Treatment of prolonged chemotherapy induced severe thrombocytopenia with recombinant human interleukin-3--a report on four cases.

Interleukin-3 (IL-3) is a multipotent hematopoietic growth factor, which exhibits stimulatory effects on leucocytes, reticulocytes and platelets. Due to its pronounced induction of megakaryopoiesis, IL-3 is thought to be a cytokine with the potential to prevent and to overcome chemotherapy-induced thrombocytopenia. We report on four cases (two of metastatic breast cancer, one of metastatic ovarian cancer and one of Hodgkin's disease) with prolonged chemotherapy-induced thrombocytopenia in whom rhIL-3 in combination with either recombinant human (rh) granulocyte macrophage colony stimulating factor (GM-CSF) or rh granulocyte colony stimulating factor (G-CSF) was administered. In all cases, a steady and clinically significant increase in platelet counts could be observed. No major side effects, neither due to the application of rhIL-3 nor due to rhGM-CSF or rhG-CSF, occurred; only flu-like symptoms were seen, which could effectively be treated with paracetamol. This report highlights the efficacy of combined treatment with rhIL-3 plus rhGM-CSF or rhG-CSF in chemotherapy-induced thrombocytopenia, where megakaryopoiesis could be stimulated efficiently by rhIL-3. Based on this experience, the authors conclude that established thrombocytopenia as a major side effect of myelosuppressive chemotherapy should be considered as an indication for the use of rhIL-3 in interventional treatment. Further investigations in this area are encouraged.

Chronic Lymphocytic Leukemia (B-CLL) and Immunocytoma (LP-IC): Clinical and Prognostic Relevance of this Distinction.

The Kiel classification of non-Hodgkin lymphomas (NHL) has established chronic lymphocytic leukemia (B-CLL) and immunocytoma (LP-IC) as separate entities of low-grade malignant NHL by morphological and immunohistochemical criteria. The clinical and prognostic relevance of this discrimination was evaluated in a prospective multicenter observation study by the Kiel Lymphoma Study Group. From 1975 to 1980, 430 previously untreated patients with B-CLL (n = 217) and LP-IC (n = 213)a were recruited and followed for up to 14 years. While the age and sex distribution and the incidence of clinical stages were quite similar in both entities major differences between initial manifestations in B-CLL and LP-IC became evident, e.g. in the incidence of bone marrow infiltration (99.5 vs. 86%), peripheral blood lymphocytosis (99.5 vs. 60%), or monoclonal gammopathy (1 vs. 30%). A strictly localized tumor (Ann Arbor stage I/IE) was seen in only 1.5% of the LP-IC patients who were successfully treated by local radiotherapy. In all other patients an expectative-palliative treatment concept was pursued. Long-term survival data analysis revealed significant differences between B-CLL and LP-IC and identified the pseudofollicular in B-CLL and the lymphoplasmacytic in LP-IC as the most favorable histological subtypes. The discriminative prognostic potential of clinical stage (Rai or Binet classification) for B-CLL and LP-IC varied and the pattern of prognostic risk factors obtained by multivariate analysis was not identical. Thus, the morphological distinction between B-CLL and LP-IC correlates with characteristic differences between these entities both in their initial clinical presentation and long-term prognosis.

[Thrombotic thrombocytopenic purpura (Moschcowitz syndrome) in a patient with EPH gestosis. The pathophysiologic principle of HELLP syndrome? On the question of the identity of the HELLP syndrome with thrombotic thrombocytopenic purpura]. / Thrombotische thrombozytopenische Purpura (Moschcowitz-Syndrom) bei einer Patientin mit EPH-Gestose. Die pathophysiologische Grundlage des HELLP-Syndroms? Zur Frage der Identität des HELLP-Syndroms mit der TTP.

Case history of a patient is reported who developed signs of preeclampsia in 28th week of her first gravidity. Within one day severe haemolysis and diffuse haemorrhage occurred and an emergency section was performed. Subsequently, supported respiration became necessary because of diffuse infiltrations of the lung. Laboratory data then were conclusive for a thrombotic thrombocytopenic purpura (Moschcowitz's disease) and therefore the patient was subjected to plasma exchange during seven days: this measure induced rapid and full clinical and laboratory remission. The case history is discussed on the background of the pertinent literature and the special perspective of a pathophysiological identity between the two syndromes: HELLP (haemolysis, elevated liver enzymes, low platelets) and Moschcowitz's disease (thrombotic thrombocytopenic purpura); this seems to be of special interest for an adequate therapy by plasma exchange.

