CEOP-IMVP-Dexa in the treatment of aggressive lymphomas: an Austrian multicenter trial.

PURPOSE: This trial evaluated the efficacy, toxicity, and practicability of a new intensive chemotherapy regimen in a multicenter setting of university and community hospitals. PATIENTS AND METHODS: We tested a hybrid protocol of two non-cross-resistant regimens, cyclophosphamide, epirubicin, vincristine, and prednisolone (CEOP) and ifosfamide, etoposide (VP-16), methotrexate, and dexamethasone (IMVP-Dexa) given every fourth week, three to six times according to response, in patients with untreated intermediate- and high-grade non-Hodgkin's lymphoma. Ten Austrian centers entered 81 patients onto this multicenter trial. Eleven patients were excluded. The median age was 55 years. Twenty-six of 70 patients had stage III or IV disease. The distribution among international risk categories low, intermediate-low, intermediate-high, and high was 20%, 34%, 23%, and 23%, respectively. RESULTS: Of 70 eligible patients, 56 (80%) had a complete remission and seven (10%) a partial remission. After a median observation time of 36 months, the estimated time to relapse and overall survival rates are 67% and 72%, respectively. Age and Karnofsky index were the only independent risk factors for survival. Toxicity was primarily hematologic, with a median granulocyte nadir of 0.56 x 10(9)/L. Sixty-seven percent of patients had infections; 25.7% were severe World Health Organization (WHO) grade III or IV. There were three treatment-related deaths. CONCLUSION: CEOP-IMVP-Dexa chemotherapy is safe and feasible on a groupwide basis even when used in community hospitals. Neutropenic infections are the major complications. A 72% 3-year survival rate in patients with intermediate- and high-grade non-Hodgkin's lymphoma warrants further studies. These data are the basis for a randomized trial to compare cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) with CEOP/IMVP-Dexa.

Treatment of thrombocytosis in chronic myeloproliferative disorders with interferon alfa-2b.

Thirty-six patients with chronic myeloproliferative disorders (CMPD) with thrombocytosis (essential thrombocythaemia 19 patients, chronic megakaryocytic granulocytic myelosis five, polycythaemia vera six, chronic myelogenous leukaemia six) were treated with interferon alfa-2b to reduce the platelet count. The pre-treatment platelet count was in the range 450-700 x 10(9)/L in eight patients, 700-1000 x 10(9)/L in eight and above 1000 x 10(9)/L in 20. In the induction phase of treatment 22 patients were treated with interferon alfa-2b 3 million units (MU) daily subcutaneously for 2 months or until the platelet count returned to normal, if earlier. Fourteen patients received 5 MU interferon alfa-2b daily in the same way. In the maintenance phase the doses were reduced to 3 MU and 5 MU thrice weekly, respectively. Complete response (CR), defined as a reduction of platelet count to below 450 x 10(9)/L, was achieved in 78% of patients (within 2 months of induction in 64%). The platelet depleting effect was dose dependent: CR in 2 months in 52% on 3 MU interferon alfa-2b versus 75% on 5 MU. Reduction of interferon dose was followed by an increase in platelet count in 39% of patients. The white cell count fell by 50% in Philadelphia-negative CMPD. Side effects were common, though generally mild, but led to withdrawal of treatment in six patients. Three patients suffered cerebrovascular events during treatment and one shortly thereafter.

Interferon alfa-2b with VMCP compared to VMCP alone for induction and interferon alfa-2b compared to controls for remission maintenance in multiple myeloma: interim results.

The present trial was designed to evaluate whether interferon (IFN) combined with standard induction chemotherapy and/or interferon remission maintenance treatment improve treatment results in patients with multiple myeloma. Up to now 89 patients have received IFN plus vincristine/melphalan/cyclophosphamide/prednisolone (VMCP) as induction therapy, and 86 conventional VMCP. The proportion of patients with progressive disease was significantly lower (P less than 0.005) under IFN + VMCP as compared to the VMCP treatment group. Survival times were significantly longer (P less than 0.02) after IFN + VMCP induction therapy than after VMCP alone. In the second phase of this investigation, 33 progression-free myeloma patients were assigned to receive IFN as maintenance therapy, and 41 patients served as untreated controls. Patients maintained with IFN showed a tendency towards increased progression-free survival. Haematological side effects were observed significantly more often in patients receiving IFN, with more severe haematological toxicity in patients on the combined IFN + VMCP regimen and an increased number of patients with mild haematological toxicity in the group maintained with IFN. Other side effects, such as fever and fatigue, remained within tolerable limits. In conclusion, the preliminary results of this current clinical trial indicate significant advantages of combined IFN + VMCP induction treatment in terms of reduced disease progression and prolonged survival and possible benefits of IFN maintenance therapy in patients with multiple myeloma.

