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Febrile neutropenia (FEN) was reported in patients with solid malignancies at a rate of 5-10% and in patients with hematological malignancies at a rate of 20-25%. In our study, we aimed to investigate the effects of mannose-binding lectin 2 (MBL2) (rs1800450) and suppressor of cytokine signaling-1 (SOCS1) (rs33989964) gene variants on patients with FEN.A total of 123 patients who applied to pediatric emergency department between December 2019-12/2020 included in the study. Thirteen patients were excluded from the study due to the inability to obtain DNA. Demographic-clinical features at initial diagnosis and genotype distributions were recorded. The control group consisted of volunteers with the same ethnicity, age and gender, no active infection, and no consanguinity.CA/CA genotype of SOCS1 was found to be significantly higher in the healthy control group (p = 0.028). AB/BB genotype of MBL2 was significantly higher in FEN patients with a MASCC score of high risk, AA genotype was found to be higher in patients with low risk (p = 0.001). While the rate of microbiologically documented infection (MDI) was significantly lower in patients with the AA genotype of MBL2, it was significantly higher in patients with AA/BB genotypes (p = 0.025). MDI rate in patients with the del/del genotype of SOCS1 was found to be significantly lower than in patients with CA/CA + CA/del genotypes (p = 0.026).In this study, it was revealed that low expression-related MBL2 genotypes were riskier for FEN and also, gene variants associated with high SOCS1 transcription were both protective against FEN and increased the rate of culture-negativity.

For immunocompromised patients receiving chemotherapy or bone mallow transplantation, slow-growing bacteria should also be considered one of the pathogenic microorganisms. However, there is no evidence pertaining to the microbiological tests associated with a patient with febrile neutropenia before peripheral blood stem cell harvest (PBSCH). We report a case of a 4-year-old cancer-bearing female presenting with a catheter-related bloodstream infection due to Gordonia otitidis. We detected G. otitidis from long-term blood cultures for approximately 6 days and prevented iatrogenic bacteremia by identifying the same organism from the culture of the PBSC sample and postponing the scheduled PBSCH. If febrile neutropenia occurs before PBSCH, we should collect multiple sets of blood cultures and culture them for a longer period.

Background Radiotherapy and cisplatin-based combination chemotherapy are accepted standard-of-care treatments for metastatic seminoma with excellent survival outcomes but with established short- and long-term morbidity. Carboplatin monotherapy may be a less toxic alternative; however early historic studies at AUC7 showed inferior outcomes. Objectives To evaluate multi-institutional data on and toxicity and longer-term survival for metastatic seminoma patients treated with the single-agent carboplatin AUC10. Methods We undertook a multi-institutional analysis incorporating all men with the International Germ Cell Cancer Collaborative Group good-prognosis metastatic seminoma treated until 2018. Carboplatin AUC10 was given every 21 days. Toxicity, progression-free survival (PFS), disease-specific survival (DSS) and overall survival were noted. Variables predictive of progression were identified. Results and limitations 216 patients were treated. The three-year PFS rate was 96.5%, and five-year DSS was 98.3%. There were seven relapses, of which 5 were successfully salvaged with further chemotherapy ± surgery, and three non-seminoma–related deaths. There were no treatment-related deaths. Of 148/216 evaluable patients for toxicity, 37% and 27% suffered >/ = grade III neutropenia and thrombocytopenia, respectively. Twelve percent of patients needed a platelet or blood transfusion (or both). The incidence of febrile neutropenia was 5%. Conclusion For metastatic seminoma, carboplatin AUC10 harbours a similar oncological efficacy to established therapies, with a low failure risk. The major acute toxicity was myelosuppression. Our study establishes carboplatin AUC10 as another standard-of-care treatment option for good-prognosis metastatic seminoma, with a potentially lower toxicity profile than other therapies.

The primary role of the oncology nurse practitioner in an acute tertiary cancer hospital in Australia is to provide comprehensive symptom management to adult patients undergoing systemic chemotherapy or immunotherapy. A common presentation to this service is acute febrile illness. There is a dearth of awareness surrounding the risk stratification of this patient group in Australia, which may contribute to unnecessary hospital admissions, increased nosocomial infections, and missed opportunities for maintaining quality of life. This article evaluates internationally endorsed risk stratification tools and amalgamates them to produce a proposed best-practice pathway. The pathway could be implemented within oncology units Australia-wide to guide nurse practitioner practice in managing febrile cancer patients.

Aim: To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan.Patients and methods: In this prospective, multicentre, non-randomised study, patients intended for treatment with irinotecan were pre-therapeutically genotyped for UGT1A1*28 and UGT1A1)93. Homozygous variant carriers (UGT1A1 poor metabolisers; PMs) received an initial 30% dose reduction. The primary endpoint was incidence of febrile neutropenia in the first two cycles of treatment. Toxicity in UGT1A1 PMs was compared to a historical cohort of UGT1A1 PMs treated with full dose therapy, and to UGT1A1 non-PMs treated with full dose therapy in the current study. Secondary endpoints were pharmacokinetics, feasi- bility, and costs.Results: Of the 350 evaluable patients, 31 (8.9%) patients were UGT1A1 PM and received a median 30% dose reduction. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical UGT1A1 PMs (P = 0.04) and was comparable to the incidence in UGT1A1 non-PMs treated with full dose therapy. Systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs was still slightly higher compared to a standard-dosed irinotecan patient cohort (difference: thorn 32%). Cost analysis showed that genotype-guided dosing was cost-saving with a cost reduction of V183 per patient.Conclusion: UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan, results in a therapeutically effec- tive systemic drug exposure, and is cost-saving. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve individual patient safety. (C) 2022 The Authors. Published by Elsevier Ltd.

International audience; Objectives: There is no specific recommendation about antimicrobial treatment length for documented infections in chemotherapy induced febrile neutropenia (FN). Practices have changed along time in our center regarding length of antibiotic treatment. The aim of this study was to compare long versus short antibiotic course for bloodstream infection (BSI) treatment in acute myeloid leukemia (AML) patients during FN. Methods: This monocentric retrospective comparative study included all consecutive BSI episodes among AML patients with FN for 3 years (2017-2019). Episodes were classified regarding the length of antibiotic treatment, considered as short course if the treatment lasted ≤ 7 days, except for nonfermenting bacteria and Staphylococcus aureus or lugdunensis for which the threshold was ≤ 10 days and ≤ 14 days, respectively. The primary outcome was the number of BSI relapses in both groups within 30 days of antibiotic discontinuation. Results: Among 71 AML patients, 104 BSI episodes were included; 48 (46%) received short course treatment. Only 8 (7.6%) BSI episodes relapsed within 30 days of antibiotic discontinuation, 5 having received short course treatment. No association was found between risk of relapse and short course of antibiotic treatment (p = 0.37). The only risk factor significantly associated with BSI relapse was neutropenia duration (p = 0.005). Conclusion: Antibiotic short course seemed as effective as prolonged treatment for BSI in AML patients during FN, with very few relapses at day 30. These encouraging findings should be confirmed through prospective studies.

Background Febrile neutropenia (FN) is an important oncological emergency seen in the emergency department (ED), and the American Society of Clinical Oncology recommends risk stratification of patients with febrile neutropenia using the Multinational Association for Supportive Care in Cancer (MASCC) Index, with ED discharge on oral antibiotics recommended for low-risk patients. Objectives To determine the prevalence of FN neutropenia and medical system wide ED treatment guideline adherence. Methods We performed a retrospective chart review of all patients with an ICD-10 confirmed diagnosis of FN from January 2016-2019at 13 affiliated EDs within one medical system. Only cancer/chemotherapy related FN were included. Following the MASCC guidelines, we used post-hoc calculations to classify patients as low/high-risk, and compared key clinical variables (mortality, blood culture positivity, interventions). Results 203 patients were found to have FN. 97.9% (184/203) received broad spectrum antibiotics, including 92% of the low-risk group (60/65). All patients were admitted, and no observed in-hospital mortality was noted in the low-risk group, meanwhile 5.1% (7/138) of the high-risk group died. 14/203 patients had positive blood cultures, none in the low-risk group. Conclusion The prevalence of FN is low among 13 EDs that had almost 1.7 million ED visits over a 3-year period. Guideline compliance for low-risk FN was poor. All patients were admitted, and nearly all patients received IV fluids and IV antibiotics. Improving FN management to align with national guidelines represents an opportunity to improved ED care of patients with cancer by reducing unnecessary hospitalizations.

Objectives To determine the predictors for 30-day all-cause mortality in patients with febrile neutropenia (FN) and develop a prediction score. Methods The electronic medical records of patients undergoing chemotherapy with FN between 2018 and 2019 were reviewed. Multivariate logistic regression was performed to identify factors associated with 30-day all-cause mortality to develop a parsimonious model. A prediction score was developed from the model's coefficients of each predictor. Results There were 273 FN episodes in 153 patients. The overall mortality rate was 12.5%. Pre-existing cardiovascular disease (OR 22.45), alteration of consciousness on admission (OR 18.50), anemia (OR 4.33), acute kidney injury (AKI) (OR 13.15), causative pathogen identified (OR 8.68), intensive care unit admission (OR 0.13), septic shock (OR 18.72), and the need for mechanical ventilation (OR 22.65) were associated with mortality. After exploring confounding effects between factors, septic shock, anemia, AKI, and the need for mechanical ventilation were selected to develop the prediction score which provided good sensitivity (87.88%) and specificity (90.91%) with an area under the ROC curve of 0.8939. Conclusions Septic shock, anemia, AKI, and the need for mechanical ventilation were associated with FN mortality. Our prediction score is effective in discriminating high and low-risk patients for mortality.

