159 results on '"Gerhard Heil"'
Search Results
2. A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy
- Author
-
Michael Lübbert, Björn H. Rüter, Rainer Claus, Claudia Schmoor, Mathias Schmid, Ulrich Germing, Andrea Kuendgen, Volker Rethwisch, Arnold Ganser, Uwe Platzbecker, Oliver Galm, Wolfram Brugger, Gerhard Heil, Björn Hackanson, Barbara Deschler, Konstanze Döhner, Anne Hagemeijer, Pierre W. Wijermans, and Hartmut Döhner
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background The treatment of acute myeloid leukemia of older, medically non-fit patients still poses a highly unmet clinical need, and only few large, prospective studies have been performed in this setting. Given the established activity of hypomethylating agents such as 5-aza-2'-deoxycytidine (decitabine) in myelodysplastic syndromes and acute myeloid leukemia with 20–30% bone marrow blasts, we investigated whether this drug is also active in patients with more than 30% blasts.Design and Methods To evaluate the efficacy and toxicity of decitabine in patients over 60 years old with untreated acute myeloid leukemia ineligible for induction chemotherapy, 227 patients (median age, 72 years), many with comorbidities, adverse cytogenetics and/or preceding myelodysplastic syndrome were treated with this hypomethylating agent. During the initial decitabine treatment (135 mg/m2 total dose infused intravenously over 72 hours every 6 weeks), a median of two cycles was administered (range, 1–4). All-trans retinoic acid was administered to 100 patients during course 2. Fifty-two patients who completed four cycles of treatment subsequently received a median of five maintenance courses (range, 1–19) with a lower dose of decitabine (20 mg/m2) infused over 1 hour on 3 consecutive days every 4–6 weeks.Results The complete and partial remission rate was 26%, 95% CI (20%, 32%), and an antileukemic effect was noted in 26% of patients. Response rates did not differ between patients with or without adverse cytogenetics; patients with monosomal karyotypes also responded. The median overall survival from the start of decitabine treatment was 5.5 months (range, 0–57.5+) and the 1-year survival rate was 28%, 95%CI (22%,34%). Toxicities were predominantly hematologic.Conclusions Decitabine is well tolerated by older, medically non-fit patients with acute myeloid leukemia; myelosuppression is the major toxicity. The response rate and overall survival were not adversely influenced by poor-risk cytogenetics or myelodysplastic syndrome. Because of these encouraging results, randomized studies evaluating single-agent decitabine versus conventional treatment are warranted. The study is registered with the German Clinical Trials Registry, number DRKS00000069.
- Published
- 2012
- Full Text
- View/download PDF
3. FLT3-internal tandem duplication and age are the major prognostic factors in patients with relapsed acute myeloid leukemia with normal karyotype
- Author
-
Katharina Wagner, Frederik Damm, Felicitas Thol, Gudrun Göhring, Kerstin Görlich, Michael Heuser, Irina Schäfer, Brigitte Schlegelberger, Gerhard Heil, Arnold Ganser, and Jürgen Krauter
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background Several genetic aberrations with prognostic impact in first-line therapy have been described in patients with acute myeloid leukemia and normal karyotype. However, little is known about the influence of these aberrations on outcome after relapse. This study aimed to identify clinical and molecular risk factors for patients with relapsed acute myeloid leukemia with normal karyotype.Design and Methods We analyzed 94 patients with acute myeloid leukemia and normal karyotype after first relapse for clinical and molecular risk factors for survival. All patients had received first-line treatment and follow-up within two prospective, multicenter trials. Leukemic blasts were analyzed at diagnosis for genetic aberrations in the FLT3, NPM1, CEBPA, WT1, IDH1 and IDH2 genes by polymerase chain reaction and/or direct sequencing.Results A second complete remission was achieved in 52% of patients who received re-induction therapy. The presence of an FLT3-internal tandem duplication, duration of first complete remission less than 6 months and age above the median of 47 years were associated with a significantly lower rate of second complete remission. The median survival after relapse was 11 months and the 6-year survival rate was 28%. In multivariate analysis, FLT3-internal tandem duplication and age above the median were the only independent negative prognostic factors for survival. The 6-year survival rate of patients with none of these factors was 56%, whereas it was significantly inferior in patients with one or both of these factors (15% and 6%, respectively). This was also true for patients who underwent allogeneic stem cell transplantation after relapse.Conclusions FLT3-internal tandem duplication and age are the major prognostic factors in patients with relapsed acute myeloid leukemia with a normal karyotype. Patients with at least one of these risk factors have a dismal outcome and might be considered for investigational treatment approaches after relapse. (ClinicalTrials.gov Identifier: NCT00209833)
- Published
- 2011
- Full Text
- View/download PDF
4. Prognosis of acute myeloid leukemia patients up to 60 years of age exhibiting trisomy 8 within a non-complex karyotype: individual patient data-based meta-analysis of the German Acute Myeloid Leukemia Intergroup
- Author
-
Markus Schaich, Richard F. Schlenk, Haifa K. Al-Ali, Hartmut Döhner, Arnold Ganser, Gerhard Heil, Thomas Illmer, Rainer Krahl, Jürgen Krauter, Cristina Sauerland, Thomas Büchner, and Gerhard Ehninger
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background and Objectives Trisomy 8 (+8) is among the commonest genetic aberrations seen in acute myeloid leukemia (AML). However, the prognostic significance of this aberration and the best consolidation strategy for patients with it are still not resolved. Additional prognostic indicators are needed to further classify these patients and determine their appropriate management.Design and Methods Individual patient data-based meta-analysis was performed on 131 patients (median age 50 (18–60) years) with +8 as a sole aberration or +8 with one additional aberration treated between 1993 and 2002 in eight prospective German AML treatment trials. All patients received state-of-the-art treatment including high-dose cytarabine with the option for autologous or allogeneic hematopoietic stem cell transplantation (HSCT).Results In total, the 131 patients had a 3-year overall survival (OS) of 29% and a 3-year relapse-free survival (RFS) of 32%. Independent prognostic factors contributing to shorter OS were age ≥45 years, extramedullary disease, and a percentage of +8 positive metaphases ≥80%. Combining these three prognostic variables established a hierarchical model for OS. The 3-year OS was 13% for the high-risk group, 36% for the intermediate-risk group, and 55% for the low-risk group (p
- Published
- 2007
- Full Text
- View/download PDF
5. In vivo kinetics of early, non-random methylome and transcriptome changes induced by DNA-hypomethylating treatment in primary AML blasts
- Author
-
Gabriele Greve, Geoffroy Andrieux, Pascal Schlosser, Nadja Blagitko-Dorfs, Usama-Ur Rehman, Tobias Ma, Dietmar Pfeifer, Gerhard Heil, Andreas Neubauer, Jürgen Krauter, Michael Heuser, Helmut R. Salih, Konstanze Döhner, Hartmut Döhner, Björn Hackanson, Melanie Boerries, and Michael Lübbert
- Subjects
Cancer Research ,Oncology ,ddc:610 ,Hematology - Abstract
Despite routine use of DNA-hypomethylating agents (HMAs) in AML/MDS therapy, their mechanisms of action are not yet unraveled. Pleiotropic effects of HMAs include global methylome and transcriptome changes. We asked whether in blasts and T-cells from AML patients HMA-induced in vivo demethylation and remethylation occur randomly or non-randomly, and whether gene demethylation is associated with gene induction. Peripheral blood AML blasts from patients receiving decitabine (20 mg/m2 day 1–5) were serially isolated for methylome analyses (days 0, 8 and 15, n = 28) and methylome-plus-transcriptome analyses (days 0 and 8, n = 23), respectively. T-cells were isolated for methylome analyses (days 0 and 8; n = 16). We noted massive, non-random demethylation at day 8, which was variable between patients. In contrast, T-cells disclosed a thousand-fold lesser, random demethylation, indicating selectivity of the demethylation for the malignant blasts. The integrative analysis of DNA demethylation and transcript induction revealed 87 genes displaying a significant inverse correlation, e.g. the tumor suppressor gene IFI27, whose derepression was validated in two AML cell lines. These results support HMA-induced, non-random early in vivo demethylation events in AML blasts associated with gene induction. Larger patient cohorts are needed to determine whether a demethylation signature may be predictive for response to this treatment.
- Published
- 2023
6. Outcomes of <scp>anti‐programmed death 1</scp> treatment for relapsed/refractory Hodgkin lymphoma: A German Hodgkin Study Group <scp>multicentre real‐world</scp> analysis
- Author
-
Jesko Momotow, Ina Bühnen, Karolin Trautmann‐Grill, Guido Kobbe, Dennis Hahn, Roland Schroers, Bernhard Heinrich, Tobias Gaska, Helmut Forstbauer, Burkhard Schmidt, Regina Boger, Andreas Hüttmann, Gerhard Heil, Doris M. Kraemer, William Krüger, Vanja Zeremski, Norbert Grobe, Kathleen Jentsch‐Ullrich, Frank Griesinger, Michael Fuchs, Bastian von Tresckow, Peter Borchmann, Andreas Engert, and Paul J. Bröckelmann
- Subjects
Nivolumab ,Medizin ,Humans ,Hematology ,Hodgkin Disease - Published
- 2022
7. Activity of decitabine combined with all-trans retinoic acid in oligoblastic AML: Results from a randomized 2x2 phase II trial (DECIDER)
- Author
-
Christoph Rummelt, Olga Grishina, Claudia Schmoor, Martina Crysandt, Michael Heuser, Katharina S. Götze, Richard F. Schlenk, Konstanze Döhner, Helmut R. Salih, Gerhard Heil, Carsten Müller-Tidow, Wolfram Brugger, Andrea Kündgen, Maike De Wit, Aristoteles Giagounidis, Sebastian Scholl, Andreas Neubauer, Jürgen Krauter, Gesine Bug, Haifa Kathrin Al-Ali, Ralph Wäsch, Heiko Becker, Annette M. May, Justus Duyster, Björn Hackanson, Arnold Ganser, Hartmut Döhner, and Michael Lübbert
- Subjects
Hematology - Abstract
Not available.
- Published
- 2023
8. Activity of Decitabine (DEC) Combined with All-Trans Retinoic Acid (ATRA) in oligoblastic AML: Results from a Randomized 2x2 Phase II Trial (DECIDER)
- Author
-
Christoph Rummelt, Olga Grishina, Claudia Schmoor, Martina Crysandt, Michael Heuser, Katharina S. Götze, Richard F. Schlenk, Konstanze Döhner, Helmut R. Salih, Gerhard Heil, Carsten Müller-Tidow, Wolfram Brugger, Andrea Kündgen, Maike Wit, Aristoteles Giagounidis, Sebastian Scholl, Andreas Neubauer, Jürgen Krauter, Gesine Bug, Haifa Kathrin Al-Ali, Ralph Wäsch, Heiko Becker, Annette M. May, Justus Duyster, Björn Hackanson, Arnold Ganser, Hartmut Döhner, and Michael Lübbert
- Abstract
DNA-hypomethylating agents are the backbone for non-intensive combination treatments of AML/MDS. In elderly AML patients, a combination of DEC+ATRA resulted in an improved response rate and survival compared to DEC without ATRA, also in those with prior hematologic disorder; additional valproic acid did not play a significant role (Lübbert et al., JCO 2020). To evaluate whether patients with oligoblastic AML also benefit from this combination, patients from the DECIDER cohort with 20-30% bone marrow blasts were analyzed for clinical outcome in this exploratory, not pre-planned subgroup analysis. They were newly diagnosed with AML, were unfit for induction and received DEC 20 mg/m2 day 1-5 in all arms, ATRA day 6-28 (arms C/D) and VPA p.o. continuously from day 6 (arms B/D) of each 28-day course. 200 patients were randomized and treated, 56 with oligoblastic AML. Of these, six attained a CR, 7 a CRi, and 1 a PR, resulting in an ORR of 25%. The effect on ORR of ATRA vs no ATRA was 31.8 vs 20.6% with an odds ratio of 1.85 (95% CI 0.54-6.37, p=0.33). With 48 deaths out of 56 patients, median OS was 9.1 months. The effect on OS of ATRA vs. no ATRA was 11.5 vs 7.6 months with a HR of 0.71 (95% CI 0.40-1.29, p=0.26). In elderly patients with oligoblastic AML ineligible for induction chemotherapy, the addition of ATRA to DEC resulted in a clinically meaningful survival benefit. We hypothesize that the combination of an HMA with a retinoid may also be active in MDS with excess blasts.
- Published
- 2022
9. Valproate and Retinoic Acid in Combination With Decitabine in Elderly Nonfit Patients With Acute Myeloid Leukemia: Results of a Multicenter, Randomized, 2 × 2, Phase II Trial
- Author
-
Richard F. Schlenk, Gesine Bug, Decider Study Team, Arnold Ganser, Wolfram Brugger, Helmut R. Salih, Claudia Schmoor, Hans-Walter Lindemann, Ralph Wäsch, Michael Lübbert, Konstanze Döhner, Olga Grishina, Carsten Schwaenen, Michael Heuser, Andreas Neubauer, Katharina Götze, Ulrich Germing, Marcus M Schittenhelm, Justus Duyster, Gerhard Heil, Andrea Kuendgen, Aristoteles Giagounidis, Martina Crysandt, Hartmut Döhner, Björn Hackanson, Felicitas Thol, Edgar Jost, Jürgen Krauter, Maike de Wit, Annette M. May, Sebastian Scholl, Heiko Becker, and Carsten Müller-Tidow
- Subjects
Male ,Cancer Research ,Myeloid ,Retinoic acid ,Decitabine ,Tretinoin ,Disease-Free Survival ,law.invention ,chemistry.chemical_compound ,Randomized controlled trial ,law ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Aged ,Aged, 80 and over ,business.industry ,Valproic Acid ,Myeloid leukemia ,Middle Aged ,medicine.disease ,Clinical trial ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Oncology ,chemistry ,Cancer research ,Female ,Histone deacetylase ,business ,medicine.drug - Abstract
PURPOSE DNA-hypomethylating agents are studied in combination with other epigenetic drugs, such as histone deacetylase inhibitors or differentiation inducers (eg, retinoids), in myeloid neoplasias. A randomized, phase II trial with a 2 × 2 factorial design was conducted to investigate the effects of the histone deacetylase inhibitor valproate and all- trans retinoic acid (ATRA) in treatment-naive elderly patients with acute myeloid leukemia (AML). PATIENTS AND METHODS Two hundred patients (median age, 76 years; range, 61-92 years) ineligible for induction chemotherapy received decitabine (20 mg/m2 intravenously, days 1 to 5) alone (n = 47) or in combination with valproate (n = 57), ATRA (n = 46), or valproate + ATRA (n = 50). The primary endpoint was objective response, defined as complete and partial remission, tested at a one-sided significance level of α = .10. Key secondary endpoints were overall survival, event-free survival, and progression-free survival and safety. RESULTS The addition of ATRA resulted in a higher remission rate (21.9% with ATRA v 13.5% without ATRA; odds ratio, 1.80; 95% CI, 0.86 to 3.79; one-sided P = .06). For valproate, no effect was observed (17.8% with valproate v 17.2% without valproate; odds ratio, 1.06; 95% CI, 0.51 to 2.21; one-sided P = .44). Median overall survival was 8.2 months with ATRA v 5.1 months without ATRA (hazard ratio, 0.65; 95% CI, 0.48 to 0.89; two-sided P = .006). Improved survival was observed across risk groups, including patients with adverse cytogenetics, and was associated with longer response duration. With valproate, no survival difference was observed. Toxicities were predominantly hematologic, without relevant differences between the 4 arms. CONCLUSION The addition of ATRA to decitabine resulted in a higher remission rate and a clinically meaningful survival extension in these patients with difficult-to-treat disease, without added toxicity.
- Published
- 2020
10. Transformation process meets innovation leadership—an analysis of new challenges in change theory
- Author
-
Gerhard Heilemann and Werner G. Faix
- Subjects
Change process ,Change model ,Transformation process ,Innovation ,Leadership ,Management. Industrial management ,HD28-70 ,Business ,HF5001-6182 - Abstract
Abstract The continuous changes in the business environment require transformation processes and innovation in organizational structures to maintain competitiveness. Innovation is required for future orientation and need an appropriate leadership style to be implemented in the company successfully. Various studies in the literature examine the topic of change models and the requirements for effective implementation of changes. Based on the constant change in the labor market, which is due to ongoing digitalization, the need for research of transformation, change-management and radical or disruptive innovation remains topical. A new challenge arises with a transformation in the entire company which affects all essential business processes. Because several levels are simultaneously affected by the transformation process, a more complex concept is required for the implementation than it could be found in the literature. There is a lack of empirical research in general for innovation-driven transformation processes and a missing connection to the implementation of radical or disruptive innovation in company. The aim of this paper is to investigate the need for new research in change theory. The focus is on the importance of innovation leadership for a radical or disruptive innovation change process, what is to be classified under a comprehensive transformation process in the company. In addition, the need for an innovation transformation model is established.
- Published
- 2023
- Full Text
- View/download PDF
11. Baseline and interim PET-based outcome prediction in peripheral T-cell lymphoma:A subgroup analysis of the PETAL trial
- Author
-
Heinz Dürk, Arnold Ganser, Jan Rekowski, Andreas Hertel, Bernd Hertenstein, Lars Kurch, Matthias Sandmann, Winfried Brenner, Christiane Kreisel-Büstgens, Christiane Franzius, Wolfram Klapper, Matthias Weckesser, Aristoteles Giagounidis, Martin Freesmeyer, Thomas Krohn, Volker Runde, Dirk Behringer, Michael Heike, Stefan P. Müller, Frank Kroschinsky, Regina Moeller, Rolf Larisch, Hubertus Hautzel, Christine Schmitz, Gerhard Heil, Rolf M. Mesters, Ulrich Dührsen, Karl-Heinz Jöckel, Ferras Alashkar, Helga Bernhard, Dietmar Wacker, Uwe M. Martens, Stefan Mahlmann, Stefan Wilop, Jörg Kotzerke, Ronald Boellaard, Paul La Rosée, Gabriele Prange-Krex, Andreas Hüttmann, Heinz Gert Hoeffkes, Uwe Haberkorn, Guido Trenn, Dieter Hoelzer, Marcus Brinkmann, Frank M. Bengel, Radiology and nuclear medicine, and CCA - Imaging and biomarkers
- Subjects
Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Population ,Medizin ,Standardized uptake value ,Subgroup analysis ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Fluorodeoxyglucose F18 ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Anaplastic lymphoma kinase ,Humans ,Prospective cohort study ,education ,Aged ,Aged, 80 and over ,education.field_of_study ,business.industry ,Hazard ratio ,Lymphoma, T-Cell, Peripheral ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Prognosis ,Peripheral T-cell lymphoma ,Lymphoma ,Survival Rate ,030220 oncology & carcinogenesis ,Positron-Emission Tomography ,Female ,Radiopharmaceuticals ,business ,030215 immunology ,Follow-Up Studies - Abstract
The prospective randomized Positron Emission Tomography (PET)-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial was designed to test the ability of interim PET (iPET) to direct therapy. As reported previously, outcome remained unaffected by iPET-based treatment changes. In this subgroup analysis, we studied the prognostic value of baseline total metabolic tumor volume (TMTV) and iPET response in 76 patients with T-cell lymphoma. TMTV was measured using the 41% maximum standardized uptake value (SUV41max) and SUV4 thresholding methods. Interim PET was performed after two treatment cycles and evaluated using the ΔSUVmax approach and the Deauville scale. Because of significant differences in outcome, patients with anaplastic lymphoma kinase (ALK)-positive lymphoma were analyzed separately from patients with ALK-negative lymphoma. In the latter, TMTV was statistically significantly correlated with progression-free survival, with thresholds best dichotomizing the population, of 232 cm3 using SUV41max and 460 cm3 using SUV4. For iPET response, the respective thresholds were 46.9% SUVmax reduction and Deauville score 1-4 vs 5. The proportion of poor prognosis patients was 46% and 29% for TMTV by SUV41max and SUV4, and 29% and 25% for iPET response by ΔSUVmax and Deauville, respectively. At diagnosis, the hazard ratio (95% confidence interval) for poor prognosis vs good prognosis patients according to TMTV was 2.291 (1.135-4.624) for SUV41max and 3.206 (1.524-6.743) for SUV4. At iPET, it was 3.910 (1.891-8.087) for ΔSUVmax and 4.371 (2.079-9.187) for Deauville. On multivariable analysis, only TMTV and iPET response independently predicted survival. Patients with high baseline TMTV and poor iPET response (22% of the population) invariably progressed or died within the first year (hazard ratio, 9.031 [3.651-22.336]). Due to small numbers and events, PET did not predict survival in ALK-positive lymphoma. Baseline TMTV and iPET response are promising tools to select patients with ALK-negative T-cell lymphoma for early allogeneic transplantation or innovative therapies.
