levels, differentiation of leukemic blasts and increased survival. Early clinical data in patients with relapsed/refractory IDH2-mutant acute myeloid leukemia show that enasidenib is well tolerated and induces durable complete remissions as a single agent in about 20% of cases. One notable drug-related adverse effect is differentiation syndrome. On the basis of these results the compound has recently been approved for the treatment of relapsed/refractory IDH2-mutant acute myeloid leukemia in the USA. Although no data are available yet, clinical trials on the treatment of patients with several types of IDH2-mutant solid tumors including gliomas, chondrosarcomas and cholangiocarcinomas are currently being performed.
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- 2018
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33. Clinical impact of KMT2C and SPRY4 expression levels in intensively treated younger adult acute myeloid leukemia patients.
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Kayser S, Feszler M, Krzykalla J, Schick M, Kramer M, Benner A, Thol F, Platzbecker U, Müller-Tidow C, Ho AD, Ehninger G, Heuser M, Schlenk RF, Thiede C, Röllig C, and Krämer A
- Subjects
- Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor, Combined Modality Therapy, Female, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Humans, Kaplan-Meier Estimate, Karyotype, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute therapy, Male, Middle Aged, Mutation, Treatment Outcome, Young Adult, Gene Expression, Intracellular Signaling Peptides and Proteins genetics, Leukemia, Myeloid, Acute genetics, Nerve Tissue Proteins genetics
- Abstract
Objective: To evaluate the prognostic impact of gene expression levels (ELs) of two tumor suppressor genes, sprouty 4 (SPRY4, located on 5q) and lysine methyltransferase 2C (KMT2C, located on 7q) in correlation with clinical characteristics and genetic abnormalities assessed at initial diagnosis in acute myeloid leukemia (AML)., Method: Gene expression levels were measured on cDNA by RT-qPCR from diagnostic bone marrow samples of 275 intensively treated adult AML patients (median age, 48 years)., Results: KMT2C ELs were significantly lower in abn7q/-7 (P = .001), whereas SPRY4 ELs were not associated with abn5q/-5. Higher KMT2C and SPRY4 ELs were significantly associated with lower genetic risk groups as defined by the European LeukemiaNet classification. Additionally, KMT2C ELs were lower in cytogenetically normal patients with DNMT3A (P = .01) or FLT3-ITD mutations (P = .05). KMT2C ELs were not associated with prognosis, whereas higher SPRY4 ELs showed a favorable impact on event-free (EFS, P = .01), relapse-free (RFS, P = .01) and in-trend on overall survival (P = .06) for cytogenetically abnormal patients, which was confirmed in multivariable analysis for EFS (HR, 0.84; 95%-CI, 0.73-0.97; P = .02) and RFS (HR, 0.85; 95%-CI, 0.73-0.98; P = .02)., Conclusion: Our data indicate that KMT2C ELs are associated with specific genetic features and that SPRY4 ELs may add prognostic information., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2017
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34. Marker chromosomes can arise from chromothripsis and predict adverse prognosis in acute myeloid leukemia.
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Bochtler T, Granzow M, Stölzel F, Kunz C, Mohr B, Kartal-Kaess M, Hinderhofer K, Heilig CE, Kramer M, Thiede C, Endris V, Kirchner M, Stenzinger A, Benner A, Bornhäuser M, Ehninger G, Ho AD, Jauch A, and Krämer A
- Subjects
- Abnormal Karyotype, Adolescent, Adult, Aged, Aged, 80 and over, Comparative Genomic Hybridization, Disease-Free Survival, Female, Humans, In Situ Hybridization, Fluorescence, Kaplan-Meier Estimate, Karyotyping, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Prognosis, Proportional Hazards Models, Young Adult, Biomarkers, Tumor genetics, Chromothripsis, Leukemia, Myeloid, Acute genetics
- Abstract
Metaphase karyotyping is an established diagnostic standard in acute myeloid leukemia (AML) for risk stratification. One of the cytogenetic findings in AML is structurally highly abnormal marker chromosomes. In this study, we have assessed frequency, cytogenetic characteristics, prognostic impact, and underlying biological origin of marker chromosomes. Given their inherent gross structural chromosomal damage, we speculated that they may arise from chromothripsis, a recently described phenomenon of chromosome fragmentation in a single catastrophic event. In 2 large consecutive prospective, randomized, multicenter, intensive chemotherapy trials (AML96, AML2003) from the Study Alliance Leukemia, marker chromosomes were detectable in 165/1026 (16.1%) of aberrant non-core-binding-factor (CBF) karyotype patients. Adverse-risk karyotypes displayed a higher frequency of marker chromosomes (26.5% in adverse-risk, 40.3% in complex aberrant, and 41.2% in abnormality(17p) karyotypes, P < .0001 each). Marker chromosomes were associated with a poorer prognosis compared with other non-CBF aberrant karyotypes and led to lower remission rates (complete remission + complete remission with incomplete recovery), inferior event-free survival as well as overall survival in both trials. In multivariate analysis, marker chromosomes independently predicted poor prognosis in the AML96 trial ≤60 years. As detected by array comparative genomic hybridization, about one-third of marker chromosomes (18/49) had arisen from chromothripsis, whereas this phenomenon was virtually undetectable in a control group of marker chromosome-negative complex aberrant karyotypes (1/34). The chromothripsis-positive cases were characterized by a particularly high degree of karyotype complexity, TP53 mutations, and dismal prognosis. In conclusion, marker chromosomes are indicative of chromothripsis and associated with poor prognosis per se and not merely by association with other adverse cytogenetic features., (© 2017 by The American Society of Hematology.)
