Higher Risk Of Neutropenia Research Articles

Incidence of Pneumocystis jirovecii Pneumonia and Prophylaxis-Associated Adverse Events Among Patients with Systemic Lupus Erythematosus.

Pneumocystis jirovecii Pneumonia (PJP) is an opportunistic infection that may affect patients with systemic lupus erythematosus (SLE). The objective of this project was to describe the incidence of PJP among patients with SLE. A retrospective cohort analysis of the TriNetX database. Included patients had ≥2 ICD9- CM/ICD10-CM codes for SLE separated by at least 30 days and were new users of mycophenolate mofetil or cyclophosphamide. The incidence of PJP over the first six months of therapy was calculated; adverse events were assessed using incident rate ratios (IRR) and Cox proportional hazards regressions. A total of 6,017 patients with SLE were identified. Most were female (5,176, 86%) and Black or African American (2,138, 35.5%). Induction medications included mycophenolate mofetil (5,208, 86.6%), cyclophosphamide (505, 8.4%), or both (304, 5.1%); the most common PJP prophylaxis was trimethoprim/sulfamethoxazole (1,126, 18.7%). Five PJP cases were identified over 2,752 person years, one of whom received PJP prophylaxis, for an incidence rate of 1.8 cases per 1000 person years. In adjusted analysis, patients who received prophylaxis had a higher risk of neutropenia (hazard ratio (HR) 2.5, CI 1.4-4.4), leukopenia (HR 1.9, CI 1.3-2.8), nephropathy (HR 1.7, CI 1.4-2.1), and hyperkalemia (HR 1.4, CI 0.9-2.0). PJP rarely affects patients with SLE undergoing therapy with mycophenolate mofetil or cyclophosphamide; prophylaxis against PJP is associated with adverse events. The majority of patients with SLE and PJP had structural lung disease. These data do not support universal prescribing of PJP prophylaxis for patients with SLE without lung disease.

The long-term impact of an antimicrobial stewardship program in febrile neutropenia: an 8 years follow up.

To describe the long-term effects of an ASP among febrile neutropenia (FN) patients. A quasi-experimental study was conducted between 2015 and 2023 at a tertiary care hospital in Istanbul, Türkiye. The ASP was implemented for FN patients, and the effects were assessed before and after the ASP interventions, which included FN clinical pathways and regular multi-disciplinary meetings with relevant healthcare workers. A total of 489 FN episodes of 290 patients were included, 42% were female, and the mean age was 56 years (SD: 15, range: 18-89 years). After the intervention, the rate of appropriate antimicrobial therapy at the levels of starting (p = 0.005), switching (p < 0.001), and de-escalation/discontinuation, (p < 0.001) significantly increased. Another positive impact of the ASP was a significant reduction in candidemia (from 4.88 to 0.74, p = 0.004), as well as a significant reduction in the 90-day mortality rate (from 19 to 5%, p < 0.001). In multivariate analysis, having a gram-negative bloodstream infection, prolonged days with fever, and a high risk for neutropenia were found to be significant predictors of 90-day mortality, while follow-up with ASP significantly reduced mortality. Implementation of ASP led to reduced candidemia and LOS without increasing mortality, even in a country with a high rate of antimicrobial resistance. Implementation of sustainable ASP for FN patients is critical in combating antimicrobial resistance.

Patient characteristics associated with primary prophylactic granulocyte colony-stimulating factor (G-CSF) use among women treated for early-stage breast cancer.

e12605 Background: The National Comprehensive Cancer Network (NCCN) recommends several chemotherapy regimens for early-stage breast cancer that have elevated risk of neutropenia (&gt;20%). In these regimens, primary prophylactic use of granulocyte colony-stimulating factor (G-CSF) is recommended. Little is known about how patient-level factors relate to receipt of prophylactic G-CSF among women receiving these regimens. Methods: In the Optimal Breast Cancer Chemotherapy Dosing (OBCD) Study, we examined use of G-CSF among women with stage I-IIIA breast cancer between 2005-2019 in Kaiser Permanente Northern California (KPNC) and Kaiser Permanente Washington (KPWA). We evaluated the patient-level factors associated with primary prophylactic G-CSF use (≤7 days before to ≤3 days after first day of chemotherapy) among women receiving chemotherapy regimens with high risk of neutropenia, for which the NCCN guidelines recommend prophylactic G-CSF use. Multivariable-adjusted prevalence ratios (PR) and their corresponding 95% Confidence Intervals (95% CI) were calculated using generalized linear models of the Poisson family with a log link-function and robust standard errors. Results: Overall, while all 3,083 women receiving these regimens ultimately received G-CSF, 2412 (79%) received primary prophylactic G-CSF within the period 7 days prior to 3 days post first cycle. Younger women had higher prevalence of prophylactic G-CSF receipt (82.7% in ages 18-39 years vs. 58.1% in 70+ years). Black women had higher prevalence of receipt compared to white women (82.7% in non-Hispanic Black women vs 76.1% in White women). Women with a higher body mass index (BMI) had lower prevalence of receipt compared to normal weight women (73.3% in 35+ kg/m2 group vs 81.5% in 18.5-&lt;25 kg/m2 group). In multivariable models, older women were less likely to receive prophylactic G-CSF (PR70+ vs 18-39: 0.69; 95% CI: 0.57-0.84; p-trend&lt;0.001), as were those with a higher BMI (PRBMI 35+ vs 18.5-&lt;25: 0.92; 95% CI: 0.85, 0.97; p-trend=0.006), and a later year of diagnosis (PR2016-19 vs 2005-07: 0.81; 95% CI: 0.77, 0.85; p-trend&lt;0.001). Although race/ethnicity was not significantly associated with receipt of prophylactic G-CSF use overall in multivariable models, we observed Non-Hispanic Black women to experience slightly higher likelihood of G-CSF receipt than Non-Hispanic White women (PR: 1.08; 95% CI: 1.02, 1.15). Conclusions: Women of older age and those with higher BMI were less likely to receive primary prophylactic G-CSF, as were women treated in later years. Further research looking at timing of G-CSF use is warranted, as are studies examining provider/facility-level factors in relation to patterns of G-CSF use, G-CSF’s impact on survival outcomes, and the real-world impact of decisions around G-CSF use across age, BMI, and racial/ethnic groups.

