First Episode Of Febrile Neutropenia Research Articles

All-Cause Mortality and Its Predictors in Haemato-Oncology Patients with Febrile Neutropenia.

Febrile neutropenia (FN) is one of the most important life-threatening complications in haemato-oncology. Our objective was to report all-cause mortality rates in patients ill with a hematological malignancy (HM) hospitalized with a first FN episode and to identify predictors for mortality. We conducted a historical retrospective cohort study of consecutive patients with an HM, >18 years of age, admitted between January 2012 and August 2018 for a first episode of FN. Data on all-cause mortality 12 months after admission for FN were obtained. The Kaplan-Meier curve was used to describe mortality during the follow-up period. Univariate and multivariable analyses identified predictors for 1,3 and 12-month mortality. One hundred and fifty-eight patients (mean age 69.5, 49.4% males) were included. Overall, 54 patients died (15.8%, 25.9%, and 34.1% died after 1, 3, and 12 months, respectively). Lower serum albumin, higher serum gamma-glutamyl transferase (GGT), lower estimated glomerular filtration rate (eGFR), older age, higher temperature, and lower absolute lymphocyte count at admission were independent predictors of all-cause mortality after 12 months. Further studies are needed to confirm our results and identify therapeutic strategies to improve survival.

D-index and invasive fungal infections (IFIs) in adult acute myeloid leukemia (AML) patients with the first episode of febrile neutropenia.

This study aimed to evaluate the performance of the D-index, a calculated measure of neutropenic burden, in predicting the risk of invasive fungal infections (IFIs) in acute myeloid leukemia (AML) patients. A retrospective study of adult AML patients who received the first induction chemotherapy and developed febrile neutropenia was conducted. Clinical characteristics, laboratory data, and the calculation of the D-index and cumulative D-index (c-D-index) were collected and analyzed between patients with and without IFIs. A total of 101 patients were included, with 16 (15.8%) patients who developed IFIs. Clinical characteristics, antifungal prophylaxis, and AML cytogenetic risk were similar between patients with or without IFIs. The results showed that the D-index and c-D-index were more effective in predicting IFIs than the duration of neutropenia. With the D-index cutoff of 7083, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 81.3%, 83.5%, 48.2%, and 95.9%, respectively. c-D-index at 5625 revealed sensitivity, specificity, PPV, and NPV for IFIs of 68.8%, 68.2%, 28.9%, and 92.1%, respectively. Using this cutoff of c-D-index, patients without IFIs were overtreated with an antifungal regimen in 45 (52.9%) cases. The D-index and c-D-index were helpful indicators for defining the risk of IFIs in AML patients with febrile neutropenia.

Value-Based Care for Healthy Children With First Episode of Febrile Neutropenia.

There is a lack of guidance on the management of febrile neutropenia in otherwise healthy children, including the need for hospitalization and antibiotic administration, leading to significant practice variation in management. The aim of this initiative was to decrease the number of unnecessary hospitalizations and empirical antibiotics prescribed by 50% over a 24-month period for well-appearing, previously healthy patients older than 6 months presenting to the emergency department with a first episode of febrile neutropenia. A multidisciplinary team of stakeholders was assembled to develop a multipronged intervention strategy using the Model for Improvement. A guideline for the management of healthy children with febrile neutropenia was created, coupled with education, targeted audit and feedback, and reminders. Statistical control process methods were used to analyze the primary outcome of the percentage of low-risk patients receiving empirical antibiotics and/or hospitalization. Balancing measures included missed serious bacterial infection, emergency department (ED) return visit, and a new hematologic diagnosis. Over the 44-month study period, the mean percentage of low-risk patients hospitalized and/or who received antibiotics decreased from 73.3% to 12.9%. Importantly, there were no missed serious bacterial infections, no new hematologic diagnoses after ED discharge, and only 2 ED return visits within 72 hours without adverse outcomes. A guideline for the standardized management of febrile neutropenia in low-risk patients increases value-based care through reduced hospitalizations and antibiotics. Education, targeted audit and feedback, and reminders supported sustainability of these improvements.

