Consensus survey on the management of children with chemotherapy-induced febrile neutropenia and at low risk of severe infection.

Our aim was to identify national consensus criteria for the management of children with chemotherapy-induced febrile neutropenia (FN), for evidence-based step-down treatment approaches for patients classified at low risk of severe infection. In 2018, a five-section, 38-item survey was e-mailed to all pediatric hematology and oncology units in France (n = 30). The five sections contained statements on possible consensus criteria for the (i) definition of FN, (ii) initial management of children with FN, (iii) conditions required for initiating step-down therapy in low-risk patients, (iv) management strategy for low-risk patients, and (v) antibiotic treatment on discharge. Consensus was defined by respondents' combined answers (somewhat agree and strongly agree) at 75% or more. Sixty-five physicians (participation rate: 58%), all specialists in pediatric onco-hematology, from 18 centers completed the questionnaire. A consensus was reached on 22 of the 38 statements, including the definition of FN, the criteria for step-down therapy in low-risk children, and the initial care of these patients. There was no consensus on the type and duration of antibiotic therapy on discharge. In conclusion, a consensus has been reached on the criteria for initiating evidence-based step-down treatment of children with FN and a low risk of severe infection but not for the step-down antimicrobial regimen.

Two decades of pegfilgrastim: what have we learned? Where do we go from here?

Chemotherapy-induced febrile neutropenia (FN) is a medical emergency that may occur in patients with malignancies receiving myelosuppressive chemotherapy. FN requires early therapeutic intervention since it is associated with increased hospitalizations and high mortality risk of 5%-20%. FN-related hospitalizations are higher in patients with myeloid malignancies than in those with solid tumors due to the myelotoxicity of chemotherapy regimens and the compromised bone marrow function. FN increases the burden of cancer by causing chemotherapy dose reductions and delays. The administration of the first granulocyte colony-stimulating factor (G-CSF) filgrastim reduced the incidence and duration of FN in patients undergoing chemotherapy. Filgrastim later evolved into pegfilgrastim, which has a longer half-life than filgrastim and is associated with a lower rate of severe neutropenia, chemotherapy dose reduction, and treatment delay. Nine million patients have received pegfilgrastim since its approval in early 2002. The pegfilgrastim on-body injector (OBI) is an innovative device facilitating the time-released auto-injection of pegfilgrastim approximately 27 h after chemotherapy, as clinically recommended for the prevention of FN, thus eliminating the need for a next-day hospital visit. Since its introduction in 2015, one million patients with cancer have received pegfilgrastim using the OBI. Subsequently, the device was approved in the United States (US), European Union, Latin America, and Japan, with studies and a postmarketing commitment demonstrating device reliability. A recent prospective observational study conducted in the US demonstrated that the OBI substantially improved the adherence to and compliance with clinically recommended pegfilgrastim therapy; patients receiving pegfilgrastim via the OBI experienced a lower incidence of FN than those receiving alternatives for FN prophylaxis. This review discusses the evolution of G-CSFs leading to the development of the OBI, current recommendations for G-CSF prophylaxis in the clinic, continued evidence supporting next-day pegfilgrastim administration, and improvements in patient care made possible with the OBI.

For over 20 years, treatment with pegfilgrastim (a therapy that supports the growth of immune cells) has been used in patients with cancer to prevent febrile neutropenia (FN) ­ an unwanted effect of cancer treatment or chemotherapy. FN is defined as the loss of healthy immune cells and development of fever possibly due to an infection. Patients with FN may be very ill or may die, depending on the seriousness of the condition. However, treatment with pegfilgrastim reduces the occurrence of FN and improves survival.Treatment guidelines recommend that pegfilgrastim should be given 24 h after chemotherapy, requiring patients to travel to the hospital on the next day of chemotherapy. Some patients may choose the less helpful option of receiving pegfilgrastim on the same day of chemotherapy to avoid travel. This need led to the development of an on-body injector (OBI) device that is applied on the skin on the last day of chemotherapy and administers pegfilgrastim approximately 27 h after chemotherapy. The highly reliable OBI ensures timely delivery of therapy with a success rate of 99.9%, reduces the travel burden, and helps in following the recommended guidelines for pegfilgrastim administration. For two decades, pegfilgrastim has played a significant role in the treatment and prevention of FN, and the new OBI device provides the required treatment support for improving patient care.

