Current results on the use of imatinib mesylate in patients with relapsed philadelphia chromosome positive leukemia after allogeneic or syngeneic hematopoietic stem cell transplantation

Here, we describe a patient diagnosed with chronic myelogenous leukemia who relapsed after matched unrelated donor SCT. The patient was treated with imatinib mesylate and donor lymphocyte infusions, and achieved a complete molecular remission. Additionally, safety and efficacy of imatinib mesylate in a total of 134 patients from 8 centers who underwent allogeneic or syngeneic stem cell transplantation (SCT) and had a relapse of Philadelphia chromosome positive leukemia was reviewed. Data was compiled from abstracts accepted as oral or poster presentations at the ASH (American Society of Hematology) 2001 and EBMT (European Group for Blood and Marrow Transplantation) 2001 & 2002 meetings and …

Posaconazole vs Standard Azole (FLU/ITRA) Therapy for Prophylaxis of Invasive Fungal Infections (IFIs) among High-Risk Neutropenic Patients: Results of a Randomized, Multicenter Trial.

Abstract Background: Patients with severe and prolonged neutropenia are at high-risk of developing life-threatening IFIs. Despite current treatment option, IFIs are difficult to treat and frequently associated with high mortality rates. Antifungal prophylaxis has shown benefits in high-risk populations and is a standard practice in many institutions. We compared Posaconazole (POS), a new broad-spectrum triazole, vs Standard Azoles for the prevention of IFIs in patients with a new diagnosis or first relapse of acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) being treated with intensive chemotherapy. Methods: Patients in this randomized, evaluator-blinded, active controlled…

Accumulated safety data of micafungin in therapy and prophylaxis in fungal diseases

To define better the safety profile of micafungin, an analysis of micafungin clinical trial safety data was undertaken.Adverse event data were pooled worldwide from 17 clinical efficacy and safety studies. Adverse events were coded using the Medical Dictionary for Regulatory Activities version 5.0.In the pooled clinical trial data set, 3028 patients received at least one dose of micafungin. The mean age of patients was 41.4 years; with 296 (9.8%) children (16 years) and 387 (12.8%) elderly patients (≥ 65 years). Common underlying conditions were hematopoietic stem cell and other transplantations (26.1%), malignancies (20.8%) and HIV (32.9%). Mean exposure was 18 days for adults and 29 days …

Efficacy of posaconazole and amphotericin B in experimental invasive pulmonary aspergillosis in dexamethasone immunosuppressed rats

Objectives: Invasive pulmonary aspergillosis is associated with high mortality. To assess new antifungal therapy options, animal models have to be developed to assess, in an appropriate setting, the activity of new drugs. Methods: Male albino CD rats (125–150 g) were fed with a protein-free diet and received dexamethasone thrice weekly subcutaneously during the whole experiment. After 2 weeks, an inoculum of 10 6 conidia of Aspergillus fumigatus (H11-20) was injected intratracheally. Antifungal treatment was initiated and continued for a total of 7 days. Animals were grouped in numbers of 10. One group of animals served as untreated control, whereas the others were treated with amphotericin…

Posaconazole or Fluconazole for Prophylaxis in Severe Graft-versus-Host Disease

Invasive fungal infections are an important cause of morbidity and mortality after allogeneic hematopoietic stem-cell transplantation.In an international, randomized, double-blind trial, we compared oral posaconazole with oral fluconazole for prophylaxis against invasive fungal infections in patients with graft-versus-host disease (GVHD) who were receiving immunosuppressive therapy. The primary end point was the incidence of proven or probable invasive fungal infections from randomization to day 112 of the fixed treatment period of the study.Of a total of 600 patients, 301 were assigned to posaconazole and 299 to fluconazole. At the end of the fixed 112-day treatment period, posaconazole wa…

Antimicrobial prophylaxis in allogeneic bone marrow transplantation. Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Haematology and Oncology

Patients undergoing allogeneic stem cell transplantation are at high risk for infection with a variety of pathogens during different phases of the procedure. Bacteria and fungi predominate the first phase until engraftment. During the second phase, from engraftment to about day 100, major infectious problems are caused by fungi and cytomegalovirus. Both pathogens remain important under continued immunosuppression, however, in the late post-transplantation period infections with encapsulated bacteria may become a problem. In this review the Infectious Diseases Working Party of the DGHO gives recommendations for prophylaxis of infections under allogeneic stem cell transplantation with drugs a…

208: Impact of posaconazole (POS) vs fluconazole (FLU) on cyclosporine (CsA) and tacrolimus (TAC) dosing in hematopoietic stem cell transplant (HSCT) recipients with graft-vs-host disease (GVHD)

Prophylaxis of invasive fungal infections in patients with hematological malignancies and solid tumors

Morbidity and mortality in patients with malignancies, especially leukemia and lymphoma, are increased by invasive fungal infections. Since diagnosis of invasive fungal infection is often delayed, antifungal prophylaxis is an attractive approach for patients expecting prolonged neutropenia. Antifungal prophylaxis has obviously attracted much interest resulting in dozens of clinical trials since the late 1970s. The non-absorbable polyenes are probably ineffective in preventing invasive fungal infections, but may reduce superficial mycoses. Intravenous amphotericin B and the newer azoles were used in clinical trials, but their role in antifungal prophylaxis is still not well defined. Allogene…

A double-blind trial on prophylactic voriconazole (VRC) or placebo during induction chemotherapy for acute myelogenous leukaemia (AML).