BACKGROUND The orally administered combination trifluridine/tipiracil has been approved as third line treatment in mCRC, demonstrating survival benefit and acceptable toxicity profile in the phase III RECOURSE study. PATIENT AND METHODS We performed a multicenter retrospective real-world analysis of patients with mCRC receiving trifluridine/tipiracil between 2016 and 2019 in eight cancer centers across the United Kingdom. RESULTS A total of 236 patients were included with median age of 69 years. All patients had received at least 2 lines of fluoropyrimidine-based chemotherapy doublet with oxaliplatin or irinotecan. About 10% of patients had ECOG ≥ 2. Median duration of trifluridine/tipiracil treatment was 3 months with an ORR of 2.1% and disease control rate of 21.6%. Median OS was 7.6 and median PFS 3.3 months. A dose reduction was required in 27% of patients, while 7.6% discontinued treatment due to toxicity. The most common grade 3 toxicities were neutropenia (34%), fatigue (10%), anemia (9%) and febrile neutropenia (5%). Baseline NLR

Background: Antibiotics have been widely and efficaciously used for febrile neutropenia in pediatric patients. However, reports are scant regarding the risk factors for recurrent fever after discontinuation of antibiotics in a neutropenic state. Here, we investigated these factors using data from our previously reported randomized study regarding meropenem and piperacillin/tazobactam for pediatric patients with febrile neutropenia. Procedure: We analyzed a total of 170 febrile episodes where first line antibiotic treatment was effective and discontinued before neutrophil recovery. Results: Recurrent fever was observed in 31 episodes (18%). The median interval from antibiotics discontinuation to recurrent fever was 5 days (0–27 days). Risk factors for recurrent fever were: incomplete remission of original disease; and high white blood cell count, neutrophil count, and C reactive protein levels at start of antibiotics. Moreover, lower neutrophil count at discontinuation of antibiotics, duration of neutropenia, and onset day of febrile neutropenia from start of neutropenia were also risk factors of recurrent fever. In multivariate analysis, neutrophil count at discontinuation of antibiotics

BACKGROUND: Patients with cancer have an increased risk of complications from SARS-CoV-2 infection. Vaccination to prevent COVID-19 is recommended, but data on the immunogenicity and safety of COVID-19 vaccines for patients with solid tumours receiving systemic cancer treatment are scarce. Therefore, we aimed to assess the impact of immunotherapy, chemotherapy, and chemoimmunotherapy on the immunogenicity and safety of the mRNA-1273 (Moderna Biotech, Madrid, Spain) COVID-19 vaccine as part of the Vaccination Against COVID in Cancer (VOICE) trial.METHODS: This prospective, multicentre, non-inferiority trial was done across three centres in the Netherlands. Individuals aged 18 years or older with a life expectancy of more than 12 months were enrolled into four cohorts: individuals without cancer (cohort A [control cohort]), and patients with solid tumours, regardless of stage and histology, treated with immunotherapy (cohort B), chemotherapy (cohort C), or chemoimmunotherapy (cohort D). Participants received two mRNA-1273 vaccinations of 100 μg in 0·5 mL intramuscularly, 28 days apart. The primary endpoint, analysed per protocol (excluding patients with a positive baseline sample [>10 binding antibody units (BAU)/mL], indicating previous SARS-CoV-2 infection), was defined as the SARS-CoV-2 spike S1-specific IgG serum antibody response (ie, SARS-CoV-2-binding antibody concentration of >10 BAU/mL) 28 days after the second vaccination. For the primary endpoint analysis, a non-inferiority design with a margin of 10% was used. We also assessed adverse events in all patients who received at least one vaccination, and recorded solicited adverse events in participants who received at least one vaccination but excluding those who already had seroconversion (>10 BAU/mL) at baseline. This study is ongoing and is registered with ClinicalTrials.gov, NCT04715438.FINDINGS: Between Feb 17 and March 12, 2021, 791 participants were enrolled and followed up for a median of 122 days (IQR 118 to 128). A SARS-CoV-2-binding antibody response was found in 240 (100%; 95% CI 98 to 100) of 240 evaluable participants in cohort A, 130 (99%; 96 to >99) of 131 evaluable patients in cohort B, 223 (97%; 94 to 99) of 229 evaluable patients in cohort C, and 143 (100%; 97 to 100) of 143 evaluable patients in cohort D. The SARS-CoV-2-binding antibody response in each patient cohort was non-inferior compared with cohort A. No new safety signals were observed. Grade 3 or worse serious adverse events occurred in no participants in cohort A, three (2%) of 137 patients in cohort B, six (2%) of 244 patients in cohort C, and one (1%) of 163 patients in cohort D, with four events (two of fever, and one each of diarrhoea and febrile neutropenia) potentially related to the vaccination. There were no vaccine-related deaths.INTERPRETATION: Most patients with cancer develop, while receiving chemotherapy, immunotherapy, or both for a solid tumour, an adequate antibody response to vaccination with the mRNA-1273 COVID-19 vaccine. The vaccine is also safe in these patients. The minority of patients with an inadequate response after two vaccinations might benefit from a third vaccination.FUNDING: ZonMw, The Netherlands Organisation for Health Research and Development.

Background Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) is a front-line treatment for patients with aggressive B-cell lymphomas. Bcl-2 is associated with chemoresistance due to BCL2 gene rearrangement or protein overexpression and is antagonised by venetoclax. We aimed to assess the safety of venetoclax with dose-adjusted EPOCH-R as initial therapy in aggressive B-cell lymphoma. Methods We conducted a single-arm, phase 1 study across seven treatment centres in the USA. Eligible patients were aged 18-80 years with histologically confirmed, previously untreated diffuse large B-cell lymphoma, transformed indolent non-Hodgkin lymphoma, high-grade B-cell lymphoma with double-hit or not otherwise specified, or primary mediastinal B-cell lymphoma, with Ann Arbor stage II-IV and Eastern Cooperative Oncology Group performance status of 0-2. Participants received six cycles of oral venetoclax 400 mg, 600 mg, or 800 mg once daily for 10 days per cycle with dose-adjusted EPOCH-R (one cycle every 3 weeks; baseline doses were intravenous rituximab 375 mg/m2 on day 1, intravenous etoposide 50 mg/m2 on days 1-4, oral prednisone 60 mg/m2 twice daily on days 1-5, intravenous vincristine 0·4 mg/m2 on days 1-4, intravenous cyclophosphamide 750 mg/m2 on day 5, and intravenous doxorubicin 10 mg/m2 on days 1-4). A subsequent cohort received venetoclax 600 mg once daily for 5 days per cycle. The primary endpoints were the maximum tolerated dose, dose-limiting toxicities, and the recommended phase 2 dose of venetoclax. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov, NCT03036904, and enrolment is now closed. Findings Between Feb 3, 2017, and June 4, 2019, 34 patients were assessed for eligibility, and 30 were enrolled and received venetoclax with dose-adjusted EPOCH-R. The median patient age was 64·0 years (IQR 51·6-69·4). The maximum tolerated dose was 800 mg for 10 days and the established recommended phase 2 dose was 600 mg for 5 days due to tolerability for treatment duration. One (3%) of 30 patients had a dose-limiting toxicity in cycle one (grade 4 thrombocytopenia with 800 mg dose). The most common grade 3-4 adverse events were cytopenias (28 [93%] of 30 patients); febrile neutropenia occurred in 19 (63%) patients. Grade 3-4 non-haematological adverse events included hypophosphataemia (n=10), hypokalaemia (n=7), and hyperglycaemia (n=5). Serious adverse events included infection (n=7) and gastrointestinal toxicities including abdominal pain (n=3), colonic perforation (n=1), and small intestinal obstruction (n=1). There was one treatment-related death (sepsis). Overall response rate was 96·7% (95% CI 82·8-99·9); 28 (93·3% [77·9-99·2]) of 30 patients had complete response and one (3·3% [0·1-17·2]) had a partial response. Interpretation Venetoclax with dose-adjusted EPOCH-R showed an acceptable safety profile at the recommended phase 2 dose and had encouraging preliminary activity in this population at high risk of adverse outcomes, and is worthy of further study. The combination is being investigated in Alliance 051701 (NCT03984448). Funding Genentech.

CPX-351 is a liposome encapsulating cytarabine and daunorubicin for treating Acute Myeloid Leukemia (AML) patients. To what extent differences in cytidine deaminase (CDA) activity, the enzyme that catabolizes free cytarabine in the liver, can affect the pharmacokinetics of liposomal cytarabine as well, is unknown. We have studied the pharmacokinetics (PK) of released, liposomal and total cytarabine using a population-modeling approach in 9 adult AML patients treated with liposomal CPX-351. Exposure levels and PK parameters were compared with respect to the patient's CDA status (i.e., Poor Metabolizer (PM) vs. Extensive Metabolizer (EM)). Overall response rate was 75%, and 56% of patients had non-hematological severe toxicities, including one lethal toxicity. All patients had febrile neutropenia. A large (>60%) inter-individual variability was observed on pharmacokinetics parameters and subsequent drug levels. A trend towards severe toxicities was observed in patients with higher exposure of cytarabine. Results showed that liposomal CPX-351 led to sustained exposure with reduced clearance (Cl = 0.16 L/h) and prolonged half-life (T1/2 = 28 h). Liposomal nanoparticles were observed transiently in bone marrow with cytarabine levels 2.3-time higher than in plasma. Seven out of 9 patients were PM with a strong impact on the PK parameters, i.e., PM patients showing higher cytarabine levels as compared with EM patients (AUC: 5536 vs. 1784 ng/mL.h), sustained plasma exposure (T1/2: 33.9 vs. 13.7 h), and reduced clearance (Cl: 0.12 vs. 0.29 L/h). This proof-of-concept study suggests that CDA status has a major impact on cytarabine PK and possibly safety in AML patients even when administered as a liposome.

Background Intensified immunochemotherapy with rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) improves outcomes in younger adults with diffuse large B-cell lymphomas (DLBCL) compared with R-CHOP. Due to vindesine unavailability, we assessed the safety and efficacy of replacing vindesine with vincristine in a modified R-ACVBP protocol (mR-ACVBP). Methods This is a retrospective study including all consecutive adult patients with newly diagnosed DLBCL who received first-line mR-ACVBP. Vindesine was replaced with vincristine 1.5 mg on days 1 and 5 of each cycle. Responders continued with published R-ACVBP consolidation. Patients with inadequate response on interim imaging were offered consolidative autologous stem cell transplantation. Results We identified 56 patients with DLBCL, with a median age of 41 years (range, 21-67). Thirty-seven (66%) patients had an age-adjusted International Prognostic Index of ≥ 2. Complete response was achieved in 41 (80%) patients and partial response in 6 (12%). The most common adverse events during induction were anemia (91%), febrile neutropenia (64%; grade 4 in 46%), thrombocytopenia (39%), and mucositis (21%). Peripheral neuropathy was encountered in 7 (12%) patients (grade 3; n = 1). Two deaths from septic shock were reported in patients with initial poor performance status. After a median follow-up of 17 months, the 2-year progression-free survival and overall survival rates were 86% and 87%, respectively. Conclusion The replacement of vindesine with vincristine in mR-ACVBP seems feasible, with manageable adverse events and excellent 2-year progression-free survival. These data need validation in larger prospective trials.

