Epidemiology, patient adherence, and costs of oral mucositis in routine care in stem cell transplantation.

PURPOSE: Limited data about oral mucositis (OM) in stem cell transplant patients with underlying hematological disease is available in Germany. The purpose of this feasibility study was to determine the incidence, treatment patterns, patients' adherence, and costs of OM. METHODS: Prospective, noninterventional single-center observational study. INCLUSION CRITERIA: allogenic/autologous stem cell transplant patients ≥ 18 years, high-dose chemotherapy. OM assessment: WHO Oral Toxicity Scale. Adherence was measured in patient interviews. Preventive and therapeutic measures were extracted from patients' charts. RESULTS: Forty-five patients (25 allogenic, 20 autologous) were enrolled. Twenty-six (58%) patients developed OM (54% grade I/II, 46% grade III/IV). Age ≥ 65 (31% vs 69%, p = 0.021) was associated with a lower OM incidence. A positive history of smoking (1.77 vs 2.69, p = 0.036) was associated with a lower OM grade, patients with unrelated donors (2.63 vs 1.29, p = 0.014) were associated with higher OM grades and females (80% vs 47%, RR = 1.71, p = 0.035) with a higher incidence. OM patients were less adherent to recommended daily mouth rinses (35% vs 68%, p = 0.027). More analgesic treatment (80% vs 32%, p = 0.001) and intravenous opioids (24% vs 0%, p = 0.023) were prescribed in OM patients. Total drug treatment and nutrition costs were 824€ (p = 0.037) higher in autologous transplanted patients. CONCLUSION: Initial risk and consecutive OM assessment, determination of patients' adherence, resource consumption, and costs are prerequisites to evaluate OM care. In the best case, several centers will follow the same methodological approach and the collected data will serve as a basis for benchmarking analyses to optimize OM care where required.

Plerixafor in non-Hodgkin's lymphoma patients: a German analysis of time, effort and costs.

Mobilization and collection of peripheral blood stem cells is part of the standard treatment procedure for non-Hodgkin's lymphoma patients eligible for high-dose chemotherapy with autologous stem cell transplantation. Mobilization is usually achieved with chemotherapy and/or cytokines, but plerixafor might be added in case of poor mobilization. Due to the high cost several institutions have developed their own management pathway to optimize use of plerixafor. Such models are however rarely generalizable; in a multi-center, European, non-interventional study, evaluating the impact of plerixafor in poor mobilizers, country specific differences in patient treatment and cost structure were obvious. For German centers, there was a non-significant reduction in the number of apheresis sessions carried out and in apheresis costs. In contrast to other European countries the majority of German Plerixafor patients were very poor mobilizing patients with initial CD34+ cell count ≤ 10/µl (40/51). In this group the number of apheresis sessions decreased from 2.1 to 1.6 sessions per patient (p = 0.01) and costs decreased from €6246 to €4758 (p = 0.01). Our results show that preemptive plerixafor use has a strong effect in poor mobilizers with an initial CD34+ cell count ≤ 10 cells/µl.

Diagnosis and empirical treatment of fever of unknown origin (FUO) in adult neutropenic patients: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO).

Fever may be the only clinical symptom at the onset of infection in neutropenic cancer patients undergoing myelosuppressive chemotherapy. A prompt and evidence-based diagnostic and therapeutic approach is mandatory. A systematic search of current literature was conducted, including only full papers and excluding allogeneic hematopoietic stem cell transplant recipients. Recommendations for diagnosis and therapy were developed by an expert panel and approved after plenary discussion by the AGIHO. Randomized clinical trials were mainly available for therapeutic decisions, and new diagnostic procedures have been introduced into clinical practice in the past decade. Stratification into a high-risk versus low-risk patient population is recommended. In high-risk patients, initial empirical antimicrobial therapy should be active against pathogens most commonly involved in microbiologically documented and most threatening infections, including Pseudomonas aeruginosa, but excluding coagulase-negative staphylococci. In patients whose expected duration of neutropenia is more than 7 days and who do not respond to first-line antibacterial treatment, specifically in the absence of mold-active antifungal prophylaxis, further therapy should be directed also against fungi, in particular Aspergillus species. With regard to antimicrobial stewardship, treatment duration after defervescence in persistently neutropenic patients must be critically reconsidered and the choice of anti-infective agents adjusted to local epidemiology. This guideline updates recommendations for diagnosis and empirical therapy of fever of unknown origin in adult neutropenic cancer patients in light of the challenges of antimicrobial stewardship.

