Clopidogrel-induced neutropenia in an 80-year-old patient with chronic kidney disease who underwent percutaneous coronary intervention: a case report and literature review.

BACKGROUND: Clopidogrel is a widely-used antiplatelet and acts as an adenosine diphosphate receptor inhibitor. Neutropenia is a rare but serious adverse effect of clopidogrel. It is unknown whether this adverse effect has any association with impaired kidney function. CASE PRESENTATION: An 80-year-old male with chronic kidney disease was diagnosed with non-ST elevation myocardial infarction and underwent percutaneous coronary intervention. During hospitalization, the patient was diagnosed with contrast-induced nephropathy, treated symptomatically, and discharged with a back-to-baseline creatinine level. Two weeks later, the patient presented to the emergency department with fever and chills. Complete blood count showed leukopenia (0.84 × 103/mm3) and severe neutropenia (0.13 × 103/mm3). Blood cultures were positive for Pseudomonas aeruginosa. Clopidogrel was stopped immediately and switched into ticagrelor. Imipenem and granulocyte colony-stimulating factor were administered to the patient. The patient's white blood cell and absolute neutrophil count were within the normal range after four days of treatment. The patient was discharged after a 10-day hospitalization, and his complete blood counts were normal during further follow-ups. CONCLUSIONS: Clopidogrel was the most likely primary cause of neutropenia in our case. The incidence of clopidogrel-induced neutropenia is low and the exact mechanism is not fully explained. We provide suggestions on the management of clopidogrel-associated neutropenia, and summarize all five cases of clopidogrel-induced neutropenia in patients with impaired kidney function.

Absolute Neutrophil Count after the First Chemotherapy Cycle as a Surrogate Marker for Treatment Outcomes in Patients with Neuroblastoma.

PURPOSE: We performed this study to determine whether the degree of neutropenia after the first chemotherapy cycle can be used as a surrogate marker of individual susceptibility to chemotherapeutic agents affecting treatment outcome in patients with neuroblastoma. MATERIALS AND METHODS: The study included 313 patients who received the first cycle chemotherapy with a CEDC (cisplatin+etoposide+doxorubicin+cyclophosphamide) regimen and had absolute neutrophil count (ANC) data available. The cumulative incidences of progression and treatment-related mortality (TRM) were estimated. To identify genetic variations associated with the ANC, a genome-wide association study (GWAS) was performed. RESULTS: An ANC of 32.5/µL was determined as the cutoff point to categorize patients into the good and poor prognosis subgroups in terms of progression. Patients with a high nadir ANC had a higher cumulative incidence of progression than those with a low nadir ANC (p < 0.001). In multivariate analysis, high nadir ANC, age, bone marrow involvement, and unfavorable histology were poor prognostic factors. With regard to the TRM, patients with a low nadir ANC (ANC < 51.0/µL) had a higher cumulative incidence of TRM than those with a high nadir ANC (p=0.010). In GWAS, single-nucleotide polymorphisms of LPHN2 and CRHR1 were significantly associated with the nadir ANC. CONCLUSION: In neuroblastoma patients, the degree of neutropenia after the first chemotherapy cycle can be used as a surrogate marker to predict an individual's susceptibility to chemotherapeutic agents. Tailoring of treatment based on the degree of neutropenia needs to be considered.

Changing epidemiology of catheter-related bloodstream infections in neutropenic oncohematological patients.