Summary Background In the primary analysis of the pivotal JULIET trial of tisagenlecleucel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, the best overall response rate was 52% and the complete response rate was 40% in 93 evaluable adult patients with relapsed or refractory aggressive B-cell lymphomas. We aimed to do a long-term follow-up analysis of the clinical outcomes and correlative analyses of activity and safety in the full adult cohort. Methods In this multicentre, open-label, single-arm, phase 2 trial (JULIET) done at 27 treatment sites in ten countries (Australia, Austria, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, and the USA), adult patients (≥18 years) with histologically confirmed relapsed or refractory large B-cell lymphomas who were ineligible for, did not consent to, or had disease progression after autologous haematopoietic stem-cell transplantation, with an Eastern Cooperative Oncology Group performance status of 0–1 at screening, were enrolled. Patients received a single intravenous infusion of tisagenlecleucel (target dose 5 × 108 viable transduced CAR T cells). The primary endpoint was overall response rate (ie, the proportion of patients with a best overall disease response of a complete response or partial response using the Lugano classification, as assessed by an independent review committee) at any time post-infusion and was analysed in all patients who received tisagenlecleucel (the full analysis set). Safety was analysed in all patients who received tisagenlecleucel. JULIET is registered with ClinialTrials.gov , NCT02445248 , and is ongoing. Findings Between July 29, 2015, and Nov 2, 2017, 167 patients were enrolled. As of Feb 20, 2020, 115 patients had received tisagenlecleucel infusion and were included in the full analysis set. At a median follow-up of 40·3 months (IQR 37·8–43·8), the overall response rate was 53·0% (95% CI 43·5–62·4; 61 of 115 patients), with 45 (39%) patients having a complete response as their best overall response. The most common grade 3–4 adverse events were anaemia (45 [39%]), decreased neutrophil count (39 [34%]), decreased white blood cell count (37 [32%]), decreased platelet count (32 [28%]), cytokine release syndrome (26 [23%]), neutropenia (23 [20%]), febrile neutropenia (19 [17%]), hypophosphataemia (15 [13%]), and thrombocytopenia (14 [12%]). The most common treatment-related serious adverse events were cytokine release syndrome (31 [27%]), febrile neutropenia (seven [6%]), pyrexia (six [5%]), pancytopenia (three [3%]), and pneumonia (three [3%]). No treatment-related deaths were reported. Interpretation Tisagenlecleucel shows durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas. For patients with large B-cell lymphomas that are refractory to chemoimmunotherapy or relapsing after second-line therapies, tisagenlecleucel compares favourably with respect to risk–benefit relative to conventional therapeutic approaches (eg, salvage chemotherapy). Funding Novartis Pharmaceuticals.

Summary Background The WHO Model List of Essential Medicines classified antibiotics into Access, Watch, and Reserve (AWaRe) categories for the treatment of 31 priority bacterial infections as a tool to facilitate antibiotic stewardship and optimal use. We compared the listing of antibiotics on national essential medicines lists (NEMLs) to those in the 2019 WHO Model List and the AWaRe classification database to determine the degree to which NEMLs are in alignment with the AWaRe classification framework recommended by WHO. Methods In this cross-sectional study, we obtained up-to-date (data after 2017) NEMLs from our Global Essential Medicines (GEM) database, WHO online resources, and individual countries' websites. From the 2019 WHO Model List we extracted, as a reference standard, a list of 37 antibiotics (44 unique antibiotics after accounting for combination drugs or therapeutically equivalent drugs as specified by WHO) that were considered essential in treating 31 of the most common and severe clinical infectious syndromes (priority infections). From the WHO AWaRe Classification Database, which contains commonly used antibiotics globally, we extracted a list of 122 AWaRe antibiotics listed by at least one country in the GEM database. We then assessed individual countries' NEMLs for listing of the 44 essential and 122 commonly used antibiotics, overall and according to AWaRe classification group. We also evaluated and summarised the listing of both first-choice and second-choice treatments for the 31 priority infections. A total coverage score was calculated for each country by assigning a treatment score of 0–3 for each priority infection on the basis of whether first-choice and second-choice treatments, according to the 2019 WHO Model List, were included in the country's NEML. Coverage scores were then compared against the score of the 2019 WHO Model List and across World Bank income groups and WHO regions. Findings As of July 7, 2020, we had up-to-date NEMLs for 138 countries. Of the 44 unique essential antibiotics, 24 were Access, 15 were Watch, and five were Reserve. The median number of total essential antibiotics listed across the 138 NEMLs was 26 (IQR 21–32). 102 (74%) countries listed at least 22 (50%) of the 44 essential antibiotics. The median number of total AWaRe antibiotics listed by the 138 countries was 35 (IQR 29–46), of Access antibiotics was 18 (16–21), of Watch antibiotics was 16 (11–22), and of Reserve antibiotics was one (0–2). 56 (41%) countries did not list any essential Reserve antibiotics. 131 (95%) countries had coverage scores of at least 60, equivalent to at least 75% of the score of the 2019 WHO Model List, which was 80. Nine (7%) countries listed fewer than 12 of 24 essential Access antibiotics, and seven (5%) did not list sufficient first-choice and second-choice treatments for priority infections (ie, they had coverage scores lower than 60). Of the 31 priority infections, acute neonatal meningitis and high-risk febrile neutropenia did not have enough listed treatments, with 82 (59%) countries listing no treatment for acute neonatal meningitis and 84 (61%) countries listing only a first-choice treatment, only a second-choice treatment, or no treatment for high-risk febrile neutropenia. Coverage scores differed between countries on the basis of World Bank income groups (p=0·025). Interpretation Our findings highlight potential changes to the antibiotics included in NEMLs that would increase adherence to international guidance aimed at effectively treating infectious diseases while addressing antimicrobial resistance. Funding Canadian Institutes of Health Research and Ontario Strategy for Patient Oriented Research Support Unit.

Background Pre-clinical data suggest that docetaxel and enzalutamide interfere with androgen receptor translocation and signalling. The aim of this study is to assess the efficacy of their concurrent administration in the first-line treatment for metastatic castration-resistant prostate cancer (mCRPC). Methods In this open-label, randomised, phase II trial, previously untreated mCRPC patients were randomised 1:1 to receive eight 21-d courses of docetaxel 75 mg/m2, oral prednisone 5 mg twice daily and oral enzalutamide 160 mg/d (arm DE), or the same treatment without enzalutamide (arm D). The primary end-point was the percentage of patients without investigator-assessed disease progression 6 months after the first docetaxel administration. Results The 246 eligible patients were randomly assigned to receive docetaxel, prednisone and enzalutamide (n = 120) or docetaxel and prednisone (n = 126). The 6-month progression rate was 12.5% (95% confidence interval [CI] 8.1–20.6) in arm DE and 27.8% (95% CI 22.8–39.4) in arm D (chi-squared test 10.01; P = 0.002). The most frequent grade III–IV adverse events were fatigue (12.5% in arm DE versus 5.6% in arm D), febrile neutropenia (9.3% versus 4.0%) and neutropenia (7.6% versus 5.6%). Conclusions The combination of enzalutamide and docetaxel appears to be more clinically beneficial than docetaxel alone in previously untreated mCRPC patients, although serious adverse events were more frequent. Our findings suggest that first-line treatment with this combination could lead to an additional clinical benefit when prompt and prolonged disease control is simultaneously required. Clearly, these results should be considered cautiously because of the study’s phase II design and the absence of an overall survival benefit. Trial registration numbers EudraCT 2014-000175-43 – NCT02453009.

Background Primary febrile neutropenia (FN) prophylaxis with ciprofloxacin or granulocyte-colony stimulating factors (G-CSF) is recommended with docetaxel-cyclophosphamide (TC) chemotherapy for early-stage breast cancer (EBC). A pragmatic randomised trial compared the superiority of G-CSF to ciprofloxacin and a cost-utility analysis were conducted. Methods EBC patients receiving TC chemotherapy were randomised to ciprofloxacin or G-CSF. The primary outcome was a composite of FN and non-FN treatment-related hospitalisation. Secondary outcomes included; rates of FN, non-FN treatment-related hospitalisation, chemotherapy dose reductions/delays/discontinuations. Primary analysis was performed with the intention to treat population. Cost-utility analyses were conducted from the Canadian public payer perspective. Results 458 eligible patients were randomised: 228 to ciprofloxacin and 230 to G-CSF. For the primary endpoint there was non-statistically significant difference (Risk difference = −6.7%, 95%CI = −13.5%–0.1%, p = 0.061) between ciprofloxacin patients (46,20.2%) and G-CSF (31,13.5%). Patients receiving ciprofloxacin were more likely to experience FN (36/228, 15.8% vs 13/230, 5.7%) than patients receiving G-CSF (p, Highlights • Primary febrile neutropenia (FN) prophylaxis is indicated for docetaxel-cyclophosphamide (TC) chemotherapy. • In this multicentre trial 458 breast cancer patients receiving TC chemotherapy were randomised to ciprofloxacin or to G-CSF. • For the primary endpoint of FN and non-FN treatment-related hospitalizations, G-CSF was not superior over ciprofloxacin. • While there were reduced FN rates with G-CSF, the incremental cost-effectiveness ratio was C$1,760,796 per one QALYWALY gained.

Summary Background Relapsed or refractory classical Hodgkin lymphoma could be treated with multiagent salvage chemotherapy followed by autologous haematopoietic stem-cell transplantation. The aim of this study is to establish the safety and activity of dose-dense brentuximab vedotin combined with ifosfamide, carboplatin, and etoposide (BV-ICE) chemotherapy in second-line treatment of classical Hodgkin lymphoma. Methods We conducted a single-arm, open-label, phase 1/2 study of dose-dense BV-ICE at the Seattle Cancer Care Alliance, University of Washington (Seattle, WA, USA). Eligibility criteria were age 18 years or older; diagnosis of first relapse, primary refractory classical Hodgkin lymphoma after one previous line of therapy; measurable disease of at least 1 cm in the longest axis, CT of chest, abdomen, and pelvis with PET within the past 28 days; Eastern Cooperative Oncology Group performance status of 0–1; and adequate organ function. A 3 + 3 dose escalation study was done for the phase 1 part of the trial to establish the maximum tolerated dose to be used for the phase 2 study. Brentuximab vedotin was delivered on days 1 and 8 at either 1·2 mg/kg (dose level 1) or 1·5 mg/kg (dose level 2) intravenously (capped at 150 mg) with standard dosing of ICE on days 1–3 (ifosfamide 5 g/m2 plus mesna 5 g/m2 intravenously over 24 h on day 2, carboplatin area under the curve 5 on day 2 in one intravenous injection, and etoposide 100 mg/m2 on days 1–3 in one intravenous injection per day) for two 21-day cycles. The primary endpoint was to establish the recommended phase 2 dose (phase 1 part) and complete response rate after two cycles, with a prespecified target of 78% (phase 2 part). Safety analysis was done in all enrolled participants and the primary activity analysis was done in all patients with evaluable response data. This study is registered with ClinicalTrials.gov (NCT02227199); enrolment and study treatment are complete. Findings Between Oct 16, 2014, and Feb 10, 2020, we enrolled 45 patients with a median age of 31 years (IQR 28–45). The recommended phase 2 dose of brentuximab vedotin was established to be 1·5 mg/kg. After a median follow-up of 3·1 years (IQR 1·7–4·1), 32 (74%; 95% CI 58·8–86·5) of 43 evaluable patients had complete responses after two cycles of treatment. Grade 3–4 haematological toxic effects were common, including neutropenia (33 [73%]), anaemia (six [13%]), and thrombocytopenia (36 [80%]). The most common grade 3–4 non-haematological toxic effects were febrile neutropenia (four [9%]), sepsis (six [13%]), increased alanine aminotransferase (five [11%]), hyperglycaemia (three [7%]), pulmonary embolism (two [4%]), and increased aspartate aminotransferase (two [4%]). There was one (2%) on-treatment death due to multisystem organ failure that was considered treatment related. Serious adverse events occurred in 13 (29%) patients. Interpretation Our data suggest that dose-dense BV-ICE is a rapidly administered and active salvage regimen for patients with relapsed or refractory classical Hodgkin lymphoma despite a complete response in this trial lower than the prespecified phase 2 target. Although cross-trial comparisons should be made with caution, activity results seem to be similar to previously presented brentuximab vedotin chemotherapy salvage combinations delivered over much longer durations and can be considered in young ( Funding Seagen, Lymphoma Research Foundation, National Institutes of Health/National Cancer Institute, and generous philanthropic donations to the University of Washington from numerous individuals and families in support of lymphoma research.