Applicability of the EORTC/MSG criteria for IFD in clinical practice.

Invasive fungal disease (IFD) is a feared complication in patients with hematological malignancies. In 2008, the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycosis Study Group (EORTC/MSG) published updated criteria for the diagnostic workup within clinical studies for immunosuppressed patients with suspected fungal infection. We applied these criteria in a routine clinical setting with regard to their feasibility for bedside practice at our institution in a 1-year period. One hundred seventy consecutive patients with a recent history of chemotherapy-induced neutropenia (n = 100) or allogeneic stem cell recipients (n = 70) who had received a CT scan of the chest in search of pulmonary IFD were examined. We analyzed all available radiological and microbiological data according to the EORTC/MSG criteria. The quality of images was good in 94.7%, microbiological diagnostics performed in 94.1% patients. Five patients had histopathologic-proven IFD, 18 patients were classified as "probable," 55 patients as "possible" IFD, and 92 patients did not fulfill any criteria ("no IFD"). Microbiology revealed suggestive findings in 29 patients. These were either galactomannan antigen (Gm-AG) in serum (n = 18) and/or broncho-alveolar lavage (BAL) (n = 5). CT scan showed pulmonary infiltrates in 106 patients; 78 were classified as typical for IPA, further discriminated by morphology and number of nodules, as well as additional signs (halo, air crescent, cavity). We observed a better overall survival in patients without infiltrates compared to those with any type of infiltrate (p = 0.042) and a trend toward favorable survival in patients who had micronodular lesions (p = 0.058). We also found a higher probability of Gm-AG positivity in the group of allogeneic stem cell transplantation (allo-SCT) patients (p = 0.001) and a trend toward an association of Gm-AG positivity and positive findings on CT (p = 0.054). The applicability of criteria was good, both with regard to radiological and mycological evidence and sufficient for the categorization of IFD according to EORTC/MSG in the clinical setting. However, our findings suggest that feasibility improves with stringency of mycological workup, which is reflected in the two subgroups. Radiology harvests by far more suggestive findings which can only partly be correlated with mycological evidence. Although feasible, whether the EORTC/MSG criteria are the appropriate tool for early identification of IFD remains open for discussion.

[The tumor patient with an indication for intensive anticoagulation]. / Der Tumorpatient mit gleichzeitiger Indikation zur intensiven Antikoagulation.

Patients with cancer are at high risk to develop venous thromboembolism as well as arterial thrombosis. Well established treatment patterns of these vascular complications are often hampered in cancer patients by disturbances of coagulation or thrombocytopenia. Therefore standardized interventions or medical treatment can be difficult to perform. As data from clinical trials or recommendations from guidelines are sparse, complicated cases have to be dealt with an interdisciplinary single patient approach. Thus in patients with STEMI application of a drug eluting stent which might be the best treatment in a non-cancer patient may not be feasible. In cancer patients with venous thromboembolism and bleeding the implantation of a vena cava filter might be necessary.

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 aspergillosis. On average, the hospital stay for IFD patients was 12 days longer than in control patients. All patients in the IFD group and 89% of patients in the control group received antifungal drugs. Mean direct costs per patient were €51,517 in the IFD group and €30,454 in the control group. Incremental costs of €21,063 were dominated by cost for antifungal drugs (36%), hospital stay (32%) and blood products (23%). From the perspective of hospitals in Germany the economic burden of IFD in patients with AML or MDS is substantial. Therefore, prevention of IFD is necessary with respect to both clinical and economic reasons.

Current issues in the clinical management of invasive aspergillosis--the AGIHO, DMykG, ÖGMM and PEG web-based survey and expert consensus conference 2009.