Efficacy and toxicity of 2-Chlorodeoxyadenosine (Cladribine)--2 h infusion for 5 days--as first-line treatment for advanced low grade non-Hodgkin's lymphoma.

2-Chlorodeoxyadenosine (Cladribine) is a new purine analogue with high activity in pretreated low grade non-Hodgkin's lymphoma (NHL). To evaluate the efficacy of this drug in untreated patients with advanced NHL, we performed a prospective multicentre trial. Cladribine (0.12 mg/kg) was administered intravenously daily for 5 consecutive days in an out-patient setting. The treatment was repeated every 28 days for four cycles. Included were patients with a histological diagnosis of low grade NHL according to the Kiel classification and stage III or IV disease. Stage II patients were included when radiotherapy had failed. 55 patients were entered into the study. 50 patients were evaluable. The remission rate was 44/50 (88%; 95% confidence interval 82-100%), including complete remissions (CR) in 14 (28%) patients. Only 2 patients showed progression while on Cladribine treatment. The estimated overall survival, and time to treatment failure (TTF) were 85% and 51%, respectively, after a median observation time of 92 weeks. 11 (22%) patients showed grade 3 or 4 toxicity according to the WHO grading. Haematological toxicity was responsible for 86% of the overall toxicity and 100% of grade 3 and 4 toxicity. 7 patients (14%) had an infection, two of which were opportunistic. 12 (24%) patients did not experience any toxicity during the treatment. The results of this study clearly demonstrate the safety and considerable activity of this regimen. Cladribine is very effective even at lower doses than have been used so far.

Treatment of 11 patients with chronic myelogenous leukemia with interferon-alpha-2C and low-dose cytosine arabinoside.

Patients with Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) and on interferon (IFN)-alpha-2c treatment for at least two months were entered in the present pilot study. IFN-alpha treatment was maintained identically and cytosine arabinoside (Ara-C) was added at monthly cycles of 10 mg/m2/day for ten days subcutaneously. In the case of a leukocyte nadir above 10 G/l, the Ara-C dose was increased to 20 mg/m2/day for 10 days per month. Ten of the eleven patients entered in this study were evaluable for toxicity and response. They received a total of 87 IFN-alpha/Ara-C cycles (3-14/patient). Five patients received 1-5 cycles with Ara-C dose intensification to 20 mg/m2/day. The following gastrointestinal and hematological toxicities were attributable to Ara-C, as they had not been observed in these patients during the preceding IFN-alpha monotherapy period. Gastrointestinal side effects consisted of nausea grade 1 (n = 5) and diarrhea grade 2 (n = 1). Hematotoxicity was observed in eight patients, grade 1 in five patients and grades 2, 3 and 4 in one of the patients each. Both episodes of grades 3 and 4 toxicity were seen during dose escalation to 20 mg/m2. Small cytogenetic responses (4-14%) were observed in 3 patients and a larger one (50%) in one patient, hematological improvement or stable disease in an additional three patients. These preliminary data suggest that the combination of IFN-alpha and low-dose Ara-C is active in inducing cytogenetic responses in CML patients at an acceptable rate of toxicity and therefore warrant further investigation.

Interferon-alpha-2C and LD ara-C for the treatment of patients with CML: results of the Austrian multi-center phase II study.