Chemotherapy-induced neutropenia among breast Cancer patients in a tertiary care hospital: Risk and consequences.

STUDY OBJECTIVE: To identify the risk factors that may predispose breast cancer patients to Chemotherapy-induced neutropenia (CIN) and its associated complications for the years 2018 and 2020. CIN is an established complication of breast cancer treatment. Clinical Pharmacists can play an important role in the treatment of CIN through involvement in risk assessment to identify patients for oral antimicrobial therapy, drug therapy monitoring, and development of suitable guidelines or policies. METHODOLOGY: A retrospective study was performed by collecting data of 72 breast cancer patients for the last two years from department of Medical Oncology in a tertiary care hospital. RESULTS: The overall occurrence of CIN was 59.7% in our study population. Out of 72 patients studied, 43 patients were found to be neutropenic. Using Pearson Chi square test, chemotherapy-induced neutropenia was associated with older age (over 60 y) (p < 0.038), diabetes mellitus (p < 0.050), tumour stage IIIa (p < 0.024), AC (p < 0.051) and taxane chemotherapy regimens (p < 0.041). Febrile neutropenia occurred in 37.28% of patients and the incidence of infection-related mortality [severe septicaemia] was 3.38%. CONCLUSION: The incorporation of clinical pharmacist must be brought into practice in our country for providing proper guidance to the patient on CIN and its complications. By identifying risk factors for neutropenia, the safe management of CIN may be possible in patients with breast cancer.

Predictive Factors of Febrile Neutropenia After Primary Prophylactic Pegfilgrastim With DCF Chemotherapy for Esophageal Cancer.

BACKGROUND/AIM: We investigated the predictive factors of febrile neutropenia (FN) after the administration of pegfilgrastim as primary prophylaxis in patients with esophageal cancer who received neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF) to support the appropriate management of FN. We evaluated changes in neutrophil counts and relative dose intensity (RDI) after the incidence of FN. PATIENTS AND METHODS: This retrospective study involved 122 patients with esophageal cancer who were treated with DCF and pegfilgrastim at Showa University Hospital, Japan, between April 2016 and August 2021. The primary outcome was FN incidence after cycle 1 of DCF chemotherapy. The significant independent factors associated with FN incidence were selected using the multivariate analysis. Changes in neutrophil counts and RDI were compared between the FN and non-FN groups. RESULTS: One-hundred patients were included in the analysis. The incidence of FN in cycle 1 was 21%. In the multivariate analysis, geriatric nutritional risk index (GNRI) <92 [odds ratio (OR)=13.162, p<0.001] and combination of platelet and neutrophil-to-lymphocyte ratio (COP-NLR) score of 0 (OR=4.619, p=0.012) were independent predictors of FN. The neutrophil count on day 7-10 and RDI in the FN group were lower than those in the non-FN group (all p<0.05). CONCLUSION: GNRI <92 and COP-NLR score of 0 are important indicators to predict patients at high risk of DCF chemotherapy-induced FN. Furthermore, FN incidence after pegfilgrastim administration had a strong effect on delayed neutrophil recovery and reduced RDI.

Cost-effectiveness of pegfilgrastim versus filgrastim for prevention of chemotherapy-induced febrile neutropenia in patients with lymphoma: a systematic review.