- Published
- 2020
12. Outcomes of Anti-PD1 Treatment for Relapsed/Refractory Hodgkin Lymphoma: A German Hodgkin Study Group (GHSG) Multi-Center Real-World Analysis
- Author
-
William Krüger, Bernhard Heinrich, Martin Wilhelm, Vanja Zeremski, Norbert Grobe, Bastian von Tresckow, Peter Borchmann, Michael Fuchs, Jesko Momotow, Tobias Gaska, Burkhard Schmidt, Ina Bühnen, Andreas Hüttmann, Doris Kraemer, Paul J Bröckelmann, Gerhard Heil, Karolin Trautmann-Grill, Andreas Engert, Helmut Forstbauer, Guido Kobbe, and Kathleen Jentsch-Ulrich
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Medizin ,Cell Biology ,Hematology ,Biochemistry ,language.human_language ,German ,Internal medicine ,Relapsed refractory ,language ,Medicine ,Hodgkin lymphoma ,Center (algebra and category theory) ,business ,Anti pd1 - Abstract
Background: Immune-checkpoint inhibition with antibodies targeting programmed death protein 1 (PD1) was well tolerable and highly effective in pivotal phase II and III trials in relapsed or refractory (r/r) classical Hodgkin lymphoma (cHL). We aimed to evaluate emerging therapeutic sequences and the safety and efficacy of anti-PD1 antibodies in the rapidly changing routine care of r/r cHL. Methods: GHSG-affiliated hemato-oncology departments and practices in Germany were invited to participate in this retrospective study. Patients ≥18 years of age receiving anti-PD1 antibodies for r/r cHL in routine care were eligible. Patient, disease and treatment characteristics were documented by the treating physicians with standardized case report forms. Locally assessed response rates were reported as complete (CR) or partial (PR) remission, stable (SD) or progressive (PD) disease and summarized as objective response rate (ORR: CR + PR). Progression-free (PFS) and overall survival (OS) were analyzed according to Kaplan-Meier from the start of anti-PD1 treatment in routine care to PD (PFS) or death from any cause (PFS + OS). All analyses were done descriptively and conducted in SAS V9.4. Results: A total of 58 r/r cHL patients (pts.) with a median age of 48 years (range 19-89 years) and male predominance (57%) initiated anti-PD1 treatment between 11/2014 and 01/2021 at 15 sites. Median time from 1 st-line to anti-PD1 treatment was 5.5 years (0.8-26.0). The majority had received prior brentuximab vedotin (BV, 86%) or an autologous stem-cell transplantation (autoSCT, 62%) and 16% undergone prior alloSCT. Relevant co-morbidities including HIV, pre-existing autoimmune conditions, cardiovascular diseases and dialysis-dependent kidney failure were documented in 49% of patients. An impaired ECOG performance status of ≥1 was present in 57% of patients (ECOG 2: 12%, ECOG 3: 4%). At initiation of anti-PD1 treatment, 74% of patients presented with stage III/IV disease and 35% did not achieve a response to their latest prior therapy. The median duration of anti-PD1 treatment was 18.1 (0.5-79.3) months and 50% of patients still received an anti-PD1 antibody at data collection. One third (31.6%) of patients experienced grade III/IV treatment-related toxicities and a treatment delay of >6 weeks due to toxicity occurred in 15.5% of patients. Investigator-assessed ORR was 66.7% with 20.4% of patients achieving a CR and 46.3% a PR as best response (Figure 1A). With a median follow-up of 19.1 (0-74.7) months and 26.7 (0-74.7) for PFS and OS, respectively, median PFS (mPFS) and OS were 12.3 months and 32 months, respectively (Figure 1B+C). Corresponding 2-year PFS and OS estimates were 38.3% (95%CI 24.4-52.2) and 78.5% (95%CI 67.2-89.8). Median PFS was more favorable in patients achieving either a CR (30.1 months) or PR (24.9 months) compared to SD (9.3) or PD (3.4, Figure 1D), with similar trends also observed for OS. Two thirds (67%) of the 29 patients eventually experiencing PD, continued anti-PD1 treatment beyond progression at least once, with a median duration of 9.9 (3.0-25.8) until 2 nd PD. Overall, 28% patients received concomitant add-on treatments with radiotherapy (62.5%) and chemotherapy (25%) administered simultaneously most commonly. Best response to combination treatment was PR in 84.6% and SD in 15.4% of patients, and 75% of patients receiving add-on treatments achieved their best response only thereafter. Most common consecutive treatments were allogeneic stem-cell transplantation (N=5), BV-based therapy (N=5), Gemcitabine-based regimens (N=4) radiotherapy (N=4) and N=13 patients did not receive further treatment after anti-PD1 failure. Most common cause of death was cHL (58% of deaths reported), followed by non-anti-PD1 treatment-related causes (16%), infections and cardiac diseases (11% each) and second neoplasms (5%). Conclusions: In this multicenter cohort of older and frailer r/r cHL patients receiving anti-PD1 antibodies in routine care, safety and efficacy data including ORR, mPFS and mOS was similar to data reported from pivotal phase II trials. Anti-PD1 treatment for r/r cHL thereby appears feasible and able to induce meaningful clinical benefit in a broad range of patients. Despite various concomitant and subsequent treatments administered, however, cHL or subsequent treatments are by far the leading cause of death. Failure of anti-PD1 in r/r cHL hence constitutes an unmet need. Figure 1 Figure 1. Disclosures Trautmann-Grill: GSK: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Kobbe: Celgene: Research Funding. Heinrich: Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Eisai: Consultancy; Lilly: Consultancy, Research Funding; Sanofi: Consultancy; Astra: Consultancy, Research Funding; Abbvie: Research Funding. Schmidt: Incyte: Honoraria; Biotest: Honoraria; Alexion: Honoraria; AbbVie: Honoraria; Sanofi-Aventis: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Hüttmann: Celgene: Honoraria; Gilead: Honoraria; Lead Discovery Center GmbH: Consultancy; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fuchs: Lukon: Honoraria; Celgene: Honoraria; MSD: Honoraria; BMS: Honoraria; Takeda: Consultancy, Honoraria. von Tresckow: Novartis: Consultancy, Honoraria, Other: congress and travel support, Research Funding; Kite-Gilead: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Other: congress and travel support, Research Funding; Takeda: Consultancy, Honoraria, Other, Research Funding; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Pentixafarm: Consultancy, Honoraria; BMS-Celgene: Consultancy, Honoraria, Other: congress and travel support; AstraZeneca: Honoraria, Other: congress and travel support; Amgen: Consultancy, Honoraria; AbbVie: Other: congress and travel support. Borchmann: Gilead Sciences: Honoraria; BMS/Celgene: Honoraria; Janssen: Honoraria; Miltenyi Biotech: Honoraria; Novartis: Honoraria. Engert: MSD: Honoraria; Hexal: Honoraria; BMS: Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Tessa Therapeutics: Consultancy; Amgen: Honoraria; ADC Therapeutics: Consultancy. Bröckelmann: BMS: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; MSD: Research Funding; BeiGene: Research Funding.
- Published
- 2021
13. Randomized Phase II Study of All-Trans Retinoic Acid and Valproic Acid Added to Decitabine in Newly Diagnosed Elderly AML Patients (DECIDER trial): Predictive Impact of TP53 Status
- Author
-
Ralph Wäsch, Richard F. Schlenk, Heiko Becker, Katharina Goetze, Sebastian Scholl, Carsten Schwaenen, Carsten Müller-Tidow, Dennis Zimmer, Hartmut Döhner, Aristoteles Giagounidis, Andreas Neubauer, Michael Lübbert, Edgar Jost, Martina Crysandt, Gerhard Heil, Annette M. May, Björn Hackanson, Felicitas Thol, Ulrich Germing, Claudia Schmoor, Michael Heuser, Helmut R. Salih, Justus Duyster, Marcus M. Schittenhelm, Jürgen Krauter, Konstanze Döhner, Maike de Wit, Andrea Kündgen, Gesine Bug, Dietmar Pfeifer, Arnold Ganser, Wolfram Brugger, and Olga Grishina
- Subjects
Oncology ,Valproic Acid ,medicine.medical_specialty ,business.industry ,Immunology ,All trans ,Retinoic acid ,Decitabine ,Phases of clinical research ,Cell Biology ,Hematology ,Newly diagnosed ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
Background TP53 mutations are associated with adverse outcome of AML treated with cytarabine-based regimens. Interestingly, DNA-hypomethylating agents (HMAs) induce a higher response rate in TP53-mutated (MUT) compared to TP53 wildtype (WT) AML (Welch et al., N. Engl. J. Med. 2016, Döhner et al., Leukemia 2018). We conducted a randomized phase II trial (NCT00867672, 2x2 factorial design) asking whether the in vitro cooperativity of DAC with VPA or ATRA translates into clinical benefit. While VPA added to DAC affected neither objective response rate (ORR) nor overall survival (OS), ATRA significantly improved ORR and OS, without added toxicity (Lübbert et al., J. Clin. Oncol. 2020). Preclinical data suggest that HMAs and ATRA have cooperative effects also in TP53 MUT AML. We therefore performed a post-hoc analysis to determine the predictive impact of TP53 status. Patients and Methods Key inclusion criteria: newly diagnosed AML pts >60 yr (non-M3) unfit for induction, ECOG performance status (PS) 0-2. Treatment: DAC 20 mg/m 2 day 1-5 (arms A/B/C/D), VPA p.o. from day 6 (arms B/D), ATRA p.o. day 6-28 (arms C/D) of each 28-day course. For TP53 mutation analyses, the Illumina TruSight Myeloid Sequencing Panel was used for library preparation and an Illumina MiSeq device for sequencing. Key endpoints: ORR (CR/CRi/PR, ELN 2010 criteria) and OS. Original sample size calculation of a total of 200 patients (pts) was based on the primary endpoint ORR (Lübbert et al., Haematologica 2012). ORR was analyzed with logistic regression, OS with Cox regression. Odds ratios (OR) for the effect on ORR and hazard ratios (HR) for the effect on death with 95% confidence intervals (CI) are presented in the genetic subgroups TP53 MUT and TP53 WT including tests for interactions (TFI) between treatment and TP53. These are post-hoc exploratory analyses, hence p-values have to be interpreted in a descriptive sense. Results Between 12/2011 and 2/2015, 200 pts were randomized and treated. Information on TP53 status was available for 168 of 200 pts (84%); 155 of them (92%) had died at last follow-up (June 2021). 61% of pts were aged >75 years (range 61-92), ECOG PS 0/1/2: 19/62/19% (a single pt had a PS of 3); 53% had an HCT-CI >3, 19% WBC >30.000/µl, 30% adverse genetics (ELN 2010), 51% an antecedent hematologic disorder. TP53 aberrations were detected in 42 pts (25%), with 1 (n=27) or 2 mutations (n=12, median variant allele frequency 44%, range, 1.3-99%) in 39 pts, and TP53 deletions in 3 additional pts. The 42 pts with TP53 MUT showed a higher ORR (23.8%) than the 126 pts with TP53 WT (ORR 15.1%), with an OR of 2.04 (95% CI 0.83-4.98), p=0.12. OS (irrespective of treatment) in the TP53 MUT v WT pts was not different (HR, adjusted for treatment: 1.14 [95% CI 0.78-1.66], p=0.51; Fig. A). In both genetic groups, the addition of ATRA had a favorable effect on ORR (ATRA v no ATRA in TP53 MUT: 31.3% v 19.2%, OR 1.91 [95% CI 0.45-8.03]; ATRA v no ATRA in TP53 WT: 18.8% v 10.5%, OR 1.98 [95% CI 0.70-5.61]), TFI p=0.97 (Fig. B). A positive effect of ATRA on OS in both genetic groups was reflected by a median OS of 6.0 v 4.5 months (ATRA v no ATRA in TP53 MUT: HR 0.75 [95% CI 0.38-1.48]), and a median OS of 8.9 v 4.7 months (ATRA v no ATRA in TP53 WT: HR 0.58 [95% CI 0.39-0.86], all results adjusted for VPA, ECOG, HCT-CI, sLDH, Hb), TFI p=0.49 (Fig. C). VPA did not affect ORR in either of the 2 genetic groups (VPA v no VPA in TP53 MUT: 21.7% v 26.3%, OR 0.76 [95% CI 0.18-3.21]; VPA v no VPA in TP53 WT: 16.7% v 13.3%, OR 1.34 [95% CI 0.5-3.61]), TFI p=0.53. The impact of VPA on OS differed between TP53 MUT pts (VPA v no VPA: median OS of 4.2 v 5.3 months, HR 1.31 [95% CI 0.69-2.48], and TP53 WT pts (VPA v no VPA: median OS of 8.4 v 4.8 months, HR 0.67 [95% CI 0.46-0.99], all results adjusted for ATRA, ECOG, HCT-CI, sLDH, Hb; TFI p=0.08, Fig. C). Conclusions Our results confirm the reported higher response rate to DAC in pts with TP53 MUT compared to TP53 WT; the addition of ATRA led to a higher ORR. Improved OS with ATRA was observed particularly in TP53 WT pts. In contrast, VPA did not affect the ORR in either genetic group; TP53 WT pts may benefit from VPA regarding OS. Our exploratory post-hoc results need confirmation in other trials, e.g. in the DECIDER-2 study (adding ATRA or placebo to the recently approved dual treatment of a HMA combined with venetoclax). Cooperative effects of HMAs and retinoids deserve a deeper mechanistic understanding, which may have implications not only for AML but also for other malignancies with impaired TP53. Figure 1 Figure 1. Disclosures Becker: BMS: Honoraria; Pierre Fabre Pharma: Honoraria; Servier: Honoraria; MSD: Honoraria; Novartis: Honoraria. Crysandt: Incyte: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Thol: Abbvie: Honoraria; Pfizer: Honoraria; Astellas: Honoraria; Novartis: Honoraria; BMS/Celgene: Honoraria, Research Funding; Jazz: Honoraria. Heuser: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolremo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; BergenBio: Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; Astellas: Research Funding. Goetze: Abbvie: Other: Advisory Board; BMS/Celgene: Other: Advisory Board, Research Funding. Schlenk: Agios: Honoraria; Astellas: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Abbvie: Honoraria; Hexal: Honoraria; Neovio Biotech: Honoraria; Novartis: Honoraria; Pfizer: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding; AstraZeneca: Research Funding; Boehringer Ingelheim: Research Funding. Salih: Synimmune GmbH: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Celgene: Honoraria; BMS: Honoraria. Schittenhelm: Takeda: Other: advisory board; Astellas: Other: advisory board; BMS: Other: advisory board; University of Tuebingen: Patents & Royalties: patent for ASPP2k. Müller-Tidow: Pfizer: Research Funding; Janssen: Consultancy, Research Funding; Bioline: Research Funding. Germing: Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding. Giagounidis: Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Wäsch: Amgen: Consultancy, Honoraria; Pfizer: Consultancy; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy. Döhner: Jazz Roche: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Other: Advisory Board; Agios and Astex: Research Funding; Abbvie: Consultancy, Honoraria; Janssen: Honoraria, Other: Advisory Board; Astellas: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Ganser: Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria. Döhner: Astellas: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Helsinn: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Berlin-Chemie: Consultancy, Honoraria; Astex: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Ulm University Hospital: Current Employment; Jazz: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; GEMoaB: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding. Hackanson: Roche: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; MSD: Consultancy, Honoraria. Lübbert: Cheplapharm: Other: study drug (ATRA); TEVA: Other: study drug (valproic acid); Janssen: Consultancy, Other: study drug (decitabine), Research Funding; Syros: Consultancy, Honoraria; Aristopharm: Other: study drug ; Imago BioSciences: Consultancy, Other: study support with study drug; AbbVie: Consultancy, Honoraria; Astex: Consultancy, Honoraria. OffLabel Disclosure: ATRA, in non-M3 AML valproic acid, in non-M3 AML
- Published
- 2021
14. Activity of Decitabine (DAC) Combined with All-Trans Retinoic Acid (ATRA) in Oligoblastic AML: Subgroup Analysis of a Randomized 2x2 Phase II Trial
- Author
-
Ulrich Germing, Andreas Neubauer, Carsten Mueller-Tidow, Justus Duyster, Aristoteles Giagounidis, Gerhard Heil, Claudia Schmoor, Björn Hackanson, Felicitas Thol, Sebastian Scholl, Hartmut Döhner, Ralph Wäsch, Jürgen Krauter, Carsten Schwaenen, Annette M. May, Maike de Wit, Richard F. Schlenk, Andrea Kündgen, Christoph Rummelt, Gesine Bug, Martina Crysandt, Michael Luebbert, Konstanze Döhner, Heiko Becker, Michael Heuser, Stephan Kremers, Marcus M. Schittenhelm, Arnold Ganser, Wolfram Brugger, Helmut R. Salih, Edgar Jost, Olga Grishina, and Katharina Götze
- Subjects
Chemistry ,Immunology ,Retinoic acid ,All trans ,Decitabine ,Subgroup analysis ,Cell Biology ,Hematology ,Biochemistry ,chemistry.chemical_compound ,Phase (matter) ,Cancer research ,medicine ,medicine.drug - Abstract
