Mean Absolute Neutrophil Count Research Articles

Management of Febrile Neutropenia in Patients receiving Chemotherapy for Solid Tumors: A Retrospective Study of Twenty Cases from the Radiotherapy Centre, Accra, Ghana

One in ten patients on anticancer medication will develop febrile neutropenia irrespective of tumour type. There is need to protect our patients from this fatal condition while optimising chemotherapy. This may be difficult for a poor country. to assess the management of cancer patients with febrile neutropenia in a low resource setting. records of 20 cancer patients with febrile neutropenia (fn) over a three-year period were retrospectively analysed. data retrieved included age, sex, type of cancer and number of cycles of chemotherapy taken. Other parameters included initial temperature, site of infection, absolute neutrophil count (ANC) at presentation and antibiotic choice. Use of antifungal drugs, duration of fever and overall treatment outcome were also assessed. the male : female ratio was 3:2 with a median age of 24 years (range: 15 - 68 years), and a mean temperature of 38.8 oC (range 38.0-39.8 0C). Mean absolute neutrophil count was 0.2 x 109 (range: 0.0 to 0.6 x 109). Thirteen (65%) received Cisplatin, five (25%) received Adriamycin, two (10%) received Paclitaxel or Cyclophosphomide-Methotrexate-5, Fluorouracil (CMF). Ten(50%) developed FN with the first cycle of chemotherapy, and six(30%) in the second cycle. Twelve (60%) had oral infection, four(20%) had gastroenteritis and single episodes of respiratory and urinary tract infections. Eleven (55%), received Ceftriaxone and Gentamycin, five (25%) cases received Levofloxacin or ciprofloxacin and Amoxicillin/clavunate + metronidazole; two cases(10%), Ceftazidime and Gentamycin; two cases(10%) received Meropenem. Twelve (60%) patients had antifungal therapy for oral candidiassis. Eight (40%) patients received growth factors. The mean fever duration was 4.5 days (range 1-10 days). Two (10%) of the patients died. febrile neutropenia in resource limited countries can be managed with good history and physical examination skills. Aminoglycosides are important components of empiric treatment in Ghana.

Discriminative accuracy of novel and traditional biomarkers in children with suspected appendicitis adjusted for duration of abdominal pain.

The objective was to assess the accuracy of novel and traditional biomarkers in patients with suspected appendicitis as a function of duration of symptoms. This was a prospective cohort study, conducted in a tertiary care emergency department (ED). The authors enrolled children 3 to 18 years old with acute abdominal pain of less than 96 hours and measured serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP), white blood cell (WBC) count, and absolute neutrophil count (ANC). Final diagnosis was determined by histopathology or telephone follow-up. Trends in biomarker levels were examined based on duration of abdominal pain. The accuracy of biomarkers was assessed with receiver operating characteristic (ROC) curves. Optimal cut-points and test performance characteristics were calculated for each biomarker. Of 280 patients enrolled, the median age was 11.3 years (interquartile range [IQR] = 8.6 to 14.8), 57% were male, and 33% had appendicitis. Median IL-6, median CRP, mean WBC count, and mean ANC differed significantly (p < 0.001) between patients with nonperforated appendicitis and those without appendicitis; median IL-8 levels did not differ between groups. In nonperforated appendicitis, median IL-6, WBC, and ANC levels were maximal at less than 24 hours of pain, while CRP peaked between 24 and 48 hours. In perforated appendicitis, median IL-8 levels were highest by 24 hours, WBC count and IL-6 by 24 to 48 hours, and CRP after 48 hours of pain. The WBC count appeared to be the most useful marker to predict appendicitis in those with fewer than 24 or more than 48 hours of pain, while CRP was the most useful in those with 24 to 48 hours of pain. In this population, the serum levels and accuracy of novel and traditional biomarkers varies in relation to duration of abdominal pain. IL-6 shows promise as a novel biomarker to identify children with appendicitis.

Neutropenic Colitis in Children

Neutropenic colitis (NC) or typhlitis has an incidence of approximately 5% in patients receiving chemotherapy for malignancy. The precise cause is unknown, but almost all patients are neutropenic; most profoundly so. We reviewed our experience with neutropenic colitis over the past 10 y to assess the incidence, management, and outcome. Hospital records were reviewed after obtaining IRB approval (# 10-10-184E). There were 1224 children treated for cancer at our institution over the study interval. Neutropenic colitis was strictly defined as the presence of both clinical and radiographic findings consistent with the diagnosis, since there are no definitive diagnostic criteria. Patients with confirmed appendicitis were excluded. Medical management consisted of bowel rest and/or decompression, broad-spectrum IV antibiotics and anti-fungal coverage, and serial clinical exams and radiographic studies. Clinical deterioration and free air were the primary indications for surgery. Demographic factors, signs, symptoms, clinical presentation, underlying disease process, white blood cell count (WBC), and absolute neutrophil count (ANC) prior to the onset of the disease, treatment, and outcome were analyzed. Neutropenic colitis was confirmed in 17 children (1.4% incidence). Three patients had more than one episode. Leukemia was the most common underlying diagnosis (53%). There was no gender predominance, and the mean age at diagnosis was 8.4 y. Mean WBC and ANC at onset were 670 and 164, respectively. A sharp decline in the ANC usually immediately preceded the onset of NC; 2/17 (12%) underwent operation, but both patients had only pneumatosis at exploration. Overall survival was 9/17 (53%), but no deaths were directly attributable to the colitis. Neutropenic colitis is an uncommon occurrence in children with neoplasia (1.4% in the current study). Leukemia is the most common cause. A precipitous decline in ANC usually occurs prior to the onset of NC. Most patients do not require operation and the overall mortality directly attributable to NC is low.