Summary Objectives Invasive fungal infections remain a frequent cause of morbidity and mortality in long-term neutropenic patients. The availability of tolerable broad-spectrum antifungals like voriconazole stimulated the discussion about optimal timing of antifungal therapy. We conducted a trial to analyze the efficacy and safety of voriconazole in the prevention of lung infiltrates during induction chemotherapy for acute myelogenous leukaemia (AML). Methods This was a prospective, randomised, double-blind, placebo-controlled phase III trial in AML patients undergoing remission induction chemotherapy. Oral voriconazole 200mg twice daily or placebo was administered until detection of a lung…

Treatment of invasive fungal diseases in cancer patients—Revised 2019 Recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO)

Background Invasive fungal diseases remain a major cause of morbidity and mortality in cancer patients undergoing intensive cytotoxic therapy. The choice of the most appropriate antifungal treatment (AFT) depends on the fungal species suspected or identified, the patient's risk factors (eg length and depth of granulocytopenia) and the expected side effects. Objectives Since the last edition of recommendations for 'Treatment of invasive fungal infections in cancer patients' of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) in 2013, treatment strategies were gradually moving away from solely empirical therapy of presumed or possib…

Review of the safety, tolerability, and drug interactions of the new antifungal agents caspofungin and voriconazole

Managing invasive fungal infections often presents a challenge for clinicians in the treatment of immunocompromised patients. Two very different systemic antifungal agents, voriconazole and caspofungin, have recently been introduced into the market place. Voriconazole is a new triazole antifungal, while caspofungin is the first echinocandin antifungal. Voriconazole acts by inhibiting the synthesis of ergosterol in the fungal cell membrane. Caspofungin inhibits beta-1,3-D-glucan synthesis in the cell wall, a target present in fungal cells, but absent from mammalian cells. Both agents are broad-spectrum, with efficacy against invasive Aspergillus and Candida infections. The safety and tolerab…

Mycobacterial Infection: A Difficult and Late Diagnosis in Stem Cell Transplant Recipients

The Infectious Diseases Working Party of the European Blood and Marrow Transplant Group conducted a survey to obtain information about the frequency, presentation, and treatment of mycobacterial infection (MBI) in stem cell transplant (SCT) recipients. Among 29 centers, MBI was diagnosed in 0.79% of 1513 allogeneic and 0.23% of 3012 autologous SCT recipients during 1994-1998 a median of 160 days after transplantation. The mean interval between first symptoms and diagnosis was 29 days and was still longer for patients with atypical MBI or recipients of corticosteroid therapy. The prevalence of MBI was highest among those who received matched unrelated or mismatched STCs from related donors. …

Immune response to the 23-valent polysaccharide pneumococcal vaccine after the 7-valent conjugate vaccine in allogeneic stem cell transplant recipients: Results from the EBMT IDWP01 trial

The current recommendations for active immunization after stem cell transplant (SCT) include 3 doses of 7-valent pneumococcal conjugate vaccine (PCV7) from 3 months after transplant, followed by a 23-valent polysaccharide pneumococcal vaccine (PPV23). However, until now, the immune response to PPV23 after PCV7 has not been assessed after SCT. In the EBMT IDWP01 trial, 101 patients received 1 dose of PPV23 at 12 or 18 months, both after 3 doses of PCV7. The efficacy of PPV23 was assessed 1 month later and at 24 months after transplant by the pneumococcal serotype 1 and 5 antibody levels. Serotype 1 and 5 are not included in PCV7. Although the geometric mean concentrations were significantly …

Forty-one recent cases of invasive zygomycosis from a global clinical registry.

Background Invasive zygomycosis accounts for a significant proportion of all invasive fungal diseases (IFD), but clinical data on the clinical course and treatment response are limited. Patients and methods Fungiscope-A Global Rare Fungal Infection Registry is an international university-based case registry that collects data of patients with rare IFD, using a web-based electronic case form at www.fungiscope.net. Results Forty-one patients with invasive zygomycosis from central Europe and Asia were registered. The most common underlying conditions were malignancies (n = 26; 63.4%), diabetes mellitus (n = 7; 17.1%) and solid organ transplantation (n = 4; 9.8%). Diagnosis was made by culture …

Prophylactic transfer of CD8-depleted donor lymphocytes after T-cell–depleted reduced-intensity transplantation

AbstractAllogeneic hematopoietic stem cell transplantation (SCT) regimens incorporating the lymphocytotoxic CD52 antibody alemtuzumab demonstrate efficient engraftment and reduced graft-versus-host disease (GVHD). However, these protocols substantially impair posttransplantation antiviral and antitumor immunity. To accelerate immune reconstitution after alemtuzumab-based reduced-intensity SCT, we administered prophylactic CD8-depleted donor lymphocyte infusions (DLIs) starting on days 60 and 120 after transplantation. DLIs were processed in an immunomagnetic good manufacturing practice depletion procedure resulting in a 2.5- to 6-log reduction in CD8 T cells. Of 23 high-risk patients with h…

Forty-One Recent Cases of Invasive Zygomycosis From a Global Clinical Registry.