[Results with the use of the M-2 protocol in plasmacytoma]. / Ergebnisse mit dem M-2-Protokoll bei Plasmozytom.

99 patients with multiple myeloma were treated over a period of 6 1/2 years; 62 of these were initially treated with vincristine, carmustine, cyclophosphamide, melphalan and prednisone: M 2-Protocol. Response to this therapy was assessed after three therapy cycles had been completed, which had been given at intervals of 5-6 weeks. In patients responding to the therapy, treatment was continued until a maximum regression of the paraproteins was achieved. By the end of May 1985, the data of 52 patients could be evaluated, in 31 (60%) of whom remission was observed. Median survival time of all patients was 27 months. In 18 patients with "complete" remission the median has not yet been reached after 40 months. In 13 patients with partial remission, the median survival time was 36 months. In patients with complete remission, the median remission period was 26.5 months, in patients with partial remission 13.9 months.

Subtypes of T-cell chronic lymphatic leukemia.

Thirteen cases of T-cell chronic lymphatic leukemia (T-CLL) (including T-cell prolymphocytic leukemia) are presented. Five subtypes were distinguished according to morphologic and functional parameters of the leukemic cells: prolymphocytic; lymphocytic, small; lymphocytic, Sézary-like; lymphocytic, abundant cytoplasm; lymphocytic, abundant cytoplasm and granules. The subtype can be recognized by light and by electron microscopic investigation. Cytochemistry (APh and ANAE) may be helpful to delimit T-CLL from B-CLL, and acid phosphatase to recognize the subtype characterized by abundant cytoplasm and granules. Membrane marker investigations support the diagnosis of T-type CLL. When functional properties of the leukemic cells were tested, cells of one patient (T-PLL) were shown to help in B-lymphocyte differentiation and Ig-secretion, whilst the cells of a second patient (lymphocytic, abundant cytoplasm and granules) were proven to act as effectors in natural killing and antibody-dependent cytotoxicity. The T-helper lymphocyte nature of some of the leukemic cells was supported by demonstration of the Fc mu-receptor in three cases. In one of these patients, monoclonal IgM was detected in the serum. Response to therapy and prognosis were rather poor in this limited number of patients when compared with B-CLL.

Chronic lymphocytic leukemia: a proliferative or accumulative disorder?

In two untreated patients with progressive CLL, quantitative 14C autoradiography of lymph nodes and, subsequently, continuous infusion of [3H] thymidine over eight and nine days, respectively, were performed in order to analyse the lymph node cell kinetics. Simultaneously, the turnover of labelled lymphocytes in the peripheral blood was evaluated. From another CLL patient a regional lymph node was removed 6 h after an intralymphatic flash injection of [3H] thymidine and sectioned for autoradiographic study of the distribution of labelled cells within the lymph node tissue. While the durations of DNA synthesis were found to be normal, the labelling indices were reduced. The relative cell production rate was far lower than normal. Very small growth fractions were calculated, amounting to less than 1% in one patient, and to 2.4% in the other. The distribution of labelled cells in the lymph nodes was focal, which supports the finding of low growth fractions. According to the present data, CLL is a disorder in which a very small number of cells cycle at a roughly normal rate. A kinetic definition of accumulative and proliferative tumour growth is introduced. Tumour growth is termed accumulative if growth appears to result from a decreased relative cell loss rate rather than an increased relative cell production rate. According to this definition, the kinetics in CLL may be classified as accumulative. In absolute terms, however, the number of lymphoid cells produced per unit of time was found to be far higher in CLL than in the healthy state.

Prognostic significance of lymphocyte density distribution profiles in adult non-Hodgkin lymphomas.