A Single Dose Filgastrim In the Treatment of Chemotherapy Induced Neutropenia

AbstractAbstract 4774 Background:Chemotherapy induced neutropenia (CIN) was a challenge to physicians until the discovery of growth factors. Neutropenia predisposes the patient to infection with increased morbidity, mortality, and cost of hospitalization. Not only does CIN leads to a delay in chemotherapy but also a dose reduction, which results in decreased efficacy and impact on survival. Filgrastim is a granulocyte colony stimulating factor that leads to the proliferation, differentiation and function of neutrophils. With an increase in the neutrophil count and function, Filgrastim reduces the incidence of neutropenia and the complications associated with febrile neutropenia (FN), making it possible to deliver chemotherapy on time, without dose adjustment. ASCO guidelines recommend that Filgastrim be given at 5 mcg/kg/day starting from days 1–3 after chemotherapy for patients with the risk of FN greater than 20% until the absolute neutrophil count is near-normal. It was recently reported that two doses of Filgrastim were comparable to higher number doses to prevent the nadir. We hypothesized that only a single dose is sufficient to prevent the nadir and delay in treatment. Patients and Methods:A retrospective analysis of chart data from all patients treated at The Brooklyn Hospital Center ambulatory clinic was reviewed after the initiation of chemotherapy. Data collected included the white cell count, neutrophil count, dates of chemotherapy and Filgrastim administration. Patients who received one dose of Filgastrim within 2–3 days, but not less than 24 hours prior to receiving subsequent chemotherapy comprised the study population. Data was analyzed for each individual cycle of chemotherapy. Results:The study population consisted of 11 patients with a total of 33 cycles of chemotherapy. Of the 11 patients, 9 had breast cancer, 1 had embryonal cancer, and 1 had colon cancer. Chemotherapy varied from Etoposide and Cisplatin, FOLFOX with Bevacizumab, and Adriamycin with Cyclophosphamid (AC) followed by Paclitaxel where the AC was given as a dose dense regimen. All the cycles had adequate response in neutrophil count to a single dose of Filgrastim when it was delivered within 2–3 days, but not before 24 hours of receiving chemotherapy. The mean absolute neutrophil count prior to Filgrastim was 0.8 compared to 6.0 (p=0.0001) after a single dose. There was no delay in treatment noticed as a result of the single dose of Filgrastim in all the 33 cycles. Conclusion:Filgrastim as a single dose is sufficient to treat CIN and prevent delay in subsequent treatment. Disclosures:No relevant conflicts of interest to declare.

GMI-1070, a Pan-Selectin Inhibitor: Safety and PK In a Phase 1/2 Study In Adults with Sickle Cell Disease

AbstractAbstract 1632GMI-1070 is a pan-selectin inhibitor that targets E-, P-, and L-selectins and has shown activity in multiple animal models of disease. Sickle cell disease (SCD) is characterized by periodic vaso-occlusive (VOC) episodes in which cell adhesion and aggregation play a crucial role. GMI-1070 has previously been shown to restore blood flow and improve survival in a mouse model of VOC, and safety and PK have been evaluated in normal, healthy volunteers in phase 1. Here we report clinical, safety, and PK results from the first study of GMI-1070 in individuals with SCD. Methods: An open-label phase 1/2 study was performed, enrolling adults with SCD at steady state. GMI-1070 was administered in two IV doses given on the same day: 20 mg/kg in the first dose, followed 10 hours later by 10 mg/kg. Patients were evaluated for safety on days 0, 1, 2, 7 and 28, including adverse events (AEs), routine clinical labs, and clinical exam. Plasma and urine concentrations of GMI-1070 were measured on days 0, 1, and 2, and PK parameters calculated and compared with those from healthy volunteers. Results: Fifteen adults were enrolled at three centers; 13 with HbSS, 2 with HbSB0thal. All were African-American, 9 were male, mean age was 32 years (range 18–50), mean weight was 64.7 kg; 4 were on hydroxyurea. In the past year, 6 had experienced VOC requiring medical care; 2 had ACS; 2 required transfusions; and 1 had an episode of priapism. Five were hospitalized in the past year; 12 were hospitalized in the past 5 years. All subjects received both doses of study drug; all but one were followed for 28 days. The PK in adults with SCD was in good agreement with that in the controls. The elimination half-life of GMI-1070 averaged 7.73 ± 2.45 hours (Figure). Renal clearance averaged 18.0 ± 7.93 mL/min and accounted for essentially all elimination. Physical exam parameters after dosing were unchanged, and all infusions were well tolerated. Four subjects reported headache within 24 hours of dosing, all of which were mild or moderate and resolved within 24 hours. Two subjects experienced VOC not requiring hospitalization, at 2 and 4 weeks after dosing. One subject had worsening anemia requiring transfusion 5 days after dosing. Other adverse events typical of SCD were reported without apparent association with study drug; none were serious adverse events. Routine labs demonstrated no changes from baseline (Hb, reticulocytes, platelets, electrolytes, glucose, ALT, LDH, BUN, Cr, bilirubin, urinalysis) with the exception of white blood cell counts (WBC) and absolute neutrophil counts (ANC). At 24 hours, mean WBC change from baseline was 1.9K/mm3, or 20% (p=0.076, using parametric test with mixed model); mean ANC change was 2.7, or 67% (p=0.019); all returned to baseline by 7 days. One individual had marked leukocytosis 24 hours after dosing (from 10.4 to 28K/mm3), returning to baseline by day 7; no other effects were observed in this subject. Mean C-reactive protein (CRP) increased at 24 and 48 hours, returning to baseline by day 7. Two subjects had marked increases in CRP: one exhibited leukocytosis with dosing and the other had a high baseline WBC count. There was otherwise no apparent correlation between PK, WBC/ANC, hydroxyurea use, or adverse events. In conclusion, GMI-1070, a pan-selectin inhibitor, when administered to adults with SCD at steady state, has a similar safety and PK profile to that in healthy volunteers. However, SCD patients had moderate WBC and ANC increases at 24–48 hours after dosing, which return to baseline without other observed symptomatic adverse events. This study supports further evaluation of GMI-1070 for the treatment of vaso-occlusive crisis. [Display omitted] Disclosures:Styles:GlycoMimetics: Consultancy, clinical trial sponsorship. Wun:GlycoMimetics: Consultancy, clinical trial sponsorship. De Castro:GlycoMimetics: clinical trial sponsorship. Telen:GlycoMimetics: Consultancy, clinical trial sponsorship. Kramer:GlycoMimetics: Consultancy. Flanner:GlycoMimetics: Employment, Equity Ownership. Magnani:GlycoMimetics: Employment, Equity Ownership. Thackray:GlycoMimetics: Employment, Equity Ownership. Off Label Use: This drug (GMI-1070) has not been approved for any clinical indication.

