Neutropenia Fever Research Articles

Induction Therapy with Idarubicin and Etoposide Combined with Sequential or Concurrent Azacitidine In Patients with High-Risk Acute Myeloid Leukemia: Pilot-Phase of the AMLSG 12-09 Study

AbstractAbstract 2184 Background:Treatment outcome in patients with cytogenetically and/or molecularly defined high-risk acute myeloid leukemia (AML) is dismal with low complete remission (CR) rates after intensive induction therapy and 5-year overall survival of about 25% in patients 60 years and younger and far below 5% in patients above the age of 60 years. In younger patients, allogeneic hematopoietic stem cell transplantation (allo-HSCT) from matched related or unrelated donors results in significantly better clinical outcome especially if patients are transplanted early in first CR (Schlenk et al., J. Clin. Oncol. 2010, in press). Azacitidine is a demethylating agent showing promising results as a single agent in AML patients with bone marrow blast counts between 20 and 30%. Therefore, the randomized AMLSG 12-09 trial will evaluate the combination of idarubicin/etoposide chemotherapy combined with azacitidine instead of cytarabine as compared to induction with idarubicin/etoposide/cytarabine (ICE) in an attempt to increase CR rates in these high-risk patients. Aim:To evaluate feasibility of the investigational induction therapy with idarubicin and etoposide in combination with sequentially or concurrently administered subcutaneous (sc) azacitidine. Methods:Patients were treated according to the investigational treatment schedules of the AMLSG 12-09 protocol. Patients received idarubicin 12 mg/sqm on days 1, 3 and 5 and etoposide 100 mg/sqm on days 1, 2 and 3 (patients above the age of 65 years received idarubicin 12 mg/sqm and etoposide 100 mg/sqm only on days 1 and 3, respectively). Azacitidine 100 mg/sqm sc was added on days -5 to -1 in 7 patients (schedule A), days 1 to 5 in 6 patients (schedule B), and days 4 to 8 in 5 patients (schedule C). Results:18 patients have been treated (13 males and 5 females). Median age was 62.5 years (range, 28–76). The cytogenetic and molecular risk profile of the 18 AML was as follows: Eight AML had MDS-related cytogenetic changes (WHO 2008) including five exhibiting a complex karyotype and two had 3q abnormalities; three AML had balanced t(v;11q23), and six exhibited a normal karyotype together with triple negative genotype (NPM1-wt, FLT3-wt and CEBPA-wt). In one case, there were no metaphases available, however molecularly NPM1-wt, FLT3-wt, CEBPA-wt, no core binding factor AML, no t(15;17) and or t(9;11) were present. Median WBC was 4.6/nl (range, 0–6-75/nl).Overall response to induction therapy was CR n=7, partial remission (PR) n=3, refractory disease (RD) n=7 and one patient died during induction therapy (ED). Moreover, two patients with RD achieved CR after additional cycles of single agent azacitidine treatment. Overall response rates (CR and PR) according to treatment schedule were 43% (3/7), 67% (4/6) and 80% (4/5) for schedules A, B and C, respectively. Most common azacitidine-related toxicity was local reactions at injection site not exceeding CTC-grade 2. As expected, fever in neutropenia was the most common severe toxicity (83%). In addition, one patient with history of epilepsy had seizures during induction therapy and one patient with history of Crohn's disease had mucositis CTC-grade 3. Allo-HSCT has been performed in three patients and is planned in five. After a median time of 7.5 months, 16 of 18 patients are alive. Conclusion:Azacitidine administered sc can be given safely either sequentially or concurrently in combination with idarubicine/etoposide induction chemotherapy. Response rate of this high-risk population appears promising and the toxicity profile was favorable. The question which schedule is the most effective will be addressed in the randomized AMLSG trial (NCT01180322) Disclosures:Stilgenbauer: Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding. Döhner: Pfizer: Research Funding. Schlenk: Celgene, Pfizer, Novartis, Cephalon, Amgen: Research Funding.