Background: DNA-hypomethylating agents are providing a very well-accepted backbone for non-intensive combination treatment of AML/MDS patients (pts), and an in vivo synergism has been demonstrated for the azacitidine+venetoclax combination in the VIALE-A trial (DiNardo et al., EHA 2020). The DAC+ATRA combination also resulted in an improved response rate and survival compared to DAC without ATRA (DECIDER trial, Lübbert et al., J. Clin. Oncol. 2020), also in pts with prior hematologic disorder (mostly MDS); no benefit was seen when valproic acid (VPA) was added to DAC (2x2 factorial design). In a previous study, we had investigated the outcome of elderly pts with oligoblastic AML (i.e. with 20-30% bone marrow blasts, defined as MDS RAEBt according to the French-American-British classification) treated with either DAC or best supportive care within the EORTC 06011 phase III trial (Becker et al., Ann. Hematol. 2015), observing a median overall survival (OS) of 8.0 months (mths) in DAC-treated RAEBt pts. We now hypothesized that the outcome of pts with oligoblastic AML may be improved by the addition of ATRA to DAC. Therefore, in the present exploratory subgroup analysis, pts from the DECIDER cohort with 20-30% bone marrow blasts were analyzed for clinical outcome. Patients and Methods: Key inclusion criteria: newly diagnosed pts >60 years (yr), unfit for induction with non-M3 AML (WHO, de novo or after antecedent hematologic disorder [AHD], therapy-associated [t]AML), ECOG performance status (PS) 0-2. Treatment: DAC 20 mg/m2 day 1-5 (treatment arms A/B/C/D), ATRA p.o. day 6-28 (arms C/D), VPA p.o. continuously from day 6 (arms B/D), of each 28-day course (repeated until relapse/progression, prohibitive toxicity, withdrawal or death). Key endpoints: objective response rate (ORR): CR/CRi/PR, overall (OS) and event-free survival (EFS). Sample size calculation was based on the primary endpoint ORR, assuming an ORR of 25% in arm A (Lübbert et al., Haematologica 2012). For a power of 80% (test in this phase II study at 1-sided alpha=0.1) for an increase of ORR to 40% with ATRA or VPA, 176 pts were necessary, planned sample size 200. Between 12/2011 and 2/2015, 200 pts were randomized and treated. Efficacy analyses were performed in the intention-to-treat (ITT) population. ATRA was investigated by comparing arms C+D vs arms A+B, VPA by comparing arms B+D vs arms A+C, ORR was analyzed with logistic regression estimating odds ratios (OR), OS/EFS with Cox regression estimating hazard ratios (HR), each with 95% confidence intervals (CI), and presented with descriptive two-sided p values of the tests of no treatment effect. Central hematopathologic review (blinded as to treatment arms) was conducted by an independent morphologist. Results: In 56/200 pts of the DECIDER cohort, bone marrow blasts were 20-30% (median, 25%). The number of pts in the randomized arms were: 13 in arm A, 21 in arm B, 9 in arm C, 13 in arm D. Baseline pt characteristics were as follows: male 77%, median age: 75 yr (range 61-88), median WBC: 3400/µl (range 500-52,600), adverse genetics (ELN 2010) present in 25%, ECOG 2 in 13%, comorbidities (HCT-CI) ≥ 3 in 48%, AHD in 68%, tAML in 11% (only slight random imbalances across randomized treatment arms). A median of 5 DAC courses were administered (per arm: 2/5/11/4). Six pts attained a CR, 7 pts a CRi, and 1 pt a PR, resulting in an ORR of 25% (arm A: 7.7%, arm B: 28.6%, arm C: 33.3%, arm D: 30.8%, respectively). Effect on ORR of ATRA vs no ATRA (31.8 vs 20.6%): OR 1.85, CI [0.54,6.37], p=0.33; and of VPA vs no VPA (29.4 vs 18.2%): OR 1.93, CI [0.51,7.24], p=0.33. With 40 deaths out of 56 pts, median OS was 9.5 mths (arm A: 7.6 mths, arm B: 8.9 mths, arm C: 37.2 mths, arm D: 11.2 mths, respectively). Effect on OS of ATRA vs no ATRA (12.5 vs 7.6 mths median OS): HR 0.47, CI [0.24,0.94], p=0.032 (after adjustment for PS, HCT-CI, WBC, LDH, genetic risk: HR 0.42, CI [0.19,0.90], p=0.025); and of VPA vs no VPA (10.0 vs 8.4 mths median OS): HR 0.99, CI [0.51,1.92], p=0.98: A comparable benefit on EFS of ATRA vs no ATRA (but not VPA vs no VPA) was observed. Conclusion: In elderly pts with oligoblastic AML ineligible for induction chemotherapy, the addition of ATRA, but not VPA, to DAC resulted in a clinically meaningful survival benefit; OS of pts receiving DAC without ATRA was very similar to that observed in a previous study. It is tempting to speculate that the combination of an HMA with a retinoid such as ATRA may also be active in MDS pts with excess of blasts. Disclosures Jost: JAZZ: Other: travel support; Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: travel support. Thol:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Heuser:Amgen: Research Funding; Bayer: Consultancy, Research Funding; BerGenBio ASA: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Stemline Therapeutics: Consultancy; Janssen: Consultancy; PriME Oncology: Honoraria; Karyopharm: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Astellas: Research Funding; Roche: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Götze:Celgene: Research Funding. Schlenk:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Roche: Research Funding; AstraZeneca: Research Funding; PharmaMar: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Döhner:Sunesis Pharmaceuticals: Research Funding; Abbvie: Consultancy; Agios: Consultancy; Amgen: Consultancy, Research Funding; Astellas Pharma: Consultancy; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Arog: Research Funding; Roche: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy; Janssen: Consultancy, Honoraria; Daiichi Sankyo: Honoraria; Celgene: Consultancy, Honoraria; Novartis: Honoraria, Research Funding. Salih:Synimmune: Consultancy, Research Funding; Philogen: Consultancy; Medigene: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Schittenhelm:Pfizer: Consultancy; Astellas: Consultancy. Mueller-Tidow:Jose-Carreras-Siftung: Research Funding; Wilhelm-Sander-Stiftung: Research Funding; BMBF: Research Funding; Deutsche Krebshilfe: Research Funding; Deutsche Forschungsgemeinschaft: Research Funding; Janssen-Cilag Gmbh: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Research Funding; Daiichi Sankyo: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer AG: Research Funding. Brugger:MorphoSys: Current Employment. Bug:Jazz: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Hexal: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Eurocept: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Sanofi: Other: Travel; Neovii: Other: Travel. Wäsch:Pfizer: Consultancy; Amgen: Consultancy; Janssen: Consultancy. Ganser:Celgene: Consultancy; Novartis: Consultancy. Döhner:AstraZeneca: Consultancy, Honoraria; Sunesis: Research Funding; Roche: Consultancy, Honoraria; Pfizer: Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Helsinn: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Astex: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; AROG: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; GEMoaB: Consultancy, Honoraria. OffLabel Disclosure: ATRA is approved for APL treatment but not for non-APL AML
- Published
- 2020
15. The hypomorphic TERT A1062T variant is associated with increased treatment-related toxicity in acute myeloid leukemia
- Author
-
Aruna Raghavachar, Jürgen Krauter, Walter Fiedler, Michael Heuser, Gerhard Heil, Felicitas Thol, Frederik Damm, Gudrun Göhring, Hartmut Kirchner, Mohammed Wattad, Anna Both, Lothar Kanz, Michael Lübbert, Arnold Ganser, Wolfram Brugger, Günter Schlimok, Brigitte Schlegelberger, Katharina Wagner, and Oliver G. Ottmann
- Subjects
Adult ,Diarrhea ,Male ,Mucositis ,0301 basic medicine ,medicine.medical_specialty ,Adolescent ,Biology ,Gene mutation ,Polymorphism, Single Nucleotide ,Gastroenterology ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Multicenter Studies as Topic ,Point Mutation ,Prospective Studies ,Risk factor ,Adverse effect ,Telomerase ,Clinical Trials as Topic ,Hematology ,Induction chemotherapy ,Myeloid leukemia ,General Medicine ,Middle Aged ,Prognosis ,medicine.disease ,Combined Modality Therapy ,Survival Analysis ,Leukemia ,Treatment Outcome ,030104 developmental biology ,Leukemia, Myeloid ,030220 oncology & carcinogenesis ,Acute Disease ,Multivariate Analysis ,Toxicity ,Immunology ,Female ,Stem Cell Transplantation - Abstract
Hypomorphic germline variants in TERT, the gene encoding the reverse transcriptase component of the human telomerase complex, occur with a frequency of 3-5% in acute myeloid leukemia. We analyzed the clinical and prognostic impact of the most common TERT A1062T variant in younger patients with acute myeloid leukemia intensively treated within two prospective multicenter trials. Four hundred and twenty patients (age 17-60 years) were analyzed for the TERT A1062T variant by direct sequencing. Fifteen patients (3.6%) carried the TERT A1062T variant. Patients with the TERT A1062T variant had a trend towards less favorable and more intermediate 2/adverse karyotypes/genotypes according to the European Leukemia Net classification. In univariate and multivariate analysis, patients with the TERT A1062T variant had a significantly inferior overall survival compared to wild-type patients (6-year overall survival 20 vs. 41%, p = 0.005). Patients with the TERT A1062T variant showed a high rate of treatment-related mortality: 5/15 (33%) died during induction therapy or in complete remission as compared to 62/405 (15%) of the wild-type patients. In patients with the TERT variant, 14/15 (93%) suffered from non-hematological/non-infectious grade 3/4 adverse events (mostly hepatic and/or mucosal) as compared to 216/405 (53%) wild-type patients (p = 0.006). In multivariate analysis, the TERT A1062T variant was an independent risk factor predicting for adverse events during induction chemotherapy. In conclusion, the TERT A1062T variant is an independent negative prognostic factor in younger patients with acute myeloid leukemia and seems to predispose those patients to treatment-related toxicity.
- Published
- 2017
16. Acute myeloid leukemia derived from lympho-myeloid clonal hematopoiesis
- Author
-
Bernd Hertenstein, M. Wattad, Jürgen Krauter, Peter Paschka, Gesine Bug, Gerhard Heil, Lars Bullinger, Jana Fabisch, Walter Fiedler, Verena I. Gaidzik, Hartmut Döhner, Sabrina Klesse, Arnold Ganser, Hartmut Kirchner, Brigitte Schlegelberger, Felicitas Thol, Alessandro Liebich, Arnold Kloos, Michael Heuser, Hubert Serve, Gudrun Göhring, Razif Gabdoulline, Anuhar Chaturvedi, Doris Kraemer, Richard F. Schlenk, L Köhler, Martin Wichmann, Konstanze Döhner, and Michael Lübbert
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Myeloid ,medicine.medical_treatment ,Clone (cell biology) ,Hematopoietic stem cell transplantation ,DNA Methyltransferase 3A ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,DNA (Cytosine-5-)-Methyltransferases ,Aged, 80 and over ,Hematopoietic Stem Cell Transplantation ,High-Throughput Nucleotide Sequencing ,Myeloid leukemia ,Hematology ,Lymphoid Progenitor Cells ,Middle Aged ,Prognosis ,Combined Modality Therapy ,3. Good health ,Survival Rate ,Leukemia, Myeloid, Acute ,Leukemia ,Haematopoiesis ,medicine.anatomical_structure ,Oncology ,RUNX1 ,030220 oncology & carcinogenesis ,Female ,Adult ,Adolescent ,Article ,Young Adult ,03 medical and health sciences ,Biomarkers, Tumor ,Humans ,Myeloid Progenitor Cells ,Aged ,Neoplasm Staging ,business.industry ,Myelodysplastic syndromes ,medicine.disease ,Clone Cells ,Hematopoiesis ,030104 developmental biology ,chemistry ,Drug Resistance, Neoplasm ,Mutation ,Immunology ,Cancer research ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies - Abstract
We studied acute myeloid leukemia (AML) patients with lympho-myeloid clonal hematopoiesis (LM-CH), defined by the presence of DNA methyltransferase 3A (DNMT3A) mutations in both the myeloid and lymphoid T-cell compartment. Diagnostic, complete remission (CR) and relapse samples were sequenced for 34 leukemia-related genes in 171 DNMT3A mutated adult AML patients. AML with LM-CH was found in 40 patients (23%) and was associated with clonal hematopoiesis of indeterminate potential years before AML, older age, secondary AML and more frequent MDS-type co-mutations (TET2, RUNX1 and EZH2). In 82% of AML patients with LM-CH, the preleukemic clone was refractory to chemotherapy and was the founding clone for relapse. Both LM-CH and non-LM-CH MRD-positive AML patients who achieved CR had a high risk of relapse after 10 years (75% and 75%, respectively) compared with patients without clonal hematopoiesis in CR with negative MRD (27% relapse rate). Long-term survival of patients with LM-CH was only seen after allogeneic hematopoietic stem cell transplantation (HSCT). We define AML patients with LM-CH as a distinct high-risk group of AML patients that can be identified at diagnosis through mutation analysis in T cells and should be considered for HSCT.
- Published
- 2016
17. Adding dasatinib to intensive treatment in core-binding factor acute myeloid leukemia-results of the AMLSG 11-08 trial
- Author
-
Hartmut Döhner, Verena I. Gaidzik, Jürgen Krauter, Michael Heuser, Michael Girschikofsky, Veronica Teleanu, Andrea Kündgen, Heinz-A. Horst, Arnold Ganser, Doris Kraemer, Bernd Hertenstein, Gerald Wulf, Mark Ringhoffer, Markus P. Radsak, Karin Mayer, Peter Paschka, Carsten Schwänen, Thomas Heinicke, Walter Fiedler, Elisabeth Lange, Axel Benner, Gudrun Göhring, Uwe M. Martens, Daniela Weber, Richard F. Schlenk, Gerhard Heil, Felicitas Thol, Lars Bullinger, Helmut R. Salih, Konstanze Döhner, Mridul Agrawal, Michael Pfreundschuh, Richard Greil, and Michael Lübbert
- Subjects
0301 basic medicine ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Myeloid ,Dasatinib ,Gastroenterology ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Recurrence ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Biomarkers, Tumor ,Humans ,Cumulative incidence ,Core binding factor acute myeloid leukemia ,Aged ,business.industry ,Core Binding Factors ,Remission Induction ,Myeloid leukemia ,Hematology ,Middle Aged ,medicine.disease ,Confidence interval ,Leukemia ,Leukemia, Myeloid, Acute ,Proto-Oncogene Proteins c-kit ,030104 developmental biology ,medicine.anatomical_structure ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Toxicity ,Mutation ,Female ,business ,medicine.drug - Abstract
In this phase Ib/IIa study (ClinicalTrials.gov Identifier: NCT00850382) of the German-Austrian AML Study Group (AMLSG) the multikinase inhibitor dasatinib was added to intensive induction and consolidation chemotherapy and administered as single agent for 1-year maintenance in first-line treatment of adult patients with core-binding factor (CBF) acute myeloid leukemia (AML). The primary combined end point in this study was safety and feasibility, and included the rates of early (ED) and hypoplastic (HD) deaths, pleural/pericardial effusion 3°/4° and liver toxicity 3°/4°, and the rate of refractory disease. Secondary end points were cumulative incidence of relapse (CIR) and death in complete remission (CID), and overall survival (OS). Eighty-nine pts [median age 49.5 years, range: 19-73 years; t(8;21), n = 37; inv (16), n = 52] were included. No unexpected excess in toxicity was observed. The rates of ED/HD and CR/CRi were 4.5% (4/89) and 94% (84/89), respectively. The 4-year estimated CIR, CID, and OS were 33.1% [95%-CI (confidence interval), 22.7-43.4%], 6.0% (95% CI, 0.9-11.2%), and 74.7% (95% CI, 66.1-84.5%), respectively. On the basis of the acceptable toxicity profile and favorable outcome in the AMLSG 11-08 trial, a confirmatory randomized phase III trial with dasatinib in adults with CBF-AML is ongoing (ClinicalTrials.gov Identifier: NCT02013648).
- Published
- 2018
18. Prognostic value of circulating Bcl-2/IgH levels in patients with follicular lymphoma receiving first-line immunochemotherapy
- Author
-
Dorothea Kofahl-Krause, Ralf Kronenwett, Wolfram Brugger, Sabrina Pechtel, Ingmar Bruns, Juergen Barth, Gerhard Heil, Mathias J. Rummel, Norbert Niederle, Ulrich Germing, Rainer Haas, Manfred Welslau, Christoph Losem, Fabian Zohren, Akos Czibere, Thomas Schroeder, Roland Fenk, Georg Maschmeyer, and Guido Kobbe
- Subjects
Male ,medicine.medical_specialty ,Vincristine ,Oncogene Proteins, Fusion ,Cyclophosphamide ,Immunology ,Follicular lymphoma ,Phases of clinical research ,Kaplan-Meier Estimate ,Biochemistry ,Gastroenterology ,Disease-Free Survival ,Prednisone ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Bendamustine Hydrochloride ,Humans ,Lymphoma, Follicular ,Aged ,business.industry ,Cell Biology ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Confidence interval ,Lymphoma ,Doxorubicin ,Cancer research ,Female ,Rituximab ,business ,Follow-Up Studies ,medicine.drug - Abstract
Bcl-2/IgH rearrangements can be quantified in follicular lymphoma (FL) from peripheral blood (PB) by polymerase chain reaction (PCR). The prognostic value of Bcl-2/IgH levels in FL remains controversial. We therefore prospectively studied PB Bcl-2/IgH levels from 173 first-line FL patients who were consecutively enrolled, randomized, and treated within the multicenter phase 3 clinical trial NHL1-2003 comparing bendamustine-rituximab (B-R) with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone. From April 2005 to August 2008, 783 pre- and posttreatment PB samples were quantified by quantitative PCR. At inclusion, 114 patients (66%) tested positive and 59 (34%) were negative for Bcl-2/IgH. High pretreatment Bcl-2/IgH levels had an adverse effect on progression-free survival (PFS) compared with intermediate or low levels (high vs intermediate: hazard [HR], 4.28; 95% confidence interval [CI], 1.70-10.77; P = .002; high vs low: HR, 3.02; 95% CI, 1.55-5.86; P = .001). No PFS difference between treatment arms was observed in Bcl-2/IgH-positive patients. A positive posttreatment Bcl-2/IgH status was associated with shorter PFS (8.7 months vs not reached; HR, 3.15; 95% CI, 1.51-6.58; P = .002). By multivariate analysis, the pretreatment Bcl-2/IgH level was the strongest predictor for PFS. Our data suggest that pre- and posttreatment Bcl-2/IgH levels from PB have significant prognostic value for PFS in FL patients receiving first-line immunochemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT00991211 and at the German Federal Institute for Drugs and Medical Devices as #BfArM-4021335.