133 Value-based care for healthy children with first episode of febrile neutropenia

Abstract Primary Subject area Emergency Medicine - Paediatric Background While the management of febrile neutropenia in patients with cancer has clear, evidence-based guidelines, the management of previously healthy, immunocompetent children with a febrile illness and first episode of neutropenia is less understood. These patients are often similarly treated with empiric antibiotics and hospitalization despite studies demonstrating that this population, if they are well-appearing with a short history of neutropenia, is at low risk of serious bacterial infections. Therefore, less aggressive management should be considered in patients meeting low risk criteria. Objectives The aim of our quality improvement (QI) study was to decrease the number of unnecessary hospitalizations and empiric antibiotics prescribed by 50% over a 12-month period for otherwise healthy, well appearing patients presenting to the emergency department (ED) with a first episode of febrile neutropenia. Design/Methods A team of stakeholders from Hematology, Infectious Disease, Pediatrics and Emergency Medicine was assembled. A review of the literature, peer institutions and local practices of managing febrile neutropenia in healthy children was performed. Using the Model for Improvement, a guideline for the management of healthy children with first episode of febrile neutropenia was developed and refined using PDSA cycles. In January 2020, the guideline was launched for clinical use in the ED. Education, targeted audit and feedback, pathway modifications, and reminders were used to address knowledge gaps and staff turnover. A family of measures was analyzed using run charts and statistical process control (SPC) methods. Results Eighteen months of baseline data identified nineteen low risk patients with 84% either hospitalized and/or received antibiotics. It was also uncovered that many patients were misdiagnosed with neutropenia by excluding bands from the absolute neutrophil count (ANC). After the first twelve months of the intervention, sixteen patients met low risk criteria. Hospitalization and/or antibiotics use for this population decreased to 25% and all blood cultures were negative. Recognition of true severe febrile neutropenia also improved. Forty-one patients had a neutrophil count < 0.5, but an ANC > 0.5. Hospitalization and/or antibiotics use for this population decreased from 52% to 10%. Conclusion Through a multi-faceted, multidisciplinary QI study, we improved resource stewardship and value-based care by reducing unnecessary hospitalizations and antibiotics in low risk patients with a first episode of febrile neutropenia. Next steps include iterations to the guideline to increase impact along with sustainability planning. This work can easily be adopted by other pediatric and community sites caring for children.

A Prospective Registry Study of Peg-G-CSF Prophylaxis for Patients with Diffuse Large B-Cell Lymphoma (CISL 1403)

BackgroundFebrile neutropenia (FN) is the most important side effect of chemotherapy in diffuse large B cell lymphoma (DLBCL) causing not only treatment-related morbidity but also suboptimal chemotherapy delivery. Prophylactic use of granulocyte colony stimulating factor (G-CSF) or pegylated G-CSF (PEG-G-CSF) is known to reduce the incidence of both neutropenia and FN. We conducted a prospective registry study to evaluate prophylactic effect of PEG-G-CSF in DLBCL patients treated with R-CHOP regimen (ClinicalTrials.gov Identifier: NCT02474550).Patients and MethodSince January 1st 2015, after written informed consent, patients receiving R-CHOP therapy with curative intent were registered and prospectively monitored. All patients were pathologically confirmed with DLBCL according to World Health Organization Classification 2008. Prophylactic Peg-G-CSF was given 24 hours after R-CHOP chemotherapy subcutaneously. The incidence of neutropenia and neutropenic fever were studied. Febrile neutropenia (FN) is defined as an oral temperature >38.5°C or two consecutive readings of >38.0°C for 2h and an absolute neutrophil count <0.5 × 109/l, or expected to fall below 0.5 × 109/l. This interim-analysis was performed as of 1st June 2017.ResultsA total of 2957 cycles in 694 patients were included in the analysis. Base-line characteristics are summarized in Table 1. Median age at diagnosis was 62 (10-86) with a predominance of males (67%). Most patients had extranodal involvement (90.7%) and 257 patients (37%) had two or more extra-nodal involvements. The most common extranodal involvement sites were stomach (16.6%), bone (11.7%), intestine (11.4%) and lung (8.8%). Bone marrow involvement was observed in 281 patients (40.5%). At the time of analysis 407 (58.6%) patients completed 6 cycles of R-CHOP therapy. Forty-three patients (6%) experienced primary failure with R-CHOP treatment. Treatment related mortality occurred in 41 patients (5.9%). Grade III/IV neutropenia was developed with the incidence of 13.6% (402/2957 cycles) in the patients. FN developed in 74 (10.7%) patients with the overall incidence of 4.2% (124/2957) in the cycles (Table 2.). Twenty-five patients (33.7%) had multiple episodes of FN. Most patients (78.9%) experienced the first episode of FN within three cycles. Among pretreatment clinical factors analyzed, age, ECOG performance status and LDH level were related with the development of FN (Table 3.). Vitamin D deficiency at diagnosis was observed in 74.6% (347/501) of the patients but not associated with the development of FN. Deranged Light chain level is detected in 23.3% (112/479) of the patients, but not associated with the development of FN as well.ConclusionThis interim analysis showed clinical feature of FN with PEG-G-CSF prophylaxis in DLBCL patients. Peg-G-CSF prophylaxis was effective in reducing the incidence of neutropenia and FN. However, the patients who were elderly, with poor performance status or high LDH level still had high incidence of FN. We will further study whether this result could be translated into better treatment outcomes in the patients. [Display omitted] DisclosuresKim:Celltrion, Inc: Consultancy, Honoraria; Takeda: Research Funding; Kyowa-Kirin: Research Funding; J&J: Research Funding; Novartis: Research Funding; Donga: Research Funding; Mundipharma: Research Funding; Roche: Research Funding.

