-
Felicitas Thol,
Claudia Winschel,
Ann-Kathrin Sonntag,
Frederik Damm,
Katharina Wagner,
Anuhar Chaturvedi,
Gudrun Göhring,
Brigitte Schlegelberger,
Michael Lübbert,
Walter Fiedler, Hartmut Kirchner,
Jürgen Krauter,
Arnold Ganser,
Michael Heuser
[show abstract]
[hide abstract]
ABSTRACT: Deregulation of the hematopoietic stem cell (HSC) compartment represents a hallmark of acute myeloid leukemia (AML). Recently, in vivo screening for genes that are involved in the regulation of HSCs has led to the discovery of Musashi-2 (MSI2) as a key regulator of HSCs and as a suppressor of NUMB. In order to analyze the prognostic importance of MSI2 and NUMB expression in AML, MSI2 and NUMB transcript levels from 454 AML patients treated in multicenter trials AML SHG 0199 (ClinicalTrials Identifier NCT00209833) and 0295, and 38 healthy volunteers were analyzed by reverse transcriptase PCR in the context of other molecular markers (NPM1, FLT3, CEBPA, IDH1/IDH2, DNMT3A, NRAS, WT1, KIT, MN1, BAALC, ERG, and WT1). In AML, patients with high MSI2 expression were more likely to be FLT3-ITD positive (P < .001), NPM1 (P < .001), and DNMT3A (P = .003) mutated. Overall survival (OS) was shorter in AML patients with high MSI2 expression (hazard ratio, 1.48; 95 % confidence interval, 1.13-1.95, P = .005). However, relapse-free survival (RFS, P = .15) and complete remission (CR, P = .39) rates were not influenced by MSI2 expression. In multivariate analysis, MSI2 expression remained an independent prognostic factor for OS (P = .03). NUMB expression had no impact on survival (OS, P = .47; RFS, P = .59) and CR rate (P = .39). MSI2 but not NUMB is associated with shorter OS in AML patients and may indicate a more aggressive form of AML.
Annals of Hematology 12/2012; · 2.62 Impact Factor
-
Felicitas Thol,
Frederik Damm,
Andrea Lüdeking,
Claudia Winschel,
Katharina Wagner,
Michael Morgan,
Haiyang Yun,
Gudrun Göhring,
Brigitte Schlegelberger,
Dieter Hoelzer,
Michael Lübbert,
Lothar Kanz,
Walter Fiedler, Hartmut Kirchner,
Gerhard Heil,
Jürgen Krauter,
Arnold Ganser,
Michael Heuser
[show abstract]
[hide abstract]
ABSTRACT: To study the incidence and prognostic impact of mutations in DNA methyltransferase 3A (DNMT3A) in patients with acute myeloid leukemia.
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).
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.
DNMT3A mutations are frequent in younger patients with AML and are associated with an unfavorable prognosis.
Journal of Clinical Oncology 06/2011; 29(21):2889-96. · 18.37 Impact Factor
-
Andreas Engert,
Annette Plütschow,
Hans Theodor Eich,
Andreas Lohri,
Bernd Dörken,
Peter Borchmann,
Bernhard Berger,
Richard Greil,
Kay C Willborn,
Martin Wilhelm, [......],
Arnold Ganser,
Lorenz Trümper,
Carsten Bokemeyer, Hartmut Kirchner,
Jörg Schubert,
Zdenek Král,
Michael Fuchs,
Hans-Konrad Müller-Hermelink,
Rolf-Peter Müller,
Volker Diehl
[show abstract]
[hide abstract]
ABSTRACT: Whether it is possible to reduce the intensity of treatment in early (stage I or II) Hodgkin's lymphoma with a favorable prognosis remains unclear. We therefore conducted a multicenter, randomized trial comparing four treatment groups consisting of a combination chemotherapy regimen of two different intensities followed by involved-field radiation therapy at two different dose levels.
We randomly assigned 1370 patients with newly diagnosed early-stage Hodgkin's lymphoma with a favorable prognosis to one of four treatment groups: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gy of radiation therapy (group 1), four cycles of ABVD followed by 20 Gy of radiation therapy (group 2), two cycles of ABVD followed by 30 Gy of radiation therapy (group 3), or two cycles of ABVD followed by 20 Gy of radiation therapy (group 4). The primary end point was freedom from treatment failure; secondary end points included efficacy and toxicity of treatment.