Open-Label, Multi-Center Phase I Dose Escalation Study with Lenalidomide In Patients with Acute Myeloid Leukemia

AbstractAbstract 3297 Background:Lenalidomide is an immunomodulatory drug, which has antiangiogenic and antineoplastic properties. There have been some case reports and small phase I/II trials showing clinical efficacy of lenalidomide in AML. However, dosage and duration of lenalidomide treatment in patients with AML are unclear. Aim:To define dose-limiting toxicities (DLT) and the maximally tolerated dose (MTD) for single agent treatment with lenalidomide in AML patients. Methods:A phase-I trial was initiated in March 2009 for younger patients in second or higher relapse, patients above the age of 60 years with refractory or relapsed AML, and patients not eligible for intensive chemotherapy. The trial followed a modified (3+3) Fibonacci design. The starting dose of lenalidomide was 25mg per day for a maximum of 56 days in an induction-type dosing schedule. Additional cycles of 28 days duration were possible for responding patients. DLT was defined as hematological (grade ≥4) or non-hematological (grade ≥3) toxicity or a shift of CTC graded toxicity by 2 grades from baseline in the first cycle attributable to study drug. Results:11 patients have so far been enrolled (7 males and 4 females). Median age was 72 years (range 36–83). 4 patients had previously untreated AML, 7 patients suffered from relapsed or refractory disease. Type of AML was de novo in 3, secondary AML after a preceding MDS in 6, and therapy-related AML in 2 patients. Initial median blast counts in bone marrow were 64% (range 40–75%) and 36,5% in the peripheral blood (range 0–65,4%); 5 patients showed a complex karyotype (including del(5q) in 4 of them), 2 had a single monosomy 7, one patient had a t(1;3) and a monosomy 7, 3 revealed a normal karyotype.In the first dose level of 25mg/day, 4 patients were treated and 3 were evaluable for DLT. One patient dropped out due to rapidly progressive disease. No DLT was observed in these patients. Therefore, dose was escalated to 50mg and 7 patients were treated in this dose level, 3 were evaluable for DLT assessment. DLT occurred in two patients, both developed CTC-grade 3 sensory polyneuropathy at day 15 and day 20, respectively. According to the design of the study, dose level was decreased back to 25mg/day for the next cohort.Toxicities not classifying as DLT were fever in neutropenia (n=6), anemia (n=6), dyspnea (n=4).Seven patients were evaluable for response on day 22. The other 4 patients dropped out due to rapidly progressive AML or severe concomitant disease. Five of the evaluable patients had refractory or relapsed disease, two had de novo AML.In one patient a short partial remission of 34 days and in 4 patients a short-lasting stable disease was observed (8-36 days of stable disease). However, all patients eventually experienced progressive disease. All but one of the 11 patients have died between 16 and 144 days after entry into the study. Conclusion:Sensory polyneuropathy is the dose limiting toxicity in induction type dosing of lenalidomide in AML. In this phase I study using an induction-type dosage regimen, limited clinical activity was seen. Disclosures:Fiedler:Pfizer: Consultancy, Research Funding.

M-ficolin in children with cancer

Objectives M-ficolin (ficolin-1) is a complement-activating pattern-recognition molecule structurally related to mannan-binding lectin. It is produced by monocytes and neutrophils, and is found in serum. Its biological role is largely unknown. We assessed M-ficolin concentration in serum from pediatric cancer patients. The aim of this study was to explore association of M-ficolin with clinical and hematological parameters, and to investigate whether the risk of chemotherapy-related infections was related to M-ficolin concentrations in serum. Methods M-ficolin was measured by time-resolved immunofluorometric assay in serum taken at cancer diagnosis and was correlated with peripheral blood counts and bone marrow examinations performed at the same time. Results Median M-ficolin concentration in 94 children with cancer was 1.6 μg/mL (interquartile range, 0.57–2.7; range, 0.055–25.8), and was not different from age-matched controls (median, 1.7 μg/mL; p = 0.92). M-ficolin was strongly associated with absolute counts of neutrophils (Spearman's rho, 0.45; 95%-CI, 0.26–0.65; p < 0.001), monocytes (0.34; 0.12–0.55; p < 0.001), and thus phagocytes (0.42; 0.20–0.63; p < 0.001) in peripheral blood. Similarly, M-ficolin correlated strongly with neutrophils (0.36; 0.14–0.59; p = 0.002) and phagocytes (0.31; 0.08–0.54; p = 0.009) in bone marrow. Low serum M-ficolin (≤0.5 μg/mL) was not associated with an increased incidence of fever in neutropenia during chemotherapy (multivariate Poisson rate ratio, 1.04; 95%-CI, 0.68–1.60; p = 0.85). Conclusions The concentration of M-ficolin in serum from children with cancer was strongly associated with neutrophil and monocyte counts in blood and bone marrow. These results suggest that M-ficolin concentrations in serum reflect the pool of phagocytes.