Abstract Abstract 4736 Background Invasive zygomycosis accounts for a significant proportion of all invasive fungal diseases (IFD), but clinical data on the clinical course and treatment response is limited. Methods Fungiscope” - A Global Rare Fungal Infection Registry is a university-based case registry that collects data of patients with rare IFD, using a web-based electronic case form at www.fungiscope.net. Results Fourty-one patients with invasive zygomycosis were registered. Five were pediatric (12.2%), 28 (68.3%) male. Median age was 49 years (range 2-88). Most common underlying conditions were malignancies (n=26; 63.4%), diabetes mellitus (n=7; 17%) and solid organ transplant (n=4; 9…

Impact of antifungal prophylaxis on colonization and azole susceptibility of Candida species.

ABSTRACT Two large studies compared posaconazole and fluconazole or itraconazole for prophylaxis in subjects undergoing allogeneic hematopoietic stem cell transplantation or subjects with acute myelogenous leukemia. To assess the impact of prophylaxis on colonization and the development of resistance in Saccharomyces yeasts, identification and susceptibility testing were performed with yeasts cultured at regular intervals from mouth, throat, and stool samples. Prior to therapy, 34 to 50% of the subjects were colonized with yeasts. For all three drugs, the number of positive Candida albicans cultures decreased during drug therapy. In contrast, the proportion of subjects with positive C. glab…

Sustained Complete Molecular Remissions After Treatment With Imatinib-Mesylate in Patients With Failure After Allogeneic Stem Cell Transplantation for Chronic Myelogenous Leukemia: Results of a Prospective Phase II Open-Label Multicenter Study

Purpose In the era of molecular therapy of chronic myelogenous leukemia (CML) applying BCR-ABL tyrosine kinase inhibitors, the usefulness of molecular end points, in particular, quantitative polymerase chain reaction (PCR) for BCR-ABL in monitoring responses has been broadly accepted. Therefore, we have designed a prospective phase II trial in CML, which, for the first time, evaluated the feasibility and safety of molecular end points as surrogate markers to guide through a stratified treatment algorithm within a multicenter trial. Patients and Methods As a clinical model, we adopted minimal residual disease (MRD) found in relapse after allogeneic stem cell transplantation (SCT) in CML. For…

European expert opinion on the management of invasive candidiasis in adults

Item does not contain fulltext This report discusses the present status of antifungal therapy and treatment options for candidaemia, considered by experts in the field in Europe. A conference of 26 experts from 13 European countries was held to discuss strategies for the treatment and prevention of invasive candidiasis, with the aim of providing a review on optimal management strategies. Published and unpublished comparative trials on antifungal therapy were analysed and discussed. Commonly asked questions about the management of candidaemia were selected, and possible responses to these questions were discussed. Panellists were then asked to respond to each question by using a touchpad ans…

Toxoplasmosis after hematopoietic stem cell transplantation.

In immunocompromised individuals, toxoplasmosis mostly occurs as a reactivation of a latent infection, causing severe to life-threatening disease. Thus, recipients who are seropositive for Toxoplasma gondii before an allogeneic hematopoietic stem cell transplant (HCT) are at highest risk, although primary infections may also cause severe toxoplasmosis. The disease most often affects the central nervous system, but in HCT recipients other organs are involved in more than half of the cases. Because of the alteration of the immune response in these patients, serodiagnosis is not sufficiently reliable in the diagnosis of post-HCT toxoplasmosis, and direct detection of the causative agent is req…

Pharmacokinetics of Oral Posaconazole in Allogeneic Hematopoietic Stem Cell Transplant Recipients with Graft-versus-Host Disease

Study Objective. To analyze the pharmacokinetics of posaconazole administered as prophylaxis for invasive fungal infections in recipients of hematopoietic stem cell transplants (HSCTs) who have graft-versus-host disease (GVHD). Design. Pharmacokinetic analysis in a subset of posaconazole-treated patients from a large, multicenter, phase III, randomized, double-blind, double-dummy, parallel-group trial that compared posaconazole with fluconazole. Setting. Ninety international medical centers. Patients. The subset of patients comprised 246 HSCT recipients for whom pharmacokinetic data were available. Intervention. All patients received posaconazole 200 mg oral suspension 3 times/day for a max…

Pharmacokinetics, safety, and efficacy of posaconazole in patients with persistent febrile neutropenia or refractory invasive fungal infection.

