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Publications (137)
Despite recent advances, treatment of elderly patients with AML remains a challenge because of adverse disease biology, comorbidities and therapy related toxicities. The balance between effectivity and toxicity of treatment strategies play a key role. Since comparative studies are lacking, a prospective randomized trial was designed among German AM...
Leukemia accepted article preview online, 11 March 2016. doi:10.1038/leu.2016.54.
We randomized 3375 adults with newly-diagnosed AML or high-risk myelodysplastic syndrome (MDS) to test whether increasingly-intensive chemotherapies assigned at study-entry and analyzed on an intent-to-treat basis improved outcomes. 1529 subjects <60 years were randomized to receive: (1) a 1st course of induction therapy with high-dose cytarabine a...
As a global approach to acute myeloid leukemia the AMLCG started a clinical trial in 1999 with the intention to clarify the influence of baseline characteristics as well as treatment variables on patients’ outcome. The heterogeneity of this disease in mind, all randomization was done stratified for potential risk factors. Furthermore, all randomiza...
NPM1 mutations represent frequent genetic alterations in patients with acute myeloid leukemia (AML) associated with a favorable prognosis. Different types of NPM1 mutations have been described. The purpose of our study was to evaluate the relevance of different NPM1 mutation types with regard to clinical outcome. Our analyses were based on 349 NPM1...
Background
Data on benefit and toxicity by treatment intensification for AML are now available and allow rediscussing current dosing.
Methods
In a multicenter trial involving patients between 16 and 86 years of age, patients below 60 years received uniform double induction by the 1st course with standard dose araC/ daunorubicin (60mg/m²x3)/ thiogu...
Background
Cytogenetically normal acute myeloid leukemia (CN-AML) is the largest and most heterogeneous cytogenetic AML subgroup. For the practicing clinician it is difficult to know how to use the prognostic information of the growing number of clinical and molecular markers. Our purpose was to develop a widely applicable prognostic model by combi...
Chemo-modulation of cytarabine by fludarabine has been attributed with a higher anti-leukemic efficacy, but randomized trials to address this question are rare. We therefore conducted a multicenter, randomized phase III study to evaluate the antileukemic efficacy of adding fludarabine to sequential high-dose cytarabine+idarubicin (SHAI) re-inductio...
1974
Most available data on the relative value of allogeneic stem cell transplantation (allo-SCT) for acute myeloid leukemia (AML) in first complete remission (CR1) in the past, were generated from donor versus no-donor comparisons, focusing on documented tissue-typed patients and their siblings. The inclusion of patients who are not HLA-typed, for...
1509
Introduction
Both, patients' age and genetic groups are important predictors of outcome in AML while their influence remains poorly quantified and compared.
Methods
In the AMLCG (Acute Myeloid Leukemia Cooperative Group) 1999 trial 1470 patients (pts) were 16–59y and 1747 pts were 60–85y of age. 95% of pts could be classified according to ge...
6610
Background: Patients’ age is an important issue in treatment decisions for AML, while its role in this disease remains poorly explained. Methods: In the AMLCG 1999 trial 1223 patients (pts) were 16-59y and 1470 pts were 60-85y of age. Their treatment was randomized between TAD-HAM vs HAM-HAM induction (TAD, standard dose thioguanine, cytarabin...
425
The introduction of all-trans-retinoic acid (ATRA) in front line therapy of acute promyelocytic leukemia (APL) has improved the outcome of all age groups. In the elderly patients (pts), multi-morbidity and higher vulnerability to chemotherapy-related toxicity are the main problems reducing the chance of cure. This has led to recommendations to...
2773
Introduction
For patients with high-risk myelodysplastic syndromes an epigenetic therapy with hypomethylating agents is considered standard of care. Intensive chemotherapy can be offered to a subset of patients; however, data about the long-term outcome of MDS patients receiving intensive chemotherapy are scarce.
Methods
For this evaluation,...
6618 Background: Until recently, elderly patients with AML were treated in protocols for younger pts or outside protocols. In order to evaluate the outcome of these pts in more detail, an intergroup study involving the AMLCG and the OSHO study groups was initiated and a 10:1 randomization in a common arm was established. Methods: The common arm con...
2696
Introduction
The prognosis of older patients (≥ 60 years) with acute myeloid leukemia (AML) is generally poor. The decision whether or not to use intensive chemotherapy in this patient cohort is challenging since only half of all older AML patients will eventually achieve a complete remission (CR) with an intensive approach. We therefore soug...