Dose‐Dependent Risk of Neutropenia after 7‐Day Courses of Artesunate Monotherapy in Cambodian Patients with AcutePlasmodium falciparumMalaria

Fears of emerging artemisinin resistance in western Cambodia have prompted a series of clinical trials investigating whether slow responses to antimalarial treatment can be overcome by increasing doses of drug. Patients with uncomplicated malaria were allocated 1 of 3 oral artesunate monotherapy regimens (2, 4, or 6 mg/kg/day for 7 days) and were observed for 42 days. A series of safety measures, including complete blood count on days 0, 3, 6, and 14, was implemented because of a lack of safety data for these experimental doses. After 3 doses, geometric mean absolute neutrophil counts were reduced in all groups, and 2 patients required artesunate to be discontinued because of neutropenia (absolute neutrophil count, <1.0 × 10(3) cells/μL). Recipients of the 6 mg/kg/day dosage had significantly lower geometric mean absolute neutrophil counts than did recipients of the 2 and 4 mg/kg/day dosages at 6 and 14 days (P < .001 for each). Overall, 5 (19%) of 26 patients who received the 6 mg/kg/day dosage became neutropenic within 14 days, triggering a cohort-halting rule and ending the trial early. Pharmacokinetic data from neutropenic patients showed wide variance, with plasma clearance occurring significantly slower in neutropenic patients than in nonneutropenic patients. Artesunate remains a crucial drug for the treatment of malaria, and determining optimal dosing regimens is vital to overcome emerging resistant parasite strains along the Thai-Cambodian border. However, future experimental dosing studies must be designed with care, because the safety of such regimens can no longer be assumed. The artemisinin derivatives remain one of the safest classes of antimalarial drugs, but this study demonstrates that the dosing limit may have been reached.

Interpreting Complete Blood Counts Soon After Birth in Newborns at Risk for Sepsis

A complete blood count (CBC) with white blood cell differential is commonly ordered to evaluate newborns at risk for sepsis. To quantify how well components of the CBC predict sepsis in the first 72 hours after birth. For this retrospective cross-sectional study we identified 67 623 term and late-preterm (≥ 34 weeks gestation) newborns from 12 northern California Kaiser hospitals and 1 Boston, Massachusetts hospital who had a CBC and blood culture within 1 hour of each other at <72 hours of age. We compared CBC results among newborns whose blood cultures were and were not positive and quantified discrimination by using receiver operating characteristic curves and likelihood ratios. Blood cultures of 245 infants (3.6 of 1000 tested newborns) were positive. Mean white blood cell (WBC) counts and mean absolute neutrophil counts (ANCs) were lower, and mean proportions of immature neutrophils were higher in newborns with infection; platelet counts did not differ. Discrimination improved with age in the first few hours, especially for WBC counts and ANCs (eg, the area under the receiver operating characteristic curve for WBC counts was 0.52 at <1 hour and 0.87 at ≥ 4 hours). Both WBC counts and ANCs were most informative when very low (eg, the likelihood ratio for ANC < 1000 was 115 at ≥ 4 hours). No test was very sensitive; the lowest likelihood ratio (for WBC count ≥ 20 000 at ≥ 4 hours) was 0.16. Optimal interpretation of the CBC requires using interval likelihood ratios for the newborn's age in hours.