A phase I dose escalation study of TTI-237 in patients with advanced malignant solid tumors

This study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of TTI-237, a novel anti-tubulin drug, administered weekly in patients with refractory solid tumors. Using an accelerated dose escalation design, patients with refractory solid tumors were enrolled in this study and treated with TTI-237 intravenously on days 1, 8 and 15 of a 28-day cycle. The starting dose was 4.5 mg/m(2). Pharmacokinetic studies were performed in patients at all dose levels. Twenty-eight patients were enrolled and treated with TTI-237 at dose of 4.5, 9, 15, 22.5 and 31.5 mg/m(2). One dose-limiting toxicity neutropenia fever was observed at 31.5 mg/m(2), and all seven patients developed grade 3 or 4 neutropenia at that dose level. TTI-237 dosage was de-escalated to 22.5 and 18 mg/m(2). Six patients were treated at the 18 mg/m(2) dose level without dose-limiting toxicity prior to trial termination. The mean terminal-phase elimination half-life (t(1/2)) for TTI-237 was 25-29 h, and the mean area under the concentration time curve at 31.5 mg/m(2) was 2,768 ng•h/mL. A protocol defined maximum tolerated dose was not determined because of early termination of the TTI-237 trial by the sponsor. 18 mg/m(2) may be a tolerable dose of TTI-237.

C-Reactive Protein and Soluble IL-2Receptor Correlate with High Risk of Clinical Sepsis Among Children with Fever and Neutropenia.

Abstract 1406Poster Board I-428 Introduction:Patients receiving chemotherapy for malignancies are at increased risk for fever-neutropenia (F-N), which may lead to sepsis. A strategy to identify and differentiate “high-risk” patients at presentation would be of critical significance so that these patients may receive timely aggressive intervention. Conversely, early identification of “low-risk” patients allows for development of appropriate risk-stratified management. We hypothesize that certain acute phase reactants at the time of F-N presentation could be used to predict clinical outcome. Methods:Children (age 1-21 years) receiving chemotherapy for various malignancies were enrolled in this prospective study. Blood samples from F-N episodes were collected at presentation and thereafter on three consecutive days. These samples were tested for high-sensitivity C-reactive protein (hs-CRP), Soluble IL-2 receptor (s-IL2R), interleukins (IL)-1,3,6,8,10 and Tumor Necrosis Factor-alpha (TNF-a). Samples were analyzed by Luminex technology (Miliplex Cytokine Kit). Clinical outcome data were collected and correlated with the respective bio-markers at presentation. “High-risk” patients were defined as those with any one of the following criteria: prolonged hospitalization (>7 days), admission to pediatric intensive care unit, or a positive bacterial blood culture. “Low- risk” patients had none of the above criteria. Data were analyzed using SAS 9.2 software. Cluster analysis was performed on all variables using the Pearson correlation coefficient. Multivariate logistic regression analysis was performed to develop a risk based predictive model, which was validated using a Receiver Operating Characteristic (ROC) curve. Results:An interim analysis was performed on the acute phase reactant dataset that included 29 children (males 56%, females 44%) representing 51 F-N event. Univariate analysis showed that 56% of events met “high-risk” criteria while 44% of events were “low-risk”. At presentation, significant differences were observed for median values for hs-CRP, s-IL2R, IL-6, and IL-8 between the “high-risk” and the “low-risk” groups (Table 1).Cluster analysis showed a strong correlation between IL-6, IL-8, IL-10 and TNF-a. Within this cluster, IL-6 was selected as critical biomarker, since it explained most of the variability within the cluster. IL-6 was subsequently analyzed with other significant variables (hs-CRP and s-IL2R) in multivariate logistic regression. Logistic regression analysis showed that at F-N presentation, hs-CRP (p=0.02) and s-IL2R (p=0.06) were the most significant bio-markers that correlated with “high-risk” clinical course (Figure-1). Calculated “half-sample” Odds Ratio (OR) for hs-CRP was 6.87 (CI 1.35-34.96, p=0.02) and for s-IL2R was 4.94 (CI 0.94-26.01, p=0.06). After controlling for other variables in study, the analysis found that at F-N presentation, an increase in hs-CRP levels from 42 mg/L to 196 mg/L was associated with 7-fold increased likelihood of subsequent “high-risk” clinical course. Similarly, a rise in s-IL-2R from 262 pg/ml to 692 pg/ml increased the likelihood of “high-risk” by almost 5-fold. However, a rise in IL-6 from 39 pg/ml to 878 pg/ml at presentation was not statistically significant and did not predict an increased risk for complicated F-N course (OR 1.16, CI 0.72-1.88, p=0.54). This risk stratified predictive model was validated using Receiver Operating Characteristic (ROC) curve analysis (Area-Under-Curve AUC=0.84) Figure-2. Conclusion:High-sensitivity CRP and sIL-2R at presentation may represent biomarkers of “high-risk” for clinical sepsis and complicated course among children with fever neutropenia. These biomarkers should be further tested as screening tools for risk-stratification and as response variables to assess the effectiveness of interventions in children with fever neutropenia.Table 1Bio-marker distribution at F-N presentation.Bio-MarkerHigh Risk MedianLow Risk MedianCRP mg/L17542IL-1 alpha pg/ml55sIL-2R pg/ml614262IL-3 pg/ml39IL-6 pg/ml27837IL-8 pg/ml21631IL-10 pg/ml3916TNF-alpha pg/ml85 [Display omitted] [Display omitted] Disclosures:Mian: Arkansas Children's Hospital Research Institute (ACHRI), Little Rock, Arkansas. : Research Funding.

