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Background Isavuconazole was compared to caspofungin followed by oral voriconazole in a Phase 3, randomized, double-blind, multinational clinical trial for the primary treatment of patients with candidemia or invasive candidiasis. Methods Adult patients were randomized 1:1 to isavuconazole (200 mg intravenous [IV] three-times-daily [TID] for 2 days, followed by 200 mg IV once-daily [OD]) or caspofungin (70 mg IV OD on day 1, followed by 50 mg IV OD [70 mg in patients > 80 kg]) for a maximum of 56 days. After day 10, patients could switch to oral isavuconazole (isavuconazole arm) or voriconazole (caspofungin arm). Primary efficacy endpoint was successful overall response at the end of IV therapy (EOIVT) in patients with proven infections who received ≥1 dose of study drug (modified-intent-to-treat [mITT] population). The pre-specified noninferiority margin was 15%. Secondary outcomes in the mITT population were successful overall response at 2 weeks after the end of treatment, all-cause mortality at days 14 and 56, and safety. Results Of 450 patients randomized, 400 comprised the mITT population. Baseline characteristics were balanced between groups. Successful overall response at EOIVT was observed in 60.3% of patients in the isavuconazole arm and 71.1% in the caspofungin arm (adjusted difference -10.8, 95% confidence interval -19.9–-1.8). The secondary endpoints, all-cause mortality, and safety were similar between arms. Median time to clearance of the bloodstream was comparable between groups. Conclusions This study did not demonstrate non-inferiority of isavuconazole to caspofungin for primary treatment of invasive candidiasis. Secondary endpoints were similar between both groups. Clinical Trials Registration NCT00413218. [ABSTRACT FROM AUTHOR]

Introduction: The frequency of invasive fungal diseases (IFDs) has increased in recent years. Within a context where both treatments and guidelines are fast evolving, we aim to shed new light on IFD management in hematologic departments in France.Methods: A multicenter cross-sectional observational study was prospectively conducted in 24 French centers in September and October 2013.Results: Four hundred ninety-four hospitalized children and adult patients suffering from hematologic malignancy were enrolled: 147 (30%) were allogeneic hematopoietic stem cell transplant (HSCT) recipients, 131 (27%) were patients with acute myeloblastic leukemia or myelodysplastic syndrome (MDS), 71 (14%) were patients with acute lymphoblastic leukemia who did not undergo allogeneic HSCT, and the 145 (29%) remaining patients did not belong to the three above groups. Two hundred forty-six patients (50%) received antifungal treatment, which was prophylactic in 187 (76%) treated patients. These rates were similar across all groups (63-80%). Patients received prophylaxis with an azole (79%), intravenous amphotericin B formulation (10%), echinocandin (9%), or two combination drugs (2%).Conclusion: Results indicate that prophylaxis is the leading antifungal strategy in French hematology units, regardless of the disease condition, representing 76% of prescriptions for antifungal therapy.Funding: Astellas Pharma France. [ABSTRACT FROM AUTHOR]

Recently, several randomized studies have been published that will shape treatment decisions in the prevention and management of invasive mould infections. Liposomal amphotericin B is an option for empirical or targeted treatment of invasive aspergillosis or mucormycosis, but for prophylaxis therapy, the triazole class now predominates. The triazole voriconazole is currently regarded as a drug of choice for the treatment of proven or probable invasive aspergillosis, and has shown significantly higher response rates than amphotericin B deoxycholate in this setting, with fewer severe drug-related adverse events. Isavuconazole, the newest triazole agent, offers the advantages of once-daily dosing, a wider spectrum of antifungal activity than voriconazole, predictable pharmacokinetics and fewer CYP enzyme-mediated drug interactions. A recent large randomized clinical trial showed mortality to be similar under isavuconazole or voriconazole in patients with invasive mould disease, with fewer drug-related adverse events in isavuconazole-treated patients. Another study has indicated that isavuconazole is also effective in mucormycosis infections but patient numbers were small and confirmation is awaited. Experimental studies combining different drug classes with antimould activity have been promising, but the clinical database is limited. A large randomized trial of combination therapy compared voriconazole plus the echinocandin anidulafungin versus voriconazole monotherapy in patients with invasive aspergillosis. Results showed the overall response rate to be similar, but combination therapy improved survival for the subpopulation of patients in whom the diagnosis was confirmed by serum and/or bronchoalveolar lavage fluid galactomannan positivity. This active field of research is likely to continue evolving rapidly in the coming years. [ABSTRACT FROM AUTHOR]

