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Current Opinion in Hematology Jan 2016Neutropenia absolute neutrophil count (ANC) less than 1.5 × 10(9)/l is a common hematological finding, and severe neutropenia, that is, ANC less... (Review)
Review
PURPOSE OF REVIEW
Neutropenia absolute neutrophil count (ANC) less than 1.5 × 10(9)/l is a common hematological finding, and severe neutropenia, that is, ANC less than 0.5 × 10(9)/l is a well known risk factor for susceptibility to bacterial infections. This review provides a succinct clinical approach to the diagnosis and treatment of neutropenia with specific recommendations on the treatment of severe chronic neutropenia with the myeloid growth factor, granulocyte colony-stimulating factor (G-CSF).
RECENT FINDINGS
Experts agree that patients with acute febrile neutropenia should be treated with antibiotics and that patients at high risk of severe neutropenia (>20% risk) after myelosuppressive chemotherapy should be treated prophylactically with a myeloid growth factor, usually G-CSF. The diversity of causes and consequences of chronic neutropenia make the diagnosis and management of these patients more complicated.
SUMMARY
The review provides a stepwise approach to neutropenia focusing first on reaching a provisional diagnosis and treatment plan then steps to a final diagnosis. It also provides specific recommendations on the treatment of severe chronic neutropenia with G-CSF.
Topics: Humans; Neutropenia
PubMed: 26554885
DOI: 10.1097/MOH.0000000000000208 -
Journal of Clinical Oncology : Official... Mar 2023To update a clinical practice guideline (CPG) for the empiric management of fever and neutropenia (FN) in pediatric patients with cancer and hematopoietic cell...
PURPOSE
To update a clinical practice guideline (CPG) for the empiric management of fever and neutropenia (FN) in pediatric patients with cancer and hematopoietic cell transplantation recipients.
METHODS
The International Pediatric Fever and Neutropenia Guideline Panel reconvened to conduct the second update of this CPG. We updated the previous systematic review to identify new randomized controlled trials (RCTs) evaluating any strategy for the management of FN in pediatric patients. Using the Grading of Recommendations Assessment, Development and Evaluation framework, evidence quality was classified as high, moderate, low, or very low. The panel updated recommendations related to initial management, ongoing management, and empiric antifungal therapy. Changes from the 2017 CPG were articulated, and good practice statements were considered.
RESULTS
We identified 10 new RCTs in addition to the 69 RCTs identified in previous FN CPGs to inform the 2023 FN CPG. Changes from the 2017 CPG included two conditional recommendations regarding (1) discontinuation of empiric antibacterial therapy in clinically well and afebrile patients with low-risk FN if blood cultures remain negative at 48 hours despite no evidence of marrow recovery and (2) pre-emptive antifungal therapy for invasive fungal disease in high-risk patients not receiving antimold prophylaxis. The panel created a good practice statement to initiate FN CPG-consistent empiric antibacterial therapy as soon as possible in clinically unstable febrile patients.
CONCLUSION
The updated FN CPG incorporates important modifications on the basis of recently published trials. Future work should focus on addressing knowledge gaps, improving CPG implementation, and measuring the impact of CPG-consistent care.
Topics: Child; Humans; Antifungal Agents; Neutropenia; Neoplasms; Fever; Anti-Bacterial Agents; Hematopoietic Stem Cell Transplantation; Febrile Neutropenia
PubMed: 36689694
DOI: 10.1200/JCO.22.02224 -
Journal of Immunology (Baltimore, Md. :... Aug 2015G-CSF and GM-CSF are used widely to promote the production of granulocytes or APCs. The U.S. Food and Drug Administration approved G-CSF (filgrastim) for the treatment... (Review)
Review
G-CSF and GM-CSF are used widely to promote the production of granulocytes or APCs. The U.S. Food and Drug Administration approved G-CSF (filgrastim) for the treatment of congenital and acquired neutropenias and for mobilization of peripheral hematopoietic progenitor cells for stem cell transplantation. A polyethylene glycol-modified form of G-CSF is approved for the treatment of neutropenias. Clinically significant neutropenia, rendering an individual immunocompromised, occurs when their number is <1500/μl. Current guidelines recommend their use when the risk for febrile neutropenia is >20%. GM-CSF (sargramostim) is approved for neutropenia associated with stem cell transplantation. Because of its promotion of APC function, GM-CSF is being evaluated as an immunostimulatory adjuvant in a number of clinical trials. More than 20 million persons have benefited worldwide, and >$5 billion in sales occur annually in the United States.