Small pilot studies of patients with CML have reported on encouraging response rates after treatment with interferon-alpha (IFNalpha) in combination with low-dose cytosine arabinoside (LD ara-C). We therefore initiated a multi-center phase II trial in order to investigate the efficacy and tolerability of this combination in newly diagnosed patients with Ph-positive chronic myelogenous leukemia (CML). Eighty-four patients were treated with IFN-alpha-2c at daily subcutaneous doses of 3.5 MU and LD ara-C added subcutaneously for 10 days every month at a dose of 10 mg/m2, following an initial reduction of WBC to less than 20 x 10(9)/l with hydroxyurea (HU). Within a median observation period of 28 (5-59) months the patients received a median of 7 (1-35) IFNalpha and LD ara-C cycles. Treatment was stopped due to side effects in 16 cases (19%) and to primary or secondary treatment failure in 38 cases (45%). In 45 patients (54%) complete hematological response (CHR) was achieved; in 39 patients (46%) cytogenetic responses including 15 (18%) complete cytogenetic responses (CHR) were observed. Median duration of cytogenetic responses was 15 months. Relapses were seen in 8/15 patients (53%) with complete cytogenetic remission (CCR), in 3/6 patients (50%) with partial cytogenetic response and in 9/18 patients (50%) with minor cytogenetic response. In conclusion, the combination of IFNalpha and LD ara-C resulted in encouraging rates of hematological and cytogenetic responses in patients with CML with low to moderate toxicity.

A randomized study comparing interferon (IFN alpha) plus low-dose cytarabine and interferon plus hydroxyurea (HU) in early chronic-phase chronic myeloid leukemia (CML).

This multicenter randomized phase III study was designed to compare the efficacy and toxicity of IFN alpha-2c (3.5 MU/d) in combination with either araC (10 mg/m(2) d1-10) or hydroxyurea (HU: 25 mg/kg per day) in newly diagnosed CML patients. A total of 114 patients were randomized. Following a median observation period of 36 (range 1-73) months the major cytogenetic response rates were 25 and 27% and the 4-year survival probabilities 62.5 and 63% for the araC and HU group, respectively. While the overall toxicity profile was comparable between both groups, patients in the HU arm exhibited a slightly higher degree of WHO grades 3 and 4 non-hematological toxicities.

Chronic myeloid leukemia with a rare variant Philadelphia translocation: t(9;10;22)(q34;q22;q11).

We report a 59-year-old, male, chronic myeloid leukemia patient with a rare variant Philadelphia (Ph) translocation t(9;10;22)(q34;q22;q11). Fluorescence in situ hybridization with whole chromosome paints was used to confirm the cytogenetic findings. With a BCR/ABL-specific probe, the known rearrangement on the derivative chromosome 22 was found. The prognostic implications as well as the relevance of the additional breakpoint region 10q22 are discussed.

Persisting bone marrow aplasia following interferon-alpha combined with ara-C for chronic myelogenous leukemia.

A 37-year-old man with a newly diagnosed chronic myelogenous leukemia received induction therapy with hydroxyurea and interferon-alpha, and maintenance therapy with low-dose ara-C and interferon-alpha. Subsequent to a rapid hematological remission, a continuously aggravating pancytopenia with bone marrow aplasia developed which persisted after withdrawal of maintenance therapy. Bone marrow examination exhibited aplastic areas and residual hematopoiesis with impaired maturation; cytogenetically, there was a 100% persistence of Philadelphia chromosome-positive metaphases. By allogeneic bone marrow transplantation, a complete reconstitution of hematopoiesis was achieved.

Dose escalation of ara-c may improve response rates in a subgroup of chronic myeloid leukemia patients with poor response to interferon-alpha and low-dose ara-C.

The present analysis was performed to evaluate the impact of cytosine arabinoside (ara-C) dose escalation on hematological and cytogenetic responses in patients with chronic myelogenous leukemia (CML) who failed to respond to low-dose ara-C (LD ara-C) at a dose of 10 mg/m2/d over 10 days per month and interferon-alpha (IFNalpha, 3.5 MU/d). Following the same administration schedule, dose escalation of ara-C to 15 and 20 mg/m2/d 1-10 was performed in 36 of 119 patients (30%) due to inadequate hematological response and/or disease progression. As a result, improvement of hematological and cytogenetic responses was achieved in 22 (61%) and nine (25%) patients, respectively. Escalated ara-C dose levels were usually well tolerated, although some patients experienced deterioration of preexisting side effects. Our results support the critical role of ara-C dose towards a better disease control in CML.

[Transformation of a myelodysplastic to a myeloproliferative syndrome (chronic granulocytic leukemia)]. / Transformation eines myelodysplastischen in ein myeloproliferatives Syndrom (chronisch-granulozytäre Leukämie).