Characteristics of gram-negative bacteremia during febrile neutropenia among allogeneic hematopoietic stem cell transplant recipients on levofloxacin prophylaxis.

The aim of this study is to clarify the characteristics of gram-negative bacteremia (GNB), including extended-spectrum β-lactamase (ESBL)-producing pathogens, among allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients on levofloxacin (LVFX) prophylaxis. A retrospective analysis on GNB at the first episode of febrile neutropenia (FN) was conducted among allo-HSCT recipients (age ≥ 20years) on 500mg/day of oral LVFX prophylaxis. Epidemiological and microbiological features of GNB were investigated and compared between the inappropriate and appropriate empiric therapy groups. In total, FN occurred in 414 allo-HSCT cases, and bacteremia at the first episode of FN occurred in 169 cases. Overall, 29 GNB cases were documented, and the causative organisms identified were Escherichia coli in 21 cases (including 10 ESBLs), Klebsiella pneumoniae in 2, Pseudomonas aeruginosa in 2, and other in 4. The crude 30-day mortality rate was not significantly different among cases of GNB (6.9%), gram-positive bacteremia (GPB) (7.1%), or non-bacteremia (5.4%; P = 0.78). Cefepime (CFPM) was administered in all cases in the inappropriate empiric therapy group, and all causative organisms were ESBL-producing E. coli (ESBL-EC). All patients in the inappropriate empiric therapy group had a low Pitt bacteremia score (≤ 2). Thirty-day mortality did not differ significantly between the inappropriate and appropriate empiric therapy groups (1/10 vs. 1/15, P = 0.61). In conclusion, GNB was not a significant cause of death. In LVFX breakthrough ESBL-EC bacteremia among allo-HSCT recipients, the administration of CFPM as empiric therapy did not lead to significantly poor prognosis. Empiric CFPM administration might be an acceptable strategy.

Gut Microbiota Profiles of Treatment-Naïve Adult Acute Myeloid Leukemia Patientswith Neutropenic Fever during Intensive Chemotherapy