BACKGROUND: We aimed to describe the epidemiology of catheter-related bloodstream infections (CRBSIs) in onco-hematological neutropenic patients during a 25-year study period, to evaluate the risk factors for Gram-negative bacilli (GNB) CRBSI, as well as rates of inappropriate empirical antibiotic treatments (IEAT) and mortality. MATERIALS/METHODS: All consecutive episodes of CRBSIs were prospectively collected (1994-2018). Changing epidemiology was evaluated comparing five-year time spans. A multivariate regression model was built to evaluate risk factors for GNB CRBSIs. RESULTS: 482 monomicrobial CRBSIs were documented. The proportion of CRBSIs among all BSIs decreased over time from 41.2% to 15.8% (p<0.001). CRBSIs epidemiology has been changing: the rate of GNB increased over time (from 11.9% to 29.4%; p<0.001), as well as the absolute number and rate of multidrug-resistant (MDR) GNB (from 9.5% to 40.0%; p = 0.039). P. aeruginosa increased and comprised up to 40% of all GNB. Independent factors related with GNB-CRBSIs were: longer duration of in-situ catheter (OR 1.007; 95%CI 1.004-1.011), older age (OR 1.016; 95%CI 1.001-1.033), prior antibiotic treatment with penicillins (OR 2.716; 95%CI 1.306-5.403), and current antibiotic treatment with glycopeptides (OR 1.931; 95%CI 1.001-3.306). IEATs were administered to 30.7% of patients, with the highest percentage among MDR P. aeruginosa (76.9%) and S. maltophillia (92.9%). Mortality rate was greater among GNB than GPC-CRBSI (14.4% vs 5.4%; p = 0.002), with mortality increasing over time (from 4.5% to 11.2%; p = 0.003). CONCLUSION: A significant shift towards GNB-CRBSIs was observed. Secondarily, and coinciding with an increasing number of GNB-MDR infections, mortality increased over time.

Using blood calprotectin as a measure of blood neutrophils.

Presently, bed-side or at home quantification of neutrophils in blood (b-neutrophils) is not practical, because cytometric methods are too expensive and technically demanding. We have explored whether calprotectin concentration in whole blood (b-calprotectin) might be a valid measure of b-neutrophils because this principle might be used in a simple and robust immunoassay device. We obtained heparin blood samples from 77 patients with possible neutropenia, most of them cancer patients treated with cytostatic drugs, and compared b-calprotectin with their b-neutrophils in a simultaneously taken EDTA-blood sample. The Spearman rank correlation coefficient between b-calprotectin and b-neutrophils was 0.986 (p < .0001). In a regression model of b-neutrophils as a function of age, gender, type of hematology instrument, total leukocyte count minus neutrophils, b-calprotectin, and plasma calprotectin (p-calprotectin), only b-calprotectin was a statistically significant predictor. B-neutrophils below 1 × 109/L was unlikely if b-calprotectin was above 50 mg/L. In conclusion, b-calprotectin, without adjusting for p-calprotectin, correlates closely with b-neutrophils and could be used to detect b-neutrophils below 1 × 109/L.

Post-transplant primary cutaneous peripheral T-cell lymphoma not otherwise specified in a pediatric patient.

Solid organ and hematopoietic stem cell transplantation may be complicated by the development of post-transplant lymphoproliferative disorders (PTLDs). The World Health Organization categorizes PTLDs into four entities including non-destructive, monomorphic, polymorphic, and classical Hodgkin lymphoma types. The most common PTLDs are B-cell lymphomas, with T-cell lymphomas accounting for only a few cases. Cutaneous T-cell lymphomas are rarer still in post-transplant patients with primary cutaneous peripheral T-cell lymphoma being an extraordinarily rare subtype in this population. PTLDs may be aggressive and are often associated with high morbidity and mortality. Advances in medicine have led to increased awareness of PTLDs and improved diagnostic tools which assist in the diagnosis of these conditions. However, the clinical and histopathologic heterogeneity of PTLDs may make diagnosis a challenge. In the transplant patient population, the cutaneous manifestations of the lymphoproliferative disease may mimic other conditions, such as eczematous dermatitis and graft-vs-host disease. Herein, we report a case of post-transplant primary cutaneous peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) in a pediatric heart transplant patient and describe the clinical presentation and diagnostic histopathologic features.

Development and utility assessment of a machine learning bloodstream infection classifier in pediatric patients receiving cancer treatments.

