A systematic cytogenetic study was started in 1977 to investigate the incidence, types, and possible relations with prognosis of childhood acute nonlymphocytic leukemia (ANLL). We report on the findings of 130 de novo childhood ANLL studied at diagnosis in one department and in the same laboratories for cytology and cytogenetics between September 1977 and December 1986.
The description of a decrease in the intracellular accumulation of a number of cytostatics, such as anthracyclines, vinca alkaloids, epipodophyllotoxins, and actinomycin D, in drug-resistant malignant cells — first demonstrated for colchicine in hamster ovary cells [4] caused by an energy-dependent outward pump in connection with the expression of the 170 000-dalton plasma membrane glycoprotein PI 70 [2] — has substantially contributed to the understanding of “multidrug resistance” [6]. Accordingly, the responsiveness of malignant cells to these cytotoxic drugs may more critically depend on their cellular tumor pharmacokinetics and metabolism than on their plasma pharmacokinetics, which in general only poorly correlates with their pharmacodynamics [7].
From the early 1950s to the mid-1970s all acute lymphoblastic leukemias (ALLs) in childhood were treated according to a unique protocol. It became evident that some parameters had prognostic significance: age, sex, white blood cell count, lymphoma syndrome, initial meningeal involvement, mediastinal mass, treatment efficacy, and more recently immune markers and cytogenetics [8]. In 1974 we were the first to tailor the treatment according to initial prognostic factors: treatment was increased by one-third in high-risk patients, and decreased by one-third in low-risk patients [3].
Several of the major complications of blood transfusion result from white cell contamination of blood components, such as nonhemolytic febrile reactions, refractoriness to platelet transfusion, and virus transmission [1, 2, 5, 7]. There is evidence that mainly lymphocyte-contaminated blood products are the major cause of alloimmunizationand refractoriness of the recipients [3, 6]. Repeated transfusion of platelet concentrates leads to HLA alloimmunization in 40% of patients [3]. The management of alloimmunized patients represents a difficult and expensive challenge and any means by which the rate of alloimmunization can be reduced is to be welcomed. Therefore, blood component therapy aims to transfuse standardized blood products as purely as possible in a very selective way in order to provide optimal therapeutic efficacy and minimal side effects.
At the present time 60%-80% of adult patients suffering from acute myelogenous leukemia (AML) will achieve complete remission with the available induction chemotherapy including anthracycline antibiotics and cytosine arabinoside [1–5]. With standard chemotherapy, however, the majority of the patients will suffer leukemia relapse within the first 2 years after complete remission and only about 20% of the complete responders will have long-term disease-free survival. Substantially better results can be achieved with allogeneic bone marrow transplantation, which provides long-term remission in 50% or more of the patients who are transplanted in first remission with bone marrow grafts from histocompatible siblings [6, 7].
We describe some of our efforts to identify prognostic factors for achievement of complete remission (CR) and duration of relapse- free survival. So far the results have not been very encouraging.
Fibronectin (FN) is a glykoprotein found in plasma [1, 2] and in cell-surface membranes [2]. It occurs in both soluble and insoluble forms. FN has been intensively studied because of its frequent interactions with cells and macromolecules. It may influence a number of physiological processes including phagocytosis [3, 4] remodeling during embryogenesis and wound healing [5]. The concentration of plasma FN is altered in certain disease states. Low FN levels have been seen in sepsis [6–9], burn injury [6, 7, 10], and acute lymphoblastic leukemia (ALL) in adults [11,12]. In our previous study [13], we noticed that the plasma FN level in patients with ALL prior to chemotherapy was significantly lower than during remission. A significant fall in plasma FN level was found in patients with viral or bacterial infections undergoing chemotherapy, and a subsequent increase in plasma FN level when the infection was treated successfully. Changes in FN concentration related to stage of disease, clinical condition, and subsequent complications as presented above have encouraged us to start clinical trials of this drug in substitutive treatment of patients with acute leukemia.
The use of anthracyclines and anthrachinones in antineoplastic treatment is limited by the possible induction of irreversible cardiomyopathy [1, 2, 6, 7, 9]. In 1976, Daniels et al. observed a protective effect of subcutaneously administered verapamil in white rabbits [4]. Mullerleile et al. reported a beneficial effect of low-dose oral verapamil in 22 patients with different tumors treated with doxorubicin [10]. The aim of this study was to determine whether verapamil can protect against anthracycline cardiomyopathy without altering the clinical efficiency of the antineoplastic regimen in patients with acute myeloid leukemia (AML) [8, 10–12].
It has become well accepted that the onset of fever in a neutropenic patient requires the prompt initiation of empirical antimicrobial therapy. The main goal of empirical antibiotics is to protect against the early morbidity and mortality associated with untreated bacterial infections in the neutropenic population.
