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Purpose: Busulfan (BU) used as cytoreductive conditioning prior to hematopoietic stem cell transplantation (HSCT) is available as intravenous (IV) and oral (O) preparation. IV-BU has clinical advantages associated with relevant incremental costs. The aim was to determine the economic impact of IV-BU versus O-BU in adult HSCT recipients from a German health care providers' perspective.Methods: A budget-impact model (BIM) including costs and risks for oral mucositis (OM), infection with OM, and hepatic sinusoidal obstruction syndrome (SOS) was developed. Model inputs are literature data comparing clinical effects of IV-BU versus O-BU and German cost data (conditioning therapy, treatment of OM, infections, SOS without/with multiorgan failure) from literature and tariff lists.Results: Base case calculations resulted the following: total costs of adverse events were €86,434 with O-BU and €44,376 with IV-BU for ten patients each. Considering costs of adverse events and drugs, about €5840 for ten patients receiving IV-BU are saved. Sensitivity analyses were conducted in several ways. Cost savings range between €4910 and €12,640 per ten patients for all adverse events and €2070 or €1140 per ten patients considering SOS only. Drug treatment of SOS and treatment of multiorgan failure during severe SOS are major cost drivers. Worst case scenario calculations (assuming -25% risk of all adverse events for O-BU and +25% for IV-BU) yield up to €27,570 per ten patients with IV-BU.Conclusions: Considering costs of adverse events and drugs, IV-BU is the dominant alternative from a German providers' perspective. For more comprehensive economic evaluations, additional epidemiological data, evidence on clinical outcomes, patient-reported outcomes, and treatment patterns are needed. [ABSTRACT FROM AUTHOR]

Invasive fungal infections cause substantial morbidity and mortality in immunocompromised patients, particularly in those with haematological malignancies and recipients of allogeneic haematopoietic stem cell transplantation. Difficulties in diagnosing invasive fungal infections and subsequent delays in treatment initiation lead to unfavourable outcomes and emphasise the importance of prophylaxis. Since the recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology in 2009, results of 14 additional clinical studies have been published comprising 2,899 patients and initiating this update. Key recommendations for adult patients are as follows: Posaconazole remains the drug of choice during remission-induction chemotherapy in acute myeloid leukaemia, myelodysplastic syndrome and allogeneic haematopoietic stem cell transplantation with graft versus host disease (AI). In the pre-engraftment period of allogeneic transplantation, several antifungals are appropriate and can be recommended with equal strength: voriconazole (BI), micafungin (BI), fluconazole (BI) and posaconazole (BII). There is poor evidence regarding antifungal prophylaxis in the post-engraftment period of allogeneic haematopoietic stem cell transplantation if no steroids for treatment of graft versus host disease are required. Aerosolised liposomal amphotericin B inhalation in conjunction with fluconazole can be used in patients with prolonged neutropenia (BII). [ABSTRACT FROM AUTHOR]

Sepsis is a major cause of mortality during the neutropenic phase after intensive cytotoxic therapies for malignancies. Improved management of sepsis during neutropenia may reduce the mortality of cancer therapies. Clinical guidelines on sepsis treatment have been published by others. However, optimal management may differ between neutropenic and non-neutropenic patients. Our aim is to give evidence-based recommendations for haematologist, oncologists and intensive care physicians on how to manage adult patients with neutropenia and sepsis. [ABSTRACT FROM AUTHOR]

The Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) here presents its updated recommendations for the treatment of documented fungal infections. Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. In recent years, new antifungal agents have been licensed, and agents already approved have been studied in new indications. The choice of the most appropriate antifungal treatment depends on the fungal species suspected or identified, the patient's risk factors (e.g., length and depth of neutropenia), and the expected side effects. This guideline reviews the clinical studies that served as a basis for the following recommendations. All recommendations including the levels of evidence are summarized in tables to give the reader rapid access to the information. [ABSTRACT FROM AUTHOR]

Since two large-scale, randomised studies on posaconazole prophylaxis have demonstrated a clear benefit for patients at high risk for contracting invasive fungal disease ( IFD), posaconazole prophylaxis has been adopted as standard of care for this patient collective. Several years on from implementation at our institution, we wanted to evaluate its impact on the incidence and use of empirical antifungal therapy in a real-life setting. We analysed retrospectively incidence and severity of IFD in high-risk patients with prophylaxis, using a historical cohort as comparator. A total of 200 patients had either received the extended spectrum triazole posaconazole in prophylactic dosage of 200 mg tid or empirical antifungal therapy. Disease events were analysed by application of the revised EORTC/ MSG definitions for IFD. Before posaconazole prophylaxis, we recorded 57/100 cases of IFD which was reduced to 28/100 with prophylaxis. The empirical use of antifungal drugs was reduced to 41% from 91% in the non-prophylaxis cohort. Furthermore, we observed a shift in the categorisation of IFD according to EORTC/ MSG criteria. Our data suggest that posaconazole was effective in reducing the rate and probability of invasive fungal disease in high-risk patients. [ABSTRACT FROM AUTHOR]

Background:Extensive sets of data are required to investigate the potential use of a therapeutic drug monitoring with individualization of dosage of the antimycotic compound caspofungin. The goal was to develop an improved liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for this aim. Methods:Following protein precipitation, on-line solid phase extraction was performed for sample preparation. As the internal standard compound the veterinary drug tylosin was used. A standard validation protocol was applied. Results:Good reproducibility and accuracy of the method were observed. On-line solid phase extraction resulted in a convenient work-flow and good robustness of the method. Conclusions:This improved LC-MS/MS method was found reliable and convenient. It can be suggested for further work on the clinical pharmacology of caspofungin in the setting of clinical research laboratories. [ABSTRACT FROM AUTHOR]