333
Background
Standard chemotherapy for elderly AML patients results in a median overall survival of only about one year. Case reports and early phase I/II data have shown that the kinase inhibitor Sorafenib might show clinical benefit for Flt3-ITD-positive AML patients (Metzelder S Blood 2009; 113:6567) and that its addition to standard chemothe...
2635
Poster Board II-611
Background
Cytogenetically normal acute myeloid leukemia (CN-AML) is associated with an intermediate outcome. A number of clinical and molecular risk factors have been characterized pointing to the heterogeneity of this group. The purpose of the study was to define a prognostic model based on pre-treatment patient characte...
4693
Loss of Structural Maintenance of Chromosomes 1A Protein Expression is Associated with a Poor Prognosis in Acute Myeloid Leukemia
Utz Krug, Claudia Hömme, Nicola Tidow, Horst Bürger, Gabriele Köhler, Achim Heinecke, Thomas Büchner, Wolfgang E. Berdel, Steffen Koschmieder, Carsten Müller-Tidow
Introduction
Acute myelogenous leukemia is a genet...
327
Introduction
Older patients (≥ 60 years) with acute myeloid leukemia (AML) display a dismal prognosis with only half of the patients reaching a complete remission after intensive induction therapy. The decision whether or not to use intensive chemotherapy is often difficult given the limited number of known markers that might predict the chanc...
398
In recent years, the classification of cytogenetically normal acute myeloid leukemia (CN-AML) has seen a turnaround from morphological characterisation towards the identification of novel molecular prognostic factors. Besides the well-recognized prognostic influence of mutations in NPM1, CEPBA, FLT3 and other genes, high transcript levels of ER...
485
In order to assess the relative value of major treatment variables for AML and subgroups in a representative setting 2693 patients were treated in a multicenter trial. To avoid a selection during treatment and to provide intention-to-treat conditions in a factorial design patients were randomized up-front in one step to receive TAD-HAM versus H...
The objective of this study for newly diagnosed acute promyelocytic leukemia (APL) was to evaluate the efficacy of an intensified double induction chemotherapy including high dose ara-C (HD) and all-trans retinoic acid (ATRA) followed by consolidation and 3 years maintenance therapy. In contrast to APL studies stratifying therapy according to pretr...
Evaluate the clinical benefit of external beam radiotherapy (RTx) for locally invasive thyroid carcinoma with follicular cell differentiation (DTC).
The Multicentre Study on Differentiated Thyroid Cancer (MSDS) was planned as a prospective multicenter trial on the benefit of adjuvant RTx in locally invasive DTC (pT4; UICC 1997) with or without lymp...
Compelling evidence indicates that microvessel density (MVD) is a prognostic marker in early nonsmall cell lung cancer (NSCLC). However, its role in lymph node metastases in stage III NSCLC receiving multimodality treatment is unknown.
Lymph nodes of 142 patients with stage III NSCLC, treated in a trial of the German Lung Cancer Cooperative group,...
Background: Long-term survival in NK-AML is influenced by different clinical and molecular markers. Whereas the presence of a NPM-1 mutation is associated with a positive prognostic effect on long-term outcome, the presence of a FLT3-ITD mutation has a negative impact on survival. Interestingly, a significant interaction between NPM-1 and FLT3-ITD...
Among the entire patients with AML the majority is 60 years of age or older. In present German multicenter AML Cooperative Group (AMLCG) trial the proportion of these older patients amounts to 54% of all 2734 patients enrolled and receiving intensive chemotherapy. While older age AML is increasingly recognized as a main challenge the therapeutic ou...
7058
Background: In 2602 pts entering two sequential trials the 47% pts of 60+y compared to the younger pts achieved 55 vs 71% CR, 19 vs 41% OS and 77 vs 54% RR (relapse risk) at 3 years. While the trials addressed various options for both de-novo and secondary AML understanding the age related biology of AML required restriction to pts comparable...
In order to test current risk factors in a prospective multicenter setting we evaluated the AMLCG 99 trial. Patients were randomly assigned to induction by TAD-HAM (HAM with araC 3 for age <60y and 1 for age ≥60y g/m2 × 6), or HAM-HAM, and also to TAD consolidation and maintenance or (age <60y) myeloablative chemotherapy and autologous SCT. Patient...
