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Department of Internal Medicine III - a world-renowned institution

The Department of Internal Medicine III is nationally and internationally one of the most renowned institutions for the research, diagnosis and treatment of acute myeloid leukaemia (AML). The clinic is the headquarters of the German-Austrian AML Study Group (AMLSG), currently one of the largest study groups in the world with around 80 trial centres in Germany and Austria. The Department of Internal Medicine III treats around 150 patients with newly diagnosed AML every year.

Diagnostics

Initial diagnostics are carried out as part of the AMLSG BiO(Biologyand Outcome) registry study (clinicaltrials.gov NCT01252485). In this registry study, patients give their consent to genetic diagnostics, to the documentation of their clinical data and to biobanking, i.e. cell samples are stored for future research projects. The diagnostics are based on the 2022 recommendations of the European LeukaemiaNet (ELN) (Döhner at al. Blood 2022).

In addition to the morphological assessment of bone marrow and blood smears, diagnostics include immunophenotypic, cytogenetic and molecular genetic diagnostics. Morphological and immunophenotypic diagnostics are carried out on the day the sample is taken. For many years, we have established a unique diagnostic platform for molecular genetic diagnostics that allows us to analyse a panel of genetic markers (gene fusions, gene mutations) within 24-48 hours and transmit the findings. The establishment of this rapid molecular screening became necessary with the introduction of the first molecularly targeted therapies (especially FLT3 inhibitors). The result of the cytogenetic analysis is available within 5-7 days.

Genetic risk stratification

Genetic markers are not only essential for accurate diagnosis, they are also among the most important prognostic factors (see 2022 ELN risk stratification). For example, genetic markers are used to decide whether or not to recommend an allogeneic haematopoietic stem cell transplant to a patient. In addition, genetic markers are increasingly identifying patients for molecularly targeted therapies. Prominent examples of this are mutations in the receptor tyrosine kinase FLT3 and the IDH enzymes IDH1 and IDH2. Inhibitors have now been successfully developed and approved for these forms of AML.

Detection of minimal residual disease

During the course of treatment, bone marrow and blood samples are usually analysed for minimal or measurable residual disease (MRD) after each treatment cycle. In principle, two methods are available for these analyses: molecular genetic assays (e.g. detection of gene fusions or gene mutations using highly sensitive quantitative PCR or next-generation sequencing), and multi-parameter flow cytometry.

Selected research projects

An important goal of our research projects is the elucidation of the molecular pathogenesis of the disease. This includes the identification and characterisation of genetic markers, as well as the determination of the prognostic and predictive significance of these markers. For this purpose, we have access to the world's largest biobank of primary cell samples from AML patients. All modern methods of molecular genetics (e.g. conventional DNA sequencing, next-generation sequencing, polymerase chain reaction [PCR], quantitative PCR, digital PCR, gene expression analyses) and flow cytometry are established.

Whenever possible, our patients are treated as part of clinical therapy studies. In most cases, these are innovative therapy studies that we conduct under our leadership as part of the AMLSG. In addition, our reputation and large number of patients make us an attractive partner for the pharmaceutical industry for pharmaceutical-sponsored studies.

Further information on active studies can be found at

Study Centre >> Clinical Trials >> AML

Our study centre is part of the Centre for Clinical Studies under the umbrella of the Comprehensive Cancer Center Ulm (CCCU). The study centre is certified according to DIN EN ISO 9001:2008 and fulfils the requirements of the criteria catalogue of the German Society for Haematology and Oncology (DGHO).

The haematology laboratory, the flow cytometry laboratory and the cytogenetic and molecular genetic diagnostics laboratory are accredited in accordance with DIN EN ISO 15189:2014 (medical laboratory diagnostics) and DIN EN ISO/IEC 17025:2005 (medical laboratory tests in the context of clinical studies).

The number of new cases of AML is currently estimated at around 2-4 people per 100,000 inhabitants per year and rises continuously with age up to a peak of over 15 per 100,000 inhabitants per year in the over 65 age group. AML is therefore a disease of older people, with the average age of onset being around 70 years.

Substances that alter the genetic material and radioactive radiation can increase the risk of developing AML or other cancers. The occurrence of so-called therapy-associated myeloid diseases is particularly common after previous radiotherapy and chemotherapy due to a previous cancer. Furthermore, an existing bone marrow disease, such as myelodysplasia syndrome (MDS) or myeloproliferative neoplasia (MPN), can develop into secondary AML.