BACKGROUND: Febrile neutropenia (FN) is a prevalent and potentially life-threatening complication in patients with lymphoma receiving myelosuppressive chemotherapy. Pegfilgrastim is more effective than filgrastim as prophylaxis for FN. However, its usage has been limited because of its higher cost. Pegfilgrastim's value for money remains unclear. OBJECTIVE: To systematically review the cost-effectiveness of pegfilgrastim compared to filgrastim as a primary or secondary prophylaxis for chemotherapy-induced FN among patients with lymphoma. METHODS: A systematic literature search was conducted in PubMed, EMBASE, Cochrane Library databases, and Google Scholar. The most widely used economic evaluations (cost-effectiveness analysis, cost-utility analysis and cost-benefit analysis) were included in the review. Data extraction was guided by the Consolidated Health Economic Evaluation Reporting Standards checklist, and the quality of reviewed articles was assessed using the Joanna Briggs Institute (JBI) checklist. Cost-effectiveness data were rigorously summarized and synthesized narratively. Costs were adjusted to US$ 2020. RESULTS: We identified eight economic evaluation studies (two cost-utility analyses, three cost-effectiveness analyses, and three studies reporting both cost-effectiveness and cost-utility analyses). Half of these studies were from Europe (n = 4), the other half were from Iran, USA, Canada, and Singapore. Six studies met > 80% of the JBI quality assessment criteria. Cost-effectiveness estimates in the majority (n = 6) of these studies were for Non-Hodgkin Lymphoma patients receiving myelosuppressive chemotherapy with high-risk of FN (> 20%). The studies considered a wide range of baseline FN risk (17-97.4%) and mortality rates (5.8-8.9%). Reported incremental cost-effectiveness ratios ranged from US$ 2199 to US$ 8,871,600 per quality-adjusted life-year (QALY) gained, dominant to US$ 44,358 per FN averted, and US$ 4261- US$ 7251 per life-years gained. The most influential parameters were medication and hospitalization costs, the relative risk of FN, and assumptions of mortality benefit. CONCLUSIONS: Most studies showed that pegfilgrastim is cost-effective compared to filgrastim as primary and secondary prophylaxis for chemotherapy-induced FN among patients with lymphoma at a cost-effectiveness threshold of US$ 50,000 per QALY gained. The findings could assist clinicians and healthcare decision-makers to make informed decisions regarding resource allocation for the management of chemotherapy-induced FN in settings similar to those studied.

Evaluating the safety and effectiveness of PegaGen® (pegfilgrastim) for the prevention of chemotherapy-induced febrile neutropenia: a post-marketing surveillance study.

PURPOSE: Phase IV clinical trials are required to evaluate the real-world safety and effectiveness of drugs. This study aimed to evaluate the safety and effectiveness of once-per-cycle administration of PegaGen® (pegfilgrastim, CinnaGen, Iran) in cancer patients. METHODS: In this open-label, multicenter, prospective, real-world, post-marketing surveillance study, patients with any type of cancer receiving chemotherapy regimens with a high risk of febrile neutropenia (FN) were included if they were prescribed pegfilgrastim for FN prophylaxis. The primary objective of this study was to assess the safety and the secondary objective was to assess the effectiveness of pegfilgrastim in the prevention of FN in cancer patients. RESULTS: A total of 654 patients (51.73 ± 15.12 years of age) were enrolled and 3615 cycles of pegfilgrastim injections were recorded. The most common malignancies among the study patients were breast cancer (n = 192, 29.36%), lymphoma (n = 131, 20.03%), and gastric cancer (n = 65, 9.94%). The median (Q1, Q3) number of pegfilgrastim cycles per patient was 6 (4, 7). A single 6 mg dose was injected in 99.17% of the cycles. A total number of 816 adverse events (AEs) were reported in 246 patients (37.62%). Bone pain was recorded in 141 patients (21.56%) and in 440 cycles (12.17%). Among all patients, 45 patients (6.88%) experienced FN 51 times, and FN frequency was 1.4% among cycles. Moreover, 14 (2.14%) patients were hospitalized following FN. Antibiotics were administered to 24 patients (3.67%) for FN treatment. CONCLUSION: The results from this post-marketing surveillance study support the safety and effectiveness of PegaGen® used for the prevention of chemotherapy-induced FN in patients with various types of cancer and treatment regimens. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04460079.

Chemotherapy-Induced Neutropenia and Febrile Neutropenia in the US: A Beast of Burden That Needs to Be Tamed?

Neutropenia and febrile neutropenia (FN) are common complications of myelosuppressive chemotherapy. This review provides an up-to-date assessment of the patient and cost burden of chemotherapy-induced neutropenia/FN in the US, and summarizes recommendations for FN prophylaxis, including the interim guidance that was recommended during the coronavirus disease 2019 (COVID-19) pandemic. This review indicates that neutropenia/FN place a significant burden on patients in terms of hospitalizations and mortality. Most patients with neutropenia/FN presenting to the emergency department will be hospitalized, with an average length of stay of 6, 8, and 10 days for elderly, pediatric, and adult patients, respectively. Reported in-hospital mortality rates for neutropenia/FN range from 0.4% to 3.0% for pediatric patients with cancer, 2.6% to 7.0% for adults with solid tumors, and 7.4% for adults with hematologic malignancies. Neutropenia/FN also place a significant cost burden on US healthcare systems, with average costs per neutropenia/FN hospitalization estimated to be up to $40 000 for adult patients and $65 000 for pediatric patients. Evidence-based guidelines recommend prophylactic granulocyte colony-stimulating factors (G-CSFs), which have been shown to reduce FN incidence while improving chemotherapy dose delivery. Availability of biosimilars may improve costs of care. Efforts to decrease hospitalizations by optimizing outpatient care could reduce the burden of neutropenia/FN; this was particularly pertinent during the COVID-19 pandemic since avoidance of hospitalization was needed to reduce exposure to the virus, and resulted in the adaptation of recommendations to prevent FN, which expanded the indications for G-CSF and/or lowered the threshold of use to >10% risk of FN.