A report is presented of the course of a case of the myelodysplastic syndrome which transformed after 16 months into Philadelphia chromosome-negative chronic granulocytic leukaemia. Such a transformation into the myeloproliferative syndrome is considered to be a rare event and some views on the mechanism of this metamorphosis are discussed.

[Comparative clinical and histological investigations in chronic myeloid leukaemias ]. / Vergleichende klinisch-histologische Untersuchungen bei 76 chronischen Myelosen.

76 cases of CML were divided according to clinical parameters (duration of illness prior to diagnosis, size of spleen, leucocyte and platelet counts, ALP index, bone marrow cytology and others) into groups showing a classical or an atypical course of the disease. All patients were submitted to bone marrow biopsy, using the method of Jamshidi and Swaim. The histological subtypes of CML, i.e. chronic granulocytic leukaemia and chronic megakaryocytic granulocytic myelosis were correlated with the two clinical types of disease. The classical form of CML was histologically inhomogeneous and was subdivided into 40% cases of chronic granulocytic leukaemia and 60% cases of chronic megakaryocytic granulocytic myelosis. At the time of bone marrow biopsy 20% of patients with classical leukaemia were already found to have myelofibrosis. The atypical myeloses consisted of chronic megakaryocytic granulocytic myelosis only and myelofibrosis was present initially in 50% of patients. In view of these findings agnogenic myeloid metaplasia is considered to be merely a variant of chronic myeloid leukaemia and the term "atypical myelosis" is preferred.

[Results of Primary chemotherapy and Delayed Surgical Resection in Osteosarcoma (author's transl)]. / Erfahrungen mit der primären Chemotherapie und verzögerten extremitätenerhaltenden Operation beim Osteosarkom.

Primary systemic therapy with delayed surgical intervention has been employed for the treatment of malignant bone tumours since 1977 at the Universitäts-Kinderklinik and III. Medizinische Abteilung Graz. Improved therapeutic results, as originally reported on a large number of patients at the Memorial Sloan Kettering Cancer Center (MSKCC) seem to have been attained with a small group of patients (n = 5).

[The hemolytic syndrome in subacute bacterial endocarditis]. / Das hämolytische Syndrom bei subakuter bakterieller Endokarditis.

Long lasting subacute bacterial endocarditis often presents with marked anemia. Infective mechanisms and hemolysis are considered as most important pathophysiological mechanisms. Pronounced hemolytic anemia, thrombocytopenia and edema observed in two cases are possible misleading symptoms in the diagnosis of subacute bacterial endocarditis.

[Subacute idiopathic autoimmunehemolytic anemia with prolonged aplastic phase and erythremic reaction (author's transl)]. / Subakute idiopathische autoimmunhämolytische Anämie mit protrahierter aplastischer Phase und erythrämischer Reaktion.

A case of idiopathic autoimmune hemolytic anemia with subacute onset and peculiar course is reported. In the beginning of the disease there was a long lasting severe aplastic phase, during which numerous blood transfusions were required. The low antiglobuline test titre compared with the severe hemolytic activity and the ineffective erythropoesis suggested first of all the presence of pure red cell anemia. Later on blood regeneration with erythroblastosis started and resembled the picture of erythremic myelosis. The transient course of the disease with full normalisation of all blood values and continuous remission lasting now for more than one year is a peculiar variant of idiopathic autoimmune hemolytic anemia.

[Jamshidi biopsy in clinical hematology. Method, indications and results of over 1,000 completed biopsies with special reference to chronic myeloproliferative diseases]. / Die Jamshidibiopsie in der klinischen Hämatologie. Methode, Indikationen und Ergebnisse an über 1000 durchgeführten Biopsien unter besonderer Berücksichtigung chronischer myeloproliferativer Erkrankungen.

