Intensified induction and consolidation with or without maintenance chemotherapy for acute myeloid leukemia (AML): two multicenter studies of the German AML Cooperative Group.

In two multicenter trials, a total of 576 patients with acute myeloid leukemia (AML) were treated and found to be evaluable. Two hundred forty-two patients were in a 1978 pilot study and 334 patients were in a 1982 randomized study. Ages were between 15 and 78 years (median, 48). The uniform remission induction therapy in both studies consisted of one to two courses of a 9-day combination of 6-thioguanine (TG) with cytosine arabinoside (ARA-C) and daunorubicin (DNR) [TAD9]. The timing and sequencing of TAD9 was designed according to cell kinetic effects of ARA-C. A complete remission (CR) was achieved in 65% (70% and 61%, respectively) of patients within a median of 33 days, and in 68% of responders after only one course. The CR rate in patients 60 to 78 years of age was 51% (66% and 39%, respectively). In the 1978 pilot study, different protocols of post-remission treatment were applied at the different centers: monthly 5-day maintenance, TAD9 consolidation, both consolidation and maintenance, or no further therapy. The group receiving treatment during CR showed 24% probability of remissions at 4 years v 0% probability of remissions in the untreated group. Between the different post-remission protocols, no significant differences were observed. Remission duration was not influenced by age, WBC, or morphologic cell type, but was longer in patients achieving CR within 30 days (P = .017). In the subsequent 1982 study, 145 patients in CR were randomized for TAD9 consolidation with or without monthly maintenance. The updated life-table analysis revealed a predicted rate of continuous remission at 2 1/2 years of 30% for the maintenance and 17% for the nonmaintenance arm (P = .003). These results of response and remission duration in adult patients of all ages support the validity of intensified induction therapy and of consequent myelosuppressive treatment in remission.

Multicentre study on intensified remission induction therapy for acute myeloid leukemia.

In a cooperative study at 13 centres in the Federal Republic of Germany, 213 adult patients with AML were treated for remission induction by a 9-day regimen consisting of cytosine arabinoside, daunorubicin and thioguanine (TAD) according to previously described sequencing. Complete remission was achieved in 70% of all patients. Complete remission rate was 57% in the 49 patients 60 years of age and older and 74% in the 164 patients under 60 years. Sixty-eight per cent of all complete remissions and 75% of those in the higher age group were induced by one induction course. Median survival was 10 months for all patients treated and 16 months for responders. Median remission duration was 13 months with 72 patients still in continuous remission for 1-31 months. Remission duration was not significantly different for patients treated either by monthly maintenance therapy or induction type consolidation without further therapy. However, patients completing two consolidation courses had a significantly longer remission duration of 22 months. Compared to similar multicentre studies on AML therapy the intensified induction regimen applied in this study shows an improvement even in older patients.

Chemotherapy in head and neck cancer with bleomycin, cisplatinum, and methotrexate.

Results of chemotherapy in head and neck cancers are reported with a regimen of cisplatinum, bleomycin and methotrexate. In 63 previously untreated patients, the overall response rate was 73%, including 13/63 CR and 33/63 PR. The response rate in 20 previously treated tumors was 20%. The chemotherapy protocol was well tolerated without severe complications. Initial chemotherapy as a third modality in addition to radiotherapy and/or surgery is discussed.

Impaired phagocytic activity of human monocytes in respect to reduced antibacterial resistance in uremia.

Resistance to bacterial infection, particularly septicemia and pneumonia, is decreased in patients with uremia. Tests of monocyte function in 21 patients with chronic uremia and in 21 normal healthy subjects showed an increase in attachment rate, spreading activity and Nirtoblue-tetrazolium reduction in the uremic subjects. In contrast, phagocytosis of IgG-coated red cells was impaired.

[Cytostatic primary therapy of squamous cell carcinoma of the oro- and hypopharynx with cisplatin, bleomycin and methotrexate]. / Zytostatische Primärtherapie von Plattenepithel-Karzinomen des Oro- und Hypopharynx mit Cisplatin, Bleomycin und Methotrexat.

This is a report on induction chemotherapy of 20 oropharyngeal and 20 hypopharyngeal squamous cell carcinomas with cis-platinum, bleomycin, and methotrexate. The response rate, defined as a tumour regression of at least 50%, was 70% for the hypopharynx and 80% for the oropharynx. The lymph nodes responded in 50% of the cases. The toxicity was low. Induction chemotherapy is considered to be significant, but it must be stressed that surgery and/or radiation therapy must follow to sustain the initial success.