Prothrombin complex concentrate (PCC) infusion is preferred for emergency reversal of coumarin therapy. Rapid infusion can potentially save crucial time; however, the possible impact of high infusion speed on PCC safety and effectiveness has not been delineated. In a prospective multinational clinical trial with 43 patients receiving PCC (Beriplex® P/N) for emergency reversal of coumarin therapy, infusion speeds were selected by the investigators. In a two-phase statistical analysis, the influence of baseline patient variables and dose on selected infusion speed was assessed. Then, the effect of infusion speed on reduction in international normalized ratio (INR) and on thrombogenicity marker pharmacokinetics was evaluated. Infusion speed ranged widely from 2.0 to 40.0 mL min−1 with a median of 7.5 mL min−1. Selection of infusion speed was not significantly influenced by gender, age, body mass index, presence of acute bleeding, indication for coumarin therapy, baseline INR, or PCC dose. Infusion speed was higher by a median of 2.2 mL min−1 (95% confidence interval, 1.0–4.3 mL min−1) among patients receiving Beriplex P/N volumes ≥80 mL compared with smaller infusion volumes. Infusion speed did not affect INR attained 30 min following PCC infusion. None of the evaluated thrombogenicity marker pharmacokinetic parameters was affected by infusion speed. Infusions in one patient with questionable hemostatic efficacy and another with a possibly PCC-related thromboembolic event were at moderate and slow speeds, respectively. This study provides the first direct evidence that Beriplex® P/N can be rapidly infused for emergency coumarin therapy reversal without altering safety or effectiveness. [ABSTRACT FROM AUTHOR]

These guidelines from the infectious diseases working party (AGIHO) of the German Society of Hematology and Oncology (DGHO) give recommendations for the management of adults with neutropenia and the diagnosis of sepsis. The guidelines are written for clinicians and focus on pathophysiology, diagnosis, and treatment of sepsis. The manuscript contains evidence-based recommendations for the assessment of the quality and strength of the data. [ABSTRACT FROM AUTHOR]

Patients developing fever in neutropenia are at high risk of infection-related complications. Their outcome is influenced by the degree of severity (sepsis, severe sepsis and septic shock). Sepsis describes clinical syndromes resulting from systemic inflammatory response. Diagnosis of sepsis is based on simple clinical criteria. Treatment of neutropenic patients with sepsis does not differ from sepsis treatment in non-neutropenic patients. A variety of treatment options have failed (e.g. anti-cytokine strategies, anti-endotoxin antibodies), however, in recent years successful targeted treatment, the use of activated protein C or the substitution of hydrocortisol has been shown to reduce mortality rates. The outcome of neutropenic sepsis is influenced by the underlying disease as well, however survival rates of neutropenic patients treated on the intensive care unit have improved during the past decade. This paper focuses on pathophysiology, diagnosis and treatment of sepsis. Evidence based medicine (EBM) criteria are used to grade treatment recommendations [50]. [ABSTRACT FROM AUTHOR]

Objectives: Fosmanogepix (APX001), a first-in-class, intravenous (IV) and oral (PO) antifungal prodrug, is being developed to treat invasive fungal diseases (IFDs). Manogepix (APX001A; active moiety) targets fungal glycosylphosphatidylinositol-anchored cell wall transfer protein 1, inhibiting cell wall synthesis causing loss of viability. This open-label, multicentre, Phase 1b study in patients with AML and neutropenia (absolute neutrophil count <500 cells/μL; >10 days) undergoing chemotherapy aimed to assess tolerability, safety and pharmacokinetics (PK) of IV and PO fosmanogepix., Methods: Of 21 adult AML patients undergoing remission induction chemotherapy, 10 received IV fosmanogepix (600 mg; q24h) and 11 received oral fosmanogepix (500 mg; q24h) over 14 days, with a 28 day follow-up. Patients also received remission induction chemotherapy [sequential high-dose cytarabine and mitoxantrone (S-HAM) or 7 + 3 regimen] for AML and IFD prophylaxis (posaconazole). A two-compartmental PK model from previous studies in healthy volunteers was fitted to manogepix plasma data., Results: Of 26 fosmanogepix-related adverse events (AEs; IV: 14; PO: 12) in 9 (42.9%) patients [IV: 5 (50%); PO: 4 (36.4%)], none were serious or resulted in fosmanogepix discontinuation. Most frequently occurring fosmanogepix-related AEs were Grade 1/2 nausea [four events in three patients (14.3%)]; vomiting, ALT increase, and delirium [two events; two patients (9.5%) each]. One patient experienced fosmanogepix-related Grade 3 hypertension. Dose-corrected geometric mean ratio of AUC (PO-to-IV) was 95%. Elimination half-lives (∼2 days) were consistent with prior studies in healthy volunteers., Conclusions: Fosmanogepix was safe and well tolerated in AML patients with neutropenia receiving remission induction chemotherapy. Safety and PK profiles were comparable to healthy volunteers., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Objectives: Patients with classical Hodgkin lymphoma (cHL) relapsing after second-line therapy have a dismal prognosis and novel approaches are required for this patient group. Based on promising (pre-)clinical data and the favourable toxicity profile, we performed a phase II clinical trial with the JAK inhibitor ruxolitinib in patients with relapsed or refractory cHL (r/r cHL)., Methods: Patients ≥18 years with histologically confirmed r/r cHL who failed second-line treatment were included. Ruxolitinib was given orally at a dose of 25 mg twice daily in continuous 28-day cycles until progression or unacceptable toxicity. Primary endpoint was the PET/CT-based overall response rate (ORR; complete response (CR) or partial response (PR)) after 2 cycles; secondary endpoints included progression-free (PFS) and overall survival (OS) as well as feasibility. The Jericho Trial adopted a 2-stage phase 2 design (Simon 1989)., Results: Among the 12 included patients in stage 1, 2 had a PR, 3 had a stable disease (SD) and 6 had progressive disease (PD) after two treatment cycles (ORR: 2/12 evaluable patients, 16.7%). Median PFS was 3.6 months, the 1-year OS estimate was 50.6% (median not reached). The toxicity profile was favourable with only one grade IV adverse event (7.1%) reported., Conclusion: Ruxolitinib exhibited a favourable side effect profile but modest activity in r/r cHL. Although the formal stopping criterion after stage 1 was not met, the trial did not continue to stage 2 due to the low response and PFS rates observed in stage 1., (© 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Objectives: To assess the usability of German hospital administrative claims data (GHACD) to determine inpatient management patterns, healthcare resource utilization, and quality-of-care in patients with multiple myeloma (PwMM)., Methods: Based on German tertiary hospital's claims data (2015-2017), PwMM aged >18 years were included if they had an International Classification of Diseases, Tenth Revision, code of C90.0 or received anti-MM therapy. Subgroup analysis was performed on stem cell transplantation (SCT) patients., Results: Of 230 PwMM, 59.1% were men; 56.1% were aged ≥65 years. Hypertension and infections were present in 50% and 67.0%, respectively. Seventy percent of PwMM received combination therapy. Innovative drugs such as bortezomib and lenalidomide were given to 36.1% and 10.9% of the patients, respectively. Mean number of admissions and mean hospitalization length/patient were 3.69 (standard deviation (SD) 2.71 (1-16)) and 12.52 (SD 9.55 (1-68.5)) days, respectively. In-hospital mortality was recorded in 12.2%. Seventy-two percent of SCT patients (n = 88) were aged ≤65 years, 22.7% required second transplantation, and 89.8% received platelet transfusion at a mean of 1.42(SD 0.63 (1-3))., Conclusion: GHACD provided relevant information essential for healthcare studies about PwMM from routine care settings. Data fundamental for quality-of-care assessment were also captured., Competing Interests: The authors have declared that no competing interests exist.