Pegfilgrastim-Apgf (Nyvepria): Biosimilar USFDA Approval for the Treatment of Chemotherapy-induced Febrile Neutropenia and Current Updates on Clinical Trials.

Pegfilgrastim-apgf (nyvepria) was currently approved by FDA for the treatment of febrile neutropenia associated with non-myeloid malignancies receiving myelosuppressive anticancer drugs. It was developed by Pfizer, USA. It is a PEGylated leukocyte growth-stimulating factor indicated to reduce the incidence of febrile neutropenia in patients receiving anticancer drugs. Nyvepria is biosimilar to pegfilgrastim, approved by FDA on June 10, 2020. It is the fourth FDA-approved drug for the treatment of infection exhibiting febrile neutropenia. This review abridges the indicators in the development of nyvepria foremost to approval for the treatment of febrile neutropenia (FN), a biosimilar regulatory framework, and current updates on the clinical trials (CTs).

Retrospective evaluation of safety and effectiveness of same-day pegfilgrastim in patients with lung cancer.

Aim: To determine the incidence of chemotherapy-induced febrile neutropenia (FN) and related outcomes after same-day pegfilgrastim in lung cancer. Materials & methods: This single-center, retrospective study evaluated electronic health records of patients with lung cancer treated between 2013-2018. The main end points were incidence of FN and grade 3/4 neutropenia after the first and across all chemotherapy cycles. Results: A total of 114 patients received same-day pegfilgrastim in 384 cycles. The incidence of FN and grade 3/4 neutropenia was 2.3 and 25% after the first chemotherapy cycle and 1.6 and 10.4% across all cycles, respectively. Conclusion: Same-day prophylactic pegfilgrastim in patients with lung cancer may be a suitable option, owing to its low incidence of FN and related outcomes.

Chemotherapy is intended to kill fast-growing cancer cells but can also kill immune cells that are needed to prevent infections. When too many immune cells are killed by chemotherapy, patients with cancer may experience febrile neutropenia, a serious condition that can lead to death in the most severe cases. To prevent this side effect of chemotherapy, a protein that helps certain immune cells to grow (pegfilgrastim) is administered on the day after chemotherapy. To avoid a second clinic visit the day after receiving chemotherapy, it has become common to administer pegfilgrastim on the same day as chemotherapy. Whether this approach is as effective and safe as next-day administration is currently unclear. This study from the University of Arizona Cancer Center showed that in patients with lung cancer who receive chemotherapy, administration of pegfilgrastim on the same day as chemotherapy is a safe, effective method to prevent febrile neutropenia.

Periodontal inflamed surface area in oral cavity associated with febrile neutropenia in patients with hematologic malignancy undergoing chemotherapy.

Febrile neutropenia (FN) is an infectious complication that develops during chemotherapy. Although the oral cavity can be an important infection route, it is unknown whether the oral environment is associated with FN. The present study examined the relationship between the oral environment using periodontal inflamed surface area (PISA), a new periodontal disease parameter, and FN in hematologic cancer patients undergoing chemotherapy. In this retrospective cohort study, 157 patients were divided into FN onset during chemotherapy (n = 75) and the FN negative groups (n = 82). The associations of risk factors related to the intraoral environment were assessed. Logistic regression analysis showed that types of blood cancer (odds ratio 1.98; P < 0.01), use of a high-risk regimen (odds ratio 4.44; P < 0.05), prophylaxis treatment with human granulocyte colony-stimulating factor (G-CSF) (odds ratio 4.15; P < 0.01) and PISA (odds ratio 1.02; P < 0.01) were independent factors associated with FN onset. Finally, propensity score matching was performed between two groups; 37 matched pairs were generated. PISA was significantly higher in the FN group than the FN negative group. There was a significant relationship between PISA and FN onset (P = 0.035). The present findings indicate that periodontitis treatment before starting cancer treatment is recommended as supportive care for preventing FN onset during chemotherapy.

