Course Of Neutropenia Research Articles

Population Pharmacokinetic/Pharmacodynamic Analyses of Pemetrexed and Neutropenia: Effect of Vitamin Supplementation and Differences between Japanese and Western Patients

The objectives of the analysis were to characterize the time course of neutropenia after pemetrexed administration using an established semimechanistic-physiologic model, characterize the relationship between pemetrexed exposure and neutropenia, and describe differences in neutropenic response by vitamin supplementation status and between Japanese and Western patients. An eight-compartment population pharmacokinetic/pharmacodynamic model was used to describe the absolute neutrophil count (ANC)-time profile (neutropenic response) following pemetrexed doses of 300 to 1,400 mg/m(2) administered every 21 days. The analyses pooled data from 13 studies including 279 patients (161 supplemented with oral folic acid and intramuscular vitamin B(12), and 118 unsupplemented; 248 Western and 31 Japanese) who received 857 treatment cycles. Vitamin supplementation status, ethnic origin, and drug exposure were the dominant predictors of neutropenic response. Vitamin supplementation diminishes neutropenic response to pemetrexed. Model-predicted ANC nadirs for the "typical" Western patient receiving 500 mg/m(2) pemetrexed +/- vitamin supplementation were 2.74 x 10(9)/L and 1.70 x 10(9)/L, respectively. Japanese patients had a less pronounced neutropenic response to pemetrexed relative to Western patients. The model-predicted ANC nadir for Japanese patients receiving 500 mg/m(2) pemetrexed with vitamin supplementation was 2.66 x 10(9)/L. Values for the 1,000 mg/m(2) dose with vitamin supplementation were 1.91 x 10(9)/L and 1.34 x 10(9)/L for Japanese and Western patients, respectively. Increased albumin, decreased cystathionine, and decreased body surface area were also associated with increased neutropenic response. The neutropenic response to higher pemetrexed doses administered with vitamin supplementation is tolerable. All other factors equal, Japanese patients have a lesser neutropenic response to pemetrexed relative to Western patients.

Clinical Characteristics in Neonates with Alloimmune Neutropenia: Significance of the Detection of Antineutrophil Antibodies

Neonate alloimmune neutropenia (NAIN) is caused by the transplacental transfer of maternal alloantibodies directed against antigens on the infant's neutrophils. To date, there are scant studies about its clinical characteristics and characterization of antineutrophil antibodies though some case reports are found. In this study we analyzed 11 cases with NAIN from January 2005 to December 2007. The diagnosis of NAIN was confirmed by the transient neutropenia less than 500/μl of absolute neutrophil count (ANC), the detection of maternal antineutrophil antibody, the incompatibility of neutrophil antigens between parents, and their mothers without autoimmune diseases. Antineutrophil antibodies were detected by granulocyte indirect immunofluorescence test using flow cytometry. To quantify the strength of the antibodies, the ratio of the mean fluorescence channel of each sample to that of control serum was expressed as relative fluorescence intensity according to the method reported previously (Blood 99: 3468, 2002). The median age at diagnosis in NAIN patients was 8 days after birth ranged from 0 to 30 days. The average of ANC at the presentation was 170/μl ranged from 0 to 500/μl. All antineutrophil antibodies detected in sera of both neonates and their mothers were against HNA-1 antigens. The alloantibody against HNA-1a was found in 2 cases, that against HNA-1b was in 6 cases, and that against FcγR IIIb was found in 3 cases. The fact that the frequencies of homozygote of HNA-1a and HNA-1b in Japanese population were approximately 50% and 12%, respectively may reflect the frequency of alloantibody specificity in NAIN. During the neutropenic period, 7 cases with NAIN showed mild to moderate infections associated with neutropenia, such as pyrexia and pyodermia. In contrast, 4 of 11 cases with NAIN did not have any infectious episodes in their clinical course. In all patients, the spontaneous recovery of neutropenia with the disappearance of alloantibody was observed within 6 months (median 85 days ranged from 3 weeks to 6 months). The duration until spontaneous resolution of neutropenia was dependent on the strength of alloantibody found in sera of the mothers and neonates. Two patients with significantly high strength of alloantibodies had the relatively long duration to restore the neutropenia(4 months and 6 months). In conclusion, the specificity of antineutrophil antibodies in patients with alloimmune neutropenia is dependent on the frequencies of neutrophil antigens in Japanese population. The quantification of alloantibodies in neonates and their mothers may be useful in considering the clinical course of neutropenia in neonates.

Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Neutropenia during Phase I Development of Liposome-Entrapped Paclitaxel

To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of liposome-entrapped paclitaxel easy-to-use (LEP-ETU) and to characterize the relationship between LEP-ETU concentrations and the time course of neutropenia in cancer patients. LEP-ETU was administered to 88 patients and 63 were evaluable for pharmacokinetic/pharmacodynamic (PK/PD) analysis following 1.5- and 3-h infusions every 3 weeks (q3w; dose range, 135-375 mg/m(2)). MTD was identified using a 3 + 3, up-and-down dose-finding algorithm. PK/PD modeling was done to describe the temporal relationship between paclitaxel concentrations and neutrophil count. Simulations assessed the influence of dose and schedule on neutropenia severity to help guide dose selection. The MTD of LEP-ETU was identified as 325 mg/m(2). DLTs occurring at 375 mg/m(2) consisted of febrile neutropenia and neuropathy. The C(max) and area under the plasma concentration-time curve of LEP-ETU were less than proportional with increasing dose. The PK/PD model showed that LEP-ETU inhibition of neutrophil proliferation was 9.1% per 10 mug/mL of total paclitaxel concentration. The incidence of grade 4 neutropenia increased from 33% to 42% across the dose range of 275 to 325 mg/m(2) q3w. For a dose of 110 mg/m(2) given weekly, grade 4 neutropenia was estimated to be 16% compared with 42% for the same total dose administered q3w. LEP-ETU can be administered safely at higher doses than Taxol. Modeling and simulation studies predict that 325 mg/m(2) LEP-ETU q3w provides acceptable neutropenic events relative to those observed at 175 mg/m(2) Taxol q3w. A 275 mg/m(2) dose may offer an improved therapeutic index.

Multiple-pool cell lifespan models for neutropenia to assess the population pharmacodynamics of unbound paclitaxel from two formulations in cancer patients

Our objective was to build a mechanism-based pharmacodynamic model for the time course of neutropenia in cancer patients following paclitaxel treatment with a tocopherol-based Cremophor-free formulation (Tocosol Paclitaxel) and Cremophor EL-formulated paclitaxel (Taxol). A randomized two-way crossover trial was performed with 35 adult patients who received 175 mg/m(2) paclitaxel as either 15 min (Tocosol Paclitaxel) or 3 h (Taxol) intravenous infusions. Paclitaxel concentrations were measured by LC-MS/MS. NONMEM VI was used for population pharmacodynamics. The cytotoxic effect on neutrophils was described by four mechanism-based models predicated on known properties of paclitaxel that used unbound concentrations in the central, deep peripheral or an intracellular compartment as forcing functions. Tocosol Paclitaxel was estimated to release 9.8% of the dose directly into the deep peripheral compartment (DPC). All models provided reasonable fitting of neutropenic effects. The model with the best predictive performance assumed that this dose fraction was released into 22.5% of the DPC which included the site of toxicity. The second-order cytotoxic rate constant was 0.00211 mL/ng per hour (variability: 52% CV). The relative exposure at the site of toxicity was 2.21 +/- 0.41 times (average +/- SD) larger for Tocosol Paclitaxel compared to Taxol. Lifespan was 11.0 days for progenitor cells, 1.95 days for maturating cells, and 4.38 days for neutrophils. Total drug exposure in blood explained half of the variance in nadir to baseline neutrophil count ratio. The relative exposure of unbound paclitaxel at the site of toxicity was twice as large for Tocosol Paclitaxel compared to Taxol. The proposed mechanism-based models explained the extent and time course of neutropenia jointly for both formulations.

Change of neutrophil count after treatment of intravenous immunoglobulin in children with idiopathic thrombocytopenic purpura