Patients with mantle cell lymphoma ( MCL) generally respond to first-line immunochemotherapy, but often show chemoresistance upon subsequent relapses, with poor outcome. Several studies of the immunomodulator, lenalidomide, have demonstrated its activity in MCL including the MCL-001 study in relapsed/refractory patients who had failed defined prior therapies of anthracyclines or mitoxantrone, cyclophosphamide, rituximab and also bortezomib. We present here the long-term efficacy follow-up of the prospective phase II MCL-001 study ( N = 134), including new exploratory analyses with baseline Ki-67 ( MIB1), a biological marker of tumour proliferation. With longer follow-up, lenalidomide showed a 28% overall response rate [ ORR; 8% complete response ( CR)/ CR unconfirmed ( CRu)]. Median duration of response ( DOR), progression-free survival and overall survival were 16·6, 4·0 and 20·9 months, respectively. Myelosuppression continued to be the most common grade 3/4 toxicity. Several studies of MCL patients treated with chemotherapy, rituximab and bortezomib have shown an inverse association between survival and Ki-67. Ki-67 data in 81/134 MCL-001 patients showed similar ORRs in both low (<30% or <50%) versus high (≥30% or ≥50%) Ki-67-expressing groups, yet lower Ki-67 levels demonstrated superior CR/ CRu, DOR and survival outcomes. Overall, lenalidomide showed durable efficacy with a consistent safety profile in heavily pretreated, relapsed/refractory MCL post-bortezomib. [ABSTRACT FROM AUTHOR]

Episodes of invasive aspergillosis (IA) recruited to the voriconazole trial were reclassified according to the revised EORTC/MSG definitions. The efficacy of voriconazole was confirmed for possible, probable, and proven IA and was still better than found for the comparator arm.Background. Strict definition of invasive aspergillosis (IA) cases is required to allow precise conclusions about the efficacy of antifungal therapy. The Global Comparative Aspergillus Study (GCAS) compared voriconazole to amphotericin B (AmB) deoxycholate for the primary therapy of IA. Because predefined definitions used for this trial were substantially different from the consensus definitions proposed by the European Organization for Research and Treatment of Cancer/Mycoses Study Group in 2008, we recategorized the 379 episodes of the GCAS according to the later definitions.Methods. The objectives were to assess the impact of the current definitions on the classification of the episodes and to provide comparative efficacy for probable/proven and possible IA in patients treated with either voriconazole or AmB. In addition to original data, we integrated the results of baseline galactomannan serum levels obtained from 249 (65.7%) frozen samples. The original response assessment was accepted unchanged.Results. Recategorization allowed 59 proven, 178 probable, and 106 possible IA cases to be identified. A higher favorable 12-week response rate was obtained with voriconazole (54.7%) than with AmB (29.9%) (P < .0001). Survival was higher for voriconazole for mycologically documented (probable/proven) IA (70.2%) than with AmB (54.9%) (P = .010). Higher response rates were obtained in possible IA treated with voriconazole vs AmB with the same magnitude of difference (26.2%; 95% confidence interval [CI], 7.2%–45.3%) as in mycologically documented episodes (24.3%; 95% CI, 11.9%–36.7%), suggesting that possible cases are true IA.Conclusions. Recategorization resulted in a better identification of the episodes and confirmed the higher efficacy of voriconazole over AmB deoxycholate in mycologically documented IA. [ABSTRACT FROM PUBLISHER]

