Thomas Büchner

Overexpression of vascular endothelial growth factor (VEGF) and its cellular receptor KDR (VEGFR-2) in the bone marrow of patients with acute myeloid leukemia

Vascular endothelial growth factor (VEGF) and its cellular receptor VEGFR-2 have been implicated as the main endothelial pathway required for tumor neovascularization. However, the importance of the VEGF/VEGFR-2 system for angiogenesis in hematologic malignancies such as AML remains to be elucidated. In 32 patients with newly diagnosed untreated AML, we observed by immunohistochemical analysis of bone marrow biopsies significantly higher levels of VEGF and VEGFR-2 expression than in 10 control patients (P <0.001). In contrast, VEGFR-1 staining levels in AML patients were in the same range as in the controls. Expression of VEGF and VEGFR-2 was significantly higher in patients with a high degree of microvessel density compared to those with a low degree (VEGF: P =0.024; VEGFR-2: P =0.040) and correlated well with bone marrow microvessel density (rs=0.566 and 0.609, respectively; P <0.001). Furthermore, in patients who achieved a complete remission following induction chemotherapy VEGFR-2 staining levels decreased into the normal range. In conclusion, our results provide evidence for increased expression of VEGF/VEGFR-2 of leukemic blasts and correlation with angiogenesis in the bone marrow of AML patients. Thus, VEGF/VEGFR-2 might constitute promising targets for antiangiogenic and antileukemic treatment strategies in AML.

Fatigue as an important aspect of quality of life in patients with acute myeloid leukemia

Quality of life (QL) was evaluated in 101 patients with AML undergoing intensive and prolonged treatment at 12 sequential time points by using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C 30 questionnaire and the profile of mood states scale (POMS). For those patients having completed the course of inpatient treatment (n=37), QL improved from the beginning of chemotherapy to the end of inpatient treatment. Patients who subsequently went off protocol did not differ significantly in their self-assessed QL when compared with patients who completed therapy. Fatigue was more closely related to QL than nausea/emesis or appetite loss, but did not correlate with hemoglobin levels.

Acute leukemias : prognostic factors and treatment strategies

After the first Miinster meeting in 1986 this second symposium was again organized by two German multicenter study groups, the German Society of Hematology and Oncology, and the German Cancer Society, and was supported by the Ministry for Research and Technology of the German Federal Government. The main emphasis has been on data from representative clinical studies. In addition, selected contributions to the biology of acute leukemias as well as new approaches in the characterization, monitoring and cure of the diseases have been presented. This report will concentrate on five major topics, either with permanent practical and clinical importance such as Prognostic factors, Chemotherapeutic strategies for AML, and Autologous bone marrow transplantation, or those opening completely new areas like Hematopoietic growth factors, and Adoptive immunotherapy.

Novel der(1)t(1;19) in two patients with myeloid neoplasias.

Cytogenetic studies can be useful in the clinical management of patients with leukemia. They may also give a clue to leukemogenesis and/or pathogenesis. Numerous disease-specific chromosomal aberrations have been and continue to be identified. Translocation (1;19)(q21 through q23;p13.3) involving the long arm of chromosome 1 and the short arm of chromosome 19 is usually associated with acute lymphoblastic leukemia. We found a new translocation involving one virtually identical breakpoint 19p13 and one distinct 1p13 in two cases of myeloid neoplasms. Studies of bone marrow and peripheral blood specimens specified in one of our patients acute myeloid leukemia and in an other myelodysplastic syndrome. Conventional cytogenetics was supplemented by spectral karyotyping (SKY), microdissection, and fluorescence in situ hybridization. Our first case showed a der(1)t(1;19)(p13;p13.1) as the sole chromosomal change. In addition to this translocation, a pericentric inversion within chromosome 10 and with a cryptic t(10;11) were detected by SKY in the second case. Translocation (1;19)(p13;p13.1) may play a role in the leukemogenesis of myeloid diseases.

Up-front randomization and common standard arm: a proposal for comparing AML treatment strategies between different studies.

Most multicenter randomized AML studies use randomizations of patients early or later in complete remission which necessarily occur with exclusions and positive selection of patients included. Since the exclusion criterias are regimen related and do not follow common standards, incomparabilities between treatment results across different studies are produced by these late randomizations. In order to overcome this problem, we here propose a cooperation of studies on the basis of a general up-front randomization with attribution of 10% patients from each study to a common standard arm. A validation of complete treatment strategies according to intent-to-treat against the standard arm and thus also across the studies is provided by this inter-group model which may contribute to accelerate the therapeutic progress in AML.

Remission induction therapy: the more intensive the better?

Abstract. Intensive induction therapy in acute myeloid leukemia (AML) as in some other systemic malignancies is a strategy fundamentally different from post-remission strategies. Approaches such as consolidation treatment, prolonged maintenance, and autologous or allogeneic transplantation in first remission are directed against the minimal residual disease in which a malignant cell population has survived induction treatment and shows resistance due to special genetic or kinetic features. In contrast, induction therapy deals with naive tumor cells possibly different from their counterparts in remission in terms of their kinetic status and sensitivity. Therefore, in AML the introduction of intensification strategies into the induction phase of treatment has been suggested as a new step in addition to intensification in the post-remission phase. As expected from the dose effects observed in post-remission treatment with high-dose cytarabine (AraC) or longer treatment, similar dose effects have been found in induction treatment both from the incorporation of high-dose AraC and from the double-induction strategy used in patients up to 60xa0years of age. As a particular effect, patients with poor-risk AML according to an unfavorable karyotype, high LDH in serum, or a delayed response show longer survival following double induction containing high-dose AraC as compared to standard-dose AraC. A corresponding dose effect in the induction treatment of patients aged 60 years and older has been found with daunorubicin 60 vs 30xa0mg/m2 as part of the thioguanine/AraC/daunorubicin (TAD) regimen with the higher dosage significantly increasing the response rate and survival in these older patients who represent a poor-risk group as a whole. Thus we have been able to demonstrate both in younger and older patients that a poor prognosis can be improved by a more intensive induction therapy. High-dose AraC in induction, however, exhibits cumulative toxicity in that repeated courses containing high-dose AraC in the post-remission period lead to long-lasting aplasias of about 6xa0weeks. Thus after intensive induction treatment, high-dose chemotherapy in remission may be practicable using stem-cell rescue and may contribute to a further improvement in the outcome in poor-risk as well as average-risk patients with AML. These approaches are currently under investigation by the German AML Cooperative Group (AMLCG). The more intensive the better is certainly not the way to go in the management of AML and other systemic malignancies but some increase in intensity may be possible and better.