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- 2017
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35. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial.
- Author
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Röllig C, Serve H, Hüttmann A, Noppeney R, Müller-Tidow C, Krug U, Baldus CD, Brandts CH, Kunzmann V, Einsele H, Krämer A, Schäfer-Eckart K, Neubauer A, Burchert A, Giagounidis A, Krause SW, Mackensen A, Aulitzky W, Herbst R, Hänel M, Kiani A, Frickhofen N, Kullmer J, Kaiser U, Link H, Geer T, Reichle A, Junghanß C, Repp R, Heits F, Dürk H, Hase J, Klut IM, Illmer T, Bornhäuser M, Schaich M, Parmentier S, Görner M, Thiede C, von Bonin M, Schetelig J, Kramer M, Berdel WE, and Ehninger G
- Subjects
- Adult, Age Factors, Antibiotics, Antineoplastic therapeutic use, Antimetabolites, Antineoplastic therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Chemotherapy, Adjuvant, Cytarabine therapeutic use, Daunorubicin therapeutic use, Disease Progression, Disease-Free Survival, Double-Blind Method, Female, Germany, Hematopoietic Stem Cell Transplantation, Humans, Kaplan-Meier Estimate, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Niacinamide adverse effects, Niacinamide therapeutic use, Phenylurea Compounds adverse effects, Proportional Hazards Models, Protein Kinase Inhibitors adverse effects, Recurrence, Risk Factors, Sorafenib, Time Factors, Transplantation, Homologous, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid, Acute drug therapy, Neoadjuvant Therapy adverse effects, Neoadjuvant Therapy mortality, Niacinamide analogs & derivatives, Phenylurea Compounds therapeutic use, Protein Kinase Inhibitors therapeutic use
- Abstract
Background: Preclinical data and results from non-randomised trials suggest that the multikinase inhibitor sorafenib might be an effective drug for the treatment of acute myeloid leukaemia. We investigated the efficacy and tolerability of sorafenib versus placebo in addition to standard chemotherapy in patients with acute myeloid leukaemia aged 60 years or younger., Methods: This randomised, double-blind, placebo-controlled, phase 2 trial was done at 25 sites in Germany. We enrolled patients aged 18-60 years with newly diagnosed, previously untreated acute myeloid leukaemia who had a WHO clinical performance score 0-2, adequate renal and liver function, no cardiac comorbidities, and no recent trauma or operation. Patients were randomly assigned (1:1) to receive two cycles of induction therapy with daunorubicin (60 mg/m(2) on days 3-5) plus cytarabine (100 mg/m(2) on days 1-7), followed by three cycles of high-dose cytarabine consolidation therapy (3 g/m(2) twice daily on days 1, 3, and 5) plus either sorafenib (400 mg twice daily) or placebo on days 10-19 of induction cycles 1 and 2, from day 8 of each consolidation, and as maintenance for 12 months. Allogeneic stem-cell transplantation was scheduled for all intermediate-risk patients with a sibling donor and for all high-risk patients with a matched donor in first remission. Computer-generated randomisation was done in blocks. The primary endpoint was event-free survival, with an event defined as either primary treatment failure or relapse or death, assessed in all randomised patients who received at least one dose of study treatment. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00893373, and the EU Clinical Trials Register (2008-004968-40)., Findings: Between March 27, 2009, and Nov 28, 2011, 276 patients were enrolled and randomised, of whom nine did not receive study medication. 267 patients were included in the primary analysis (placebo, n=133; sorafenib, n=134). With a median follow-up of 36 months (IQR 35·5-38·1), median event-free survival was 9 months (95% CI 4-15) in the placebo group versus 21 months (9-32) in the sorafenib group, corresponding to a 3-year event-free survival of 22% (95% CI 13-32) in the placebo group versus 40% (29-51) in the sorafenib group (hazard ratio [HR] 0·64, 95% CI; 0·45-0·91; p=0·013). The most common grade 3-4 adverse events in both groups were fever (71 [53%] in the placebo group vs 73 [54%] in the sorafenib group), infections (55 [41%] vs 46 [34%]), pneumonia (21 [16%] vs 20 [14%]), and pain (13 [10%] vs 15 [11%]). Grade 3 or worse adverse events that were significantly more common in the sorafenib group than the placebo group were fever (relative risk [RR] 1·54, 95% CI 1·04-2·28), diarrhoea (RR 7·89, 2·94-25·2), bleeding (RR 3·75, 1·5-10·0), cardiac events (RR 3·46, 1·15-11·8), hand-foot-skin reaction (only in sorafenib group), and rash (RR 4·06, 1·25-15·7)., Interpretation: In patients with acute myeloid leukaemia aged 60 years or younger, the addition of sorafenib to standard chemotherapy has antileukaemic efficacy but also increased toxicity. Our findings suggest that kinase inhibitors could be a useful addition to curative treatment for acute myeloid leukaemia. Overall survival after long-term follow-up and strategies to reduce toxicity are needed to determine the future role of sorafenib in treatment of this disease., Funding: Bayer HealthCare., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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36. Pretransplant metabolic distress predicts relapse of acute myeloid leukemia after allogeneic stem cell transplantation.