Background: Invasive aspergillosis (IA) is associated with poor outcomes in patients with hematologic malignancies (HMs) and hematopoietic cell transplantation (HCT). Small studies suggest a role for combination antifungal therapy. Objective: To assess the safety and efficacy of voriconazole and anidulafungin compared with voriconazole monotherapy for treatment of IA. Design: Randomized, double-blind, placebo-controlled multicenter trial. (ClinicalTrials.gov: NCT00531479) Setting: 93 international sites. Patients: 454 patients with HM or HCT and suspected or documented IA were randomly assigned to treatment with voriconazole and anidulafungin or placebo. Primary analysis was done in the modified intention-to-treat population of 277 patients in whom IA was confirmed. Measurements: The primary outcome was 6-week mortality; secondary outcomes included 12-week mortality, mortality in major subgroups, and safety measures. Results: Mortality rates at 6 weeks were 19.3% (26 of 135) for combination therapy and 27.5% (39 of 142) for monotherapy (difference, −8.2 percentage points [95% CI, −19.0 to 1.5]; P = 0.087). Secondary mortality outcomes favored combination therapy. Multivariable regression analysis suggested that maximum galactomannan value, Karnofsky score, and baseline platelet count had prognostic significance. Most patients (218 of 277 [78.7%]) had IA diagnosis established by radiographic findings and maximum galactomannan positivity. In a post hoc analysis of this dominant subgroup, 6-week mortality was lower in combination therapy than monotherapy (15.7% [17 of 108] vs. 27.3% [30 of 110]; difference, −11.5 percentage points [CI, −22.7 to −0.4]; P = 0.037). Safety measures, including hepatotoxicity, were not different. Limitations: Mortality at 6 weeks was higher than expected, and the difference in mortality was lower than expected, which reduced power to detect a treatment effect. Enrollment was restricted to patients with HM or HCT, which limited generalizability. Conclusion: Compared with voriconazole monotherapy, combination therapy with anidulafungin led to higher survival in subgroups of patients with IA. Limitations in power preclude definitive conclusions about superiority. Primary Funding Source: Pfizer. [ABSTRACT FROM AUTHOR]

An improved number of anti-fungal drugs are currently available for the treatment of invasive aspergillosis (IA). While serial galactomannan index (GMI) measurement can be used to monitor response to treatment, the extent to which different anti-fungal regimens can affect galactomannan levels is unknown. In 147 IA patients receiving either voriconazole (VCZ) or conventional amphotericin B (CAB) in a multicentre clinical trial, we performed post-hoc analyses of GMI trends in relation to outcomes. The generalized estimation equations approach was used to estimate changes in the effect size for GMI over time within patients. Patients who received VCZ primary therapy and had good treatment response 12 weeks later showed earlier decreases in GMI values at Week 1 and Week 2 (p = 0.001 and 0.046 respectively) as compared to patients who only received CAB. At end-of-randomized therapy (EORT), which was a pre-set secondary assessment point for all patients who switched from randomized primary (CAB or VCZ) to an alternative anti-fungal drug, treatment failure was associated with increasing GMI at Weeks 1 and 2 in CAB-primary treated patients (p = 0.022 and 0.046 respectively). These distinct trends highlight the variations in GMI kinetics with the use of different anti-fungal drugs and their implications in relation to IA treatment response. [ABSTRACT FROM AUTHOR]