Nutritional status associated with clinical outcomes in children with solid tumors: A retrospective cohort study from China.

To investigate the long-term changes in nutritional status in children with solid tumors during treatment and the relationship between nutritional status and clinical outcomes. This study was a retrospective medical records review of data from children who were diagnosed with solid tumors and followed up for more than 3 months from January 2016 to December 2021 in China. Patient demographics and clinical information, including nutritional status, parenteral nutrition use, intensive care unit (ICU) transfers, infection during hospitalization, hospitalization frequency, length of stay, hospitalization costs and antibiotic costs, were collected to analyze the nutritional status of children with different types of solid tumors, the dynamic changes in nutritional status during treatment, and the relationship between nutritional status and clinical outcomes. Among the 764 patients (383 males (50.1%); 381 females (49.9%); mean age: 2.58 years), 41.6% of the solid tumors were neuroblastomas, 17.1% were hepatoblastomas, and Wilms tumors as the third most common solid tumors (8.9%). The median follow-up duration was 6 months (range: 3-40 months). At diagnosis, the proportion of children who were undernourished (underweight and wasting) versus overweight or obese were 26.71% versus 5.21% (25.86% vs. 2.89% in the third month; 29.77% vs. 2.28% in the sixth month; 24.77% vs. 3.27% in the 12th month). The body mass index Z scores decreased from the initial values after the first month (-0.56 (-1.47, 0.23) vs. -0.44 (-1.29, 0.41)) but improved later and decreased again at 6 months. The children in the undernutrition group had longer hospital stays (p < 0.001), higher hospitalization costs (p < 0.001), higher antibiotic costs (p < 0.001), a higher risk of neutropenia (OR = 4.781 (95% CI: 1.571-14.553), p = 0.006), and a higher risk of ICU transfers (OR = 1.498 (95% CI: 1.010-2.224), p = 0.044). No significant differences in those associations by malnutrition and infection, ICU duration, or length of parenteral nutrition were observed. There is a considerable prevalence of malnutrition in children with solid tumors. Malnutrition is related to adverse clinical outcomes and increases in total hospital expenses and antibiotic costs.

The Impact of Omitting 5-FU Bolus From mFOLFOX6 Chemotherapy Regimen on Hematological Adverse Events Among Patients With Metastatic Colorectal Cancer.

Metastatic colorectal cancer (mCRC) is often treated with a mFOLFOX6 regimen. The 5-fluorouracil (5-FU) bolus is often omitted from the regimen to reduce the risk of hematological adverse events (AEs) in patients with poor performance status. We aimed to investigate the incidence of hematological AEs in Asian patients with mCRC who were treated with the mFOLFOX6 with and without 5-FU bolus dosing. This retrospective chart review was conducted at King Chulalongkorn Memorial Hospital, Thailand from June 2021 to June 2022. The primary endpoints were hematological AEs. Secondary endpoints were any AEs. The comparison of continuous data was conducted with an independent t-test. The Chi-squared test was used to compare categorical data. From 110 patients, we found that hematological and non-hematological AEs of any grade in the two groups were not significantly different. However, patients in the bolus arm had a significantly lower absolute neutrophil count (ANC) than those in the non-bolus arm (mean difference = 43.13 (95% confidence interval (CI): 20.74, 65.51), P-value = 0.0002). A subgroup analysis in patients who received first-line treatment with mFOLFOX6 showed that the bolus arm had a significantly lower ANC (mean difference = 46.01 (95% CI: 19.99, 72.03), P-value = 0.0007). mCRC patients who were treated with bolus 5-FU had lower ANC. The 5-FU bolus omission from the mFOLFOX6 regimen may be required in patients with a high risk of neutropenia.