Iron chelation therapy with deferasirox in patients with aplastic anemia: a subgroup analysis of 116 patients from the EPIC trial

AbstractThe prospective 1-year Evaluation of Patients' Iron Chelation with Exjade (EPIC) study enrolled a large cohort of 116 patients with aplastic anemia; the present analyses evaluated the efficacy and safety of deferasirox in this patient population. After 1 year, median serum ferritin decreased significantly from 3254 ng/mL at baseline to 1854 ng/mL (P < .001). Decreases occurred in chelation-naive (3229-1520 ng/mL; P < .001, last-observation-carried-forward analysis), and previously chelated (3263-2585 ng/mL; P = .21, last-observation-carried-forward analysis) patients and were reflective of dose adjustments and ongoing iron intake. Baseline labile plasma iron levels were within normal range despite high serum ferritin levels. The most common drug-related adverse events were nausea (22%) and diarrhea (16%). Serum creatinine increases more than 33% above baseline and the upper limit of normal occurred in 29 patients (25%), but there were no progressive increases; concomitant use of cyclosporine had a significant impact on serum creatinine levels. The decrease in mean alanine aminotransferase levels at 1 year correlated significantly with reduction in serum ferritin (r = 0.40, P < .001). Mean absolute neutrophil and platelet counts remained stable during treatment, and there were no drug-related cytopenias. This prospective dataset confirms the efficacy and well characterizes the tolerability profile of deferasirox in a large population of patients with aplastic anemia. This study was registered at www.clinicaltrials.gov as #NCT00171821.

The relationship between leukemoid reaction and perinatal morbidity, mortality, and chorioamnionitis in low birth weight infants

Neonatal leukemoid reaction (NLR) is relatively rare and considered as a white blood cell (WBC) count ≥50×10(9)/l . The aim of this study was to investigate the association of NLR with neonatal morbidity and mortality and maternal chorioamnionitis in low birth weight infants. In this case-controlled retrospective study, the medical records of 1200 newborn infants with a birth weight <2500g admitted to the neonatal unit over a period of 5 years were reviewed. The infants who developed features of NLR (n=17, 1.4%) formed the study group, while the remainder without NLR, matched for gestational age and birth weight (n=123), formed the control group. A chart review was performed and salient demographic, clinical, and laboratory data abstracted. A statistical analysis was subsequently performed on this data. The mean WBC and absolute neutrophil counts of infants with NLR were significantly higher than those in the control group. The peak time of NLR was at 7.9±3.6 (interquartile range (IQR) 1-30) days and on average it improved within 4.1±1.95 (IQR 2-9) days. It was noted that those infants with NLR were mostly born by vaginal delivery and their mothers had a higher rate of early rupture of the membranes and chorioamnionitis. NLR was associated with a 4-fold increase in sepsis, 20-fold increase in intraventricular hemorrhage, 54-fold increase in bronchopulmonary dysplasia, and 6-fold increase in mortality. In the study group, those infants whose mothers had chorioamnionitis had a higher rate of early rupture of the membranes and they developed sepsis and intraventricular hemorrhage more often than those whose mothers did not have clinical chorioamnionitis. In low birth weight newborn infants, NLR is significantly associated with sepsis, intraventricular hemorrhage, bronchopulmonary dysplasia, and a high mortality rate. Also, those infants with NLR are more likely to be born to mothers with chorioamnionitis and they face sepsis and intraventricular hemorrhage more often.

Risk factors for infection during treatment with peginterferon alfa and ribavirin for chronic hepatitis C

Neutropenia during treatment with peginterferon alfa and ribavirin for chronic hepatitis C virus (HCV) infection is a common cause of dose reductions of peginterferon alfa. These reductions are performed to prevent bacterial and fungal infections, which are common during HCV treatment and can be attributed to neutropenia. The aims of this study were to investigate the occurrence of infections and their relation to neutropenia and to identify potential risk factors for infections during HCV treatment. In this single-center cohort study, 2,876 visits of 321 patients treated with peginterferon alfa and ribavirin were evaluated for neutropenia, infections, dose reductions, and potential risk factors for infection during HCV treatment. The baseline mean absolute neutrophil count (ANC) was 3,420 cells/μL, and 16 patients had a baseline ANC of <1,500 cells/μL. During treatment, neutropenia, which was defined as ANC <750 cells/μL, was observed in 95 patients (29.7%) and ANC <375/μL was observed in 16 patients (5%). Ninety-six infections were observed in 70 patients (21.8%). Thirteen infections (13.5%) were defined as severe. Infections were not correlated with neutropenia during treatment. Dose reductions did not lead to a decrease in infection rate. Multivariate logistic regression analysis revealed that age >55 years (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.19-3.56, P = 0.01) and baseline hyperglycemia (OR 2.17, 95% CI 1.15-4.10, P = 0.016) were associated with an increased risk of infection during HCV treatment. Cirrhosis and chronic obstructive pulmonary disease were not risk factors for infection. Bacterial infections during treatment with peginterferon alfa and ribavirin are not associated with neutropenia. Older patients and patients with poorly controlled diabetes mellitus have a greater risk of developing infections during HCV treatment.