Purpose : The aim of this study was to investigate the incidence and course of neutropenia following intravenous immunoglobulin (IVIG) therapy in children with idiopathic thrombocytopenic purpura (ITP). Methods : From January 2001 to June 2006, fifty-four patients with ITP were enrolled in this study. Forty-two of 54 patients were treated with IVIG, while the other 12 were treated with anti-D immunoglobulin (Anti-D Ig). Post-treatment absolute neutrophil counts (ANC) were compared between patients who received IVIG and those who received Anti-D Ig. Comparison of post-treatment ANC between patients who treated with two different IVIG regimens (400 mg/kg/day for 5 days and 1 g/ kg/day for 2 days) was also performed. Results : Pretreatment ANC were not significantly different between the two treatment groups. After treatment with IVIG, 32 out of 42 patients (76.2%) showed more than 50% decrease of ANC from the baseline. On the other hand, only 2 out of 12 patients (16.7%) showed more than 50% decrease of ANC from the baseline after treatment Anti-D Ig. No significant difference was observed in the decline of ANC between the first IVIG treatment (42 patients) and repeated IVIG treatment groups (7 patients). There was no statistical difference in post-treatment ANC between patients who treated with two different IVIG regimens. The neutropenia induced by IVIG had resolved spontaneously in 38 out of 39 patients (97%) after several days. Conclusion : Neutropenia following IVIG administration may not be an uncommon finding in children with ITP. It seems to be transient and self limited.

A Novel Non-Invasive Method of Detecting Galactomannan in Suspected Pulmonary Aspergillosis.

Invasive pulmonary aspergillosis (IPA) is now the leading cause of infectious mortality in stem cell transplant recipients. Despite recent advances in molecular diagnostic techniques the diagnosis remains problematic. The mycological yield from bronchoalveolar lavage (BAL) is poor, especially if the patient has been exposed to antifungal drugs. Galactomannan (GM), a component of Aspergillus' cell wall is detectable in serum and BAL fluid in IPA, though its role in the latter has not been validated. Exhaled breath condensate (EBC) collection provides a non-invasive means of sampling the airway lining fluid. This method has been used in respiratory disease to detect markers of inflammation and oxidative stress. EBC is collected by breathing into a tube surrounded by a cooled insulated metal sleeve (RTube®, Respiratory Research, USA) and results in 1–2 millilitres of fluid. The application of EBC detection of volatile and non-volatile organic compounds has not been explored in this setting. We report on pilot data of the detection of GM in EBC from a subset of patients at high risk of infection forming part of a prospective study into the early diagnosis of IPA in allogeneic transplant recipients and patients with acute leukaemia. Patients were recruited prior to commencing treatment for their underlying haematological condition; the study period finished at neutrophil recovery (> 0.5 x 109/L) or discharge from hospital. EBC and serum were collected once and twice weekly respectively, throughout the study period. High resolution CT (HRCT) imaging of the chest was carried out after 72 hours of neutropenic fever unresponsive to broad-spectrum antibiotics. Where possible, BAL was carried out in the most affected lobe in patients with an abnormal HRCT chest. GM was measured in EBC, serum and, where applicable, BAL fluid using a commercially available kit (Platelia® Aspergillus, Bio-Rad, France). The likelihood of IPA was assigned using criteria published by European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) by 2 investigators blinded to clinical details (Ascioglu et al, CID 2002). Of 39 patients, 6 had proven/probable IPA, 9 possible and 24 had no evidence of IPA. Four of the 6 patients with proven/probable disease had GM-positive BAL fluid; 3 of these 4 had persistently negative GM in serum. In 1 of the 6, the EBC GM was positive 3 weeks earlier than the development of HRCT evidence of IPA and a positive BAL GM. In another, the EBC GM was positive early in the infection, whilst BAL GM remained negative. EBC and serum GM followed the same trend in all 6 patients, although the values for both EBC and serum remained below the currently recognised positive cut-off of 0.5 in 2 patients. In patients with possible or no evidence of IPA, GM was negative in all but 2 of 111 EBC samples. These results suggest that GM can be detected in EBC and follows the same trend as in serum. It may even predate GM detection in BAL fluid or abnormal HRCT signs, thereby obviating the need for more invasive investigations. Elevated EBC GM levels early in the course of neutropenia may represent infection and could be applied to the employment of pre-emptive treatment strategies.