Obinutuzumab in combination with chlorambucil in first line treatment of elderly patients with chronic lymphocytic leukemia

Introduction. Optimal therapy for elderly patients with chronic lymphocytic leukemia (CLL) is the subject of intensive research.Aim – to study the safety of obinutuzumab, as well as the selection of the optimal scheme of its use in patients with CLL, complicated by diabetes mellitus, renal insuffi ciency, cardiac comorbidity.Materials and methods. The study included primary patients with CLL having indications requiring therapy. The inclusion criteria were: Cumulative Illness Rating Scale, CIRS) (CIRS) &gt; 6 and or glomerular fi ltration rate (GFR) &lt; 70 mL/min, the lower limit of GFR was not restricted. The study focused on patients with diabetes mellitus, renal failure and signifi cant cardiac pathology. Patients with Richter’s syndrome, CNS involvement, HBs-antigen, and 17p deletion were not included. In the fi rst cycle obinutuzumab was administered at a dose of 100 or 25 mg on the fi rst day and 900 or 975 mg on the second day, then at a dose of 1000 mg on days 8 and 15. For all subsequent cycles, obinutuzumab was given at a dose of 1000 mg on day 1. The dosage of chlorambucil was 10 mg/m2 from days 1 to 7. Treatment cycles in totals of 6 were repeated every 28 days.Results. The study included 90 patients. Median age was 73.5 years, range – 60–89 years, there were 49 men (54 %) and 41 women (46 %). Twenty-four patients (27 %) had stage C, IGHV unmutated status was detected in 76 % of patients. The median creatinine clearance was 48.6 mL/min (25–110). The median CIRS score was 3 (range – 1–14). Thirty-one patients (34 %) had signifi cant cardiovascular comorbidity (previous myocardial infarction, coronary artery stenting or bypass, HF ≥ II NYHA, peripheral artery disease) as well as hemodynamically signifi cant valvular disease. Fifteen patients (17 %) had diabetes mellitus and 71 patients (79 %) had creatinine clearance &lt; 70 ml/min. Infusion reactions to obinutuzumab grade ≥ II were reported in 29 patients (32 %). Hospitalization on the day of administration or the next day after the fi rst administration was required in 5 cases (5.5 %). Twenty-seven (30 %) patients could not complete 6 cycles. The largest number of patients (14 people, 15.5 %) stopped treatment after 1 course. The causes were the development of persistent cytopenia (n = 4), grade IV reaction to obinutuzumab (n = 3), patient’s refusal (n = 2), infectious complications (n = 2), severe tumor lysis syndrome (n = 1), acute pancreatitis (n = 1) and toxicodermia (n = 1). The leading cause of premature discontinuation on subsequent cycles was persistent neutropenia. Progression during treatment occurred in 3 patients only. Overall survival was signifi cantly predicted by CIRS (maximum discriminatory value of 3, p = 0.013) as well as GFR &lt; 50 mL/min (p = 0.03). No other associations were identifi ed. At least 1 episode of grade III–IV neutropenia occurred in 41 % of patients. Grade IV neutropenia was associated with creatinine clearance &lt; 60 mL/min (p = 0.05), baseline neutrophil level &lt; 2 × 109/L (p = 0.0001), baseline monocyte level &lt; 0.3 × 109/L (p = 0.007) and age &gt; 70 years (p = 0.01). The effectiveness of treatment was evaluated in patients who completed at least 3 cycles of therapy. Complete remission was achieved in 26 patients (35 %), partial remission – in 41 (54 %), stabilization – in 4 (5 %), progression was noted in 3 (4 %). Sixteen patients (18 %) were not available to respond to the assessment. Minimal residual disease &lt; 0.01 % in the bone marrow after completion of treatment was found in 17 patients (19 %), within 0.01–0.9 % – in 25 (28 %) patients. The median follow-up from the date of therapy initiation was 39.7 months (range – 0.6–72 months). The median relapse-free survival was not reached, and 2- and 3-year survival rates were 81 and 62 %, respectively. Poor relapse-free survival signifi cantly correlated with unmutated IGHV genes (HR = 2.4, 95 % CI: 1.12–5.0, p = 0.02) and partial response as opposed to complete response (HR = 3.35; 95 % CI: 1.45–7.7, p = 0.03).Conclusion. The results of our study have practical implications as obinutuzumab is actively integrated into modern treatment regimens. Infusion reactions pose a high risk of complications in elderly patients. The dose of obinutuzumab on day 1 of administration in elderly patients, should not exceed 25 mg. The G-Clb regimen may not be optimal in patients over 75 years of age due to the unpredictable risk of complications. In patients at high risk of neutropenia, it may be appropriate to consider primary prophylaxis. ClbG is an effective regimen that resulted in high rate of MRD-negative responses and prolonged relapse-free survival.

Baseline predictors of hematological toxicity in patients with advanced cancer treated with ATR inhibitors in phase I/II clinical trials.