Studies in recent years have shown that some patients carry germline mutations that predispose them to developing AML. Such germline mutations are not only identified in childhood leukaemias, but increasingly also in adult leukaemias.

The symptoms of AML are essentially determined by the suppression of normal haematopoiesis:

• Anaemia (anaemia): A decrease in oxygen carriers results in fatigue, pallor, shortness of breath and exhaustion
• Leukopenia and neutropenia (decrease in immune cells): Infections caused by bacteria, fungi and viruses, some of which have a very severe course
• Thrombocytopenia (decrease in blood platelets): Bleeding that can become life-threatening if vital organs such as the brain are affected

Infiltration of extramedullary organs and tissues such as the liver, spleen, lymph nodes, bones, gingiva (gums), skin and central nervous system can result in various symptoms and findings:

• Hepatomegaly (enlargement of the liver)
• Splenomegaly (enlargement of the spleen)
• Lymphadenopathy (swelling of the lymph nodes)
• Bone pain
• Gingival hyperplasia (swelling of the gums)
• Non-specific neurological symptoms (e.g. headaches, dizziness, visual and sensory disturbances)

A tumour-forming leukaemia manifestation outside the bone marrow is called a chloroma.

Very high leukocyte counts can lead to symptoms of leukostasis (visual disturbances, central nervous deficits, bleeding events). Laboratory tests often reveal an increase in lactate dehydrogenase, while electrolyte disorders (hyper-/hypokalaemia) or hyperuricaemia are less common. Coagulation disorders are mainly found in acute promyelocytic leukaemia (APL) in the form of disseminated intravascular coagulation syndrome (DIC).

Standard diagnostic procedures include morphological assessment of the blood and bone marrow smear, immunophenotyping (using flow cytometry), as well as cytogenetic and molecular genetic analysis.

The blood and bone marrow smears characteristically show an increase in myeloid blasts of more than 10-20% (less than 5% in normal bone marrow). Immunophenotyping uses a panel of monoclonal antibodies to detect specific molecules on the surface and inside the leukaemia cells. Immunophenotyping is used to determine lineage affiliation (AML versus other forms of leukaemia) and to identify a leukaemia-associated phenotype (LAIP), which can be used to detect minimal residual disease during the course of treatment.

The disease is classified according to the current International Consensus Classification (ICC). This predominantly takes into account the underlying genetic changes.

Patients who are eligible / suitable for intensive chemotherapy

The treatment of AML is still based on the administration of intensive chemotherapy, whereby cytostatic drugs (drugs with an inhibitory effect on cell division) with different mechanisms of action are combined. Two main cytostatic drugs are used here, anthracyclines and cytosine arabinoside (cytarabine, Ara-C), which have been tried and tested in the treatment of AML for many years.

CPX-351 (Vyxeos®) has been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for certain high-risk forms of AML. CPX-351 is a liposomal packaging of the two cytostatic drugs cytarabine and dunorubicin.

For AML with FLT3 mutations, the FLT3 inhibitor midostaurin (Rydapt®) has been approved in combination with intensive chemotherapy.

Other promising new drugs are being tested in clinical trials with the aim of continuously improving treatment results. These drugs include, for example, the BCL-2 inhibitor venetoclax and the IDH1 and IDH2 inhibitors ivosidenib and enasidenib. We can offer all these substances to our patients as part of controlled therapy studies.

Course of treatment: In the treatment of AML, a remission of the disease must first be achieved through initial chemotherapy, known as induction chemotherapy. A complete remission is defined as a microscopically detectable reduction of the leukaemia cells ("blasts") in the bone marrow to below 5% with simultaneous normalisation of haematopoiesis. After induction chemotherapy, it is initially possible to achieve a remission of the disease in approx. 70-80% of patients aged between 18 and 60 years. Without further chemotherapeutic treatment, however, there is a very high risk that the leukaemia will return after a short time (relapse). This induction therapy is therefore followed by consolidation chemotherapy with the aim of killing the remaining leukaemia cells and ensuring permanent freedom from leukaemia. Despite intensive consolidation chemotherapy, around 30-40% of patients with AML suffer a relapse. After a relapse, the chances of success in achieving remission with a new chemotherapy are lower. It is therefore of crucial importance to prevent a relapse of the disease. It has been known for some years that certain genetic changes are associated with a higher or lower probability of recurrence. A comprehensive genetic analysis at the time of diagnosis can therefore help to estimate the risk of recurrence. For patients who have a high risk of recurrence due to the genetic changes present, we recommend performing an allogeneic haematopoietic stem cell transplant. Haematopoietic stem cell transplantation is the procedure that can most effectively prevent the risk of recurrence, but this is associated with a higher therapy-related mortality rate (see below).