Topics: Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Neutropenia; Signal Transduction
PubMed: 26254266
DOI: 10.4049/jimmunol.1500861 -
Annals of Hematology Nov 2020Wider use of clozapine, one of the most effective antipshychotic drugs, is precluded by its propensity to cause agranulocytosis. Currently, clozapine is used for... (Review)
Review
Wider use of clozapine, one of the most effective antipshychotic drugs, is precluded by its propensity to cause agranulocytosis. Currently, clozapine is used for treatment-resistant schizophrenia, with mandatory blood count monitoring for the duration of treatment. Agranulocytosis occurs in up to 0.8% of patients and presents a significant medical challenge, despite decreasing mortality rates. In this paper, we review the epidemiology of clozapine-induced agranulocytosis (CLIA), advances in identifying genetic risk factors, and the preventive measures to reduce the risk of CLIA. We discuss the pathogenesis of CLIA, which, despite receiving considerable scientific attention, has not been fully elucidated. Finally, we address the clinical management and suggest the approach to clozapine re-challenge in patients with a previous episode of neutropenia. With a significant proportion of clozapine recipients in Western hemisphere being Black, we comment on the importance of recognizing benign ethnic neutropenia as a potential impediment to clozapine administration. This review aims to aid haematologists and psychiatrists to jointly manage neutropenia and agranulocytosis caused by clozapine.
Topics: Black People; Clozapine; Humans; Neutropenia; Risk Factors
PubMed: 32815018
DOI: 10.1007/s00277-020-04215-y -
British Journal of Haematology Aug 2017Neutropenia, usually defined as a blood neutrophil count <1·5 × 10 /l, is a common medical problem for children and adults. There are many causes for neutropenia,... (Review)
Review
Neutropenia, usually defined as a blood neutrophil count <1·5 × 10 /l, is a common medical problem for children and adults. There are many causes for neutropenia, and at each stage in life the clinical pattern of causes and consequences differs significantly. I recommend utilizing the age of the child and clinical observations for the preliminary diagnosis and primary management. In premature infants, neutropenia is quite common and contributes to the risk of sepsis with necrotizing enterocolitis. At birth and for the first few months of life, neutropenia is often attributable to isoimmune or alloimmune mechanisms and predisposes to the risk of severe bacterial infections. Thereafter when a child is discovered to have neutropenia, often associated with relatively minor symptoms, it is usually attributed to autoimmune disorder or viral infection. The congenital neutropenia syndromes are usually recognized when there are recurrent infections, the neutropenia is severe and there are congenital anomalies suggesting a genetic disorder. This review focuses on the key clinical finding and laboratory tests for diagnosis with commentaries on treatment, particularly the use of granulocyte colony-stimulating factor to treat childhood neutropenia.
