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Isavuconazole is a novel triazole with broad-spectrum antifungal activity. The SECURE trial assessed efficacy and safety of isavuconazole versus voriconazole in patients with invasive mould disease.

Acute leukemia is common in the elderly and, due to the aging population and poorer prognosis, represents a major challenge. Elderly acute leukemia patients have been arbitrarily defined as =55 to 65 years of age and are underrepresented in clinical trials. There are physiologic differences between elderly and non-elderly patients. A comprehensive understanding of these differences allows the development of a systematic approach to assessing the risks for treatment-related complications. Use of a comprehensive geriatric assessment (CGA), initially developed and validated in the general geriatric population, may allow more accurate assessment of the likelihood of chemotherapy-induced complications and allow for proactive risk minimization. Once complications to therapy develop, aggressive treatment is essential. Treatment related to common complications that arise from therapy will be reviewed. Further research directed at this population is required.

Improvements in anticancer treatments, the ability to modify myelosuppression profiles, greater duration and intensity of immunosuppression, and the variety of available antimicrobial therapies have influenced the spectrum of pathogens associated with invasive fungal infection complicating treatment of hematological malignancies and hematopoietic stem cell transplantation. The approaches to the management of these infections encompass strategies of prevention for all those at risk, pre-emptive therapy based upon surrogates of infection before the onset of clinical disease, empirical therapy for patients with clinical evidence of early disease, and directed or targeted therapy for infected patients with established disease. Chemoprophylaxis is effective if applied to the highest risk patients over the duration of the risk. Pre-emptive strategies, while promising, have yet to be validated and linked to reliably predictive nonmicrobiological diagnostic techniques. Empirical antifungal therapy, as it is currently applied, now seems questionable. Patients with probable or proven invasive fungal infection still have suboptimal outcomes despite the availability of promising anti-fungal agents. Strategies examining the concept of dose-intensity and combination regimens require careful study and cannot yet be regarded as an acceptable standard of practice.

The overall clinical efficacy of the azoles antifungal agents and low-dose intravenous amphotericin B for antifungal chemoprophylaxis in patients with malignant disease who have severe neutropenia remains unclear. Randomized-controlled trials of azoles (fluconazole, itraconazole, ketoconazole, and miconazole) or intravenous amphotericin B formulations compared with placebo/no treatment or polyene-based controls in severely neutropenic chemotherapy recipients were evaluated using meta-analytical techniques. Thirty-eight trials that included 7014 patients (study agents, 3515 patients; control patients, 3499 patients) were analyzed. Overall, there were reductions in the use of parenteral antifungal therapy (prophylaxis success: odds ratio [OR], 0.57; 95% confidence interval [95% CI], 0.48–0.68; relative risk reduction [RRR], 19%; number requiring treatment for this outcome [NNT], 10 patients), superficial fungal infection (OR, 0.29; 95% CI, 0.20–0.43; RRR, 61%; NNT, 12 patients), invasive fungal infection (OR, 0.44; 95% CI, 0.35–0.55; RRR, 56%; NNT, 22 patients), and fungal infection-related mortality (OR, 0.58; 95% CI, 0.41–0.82; RRR, 47%; NNT, 52 patients). Invasive aspergillosis was unaffected (OR, 1.03; 95% CI, 0.62–1.44). Although overall mortality was not reduced (OR, 0.87; 95% CI, 0.74–1.03), subgroup analyses showed reduced mortality in studies of patients who had prolonged neutropenia (OR, 0.72; 95% CI, 0.55–0.95) or who underwent hematopoietic stem cell transplantation (HSCT) (OR, 0.77; 95% CI, 0.59–0.99). The multivariate metaregression analyses identified HSCT, prolonged neutropenia, acute leukemia with prolonged neutropenia, and higher azole dose as predictors of treatment effect. Antifungal prophylaxis reduced morbidity, as evidenced by reductions in the use of parenteral antifungal therapy, superficial fungal infection, and invasive fungal infection, as well as reducing fungal infection-related mortality. These effects were most pronounced in patients with malignant disease who had prolonged neutropenia and HSCT recipients. Cancer 2002;94:3230–46. © 2002 American Cancer Society. DOI 10.1002/cncr.10610