The objectives of this study were to identify unsolved issues in the management of invasive aspergillosis, identify controversies and achieve consensus. The German Speaking Mycological Society (Deutschsprachige Mykologische Gesellschaft, DMykG) invited other German infectious diseases (ID) and mycological societies to submit unsolved issues concerning the diagnosis and treatment of invasive aspergillosis. Based on these contributions, a digital web-based questionnaire of 12 questions on Aspergillus spp. was designed to be completed by experts of the participating societies. Controversial results were identified by a mathematical model and were discussed at a consensus conference during the 43rd Annual Meeting of the DMykG in Cologne, Germany. Forty-two individuals completed the questionnaire. Analysis showed a strong consensus on effective preventive measures, choice of antifungal agents for pre-emptive, empiric and targeted treatment, as well as the evaluation of early chest CT control scans as a measure of treatment response assessment. Opinions on the indication for a pulmonary biopsy of a halo sign in high-risk neutropenic patients and on the role of Aspergillus spp. PCR as well as galactomannan from serum in the assessment of treatment duration diverged in spite of discussion such that a consensus could not be reached. Using a recently published two-step approach - web-based survey plus classical panel discussion - expert consensus was achieved on 10 of 12 questions concerning the diagnosis and treatment of invasive aspergillosis.

Management of sepsis in neutropenic patients: guidelines from the infectious diseases working party of the German Society of Hematology and Oncology.

Sepsis is a leading cause of mortality in neutropenic cancer patients. Early initiation of effective causative therapy as well as intensive adjunctive therapy is mandatory to improve outcome. We give recommendations for the management of adults with neutropenia and sepsis. The guidelines are written for clinicians involved in care of cancer patients and focus on pathophysiology, diagnosis and treatment of sepsis during neutropenia.

[Fever of unknown origin in malignancies]. / Fieber unklarer Genese bei malignen Erkrankungen.

Fever is a common symptom in patients with malignancies. On the one hand it may be an (initial) symptom of cancer, on the other hand it may occur as a side effect of chemotherapy. Often a precise cause of fever can not be established and in these cases febrile temperatures >38.3 degrees C without proof of infection or relapse/progress of tumor is defined as fever of unknown origin. Especially hematologic neoplasias are accompanied by fever. Here, neoplastic fever must be distinguished from fever following immunosuppressive chemotherapy. In the latter severe infections due to neutropenia induced by cytoreductive chemotherapy is often identified as the cause of fever. These patients display a high morbidity and mortality, especially if an empiric anti-infectious treatment is not administered in time. A meticulous diagnostic work-up is therefore necessary, and until proven otherwise, an infectious cause must be considered and empiric antibiotic treatment initiated.

Infectious complications after allogeneic stem cell transplantation: incidence in matched-related and matched-unrelated transplant settings.

BACKGROUND: Bacterial, viral, and fungal pathogens frequently cause severe, life-threatening infections in immunocompromised patients after allogeneic hematopoietic stem cell transplantation (SCT). OBJECTIVE: To compare the frequency of infections in patients with matched-related (Group A) or with human leukocyte antigen (HLA)-matched-unrelated donors (Group B). PATIENTS AND METHODS: Patients treated at our transplantation unit between April 2004 and April 2005 were enrolled into this analysis. Documentation comprised demographic data, conditioning treatment, stem cell source, clinical course, as well as microbiological and clinical data and mortality. RESULTS: We analyzed 59 patients, 22 in Group A and 37 in Group B. Both groups were well balanced regarding demographic data. Diagnoses were acute myeloid leukemia (30 of 59 patients, 50.8%), multiple myeloma (15.2%), acute lymphoblastic leukemia (11.9%), and chronic myeloid leukemia (10.2%). Patients in Group A developed infections in 95.5% of the cases compared with 97.3% in patients in Group B. Most frequently detected pathogens were Staphylococcus species, human herpesvirus-6, and Epstein-Barr virus. Three proven fungal infections were detected in Group A compared with 9 proven fungal infections in Group B. Lung infiltrations were observed in equivalent incidence in both groups. Two years after transplantation, 55.9% of patients were alive (Group A: 68.2%; Group B: 48.6%, not significant). CONCLUSION: Allogeneic SCT from HLA-matched-unrelated donors does not have a higher infection risk than patients transplanted from matched-related donors.

Plesiomonas shigelloides pneumonia.