Therapiestrategien bei akuter myeloischer Leukämie

Zum ThemaDie akute myeloische Leukämie (AML) ist eine der aggressivsten, bis heute unbesiegten Krebsarten. Die letzten 20 Jahre brachten deutliche Fortschritte in der Therapie. Dennoch sterben auch heute die meisten AML-Patienten an ihrer Krankheit oder an Folgen der Therapie. Hohe Heilungsraten bilden Ausnahmen und beschränken sich auf seltene Subgruppen wie die Promyelozytenleukämie oder auf selektierte Patienten z. B. nach allogener Knochenmark- bzw. Stammzelltransplantation. Der steinige Weg der großen, zeitaufwendigen, randomisierten Studien führte schrittweise zu einer Therapieoptimierung, indem sich einige Varianten als signifikant überlegen erweisen. Bedeutende und zukunftsweisende Fortschritte stammen jedoch aus der kliniknahen Zellforschung mit der Beschreibung typischer Chromosomentranslokationen, den hieraus resultierenden Fusionsgenen, anderer Chromosomendefekte sowie Genmutationen. Diese erwiesen sich als prognostische Faktoren und bilden die Grundlage einer neuen WHO-Klassifikation der AML. Die betroffenen Gene spielen eine zentrale Rolle in der Zelldifferenzierung und dem Differenzierungsblock der leukämischen Blasten und bieten inzwischen Angriffsziele (Targets) für hochspezifische Geninhibitoren.

Transforming Activity of Flt3 in 32D Cells

The type III receptor tyrosine kinase Flt3 (Matthews et al., 1991) and its ligand FL (Hannum et al, 1994) play an important role in survival and self renewal of early multipotent hematopoietic progenitors, of monocytic precursors and in early lymphoid development (Lyman and Jacobsen, 1998).

Including Quality of Life as an Important End Point in Evaluating Intensive and Prolonged Treatment for Acute Myeloid Leukemia (AML)

Intensification of treatment for AML resulted in a substantial improvement in longterm prognosis (Buchner 1997). As intensive therapy might be associated with high morbidity and most patients with AML eventually relapse, quality of life (QL) of patients has become an important parameter to be assessed. This study was designed to evaluate QL in patients with AML treated according to the protocol of the German AML-Cooperative Group.

Phase I Study of Liposomal Daunorubicin (DaunoXome) in Relapsed and Refractory Acute Myeloid Leukemia

Daunorubicin (DNR) is one of the most important cytotoxic agents in the treatment of acute myeloid leukemia (AML). Its use is usually limited by drug-induced cardiotoxicity depending on the cumulative dose administered. Liposomal encapsulation of DNR (DaunoXome®, DNX) seems to reduce the risk of this severe and sometimes fatal side effect. To investigate the toxicity of DNX in a heavily pretreated patient population, we currently conduct a phase I study including patients (pts) older than 60 years with relapsed or refractory AML. DNX is used at doses of 40, 60, 75, 90 and 100 mg/m2 biweekly. Until now, 13 pts have been treated: median age 69 years (range, 63-77), median number of prior regimen 1,4 (range, 0-2), median cumulative doses of DNR 553.5 mg (range, 0-880), mitoxantrone 16.2 mg (range, 0-60) and idarubicin 33.8 mg (range, 0-80). A total of 47 courses of DNX were administered (3 pts at 40 mg/m2 with a total of 13 courses, 5 at 60 mg/m2 with a total of 20 courses, 4 at 75 mg/m2 with a total of 12 courses and 1 at 90 mg/m2 with a total of 2 courses). Mean cumulative dose of DNX administered was 386,3 mg (range, 120-1200). Hematologic and non-hematologic toxicities were monitored by clinical, laboratory and cardiologic examination (including radionuclide ventriculography and echocardiography) and by a questionaire which was repeatedly filled in by the pts. Grade 1 and 2 elevations of liver enzymes were seen in 2 pts. A 20 % decline in left ventricular ejection fraction (LVEF) without clinical signs and symptoms of heart failure was noticed after a cumulative DNX dose of 480 mg in 2 patients, one with a history of two myocardial infarctions and the other with arterial hypertension. Even at the highest cumulative doses of DNX, no further decline in LVEF was noticed (LVEF prior to DNX: median 53 % (range, 34-67), after last course: median 52,7 % (range, 46-60). Vomiting, alopecia and mucositis were absent. All patients had significant myelosuppression requiring transfusion support. During treatment, 3 pts showed a reduction of leukemic blasts in bone marrow of > 25 %, 8 pts had to be excluded due to AML progression and 2 pts died due to disease-related complications. We conclude from these preliminary data, that DNX might offer a less toxic alternative to DNR and other anthracyclines. We will give a dose recommendation for the palliative treatment of relapsed and refractory AML as soon as our phase I study is finished. A phase II study will then be initiated.