Comparison of the pharmacodynamic profiles of a biosimilar filgrastim and Amgen filgrastim: results from a randomized, phase I trial

Further to the patent expiry of Neupogen® (Amgen filgrastim), Hospira has developed a biosimilar filgrastim (Nivestim™) that may offer a clinically effective alternative for multiple hematologic and oncologic indications. Here results are reported from a phase I trial, primarily designed to compare the pharmacodynamic profiles of Hospira filgrastim and Amgen filgrastim. A phase I, single-center, double-blind, randomized trial was undertaken to demonstrate equivalence of the pharmacodynamic characteristics of Hospira filgrastim and Amgen filgrastim. Fifty healthy volunteers were randomized to receive 5 or 10 µg/kg dosing, before further randomization to treatment sequence. All volunteers received five daily subcutaneous doses of Hospira filgrastim or Neupogen, with subsequent crossover to the alternative treatment. Bioequivalence was evaluated by analysis of variance; if the estimated 90% confidence intervals (CIs) for the ratio of ‘test’ to ‘reference’ treatment means were within the conventional equivalence limits of 0.80–1.25, then bioequivalence was concluded. Forty-eight volunteers completed the study. Geometric mean absolute neutrophil count area under the curve from time 0 to the last time point at day 5 (primary endpoint) was comparable in volunteers given Hospira filgrastim or Amgen filgrastim at 5 µg/kg (ratio of means, 0.98; 90% CI, 0.92–1.05) or 10 µg/kg (ratio, 0.97; 90% CI, 0.93–1.01); 90% CIs were within the predefined range necessary to demonstrate bioequivalence. Hospira filgrastim was well tolerated with no additional safety concerns over Amgen filgrastim. Hospira filgrastim is bioequivalent with Amgen filgrastim with regard to its pharmacodynamic characteristics.

Pegfilgrastim Appears Equivalent to Daily Dosing of Filgrastim to Treat Neutropenia After Autologous Peripheral Blood Stem Cell Transplantation in Patients With Non-Hodgkin Lymphoma

Filgrastim decreases the time to neutrophil recovery after autologous peripheral blood stem cell transplantation (PBSCT). We hypothesized that single-dose pegfilgrastim would mimic multiple daily doses of filgrastim, resulting in an equivalent shortening of post-PBSCT neutropenia. Patients who were eligible for PBSCT and aged >or= 18 years were identified before high-dose chemotherapy, after the harvesting and cryopreservation of peripheral blood progenitor cells (ie, > 2.5 x 10(6) CD34-positive cells/kg). Eligible patients received either standard carmustine/etoposide/cytarabine/melphalan (BEAM) or carmustine/etoposide/cytarabine/cyclophosphamide (BEAC) high-dose chemotherapy. Before high-dose chemotherapy, patients were randomly assigned to receive pegfilgrastim 6 mg on day 1 (arm A) or weight-based, dose-adjusted filgrastim beginning on day 1 (arm B) after transplantation until neutrophil engraftment. One-hundred and one patients were enrolled between April 2003 and April 2007. Three patients were not treated. Demographics were well-balanced in terms of stage at diagnosis, Eastern Cooperative Oncology Group performance status, histology, and lines of previous therapy. Results (arm A/arm B) pertained to mean doses received (1.0/12.6), mean absolute neutrophil count recovery days (9.3/9.8), red blood cell transfusions (1.7/1.9), red blood cell transfusion units (3.1/3.8), platelet transfusions (3.1/2.8), positive blood culture rate (18%/29.2%), febrile neutropenia (FN; 18%/16.7%), and duration of FN (days; 7.1/6.9). Transplantation-related mortality and grade 3 or 4 adverse events were comparable between arms. Pegfilgrastim after PBSCT appears equivalent to multiple daily doses of filgrastim. This approach might be considered in lieu of filgrastim, thus obviating the need for multiple daily injections.

Molecular methodology to assess the impact of cancer chemotherapy on the oral bacterial flora: a pilot study

This pilot study determined the profile of the oral bacterial flora in an outpatient cancer population before and after chemotherapy using molecular techniques. We recruited 9 newly diagnosed breast cancer patients scheduled for induction chemotherapy. All were seen immediately before chemotherapy, and 7 to 14 days later. At both visits, we performed oral evaluations and obtained mucositis grading (with the World Health Organization [WHO] scale), absolute neutrophil counts (ANC), and bacterial samples from the buccal mucosa. Bacterial DNA was isolated, and 16S ribosomal RNA gene clonal libraries were constructed. Sequences of genes in the library were used to determine species identity by comparison to known sequences. After chemotherapy, WHO scores of 0 and 1 were in 3 and 6 patients, respectively, and mean ANC (+/-SD) dropped from 3326 +/- 463 to 1091 +/- 1082 cells/mm(3). From pre- and post-chemotherapy samples, 41 species were detected, with a predominance of Gemella haemolysans and Streptococcus mitis. More than 85% of species have not been previously identified in chemotherapy patients. Seven species appeared exclusively before chemotherapy and 25 after chemotherapy. After chemotherapy, the number of species per patient increased by a mean of 2.6 (SD = 4.7, P = .052). We identified species not previously identified in chemotherapy patients. Our results suggest a shift to a more complex oral bacterial profile in patients undergoing cancer chemotherapy.

Tanespimycin + Bortezomib Demonstrates Safety, Activity, and Effective Target Inhibition in Relapsed/Refractory Myeloma Patients: Updated Results of a Phase 1/2 Study.