Mechanism-based Pharmacokinetic/Pharmacodynamic Meta-analysis of Trabectedin (ET-743, Yondelis) Induced Neutropenia

Myelosuppression was found to be one of the main toxicities of trabectedin (ET-743, Yondelis) during phase I/II studies. Our objective was to develop a pharmacokinetic-pharmacodynamic (PK/PD) model that describes the time course of the absolute neutrophil counts (ANCs) in cancer patients receiving trabectedin. Data from 699 patients who received intravenous trabectedin as monotherapy (dose range: 0.006-1.8 mg/m2) as a 1-, 3-, or 24-h infusion every 21 days; 1- or 3-h infusion on days 1, 8, and 15 every 28 days; or a 1-h infusion daily for 5 consecutive days every 21 days were used to develop (N=405; ANCs=7,291) and validate (N=294; ANCs=5,029) the model. The PK/PD model comprised a trabectedin-sensitive progenitor cell compartment, linked to the peripheral blood compartment, through three transition compartments representing the maturation chain in the bone marrow. To capture the rebound effect due to endogenous growth factors, the model included a feedback mechanism. The model estimated three system-related parameters: ANC at baseline (Circ0), mean transit time in bone marrow (MTT), and a feedback parameter (gamma). A first-order process quantified by the rate constant k(e0) described the trabectedin concentrations at the effect compartment (C(e)), which were assumed to reduce the proliferation rate and/or to increase the killing rate of the progenitor cells according to the function alphaC(e)beta. The model was qualified and simulations were undertaken to evaluate the neutropenia schedule dependency and the effects of selected covariates. NONMEM software was used to perform the modeling and simulation analyses. For a typical man of 70 kg, the mean values (between-subject variability; %) of the Circ0, MTT, gamma, k(e0), alpha, and beta were estimated to be 4.46 x 10(9)/l (37.9%), 4.0 days (37.5%), 0.218 (41.8%), 2.09 h(-1) (77.9%), 2.00 l/microg (85.1%), and 1.26, respectively. Although in women, k(e0) was reduced by 29% and a 25% increase in body weight resulted in a 12.6% reduction in the beta parameter, the clinical relevance of these effects is limited. The model evaluation procedure indicated accurate prediction of the observed incidence of neutropenia grades 3 and 4 across the dosing regimens evaluated. Simulations indicated that trabectedin dose and interdose interval, but not infusion duration, are the main determinants of the neutropenia severity. The model-predicted time course of the ANC and its variability confirmed that neutropenia is reversible, of short duration, and non-cumulative. The extent and time course of neutropenia following six different dosing regimens of trabectedin were well predicted by the semiphysiological PK/PD model.

Semi-physiological pharmacokinetic/pharmacodynamic (PKPD) model for trabectedin-induced neutropenia

9575 Background: Neutropenia was the trabectedin (T) dose limiting toxicity in phase I studies. The objective of the present study was to develop a semi-physiological PKPD model that describes the time course of the absolute neutrophil counts (ANC) in cancer subjects receiving trabectedin. Methods: A total of 704 subjects receiving intravenous T as monotherapy (dose range: 0.024 - 1.8 mg/m2) as a 1, 3 or 24 hr infusion every 21 days; 1 or 3 hr infusion on day 1, 8, 15 every 28 days; or a 1 hr infusion daily for 5 consecutive days every 21 days were used to develop (N=405, ANC=7253) and validate (N=299, ANC=4977) the model. The model comprised of a trabectedin-sensitive progenitor cell compartment, linked to the peripheral blood compartment, through three transition compartments representing the maturation chain in the bone marrow. To capture the rebound effect due to endogenous growth factors, the model included a feedback mechanism. The model estimated three system-related parameters: ANC at baseline (ANC0), mean transit time in bone marrow (MTT), and a feedback parameter. T concentrations at the effect compartment were assumed to reduce the proliferation rate and/or to increase the killing rate of the progenitor cells according to a sigmoid-EMax function. Model evaluation was examined using goodness of fit plots, relative error measurements, and posterior predictive checks. Computer simulations were undertaken to evaluate the neutropenia schedule dependency. Results: The mean (between subject variability, %) of the ANC0, MTT, T potency were estimated to be 4.4 × 109/L (39%), 3.99 days (40%), and 15.6 μg/L (58%), respectively. The feedback parameter, EMax and Hill coefficient were estimated to be 0.198, 154 and 1.48. Model validation procedure evidenced accurate prediction of the incidence of grade 3/4 neutropenia. Simulations indicated that T dose and interdose interval, but not infusion duration, are the main determinants of the neutropenia severity. The model predicted time course of the ANC confirmed that neutropenia is reversible, short-lasting, and non-cumulative. Conclusions: The extent and time course of neutropenia following five different dosing regimens of T were well predicted by the semi-physiological PKPD model. [Table: see text]

Phase I dose-finding study and a pharmacokinetic/pharmacodynamic analysis of the neutropenic response of intravenous diflomotecan in patients with advanced malignant tumours