Introduction: In Germany, up to 75% of platelet concentrates (PCs) are administered to haematological and oncological patients. Only limited transparency exists on the characteristics of haematological/oncological patients receiving PC transfusions, treatment patterns, and guideline adherence in daily clinical routine care. This information would be key for managing platelet supply and optimal platelet usage strategies. This study aimed to analyse data from clinical routine transfusions to fill the aforementioned information gaps and to create an inventory as a blueprint for electronic data capturing systems that allow simplified, recurring analyses., Methods: Prospective open-label, single-centre, observational study in a German tertiary teaching haematological/oncological setting. All inpatients who received any transfusion of PCs (pathogen-inactivated or conventional) in routine use over a period of 3 months (March 2015-May 2015) were consecutively included. Except for age (≥18 years), no exclusion criteria were applied. For guideline adherence, the Cross-Sectional Guidelines for Therapy with Blood Components and Plasma Derivatives - amended edition 2020 were used. An inventory blueprint was created through a narrative literature review and the data collected in this study., Results: Ninety-four patients received 942 PCs. The mean (±SD) age was 54.6 (±13.9) years, 68% were male and 86% were diagnosed with a haematological disease. Thirteen patients received 42% of all transfused PCs. The mean ± SD number of transfused PC per patient was 10.81 ± 9.24. Five (0.5% per transfusion) minor adverse events were documented. Approximately 19% of PCs were not administered according to existing guidelines. The mean transfusion interval was 1.71 ± 1.1 days, and the mean increment was 12.62 ± 14.7 G/L. The inventory showed which platelet transfusion-specific data should be documented for answering questions in terms of quality, effectiveness, and management of PC transfusions., Conclusions: Platelet transfusions in a haematological/oncological setting are highly individual in terms of the total number of transfusions and transfusion intervals. The majority of all PC transfusions were given to only a small group of patients. Continuous, structured real-world data collection/evaluation and benchmarking with data from more centres seems essential in determining specific needs in this vulnerable patient group, assessing the quality of transfusion practices, determining effectiveness, and anticipating future demand for platelets and a sustainable blood supply. So far, not all relevant data are collected routinely. The advancing digitalization of health systems offers opportunities to collect and link data and thus make them more accessible and evaluable., (© 2022 S. Karger AG, Basel.)