ABSTRACT The pharmacokinetic profiles, safety, and efficacies of different dosing schedules of posaconazole oral suspension in patients with possible, probable, and proven refractory invasive fungal infection (rIFI) or febrile neutropenia (FN) were evaluated in a multicenter, open-label, parallel-group study. Sixty-six patients with FN and 32 patients with rIFI were randomly assigned to one of three posaconazole regimens: 200 mg four times a day (q.i.d.) for nine doses, followed by 400 mg twice a day (b.i.d.); 400 mg q.i.d. for nine doses, followed by 600 mg b.i.d.; or 800 mg b.i.d. for five doses, followed by 800 mg once a day (q.d.). Therapy was continued for up to 6 months in patients wi…

Dose Escalation of Caspofungin for Invasive Aspergillosis - A Phase II Trial

Abstract Abstract 2309 Objectives. Treatment of invasive aspergillosis (IA) fails in up to 50% of all cases and the mortality rate is at least 30%. Antifungal combination treatment has not been proven to be beneficial and dose escalation with liposomal amphotericin B did not improve outcome. New approaches are needed for patients with severe immunosuppression. Methods. Escalating high dosages of caspofungin were investigated in IA defined according to modified EORTC/MSG criteria. The tested cohort of patients received 70mg, 100mg, 150mg or 200mg QD, 8 patients each were to receive caspofungin first-line treatment for proven/probable IA for up to 28 days. Dose limiting toxicity was defined a…

Efficacy and safety of micafungin for treatment of serious Candida infections in patients with or without malignant disease

The aim of this study was to evaluate micafungin efficacy for treatment of invasive candidiasis/candidaemia in patients with cancer. Modified intent-to-treat populations were analysed from two trials: one, in adults and children with confirmed Candida infection, compared micafungin (adults 100 mg day(-1); children 2 mg kg(-1) day(-1)) with liposomal amphotericin B (L-AmB 3 mg kg(-1) day(-1)); and the other, in adults only, compared micafungin (100 or 150 mg day(-1)) with caspofungin (50 mg day(-1); 70 mg loading dose). Primary efficacy endpoint in both trials was treatment success, defined as both clinical and mycological response at end of therapy. In the micafungin/L-AmB trial, 183/489 pa…

Response to imatinib in patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia

We studied 128 patients with chronic myeloid leukemia (CML) relapsing after allogeneic stem cell transplantation (SCT). Disease at the time of treatment with Imatinib was in chronic phase (CP) in 51 patients, accelerated phase (AP) in 31 and blastic crisis (BC) in 46. Of the 51 patients in CP, 14 were in cytogenetic and two in molecular relapses. The median interval between relapse and Imatinib therapy was 5 months (0–65). A total of 50 patients had failed treatment with donor lymphocyte infusions prior to Imatinib. The overall hemato-logical response rate was 84% (98% for patients relapsing in CP). The complete cytogenetic response (CCR) was 58% for patients in CP, 48% for AP and 22% for p…

Numbers Needed to Treat with Posaconazole Prophylaxis to Prevent Invasive Fungal Infection and Death

Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial

Summary Background Invasive candidosis is increasingly prevalent in seriously ill patients. Our aim was to compare micafungin with liposomal amphotericin B for the treatment of adult patients with candidaemia or invasive candidosis. Methods We did a double-blind, randomised, multinational non-inferiority study to compare micafungin (100 mg/day) with liposomal amphotericin B (3 mg/kg per day) as first-line treatment of candidaemia and invasive candidosis. The primary endpoint was treatment success, defined as both a clinical and a mycological response at the end of treatment. Primary analyses were done on a per-protocol basis. This trial is registered with ClinicalTrials.gov, number NCT00106…

Early Cessation of a Vancomycin-Resistant Enterococci (VRE) Outbreak in a Hematology-Oncology Department after Implementation of an Enhanced Infection Control Intervention. A Single Center Experience.

Abstract Introduction: Worldwide, the incidence of nosocomial outbreaks of VRE has increased especially in high-risk patients such as hematology-oncology patients. Outbreaks reported so far, required a minimum of three months to be controlled. Such outbreaks have a serious impact on daily care and treatment of the patients and hospital economics. Patients and Methods: We describe the outcome of a VRE-outbreak in a department with 48 beds (fourteen 2-patient rooms, and 20 single-patient rooms) including allogeneic BMT. Epidemiological evaluation was initiated after two patients in the department for the first time had a blood stream infection (BSI) with VRE within one week. Two goals had to …

Antiviral prophylaxis in patients with haematological malignancies and solid tumours: Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Oncology (DGHO).