Abstract 2890Poster Board II-866 INTRODUCTION:Tanespimycin disrupts Hsp90, a key molecular chaperone for signal transduction proteins critical to myeloma growth, survival, and drug resistance. Increased Hsp70 expression is a pharmacodynamic (PD) marker for Hsp90 inhibition (Modi et al, J Clin Oncol, 2007). Tanespimycin + bortezomib has synergistic antitumor activity and enhanced proteasome inhibition in primary multiple myeloma (MM) cells. Tanespimycin + bortezomib has demonstrated durable responses in patients with relapsed/refractory MM with low rates of neutropenia and peripheral neuropathy (PN) relative to historical data on bortezomib monotherapy. In preclinical studies, tanespimycin protected against bortezomib-induced PN. Here we present PD data and updated efficacy and safety results of this phase 1/2 study of tanespimycin + bortezomib in patients with relapsed/refractory MM. METHODS:Patients with relapsed/refractory MM who had received ≥2 prior regimens were enrolled and received bortezomib (0.7, 1.0, or 1.3 mg/m2) intravenous (IV) bolus followed by a 1-hour infusion of tanespimycin (100, 150, 220, 275, or 340 mg/m2) on days 1, 4, 8, and 11 in each 21-day cycle. Peripheral blood mononuclear cells (PBMCs) were collected and lysates were analyzed for Hsp70 expression and 20S proteasome activity. Hsp70 levels, measured by Western blot, and 20S proteasome activity, measured as composite of chymotrypsin, trypsin, and caspase activity, were measured on days 1 and 11 at 0, 4, and 24 hours postdose and normalized to baseline pretreatment levels in each patient. RESULTS:Seventy-two patients were enrolled with 42 patients treated at the highest doses (340 mg/m2 tanespimycin, 1.3 mg/m2 bortezomib). The median age was 60 years and 72% had IgG subtype. Median time since MM diagnosis was 51 months and the median number of prior regimens was 5 (range 1–15) including stem cell transplant (69%), thalidomide (74%), bortezomib (69%), lenalidomide (28%), and other Hsp90 inhibitors (13%). A total of 78% of patients had a history of PN prior to study entry. In the present study, overall response rates (ORR; minimal response or better by modified EBMT) were 48% in the 21 bortezomib-naive patients, 22% in the 23 bortezomib-pretreated patients, and 13% in the 23 bortezomib-refractory patients. ORR was 64% in bortezomib-naive patients who had '3 prior regimens. The median duration of response was 12 months (n=18 patients), including 3 bortezomib-refractory patients each with durable partial responses (PRs) through months 12, 22, and 27, respectively. Of these 3 bortezomib-refractory patients with long-term responses, 2 patients had progressed while being treated with prior bortezomib (bortezomib/dexamethasone and bortezomib/thalidomide/dexamethasone). Thrombocytopenia occurred in 40% of patients (25% Grade 3/4). In cycle 1, mean platelet counts decreased from 180,000/μL on day 1 to 154,000/μL on day 11. Neutropenia was observed in only 4% of patients (3% Grade 3/4). In cycle 1, mean absolute neutrophil counts (ANC) actually increased from 3.0 × 109/L on day 1 to 4.2 × 109/L on day 11. Grade 1 or 2 PN was observed in 15 patients (21%) and importantly no Grade 3/4 PN was observed. Similarly, no severe constipation or anorexia was observed. Hsp90 inhibition was achieved at tanespimycin doses of 275 mg/m2 (n=3) and 340 mg/m2 (n=15) as exhibited by 1.9-fold and 1.5-fold Hsp70 increases, respectively, from baseline to day 1 hour 4 and 1.7-fold and 2.0-fold Hsp70 increases, respectively, from baseline to day 11 hour 0. Proteasome activity decreased from 100% at baseline to 40%, 54%, 61%, and 53% at day 11 hour 1 with tanespimycin doses of 150 (n=2), 220 (n=3), 275 (n=5), and 340 mg/m2 (n=23), and further decreased to 26%, 36%, 43%, and 34%, respectively, at day 11 hour 24. CONCLUSION:Tanespimycin and bortezomib in combination is well tolerated with a low frequency of PN and neutropenia, which compares favorably with historical data on bortezomib monotherapy. Tanespimycin + bortezomib effectively targets the proteasome (with decreased 20S proteasome activity) and Hsp90 (as reflected by increased Hsp70 expression), and is associated with durable responses in heavily pretreated MM patients. Tanespimycin + bortezomib is currently being tested in a randomized phase 3 clinical trial. Disclosures:Richardson:Millennium and Celgene: Speakers Bureau; Millennium Pharmaceuticals: Research Funding. Off Label Use: Combination uses. Chanan-Khan:Millennium, Celgene, Immunogen: Honoraria, Speakers Bureau. Lonial:Novartis: Consultancy; BMS: Consultancy; Millennium: Consultancy, Research Funding; Celgene: Consultancy; Gloucester: Research Funding. Kopit:Bristol-Myers Squibb,: Employment, Equity Ownership. Berman:Bristol-Myers Squibb: Employment. Anderson:Celgene, Novartis, Millennium, BMS: Honoraria; Celgene, Novartis, Millennium, BMS: Research Funding; Celgene, Novartis, Millennium, BMS: Consultancy.

Low Prevalence of Asymptomatic Neutropenia in Thailand.