To determine the maximum tolerated dose (MTD) of intravenous (iv) diflomotecan administered once every 3 weeks, and to characterize the relationship between pharmacokinetics and neutropenic effect, using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Twenty-four patients received a total of 75 cycles of iv diflomotecan that was administered as 20-min infusion, once every 3 weeks at escalating doses of 2, 4, 5, and 6 mg/m2. Haematological and non-haematological toxicities were evaluated. Plasma concentrations of diflomotecan were measured after the first drug administration. Dose limiting toxicity (DLT) following the first cycle occurred in 12 patients and a total of 16 patients experienced DLT at some point in the trial. During the first cycle of treatment the number of patients in the 5 and 6 mg/m2 dose groups that experienced DLT was 3 of 4, and 3 of 3, respectively. Therefore, the dose of 5 mg/m2 was considered the MTD and the dose of 4 mg/m2 the recommended dose (RD). During the first cycle, 12 patients experienced DLT, six had either infection of haematological toxicity and eight complained of fatigue. The best response was a partial response in one patient treated at the 6 mg/m2 dose level. Disease stabilization was observed in seven patients (four patients treated at 4 mg/m2 and one patient at each dose level of 2, 5, and 6 mg/m2). The remaining patients had all progressive disease. The median time to progression for all patients was 5.9 weeks. Pharmacokinetics of diflomotecan was described with a three-compartmental model. Mean population parameter estimates of the apparent volume of distribution of the central compartment (V c) increased linearly with body surface area (BSA) as: V c (L) = 41.5 x (BSA/1.85), and the mean population estimate of the apparent volume of distribution of the shallow compartment was lower in females (29.5 vs 48.8 L). Computer simulations showed the lack of clinical significance of these covariates. The time course of the neutropenic response was adequately described by a semi-mechanistic model that includes cellular processes and drug effects. The MTD and RD after a 20-min iv infusion of diflomotecan every 3 weeks are 4 and 5 mg/m2, respectively. Diflomotecan showed linear pharmacokinetic behaviour and the selected PK/PD model described adequately the time course of neutropenia. The mean model predicted values of nadir and time to nadir after a 20-min iv infusion of 4 mg/m2 of diflomotecan was 0.86 x 10(9) /L neutrophil cell counts and 11 days, respectively.

Semi-physiological model describing the hematological toxicity of the anti-cancer agent indisulam

Indisulam (N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide, GOAL, E7070) is a novel anti-cancer drug currently in phase II clinical development for the treatment of solid tumors. Phase I dose-escalation studies were conducted comparing four treatment schedules. Neutropenia and thrombocytopenia were dose limiting in all schedules. The aim of this study was to describe the extent and the time course of the hematological toxicity and its possible schedule dependency using a semi-physiological model. Data from 142 patients were analyzed using NONMEM. The semi-physiological model comprised a progenitor blood cell compartment, linked to the central circulation compartment, through 3 transition compartments representing the maturation chain in the bone marrow. Plasma concentrations of the drug were assumed to reduce the proliferation rate in the progenitor compartment according to a linear function. A feedback mechanism was included in the model representing the rebound effect of endogenous growth factors. The model was validated using a posterior predictive check. The model adequately described the extent and time course of neutropenia and thrombocytopenia. The mean transition time (MTT, i.e. maturation time in bone marrow) of neutrophils was increased by 47% in patients who received indisulam as a weekly dose administered for four out of every six weeks. For platelets, MTT was increased by 33% in patients who received this schedule and also in patients who received a continuous 120-h infusion. The validation procedure indicated that the model adequately predicts the nadir value of neutrophils and platelets and the time to reach this nadir. A semi-physiological model was successfully applied to describe the time course and extent of the neutropenia and thrombocytopenia after indisulam administration for four treatment schedules.

Models of schedule dependent haematological toxicity of 2'-deoxy-2'-methylidenecytidine (DMDC).