Morbidity and mortality in patients with malignancies are increased by viral infections. These mostly are reactivations of asymptomatic latent infections. They primarily concern clinical entities associated with the reactivation of herpes viruses, such as varicella zoster virus (VZV) and cytomegalovirus (CMV). Respiratory tract infections caused by influenza, parainfluenza or respiratory syncytial virus (RSV) are less common. Since reactivation of latent infections has major clinical impact, antiviral prophylaxis is an attractive approach for patients expecting immunosuppression. The main risk factor for clinically relevant reactivation is profound disruption of cellular immune response. Du…

Posaconazole concentrations in the central nervous system

more susceptible to the killing activity of caspofungin. This study is the first comparing caspofungin killing activity against the closely related species C. parapsilosis, C. orthopsilosis and C. metapsilosis. Killing curves, regardless of the medium used, showed a decreasing order of susceptibility to caspofungin: C. metapsilosis . C. orthopsilosis . C. parapsilosis. Based on high echinocandin MICs for C. parapsilosis sensu stricto, in the case of isolates identified as C. parapsilosis sensu lato low MICs of echinocandins may be regarded as an indicator that an isolate is in fact C. orthopsilosis or C. metapsilosis; in the case of isolates with low echinocandin MICs, DNA-based identificat…

Choosing a Study Population for the Evaluation of Antifungal Prophylaxis

Posaconazole (POS) vs fluconazole (FLU) for prophylaxis of invasive fungal infections (IFIs) in allogeneic hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD): A multicenter trial

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Phase II dose escalation study of caspofungin for invasive Aspergillosis.

ABSTRACT Our objective was to evaluate the maximum tolerated dose of caspofungin for invasive aspergillosis (IA). The safety and pharmacokinetics of escalating dosages of caspofungin were investigated in IA. Eight patients each received caspofungin 70, 100, 150, or 200 mg once a day (QD). Dose-limiting toxicity (DLT) was defined as the same non-hematological treatment-related adverse event of grade ≥4 in 2 of 8 patients or ≥3 in 4 of 8 patients in a cohort. A total of 46 patients (median age, 61 years; 21 female; 89% with hematological malignancies) received caspofungin (9, 8, 9, and 20 patients in the 70-, 100-, 150-, and 200-mg cohorts) for a median of 24.5 days. Plasma pharmacokinetics w…

Hepatic Granuloma Due to Propionibacterium acnes in a Patient with Acute Myelogenous Leukemia

Do we Need a Triple Antibiotic Therapy?

To compare the efficacy and toxicity of triple antibiotic therapy in patients undergoing autologous peripheral blood-stem-cell transplantation (PBSCT) with literature data.

Treatment outcome of invasive mould disease after sequential exposure to azoles and liposomal amphotericin B

Objectives To analyse the potential antagonism between azoles, which inhibit ergosterol synthesis, and polyenes, which bind directly to ergosterol in cell membranes, in patients receiving sequential azole-polyene treatment. Methods In an earlier randomized, double blind study of liposomal amphotericin as initial therapy for invasive filamentous fungal infection (IFFI), a 3 mg/kg/day dose had a favourable overall response rate of 50% and 12 week survival rate of 72%. No improved outcome was seen with 10 mg/kg/day for the first 14 days. The study population was further analysed for the effect of prior azole exposure on treatment responses to liposomal amphotericin B. The protocol allowed prio…

Safety of micafungin in prospective and retrospective clinical trials

Summary Managing fungal diseases remains a major challenge for clinicians despite the improved armamentarium of antifungal agents. This review identified 19 publications reporting safety data on micafungin. Two of these publications were spin off publications, the remaining 17 (15 prospective, two retrospective) were included in the main assessment. Major adverse events reported which occurred in more than 2% in the study populations were infusion-related, gastro-intestinal and hepatic (LFT parameters elevations). Micafungin demonstrated significantly less renal events compared with liposomal amphotericin B and less hepatic events compared with voriconazole. Compared with fluconazole no sig…

Risk factors for breakthrough invasive fungal infection during secondary prophylaxis.

BACKGROUND: Intensive chemotherapy with severe neutropenia is associated with invasive fungal infections (IFIs) leading to high mortality rates. During leukaemia induction chemotherapy, IFI often prohibited further curative treatment, thus predisposing for leukaemia relapse. Continuing myelosuppressive chemotherapy after diagnosis of IFI has become feasible with the now expanding arsenal of safe and effective antifungals. Secondary prophylaxis of IFI is widely administered, but reliable data on outcome and risk factors for recurrent IFI during subsequent chemotherapy are not available. This study determines risk factors for recurrent IFI in leukaemia patients. METHODS: From 25 European canc…

Persistent Legionella Infection in a Patient after Bone Marrow Transplantation

ABSTRACT We report on a patient who developed Legionella pneumonia after bone marrow transplantation. Despite appropriate antibiotic treatment, disease progressed. The patient developed a lung abscess from which Legionella and Prevotella were isolated. Cure was achieved by surgical resection. The resected material was sterile, but 16S ribosomal DNA analysis revealed Legionella DNA.

Pooled analysis of safety for micafungin

Micafungin (MICA) is an efficacious antifungal treatment for life-threatening fungal infections [1-4].