Topics: Autoimmune Diseases; Child; Granulocyte Colony-Stimulating Factor; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Neutropenia
PubMed: 28419427
DOI: 10.1111/bjh.14677 -
Cancer Treatment Reviews Sep 2022
Review
Topics: Antineoplastic Agents; Granulocyte Colony-Stimulating Factor; Humans; Neutropenia
PubMed: 35785754
DOI: 10.1016/j.ctrv.2022.102427 -
Nature Reviews. Disease Primers Jun 2017Severe congenital neutropenias are a heterogeneous group of rare haematological diseases characterized by impaired maturation of neutrophil granulocytes. Patients with... (Review)
Review
Severe congenital neutropenias are a heterogeneous group of rare haematological diseases characterized by impaired maturation of neutrophil granulocytes. Patients with severe congenital neutropenia are prone to recurrent, often life-threatening infections beginning in their first months of life. The most frequent pathogenic defects are autosomal dominant mutations in ELANE, which encodes neutrophil elastase, and autosomal recessive mutations in HAX1, whose product contributes to the activation of the granulocyte colony-stimulating factor (G-CSF) signalling pathway. The pathophysiological mechanisms of these conditions are the object of extensive research and are not fully understood. Furthermore, severe congenital neutropenias may predispose to myelodysplastic syndromes or acute myeloid leukaemia. Molecular events in the malignant progression include acquired mutations in CSF3R (encoding G-CSF receptor) and subsequently in other leukaemia-associated genes (such as RUNX1) in a majority of patients. Diagnosis is based on clinical manifestations, blood neutrophil count, bone marrow examination and genetic and immunological analyses. Daily subcutaneous G-CSF administration is the treatment of choice and leads to a substantial increase in blood neutrophil count, reduction of infections and drastic improvement of quality of life. Haematopoietic stem cell transplantation is the alternative treatment. Regular clinical assessments (including yearly bone marrow examinations) to monitor treatment course and detect chromosomal abnormalities (for example, monosomy 7 and trisomy 21) as well as somatic pre-leukaemic mutations are recommended.
Topics: Adaptor Proteins, Signal Transducing; Blood Cell Count; Congenital Bone Marrow Failure Syndromes; Core Binding Factor Alpha 2 Subunit; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Leukocyte Elastase; Mutation; Myelodysplastic Syndromes; Neutropenia; Quality of Life; Receptors, Colony-Stimulating Factor
PubMed: 28593997
DOI: 10.1038/nrdp.2017.32 -
Hematology. American Society of... Dec 2017Non-chemotherapy idiosyncratic drug-induced neutropenia (IDIN) is a relatively rare but potentially fatal disorder that occurs in susceptible individuals, with an... (Review)
Review
Non-chemotherapy idiosyncratic drug-induced neutropenia (IDIN) is a relatively rare but potentially fatal disorder that occurs in susceptible individuals, with an incidence of 2.4 to 15.4 cases per million population. Affected patients typically experience severe neutropenia within several weeks to several months after first exposure to a drug, and mortality is ∼5%. The drugs most frequently associated with IDIN include metamizole, clozapine, sulfasalazine, thiamazole, carbimazole, amoxicillin, cotrimoxazole, ticlopidine, and valganciclovir. The idiosyncratic nature of IDIN, the lack of mouse models and diagnostic testing, and its low overall incidence make rigorous studies to elucidate possible mechanisms exceptionally difficult. An immune mechanism for IDIN involving neutrophil destruction by hapten (drug)-specific antibodies and drug-induced autoantibodies is frequently suggested, but strong supporting evidence is lacking. Although laboratory testing for neutrophil drug-dependent antibodies is rarely performed because of the complexity and low sensitivity of tests currently in use, these assays could possibly be enhanced by using reactive drug metabolites in place of the parent drug. Patients typically experience acute, severe neutropenia, or agranulocytosis (<0.5 × 10 neutrophils/L) and symptoms of fever, chills, sore throat, and muscle and joint pain. Diagnosis can be difficult, but timely recognition is critical because if left untreated, there is an increase in mortality. Expanded studies of the production and mechanistic role of reactive drug metabolites, genetic associations, and improved animal models of IDIN are essential to further our understanding of this important disorder.
Topics: Animals; Chemotherapy-Induced Febrile Neutropenia; Humans; Incidence; Mice
PubMed: 29222255
DOI: 10.1182/asheducation-2017.1.187 -
Cancer Jan 2023Antibody-drug conjugates (ADCs) have complex molecular structures and have been tested in numerous clinical trials. Therefore, understanding the mechanisms of their... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Antibody-drug conjugates (ADCs) have complex molecular structures and have been tested in numerous clinical trials. Therefore, understanding the mechanisms of their toxicity when applied in medical practice is of high importance.