Patients with acute myeloid leukemia and a normal karyotype (NK AML) comprise 50% of all AML cases and show heterogeneous treatment outcomes and survival. We used gene expression profiling to develop a prognostic gene signature that predicts survival in this clinically relevant AML subgroup. Our analysis was based on data from 163 patients with new...
Background: Prognosis of AML is influenced by different clinical and molecular alterations. We performed a multivariate analysis including five molecular markers NPM1, FLT-ITD, CEBPA, FLT-TKD and MLL-PTD combined with clinical parameters at initial diagnosis to refine risk stratification.
Patients and methods: Prognostic impact of clinical and mole...
Background: Approximately 45% of AML patients have a normal karyptype (NK-AML) and an intermediate clinical prognosis. As only 20–42% of these patients show long-term survival, it is important to identify prognostic markers to distinguish patients’ outcome more precisely. Mutations in the FLT3 gene such as internal tandem duplications (ITD) in the...
We have previously shown that a monthly myelosuppressive chemotherapy proved superior to high-dose cytarabine consolidation therapy (J Clin Oncol2003,21:4496) after induction therapy and induction-type consolidation therapy. In the multicenter AMLCG 1999 trial, we reported that this maintenance therapy resulted in equal results with lower therapy-r...
Exposure to bacterial antigens and other environmental factors in combination with a genetic susceptibility have been implicated in the etiology of inflammatory bowel disease (IBD). As certain perinatal circumstances, e.g., delivery by cesarean section, predispose to a different intestinal colonizations the aim of this analysis was to define a pote...
Reconvalescence after lung resections underlies several influences. The aim of this study was to outline the effect of patient and operative factors.
Between 1/97 and 6/98 a cross sectional prospective study was undertaken at the University of Ulm. 125 patients with lung resections for various reasons via anterolateral thoracotomy were included. Va...
Einleitung: Die Rekonvaleszenz nach Lungenresektionen unterliegt zahlreichen Faktoren. Ziel dieser Studie war es, festzustellen, wie sich Eigenschaften des Patienten und der Operation auswirken. Methode: In einer prospektiven crossektionalen Studie an der Universität Ulm wurden von 1/97 bis 6/98 bei 125 Patienten mit Lungenresektionen via anterolat...
As recently reported modifications, dose or duration of treatment had no impact on outcome of AML in older patients (Burnett et al. Blood 106: 162a, 2005). We therefore evaluated 764 patients 60 years of age or older and their various prognostic subgroups in the 1992 and 1999 mulitcenter randomized trials by the German AMLCG where patients received...
After recent reports addressed prognostic factors and outcome in older age AML (Burnett et al. Blood106:162a,2005; Wheatley et al. Blood106:199a,2005; Appelbaum et al. Blood107:3481–5,2006; Farag et al. Blood108:63–73,2006) we evaluated 764 patients of 60–85 (median 66) years reduced to those with de-novo AML, known karyotype, and identical consoli...
Seventy-one patients with acute myeloid leukemia (AML), most of them (63/71) considered ineligible for conventional allogeneic hematopoietic stem cell transplantation (HSCT), were enrolled into a phase II study on reduced intensity myeloablative conditioning with fractionated 8 Gy total body irradiation (TBI) and fludarabine (120 mg/m2) (Blood. 200...
Background: Mutations in the NPM1 gene represent the most frequent alterations in patients with AML and are associated with a favourable clinical outcome.
Patients and Methods: We analyzed 803 patients that were treated in the AMLCG2000 study. Patients with de novo or secondary AML or high-risk myelodysplastic syndrome (MDS) were randomly assigned...
Therapy - related acute myeloid leukemia (t-AML) is one of the most severe long - term complications of successful cancer treatment using chemo- and/or radiotherapy. Its frequency is increasing, also in patients with autoimmune disease after cytostatic therapy. Cytogenetic and molecular biological analysis have identified several subgroups, however...
Background: The prognosis of patients with acute myeloid leukemia (AML) has improved in recent years, partly due to the use of intensive double induction chemotherapy. Patients with adverse cytogenetic risk factors, especially those with a complex aberrant karyotype, however, still have a grave prognosis. Previous results from the German AMLCG stud...
Einleitung: Die Resektion von Lungenmetastasen kann das Leben von Patienten verlängern, im Einzellfall sogar Heilung bedeuten. Welches Risiko von der Operation unter den aktuellen Bedingungen in der Thoraxchirurgie ausgeht, war Gegenstand dieser Studie. Methodik: Dafür wurden die Krankengeschichten von 199 Patienten, bei denen 300 Metastasenresekti...