Improved risk prediction of chemotherapy-induced neutropenia-model development and validation with real-world data.

BACKGROUND: The existing risk prediction models for chemotherapy-induced febrile neutropenia (FN) do not necessarily apply to real-life patients in different healthcare systems and the external validation of these models are often lacking. Our study evaluates whether a machine learning-based risk prediction model could outperform the previously introduced models, especially when validated against real-world patient data from another institution not used for model training. METHODS: Using Turku University Hospital electronic medical records, we identified all patients who received chemotherapy for non-hematological cancer between the years 2010 and 2017 (N = 5879). An experimental surrogate endpoint was first-cycle neutropenic infection (NI), defined as grade IV neutropenia with serum C-reactive protein >10 mg/l. For predicting the risk of NI, a penalized regression model (Lasso) was developed. The model was externally validated in an independent dataset (N = 4594) from Tampere University Hospital. RESULTS: Lasso model accurately predicted NI risk with good accuracy (AUROC 0.84). In the validation cohort, the Lasso model outperformed two previously introduced, widely approved models, with AUROC 0.75. The variables selected by Lasso included granulocyte colony-stimulating factor (G-CSF) use, cancer type, pre-treatment neutrophil and thrombocyte count, intravenous treatment regimen, and the planned dose intensity. The same model predicted also FN, with AUROC 0.77, supporting the validity of NI as an endpoint. CONCLUSIONS: Our study demonstrates that real-world NI risk prediction can be improved with machine learning and that every difference in patient or treatment characteristics can have a significant impact on model performance. Here we outline a novel, externally validated approach which may hold potential to facilitate more targeted use of G-CSFs in the future.

Phase II feasibility study of adjuvant chemotherapy with docetaxel/cisplatin/S-1 followed by S-1 for stage III gastric cancer.

BACKGROUND: This study aimed to evaluate the feasibility, safety, and efficacy of postoperative adjuvant chemotherapy with docetaxel/cisplatin/S-1 (DCS) following S-1 therapy in patients with stage III gastric cancer after curative gastrectomy. METHODS: Patients with stage III gastric cancer who underwent D2 gastrectomy were enrolled. Adjuvant chemotherapy was initiated within 8 weeks of gastrectomy. The first cycle of chemotherapy consisted of S-1 monotherapy (day 1-14), followed by a 7-day rest period. Cycles 2 and 3 consisted of the following: S-1 (day 1-14) administration, followed by a 14-day rest period, and an intravenous infusion of cisplatin and docetaxel on days 1 and 15. After two cycles, S-1 was administered for up to 1 year. RESULTS: Thirty patients were enrolled between 2014 and 2017. Febrile neutropenia of grade 3 or higher was the most common hematological toxicity with 4 patients (13.3%). Other hematological toxicities of grade 3 or higher were as follows: neutropenia in 3 (10.0%), leukopenia in 3 (10.0%), and anemia in 2 (6.7%) patients. Most frequent non-hematological toxicity of grade 3 was anorexia (n = 4, 13.3%) and general fatigue (n = 3, 10.0%); no grade 4 non-hematological toxicities were observed. Twenty-five patients (83.3%) completed two cycles of DCS treatment and 18 (60.0%) completed subsequent S-1 treatment for 1 year. The relative dose intensity of docetaxel and cisplatin was 0.86 and that of S-1 was 0.88. CONCLUSION: The DCS regimen can be acceptable as an adjuvant chemotherapy and offers an effective postoperative treatment option for stage III gastric cancer patients. TRIAL REGISTRATION NUMBER: UMIN000012785 . DATE OF REGISTRY: 08/01/2014.

Prophylactic pegfilgrastim to prevent febrile neutropenia among patients receiving biweekly (Q2W) chemotherapy regimens: a systematic review of efficacy, effectiveness and safety.