Background: The German Hodgkin Study Group's HD18 trial established the safety and efficacy of PET-guided eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) for the treatment of advanced-stage Hodgkin lymphoma. However, because of a protocol amendment during the enrolment period (June 1, 2011) that changed standard treatment from eight to six cycles, the results of the HD18 trial have been partially immature. We report a prespecified 5-year follow-up analysis of the completed HD18 trial., Methods: HD18 was an international, open-label, randomised, phase 3 trial done in 301 hospitals and private practices in five European countries. Patients aged 18-60 years with newly diagnosed, advanced-stage Hodgkin lymphoma and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited. After receiving an initial two cycles of eBEACOPP (1250 mg/m 2 intravenous cyclophosphamide [day 1], 35 mg/m 2 intravenous doxorubicin [day 1], 200 mg/m 2 intravenous etoposide [day 1-3], 100 mg/m 2 oral procarbazine [day 1-7], 40 mg/m 2 oral prednisone [day 1-14], 1·4 mg/m 2 intravenous vincristine [day 8], and 10 mg/m 2 intravenous bleomycin [day 8]), patients underwent a contrast-enhanced CT and PET scan (PET-2). Patients with positive PET-2 were randomly assigned to receive standard therapy (an additional six cycles of eBEACOPP; ie, eight cycles in total) or experimental therapy (an additional six cycles of eBEACOPP plus 375 mg/m 2 intravenous rituximab; ie, eight cycles in total) until June 1, 2011. After June 1, 2011, all patients with positive PET-2 were assigned to the updated standard therapy with an additional four cycles of eBEACOPP (ie, six cycles in total). Patients with negative PET-2 were randomly assigned (1:1) to receive standard therapy (an additional six cycles of eBEACOPP [ie, eight cycles in total] until June 1, 2011; an additional four cycles of eBEACOPP [ie, six cycles in total] after June 1, 2011) or experimental therapy (an additional two cycles of eBEACOPP; ie, four cycles in total). Randomisation was done centrally with the minimisation method, including a random component, stratified by centre, age, stage, international prognostic score, and sex. The primary endpoint was progression-free survival. HD18 aimed to improve 5-year progression-free survival by 15% in the PET-2-positive intention-to-treat cohort and to exclude inferiority of 6% or more in 5-year progression-free survival in the PET-2-negative per-protocol population. This study is registered with ClinicalTrials.gov, NCT00515554, and is completed., Findings: Between May 14, 2008, and July 18, 2014, 2101 patients were enrolled and 1945 were assigned to a treatment group according to their PET-2 result. In the PET-2-positive cohort, with a median follow-up of 73 months (IQR 59 to 94), 5-year progression-free survival was 89·9% (95% CI 85·7 to 94·1) in 217 patients assigned to eight cycles of eBEACOPP before the protocol amendment and 87·7% (83·1 to 92·4) in 217 patients assigned to eight cycles of rituximab plus eBEACOPP (p=0·40). Among 506 patients who received six cycles of eBEACOPP after the protocol amendment, 5-year progression-free survival was 90·1% (95% CI 87·2 to 92·9), with a median follow-up of 58 months (IQR 39 to 66). In the PET-2-negative cohort, with a median follow-up of 66 months (IQR 54 to 85) in the combined pre-amendment and post-amendment groups, 5-year progression-free survival was 91·2% (95% CI 88·4 to 93·9) in 446 patients who received eight or six cycles of eBEACOPP and 93·0% (90·6 to 95·4) in 474 patients who received four cycles of eBEACOPP (difference 1·9% [95% CI -1·8 to 5·5]). In the subgroup of PET-2-negative patients randomly assigned after protocol amendment, 5-year progression-free survival was 90·9% (95% CI 86·8 to 95·1) in 202 patients assigned to receive six cycles of eBEACOPP and 91·0% (86·6 to 95·5) in 200 patients assigned to receive four cycles of eBEACOPP (difference 0·1% [-5·9 to 6·2])., Interpretation: Long-term follow-up confirms the efficacy and safety of PET-2-guided eBEACOPP in patients with advanced-stage Hodgkin lymphoma. The reduction from eight to four cycles of eBEACOPP represents a benchmark in the treatment of early-responding patients, who can now be potentially cured with a short and safe treatment approach., Funding: Deutsche Krebshilfe, Swiss State Secretariat for Education, Research and Innovation SERI (Switzerland), and Roche Pharma., Translation: For the German translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests AM reports participation in advisory boards from Roche, Janssen, and Takeda outside the submitted work. RG reports honoraria, a consulting advisory role, research funding, travel, accommodations, and expenses from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, MSD, Sandoz, Abbvie, Gilead, Daiichi Sankyo, and Janssen outside the submitted work. JMe reports non-financial support from MSD, Bristol Myers Squibb, Takeda, Celgene, and Hexal outside the submitted work. GM reports personal fees from Amgen, Bristol Myers Squibb, Janssen, AstraZeneca, Gilead, and Merck Serono, outside the submitted work. AE reports grants and personal fees from Takeda/Millennium, Bristol Myers Squibb, Hexal, Janssen, AstraZeneca, and Merck outside the submitted work. SK, HG, IB, CK, DAE, JMZ, JMa, MFB, MS, H-JB, WW, W-DL, TP, MST, FH, MB, UBK, DK, HO, BH, WA, TV, HE, CB, HS, MF, VD, MD, and PB declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Changes in well-being of patients with multiple myeloma (MM) before and after diagnosis have not been quantified., Aims: Explore the use of secondary data to examine the changes in the well-being of older patients with MM., Methods: We used the Health and Retirement Study (HRS), linked to Medicare claims to identify older MM patients. We compared patient-reported measures (PRM), including physical impairment, sensory impairment, and patient experience (significant pain, self-rated health, depression) in the interviews before and after MM diagnosis using McNemar's test. We propensity-matched each MM patient to five HRS participants without MM diagnosis based on baseline characteristics. We compared the change in PRM between the MM patients and their matches., Results: We identified 92 HRS patients with MM diagnosis (mean age = 74.6, SD = 8.4). Among the surviving patients, there was a decline in well-being across most measures, including ADL difficulty (23% to 40%, p value = 0.016), poor or fair self-rated health (38% to 61%, p value = 0.004), and depression (15% to 30%, p value = 0.021). Surviving patients reported worse health than participants without MM across most measures, including ADL difficulty (40% vs. 27%, p value = 0.04), significant pain (38% vs. 22%, p value = 0.01), and depression (29% vs. 11%, p value = 0.003)., Discussion: Secondary data were used to identify patients with MM diagnosis, and examine changes across multiple measures of well-being. MM diagnosis negatively affects several aspects of patients' well-being, and these declines are larger than those experienced by similar participants without MM., Conclusion: The results of this study are valuable addition to understanding the experience of patients with MM, despite several data limitations.