3111 Background: Ongoing trials are exploring ATR inhibitors (ATRi) in genomically selected contexts. However, myelosuppression, particularly anemia, has limited the therapeutic window of this class of drugs. We sought to discover clinical biomarkers predicting severe hematological toxicity from ATRi. Methods: We retrospectively analyzed clinical parameters and peripheral blood cell indices retrieved from complete blood count (CBC) reports of patients (pts) pre- and during treatment with an oral ATRi on phase I/II trials at our center. Pts received ATRi monotherapy or in combination with a PD1 inhibitor (PD1i) or a PARP inhibitor (ATRi+PARPi) in dose-escalation and expansion cohorts, which included ATRi at potentially toxic doses. Results: 37553 indices from 2209 CBC reports of 141 pts treated with an ATRi from 10/2017 to 1/2022 were analyzed. 132 (93.6%) pts received ATRi +/- PD1i; 9 (6.4%) pts received ATRi+PARPi. The incidences of ≥ grade (G) 3 anemia, neutropenia and thrombocytopenia were 47.5%, 31.9% and 11.4%. 73/141 (51.8%) pts received red cell transfusion. Baseline risk factors predicting ≥G3 anemia on univariate analysis included: lower median (med) hematocrit (Hct) (hazard ratio (HR) (95% confidence interval) = 3.05 (1.82, 5.13) ≤med vs &gt; med; p &lt; 0.0001), hemoglobin (Hb) (HR = 2.74 (1.64,4.57) ≤med vs &gt; med; p = 0.0001), mean corpuscular Hb concentration (HR = 1.85 (1.11,3.10) ≤med vs &gt; med; p = 0.019); and higher median immature reticulocyte fraction (HR = 0.43 (0.25,0.71) ≤med vs &gt; med; p = 0.0012), reticulocyte count (ct) (HR = 0.59 (0.35,0.97) ≤med vs &gt; med; p = 0.037) and red cell distribution width (RDW) (HR = 0.54 (0.33,0.88) ≤med vs &gt; med; p = 0.015). On multivariate analysis, lower median Hct (HR = 3.76 (2.15, 6.6) ≤med vs &gt; med; p &lt; 0.0001), higher immature granulocyte ct (HR = 1.71 (1.30, 2.25) per 1 fold increase; p = 0.0001), higher RDW (HR = 7.83 (1.70, 36.03) per 1 fold increase; p = 0.0082) and higher ATRi starting dose (HR = 1.40 (1.05, 1.86) per 1 fold increase; p = 0.022) significantly predicted ≥G3 anemia risk. Baseline risk factors for ≥G3 neutropenia on univariate analysis included: lower median absolute neutrophil ct (ANC) (HR = 2.26 (1.18, 4.33) ≤med vs &gt; med; p = 0.015) or white blood cell ct (WBC) (HR = 2.73 (1.40, 5.33) ≤med vs &gt; med; p = 0.0032). On multivariate analysis, lower median WBC (HR = 2.85 (1.45, 5.59) ≤med vs &gt; med; p = 0.0024) was associated with higher risk of neutropenia, while ATRi+PARPi increased risk of neutropenia (ANC &lt; 0.75) (HR = 4.15 (1.40, 12.3); p = 0.01) and thrombocytopenia (HR = 3.90 (1.47, 10.4); p = 0.0064). Conclusions: ≥G3 anemia was frequent in pts receiving ATRi. At baseline, lower median Hct and higher RDW predict severe anemia, while lower WBC predicts neutropenia from ATRi. ATRi+PARPi has increased risk of neutropenia and thrombocytopenia vs ATRi +/- PD1i. These indices may inform patient selection and CBC monitoring for future ATRi trials.

Phase 1 study of the liposomal formulation of eribulin (E7389-LF): Results from the breast cancer expansion cohort

BackgroundA liposomal formulation of eribulin, E7389-LF, may provide improved pharmacokinetics and allow increased access to tumour tissues. This expansion of a phase 1 study assessed the safety and efficacy of E7389-LF in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer. MethodsPatients received E7389-LF 2.0 mg/m2 every three weeks. Tumour assessments were conducted every six weeks by the investigator by Response Evaluation Criteria in Solid Tumours v1.1. All adverse events were monitored and recorded. Serum biomarker assessments were conducted. ResultsOf 28 patients included, 75.0% had hormone receptor-positive breast cancer (HR+ BC) and 25.0% had triple-negative breast cancer (TNBC). The most common grade ≥3 treatment-related treatment-emergent adverse events included neutropenia (67.9%), leukopenia (42.9%), thrombocytopenia (32.1%), and febrile neutropenia (25.0%). Rates of neutropenia and febrile neutropenia were lower among patients who received prophylactic pegfilgrastim. Objective response rate was 35.7% (95% confidence interval [CI]: 18.6–55.9) for all patients and 42.9% (95% CI: 21.8–66.0) for patients with HR+ BC. Median progression-free survival was 5.7 months (95% CI: 3.9–8.3). The median overall survival was 18.3 months (95% CI: 13.2–not estimable). Among the 54 biomarkers assessed, 27, including 5 of 7 vascular markers, were significantly altered by E7389-LF treatment from baseline to any time point. ConclusionE7389-LF was tolerable and favourable antitumour activity was observed, particularly in patients with HR+ BC. Prophylactic pegfilgrastim can be considered in patients at high risk for neutropenia and febrile neutropenia. Clinicaltrials.gov numberNCT03207672.

Cyclin-dependent kinase 4 and 6 inhibitors in combination with neoadjuvant endocrine therapy in estrogen receptor-positive early breast cancer: a systematic review and meta-analysis.