Plesiomonas shigelloides is known to cause mild to cholera-like diarrhea in most infected persons. In immunocompromised patients extra-intestinal manifestations have been described. We report the first case of pneumonia caused by P. shigelloides in a 76-year-old woman who had undergone a curative gastrectomy and esophageal-jejunostomy due to a low differentiated adenocarcinoma of the stomach (pT2, pN1 pMx, G3, R0, Lauren: intestinal type). The patient was admitted in hospital with clinical signs of pulmonary infection. CT-scan revealed a cavernous lesion in the right upper pulmonary lobe. Bronchial lavage showed a granulocytic inflammation 105CFU/ml P. shigelloides. Although antibiotic treatment led to a decrease of inflammation parameters and decrease of the pulmonary infiltrate the patient died due to development of torsades de pointes tachycardia leading to ventricular fibrillation and hypoxic brain damage.

AraU accumulation in patients with renal insufficiency as a potential mechanism for cytarabine neurotoxicity.

Neurotoxicity of cytarabine (AraC) is believed to be related to renal insufficiency. We examined the plasma pharmacokinetics of AraC and its deamination product uracil arabinoside (AraU) in four patients with AML and concomitant severe renal insufficiency after treatment with AraC. Additionally, in one of these patients the concentration of intracellular AraCTP, the active metabolite of AraC, was analysed. Patients 2 and 3 were treated with AraC 1.0 g/m(2) infused for 3 h at 12-h intervals on days 1-4. Patient 1 received the same schedule of AraC with 0.5 g/m(2) and patient 4 with 0.25 g/m(2) AraC. Plasma concentrations of AraC, AraU and the intracellular concentration of AraCTP were analysed at different time points using HPLC. AraC pharmacokinetics in patients with severe renal insufficiency was comparable to patients with normal renal function. Peak plasma levels as well as intracellular AraCTP kinetics were also not significantly influenced by renal dysfunction. As expected from the high dose AraC pharmacokinetic parameters, the AraU serum levels accumulated during treatment. Under the conditions of renal impairment, AraU half-life was about 75 h and the AUC was about 12-fold higher than for patients with normal renal function. AraU could be the pathophysiologic cause for the known correlation between the incidence of neurotoxicity and renal insufficiency in high-dose AraC. To avoid AraU accumulation, intermittent hemodialysis during high-dose AraC treatment could be a suitable method considering the low protein-binding and low distribution volume of AraU.

Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial.

BACKGROUND: Prothrombin complex concentrate (PCC) can substantially shorten the time needed to reverse antivitamin K oral anticoagulant therapy (OAT). OBJECTIVES. To determine the effectiveness and safety of emergency OAT reversal by a balanced pasteurized nanofiltered PCC (Beriplex P/N) containing coagulation factors II, VII, IX, and X, and anticoagulant proteins C and S. PATIENTS AND METHODS: Patients receiving OAT were eligible for this prospective multinational study if their International Normalized Ratio (INR) exceeded 2 and they required either an emergency surgical or urgent invasive diagnostic intervention or INR normalization due to acute bleeding. Stratified 25, 35, or 50 IU kg(-1) PCC doses were infused based on initial INR. Study endpoints included INR normalization (

Pulmonary MRI--a new approach for the evaluation of febrile neutropenic patients with malignancies.

GOALS OF WORK: Immunocompromised patients with malignant diseases often suffer from pulmonary infections. Early detection of these life-threatening infections is crucial to start effective treatment. The gold standard for the diagnosis of these disorders is high-resolution computed tomography (HR-CT) of the chest. This method, however, has limitations, for instance, in the discrimination of early interstitial infiltrates and the use of X-rays. We conducted a study to determine the feasibility and sensitivity of magnetic resonance imaging (MRI) of the lung compared to HR-CT in immunocompromised patients with persistent fever in neutropenia and suspected pneumonia. MATERIALS AND METHODS: Between January 2003 and July 2004, 50 consecutive neutropenic patients with fever of unknown origin and negative chest X-ray were examined with HR-CT of the lungs. Patients with pulmonary infiltrates were further examined with MRI of the chest within 24 h after HR-CT using a specific lung protocol. In addition, microbiological testing was performed for the characterization of the causative pathogen. RESULTS: Of 50 patients, 35 had pulmonary infiltration according to HR-CT; these were examined with MRI of the lungs. MRI showed a high correlation (91%) with the findings in HR-CT. Both HR-CT and MRI were feasible in 94% of the examined patients. In 12 of 35 patients, fungal pathogens were identified in microbiological testing. CONCLUSIONS: MRI of the lungs is feasible in neutropenic patients with suspected pulmonary infection. Compared to HR-CT, MRI displays a high sensitivity in the detection of pulmonary infiltrates. MRI offers the opportunity of follow-up examinations without repeated X-ray exposure to the patient.