The resection of pulmonary metastases can extend life of patients, even offering the possibility of cure. A risk analysis of the surgical procedure under the current practice of the thoracic surgery has been performed in this study.
Using a prolective method, data from 199 patients with 300 lung resections for pulmonary metastases done in our unive...
Genetic and molecular techniques have provided increasing insights into the biology of acute myeloid leukemia (AML). These investigations showed that AML is not a homogeneous disease but a heterogeneous group of biologically different subentities. These subentities are currently primarily defined by cytogenetics by which three main subgroups can be...
Intensification by high-dose araC in post-remission (NEJM331:896,1994) or induction (Blood87:1710,1996; Blood88:2841,1996) therapy, and autologous stem cell transplantation (Lancet351:700,1998) are efforts to improve the cure rate in AML. Starting in 1999 the German AMLCG randomized the patients to receive double induction (Blood93:4116,1999) by TA...
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 expressi...
Acute myeloid leukemia (AML) is a heterogeneous composition of biologically defined subgroups. Modern trials aim at developing subgroup-specific therapies. The German AML Cooperative Group 1999 trial asks three questions in a randomized factorial design: high-dose vs. standard-dose AraC during induction therapy; G-CSF priming vs. no G-CSF priming;...
Allogeneic stem cell transplantation (allo-SCT) is considered the most potent postremission therapy for acute myeloid leukemia (AML). Its superior antileukemic activity is largely ascribed to the powerful graft-versus-leukemia (GvL) effects exerted by donor lymphocytes. However, due to considerable treatment-related lethality the gains in relapse p...
In the past few years increasing insights into the pathogenesis and biology of acute myeloid leukemia have been gained. These insights reveal, that the clinical picture of acute myeloid leukemia (AML) includes a variety of different subtypes which vary in their biology but also in their sensitivity to chemotherapy and treatment response [1–3]. Base...
The outcome in patients with AML appears influenced by some therapeutic variables such as different intensity chemotherapy, growth factor priming, autologous or allogeneic transplantation. Even more than by treatment variables the outcome is determined by genetic and functional features related to the individual disease biology. Open questions are...
In a trimodality treatment approach for Stage III nonsmall cell lung carcinoma (NSCLC), the prognostic impact of the ras mutation status in resection specimens was evaluated.
Forty patients with Stage III NSCLC underwent tumor resection after neoadjuvant treatment with two cycles of chemotherapy (ifosfamide, carboplatin, and etoposide) and subseque...
The study was initiated to obtain epidemiologic data and information on anatomic and histologic distribution, clinical features, and treatment results in patients with primary gastrointestinal non-Hodgkin's lymphomas (PGI NHL).
Between October 1992 and November 1996, 371 PGI NHL patients were eligible to evaluate clinical features. Radiotherapy and...
The aim of the study was to obtain data on anatomic and histologic distribution, clinical features, and treatment results of patients with primary gastrointestinal non-Hodgkin's lymphomas, particularly combined surgical and conservative treatment (CSCT) versus conservative treatment (CT) alone for primary gastric lymphoma (PGL) in localized stages....
Undertreatment of the older patients with acute myeloid leukaemia (AML) can explain, in part, their inferior outcome when compared with that of younger patients. Corresponding to the benefit to patients under the age of 60 from high-dose Ara-C there are also dose effects in those over 60 years old, in particular for daunorubicin in the induction tr...
The clinical significance of complex chromosome aberrations for adults with acute myeloid leukaemia (AML) was assessed in 920 patients with de novo AML who were karyotyped and treated within the German AML Cooperative Group (AMLCG) trials. Complex chromosome aberrations were defined as three or more numerical and/or structural chromosome aberration...
The inferior outcome in the older patients with AML when compared with that in younger patients can be explained, in part, by a traditional undertreatment in most of the published series. In correspondence to the benefit of patients under age 60 from highdose AraC there are dose effects in the over 60es in particular for daunorubicin in the inducti...
Maintenance treatment for patients with acute myeloid leukemia (AML) in remission has recently been controversially discussed and even abandoned by several groups. An analysis of 14 recently published multicenter trials, however, revealed the highest probabilities of relapse-free survival (RFS), in the range of 35% to 42% at 4 to 5 years, only in p...
A prospective multicenter study was performed to investigate the clinical and molecular results of intensified double induction therapy including high-dose cytarabine (ara-C) in combination with ATRA in newly diagnosed acute promyelocytic leukemia (APL), followed by consolidation and 3 years maintenance therapy. Fifty-one patients, diagnosed and mo...