- Published
- 2015
19. A prospective randomised phase-II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer
- Author
-
E. Weidmann, Heike Richly, Lothar Bergmann, K. Weigang-Köhler, Luise Maute, Stefan Fuxius, Iris Burkholder, Lutz Edler, G. Hartung, Bernhard Wörmann, D. Köberle, Jörn Rüssel, B. Moritz, Walter E. Aulitzky, Max E. Scheulen, and Gerhard Heil
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,education.field_of_study ,endocrine system diseases ,Sunitinib ,business.industry ,Population ,Neutropenia ,medicine.disease ,Gemcitabine ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Pancreatic cancer ,medicine ,Deoxycytidine ,Progression-free survival ,Prospective cohort study ,education ,business ,medicine.drug - Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours and is still associated with a poor prognosis in advanced disease. To improve the standard therapy with gemcitabine, we initiated a prospective randomised phase-II trial with gemcitabine (GEM) versus gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. The rational of adding sunitinib was its putative antiangiogenic mechanism of action. Methods A total of 106 eligible patients with locally advanced, unresectable or metastatic PDAC without previous system therapy were randomised to receive GEM at a dosage of 1.000 mg/m 2 d1, 8, 15 q28 versus a combination of SUNGEM at a dosage of GEM 1.000 mg/m 2 d1 + 8 and sunitinib 50 mg p.o. d1–14, q21d. The primary end-point was progression free survival (PFS), secondary end-points were overall survival (OS), toxicity and overall response rate (ORR). Results The confirmatory analysis of PFS was based on the intend-to-treat (ITT) population ( N = 106). The median PFS was 13.3 weeks (95% confidence interval (95%-CI): 10.4–18.1 weeks) for GEM and 11.6 weeks for SUNGEM (95%-CI: 7.0–18.0 weeks; p = 0.78 one-sided log-rank). The ORR was 6.1% (95%-CI: 0.7–20.2%) for GEM and for 7.1% (95%-CI: 0.9–23.5%) for SUNGEM ( p = 0.87). The median time to progression (TTP) was 14.0 weeks (95%-CI: 12.4–22.3 weeks) for GEM and 18.0 weeks (95%-CI: 11.3–19.3 weeks) for SUNGEM ( p = 0.60; two-sided log-rank). The median OS was 36.7 weeks (95%-CI: 20.6–49.0 weeks) for the GEM arm and 30.4 weeks (95%-CI: 18.1–37.6 weeks) for the SUNGEM ( p = 0.78, one-sided log-rank). In regard to toxicities, suspected SAEs were reported in 53.7% in the GEM arm and 71.2% in the SUNGEM arm. Grade 3 and 4 neutropenia was statistically significantly higher in the SUNGEM arm with 48.1% versus 27.8% in the GEM arm ( p = 0.045, two sided log-rank). Conclusions The combination SUNGEM was not sufficient superior in locally advanced or metastatic PDAC compared to GEM alone in regard to efficacy but was associated with more toxicity.
- Published
- 2015
20. In Vivo Kinetics of Early, Hypomethylating Agent-Induced Methylome and Transcriptome Changes in Primary AML Blasts: Random or Specific?
- Author
-
Carsten Müller-Tidow, Olga Grishina, Hans-Walter Lindemann, Melanie Boerries, Arnold Ganser, Hartmut Döhner, Andreas Neubauer, Carsten Schwänen, Gerhard Heil, Geoffroy Andrieux, Björn Hackanson, Michael Heuser, Jürgen Krauter, Michael Lübbert, Gabriele Greve, Dietmar Pfeifer, Pascal Schlosser, Helmut R. Salih, and Nadja Blagitko-Dorfs
- Subjects
Immunology ,Decitabine ,Cell Biology ,Hematology ,Methylation ,Biology ,Biochemistry ,Gene expression profiling ,Transcriptome ,Hypomethylating agent ,Tretinoin ,DNA methylation ,medicine ,Cancer research ,Gene silencing ,medicine.drug - Abstract
Background: The therapeutic effect of DNA-hypomethylating agents (HMAs) in AML/MDS is discussed to be via its effects on aberrant gene silencing by reactivation (e.g. through promoter hypomethylation). While this has been broadly studied in cell line models, only very few studies have addressed the global effects of HMAs in primary blasts serially isolated from AML patients (pts) undergoing HMA treatment (Claus et al., Leuk. Res. 2013, Klco et al., Blood 2013, Welch et al., N. Engl. J. Med. 2016). We therefore conducted prospective serial methylome and transcriptome analyses on AML blasts from pts of the DECIDER trial (NCT00867672), hypothesizing that both random and non-random effects of the HMA may be observed in vivo. Patients, Materials and Methods: Of a total of 200 newly diagnosed AML pts included into the DECIDER randomized phase II trial (Decitabine/DAC treatment, 20 mg/m2 intravenous 1-hour infusion over 5 days, with add-on drugs Valproic acid and/or ATRA added at day 6; Grishina et al., BMC Cancer 2015), serially obtained peripheral blood (pb) samples from a total of 28 pts yielded sufficient numbers of purified blasts at 3 timepoints (days 0, 8 and 15 from DAC treatment start) to allow a "triplet analysis" of these matched samples. Baseline pt characteristics: median WBC 11,900/µl (range 1,200 - 53,800), median pb blasts 37.5% (range 1% - 93%). Blasts were sorted using anti-CD34, CD117 MACS microbeads, respectively (median purity >90%). Methylomes were obtained using Infinium Human Methylation 450 BeadChip arrays (Illumina). For expression analyses, GeneChip Human Gene 2.0 ST arrays were used. A linear-model based approach was used to identify the differentially methylated CpGs and expressed genes post vs. prior to treatment. Results: To address in vivo methylation changes occurring at day 8 and 15 from DAC treatment start, complete "triplets" of DNA preparations (thus from purified pb blasts of all 3 time points) were interrogated. Significant hypomethylation at day 8 (Δβ Conclusions: In our study, a subset of genes was specifically targeted by hypomethylation in all pts, arguing against a completely random effect of this treatment on the methylome. Only a limited number of hypomethylating events was associated with gene reactivation. A better understanding of hypo- and remethylation kinetics in vivo may aid in schedule optimization of HMA therapy. Correlative studies on hypomethylation kinetics and treatment outcome in the DECIDER trial are therefore ongoing, as well as serial methylome analyses in the EORTC trial AML21 ("inDACtion vs. induction", NCT02172872). Disclosures Salih: Several patent applications: Patents & Royalties: e.g. EP3064507A1. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Döhner:Jazz: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AROG Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pfizer: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Seattle Genetics: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria. Lübbert:Cheplapharm: Other: Study drug; Janssen: Honoraria, Research Funding; TEVA: Other: Study drug; Celgene: Other: Travel Support.
- Published
- 2018
21. Frequency and Clinical Characteristics Associated with Putative CAR Targets ADGRE2, CCR1, CD70, and LILRB2 in Acute Myeloid Leukemia
- Author
-
Sabrina Klesse, Arnold Ganser, Martin Wichmann, Courteney K. Lai, Piroska Klement, Gerhard Heil, Christian Koenecke, Felicitas Thol, Lothar Hambach, Sagarajit Mohanty, Arne Trummer, Alessandro Liebich, Arnold Kloos, Michael Heuser, Johannes Schiller, Razif Gabdoulline, Jürgen Krauter, Blerina Neziri, Walter Fiedler, Hartmut Kirchner, Rabia Shahswar, and Zhixiong Li
- Subjects
Subset Analysis ,Oncology ,medicine.medical_specialty ,Myeloid ,biology ,business.industry ,CD3 ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Biochemistry ,Haematopoiesis ,medicine.anatomical_structure ,Antigen ,Internal medicine ,CEBPA ,biology.protein ,Medicine ,Bone marrow ,business - Abstract
Background: ADGRE2, CCR1, CD70, and LILRB2 expressed on the surface of myeloid blasts but not normal hematopoietic stem cells, T cells or other tissues have been recently suggested as candidate chimeric antigen receptor (CAR) targets for engineered T cells in acute myeloid leukemia (AML) patients. Aim: To validate the expression pattern of the recently identified candidate CAR targets ADGRE2, CCR1, CD70, and LILRB2 on leukemic blasts in a cohort of newly diagnosed AML patients. Methods: 109 patients with de novo (n=87) or secondary (n=22) AML were included in the analysis. Patients were classified according to the 2008 WHO classification and cytogenetically characterized by chromosome banding analysis. Molecular analyses were performed by Sanger and next-generation sequencing (NGS) with a panel of 46 genes. Bone marrow or peripheral blood samples from the time of first diagnosis were obtained to perform multi-color flow cytometry analysis evaluating the expression levels of ADGRE2 (also known as EMR2 or CD132), CCR1 (also known as CD191), CD70 and LILRB2 (also known as CD85d) antigens on the surface of myeloid blasts. Patients with expression of the marker on ≥20% of blast cells were defined positive. Informed consent was obtained from all patients in accordance to the declaration of Helsinki and institutional guidelines. Results: ADGRE2, CCR1, CD70 and LILRB2 were expressed in 100%, 70%, 27.5%, 27.5% of patients with a median expression on myeloid blasts of 87.8% (range 30.4-99.8%), 43.9% (range 21.1-86.2%), 29.0% (range 20.0-55.4%), and 35.6% (range 20.7-90.6%), respectively. A subset analysis was performed to determine expression levels of the candidate targets in CD3 positive cells. Of patients with positive marker expression on blast cells ADGRE2, CCR1, CD70 and LILRB2 were expressed on 14.5% (range 0.0-64.2%), 19.9% (0.0-73.0%), 15.3% (range 0.0-35.1%), and 2% (range 0.1-18.4%) of CD3+ T cells, respectively. The proportion of patients with ≥80% expression on blasts was 61.5% (n=67), 0.9% (n=1) and 3.7% (n=4) for ADGRE2, CCR1 and LILRB2, respectively. Of those 53.7%, 0%, and 100% had marker expression There were no significant differences in the distribution of age, type of AML, sex, WHO subtypes, cytogenetic risk according to 2017 ELN classification, WBC count, hemoglobin and platelet count or for the type of consolidation treatment between CCR1, CD70, and LILRB2 positive compared to negative patients except for a higher platelet count in LILRB2 positive patients (p=0.009). To evaluate the association between mean expression level and mutational profile molecular analyses were performed as mentioned above and correlated with expression levels. More blast cells expressed CCR1 in CEBPA mutated patients compared to CEBPA wildtype patients (43.7% vs. 32.8%, p=0.003), while fewer blast cells expressed LILRB2 in IDH2 mutated compared to wildtype patients (9% vs. 16.8%, p=0.027). However, no other mutations correlated with the expression of the candidate CAR targets. Next, Pearson correlation was calculated to determine co-expression of the candidate CAR targets. A positive correlation was found between CCR1 and CD70 expression on blast cells (R=0.673, p Conclusions: Our data show variable expression levels of candidate CAR targets in AML blast cells with ADGRE2 being expressed at high levels in all patients. However, expression levels were not specifically associated with patient characteristics or outcome. Our findings favor ADGRE2 as potentially suitable for CAR targeting as it had the most favorable expression profile on blasts and T cells in AML patients. Disclosures Koenecke: BMS: Consultancy; Amgen: Consultancy; abbvie: Consultancy; Roche: Consultancy. Fiedler:Daiichi Sankyo: Other: support for meeting attendance; Gilead: Other: support for meeting attendance; Amgen: Other: support for meetíng attendance; Pfizer: Research Funding; Amgen: Research Funding; Amgen: Patents & Royalties; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees, support for meeting attendance; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSO: Other: support for meeting attendance; Teva: Other: support for meeting attendance; JAZZ Pharmaceuticals: Other: support for meeting attendance. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees.
- Published
- 2018
22. Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML Study Group (AMLSG)
- Author
-
Anja Stölzle, Verena I. Gaidzik, Heinz Kirchen, Sabine Kayser, Marie von Lilienfeld-Toal, Arnold Ganser, Daniela Späth, Wolfram Brugger, Jürgen Krauter, Hans Günter Derigs, Richard F. Schlenk, Michael Girschikofsky, Volker Runde, Richard Greil, Lars Bullinger, Mohammed Wattad, Maria-Veronica Teleanu, Stephan Kremers, Andrea Kuendgen, Aruna Raghavachar, Peter Paschka, Brigitte Schlegelberger, Hartmut Döhner, Andreas L. Petzer, Michael Heuser, Gerhard Heil, Gudrun Goehring, Mark Ringhoffer, Konstanze Döhner, and Helmut R. Salih
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,NPM1 ,Myeloid ,Adolescent ,Immunology ,Context (language use) ,Gene mutation ,Biochemistry ,DNA Methyltransferase 3A ,Young Adult ,hemic and lymphatic diseases ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,DNA (Cytosine-5-)-Methyltransferases ,Prospective Studies ,Survival rate ,business.industry ,Hazard ratio ,Myeloid leukemia ,Cell Biology ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Survival Rate ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Mutation ,embryonic structures ,Female ,business ,Nucleophosmin ,Follow-Up Studies - Abstract
In this study, we evaluated the frequency and prognostic impact of DNMT3A mutations (DNMT3A(mut)) in 1770 younger adult patients with acute myeloid leukemia (AML) in the context of other genetic alterations and the European LeukemiaNet (ELN) classification. DNMT3A(mut) were found in 20.9% of AMLs and were associated with older age (P < .0001), higher white blood cell counts (P < .0001), cytogenetically normal AML (CN-AML; P < .0001), NPM1 mutations (P < .0001), FLT3 internal tandem duplications (P < .0001), and IDH1/2 mutations (P < .0001). In univariable and multivariable analyses, DNMT3A(mut) did not impact event-free, relapse-free (RFS), or overall survival (OS) in either the entire cohort or in CN-AML; a negative prognostic effect was found only in the ELN unfavorable CN-AML subset (OS, P = .011). In addition, R882 mutations vs non-R882 mutations showed opposite clinical effects-unfavorable for R882 on RFS (all: hazard ratio [HR], 1.29 [P = .026]; CN-AML: HR, 1.38 [P = .018]) and favorable for non-R882 on OS (all: HR, 0.77 [P = .057]; CN-AML: HR, 0.73 [P = .083]). In our statistically high-powered study with minimized selection bias, DNMT3A(mut) represent a frequent genetic lesion in younger adults with AML but have no significant impact on survival end points; only moderate effects on outcome were found, depending on molecular subgroup and DNMT3A(mut) type.
- Published
- 2013
23. The AML1/MTG8 Fusion Transcript in t(8;21) Positive AML and its Implication for the Detection of Minimal Residual Disease
- Author
-
Jürgen Krauter, Gerhard Heil, and Arnold Ganser
- Subjects
Acute myeloblastic leukemia ,Chromosomal translocation ,Hematology ,Biology ,Bioinformatics ,medicine.disease ,Minimal residual disease ,Fusion gene ,03 medical and health sciences ,0302 clinical medicine ,Autologous stem-cell transplantation ,Real-time polymerase chain reaction ,Fusion transcript ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,Chromosome 21 ,030215 immunology - Abstract
The reciprocal translocation t(8;21)(q22;q22) is one of the most frequent chromosomal aberrations in acute myeloblastic leukemia (AML). At the molecular level, this aberration rearranges the gene for the AML1-transcription factor on chromosome 21, which is essential for normal hematopoiesis, to the MTG8 gene on chromosome 8, thereby leading to a specific AML1/MTG8 fusion mRNA. This fusion gene is involved in leukemogenesis presumably by interfering with normal AML1-dependent transcriptional regulation. AML patients with t(8;21) have a favourable response to chemotherapy and a relatively good prognosis after intensive consolidation treatment with high dose AraC or autologous stem cell transplantation. RT-PCR for the specific AML1/MTG8 fusion transcripts can be used for the sensitive detection of residual leukemic cells during and after therapy. However, since a considerable proportion of these patients shows a positive PCR result even in long-term complete hematological remission, the prognostic value of qualitative PCR methods is doubtful. In contrast, quantitative PCR methods might be able to identify patients with a high risk of relapse by serial quantification of minimal residual disease (MRD). Because of its high degree of standardisation and automation, the recently developed real time PCR method can be used for the valid and reproducible detection of MRD in large prospective trials. This technology offers the potential to define the antileukemic efficiency of different treatment elements and the prognostic value of MRD in patients with t(8;21) positive AML.
- Published
- 2016
24. Acute Myeloid Leukemia (AML): Different Treatment Strategies Versus a Common Standard Arm—Combined Prospective Analysis by the German AML Intergroup
- Author
-
Achim Heinecke, Markus Pfirrmann, R.F. Schlenk, Verena S. Hoffmann, Joerg Hasford, Wolfgang Hiddemann, Michael Kramer, Hartmut Döhner, Markus Schaich, Maria Cristina Sauerland, Dietger Niederwieser, Utz Krug, Rainer Krahl, Konstanze Döhner, Daniela Späth, Jürgen Krauter, Dieter Hoelzer, Rüdiger Hehlmann, Arnold Ganser, Thomas Büchner, Gerhard Ehninger, Sebastian Scholl, Gerhard Heil, and Wolfgang E. Berdel
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Myeloid ,Randomization ,Adolescent ,Kaplan-Meier Estimate ,Gene mutation ,Risk Assessment ,Severity of Illness Index ,Disease-Free Survival ,Drug Administration Schedule ,law.invention ,Young Adult ,Sex Factors ,Randomized controlled trial ,law ,Germany ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Confidence Intervals ,medicine ,Humans ,Prospective Studies ,Infusions, Intravenous ,Prospective cohort study ,Proportional Hazards Models ,Dose-Response Relationship, Drug ,business.industry ,Daunorubicin ,Age Factors ,Cytarabine ,Myeloid leukemia ,Middle Aged ,Prognosis ,Survival Analysis ,Surgery ,Transplantation ,Leukemia, Myeloid, Acute ,Treatment Outcome ,medicine.anatomical_structure ,Oncology ,Female ,Neoplasm Recurrence, Local ,business ,medicine.drug - Abstract
Purpose Identifying true therapeutic progress in patients with acute myeloid leukemia (AML) requires a comparison of treatment strategies and results on the basis of uniform patient selection. To foster comparability across five clinical studies, we introduced a common standard arm combined with a general upfront randomization and performed prospective analyses with adjustment for differences in prognostic baseline characteristics. Patients and Methods Whereas the studies' own regimens differed in chemotherapies, risk adaption, and guidelines for allogeneic stem-cell transplantation, the standard arm contained uniform cytarabine- and anthracycline-based standard-dose remission induction and high-dose consolidation courses. Results Of 2,995 evaluable patients aged 16 to 60 years, 290 patients were randomly assigned to the common standard arm. Seventy percent of the 290 achieved complete remissions (62% with complete recovery, 8% with incomplete recovery; 95% CI, 65% to 76%). Five-year survival probabilities were 44.3% (95% CI, 37.7% to 50.7%) for overall survival, 44.8% (95% CI, 37.0% to 52.2%) for relapse-free survival, and 31.5% (95% CI, 25.7% to 37.4%) for event-free survival. Neither the unadjusted survival probabilities of the Kaplan-Meier method nor their adjustment for prognostic variables in multiple Cox regression models led to statistically significant different results in the three survival end points when the outcomes of each study were compared with the standard arm. Conclusion A strictly prospective comparison of different treatment strategies in patients with AML did not show clinically relevant outcome differences when compared through a common standard treatment arm. The results provide a representative basis for further therapeutic approaches.
