Chronische myeloische Leuk?mie

Survival of patients with chronic myeloid leukemia (CML) has dramatically improved with the introduction of the BCR-ABL-specific tyrosine kinase inhibitor imatinib. As a rule patients on therapy with imatinib achieve permanent complete cytogenetic and molecular remission. Patients who are primarily refractive to imatinib or lose remission achieved using imatinib are in the minority. This group has a poor prognosis. This article gives a transparent review of the diagnostics necessary when CML is primarily diagnosed and for assessment of the response during the course of the therapy. The guidelines developed for this procedure by the European leukemia network on the type and frequency of surveillance controls as well as the diagnostic criteria for imatinib resistance or suboptimal response will be presented. The indications for allogenic stem cell transplantation and the administration of second generation BCR-ABL inhibitors will be discussed as therapeutic alternatives in cases of imatinib failure in a stage-specific manner. Finally a view on therapy targets and forms of future first-line therapy of CML will be given.     

Akute myeloische Leukämie

Acute myeloid leukemia (AML) is a genetically heterogeneous disease. The genetic diagnostics have become an essential component in the initial work-up for disease classification, prognostication and prediction. More and more promising molecular targeted therapeutics are becoming available. A prerequisite for individualized treatment strategies is a fast pretherapeutic molecular screening including the fusion genes PML-RARA, RUNX1-RUNX1T1 and CBFB-MYH11 as well as mutations in the genes NPM1, FLT3 and CEBPA. Promising new therapeutic approaches include the combination of all- trans retinoic acid and arsentrioxid in acute promyelocytic leukemia, the combination of intensive chemotherapy with KIT inhibitors in core-binding factor AML and FLT3 inhibitors in AML with FLT3 mutation, as well as gemtuzumab ozogamicin therapy in patients with low and intermediate cytogenetic risk profiles. With the advent of the next generation sequencing technologies it is expected that new therapeutic targets will be identified. These insights will lead to a further individualization of AML therapy.     

Chronische lymphatische Leukämie

Chronic lymphocytic leukemia (CLL) is characterized by a highly variable clinical course. Among the biological features underlying this heterogeneity, genetic lesions and the mutational status of the immunoglobulin heavy chain variable genes (IGHV) are of importance. Therapeutic options in CLL have been considerably expanded during recent years. The combination of fludarabine, cyclophosphamide and rituximab (FCR) has become gold standard in the first-line treatment of physically fit patients. Bendamustine plus rituximab (BR) is currently being compared to FCR in studies and chlorambucil is still of relevance for elderly patients with comorbidities. Alemtuzumab is an alternative for high-risk patients (refractory CLL, 17p deletion, TP53 mutation). Allogeneic stem cell transplantation (allo-SCT) offers the only chance of cure but not without substantial mortality. Innovative approaches focus on individualized, targeted therapies. A number of novel agents are in clinical trials and show marked efficacy combined with good tolerability. This review provides an overview of the current therapeutic options and of promising novel approaches.     

Blutgruppen und Leukämie

Zusammenfassung Es wird über ungewöhnliche Blutgruppenbefunde bei Leukämie berichtet. Es handelt sich um eine Schwächung bis zu vollkommenem Schwund der Antigene. Diese Änderung wird mit den bei Gesunden gefundenen Varianten und den durch chemische Substanzen erzeugten Veränderungen verglichen. Die Möglichkeit einer somatischen Mutation von «Retikulumzellen» als Ursache der beschriebenen Antigen-veränderungen wird diskutiert.

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Summary The authors report unusual blood group findings in cases of leukaemia. The antigens are weakened or even their existence can not be demonstrated. These changes are compared with those found in variants of blood group antigens in healthy persons and with the changes produced in red cells by chemical substances. The possibility of a somatic mutation being the cause of the described antigenic changes is discussed.

     

Zur Differentialdiagnose der eosinophilen Leukämie

Zusammenfassung Mitteilung einer subakut verlaufenden Leukose mit hoher Eosinophilie und Linksverschiebung, deren Morphologie, Verlauf und autoptischer Befund die Definitionskriterien einer eosinophilen Leukämie erfüllen. Die Grenzen der differentialdiagnostischen Abgrenzung einer eosinophilen Leukämie von einer chronischen myeloischen Leukämie mit hoher Begleiteosinophilie werden anhand der Literatur und der eigenen Untersuchungsergebnisse diskutiert.

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Summary Report of a case of subacute leucosis with intense eosinophilia and shift to the left, in which the course, morphology and autopsy findings fulfilled the criteria of eosinophilic leukaemia. The distinctions between eosinophilic leukaemia and chronic myeloid leukaemia associated with great increase of eosinophils are discussed in the light of the present case and of the relevant literature.

     

Die T-Large Granular Lymphocyte Leukämie (T-LGL-Leukämie) –

T-Large Granular Lymphocyte (T-LGL) leukaemia is a rare clonal disease characterized by neutropenia and/or anaemia. Because of its strong association with rheumatoid arthritis (RA), T-LGL leukaemia is an important differential diagnosis to Felty's syndrome. This differentiation might be especially difficult since, in severe RA with extraarticular manifestations, there is often an expanded memory effector T-cell population which can hardly be separated from T-LGL leukaemia cells by means of immunophenotyping. The main criterion for T-LGL leukaemia is the detection of a clonal T-cell-receptor rearrangement by PCR. First-line therapy consists of weekly low-dose methotrexate. Alternatively, other immunosuppressives or cytotoxic agents can be useful. There are very limited data from therapy studies. The German CLL study group has initiated a protocol using parenteral low-dose methotrexate as first-line therapy and fludarabine as second-line medication.     