Bortezomib (Velcade™) Observational Study in China: Efficacy and Safety of Bortezomib-Based Regimen in 395 Relapsed or Refractory Multiple Myeloma Patients

Introduction: Multiple myeloma (MM) is a plasma-cell malignancy and overall survival for patients who have relapsed after initial therapy is approximately 2 years. Bortezomib (VELCADE TM) is a first-in-class proteasome inhibitor that has demonstrated significant anti-tumor activity in MM patients. Here we report the results of an observational study of the efficacy and safety of bortezomib-based regimens in Chinese relapsed/refractory MM patients.Methods: This was a multi-center, open-label, phase IV observational study designed to enroll 550 patients with relapsed or refractory MM. From Mar 2006 to May 2008, 500 patients with relapsed or refractory MM were enrolled from 43 medical centers in China and 395 of them were evaluated. Bortezomib (0.7 to 1.6 mg/m2 i.v.) was given on days 1, 4, 8, and 11 in in a 21-day cycle, up to a maximum of 8 cycles, combined with other agents, mainly with the addition of dexamethasone (60.1%). Major endpoint included response rate, safety and time to response. Responses of 62% patients were determined by European Group for Blood and Marrow Transplantation criteria (EBMT). Bortezomib withheld if patients developed neutropenia fever, grade 4 haematologic adverse events (AEs), or grade 3 non-haematologic AEs, and re-administered at 75% of the initial dosage after recovery.Results: In 395 evaluable cases, the median age was 59 years (range 35–82) and the male/female ratio was 1.5:1. 90% of patients were in late stage(stage II/III) and 50% of them were IgG subtype. Patients had received various prior therapies before bortezomib treatment, including VAD (31.3%), VBMCP (M2, 15.1%) and thalidomide-based regimens(14.9%), with best response rate of 10.4% complete response (CR) and 42.3% partial response (PR) from prior therapies. 311 (82%) cases of patients received 1.0–1.4mg/m2 bortezomib-based regimens treatment and 38.5% of them received at least 4 cycles of treatment. 364 patients were evaluable for response, the overall response rate was 287/364 (78.8%), 89 patients (24.5%) achieved a CR, 30(8.24%) had a nearly complete response (nCR), 168 (46.2%) had a PR, 39 (10.7%) had minimal response (MR), 24 (6.6%) had stable disease (SD), and the other 14 (3.9%) had progressive disease (PD). Median time to response was 1 cycle of treatment (range 1–6). Patients who received 4 or more cycles of bortezomib treatment achieved a higher response rate (CR+PR: 81.5%) compared to those who received fewer cycles (partly due to adverse events). And prognosis-related analysis showed that the dosage of bortezomib at 1.0 mg/m2 or more had a significant influence on the time to response and response rate, but no obvious effect on response duration, time to progress or the survival time. Drug related adverse events (AEs) were reported in 50.4% of patients during treatment, including hematologic AEs (mainly thrombocytopenia, 22.5%), gastrointestinal AEs (24.8%), and peripheral neuropathy (22.5%). The rates of grade 3–4 AEs of them were 46.1%, 11.2% and 15.7%, respectively. Serious AEs occurred in 33 (8.4%) cases and 23 (70%) patients recovered finally. Most AEs were predictable and manageable.Conclusion: Bortezomib-based regimen is effective treatment with higher response rate and is well tolerated in most Chinese patients with relapsed and refractory MM patients. Long-term follow-up is continuing.