- Published
- 2012
25. Incidence and Prognostic Influence of DNMT3A Mutations in Acute Myeloid Leukemia
- Author
-
Walter Fiedler, Jürgen Krauter, Andrea Ludeking, Katharina Wagner, Michael Heuser, Dieter Hoelzer, Claudia Winschel, Gerhard Heil, Felicitas Thol, Lothar Kanz, Michael A. Morgan, Hartmut Kirchner, Arnold Ganser, Frederik Damm, Gudrun Göhring, Brigitte Schlegelberger, Michael Lübbert, and Haiyang Yun
- Subjects
Adult ,Oncology ,Cancer Research ,NPM1 ,medicine.medical_specialty ,Time Factors ,Myeloid ,Adolescent ,DNA Mutational Analysis ,medicine.disease_cause ,Risk Assessment ,Disease-Free Survival ,DNA Methyltransferase 3A ,Young Adult ,Risk Factors ,Germany ,Internal medicine ,CEBPA ,Biomarkers, Tumor ,medicine ,Humans ,Genetic Predisposition to Disease ,DNA (Cytosine-5-)-Methyltransferases ,Survival rate ,BAALC ,Mutation ,Gene Expression Regulation, Leukemic ,business.industry ,Age Factors ,Myeloid leukemia ,DNA Methylation ,Middle Aged ,medicine.disease ,Survival Analysis ,Survival Rate ,Leukemia, Myeloid, Acute ,Leukemia ,Treatment Outcome ,medicine.anatomical_structure ,embryonic structures ,Cancer research ,business ,Nucleophosmin - Abstract
Purpose To study the incidence and prognostic impact of mutations in DNA methyltransferase 3A (DNMT3A) in patients with acute myeloid leukemia. Patients and Methods A total of 489 patients with AML were examined for mutations in DNMT3A by direct sequencing. The prognostic impact of DNMT3A mutations was evaluated in the context of other clinical prognostic markers and genetic risk factors (cytogenetic risk group; mutations in NPM1, FLT3, CEBPA, IDH1, IDH2, MLL1, NRAS, WT1, and WT1 SNPrs16754; expression levels of BAALC, ERG, EVI1, MLL5, MN1, and WT1). Results DNMT3A mutations were found in 87 (17.8%) of 489 patients with AML who were younger than 60 years of age. Patients with DNMT3A mutations were older, had higher WBC and platelet counts, more often had a normal karyotype and mutations in NPM1, FLT3, and IDH1 genes, and had higher MLL5 expression levels as compared with patients with wild-type DNMT3A. Mutations in DNMT3A independently predicted a shorter overall survival (OS; hazard ratio [HR], 1.59; 95% CI, 1.15 to 2.21; P = .005) by multivariate analysis, but were not associated with relapse-free survival (RFS) or complete remission (CR) rate when the entire patient cohort was considered. In cytogenetically normal (CN) AML, 27.2% harbored DNMT3A mutations that independently predicted shorter OS (HR = 2.46; 95% CI, 1.58 to 3.83; P < .001) and lower CR rate (OR, 0.42; 95% CI, 0.21 to 0.84; P = .015), but not RFS (P = .32). Within patients with CN-AML, DNMT3A mutations had an unfavorable effect on OS, RFS, and CR rate in NPM1/FLT3-ITD high-risk but not in low-risk patients. Conclusion DNMT3A mutations are frequent in younger patients with AML and are associated with an unfavorable prognosis.
- Published
- 2011
26. Integrative prognostic risk score in acute myeloid leukemia with normal karyotype
- Author
-
Ewa Surdziel, Michael Lübbert, Peter J. M. Valk, Anika Grosshennig, Michael Morgan, Christoph W. M. Reuter, Kerstin Görlich, Michael Heuser, Iyas Hamwi, Arnold Ganser, Gerhard Heil, Felicitas Thol, Ruud Delwel, Katharina Wagner, Bob Löwenberg, Lothar Kanz, Frederik Damm, Jürgen Krauter, Walter Fiedler, and Hematology
- Subjects
Adult ,Oncology ,medicine.medical_specialty ,NPM1 ,Adolescent ,Immunology ,Single-nucleotide polymorphism ,Biochemistry ,Young Adult ,Predictive Value of Tests ,Risk Factors ,Internal medicine ,CEBPA ,Biomarkers, Tumor ,medicine ,Humans ,Multicenter Studies as Topic ,Transplantation, Homologous ,BAALC ,Proportional Hazards Models ,Clinical Trials as Topic ,PRAME ,Hematology ,Framingham Risk Score ,business.industry ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Cell Biology ,Middle Aged ,Prognosis ,Leukemia, Myeloid, Acute ,Karyotyping ,business ,Nucleophosmin - Abstract
To integrate available clinical and molecular information for cytogenetically normal acute myeloid leukemia (CN-AML) patients into one risk score, 275 CN-AML patients from multicenter treatment trials AML SHG Hannover 0199 and 0295 and 131 patients from HOVON/SAKK protocols as external controls were evaluated for mutations/polymorphisms in NPM1, FLT3, CEBPA, MLL, NRAS, IDH1/2, and WT1. Transcript levels were quantified for BAALC, ERG, EVI1, ID1, MN1, PRAME, and WT1. Integrative prognostic risk score (IPRS) was modeled in 181 patients based on age, white blood cell count, mutation status of NPM1, FLT3-ITD, CEBPA, single nucleotide polymorphism rs16754, and expression levels of BAALC, ERG, MN1, and WT1 to represent low, intermediate, and high risk of death. Complete remission (P = .005), relapse-free survival (RFS, P < .001), and overall survival (OS, P < .001) were significantly different for the 3 risk groups. In 2 independent validation cohorts of 94 and 131 patients, the IPRS predicted different OS (P < .001) and RFS (P < .001). High-risk patients with related donors had longer OS (P = .016) and RFS (P = .026) compared with patients without related donors. In contrast, intermediate-risk group patients with related donors had shorter OS (P = .003) and RFS (P = .05). Donor availability had no impact on outcome of patients in the low-risk group. Thus, the IPRS may improve consolidation treatment stratification in CN-AML patients. Study registered at www.clinicaltrials.gov as #NCT00209833.
- Published
- 2011
27. Prognostic Importance of Histone Methyltransferase MLL5 Expression in Acute Myeloid Leukemia
- Author
-
Ewa Surdziel, Arnold Ganser, Gerhard Heil, Karoline Bomm, Brigitte Schlegelberger, Richard F. Schlenk, Felicitas Thol, Michael Morgan, Anuhar Chaturvedi, Lothar Kanz, Hartmut Döhner, Michael Lübbert, Gudrun Göhring, Katharina Wagner, Michael Heuser, Tina Oberacker, Frederik Damm, Jürgen Krauter, Konstanze Döhner, and Walter Fiedler
- Subjects
Adult ,Oncology ,Cancer Research ,medicine.medical_specialty ,NPM1 ,Myeloid ,Adolescent ,Gene mutation ,Young Adult ,Internal medicine ,CEBPA ,Biomarkers, Tumor ,medicine ,Humans ,Multicenter Studies as Topic ,BAALC ,Reverse Transcriptase Polymerase Chain Reaction ,business.industry ,Gene Expression Profiling ,Myelodysplastic syndromes ,Myeloid leukemia ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,DNA-Binding Proteins ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Immunology ,business ,Nucleophosmin - Abstract
Purpose To assess the prognostic importance of mixed lineage leukemia 5 (MLL5) expression in acute myeloid leukemia (AML). Patients and Methods MLL5 transcript levels from 509 patients with AML who were treated in multicenter trials AML SHG 0199 and AML SHG 0295 and 48 healthy volunteers were analyzed by real-time reverse-transcription polymerase chain reaction in the context of other molecular markers (NPM1, FLT3, CEBPA, IDH1/IDH2, NRAS, KIT, MN1, BAALC, ERG, and WT1). Results Patients with high (n = 127) compared with low (n = 382) MLL5 expression had a higher complete response rate in multivariate analysis (odds ratio, 1.87; 95% CI, 1.08 to 3.24; P = .026). In multivariate analysis, high MLL5 expression was a favorable prognostic marker for overall survival (OS; hazard ratio [HR], 0.66; 95% CI, 0.49 to 0.89; P = .007) and relapse-free survival (RFS; HR, 0.72; 95% CI, 0.52 to 1.01; P = .057). Patient characteristics, cytogenetic aberrations, and gene mutations were similarly distributed between patients with high and low MLL5 expression except for a higher platelet count in those with high MLL5 expression. MLL5 expression independently predicted prognosis in cytogenetically normal AML patients (n = 268; OS: HR, 0.53; 95% CI, 0.33 to 086; P = .011; RFS: HR, 0.61; 95% CI, 0.38 to 0.99; P = .05) and in patients with core-binding factor leukemias (n = 81; OS: HR, 0.12; 95% CI, 0.02 to 0.91; P = .04; RFS: HR, 0.18; 95% CI, 0.04 to 0.77; P = .02). The prognostic importance of high MLL5 expression was independently validated in 167 patients treated in the AMLSG 07/04 trial (OS: HR, 0.5; 95% CI, 0.27 to 0.92; P = .023; RFS: HR, 0.49; 95% CI, 0.25 to 0.96; P = .033). Conclusion High MLL5 expression levels are associated with a favorable outcome and may improve risk and treatment stratification in AML.
- Published
- 2011
28. Impact of IDH1 R132 Mutations and an IDH1 Single Nucleotide Polymorphism in Cytogenetically Normal Acute Myeloid Leukemia: SNP rs11554137 Is an Adverse Prognostic Factor
- Author
-
Gudrun Göhring, Manuela Zucknick, Kerstin Görlich, Katharina Wagner, Gerhard Heil, Arnold Ganser, Wolfram Brugger, Brigitte Schlegelberger, Aruna Raghavachar, Irina Schäfer, Lothar Kanz, Michael Heuser, Günter Schlimok, Michael Lübbert, Oliver G. Ottmann, Jürgen Krauter, Hartmut Kirchner, Walter Fiedler, Wolfgang Heit, and Frederik Damm
- Subjects
Adult ,Male ,Cancer Research ,NPM1 ,Time Factors ,Myeloid ,Adolescent ,Genotype ,DNA Mutational Analysis ,Single-nucleotide polymorphism ,Kaplan-Meier Estimate ,Polymorphism, Single Nucleotide ,Risk Assessment ,Disease-Free Survival ,Gene Expression Regulation, Enzymologic ,Young Adult ,Exon ,Recurrence ,Risk Factors ,Germany ,CEBPA ,Odds Ratio ,medicine ,Humans ,SNP ,RNA, Messenger ,Proportional Hazards Models ,Chi-Square Distribution ,Gene Expression Regulation, Leukemic ,business.industry ,Exons ,Middle Aged ,medicine.disease ,Isocitrate Dehydrogenase ,Leukemia, Myeloid, Acute ,Leukemia ,Phenotype ,Treatment Outcome ,medicine.anatomical_structure ,Oncology ,Karyotyping ,Mutation ,Cancer research ,Female ,business ,Nucleophosmin - Abstract
Purpose We assessed the prognostic impact of IDH1 R132 mutations and a known single nucleotide polymorphism (SNP) located in the same exon of the IDH1 gene in patients with cytogenetically normal acute myeloid leukemia (CN-AML) in the context of other prognostic markers. Patients and Methods IDH1 exon four was directly sequenced in 275 CN-AML patients from two subsequent AML multicenter treatment trials and 120 healthy volunteers. Moreover, mutations in NPM1, FLT3, CEBPA, and WT1 were analyzed, and mRNA expression of IDH1 was quantified. Results IDH1 R132 mutations were found in 10.9% of CN-AML patients. IDH1 SNP rs11554137 was found in 12% of CN-AML patients and 11.7% of healthy volunteers. IDH1 R132 mutations had no impact on prognosis. In contrast, IDH1 SNP rs11554137 was an adverse prognostic factor for overall survival in univariate and multivariate analysis. Other significant factors were age, NPM1/FLT3 mutational status, WT1 SNP rs16754, and platelet count. The impact of IDH1 SNP rs11554137 was most pronounced in the NPM1/FLT3 high-risk patients (either NPM1 wild-type or FLT3–internal tandem duplication positive). Patients with IDH1 SNP rs11554137 had a higher expression of IDH1 mRNA than patients with two wild-type alleles. Conclusion IDH1 SNP rs11554137 but not IDH1 R132 mutations are associated with an inferior outcome in CN-AML.
- Published
- 2010
29. Single Nucleotide Polymorphism in the Mutational Hotspot of WT1 Predicts a Favorable Outcome in Patients With Cytogenetically Normal Acute Myeloid Leukemia
- Author
-
Jürgen Krauter, Arnold Ganser, Brigitte Schlegelberger, Walter Fiedler, Frederik Damm, Hartmut Döhner, Oliver G. Ottmann, Gudrun Göhring, Wolfgang Heit, Haiyang Yun, Michael Morgan, Konstanze Döhner, Hartmut Kirchner, Günter Schlimok, Michael Heuser, Lothar Kanz, Aruna Raghavachar, Gerhard Heil, Anika Grosshennig, and Michael Lübbert
- Subjects
Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,NPM1 ,Adolescent ,Context (language use) ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,Young Adult ,Internal medicine ,Genotype ,CEBPA ,Biomarkers, Tumor ,medicine ,Humans ,SNP ,Allele ,WT1 Proteins ,Neoplasm Staging ,Oligonucleotide Array Sequence Analysis ,Gene Expression Regulation, Leukemic ,business.industry ,Gene Expression Profiling ,Nuclear Proteins ,Histone-Lysine N-Methyltransferase ,Middle Aged ,Prognosis ,Survival Rate ,Minor allele frequency ,Leukemia, Myeloid, Acute ,Treatment Outcome ,fms-Like Tyrosine Kinase 3 ,Karyotyping ,Mutation ,CCAAT-Enhancer-Binding Proteins ,Cancer research ,Female ,business ,Nucleophosmin ,Myeloid-Lymphoid Leukemia Protein - Abstract
Purpose We assessed the prognostic impact of a known single nucleotide polymorphism (SNP) located in the mutational hotspot of WT1 in patients with cytogenetically normal acute myeloid leukemia (CN-AML) in the context of other prognostic markers. Patients and Methods WT1 exons 7 and 9 from 249 CN-AML patients from multicenter treatment trials AML-SHG Hannover 0199 (Clinical Trials Identifier NCT00209833) and 0295, and 50 healthy volunteers were analyzed by direct sequencing. NPM1, FLT3, CEBPA, and MLL were assessed for mutations and WT1 expression was quantified. Results The minor allele of SNP rs16754 (WT1AG/GG) was found in 25.7% of CN-AML patients' blasts and germline DNA and in 36% of healthy volunteers. Patient characteristics, frequencies of mutations, or WT1 expression levels were similarly distributed between patients homozygous for the major allele compared with patients heterozygous or homozygous for the minor allele. SNP rs16754 status was an independent predictor of relapse-free survival (RFS; hazard ratio [HR], 0.49; 95% CI, 0.3 to 0.81; P = .005) and overall survival (OS; HR, 0.44; 95% CI, 0.27 to 0.74; P = .002) in multivariate analysis. The favorable effect of SNP rs16754 was stronger in NPM1/FLT3-ITD (internal tandem duplication of the FLT3 gene) high-risk patients compared with NPM1/FLT3-ITD low-risk patients. Favorable prognosis could not be identified by any other known low-risk marker in half the patients with at least one minor allele (13% of all patients). No difference for complete remission rate, RFS, or OS was found between patients with or without acquired WT1 mutations. Conclusion WT1 SNP rs16754 may be a novel independent favorable-risk marker in CN-AML patients that might improve risk and treatment stratification.
- Published
- 2010
30. Evolution of FLT3-ITD and D835 activating point mutations in relapsing acute myeloid leukemia and response to salvage therapy
- Author
-
Annette Westermann, Andreas Czwalinna, Arnold Ganser, Carsten Müller-Tidow, Walter Verbeek, Jürgen Krauter, Gerhard Heil, Jens Tiesmeier, Mandy Hoffmann, and Hubert Serve
- Subjects
Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Clone (cell biology) ,Salvage therapy ,Biology ,fluids and secretions ,Recurrence ,Gene Duplication ,hemic and lymphatic diseases ,Internal medicine ,Gene duplication ,medicine ,Humans ,Point Mutation ,Aged ,Salvage Therapy ,Chemotherapy ,Point mutation ,Myeloid leukemia ,hemic and immune systems ,Exons ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Leukemia ,fms-Like Tyrosine Kinase 3 ,Leukemia, Myeloid ,Tandem Repeat Sequences ,Acute Disease ,embryonic structures ,Mutation (genetic algorithm) ,Immunology ,Female ,psychological phenomena and processes - Abstract
Internal tandem duplications (ITDs) of the juxtamembrane region of the FLT3 tyrosine kinase receptor are the most frequent genetic alterations in acute myeloid leukemia (AML). The presence of this mutation has been recognized as an independent poor prognostic factor. In this study, we compared the FLT3 mutational status between diagnosis and subsequent relapses in 31 patients with AML. At diagnosis, seven patients were identified to contain FLT3-ITD mutations and one patient to harbor the D835 mutation. Five patients remained FLT3-ITD positive throughout the disease course (+/+). Three patients lost the FLT3 gene mutation at first (one FLT3-ITD, one D835 mutation), or second relapse (one FLT3-ITD) (+/-). One additional patient lost a small FLT3-ITD positive clone at relapse and at the same time gained an apparently unrelated FLT3-ITD positive clone. One patient without FLT3 mutation at diagnosis relapsed with an FLT3-ITD mutation (-/+). A shorter median duration of first remission (6 months versus 11.5 months) and a higher relapse rate after salvage therapy (e.g. allogeneic peripheral blood stem cell transplantation) resulted in a lower leukemia-free survival in the FLT3 mutated group (11% versus 31%). The loss of a clone with a mutation in the FLT3 gene at relapse did not improve the prognosis.
- Published
- 2004
31. Individual Patient Data–Based Meta-Analysis of Patients Aged 16 to 60 Years With Core Binding Factor Acute Myeloid Leukemia: A Survey of the German Acute Myeloid Leukemia Intergroup
- Author
-
Rainer Krahl, Richard F. Schlenk, Rita Pasold, Thomas Büchner, Axel Benner, Dietger Niederwieser, Gerhard Heil, Jürgen Krauter, Hartmut Döhner, Cristina Sauerland, Markus Schaich, Brigitte Mohr, G. Ehninger, K Döhner, and Arnold Ganser
- Subjects
Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Pediatrics ,Prognostic variable ,Adolescent ,Acute myeloblastic leukemia ,medicine.medical_treatment ,Trisomy ,Transplantation, Autologous ,Disease-Free Survival ,Sex Factors ,Recurrence ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Transplantation, Homologous ,Autologous transplantation ,Core binding factor acute myeloid leukemia ,Bone Marrow Transplantation ,Chemotherapy ,business.industry ,Core Binding Factor alpha Subunits ,Myeloid leukemia ,Middle Aged ,Prognosis ,medicine.disease ,DNA-Binding Proteins ,Transplantation ,Leukemia ,Transcription Factor AP-2 ,Leukemia, Myeloid ,Acute Disease ,Female ,business ,Transcription Factors - Abstract
Purpose To evaluate prognostic factors for relapse-free survival (RFS) and overall survival (OS) and to assess the impact of different postremission therapies in adult patients with core binding factor (CBF) acute myeloid leukemias (AML). Patients and Methods Individual patient data–based meta-analysis was performed on 392 adults (median age, 42 years; range, 16 to 60 years) with CBF AML (t(8;21), n = 191; inv(16), n = 201) treated between 1993 and 2002 in prospective German AML treatment trials. Results RFS was 60% and 58% and OS was 65% and 74% in the t(8;21) and inv(16) groups after 3 years, respectively. For postremission therapy, intention-to-treat analysis revealed no difference between intensive chemotherapy and autologous transplantation in the t(8;21) group and between chemotherapy, autologous, and allogeneic transplantation in the inv(16) group. In the t(8;21) group, significant prognostic variables for longer RFS and OS were lower WBC and higher platelet counts; loss of the Y chromosome in male patients was prognostic for shorter OS. In the inv(16) group, trisomy 22 was a significant prognostic variable for longer RFS. For patients who experienced relapse, second complete remission rate was significantly lower in patients with t(8;21), resulting in a significantly inferior survival duration after relapse compared with patients with inv(16). Conclusion We provide novel prognostic factors for CBF AML and show that patients with t(8;21) who experience relapse have an inferior survival duration.
