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Purpose Favorable outcomes were achieved for children with acute lymphoblastic leukemia (ALL) with the first Russian multicenter trial Moscow–Berlin (ALL-MB) 91. One major component of this regimen included a total of 18 doses of weekly intramuscular (IM) native Escherichia coli-derived asparaginase (E. coli-ASP) at 10000 U/m2 during three consolidation courses. ASP was initially available from Latvia, but had to be purchased from abroad at substantial costs after the collapse of Soviet Union. Therefore, the subsequent trial ALL-MB 2002 aimed at limiting costs to a reasonable extent and also at reducing toxicity by lowering the dose for standard risk (SR−) patients to 5000 U/m2 without jeopardizing efficacy. Methods Between April 2002 and November 2006, 774 SR patients were registered in 34 centers across Russia and Belarus, 688 of whom were randomized. In arm ASP-5000 (n = 334), patients received 5000 U/m2 and in arm ASP-10000 (n = 354) 10 000 U/m2 IM. Results Probabilities of disease-free survival, overall survival and cumulative incidence of relapse at 10 years were comparable: 79 ± 2%, 86 ± 2% and 17.4 ± 2.1% (ASP-5000) vs. 75 ± 2% and 82 ± 2%, and 17.9 ± 2.0% (ASP-10000), while death in complete remission was significantly lower in arm ASP-5000 (2.7% vs. 6.5%; p = 0.029). Conclusion Our findings suggest that weekly 5000 U/m2E. coli-ASP IM during consolidation therapy are equally effective, more cost-efficient and less toxic than 10000 U/m2 for SR patients with childhood ALL. Electronic supplementary material The online version of this article (10.1007/s00432-019-02854-x) contains supplementary material, which is available to authorized users.

Der nunmehr 6-jahrige Sebastian kommt mit Kopfschmerzen und Erbrechen in die Ambulanz der ha matologisch-onkologischen Abteilung. Vor fast 3 Jahren war er wegen einer akuten lymphoblastischen Leukamie, einer TEL/AML1 positiven common-ALL, gemas dem Protokoll ALL-BFM 2000 behandelt worden. Ein sogleich angefertigtes Blutbild zeigt einen Abfall von Hamoglobin und Thrombozyten. Daruber hinaus fi nden sich einzelne leukamieverdachtige Zellen im Ausstrich. Es werden eine Lumbal- und eine Knochenmarkpunktion durchgefu hrt. Im Liquorpraparat fi nden sich lymphoblastische Leukamiezellen mit der fur das Liquormilieu typischen Morphologie. Der Knochenmarkausstrich zeigt eine leukamische Metaplasie mit 90% Leukamiezellen. Bei einer umfangreichen klinischen sowie sonographischen und rontgenologischen Untersuchung fi ndet sich keine weitere Organmanifestation. Es bestatigt sich somit ein spates kom biniertes Knochenmarkrezidiv einer TEL/AML1-positiven c-ALL mit ZNS-Beteiligung.

Polarographie und Voltammetrie sind Bezeichnungen fur analytische Methoden, denen Strom-Spannungs-Messungen an elektrochemischen Zellen zugrunde liegen. Das analytische Signal ist der Strom, der bei einer Reaktion des Analyten an der Arbeitselektrode durch die Zelle fliest. Die Strom-Spannungs-Kurven werden unter potentiodynamischen Bedingungen registriert, ahnlich wie das bei der galvanostatischen Coulometrie oder bei der Coulometrie mit linearer Potentialanderung (potential scanning coulometrie) der Fall ist. Der Unterschied liegt hauptsachlich in der Geometrie der Arbeitselektroden. Coulometrische Bestimmungen werden mit grofssachlgen Elektroden (bei grosem Verhaltnis von Elektrodenoberflache zu Probevolumen) durchgefuhrt, damit der Analyt moglichst vollstandig am Elektrodenprozes (Reduktion oder Oxidation der Ionen oder Molekulen) teilnehmen kann. Dagegen sind die Arbeitselektroden fur polarographische und voltammetrische Untersuchungen so klein, das der Umsatz des Analyten an der Elektrodenoberflache vernachlassigt werden kann.

Die Methoden der Polarographie — bzw.Voltammetrie — unterscheiden sich in der Mestechnik und in der Form der elektrischen Spannung, mit welcher der Bestimmungsvorgang angeregt wird; das Messignal ist der Faradaysche Strom oder in wenigen Fallen der kapazitive Strom.