The combination of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors and endocrine treatment has benefited patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER + /HER2-) metastatic breast cancer; however, its effects in the neoadjuvant setting for ER + /HER2- early breast cancer (EBC) are unclear. Systematic searches were performed in PubMed, Embase, Cochrane Library, and major oncological meetings for trials of CDK4/6 inhibitors plus neoadjuvant endocrine treatment (NET) vs. NET/neoadjuvant chemotherapy (NACT) alone up to January 30, 2021. We assessed the efficacy of CDK4/6 inhibitors plus NET vs. NET/NACT alone in ER + /HER2- EBC. Six studies that included 803 patients treated with CDK4/6 inhibitors plus NET vs. NET/NACT alone were used. Compared with NET/NACT alone, CDK4/6 inhibitors plus NET increased the complete cell cycle arrest (CCCA) rate (OR, 9.00; 95% CI, 5.42-14.96; P < 0.001). Nonsignificant differences between CDK4/6 inhibitors and NET/NACT alone occurred in the preoperative endocrine prognostic index (PEPI)-0 rate (OR, 1.13; 95% CI, 0.59-2.18; P = 0.71), pathological complete response (pCR) rate (OR, 0.75; 95% CI, 0.13-4.29; P = 0.74), objective response rate (ORR) (OR, 0.70; 95% CI, 0.21-2.29; P = 0.55), and disease control rate (DCR) (OR, 1.16; 95% CI, 0.47-2.89; P = 0.74). CDK4/6 inhibitors plus NET indicated a high risk of neutropenia (OR, 56.43; 95% CI, 15.76-202.11; P < 0.001) as an adverse effect (AE) and elevated alanine aminotransferase (ALT) level (OR, 15.30; 95% CI, 2.02-115.98; P = 0.008) as grade 3/4 AEs. Compared with NET/NACT alone, CDK4/6 inhibitors plus NET increased CCCA rate in ER + /HER2- EBC patients. CDK4/6 inhibitors plus NET did not substantially improve the PEPI-0 rate, pCR rate, ORR, or DCR. The combination increased the risk of neutropenia and elevated ALT levels. In the neoadjuvant setting, addition of CDK4/6 inhibitors to NET may be an option for treating ER + /HER2- EBC.

Chemotherapy limiting neutropenia. Is prevention required?

Neutropenia is the most common hematologic toxicity of chemotherapy. Severe and prolonged neutropenia can cause treatment delay and dose reduction. Clinical studies indicate that reducing the relative dose intensity of regimens harms treatment outcomes, especially in breast, ovarian, and pancreatic cancers. Therefore, screening of patients at high risk of neutropenia that limits planned chemotherapy is of practical importance. Unfortunately, most clinical studies indicate only the incidence of myelotoxicity with each chemotherapy regimen, and only a few have analyzed the potential risks associated with this complication. That is significant importance in highly chemotherapy-sensitive malignancies. Such patients often receive dose intense and dose dens chemotherapy. The risk of severe neutropenia in such patients and failure to adhere to planned chemotherapy may reduce the chances of cure. Currently, there is no consensus among oncologists on the management strategy for patients with neutropenia limiting chemotherapy. This topic is a worldwide discussion. The article presents scientific evidence and clinical studies dedicated to this problem. A general analysis of clinical data and experience of oncologists will allow the medical community to develop approaches to prevent this complication.

Population Pharmacokinetics and Exposure-Safety Relationship of Paclitaxel Liposome in Patients With Non-small Cell Lung Cancer.

PurposePaclitaxel liposome (Lipusu) is the first commercialized liposomal formulation of paclitaxel. There has been little data collected on the pharmacokinetics (PK) of paclitaxel liposome, especially in relation to patient use. This study aimed to build a population pharmacokinetic (PopPK) model and further explore the exposure–safety relationship for paclitaxel liposome in patients with non-small cell lung cancer (NSCLC).MethodsData from 45 patients with a total of 349 plasma concentrations were analyzed. The PopPK model was built using the non-linear mixed effect modeling technique.ResultsThe PK of paclitaxel liposome were well described by a three-compartment model with first-order elimination. For a dose of 175 mg m–2, the estimated clearance of total plasma paclitaxel was 21.55 L h–1. Age, sex, body weight, total bilirubin, albumin, serum creatinine, and creatinine clearance did not influence the paclitaxel PK. Exposure to paclitaxel had no significant change in the presence of the traditional Chinese medicine, aidi injection. The exploratory exposure–safety relationship was well described by a generalized linear regression model. Higher probabilities of grade >1 neutropenia were observed in patients with higher exposure to paclitaxel.ConclusionThis PopPK model adequately described the PK of paclitaxel liposome in patients with NSCLC. Predicted exposure of paclitaxel did not change in the presence of the traditional Chinese medicine, aidi injection. The exposure–safety analysis suggested that a higher risk of neutropenia was correlated with higher exposure to paclitaxel.

A split strategy to prevent cytomegalovirus after kidney transplantation using prophylaxis in serological high-risk patients and a pre-emptive strategy in intermediate-risk patients: Combining the best of two options?