- Published
- 2004
32. Risk-adapted induction and consolidation therapy in adults with de novo AML aged =�60�years: results of a prospective multicenter trial
- Author
-
Lothar Bergmann, G. Schlimok, Dieter Hoelzer, Walter Fiedler, Hartmut Kirchner, Aruna Raghavachar, Lucien Noens, Arnold Ganser, Jürgen Krauter, Michael Lübbert, Renate Arnold, and Gerhard Heil
- Subjects
Adult ,Amsacrine ,Male ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Risk Assessment ,Gastroenterology ,Internal medicine ,Multicenter trial ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Prospective Studies ,Etoposide ,Chemotherapy ,Hematology ,business.industry ,Daunorubicin ,Remission Induction ,Cytarabine ,Myeloid leukemia ,General Medicine ,Middle Aged ,Prognosis ,Combined Modality Therapy ,Survival Analysis ,Autotransplantation ,Surgery ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Karyotyping ,Female ,Bone marrow ,Idarubicin ,business ,Stem Cell Transplantation ,Allotransplantation ,medicine.drug - Abstract
We treated 305 de novo acute myeloid leukemia (AML) patients aged/=60 years with risk-adapted therapy. Patients with CBF leukemias or normal karyotype and good response to induction I [/=5% bone marrow (BM) blasts on day 15] were considered standard risk (SR), all others as high risk (HR). Patients with t(15;17) were excluded. Chemotherapy comprised double induction followed by early consolidation. As late consolidation, SR patients received high-dose cytarabine/daunorubicin (AraC/DNR). SR patients with normal karyotype were allotransplanted from HLA-matched siblings. HR patients were allotransplanted or if no sibling donor was available autotransplanted with peripheral blood progenitor cells (PBSC) harvested after early consolidation. 89% of the SR and 60% of the HR patients achieved CR. The continuous complete remission (CCR) rate at 80 months (median follow-up: 48 months) was 48% for SR and 32% for HR. The CCR rate was 54% for t(8;21), 47% for normal karyotype, and 33% for inv(16) patients. In the HR group, the CCR rate did not differ significantly for patients with bad response to IVA-I, unfavorable karyotype, or both. Forty-five HR patients were autotransplanted (n=20) or allotransplanted (n=25). The probability of CCR was 44% for autotransplantation vs 33% for allotransplantation. In conclusion, our risk-adapted strategy produced encouraging results in SR patients. Early response to therapy is a strong prognostic factor that predicts the probability of CR and long-term outcome.
- Published
- 2004
33. Expression of the p14ARF tumor suppressor predicts survival in acute myeloid leukemia
- Author
-
Carsten Müller-Tidow, Packeisen J, Th. Büchner, Arnold Ganser, K. Kügler, Horst Buerger, W.-D. Ludwig, Wolfgang E. Berdel, Achim Heinecke, Metzelder Sk, Adigüzel G, Hubert Serve, Joachim Schwäble, Gerhard Heil, and Björn Steffen
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Tumor suppressor gene ,Biology ,p14arf ,Bone Marrow ,Proto-Oncogene Proteins ,Internal medicine ,Tumor Suppressor Protein p14ARF ,medicine ,Cluster Analysis ,Humans ,RNA, Neoplasm ,Aged ,Hematology ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Cell Cycle ,Nuclear Proteins ,Cancer ,Myeloid leukemia ,Proto-Oncogene Proteins c-mdm2 ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,Leukemia ,medicine.anatomical_structure ,Oncology ,Leukemia, Myeloid ,Case-Control Studies ,Acute Disease ,Cancer research ,Female ,Bone marrow ,Tumor Suppressor Protein p53 ,Cyclin A1 - Abstract
Cell cycle aberrations are associated with therapy outcome in many types of cancer. We analyzed mRNA expression levels of 18 cell cycle-related genes in bone marrow samples from 78 acute myeloid leukemia (AML) patients and six controls using high-throughput quantitative RT-PCR. Samples of AML patients contained significantly increased mRNA expression levels of the mdm2 and c-myc oncogenes. Also, the average expression levels of p14ARF and p16INK4A were higher in patient samples compared to controls. Leukemic blasts and control bone marrow samples did not differ significantly in the expression levels of proliferation-associated genes such as cyclin A2 and pcna. When single genes were analyzed for prognostic significance in Kaplan-Meier and Cox regression analyses, a low p14ARF level emerged as a strong and independent predictor for poor survival (P=0.04 and 0.029). Subsequently, p14ARF mRNA levels were analyzed in a second, independent patient population (n=57). Again, low p14ARF levels were associated with a worse outcome. Finally, immunohistochemistry analysis of AML tissue arrays confirmed the widespread expression of c-myc and p14ARF in AML on the protein level. Taken together, the expression of the p53 regulators mdm2 and p14ARF are altered in AML, and low p14ARF levels indicate a poor prognosis.
- Published
- 2004
34. Evidence for allelic evolution of C/EBPalpha mutations in acute myeloid leukaemia
- Author
-
Walter Verbeek, Gerhard Heil, Jens Tiesmeier, Hubert Serve, Jürgen Krauter, Arnold Ganser, Carsten Müller-Tidow, and Andreas Czwalinna
- Subjects
Biallelic Mutation ,Enhancer binding ,Point mutation ,digestive, oral, and skin physiology ,Mutation (genetic algorithm) ,Cancer research ,Clone (cell biology) ,Hematology ,Allele ,Biology ,Gene ,Frameshift mutation - Abstract
Transcription factor CCAAT/enhancer binding protein alpha (C/EBPalpha) is mutated in 6-10% of patients with acute myeloid leukaemia (AML). Recently, we reported the emergence of an N-terminal C/EBPalpha mutation after chemotherapy in a patient with secondary AML. The clone carrying the mutation became the dominant clone at relapse. This observation prompted us to compare the C/EBPalpha mutational status of 26 de novo non-core binding factor AML patients at diagnosis and at relapse after induction and consolidation chemotherapy. Four mutations in the C/EBPalpha gene were identified in two out of 26 patients. In both these cases, a biallelic mutation was present at diagnosis and at relapse: an amino-terminal frameshift mutation and a mutation of the fork/leucine finger 1 region. In patient 1, the amino-terminal frameshift mutation was duplicated and found on both alleles at relapse. In patient 2, the amino-terminal frameshift mutation and a mutation in the fork region were found either alone or combined on the same allele, suggesting a subclone formation. None of the patients without a C/EBPalpha mutation at diagnosis showed a mutation at relapse. This is the first report of an evolution of the C/EBPalpha gene between diagnosis and relapse in AML.
- Published
- 2003
35. AML1/MTG8 oncogene suppression by small interfering RNAs supports myeloid differentiation of t(8;21)-positive leukemic cells
- Author
-
Matthias John, Gerhard Heil, Olaf Heidenreich, Philipp Hadwiger, Juergen Krauter, Alfred Nordheim, Heidemarie Riehle, and Hans-Peter Vornlocher
- Subjects
Small interfering RNA ,Oncogene Proteins, Fusion ,Chromosomes, Human, Pair 21 ,Cellular differentiation ,Immunology ,Transitive RNA interference ,Receptor, Macrophage Colony-Stimulating Factor ,Transfection ,Biochemistry ,Translocation, Genetic ,Transforming Growth Factor beta1 ,RUNX1 Translocation Partner 1 Protein ,Transforming Growth Factor beta ,hemic and lymphatic diseases ,Enhancer binding ,CCAAT-Enhancer-Binding Protein-alpha ,Tumor Cells, Cultured ,Humans ,RNA, Messenger ,RNA, Small Interfering ,neoplasms ,Tumor Stem Cell Assay ,Cell Size ,Cholecalciferol ,CD11b Antigen ,Ccaat-enhancer-binding proteins ,Oncogene ,biology ,Gene Expression Regulation, Leukemic ,Myeloid leukemia ,Cell Differentiation ,Cell Biology ,Hematology ,Transforming growth factor beta ,Molecular biology ,Neoplasm Proteins ,Leukemia, Myeloid ,Drug Design ,Acute Disease ,Core Binding Factor Alpha 2 Subunit ,Cancer research ,biology.protein ,RNA Interference ,Chromosomes, Human, Pair 8 ,Transcription Factors - Abstract
The translocation t(8;21) yields the leukemic fusion gene AML1/MTG8 and is associated with 10%-15% of all de novo cases of acute myeloid leukemia. We demonstrate the efficient and specific suppression of AML1/MTG8 by small interfering RNAs (siRNAs) in the human leukemic cell lines Kasumi-1 and SKNO-1. siRNAs targeted against the fusion site of the AML1/MTG8 mRNA reduce the levels of AML1/MTG8 without affecting the amount of wild-type AML1. These data argue against a transitive RNA interference mechanism potentially induced by siRNAs in such leukemic cells. Depletion of AML1/MTG8 correlates with an increased susceptibility of both Kasumi-1 and SKNO-1 cells to tumor growth factor β1 (TGFβ1)/vitamin D3–induced differentiation, leading to increased expression of CD11b, macrophage colony-stimulating factor (M-CSF) receptor, and C/EBPα (CAAT/enhancer binding protein). Moreover, siRNA-mediated AML1/MTG8 suppression results in changes in cell shape and, in combination with TGFβ1/vitamin D3, severely reduces clonogenicity of Kasumi-1 cells. These results suggest an important role for AML1/MTG8 in preventing differentiation, thereby propagating leukemic blast cells. Therefore, siRNAs are promising tools for a functional analysis of AML1/MTG8 and may be used in a molecularly defined therapeutic approach for t(8;21)-positive leukemia.
- Published
- 2003
36. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent lymphomas: Nine-year updated results from the StiL NHL1 study
- Author
-
Heinz Dürk, Georg Maschmeyer, Harald Ballo, Manfred Welslau, Eckhart Weidmann, Christina Balser, Ulrich Kaiser, Christoph Losem, Alexander Burchardt, Wolfram Brugger, Gerhard Heil, Frank Kauff, Ulrich von Gruenhagen, Wolfgang Blau, Martina Stauch, Andrea Heider, Mathias J. Rummel, Arnold Ganser, and Juergen Barth
- Subjects
Bendamustine ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,CHOP ,medicine.disease ,Surgery ,First line treatment ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Clinical endpoint ,Rituximab ,Mantle cell lymphoma ,In patient ,Indolent lymphomas ,business ,030215 immunology ,medicine.drug - Abstract
7501 Background: This multicenter, randomized, phase III study compared B-R and CHOP-R as first-line treatment in patients (pts) with indolent lymphomas or mantle cell lymphoma and was first published in The Lancet in 2013. The final analysis demonstrated a significantly prolonged progression-free survival (PFS) in the B-R group compared to the CHOP-R group, with a median PFS of 69.5 vs. 31.2 months, respectively. In the current analysis, we present updated results for overall survival (OS), time-to-next-treatment (TTNT), and secondary malignancies (sNPL) with a median follow-up of 113 months for patients with indolent lymphomas (excluding MCL). Methods: 447 pts with indolent lymphomas were randomized to receive B-R or CHOP-R for a maximum of 6 cycles. The primary endpoint was PFS; secondary endpoints included OS, TTNT, and sNPL. Results: Patient characteristics were well balanced between arms; median age was 64 years. The difference in OS between the two treatment arms was not statistically significant, with 60 deaths in the B-R group vs 68 deaths with CHOP-R (HR 0.82, 95% CI 0.58 – 1.15, p = 0.249). The estimated 10-year survival rates were 71% for B-R and 66% for CHOP-R. TTNT was significantly prolonged with B-R compared with CHOP-R (HR 0.52, 95% CI 0.38 – 0.69, p < 0.001). Median TTNT was not yet reached in the B-R group (95% CI 124.9 – n.y.r) vs. 56 months in the CHOP-R group (95% CI 39.1 – 82.0). Patients treated initially with B-R needed fewer second-line treatments due to disease progression compared to CHOP-R treated pts: 73 pts (34%) in the B-R group received salvage treatment compared with 106 pts (52%) in the CHOP-R group. For B-R pts, CHOP-R was used as second-line therapy 26 times (36%), whereas B-R was used for pts initially treated with CHOP-R 49 times (46%). 36 pts with sNPL were observed in the B-R group compared with 39 in the CHOP-R group, with 7 hematological malignancies in both groups to date. Conclusions: In pts with previously untreated indolent lymphomas, B-R demonstrates a PFS and TTNT benefit over CHOP-R. Clinical trial information: NCT00991211.
- Published
- 2017
37. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial
- Author
-
Jens Stieler, Uwe Pelzer, Tim F. Greten, Jörg Seraphin, Volker Lakner, Gerhard Heil, Ingo Schwaner, Helmut Oettle, Hanno Riess, Martin Görner, Sven Bischoff, Marianne Sinn, Matthias Mölle, and Bernd Dörken
- Subjects
Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Organoplatinum Compounds ,Leucovorin ,Deoxycytidine ,law.invention ,Folinic acid ,Randomized controlled trial ,law ,Pancreatic cancer ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,Aged ,Aged, 80 and over ,business.industry ,Middle Aged ,medicine.disease ,Survival Analysis ,Gemcitabine ,Oxaliplatin ,Clinical trial ,Pancreatic Neoplasms ,Regimen ,Treatment Outcome ,Fluorouracil ,Drug Resistance, Neoplasm ,Disease Progression ,Female ,business ,medicine.drug - Abstract
Purpose To assess the efficacy of a second-line regimen of oxaliplatin and folinic acid–modulated fluorouracil in patients with advanced pancreatic cancer who have experienced progression while receiving gemcitabine monotherapy. Patients and Methods A randomized, open-label, phase III study was conducted in 16 institutions throughout Germany. Recruitment ran from January 2004 until May 2007, and the last follow-up concluded in December 2012. Overall, 168 patients age 18 years or older who experienced disease progression during first-line gemcitabine therapy were randomly assigned to folinic acid and fluorouracil (FF) or oxaliplatin and FF (OFF). Patients were stratified according to the presence of metastases, duration of first-line therapy, and Karnofsky performance status. Results Median follow-up was 54.1 months, and 160 patients were eligible for the primary analysis. The median overall survival in the OFF group (5.9 months; 95% CI, 4.1 to 7.4) versus the FF group (3.3 months; 95% CI, 2.7 to 4.0) was significantly improved (hazard ratio [HR], 0.66; 95% CI, 0.48 to 0.91; log-rank P = .010). Time to progression with OFF (2.9 months; 95% CI, 2.4 to 3.2) versus FF (2.0 months; 95% CI, 1.6 to 2.3) was significantly extended also (HR, 0.68; 95% CI, 0.50 to 0.94; log-rank P = .019). Rates of adverse events were similar between treatment arms, with the exception of grades 1 to 2 neurotoxicity, which were reported in 29 patients (38.2%) and six patients (7.1%) in the OFF and FF groups, respectively (P < .001). Conclusion Second-line OFF significantly extended the duration of overall survival when compared with FF alone in patients with advanced gemcitabine-refractory pancreatic cancer.
- Published
- 2014
38. Valproic acid in combination with all-trans retinoic acid and intensive therapy for acute myeloid leukemia in older patients
- Author
-
Michela Tassara, Stephan Kremers, Claus-Henning Köhne, Heinz Kirchen, Richard F. Schlenk, Richard Greil, Martin Göttlicher, Mark Ringhoffer, Wolfram Brugger, Peter Brossart, Heinz-A. Horst, Mohammed Wattad, Aruna Raghavachar, Peter Paschka, Katharina Götze, Gerhard Heil, Verena I. Gaidzik, Hartmut Döhner, Axel Matzdorff, David Nachbaur, Gerhard Held, Gerald Wulf, Hans Günter Derigs, Elisabeth Koller, and Konstanze Döhner
- Subjects
Male ,medicine.medical_specialty ,Myeloid ,Critical Care ,medicine.medical_treatment ,Immunology ,Antineoplastic Agents ,Tretinoin ,Pharmacology ,Biochemistry ,Gastroenterology ,Disease-Free Survival ,Internal medicine ,medicine ,Idarubicin ,Humans ,Enzyme Inhibitors ,Survival rate ,Aged ,Aged, 80 and over ,Chemotherapy ,Valproic Acid ,business.industry ,Cytarabine ,Myeloid leukemia ,Nuclear Proteins ,Drug Synergism ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Survival Rate ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Mutation ,lipids (amino acids, peptides, and proteins) ,Female ,business ,Nucleophosmin ,medicine.drug ,Follow-Up Studies - Abstract
The outcome of patients with acute myeloid leukemia who are older than 60 years has remained poor because of unfavorable disease characteristics and patient-related factors. The randomized German-Austrian AML Study Group 06-04 protocol was designed on the basis of in vitro synergistic effects of valproic acid (VPA) and all-trans retinoic acid with chemotherapy. Between 2004 and 2006, 186 patients were randomly assigned to receive 2 induction cycles with idarubicin, cytarabine, and all-trans retinoic acid either with VPA or without (STANDARD). In all patients, consolidation therapy was intended. Complete remission rates after induction tended to be lower in VPA compared with STANDARD (40% vs 52%; P = .14) as a result of a higher early death rate (26% vs 14%; P = .06). The main toxicities attributed to VPA were delayed hematologic recovery and grade 3/4 infections, observed predominantly during the second induction cycle. After restricting VPA to the first induction cycle and reducing the dose of idarubicin, these toxicities dropped to rates observed in STANDARD. After a median follow-up time of 84 months, event-free and overall survival were not different between the 2 groups (P = .95 and P = .57, respectively). However, relapse-free-survival was significantly superior in VPA compared with STANDARD (24.4% vs 6.4% at 5 years; P = .02). Explorative subset analyses revealed that AML with mutated Nucleophosmin 1 (NPM1) may particularly benefit from VPA. This trial was registered at www.clinicaltrials.gov as #NCT00151255.
- Published
- 2014
39. Cleavage of AML1/MTG8 by asymmetric hammerhead ribozymes
- Author
-
Stefan Nagel, Frank E. Münchberg, Alfred Nordheim, Olaf Heidenreich, Mara Szyrach, Heidemarie Riehle, Gerhard Heil, and Jürgen Krauter
- Subjects
Ribozyme ,RNA ,Biology ,Stem-loop ,Biochemistry ,Molecular biology ,RNA silencing ,hemic and lymphatic diseases ,biology.protein ,Mammalian CPEB3 ribozyme ,Hairpin ribozyme ,neoplasms ,Ligase ribozyme ,VS ribozyme - Abstract
The chromosomal translocation t(8;21) is one of the most frequent aberrations associated with acute myeloid leukaemia. It joins the 5′ section of the AML1 gene with the almost complete open reading frame of MTG8 (ETO). The resulting fusion RNA represents a leukaemia-specific target for antisense/ribozyme inhibition. We tested several asymmetric hammerhead ribozymes targeted against the fusion site for their ability to cleave the AML1/MTG8 RNA at low magnesium concentrations. One ribozyme cleaves AML1/MTG8 RNA with high catalytic efficiency without binding or cleaving the wild-type AML1 transcript. The presence of cellular RNA does not affect the cleavage. Injection of AML1/MTG8 RNA and ribozyme RNA into Xenopus eggs or oocytes causes a specific reduction of AML1/MTG8 protein expression. Asymmetric anti-AML1/MTG8 ribozymes may be valuable modulators of AML1/MTG8 expression in leukaemic cells.