Die Verfahren der Stripping-Voltammetrie sind die leistungsfahigsten elektrochemischen Techniken fur die Spuren- und Speziesanalyse. Die ausergewohnlich hohe Empfindlichkeit und Selektivitat beruht darauf, das der Analyt vor seiner Bestimmung angereichert wird und das Anreicherung und Bestimmung elektrochemische Prozesse sind, die in ihrem Ablauf reguliert werden konnen.

Despite modern intensive treatment, relapses occur in about 25% children with acute lymphoblastic leukemia (ALL). After the central nervous system (CNS), the testes are the second most frequent site of an extramedullary relapse [1]. The incidence of testicular relapses has been decreased by intensification of front-line regimens, mainly by the introduction of intermediate-dose or high-dose methotrexate (MTX) [2–6]. When salvage therapy of an isolated relapse consisted of local treatment, alone or in combination with mild chemotherapy, a subsequent bone marrow relapse occurred in a high percentage of boys [3, 7–9]. Therefore, intensive systemic salvage therapy is necessary to achieve favorable results in boys with isolated as well as combined testicular relapse [10–13]. The aim of this study was to evaluate the efficacy of tumor load-adapated chemotherapy in boys with first overt testicular relapse, treated according to four consecutive Berlin-Frankfurt-Munster (BFM) relapse protocols.

In recent years front-line therapy for acute lymphoblastic leukemia (ALL) in childhood has been intensified in most international trials [1, 2, 3]. In Germany, intensive induction/consolidation and reinduction regimens have been applied since the mid seventies [4, 5, 6]. With these types of front-line therapy cure rates have now approached 70–75%. However, increasing success with more aggressive front-line protocols has led to challenges for effective salvage regimens for the 25% of children in whom the first treatment attempt has failed. Systematic trials for relapsed ALL have been carried out in the BFM study group since 1983.

Children suffering from ALL with high risk factors such as relapse within 18 months of diagnosis, relapsed T- or B-ALL or multiple relapses can not be cured by conventional salvage chemotherapy. Those patients are candidates for allogeneic bone marrow transplantation (BMT) even if relapse occurred after 18 months. If no donor is available which applies for the majority of patients autologous BMT can be considered as an alternative treatment. The value of autologous compared to allogeneic BMT remains to be determined. Here we report on our results of autologous and allogeneic BMT in children who were uniformly treated according to BFM chemotherapy protocol [1,2] prior to BMT and uniformly conditioned by fractionated total body irradiation (TBI) and high-dose VP-16 [3,4].

Graft-versus-host disease (GvHD) complicates allogeneic bone marrow transplantation (BMT) in up to 25%–50% of patients receiving human leukocyte antigen (HLA) compatible grafts. The diagnosis is mainly based on the clinical findings of a skin rash, watery diarrhea, and cholestatic hepatitis, often confirmed by histopathological examination. Frequently the effects of drug toxicity or infections are difficult to discriminate from GvHD. Therefore, there is need for criteria that additionally define the diagnosis of GvHD and which possibly help to predict the occurrence of GvHD [1].

At the first Symposium on Acute Leukemias in SMiinster, 1987, we reported on preliminary results obtained in two subsequent trials on relapsed childhood acute lymphoblastic leukemia, ALL-REZ BFM 83 and 85 [1]. The present paper is an update of the results after both studies have been closed for patient entry and follow-up periods have reached 5 Vi and 3 V2 years, respectively.

The treatment of acute leukemias in child-hood has been very successful in the Federal Republic of Germany. Multicenter trials for both, acute lymphoblastic leukemia (ALL) and acute nonlymphoblastic leukemia (AML), have existed for more than 10 years now and since about 1980 almost 90% of children have been treated within the two BFM trials [1, 2] or the COALL trial [3]. Intensive induction therapy has led to results which belong to the best cure rates so far achieved in these childhood malignancies. An overall disease-free survival of 70% for ALL and at least 50% for AML has been documented. For ALL, conventional chemotherapy is able to cure even a distinct part of those children where late relapses occur (gt;1/2 year after the end of maintenance therapy). This is not true, however, for children suffering from ALL with early relapses and those with AML for whom the outcome of therapy following a relapse is very unfavorable.