Cytomegalovirus (CMV) remains an important challenge after kidney transplantation. Current Transplantation Society International Consensus Guidelines recommend antiviral prophylaxis or pre-emptive therapy for high-risk CMV-seronegative recipients with a CMV-seropositive donor (D+/R-) and moderate-risk CMV-seropositive recipients (R+). However, a split strategy according to CMV serostatus is not specifically mentioned. We evaluated a split strategy to prevent CMV infection after kidney transplantation in which D+/R- patients received valganciclovir (VGC) prophylaxis for 200days, and R+patients were treated pre-emptively according to CMV DNAemia. Patients were followed until 1-year post-transplant. Between April 2014 and March 2018, 40 D+/R- and 92 R+patients underwent kidney transplantation. Forty-six percent received antithymocyte globulin (ATG) induction, and 98% was treated with calcineurin inhibitors, mycophenolic acid (MPA), and steroids. No D+/R- patient developed CMV disease during prophylaxis (median 200days), but 15% developed post-prophylaxis or late-onset disease. Fifty-three percent developed neutropenia during prophylaxis, including 16/40 (40%) grade 3 or 4 neutropenia requiring reduction/discontinuation of MPA (30%) and/or VGC (35%), and an occasional need for granulocyte colony-stimulating factor (5%). In the R+group, 40% received antiviral therapy for a median duration of 21days; 5% developed early-onset CMV disease. Only 5% developed neutropenia. D+/R+status (hazard ratio (HR) 2.09,P=.004) and ATG use (HR 2.81, P<.0001) were risk factors for CMV reactivation. Prophylaxis leads to acceptable CMV control in high-risk patients but comes with a high risk of neutropenia. Pre-emptive therapy is effective and limits drug exposure in those at lower risk of CMV.

P1765COMBINING THE BEST OF TWO OPTIONS: A SPLIT STRATEGY WITH PROPHYLAXIS OR PRE-EMPTIVE THERAPY TO PREVENT CYTOMEGALOVIRUS AFTER KIDNEY TRANSPLANTATION

Abstract Background and Aims Cytomegalovirus (CMV) remains an important challenge after kidney transplantation. Current Transplantation Society International Consensus Guidelines recommend antiviral prophylaxis or pre-emptive therapy for either high risk CMV-seronegative recipients of a CMV-seropositive donor (D+/R-) and moderate-risk CMV-seropositive recipients (R+). A split strategy according to CMV risk, however, is not specifically mentioned. Method We evaluated a split strategy to prevent cytomegalovirus infection after kidney transplantation. D+/R- patients received valganciclovir (VGC) prophylaxis during 200 days and R+ patients were treated pre-emptively according to CMV DNAemia. Results Between April 2014 and March 2018, 40 D+/R- and 92 R+ patients underwent kidney transplantation. Forty-six % received antithymocyte globuline (ATG) induction and 98 % were treated with calcineurin inhibitors, mycophenolic acid (MPA) and steroids. No D+/R- patient developed CMV disease during prophylaxis (median 200 days), 15 % developed late-onset disease. Fifty-three % developed neutropenia during prophylaxis, including 16/40 (40 %) grade 3 or 4 neutropenia requiring reduction/discontinuation of MPA (30 %) and/or VGC (30 %), and occasional need for granulocyte colony stimulating factors (5 %). In the R+ group, 40 % received antiviral therapy for a median duration of 21 days. Five percent developed CMV disease. Only 5 % developed neutropenia. D+/R+ status (hazard ratio (HR) 2.09, P 0.004) and ATG use (HR 2.81, P &amp;lt; 0.0001) were risk factors for CMV reactivation. Conclusion Prophylaxis leads to acceptable CMV control in high risk patients, but comes with a high risk of neutropenia. Pre-emptive therapy is effective and limits drug exposure in those at lower risk for CMV.

Assessing the Impact of ED Triage Directives on Febrile Oncology Patient Wait Times

IntroductionFever during chemotherapy is a common and potentially severe complication being increasingly evaluated in emergency departments to minimize morbidity and mortality. Streamlining triage of these patients may improve health outcomes and wait times in the health care system. MethodsA retrospective chart review of febrile patients undergoing chemotherapy was conducted at a local emergency department to assess the impact of nurse-initiated protocols on wait times. ResultsWe identified 315 patients undergoing current chemotherapy presenting with fever. Of these, 140 (44%) and 87 (28%) were initiated on the sepsis and febrile neutropenia nurse-initiated protocols, respectively. In total, 197 (63%) were admitted. The febrile neutropenia protocol had a shorter wait time from triage to disposition than the sepsis protocol (403 minutes [SD = 23] vs 329 minutes [SD = 19], t = 1.71, P = 0.01). Furthermore, the febrile neutropenia protocol demonstrated shorter times from both triage to lab results reported, in addition to the physician initial assessment in the admitted patient subgroup. DiscussionDecreased wait times from triage associated with the use of a febrile neutropenia protocol could be accounted for by a lower number of lab results required through this protocol in addition to shorter physician assessment times in the admitted population. This study shows that nurse-initiated protocols may influence door-to-antibiotic time for patients undergoing chemotherapy. By having a targeted protocol for the cancer population, health care centers may be able to demonstrate decreased health care expenditure and increased resource availability. Furthermore, as the current population of patients undergoing chemotherapy is at a high risk for neutropenia, prompt management is crucial to minimize mortality.