Background : The intestinal bacterial flora of febrile neutropenic patients has been found to be significantly diverse and may play a role in clinical decisions regarding antimicrobial de-escalation with predictive complications. However, there are few reports of microbiota alteration of adult acute myeloid leukemia (AML) patients. Methods : Stool samples of each treatment-naïve AML patient were collected the day before the initiation of induction chemotherapy (pretreatment), on the first date of neutropenic fever and first date of bone marrow recovery. Bacterial DNA was extracted from stool samples and bacterial 16s ribosomal RNA genes were sequenced by next-generation sequencing. Relative abundance, overall richness, Shannon's diversity index and Simpson's diversity index were calculated. Results : Ten AML patients (4 men and 6 women) were included with a median age of 39 years (range: 19-49). Twenty-four stool samples were collected and assigned into three groups: (1) pretreatment (n = 10); (2) first date of febrile neutropenia (n=9); and (3) first date of bone marrow recovery (n=5). All of patients developed febrile neutropenia; three patients had detectable infectious organisms and all of these cases had invasive pulmonary aspergillosis with two being co-infected with Pseudomonas pneumonia and Escherichia coli septicemia. Median absolute neutrophil count was 2.85 x 109/L (range: 1.42-7.67 x 109/L), 0.04 x 109/L (range: 0.01-0.43 x 109/L) and 3.65 x 109/L (range: 2.09-5.78 x 109/L) at pretreatment, first date of febrile neutropenia and first date of bone marrow recovery, respectively. At the phylum level, Firmicutes dominated over the period of neutropenic fever, subsequently declining after bone marrow recovery a pattern in contrast to that shown by Bacteroidetes and Proteobacteria. At the genus level, Enterococcus was more abundant in the febrile neutropenia period compared to pretreatment (mean difference of 20.2, [95%CI (5.9, 34.6)]; P &amp;lt;0.01) whileBacteroides and Escherichia notably declined during the same period (mean difference of -11.7, [95%CI (-21.9, -1.4)]; P= 0.027 and -11.6, [95%CI (-22.7, -0.4)]; P = 0.034, respectively). At the operational taxonomic units (OTUs) level, there was a significantly higher level of overall richness in the pretreatment period than in the febrile neutropenic episode (mean OTUs of 203.1 vs. 131.7; P = 0.012). Both of the diversity indexes of Shannon and Simpson showed a significant decrease in the febrile neutropenic period. Conclusions : Adult AML patients with a first episode of febrile neutropenia after initial intensive chemotherapy demonstrated a significant decrease in gut microbiota diversity and the level of diversity remained constant despite recovery of bone marrow. Figure Disclosures No relevant conflicts of interest to declare.

Gut microbiota profiles of treatment-naïve adult acute myeloid leukemia patients with neutropenic fever during intensive chemotherapy.

The intestinal bacterial flora of febrile neutropenic patients has been found to be significantly diverse. However, there are few reports of alterations of in adult acute myeloid leukemia (AML) patients. Stool samples of each treatment-naïve AML patient were collected the day before initiation of induction chemotherapy (pretreatment), on the first date of neutropenic fever and first date of bone marrow recovery. Bacterial DNA was extracted from stool samples and bacterial 16s ribosomal RNA genes were sequenced by next-generation sequencing. Relative abundance, overall richness, Shannon's diversity index and Simpson's diversity index were calculated. No antimicrobial prophylaxis was in placed in all participants. Ten cases of AML patients (4 male and 6 female) were included with a median age of 39 years (range: 19-49) and all of patients developed febrile neutropenia. Firmicutes dominated during the period of neutropenic fever, subsequently declining after bone marrow recovery a pattern in contrast to that shown by Bacteroidetes and Proteobacteria. Enterococcus was more abundant in the febrile neutropenia period compared to pretreatment (mean difference +20.2; p < 0.0001) while Escherichia notably declined during the same period (mean difference -11.2; p = 0.0064). At the operational taxonomic unit (OTU) level, there was a significantly higher level of overall richness in the pretreatment period than in the febrile neutropenic episode (mean OTU of 203.1 vs. 131.7; p = 0.012). Both of the diversity indexes of Shannon and Simpson showed a significant decrease during the febrile neutropenic period. Adult AML patients with a first episode of febrile neutropenia after initial intensive chemotherapy demonstrated a significant decrease in gut microbiota diversity and the level of diversity remained constant despite recovery of bone marrow.