Fungal colonization profiles from four different anatomical sites were evaluated in 266 neutropenic cancer patients receiving intensive cytotoxic therapy for acute leukaemia or for autologous marrow transplantation. At the beginning of chemotherapy patients were allocated randomly to receive oral fluconazole 400 mg daily or an identical placebo until prophylaxis failure or marrow recovery. Candida albicans colonization was reduced from 30 to 10% in the fluconazole recipients while it increased from 32 to 57% in the placebo patients (P < 0.001). By the end of prophylaxis, colonization with non-albicans Candida species increased from 7 to 21% and 8 to 18% in the fluconazole and placebo patients, respectively (P = 0.396). Although Candida glabrata was isolated more frequently at the end of the prophylactic period in the fluconazole patients than in the placebo patients (16 versus 7%), only one definite invasive C. glabrata infection was noted. Overall, definite invasive fungal infections were documented in 26 patients [four fluconazole versus 22 placebo patients (P≤ 0.001)]. In 23 (92%) patients the infections were caused by persistently colonizing or newly acquired organisms. While probable invasive fungal infections were noted in five fluconazole patients, 10 placebo patients were also affected (P = 0.19). An end-of-prophylaxis colonization index >0.25 was 76% sensitive but only 69% specific for invasive fungal infection. However, a colonization index ≤ 0.25 at baseline had a negative predictive value of 88% for development of invasive fungal infection. Fluconazole prophylaxis decreased colonization by fungi and subsequent invasive fungal infections in neutropenic cancer patients.

The safety and efficacy of idarubicin, etoposide, and carboplatin as remission induction therapy for patients younger than 60 years with untreated acute myeloid leukemia was studied as an alternative to standard regimens based on cytarabine plus anthracycline. Eligible patients received idarubicin (36-40 mg/m²), etoposide (500 mg/m²), and carboplatin (1000-1500 mg/m²) over 5 days. Those who achieved complete remission received a single course of cytarabine 1.5 gm/m² every 12 hours for a total of 12 doses. D-xylose absorption was studied as a marker for cytotoxic therapy-induced gut mucosal damage. Cytogenetic and immunophenotyping studies were performed at the time of diagnosis and examined for prognostic importance. Remission was achieved in 29 (67%) of 43 patients with a single induction course. The median leukemia free and overall survival times were 15.4 months (95% CI 6.5-24.2) and 12.5 months (95% CI 5.9-19.1), respectively. Induction mortality was 14%. Karyotype (normal, simple, or complex vs. very complex) was the strongest predictor of remission (79% vs. 25%, P = 0.01), leukemia free survival (odds ratio [OR] 19.3, 95% CI 2.7-138.9), and overall survival (OR 5.4, 95% CI 2.1-13.9). Dose-limiting gut mucosal toxicity was greatest during Weeks 2 and 3. Bloodstream infections occurred in 49% of patients at a median of 12 days. Grade 3-4 diarrhea, nausea, stomatitis, esophagitis/dysphagia, and vomiting developed in 33%, 26%, 23%, 9%, and 2% of cases, respectively, at a median of 17, 16, 11, 15.5, and 21 days, respectively. This regimen was active in adults younger than 60 years with untreated acute myeloid leukemia and normal, simple, or complex karyotypes. Remission duration was confounded by karyotype. Mucosal toxicity limited the tolerability of this regimen. These adverse effects might be overcome by increasing the intensity of postremission therapy and modifying the dosing schedule. Cancer 1998;83:1344-1354. © 1998 American Cancer Society.

• During a multicenter prospective randomized trial in febrile neutropenic patients (neutrophil count, &lt;1,000/cu mm), 103 episodes were treated with tobramycin sulfate plus ticarcillin disodium (TT) while 117 were treated with moxalactam plus ticarcillin disodium (MT). The majority of patients had an underlying diagnosis of leukemia (60%) and most (62.8%) had granulocyte counts of less than 100/cu mm at the start of therapy. The response rates for clinically or microbiologically documented episodes were 38 of 60 (55.1%) for TT and 38 of 64 (59.4%) for MT. The MT regimen appeared to be more effective for gram-positive infections (56% vs 33%) while TT appeared more effective for gram-negative infections (64% vs 40%). Nephrotoxicity attributable to study drugs occurred in only 2.3% of cases (one on each treatment arm). Prolongation of the prothrombin time was observed in only six of 78 (7.7%) in the TT arm as compared with 39 of 103 (38%) in the MT arm. Neither regimen was adequate for the unusually high frequency of gram-positive pathogens seen during this study.(Arch Intern Med 1985;145:1083-1088)

