Towards a pathogenesis-oriented therapy of acute myeloid leukemia.

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 discriminated: AML with balanced translocations, AML with unbalanced aberrations and AML without cytogenetically detectable aberrations. Within the latter group molecular alterations are identified in more than half of cases such as NPM mutations, FLT3 mutations, MLL duplications and mutations of CEBP-alpha. The clinical meaning of these findings is illustrated by substantial differences in response to therapy and long-term outcome. As demonstrated by the recent multicenter trial of the German AML Cooperative Group (AMLCG) and other studies intensification of induction therapy may improve the results in distinct subtypes but fails to do so in others. Therefore, new strategies need to be explored which incorporate the knowledge about the biology of AML to develop biology adapted treatment strategies. This process has just begun and is predominantly determined by the availability of new agents and their evaluation in clinical phase I and II studies. A variety of targets are currently explored and some trials have yielded promising results already. The step towards a biology adapted treatment of AML is long and requires the combined efforts of researchers, clinicians and the pharmaceutical industry. The first steps towards this goal have been taken and give rise to the hope for more effective and more specific therapies of AML.

[The competence network "acute and chronic leukemias"]. / Das Kompetenznetzwerk "Akute und chronische Leukämien".

Leukemias are a challenge and a cost factor to society because of their frequency in all age groups. They also serve as a model for a variety of diseases and possess exemplary relevance for basic research and patient care. Leukemia research and therapy have achieved high standards and even a leading position in Germany with regard to clinical trials, standardization of diagnostics and molecular studies of prognostic factors, signal transduction and gene expression. Progress is hampered, however, by fragmentation of leukemia trial groups, diagnostic approaches and treatment research activities. A network was therefore created to integrate the leading leukemia trial groups on chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphatic leukemia (ALL), myelodysplastic syndromes (MDS) and chronic myeloproliferative diseases (CMPD) and their interdisciplinary partners (diagnostics, treatment research, biometry) in cooperation with basic research and pharmaceutical industry to foster advancements in leukemia-related research and health care through clinical trials, promotion of translational research, introduction of standards for diagnostics and therapy, and development of evidence-based guidelines. Achievements include establishment of central information, communication and management structures, creation of an AML intergroup comprising five study groups, formation of a myelodysplastic syndromes study group and establishment of platforms for diagnostics, genomics and proteomics, and medical informatics. Exchange of scientific progress is mediated by intra- and internet, bi-annual newsletters, regular project group meetings and annual network symposia. Already now, the network structures leukemia therapy and research in Germany and supports the spread of scientific excellence in the field of leukemias.

Risk-adapted therapy of AML: the AMLCG experience.

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; and autologous stem cell transplantation vs. maintenance therapy. An interim analysis with 938 patients reveals subgroup-specific differences in treatment efficacies. Thus, the application of high-dose AraC during induction results in a superior outcome as compared to standard-dose AraC in patients with unfavorable prognosis but not in other patients. These results underline the need for large comprehensive trials to allow the detection of therapy effects in biologically defined subgroups of AML.