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.

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.

[Induction and maintenance treatment of acute myelogenous leukemia in adults by sequential use of combination chemotherapy (author's transl)]. / Induktions- und Erhaltungstherapie der akuten myeloischen Leukämie des Erwachsenen durch sequentielle Anwendung zytostatischer Chemotherapiekombinationen

The therapeutic regimens for acute myelogenous leukemia in 2 different periods of time will be described with comparison of their results. A. 28 adults were treated with cytosine arabinoside and 6-thioguanine only. Thereby, 28% complete and 16% partial remissions were achieved. The mean duration of the complete remissions was 23 weeks. The mean survival time of the patients with complete remission amounted to 53 weeks B. 46% complete and 12% partial remissions were obtained in 37 patients treated with cytosine arabinoside and 6-thioguanine doubling the dosage of the above mentioned regimen followed by 3 cycles of TRAP (and COAP). Using a maintenance therapy with modified TRAP, COAP, and POMP cycles the complete remissions lasted 47 weeks at an average. The mean survival time of patients with complete remission was 87 weeks after start of treatment.

Idarubicin in refractory acute leukemia.

10 patients with resistant or relapsed acute leukemia (9 AML, 1 ALL) were treated with idarubicin (4-demethoxydaunorubicin) in combination with cytosine arabinoside +/- etoposide. All patients had been heavily pretreated. 9 AML-patients had previously received 2-4 cycles of TAD-9 regimen. 2 complete and 1 partial remission were achieved. 1 patient died from septicemia in bone marrow aplasia without leukemic cells. 6 patients did not respond to idarubicin-based salvage treatment. The median survival from start of therapy was 4 months. Idarubicin-based combination chemotherapy is effective in relapsed acute leukemia, even in patients intensively pretreated with anthracyclines.

[Therapy of chronic myeloid leukemia with interferon]. / Therapie der chronischen myeloischen Leukämie mit Interferon.

Several modalities are used for treatment of the chronic phase of chronic myelogenous leukemia. Most patients are treated with single agent chemotherapy. However, patients are cured only by isogenic or allogeneic bone marrow transplantation; otherwise the disease regularly proceeds to fatal blastic crisis. Alpha-interferon has an antiproliferative activity against hematopoietic cells in vitro and in vivo. We have treated 10 patients with the chronic phase of Philadelphia--chromosome-positive chronic myelogenous leukemia with alpha-interferon. The median duration of the disease was 10 months. Five patients were previously untreated and five achieved hematologic remission. Patients with a disease duration of less than 1 year, who had had no or only minimal pretreatment, showed the best response rates. These experiences confirm published data on interferon therapy. It remains to be determined whether interferon treatment and the hereby induced suppression of the Philadelphia-chromosome-positive cell clone in some patients will improve survival.

Chemoprophylaxis of bacterial infections in granulocytopenic patients with ciprofloxacin.

The trial was conducted to evaluate the antimicrobial prophylactic efficacy of ciprofloxacin in reducing the frequency of infections in granulocytopenic patients. The frequency of infections was evaluated in 34 patients with acute non-lymphoblastic leukemia, acute lymphoblastic leukemia, blast crisis of chronic myelogenous leukemia and other malignancies. 46 courses of oral prophylactic treatment with 500 mg ciprofloxacin twice daily were administered. While there was no infection in 61% of treatment courses, fever over 38 degrees C (axillary) occurred in 39%. 6 patients had a fungal pulmonary infection, one patient a supposed viral pneumonia, and only two patients had a documented bacterial infection. There were no severe side effects. We conclude that ciprofloxacin is a potent drug in prophylaxis of bacterial infections in cancer patients with therapy-induced granulocytopenia.

[Clinical results with granulocyte transfusion (author's transl)]. / Klinische Ergebnisse bei der Anwendung von Granulozytentransfusionen.

16 adult patients with granulocytopenia and septicemia resistant to antibiotics received 42 granulocyte transfusions. The granulocytes were obtained from healthy donors with a blood cell separator by continuous flow centrifugation. Adding hydroxyethyl-starch an average of 1.8 X 10(10) leukocytes with 69% granulocytes were harvested in 3.5 hours. A small leukocyte increment after the transfusion was seen in half of the recipients. No correlation could be found between fever lysis and survival of the infection, which occurred in half of the cases too. A granulocyte transfusion is indicated in patients, who have granulocytopenia, sepsis and no evidence of bone marrow recovery.