Pure red cell aplasia (PRCA) is a rare paraneoplastic syndrome observed in 2-5 % of thymomas. Literature reports great variability in its management. Based on an illustrative clinical case, we present a systematic literature review whose main objective is to evaluate the therapeutic management of PRCA. The literature search was performed based on the PICO method in the Medline and Scopus databases. The reference clinical case concerns a 51-year-old woman with stage IVa thymoma. After initial response to chemotherapy, a locoregional progression occurred with PRCA development that responded favorably under second line chemotherapy. The patient finally died in a context of bicytopenia with febrile neutropenia. The systematic review covers 135 articles published between 1950 and 2019. Thymectomy alone or in combination with other therapies showed a 31 % complete remission (CR) rate for PRCA of, whereas none was reported with anti-tumor treatments without thymectomy. Among immunomodulatory therapies, cyclosporin gave the highest percentage of CR (74 %). Finally, the combination of thymectomy and immunomodulatory treatments showed a CR rate of 45 %. Thymectomy appeared to be the most effective anti-tumor treatment for PRCA. Immunomodulatory therapies, particularly cyclosporine, are shown effective, but the risk of infectious complications must be considered. The optimal place of anti-tumor and immunomodulatory therapies against PRCA has yet to be determined.

Objectives To study the impact of the implementation of the Pediatric Surviving Sepsis Campaign protocol on early recognition of sepsis, 1 -h treatment bundle and mortality. Methods Retrospective, single-center study, before and after the implementation of the sepsis protocol. Outcomes: sepsis recognition, compliance with the 1 -h bundle (fluid resuscitation, blood culture, antibiotics), time interval to fluid resuscitation and antibiotics administration, and mortality. Patients with febrile neutropenia were excluded. The comparisons between the periods were performed using non-parametric tests and odds ratios or relative risk were calculated. Results We studied 84 patients before and 103 after the protocol implementation. There was an increase in sepsis recognition (OR 21.5 [95% CI: 10.1-45.7]), in the compliance with the 1 -h bundle as a whole (62% x 0%), and with its three components: fluid resuscitation (OR 31.1 [95% CI: 3.9−247.2]), blood culture (OR 15.9 [95% CI: 3.9−65.2]), and antibiotics (OR 35.6 [95% CI: 8.9−143.2]). Significant reduction between sepsis recognition to fluid resuscitation (152min × 12min, p < 0.001) and to antibiotics administration (137min × 30min) also occurred. The risk of death before protocol implementation was four times greater (RR 4.1 [95% CI: 1.2-14.4]), and the absolute death risk reduction was 9%. Conclusion Even if we considered the low precision of some estimates, the lower limits of the Confidence Intervals show that the implementation of the Pediatric Surviving Sepsis Campaign guidelines alongside a qualitive assurance initiative has led to improvements in sepsis recognition, compliance with the 1 -h treatment bundle, reduction in the time interval to fluid resuscitation and antibiotics, and reduction in sepsis mortality.

Paediatric patients with cancer and those undergoing haematopoietic cell transplantation are at high risk of bacterial infections. The 8th European Conference on Infections in Leukaemia (ECIL-8) convened a Paediatric Group to review the literature and to formulate recommendations for the use of antibiotics according to the European Society of Clinical Microbiology and Infectious Diseases grading system. The evaluation of antibacterial prophylaxis included mortality, bloodstream infection, febrile neutropenia, emergence of resistance, and adverse effects as endpoints. Initial antibacterial therapy and antibiotic de-escalation or discontinuation focused on patients with a clinically stable condition and without previous infection or colonisation by resistant bacteria, and on patients with a clinically unstable condition or with previous infection or colonisation by resistant bacteria. The final considerations and recommendations of the ECIL-8 Paediatric Group on antibacterial prophylaxis, initial therapy, and de-escalation strategies are summarised in this Policy Review.

The study aimed to evaluate the clinical outcomes of tailored adjuvant chemotherapy according to human equilibrative nucleoside transporter 1 (hENT1) expression in resected pancreatic ductal adenocarcinoma (PDA).Patients who underwent pancreatectomy for PDA were enrolled prospectively. According to intra-tumoral hENT1 expression, the high hENT1 (≥50%) group received gemcitabine and the low hENT1 (50%) group received 5-fluorouracil plus folinic acid (5-FU/FA). The propensity score-matched control consisted of patients who received hENT1-independent adjuvant chemotherapy. The primary outcome was recurrence free survival (RFS) and the secondary outcomes were overall survival (OS) and toxicities.Between May 2015 and June 2017, we enrolled 44 patients with resected PDA. During a median follow-up period of 28.5 months, the intention-to-treat population showed much longer median RFS [22.9 (95% CI, 11.3-34.5) vs. 10.9 (95% CI, 6.9-14.9) months, P = 0.043] and median OS [36.2 (95% CI, 26.5-45.9) vs. 22.1 (95% CI, 17.7-26.6) months, P = 0.001] compared to the controls. Among 5 patients in the low hENT1 group who discontinued treatment, 2 patients receiving 5-FU/FA discontinued treatment due to drug toxicities (febrile neutropenia and toxic epidermal necrolysis).Tailored adjuvant chemotherapy based on hENT1 staining provides excellent clinical outcomes among patients with resected PDA.clinicaltrials.gov identifier: NCT02486497.

Background Pembrolizumab has modest activity if used in patients with hormone-receptor–positive (HR+), HER2-negative, previously treated metastatic breast cancer (BC). Our study investigated whether there would be any clinical benefit in combining chemotherapy with pembrolizumab in a similar patient population. Methods This single-arm, phase Ⅱ trial enrolled women aged ≥18 years with HR+, HER2-negative, inoperable, locally recurrent or metastatic BC. Patients were previously treated with hormonal therapy and 1–2 chemotherapy regimens for locally recurrent and/or metastatic BC. On each 21-day cycle, patients received intravenous pembrolizumab 200 mg on day 1 and eribulin 1∙23 mg/m2 on days 1 and 8. The primary endpoint was the clinical benefit rate. Analysis of safety and activity was carried out in all patients who met the screening criteria and received at least 1 dose of study treatment. The trial is registered at ClinicalTrials.gov, NCT03222856. Results Of the 44 patients enrolled between January 29 and October 17, 2018, clinical benefit was achieved in 25 (56∙8%, 95% confidence interval [CI]: 41∙0–71∙7), objective response in 18 (40∙9%, 95% CI: 26∙3–56∙8), median progression-free survival was 6∙0 months (95% CI: 3∙7–8∙4), and 1-year overall survival was 59∙1% (95% CI: 45∙8–76∙2). The most common treatment-emergent adverse events (AEs) of any grade were neutropenia (20 [45∙5%]), anaemia (17 [38∙6%]), alopecia (19 [43∙2%]), asthenia (19 [43∙2%]), diarrhoea (14 [31∙8%]), fatigue (14 [31∙8%]), and peripheral neuropathy (12 [27∙3%]). Serious AEs occurred in 14 (31∙8%) patients including febrile neutropenia (3 [6∙8%]), neutropenia (2 [4∙5%]), fever (2 [4∙5%]) and peripheral neuropathy (2 [4∙5%]). Immune-related AEs occurred in 11 (25∙0%) patients. One (2∙3%) patient died of cardiac arrest unrelated to study treatment. Conclusion Pembrolizumab plus eribulin demonstrates encouraging antitumour activity in patients with heavily pre-treated, HR+, HER2-negative, locally recurrent or metastatic BC. The safety and tolerability of the combination is similar to eribulin or pembrolizumab monotherapy.

Objective To evaluate how women with epithelial ovarian cancer (EOC), dichotomized by BRCA status, tolerate intravenous (IV) or intraperitoneal (IP) chemotherapy given with veliparib and bevacizumab (bev) on a GOG phase I study (GOG 9923, NCT00989651). Methods This is an unplanned, post hoc analysis of an IRB approved, multi-institutional, prospective study (GOG 9923). Clinical characteristics and toxicity data based on BRCA status were evaluated and descriptive statistics were used to summarize baseline patient characteristics and toxicities. The Kaplan Meier method was used to generate survival estimates. Results Four hundred twenty-four patients were evaluable. Patients were treated with IV carboplatin, paclitaxel, and bev every 21 days (regimen 1), weekly IV paclitaxel with carboplatin and bev (regimen 2) or IV paclitaxel and bev with IP cisplatin (regimen 3). Bev was continued as maintenance in all arms. Within each of these regimens, veliparib was given either twice daily for the entirety of each cycle (continuous) or on days −2 to 5 (intermittent). Ten percent of patients treated on regimen 1, 12% on regimen 2, and 19.8% on regimen 3 had BRCA-associated tumors. Patients with BRCA-associated tumors, when compared to wild type, experienced similar rates of anemia, febrile neutropenia (, abdominal pain, colonic perforation, nausea, vomiting, and peripheral sensory neuropathy. Median progression free survival (PFS) was not significantly different between BRCA-associated and wild type cancers (HR 0.96, CI 0.65–1.42), though this study's primary aim was not to evaluate outcomes. Conclusions Germline BRCA mutations positively affect chemosensitivity in EOC, but whether differences in toxicities among BRCA-associated and BRCA wild type tumors existed was previously not reported. In this population with newly diagnosed ovarian cancer no differences in reported toxicity between the two groups was observed.

Background Various risk-stratification scores have been developed to identify low-risk febrile neutropenia (FN). The Multinational Association of Supportive Care in Cancer (MASCC) score is a commonly used validated scoring system, although its performance varies due to its subjectivity. Biomarkers like procalcitonin (PCT) are being used in patients with FN to detect bacteremia and additional complications. Objective Our objective was to compare the performance of MASCC score with PCT in predicting adverse outcomes in patients with FN. Methods This was a prospective observational study that included chemotherapy-induced FN in hematologic or solid malignancy. The MASCC score, PCT levels, and blood cultures were taken at the first point of contact, and patient treatment was managed according to routine institutional protocol. The primary outcome was mortality at 30 days. Results A total of 100 patients were recruited, of which 92 had hematologic malignancy and 8 had solid malignancy. Forty-six patients were classified as low risk by MASCC score (≥21). The PCT threshold, 1.42 ng/mL, was taken as a cutoff value, with area under the receiver operating characteristic curve (AUROC) of 0.664 (95% confidence interval [CI] –0.55 to 0.77) for predicting mortality. AUROC for MASCC was 0.586 (95% CI 0.462 to 0.711). Conclusions PCT is a useful marker with better prognostic efficacy than MASCC score in patients with FN and can be used as an adjunct to the score in risk-stratifying patients with FN.

