Torsade de pointes in a patient with severe hypercalcaemia and multiple myeloma.

We report a case of a 48-year-old female patient with newly diagnosed multiple myeloma. She developed recurrent torsade de pointes and required cardiopulmonary resuscitation and defibrillation. Atrial arrhythmias in patients with multiple myeloma and hypercalcaemia have been described, but, to the best of our knowledge, this is the first report of torsade de pointes in this setting.

Primary gastric B-cell lymphoma: results of a prospective multicenter study. The German-Austrian Gastrointestinal Lymphoma Study Group.

BACKGROUND & AIMS: Appropriate management of primary gastric lymphoma is controversial. This prospective, multicenter study aimed to evaluate the accuracy of endoscopic biopsy diagnosis and clinical staging procedures and assess a treatment strategy based on Helicobacter pylori status and tumor stage and grade. METHODS: Of 266 patients with primary gastric B-cell lymphoma, 236 with stages EI (n = 151) or EII (n = 85) were included in an intention-to-treat analysis. Patients with H. pylori-positive stage EI low-grade lymphoma underwent eradication therapy. Nonresponders and patients with stage EII low-grade lymphoma underwent gastric surgery. Depending on the residual tumor status and predefined risk factors, patients received either radiotherapy or no further treatment. Patients with high-grade lymphoma underwent surgery and chemotherapy at stages EI/EII, complemented by radiation in case of incomplete resection. RESULTS: Endoscopic-bioptic typing and grading and clinical staging were accurate to 73% and 70%, respectively, based on the histopathology of resected specimens. The overall 2-year survival rates for low-grade lymphoma did not differ in the risk-adjusted treatment groups, ranging from 89% to 96%. In high-grade lymphoma, patients with complete resection or microscopic tumor residuals had significantly better survival rates (88% for EI and 83% for EII) than those with macroscopic tumor residues (53%; P < 0.001). CONCLUSIONS: There is a considerable need for improvement in clinical diagnostic and staging procedures, especially with a view toward nonsurgical treatment. With the exception of eradication therapy in H. pylori-positive low-grade lymphoma of stage EI and the subgroup of locally advanced high-grade lymphoma, resection remains the treatment of choice. However, because there is an increasing trend toward stomach-conserving therapy, a randomized trial comparing cure of disease and quality of life with surgical and conservative treatment is needed.

Chemotherapy in patients with acquired immunodeficiency virus syndrome associated with non-Hodgkin's lymphoma.

We retrospectively analyzed our chemotherapy results in patients with the Acquired Immunodeficiency Virus syndrome (AIDS) and lymphoma over a 10 year period. Thirty out of 492 (6%) Human Immunodeficiency Virus (HIV) positive patients developed a non-Hodgkin's lymphoma. Thirteen patients with high-grade histology were treated with chemotherapy, 6 patients received CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) and 7 patients received CEOP/IMVP-Dexa (cyclophosphamide, epirubicin, vincristine, prednisolone, ifosfamide, methotrexate, VP-16, and dexamethasone). The overall response rate was 77%, with no difference between the CHOP and CEOP/IMVP-Dexa regimens. There was no difference between the two treatment groups with respect to median overall survival (9 months for CHOP and 11.4 months for CEOP/IMVP-Dexa) or median lymphoma free survival (10.7 months for CHOP and not reached for CEOP/IMVP-Dexa). All patients treated with CEOP/IMVP-Dexa had WHO grade 3 or 4 infections, while only 2 of 6 patients treated with CHOP had WHO grade infections, and no grade 4 infection occurred (P < 0.01). Intensive regimens such as CEOP/IMVP-Dexa seem to be too toxic for patients with HIV-associated non-Hodgkin's lymphoma.

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.

Randomized open label phase III trial of CEOP/IMVP-Dexa alternating chemotherapy and filgrastim versus CEOP/IMVP-Dexa alternating chemotherapy for aggressive non-Hodgkin's lymphoma (NHL). A multicenter trial by the Austrian Working Group for Medical Tumor Therapy.