[Diagnosis and differential diagnosis of hairy cell leukemia]. / Diagnose und Differentialdiagnose der Haarzell-Leukämie ("Hairy cell leukaemia", "Leukämische Retikuloendotheliose")

On account of 2 own observations, main clinical and diagnostic features of Hairy cell leukemia (HCL) will be discussed. HCL is a rare, unusual type of chronic leukemia and is predominantly particular of middle-aged men. The occurrence of middle-sized lymphoid cells having a hairy cytoplasmic edge, and a tartrate-resistant acid PHOsphatase isoenzyme are the characteristic criteria of the HCL. The diffuse infiltration by hairy cells affecting primarily the spleen and bone marrow results in anaemia, granulocytopenia, thrombocytopenia and splenomegaly. Differential diagnosis have to be made in relation to other lymphatic leukemias, leukemic malignant lymphomas and monoclonal gammopathies as well as lymphotropic viral infections. Immunologic behaviour of hairy cells is like that of B-lymphocytes. Therefore, the term "leukemic reticuloendotheliosis" should no longer be applied.

[Myelomonocytic leukemia: clinical, cytological, and cytogenetic studies of acute, subacute, and chronic forms (author's transl)]. / Myelomonozytäre Leukämie: Klinische, zytologische und zytogenetische Studien bei akuten, subakuten und chronischen Verlaufsformen.

44 patients suffering from myelomonocytic leukemia (MML) have been observed over the last four years. They have been subclassified in acute myelomonocytic and acute monoblastic leukemias (AMML, n = 12; AMoL, n = 10), subacute myelomonocytic leukemias (SMML, n = 13), and chronic myelomonocytic leukemias (CMML, n = 9) on the basis of bone marrow cytology(blast and promonocyte counts, maturation of granulopoesis) and cytochemical findings (peroxydase and unspecific esterase reaction). This subclassification has been proved to be of prognostic relevance by its good correlation with the mean survival times (AMML : 4.5 months, AMoL : 2.4 months, SMML : 8 months, CMML : 18 months). The acute forms have been treated in general with combined cytostatic chemotherapy, whereas SMML and CMML have been treated this way only in case of progression to an acute phase. These progressions to an AMML have been observed more often and earlier in subacute forms than in chronic forms. The diagnosis of SMML and CMML is supported by the finding of sea-blue histiocytes in the bone marrow, increased lysozyme levels in serum and urine and by the absence of the Philadelphia-Chromosome.

Adjuvant specific immunotherapy in maintenance treatment of adult acute non-lymphocytic leukemia.

From 1976 until 1978, 136 adult patients with acute leukemia were treated in four hospitals in Berlin. A complete remission was achieved in 47 patients (35%). Twenty-six patients with non-lymphocytic acute leukemia, who had achieved a complete remission with induction chemotherapy consisting of daunorubicin (45 mg/m2/day, day 1, 2 and 3) and cytosine-arabinoside (100 mg/m2/day, continuous infusion, day 1 to day 7) were entered into a randomized trial. Thirteen patients were treated with an intermittent combination chemotherapy at 4-week intervals; the other group of patients received in addition a specific immunotherapy consisting of neuraminidase-modified allogeneic blast cells. The results revealed that the addition of this kind of immunotherapy did not increase the duration of first remission or survival.

[Therapy of hairy cell leukemia with interferon]. / Therapie der Haarzell-Leukämie mit Interferon.

Hairy cell leukemia is a rare lymphoproliferative disorder which is morphologically characterized by circulating lymphatic cells with prominent 'hairy' cytoplasmatic projections. Patients typically present with pancytopenia and splenomegaly. The bone marrow cannot be aspirated because of reticulin fibrosis. Chemotherapy was unable to influence the course of the disease satisfactorily. Therefore, splenectomy was the treatment of choice. The introduction of alpha-interferons into the therapy of hairy cell leukemia was a decisive breakthrough and is exemplary for the use of interferons in the treatment of malignant diseases. However, there are still many questions to be answered. The discussion of clinical implications is achieving growing importance in consequence of the availability of diverse commercial alpha-interferons for treatment of hairy cell leukemia.

[The effect of mesterolone in panmyelopathic anemia and anemia of renal failure]. / Die Wirkung von Mesterolon bei Panmyelopathien und renalen Anämien

A controlled randomized multicenter trial was carried out to examine the therapeutic value of the androgen mesterolone in aplastic anemia and anemia of renal failure. the drug was given in a dose of 2 mg/kg orally for 6 months. Control patients received no androgens but were otherwise similarily treated. 31 patients with aplastic anemia could be evaluated. No significant difference was found between androgen treated control cases in respect to bone marrow cellularity, improvement of peripheral blood cell counts or survival. In a group of 14 patients not being hemodialyzed with anemia from renal failure, 3 of the androgen treated and none of the control patients showed progressive and significant improvement of erythropoiesis; however, this was not a statistically significant difference when the both groups of patients were compared. The results do not suggest that the androgen mesterolone is of therapeutic value in the majority of adult patients with aplastic anemia. Possible reasons of the discrepancy to positive results reported in the literature are discussed.