Risk prediction of fever in neutropenia in children with cancer: A step towards individually tailored supportive therapy?

Fever in severe chemotherapy-induced neutropenia (FN) is the most frequent manifestation of a potentially lethal complication of current intensive chemotherapy regimens. This study aimed at establishing models predicting the risk of FN, and of FN with bacteremia, in pediatric cancer patients. In a single-centre cohort study, characteristics potentially associated with FN and episodes of FN were retrospectively extracted from charts. Poisson regression accounting for chemotherapy exposure time was used for analysis. Prediction models were constructed based on a derivation set of two thirds of observations, and validated based on the remaining third of observations. In 360 pediatric cancer patients diagnosed and treated for a cumulative chemotherapy exposure time of 424 years, 629 FN were recorded (1.48 FN per patient per year, 95% confidence interval (CI), 1.37-1.61), 145 of them with bacteremia (23% of FN; 0.34; 0.29-0.40). More intensive chemotherapy, shorter time since diagnosis, bone marrow involvement, central venous access device (CVAD), and prior FN were significantly and independently associated with a higher risk to develop both FN and FN with bacteremia. The prediction models explained more than 30% of the respective risks. The two models predicting FN and FN with bacteremia were based on five easily accessible clinical variables. Before clinical application, they need to be validated by prospective studies.

Empiric vs. preemptive antifungal treatment: an appraisal of treatment strategies in haematological patients

Neutropenic patients are at high risk to develop invasive fungal infections (IFI). Immediate antifungal treatment has been considered necessary for the treatment of these patients. However, only a minority of patients have 'probable' or 'proven' IFI according to EORTC-/MSG-criteria. The majority of the patients present with ongoing fever in neutropenia or 'possible' IFI only. To date, two treatment strategies are used for patients with fever in neutropenia and suspected IFI: empirical or preemptive antifungal therapy. Both regimens are discussed controversially as there is no clear evidence as to which strategy is superior. Empirical treatment bears the danger of 'overtreatment' with potentially toxic and expensive drugs, whereas preemptive therapy may sometimes be initiated too late to work efficiently against fungal disease. This article reviews both treatment options and discusses advantages and draw-backs of either strategy.

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

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. 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. 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. 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.

Serum levels of mannose‐binding lectin and the risk of fever in neutropenia pediatric cancer patients

Fever in neutropenia (FN) is a frequent complication in pediatric oncology. Deficiency of mannose-binding lectin (MBL), an important component of innate immunity, is common due to genetic polymorphisms, but its impact on infections in oncologic patients is controversial. This study investigated whether MBL serum levels at cancer diagnosis are associated with the development of FN in pediatric cancer patients. Serum MBL was measured using ELISA. Frequency, duration, and cause of FN were assessed retrospectively. Association with MBL level was analyzed using uni- and multivariate Poisson regression taking into account both intensity and duration of chemotherapy. In 94 children, with a cumulative follow-up time of 81.7 years, 177 FN episodes were recorded. Patients with both very low MBL levels (<100 microg/L; risk ratio (RR), 1.93; 95% CI, 1.14-3.28; P = 0.014) and normal MBL levels (>or=1,000 microg/L; RR, P = 0.011) had significantly more frequent FN episodes than patients with low MBL levels (100-999 microg/L). Patients with very low MBL levels had significantly more episodes of FN with severe bacterial infection (bacteremia or pneumonia; RR, 4.49; 1.69 = 11.8; P = 0.003), while those with normal MBL levels had more FN episodes with no microbial etiology identified (RR, 1.85; 1.14 = 3.03; P = 0.014). Very low MBL levels are associated with more frequent FN episodes, mainly due to severe bacterial infections. The surprising finding that children with normal MBL levels had more frequent FN episodes than those with low MBL levels needs testing in prospective studies.