Acute promyelocytic leukaemia (APL) is a rare form of AML that generally requires a different therapy. APL is characterised by the chromsomal translocation t(15;17) with the resulting PML-RARA gene fusion. The therapy for this form of leukaemia consists of combination treatment with the vitamin A derivative all-trans retinoic acid (ATRA) and arsenic trioxide. With this 'chemotherapy-free' combination treatment, this form of leukaemia can now be cured in over 90% of cases.

Elderly patients who are not eligible/suitable for intensive chemotherapy

The therapy results in older patients (>65-70 years) are significantly worse than those in younger patients. The rate of complete remissions - i.e. normalisation of the blood count and elimination of blasts in the bone marrow (<5%) - is between 50% and 70% in older patients. This is caused on the one hand by patient-related factors, i.e. concomitant diseases such as high blood pressure, diabetes mellitus, which lead to complications, and on the other hand by the presence of prognostically unfavourable genetic factors.

Depending on the genetic subgroup of leukaemia and the concomitant diseases, there are various forms of therapy that differ in terms of toxicity and effect. With conventional chemotherapy, long-term remissions are only achieved in approx. 10-15% of patients. In principle, allogeneic stem cell transplantation is also possible in older patients, although the patient's general condition and the presence of concomitant diseases are of decisive importance here.

For patients who are not suitable for conventional intensive chemotherapy, the combination of a so-called hypomethylating agent (azacytidine, decitabine) with the BCL-2 inhibitor venetoclax (VENCLYXTO®) is the therapy of choice. With these therapies, remission can be achieved in approx. 60% of cases, but the median life expectancy is only approx. 12-15 months. Numerous new therapy combinations are currently undergoing clinical trials.

Allogeneic stem cell transplantation

Allogeneic bone marrow or haematopoietic stem cell transplantation (allogeneic SCT) is currently the only curative treatment option for many younger, but now also many older AML patients, especially those with a high-risk constellation. Allogeneic SCT is a treatment procedure that should be carried out at a highly specialised centre that has a team of doctors and nursing staff with many years of expertise and the necessary infrastructure.

Allogeneic SCT has two therapeutic principles. Firstly, the patient receives intensive chemotherapy (possibly in combination with whole-body radiotherapy), which should lead to the destruction of the leukaemia. Secondly, the infusion of the donor transplant causes an immune reaction of the donor immune cells against the remaining leukaemia cells in the recipient (so-called graft versus leukaemia effect). The adverse reaction and therefore the risk of allogeneic SCT is primarily that the donor immune cells not only act against the leukaemia cells, but also trigger an immune reaction against other organs (e.g. skin, liver, gastrointestinal tract; so-called graft versus host disease). This GvHD reaction is the main cause of therapy-associated mortality in allogeneic SCT, which is between 10% and 25%.

In allogeneic SCT, stem cells are transferred from a suitable donor to the recipient. The suitability of a donor is determined by a blood test, known as HLA typing. Either HLA-identical family donors (especially siblings) or, if no suitable family donor is available, an HLA-compatible unrelated donor is used as a stem cell donor. More than 10 million unrelated donors are available in the various donor centres worldwide. It is currently possible to find a suitable unrelated donor for 90% of all patients within 1-3 months.

• Biomedical and pharmaceutical industry
• German Research Foundation (DFG), e.g. Collaborative Research Centre 1074
• Federal Ministry of Education and Research (BMBF)
• German Cancer Aid
• European Union
• Building Block and Clinician Scientist Programme, Medical Faculty of the University of Ulm
• Else Kröner-Fresenius Foundation

AML Laboratory

Clinical Studies - AML

AML Study Group

German Cancer Aid

European Leukaemia Net

Competence Network Leukaemia

Status: 5 February 2023