Partial tandem duplications of the MLL gene have been associated with trisomy 11 in acute myeloid leukemia (AML) and recently, have also been reported for karyotypically normal AML. In order to test the incidence and prognostic importance of this molecular marker, we have analyzed eight cases of AML with trisomy 11 and 387 unselected consecutive ca...
Serious doubts about the relative value of allogeneic BMT in 1 st remission AML have been raised by recent publications (NEJM 332:217,1995; NEJM 334:1428,1996; Blood 90:2978,1997; NEJM 339:1649,1998). In these studies patients were compared on intentto-treat according to donor vs no-donor and additional assignment criteria. In order to maximize the...
Acute myeloid leukemia (AML) at older age is associated with several biologic and clinical characteristics. Hence, it may arise from an early level of hematopoietic stem cells and has a high frequency of blast cells with multidrug resistance glycoprotein MDR1 expression and particularly a high incidence of poor prognostic karyotypes. These factors,...
Early intensification of chemotherapy with high-dose cytarabine either in the postremission or remission induction phase has recently been shown to improve long-term relapse-free survival (RFS) in patients with acute myeloid leukemia (AML). Comparable results have been produced with the double induction strategy. The present trial evaluated the con...
Because of conflicting reports on the prognosis of patients with c-kit receptor positive AML and lacking correlations with cytogenetic analyses, we prospectively evaluated the c-kit receptor expression in 917 AML patients (750 adult patients; 167 children) using flow cytometry and compared the results to the immunophenotype, morphological and cytog...
A prospective, randomized, double-blind placebo-controlled trial was designed to evaluate the impact of granulocyte/macrophage-colony-stimulating factor (GM-CSF) on the efficacy of sequential high-dose cytosine arabinoside/mitoxantrone chemotherapy (S-HAM) in adult patients with high-risk myelodysplastic syndromes (MDS). GM-CSF or placebo was given...
The need for scientific investigation into the benefits of thoracoscopy in comparison to thoracotomy as well as State intervention to assure quality in the field of surgery motivated the members of the commission of endoscopic surgery of the German Society of Thoracic Surgery to conduct a pilot project at their hospitals. This pilot project was exp...
This paper investigates which angles of acetabular (AA) and femoral antversion (FA) have to be considered as normal and which ones cause changes in range of movements, pain and osteoarthrosis. METHOD OF INVESTIGATION: 15-20 degrees of anteversion of AA and FA were tested regarding normality. Diminished anteversion angles were divided in groups -2 a...
ETIOLOGY:
Differences in the anteversion of the acetabulum and the femur must be attributed to the different rotational postures of the fetus as investigations and experiments have shown. After delivery there is a spontaneous improvement, but in perhaps 15% of the joints, diminished or increased acetabular or femoral anteversion will persist during...
Lesions of the acetabular labrum should be treated by correcting the causes. In a steep acetabulum where the femoral head brings the acetabular labrum under tension and traction, the acetabulum should be rotated by triple pelvic osteotomy to slightly over-corrected acetabular measurements. Severely diminished acetabular and femoral anteversion can...
Lesions of the acetabular labrum should be treated by correcting the causes. In a steep acetabulum where the femoral head brings the acetabular labrum under tension and traction, the acetabulum should be rotated by triple pelvic osteotomy to slightly overcorrected acetabular measurements. Severely diminished acetabular and femoral anteversion can a...
Trisomy 8 is the most frequent numerical chromosome aberration in acute myeloid leukaemia (AML). It occurs either as the sole anomaly or together with other clonal chromosome aberrations. We investigated whether accompanying chromosome anomalies influence the clinical outcome in patients with trisomy 8 and de novo AML. Since 1986, in 713 AML cases...
In November 1994, the AML Cooperative Group (AMLCG) started a still ongoing trial for treatment of patients with acute promyelocytic leukemia (APL). The therapy consists of TAD/HAM double induction chemotherapy in combination with all-trans retinoic acid (ATRA) until complete remission, followed by TAD consolidation and monthly maintenance. After s...
HAM as a combination of high-dose AraC and mitoxantrone produced 53% complete remissions in patients with refractory AML according to rigid criteria. Its sequential version S-HAM even proved successful in salvage treatment for patients pretreated with HAM. In first line treatment TAD-HAM double induction improved the long term remission rate by mor...