Marcus Gorschlüter

Itraconazole Prevents Invasive Fungal Infections in Neutropenic Patients Treated for Hematologic Malignancies: Evidence From a Meta-Analysis of 3,597 Patients

PURPOSE Efficacy of antifungal prophylaxis has not yet been convincingly proven in numerous trials of various antifungals. New evidence and the anti-Aspergillus efficacy of itraconazole prompted a new look at the data for the prevention of invasive fungal infections. PATIENTS AND METHODS Randomized, controlled studies with itraconazole for antifungal prophylaxis in neutropenic patients with hematologic malignancies were identified from electronic databases and hand searching. RESULTS Thirteen randomized trials included 3,597 patients who were assessable for invasive fungal infections. Itraconazole reduced the incidence of invasive fungal infection (mean relative risk reduction, 40% +/- 13%; P =.002), the incidence of invasive yeast infections (mean, 53% +/- 19%; P =.004) and the mortality from invasive fungal infections (mean, 35% +/- 17%; P =.04) significantly. The incidence of invasive Aspergillus infections was only reduced in trials using the itraconazole cyclodextrine solution (mean, 48% +/- 21%; P =.02) and not itraconazole capsules (mean, 75% +/- 73% increase; P =.3). The overall mortality was not changed. Adverse effects were rare, hypokalemia was noted in three studies, and a higher rate of drug discontinuation was found in trials that compared itraconazole cyclodextrine solution to a control without cyclodextrine. The effect of prophylaxis was clearly associated with a higher bioavailable dose of itraconazole. CONCLUSION Antifungal prophylaxis with itraconazole effectively prevents proven invasive fungal infections and-shown for the first time for antifungal prophylaxis-reduces mortality from these infections and the rate of invasive Aspergillus infections in neutropenic patients with hematologic malignancies. Adequate doses of the oral cyclodextrine solution (at least 400 mg/d) or i.v. formulations (200 mg/d) of itraconazole are necessary for these effects.

A systematic review of phase‐II trials of thalidomide monotherapy in patients with relapsed or refractory multiple myeloma

The activity of thalidomide in relapsed or refractory multiple myeloma is widely accepted but not yet demonstrated in a randomised‐controlled trial. A systematic review of the published clinical trials of these patients could reduce the possible bias of single phase‐II studies. A systematic search identified 42 communications reporting on 1674 patients. Thirty‐two trials used an escalating dosing regimen and four a fixed dose regimen (one dose with 50 mg/d, three doses with 200 mg/d). The target dose in the dose escalating trials was 800 mg/d in 17 trials, 400–600 mg/d in 10 and 200 mg/d in one trial. The intention‐to‐treat population for efficacy was 1629 patients with a median age of 62 years. The complete and partial (>50% reduction in monoclonal protein) response rate was 29·4% (95%‐confidence interval, 27–32%). The rates for minor responses or stable disease were 13·8% (12–16%) and 11·0% (9–13%). Progressive disease was reported in 9·9% (8–11%). The median overall survival from all trials was reported at 14 months. Severe adverse events (grade III–IV) included somnolence 11%, constipation 16%, neuropathy 6%, rash 3%, thrombo‐embolism 3%, cardiac 2%. In conclusion, thalidomide monotherapy achieved complete and partial responses in 29·4% of patients with relapsed or refractory multiple myeloma.

Neutropenic enterocolitis in adults: systematic analysis of evidence quality.

Abstract:  Objective: Neutropenic enterocolitis is a life‐threatening complication occurring most frequently after intensive chemotherapy in acute leukaemias. The literature is heterogenous and a systematic review is lacking. Methods: Following a systematic search we categorised all relevant reports according to their quality and extracted evidence to answer the questions: Which diagnostic criteria are appropriate? What is the incidence of neutropenic enterocolitis? Are there good quality studies supporting specific interventions: Which empiric antimicrobial therapy is recommendable? Is neutropenic enterocolitis without surgical emergency complications an indication for bowel resection? Results: We found and analysed 145 articles of these reports: 64 were reports of single cases, 30 papers reported of two or three cases, 13 were narrative reviews, 34 were retrospective case series of more than three cases and four were prospective diagnostic studies. There were no prospective trials or case control studies on the therapy of neutropenic enterocolitis. There was no consensus on diagnostic criteria. We discuss the difficulty to define diagnostic criteria without having a disease definition. Histology is mostly not available in the living patients. We suggest applying a combination of clinical and radiological criteria: fever, abdominal pain and any bowel wall thickening >4 mm detected by ultrasonography (US) or computed tomography. We calculated a pooled incidence rate from 21 studies of 5.3% (266/5058; 95% CI: 4.7%–5.9%) in patients hospitalised for haematological malignancies, for high‐dose chemotherapy in solid tumours or for aplastic anaemia. Conclusions: This systematic review provides diagnostic criteria for neutropenic enterocolitis, presents a quantitative synthesis on its incidence and discusses its treatment recommendations. Prospective studies are clearly warranted.