A rare case of oromandibular Rhizopus oryzae infection is described in a 55-year-old woman with acute myeloid leukaemia and decompensated diabetes mellitus. The infection developed during induction chemotherapy when the patient was neutropenic. She was treated with a combination of amphotericin B lipid formulation and caspofungin plus surgery. Debridement surgery included excision of the lower lip, chin, floor of the mouth, a portion of the tongue, as well as mandibular resection at the level of the horizontal branches. Eight weeks of combined antifungal therapy were followed by secondary prophylaxis with amphotericin B lipid formulation during consolidation chemotherapy after achieving complete response of both leukaemia and mucormycosis. Reconstructive surgery was carried out including insertion of a new biomaterial porous mandibular prosthesis, which showed excellent functionality after long-term follow-up, followed by several plastic surgery procedures once good tolerability and no adverse effects of the prosthesis were observed. This case shows that a well-coordinated multidisciplinary approach is critical to increase the chances of clinical success in this life-threatening infection. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background. The standard caspofungin treatment regimen (50 mg/day after a 70-mg dose on day 1) is effective and well tolerated for the treatment of invasive candidiasis, but experience with higher doses of caspofungin is limited. We evaluated the safety and efficacy of caspofungin at 3 times the standard dosing regimen. Methods. Patients with proven invasive candidiasis were randomized to receive a standard or high-dose (150 mg/day) caspofungin treatment regimen. Safety was assessed in all patients as treated. Efficacy was assessed as a secondary objective in a full-analysis-set population. A favorable overall response was defined as symptomresolution and microbiological clearance at the end of caspofungin therapy. Results. A total of 204 patients were included in the safety analysis (104 received the standard regimen, and 100 received the high-dose regimen), and 197 were included in the efficacy analysis (102 and 95 in the standard and high-dose treatment groups, respectively). Patient demographic characteristics, neutropenia status (6.7% and 8.0% had neutropenia, respectively), and Acute Physiology and Chronic Health Evaluation II scores (mean, 16.5 and 17, respectively) were similar between treatment groups. Significant drug-related adverse events occurred in 1.9% of patients receiving the standard regimen and 3.0% of patients receiving the high-dose regimen (difference, 1.1%; 95% confidence interval, -4.1% to 6.8%). The most-common drug-related adverse events in the standard and high-dose treatment groups were phlebitis (3.8% and 2.0%, respectively), increased alkaline phosphatase level (6.9% and 2.0%, respectively), and increased aspartate transaminase level (4.0% and 2.0%, respectively). Overall, 71.6% of patients who received the standard regimen and 77.9% of patients who received the high-dose regimen had favorable overall responses (difference, 6.3%; 95% confidence interval, -5.9% to 18.4%; not statistically significant). Mortality at 8 weeks after therapy was similar between groups. Conclusions. Both caspofungin dosing regimens were effective and well tolerated in patients with invasive candidiasis. No safety concerns were found for caspofungin at a dosage of 150 mg/day. [ABSTRACT FROM AUTHOR]

The article focuses on the guidelines of the Infectious Diseases Society of America to treat the life-threatening infection aspergillosis. There are three major forms of aspergillosis including invasive aspergillosis, chronic forms of aspergillosis and allergic forms of aspergillosis. Based on the randomized controlled trials, voriconazole is considered the primary treatment for invasive aspergillosis. In addition, the liposomal amphotericin B (L-AMB) is considered an effective alternative primary therapy to some patients.

Background: Invasive aspergillosis (IA) has a poor prognosis in immunocompromised patients. Combinations of drugs that act on different targets are expected to improve the clinical efficacy of separate compounds.Methods: Patients with proven or probable IA were randomized in a prospective, open pilot study to receive either a combination of liposomal amphotericin B (AmB) at the standard dose (3 mg/kg daily) and caspofungin at the standard dose or monotherapy with a high-dose AmB regimen (10 mg/kg daily).Results: Thirty patients (21 men and 9 women) with hematologic malignancies were analyzed, and there were 15 patients in each arm. The median duration of treatment was 18 days for the combination group and 17 days for the high-dose monotherapy group. At the end of treatment, there were significantly more favorable overall responses (partial or complete responses; P = .028) in the combination group (10 of 15 patients; 67%) compared with the high-dose monotherapy group (4 of 15 patients; 27%). Survival rates at 12 weeks after inclusion were 100% and 80%, respectively. Infusion-related reactions occurred in 3 patients in the high-dose monotherapy group. A 2-fold increase in serum creatinine occurred in 4 of 17 patients (23%) who received high-dose monotherapy and 1 of 15 patient (7%) who received combination therapy; hypokalemia <3 mmol/L occurred in 3 patients and 2 patients, respectively.Conclusions: The combination of liposomal AmB and caspofungin was promising as therapy for IA compared with monotherapy. A trial that includes more patients will be required next to confirm the results of this pilot study. [ABSTRACT FROM AUTHOR]