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Dietrich S, Radujkovic A, Stölzel F, Falk CS, Benner A, Schaich M, Bornhäuser M, Ehninger G, Krämer A, Hegenbart U, Ho AD, Dreger P, and Luft T
- Subjects
- Blood Proteins analysis, Body Mass Index, Humans, Leptin blood, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute therapy, Recurrence, Retrospective Studies, Transplantation, Homologous, Weight Loss, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute etiology, Nutritional Status
- Abstract
Background: The impact of nutritional status on outcome of allogeneic stem cell transplantation (alloSCT) is controversial. This study investigates the influence of pretransplant weight loss and serologic indicators of nutritional homeostasis on relapse and death of acute myeloid leukemia (AML) after alloSCT., Methods: Pretransplant weight loss along with serum levels of total serum protein (TSP), albumin, C-reactive protein, and leptin were collected retrospectively in a training cohort (n = 149) and correlated with clinical outcome. Metabolic risk groups were defined and tested in an independent validation cohort (n = 167)., Results: We identified pretransplant weight loss and TSP as strong independent predictors of relapse and death. Patients in the metabolic high-risk group (low TSP and weight loss) had an increased risk for relapse (P = 0.0002) and death (P = 0.002), but a similar risk for acute graft-versus-host disease. Weight loss coincided with reduced pretransplant serum leptin levels. The adverse influence of weight loss and high metabolic risk on relapse and overall survival could be confirmed in the validation cohort and similarly in patients with less than or more than 5% blasts before alloSCT. Multivariate analysis of both cohorts revealed a hazard ratio for relapse of 7.78 (2.59-23.36, P = 0.0003) in the metabolic high risk group., Conclusion: Altered nutritional homeostasis before alloSCT correlates with recurrence of AML after transplantation. Studies addressing pretransplant nutritional interventions to reduce AML relapse rates are warranted.
- Published
- 2015
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37. Allogeneic stem-cell transplantation in patients with NPM1-mutated acute myeloid leukemia: results from a prospective donor versus no-donor analysis of patients after upfront HLA typing within the SAL-AML 2003 trial.
- Author
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Röllig C, Bornhäuser M, Kramer M, Thiede C, Ho AD, Krämer A, Schäfer-Eckart K, Wandt H, Hänel M, Einsele H, Aulitzky WE, Schmitz N, Berdel WE, Stelljes M, Müller-Tidow C, Krug U, Platzbecker U, Wermke M, Baldus CD, Krause SW, Stölzel F, von Bonin M, Schaich M, Serve H, Schetelig J, and Ehninger G
- Subjects
- Adult, Clinical Trials as Topic, Disease-Free Survival, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Nucleophosmin, Prospective Studies, Retrospective Studies, Siblings, Transplantation, Autologous, Transplantation, Homologous, Treatment Outcome, Hematopoietic Stem Cell Transplantation, Histocompatibility Testing, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute surgery, Mutation, Nuclear Proteins genetics, Tissue Donors
- Abstract
Purpose: The presence of a mutated nucleophosmin-1 gene (NPM1(mut)) in acute myeloid leukemia (AML) is associated with a favorable prognosis. To assess the predictive value with regard to allogeneic stem-cell transplantation (SCT), we compared the clinical course of patients with NPM1(mut) AML eligible for allogeneic SCT in a donor versus no-donor analysis., Patients and Methods: Of 1,179 patients with AML (age 18 to 60 years) treated in the Study Alliance Leukemia AML 2003 trial, we identified all NPM1(mut) patients with an intermediate-risk karyotype. According to the trial protocol, patients were intended to receive an allogeneic SCT if an HLA-identical sibling donor was available. Patients with no available donor received consolidation or autologous SCT. We compared relapse-free survival (RFS) and overall survival (OS) depending on the availability of a suitable donor., Results: Of 304 eligible patients, 77 patients had a sibling donor and 227 had no available matched family donor. The 3-year RFS rates in the donor and no-donor groups were 71% and 47%, respectively (P = .005); OS rates were 70% and 60%, respectively (P = .114). In patients with normal karyotype and no FLT3 internal tandem duplication (n = 148), the 3-year RFS rates in the donor and no-donor groups were 83% and 53%, respectively (P = .004); and the 3-year OS rates were 81% and 75%, respectively (P = .300)., Conclusion: Allogeneic SCT led to a significantly prolonged RFS in patients with NPM1(mut) AML. The absence of a statistically significant difference in OS is most likely a result of the fact that NPM1(mut) patients who experienced relapse responded well to salvage treatment. Allogeneic SCT in first remission has potent antileukemic efficacy and is a valuable treatment option in patients with NPM1(mut) AML with a sibling donor., (© 2014 by American Society of Clinical Oncology.)
- Published
- 2015
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38. Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy.