Safety and Pharmacokinetics of Isavuconazole as Antifungal Prophylaxis in Acute Myeloid Leukemia Patients with Neutropenia: Results of a Phase 2, Dose Escalation Study

ABSTRACT Isavuconazole is a novel broad-spectrum triazole antifungal agent. This open-label dose escalation study assessed the safety and pharmacokinetics of intravenous isavuconazole prophylaxis in patients with acute myeloid leukemia who had undergone chemotherapy and had preexisting/expected neutropenia. Twenty-four patients were enrolled, and 20 patients completed the study. The patients in the low-dose cohort ( n = 11) received isavuconazole loading doses on day 1 (400/200/200 mg, 6 h apart) and day 2 (200/200 mg, 12 h apart), followed by once-daily maintenance dosing (200 mg) on days 3 to 28. The loading and maintenance doses were doubled in the high-dose cohort ( n = 12). The mean ± …

Toxoplasmosis after hematopoietic stem transplantation. Report of a 5-year survey from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation

Toxoplasmosis after hematopoietic stem transplantation. Report of a 5-year survey from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation

Safety of Long-Term Oral Posaconazole Use in the Treatment of Refractory Invasive Fungal Infections

Background Invasive fungal infections are found most frequently in immunosuppressed and critically ill hospitalized patients. Antifungal therapy is often required for long periods. Safety data from the clinical development program of the triazole antifungal agent, posaconazole, were analyzed. Methods A total of 428 patients with refractory invasive fungal infections (n = 362) or febrile neutropenia (n = 66) received posaconazole in 2 phase II/III open-label clinical trials. Also, 109 of these patients received posaconazole therapy for > or = 6 months. Incidences of treatment-emergent, treatment-related, and serious adverse events and abnormal laboratory parameters were recorded during these…

Phase 1B Study of the Pharmacokinetics and Safety of Posaconazole Intravenous Solution in Patients at Risk for Invasive Fungal Disease

ABSTRACT This was a phase 1B, dose-ranging, multicenter, pharmacokinetics, and safety study of cyclodextrin-based posaconazole intravenous (i.v.) solution administered through a central line to subjects at high risk for invasive fungal disease (part 1 of a 2-part study [phase 1B/3]). Initially, the safety and tolerability of single-dose posaconazole i.v. 200 mg ( n = 10) were compared with those of a placebo ( n = 11). Subsequently, 2 doses were evaluated, posaconazole i.v. 200 mg once daily (q.d.) ( n = 21) and 300 mg q.d. ( n = 24). The subjects received twice-daily (b.i.d.) posaconazole i.v. on day 1, followed by 13 days of posaconazole i.v. q.d., then 14 days of posaconazole oral suspen…

Randomized Study of Early versus Late Immunization with Pneumococcal Conjugate Vaccine after Allogeneic Stem Cell Transplantation

BACKGROUND: Invasive pneumococcal disease is a life-threatening complication after allogeneic stem cell transplantation, and at least 20% of cases occur within 1 year after transplantation. The 23-valent pneumococcal polysaccharide vaccine (PPV23) has limited efficacy, especially during the first year after transplantation. The immune response to the conjugated vaccines is expected to be better than that to the polysaccharide vaccine, but the optimal timing of vaccination is not defined. Our objective was to show that a 7-valent pneumococcal conjugate vaccine (PCV7; Prevnar) was not inferior when first given 3 months after transplantation, compared with when first given 9 months after trans…

An EORTC Phase II study of caspofungin as first-line therapy of invasive aspergillosis in haematological patients.

OBJECTIVES: Caspofungin was evaluated as first-line monotherapy of invasive aspergillosis (IA) in patients with haematological malignancies and undergoing autologous transplants. METHODS: Adults with proven or probable IA, defined strictly according to EORTC-MSG criteria, were eligible. Those with possible IA were enrolled, but were not evaluable for efficacy unless upgraded to proven/probable disease within 7 days of registration based on investigations performed within 48 h after enrolment. Caspofungin dosage was 70 mg (day 1) followed by 50 mg/day. The primary endpoint was the proportion of patients with complete or partial response at the end of caspofungin therapy in the modified inten…

Early detection of Toxoplasma infection by molecular monitoring of Toxoplasma gondii in peripheral blood samples after allogeneic stem cell transplantation

International audience; Background. Isolated case reports have shown that recipients of allogeneic hematopoietic stem cell transplants ( HSCTs) who develop toxoplasmosis may have circulating Toxoplasma gondii DNA in peripheral blood before the onset of clinical symptoms. Methods. We prospectively studied 106 T. gondii - seropositive adult recipients of HSCTs for the incidence of reactivation of toxoplasmosis in the first 6 months after transplantation. Toxoplasmosis infection ( TI) was defined by a positive result of polymerase chain reaction ( PCR) of peripheral blood specimens, whereas toxoplasmosis disease ( TD) was defined as an invasive infection. Results. The incidence of TI was 16% (…

Nephrotoxicity in the setting of invasive fungal diseases

Amphotericin B, a broad spectrum antifungal agent, is widely used despite significant adverse events including nephrotoxicity. Nephrotoxicity occurs frequently in patients receiving amphotericin B. Different definitions for nephrotoxicity are reviewed in the context of outcome in patients with invasive fungal diseases. In most publications, mortality was higher in patients experiencing nephrotoxicity and mean hospital length of stay was prolonged. As a consequence, the use of less nephrotoxic antifungal agents could improve treatment outcomes.