BACKGROUND: Pegfilgrastim, a long-acting granulocyte colony-stimulating factor (G-CSF), is commonly used to prevent febrile neutropenia (FN), a potentially life-threatening complication, following myelosuppressive chemotherapy. The FDA label for pegfilgrastim specifies that it should not be administered 14 days before or within 24 h of administration of myelosuppressive chemotherapy, precluding the use of pegfilgrastim in biweekly (Q2W) regimens. The National Comprehensive Cancer Network and the European Organisation for Research and Treatment of Cancer guidelines support the use of prophylactic pegfilgrastim in patients receiving Q2W regimens. The objective of this study was to systematically review evidence from randomized clinical trials (RCTs) and observational studies that describe the effectiveness and safety of prophylactic pegfilgrastim in preventing FN among patients receiving Q2W regimens. METHODS: An Ovid MEDLINE, Embase, and Cochrane Library literature search was conducted to evaluate the evidence regarding efficacy, effectiveness, and safety of prophylactic pegfilgrastim versus no prophylactic pegfilgrastim or prophylaxis with other G-CSF in patients who were receiving Q2W chemotherapy regimens with high (> 20%) or intermediate (10-20%) risk of FN for a non-myeloid malignancy. Studies that addressed absolute or relative risk of FN, grade 1-4 neutropenia, all-cause or any hospitalization, dose delays or dose reductions, adverse events, or mortality were included. Studies where the comparator was a Q3W chemotherapy regimen with primary prophylactic pegfilgrastim were also included. RESULTS: The initial literature search identified 2258 publications. Thirteen publications met the eligibility criteria, including eight retrospective, one prospective, one phase 1 dose escalation study, and three RCTs. In nine of the 13 studies reporting incidence of FN, and in seven of the nine studies reporting incidence of neutropenia, administration of prophylactic pegfilgrastim in patients receiving Q2W regimens resulted in decreased or comparable rates of FN or neutropenia compared with patients receiving filgrastim, no G-CSF, lipefilgrastim or pegfilgrastim in Q3W regimens. In six of the nine studies reporting safety data, lower or comparable safety profiles were observed between pegfilgrastim and comparators. CONCLUSIONS: In a variety of non-myeloid malignancies, administration of prophylactic pegfilgrastim was efficacious in reducing the risk of FN in patients receiving high- or intermediate-risk Q2W regimens, with an acceptable safety profile. TRIAL REGISTRATION: PROSPERO registration no: CRD42019155572 .

Prospective Multicenter Phase II Study of Biweekly TAS-102 and Bevacizumab for Metastatic Colorectal Cancer.

BACKGROUND: This study assessed the efficacy and safety of biweekly trifluridine and tipiracil hydrochloride (TAS-102) with bevacizumab combination therapy for patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: We included 19 patients with mCRC who received TAS-102 and bevacizumab combination therapy biweekly as third-line chemotherapy. The primary endpoint was progression-free survival. RESULTS: Patients had a median age of 73 years and most (73.4%) were men. The median progression-free and overall survival were 5.6 and 11.5 months, respectively. Five (26.3%) patients achieved a response and the disease control rate was 12/19 (63.1%). One patient (5.2%) experienced neutropenia grade 3 or more. The median time from baseline performance status 0/1 to worsening to 2 or more was 10.3 months. CONCLUSION: Biweekly TAS-102 plus bevacizumab facilitates tumor shrinkage by reducing the incidence of grade 3 or more neutropenia, improving survival, and maintaining performance status. This combination may represent a treatment option for patients with late-stage mCRC receiving third- or later-line therapy.

Role of HMOX1 Promoter Genetic Variants in Chemoresistance and Chemotherapy Induced Neutropenia in Children with Acute Lymphoblastic Leukemia.

Whilst the survival rates of childhood acute lymphoblastic leukemia (ALL) have increased remarkably over the last decades, the therapy resistance and toxicity are still the major causes of treatment failure. It was shown that overexpression of heme oxygenase-1 (HO-1) promotes proliferation and chemoresistance of cancer cells. In humans, the HO-1 gene (HMOX1) expression is modulated by two polymorphisms in the promoter region: (GT)n-length polymorphism and single-nucleotide polymorphism (SNP) A(-413)T, with short GT repeat sequences and 413-A variants linked to an increased HO-1 inducibility. We found that the short alleles are significantly more frequent in ALL patients in comparison to the control group, and that their presence may be associated with a higher risk of treatment failure, reflecting the role of HO-1 in chemoresistance. We also observed that the presence of short alleles may predispose to develop chemotherapy-induced neutropenia. In case of SNP, the 413-T variant co-segregated with short or long alleles, while 413-A almost selectively co-segregated with long alleles, hence it is not possible to determine if SNPs are actually of phenotypic significance. Our results suggest that HO-1 can be a potential target to overcome the treatment failure in ALL patients.