DMDC (2'-deoxy-2'-methylidenecytidine) is-a potential antitumour deoxycytidine analogue of cytosine arabinoside. The major dose-limiting toxicity of DMDC is haematological depression, particularly neutropenia, and therefore quantitative exposure-toxicity relationships for DMDC are warranted. Data on the survival fraction at nadir of leukocytes, neutrophils and platelets from 66 patients receiving a once-daily regimen and 85 patients receiving a twice-daily regimen of DMDC were related to DMDC concentration-time profiles using area under the plasma concentration-time curve (AUC), threshold and general models. A semiphysiological model of neutrophils versus time after DMDC administration included transient compartments to imitate the differentiation stages in the bone marrow. The relationship between plasma DMDC concentration-time profiles and the haematological toxicity at nadir was best described using an AUC-dependent model with separate functions for once- and twice-daily dosing, indicating schedule dependence of DMDC effects, even if differences in treatment duration had a similar explanatory value. Twice-daily dosing was associated with greater toxic effects than once-daily dosing. The AUC required for a 70% reduction in the neutrophils was 16 mg.h/l and 4.2 mg.h/l for the once- and twice-daily regimens, respectively. The semiphysiological model included nine proliferating transient compartments that were sensitive to DMDC in a schedule-dependent manner, five non-mitotic, non-sensitive compartments and one compartment for circulating neutrophils. The haematological toxicity of DMDC is schedule dependent. The survival fractions of leukocytes, neutrophils and platelets are predicted to be lower when given on a twice-daily regimen than on a once-daily regimen. A semiphysiological model with transient compartments successfully described the entire time course of neutropenia after DMDC administration.

Neutropenia, neutrophil dysfunction, and inflammatory bowel disease in glycogen storage disease type Ib: Results of the European Study on Glycogen Storage Disease Type I

Objective: To investigate the incidence, the severity, and the course of neutropenia, neutrophil dysfunction, and inflammatory bowel disease (IBD) in glycogen storage disease (GSD) type Ib. Method: As part of a collaborative European Study on GSD type I, a retrospective registry was established in 12 European countries that included all patients with GSD-I who were known at the centers and were born from 1960 to 1995. Of a total of 288 patients with GSD-I, 57 who had GSD-Ib form the basis of this study. Results: Neutropenia (defined as an absolute neutrophil count <1 × 109/L) was found in 54 patients. In 64% of the patients neutropenia was documented before the age of 1 year, but in 18% of the patients neutropenia was first noted between the ages of 6 and 9 years. Neutropenia was persistent in 5 patients and intermittent without any clear cyclical course in 45. Neutrophil function was investigated in 18 patients with neutropenia and was abnormal in all. Perioral infections were reported in 37 patients, perianal infections in 27 patients, and protracted diarrhea in 23 patients. Findings on colonoscopy and radiologic studies in 10 of 20 patients suspected to have IBD were abnormal in all. All patients with IBD, perioral infections, and perianal infections had neutropenia. Conclusions: Intermittent severe neutropenia is frequently found in patients with GSD-Ib. The study also indicates that IBD in GSD-Ib is underdiagnosed; up to 77% of the patients studied had evidence of IBD, all of whom had neutropenia. IBD was not detected in those with normal neutrophil counts. These findings support the notion that neutropenia and/or neutrophil dysfunction in GSD-Ib and IBD are causally related. (J Pediatr 2000;137:187-91)

Surgical Management of Invasive Pulmonary Aspergillosis in Neutropenic Patients

The aim of our study was to clarify the indications for operation in invasive pulmonary aspergillosis. Nineteen patients with hematologic malignancy, in whom invasive pulmonary aspergillosis developed during the course of neutropenia, had operations. Neutropenia lasted 28 days (range, 15 to 45 days). The preoperative diagnosis of invasive pulmonary aspergillosis was based on computed tomographic scan findings (halo or air crescent signs). Eight patients underwent emergency operations, before marrow recovery, for prevention of massive hemoptysis. The criterion for operation was an aspergillosis lesion that contacted the pulmonary artery on computed tomography. A lobectomy was performed in all cases. A sleeve resection of the pulmonary artery was necessary on two occasions. There was one postoperative death due to extensive aspergillosis. The length of hospitalization after operation was 13 days (range, 6 to 18 days). Seven patients were treated by elective resection of a residual mass (before hematologic therapy in 6 cases). The types of resection performed were lobectomy (n = 4), lingulectomy (n = 1), and wedge resection (n = 2). There were no postoperative deaths. The average length of stay before discharge from the hospital was 11 days (range, 7 to 20 days). The surgical resection was performed as a diagnostic procedure in the 4 remaining patients after an allotted time of 14 days (range, 4 to 24 days) from initiation of antifungal therapy. The combination of antifungal agents and surgical resection is an efficient strategy for the treatment of invasive pulmonary aspergillosis in patients with hematologic malignancy.