Once-Daily Oral Levofloxacin Monotherapy versus Piperacillin/Tazobactam Three Times a Day: A Randomized Controlled Multicenter Trial in Patients with Febrile Neutropenia

A prospective, randomized, controlled multicenter trial was performed to evaluate the efficacy and safety of once-daily oral monotherapy with 500 mg levofloxacin in comparison with 4.5 g piperacillin/tazobactam 3 times a day in patients with low-risk febrile neutropenia. Low risk was defined by oral temperatureor = 38.5 degrees C on one occasion oror = 38.0 degrees C twice within 24 hours and granulocytopeniaor = 500/microL for less than 10 days. The primary end point was defined as defervescence after 72 hours followed by at least 7 afebrile days. Secondary end points were overall response, time to defervescence, survival on day 30, and toxicity. Thirty-four episodes were included. Fever o…

Caspofungin first-line therapy for invasive aspergillosis in allogeneic hematopoietic stem cell transplant patients: an European Organisation for Research and Treatment of Cancer study.

Caspofungin at standard dose was evaluated as first-line monotherapy of mycologically documented probable/proven invasive aspergillosis (IA) (unmodified European Organisation for Research and Treatment of Cancer/Mycosis Study Group criteria) in allogeneic hematopoietic SCT patients. The primary efficacy end point was complete or partial response at end of caspofungin treatment. Response at week 12, survival and safety were additional end points. Enrollment was stopped prematurely because of low accrual, with 42 enrolled and 24 eligible, giving the study a power of 85%. Transplant was from unrelated donors in 16 patients; acute or chronic GVHD was present in 15. In all, 12 patients were neut…

Treatment cost of invasive fungal disease (Ifd) in patients with acute myelogenous leukaemia (Aml) or myelodysplastic syndrome (Mds) in German hospitals

Invasive fungal disease (IFD) causes increasing morbidity and mortality in haematological cancer patients. Reliable cost data for treating IFD in German hospitals is not available. Objective of the study was to determine the institutional cost of treating the IFD. Data were obtained by retrospective chart review in German hospitals. Patients had either newly diagnosed or relapsed acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS). Direct medical cost was calculated from hospital provider's perspective. A total of 108 patients were enrolled at 5 tertiary care hospitals, 36 IFD patients and 72 controls. The vast majority of IFD patients (74%) were diagnosed with invasive aspergil…

Antifungal prophylaxis for invasive mycoses in high risk patients.

New broader spectrum antifungal agents with favorable safety profiles have been available for the last 15 years making prophylaxis feasible. The purpose of this article is to review recent studies in patient populations at high risk for invasive fungal infections.Itraconazole, lipid formulations of amphotericin B, posaconazole, caspofungin and micafungin have been utilized for prophylaxis in different immunocompromised host settings. Itraconazole and caspofungin remain an option especially in patients with hematological diseases. Low dose liposomal amphotericin B shows a lower morbidity rate in patients treated for acute myeloid leukemia. Posaconazole demonstrated survival benefits in this …

Efficacy of caspofungin and itraconazole as secondary antifungal prophylaxis: analysis of data from a multinational case registry

Patients surviving invasive fungal disease (IFD) and needing further antineoplastic chemotherapy are at high risk of recurrent fungal infection. In the absence of randomised controlled trials in this area, secondary prophylactic regimens are diverse. From 448 patients registered with the Multinational Case Registry of Secondary Antifungal Prophylaxis, we performed an analysis of patients receiving caspofungin (CAS) or itraconazole (ITC). All patients had an underlying haematological malignancy and had been diagnosed with an episode of IFD earlier in their course of treatment. Data collected comprised demographics, underlying disease, first episode of IFD, antifungal prophylaxis, incidence a…

A multicenter, randomized trial of posaconazole (POS) vs fluconazole (FLU) or itraconazole (ITZ) for prophylaxis of invasive fungal infections (IFIs) in neutropenic patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) receiving intensive chemotherapy

Posaconazole vs. Fluconazole or Itraconazole Prophylaxis in Patients with Neutropenia

Patients with neutropenia resulting from chemotherapy for acute myelogenous leukemia or the myelodysplastic syndrome are at high risk for difficult-to-treat and often fatal invasive fungal infections.In this randomized, multicenter study involving evaluators who were unaware of treatment assignments, we compared the efficacy and safety of posaconazole with those of fluconazole or itraconazole as prophylaxis for patients with prolonged neutropenia. Patients received prophylaxis with each cycle of chemotherapy until recovery from neutropenia and complete remission, until occurrence of an invasive fungal infection, or for up to 12 weeks, whichever came first. We compared the incidence of prove…