Background. In a previous randomized trial of voriconazole versus amphotericin B deoxycholate for primary therapy of invasive aspergillosis, voriconazole demonstrated superior efficacy and better survival. In that trial, treatment with voriconazole or amphotericin B deoxycholate could be followed with other licensed antifungal therapies (OLAT). Here, we report the impact of OLAT on the outcome of patients with invasive aspergillosis. Methods. Data on dose, duration, and the reason for switching to the first OLAT were analyzed, and outcome at week 12 was assessed. Results. Fewer patients in the voriconazole group (52 [3 6%] of 144) switched to OLAT, compared with patients in the amphotericin B deoxycholate group (107 [80%] of 133). Lipid formulations of amphotericin B were the most common OLAT (38% of patients). Switches were made because of intolerance or insufficient response in 70% for patients in the amphotericin B deoxycholate group, compared with 24% of patients in the voriconazole group. Favorable responses to OLAT in the amphotericin B deoxycholate group occurred in only 19% of patients with initial insufficient response and 38% of patients with intolerance. Salvage therapy with a lipid formulation of amphotericin B after initial treatment with amphotericin B deoxycholate was successful for only 30% of patients (14 of 47). Treatment success among patients randomized to receive amphotericin B, including those whose treatment was switched to OLAT, was 32%, compared with 55% among patients who received voriconazole alone (P <.001). Conclusions. This study highlights the limited efficacy of salvage antifungal therapy, including therapy with lipid formulations of amphotericin B, and demonstrates the importance of effective initial therapy in invasive aspergillosis. [ABSTRACT FROM AUTHOR]

Background. Bone aspergillosis remains a rare but potentially devastating fungal disease. Although voriconazole is effective for invasive pulmonary aspergillosis, evidence of its efficacy for aspergillosis located in bone is limited. Methods. We report our experience with voriconazole in 4 cases of invasive bone aspergillosis. In addition, all cases of probable and definite bone aspergillosis from the Pfizer clinical database were reviewed and analyzed to determine the safety and efficacy of voriconazole treatment. Global response was evaluated at the end of therapy on the basis of a composite assessment of overall clinical, radiological, and mycological responses. Results. Twenty patients are described, of whom 18 had definite bone involvement diagnosed (spondylodiskitis in 9, sternum/rib osteomyelitis in 6, and peripheral bone involvement in 5). Of 20 patients, 14 were immuno-compromised. Oral or intravenous voriconazole was given as salvage therapy for 18 patients; 2 patients received voriconazole as first-line therapy. Median duration of voriconazole treatment was 83.5 days (range, 4-3 95 days). Global response at end of therapy was satisfactory in 11(55%) of 20 patients, including complete responses in 4 patients and partial responses in 7 patients; there were no relapses of infection in the 4 patients with complete response to therapy with voriconazole. Treatment was generally well tolerated. Conclusions. Long-term voriconazole treatment is a new therapeutic option for invasive aspergillosis with bone involvement. [ABSTRACT FROM AUTHOR]

There is inferential evidence that some patients with prolonged neutropenia and fever not responding to antibacterial agents are at sufficient risk of deep mycoses to warrant empirical therapy, although superiority of an antifungal agent over placebo has not been conclusively demonstrated. Amphotericin B deoxycholate, liposomal amphotericin B, and intravenous itraconazole followed by oral itraconazole solution are licensed in the United States for this indication. Fluconazole and voriconazole have given favorable results in clinical trials of patients with low and high risk of deep mold infections, respectively. Design features that can profoundly influence outcome of empirical trials are (1) inclusion of low-risk patients, (2) failure to blind the study, (3) obscuration of antifungal effects by changing antibacterial antibiotics, (4) failure to balance both arms of the study in terms of patients with prior antifungal prophylaxis or with severe comorbidities, (5) the merging of end points evaluating safety with those of efficacy, and (6) choice of different criteria for resolution of fever. [ABSTRACT FROM AUTHOR]