Biopsy material from 24 adults with advanced stages of non-Hodgkin lymphomas (NHL) were examined for the distribution profiles of infiltrating cells following centrifugation to equilibrium on linear density gradients. Seven of these biopsies were predominantly composed of cells with high buoyant densities and 9 further biopsies predominantly of cells with intermediate buoyant densities. Both patterns were associated with favorable histologic features and with low proliferation of lymphoma cells. Intensive polychemotherapy was rarely required to achieve long-lasting disease control; in both groups, only 28% of patients died within a minimal observation period of 40 mo. In 8 biopsies, a predominance of light lymphoma cells was observed. This pattern was frequently associated with unfavorable histology and with high spontaneous tumor cell proliferation. Despite intensive polychemotherapy, rapid disease progression occurred in all cases, leading to death in 75% of the patients within a minimal observation period of 40 mo. Surface marker studies excluded the hypothesis that only the variable proportions of normal lymphocytes contaminating the lymphoma suspensions were responsible for the differences in the density distribution patterns described above; they rather suggested that these patterns reflect the individual capacity of a lymphoma to differentiate into dense tumor clones with low spontaneous proliferation.

[Density distribution of human lymphocytes. II. Distribution patterns of malignant lymphocytes and their prognostic significance in patients with non-Hodgkin's lymphoma]. / Dichteverteilung menschlicher Lymphozyten. II. Verteilungsmuster maligner Lymphozyten und prognostische Signifikanz bei Patienten mit non-Hodgkin Lymphomen.

The aim of this study was to investigate the prognostic significance of density distribution profiles in non-Hodgkin lymphomas. Density profiles were evaluated by equilibrium centrifugation on linear polysucrose-metrizoat gradients. Biopsy cells from 44 untreated non-Hodgkin lymphomas in advanced stages according to their density patterns could be classified into one of two distinct groups: Group A lymphomas exhibited high to intermediate densities and resembled normal resting B or T lymphocytes; they showed low spontaneous proliferation and favourable histologies. Group B lymphomas exhibited light densities, resembling activated lymphocytes and frequently revealed high spontaneous proliferation and unfavourable histology. Within a minimal time of observation of 40 months only 28% of the group A but 75% of the Group B lymphomas died. Simultaneously performed surface marker studies excluded the possibility that variable proportions of normal lymphocytes contaminating the lymphoma suspensions are responsible for the two density groups. They rather suggested that these patterns reflect the individual capacity of a lymphoma to differentiate into denser tumour clones with low spontaneous proliferation. We therefore conclude that analyses of density profiles from non-Hodgkin lymphomas represenmts a promising method for the prognostic classification of this disease.

Treatment of non-hodgkin's lymphoma of low-grade malignancy with human fibroblast interferon.

10 patients with advanced non-Hodgkin's lymphoma of low malignancy were treated with partially purified HulFN-beta. They received daily i.v. infusions of 4.5 X 10(6) IU for 4 weeks, followed by 9 X 10(6) IU daily for 2 weeks. Patients with stable disease during this period received consolidation therapy with 4.5 X 10(6) IU three times per week for a maximum of 20 weeks. Six out of 10 patients had progressive disease after the initial 6 week treatment and 4 had stable disease. Two of the latter developed progressive disease during consolidation therapy, one had a complete remission of minimal bone marrow involvement, and one was in partial remission with a loss of bone marrow infiltration but unchanged lymph node enlargement.

[Clinical course of hairy cell leukemias]. / Beobachtungen zum Verlauf von Hairy-cell-Leukosen.

When analyzing 20 cases of hairy-cell leukosis we can compare a group with a medium survival time (16 months since clinical beginning of the illness) to a group with a long survival time (80 months). Patients (historically older) with short survival times are characterized by a combination of short anamnestic dormancy, younger age, severe symptoms and the applying of a steroid and cytostatic therapy instead of splenectomy. Prevalent causes of death were infections which seemed to increase by cytostasis. Patients with a longer survival time were characterized by a longer survival time were characterized by a longer anamnestic dormancy (up to 15 years), and clinically bland indications that permitted splenectomy. In this group we find interesting cases in which after splenectomy the infiltration of the bone marrow was greatly reduced, being in one case merely 10% after 10 years. These findings ought to be discussed with respect to the aspect of the extremely slow and spleen dependent kinetics of the pathognomy of the cell fractions. As to the origin of the hairy cells and to mark the difference to other lymphomas of the spleen it is necessary to stress the fact that the rate of immunoglobuline did not change in any of the 20 cases observed.