One thousand and five bone marrow biopsies were performed in patients with haematologic or oncologic disorders during a ten year period from 1976 to 1985 according to the method of Jamshidi and Swaim. Indications and method of biopsy are discussed in detail. Major side effects were not observed, however minor accidents (0.2%) as well as problems in yielding biopsy-material (1.6%) are reported. The rate of biopsy-failure, including biopsies with insufficient (crushed) material, was 5%. In our hands the predominant value of the Jamshidi-biopsy for diagnosis of hematologic disorders is given by the following reasons: Bone marrow histology gives a more detailed architectural picture than cytologic smears. Sampling of bone marrow for both methods (cytology and histology) through the same instrument is possible. The procedure is easily performed and gives the patient no more discomfort than a simple sternal puncture. Chronic myeloproliferative disorders (CMPD, 31%), malignant lymphomas (40%) and aplastic (hypoplastic) syndromes (4%) were the most frequent indications for bone marrow biopsy. Clinical and histological findings were compared in 235 patients with CMPD. The histological defined entity of chronic megacaryocytic-granulocytic myelosis could be differentiated easily from chronic granulocytic leukemia (CGL), however it was not always distinguishable from primary thrombocythemia by means of clinical and hematological criteria. Myelofibroses on the basis of CGL were separated from idiopathic or postpolycythemic fibroses by hematological findings. The diagnostic value of bone marrow biopsies was superior to cytology in all CMPD and proved to be an essential diagnostic method in cases with high platelet count. Marrow involvement was found in 59% of 218 previously untreated patients with non Hodgkin's lymphomas and in 9% of 123 patients with Hodgkin's disease. Jamshidi-biopsy proved to be a simple and indispensable procedure in staging of Hodgkin's and non-Hodgkin's lymphomas.

[Interferon therapy in essential thrombocythemia]. / Interferontherapie bei essentiellen Thrombozythämien.

Interferon-alpha (IFN-alpha) exhibits a clear platelet reductive effect in patients with essential thrombocythemia as well as in other chronic myeloproliferative disorders with thrombocytosis. In a total of 51 patients with chronic myeloproliferative disorders with thrombocytosis we analyzed the effect of IFN-alpha in respect to platelet reduction, remission rates, induction- and maintenance dosage, long term tolerance and side effects. According to our classification CML 6, chronic mega-karyocytic granulocytic myelosis 5, essential thrombocythemia 26 and polycythemia vera 15 patients were treated. Treatment consisted of induction with 3 or 5 MU IFN-alpha daily followed by a maintenance therapy with 3 or 5 MU thrice weekly. Platelet reduction was found in all patients, CR (platelets < 450 G/l) in 78%. Within 2 months of induction therapy, CR in patients treated with 5 MU IFN daily was found in 75% compared to 52% in patients treated with 3 MU IFN daily. Dosage reduction in maintenance periode caused an increase of platelets to more than 450 G/l in 39% of patients. Out of 40 Philadelphia-negative chronic myeloproliferative disorders treated for more than 3 months in 10 patients treatment was disrupted after 5 to 18 months because of the following side effects: nausea, fatigue, vertigo, fever, headache, diarrhea, anorexia, heartburn, hairloss, myalgia, and thrombocytopenia. Due to the mutagenic effect of alkylating cytostatics and Radiophosphorus, IFN-alpha treatment represents a first line strategy for chronic myeloproliferative disorders with thrombocytosis especially in younger patients who are symptomatic and in those who suffered from episodes of bleeding or thrombosis.

[Laparotomy and splenectomy in Hodgkin's disease]. / Zur Laparotomie und Splenektomie bei Morbus Hodgkin.

Explorative laparotomy and splenectomy represents the most accurate methode to recognize a lymphogranulomatous process below the diaphragm. The demonstration or exclusion of a subdiaphragmatic propagation of disease plays an essential role in therapy. Since 1973 we have performed explorative laparotomy and splenectomy in stage (I) II-III a of Hodgkin's disease. In the course of this invasive diagnostic procedures (39 primary and 12 reassessing laparotomies and splenectomies) no case of death and no persisting postoperative complications were noticed. Clinical staging was altered in 47% of cases by the procedure but in only one quarter of patients this result influenced therapeutic regimen.

Chemohormonal and immunohormonal approaches in advanced prostatic carcinoma.

The standard palliative treatment for patients with advanced prostate cancer has for the past 50 years been androgen withdrawal. However, owing to the presence of hormone-insensitive cell clones, the benefits of this approach have now appeared to reach their optimum. It is now generally believed that further major therapeutic advances in the treatment of prostate cancer are unlikely, unless consideration is given to these hormonally independent cells. Two possible alternative strategies which address this problem are chemohormonal and immunohormonal approaches, both of which are discussed in detail in this article.