Abstract 1411Poster Board I-434 Background:The prevalence and etiology of asymptomatic neutropenia in Asians are still unknown. Therefore, we conducted the epidemiologic study to survey the frequency and related factors of neutropenia in general Thai population. Method:Blood samples from healthy Thai citizens resided in Bangkok and 4 provinces from different areas were collected from October 2008-May 2009. Absolute neutrophil count (ANC) < 1.50 ×109/l was used as the cut-off point for neutropenia.[1] Results:Six thousand nine hundred and seventy one samples were analyzed. There were 2,422 male and 4,549 female. The median age was 49 years (range 15-93 years). The subjects from Bangkok (n=4,297) are younger and are more commonly male compared to those from non-urban areas (n=2,674) (p<0.01). The overall mean white blood cell count (WBC) and ANC were 7.57±4.07 ×109/l (mean ± 2SD) and 4.18 ±3.05 ×109/l (mean ± 2SD), respectively. The prevalence of neutropenic cases were 0.43% (30 cases, 95%CI 0.41-0.44). The mean percentage of the circulating neutrophil count was 54.58±17.25% (mean ± 2SD). It was notable that 1.87% of the participants had the circulating WBC ≥ 12.6 ×109/l. There was no influence of age, sex or survey sites on the prevalence of neutropenia. The neutropenia subjects defined as ANC lower than 2SD of the studied populations (1.13 ×109/l) were only 8 cases (0.11%). The prevalence of cases, which ANC < 1.0 and 0.5 ×109/l, were 0.03% and 0% respectively. Conclusion:The frequency of asymptomatic neutropenia in Thai was 0.43% defined by ANC < 1.50 ×109/l. Compared with the previous largest population report[1], the prevalence were lower than that of American white (0.79%, 95%CI 0.57-1.01), African American (4.47%95%CI 3.92-5.02) and similar to Mexican American (0.38%, 95%CI 0.24-0.52). The underlying cause of these racial discrepancies remains to be explored.[1] Hsieh MM, Everhart JE, Byrd-Holt DD, Tisdale JF, Rodgers GP. Prevalence of neutropenia in the U.S. population: age, sex, smoking status, and ethnic differences. Ann Intern Med. 2007 Apr 3;146(7):486-92. Disclosures:No relevant conflicts of interest to declare.

Effect of experimental feeding of Codiaeum variegatum leaves on growth, hematology, gonadal, and extra-gonadal sperm reserves of adult albino rats

Twenty-four male adult albino rats, weighing between 130 and 239 g, were randomly divided into four groups of six rats per group (A to D). The rats were fed either normal pelleted commercial feed containing 14.5% crude protein alone (group A) or feed supplemented with pulverized dry leaves of Codiaeum variegatum (garden croton) at the levels of 0.25% (B), 0.5% (C), and 1.0% (D). All four groups of rats were fed for 12 weeks, during which period clean water was provided ad libitum. Every 2 weeks, body weights of individual rats were taken and blood collected for hematology (packed cell volume (PCV), total and differential leukocyte counts). Hemoglobin concentration was determined at 4-week intervals. At the end of the 12-week study period, all rats were sacrificed; testes and epididymes of individual rats were weighed separately to calculate the organosomatic index for both organs. Thereafter, testicular and epididymal sperm counts were performed. Supplementing rat feed with C. variegatum leaves in treated groups (B, C, and D) resulted in reduced weight gain such that by the 12th week of study, the mean body weight of group D rats was significantly lower than that of the unsupplemented control (group A) rats. The testicular and epididymal organosomatic index for the different treatment groups were not significantly (P > 0. 05) different from the mean values for group A rats. The hematological evaluation of the rats showed that supplementation at any of the level used did not significantly (P > 0. 05) alter the mean PCV values. The mean total leukocyte and the mean absolute neutrophil counts (by the fourth week) for the treated groups were significantly (P 0.05) from the mean values for the control group. On the other hand, the mean epididymal sperm counts for the treated rat groups were significantly (P < 0. 05) lower than the mean values for the control in a dose-dependent pattern. This study has shown that feeding male rats in particular and probably other animals in general on the leaves of garden croton at a level as low as 0.25% level of supplementation has the tendency to stimulate the immune function of animals but could severely reduce the testicular and epididymal sperm reserve counts, thereby reducing the reproductive efficiency of male animals. These results recommend further studies in respect to the immunostimulating and spermatotoxic properties of the leaves of this plant.

Obtaining Routine Blood Cultures During Interleukin-2-Containing Therapy Is Unnecessary

To evaluate the usefulness of routine blood cultures in patients who develop temperatures of 38.5 degrees C or higher while treated with interleukin-2 (IL-2). Retrospective chart review study. Charts of patients treated with high-dose IL-2 or biochemotherapy for metastatic melanoma were reviewed at the University of Louisville from 2005 to 2007. The study objective was to estimate the frequency of true and false positive blood cultures. A total of 205 blood cultures in 46 patients (27 male, 19 female) were reviewed. The average age was 53 years (25-71 years). The patients had an average of 3 cycles of therapy. The mean temperature of the febrile episodes was 38.7 degrees C. The mean absolute neutrophil count was 5.1 K/microL. Of these 205 febrile episodes, only 1 blood culture was true positive. The patient had methicillin sensitive staphylococcus aureus bacteremia. There were 5 false positive blood cultures. Four hundred thirty-four further febrile episodes were documented without blood cultures drawn. None of these patients were found to be infected. The yield of true positive blood cultures in this setting was 0.5% (0%-3%, CI). There was, however, a higher number of false positive blood cultures, 2.4% (0.5%-4.5%, CI). Blood cultures during IL-2 containing therapy are very inefficient to differentiate between infections versus IL-2-related fever.