- Author
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Döhner H, Lübbert M, Fiedler W, Fouillard L, Haaland A, Brandwein JM, Lepretre S, Reman O, Turlure P, Ottmann OG, Müller-Tidow C, Krämer A, Raffoux E, Döhner K, Schlenk RF, Voss F, Taube T, Fritsch H, and Maertens J
- Subjects
- Age Factors, Aged, Aged, 80 and over, Contraindications, Cytarabine adverse effects, Disease-Free Survival, Female, Humans, Induction Chemotherapy, Kaplan-Meier Estimate, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Male, Middle Aged, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors pharmacokinetics, Pteridines adverse effects, Pteridines pharmacokinetics, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Cytarabine administration & dosage, Leukemia, Myeloid, Acute drug therapy, Pteridines administration & dosage
- Abstract
Treatment outcomes for older patients with acute myeloid leukemia (AML) have remained dismal. This randomized, phase 2 trial in AML patients not considered suitable for intensive induction therapy compared low-dose cytarabine (LDAC) with or without volasertib, a highly potent and selective inhibitor of polo-like kinases. Eighty-seven patients (median age 75 years) received LDAC 20 mg twice daily subcutaneously days 1-10 or LDAC + volasertib 350 mg IV days 1 + 15 every 4 weeks. Response rate (complete remission and complete remission with incomplete blood count recovery) was higher for LDAC + volasertib vs LDAC (31.0% vs 13.3%; odds ratio, 2.91; P = .052). Responses in the LDAC + volasertib arm were observed across all genetic groups, including 5 of 14 patients with adverse cytogenetics. Median event-free survival was significantly prolonged by LDAC + volasertib compared with LDAC (5.6 vs 2.3 months; hazard ratio, 0.57; 95% confidence interval, 0.35-0.92; P = .021); median overall survival was 8.0 vs 5.2 months, respectively (hazard ratio, 0.63; 95% confidence interval, 0.40-1.00; P = .047). LDAC + volasertib led to an increased frequency of adverse events that was most pronounced for neutropenic fever/infections and gastrointestinal events; there was no increase in the death rate at days 60 + 90. This study was registered at www.clinicaltrials.gov as #NCT00804856., (© 2014 by The American Society of Hematology.)
- Published
- 2014
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39. Azacitidine and low-dose cytarabine in palliative patients with acute myeloid leukemia and high bone marrow blast counts--a retrospective single-center experience.
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Radujkovic A, Dietrich S, Bochtler T, Krämer A, Schöning T, Ho AD, Dreger P, and Luft T
- Subjects
- Adult, Aged, Aged, 80 and over, Azacitidine adverse effects, Bone Marrow drug effects, Cytarabine adverse effects, Drug Administration Schedule, Female, Hemorrhage chemically induced, Humans, Karyotyping, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Neutropenia chemically induced, Palliative Care, Pneumonia chemically induced, Retrospective Studies, Survival Analysis, Antineoplastic Combined Chemotherapy Protocols, Azacitidine administration & dosage, Bone Marrow pathology, Cytarabine administration & dosage, Leukemia, Myeloid, Acute drug therapy
- Abstract
We retrospectively analyzed and compared the efficacy and toxicity of azacitidine (AZA) and low-dose cytarabine (LD-Ara-C) in 65 palliative patients with acute myeloid leukemia (AML) showing high bone marrow blast counts (≥30%) before start of treatment. Twenty-seven and 38 patients received AZA and LD-Ara-C, respectively. The median patient age was 71 yr. Patient and disease characteristics did not differ between the treatment groups, except for BM blast counts, and peripheral leukocyte and blast counts which were significantly higher in the LD-Ara-C group. AZA and LD-Ara-C were first-line treatment in 12 (44%) and 17 patients (45%), respectively. Response and hematologic improvement rates were low and similar in both treatment groups. In both treatment groups, most common non-hematologic toxicities included febrile neutropenia, pneumonia, and bleedings without significant differences regarding frequencies. Estimated 1-yr survival rates were 15% (95% CI 8-22) and 13% (95% CI 7-19) in the AZA and LD-Ara-C groups, respectively, without statistically significant difference. In multivariate analysis (n = 65), previous treatment (HR 2.27, 95% CI 1.00-5.22, P = 0.05) and adverse cytogenetics (HR 2.50, 95% CI 1.20-5.22, P = 0.02) were independent predictors of poor survival. In our center and within the limitations of a retrospective study, both treatment regimens showed similar but limited efficacy in palliative patients with AML and high BM blast counts., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2014
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40. Requirement for CDK6 in MLL-rearranged acute myeloid leukemia.