Invasive fungal disease (IFD), predominantly aspergillosis, is associated with significant morbidity and mortality in immunocompromised patients, especially those with haematological malignancies and recipients of allogeneic haematopoietic stem cell transplantation. There has been a great deal of scientific debate as to the effectiveness of antifungal prophylaxis in preventing infection in different patient groups and in which patients it is an appropriate management option. Deciding on an appropriate prophylaxis regimen for IFD is challenging as the incidence varies among different patient groups, due to the varied nature of their underlying haematological disease, and in different regions and centres. Attempts have been made to define risk factors and include them in treatment protocols. Impaired immune status of the patient, especially neutropenia, is a key risk factor for IFD and can sometimes be related to specific polymorphisms of genes controlling innate immunity. Risk factors also vary according to the type of fungal pathogen. Consequently, prophylaxis needs to be tailored to individual patient groups. Furthermore, the choice of antifungal agent for prophylaxis depends on the potential for drug–drug interactions with the patients' concomitant medications. Additional challenges are optimal timing of antifungal prophylaxis, when to change from prophylaxis to antifungal treatment and how to prevent recurrence of IFD. This article considers the use of antifungal prophylaxis for patients at risk of IFD in daily clinical practice, with clinical profiles that may be distinct from those covered by guidelines, and aims to provide practical advice for treatment of these patient groups. [ABSTRACT FROM PUBLISHER]

Randomized controlled trials (RCTs) provide the most reliable estimates of the effects of treatments. However, not all treatments are compared in available RCTs, making comparison of treatments problematic. Mixed treatment comparisons (MTCs) can provide estimates of the comparative effects of treatments across a range of available therapeutic options. MTCs use networks of available direct comparisons to estimate differences in treatments that have not been estimated in trials via a common comparator. We conducted a systematic review and MTCs of comparative RCTs in haematological patients of anti-mould active agents used for the empirical treatment of febrile neutropenia (Analysis 1), and pre-emptive therapy (Analysis 2) of invasive mould diseases. In addition, we summarized the evidence available associated with the use of directed treatment strategies (Analysis 3). For empirical therapy, caspofungin proved superior to amphotericin B, liposomal amphotericin B, amphotericin B lipid complex and voriconazole in the outcome of survival, but no agents showed superiority for treatment response. There was no evidence of a difference between pre-emptive and empirical strategies on mortality outcomes. For directed therapy, voriconazole was superior to amphotericin B for overall survival, and both voriconazole and liposomal amphotericin B were superior to amphotericin B and amphotericin B colloidal dispersion on the outcome of response. While limited to some degree by the availability of RCTs, the MTCs reported here provide the best available evidence of relative therapeutic success for different available treatment strategies. [ABSTRACT FROM PUBLISHER]

Background: Mucormycosis is an uncommon invasive fungal disease with high mortality and few treatment options. Isavuconazole is a triazole active in vitro and in animal models against moulds of the order Mucorales. We assessed the efficacy and safety of isavuconazole for treatment of mucormycosis and compared its efficacy with amphotericin B in a matched case-control analysis.Methods: In a single-arm open-label trial (VITAL study), adult patients (≥18 years) with invasive fungal disease caused by rare fungi, including mucormycosis, were recruited from 34 centres worldwide. Patients were given isavuconazole 200 mg (as its intravenous or oral water-soluble prodrug, isavuconazonium sulfate) three times daily for six doses, followed by 200 mg/day until invasive fungal disease resolution, failure, or for 180 days or more. The primary endpoint was independent data review committee-determined overall response-ie, complete or partial response (treatment success) or stable or progressive disease (treatment failure)-according to prespecified criteria. Mucormycosis cases treated with isavuconazole as primary treatment were matched with controls from the FungiScope Registry, recruited from 17 centres worldwide, who received primary amphotericin B-based treatment, and were analysed for day-42 all-cause mortality. VITAL is registered with ClinicalTrials.gov, number NCT00634049. FungiScope is registered with ClinicalTrials.gov, number NCT01731353.Findings: Within the VITAL study, from April 22, 2008, to June 21, 2013, 37 patients with mucormycosis received isavuconazole for a median of 84 days (IQR 19-179, range 2-882). By day 42, four patients (11%) had a partial response, 16 (43%) had stable invasive fungal disease, one (3%) had invasive fungal disease progression, three (8%) had missing assessments, and 13 (35%) had died. 35 patients (95%) had adverse events (28 [76%] serious). Day-42 crude all-cause mortality in seven (33%) of 21 primary-treatment isavuconazole cases was similar to 13 (39%) of 33 amphotericin B-treated matched controls (weighted all-cause mortality: 33% vs 41%; p=0·595).Interpretation: Isavuconazole showed activity against mucormycosis with efficacy similar to amphotericin B. Isavuconazole can be used for treatment of mucormycosis and is well tolerated.Funding: Astellas Pharma Global Development, Basilea Pharmaceutica International. [ABSTRACT FROM AUTHOR]