- Published
- 2001
40. Impact of Age and Midostaurin-Dose on Response and Outcome in Acute Myeloid Leukemia with FLT3-ITD: Interim-Analyses of the AMLSG 16-10 Trial
- Author
-
Daniel Schöndube, Michael Girschikofsky, Richard F. Schlenk, Elisabeth Lange, Gerhard Heil, Felicitas Thol, Frank Griesinger, Hartmut Döhner, Gerhard Held, Carsten Schwänen, David Nachbaur, Daniela Weber, Axel Benner, Peter Reimer, Volker Runde, Arnold Ganser, Heinz-August Horst, Bernd Hertenstein, Wolff Schmiegel, Thomas Südhoff, Thomas Kindler, Konstanze Döhner, Maria-Veronica Teleanu, Peter Brossart, Frauke Theis, Peter Paschka, Beate Schultheis, Mark Ringhoffer, Stephan Kremers, Martin Griesshammer, Walter Fiedler, Uwe M. Martens, Jürgen Krauter, Maike de Wit, Andrea Kündgen, Jörg Westermann, Helmut R. Salih, Hartmut Kirchner, Anja Münnich, Doris Kraemer, Richard Greil, Andreas L. Petzer, Michael Heuser, Hans-Juergen Salwender, Verena I. Gaidzik, Nadezda Basara, Jochen Greiner, Gerald Wulf, Elisabeth Koller, Katharina Goetze, Tanja Hesse, Holger Hebart, Michael Lübbert, and Heinz Kirchen
- Subjects
Posaconazole ,medicine.medical_specialty ,business.industry ,Immunology ,Induction chemotherapy ,Cell Biology ,Hematology ,Biochemistry ,Chemotherapy regimen ,3. Good health ,Transplantation ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,Maintenance therapy ,030220 oncology & carcinogenesis ,Internal medicine ,Cytarabine ,medicine ,Cumulative incidence ,Midostaurin ,business ,030215 immunology ,medicine.drug - Abstract
Background: Internal tandem duplications (ITD) in the receptor tyrosine kinase FLT3 occur in roughly 25% of younger adult patients (pts) with acute myeloid leukemia (AML). The multi-targeted kinase inhibitor midostaurin combined with intensive chemotherapy has shown activity against AML with FLT3 mutations. However, toxicity and potential drug-drug interactions with strong CYP3A4 inhibitors such as posaconazole may necessitate dose reduction. Aims: To evaluate the impact of age and midostaurin dose-adaptation after intensive induction chemotherapy on response and outcome in AML with FLT3-ITD within the AMLSG 16-10 trial (NCT01477606). Methods: The study included adult pts (age 18-70 years (yrs)) with newly diagnosed FLT3-ITD positive AML enrolled in the ongoing single-arm phase-II AMLSG 16-10 trial. Pts with acute promyelocytic leukemia were not eligible. The presence of FLT3-ITD was analyzed within our diagnostic study AMLSG-BiO (NCT01252485) by Genescan-based DNA fragment-length analysis. Induction therapy consisted of daunorubicin (60 mg/m², d1-3) and cytarabine (200 mg/m², continuously, d1-7); midostaurin 50 mg bid was applied from day 8 until 48h before start of the next treatment cycle. A second cycle was allowed in case of partial remission (PR). For consolidation therapy, pts proceeded to allogeneic hematopoietic-cell transplantation (HCT) as first priority; if alloHCT was not feasible, pts received three cycles of age-adapted high-dose cytarabine (HDAC) in combination with midostaurin starting on day 6. In all pts one-year maintenance therapy with midostaurin was intended. The first patient entered the study in June 2012 and in April 2014, after recruitment of n=147 pts, the study was amended including a sample size increase to 284 pts and a dose reduction to 12.5% of the initial dose of midostaurin in case of co-medication with strong CYP3A4 inhibitors (e.g. posaconazole). This report focuses on age and the comparison between the first (n=147) and the second cohort (n=137) of the study in terms midostaurin dose-adaptation. Results: Patient characteristics were as follows: median age 54 yrs (range, 18-70; younger, 68% < 60 yrs; older, 32% ≥ 60 yrs); median white cell count 44.7G/l (range 1.1-1543 G/l); karyotype, n=161 normal, n=16 high-risk according to ELN recommendations; mutated NPM1 n=174 (59%). Data on response to first induction therapy were available in 277 pts; complete remission (CR) including CR with incomplete hematological recovery (CRi) 60%, PR 20%, refractory disease (RD) 15%, and death 5%. A second induction cycle was given in 54 pts. Overall response (CR/CRi) after induction therapy was 76% (76%, younger; 76%, older) and death 6% (4%, younger; 10% older). The dose of midostaurin during first induction therapy was reduced in 53% and 71% of patients in cohort-1 and cohort-2, respectively. Reasons for dose reduction were in 58% and 49% toxicity, and in 9% and 23% co-medication in cohort-1 and cohort-2, respectively. No difference in response to induction therapy was noted between cohorts (p=0.81). Median follow-up was 18 months. Overall 146 pts received an alloHCT, 128 in first CR (n=94 younger, n=34 older; n=92 from a matched unrelated and n=36 from a matched related donor). In pts receiving an alloHCT within the protocol in median two chemotherapy cycles were applied before transplant (range 1-4). The cumulative incidence of relapse (CIR) and death after transplant were 13% (SE 3.2%) and 16% (SE 3.5%) without differences (p=0.97, p=0.41, respectively) between younger and older patients. So far maintenance therapy was started in 86 pts, 61 pts after alloHCT and 25 pts after HDAC. Fifty-five adverse events 3°/4° were reported being attributed to midostaurin; cytopenias after alloHCT were the most frequent (29%). CIR in patients starting maintenance therapy was 20% one year after start of maintenance without difference between alloHCT and HiDAC (p=0.99). In addition, no difference in CIR was identified in patients after consolidation with alloHCT or HDAC according to dose reduction of midostaurin during first induction therapy (p=0.43, p=0.98, respectively). Median overall survival was 25 months (younger, 26 months; older 23 months; p=0.15). Conclusions: The addition of midostaurin to intensive induction therapy and as maintenance after alloHCT or HDAC is feasible and effective without an impact of age and dose adaptation on outcome. Disclosures Schlenk: Amgen: Research Funding; Pfizer: Honoraria, Research Funding. Fiedler:GSO: Other: Travel; Pfizer: Research Funding; Kolltan: Research Funding; Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding; Gilead: Other: Travel; Ariad/Incyte: Consultancy; Novartis: Consultancy; Teva: Other: Travel. Lübbert:Celgene: Other: Travel Funding; Janssen-Cilag: Other: Travel Funding, Research Funding; Ratiopharm: Other: Study drug valproic acid. Greil:Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Merck: Honoraria; AstraZeneca: Honoraria; Boehringer-Ingelheim: Honoraria; GSK: Research Funding; Ratiopharm: Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria; Pfizer: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Sanofi Aventis: Honoraria; Eisai: Honoraria; Amgen: Honoraria, Research Funding. Greiner:BMS: Research Funding. Paschka:ASTEX Pharmaceuticals: Consultancy; Novartis: Consultancy; Medupdate GmbH: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer Pharma GmbH: Honoraria; Celgene: Honoraria. Heuser:Bayer Pharma AG: Research Funding; Karyopharm Therapeutics Inc: Research Funding; Novartis: Consultancy, Research Funding; Celgene: Honoraria; Pfizer: Research Funding; BerGenBio: Research Funding; Tetralogic: Research Funding.
- Published
- 2016
41. Condensed Versus Standard Schedule of High-Dose Cytarabine Consolidation Therapy with Pegfilgrastim Growth Factor Support in Acute Myeloid Leukemia
- Author
-
Richard F. Schlenk, Daniela Weber, Volker Runde, Jürgen Krauter, Gudrun Russ, Bernd Hertenstein, Andrea Kündgen, Thomas Kindler, Martin Bentz, Peter Brossart, Walter Fiedler, Hartmut Döhner, Michael Lübbert, Sonia Jaramillo, Heinz-A. Horst, Axel Benner, M. Wattad, Hans Martin, K Döhner, Gerhard Heil, Hans-Juergen Salwender, Katharina Götze, Claus-Henning Köhne, Gudrun Göhring, Stephan Kremers, Arnold Ganser, Heinz Kirchen, Helmut R. Salih, Gerhard Held, Gerald Wulf, Elisabeth Koller, Aruna Raghavachar, and David Nachbaur
- Subjects
Male ,Oncology ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Gastroenterology ,Biochemistry ,Polyethylene Glycols ,0302 clinical medicine ,Maintenance therapy ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Cytarabine ,Myeloid leukemia ,Hematology ,Middle Aged ,Chemotherapy regimen ,3. Good health ,Survival Rate ,Leukemia, Myeloid, Acute ,Leukemia ,030220 oncology & carcinogenesis ,Original Article ,Female ,Pegfilgrastim ,medicine.drug ,Adult ,medicine.medical_specialty ,Adolescent ,Filgrastim ,Immunology ,Platelet Transfusion ,Disease-Free Survival ,03 medical and health sciences ,Internal medicine ,Humans ,Idarubicin ,Survival rate ,Chemotherapy ,business.industry ,Daunorubicin ,Consolidation Chemotherapy ,Cell Biology ,Length of Stay ,medicine.disease ,Surgery ,Transplantation ,Platelet transfusion ,business ,030215 immunology - Abstract
Background: The concept of intensive post-remission chemotherapy in acute myeloid leukemia (AML) is based on the observation that despite achievement of a first complete remission (CR) after intensive induction therapy virtually all patients relapse in the absence of further treatment. Moreover, randomized studies showed that intensive post-remission consolidation chemotherapy was superior to prolonged low-dose maintenance therapy in younger patients. With regard to consolidation therapy, the landmark study conducted by the Cancer and Leukemia Group B established the current standard for patients aged 60 years and younger with high-dose cytarabine (HDAC) 3g/m² bidaily on days days 1, 3, and 5. Aims: to compare a compressed schedule of high-dose cytarabine (HDAC) on days 1, 2, and 3 with the standard HDAC given on days 1, 3, and 5 as well as to evaluate the prophylactic use of pegfilgrastim after chemotherapy in patients in first CR receiving repetitive consolidation cycles for acute myeloid leukemia. Methods: Patients (18 to 60 years) were accrued between 2004 and 2009. They were randomized up-front 1:10 between the standard German intergroup-arm (Büchner et al. J Clin Oncol. 2012;30:3604-10) and the AMLSG 07-04 study (NCT00151242). Induction therapy in the AMLSG 07-04 study consisted of two cycles of idarubicin, cytarabine and etoposide +/- all-trans retionoic acid (ATRA) and +/- valproic acid (VPA) in a 2 by 2 factorial design. After recruitment of 392 patients the randomization for VPA was stopped due to toxicity. For consolidation therapy, patients with high-risk AML, defined either by high-risk cytogenetics or induction failure, were assigned to receive allogeneic hematopoietic cell transplantation from a matched related or unrelated donor. All other patients were assigned to 3 cycles of HDAC from 2004 to November 2006 with cytarabine 3g/m² bidaily, on days 1, 3, 5 and pegfilgrastim on day 10 (HDAC-135) and from December 2006 to 2009 patients were treated with a condensed schedule with cytarabine 3g/m², bidaily, on days 1,2,3 and pegfilgrastim on day 8 (HDAC-123). Patients randomized into the German AML intergroup arm were treated for consolidation therapy with cytarabine 3g/m² bid on days 1, 3, 5 (HDAC-135) without prophylactic growth-factor support. Results:Overall 568 patients receiving 1376 consolidation cycles were included into the study. According to up-front randomization 41 were treated with HDAC-135 without prophylactic growth factor support in the German AML Intergroup protocol, 135 with HDAC-135 and 392 with HDAC-123 with intended prophylactic pegfilgrastim at day 10 and 8, respectively, in the AMLSG 07-04 protocol. Time from start to chemotherapy until hematological recovery with leukocytes >1.0G/l and neutrophils >0.5G/l was significantly (p Conclusion: Data from our study suggest that consolidation therapy with a condensed schedule of HDAC-123 is superior to that of standard HDAC-135 in terms of faster hematological recovery, lower infection rate and fever days in hospital. In addition, the administration of one dose of pegfilgrastim after chemotherapy further shortened hematological recovery and reduced infection rate. Importantly, similar efficacy in terms of relapse-free and overall survival rates after HDAC-123 and HDAC-135 were observed. Disclosures Lübbert: Ratiopharm: Other: Study drug valproic acid; Janssen-Cilag: Other: Travel Funding, Research Funding; Celgene: Other: Travel Funding. Fiedler:GSO: Other: Travel; Pfizer: Research Funding; Teva: Other: Travel; Gilead: Other: Travel; Novartis: Consultancy; Ariad/Incyte: Consultancy; Kolltan: Research Funding; Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding. Schlenk:Amgen: Research Funding; Pfizer: Honoraria, Research Funding.
- Published
- 2016
42. Positron Emission Tomography (PET) Guided Therapy of Aggressive Lymphomas - Interim PET-Based Outcome Prediction and Treatment Changes in Patients with T Cell Lymphomas Participating in the PETAL Trial
- Author
-
Claudia Ose, Heinz Dürk, Agnieszka Korfel, Matthias Sandmann, Regina Moeller, Anke Franzke, Gerhard Heil, Jörg Kotzerke, Stefan Wilop, Wolfram Klapper, Matthias Weckesser, Winfried Brenner, Dirk Behringer, Andreas Hüttmann, Christiane Kreisel-Büstgens, Otto Kloke, Gabriele Prange-Krex, Aristoteles Giagounidis, Dirk Strumberg, Uwe M. Martens, Stefan Mahlmann, Karl-Heinz Jöckel, Thomas Krohn, Frank Kroschinsky, Uwe Haberkorn, Martin Freesmeyer, Bernd Hertenstein, Heinz-Gert Hoeffkes, Tu-Anh Dang, Paul La Rosée, Guido Trenn, Michael Heike, Andreas Hertel, Christiane Franzius, Ulrich Duehrsen, Hubertus Hautzel, Dieter Hoelzer, Marcus Brinkmann, Rolf M. Mesters, Jan Rekowski, Volker Runde, Frank M. Bengel, and Stefan P. Müller
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Follicular lymphoma ,Cell Biology ,Hematology ,CHOP ,medicine.disease ,Biochemistry ,030218 nuclear medicine & medical imaging ,Lymphoma ,03 medical and health sciences ,Regimen ,0302 clinical medicine ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,Multicenter trial ,Medicine ,Rituximab ,business ,Anaplastic large-cell lymphoma ,Diffuse large B-cell lymphoma ,medicine.drug - Abstract
Introduction: The PETAL trial is a multicenter randomized controlled study for patients with aggressive lymphomas of diverse histologies (EudraCT 2006-001641-33, NCT00554164). In the study population as a whole interim PET (iPET) reliably predicted time to treatment failure (TTTF) and overall survival (OS). Interim PET-based treatment changes, however, had no impact on outcome (ASH 2014, abstract 391). Here we report the exploratory analysis for peripheral T cell lymphomas (PTCL). Methods: Pts. aged 18 to 80 yrs. with newly diagnosed aggressive lymphomas and a positive baseline PET received 2 cycles of rituximab (R), cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) followed by iPET. R was omitted in pts. with CD20-negative lymphomas. The conditions of iPET were strictly defined: 3-week interval between the 2nd (R-)CHOP cycle and iPET to avoid inflammatory reactions (Eur J Nucl Med Mol Imaging 30:682, 2003), no G-CSF after the 2nd cycle to avoid altered glucose biodistribution (J Nucl Med 47:950, 2006), standardized uptake value (SUV)-based PET interpretation to improve reproducibility (favorable iPET response: reduction of maximum SUV by > 66 % compared to baseline; J Nucl Med 48:1626, 2007). PTCL pts. with CD20-negative lymphomas and a favorable iPET uniformly received 4 additional cycles of CHOP (part A of the trial). Pts. with an unfavorable iPET were randomized to continue CHOP for 6 additional cycles or receive 6 blocks of a more complex methotrexate-, cytarabine- and etoposide-based regimen originally designed for Burkitt lymphoma (Blood 124: 3870, 2014; part B). Sample size of the entire study population was based on the empirically derived assumption that treatment failure after 2 yrs. (progression, relapse, treatment discontinuation due to toxicity, start of alternative therapy, death of any cause) could be improved from 30 % to 45 % in part B (alpha=0.05, power=0.8). Secondary endpoints included OS and toxicity. Results: Fifty-seven oncological centers and 23 nuclear medicine institutions participated in the trial. Between 2007 and 2012 1072 pts. were registered, and 862 (80.4 %) had a positive baseline PET, received 2 cycles (R-)CHOP, underwent iPET and were allocated to one of the post-iPET treatment arms detailed above. Reference pathology was available in 98 %, and median follow-up is 52 months. All in all, there were 76 pts. (8.8 % of all treated pts.) with T-cell lymphomas of whom 21 had ALK+ anaplastic large cell lymphoma (ALCL), 13 ALK- ALCL, 18 angioimmunoblastic T-cell lymphoma (AITL) and 20 PTCL not otherwise specified (NOS). Interim PET was favorable in 57 pts. (75 %) and unfavorable in 19 pts. with T-cell lymphomas (25 %). It was highly predictive of outcome, TTTF and OS being significantly higher in part A than B (2-year probability for TTTF: 63 % vs. 21 %; univariate hazard ratio (HR) for B 3.4, 95 % confidence interval (CI) 1.8 - 6.4, p TTTF (2-year probability: 81 % vs. 46 % vs. 49 % vs. 35 %; p=0.0110) and OS (90 % vs. 69 % vs. 52 % vs. 50 %; p=0.0026) were better in ALK+ ALCL than in ALK- ALCL, AITL or PTCL NOS. In pts. with an unfavorable iPET response, a switch from CHOP to the alternative regimen failed to improve TTTF or OS. The latter was associated with more frequent grade 3/4 neutropenia (40 % vs. 0 % vs. 11 %, p=0.0279), thrombocytopenia (70 % vs. 33 % vs. 23 %; p=0.0106), infection (60 % vs. 44 % vs. 18 %, p=0.0057) and mucositis (40 % vs. 33 % vs. 4 %, p=0.0025) as compared to 6 or 4 post-iPET cycles of CHOP, respectively, but treatment-related mortality was similar in all treatment arms (2 vs. 1 vs. 2 deaths). Conclusion: In this large multicenter trial iPET proved highly predictive of outcome in PTCL. A favorable iPET was found in 75 % of pts., and this was associated with long-term survival in about 70 %. In pts. with an unfavorable iPET response, outcome was dismal and could not be improved by switching to a more aggressive regimen. Novel strategies are required for PTCL pts. failing to respond to the first 2 cycles of CHOP. Disclosures Hüttmann: Gilead, Amgen: Other: Travel cost; Bristol-Myers Squibb, Takeda, Celgene, Roche: Honoraria. Giagounidis:Celgene Corporation: Consultancy. Klapper:Roche, Novartis, Amgen, Takeda: Research Funding. Duehrsen:Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding.