Multicentre randomized therapeutic trial for advanced centrocytic lymphoma: anthracycline does not improve the prognosis.

Within a multicentre observation study on non-Hodgkin lymphomas (NHL) diagnosed according to the Kiel classification advanced stages III and IV of centrocytic (CC) lymphoma exhibited the worst prognosis among lymphomas of low-grade malignancy with a 5-year survival probability of less than 10 per cent. Treatment had been solely expectative and palliative with treatment results showing a prognostic superiority of patients achieving partial and complete remissions over non-responders. Therefore, a randomized multicentre study was initiated to compare the remission-inducing potential of the COP regimen (Bagley et al., 1972) with that of the more intensive adriamycin-containing CHOP regimen (McKelvey et al., 1976). From 91 newly diagnosed CC lymphomas 63 fulfilled randomization criteria with 37 patients assigned to the COP regimen and 26 patients to the CHOP regimen. Between the COP- and CHOP-treated patients no significant differences could be demonstrated with respect to initial clinical parameters, rate of complete (41 per cent versus 58 per cent) or partial remissions (43 per cent versus 31 per cent), median overall survival probability (32 versus 37 months), relapse-free survival (10 versus 7 months) and rates of relapse (73 per cent versus 67 per cent) and death (57 per cent versus 50 per cent). It can be concluded that CC lymphoma is a typical lymphoma of low-grade malignancy with its inability to reach stable remissions while the demonstration of identical survival probabilities for patients with complete and partial remissions constitutes a unique feature of this lymphoma entity. These observations prove advanced CC lymphoma to represent an incurable neoplastic disease under conventional therapeutic approaches.

Clinical and prognostic relevance of the Kiel classification of non-Hodgkin lymphomas results of a prospective multicenter study by the Kiel Lymphoma Study Group.

Clinical and prognostic relevance of the Kiel classification of non-Hodgkin lymphomas (NHL) was investigated in 1127 patients entering a prospective multicenter observation study. Survival of the 782 (69.4 per cent) patients with low-grade malignant NHL (lymphocytic lymphomas, predominantly B-CLL, LP immunocytoma, centrocytic lymphoma, centroblastic-centrocytic lymphoma) exceeded that of the 341 patients (30.2 per cent) with high-grade malignant NHL (centroblastic, immunoblastic, lymphoblastic lymphomas). Prognosis was best in centroblastic-centrocytic lymphoma and in B-CLL and least favorable in immunoblastic and lymphoblastic lymphomas. Survival of LP immunocytoma and centrocytic lymphoma patients was intermediate after 2 to 2.5 years of follow-up. Corresponding to histopathology, pattern of survival curves of low-grade malignant NHL (slow decline, no plateauing) differed from that of high-grade malignant NHL (rapid decline, subsequent plateauing). Prognosis of B-CLL was superior to that of LP immunocytoma. Stages I and II were more frequent in centroblastic-centrocytic lymphoma (21 per cent) than in LP immunocytoma (2.5 per cent) and centrocytic lymphoma (11 per cent). Ability of radiotherapy to induce stable complete remissions in stage III of centroblastic-centrocytic lymphoma indicates prolonged restriction of lymphoma to the lymphatic system. In immunoblastic and centroblastic lymphomas, stages I and II were diagnosed in 34 and 38 per cent of cases, respectively, but only in stage I/IE of centroblastic lymphoma prolonged remissions were achieved by radiotherapy. In advanced high-grade malignant NHL marked improvement of prognosis was solely possible by induction of complete remissions whereas in corresponding low-grade malignant lymphomas also partial remissions were prognostically relevant.

[Clinical and prognostic relevance of the Kiel classification of non-Hodgkin lymphomas]. / Klinische und prognostische Relevanz der Kiel-Klassifikation der Non-Hodgkin-Lymphome.