During the past 5 years, in the German Berlin-Frankfurt-Mimster (BFM) study group a standard treatment has been established for relapse of childhood acute lymphoblastic leukemia (ALL) [1]. In study ALL-REZ BFM 85 remission rates were improved compared with the preceding study ALL-REZ BFM 83. Furthermore, by use of methotrexate (MTX) given at a dose of 1 g/m2 for 36 h there is good evidence for more effective control of bone marrow leukemia (G. Henze et al., this volume). No clear improvement was found, however, in terms of long-term event-free survival of these children, so far, because of an inappropriate high incidence of second extracompartmental relapses, especially in the CNS. The purpose of this report is to evaluate the impact of secondary CNS relapses on the prognosis of children with first isolated marrow relapse and the interrelationship between the duration of systemic disease control and the risk of subsequent extracompartmental leukemia.

In children with acute lymphoblastic leukemia (ALL), relapse in the CNS is still a major limiting factor for cure [1]. CNS relapse prevention by cranial irradiation plus intrathecal methotrexate [2], while adequately protective for most patients, is stigmatized by considerable neurological and other sequelae [3]. For standard-risk ALL children (60% of all patients), the BFM study group has addressed the necessity of cranial irradiation in a risk-adapted and randomized fashion in trials ALL-BFM 81 and 83. Together with the historical controls of the preceding trials ALL-BFM 70, 76, and 79, the overall as well as the CNS relapse incidence in these trials is presented here.

In addition to all the biological properties and clinical features of individual patients with acute leukemia, the quality of therapy itself has evolved as the most relevant predictive factor for cure or failure. Leukemia is still a life-threatening condition and needs adequate management, irrespective of the phenotypic or genotypic characterization of the leukemic clone.

Acute lymphoblastic leukemias (ALL) and non-Hodgkin’s lymphomas (NHL) are clonal lymphoproliferative disorders at specific stages of differentiation. Recently, the introduction and application of molecular genetic methods have become a valuable addition to the established cytological, cytogenetic, histological, and immunological techniques in the diagnosis, classification, and monitoring of therapy of leukemias and lymphomas [1–4].

Polarography and voltammetry are suited for the trace analysis of numerous ecotoxic metals, metalloids and various organic pollutants. Moreover, these methods are useful for the differentiation of oxidation states and the characterization of metal complexes (Henze and Neeb 1986). Therefore, they are of interest in environmental research, particularly for metal speciation, and a number of papers appeared on this subject in recent years (Florence 1986, Florence and Batley 1980, Nurnberg 1983, Mizuike 1987).

Development of effective treatment programs for childhood acute lymphoblastic leukemia (ALL) has led to marked improvement of prognosis. The proportion of patients remaining in first remission for at least 5 years is generally estimated to be in the range of 50% once remission is achieved (Frei and Sallan 1978: Riehm et al. 1980: Robison et al. 1980). Since remission rates have been shown to be 90%–95% with currently used induction therapy, successful induction of remission is no longer an essential problem. Nevertheless, the quality of remission is apparently unsatisfactory in about one-half of the patients, eventually resulting in recurrence of the disease. Predictors of outcome have been defined and include white blood count (WBC), sex, thymic involvement, central nervous system disease at diagnosis, immunologic markers, unfavorable age, and blast cell morphology (Dow et al. 1977; Henze et al. 1979; Mathe et al. 1971; Sallan et al. 1978: Simone et al. 1975: Wagner and Baehner 1979; Working Party on leukemia in Childhood 1978): but attempts to adapt the therapeutic strategy to the presence of factors associated with a poor prognosis have not been able to enhance significantly therapeutic results. The approach of the BFM study group with the concept of intensive multidrug remission induction gives hope for an overall 75 % relapse-free survival in childhood ALL.

Recent improvements in cytogenetic technology provided the means to identify chromosomal abnormalities in the majority of children with acute lymphoblastic leukemia (ALL) [1–8]. In addition to numeric aberrations, detected in 23% to 39% of all cases with evaluable metaphases [1–4], specific nonrandom translocations have been described [5–8]. Cytogenetic studies have also emphasized the clinical significance of chromosomal aberrations in relation to previously identified risk factors such as male sex, high white blood cell count (WBC), age and T-cell phenotype [2, 3]. The applicability of cytogenetic techniques, however, is limited by the laborious and time consuming processing of samples and requires cell proliferation in vitro for the evaluation of metaphases.