Current approaches for risk stratification of infectious complications in pediatric oncology

Infections are serious complications of cytoreductive therapy in pediatric cancer patients presenting with febrile neutropenia. It is standard of care to initiate empirical intravenous broad-spectrum antibiotics until the fever and neutropenia resolve. However, it might be effective and safe to allow for early hospital discharge in certain subgroups of patients. Two strategies for risk stratification of pediatric cancer patients with regard to infectious complications are discussed in this review: (1) clinical risk parameters and laboratory measures to assist therapeutic management at presentation with fever in neutropenia, and (2) investigations of individual genetic susceptibility factors to tailor potential prophylactic approaches. Given the data available from a significant number of small studies, a large prospective non-inferiority trial is essential to assess low-risk clinical factors and additional laboratory or genetic markers for their predictive value.

Reduced-toxicity conditioning with fludarabine and treosulfan prior to allogeneic stem cell transplantation in multiple myeloma

In recent years, reduced-intensity conditioning (RIC) regimens before allogeneic stem cell transplantation (SCT) are increasingly used in patients not eligible for conventional conditioning. We did a retrospective, multicenter analysis to assess the feasibility of conditioning with fludarabine and treosulfan before allogeneic SCT in multiple myeloma patients. Thirty-four patients with a median age of 51.5 years were included in the analysis. All patients underwent myeloablation after conditioning followed by stable engraftment, and 29 of 31 evaluable patients (94%) showed early complete hematopoietic chimerism. Non-hematological toxicities were limited and encompassed mainly fever in neutropenia and infections. Grade II-IV acute and chronic graft-versus-host disease was observed in 33 and 39%, respectively. With a median follow-up of 708 days (range 60-1729 days), the median progression-free survival was 180 days. The treatment-related mortality was 10% on day 100 and 25% after 1 year. The median overall survival has not yet been reached. Our data indicate that conditioning with fludarabine and treosulfan before allogeneic SCT is feasible in intensively pretreated multiple myeloma patients and leads to stable engraftment and complete hematopoietic chimerism. Randomized trials are warranted to determine if this approach might be incorporated in an algorithm of multiple myeloma treatment.

Granulocyte Transfusions for Treatment or Prophylaxis of Severe Infections in Immunocompromized Neutropenic Patients - A Randomized Clinical Trial.

Background: Despite availability of potent anti-bacterial, anti-mycotic drugs and hematopoietic growth factors invasive bacterial or fungal infections remain a severe threat to neutropenic patients after chemotherapy or hematopoietic stem cell transplantation (HSCT). Granulocyte transfusions (GT) from granulocyte colony stimulating factor (G-CSF)-stimulated donors have been shown to increase the leukocyte count prior to expected hematopoietic regeneration, resulting in a shorter period of neutropenia and thus offer a therapeutic option for the control of severe infections. However, published studies rely on clinical observations of individual cases as no statistical comparison with control groups could have been established. The aim of this study was to define the clinical benefit and the leukocyte increment/duration of neutropenia after randomized administration of leukocyte transfusions in immunocompromized neutropenic patients.Patients and methods: Between 1999 and 2005 80 patients with underlying hematological diseases with or without allogeneic or autologous HSCT were randomized to receive either G-CSF, anti-infective treatment according to local standards with or without therapeutic or prophylactic application of GT from G-CSF-stimulated volunteer donors. The mean age was 47 years (range, 14 – 62 y). Indications were either fever in neutropenia and pulmonary infiltrates or soft tissue infiltration (therapeutic) or the history of invasive fungal infection during episodes of neutropenia following earlier chemotherapy courses and anticipated neutropenia of > 10 days (prophylactic).Results: 10 centers participated in the trial, however only five centers recruited patients (n=80) for randomization during the study period. This corresponds to ~50% of the expected sample size of 160 patients, hence results are statistically insignificant. Patient characteristics were comparable within the randomized cohorts (underlying disease, stage of disease, indication for GT, lenght of neutropenia). No significant difference in the clinical outcome was found between patients who received either therapeutic or prophylactic GT from G-CSF stimulated donors or no GT. The probability of survival on day 28 was 85% in both groups. Furthermore, no difference in the incidence and causes of death could be identified within the compared cohorts.Conclusion: The high percentage of infection clearance and survival in patients with severe infections in both groups contrasts with published results and own experiences. We speculate whether this is due a bias in including predominantly patients into the randomized study who presented with relatively favourable prognostic factors, as in the observation period numerous GT were performed in the participating centers without randomization. Most likely, existing clinical evidence for the benefit of this therapeutic measure was sufficient in many cases to exclude patients in serious conditions from randomization. Although well designed, a randomized trial may not always provide the expected results.