[Nitroblue-tetrazolium test in isolated human monocytes]. / Nitroblau-Tetrazolium (NBT)-Test bei isolierten menschlichen Monozyten

Depending upon the NBT charge 50 to 80% of isolated non stimulated human monocytes reduce NBT ro morphologically demonstrable Formazan. Similar to neutrophils two different patterns of reaction are exhibited: discrete load with finely distributed Formazan granula surrounding the nucleus; massive reaction with large distributed Formazan granula surrounding the nucleus; massive reaction with large Formazan deposits throughout the cytoplasma. In a low percentage morphologically desintegrated, massive loaden cells appear. After an additional incubation in medium without NBT the number of these necrotic cells increases. The phagocytosis of IgG-coated red cells is impaired after incubation of the monocytes in NBT. In the presence of an alkylating agent not only the NBT-reaction is inhibited; the number of necrotic cells is also diminished. Apparently the Formazan is cytotoxic. The significance of these results in particular in cases of enhanced NBT reduction is discussed. Compared with the findings of other authors concerning the neutrophils the monocytes possess a markedly stronger NBT reducing activity. Considering the lower bactericidal capacity of the monocytes NBT reduction does not in every case parallel bactericidal activity.

Reduced monocyte phagocytosis in patients with advanced Hodgkin's disease and lymphosarcoma.

The monocytes of 7 patients with advanced Hdgkin's disease (stages III and IV) and of two patients with generalized lymphosarcoma exhibited a highly significant impairment of the phagocytosis of IgG-coated red cells, regardless of receiving therapy or not. In contrast three patients with M. Hodgkin, stage II B, and one with lymphosarcoma in complete remission showed a rather elevated monocyte phagocytic acitivity. The nitroblue tetrazolium reduction by monocytes in the mean was significantly enhanced in all patients investigated, compared with normal persons, although only in one patient a bacterial infection was apparent at the time of the test. The possible implication of the findings in the well known immunodeficiency present in M. Hodgkin and lymphosarcoma is discussed.

Intensified remission induction therapy for acute nonlymphocytic leukemia (ANLL). Treatment report on 60 patients.

Sixty patients with ANLL were given intensified remission induction therapy consisting of thioguanine, cytosine arabinoside and daunorubicin (TAD). The mean age of patients was 47.6 years (range 18 to 74 years). Basing on leukemic cell kinetic data time sequencing of drugs was different from the original TAD protocol. Complete remission (CR) waa achieved in 43/60 patients (72%) with 10 CR in 15 patients over 60 years of age. Seventy-nine percent of the CR were induced by one cycle vs thirty percent reported from the original TAD regimen. The major cause of induction failure--in ten of the 60 patients--was thrombocytopenia refractory to platelet transfusions. Persisting leukemia after two induction cycles was documented in only two patients. Median remission duration by life table analysis is 10 months with 17 patients in continuous CR for 1+ to 22+ months.

[AMSA/etoposide (VP 16-213). A phase I/II study in refractory acute myeloid leukemia]. / AMSA/Etoposid (VP 16-213). Eine Phase I/II Studie bei refraktärer akuter myeloischer Leukämie.

In a phase I/II study the tolerable doses and antileukemic efficacy of the combination AMSA and etoposide (VP 16-213) was assessed in 20 patients with refractory acute myeloid leukemia. The following 5 day treatment course was found tolerable and effective: AMSA 210 mg/m2/die on days 2, 3 and 4, and etoposide on days 1 and 5 as a 1 h infusion of 100 mg/m2 followed by a 23-h continuous infusion of 230 mg/m2. In 5 of 20 patients partial remissions were achieved; 4 of these patients were primarily resistant against two TAD induction cycles. Bone marrow aplasia without a residual blast population was achieved in 7 of the 8 patients with primary TAD resistance. AMSA/etoposide thus seems to express an antileukemic efficacy without cross-resistance against TAD.

Bone marrow findings in adult patients with urticaria pigmentosa.

In order to better assess the prognosis of adult patients with urticaria pigmentosa, 35 patients with generalized maculopapular skin lesions and biopsy-proved cutaneous mast cell increase had light and electron microscopic examinations of their bone marrow; 46% had an increased mast cell content that was focal in all but four patients. Additional frequent findings in this group were an increased cellularity, nuclear-cytoplasmic dissociation of maturation, eosinophilia, and macrophages that contained ingested nuclei. Similar changes were found in far fewer patients without increased marrow mast cells. Only one patient with massive cutaneous mastocytosis had mast cells with relatively large nuclei and immature granules in the extensively involved marrow. Repeated biopsies in this and in six other patients over 3 years showed no worsening of the marrow findings, and the clinical course of all patients was stable over up to 10 years of follow-up. The variable findings in the patients suggest that mastocytosis with cutaneous involvement is a heterogeneous disease where diverse stimuli may cause an increase of mast cells. The clinical course is, however, relatively stable.