Clostridium difficile infection in patients with neutropenia.

Clostridium difficile is the most important cause of nosocomial infectious diarrhea. The importance of C. difficile-associated diarrhea (CDAD) has been poorly investigated in patients with neutropenia who have hematologic malignancies. A retrospective chart review of all patients treated in the leukemia ward of a university medical center during 1991-2000 determined that 875 courses of myelosuppressive chemotherapy were administered. CDAD occurred in 7.0% of all cycles. In 8.2% of the patients, severe enterocolitis developed. Two patients died while they had diarrhea. However, in no patient was C. difficile infection clinically considered to be the primary cause of death. The response rate to oral metronidazole was 90.9%. These data indicate that C. difficile infection is not rare and should be suspected whenever a hospitalized patient with neutropenia develops diarrhea. Oral metronidazole can be recommended as initial drug of choice for treatment of patients with neutropenia who have hematologic malignancies and CDAD.

Abdominal infections in patients with acute leukaemia: a prospective study applying ultrasonography and microbiology

Summary.  A prospective study of 62 chemotherapy‐ induced neutropenic episodes in patients with acute leukaemia was conducted to determine the incidence and causes of abdominal infections, and to assess the diagnostic value of the combined use of ultrasonography (US) and microbiology. Each patient underwent US of liver, gallbladder and complete bowel before chemotherapy, on days 2–4 after the end of chemotherapy and in cases of fever, diarrhoea or abdominal pain. US was combined with a standardized clinical examination and a broad spectrum of microbiological investigations. From January to August 2001, 243 US examinations were performed. The overall incidence of abdominal infectious diseases was 17·7% (11 out of 62, 95% confidence interval (CI): 9–29%). Four patients (6·5%) developed neutropenic enterocolitis; two of them died, two survived. Bowel wall thickening (BWT) > 4 mm in these four patients ranged from 5·8 to 23·6 mm and was detected only in one patient with mucositis. In three other patients (4·8%) Clostridium difficile, and in one patient (1·6%) Campylobacter jejuni, caused enterocolitis without BWT. Cholecystitis was diagnosed in three patients (4·8%) and hepatic candidiasis was strongly suspected in one patient. Abdominal infections caused by gastroenteritis viruses, cytomegalovirus (CMV) or Cryptosporidium were not observed. We conclude that in neutropenic patients with acute leukaemia receiving chemotherapy: (i) BWT is not a feature of chemotherapy‐induced mucositis and should therefore be considered as sign of infectious enterocolitis; (ii) viruses, classic bacterial enteric pathogens (Salmonella, Shigella, Yersinia, Campylobacter, Aeromonas, Vibrio subsp., enterohaemorrhagic Escherichia coli) and Cryptosporidium have a very low incidence; and (iii) abdominal infections may be underestimated when US is not used in every patient with abdominal pain.

Novel non-viral method for transfection of primary leukemia cells and cell lines.

BackgroundTumor cells such as leukemia and lymphoma cells are possible targets for gene therapy. However, previously leukemia and lymphoma cells have been demonstrated to be resistant to most of non-viral gene transfer methods.MethodsThe aim of this study was to analyze various methods for transfection of primary leukemia cells and leukemia cell lines and to improve the efficiency of gene delivery. Here, we evaluated a novel electroporation based technique called nucleofection. This novel technique uses a combination of special electrical parameters and specific solutions to deliver the DNA directly to the cell nucleus under mild conditions.ResultsUsing this technique for gene transfer up to 75% of primary cells derived from three acute myeloid leukemia (AML) patients and K562 cells were transfected with the green flourescent protein (GFP) reporter gene with low cytotoxicity. In addition, 49(+/- 9.7%) of HL60 leukemia cells showed expression of GFP.ConclusionThe non-viral transfection method described here may have an impact on the use of primary leukemia cells and leukemia cell lines in cancer gene therapy.