The two chemotherapy regimens did not differ significantly with respect to freedom from treatment failure (P=0.39) or overall survival (P=0.61). At 5 years, the rates of freedom from treatment failure were 93.0% (95% confidence interval [CI], 90.5 to 94.8) with the four-cycle ABVD regimen and 91.1% (95% CI, 88.3 to 93.2) with the two-cycle regimen. When the effects of 20-Gy and 30-Gy doses of radiation therapy were compared, there were also no significant differences in freedom from treatment failure (P=1.00) or overall survival (P=0.61). Adverse events and acute toxic effects of treatment were most common in the patients who received four cycles of ABVD and 30 Gy of radiation therapy (group 1).
In patients with early-stage Hodgkin's lymphoma and a favorable prognosis, treatment with two cycles of ABVD followed by 20 Gy of involved-field radiation therapy is as effective as, and less toxic than, four cycles of ABVD followed by 30 Gy of involved-field radiation therapy. Long-term effects of these treatments have not yet been fully assessed. (Funded by the Deutsche Krebshilfe and the Swiss Federal Government; ClinicalTrials.gov number, NCT00265018.)
New England Journal of Medicine 08/2010; 363(7):640-52. · 53.30 Impact Factor
-
Felicitas Thol,
Frederik Damm,
Katharina Wagner,
Gudrun Göhring,
Brigitte Schlegelberger,
Dieter Hoelzer,
Michael Lübbert,
Wolfgang Heit,
Lothar Kanz,
Günter Schlimok,
Aruna Raghavachar,
Walter Fiedler, Hartmut Kirchner,
Gerhard Heil,
Michael Heuser,
Jürgen Krauter,
Arnold Ganser
[show abstract]
[hide abstract]
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 as #NCT00209833.
Blood 07/2010; 116(4):614-6. · 9.90 Impact Factor
-
Frederik Damm,
Michael Heuser,
Michael Morgan,
Haiyang Yun,
Anika Großhennig,
Gudrun Göhring,
Brigitte Schlegelberger,
Konstanze Döhner,
Oliver Ottmann,
Michael Lübbert,
Wolfgang Heit,
Lothar Kanz,
Günter Schlimok,
Aruna Raghavachar,
Walter Fiedler, Hartmut Kirchner,
Hartmut Döhner,
Gerhard Heil,
Arnold Ganser,
Jürgen Krauter
[show abstract]
[hide abstract]
ABSTRACT: 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.
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.
The minor allele of SNP rs16754 (WT1(AG/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.
WT1 SNP rs16754 may be a novel independent favorable-risk marker in CN-AML patients that might improve risk and treatment stratification.
Journal of Clinical Oncology 02/2010; 28(4):578-85. · 18.37 Impact Factor
-
Ulrike Anneliese Nitz,
Svjetlana Mohrmann,
Johannes Fischer,
Walter Lindemann,
Wolfgang E Berdel,
Christian Jackisch,
Christoph Werner,
Carsten Ziske, Hartmut Kirchner,
Bernd Metzner, [......],
Jörg Baltzer,
Iris Schrader,
Herrmann Wiebringhaus,
Yon Ko,
Siegfried Rösel,
Thomas Schwenzer,
Peter Wernet,
Axel Hinke,
Hans Georg Bender,
Markus Frick
[show abstract]
[hide abstract]
ABSTRACT: Breast cancer with extensive axillary-lymph-node involvement has a poor prognosis after conventional treatment. In trials with historical controls, high-dose chemotherapy produced improved outcomes. We compared an intensive double-cycle high-dose chemotherapy regimen with an accelerated conventionally dosed regimen in high-risk breast cancer in a multicentre trial.
Patients with at least nine positive nodes were randomly assigned either two courses of accelerated (2-week intervals, with filgrastim support), conventionally dosed epirubicin and cyclophosphamide followed by two courses of high-dose chemotherapy (epirubicin, cyclophosphamide, and thiotepa supported by peripheral-blood progenitors) or four identical cycles of epirubicin and cyclophosphamide followed by three cycles of accelerated cyclophosphamide, methotrexate, and fluorouracil. The primary endpoint was event-free survival. Analyses were done both by intention to treat and per protocol.
403 patients were enrolled; 201 were assigned high-dose chemotherapy and 202 conventional treatment. The mean number of positive nodes was 17.6, and median follow-up was 48.6 months. 4-year event-free survival (intention-to-treat analysis) was 60% (95% CI 53-67) in the high-dose chemotherapy group and 44% (37-52) in the control group (p=0.00069). The corresponding overall survival was 75% (69-82) versus 70% (64-77; p=0.02). There were no treatment-related deaths.