Treatment of refractory acute myeloid leukemia with mAMSA and VP 16-213 in combination: results of a clinical phase I/II study.

Twenty patients with refractory AML were treated with mAMSA and VP 16-213 in combination to assess the toxicity and anti-leukemic activity of the two-drug regimen. Refractoriness was defined according to the response to induction therapy consisting of 6-thioguanine, cytosine arabinoside and daunorubicin (TAD9) and the duration of the preceding remission. Patients were eligible for AMSA/VP 16-213 if they were primary non-responders against two TAD9 induction courses, had early relapses within the first six months, were nonresponders to one additional TAD9 course at later relapses or were at second or subsequent relapses. Therapy consisted of a five-day course of mAMSA 210 mg/m2/d on days 2, 3 and 4. VP 16-213 was applied on days 1 and 5 by a 1-h infusion of 100 mg/m2 followed by a 23 h infusion, the dosage of which was escalated in three steps from 110 mg/m2 over 200 mg/m2 to 230 mg/m2 in subsequent patients. Even at the highest dose of VP 16-213, toxicity was mild to moderate except for mucositis of grade III after two cycles and severe intrahepatic cholestasis in one case. Four of the 20 patients died within the first three weeks after the onset of treatment and were not evaluable for the assessment of antileukemic efficacy. From the remaining 16 patients five achieved partial remissions while no complete remission was obtained. Four of the five PR occurred in the eight patients with primary TAD9 resistance. These data indicate that AMSA/VP 16-213 reveals a moderate toxicity only, and that the combination may not be completely cross-resistant with TAD9. The overall anti-leukemic activity is limited however, and seems inferior compared to other presently available salvage regimens in refractory AML.

[Intracranial forms of malignant lymphoma manifestations]. / Intrakranielle Manifestationsformen maligner Lymphome.

Approximately 10% of patients with malignant lymphoma will show neurological symptoms at some time during the course of their illness. In non-Hodgkin lymphoma, CNS involvement is more frequent than in Hodgkin's disease. Diffuse histiocytic and poorly differentiated lymphomas, bone marrow involvement, advanced tumor stage and hematogenous spread are particular risk factors. Invasion of the spinal canal is the most common type of CNS involvement. Intracranial lesions, which are comparatively rare, may present as intracerebral metastases, epi- or subdural masses or focal or diffuse leptomeningeal disease. Lymphomatous leptomeningitis usually cannot be demonstrated by CT. On the other hand, dural and cerebral parenchymal lesions are sometimes highly characteristic of lymphoma as a result of their features and location.

Lysostaphin-based assay of human granulocyte functions: a reevaluation.

Lysostaphin, a staphylococcus-derived staphylocidal substance, has widely been used in assays of granulocyte phagocytic and bactericidal capability. It rapidly kills extracellular bacteria. Thus, a separate determination of intracellular surviving bacteria can be performed. One prerequisite for this approach is the safe inactivation of lysostaphin (usually brought about by trypsin) before the intracellular bacteria are externalized for plating. This inactivation has been found by others to be incomplete. Data are presented demonstrating a safe inactivation of lysostaphin by trypsin, if the pH value is maintained within the alkaline range. A low variation of results is obtained by plotting the total number of bacteria killed per incubate vs the logarithm of initial bacterial inoculum or of the intracellular surviving bacteria, leading to linear regression lines. The variation of the results increases greatly for initial bacteria/granulocyte proportions of greater than 5/1. The results obtained for two different St. aureus strains are significantly different. Dexamethasone pretreatment (12 mg p.o. within 8 h) had no detectable influence, when fresh blood was assayed, while blood storage at room temperature for 12 h (without dexamethasone pretreatment) led to a significant functional impairment, mainly of bactericidal capability when analyzed in a pairwise fashion. A major limitation of this kind of assays is that killed bacteria cannot be determined directly.

Immunotherapy in the treatment of acute myelogenous leukemia (AML): rationale, results and future prospects.