Objectives This post hoc analysis assessed the safety of pemetrexed and platinum in combination with pembrolizumab, including time-to-onset and time-to-resolution of all-cause any-grade and grade ≥3 adverse events (AEs) and renal AEs. Materials and Methods Patient-level data from KEYNOTE-189 were analyzed in the all-subjects-as-treated population (pembrolizumab arm, n = 405; placebo arm, n = 202), and among patients who received ≥5 cycles of pemetrexed (pemetrexed/pembrolizumab/platinum arm, n = 310; pemetrexed/placebo/platinum arm, n = 135). All-cause AEs were selected based on ≥2 % incidence from previously reported KEYNOTE-189 data and included neutropenia, febrile neutropenia, anemia, thrombocytopenia, asthenia, fatigue, dyspnea, diarrhea, nausea, vomiting, pneumonitis, and renal events. Descriptive statistics summarized all-cause AEs. Medians and interquartile ranges were used to examine time-to-onset and time-to-resolution. The data cutoff was November 8, 2017. Results In both treatment arms, most non-hematologic (nausea, vomiting, diarrhea, and asthenia), and hematologic (febrile neutropenia, thrombocytopenia, and neutropenia) grade ≥3 AEs with ≥2 % incidence had a median time-to-onset within the first 4 cycles, and a median time-to-resolution of within 2 weeks from onset. A small number of AEs had longer median time-to-onset (pneumonitis and fatigue) and median time-to-resolution (pneumonitis, fatigue, acute kidney injury, and anemia). Among patients who received ≥5 cycles of pemetrexed, the incidence of any-grade renal toxicity in the pemetrexed/pembrolizumab/platinum arm was 2.3 % in Cycles 1−4, 4.8 % in Cycles 5−8, 2.6 % in Cycles 9−12, and 2.5 % in Cycles ≥13; and, in the pemetrexed/placebo/platinum arm, 0.7 % in Cycles 1−4, 1.5 % in Cycles 5−8, 1.3 % in Cycles 9−12, and 2.0 % in Cycles ≥13. Conclusion Pemetrexed/pembrolizumab/platinum has manageable toxicity with longer duration of treatment. While the incidence of renal toxicity was slightly higher in the pembrolizumab combination as compared to pemetrexed, the incidence did not increase in later treatment cycles. These results support the safe use of the KEYNOTE-189 regimen in clinical practice. Clinical Trial Registration Number NCT02578680 ( clinicaltrials.gov ).

Summary Background Patients with chronic lymphocytic leukaemia and high-risk features have poorer outcomes on ibrutinib than those without high-risk features. The aim of this study was to assess the benefit of adding ublituximab, an anti-CD20 monoclonal antibody, to ibrutinib therapy in this population. Methods We did a randomised, phase 3, multicentre study (GENUINE) of patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia with at least one of 17p deletion, 11q deletion, or TP53 mutation, at 119 clinics in the USA and Israel. Eligible patients had received at least one previous chronic lymphocytic leukaemia therapy and had an Eastern Cooperative Oncology Group performance status of 2 or lower. We randomised patients (1:1) using permuted block randomisation with a block size of four and stratified by previous lines of therapy (one vs two or more) to receive ibrutinib alone or ibrutinib in combination with ublituximab. Treatment allocation was not masked to patients or investigators. Ibrutinib was given orally daily at 420 mg for all cycles. Ublituximab was given intravenously in 28-day cycles, with increasing doses during cycle 1 (≤150 mg on day 1, 750 mg on day 2, and 900 mg on days 8 and 15) and continuing at 900 mg on day 1 of cycles 2–6. After cycle 6, ublituximab was given at 900 mg every three cycles. The study was initially designed with co-primary endpoints of progression-free survival and overall response rate but due to protracted patient accrual, the protocol was amended to have a single primary endpoint of independent review committee-assessed overall response rate (defined as the proportion of patients who had a partial response, complete response, or complete response with incomplete marrow recovery according to the 2008 International Workshop on CLL criteria) in the intention-to-treat population. Safety was evaluated in the population of patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov , NCT02301156 , and the final analysis is presented. Findings 224 patients were assessed for eligibility, of whom 126 patients were enrolled and randomly assigned to receive ublituximab plus ibrutinib (n=64) or ibrutinib alone (n=62) between Feb 6, 2015, and Dec 19, 2016. After a median follow-up of 41·6 months (IQR 36·7–47·3), the overall response rate was 53 (83%) of 64 patients in the ublituximab plus ibrutinib group and 40 (65%) of 62 patients in the ibrutinib group (p=0·020). 117 patients, including 59 in the ublituximab plus ibrutinib group and 58 in the ibrutinib group, received at least one dose of treatment and were included in safety analyses. Most adverse events were grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and seven [12%] in the ibrutinib group), anaemia (five [8%] and five [9%]), and diarrhoea (six [10%] and three [5%]). The most common serious adverse events were pneumonia (six [10%] in the ublituximab plus ibrutinib group and four [7%] in the ibrutinib group), atrial fibrillation (four [7%] and one [2%]), sepsis (four [7%] and one [2%]), and febrile neutropenia (three [5%] and one [2%]). Two patients in the ublituximab plus ibrutinib group died due to adverse events (one cardiac arrest and one failure to thrive), neither of which were treatment-related. Five patients in the ibrutinib group died due to adverse events, including one cardiac arrest, one cerebral infarction, one intracranial haemorrhage, one Pneumocystis jirovecii pneumonia infection, and one unexplained death; the death due to cardiac arrest was considered to be treatment-related. Interpretation The addition of ublituximab to ibrutinib resulted in a statistically higher overall response rate without affecting the safety profile of ibrutinib monotherapy in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia. These findings provide support for the addition of ublituximab to Bruton tyrosine kinase inhibitors for the treatment of these patients. Funding TG Therapeutics.

Summary Background Findings of preclinical and clinical trials in colorectal cancer have shown promising antitumour effects of the co-formulation trifluridine/tipiracil and VEGF inhibition. We aimed to investigate the safety and activity of trifluridine/tipiracil and ramucirumab for previously treated advanced gastric cancer. Methods We did an open-label, single-arm, two-cohort, phase 2 study at eight centres in Japan. We enrolled patients with unresectable advanced gastric cancer or gastro-oesophageal junction adenocarcinoma. Cohort A included patients previously treated with one line of chemotherapy without ramucirumab and cohort B included patients previously treated with two to four lines of chemotherapy, including ramucirumab. Patients received trifluridine/tipiracil (35 mg/m2) orally twice daily on days 1–5 and days 8–12 of each 28-day treatment cycle, plus intravenous ramucirumab (8 mg/kg) on days 1 and 15. The primary endpoint was the disease control rate, assessed by investigators and defined as the proportion of patients with a confirmed best overall response, according to Response Evaluation Criteria in Solid Tumors version 1.1. This trial is registered on JapicCTI (JapicCTI-194596) and is ongoing but not recruiting. Findings Between April 8 and Oct 11, 2019, 64 patients were enrolled and included in the safety and activity analyses, 33 in cohort A and 31 in cohort B. In cohort A, the disease control rate was 85% (95% CI 68–95; 28 of 33 patients) and in cohort B it was 77% (59–90; 24 of 31 patients). Common treatment-related adverse events of grade 3 or worse were neutrophil count decreased (27 [82%] in cohort A and 23 [74%] in cohort B), white blood cell count decreased (eight [24%] and seven [23%]), and platelet count decreased (eight [24%] and four [13%]). Serious treatment-related adverse events were recorded in three patients in cohort A (fatigue and neutrophil count decreased; large intestine perforation; and febrile neutropenia, platelet count decreased, and anaemia). No patients in cohort B had a serious treatment-related adverse event, and no treatment-related deaths were reported in either cohort. Interpretation Trifluridine/tipiracil and ramucirumab showed an acceptable safety profile and clinical activity in patients with previously treated advanced gastric cancer regardless of previous ramucirumab exposure. Funding Taiho Pharmaceutical and Eli Lilly.

Objectives: The use of granulocyte colony-stimulating factors (G-CSF) during concurrent chemo-radiotherapy (cCTRT) for small cell lung cancer is not recommended by the American Society of Clinical Oncology due to safety concerns. This secondary analysis explored the safety and the role of prophylactic G-CSF (proG-CSF) in the delivery of cCTRT. Material and methods: Secondary analysis of 487 patients treated as per protocol on the phase 3 CONVERT trial which randomized patients between once-daily RT or twice-daily. Results: 180 of 487 eligible patients (37 %) received proG-CSF, 60 (33 %) as primary prophylaxis and 120 (67 %) as secondary prophylaxis following myelotoxic events. The regimen incidence of febrile neutropenia (FN) was 22 %. Its incidence in the proG-CSF group reduced significantly when proG-CSF was administered (22 % vs 10 %; OR 0.4; 95 %CI 0.2-0.7; p = 0.002). The rate of blood transfusion was higher in the proG-CSF group (51 % vs 31 %; OR 2.4; 95 %CI 1.6-3.5; p < 0.001). The incidence of severe thrombocytopenia was also higher is this group (28 % vs 15 %; OR 2.2; 95 %CI 1.4-3.5; p = 0.001). But this was significantly higher in those on secondary vs primary prophylaxis (34 % vs 15 %; OR 2.9; 95 %CI 1.3-7.4 p = 0.009) No differences observed in RT-related toxicity, treatment-related mortality or any survival outcomes. The optimal dose intensity (85 % or higher) of cisplatin was achieved in more patients within the proG-CSF group (75 % vs 67 %; OR 1.5; 95 %CI 0.9-2.3; p = 0.056). Conclusion: There was no evidence that G-CSF directly caused myelotoxicity, instead most patients started G-CSF due to higher myelotoxicity risk. G-CSF maintained the planned dose intensity and there was no detrimental effect on survival. G-CSF may be considered as a supportive measure in this setting.

Introduction Invasive fungal diseases are crucial causes of morbidity and mortality among patients with febrile neutropenia (FN). Though liposomal amphotericin B (L-AMB) is one of the agents recommended for first-line empirical antifungal therapy in patients with FN, large-scale clinical studies have not been performed in Japan. Methods An open-label prospective multi-center study was carried out to evaluate the safety and efficacy of L-AMB in Japanese patients with FN suspected of having fungal infection. Results Of the 426 patients registered, safety and efficacy evaluations were conducted for 424 and 399, respectively. By clinical response criteria using 5 composite endpoints, the response rate was 46.6% (186/399). The response rate by age were 54.5% (child: 30/55), 47.5% (adult: 97/204), 42.1% (elderly: 59/140) respectively. Regarding the composite endpoints, resolution of fever was observed in 61.2% (244/399), no breakthrough fungal infection in 99.0% (395/399), survival for 7 days or longer after the completion of treatment in 83.7% (334/399), no discontinuation of treatment due to toxicity or lack of efficacy in 60.9% (243/399), and successful treatment of any baseline fungal infection in 10/18. Adverse drug reactions (ADRs) developed in 61.1% (259/424), and frequent ADRs were hypokalemia, kidney dysfunction, and liver dysfunction, as previously reported. Conclusions The safety and efficacy profile of L-AMB in Japanese patients with FN suspected of having fungal infection were elucidated for the first time, through the analysis of a large number of cases including pediatric patients under real-world clinical settings collected in this nationwide study.