De-Escalation of Antimicrobials in Adult Hematopoietic Cell Transplantation Recipients with Febrile Neutropenia of Unknown Origin

De-Escalation of Antimicrobials in Adult Hematopoietic Cell Transplantation Recipients with Febrile Neutropenia of Unknown Origin

Incidence and outcome changes in the first episode of febrile neutropenia following a hematopoietic stem cell transplantation (HSCT) after discontinuing systematic prophylaxis with fluoroquinolones

Background: The role of fluoroquinolone prophylaxis on morbidity and mortality when used after HSCT is still an issue of debate. The aim of our study was to compare the incidence and outcome of febrile neutropenia in patients following a HSCT between those who received fluoroquinolone prophylaxis and those who did not. Methods & Materials: We conducted a retrospective review of 143 adult patients who underwent a HSCT between nov-2010 y aug-2017. We analyzed demographic, clinical, microbiological and outcome variables comparing patients who received ciprofloxacin and those who didn’t. Results: 81 (56.6%) patients received ciprofloxacin and 61 (42.6%) did not. We found no differences in baseline characteristics between both groups: age, sex, HSCT type and days of neutropenia (p = NS). No differences were found when we compared length of hospital stay (25 days in the prophylaxis group vs 28 days in the other, p = 0.13). Patients who received prophylaxis had significant lower risk of febrile neutropenia [P = 0,006; OR = 0.09 (0.01-0.7)] and bacteremia [p = 0,001; OR = 0.26 (0.12-0.57)]. Days of neutropenia until the febrile episode (3 in both groups, p = NS) and bacteremia (5 in both groups, P = NS) were similar. Similar frequency of clinically (52 vs. 43%, p = 0.39) and microbiologically (22 vs. 32%, p = 0.18) documented infections were observed in both groups. Patients without prophylaxis required intensive care unit admission more frequently than those with prophylaxis (9% vs 14,5%) but the difference was not significant (p = 0.07). Gram negative bacilli were more frequently isolated in the non-prophylaxis group (21% vs 5%, p = 0,007), but no differences were observed regarding frequency of multidrug resistance (3.7% in the prophylaxis group vs 10% in non-prophylaxis group, p = NS). Frequency of Gram positive isolation was similar (12.3% vs 19.3%; p = NS). By day 30, 4 patients died of all causes. They all belonged to the non-prophylaxis group (p = 0.03). Conclusion: In our report, fluoroquinolone prophylaxis in HSCT patients reduced the incidence of first episode of febrile neutropenia, bacteremia and mortality of all causes with no impact on antibiotic resistance. Prophylaxis with fluoroquinolones should be individualized according to risk groups and local epidemiology.

Attitudes and practice patterns for maintaining relative dose intensity of chemotherapy in outpatient clinics: results of a Japanese web-based survey.

BackgroundThis analysis was undertaken to evaluate the practice patterns of Japanese physicians regarding curative-intent chemotherapy, especially in outpatient settings, and to define factors negatively affecting the maintenance of relative dose intensity (RDI).MethodsWe performed a web-based questionnaire survey of Japanese physicians involved in malignant lymphoma chemotherapy (Group ML) or in breast cancer chemotherapy (Group BC). The questionnaire inquired how they manage low-risk febrile neutropenia (FN) caused by initial chemotherapy for diffuse large B-cell lymphoma(DLBCL) or by adjuvant chemotherapy for breast cancer in an outpatient setting.ResultsValid responses were obtained from 185 physicians in Group ML and 160 in Group BC. In Group ML, 76 % (n = 141) of the physicians were board-certified hematologists, while 82 % (n = 131) of the physicians in Group BC were board-certified surgeons. A significantly higher proportion of physicians in Group ML responded that “dose reduction is not required for the subsequent course of chemotherapy after the first episode of FN” than in Group BC (ML versus BC; 77 % versus 31 %; P < 0.001). Significantly higher proportions of physicians in Group ML were more likely to prophylactically administer antibiotics or granulocyte-colony stimulating factor (G-CSF; ML versus BC; antibiotics: 36 % versus 26 %, P = 0.049; G-CSF: 25 % versus 16 %, P = 0.047). Eighty six percent (n = 159) of Group ML and 70 % (n = 112) of Group BC responded that “emergency outpatient unit is open at all hours”.ConclusionsJapanese physicians are more likely to administer reduced doses of chemotherapy to patients with breast cancer than to patients with malignant lymphoma. Supportive infrastructures should be improved to ensure the provision of adequate chemotherapy to all cancer patients.