Background: 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.Methods: This was a phase 3, double-blind, global multicentre, comparative-group study. Patients with suspected invasive mould disease were randomised in a 1:1 ratio using an interactive voice-web response system, stratified by geographical region, allogeneic haemopoietic stem cell transplantation, and active malignant disease at baseline, to receive isavuconazonium sulfate 372 mg (prodrug; equivalent to 200 mg isavuconazole; intravenously three times a day on days 1 and 2, then either intravenously or orally once daily) or voriconazole (6 mg/kg intravenously twice daily on day 1, 4 mg/kg intravenously twice daily on day 2, then intravenously 4 mg/kg twice daily or orally 200 mg twice daily from day 3 onwards). We tested non-inferiority of the primary efficacy endpoint of all-cause mortality from first dose of study drug to day 42 in patients who received at least one dose of the study drug (intention-to-treat [ITT] population) using a 10% non-inferiority margin. Safety was assessed in patients who received the first dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00412893.Findings: 527 adult patients were randomly assigned (258 received study medication per group) between March 7, 2007, and March 28, 2013. All-cause mortality from first dose of study drug to day 42 for the ITT population was 19% with isavuconazole (48 patients) and 20% with voriconazole (52 patients), with an adjusted treatment difference of -1·0% (95% CI -7·8 to 5·7). Because the upper bound of the 95% CI (5·7%) did not exceed 10%, non-inferiority was shown. Most patients (247 [96%] receiving isavuconazole and 255 [98%] receiving voriconazole) had treatment-emergent adverse events (p=0·122); the most common were gastrointestinal disorders (174 [68%] vs 180 [69%]) and infections and infestations (152 [59%] vs 158 [61%]). Proportions of patients with treatment-emergent adverse events by system organ class were similar overall. However, isavuconazole-treated patients had a lower frequency of hepatobiliary disorders (23 [9%] vs 42 [16%]; p=0·016), eye disorders (39 [15%] vs 69 [27%]; p=0·002), and skin or subcutaneous tissue disorders (86 [33%] vs 110 [42%]; p=0·037). Drug-related adverse events were reported in 109 (42%) patients receiving isavuconazole and 155 (60%) receiving voriconazole (p<0·001).Interpretation: Isavuconazole was non-inferior to voriconazole for the primary treatment of suspected invasive mould disease. Isavuconazole was well tolerated compared with voriconazole, with fewer study-drug-related adverse events. Our results support the use of isavuconazole for the primary treatment of patients with invasive mould disease.Funding: Astellas Pharma Global Development, Basilea Pharmaceutica International. [ABSTRACT FROM AUTHOR]

Abstract: We report a series of 43 consecutive therapy-related myelodysplastic syndromes (t-MDS) or acute myeloid leukemias (t-AML) observed for 6 years. This series consisted of 26 women and 17 men, ages ranging from 9 to 85 years. These cases were classified into three groups according to the primary diagnosis. Conventional cytogenetic and flurosecence in situ hybridization (FISH)/ multiplex FISH (M-FISH) methods were used to analyze cytogenetic characteristics of secondary MDS/AML. The features of chromosomal abnormalities were linked to the nature of the therapy and protocols used. A considerable proportion of recurrent balanced translocations characterized t-AML secondary to therapy. FISH techniques showed that conventional cytogenetics often underestimated associated translocations; some deletions were in fact derivative chromosomes associated with deletions. After treatment for lymphomas and chronic myeloproliferative diseases, there were more complex unbalanced abnormalities than the control group. Compared to other series, recurrent translocations appeared to be more numerous (25%), probably reflecting an evolution of therapeutic modalities. [Copyright &y& Elsevier]