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Placke T, Faber K, Nonami A, Putwain SL, Salih HR, Heidel FH, Krämer A, Root DE, Barbie DA, Krivtsov AV, Armstrong SA, Hahn WC, Huntly BJ, Sykes SM, Milsom MD, Scholl C, and Fröhling S
- Subjects
- Animals, Cell Line, Tumor, Flow Cytometry, Gene Expression Profiling, Humans, Immunoblotting, Mice, Mice, Inbred C57BL, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion metabolism, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, Transduction, Genetic, Cyclin-Dependent Kinase 6 metabolism, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Myeloid-Lymphoid Leukemia Protein genetics
- Abstract
Chromosomal rearrangements involving the H3K4 methyltransferase mixed-lineage leukemia (MLL) trigger aberrant gene expression in hematopoietic progenitors and give rise to an aggressive subtype of acute myeloid leukemia (AML). Insights into MLL fusion-mediated leukemogenesis have not yet translated into better therapies because MLL is difficult to target directly, and the identity of the genes downstream of MLL whose altered transcription mediates leukemic transformation are poorly annotated. We used a functional genetic approach to uncover that AML cells driven by MLL-AF9 are exceptionally reliant on the cell-cycle regulator CDK6, but not its functional homolog CDK4, and that the preferential growth inhibition induced by CDK6 depletion is mediated through enhanced myeloid differentiation. CDK6 essentiality is also evident in AML cells harboring alternate MLL fusions and a mouse model of MLL-AF9-driven leukemia and can be ascribed to transcriptional activation of CDK6 by mutant MLL. Importantly, the context-dependent effects of lowering CDK6 expression are closely phenocopied by a small-molecule CDK6 inhibitor currently in clinical development. These data identify CDK6 as critical effector of MLL fusions in leukemogenesis that might be targeted to overcome the differentiation block associated with MLL-rearranged AML, and underscore that cell-cycle regulators may have distinct, noncanonical, and nonredundant functions in different contexts., (© 2014 by The American Society of Hematology.)
- Published
- 2014
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41. Clonal heterogeneity as detected by metaphase karyotyping is an indicator of poor prognosis in acute myeloid leukemia.
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Bochtler T, Stölzel F, Heilig CE, Kunz C, Mohr B, Jauch A, Janssen JW, Kramer M, Benner A, Bornhäuser M, Ho AD, Ehninger G, Schaich M, and Krämer A
- Subjects
- Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Chromosome Aberrations, Female, Humans, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Multicenter Studies as Topic, Prognosis, Randomized Controlled Trials as Topic, Treatment Outcome, Young Adult, Karyotyping methods, Leukemia, Myeloid, Acute genetics, Metaphase genetics
- Abstract
Purpose: In acute myeloid leukemia (AML), studies based on whole-genome sequencing have shown genomic diversity within leukemic clones. The aim of this study was to address clonal heterogeneity in AML based on metaphase cytogenetics., Patients and Methods: This analysis included all patients enrolled onto two consecutive, prospective, randomized multicenter trials of the Study Alliance Leukemia. Patients were newly diagnosed with non-M3 AML and were fit for intensive chemotherapy., Results: Cytogenetic subclones were detected in 418 (15.8%) of 2,639 patients from the whole study population and in 418 (32.8%) of 1,274 patients with aberrant karyotypes. Among those, 252 karyotypes (60.3%) displayed a defined number of distinct subclones, and 166 (39.7%) were classified as composite karyotypes. Subclone formation was particularly frequent in the cytogenetically adverse group, with subclone formation in 69.0%, 67.1%, and 64.8% of patients with complex aberrant, monosomal, and abnl(17p) karyotypes (P < .001 each). Two-subclone patterns typically followed a mother-daughter evolution, whereas for ≥ three subclones, a branched pattern prevailed. In non-core binding factor AML, subclone formation was associated with inferior event-free and overall survival and was confirmed as an independent predictor of poor prognosis in multivariate analysis. Subgroup analysis showed that subclone formation adds prognostic information particularly in the cytogenetic adverse-risk group. Allogeneic stem-cell transplantation improved the prognosis of patients with subclone karyotypes as shown in landmark analyses., Conclusion: Cytogenetic subclones are frequent in AML and permit tracing of clonal evolution and architecture. They bear prognostic significance with clonal heterogeneity as an independent adverse prognostic marker in cytogenetically adverse-risk AML.
- Published
- 2013
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42. A randomized, open-label, phase I/II trial to investigate the maximum tolerated dose of the Polo-like kinase inhibitor BI 2536 in elderly patients with refractory/relapsed acute myeloid leukaemia.
- Author
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Müller-Tidow C, Bug G, Lübbert M, Krämer A, Krauter J, Valent P, Nachbaur D, Berdel WE, Ottmann OG, Fritsch H, Munzert G, Garin-Chesa P, Fleischer F, Taube T, and Döhner H
- Subjects
- Age Factors, Aged, Aged, 80 and over, Antineoplastic Agents pharmacology, Drug Administration Schedule, Female, Humans, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute mortality, Male, Maximum Tolerated Dose, Middle Aged, Protein Kinase Inhibitors pharmacology, Pteridines pharmacology, Recurrence, Treatment Outcome, Polo-Like Kinase 1, Antineoplastic Agents therapeutic use, Cell Cycle Proteins antagonists & inhibitors, Leukemia, Myeloid, Acute drug therapy, Protein Kinase Inhibitors therapeutic use, Protein Serine-Threonine Kinases antagonists & inhibitors, Proto-Oncogene Proteins antagonists & inhibitors, Pteridines therapeutic use
- Abstract
Polo-like kinases (Plks) play an important role in cell cycle checkpoint controls and are over-expressed in acute myeloid leukaemia (AML). BI 2536, a novel Plk inhibitor, induces mitotic arrest and apoptosis. In this phase I/II trial of BI 2536 in 68 elderly patients with relapsed/refractory AML, three schedules were investigated (day 1, days 1-3, and days 1 + 8). Maximum tolerated dose was 350 and 200 mg in the day 1 and days 1 + 8 schedules, respectively. The day 1-3 schedule appeared equivalent to the day 1 schedule and was discontinued early. BI 2536 exhibited multi-compartmental pharmacokinetic behaviour. The majority of patients showed an increase of bone marrow cells in G2/M with a characteristic pattern of mitotic catastrophe. The overall response rate in the day 1 and day 1 + 8 schedules was 9% (5/54) with 2 complete and 3 partial responses. The majority of drug-related adverse events grade ≥3 were haematological. Taken together, Plk inhibition induced cell cycle arrest in AML blasts in vivo and BI 2536 monotherapy showed modest clinical activity in this poor prognosis patient group., (© 2013 John Wiley & Sons Ltd.)