Prospective study of amphotericin B formulations in immunocompromised patients in 4 European countries

Background. Amphotericin B is a widely used broad-spectrum antifungal agent, despite being associated with significant adverse events, including nephrotoxicity. Methods. The present prospective study collected data on outcomes for 418 adult patients treated consecutively with polyenes in hematology and oncology wards in 20 hospitals in Europe. Results. Patients initially received amphotericin B deoxycholate (62% of patients), liposomal amphotericin B (27%), or other lipid formulations of amphotericin B (11%). Of the patients initially treated with amphotericin B deoxycholate, 36% had therapy switched to lipid formulations of amphotericin B, primarily because of increased serum creatinine le…

Failure of sustained engraftment after non-myeloablative conditioning with low-dose TBI and T cell-reduced allogeneic peripheral stem cell transplantation

We investigated whether a T cell-reduced allogeneic stem cell transplant (SCT) with minimal conditioning and subsequent donor lymphocyte infusions (DLI) could reduce the incidence and severity of GVHD while retaining stable engraftment. Five patients with hematological malignancies (three MM, one CLL, one Chediak-Higashi syndrome) were conditioned with TBI (200 cGy). One patient additionally received fludarabine (120 mg/m(2)). CsA and mofetyl-mycophenolate (MMF) were administered to prevent GVHD. All patients were grafted with >3 x 10(6)/kg highly purified CD34(+) cells together with 2 x 10(6)/kg CD3(+) cells (three patients) or 1 x 10(5)/kg CD3(+) cells (two patients). Quick hematopoietic …

Durable Molecular Remissions in Patients with Relapsed CML Post Allogeneic Stem Cell Transplantation upon Treatment with Imatinib-Mesylate (Glivec®, STI-571). Follow-Up Results of a Phase II Open-Label Study.

Abstract Purpose: In a phase II clinical trial we have previously reported on the safety and efficacy of imatinib mesylate (IM) to induce hematologic, cytogenetic and molecular remissions in case of relapse post allogeneic stem cell transplantation (SCT) in patients with chronic myelogenous leukaemia (CML). Here we report on an extended follow-up phase, which was performed to monitor stability of responses and further disease course in patients enrolled. Patients and Methods: Within the trial, patients, transplanted in chronic phase (CP) CML with molecular or cytogenetic relapse (n=37), received IM at a starting dose of 400mg. Close monitoring was performed, which, besides evaluation of sid…

Immune Response to the 23-Valent Polysaccharide Pneumococcal Vaccine (PPV23) after the 7-Valent Conjugate Vaccine (PCV7) in Allogeneic Stem Cell Transplant (SCT) Recipients: Results of the EBMT IDWP01 Trial

Abstract Background: Pneumococcal infections are causes of death after SCT. The IDWP01 trial compared early (E) vs late (L) pneumococcal immunization after allogeneic SCT, starting either at 3, or at 9 months post-transplant with 3 doses of PCV7 given at 1 month intervals,. This study has shown that the early immunization was not inferior in the proportion of responders one month after the last PCV7 dose. In addition, all patients received one dose of PPV23 after the 3 doses of PCV7 at 12 months and 18 months in the E and L groups, respectively. The goal of this supplementary analysis was to look at the immune response to the PPV23 according to the time of its administration. Methods: 158 p…

Itraconazole versus Fluconazole for Antifungal Prophylaxis

Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis

Background: Micafungin (FK463) is a new lipopeptide compound (echinocandin) with activity against Aspergillus and Candida species. This study evaluated the safety and efficacy of micafungin in patients with proven or probable invasive aspergillosis (IA). Methods: A multinational, non-comparative study was conducted to examine proven or probable (pulmonary only) Aspergillus species infection in a wide variety of patient populations. The study employed an open-label design utilizing micafungin alone or in combination with another systemic antifungal agent. Criteria for IA and therapeutic responses were judged by an independent panel. Results: Of the 331 patients enrolled, only 225 met diagnos…

Economic evaluation of caspofungin vs liposomal amphotericin B for empirical therapy of suspected systemic fungal infection in the German hospital setting

As antifungal agents are frequently used in hematology and oncology, economic data on the empirical therapy of suspected systemic fungal infection are pivotal. Data were analyzed according to: (1) the rate of nephrotoxicity related to treatment with caspofungin in comparison to liposomal amphotericin B (L-AmB) from a randomized clinical trial, (2) the effect of nephrotoxicity on length of hospital stay from a European observational study, and (3) an example of total bottom-up cost in a department of hematology in Germany. All estimates include 95% confidence intervals (CI) using two-stage Monte Carlo simulation on binominal and Gaussian random variables from separate studies with comparable…