Patients with AML in complete remission (CR) are immunosuppressed; remission lymphocytes of at least a part of the patients are able to recognize autologous leukemic blasts; the CR represents a minimal residual disease. Thus, important conditions for a potentially successful active immunotherapy are given. Results of most earlier randomized trials on immunotherapy revealed some, but limited benefit with respect to survival. Encouraging effects, however, have been achieved by immunizing CR patients with high-dose neuraminidase-treated allogeneic blasts. Because these data have not been confirmed until now we recently initiated a randomized study utilizing identical treatment protocols. The preliminary results of the ongoing study still do not allow to draw any firm conclusions. Specific monoclonal antibodies or autologous cytotoxic T-cells may be useful tools for future immunotherapy of AML.

[The Münster study of intensive induction and consolidation therapy without maintenance therapy of acute myeloid leukemia. Results of 93 patients--cellular determinants for response and length of remission]. / Die Studie Münster über intensivierte Induktions- und Konsolidierungstherapie ohne Erhaltungstherapie der AML. Resultate bei 93 Patienten--Zelluläre Determinanten für Response und Remissionsdauer.

A 9-day high-dose 3-drug induction regimen including ARA-C, DNR, and TG at special time sequencing was given to 93 patients with AML, 15-74 (median 52) years old. After 1-2 courses for remission induction and, if possible, 2 identical courses of consolidation, no further therapy was applied during remission. Complete remission (CR) was achieved in 71% of all patients and in 74% of responders by 1 course only. Median remission duration is at 1 year with 13 patients in continuous CR for 13-38 (median 24) months. Patients completing consolidation reached a median remission duration of 22 months and those with rapid response to 1 induction course and with complete consolidation 38+ months. Patients monitoring included bone marrow DNA-histograms by flow cytometry, blood counts, percentage, and absolute number of blasts in bone marrow and LDH in serum. Among pretherapeutic parameters only LDH (inversely) correlated with CR duration. In contrast during early therapy rapid blast reduction, decrease of S-phase-index and of LDH as well as short recovery time of platelets and neutrophils predicted for low risk (when high risk included non-response and early relapse). Thus, monitoring of early cellular response parameters reflecting cellularity and proliferation seems to provide important individual determinants of therapeutic outcome.

[Clinical and cell kinetic data on the combination of cytosine arabinoside with daunorubicin, isosfamide, thioguanine, and vincristine for remission induction and maintenance in patients with acute myelocytic leukaemia (author's transl)]. / Induktionsbehandlung der akuten myeloischen Leukämie mit Cytosin-Arabinosid -- Daunorubicin, zusätzlicher Effekt von Ifosfamid und Vincristin.

31 adult patients (study A) with acute myelocytic leukaemia were treated for remission induction with cytosine arabinoside (ARA-C, 100 mg/m2/day) by a 7 (5) day continuous infusion. 3 (2) doses of daunorubicin (DNR, 45 mg/m2 i.v.) were added at daily intervals. For maintenance 5 day ARA-C was given monthly in sequential combination with DNR, thioguanine (TG), or ifosfamide (IFOS). 16 (52%) patients achieved complete remission (C.R.) after 1.8 (1-3) courses and 6.7 (3-10) weeks from treatment start. The median survival for responders and non-responders was 11.5 months, early death rate within 6 weeks was 3 (10%). Median remission duration was 13.5 months. Among 11 patients surving for 7-22 months 7 patients are in first remission for 5.5-20.5 months. DNR, IFOS and TG were given before the 3rd day of ARA-C infusion. In a previous group of 34 leukaemic patients and in 44 therapy courses DNA histograms of bone marrow cells using pulse cytophotometry showed marked accumulation in S-phase for 75% of courses. Also (G2 + M)-cells in the DNA distribution and thymidine pulse labelling indices were markedly increased in most cases, whereas thymidine uptake by scintillation counter was diminished and mitotic indices had not changed significantly. In now 15 patients (study B) the induction regimen was intensified by adding vincristine (VCR, 2 mg i.v.) and 3 doses of IFOS (600 mg/m2 i.v.). Preliminary results are 50% C.R. after 1,7 (1-2) courses and 6.8 (5-10) weeks from initiation of therapy. 2 patients died in the first 6 weeks.

[Monocyte function in chronic uremia (author's transl)]. / Zur Monocyten-Funktion bei Kranken mit terminaler Niereninsuffizienz

Monocyte function studies in vitro have been performed in 21 patients with terminal, dialysis-treated uremia and, in parallel, in 21 healthy normal subjects. In uremia the attachment, spreading activity, and reduction of nitroblue tetrazolium were shown to be significantly enhanced, indicating a metabolic activation of the monocytes. The phagocytosis of IgG-coated red cells, however, was significantly impaired. A modification of the monocyte IgG-receptor in uremic conditions is supposed; its relevance for the immunosuppression in uremic states is discussed.