Background: First-line antifungal treatment for invasive mucormycosis (IM) consists of liposomal amphotericin B. Salvage treatment options are limited and often based on posaconazole oral suspension. With the approval of posaconazole new formulations, patients could benefit from improved pharmacokinetics, safety and tolerability., Objectives: Our aim was to assess the effectiveness of posaconazole new formulations for IM treatment., Methods: We performed a case-matched analysis with proven or probable IM patients from the FungiScope® Registry. First-line posaconazole new formulations (1st-POSnew) and first-line amphotericin B plus posaconazole new formulations (1st-AMB+POSnew) cases were matched with first-line amphotericin B-based (1st-AMB) treatment controls. Salvage posaconazole new formulations (SAL-POSnew) cases were matched with salvage posaconazole oral suspension (SAL-POSsusp) controls. Each case was matched with up to three controls (based on severity, haematological/oncological malignancy, surgery and/or renal dysfunction)., Results: Five patients receiving 1st-POSnew, 18 receiving 1st-AMB+POSnew and 22 receiving SAL-POSnew were identified. By day 42, a favourable response was reported for 80.0% (n = 4/5) of patients receiving 1st-POSnew, for 27.8% (n = 5/18) receiving 1st-AMB+POSnew and for 50.0% (n = 11/22) receiving SAL-POSnew. Day 42 all-cause mortality of patients receiving posaconazole new formulations was lower compared with controls [20.0% (n = 1/5) in 1st-POSnew versus 53.3% (n = 8/15) in 1st-AMB; 33.3% (n = 6/18) in 1st-AMB+POSnew versus 52.0% (n = 26/50) in 1st-AMB; and 0.0% (n = 0/22) in SAL-POSnew versus 4.4% (n = 2/45) in SAL-POSsusp]., Conclusions: Posaconazole new formulations were effective in terms of treatment response and associated mortality of IM. While posaconazole new formulations may be an alternative for treatment of IM, the limited sample size of our study calls for a cautious interpretation of these observations., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: In recent years antifungal stewardship (AFS) programmes have been increasingly recommended to provide optimal antifungal treatment. In a previous study (study I) in the department of haematology and oncology of a German tertiary care hospital we found areas for improvement concerning antifungal prescription. Subsequently, AFS measures were implemented and their impact on quality of antifungal use was assessed in this study., Methods: AFS measures included medical training (two sessions), a pocket card summarising main recommendations for antifungal use, and daily pharmaceutical counselling on the ward. In a 6-month observational study, antifungal prescriptions were analysed and compared to the previously collected data (study I) concerning indication, choice of drug, dosing, duration and drug-drug interactions. The study was approved by the university hospital ethical review board., Results: Antifungal agents were prescribed for 103/1169 inpatients. Compared to study I, a significant increase in dosage accuracy (+ 19.3%; p < 0.05) and correct choice of drug (+ 15.9%; p < 0.05) was noted, as well as a decrease in potential clinically relevant drug-drug interactions with concomitant medication (- 13.9%; p < 0.05). However, no significant improvement in indication and duration of antifungal treatment was identified. 56 recommendations were given to the prescribing physicians (acceptance rate: 66.1%)., Conclusions: The implementation of AFS interventions based on pharmaceutical presence on the ward was associated with an improvement in antifungal use; however, indication and duration of therapy need to be communicated by infectious disease specialists. Considering the proportionally short observation period, the long-term effects of our AFS interventions need to be further investigated.

High-dose chemotherapy alongside peripheral blood stem cell (PBSC) infusion has become the standard of care in different hematologic malignancies. The goal of PBSC mobilization is to allow collection of sufficient CD34+ cells to proceed to transplantation. The current mobilization regimen with granulocyte colony-stimulating factor (G-CSF), alone or in combination with chemotherapy, still fails in 10-25% of patients. Plerixafor is able to rescue most of these patients from mobilization failure. In this study, we investigated the impact of plerixafor on the cost and time spent on apheresis in patients who were considered poor mobilizers, with <20 × 10 6 /µl peripheral CD34+ cells after mobilization but prior to apheresis. Patient hospital records from ten centers in three European countries were reviewed and compared during two time periods, namely prior and after plerixafor introduction to the market. During the plerixafor period, patients spent less time on apheresis (350 vs. 461  min). Poor mobilizers given plerixafor collected more CD34+ cells during the first apheresis session, leading to a decrease in the average number of apheresis sessions needed. The total apheresis yield was unaffected. This analysis shows that the use of plerixafor lessens the time-effort associated with the management of poor mobilizers and reduces apheresis costs.