We gave 4 days of high-dose Ara-C followed 2 days later by rHUGM-CSF (which continued until the neutrophil count was greater than 1000/microliters) to 12 patients with newly diagnosed AML and a relatively poor prognosis. Six CRs occurred, there were four deaths during induction, and in only one case was there an rHUGM-CSF-associated growth of leukemia. The pattern of hematologic recovery was variable but in some patients rHUGM-CSF seemed to accelerate normal myelopoiesis following chemotherapy. Continued investigation of rHUGM-CSF and chemotherapy in AML is warranted.
Complotyping, i.e., definition of the MHC-encoded polymorphic complement components Bf, C2, C4A, and C4B. The C4A and C4B allotypes are as polymorphic as the HLA-A and HLA-B antigens, with 12 C4A and 18 C4B variants. In addition, a duplication of one of the C4 genes is observed in 1% of the cases [2].
This study was carried out to assess patients with acute leukemia who were not suited for bone marrow transplantation. Therefore age limits were 35-60 years. The TADVP regimen was compared with ADVP (Table 2) because of repeated doubts concerning the efficacy of thioguanine.
Acute leukemias are thought to arise from a single abnormal progenitor cell in which expression of differentiation is restricted to either myeloid or lymphoid pathways [1]. Recently, however, this concept has been challenged by the fact that the availability of monoclonal antibodies (moAbs) to lineage-associated surface antigens and their use to characterize immature leukemic cells demonstrate an increasing amount of multilineage differentiation and phenotypic ambiguity (reviewed in [2]). Furthermore, application of molecular biological techniques has revealed that clonal rearrangements of the Ig heavy-chain (IgH) or T-cell receptor (TCR) genes occur in leukemic cells of the “inappropriate” lineage (reviewed in [3]).
Following the introduction of anthracyclines and cytosine arabinoside (Ara-C) into clinical practice in the late 1960s, response rates of 50%–80% in previously untreated patients with acute myeloblasts leukemia (AML) have been obtained [1, 2]. Despite a variety of postremission treatments the remission duration remains 12–15 months, with 20%–25% of patients staying in long-term disease-free state and possibly being cured [3, 4]. One-third of the patients who failed to achieve an initial complete remission do so because of persistence of leukemia cells [5], and 75%–80% of patients who achieve a remission have recurrence of leukemia [3, 4]. Both of these patient populations are eligible for salvage therapy.
We analyzed LFS in adults, adolescents, and children with ALL treated by using different therapies and therapeutic strategies. In most instances, the strategy of initial chemotherapy followed by transplantation in those who relapse produced the highest LFS. Results of HLA-identical transplants were generally superior to those of autotransplants. However, many persons do not have donors and should be considered for autotransplants or possibly for transplants from partially or fully HLA-matched related or unrelated donors. These persons are also potential candidates for evolving therapeutic strategies such as immune therapy or lymphoid growth factors.
The primary treatment of acute lymphocytic leukemia (ALL) has been considerably improved. In the first German multicenter study, 01/81 complete remissions have been induced in 272 of 368 patients (73.9%), and in the second study 02/84 in 350 of 442 (79.2%) [1]. Though 35% of the patients remain disease free after 7.5 years in the first study and 48% after 3 years in the second, relapsing and refractory disease is still the most prevalent problem in ALL. The development of effective salvage therapies is warranted. Against this background the German Multicenter ALL Study Group has evaluated an intensive protocol for patients with relapsed or refractory ALL.
Acute megakaryoblastic leukemia (M7) recently included in the French-American- British (FAB) classification for acute leukemias [1] is a rare hematological disease with poor prognosis. We present a case of acute megakaryoblastic leukemia with poor response to cytostatic treatment and a review of the therapeutic attempts in the literature.
The presence of chromosomal abnormalities at diagnosis has been demonstrated to have an independent prognostic value in child-hood acute lymphoblastic leukemia (ALL) [1–5]. Individuals with a hyperdiploid (> 50) clone show the most favorable treatment response whereas those with a pseu dodiploid clone have the poorest responses [2]. Chromosomal translocations have been shown to have the most profound impact on treatment outcome [6–8].
The frequency of induced sister chromatid exchange (SCE) is a sensitive tool for the monitoring of DNA damage and has been shown to indicate chemotherapy resistance. Mafosfamide is presently used for the purging of bone marrow in autologous bone marrow transplantation in the treatment of acute leukemia. We studied the SCE-inducing effect of mafosfamide on leukemic cells of Philadelphia (Ph)-positive chronic myeloid leukemia (CML) as a model for leukemic cells. Corresponding data from normal bone marrow were analyzed for comparison. A positive linear correlation (r = 0.99, P = 0.0005) was found between the dose of mafosfamide and induced SCE in Ph-positive CML and normal bone marrow. The concentration of mafosfamide used was 0.1, 0.2, 0.4, and 0.8 micrograms/ml. Additionally, we analyzed five cases of CML and six cases of normal bone marrow. A significant difference in the frequency of induced SCE/metaphase was found between CML and normal bone marrow even after addition of 0.8 micrograms/ml mafosfamide. Also, spontaneous SCE was significantly lower in CML. Our data indicate a lower sensitivity of the leukemic cells to mafosfamide as shown by the induction of a lower frequency of SCE events.
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.