- Published
- 2013
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43. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial.
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Serve H, Krug U, Wagner R, Sauerland MC, Heinecke A, Brunnberg U, Schaich M, Ottmann O, Duyster J, Wandt H, Fischer T, Giagounidis A, Neubauer A, Reichle A, Aulitzky W, Noppeney R, Blau I, Kunzmann V, Stuhlmann R, Krämer A, Kreuzer KA, Brandts C, Steffen B, Thiede C, Müller-Tidow C, Ehninger G, and Berdel WE
- Subjects
- Aged, Aged, 80 and over, Double-Blind Method, Female, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Mutation, Niacinamide administration & dosage, Sorafenib, fms-Like Tyrosine Kinase 3 antagonists & inhibitors, fms-Like Tyrosine Kinase 3 genetics, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid, Acute drug therapy, Niacinamide analogs & derivatives, Phenylurea Compounds administration & dosage, Protein Kinase Inhibitors administration & dosage
- Abstract
Purpose: The prognosis of elderly patients with acute myeloid leukemia (AML) is still dismal even with intensive chemotherapy. In this trial, we compared the antileukemic activity of standard induction and consolidation therapy with or without the addition of the kinase inhibitor sorafenib in elderly patients with AML., Patients and Methods: All patients received standard cytarabine and daunorubicin induction (7+3 regimen) and up to two cycles of intermediate-dose cytarabine consolidation. Two hundred one patients were equally randomly assigned to receive either sorafenib or placebo between the chemotherapy cycles and subsequently for up to 1 year after the beginning of therapy. The primary objective was to test for an improvement in event-free survival (EFS). Overall survival (OS), complete remission (CR) rate, tolerability, and several predefined subgroup analyses were among the secondary objectives., Results: Age, sex, CR and early death (ED) probability, and prognostic factors were balanced between both study arms. Treatment in the sorafenib arm did not result in significant improvement in EFS or OS. This was also true for subgroup analyses, including the subgroup positive for FLT3 internal tandem duplications. Results of induction therapy were worse in the sorafenib arm, with higher treatment-related mortality and lower CR rates. More adverse effects occurred during induction therapy in the sorafenib arm, and patients in this arm received less consolidation chemotherapy as a result of higher induction toxicity., Conclusion: In conclusion, combination of standard induction and consolidation therapy with sorafenib in the schedule investigated in our trial is not beneficial for elderly patients with AML.
- Published
- 2013
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44. EVI1 inhibits apoptosis induced by antileukemic drugs via upregulation of CDKN1A/p21/WAF in human myeloid cells.
- Author
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Rommer A, Steinmetz B, Herbst F, Hackl H, Heffeter P, Heilos D, Filipits M, Steinleitner K, Hemmati S, Herbacek I, Schwarzinger I, Hartl K, Rondou P, Glimm H, Karakaya K, Krämer A, Berger W, and Wieser R
- Subjects
- Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Cell Differentiation drug effects, Cell Line, Tumor, Cell Proliferation drug effects, DNA-Binding Proteins genetics, Daunorubicin pharmacology, Etoposide pharmacology, Female, Humans, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, MDS1 and EVI1 Complex Locus Protein, Mice, Myeloid Cells metabolism, Myeloid Cells pathology, Proto-Oncogenes genetics, Transcription Factors genetics, Apoptosis drug effects, Cyclin-Dependent Kinase Inhibitor p21 metabolism, DNA-Binding Proteins metabolism, Drug Resistance, Neoplasm, Leukemia, Myeloid, Acute pathology, Myeloid Cells drug effects, Transcription Factors metabolism, Up-Regulation drug effects
- Abstract
Overexpression of ecotropic viral integration site 1 (EVI1) is associated with aggressive disease in acute myeloid leukemia (AML). Despite of its clinical importance, little is known about the mechanism through which EVI1 confers resistance to antileukemic drugs. Here, we show that a human myeloid cell line constitutively overexpressing EVI1 after infection with a retroviral vector (U937_EVI1) was partially resistant to etoposide and daunorubicin as compared to empty vector infected control cells (U937_vec). Similarly, inducible expression of EVI1 in HL-60 cells decreased their sensitivity to daunorubicin. Gene expression microarray analyses of U937_EVI1 and U937_vec cells cultured in the absence or presence of etoposide showed that 77 and 419 genes were regulated by EVI1 and etoposide, respectively. Notably, mRNA levels of 26 of these genes were altered by both stimuli, indicating that EVI1 regulated genes were strongly enriched among etoposide regulated genes and vice versa. One of the genes that were induced by both EVI1 and etoposide was CDKN1A/p21/WAF, which in addition to its function as a cell cycle regulator plays an important role in conferring chemotherapy resistance in various tumor types. Indeed, overexpression of CDKN1A in U937 cells mimicked the phenotype of EVI1 overexpression, similarly conferring partial resistance to antileukemic drugs.