Germline BRCA1/2 mutations and severe haematological toxicities in patients with breast cancer treated with neoadjuvant chemotherapy.

BACKGROUND: BRCA1 and BRCA2 play a central role in DNA repair. Therefore, patients harbouring germline (g) BRCA1/2 mutations (m) treated with chemotherapy might be at higher risk of haematological toxicities. METHODS: Patients from German Breast Group (GBG) and Arbeitsgemeinschaft Gynäkologische Onkologie-breast group studies with early triple-negative breast cancer (TNBC) and known gBRCA1/2m status treated with anthracycline-taxane-based neoadjuvant chemotherapy were analysed. Primary objective was the rate of neutropenia grade (G)III-IV in cycle 1 (C1). Secondary objectives included effects on overall and other haematological toxicities GIII-IV in C1, cumulative haematological toxicity across all cycles, relative total dose intensity, and granulocyte-colony stimulating factor prophylaxis. Haematological toxicities under taxanes, carboplatin, and cyclophosphamide were explored. RESULTS: Two hundred nine of 1171 (17.8%) evaluated patients had gBRCA1/2m. In C1, 37.4% gBRCA1/2m versus 35.7% wild-type patients had neutropenia GIII-IV (P = 0.683). For C1, gBRCA1/2m predicted neither for neutropenia GIII-IV (odds ratio [OR]: 1.26, 95% confidence intervals [CI]: 0.87-1.82, P = 0.226) nor for other haematological toxicities GIII-IV (OR: 0.91, 95% CI: 0.64-1.31, P = 0.625) in multivariable regression models. Analyses of cumulative toxicities across all cycles yielded similar results except thrombocytopaenia GIII-IV, which was increased in gBRCA1m patients. In patients treated with taxanes, the rate of haematological toxicities GIII-IV was higher in gBRCA1/2m compared with wild-type (59.5% versus 43.1%; p < 0.001). No difference was seen under cyclophosphamide or platinum-containing chemotherapies. CONCLUSIONS: gBRCA1/2m was not associated with higher risk of overall severe haematological toxicities in the first cycle or cumulatively across all cycles under standard chemotherapy for TNBC. Under taxane, patients with gBRCA1/2m might have a higher risk of haematological toxicities GIII-IV, requiring further research.

Clostridium perfringens sepsis in three patients with acute leukemia and review of the literature.

In this study, we aimed to improve understanding of the clinical manifestations, laboratory findings, and risk factors of Clostridium perfringens sepsis in patients with acute leukemia and to analyze treatment strategies for improving prognosis. We analyzed clinical manifestations, laboratory data, diagnosis, and treatment strategies in three cases of C. perfringens sepsis in patients with acute leukemia. We also reviewed and analyzed the relevant literature, incorporating our findings into the discussion. All three patients developed septic shock with neutropenia following chemotherapy. Analysis of blood samples confirmed the presence of C. perfringens, and two patients had fulminant intravascular hemolysis and developed multiple organ dysfunction syndrome. Two patients survived and one died despite timely and full-dose antibacterial treatments, blood purification, and noninvasive positive pressure ventilation. Overall, our findings showed that C. perfringens sepsis is rare in patients with acute leukemia but progresses rapidly. A high mortality rate was observed, and patients often experienced refractory shock and intravascular hemolysis. This demonstrates the importance of early detection and diagnosis. Multimodal treatments, including fluid resuscitation, antibiotics, organ support, and blood purification, are essential for success.

Risk of chemotherapy-induced febrile neutropenia in patients with metastatic cancer not receiving granulocyte colony-stimulating factor prophylaxis in US clinical practice.