Dexamethasone, high-dose cytarabine, and cisplatin in combination with rituximab as salvage treatment for patients with relapsed or refractory aggressive non-Hodgkin's lymphoma.

We designed a multicenter Phase II trial to prospectively evaluate the efficacy and safety of the combination of rituximab with the DHAP regimen (dexamethasone, high-dose cytarabine, cisplatin) in patients who relapsed after or were resistant to a CHOP-like regimen. A total of 53 patients with relapsed or resistant aggressive B-cell NHL were analyzed. The overall response rate was 62.3 percent. With a median follow-up of 24.9 months, median overall and progression-free survivals were 8.5 and 6.7 months, respectively. Immunochemotherapy with rituximab and DHAP proved to be feasible and effective in this patient population.

Invasive fungal infections in neutropenic enterocolitis: A systematic analysis of pathogens, incidence, treatment and mortality in adult patients

BackgroundNeutropenic enterocolitis is a life-threatening complication most frequently occurring after intensive chemotherapy in acute leukaemias. Gramnegative bacteria constitute the most important group of causative pathogens. Fungi have also been reported, but their practical relevance remains unclear. The guidelines do not address concrete treatment recommendations for fungal neutropenic enterocolitis.MethodsHere, we conducted a metaanalysis to answer the questions: What are frequency and mortality of fungal neutropenic enterocolitis? Do frequencies and microbiological distribution of causative fungi support empirical antimycotic therapy? Do reported results of antimycotic therapy in documented fungal neutropenic enterocolitis help with the selection of appropriate drugs? Following a systematic search, we extracted and summarised all detail data from the complete literature.ResultsAmong 186 articles describing patients with neutropenic enterocolitis, we found 29 reports describing 53 patients with causative fungal pathogens. We found no randomised controlled trial, no good quality cohort study and no good quality case control study on the role of antifungal treatment. The pooled frequency of fungal neutropenic enterocolitis was 6.2% calculated from all 860 reported patients and 3.4% calculated from selected representative studies only. In 94% of the patients, Candida spp. were involved. The pooled mortality rate was 81.8%. Most authors did not report or perform antifungal therapy.ConclusionIn patients with neutropenic enterocolitis, fungal pathogens play a relevant, but secondary role compared to bacteria. Evidence concerning therapy is very poor, but epidemiological data from this study may provide helpful clues to select empiric antifungal therapy in neutropenic enterocolitis.

Advances in the treatment of hairy-cell leukaemia.

Hairy-cell leukaemia (HCL) is an uncommon B-cell chronic lymphoproliferative disorder that accounts for about 2% of all leukaemias. Although the disease is generally indolent in its natural course, the majority of patients require treatment for life-threatening infections due to pancytopenia or symptomatic splenomegaly. During the past 20 years, remarkable progress has been made in the treatment of HCL. Since the introduction of interferon-alpha, splenectomy, which was formerly the standard therapy, has been rarely used. With the purine analogues cladribine and pentostatin, response rates are even better than with interferon-alpha and long-lasting remissions can be achieved in most patients. Therefore, these agents are now considered the treatment of choice. Recently, immunotherapeutic approaches which use monoclonal antibodies have increased the number of therapeutic options for HCL and offer promising salvage strategies for patients who relapse or who are refractory to treatment with purine analogues. In this review the different treatment options available are discussed and recommendations for the clinical management of the HCL are summarised.

Severe Abdominal Infections in Neutropenic Patients

Abdominal infections are an important cause of morbidity and mortality in neutropenic patients. We present a retrospective series of 16 patients, mostly with acute leukemia, who developed severe abdominal infections during chemotherapy-induced neutropenia between 1991 and 1997. The frequency among patients with acute leukemia was 2.35% (13 of 553). Thirteen patients presented with enterocolitis and 3 patients presented with cholecystitis. Eight patients died. Bacteremia was present in 6 patients, 4 patients suffered from proven or strongly suspected fungal infections, and 1 patient suffered from cytomegalovirus infection. Early surgical management was required in a patient with intestinal obstruction, whereas other patients could be managed conservatively. Two patients with acute cholecystitis were treated with antibiotics until the end of neutropenia and then were resected. Severe abdominal infections in neutropenic patients, which are often fatal, were caused by nonbacterial microorganisms in one-fourth of the cases and could be managed conservatively in most instances.