- Published
- 2013
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45. Enzymatic assay for quantitative analysis of (D)-2-hydroxyglutarate.
- Author
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Balss J, Pusch S, Beck AC, Herold-Mende C, Krämer A, Thiede C, Buckel W, Langhans CD, Okun JG, and von Deimling A
- Subjects
- Alcohol Oxidoreductases analysis, Alcohol Oxidoreductases chemistry, Alcohol Oxidoreductases metabolism, Biomarkers, Tumor analysis, Biomarkers, Tumor genetics, Glutarates metabolism, Humans, Isocitrate Dehydrogenase genetics, Isocitrate Dehydrogenase metabolism, Leukemia, Myeloid, Acute genetics, Mutation genetics, Enzyme Assays methods, Glutarates analysis, Leukemia, Myeloid, Acute diagnosis
- Abstract
Levels of (D)-2-hydroxyglutarate [D2HG, (R)-2-hydroxyglutarate] are increased in some metabolic diseases and in neoplasms with mutations in the isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) genes. Determination of D2HG is of relevance to diagnosis and monitoring of disease. Standard detection methods of D2HG levels are liquid-chromatography-mass spectrometry or gas-chromatography-mass spectrometry. Here we present a rapid, inexpensive and sensitive enzymatic assay for the detection of D2HG levels. The assay is based on the conversion of D2HG to α-ketoglutarate (αKG) in the presence of the enzyme (D)-2-hydroxyglutarate dehydrogenase (HGDH) and nicotinamide adenine dinucleotide (NAD(+)). Determination of D2HG concentration is based on the detection of stoichiometrically generated NADH. The quantification limit of the enzymatic assay for D2HG in tumor tissue is 0.44 μM and in serum 2.77 μM. These limits enable detection of basal D2HG levels in human tumor tissues and serum without IDH mutations. Levels of D2HG in frozen and paraffin-embedded tumor tissues containing IDH mutations or in serum from acute myeloid leukemia patients with IDH mutations are significantly higher and can be easily identified with this assay. In conclusion, the assay presented is useful for differentiating basal from elevated D2HG levels in tumor tissue, serum, urine, cultured cells and culture supernatants.
- Published
- 2012
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46. Survey and analysis of the efficacy and prescription pattern of sorafenib in patients with acute myeloid leukemia.
- Author
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Röllig C, Brandts C, Shaid S, Hentrich M, Krämer A, Junghanß C, Schleyer E, Müller-Tidow C, Berdel WE, Ritter B, Pflüger KH, Kramer M, Haibach M, Ehninger G, Serve H, and Krause SW
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents adverse effects, Antineoplastic Agents therapeutic use, Benzenesulfonates adverse effects, Data Collection, Female, Humans, Leukemia, Myeloid, Acute epidemiology, Male, Middle Aged, Niacinamide analogs & derivatives, Phenylurea Compounds, Pyridines adverse effects, Remission Induction, Retrospective Studies, Sorafenib, Treatment Outcome, Young Adult, Benzenesulfonates therapeutic use, Leukemia, Myeloid, Acute drug therapy, Practice Patterns, Physicians' statistics & numerical data, Pyridines therapeutic use
- Abstract
Sorafenib is a multi-kinase inhibitor with activity against several intracellular kinases which may play a role in the pathogenesis of acute myeloid leukemia (AML). In vitro data and results from early clinical trials suggest that sorafenib might be an effective drug for the treatment of AML. However, clinical data are still sparse, and there are only a few reported cases of monotherapy. The aim of the present research was to collect clinical data on efficacy and safety in a systematic way by conducting a survey on clinical experience with sorafenib. Thirty institutions were asked to document all patients treated with sorafenib diagnosed with AML. Of all 29 evaluable patients, six (21%) responded to sorafenib containing treatment by achieving a complete remission (CR, n = 2) or complete remission with incomplete platelet recovery (CRi, n = 4). In 23 patients receiving sorafenib as monotherapy, the CRi rate amounted to 13% and no CRs were documented. Of the 18 FLT-ITD positive patients with sorafenib monotherapy, two patients achieved a CRi (11%). In five FLT3-ITD negative cases, one CRi was documented (20%). Our results suggest the potential ability of the drug to induce remissions in refractory or relapsed AML even when given as monotherapy.
- Published
- 2012
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47. Cytarabine dose of 36 g/m² compared with 12 g/m² within first consolidation in acute myeloid leukemia: results of patients enrolled onto the prospective randomized AML96 study.