Primary end point of this trial was to reduce neutropenic infections during the treatment of aggressive NHL with CEOP/IMVP-Dexa (cyclophosphamide, epirubicin, vincristine, prednisolone ifosfamide, methotrexate, VP-16, and dexamethasone). Further, we studied the influence of filgrastim on dose intensity of CEOP/IMVP-Dexa, on the rate of complete remissions, on the time to relapse, and on survival. Eighty-five patients with untreated large-cell NHL were randomized to one of two treatment arms; 74 patients were eligible. Thirty-eight patients in arm 1 were treated with CEOP/IMVP-Dexa chemotherapy and filgrastim, 36 in arm 2 with CEOP/IMVP-Dexa chemotherapy alone. In arm 1 filgrastim was self-injected by the patients at 5 micrograms/kg body wt. s.c. daily, except on the days when cytotoxic drugs were given. During treatment we did weekly complete blood counts. Median leukocyte counts were 10.91 x 10(9)/l and 5.46 x 10(9)/l in arm 1 and 2, respectively (p = 10(-6)). Median neutrophil counts were 7.7 x 10(9)/l in arm 1 and 2.72 x 10(9)/l in arm 2 (p < 10(-6)). Median neutrophil nadirs were 0.199 x 10(9)/l and 0.213 x 10(9)/l in arm 1 and 2, respectively (p = 0.09). Mean platelet nadirs were 95 and 152 x 10(9)/l (p = 0.000004) and mean hemoglobin nadirs 83.95 g/l and 92.78 g/l (p = 0.00558) in arm 1 and 2, respectively. Dose intensity of CEOP/IMVP-Dexa was 82.3% and 76.2% in arm 1 and 2, respectively (p = 0.041). Forty-two percent and 58% of patients experienced a febrile neutropenia in arm 1 and 2, respectively (not significant, NS). Median time to first neutropenic infection was in treatment week 11 and 6 in arm 1 and 2, respectively (NS). There was no significant difference in rate, duration, and kind of infection, duration of hospitalization, or antibiotic treatment. Seven toxic deaths occurred, all due to neutropenic infection, 6 and 1 in arm 1 and 2, respectively (p = 0.0732). Four of the six patients, who died of infection in arm 1 were older than 60 years. Complete remission rate was 83% and 66.7% in arm 1 and 2, respectively (NS). After a median observation time of 3 years there was no difference in time to relapse or survival. Filgrastim increases leukocyte and neutrophil counts and dose intensity, if used with CEOP/IMVP-Dexa chemotherapy in high-grade lymphomas. There was no significant effect on febrile neutropenia or infections. The more frequent fatal neutropenic infection rate in the filgrastim arm was not statistically significant. It is most appropriate to explain it by the patient's age in combination with the high dose intensity. The small increase in dose intensity had no effect on survival but probably decreased hemoglobin levels and platelet counts in arm 1. We were unable to show a benefit for filgrastim in combination with CEOP/IMVP-Dexa.

First-line treatment of Waldenström's disease with cladribine. Arbeitsgemeinschaft Medikamentöse Tumortherapie.

PURPOSE: To assess the activity and side effects of cladribine (2-CdA) treatment in patients with advanced Waldenström's disease. PATIENTS AND METHODS: Ten symptomatic patients without prior therapy were included in a prospective multicenter trial. 2-CdA was administered daily at 0.12 mg/kg body weight in a 2-h i.v. infusion over 5 consecutive days: this was repeated every 28 days for four cycles. Patients achieving a remission received interferon alfa-2c (1F) 15 micrograms s.c. three times a week for 1 year. RESULTS: All 10 patients responded to 2-CdA (100%; 95% confidence interval, 68-100%), with one complete (CR) and eight partial responders (PR): one patient had only one 2-CdA cycle and showed a minor improvement (MR). Patients tolerated the treatment well. Despite considerable immunosuppression, an infection occurred in only two patients. After a median observation period of 57 weeks, three patients had shown progression, including one who died of lymphoma. CONCLUSION: 2-CdA induction and IF maintenance is a well-tolerated therapy for symptomatic untreated patients with advanced Waldenström's disease and offers excellent palliation.

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.

[Interferon-alpha therapy in non-Hodgkin's lymphoma]. / Interferon-alpha-Therapie beim Non-Hodgkin-Lymphom.

Interferon-alpha (IFN-alpha) has besides its known virostatic effects also differentiating, immuno-modulating, and antiproliferative effects. According to these effects the place of IFN-alpha has been tested for distinct malignant diseases. In the treatment of hematologic diseases IFN-alpha has made substantial progress in hairy-cell leukemias and for those IFN-alpha is an established indication. For other entities of low-grade non-Hodgkin lymphomas (NHL) IFN-alpha is an effective drug, remission rates of 46% in average can be achieved. The efficiency is dependent from histologic subtype and tumor mass. The remission durations mentioned in the literature are variable, however generally not longer than with conventional treatments. Recent studies suggest, that IFN-alpha could prolong chemotherapy induced remissions.

[Highly malignant non-Hodgkin's lymphomas]. / Hochmaligne Non-Hodgkin-Lymphome.