Our finding of significant improvements in both event-free and overall survival for high-dose chemotherapy compared with a dose-dense conventional regimen contrasts with the results of other studies. The discrepancy might be due partly to design differences (tandem, brief induction) between our regimen and those studied in other trials. This approach merits further study.
The Lancet 01/2006; 366(9501):1935-44. · 38.28 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A technique of hyperthermic isolated lung perfusion (ILP) chemotherapy was developed.
Since April 1999, four patients with unilateral (n=2) or bilateral (n=2) sarcoma metastasis confined to a lobe (n=2) or entire lung (n=2) entered into a pilot study of hyperthermic (41 degrees C) ILP with high doses of cisplatin (70 mg/m(2)). Eligibility included drug resistant metastasis and at least four previous surgical metastectomies. The ILP of the lung segments was carried out following metastectomy, for 20-40 min at a rate of 0.3-0.5 l/min, a mean perfusion pressure lower than the own mean pulmonary artery pressure, and an inflow temperature of 41 degrees C or higher. Before and following ILP, the isolated lung segments were flushed with normothermic saline (1 l). Flow was continuously maintained by a centrifugal pump.
All patients successfully completed 31.7+/-9 min perfusion time at 41.4+/-0.3 degrees C, and this time-point corresponded to the maximal platinum lung-uptake (93.8 ng/mg tissue). The total vascular isolation was confirmed by continuously low systemic cisplatin plasma levels. There was no systemic drug-related toxicity but all patients experienced transient pulmonary toxicity as non-cardiogenic edema of the treated lung segments. With a median follow-up of 12 months, three patients are alive and disease-free and one died from cerebral metastasis without autopsy evidence of local recurrence 13 months following ILP.
Hyperthermic perfusion chemotherapy can be done safely and effectively. It represents a new treatment modality and deserves further investigations for patients with advanced, drug resistant or surgically refractory, lung sarcoma metastasis. However, further studies are needed to limit the ILP-induced pulmonary toxicity.
European Journal of Cardio-Thoracic Surgery 08/2002; 22(1):41-6. · 2.55 Impact Factor
-
Norbert Schmitz,
Beate Pfistner,
Michael Sextro,
Markus Sieber,
Angelo M Carella,
Matthias Haenel,
Friederike Boissevain,
Reinhart Zschaber,
Peter Müller, Hartmut Kirchner,
Andreas Lohri,
Susanne Decker,
Bettina Koch,
Dirk Hasenclever,
Anthony H Goldstone,
Volker Diehl
[show abstract]
[hide abstract]
ABSTRACT: High-dose chemotherapy followed by transplantation of autologous haemopoietic stem cells (BEAM-HSCT) is frequently used to treat patients with relapsed Hodgkin's disease. We aimed to compare this treatment with conventional aggressive chemotherapy without stem-cell transplantation (Dexa-BEAM).
161 patients between 16 and 60 years of age with relapsed Hodgkin's disease were randomly assigned two cycles of Dexa-BEAM (dexamethasone and carmustine, etoposide, cytarabine, and melphalan) and either two further courses of Dexa-BEAM or high-dose BEAM and transplantation of haemopoietic stem cells. Only patients with chemosensitive disease (complete or partial remission after two courses of Dexa-BEAM) proceeded to further treatment. The primary endpoint was freedom from treatment failure for patients with chemosensitive disease. Analysis was per protocol.
17 patients were excluded from the study after randomisation (ten given Dexa-BEAM and seven given BEAM-HSCT). Median follow-up was 39 months (IQR 3-78). Freedom from treatment failure at 3 years was significantly better for patients given BEAM-HSCT (55%) than for those on Dexa-BEAM (34%; difference -21%, 95% CI -39.87 to -2.13; p=0.019). Overall survival of patients given either treatment did not differ significantly.
High-dose BEAM and transplantation of haemopoietic stem cells improves freedom from treatment failure in patients with chemosensitive first relapse of Hodgkin's disease irrespective of length of initial remission.