Reevaluation of the gastrointestinal selective decontamination effectiveness on the course of neutropenia in hematological malignancies

Reevaluation of the gastrointestinal selective decontamination effectiveness on the course of neutropenia in hematological malignancies

Protection from Chemotherapy-Induced Neutropenia by ImuVert

Neutropenia is a major cause of chemotherapy-induced morbidity. This study examines the effect of ImuVert on the course of neutropenia from Cytoxan and Adriamycin. In adult rats treated with either Cytoxan or Adriamycin and ImuVert, the absolute neutrophil count remained above 7,000 and 2,000, respectively, for the duration of ImuVert therapy. In contrast, in the control Cytoxan group the absolute neutrophil count reached 300/mm3 on day 5 and remained below 1,000 from day 4 through day 7. In the Adriamycin control group, the nadir absolute neutrophil count reached 600/mm3 on day 7 and remained below 100 from day 6 through day 8. C3H/EJ mice (endotoxin-hyporesponsive) treated with Cytoxan developed an absolute neutrophil count below 1,000 from day 4 through day 7. In contrast, in the group concomitantly treated with ImuVert, the nadir absolute neutrophil count remained below 1,000 only on days 4 and 5. The authors conclude that stimulation of endogenous cytokine production by ImuVert may provide a potentially useful approach to bone marrow rescue from chemotherapy.

On the Mechanisms of Haemodialysis-induced Neutropenia: A Study with Five New and Re-used Membranes

A prospective study was undertaken in 12 haemodialysed patients successively treated on five new as well as re-used dialyser membranes, that is cuprophane, cellulose acetate, polysulphone, polycarbonate, and polyacrylonitrile. A significant reduction of neutrophils occurred with every membrane during their first use, which improved only with cuprophane upon re-use. Thrombocytopenia was noted only when neutropenia reached very low values. Monocyte reduction occurred on cuprophane, cellulose acetate and polycarbonate, but did not improve during second use. C3d accumulation paralleled the time course of neutropenia only with cuprophane and cellulose acetate. Plasma collected at the extreme of neutropenia induced aggregation of control and predialysis cells, but did not aggregate autologous dialysed neutrophils collected at 5 min. Our data indicate that the mechanism linking complement activation to neutropenia is probably triggered by more than one factor.

Neutropenia Following Induction Therapy in acute Myeloid Leukaemia (AML) and Role of Granulocyte colony stimulating factor (G-CSF)

Context: This study was designed to observe the course of neutropenia that is onset of absolute neutropenia, depth of neutropenia and recovery pattern of neutropenia following induction chemotherapy and effect of granulocyte colony stimulating factor (G-CSF) on the course of neutropenia in adult acute myeloid leukaemia (AML) patients. Methods: A total of 34 newly diagnosed, adult, de novo AML patients opted to receive induction chemotherapy were enrolled for this study. All of them were given induction chemotherapy with cytarabine and daunorubicin as per 2+5 protocol. Four of them were dropped from this study; 2 due to early death and 2 due to resistant disease so were treated with early alternative chemotherapy regimen. So the ultimate sample of this study was 30 patients. Out of them 13 were given G-CSF following chemotherapy. Absolute Neutrophil count (ANC) of all patients were followed up until full recovery. Results: The difference in day of onset of absolute neutropenia (day 8 in G-CSF group vs. day 9 in no G-CSF group, P=.078) and number of day to reach nadir (day 11 in G-CSF treated group vs. day 12 in no G-CSF group, P=.688) was not significant between two group. The depth of neutropenia did not differ significantly as well (mean ANC 66/mm3 vs. 102/mm3, P=.184). However, recovery from absolute neutropenia was significantly (4 days) earlier in G-CSF treated patients (day 18 vs. day 22, P&lt;.001). G-CSF treated patients also showed earlier attainment of ANC e"1,000/mm3 (day 20 vs. day 25, P&lt;.001) and ANC e"1,500/mm3 (day 21 vs. day 27, P&lt;.001). Duration of severe neutropenia was significantly shorter (9.6 days vs. 12.8 days P=.001) in G-CSF treated group. Key words: Acute myeloid leukaemia (AML); neutropenia; Granulocyte colony stimulating factor (G-CSF) DOI: 10.3329/jdmc.v18i2.6278 J Dhaka Med Coll. 2009; 18(2) : 155-160