New possibilities of drug therapy for rheumatoid arthritis: focus at sarilumab

Rheumatoid arthritis (RA) is one of the most prevalent autoimmune diseases in humans and is a serious medical and social problem in the Russian Federation. Current synthetic and biological agents acting through specific molecular targets, play a significant role in the treatment of RA. Over the last few years, inhibitors of the biological effects of interleukin-6 (IL-6) have attracted increasing attention, being positioned as the first choice agents among the biologicals, especially if there is a need in monotherapy. IL-6 is a pleiotropic cytokine with a broad range of biological effects on immune cells, such as B and T lymphocytes, on hepatocytes, hematopoietic cells, vascular endothelial cells, and many others. In this regard, IL-6 is a good therapeutic target in RA. For several years, the group of inhibitors of IL-6 biological effects has been represented by one drug only, i.e. tocilizumab. The new drug of this group, sarilumab, is a human monoclonal antibody (IgG1 subtype) to the IL-6 receptor. Sarilumab binds specifically to both soluble and membrane IL-6 receptors (IL-6Rα), and inhibits IL-6-mediated signal transduction involving signal protein glycoprotein 130 (gp130) and signal proteins STAT-3. There is evidence that sarilumab has a higher affinity to the IL-6 receptor, and binds the receptor in a more stable manner than tocilizumab. Sarilumab has been approved for treatment of RA with moderate or high activity in adult patients with inadequate response or intolerability to one or several synthetic basic drugs, at a dose 150 mg or 200 mg subcutaneously biweekly in combination with methotrexate (MTX). It also can be prescribed as monotherapy in case of MTX intolerability or if treatment with MTX is inexpedient. Sarilumab is a highly active therapeutic agent with proven superiority in monotherapy over adalimumab. Therefore, sarilumab can be positioned as a first line biological agent in patients with high inflammatory activity, as well as in those resistant to tumor necrosis factor-α inhibitors. The safety profile of sarilumab is similar to that of tocilizumab; probably there is a slightly higher risk of neutropenia, but a lower risk of dyslipidemia, reactions at the injection site and gastrointestinal perforation for sarilumab than for tocilizumab.

Oncologic Emergencies: The Fever With Too Few Neutrophils.

Cancer is associated with a variety of complications, including neutropenic fever, which can result in severe morbidity and mortality. This oncologic emergency requires ED management. This narrative review provides focused updates for emergency clinicians regarding neutropenic fever. Neutropenic fever is defined by fever with oral temperature >38.3°C or temperature >38.0°C for 1 hour with an absolute neutrophil count (ANC) < 1000 cells/microL. Patients who have received chemotherapy within 6 weeks of presentation are at high risk for neutropenia. While most patients with neutropenic fever do not have an identifiable bacterial source of fever, clinicians should treat patients for bacterial infection. Rapid assessment and management are vital to improving outcomes in patients with suspected or confirmed neutropenic fever. History and examination should focus on the most common sites of infection: the gastrointestinal tract, blood, skin, lung, and urinary tract. However, physical examination and laboratory or imaging assessment may not display classic signs of infection. Blood cultures should be obtained, and broad-spectrum antibiotics are recommended. Oncology consultation is an integral component in the care of these patients. Several risk scores can assist in stratifying patients who may be appropriate for discharge home and follow-up. Neutropenic fever is an oncologic emergency. Rapid diagnosis and care of patients with neutropenic fever can improve outcomes, along with oncology consultation.

Chemoradiotherapy completion and neutropenia risk in HIV patients with cervical cancer.

Cervical cancer (CC) is one of the acquired immunodeficiency syndrome (AIDS) defining diseases and the human immunodeficiency virus (HIV) infection is thought to relate with increased acute toxicity of chemoradiotherapy (CRT).We investigated the effect of HIV status in the incidence of neutropenia associated with cisplatin-based CRT for CC and its impact in treatment completion.This is a single-center retrospective cohort study. Data collection was performed for all the consecutive stage Ib-IV CC women treated with cisplatin-based CRT from 2012 to 2016, and with known HIV status.Sixty-one patients were included, 6 were HIV+. HIV+ patients had a higher risk of neutropenia at any cycle during cisplatin CRT [adjusted odds ratio (OR) 7.3, 95% confidence interval (95% CI) 1.02–52.3; P = .05]. Despite the absolute differences, mean neutrophil count was nonsignificantly lower in HIV+ women, both at baseline [4455/μL (interquartile range, IQR: 1830–6689) vs 6340 (IQR: 1720–18,970) for HIV−, P = .98] and at the end of treatment [1752/μL (IQR: 1100–2930) vs 3147/μL (IQR: 920–18,390) in HIV−; P = .06]. Moreover, when considering the effect of time, CRT seems to induce a consistent drop of neutrophils in both groups (P = .229). No febrile neutropenia events occurred.In HIV+ women, there were more CT cycle delays (P = .013), patients were more prone to use granulocyte colony-stimulating factor (G-CSF; HIV+ 40.0% vs HIV− 4.0%; P = .04) and less likely to complete at least 5 cycles of cisplatin (P = .02). All patients received adequate dose of pelvic RT, regardless of HIV status.HIV+ patients have a significantly increased risk of neutropenia during CRT treatment for CC and are less likely to complete chemotherapy with cisplatin.

Reduced dose pegfilgrastim is associated with less bone pain without increased neutropenia: a retrospective study.