Background: The intensive polychemotherapy regimen eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) is very active in patients with advanced-stage Hodgkin's lymphoma, albeit at the expense of severe toxicities. Individual patients might be cured with less burdensome therapy. We investigated whether metabolic response determined by PET after two cycles of standard regimen eBEACOPP (PET-2) would allow adaption of treatment intensity, increasing it for PET-2-positive patients and reducing it for PET-2-negative patients., Methods: In this open-label, randomised, parallel-group phase 3 trial, we recruited patients aged 18-60 years with newly diagnosed, advanced-stage Hodgkin's lymphoma in 301 hospitals and private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. After central review of PET-2, patients were assigned (1:1) to one of two parallel treatment groups on the basis of their PET-2 result. Patients with positive PET-2 were randomised to receive six additional cycles of either standard eBEACOPP (8 × eBEACOPP in total) or eBEACOPP with rituximab (8 × R-eBEACOPP). Those with negative PET-2 were randomised between standard treatment with six additional cycles of eBEACOPP (8 × eBEACOPP) or experimental treatment with two additional cycles (4 × eBEACOPP). A protocol amendment in June, 2011, introduced a reduction of standard therapy to 6 × eBEACOPP; after this point, patients with positive PET-2 were no longer randomised and were all assigned to receive 6 × eBEACOPP and patients with negative PET-2 were randomly assigned to 6 × eBEACOPP (standard) or 4 × eBEACOPP (experimental). Randomisation was done centrally using the minimisation method including a random component, stratified according to centre, age (<45 vs ≥45 years), stage (IIB, IIIA vs IIIB, IV), international prognostic score (0-2 vs 3-7), and sex. eBEACOPP was given as previously described; rituximab was given intravenously at a dose of 375 mg/m 2 (maximum total dose 700 mg). The primary objectives were to show superiority of the experimental treatment in the PET-2-positive cohort, and to show non-inferiority of the experimental treatment in the PET-2-negative cohort in terms of the primary endpoint, progression-free survival. We defined non-inferiority as an absolute difference of 6% in the 5-year progression-free survival estimates. Primary analyses in the PET-2-negative cohort were per protocol; all other analyses were by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT00515554., Findings: Between May 14, 2008, and July 18, 2014, we recruited 2101 patients, of whom 137 were found ineligible before randomisation and a further 19 were found ineligible after randomisation. Among 434 randomised patients (217 per arm) with positive PET-2, 5-year progression-free survival was 89·7% (95% CI 85·4-94·0) with eBEACOPP and 88·1% (83·5-92·7) with R-eBEACOPP (log-rank p=0·46). Patients with negative PET-2 randomly assigned to either 8 × eBEACOPP or 6 × eBEACOPP (n=504) or 4 × eBEACOPP (n=501) had 5-year progression-free survival of 90·8% (95% CI 87·9-93·7) and 92·2% (89·4-95·0), respectively (difference 1·4%, 95% CI -2·7 to 5·4). 4 × eBEACOPP was associated with fewer severe infections (40 [8%] of 498 vs 75 [15%] of 502) and organ toxicities (38 [8%] of 498 vs 91 [18%] of 502) than were 8 × eBEACOPP or 6 × eBEACOPP in PET-2-negative patients. Ten treatment-related deaths occurred: four in the PET-2-positive cohort (one [<1%] in the 8 × eBEACOPP group, three [1%] in the 8 × R-eBEACOPP group) and six in the PET-2-negative group (six [1%] in the 8 × eBEACOPP or 6 × eBEACOPP group)., Interpretation: The favourable outcome of patients treated with eBEACOPP could not be improved by adding rituximab after positive PET-2. PET-2 negativity allows reduction to only four cycles of eBEACOPP without loss of tumour control. PET-2-guided eBEACOPP provides outstanding efficacy for all patients and increases overall survival by reducing treatment-related risks for patients with negative PET-2. We recommend this PET-2-guided treatment strategy for patients with advanced-stage Hodgkin's lymphoma., Funding: Deutsche Krebshilfe, Swiss State Secretariat for Education and Research, and Roche Pharma AG., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Advanced stage Hodgkin's lymphoma represents a heterogeneous group of patients with different risk profiles. Data suggests that interim PET assessment during chemotherapy is superior to baseline international prognostic scoring in terms of predicting long-term treatment outcome in patients with Hodgkin's lymphoma. We therefore hypothesised that early interim PET-imaging after two courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) might be suitable for guiding treatment in patients with advanced stage Hodgkin's lymphoma. We aimed to assess whether intensifying standard chemotherapy (BEACOPP escalated ) by adding rituximab would improve progression-free survival in patients with positive PET after two courses of chemotherapy., Methods: In this open-label, international, randomised, phase 3 study, we recruited patients aged 18-60 years with newly diagnosed, advanced stage Hodgkin's lymphoma from 160 hospitals and 77 private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. Interim PET-imaging was done after two cycles of BEACOPP escalated and centrally assessed by an expert panel. Patients with a positive PET after 2 cycles of BEACOPP escalated chemotherapy (PET-2) were randomly assigned (1:1) to receive six additional courses of either BEACOPP escalated (BEACOPP escalated group) or BEACOPP escalated plus rituximab (R-BEACOPP escalated group). PET-2 was assessed using a 5-point scale with 18 FDG uptake higher than the mediastinal blood pool (corresponding to Deauville scale 3) defined as positive. BEACOPP escalated was given as previously described; rituximab was given intravenously at a dose of 375 mg/m 2 (maximum total dose 700 mg), the first administration starting 24 h before starting the fourth cycle of BEACOPP escalated (day 0 and day 3 in cycle 4, day 1 in cycles 5-8). Randomisation was done centrally and used the minimisation method including a random component, stratified according to centre, age, stage, international prognostic score, and sex. The primary efficacy endpoint was 5 year progression-free survival, analysed in the intention-to-treat population. We are reporting this second planned interim analysis as the final report of the trial. The trial is registered with ClinicalTrials.gov, number NCT00515554., Findings: Between May 14, 2008, and May 31, 2011, we enrolled 1100 patients. 440 patients had a positive PET-2 and were randomly assigned to either the BEACOPP escalated group (n=220) or the R-BEACOPP escalated group (n=220). With a median follow-up of 33 months (IQR 25-42) for progression-free survival, estimated 3 year progression-free survival was 91·4% (95% CI 87·0-95·7) for patients in the BEACOPP escalated group and 93·0% (89·4-96·6) for those in the R-BEACOPP escalated group (difference 1·6%, 95% CI -4·0 to 7·3; log rank p=0·99). Common grade 3-4 adverse events were leucopenia (207 [95%] of 218 patients in the BEACOPP escalated group vs 211 [96%] of 220 patients in the R-BEACOPP escalated group), and severe infections (51 [23%] vs 43 [20%] patients). Based on a futility analysis, the independent data monitoring committee recommended publication of this second planned interim analysis as the final result. Six (3%) of 219 patients in the BEACOPP escalated group and ten (5%) of 220 in the R-BEACOPP escalated group died; fatal treatment-related toxic effects occurred in one (<1%) patient in the BEACOPP escalated group and three (1%) in the R-BEACOPP escalated group, all of them due to infection., Interpretation: The addition of rituximab to BEACOPP escalated did not improve the progression-free survival of PET-2 positive patients with advanced stage Hodgkin's lymphoma. However, progression-free survival for PET-2 positive patients was much better than expected, exceeding even the outcome of PET-2-unselected patients in the previous HD15 trial. Thus, PET-2 cannot identify patients at high-risk for treatment failure in the context of the very effective German Hodgkin Study Group standard treatment for advanced stage Hodgkin's lymphoma., Funding: Deutsche Krebshilfe; Swiss State Secretariat for Education, Research and Innovation (SERI); and Roche Pharma., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: BK-virus and JC-virus are the most common polyomaviridae associated with hemorrhagic cystitis in the allogeneic transplant setting. Hemorrhagic cystitis and symptomatic viruria caused by these viruses are a major cause of morbidity in patients undergoing allogeneic stem cell transplantation., Methods: We performed a retrospective evaluation on a highly uniform study population of 73 patients receiving allogeneic stem cell transplantation. Patients were treated according to the FLAMSA-RIC-protocol, and were examined for the incidence of BK-/JC-viruria and late-onset BK-positive hemorrhagic cystitis within a two-year period., Results: The occurrence of BK-viruria was correlated with published risk factors (acute GvHD, oral mucositis, donor type, conditioning, age, gender). Thirty patients (41 %) were found to excrete either BK-virus (n = 17), JC-virus (n = 3) or both (n = 10), of whom 18 patients (60 %) developed higher-grade hemorrhagic cystitis as opposed to none in the virus-negative control group. Higher grade GvHD (grade B-D) was more common in patients with viruria (p = 0.013) and also more common in patients with manifest hemorrhagic cystitis (p = 0.048). Similarly, oral mucositis was associated both with viruria (p = 0.014) and hemorrhagic cystitis (p = 0.005). Manifest cystitis but not viruria was significantly associated with male gender (p = 0.016). No significant correlation was found with age, conditioning with busulfane vs total body irradiation or related vs unrelated donor., Conclusions: Severe GvHD and oral mucositis are significantly associated with reactivation of polyomaviridae in the genitourinary-tract already at the level of asymptomatic viruria.