Summary Objectives Patients with febrile neutropenia presenting a cutaneous portal of entry for an infectious agent are at high risk of death (19-32%). If medical management is well codified, surgical management represents a therapeutic dilemma because the only available option is an aggressive debridement of the infected area which is associated with a high morbidity rate. Our objective was to implement a low-risk technique that is quick to perform and does not delay major surgical debridement if the latter turns out to be necessary. Patients and methods We performed an early subcutaneous drainage of the infected areas by percutaneous approach in order to avoid the evolution towards skin and subcutaneous necrosis. Five consecutive patients were treated with this technique associated with the recommended medical treatment between March and September 2017. This technique is based on the mechanical concept of the evacuation of the edema from the inflammatory area which would allow a better efficiency of the antibiotic treatment thanks to a better blood perfusion and a higher tissue concentration of antibiotics. Results Of the 5 patients managed in the department, no skin necrosis occurred, no surgical debridement was necessary, and no patient died during the episode of febrile neutropenia. Conclusion Early subcutaneous drainage by percutaneous approach of an area of skin infection in a patient with febrile neutropenia may be considered as an interesting option. This technique allows without loss of chance for the patient to increase survival and decrease the number of aggressive surgical debridement and their high morbidity.

Background There are several regimens recommended by the National Comprehensive Cancer Network (NCCN) for HER2-negative operable breast cancer. To our knowledge, no trials have yet been performed comparing these regimens head to head. We performed a network meta-analysis comparing the efficacy of NCCN-recommended chemotherapy regimens. Methods We searched Medline, Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and World Health Organization (WHO) International Clinical Trials Registry Platform from inception to February 2020. We included randomized clinical trials comparing adjuvant regimens in predominantly node-positive operable breast cancer patients. We compared (1) DDACT, (2) TCx4 cycles, (3) TAC, and (4) ACWKT. Common comparators were (5) AC, (6) ACT, and (7) ACD. Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were followed. The Cochrane risk of bias tool assessed quality of the studies. Odds ratios (ORs) were calculated as measures of treatment effects with AC as reference. We used Bayesian hierarchical random-effects models with noninformative priors for mixed multiple treatment comparisons. Effectiveness was estimated by disease-free and overall survival using ORs. Sensitivity analyses were performed. Safety outcomes included febrile neutropenia. Results We identified 7 randomized controlled trials with 16,332 patients. TC (odds ratio [95% confidence interval], 0.71 [0.36-1.40]), TAC (0.77 [0.37-1.57]), ACWKT (0.68 [0.34-1.38]), and DDACT (0.72 [0.35-1.42]) were similar for overall survival. TC (0.64 [0.36-1.14]), TAC (0.67 [0.39-1.15]), ACWKT (0.63 [0.37-1.07]), and DDACT (0.59 [0.35-1.01]) had similar disease-free survival benefit. With regard to toxicity, TAC (2.67 [0.30-21.04]) had the highest odds of febrile neutropenia. Conclusion The current generation of regimens are similar in efficacy. Given the lower toxicity of TCx4 comparatively, it is an acceptable alternative for lower-risk early-stage HER2-negative breast cancers.

Background: Carbapenem-Resistant Gram-Negative (CRGN) Bloodstream Infections (BSI) represent a therapeutic challenge, especially in the context of Febrile Neutropenia (FN) in cancer patients. Methods: We characterized pathogens causing BSI in patients aged ≥18 years who had undergone systemic chemotherapy for solid or hematological cancers between 2012 and 2021 in Porto Alegre, Brazil. Predictors of CRGN were evaluated through a case-control analysis. Each case was matched to two controls from whom CRGN were not isolated and had the same sex and year of inclusion in the study. Results: From 6094 blood cultures evaluated, 1512 (24.8%) showed positive results. Gram-negative bacteria accounted for 537 (35.5%) of the isolated bacteria, of which 93 (17.3%) were carbapenem-resistant. From 105 patients included in the case-control analysis, all cases had baseline hematological malignancies (60% acute myeloid leukemia). Variables related to CRGN BSI in Cox regression analysis were the first chemotherapy session (p

Background: Despite high cure rates, treatment-related mortality in children with acute lymphoblastic leukemia (ALL) remains significant. About 4% of patients die during remission induction therapy and approximately two-thirds of treatment-related deaths are due to infectious complications. Methods: From May 2021 to June 2022, children aged one through 18 years, with a recent diagnosis of ALL, admitted to three pediatric oncology centers in Brazil, were enrolled in this multicenter, open-label, randomized, phase 3 clinical trial. Eligible patients were randomly divided into two groups, based on a 1:1 allocation ratio, to receive, or not, levofloxacin as a prophylactic agent during the induction phase. All patients were treated according to the IC-BFM 2009 chemotherapy protocol. Primary endpoints were carbapenemase-producing Enterobacteriaceae (CPE) colonization, Clostridioides difficile diarrhea, and other adverse events related to the use of levofloxacin. The secondary endpoint was febrile neutropenia during induction. The median follow-up was 289 days. Results: Twenty patients were included in this trial, 10 in each group (control and levofloxacin). Mild adverse reactions related to levofloxacin were observed in three patients (30%). Three patients had Clostridioides difficile diarrhea, two in the levofloxacin group and one in the control group (p > 0.99). Only one patient presented colonization by CPE. This patient belonged to the levofloxacin group (p > 0.99). Nine patients presented febrile neutropenia, five in the control group and four in the levofloxacin intervention group (p > 0.99), one patient died due to febrile neutropenia. Conclusion: The use of levofloxacin was shown to be safe in the induction phase in children with de novo ALL. The use of this medication did not increase the rate of colonization by CPE nor the rate of diarrhea by C. difficile. All adverse reactions were mild and remitted either spontaneously or after switching medicine administration from oral to intravenous route.

Objective Febrile neutropenia though a dreaded complication of chemotherapy, not all patients need inpatient treatment. Risk score indices like MASCC and CISNE have been developed to identify low risk patients eligible for outpatient management. We undertook this study to compare the performances of MASCC and CISNE. Methods This was a prospective observational study conducted in a tertiary care centre from August 2017 to April 2019 where patients with chemotherapy induced febrile neutropenia were included. Basic demographic data and primary site of cancer were collected with characteristics required to calculate both MASCC and CISNE scores. The primary outcome measure was 30-day mortality. Apart from the 3 group risk stratification of CISNE, apriori it was decided that two-tier CISNE score will be calculated with 0 or 1 score as low risk and ≥2 as high risk. Descriptive statistics are reported and predictive performance of each score was analysed. Results Total of 129 patients were recruited. The performance of three-tier CISNE score was more specific (90.6%, 95% CI 76.9–96.9) but sensitivity (25.1%, 95% CI 17.0–36.3) was low compared to that of MASCC score (sensitivity 58.1%, 95% CI 47.0–68.5; specificity 65.1, 95% CI 49.0–78.5%). However, analysis with two-tier CISNE score demonstrated a better sensitivity (56.9%, 95%CI 45.8–67.4). Kappa for agreement between the two scores was 0.520 (95% CI 0.373–0.667, p Conclusion CISNE and MASCC have fair discriminatory power in identifying low risk febrile neutropenia cases. Two group stratification on CISNE scoring will help in better decision making in emergency department.

Evaluate the relationship between duration of primary prophylactic short-acting granulocyte colony-stimulating factor (PP-sG-CSF) and risk of neutropenia-related hospitalization (NRH) in older patients receiving myelosuppressive chemotherapy.Using the Medicare claims database, we conducted a nested case-control study in a cohort of patients aged ≥66 years with breast, colorectal, lung, ovarian, or prostate cancer, or non-Hodgkin lymphoma who initiated a first cycle of any myelosuppressive chemotherapy January 1, 2008-September 30, 2016, and received PP-sG-CSF. We matched up to four controls to each NRH case by age, cancer type, regimen febrile neutropenia (FN) risk category, and year using incidence density sampling. We used conditional logistic regression adjusted for race, sex, and modified Charlson comorbidity index (CCI) to estimate relative risk of NRH related to duration of PP-sG-CSF categorized as5 and ≥ 5 days.Of 2148 patients receiving PP-sG-CSF, 108 (5%) experienced NRH in the first cycle. We matched 333 controls to 96 cases. Cases were similar to controls in mean age, tumor type, and intermediate/high-risk regimen, but were more likely to have CCI ≥5 and less likely to use PP-sG-CSF ≥5 days (31% vs. 39%). Adjusted ORs (95% CI) for NRH were 0.69 (0.40-1.19) for ≥5 vs.5 days of PP-sG-CSF among patients receiving any myelosuppressive chemotherapy, 0.43 (0.21-0.89) for intermediate/high-risk regimen, and 0.42 (0.19-0.89) for any myelosuppressive chemotherapy with all agents given on cycle day one only.Among older patients with cancer who are receiving PP-sG-CSF, ≥5 days of use was associated with substantial reduction in NRH risk.

Certain anaerobic bacteria are important for maintenance of gut barrier integrity and immune tolerance and may influence the risk of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a single-center retrospective cohort study of allogeneic HSCT recipients to evaluate associations between receipt of antibiotics with an anaerobic spectrum of activity and GVHD outcomes. We identified 1214 children and adults who developed febrile neutropenia between 7 days before and 28 days after HSCT and compared GVHD risk and mortality among patients who received anaerobic antibiotics (piperacillin-tazobactam or carbapenems; n=491) to patients who received only antibiotics with minimal activity against anaerobes (aztreonam, cefepime, or ceftazidime; n=723). We performed metagenomic sequencing of serial fecal samples from 36 pediatric patients to compare the effects of specific antibiotics on the gut metagenome. Receipt of anaerobic antibiotics was associated with higher hazards of acute gut/liver GVHD (hazard ratio: 1.26; 95% confidence interval: 1.03–1.54) and acute GVHD mortality (hazard ratio: 1.63; 95% confidence interval: 1.08–2.46), but not chronic GVHD diagnosis (hazard ratio: 1.04; 95% confidence interval: 0.84–1.28) or chronic GVHD mortality (hazard ratio: 0.88; 95% confidence interval: 0.53–1.45). Anaerobic antibiotics resulted in decreased gut bacterial diversity, reduced abundances of Bifidobacteriales and Clostridiales, and loss of bacterial genes encoding butyrate biosynthesis enzymes from the gut metagenome. Acute gut/liver GVHD was preceded by a sharp decline in bacterial butyrate biosynthesis genes with antibiotic treatment. Our findings demonstrate that exposure to anaerobic antibiotics is associated with increased risks of acute gut/liver GVHD and acute GVHD mortality after allogeneic HSCT. Use of piperacillin-tazobactam or carbapenems should be reserved for febrile neutropenia cases in which anaerobic or multidrug-resistant infections are suspected.