Chemotherapy for breast cancer is associated with a high risk of neutropenia. Pegfilgrastim reduces the risk of neutropenic fever but commonly causes bone pain. Evaluate whether a reduced dose of pegfilgrastim (3mg) reduced the frequency of bone pain without compromising efficacy. Records reviewed from breast cancer patients who received at least one 3mg dose of pegfilgrastim, white blood count (WBC), and absolute granulocyte counts (AGC) were collected. Musculoskeletal pain scale was collected at each visit. 265 treatments from 36 women were analyzed. There was no difference in post-treatment AGC between 3 versus 6mg. Leukocytosis (WBC > 20,000 cells/cu mm) was more likely for those treated with 6mg (chi-square 5.265, p = 0.0215). There was higher change in bone pain in patients who received 6mg doses compared to none or 3mg. In this retrospective, non-randomized study, we found the majority of patients received the reduced 3mg dose after intolerance to the 6mg dose. It is unknown if smaller or larger doses than 3mg would achieve similar results or whether 3mg dose would be effective as an initial therapy or for patients receiving different chemotherapy regimens. Pain is observed despite premedication with naproxen and/or loratidine. Reduced dose of pegfilgrastim 3mg was less likely to cause bone pain. The reduced dose was not associated with a significant difference in post-treatment AGC or rate of serious infection.

Triplet Chemotherapy (FOLFOXIRI) Plus Bevacizumab Versus Doublet Chemotherapy (FOLFOX/FOLFIRI) Plus Bevacizumab in Conversion Therapy for Metastatic Colorectal Cancer: a Meta-Analysis

Background/Aims: Conversion therapy can convert unresectable metastatic colorectal cancer (mCRC) into resectable. However, the optimal conversion regimen was not yet defined. This meta-analysis aimed to compare the efficacy and safety of the triplet chemotherapy (FOLFOXIRI) plus bevacizumab (Bev) with doublet chemotherapy (FOLFOX/FOLFIRI) plus Bev in conversion therapy. Methods: Randomized controlled trials (RCTs) from databases, including Pubmed, EMBASE, Cochrane clinical trials, clinicaltrial.gov and some conferences, were searched from the inception to November 2017. The R0 resection, objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and the incidence of adverse events were pooled with the use of hazard ratio (HR) or risk ratio (RR). Results: Four RCTs with 1013 patients were included. FOLFOXIRI plus Bev regimen significantly improved the overall R0 resection rate (RR 1.41, 95% confidence interval (CI) 1.07-1.85, I2=37%), liver R0 resection rate (RR 2.28, 95% CI 1.34-3.89, I2=0%), ORR (RR 1.20, 95% CI 1.09-1.32, I2=0%), PFS (HR 0.72, 95% CI 0.62-0.84, I2=36%) and OS (HR 0.80, 95% CI 0.66-0.97, I2=0%). There was no significant difference in any Grade≥3 adverse event (RR 1.08, 95% CI 0.99-1.17, I2=0%) between two regimens. FOLFOXIRI-Bev was associated with a higher risk of neutropenia (RR 1.77, 95% CI 1.13-2.79, I2=68%) and diarrhea (RR 1.65, 95% CI 1.17-2.32, I2=0%). Conclusions: Triplet chemotherapy plus Bev significantly improved the R0 resection rates, ORR, PFS and OS in comparison with doublet chemotherapy plus Bev in conversion therapy for mCRC patients, with a higher risk of neutropenia and diarrhea.

The efficacy and safety of different pharmacological interventions for patients with advanced biliary tract cancer: A network meta-analysis.

Biliary tract cancer (BTC) is the second common cancer in liver cancer. Chemotherapy is the mainstay of treatments for patients with advanced or metastatic disease, while fluorouracil (FU)-based and gemcitabine (GEM)-based treatments are most widely applied. This NMA aimed to figure out whether the addition of platinum (PLA) and target agents (TAR) can influence the efficacy and safety of standard chemotherapy. Network meta-analysis (NMA) was conducted based on the records from PubMed, Embase and Cochrane. Eligible data was extracted from available qualified trials and outcomes. Software R 3.2.3 and STATA 13.0 were used to conduct the Bayesian NMA, calculating odds ratios (ORs) and hazard ratios (HRs) with 95% credible interval (CrI) to evaluate different treatments.Almost all treatments were superior to best supportive care (BSC) and FU in terms of 1-OS, 2-OS and 1-PFS. GEM+PLA and GEM+PLA+TAR exhibited better efficacy than most treatments in 1-OS, 2-OS and 1-PFS, and yielded better results than BSC and GEM+FU in terms of 2-PFS. Most drug-containing treatments reported higher overall response rate (ORR) than BSC. GEM and GEM+FU were associated with a higher risk of neutropenia and thrombocytopenia compared to FU, FU+PLA and GEM+PLA. No statistical difference was detected in terms of nausea and vomiting.GEM+PLA and GEM+PLA+TAR were both efficacious and were associated with fewer adverse events. In conclusion, the addition of PLA can significantly improve the efficacy of FU and GEM-based treatments, and the addition of TAR to GEM+PLA can contribute to further improvement, but with a mild increase of adverse events.