Objective: To describe and compare the mortality associated with nosocomial pneumonia due to Pseudomonas aeruginosa (Pa-NP) according to pneumonia classification (community-onset pneumonia [COP], hospital-acquired pneumonia [(HAP], and ventilator-associated pneumonia [VAP])., Design: We conducted a retrospective cohort study of adults with Pa-NP. We compared mortality for Pa-NP among patients with COP, HAP, and VAP and used logistic regression to identify risk factors for hospital mortality and inappropriate initial antibiotic therapy (IIAT)., Setting: Twelve acute care hospitals in 5 countries (United States, 3; France, 2; Germany, 2; Italy, 2; and Spain, 3)., Patients/participants: A total of 742 patients with Pa-NP., Results: Hospital mortality was greater for those with VAP (41.9%) and HAP (40.1%) compared with COP (24.5%) (P<.001). In multivariate analyses, independent predictors of hospital mortality differed by pneumonia classification (COP: need for mechanical ventilation and intensive care; HAP: multidrug-resistant isolate; VAP: IIAT, increasing age, increasing Charlson comorbidity score, bacteremia, and use of vasopressors). Presence of multidrug resistance was identified as an independent predictor of IIAT for patients with COP and HAP, whereas recent antibiotic administration was protective in patients with VAP., Conclusions: Among patients with Pa-NP, pneumonia classification identified patients with different risks for hospital mortality. Specific risk factors for hospital mortality also differed by pneumonia classification and multidrug resistance appeared to be an important risk factor for IIAT. These findings suggest that pneumonia classification for P. aeruginosa identifies patients with different mortality risks and specific risk factors for outcome and IIAT.

Introduction: Pseudomonas aeruginosa nosocomial pneumonia (Pa-NP) is associated with considerable morbidity, prolonged hospitalization, increased costs, and mortality., Methods: We conducted a retrospective cohort study of adult patients with Pa-NP to determine 1) risk factors for multidrug-resistant (MDR) strains and 2) whether MDR increases the risk for hospital death. Twelve hospitals in 5 countries (United States, n = 3; France, n = 2; Germany, n = 2; Italy, n = 2; and Spain, n = 3) participated. We compared characteristics of patients who had MDR strains to those who did not and derived regression models to identify predictors of MDR and hospital mortality., Results: Of 740 patients with Pa-NP, 226 patients (30.5%) were infected with MDR strains. In multivariable analyses, independent predictors of multidrug-resistance included decreasing age (adjusted odds ratio [AOR] 0.91, 95% confidence interval [CI] 0.96-0.98), diabetes mellitus (AOR 1.90, 95% CI 1.21-3.00) and ICU admission (AOR 1.73, 95% CI 1.06-2.81). Multidrug-resistance, heart failure, increasing age, mechanical ventilation, and bacteremia were independently associated with in-hospital mortality in the Cox Proportional Hazards Model analysis., Conclusions: Among patients with Pa-NP the presence of infection with a MDR strain is associated with increased in-hospital mortality. Identification of patients at risk of MDR Pa-NP could facilitate appropriate empiric antibiotic decisions that in turn could lead to improved hospital survival.