METHODS
In a systematic review and meta-analysis of data gathered from different scientific databases (PubMed, Embase, Cochrane, and Web of Science) between January 1, 2000, and June 7, 2022, the authors applied a random-effects model with logit transformation and evaluated the heterogeneity between studies using I statistics. The primary outcome was the incidence and 95% confidence interval (CI) for all-grade and grade ≥3 treatment-related adverse events and differences between different drugs, molecular structures, and cancer types.
RESULTS
In total, 2511 records were identified that included 169 clinical trials involving 22,492 patients. The overall incidence of treatment-related adverse events was 91.2% (95% CI, 90.7%-91.7%; I = 95.9%) for all-grade adverse events and 46.1% (95% CI, 45.2%-47.0%; I = 96.3%) for grade ≥3 adverse events. The most common all-grade adverse events were lymphopenia (53.0%; 95% CI, 48.7%-57.3%), nausea (44.1%; 95% CI, 43.2%-44.9%), neutropenia (43.7%; 95% CI, 42.6%-44.9%), blurred vision (40.5%; 95% CI, 37.4%-43.6%), and peripheral neuropathy (39.6%; 95% CI, 38.2%-41.1%); and the most common grade ≥3 adverse events were neutropenia (31.2%; 95% CI, 30.2%-32.3%), hypoesthesia (23.3%; 95% CI, 10.6%-35.9%), thrombocytopenia (22.6%; 95% CI, 21.3%-23.9%), febrile neutropenia (21.2%; 95% CI, 19.3%-23.1%), and lymphopenia (21.0%; 95% CI, 18.2%-23.7%).
CONCLUSIONS
Different ADCs appear to affect various treatment-related adverse events and provide comprehensive data on treatment-related adverse events for ADCs. The current results provide an important reference for clinicians and patients on how to care for toxicities from ADCs in clinical practice.
LAY SUMMARY
Unique anticancer drugs called antibody-drug conjugates (ADCs) have made significant progress in oncology in recent years because of their great success, and they are rapidly being used in the clinic as well as in hundreds of ongoing trials exploring their further use. The occurrence of serious side effects (adverse events) related to the receipt of ADCs was studied using data from 169 clinical trials involving 22,492 patients to determine the treatment-related causes of higher toxicity and adverse events in patients who receive ADCs, because these data are crucial for informing physicians how to safely treat patients using ADCs. The results indicate that different ADCs appear to affect various adverse events related to their use, providing comprehensive data on these ADCs that provide an important reference for clinicians and patients on how to care for toxicities from ADCs in clinical practice.
Topics: Humans; Immunoconjugates; Antineoplastic Agents; Neoplasms; Neutropenia; Lymphopenia
PubMed: 36408673
DOI: 10.1002/cncr.34507 -
Experimental and Clinical... Oct 2021Renal transplant is considered the best therapeutic option for suitable patients with end-stage kidney failure. Hematological complications that occur after kidney... (Review)
Review
Renal transplant is considered the best therapeutic option for suitable patients with end-stage kidney failure. Hematological complications that occur after kidney transplant include posttransplant anemia, leukopenia, neutropenia, and thrombocytopenia. Severely persistent leukopenia and neutropenia events predispose patients to infection, including opportunistic infections. The mainstay tactic for such complications is to reduce the burden of the immunosuppression by the offending agent, but this tactic is associated with increased risk of acute rejection. Given the absence of laboratory investigations to specifically identify the culprit, a complete withdrawal of these agents may be the ultimate diagnostic option. Future therapeutic strategies, however, should focus on reducing the immunosuppressive burden, the introduction of less myelotoxic agents, early recognition, and prompt treatment of infectious episodes. This will help in the optimization of the myelopoietic function and normalization of the hematological profile, resulting in better allograft and patient survival.
Topics: Anemia; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Neutropenia; Treatment Outcome
PubMed: 33736582
DOI: 10.6002/ect.2020.0100