- Author
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Schaich M, Röllig C, Soucek S, Kramer M, Thiede C, Mohr B, Oelschlaegel U, Schmitz N, Stuhlmann R, Wandt H, Schäfer-Eckart K, Aulitzky W, Kaufmann M, Bodenstein H, Tischler J, Ho A, Krämer A, Bornhäuser M, Schetelig J, and Ehninger G
- Subjects
- Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cytogenetics, Disease-Free Survival, Female, Humans, Male, Middle Aged, Proportional Hazards Models, Prospective Studies, Remission Induction, Risk, Treatment Outcome, Cytarabine administration & dosage, Leukemia, Myeloid, Acute drug therapy, Mitoxantrone administration & dosage
- Abstract
Purpose: To assess the optimal cumulative dose of cytarabine for treatment of young adults with acute myeloid leukemia (AML) within a prospective multicenter treatment trial., Patients and Methods: Between 1996 and 2003, 933 patients (median age, 47 years; range 15 to 60 years) with untreated AML were randomly assigned at diagnosis to receive cytarabine within the first consolidation therapy at either a intermediate-dose of 12 g/m² (I-MAC) or a high-dose of 36 g/m² (H-MAC) combined with mitoxantrone. Autologous hematopoietic stem-cell transplantation or intermediate-dose cytarabine (10 g/m²) were offered as second consolidation. Patients with a matched donor could receive an allogeneic transplantation in a risk-adapted manner., Results: After double induction therapy including intermediate-dose cytarabine (10 g/m²), mitoxantrone, etoposide, and amsacrine, complete remission was achieved in 66% of patients. In the primary efficacy analysis population, a consolidation with either I-MAC or H-MAC did not result in significant differences in the 5-year overall (30% v 33%; P = .77) or disease-free survival (37% v 38%; P = .86) according to the intention-to-treat analysis. Besides a prolongation of neutropenia and higher transfusion demands in the H-MAC arm, rates of serious adverse events were comparable in the two groups., Conclusion: In young adults with AML receiving intermediate-dose cytarabine induction, intensification of the cytarabine dose beyond 12 g/m² within first consolidation did not improve treatment outcome.
- Published
- 2011
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48. Antiapoptotic function of charged multivesicular body protein 5: a potentially relevant gene in acute myeloid leukemia.
- Author
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Shahmoradgoli M, Mannherz O, Engel F, Heck S, Krämer A, Seiffert M, Pscherer A, and Lichter P
- Subjects
- Blotting, Western, Caspases metabolism, Cell Line, Cell Line, Tumor, Endosomal Sorting Complexes Required for Transport genetics, Gene Silencing, Humans, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Apoptosis physiology, Endosomal Sorting Complexes Required for Transport physiology, Leukemia, Myeloid, Acute genetics
- Abstract
In recent years, RNA interference (RNAi) has been widely used to uncover gene function or pathway context of novel genes. In our study, we describe a short-hairpin RNA-based RNAi screening of a set of functionally uncharacterized human genes for their possible capability to inhibit apoptosis. We thereby identified a new antiapoptotic function for CHMP5 (charged multivesicular body protein 5), which was confirmed by overexpression and rescue assays. Furthermore, caspase assays showed that CHMP5 silencing induced caspase cascade activation mainly through extrinsic apoptosis pathway. Based on genome-wide expression array profiling, a possible regulatory role of CHMP5 on apoptosis-associated genes and different signaling pathways including nuclear factor kappa B was revealed. In addition, we found significantly higher CHMP5 mRNA levels in acute myeloid leukemia patients. This observation together with the antiapoptotic feature of CHMP5 suggests a possible oncogenic function for this gene in leukemogenesis., (Copyright © 2010 UICC.)
- Published
- 2011
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49. Increased levels of 2-hydroxyglutarate in AML patients with IDH1-R132H and IDH2-R140Q mutations.
- Author
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Sellner L, Capper D, Meyer J, Langhans CD, Hartog CM, Pfeifer H, Serve H, Ho AD, Okun JG, Krämer A, and Von Deimling A
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Glutarates analysis, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute genetics, Mutation, Missense
- Published
- 2010
- Full Text
- View/download PDF
50. Impact of IDH1 and IDH2 mutational subgroups in AML patients after allogeneic stem cell transplantation
- Author
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Kunadt, Desiree, Stasik, Sebastian, Metzeler, Klaus H., Röllig, Christoph, Schliemann, Christoph, Greif, Philipp A., Spiekermann, Karsten, Rothenberg-Thurley, Maja, Krug, Utz, Braess, Jan, Krämer, Alwin, Hochhaus, Andreas, Scholl, Sebastian, Hilgendorf, Inken, Brümmendorf, Tim H., Jost, Edgar, Steffen, Björn, Bug, Gesine, Einsele, Hermann, Görlich, Dennis, Sauerland, Cristina, Schäfer-Eckart, Kerstin, Krause, Stefan W., Hänel, Mathias, Hanoun, Maher, Kaufmann, Martin, Wörmann, Bernhard, Kramer, Michael, Sockel, Katja, Egger-Heidrich, Katharina, Herold, Tobias, Ehninger, Gerhard, Burchert, Andreas, Platzbecker, Uwe, Berdel, Wolfgang E., Müller-Tidow, Carsten, Hiddemann, Wolfgang, Serve, Hubert, Stelljes, Matthias, Baldus, Claudia D., Neubauer, Andreas, Schetelig, Johannes, Thiede, Christian, Bornhäuser, Martin, Middeke, Jan M., and Stölzel, Friedrich
- Subjects
Leukemia, Myeloid, Acute ,Cancer Research ,Oncology ,Mutation ,Medizin ,Hematopoietic Stem Cell Transplantation ,Humans ,Hematology ,ddc:610 ,Prognosis ,Nucleophosmin ,Molecular Biology ,Isocitrate Dehydrogenase - Abstract
Journal of hematology & oncology 15, 126 (2022). doi:10.1186/s13045-022-01339-8, Published by Biomed Central, London
- Published
- 2022
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