Background: Future shortages in platelet supply are expected in Germany due to demographic changes. A rising cancer incidence will lead to an increasing demand for platelet concentrates (PCs) while the number of potential donors will decrease. Pathogen inactivation (PI) aims to inactivate various infectious agents including emerging pathogens to extend the shelf-life of PCs and reduce the frequency of acute transfusion reactions (ATRs). In this context, the clinical and economic impact of PI on platelet transfusion was evaluated., Material and Methods: Model calculations were conducted for 2 scenarios considering different production settings. Frequencies of ATRs were based on literature analyses, platelet and ATR costs on cost analyses., Results: The estimated average costs for ATRs of grade 1 and 2, irrespective of origin, and grade 3 (allergic) were € 104, € 238, and € 1,200, respectively. Approximately 400 PC-related ATRs per 10(5) transfusions can be avoided, with estimated savings amounting to € 77,000. The total cost increase was calculated to approximately € 30-50 per PI-treated PC., Conclusion: PI potentially saves plasma, prolongs shelf-life, decreases donor deferral, and reduces ATRs. Model calculations considering clinical and safety benefits of PI show a rational cost increase. The impact of PI should be further evaluated from a societal perspective regarding future blood supply and infectious disease globalization., (Copyright © 2013 S. Karger AG, Basel.)

Background: German data on economic consequences of immune thrombocytopenia (ITP) are limited., Patients and Methods: A retrospective, observational study based on chart review of adult patients with a confirmed diagnosis of ITP was conducted at a German university hospital. Costs are presented from the hospital perspective., Results: Of 50 eligible patients, 45 could be classified by disease duration: 19 patients < 3 months (38%, newly diagnosed ITP), 12 patients ≥ 3 to < 12 months (24%, persistent ITP), 19 patients ≥ 12 months (38%, chronic ITP). Complications included 85 bleeding events in 43 patients, including 3 intracranial haemorrhages. Documented were 955 outpatient visits in 43 patients (86%) and 92 inpatient hospital admissions in 45 patients (90%). Of the 46 patients (92%) treated, all received corticosteroids, 25 (50%) intravenous immunoglobulin, and 7 (14%) further therapies. 12 patients (24%) underwent splenectomy. Average total direct medical costs (mean (standard deviation)) were 17,091 (18,859) per patient, 12,749 (11,663) in 17 newly diagnosed ITP patients with a 0.88-month (0.65 months) average disease duration, and 29,868 (29,397) in 13 chronic ITP patients with a 33.5-month (16.8 months) average disease duration. Inpatient stays were the main cost drivers., Conclusion: These data concerning current healthcare provision for ITP patients in Germany indicate considerable resource consumption and the need for more effective treatment options in individual patients., (Copyright © 2012 S. Karger AG, Basel.)

Background: Extensive sets of data are required to investigate the potential use of a therapeutic drug monitoring with individualization of dosage of the antimycotic compound caspofungin. The goal was to develop an improved liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for this aim., Methods: Following protein precipitation, on-line solid phase extraction was performed for sample preparation. As the internal standard compound the veterinary drug tylosin was used. A standard validation protocol was applied., Results: Good reproducibility and accuracy of the method were observed. On-line solid phase extraction resulted in a convenient work-flow and good robustness of the method., Conclusions: This improved LC-MS/MS method was found reliable and convenient. It can be suggested for further work on the clinical pharmacology of caspofungin in the setting of clinical research laboratories.

Traditionally, anti-platelet autoantibodies accelerating platelet clearance from the peripheral circulation have been recognized as the primary pathopysiological mechanism in chronic immune thrombocytopenia (ITP). Recently, increasing evidence supports the co-existence of insufficient megakaryopoiesis. Inadequate low thrombopoietin (TPO) levels are associated with insufficient proliferation and differentiation of megakaryocytes, decreased proplatelet formation, and subsequent platelet release. Recently two novel activators of TPO receptors have been made available: romiplostim and eltrombopag. In several phase III studies, both agents demonstrated increase of platelet counts in about 80% of chronic ITP patients within 2 to 3 weeks. These agents substantially broaden the therapeutic options for patients with chronic ITP although long-term results are still pending. This review will provide an update on the current conception of underlying mechanisms in ITP and novel, pathophysiologically based treatment options.

Invasive fungal infections (IFI) are a major cause of morbidity and mortality in patients with haematological malignancies. Antifungal combination therapy is a promising treatment option. However, available data on feasibility, toxicity and efficacy of this therapy are limited. Therefore, this study was conducted to evaluate the feasibility, toxicity and outcome of different antifungal combination therapies. Patients with haematological malignancies receiving antifungal combination therapy for IFI were retrospectively analysed. Toxicity and response were documented at the end of therapy. Survival was evaluated at the end of therapy and after 12 weeks. Fifty-six patients were treated with different antifungal combinations in the period between 2001 and 2007. The majority of patients (63%) received a combination of liposomal amphotericin B and caspofungin as antifungal combination treatment. Toxicity of all applied combinations was tolerable. At the end of combination therapy, favourable response was 65%, whereas unfavourable outcome occurred in 35% of the cases. Mortality at the end of treatment was 11% and 34% 3 months after initiation of combination therapy. Antifungal combination therapy is feasible and efficient in haematological cancer patients and allogeneic stem cell transplant recipients with IFI. Prospective studies to evaluate the optimal combinations are needed.