- Published
- 2016
43. Detection and quantification ofCBFB/MYH11 fusion transcripts in patients with inv(16)-positive acute myeloblastic leukemia by real-time RT-PCR
- Author
-
Jürgen Krauter, Donald Bunjes, Mike P. Wattjes, Arnold Ganser, Olaf Heidenreich, Stefan Nagel, Wolf Hoellge, and Gerhard Heil
- Subjects
Cancer Research ,Neoplasm, Residual ,Oncogene Proteins, Fusion ,Acute myeloblastic leukemia ,medicine.medical_treatment ,Biology ,Polymerase Chain Reaction ,Sensitivity and Specificity ,Reference Values ,Genetics ,MYH11 ,medicine ,Humans ,In patient ,RNA, Messenger ,Cbfb myh11 ,Chemotherapy ,medicine.disease ,Molecular biology ,Transplantation ,Leukemia, Myeloid, Acute ,Real-time polymerase chain reaction ,Chromosome Inversion ,Cancer research ,Stem cell ,Chromosomes, Human, Pair 16 - Abstract
We used a newly established real-time RT-PCR assay for the quantification of the leukemia-specific CBFB/MYH11 transcripts in inv(16)-positive acute myeloblastic leukemia. CBFB/MYH11 could be quantified over a five log range, with a detection limit of 10 molecules of a CBFB/MYH11 plasmid and a 1:105 dilution of RNA of the inv(16)-positive ME-1 cell line, respectively. The fusion transcripts were also quantified in 19 patients with acute myeloblastic leukemia and an inv(16) at initial diagnosis. The expression of CBFB/MYH11 varied over a two log range without correlation to clinical response or relapse rate. In nine patients, CBFB/MYH11 was also quantified during/after chemotherapy and autologous or allogeneic stem cell transplantation. All of these patients showed a similar decline of CBFB/MYH11 after intensive therapy. Six of these patients are in complete remission with a stable low-level or absent CBFB/MYH11 expression. Three patients relapsed, and their CBFB/MYH11 transcripts rose again to pretreatment levels. In two patients, this increase in CBFB/MYH11 could be detected by real-time PCR before hematological relapse. These data indicate that real-time RT-PCR can be used for the sensitive detection and quantification of CBFB/MYH11 transcripts in the follow-up of patients with inv(16)-positive AML. © 2001 Wiley-Liss, Inc.
- Published
- 2001
44. Prognostic impact of IDH2 mutations in cytogenetically normal acute myeloid leukemia
- Author
-
Arnold Ganser, Aruna Raghavachar, Brigitte Schlegelberger, Wolfgang Heit, Frederik Damm, Walter Fiedler, Lothar Kanz, Michael Heuser, Jürgen Krauter, Dieter Hoelzer, Gerhard Heil, Felicitas Thol, Katharina Wagner, Gudrun Göhring, Günter Schlimok, Michael Lübbert, and Hartmut Kirchner
- Subjects
Adult ,medicine.medical_specialty ,IDH1 ,DNA Mutational Analysis ,Immunology ,Biology ,medicine.disease_cause ,Biochemistry ,IDH2 ,Recurrence ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Multicenter Studies as Topic ,Clinical Trials as Topic ,Mutation ,Hematology ,Cytogenetics ,Myeloid leukemia ,Cancer ,Cell Biology ,Prognosis ,medicine.disease ,Survival Analysis ,Isocitrate Dehydrogenase ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Isocitrate dehydrogenase ,Cytogenetic Analysis ,Cancer research - Abstract
Mutations in the nicotinamide adenine dinucleotide phosphate+–dependent isocitrate dehydrogenase gene 2 ( IDH2 ) have recently been found in patients with acute myeloid leukemia (AML) as well as in patients with leukemic transformation of myeloproliferative neoplasms. We analyzed 272 adult patients with cytogenetically normal AML (CN-AML) for the presence of IDH2 mutations in codons R140 and R172. IDH2 mutations of amino acid 140 or 172 could be identified in 12.1% of CN-AML patients, with the majority of mutations (90%) occurring at position R140. The incidence of IDH2 mutations in AML patients with aberrant karyotypes (n = 130) was significantly lower (3.8%, P = .006). IDH2 mutations were mutually exclusive with mutations in IDH1. IDH2 mutation status alone or in combination with IDH1 mutations had no impact on response to therapy, overall survival, and relapse-free survival in patients with CN-AML. In conclusion, IDH2 mutations are frequently found in CN-AML, but in our analysis these mutations did not influence treatment outcome. This study was registered at [www.clinicaltrials.gov][1] as #[NCT00209833][2]. [1]: http://www.clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00209833&atom=%2Fbloodjournal%2F116%2F4%2F614.atom
- Published
- 2010
45. Immunoelectron microscopic analysis of CD 54 surface distribution and its role in homotypic interaction on normal monocytes and blasts of acute myeloid leukemia
- Author
-
Jürgen Krauter, Arnold Ganser, Gerhard Heil, and C. Westphal-Frösch
- Subjects
Pathology ,medicine.medical_specialty ,medicine.drug_class ,Immunoelectron microscopy ,Monocyte ,Intercellular Adhesion Molecule-1 ,Myeloid leukemia ,Cell migration ,Hematology ,General Medicine ,Biology ,Monoclonal antibody ,Molecular biology ,Monocytes ,Immunophenotyping ,medicine.anatomical_structure ,Cell–cell interaction ,Leukemia, Myeloid ,Acute Disease ,Antigens, Surface ,medicine ,Humans ,Microscopy, Immunoelectron ,Filopodia - Abstract
The role of CD 54 in the homotypic interaction of normal monocytes and the blasts of five cases of acute myeloid leukemia (AML) was analyzed by immunoelectron microscopy (IEM). The cells were seeded on glass coverslips precoated with an electrontransparent melamine resin, which allowed their in situ labeling with monoclonal antibodies (MoAb) and subsequent analysis by whole mount immunoelectron microscopy (WM-IEM) or transmission immunoelectron microscopy (TIEM). Timed incubation of the cells in serum-free medium +/- interferon-gamma (IFN-gamma, 500 U/ml) induced a spreading of the monocytes and the blasts of four out of five leukemias, characterized by the development of numerous filopodia which led to initial cell-cell contacts. In parallel, an increase in CD 54 surface density in four out of five leukemias could be detected, while no evidence of a CD 54 redistribution (capping) on single cells could be observed. WM-IEM studies detected no CD 54 molecules in the "early" cell-cell contacts, while "later" cell-cell contacts displayed strong CD 54 positivity. These data indicate that CD 54 is not involved in initial cell-cell contacts but is shifted secondarily to the cell contact sides and may thereby stabilize the adjacent membrane areas. The absence of spreading of the CD 54 negative blasts in one out of five leukemias and the blockade of the cellular migration by an anti-CD 54 MoAb (Clone 84H10) in the remaining cases suggest that CD 54 expression is necessary for cellular locomotion. The observed inhibitory effect of the anti-CD 54 MoAb probably mimics a negative circuit that serves to control cellular migration.
- Published
- 2000
46. Der onkologische Patient auf der Intensivstation - Grenzen der Indikation
- Author
-
Gerhard Heil, B. Hertenstein, and Arnold Ganser
- Subjects
Gynecology ,medicine.medical_specialty ,business.industry ,Emergency Medicine ,Medicine ,Emergency Nursing ,Critical Care and Intensive Care Medicine ,business - Abstract
Die Prognose von Patienten, die mit malignen Erkrankungen auf Intensivstationen behandelt werden mussen, ist schlecht. Die Krankenhausmortalitat von beatmeten onkologischen Patienten reicht von 70–90% bei Patienten mit soliden Tumoren zu 75–90% bei Patienten mit hamatologischen Neoplasien und bis zu 95% bei Patienten nach Knochenmarktransplantation. Durch Verbesserungen der allgemeinen onkologischen Therapien nimmt die Zahl der auf Intensivstationen verlegten onkologischen Patienten jedoch zu. Diese Situation fuhrt immer wieder zu kontroversen Diskussionen uber den Sinn intensivmedizinischer Therapien bei diesen Patienten. Da die individuelle Prognose der Patienten vor Einleitung der Intensivtherapie nicht verlasslich vorhergesagt werden kann, erscheint es nicht gerechtfertigt onkologischen Patienten generell eine intensivmedizinische Behandlung zu verwehren. Sinnvoll und praktikabel erscheint indes eine Reevaluation des Patienten nach Einleitung der Intensivtherapie zu vordefinierten Zeitpunkten und nach vordefinierten Kriterien. Fur Patienten, die nach einer Knochenmarktransplantation beatmungspflichtig werden, gilt, das die Patienten, die fur langere Zeit mit Vasopressoren behandelt werden mussen und/oder ein kombiniertes Leber- und Nierenversagen entwickeln, nicht uberleben werden. Fur diese Patienten kann die Beendigung der intensivtherapeutischen Masnahmen erwogen werden. Bei Patienten, die diese Kriterien nicht erfullen, ist die Fortfuhrung der Intensivtherapie sinnvoll. Die Therapieergebnisse sind denen bei nicht-onkologischen Patienten vergleichbar. Fur andere Patienten mit onkologischen Erkrankungen kann die Anwendung eines neueren, speziell fur onkologische Patienten entwickelten Score Systems Hilfestellung in der klinischen Entscheidung geben.
- Published
- 2000
47. Comparison of nested competitive RT-PCR and real-time RT-PCR for the detection and quantification of AML1/MTG8 fusion transcripts in t(8;21) positive acute myelogenous leukemia
- Author
-
Gerhard Heil, Stefan Nagel, Mike P. Wattjes, Arnold Ganser, Olaf Heidenreich, and Jürgen Krauter
- Subjects
Cancer Research ,Neoplasm, Residual ,Chromosomes, Human, Pair 21 ,Biology ,Sensitivity and Specificity ,Translocation, Genetic ,law.invention ,Myelogenous ,law ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,medicine ,Humans ,neoplasms ,Polymerase chain reaction ,Reverse Transcriptase Polymerase Chain Reaction ,Hybridization probe ,Reproducibility of Results ,Myeloid leukemia ,DNA, Neoplasm ,Hematology ,medicine.disease ,Molecular biology ,Minimal residual disease ,Neoplasm Proteins ,Leukemia, Myeloid, Acute ,Leukemia ,Real-time polymerase chain reaction ,Oncology ,Fusion transcript ,DNA Probes ,Chromosomes, Human, Pair 8 ,Transcription Factors - Abstract
The chromosomal translocation t(8;21)(q22;q22) is one of the most frequent karyotypic aberrations in acute myeloid leukemia (AML) and results in a chimeric fusion transcript AML1/MTG8. Since AML1/MTG8 fusion transcripts remain detectable by RT-PCR in t(8;21) AML patients in long-term hematological remission, quantitative assessment of AML1/MTG8 transcripts is necessary for the monitoring of minimal residual disease (MRD) in these patients. Competitive RT-PCR and recently real-time RT-PCR are increasingly used for detection and quantification of leukemia specific fusion transcripts. For the direct comparison of both methods we cloned a 42 bp DNA fragment into the original AML1/MTG8 sequence. The resulting molecule was used as an internal competitor for our novel competitive nested RT-PCR for AML1/MTG8 and as an external standard for the generation of AML1/MTG8 standard curves in a real-time PCR assay. Using this standard molecule for both PCR techniques, we compared their sensitivity, linearity and reproducibility. Both methods were comparable with regard to all parameters tested irrespective of analyzing serial dilutions of plasmids, cell lines or samples from t(8;21) positive AML patients at different stages of the disease. Therefore, both techniques can be recommended for the monitoring of MRD in these particular AML patients. However, the automatization of the real-time PCR technique offers some technical advantages.
- Published
- 2000
48. Intensive chemotherapy with idarubicin, ara-C, etoposide, and m-AMSA followed by immunotherapy with interleukin-2 for myelodysplastic syndromes and high-risk Acute Myeloid Leukemia (AML)
- Author
-
Arnold Ganser, N. Brack, W. Langer, J. T. Fischer, Klaus Höffken, H. G. Fuhr, Wolf-K. Hofmann, Gernot Seipelt, P Knuth, W. Brockhaus, Dieter Hoelzer, Karin Kolbe, Gerhard Heil, T. H. Ittel, and Lothar Bergmann
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Gastroenterology ,Internal medicine ,Multicenter trial ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Idarubicin ,Prospective Studies ,Survival rate ,Etoposide ,Aged ,Dose-Response Relationship, Drug ,business.industry ,Myelodysplastic syndromes ,Cytarabine ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Surgery ,Survival Rate ,Leukemia ,Leukemia, Myeloid ,Myelodysplastic Syndromes ,Acute Disease ,Interleukin-2 ,Female ,Immunotherapy ,business ,Refractory anemia with excess of blasts ,medicine.drug - Abstract
Intensive chemotherapy followed by treatment with interleukin-2 (IL-2) was evaluated in a prospective, randomized, multicenter trial including 18 patients with refractory anemia with excess of blasts in transformation (RAEB-T), 86 patients with acute myeloid leukemia (AML) evolving from myelodysplastic syndromes, and six patients with secondary AML after previous chemotherapy. Median age was 58 years (range: 18-76 years). Forty-nine patients (45%) achieved a complete remission (CR) after two induction cycles with idarubicin, ara-C, and etoposide, 52% of them aged/=60 years and 35% aged60 years (p=0.06). After two consolidation courses, patients were randomized to four cycles of either high- or low-dose IL-2. Patients aged up to 55 years with an HLA-identical sibling donor were eligible for allogeneic bone marrow transplantation. The median relapse-free survival was 12.5 months, with a probability of ongoing CR at 6.5 years of 19%. Overall survival of all patients was 8 months, and 21 months for the CR patients. Median survival was significantly longer among patients aged/=60 years than among the older patients (16 vs 6 months, p0.001). Median duration of survival and relapse-free survival were not statistically different in the two IL-2 treatment arms.
- Published
- 2000
49. A Randomized, Double-Blind, Placebo-Controlled Study With Pegylated Recombinant Human Megakaryocyte Growth and Development Factor (PEG-rHuMGDF) as an Adjunct to Chemotherapy for Adults With De Novo Acute Myeloid Leukemia
- Author
-
Dieter Hoelzer, Caroline O’Brien-Ewen, Hervé Dombret, Klaus Lechner, Gerhard Heil, Eric Archimbaud, Miguel A. Sanz, Alan Barge, John A. Liu Yin, Oliver G. Ottmann, J Matcham, Wolfram Brugger, and Pierre Fenaux
- Subjects
Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,REMISSION INDUCTION ,INDUCED THROMBOCYTOPENIA ,Placebo-controlled study ,Placebo ,Biochemistry ,Gastroenterology ,Polyethylene Glycols ,Double-Blind Method ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Thrombopoietin ,Aged ,Chemotherapy ,Myelosuppressive Chemotherapy ,ACUTE MYELOGENOUS LEUKEMIA ,C-MPL LIGAND ,Thrombocytosis ,business.industry ,NONHUMAN-PRIMATES ,Myeloid leukemia ,BONE-MARROW TRANSPLANTATION ,IN-VITRO ,Cell Biology ,Hematology ,Middle Aged ,COLONY-STIMULATING FACTOR ,medicine.disease ,PHASE-III ,Recombinant Proteins ,Leukemia ,Treatment Outcome ,Endocrinology ,Leukemia, Myeloid ,Acute Disease ,Female ,business ,RECEPTOR MPL - Abstract
To determine the safety, biologic, and clinical benefits of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF; Amgen, Thousand Oaks, CA) after myelosuppressive chemotherapy in acute myeloid leukemia (AML),108 adult patients with de novo AML were randomized to receive either PEG-rHuMGDF (2.5 mu g/kg/d or 5 mu g/kg/d) for up to 21 doses (group A), a single dose of 2.5 mu g/kg PEG-rHuMGDF, 7 daily doses of 2.5 mu g/kg PEG-rHuMGDF (group B), or placebo. The greatest biologic activity was seen in group A with a median peak platelet count of 1,084 x 10(9)/L, occurring at a median 9 days after the last dose of study drug, compared with 517 x 10(9)/L and 396 x 10(9)/L in group B and placebo group, respectively. Thrombocytosis (platelets >1,000 x 10(9)/L) was seen at rates of 52%, 8%, and 9% in groups A, B, and placebo, respectively, but were not associated with any adverse event. There was no effect on median time to transfusion independent platelet recovery (greater than or equal to 20 x 10(9)/L). The median time to neutrophil recovery (greater than or equal to 500/mu L) and red blood cell transfusion requirements were similar in all groups, and there was no apparent stimulation of leukemia. PEG-rHuMGDF was biologically active and well tolerated. Further investigation of dose and scheduling is required, specifically earlier dosing before and during chemotherapy. (C) 1999 by The American Society of Hematology.
- Published
- 1999
50. Real-time RT-PCR for the detection and quantification of AML1/MTG8 fusion transcripts in t(8;21)-positive AML patients
- Author
-
Lothar Bergmann, Donald Bunjes, Arnold Ganser, Jürgen Krauter, Sabine Kafert, Mike P. Wattjes, Stefan Nagel, Gerhard Heil, Utz Krug, and Olaf Heidenreich
- Subjects
Oncology ,Chemotherapy ,medicine.medical_specialty ,Pathology ,medicine.medical_treatment ,Cytogenetics ,Chromosomal translocation ,Hematology ,Biology ,Nucleotidyltransferase ,Minimal residual disease ,Housekeeping gene ,law.invention ,Real-time polymerase chain reaction ,law ,hemic and lymphatic diseases ,Internal medicine ,medicine ,neoplasms ,Polymerase chain reaction - Abstract
AML1/MTG8 was quantified relative to the expression of the GAPDH housekeeping gene by real-time RT-PCR in 22 patients with t(8;21)-positive acute myeloblastic leukaemia (AML) at initial diagnosis and in seven of these patients also during/after chemotherapy and allogeneic bone marrow transplantation. Real-time PCR was able to specifically detect and quantify AML1/MTG8 over a 5 log range. The detection limit for t(8;21)-positive cells was a dilution of 1:105. The AML1/MTG8 expression varied considerably among the 22 AML patients at intial diagnosis with a ratio AML1/MTG8:GAPDH of 0.5135±0.536 (range 0.1–2.14, median 0.318). In six patients with t(8;21)-positive AML a marked decline of AML1/MTG8 could be induced by chemotherapy. These patients are in ongoing complete haematological remission (CR) with a constant low-level AML1/MTG8 expression. In another patient a rapid rise of AML1/MTG8 transcripts could be detected in CR after allogeneic bone marrow transplantation and the patient relapsed 10 weeks later. In conclusion, real-time RT-PCR is a suitable approach for the quantification of AML1/MTG8 transcripts in the monitoring of AML patients with t(8;21) during/after chemotherapy and can provide data of prognostic relevance.
- Published
- 1999
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.