An aneuploid DNA stem line has been detected by flow cytometric measurements in 17 (29%) out of 59 children entered in the BFM 83 pilot study for ALL relapse. Of 17 DNA aneuploidies, 15 were hyperdiploid. Euploidy was observed in 28 of 34 patients with an early relapse, whereas 11 of 25 children suffering a late recurrence of disease showed aneuploid DNA stem lines. In contradistinction to ALL relapse, a significantly higher frequency (38%) of pretreatment DNA aneuploidy was measured in 376 newly diagnosed patients of the BFM trials. Our findings may reflect the impact of therapy on leukemic cell clones and their relapse pattern.

Prognosis in childhood acute lymphoblastic leukemia (ALL) after risk-adapted therapy is first of all dependent on the quality of therapy. Conventional risk factors such as WBC, age, sex, organ involvement, and other features certainly have lost their prognostic significance in varying degrees during the evolution of risk-adapted and necessarily intensive therapy. Still, the tumor burden and other ill-defined or unknown factors are responsible for therapy failure. Obviously, the patient group with therapy failure must be the target of future efforts.

Oxidations- und Reduktionsvorgange an Elektroden, die auch in Verbindung mit kinetischen, katalytischen und adsorptiven Prozessen ablaufen konnen, sind die Grunderscheinungen bei allen elektrochemischen Bestimmungsverfahren mit stromdurchflossenen Elektroden. Elemente und Ionen, die in dem zur Verfugung stehenden Potentialbereich keine Redoxvorgange geben, konnen uber indirekte Verfahren oder nach Derivatisierung bestimmt werden. Die Messung der Anderung der Doppelschichtkapazitat durch Adsorption von Ionen oder Molekulen ist ein auf wenige, meist organische Verbindungen begrenzter Sonderfall einer elektrochemischen Bestimmungsmethode (s. Abschn. 3.3). Fur die Analyse anorganischer Ionen sind solche Vorgange von geringer Bedeutung.

An intensive 7-day combination chemotherapy protocol was designed to reinduce children with early bone marrow relapse of acute lymphoblastic leukemia (less than 6 months after the end of or during preceding treatment). This aggressive approach seemed to be justified for a group of patients who were at the highest risk for ultimate treatment failure. In all, 38 children were enrolled for study. The ratio of male (median age, 10 years) to female (median age, 13 years) subjects was 27:11. Thirty patients were treated for their first relapse and eight for their second or subsequent relapse. Isolated bone marrow involvement was present in 24 cases. All patients had received heavy pretreatment including anthracyclines with cumulative doses of between 120 and 240 mg/m2.

Major progress in the treatment of children with acute myelogenous leukemia has occurred in the past decade. Advances in chemotherapy and supportive care have been associated with an increase in the complete remission (CR) rate, and more important, an increase in the duration of first remission [1, 5]. In addition, bone marrow transplantation in first remission may provide a new approach for a selected group of patients to improve further on treatment results for AML [3, 4]. In 1978 the AML-BFM-78 chemotherapy protocol was initiated by the German cooperative group with encouraging early results [1, 2]. This report is an update of the trial.

Elektroanalytische Methoden sind fur die Wasseranalyse besonders geeignet. In wenig belasteten Wassern (See-, Regen-, Trink-, Grund- und einigen Flus- und Bachwassern) konnen sie haufig unmittelbar bzw. nach einfacher Probenvorbereitung angewandt werden. In starker belasteten Wassern sind ionensensitive Elektroden gelegentlich noch direkt, polarographische und voltammetrische Verfahren nach Aufschlus der Probe einsetzbar. Im Vordergrund der elektroanalytischen Bestimmung stehen die Elemente, deren Grenzkonzentrationen bzw. Einleitungsgrenzen durch die Trinkwasserverordnung (TWVO) bzw. durch das Abwasserabgabegesetz vorgegeben sind. Auf die Bestimmung dieser Elemente und Ionen wird daher besonders eingegangen.

Different mechanisms may be responsible for the occurrence of relapse of acute lymphoblastic leukemia (ALL). As a consequence, treatment schedules for relapse should take into account the possible or assumed mechanism with the aim of attempting to develop adequate treatment strategies.