The Kiel classification provides a new subdivision of non-Hodgkin lymphomas into distinct entities showing different clinical and prognostic properties. In comparison with earlier classifications this system defines additional types of lymphoma (e.g. CC lymphoma, LP immunocytoma) (for abbreviations see text) which are to be considered separate entities also from a clinical point of view. By data derived from a multicenter prospective observation study (1,127 patients recruited from 1975 to 1980, follow-up until 1985) a precise definition of the clinical features of each lymphoma entity (e.g. frequency, age and sex distribution, patterns of initial involvement and spread of disease) was possible. In addition, the effect of radio- and/or chemotherapeutic measures was evaluated. Strictly localized disease (stage I/IE according to the Ann Arbor classification) occurred in 1.5 to 8% of patients with NHL of low-grade malignancy (comprising 69.4% of cases studied) and in 8 to 17% of patients with high-grade malignant NHL (comprising 30.2% of cases studied). Loco-regional irradiation alone was able to induce complete remission in 86 to 89% (CB and IB lymphomas) and in 100% (LP immunocytoma, CB-CC and CC lymphomas), respectively, of stage I/IE patients. Only CC and IB lymphomas showed a relevant risk of relapse (40% and 50%, respectively). Total lymphoid irradiation as able to induce stable complete remissions in about 50% of patients with stage III of CB-CC lymphoma. Probabilities of survival of patients with initial stages III and IV treated by several types of chemotherapy reflect different prognostic features of individual lymphoma entities.(ABSTRACT TRUNCATED AT 250 WORDS)

Lymphoplasmacytic/lymphoplasmacytoid lymphoma: a clinical entity distinct from chronic lymphocytic leukaemia?

Clinical data of 116 patients with chronic lymphocytic leukaemia (CLL) and of 114 patients with lymphoplasmacytic/lymphoplasmacytoid lymphoma (synonym: LP immunocytoma, IC) as diagnosed according to the Kiel classification were compared. This interim evaluation of a prospective multicenter study of the Kiel Lymphoma Study Group characterizes IC the less favorable lymphoma entity as evidenced by a more rapid lymph node enlargement, by a higher incidence of constitutional symptoms and of marked anaemia, and by a higher percentage of patients requiring early treatment. In addition, in IC autoimmune haemolytic anaemia was detected in 11.2% of investigated patients as compared to none of the patients with CLL, and monoclonal gammopathy was disclosed in 34.2% of investigated patients as compared to only three patients with CLL who could be, however, unrecognized cases of IC. Actuarial survival data after a follow-up period of 40 months are in favor of an overall better prognosis of patients with CLL than of patients with IC.

Germinal center cell lymphomas: prognostic significance of their histopathological differentiation.

Clinical data of 48 patients with centrocytic, 83 patients with centroblastic/centrocytic and 64 patients with centroblastic lymphoma who had entered a prospective multicenter study of the Kiel Lymphoma Study Group since October 1975 were compared. Advanced (stage IV) disease at time of diagnosis, predominantly due to bone marrow infiltration, was most frequent in centrocytic (69% of patients) and in centroblastic/centrocytic (51% of patients) lymphomas as compared to only 28% of patients with centroblastic lymphoma. High survival probability of patients with localized centrocytic and centroblastic/centrocytic lymphomas after radiotherapy, contrasting with a worse prognosis of corresponding patients with centroblastic lymphoma, is compatible with the classification of these lymphoma entities as neoplasias of low-grade malignancy. However, as shown by this prospective and previous retrospective trials overall survival probability of patients with advanced centrocytic lymphoma was inferior to that observed in corresponding patients with centroblastic/centrocytic lymphoma. These findings suggest the possibility that patients with advanced centrocytic lymphoma occupy an intermediate position between typical low-grade and typical high-grade malignant non-Hodgkin lymphomas.

Clinical and prognostic heterogeneity of non-Hodgkin lymphomas of high-grade malignancy.

Comparison of clinical data of 64 patients with centroblastic lymphoma, 55 patients with immunoblastic lymphoma and 31 patients with lymphoblastic lymphoma not only confirmed the original assumption of high-grade malignancy as proposed by the concept of the Kiel classification but also demonstrated distinct clinical differences, particularly between lymphoblastic lymphoma and the two other entities. Rapid lymph node enlargement as well as steep fall of survival curves within the first year after diagnosis were common characteristics. Bimodal age distribution, predominance of males and early generalization of disease were typical features of lymphoblastic lymphoma; elderly patients and patients with the unclassified subtypes of lymphoblastic lymphoma exhibited the worst prognosis. Whereas patients with centroblastic and immunoblastic lymphomas showed similar distribution of age, sex and initial stage of disease, patients with immunoblastic lymphoma presented more frequently with a reduced performance status and showed a poorer response to radio- and chemotherapy resulting in a worse prognosis discernible after the first year of follow-up. Generalization during course of the disease was significantly more frequent in immunoblastic than in centroblastic lymphoma.