BACKGROUND: Objectives were to build a machine learning algorithm to identify bloodstream infection (BSI) among pediatric patients with cancer and hematopoietic stem cell transplantation (HSCT) recipients, and to compare this approach with presence of neutropenia to identify BSI. METHODS: We included patients 0-18 years of age at cancer diagnosis or HSCT between January 2009 and November 2018. Eligible blood cultures were those with no previous blood culture (regardless of result) within 7 days. The primary outcome was BSI. Four machine learning algorithms were used: elastic net, support vector machine and two implementations of gradient boosting machine (GBM and XGBoost). Model training and evaluation were performed using temporally disjoint training (60%), validation (20%) and test (20%) sets. The best model was compared to neutropenia alone in the test set. RESULTS: Of 11,183 eligible blood cultures, 624 (5.6%) were positive. The best model in the validation set was GBM, which achieved an area-under-the-receiver-operator-curve (AUROC) of 0.74 in the test set. Among the 2236 in the test set, the number of false positives and specificity of GBM vs. neutropenia were 508 vs. 592 and 0.76 vs. 0.72 respectively. Among 139 test set BSIs, six (4.3%) non-neutropenic patients were identified by GBM. All received antibiotics prior to culture result availability. CONCLUSIONS: We developed a machine learning algorithm to classify BSI. GBM achieved an AUROC of 0.74 and identified 4.3% additional true cases in the test set. The machine learning algorithm did not perform substantially better than using presence of neutropenia alone to predict BSI.

Effect of renal function on neutrophil decreases following eribulin administration.

BACKGROUND: Eribulin therapy has recently attracted attention from various viewpoints, including quality of life, and is considered a standard therapy for inoperable or recurrent breast cancer. Although a reduction in renal function reportedly decreases total eribulin clearance, its association with dose-limiting toxicity and the reduction of neutrophils remain unclear. AIM: This study was aimed at analyzing the association between decreased renal function prior to eribulin administration and the occurrence of neutrophil reduction and time to treatment failure in patients with breast cancer. METHODS AND RESULTS: We retrospectively assessed patients with breast cancer, who underwent eribulin therapy between July 2011 and March 2018. Multivariate analysis revealed creatinine clearance <70 mL/min and serum albumin levels <3.9 mg/dL as predictive factors for neutrophil reduction. Even on increasing the relative dose intensity by these factors, no difference in time to treatment failure was observed, suggesting that treatment efficacy is potentially unaffected. CONCLUSIONS: For continuous eribulin therapy, eribulin may need to be administered to individual patients in accordance with renal function and albumin levels before treatment initiation.

Dual roles of neutrophils in metastatic colonization are governed by the host NK cell status.

The role of neutrophils in solid tumor metastasis remains largely controversial. In preclinical models of solid tumors, both pro-metastatic and anti-metastatic effects of neutrophils have been reported. In this study, using mouse models of breast cancer, we demonstrate that the metastasis-modulating effects of neutrophils are dictated by the status of host natural killer (NK) cells. In NK cell-deficient mice, granulocyte colony-stimulating factor-expanded neutrophils show an inhibitory effect on the metastatic colonization of breast tumor cells in the lung. In contrast, in NK cell-competent mice, neutrophils facilitate metastatic colonization in the same tumor models. In an ex vivo neutrophil-NK cell-tumor cell tri-cell co-culture system, neutrophils are shown to potentially suppress the tumoricidal activity of NK cells, while neutrophils themselves are tumoricidal. Intriguingly, these two modulatory effects by neutrophils are both mediated by reactive oxygen species. Collectively, the absence or presence of NK cells, governs the net tumor-modulatory effects of neutrophils.

Pharmacokinetic and pharmacodynamic analysis of neutropenia following nab-paclitaxel administration in Japanese patients with metastatic solid cancer.

PURPOSE: To develop a pharmacokinetic (PK) and pharmacodynamic (PD) model for neutropenia following nab-paclitaxel administration and identify factors associated with drug disposition and changes in neutrophil counts in patients with solid cancer. METHODS: PK/PD analysis by nonlinear mixed effects approach was performed using the data from 27 patients who participated in phase I studies of nab-paclitaxel monotherapy conducted in Japan. The patients were treated with either weekly (80, 100, or 125 mg/m2) or every 3 weeks (200, 260, or 300 mg/m2). The observed paclitaxel concentrations in whole blood and neutrophil counts in the first cycle were used for PK/PD analysis. Covariate analysis was performed to identify factors affecting PK and the decrease in neutrophil counts. RESULTS: The developed 3-compartment, non-linear PK model described relationships of body surface area with total body clearance and volume of distribution for the peripheral compartment. Covariate factors affecting neutrophil counts were age and serum albumin level. Simulation based on the developed PK/PD model showed a substantial impact of age and serum albumin level on the time course of neutrophil counts after nab-paclitaxel administration. Advanced age was related to greater decrease in neutrophil counts, and serum albumin level, inversely related to change in neutrophil counts. CONCLUSION: We have developed a novel PK/PD model for nab-paclitaxel in which age and serum albumin level were considered clinically important covariate factors. This model needs to be further validated using a larger patient population.