Primary autoimmune neutropenia in children in Taiwan

Autoimmune neutropenia in children is caused by granulocyte-specific autoantibodies. These antibodies react to the patient's own neutrophils but disappear when the neutropenia spontaneously remits. This study reviewed our experience with autoimmune neutropenia in children and investigated possible associations with HLA-DR and HLA-DQ alleles. From 1993 to 2006, our laboratory received 155 blood samples from children with neutropenia. Of these samples, 55 had granulocyte-specific autoantibodies on the indirect granulocyte immunofluorescence test. As the children had no other disorders associated with neutropenia, they were diagnosed with primary autoimmune neutropenia. HLA-DRB1 and -DQB1 allele typing was performed in 31 cases, and the results were compared with those of 190 normal healthy unrelated Taiwanese controls. The mean ages of onset and resolution of neutropenia were 9.8 months (median, 9.0 months; range, 4-28 months) and 22.5 months (median, 20.0 months; range, 13-44 months), respectively. The male-to-female ratio was 1.2:1. The mean absolute neutrophil count was 190 per microL (standard deviation, 213/microL). Most patients (74%) had antibodies against HNA-1a. Autoimmune neutropenia in children in Taiwan was significantly associated with HLA-DQB1*0503 (odds ratio, 6.48; p = 0.0002; p(c) = 0.003) allele. In Taiwan, autoimmune neutropenia in children is associated with HLA-DQB1*0503. The autoantibody in autoimmune neutropenia is most commonly anti-HNA-1a.

Granulocyte transfusion therapy in abdominal organ transplant recipients

Patients with neutropenia are at increased risk for infections. Granulocyte transfusions (GT) have had mixed success in treatment of neutropenic infections in adult patients with hematologic malignancy. This study examined the outcomes of GT therapy in neutropenic solid organ transplant recipients, a novel population for this therapy. We performed a retrospective examination of the transfusion and medical records of all 14 solid organ-transplant recipients without hematologic malignancy who experienced neutropenia and received GT therapy from 2004 to 2006. Twelve patients received GT therapy for an active infection and two patients for infection prophylaxis. The mean absolute neutrophil count (ANC) one day increment per GT in these patients was 526/microl (median 215/microl). The mean ANC one day increment per dose of 10(10) granulocytes was 246/microl (median 86/microl). Of the 12 infected patients, four patients (33%) showed a clinical response to GT with improvement or resolution of the infection, 7 (58%) patients had no clinical response and one additional patient had a clinical response to a course of GT but died during a second GT course. Neither patient receiving GT for prophylaxis developed an infection. We observed temporal increases in ANC to levels above 1,000/microl in 15/18 (83.3%) courses of GT. We observed a clinical response to infection in 5/12 (42%) patients, the remaining infected patients had no clinical response. Our results suggest that GT therapy in neutropenic solid organ transplant recipients can boost peripheral blood neutrophil counts. Additional studies are needed to document an independent clinical benefit for GT in this patient population.

The safety and efficacy of day 1 versus day 2 administration of pegfilgrastim in patients receiving myelosuppressive chemotherapy for gynecologic malignancies

Objective Pegfilgrastim is indicated to decrease the incidence of febrile neutropenia in patients with gynecologic malignancies who are receiving myelosuppressive chemotherapy. We sought to compare the safety and efficacy of day 1 pegfilgrastim administration to day 2 administration in patients with gynecologic malignancies. Methods We retrospectively evaluated patients receiving both chemotherapy and pegfilgrastim from June 1, 2006 to August 31, 2007 for a gynecologic malignancy. Abstracted data included patient demographics, pathology, blood counts, toxicity, and chemotherapy. After administration of chemotherapy, all patients either received 6 mg of pegfilgrastim subcutaneously on day 1 or day 2. Results 1226 administrations of pegfilgrastim in 230 patients were identified. 490 administrations of pegfilgrastim were given on day 1 compared to 736 on day 2. 70% of patients had ovarian cancer with a median age of 64 years (range 15–88). 79% of patients had stage III, IV, or recurrent disease and 67% were undergoing primary chemotherapy. The most common chemotherapy was docetaxel/carboplatin (53%) followed by paclitaxel/carboplatin (19%). The mean absolute neutrophil count (ANC) nadir was 4810/mm 3 in the day 1 cohort compared to 4212/mm 3 in the day 2 cohort ( p = .004). The incidence of Grade 3/4 neutropenia was similar in both groups (4.9% in day 1 vs. 5.7% in day 2; p = .63). Grade 3/4 febrile neutropenia was uncommon in both cohorts (0 episodes vs. 3 episodes; p = .41). Treatment delays were similar in both cohorts (5.9% vs. 7.5%; p = .35). Dose modifications were also similar in both cohorts (2.8% vs. 5.3%; p = .06). Conclusion Day 1 administration of pegfilgrastim is as effective as day 2 administration in the prevention of neutropenia in patients with gynecologic malignancies. Treatment delays and dose modifications were not increased after day 1 administration of pegfilgrastim. Administering pegfilgrastim on day 1 appears to be safe, effective, and convenient in selected patients receiving myelopsuppressive chemotherapy for gynecologic malignancies.