The Lancet 07/2002; 359(9323):2065-71. · 38.28 Impact Factor
-
Markus Sieber,
Hans Tesch,
Beate Pfistner,
Ulrich Rueffer,
Bernd Lathan,
Oana Brosteanu,
Ursula Paulus,
Tina Koch,
Michael Pfreundschuh,
Markus Loeffler, [......],
Axel Georgii,
Klaus-Peter Schalk, Hartmut Kirchner,
Gottfried Doelken,
Reinhold Munker,
Peter Koch,
Richard Herrmann,
Richard Greil,
Anna Paola Anselmo,
Volker Diehl
[show abstract]
[hide abstract]
ABSTRACT: To investigate whether treatment results in intermediate-stage Hodgkin's lymphoma can be improved by rapid application of non-cross-resistant drugs, the 10-drug regimen cyclophosphamide, vincristine, procarbazine, and prednisone (COPP), doxorubicin, bleomycin, and vinblastine (ABV), and ifosfamide, methotrexate, etoposide, and prednisone (IMEP), repeated every 6 weeks, was compared with conventional alternating COPP/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) administered every 8 weeks.
From January 1988 to January 1993, 996 patients in stage I or II Hodgkin's lymphoma with at least one risk factor (massive mediastinal tumor, massive spleen involvement, extranodal disease, elevated ESR, or more than two lymph node areas involved) and all patients in stage IIIA Hodgkin's lymphoma were randomized to receive two cycles of COPP/ABVD or COPP/ABV/IMEP followed by extended-field radiotherapy.
Both regimens produced similar rates for treatment responses (complete remission, 93% v 94%), freedom from treatment failure (80% v 79%), and overall survival (88% for both regimens) at a median follow-up time of 7 years. Most serious toxicities during chemotherapy were similar in both regimens. However, World Health Organization grade 3 and 4 leukocytopenia occurred significantly more frequently in the COPP/ABV/IMEP arm (53% v 44% of patients; P =.010). There were no differences in the number of serious infections and toxic deaths during therapy. The number of second malignancies was also the same in both arms (22 each).
Alternating COPP/ABVD and rapid alternating COPP/ABV/IMEP in combination with extended-field radiotherapy are equally effective in intermediate-stage Hodgkin's lymphoma and produce excellent long-term treatment results.
Journal of Clinical Oncology 02/2002; 20(2):476-84. · 18.37 Impact Factor
-
Jürgen Krauter,
Wolfgang Peter,
Ulrich Pascheberg,
Barbara Heinze,
Lothar Bergmann,
Dieter Hoelzer,
Michael Lübbert,
Günther Schlimok,
Renate Arnold, Hartmut Kirchner,
Maria Port,
Arnold Ganser,
Gerhard Heil
[show abstract]
[hide abstract]
ABSTRACT: In 140 patients with de novo acute myeloid leukaemia (AML) standard cytogenetics were compared with RT-PCR for the detection of t(8;21), t(15;17) and inv(16) and fluorescence in situ hybridization (FISH) for numerical aberrations of chromosomes 7, 8, X and Y. RT-PCR detected 18 cases with t(8;21), 12 with t(15;17) and seven with inv(16). In two cases with t(8;21), two with t(15;17) and four with inv(16) these aberrations had not been detected by standard cytogenetics. There were no false negative PCR results. In 12 patients with these chromosomal changes, standard cytogenetics revealed additional chromosomal aberrations. In 16 patients sole numerical aberrations of the chromosomes 7, 8, X or Y were found by FISH. In these patients the sensitivity of FISH and standard cytogenetics was comparable. In 87 patients no aberrations could be found by PCR and FISH whereas in 24 of these patients standard cytogenetics revealed an abnormal karyotype. These data recommend the combination of standard cytogenetics and molecular techniques to improve the sensitivity for the detection of genetic lesions in AML. Once chromosomal markers have been identified by combined analysis these markers could be used to monitor residual disease during/after chemotherapy, by RT-PCR and/or FISH.
British Journal of Haematology 01/2002; 103(1):72 - 78. · 4.94 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This work was performed with L 428, a cell line established in 1978 from a patient with Hodgkin's disease. These in vitro cells represent counterparts of in vivo Hodgkin and Sternberg-Reed cells. L 428 and its derived sublines produce a significant amount of colony-stimulatling factor (CSF) compared to standard preparations of CSF (fetal liver conditioned medium). Hodgkin-cell-derived conditioned medium, tested in cord-blood assays and in semi-solid agar systems, induced myeloproliferation predominantly. Production of CSF is independent of fetal calf serum concentration in the cultures. L 428-conditioined medium could provide an excellent source for characterization and purification of granulocyte CSF.
International Journal of Cancer 03/1983; 31(3):269 - 274. · 5.44 Impact Factor