Erythroblasten-Leukämie nach Injektion von Virus der myeloischen Leukämie der Maus

Zusammenfassung Es wird über die Pathologie und zellfreie übertragbarkeit einer nach Injektion des myeloischen Leukämievirus der Maus aufgetretenen Erythroblasten-Leukämie berichtet. Makroskopisch ist die Erkrankung durch eine ausgeprägte Hepatosplenomegalie, hämatologisch durch eine starke Vermehrung maligner Erythroblasten in der Peripherie gekennzeichnet. Histologisch zeigen Leber und Milz ausgedehnte Infiltrationen durch maligne Erythroblasten. Durch das ausschließliche Auftreten intralobulärer Infiltrationen unterscheidet sich diese Leukoseform von allen virusinduzierten Mäuseleukämien. Nach zellfreier Übertragung der Erythroblastose tritt eine Aufspaltung in hämatologisch differente Leukämietypen und eine Bildung echter Mischleukämien auf. Cytochemische Untersuchungen ergaben eine starke Positivität der Naphthylacetat-Esterase in den leukämischen Erythroblasten.

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Summary A report is made of the pathology and transmittability of an erythroblastic leukemia occuring after the injection of the myelogenous leukemia virus of the mouse. Macroscopically, the disease is characterized by a pronounced hepatosplenomegaly, and hematologically by a sharp increase of malignant erythroblasts in the periphal blood. The liver and spleen histologically reveal extensive infiltrations of malignant erythroblasts. This form of leukosis may be differentiated from all virus-induced leukemias of the mouse by the exclusive occurrence of intralobular infiltrations. After the cell-free transplantation of the erythroblastosis, a division into hematologically different types of leukemia occurs, with true, mixed leukemias developing. Cytochemically an intense, positive reaction of the naphthylacetate esterase was found in the leukemic erythroblasts.

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Mit 3 Textabbildungen

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Herrn Prof. Dr. Dr. h. c. K. H. Bauer zum 75. Geburtstag gewidmet

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Für die Synthese des Substrats danken wir Herrn Dipl.-Chem. M. Schütt aus unserem Institut     

Maßgeschneiderte Therapie der chronischen myeloischen Leukämie

State of the art management of chronic myeloid leukemia (CML) patients with the selection of best available treatment options requires systematic cytogenetic and molecular monitoring. The choice of the first-line tyrosine kinase inhibitor depends on integration of comorbidities and individual treatment goals. Clinical prognostic scores should be used for cohort comparison and for stratification in randomized trials. Their relevance for individual treatment decisions has not yet been established. Essential for therapeutic decision-making is the achievement of predefined cytogenetic and molecular milestones in the course of the disease. In cases of treatment resistance or relapse the analysis of potential causes is required. After exclusion of compliance issues bone marrow analysis for the accurate characterization of the hematologic disease state and exclusion of clonal evolution is recommended. In parallel, BCR-ABL mutation analysis should be performed. The choice of second-line treatment depends on the predicted sensitivity of any BCR-ABL mutation detected and the clinical history of the patient. Most important is prevention of disease progression as treatment results in advanced disease are still not satisfying. Therefore, allogeneic stem cell transplantation should be considered early in resistant disease, when high-risk parameters (e.g. multiresistant mutations) have been detected.     

Experimentelle Leukämie durch Indican (Indoxylschwefelsaures Kalium)

Ohne Zusammenfassung     

Chronische Niereninsuffizienz mit Hyperkalzämie bei einem 60-jährigen Patienten

A 60-year-old man developed stomach pains and early morning vomiting as well as fatigue over the last few months. Severe hypercalcemia was found in combination with a significantly reduced renal function. Laboratory tests as well as histological findings from the kidneys led to the working diagnosis of sarcoidosis with renal and possible osseous manifestations. After 14 days of oral medication with steroids the symptoms were significantly improved and renal parameters normalized.     

Unklare Leberraumforderungen bei einer 19-jährigen Patientin mit akuter myeloischer Leukämie

A 19-year old woman with acute myeloid leukemia presented with newly observed liver lesions during ongoing consolidation therapy. Due to unexplained cholestasis during induction, biliary duct drainage was performed. Microbiologic and histologic examinations revealed the presence of atypical mycobacteria, namely Mycobacterium abscessus. With an appropriate antiinfective regime which was continuously administered using a portable pump in the outpatient setting, further mycobacterial spread during simultaneous chemotherapy-associated neutropenia was prevented. Despite multiple bacterial resistance mechanisms, proper treatment of leukemia with curative intention could be ensured.     

Chronische Nierentransplantatschädigung

Chronic functional deterioration with premature loss of renal allografts remains the greatest single challenge in renal transplant medicine. The CAN (chronic allograft nephropathy) concept has been established in the literature as the major cause of graft failure: Essentially all kidney transplants experience multifactorial, relentlessly progressive fibrosis and atrophy, which cannot be ameliorated by any specific therapy. However, recent data indicate that the CAN concept is invalid. In >80% of all chronically damaged and failed kidney transplants a specific underlying disease process is identifiable. Glomerular pathologies either caused by glomerulonephritis or anti-HLA antibody mediated injury to the microcirculation are by far the most frequent disease processes (>80%) to cause allograft failure. By abandoning the non-specific CAN concept and replacing it with specific diagnostic approaches to chronic allograft damage, the development of causative therapies becomes more feasible.