OBJECTIVES: To evaluate the use of granulocyte colony-stimulating factor (G-CSF) prophylaxis in US patients with selected metastatic cancers and chemotherapy-induced febrile neutropenia (FN) incidence and associated outcomes among the subgroup who did not receive prophylaxis. METHODS: This retrospective cohort study was conducted at four US health systems and included adults with metastatic cancer (breast, colorectal, lung, non-Hodgkin lymphoma [NHL]) who received myelosuppressive chemotherapy (2009-2017). Patients were stratified by FN risk level based on risk factors and chemotherapy (low/unclassified risk, intermediate risk without any risk factors, intermediate risk with ≥ 1 risk factor [IR + 1], high risk [HR]). G-CSF use was evaluated among all patients stratified by FN risk, and FN/FN-related outcomes were evaluated among patients who did not receive first-cycle G-CSF prophylaxis. RESULTS: Among 1457 metastatic cancer patients, 20.5% and 28.1% were classified as HR and IR + 1, respectively. First-cycle G-CSF prophylaxis use was 48.5% among HR patients and 13.9% among IR + 1 patients. In the subgroup not receiving first-cycle G-CSF prophylaxis, FN incidence in cycle 1 was 7.8% for HR patients and 4.8% for IR + 1 patients; during the course, corresponding values were 16.9% and 15.9%. Most (> 90%) FN episodes required hospitalization, and mortality risk ranged from 7.1 to 26.9% across subgroups. CONCLUSION: In this retrospective study, the majority of metastatic cancer chemotherapy patients for whom G-CSF prophylaxis is recommended did not receive it; FN incidence in this subgroup was notably high. Patients with elevated FN risk should be carefully identified and managed to ensure appropriate use of supportive care.

Toxic erythema of chemotherapy secondary to gemcitabine and paclitaxel.

Toxic erythema of chemotherapy (TEC) is an infrequently reported cutaneous condition, with diagnosis predominately based on clinical presentation, histologic findings, and known reported associations. Therefore, it is important to both recognize common presentations of TEC and be mindful of chemotherapeutic agents associated with this cutaneous side effect to prevent misdiagnosis and prolonged time to treatment. Herein, we present a patient with TEC occurring in intertriginous skin (malignant intertrigo) with classic clinical and histologic findings. In our patient this was associated with a combination neoadjuvant gemcitabine and paclitaxel therapy, a relationship that, to our knowledge, has yet to be reported in the literature.

Randomized Comparison of Pazopanib and Doxorubicin as First-Line Treatment in Patients With Metastatic Soft Tissue Sarcoma Age 60 Years or Older: Results of a German Intergroup Study.

PURPOSE: Doxorubicin is a standard of care in patients with advanced, inoperable soft tissue sarcoma (STS). We tested whether pazopanib has efficacy comparable to that of doxorubicin in elderly patients with STS and offers superior tolerability for hematologic toxicity. PATIENTS AND METHODS: Patients age 60 years or older without previous systemic treatment for progressive advanced or metastatic STS who had Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate organ function were included. Treatment consisted of pazopanib 800 mg once per day or doxorubicin 75 mg/m2 once every 3 weeks (≤ 6 cycles) after being randomly assigned in a 2:1 ratio. Noninferiority was assumed for progression-free survival (PFS), if the upper limit of the 95% CI for the hazard ratio (HR) was less than 1.8. Neutropenia and febrile neutropenia were key secondary end points. The European Organisation for Research and Treatment of Cancer (30-item) Quality of Life Questionnaire and geriatric assessment were used to measure patient-reported outcomes. Cox regression analysis and Kaplan-Meier curves were used for analysis. RESULTS: Pazopanib and doxorubicin were given to 81 and 39 patients, respectively. The median age was 71 years (range, 60-88 years). PFS was noninferior (HR, 1.00; 95% CI, 0.65 to 1.53) and the incidence of grade 4 neutropenia and febrile neutropenia favored pazopanib. Objective response rates for pazopanib and doxorubicin were 12.3% and 15.4%, respectively. Overall survival did not differ significantly between arms (HR, 1.08; 95% CI, 0.68 to 1.72; P = .735). Geriatric assessment revealed 2 or more comorbidities in 15.8% of the patients and impairment of activities of daily living in 28.3% of patients. CONCLUSION: Pazopanib was noninferior to doxorubicin, rendering pazopanib a putative therapeutic option in the first-line treatment of STS in patients age 60 years or older. The distinct adverse event profile may be used to counsel patients and tailor therapy to individual needs.