How I investigate neutropenia.

Neutropenia is a common laboratory finding in adults and children. Its underlying causes are extremely heterogeneous and include benign conditions, autoimmune disorders, infections, and malignancies. The clinical laboratory plays a central role in the diagnosis of these disorders, including data derived from hematology, microbiology, molecular biology/cytogenetics, and clinical chemistry. The purpose of this review is to (a) highlight the clinical, hematologic, and molecular genetic features of the major entities resulting in neutropenia and (b) outline an algorithm-based approach to permit the classification of neutropenias.

Quantification of Radiation Injury on Neutropenia and the Link between Absolute Neutrophil Count Time Course and Overall Survival in Nonhuman Primates Treated with G-CSF.

PURPOSE: To model absolute neutrophil count (ANC) suppression in response to acute radiation (AR) exposure and evaluate ANC time course as a predictor of overall survival (OS) in response to AR exposure with or without treatment with granulocyte colony-stimulating factor in nonhuman primates. METHODS: Source data were obtained from two pivotal studies conducted in rhesus macaques exposed to 750 cGy of whole body irradiation on day 0 that received either placebo, daily filgrastim, or pegfilgrastim (days 1 and 8 after irradiation). Animals were observed for 60 days with ANC measured every 1 to 2 days. The population model of ANC response to AR and the link between observed ANC time course and OS consisted of three submodels characterizing injury due to radiation, granulopoiesis, and a time-to-event model of OS. RESULTS: The ANC response model accurately described the effects of AR exposure on the duration of neutropenia. ANC was a valid surrogate for survival because it explained 76% (95% CI, 41%-97%) and 73.2% (95% CI, 38.7%-99.9%) of the treatment effect for filgrastim and pegfilgrastim, respectively. CONCLUSION: The current model linking radiation injury to neutropenia and ANC time course to OS can be used as a basis for translating these effects to humans.

High prevalence of peribronchial focal lesions of airway invasive aspergillosis in hematological cancer patients with prolonged neutropenia.

OBJECTIVE: The aim of this study is to characterize chest CT findings of neutropenic patients with proven/probable invasive pulmonary aspergillosis (IPA). METHODS: Hematological cancer patients admitted to our institution (2007-2017) were retrospectively enrolled if the diagnostic criteria of proven/probable IPA during the neutropenia were met (EORTC/MSG). Galactomannan (GM) was routinely measured in serum and chest CT-scan was routinely performed in case of recurrent/persistent fever. Bronchoscopy was performed in case of chest CT-scan abnormalities. Chest CT-scan and GM dosage were analyzed at the time of IPA suspicion. Chest lesions were classified using a clinical report form by two expert radiologists. RESULTS: 35 patients were identified. Peribronchial focal lesions were observed in 29 IPA (82.9%) by the first radiologist and in 31 (88.5%) by the second (k = 0.768). 12 weeks mortality was 20%. CONCLUSION: Peribronchial focal lesions are a common finding in early-IPA whatever the GM value during neutropenia and our findings reinforce the efficiency of a preemptive approach. ADVANCES IN KNOWLEDGE;: Peribronchial focal lesions, which are classically described in airway invasive aspergillosis, are a common finding in early-IPA in hematological cancer patients with prolonged neutropenia regardless of the GM value, and such peribronchial lesions should reinforce the possibility of IPA.

Intratumoral Comparison of Nanoparticle Entrapped Docetaxel (CPC634) with Conventional Docetaxel in Patients with Solid Tumors.