[Liposomal amphotericin B in the treatment of severe fungal infections. Results of a clinical cohort trial]. / Liposomales Amphotericin B bei schweren systemischen Mykosen. Ergebnisse einer klinischen Kohorten-Studie.

BACKGROUND: Activity and efficacy of liposomal amphotericin B have been established for the treatment of severe fungal infections. Nephrotoxic side effects, especially during prolonged administration, are regarded as a major disadvantage. In this study we examined the response rates and side effects, particularly nephrotoxicity, of treatment with liposomal amphotericin B in a large cohort of patients. PATIENTS AND METHODS: 406 patients treated with liposomal amphotericin B between January 1999 and August 2003 in participating German hospitals were included. Documentation included demographic and clinical data, reason for the treatment with liposomal amphotericin B, length of treatment, response to antifungal treatment and side effects. RESULTS: 42.4% of the 406 patients were females. Their ages ranged from 1 day to 77 years. 83 % of the patients had malignancies and 65.5 % had fever of unknown origin (FUO). Mean duration of treatment with liposomal amphotericin B was 20 +/- 20 days, at an average dose of 2.3 mg/kg/d. 209 patients (51.5 %) showed complete response (CR),105 patients (25.9 %) partial response (PR) and 51 (12.6 %) patients died during the observation. 80.0 % of patients with FUO showed complete or partial response of symptoms. Mean serum creatinine increased from 0.9 mg/kg before start of therapy with liposomal amphotericin B to 1.1 mg/kg during treatment. Side effects (common toxicity criteria > grade 1) occurred in 94 patients (23/2 %). Among these hypokalemia (6.2 %) and liver damage (5,2 %) were the most common. Nephrotoxicity was documented in 17 patients (4.2 %). CONCLUSION: Liposomal amphotericin B is a safe and efficacious antifungal drug in the treatment of severe invasive fungal infections and fever of unknown origin. Nephrotoxicity is usually not a limiting factor when using liposomal amphotericin B, if it is administered in approved dosage.

Breakthrough infection of Trichosporon asahii during posaconazole treatment in a patient with acute myeloid leukaemia.

A neutropenic patient with acute myeloid leukaemia experienced a breakthrough infection of Trichosporon asahii during posaconazole treatment. After treatment was changed to a combination therapy with voriconazole and liposomal amphotericin B, the infection resolved. Posaconazole works effectively as an antifungal prophylaxis and salvage therapy in rare invasive fungal infections. This case however illustrates that breakthrough infections with T. asahii may occur during posaconazole treatment.

A prospective, randomized multicenter trial of the empirical addition of antifungal therapy for febrile neutropenic cancer patients: results of the Paul Ehrlich Society for Chemotherapy (PEG) Multicenter Trial II.

BACKGROUND: The aim of the study was to compare the efficacy of empirical antifungals in combination with broad spectrum antibiotics with that of antibiotics alone in high risk febrile neutropenic cancer patients not responding to initial antibacterial therapy. PATIENTS AND METHODS: A prospective, randomized controlled trial was conducted at 22 cancer centers in Germany. Patients with fever of unknown origin were randomized to either piperacillin (Pip) plus an aminoglycoside (AMG) (arm A) or a third generation cephalosporin (Ceph) plus AMG (arm B). Patients not responding after 4-6 days were randomized to either imipenem (Imi) plus glycopeptide (GLP) (arm C), or Imi/GLP plus amphotericin B deoxycholate (AmB) plus 5-flucytosine (5-FC) (arm D), or Imi/GLP plus fluconazole (Fluco) (arm E). A successful outcome was defined as resolution of fever. RESULTS: In arm A, 192 of 373 patients (51.5%) responded as compared to 176 of 344 patients (51.2%) in arm B. The response rates of 155 patients randomized for further empirical treatment were 55.6%, 77.8% and 62.5% in arm C, D and E, respectively. The difference between arm C and D was of borderline statistical significance (p = 0.06) after correction for multiple testing. CONCLUSION: In neutropenic cancer patients with persistent fever the combination of antibiotics with AmB/5-FC is superior to salvage antibacterial therapy alone. There is no difference in efficacy between Pip and third generation Ceph given as initial empirical therapy in combination with an AMG.