Treatment strategies for low-risk febrile neutropenia in adult cancer patients: A cost-utility analysis.

6102 Background: Febrile neutropenia remains a frequent complication of chemotherapy for adult cancer patients. There is uncertainty as to whether low-risk episodes are best managed in the inpatient or outpatient setting. Methods: A cost-utility model was created to compare four treatment strategies for low-risk febrile neutropenia in adult cancer patients. Event probabilities were retrieved from a formal systematic review and meta-analysis. Utilities were obtained from adult cancer patients. The base case was assumed to be an adult cancer patient with a first episode of low- risk febrile neutropenia. The model used a healthcare payer perspective in Ontario/Canada, and a time horizon of 30 days corresponding to one episode of febrile neutropenia. Four treatment strategies were evaluated: (1) entire treatment in hospital with intravenous antibiotics (HospIV), (2) early discharge strategy consisting of 48 hours inpatient observation with intravenous antibiotics, subsequently followed by oral outpatient treatment (EarlyDC), (3) entire outpatient management with intravenous antibiotics (HomeIV), and (4) entire outpatient management with oral antibiotics (HomePO). Outcome measures were quality-adjusted life months (QALMs), costs, and incremental cost-effectiveness ratios (ICER). Results: HomeIV was associated with both better health outcomes (0.797 QALM) and lower costs ($2,129) as compared to the other 3 strategies. Since HomePO (0.763 QALM; $2,309), EarlyDC (0.664 QALM; 5,647), and HospIV (0.661 QALM; $13,517) were all dominated, ICERs could not be determined. These results were sensitive to several event probabilities, utilities and costs. Beyond certain thresholds, the best strategy changed from HomeIV to the HomePO strategy. However, HospIV or EarlyDC management were never the preferred strategy in sensitivity analyses. Conclusions: For adult cancer patients with a first episode of febrile neutropenia, outpatient strategies were more effective and less costly compared with standard inpatient management. However, uncertainty remains whether intravenous or oral treatment might be the preferable route of drug administration in an ambulatory setting. No significant financial relationships to disclose.

A European Organization for Research and Treatment of Cancer-International Antimicrobial Therapy Group Study of Secondary Infections in Febrile, Neutropenic Patients with Cancer

Neutropenic patients with cancer may develop several episodes of fever and infection during chemotherapy-induced myeloaplasia. To identify risk factors for secondary infectious episodes among patients who responded to initial antibiotic therapy, we retrospectively analyzed 2 consecutive, prospective, randomized clinical trials performed by the International Antimicrobial Therapy Group of the European Organization for Research and Treatment of Cancer during 1991-1994. Of 1720 patients with their first episode of febrile neutropenia, 836 responded to the initial antibiotic regimen and were therefore suitable for our analysis. A secondary infection was observed in 129 (15%) of 836 patients that occurred at a median of 10 days (range, 1-28 days) after the onset of the primary febrile episode. Factors at both baseline and day 4 were analyzed. Age of >16 years (odds ratio [OR], 3.46; P<.001), acute leukemia in first induction (OR, 3.17; P<.001), presence of intravenous line (OR, 1.88; P=.04), severe neutropenia (defined as an absolute granulocyte count of <100 cells/mm(3)) on day 4 (OR, 2.72; P<.001), and type of documentation of the primary episode (i.e., microbiologically documented cause or unexplained fever; OR, 2.56; P=.001) were found to be risk factors for secondary infection. The risk of death was higher among patients who developed a secondary infectious episode than among those who did not (5.4% vs. 1.4%; P<.01). The clinical parameters described above may help to identify neutropenic patients at risk of developing secondary infection.

Serum IL-12:IL-6 Ratio Reliably Distinguishes Infectious from Non-Infectious Causes of Fever during Autologous Stem Cell Transplantation (ASCT).