High malignant non-Hodgkin's lymphomas are rare diseases, with a rising incidence. A qualified histological classification and a thorough staging are the most important points in the further management. The treatment is primarily chemotherapeutic; radiation is only used in selected situations. The success of the very first therapy is most important for the outcome. To date no one of the modern intensive treatment regimens could show an advantage over conventional CHOP. For treatment failures autologous or allogenic bone-marrow-transplantation is the best option. Whether bone-marrow-transplantation in first remission can improve the treatment results waits to be answered. HIV-associated lymphomas are an increasing problem. For selected patients intensive chemotherapy with growth factors seems to improve the results. Conflicting are the therapy data in elderly patients. Most centers accept a higher lymphoma mortality with reduced doses. With special designed treatment regimens it is probably possible to come to an acceptable outcome even in elderly patients.

Toxicity and preliminary results with a new eight-drug regimen (CEOP-IMVP-DEXA) in the treatment of aggressive lymphomas.

A combination of two non-cross-resistant regimens, CEOP and IMVP-Dexa given every 4 weeks, three to six times according to response was tested in patients with untreated histological proven high and intermediate grade non-Hodgkin's lymphoma. To date eight Austrian centres entered 37 patients in this multicentre trial. Data are available from 33 patients, three were excluded, two because of pretreatment, one because of wrong histology. Twenty-five patients are evaluable for response, 21 had a complete and three a partial remission, two of them entered a complete remission after radiotherapy to residual disease, resulting in a complete remission rate of 92 per cent. Only one patient progressed during therapy. Until now three patients relapsed after achieving a remission. Observation time is 0.4-23.8 months, median 8.8 months. Toxicity was primarily hematologic with 53.3 per cent of patients having granulocyte nadirs below 0.5 x 10(9)/L and 3.3 per cent below 0.1 x 10(9)/L. Although 60 per cent of patients had infections, there was only one life-threatening infection in an AIDS patient. CEOP-IMVP-Dexa can be safely given even in smaller hematologic centres and is able to achieve a high rate of complete responses in patients with high and intermediate grade malignant non-Hodgkin's lymphomas.

Morphological and immunological changes of hairy cell leukemia during alpha-2-interferon therapy.

We describe a patient who presented with the clinical picture of hairy cell leukemia (HCL). Bone marrow and peripheral blood lymphoma cells showed morphological and immunological features of HCL. Under recombinant alpha-2-interferon (alpha-2-IF) therapy the characteristic morphology changed from HCL to prolymphocytic leukemia (PLL). At diagnosis the lymphoma cells expressed CD24 and FMC7 surface antigen, but stained negative for surface immunoglobulins, light chains and anti-CD5. During alpha-2-IF treatment surface antigen expression changed to CD24, CD5 and FMC7. Surface IgD and lambda light chains became strongly positive. Southern Blot analysis of peripheral blood mononuclear cells showed two rearranged immunoglobulin bands at diagnosis but only one upon alpha-2-IF therapy. These data suggest, that this patient suffered from a biclonal lymphoma, HCL and PLL. While undergoing alpha-2-IF treatment the HCL came into remission, whereas the PLL clone proved to be poorly sensitive to alpha-2-IF therapy.

Low dose cytosine arabinoside in refractory anemia with excess of blasts in transformation.

Myelodysplastic syndromes (MDS) are heterogeneous diseases. Patients with blast counts of more than 20% of nucleated bone marrow cells have a high risk of short survival. We treated six patients with refractory anemia with excess of blast in transformation (RAEBiT) with low dose cytosine arabinoside (LD Ara-C). We had one partial remission (PR), surviving 16 weeks and two complete remissions (CR), surviving 22 and 55+ months. Myelosuppression was dominant in all patients, but was not as serious as with conventional remission-induction treatments for leukemias. Bone marrow aplasia occurred in all responding patients, but a differentiation effect is possible too. Maintenance therapy with LD Ara-C may be important for the two long-lasting CR.

[Imipenem/cilastatin as monotherapy in neutropenic patients with fever]. / Imipenem/Cilastatin als Monotherapie bei neutropenischen Patienten mit Fieber.

We treated 20 febrile episodes in 14 patients with granulocytopenia under 1.0 x 10(9)/L. 6 episodes were pretreated, in 14 Imipenem/Cilastatin was the initial therapy. The age was between 36 and 78 years, mean 57 years. Predominant underlying disease was acute leukemia. 8 out of 20 episodes became afebrile. Counting only proven bacterial infections the response rate was 6 out of 12. There was a statistical difference between not pretreated and pretreated patients. The treatment had no success in the latter. There was also a significant difference between febrile episodes of patients with granulocytes increasing under treatment to those remaining unchanged. 5 of 6 of the first group but none of the 9 episodes of the second group resolved. 7 patients died while on treatment between the 9th and 32nd day after therapy had started. There was no connection between the Imipenem treatment and the deaths. Tolerance of therapy was good. The most common side effect was nausea, which was reversible with reduction of the infusion rate. Most important advantage of imipenem is the easy handling and the low inconvenience to the patient. We had only moderate efficacy in our series.