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A retrospective survey was conducted over a 10-year period (1990-99) among 52 haematology divisions in order to evaluate the clinical and laboratory characteristics and outcome of patients with proven Pneumocystis carinii pneumonia (PCP) complicating haematological diseases. The study included 55 patients (18 with non-Hodgkin's lymphoma, 10 with acute lymphoblastic leukaemia, eight with acute myeloid leukaemia, five with chronic myeloid leukaemia, four with chronic lymphocytic leukaemia, four with multiple myeloma, three with myelodys-plastic syndrome, two with myelofibrosis and one with thalassemia) who developed PCP. Among these, 18 (33%) underwent stem cell transplantation; only two received an oral prophylaxis with trimethroprim/sulphamethoxazole. Twelve patients (22%) developed PCP despite protective isolation in a laminar airflow room. The most frequent symptoms were: fever (86%), dyspnoea (78%), non-productive cough (71%), thoracic pain (14%) and chills (5%); a severe hypoxaemia was present in 39 patients (71%). Chest radiography or computerized tomography showed interstitial infiltrates in 34 patients (62%), alveolar infiltrates in 12 patients (22%), and alveolar-interstitial infiltrates in nine patients (16%). Bronchoalveolar lavage was diagnostic in 47/48 patients, induced sputum in 9/18 patients and lung biopsy in 3/8 patients. The diagnosis was made in two patients at autopsy. All patients except one started a specific treatment (52 patients trimethroprim/sulphamethoxazole, one pentamidine and one dapsone). Sixteen patients (29%) died of PCP within 30 d of diagnosis. Multivariate analysis showed that prolonged steroid treatment (P < 0.006) and a radiological picture of diffuse lung involvement (P < 0.003) were negative diagnostic factors.

BACKGROUND AND OBJECTIVES: To evaluate the clinical characteristics of patients with hematologic malignancies developing a filamentous fungi infection (FFI) and to define the prognostic factors for their outcome. DESIGN AND METHODS: A retrospective study, conducted on patients admitted to 14 Hematology divisions of tertiary care or university hospitals, participating in the GIMEMA Infection Program, over a ten-year period (1988-1997). The study included patients with hematological malignancies and a histologically and/or microbiologically proven or probable FFI. RESULTS: We included 391 patients (male/female: 262/129, median age 49 years) with hematologic malignancies (225 acute myeloid leukemia, 67 acute lymphocytic leukemia, 30 chronic myeloid leukemia, 22 non-Hodgkin's lymphoma, 12 myelodysplastic syndrome, 10 aplastic anemia, 7 Hodgkin's disease, 8 chronic lymphocytic leukemia, 5 multiple myeloma, and 5 hairy cell leukemia) who developed a proven FFI. Eighty percent of the patients had been neutropenic for an average of 14 days before the infection, and 71% had an absolute neutrophil count lower than 0.5 x 10(9)/L at the time of FFI diagnosis. The primary sites of infection were: lungs (85%), nose and paranasal sinus (10%), and other sites (5%). The diagnosis was made while still alive in 310 patients (79%), and at autopsy in the remaining 81 patients (21%). Chest X-ray was diagnostic in 77% of patients with pulmonary FFI, while computed tomography (CT) scan of the thorax was positive in 95% of cases. A significant diagnostic advantage for CT scan was observed in 145 patients who had both a chest X-ray and CT scan. Aspergillus was identified as the cause of FFI in 296 patients, Mucorales in 45 patients, Fusarium in 6 patients and other filamentous fungi species in 4 patients, while in a further 40 patients no agent was identifiable. The overall mortality rate three months after the diagnosis of FFI was 74%, and fungal infection had been the cause of death in 51% of patients. INTERPRETATION AND CONCLUSIONS: Our retrospective study shows that FFI still remains a life-threatening complication in neutropenic patients. Despite appropriate treatment, half of the patients die due to this complication. The use of glucocorticoids and recovery from neutropenia are the most important prognostic factors. Mucorales infections are associated with a significantly poorer prognosis than those due to Aspergillus spp.

Refractory acute myeloid leukemia (R-AML), defined as primary resistance to induction chemotherapy, early relapse (within 6-12 months from remission), and second or subsequent relapse, is typically a multidrugresistant illness, for which effective treatment is presently lacking. We have treated R-AML patients with a combination of intermediatedose ara-C, carboplatin and either mitoxantrone or idarubicin in a cross-over design, obtaining an encouraging response rate (46%) in a small group of 13 R-AML patients who were given an amended, low-toxicity regimen [1]. Five more patients were treated with a similar carboplatin-containing schedule delivered in a sequential manner, but only one remission was achieved, to an overall response rate of 33% (6/18). This result prompted a further change in retreatment strategy. In R-AML, clinical multidrug resistance is often associated with functional overexpression of the MDR1 drug efflux machinery and/or other mechanisms such as LRP (lung-related protein) and MRP (multidrug resistance-associated protein) [2-11]. Theoretically, in view of the high incidence of MDR1 activation in R-AML and its adverse clinical significance, functional MDR1 inhibition with cyclosporin A (CsA), verapamil, tamoxifen, PSC 833, quinine [12-19] or the use of drugs scarcely (Idarubicin=IDR) or not (high-dose ara-C=HiDAC, carboplatin) MDR1-sensitive could underlie therapeutic improvement. In preclinical in vitrostudies on a MDR1+ human leukemic cell line [20,21], we found that both cellular uptake and pro-apoptotic effects of IDR used at therapeutic concentration (50-100 ng/ml, corresponding to the ranges of peak plasma level obtainable after rapid intravenous administration of IDR 10-12 mg/m2) were significantly increased by co-incubation with CsA 1500 ng/ml. Interestingly, CsA enhanced IDR-related cytotoxicity only in the early phase of IDR-blast cell interaction while, contrary to daunorubicin, 12-hour IDR retention by blast cells was not modified by CsA. The study conclusion was that both cellular uptake of and related biologic effects from IDR can be upregulated by CsA in MDR1+ cells but, partly because IDR is highly lypophilic and partly because it is less vulnerable to MDR1, this effect does not require a prolonged CsA exposure. On this basis we initiated a new clinical study, using CsA and aiming to determine the upper IDR concentration tolerated by patients with R-AML. This new sequential regimen included HiDAC 3 g/m2 every 12 hours for two consecutive days followed by IDR 12.5 mg/m2 as starting dose level (both drugs were given for two times on days 1-3 and 8-10) together with CsA 6 mg/kg over 1 hour and then 7.5 mg/kg over 11 hours according to the List schedule [22]. IDR was delivered 4 hours after starting CsA. The three-day sequence was repeated on days 8-10. Recombinanat human granulocyte colony-stimulating factor (G-CSF) was administered from day 11 until response evaluation. We report the therapeutic results obtained in the first 10 patients, who received IDR from 12.5 to 17.5 mg/m2/dose.