Fever occurs commonly in patients (pts) undergoing ASCT, both during neutropenia and after neutrophil engraftment, but infectious etiologies are infrequently identified. A reliable and rapid method to distinguish infectious from non-infectious etiologies of fever may be able to reduce unnecessary diagnostic testing and empiric antimicrobial administration, leading to decreased costs, duration of hospital stays, and treatment related complications. We hypothesized that the serum cytokine profile during fever due to clinically significant infection is distinct from that during non-infectious febrile episodes. In a prospective exploratory study we assessed serum IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12, TNFα, and IFNγ levels by sandwich ELISA in 65 pts undergoing ASCT for non-Hodgkin's lymphoma (n=20), Hodgkin's disease (n=22), multiple myeloma (n=14), or AL amyloidosis (n=9). Cytokine levels were measured at multiple pre-defined times during ASCT; the results presented here are based on measurements upon admission, during the first episode of febrile neutropenia, during the first episode of fever within 72 hours after neutrophil engraftment, and upon discharge. Standard evaluation of fever included chest x-rays and blood and urine cultures. Other diagnostic testing, eg stool cultures and CT scans, were performed at the discretion of the responsible physicians as deemed appropriate by patients' symptoms. 69 febrile episodes occurred in 54 pts: 39 episodes occurred during neutropenia (12 due to documented infections); 30 episodes occurred after engraftment, 17 of which were preceded within 72 hours by fever during neutropenia (5 infectious, 12 non-infectious). Only 2 of the 13 new-onset post-engraftment fevers had an identifiable infectious etiology. Levels of IL-1β, IL-2, IL-8, IL-10, TNFα, and IFNγ did not distinguish infectious from non-infectious etiologies of fever. Mean IL-12 levels at the time of fever were significantly higher among pts without infection compared to pts with infection, regardless of neutrophil count; conversely, mean IL-6 levels were lower in febrile pts without infection. Compared to febrile pts with infection, the mean IL-12:IL-6 ratio was significantly higher in febrile pts without infection, both during neutropenia and after neutrophil engraftment. IL-12 and IL-6 levels and IL-12:IL-6 ratio did not vary significantly by histology, either at diagnosis or at discharge.IL-12:IL-6 ratio during feverFebrile periodInfectionNo infectionP-valueNeutropenia1.058.7<0.001Post-engraftment5.2884.60.01The IL-12:IL-6 ratio on the day of neutrophil engraftment in 11 pts without fever during the entire ASCT course was similar to that of normal healthy volunteers (904.6 vs. 708.0, P=NS) and significantly higher than among pts with infection during neutropenia (P<0.001) or after engraftment (P=0.006). These data suggest that the IL-12:IL-6 ratio reliably distinguishes infectious from non-infectious etiologies of fever during the course of ASCT. Most febrile episodes that occur after neutrophil engraftment are not due to infection. Prospective studies to determine the sensitivity and specificity of an IL-12:IL-6 ratio threshold that distinguishes infectious from non-infectious causes of fever in the transplant and non-transplant settings are warranted.

Phase II non-randomized study of three different sequences of docetaxel and vinorelbine in patients with advanced non-small cell lung cancer

Docetaxel and vinorelbine as single agents and in combination with cisplatin have shown significant activity in advanced non-small cell lung cancer (NSCLC). Significant neutropenia has been observed with the combination of docetaxel/vinorelbine. To gain insight into the potential synergism of this combination, we examined three different sequences of docetaxel 75 and vinorelbine 20 mg/m 2, every 3 weeks, in locally advanced and metastatic NSCLC patients. About 14 patients were evaluable in each schedule: schedule A, docetaxel day 1, vinorelbine days 1 and 6; schedule B, docetaxel day 6, vinorelbine days 1 and 6; schedule C, docetaxel day 1, vinorelbine days 6 and 15. Response rates were: 42.8, 7.1 and 21.4% for schedules A, B and C, respectively ( P=0.01, schedule A vs. B). Median survival time was 16, 6.5 and 10.6 months for schedules A, B and C, respectively ( P=0.04, schedule A vs. B). Neutropenia was the commonest toxicity; 43% of patients in schedule A and 57% of patients in schedule B had a febrile neutropenia episode. Prophylactic granulocyte-colony stimulating factor (G-CSF) was prescribed in schedule C after the first episode of febrile neutropenia. Non-hematologic toxicities were mild in all three schedules. For future studies, schedule A with lower doses is recommended.