Bedrohliches Fieber

Fever is a frequent symptom which can arise as a consequence of bacterial, viral and parasitic infections. Additionally, fever is a frequent symptom in non-infectious diseases, e.g. autoimmune diseases or lymphomas. The term dangerous fever describes febrile conditions which are associated with high mortality and, in most cases, mandate hospitalization, and even monitoring in an intensive care unit. As a rule, infections (bacterial infections in particular) may begin harmlessly; however, they can instantaneously change into life-threatening conditions even a few days later. In the following report we focus on some critical syndromes which must be recognized quickly, such as severe sepsis, septic shock, fever in neutropenia, and fever in the immunocompromised patient.

Fever in neutropenia in children and adolescents: Evolution over time of main characteristics in a single center, 1993?2001

To assess the evolution over time of main characteristics of episodes of fever in severe chemotherapy-induced neutropenia (FN) in children and adolescents with cancer treated for FN following nonmyeloablative chemotherapy, to compare the results with the experiences of other centers, and to assess the impact of the changes found on management of FN and on risk prediction rules. Retrospective cohort study of all children and adolescents up to 18 years presenting with FN in a single pediatric oncology unit between 1993 and 2001. In 132 patients, 364 episodes of FN were reported. The relative incidence of FN increased significantly over time in patients with precursor B-cell acute lymphoblastic leukemia (PBC-ALL), reflecting the increased intensity of chemotherapy. At presentation with FN, the proportions of patients (1) with PBC-ALL versus other malignancies, (2) with other malignancies being in complete remission, (3) with a central venous catheter, and (4) with shaking chills all significantly increased over time (overall proportions, 64%, 60%, 50%, and 5%, respectively; p <0.001 for all). In 337 (93%) episodes, ceftriaxone plus amikacin was used as empirical broad spectrum antimicrobial therapy. This study demonstrates that some characteristics of FN, though not necessarily its management, change over time, implying regular update of risk prediction rules. In contrast to other centers, the first-line antimicrobial therapy did not need modification because of changing resistance patterns.

Soluble tumor necrosis factor receptor type II in the early diagnosis of fever in neutropenia.

Sepsis in chemotherapy-associated neutropenia is a major cause of mortality in the treatment of acute myeloid leukemia (AML). Early diagnosis of sepsis is crucial for patient survival. We analyzed the value of prospectively measuring serum concentrations of soluble tumor necrosis factor receptor type II (sTNF-RII) in patients with AML for early diagnosis of sepsis in neutropenia. Therefore, 54 adult patients with AML and neutropenia were followed around the onset of fever. A total of 59 febrile episodes were documented. We could not demonstrate a significant increase in sTNF-RII levels prior to fever. sTNF-RII concentrations were not predictive of the severity of a febrile episode. Based on these data, we cannot recommend the routine screening of sTNF-RII for early detection of septic complications in patients undergoing cytoreductive therapy of AML.

Imipenem compared with ceftazidime plus vancomycin as initial therapy for fever in neutropenic children with cancer

Two antibiotic regimens were assessed, imipenem as monotherapy and ceftazidime plus vancomycin as combination therapy, for initial empiric therapy in febrile neutropenic children with cancer. In a prospective randomized trial of 89 evaluable consecutive episodes, 45 were treated with imipenem and 44 with ceftazidime-vancomycin. In 87% of the episodes the neutropenia was severe. Of the 89 episodes 20% were bacteremias, 10% were clinically defined focal infections and 70% were considered fevers of unknown origin. The initial treatment was successful in 82% of the imipenem group and 59% of the ceftazidime plus vancomycin group. Both regimens were well-tolerated. There was no mortality, probably owing to the prompt admission and institution of antimicrobial therapy. All of the patients were treated until neutrophil recovery; no recurrent infections were seen. In conclusion imipenem monotherapy was well-tolerated and effective as initial therapy for fever in neutropenia in children.