Background Chemotherapy is effective in metastatic pancreatic adenocarcinoma (mPA), but new approaches are still needed to improve patients' survival and quality of life. We have previously published good efficacy and tolerability results on a sequential treatment strategy of gemcitabine followed by an intensified FOLFIRI (5FU+irinotecan) regimen. In the present study, we evaluated the same sequence but replaced gemcitabine by the new gemcitabine + nab-paclitaxel standard first-line combination. Patients and methods We randomised chemotherapy-naive patients with proven mPA, bilirubin levels ≤1.5 upper limit of normal values and performance status 0–2 to alternately receive gemcitabine + nab-paclitaxel for 2 months then FOLFIRI.3 for 2 months in arm A, or gemcitabine + nab-paclitaxel alone until progression in arm B. The primary objective was to increase the 6-month progression-free survival (PFS) rate from 40% (H0) to 60% (H1); using the binomial exact method, 124 patients were required. Analyses were carried out in preplanned modified intention-to-treat (mITT) and per-protocol (PP) populations. Results Between November 2015 and November 2016, 127 patients were enrolled. Main grade III–IV toxicities (% in arm A/B) were: diarrhoea (12.5/1.7), neutropenia (46.9/31, including febrile neutropenia: 1.6/0), skin toxicity (6.3/13.8), and peripheral neuropathy (6.3/8.6). No toxic deaths occurred. The objective response rate was 40.3% (95% confidence interval [CI]: 28.1–53.6) in arm A and 26.7% (95% CI: 16.1–39.7) in arm B. The primary end-point (6-month PFS rate) was 45.2% [one-sided 95% CI: 34.3–56.4] in arm A and 23.3% in arm B [one-sided 95% CI: 14.3–32.3] in the mITT population. In the PP population, median PFS and OS were 7.6 months and 6 months and 14.5 months and 12.2 months in arm A and B, respectively. Conclusions The FIRGEMAX strategy with gemcitabine + nab-paclitaxel alternating with FOLFIRI.3 every 2 months, appears feasible and effective, with manageable toxicities, in patients able to reach >2mo of treatment. Trial registration information EudraCT: 2014-004449-28: NCT: 0282701.

Background Talazoparib combined with irinotecan and temozolomide demonstrated efficacy in a murine Ewing sarcoma model. Based on these data, we conducted a phase I trial of talazoparib and irinotecan with/without temozolomide in paediatric patients with recurrent/refractory solid malignancies. Patients and methods Cohorts of 3–6 patients with recurrent/refractory solid malignancies received escalating doses of oral talazoparib and intravenous irinotecan (arm A) and oral talazoparib, oral temozolomide and intravenous irinotecan (arm B) in a 3 + 3 design. Talazoparib was administered on days 1–6, and intravenous irinotecan and oral temozolomide were administered on days 2–6, of a 21-day course. Serum for talazoparib and irinotecan pharmacokinetics was obtained during course 1. UGT1A1 polymorphism and Schlafen family member 11 (SLFN11) immunohistochemical staining were performed. Results Forty-one patients (20 males; median age, 14.6 years; 24 with recurrent disease) were evaluable for dose escalation. Twenty-nine and 12 patients were treated on arm A and arm B, respectively, for a total of 208 courses. The most common diagnosis was Ewing sarcoma (53%). The most common ≥grade III haematologic toxicities in arms A and B included neutropenia (78% and 31%, respectively) and thrombocytopenia (42% and 31%, respectively). In arms A and B, febrile neutropenia (24% and 14%, respectively) and diarrhoea (21% and 7%, respectively) were the most common ≥grade III non-hematologic toxicities. Six patients (Ewing sarcoma [5 patients] and synovial sarcoma [1 patient]) had a response (1 with a complete response, 5 with a partial response). The objective response rates were 10.3% (arm A) and 25% (arm B). Pharmacokinetic testing demonstrated no evidence of drug-drug interaction between talazoparib and irinotecan. UGT1A1 was not related to response. SLFN11 positivity was associated with best response to therapy. Conclusions The combination of talazoparib and irinotecan with/without temozolomide is feasible and active in Ewing sarcoma, and further investigation is warranted.

Objective Organ transplant recipients (OTR) have an increased risk of developing post-transplant malignancies with lung cancer being one of the most common. In this retrospective study, we investigated incidence, use of systemic therapy and outcomes from lung cancer in OTR. Materials and Methods: Patients diagnosed with lung cancer following a solid organ transplant at the University Health Network, Toronto, ON, CA, from January 1, 1980 to June 30, 2016 were included. Data for the study population, patient characteristics, treatments and outcomes were abstracted from solid OTR databases, our cancer registry and patient charts. Univariate Kaplan-Meier curves estimated median overall survival (OS) by histology, stage and systemic therapy. Results Amongst 7944 OTR (heart [N = 765], lung [n = 1668], liver [n = 2238], kidney [n = 3273]), 101 (1.3 %) developed lung cancer which were included in our analyses. Of these, 81 % were non-small cell lung cancer (NSCLC), 11 % small cell lung cancer (SCLC) and 8% neuroendocrine tumor (NET). Median OS (months) was 25 in those that presented with Stage I/II NSCLC (44 %); 25 for Stage III NSCLC (7%); 3 for Stage IV NCLC (31 %); 10 for Limited stage SCLC (6%); 2 for Extensive stage (ES) SCLC (5%). NSCLC patients that received palliative chemotherapy had an OS of 8 months; ES-SCLC patients that received chemotherapy had an OS of 6 months. Of all patients who received platinum doublets (n = 16), 10 (62.5 %) required dose reductions at some point. Five patients experienced febrile neutropenia (31 %); two (12 %) had other toxicities leading to discontinuation. Conclusion Patients with stage I/II NSCLC and NET had poorer survival compared to historical norms in non-transplant patients. Patients who had stage III NSCLC or received palliative systemic therapy had survivals at or slightly below historic norms, although numbers were small. Chemotherapy can be administered in selected OTR patients though dose reductions and febrile neutropenia were common.

Purpose Neutropenic fever in a pediatric oncology patient necessitates emergent initiation of efficacious broad spectrum antibiotics. We have utilized cefepime+/-vancomycin in this context for over two decades, and sough to evaluate the efficacy of this combination at our institution and, if necessary, to identify an optimal alternative regimen. Methods Blood culture isolates from pediatric oncology patients were reviewed over 12 years. Antibiotic susceptibilities for all unique isolates were analyzed via minimum inhibitory concentration breakpoints and interpretive categories as per the Clinical and Laboratory Standards Institute M100/M45 manuals. Percentage susceptibility was calculated, antibiograms generated, and intraspecies antibiotic susceptibility comparisons made. Billing data was analyzed to identify the number of oncology patients admitted for fever during this interval. Results 697 unique isolates were identified: 188 Gram-negative and 509 Gram-positive (155 Gram-positive and 343 total isolates, excluding coagulase negative Staphylococcal (CONS) species). Cefepime and meropenem each covered 95.7% of tested Gram-negatives. Stenotrophomonas (Xanthomonas) maltophilia was the most resistant Gram-negative organism; no antibiotic covered all Gram-negatives. No antibiotic offered significantly improved coverage compared to cefepime. 96.0% of total tested Gram-positives were vancomycin-susceptible (including all CONS); resistant organisms included Enterococcus faecium and Enterococcus faecalis. Linezolid did not offer significantly improved coverage, while daptomycin did. Including and excluding CONS, 46.3% and 72.5% of total Gram-positive isolates were cefepime-sensitive. Blood cultures were positive in 33.7% of admissions. Central venous catheters were routinely utilized in this patient population. Prophylactic antibacterial agents were not utilized. Conclusions Cefepime+/-vancomycin remains efficacious as first-line empiric therapy for febrile neutropenia, with notable minor exceptions. Unit-specific surveillance of antibiotic resistance is warranted to ensure ongoing appropriate empiric antibiotic usage.

Summary Background Topotecan is currently the only drug approved in Europe in a second-line setting for the treatment of small-cell lung cancer. This study investigated whether the doublet of carboplatin plus etoposide was superior to topotecan as a second-line treatment in patients with sensitive relapsed small-cell lung cancer. Methods In this open-label, randomised, phase 3 trial done in 38 hospitals in France, we enrolled patients with histologically or cytologically confirmed advanced stage IV or locally relapsed small-cell lung cancer, who responded to first-line platinum plus etoposide treatment, but who had disease relapse or progression at least 90 days after completion of first-line treatment. Eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group performance status 0–2. Enrolled patients were randomly assigned (1:1) to receive combination carboplatin plus etoposide (six cycles of intravenous carboplatin [area under the curve 5 mg/mL per min] on day 1 plus intravenous etoposide [100 mg/m2 from day 1 to day 3]) or oral topotecan (2·3 mg/m2 from day 1 to day 5, for six cycles). Randomisation was done using the minimisation method with biased-coin balancing for ECOG performance status, response to the first-line chemotherapy, and treatment centre. The primary endpoint was progression-free survival, which was centrally reviewed and analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , NCT02738346 . Findings Between July 18, 2013, and July 2, 2018, we enrolled and randomly assigned 164 patients (82 in each study group). One patient from each group withdrew consent, therefore 162 patients (81 in each group) were included in the intention-to-treat population. With a median follow-up of 22·7 months (IQR 20·0−37·3), median progression-free survival was significantly longer in the combination chemotherapy group than in the topotecan group (4·7 months, 90% CI 3·9–5·5 vs 2·7 months, 2·3–3·2; stratified hazard ratio 0·57, 90% CI 0·41–0·73; p=0·0041). The most frequent grade 3–4 adverse events were neutropenia (18 [22%] of 81 patients in the topotecan group vs 11 [14%] of 81 patients in the combination chemotherapy group), thrombocytopenia (29 [36%] vs 25 [31%]), anaemia (17 [21%] vs 20 [25%]), febrile neutropenia (nine [11%] vs five [6%]), and asthenia (eight [10%] vs seven [9%]). Two treatment-related deaths occurred in the topotecan group (both were febrile neutropenia with sepsis) and no treatment-related deaths occurred in the combination group. Interpretation Our results suggest that carboplatin plus etoposide rechallenge can be considered as a reasonable second-line chemotherapy option for patients with sensitive relapsed small-cell lung cancer. Funding Amgen and the French Lung Cancer Group (Groupe Francais de Pneumo-Cancerologie).

Prophylaxis with fluoroquinolone (FQ) for patients undergoing autologous stem cell transplantation (ASCT) remains controversial. We performed a retrospective review of patients undergoing ASCT with and without bacterial prophylaxis to compare endpoints of interest. In accordance with institutional policy, patients undergoing ASCT for multiple myeloma routinely receive levofloxacin prophylaxis during their period of neutropenia, whereas patients undergoing the ASCT for lymphoma do not. We retrospectively examined patients with multiple myeloma (MM) or lymphoma undergoing ASCT between July 2015 and July 2018 for evidence of positive blood cultures. A total of 172 patients underwent ASCT for lymphoma and 343 underwent ASCT for MM. The 2 cohorts were similar in terms of baseline characteristics. Almost 20% (35 of 172) of the patients with lymphoma and 5.2% (18 of 342) of those with MM had a bloodstream infection (BSI). BSI occurred an average of 2 days earlier in patients with lymphoma compared with patients with MM (day +5 versus day +7; P = .0003). The 2 cohorts recovered absolute neutrophil count at the same time. Hospital length of stay was 2 days shorter for patients with MM (median, 20 days versus 18 days; P = .01). The majority of the organisms were gram-negative in both cohorts. Of the organisms commonly tested for FQ sensitivity, only 1 of 25 was resistant in the lymphoma cohort, compared with 7 of 9 in the MM cohort (P.0001), with 4 being multidrug resistant. The odds of developing a BSI were 4.6 times greater in the lymphoma cohort compared with the MM cohort (95% confidence interval [CI], 2.52 to 8.40; P.0001). In total, 23 of 172 patients with lymphoma (13.4%) and 28 of 342 patients with MM (8.2%) developed Clostridium difficile infection (odds ratio, 1.73; 95% CI, .96 to 3.11; P = .066). Two infection-related deaths occurred in the MM cohort. Our data indicate that FQ prophylaxis reduces the risk of BSI in patients undergoing ASCT but increases the incidence of resistant organisms. We recommend routine antimicrobial prophylaxis in patients undergoing ASCT to reduce the risk of BSI, along with a systematic and regular review of outcomes.