Background: Outcomes of unselected adult ALL patients (pts) have not been well studied at a population level. Whether such pts behave differently to those in formal clinical trials is unclear. We developed a uniform therapeutic protocol as the provincial standard of care in Manitoba, a province with 1.2 million people, for adult pts since 1989 (“ALL89-1”). The aim of this retrospective study was: to ascertain the local epidemiology of adult ALL; to analyze the efficacy and toxicity of the ALL89-1 regimen and any other regimens given to pts in a population-based setting. Methods: All pts aged ≥18 years (yrs) diagnosed with ALL in Manitoba between 01/1989 and 11/2004 were identified via the provincial cancer registry. A review of computerized and paper charts was conducted. We focused on demographics, diagnostic clinical characteristics, therapy, treatment related toxicities, and whether stem cell transplantation (SCT) was performed. Results: There were 81 pts with a median age of 44yrs (range, 18–90). 53 (65%) pts were male. 58 pts received ALL89-1, 12 received other regimens and 11 patients received palliation only. Thirteen pts were Philadelphia chromosome positive (Ph+). Complete remission (CR) rate after one cycle of induction therapy was 74% for all pts, and 74% for ALL89-1 pts. At a median follow-up of 56 months (range 7–265), estimated overall survival (OS) and leukemia free survival (LFS) at 5 years was 26% (95% Confidence interval [C.I.], 15–36) and 24%( 95% C.I. 14–35). The 5 year OS and LFS for the ALL89–1 group was 23% (95% C.I. 11–35) and 20% (95% C.I. 8–32). There were 13 treatment related deaths in the 58 ALL 89-1 pts, 4 of whom died post SCT. In multivariate analysis for all 81 pts, attainment of CR post induction chemotherapy independently predicted improved survival (hazard ratio 0.23, 95% C.I. 0.11–0.5). In contrast, age > 55yrs, Ph+ status, and high WBC at diagnosis were not significant survival predictors. Palliative pts survived for a median of 10 days (range, 0–53) from diagnosis. Conclusions: This comprehensive province-wide study of adult ALL pts treated at a single cancer centre shows that durable leukemia free survival is possible, but for only a small subgroup. These results appear inferior to results of published clinical trials. The reasons for the relatively poor outcomes require further analysis in this and other jurisdictions.

Background: Outcomes of unselected adult ALL patients (pts) have not been well studied at a population level. Whether such pts behave differently to those in formal clinical trials is unclear. We developed a uniform therapeutic protocol as the provincial standard of care in Manitoba, a province with 1.2 million people, for adult pts since 1989 (“ALL89-1”). The aim of this retrospective study was: to ascertain the local epidemiology of adult ALL; to analyze the efficacy and toxicity of the ALL89-1 regimen and any other regimens given to pts in a population-based setting.

The role of the anaerobic intestinal flora in maintaining colonization resistance was examined in a study of empiric therapy in febrile neutropenic patients who received aztreonam plus tobramycin, aztreonam plus cloxacillin, or moxalactam plus tobramycin, regimens with differential effects on the anaerobic intestinal flora. Surveillancecultures showed that all regimens eradicated fecal carriage of enteric gram-negative bacilli but that fecal acquisition of fungi occurred in 4 (27%) of 15 aztreonam/tobramycin, 6 (43%) of 14 aztreonam/cloxacillin, and 13 (81%) of 16 moxalactam/tobramycin recipients. Fungi were acquired at 11 (22%) of 49 sites in aztreonam/tobramycin, 15(31%) of 48 sites in aztreonam/ cloxacillin, and 28 (54%) of 52 sites in moxalactam/tobramycin recipients. Aztreonam/tobramycin reduced fecal anaerobe counts by <1 log10; aztreonam/cloxacillin, by a mean of 2.5 log10 ; and moxalactam/tobramycin, by 5.l log10 colony-forming units (cfu)/g of feces by day 10 ± 3 of therapy. Elimination of the anaerobes was reflected by a reduction in concentrations of short-chain fatty acids (SCFAs)in fecal supernatants. Fecal specimens containing 106 cfu of Bacteroides fragitis group organisms/g (dry weight) contained significantly higher concentrations of succinic, propionic, and isobutyric acids. Flat SCFAchromatograms wereobserved in 90% of fecal samples from which no anaerobes were recovered. Preservation of the anaerobic flora appears critical in the prevention of fungal acquisition in neutropenic patients.

Using multivariate techniques, we studied the relationships of cytotoxic regimen, intestinal mucosal damage, and fungal colonization in the pathogenesis of invasive fungal disease in 138 patients undergoing induction therapy for untreated acute myeloid leukemia (AML) according to three institutional protocols: AML-84 (cytarabine/daunorubicin), AML-87 (high-dose cytarabine/etoposide/daunorubicin), and AML-88 (mitoxantrone/etoposide). Invasive fungal disease occurred in 36%, 6%, and 2.6% of patients participating in protocols AML-87, AML-84, and AML-88, respectively (χ2 = 23.465; P < .0001). Protocol AML-87 was the strongest independent predictor in the multivariate model (RR = 26.7; P < .0001). Cytotoxic therapy—related epithelial damage in the gut, as measured by d-xylose malabsorption, correlated with invasive fungal disease and protocol AML-87. Fungal colonization, a predictor of invasive fungal disease, correlated with frequent modifications of antibiotic regimens. These results demonstrate the role of cytotoxic regimen—related gut epithelial damage, antibiotic-prescribing behavior, and fungal colonization in the pathogenesis of invasive fungal disease in patients with leukemia.