PURPOSE: CPC634 is a novel nanoparticle entrapping docetaxel, developed to enhance the intratumoral chemotherapy exposure. This randomized cross-over study compared the intratumoral and plasma pharmacokinetics of CPC634 with conventional docetaxel. PATIENTS AND METHODS: Adult patients with solid tumors were randomized to receive CPC634 (75 mg/m2) in cycle 1, and conventional docetaxel (75 mg/m2) in cycle 2 or vice versa. The study was powered to identify a 25% increase of intratumoral total docetaxel exposure after CPC634 infusion compared with conventional docetaxel. Four patients were allocated per tumor sampling time point, that is, 24, 48, 72, and 96 hours, 7 and 14 days after infusion during both cycles. Total docetaxel and released docetaxel from the nanoparticle were determined in tumor tissue derived from a metastatic lesion and in plasma. Pharmacokinetic data were analyzed using linear mixed modeling. RESULTS: In total, 24 evaluable patients were included. In the tumor, CPC634 exhibited a 461% higher total docetaxel (P < 0.001) and a comparable released docetaxel concentration (P = 0.43). Plasma AUCinf was 27% higher (P = 0.001) and C max was 91% lower (P < 0.001) for CPC634 released docetaxel. The median observed neutrophil count nadir after conventional docetaxel treatment was lower (0.50 × 109/L) compared with CPC634 (4.30 × 109/L; P < 0.001). CONCLUSIONS: Here, we demonstrated that CPC634 enhanced the intratumoral total docetaxel exposure compared with conventional docetaxel. The lower incidence of neutropenia during CPC634 treatment is presumably related to lower plasma C max of released docetaxel. The unique pharmacokinetic profile of CPC634 nanoparticles has the potential to improve docetaxel treatment. A phase II efficacy trial of CPC634 is currently ongoing.

The stage-specific impairment of granulopoiesis in people living with HIV/AIDS (PLWHA) with neutropenia.

Neutropenia and impaired functions were common manifestation in antiretroviral therapy (ART) in both naïve and experienced PLWHA. Granulopoiesis can be divided into two phases: lineage determination and committed granulopoiesis. However, stage-specific impairment of granulopoiesis in PLWHA with neutropenia remains unclear. A total of 48 ART-naïve and 49 ART-experienced PLWHA from 2016 to 2018 were recruited and divided into non-, mild-, and moderate-to-severe-neutropenia groups according to their neutrophil counts. The bone marrow aspirates and peripheral blood were collected and analyzed by multicolor flow cytometry for granulocyte subsets, hematopoietic stem/progenitor cells (HSPC), apoptosis, and emigration and retention of different subsets. Compared with healthy donors, the percentages of circulating segmented neutrophils were significantly decreased along with an increase of immature neutrophils in both groups. ART-naïve patients with moderate to severe neutropenia exhibited decreased proportion and accelerated apoptosis of relative mature segmented neutrophils. In contrast, ART-experienced patients with neutropenia displayed decreased proportion of granulocyte macrophage progenitors, indicating a defect at a stage of lineage determination. Meanwhile, ART-experienced patients with neutropenia also the expression of CXCR4 segmented neutrophils, suggesting an increased retention of segmented neutrophils inn the bone marrow. ART-naïve patients with neutropenia is caused by increased apoptosis of relatively differentiated neutrophils at committed granulopoiesis, whereas impaired lineage determination and enhanced retention of segmented neutrophils contribute to in ART-experienced patients.

Diagnostic Value of C-reactive Protein and Interleukin-8 in Risk Stratification of Febrile Neutropenic Children with Allogeneic Hematopoietic Stem Cell Transplantation.

In this analysis, the levels of CRP and IL-8 were employed as a guide for designing the duration of antibiotics administration in the condition of febrile neutropenia. The importance of laboratory biomarkers is in the early diagnosis of critical illness and adjustment of further management. IL-8 is a useful biomarker for the early identification of critically ill patients, compared to CRP in FN.

Manufacturing biological medicines on demand: Safety and efficacy of granulocyte colony-stimulating factor in a mouse model of total body irradiation.