Background The optimal duration of filgrastim as primary febrile neutropenia (FN) prophylaxis in early breast cancer patients is unknown, with 5, 7 or 10 days being commonly prescribed. This trial evaluates whether 5 days of filgrastim was non-inferior to 7/10 days. Patients and methods In this randomised, open-label trial, early breast cancer patients who were to receive filgrastim as primary FN prophylaxis were randomly allocated to 5 versus 7 versus 10 days of filgrastim for all chemotherapy cycles. A protocol amendment in November 2017 allowed subsequent patients (N = 324) to be randomised to either 5 or 7/10 days. The primary outcome was a composite of either FN or treatment-related hospitalisations. Secondary outcomes included chemotherapy dose reductions, delays and discontinuations. Analyses were carried out by per protocol (primary) and intention-to-treat, and the non-inferiority margin was set at 3% for the risk of having FN and/or hospitalisation per cycle of chemotherapy. Results Patients (N = 466) were randomised to receive 5 (184, 39.5%), or 7/10 (282, 60.5%) days of filgrastim. In our primary analysis, the difference in risk of either FN or treatment-related hospitalisation per cycle was −1.52% [95% confidence interval (CI): −3.22% to 0.19%] suggesting non-inferiority of a 5-day filgrastim schedule compared with 7/10-days. The difference in events per cycle for FN was 0.11% (95% CI: −1.05 to 1.27) while for treatment-related hospitalisations it was −1.68% (95% CI: −2.73% to −0.63%). The overall proportions of patients having at least one occurrence of either FN or treatment-related hospitalisation were 11.8% and 14.96% for the 5- and 7/10-day groups, respectively (risk difference: −3.17%, 95% CI: −9.51% to 3.18%). Conclusion Five days of filgrastim was non-inferior to 7/10 days. Given the cost and toxicity of this agent, 5 days should be considered standard of care. ClinicalTrials.gov registration NCT02428114 and NCT02816164.

Empirical antifungal therapy is recommended in high-risk patients who have persistent febrile neutropenia (FN) despite broad-spectrum antibiotic therapy. Based on high-quality evidence, most guidelines recommend caspofungin. The aim of this study was to clarify whether echinocandins, including micafungin, are associated with improved clinical outcomes in patients with persistent FN. We conducted a meta-analysis of randomized controlled trials (RCTs) of empirical therapy with echinocandins and non-echinocandins for FN in patients with hematological disease. The primary outcome was all-cause mortality within 7 days after completion of therapy. Secondary outcomes included treatment success, and discontinuation of therapy because of adverse events. For subgroup analysis, we compared RCTs of echinocandins with liposomal amphotericin B. Six RCTs (four that evaluated caspofungin and two that evaluated micafungin) were included in the meta-analysis. Mortality and adverse events in echinocandin-treated patients were significantly lower than in those treated with non-echinocandins [risk ratio (RR) 0.70, 95% confidence interval (CI) 0.49-0.99; RR 0.48, 95% CI 0.33-0.71, respectively]. There was no significant difference in treatment success (RR 1.09, 95% CI 0.87-1.36). Mortality and adverse events in echinocandin-treated patients were significantly lower than in those treated with liposomal amphotericin B (RR 0.68, 95% CI 0.46-0.99; RR 0.53, 95% CI 0.37-0.74, respectively). In conclusion, patients with persistent FN treated with echinocandins had decreased risk of death and adverse events. Both caspofungin and micafungin may be recommended as first-line empirical antifungal therapy in these patients. However, the small number of enrolled patients and the lack of RCTs involving pediatric patients should be considered when using micafungin.

Background The phase Ib KEYNOTE-173 study was conducted to assess the safety and preliminary antitumor activity of neoadjuvant chemotherapy plus pembrolizumab in high-risk, early-stage, non-metastatic triple-negative breast cancer (TNBC). Patients and methods Six pembrolizumab plus chemotherapy regimens were evaluated (cohorts A–F). All cohorts received a pembrolizumab 200-mg run-in dose (cycle 1), then eight cycles of pembrolizumab in combination with a taxane with or without carboplatin for 12 weeks, and then doxorubicin and cyclophosphamide for an additional 12 weeks before surgery. Primary end points were safety and recommended phase II dose (RP2D); secondary end points were pathological complete response (pCR) rate, objective response rate, and event-free and overall survival. Exploratory end points were the relationship between outcome and potential biomarkers, such as tumor programmed death ligand 1 (PD-L1) expression (combined positive score) and stromal tumor-infiltrating lymphocyte levels (sTILs). Results Sixty patients were enrolled between 18 February 2016, and 28 February 2017. Dose-limiting toxicities occurred in 22 patients, most commonly febrile neutropenia (n = 10 across cohorts). Four cohorts (B, C, D, F) did not meet the RP2D threshold; two cohorts did (A, E). The most common grade ≥3 treatment-related adverse event was neutropenia (73%). Immune-mediated adverse events and infusion reactions occurred in 18 patients (30%) and were grade ≥3 in six patients (10%). The pCR rate (ypT0/Tis ypN0) across all cohorts was 60% (range 49%–71%). Twelve-month event-free and overall survival rates ranged from 80% to 100% across cohorts (100% for four cohorts). Higher pre-treatment PD-L1 combined positive score, and pre- and on-treatment sTILs were significantly associated with higher pCR rates (P = 0.0127, 0.0059, and 0.0085, respectively). Conclusion Combination neoadjuvant chemotherapy and pembrolizumab for high-risk, early-stage TNBC showed manageable toxicity and promising antitumor activity. In an exploratory analysis, the pCR rate showed a positive correlation with tumor PD-L1 expression and sTIL levels. Trial registration ClinicalTrials.gov identifier: NCT02622074.

Summary Background Few options exist for treatment of patients with small-cell lung cancer (SCLC) after failure of first-line therapy. Lurbinectedin is a selective inhibitor of oncogenic transcription. In this phase 2 study, we evaluated the acti and safety of lurbinectedin in patients with SCLC after failure of platinum-based chemotherapy. Methods In this single-arm, open-label, phase 2 basket trial, we recruited patients from 26 hospitals in six European countries and the USA. Adults (aged ≥18 years) with a pathologically proven diagnosis of SCLC, Eastern Cooperative Oncology Group performance status of 2 or lower, measurable disease as per Response Criteria in Solid Tumors (RECIST) version 1.1, absence of brain metastasis, adequate organ function, and pre-treated with only one previous chemotherapy-containing line of treatment (minimum 3 weeks before study initiation) were eligible. Treatment consisted of 3·2 mg/m2 lurbinectedin administered as a 1-h intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. The primary outcome was the proportion of patients with an overall response (complete or partial response) as assessed by the investigators according to RECIST 1.1. All treated patients were analysed for activity and safety. This study is ongoing and is registered with ClinicalTrials.gov , NCT02454972 . Findings Between Oct 16, 2015, and Jan 15, 2019, 105 patients were enrolled and treated with lurbinectedin. Median follow-up was 17·1 months (IQR 6·5–25·3). Overall response by investigator assessment was seen in 37 patients (35·2%; 95% CI 26·2–45·2). The most common grade 3–4 adverse events (irrespective of causality) were haematological abnormalities—namely, anaemia (in nine [9%] patients), leucopenia (30 [29%]), neutropenia (48 [46%]), and thrombocytopenia (seven [7%]). Serious treatment-related adverse events occurred in 11 (10%) patients, of which neutropenia and febrile neutropenia were the most common (five [5%] patients for each). No treatment-related deaths were reported. Interpretation Lurbinectedin was active as second-line therapy for SCLC in terms of overall response and had an acceptable and manageable safety profile. Lurbinectedin could represent a potential new treatment for patients with SCLC, who have few options especially in the event of a relapse, and is being investigated in combination with doxorubicin as second-line therapy in a randomised phase 3 trial. Funding Pharma Mar.

Background The Veterans Affairs Cooperative Studies Program study #553 was designed to evaluate the efficacy of adjuvant chemotherapy added to the standard of care (SOC) for patients who are at high risk for relapse after prostatectomy. Objective To test whether addition of chemotherapy to surgery for high-risk prostate cancer improves progression-free survival (PFS). Design, setting, and participants Eligible patients after prostatectomy were randomized to the SOC group with observation or to the chemotherapy group with docetaxel and prednisone administered every 3 wk for six cycles. Randomization was stratified for prostate-specific antigen, Gleason, tumor stage, and surgical margin status. Outcome measurements and statistical analysis The primary endpoint was PFS. Secondary endpoints included overall, prostate cancer–specific, and metastasis-free survival, and time to androgen deprivation therapy. Results and limitations A total of 298 of the planned 636 patients were randomized. The median follow-up was 59.1 mo (0.2–103.7 mo). For the primary endpoint, the two groups did not statistically differ in PFS (median 55.5 mo in the chemotherapy group and 42.2 mo in the SOC group; test adjusted for site via gamma frailty p = 0.21; adjusted hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.58–1.11; p = 0.18). Prespecified subgroup analyses showed benefit in PFS for patients with tumor stage ≥T3b (HR 0.54, 95% CI 0.32–0.92; p = 0.022) and patients with Gleason score ≤7 (HR 0.65, 95% CI 0.43–0.99; p = 0.046). Secondary endpoint analyses are hampered by low event rates. The most common adverse events (≥grade 3 related or possibly related to chemotherapy) included neutropenia (43%), hyperglycemia (20%), and fatigue (5%), with febrile neutropenia in 2%. Conclusions Adjuvant chemotherapy in high-risk prostate cancer using docetaxel and prednisone did not lead to statistically significant improvement in PFS for the intention-to-treat population as a whole. The analysis was challenged by lower power due to accrual limitation. Subgroup analyses suggest potential benefit for patients with Gleason grade ≤7 and stage ≥ pT3b (ClinicalTrials.gov number NCT00132301). Patient summary In this randomized trial, we tested whether addition of chemotherapy to surgery for high-risk prostate cancer decreased the risk of prostate-specific antigen rise after surgery. We found no benefit from docetaxel given after radical prostatectomy, although some subgroups of patients may benefit.