Combination of aclarubicin and etoposide for the treatment of advanced acute myeloid leukemia: results of a prospective multicenter phase II trial. German AML Cooperative Group.

In order to develop new strategies for the treatment of relapsed or refractory acute myeloid leukemia, the German AML Cooperative Group performed a prospective multicenter phase II study to evaluate the antileukemic efficacy of aclarubicin 60 mg/m2/day and etoposide 100 mg/m2/day each given for 5 days. Of 37 heavily pretreated evaluable patients (median age 42 years, range 18-81) 15 (40%) achieved a remission after one or two courses of treatment consisting of nine complete (24%) and six partial remissions (16%). Fourteen (38%) cases were non-responders and eight (22%) patients suffered from early deaths. Disease-free survival for patients in remission and overall survival were 3.2 months each. The median duration of critical neutropenia <500/microl was 27 days. The most frequent non-hematologic side-effects were stomatitis (WHO III/IV, 48%), infections (40%), nausea/vomiting (26%) and diarrhea (24%). Cardiac toxicity was mild. This study suggests a substantial antileukemic efficacy and an acceptable toxicity of aclarubicin in combination with etoposide in heavily pretreated patients with advanced acute myeloid leukemia, and warrants further evaluations in a more favorable stage of the disease.

Granulocyte colony-stimulating factor shortens duration of critical neutropenia and prolongs disease-free survival after sequential high-dose cytosine arabinoside and mitoxantrone (S-HAM) salvage therapy for refractory and relapsed acute myeloid leukemia. German AML Cooperative Group.

Patients with primary refractory or relapsed acute myeloid leukemia (AML) who undergo intensive salvage chemotherapy carry a high risk of treatment failure due to infectious complications and early relapses. The study presented here assessed the effect of granulocyte colony-stimulating factor (G-CSF) on the duration of post-treatment neutropenia, the incidence of infection-related deaths, and the disease-free and overall survival. Sixty-eight evaluable patients with relapsed and refractory AML received G-CSF 5 microg/kg per day subcutaneously starting 2 days after the completion of salvage treatment with the S-HAM regimen, consisting of high-dose cytosine arabinoside twice daily on days 1, 2, 8, and 9 and mitoxantrone on days 3, 4, 10, and 11. Ninety-one patients who were treated with the identical S-HAM regimen but without G-CSF support during a preceding study served as controls. The application of G-CSF resulted in a significant shortening of critical neutropenia of less than 500 microl (36 vs. 40 days; p = 0.008), which translated into a trend towards a lower early death rate (21% vs. 30%) and an increase of complete remissions (56% vs. 47%, p=0.11). In patients younger than 60 years a significant prolongation of time to treatment failure (159 vs. 93 days, p=0.038) and of duration of disease-free survival (203 vs. 97 days, p=0.003) was observed. These results indicate a beneficial effect of G-CSF on early mortality as well as on long-term outcome when administered after S-HAM salvage therapy for advanced AML.

Failure of fluconazole prophylaxis to reduce mortality or the requirement of systemic amphotericin B therapy during treatment for refractory acute myeloid leukemia: results of a prospective randomized phase III study. German AML Cooperative Group.

BACKGROUND: Invasive fungal infections have increasingly become a matter of concern with regard to patients receiving intensive myelosuppressive therapy for hematologic malignancies. Such infections, especially prolonged neutropenia systemic fungal infections, may contribute substantially to infectious complications and early death. Measures for early detection and effective prophylactic strategies using active and nontoxic antifungal agents are therefore urgently needed. METHODS: The current randomized study was initiated to assess the efficacy of oral fluconazole as systemic antifungal prophylaxis for high risk patients with recurrent acute myeloid leukemia undergoing intensive salvage therapy. RESULTS: Of 68 fully evaluable patients, 36 were randomized to fluconazole in addition to standard prophylaxis with oral co-trimoxazol, colistin sulphate, and amphotericin B suspension, and 32 were randomized to standard prophylaxis only. No major differences between the two groups were observed in the number of episodes of fever of unknown origin (61% vs. 50%) or clinically defined infections (56% vs. 50%). Microbiologically defined infections were more frequent in the fluconazole group (50% vs. 31%), mainly due to a higher incidence of bacteremias (42% vs. 22%). There were two cases of proven invasive fungal infections in each group. Systemic amphotericin B was administered more frequently to patients receiving fluconazole prophylaxis (56% vs. 28%). Fluconazole prophylaxis had no impact on the rate of early death or overall survival. CONCLUSIONS: For patients with high risk recurrent acute myeloid leukemia undergoing intensive salvage therapy, antifungal prophylaxis with fluconazole was not superior to standard prophylaxis only.

[Aspergillus fumigatus and Chaetomium homopilatum in a leukemic patient. Pathogenic significance of Chaetomium species]. / Aspergillus fumigatus und Chaetomium homopilatum bei einem Leukämiepatienten. Pathogene Bedeutung von Chaetomium-Arten.

From the tracheal secretion of a leukaemic patient Aspergillus fumigatus and Chaetomium homopilatum was isolated. Radiographically (HR-CT) an invasive pulmonary mycosis was diagnosed from which the patient died. As an autopsy was not performed, the role of the isolated fungi could not be clarified safely. Aspergillus fumigatus is supposed to have been responsible for the invasive mycosis. The etiopathological significance of Ch. homopilatum remained unclear. The isolation of Ch. homopilatum was a reason for reviewing the genus Chaetomium. In the literature 18 reported cases of infections by Chaetomium sp. were found. Ch. globosum was the most prevalent species and caused mostly onychomycosis. Ch. strumarium and Ch. atrobrunneum caused brain infections. The predisposing factor in case of onychomycosis and cutaneous lesions was a trauma, and the systemic mycoses were a consequence of leukaemia, renal transplantation, intravenous drug use or renal failure. The reported cases show, that Chaetomium sp. may cause infections, if predisposing factors are present. Therefore the isolation of Chaetomium sp. in clinical specimen should not regarded as a contamination, and the possible etiopathological significance should be clarified.

[Therapy of chronic myeloid leukemia with interferon-alpha. A decade of experiences]. / Therapie der chronischen myeloischen Leukämie mit Interferon alpha. Erfahrungen aus einem Jahrzehnt.

PATIENTS AND RESULTS: One hundred and fifty-nine patients with chronic myelogenous leukemia have been treated in six studies during 10 years at Hannover Medical School University Center. The prognosis of 111 patients without pretreatment has been improved compared to conventional therapy with a median survival of 5.7 years. Cytogenetic remissions have been induced in all studies followed for a longer time. The most pronounced improvement of prognosis has been observed in these patients. CONCLUSIONS: Several conclusions can be drawn on the basis of the results on the different treatment concepts: 1. Patients with pretreatment have an unfavourable response to interferon. 2. There is a likely effect of the dose of Interferon alpha on the frequency of cytogenetic remissions. 3. The combination of Interferon alpha and interferon gamma has been toxic and ineffective in a pilot study. 4. The combination of interferon and cytosine arabinoside has a positive impact on the frequency of cytogenetic remissions. A continuous parallel application of both drugs seems to be most effective in this respect. An ongoing trial has been initiated to compare a fixed combination of Interferon alpha and cytosine arabinoside and with hydroxyurea respectively. Additionally the feasibility of autologous peripheral blood stem cell transplantation will be studied in patients with insufficient response to the interferon treatment.