Protein therapeutics, also known as biologics, are currently manufactured at centralized facilities according to rigorous protocols. The manufacturing process takes months and the delivery of the biological products needs a cold chain. This makes it less responsive to rapid changes in demand. Here, we report on technology application for on-demand biologics manufacturing (Bio-MOD) that can produce safe and effective biologics from cell-free systems at the point of care without the current challenges of long-term storage and cold-chain delivery. The objective of the current study is to establish proof-of-concept safety and efficacy of Bio-MOD-manufactured granulocyte colony-stimulating factor (G-CSF) in a mouse model of total body irradiation at a dose estimated to induce 30% lethality within the first 30 days postexposure. To illustrate on-demand Bio-MOD production feasibility, histidine-tagged G-CSF was manufactured daily under good manufacturing practice-like conditions prior to administration over a 16-day period. Bio-MOD-manufactured G-CSF improved 30-day survival when compared with saline alone (p = .073). In addition to accelerating recovery from neutropenia, the platelet and hemoglobin nadirs were significantly higher in G-CSF-treated animals compared with saline-treated animals (p < .05). The results of this study demonstrate the feasibility of consistently manufacturing safe and effective on-demand biologics suitable for real-time release.

Pharmacodynamics of romiplostim alone and in combination with pegfilgrastim on acute radiation-induced thrombocytopenia and neutropenia in non-human primates.

Purpose: Evaluation of the pharmacodynamics (PD) and pharmacokinetics (PK) of romiplostim alone and in combination with pegfilgrastim in a non-human primate (NHP) model of acute radiation syndrome (ARS).Materials and methods: Male and female rhesus macaques were subjected to Cobalt-60 γ irradiation, at a dose of 550 cGy 24 h prior to subcutaneous administration of either romiplostim alone as a single (2.5 or 5.0 mg/kg on Day 1) or repeat dose (5.0 mg/kg on Days 1 and 8), pegfilgrastim alone as a repeat dose (0.3 µg/kg on Day 1 and 8), or a combination of both agents (romiplostim 5.0 mg/kg on Day 1; pegfilgrastim 0.3 µg/kg on Days 1 and 8). Clinical outcome, hematological parameters and PK were assessed throughout the 45 d study period post-irradiation.Results: Administration of romiplostim, pegfilgrastim or the combination of both resulted in significant improvements in hematological parameters, notably prevention of severe thrombocytopenia, compared with irradiated, vehicle control-treated NHPs. The largest hematologic benefit was observed when romiplostim and pegfilgrastim were administered as a combination therapy with much greater effects on both platelet and neutrophil recovery following irradiation compared to single agents alone.Conclusions: These results indicate that romiplostim alone or in combination with pegfilgrastim is effective at improving hematological parameters in an NHP model of ARS. This study supports further study of romiplostim as a medical countermeasure to improve primary hemostasis and survival in ARS.

Impairment of G-CSF receptor on granulocytic progenitor cells causes neutropenia in protein malnutrition.

OBJECTIVE: It is well known that protein malnutrition (PM) states can affect hematopoiesis, leading to severe leukopenia and reduced number of granulocytes, which act as the first line of defense, and are important to the innate immune response. The aim of this study was to elucidate some of the mechanisms involved in the impairment of granulopoiesis in PM. METHODS: Male C57BL/6 mice were submitted to PM with a low-protein diet containing 2% protein. Control mice were fed a 12% protein-containing diet. Bone marrow histology and the percentage of granulocytic progenitors were evaluated after in vivo granulocyte-colony stimulating factor (G-CSF) stimulus. Cell proliferation, STAT3 signaling, and the expression of G-CSF receptor were evaluated in hematopoietic progenitor cells. RESULTS: Malnourished animals presented with leukopenia associated with reduced number of granulocytes and reduced percentage of granulocytic progenitors; however, no differences were observed in the regulatory granulopoietic cytokine G-CSF. Additionally, the malnourished group presented with impaired response to in vivo G-CSF stimulus compared with control animals. PM was implicated in decreased ability of c-Kit+ cells to differentiate into myeloid progenitor cells and downregulated STAT3 signaling. Furthermore, the malnourished group exhibited reduced expression of G-CSF receptor on granule-monocytic progenitors. This reduced expression was not completely reversible with G-CSF treatment. CONCLUSIONS: This study implies that PM promotes intrinsic alterations to hematopoietic precursors, which result in hematologic changes, mainly neutropenia, observed in peripheral blood in PM states.