[Is there a place for granulocytes transfusions in 2023 ?] / Y a-t-il une place pour les transfusions de granulocytes en 2023 ?

Despite modern antimicrobial treatments, bacterial and fungal infections remain major complications in neutropenic patients. Granulocyte transfusions appeared in the 1950s-60s but first clinical trials were limited by the difficulty of transfusing enough viable granulocytes. The refinement of apheresis techniques as well as donor pretreatment with corticosteroids and/or granulocyte colony-stimulating growth factor (G-CSF) have led to improved collection yield. Despite this, uncertainties remain regarding the real clinical usefulness of granulocyte transfusions. Few studies have been carried out since the G-CSF era and the quality of scientific evidence remains low, mainly because of small case series. The largest prospective randomized controlled study published so far failed to demonstrate any benefit of therapeutic granulocyte transfusions on mortality or infection control. However, the quality of this trial is limited due to its low statistical power (insufficient patient recruitment). Moreover, granulocyte transfusions are complex procedures, burdensome for the donor, expensive and associated with a significant risk of adverse effects. Therefore, the current place of granulocyte transfusion in clinical practice is guided by the experience of each center. With the increasing emergence of multi-resistant germs, it is likely that granulocyte transfusion will become interesting in the coming years. Standardization of collection and administration procedures and the final proof of their (in)effectiveness will remain the challenges for the future.

En dépit des traitements antimicrobiens modernes, les infections bactériennes et fongiques restent des complications majeures chez les patients neutropéniques. Les transfusions de granulocytes (TG) sont apparues dans les années 1950-1960, mais les premiers essais cliniques ont été limités par la difficulté de transfuser un nombre suffisant de granulocytes viables. Le perfectionnement des techniques d'aphérèse ainsi que la stimulation pharmacologique du donneur par corticostéroïdes et/ou facteur de croissance granulocytaire (G-CSF) ont permis d'améliorer le rendement des collectes. Malgré cela, des incertitudes subsistent quant à la réelle utilité clinique des TG. Peu d'études ont été réalisées depuis l'ère du G-CSF et la qualité des preuves scientifiques reste faible. La plus large étude prospective contrôlée randomisée publiée à ce jour n'a pas pu démontrer de bénéfice des TG sur la mortalité ou le contrôle des infections. Cependant, la valeur de cet essai est limitée en raison de sa faible puissance statistique (recrutement de patients insuffisant). De plus, les TG sont des procédures complexes, lourdes pour le donneur, coûteuses et associées à un risque non négligeable d'effets indésirables. Par conséquent, la place actuelle des TG dans la pratique clinique est principalement guidée par l'expérience de chaque centre. Avec l'émergence croissante de germes multirésistants, il est probable que les TG suscitent à nouveau l'intérêt dans les années à venir. Les défis seront de parvenir à une détermination définitive de leur (in)efficacité et d'uniformiser les procédures de collecte et d'administration.

Extracorporeal membrane oxygenation in long-term COVID-19 with severe neutropenia and thrombocytopenia after allogeneic hematopoietic stem cell transplantation: a case report.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) was associated with potentially life-threatening complications. Among patients supported by extracorporeal membrane oxygenation (ECMO), those who underwent HSCT had a worse prognosis than those who did not. Advances in HSCT and critical care management have improved the prognosis of ECMO-supported HSCT patients. CASE: The patient in the remission stage of lymphoma after 22 months of allogeneic hematopoietic stem cell transplantation, suffered from ARDS, severe neutropenia, thrombocytopenia, and long-term COVID-19. We evaluated the benefits and risks of ECMO for the patient, including the possibility of being free from ECMO, the status of malignancy, the interval from HSCT to ARDS, the function of the graft, the amount of organ failure, and the comorbidities. ECMO was ultimately used to save his life. CONCLUSIONS: We did not advocate for the general use of ECMO in HSCT patients and we believed that highly selected patients, with well-controlled tumors, few comorbidities, and fewer risk factors for death, tended to benefit from ECMO with well ICU management.

Late-onset and long-lasting neutropenias in the young: A new entity anticipating immune-dysregulation disorders.

This study identifies a new chronic form of immune neutropenia in the young with or without detectable indirect anti-neutrophil antibodies, characterized by mild/moderate neutropenia low risk of severe infection (14%), tendency to develop autoimmune phenomena over the course of the disease (cumulative incidence of 58.6% after 20 years of disease duration), leukopenia, progressive reduction of absolute lymphocyte count and a T- and B-cell profile similar to autoimmune disorders like Sjogren syndrome, rheumatoid arthritis, and systemic lupus erythematosus (increased HLADR+ and CD3 + TCRγδ cells, reduced T regulatory cells, increased double-negative B and a tendency to reduced B memory cells). In a minority of patients, P/LP variants related to primary immuno-regulatory disorders were found. This new form may fit the group of "Likely acquired neutropenia," a provisional category included in the recent International Guidelines on Diagnosis and Management of Neutropenia of EHA and EUNET INNOCHRON ACTION 18233. The early recognition of this form of neutropenia would help clinicians to delineate better specific monitoring plans, genetic counseling, and potentially targeted therapies.

Clinical practice guideline-inconsistent management of fever and neutropenia in pediatric oncology: A Children's Oncology Group study.

BACKGROUND: The primary objective was to measure the proportion of episodes where care delivery was inconsistent with selected recommendations of a clinical practice guideline (CPG) on fever and neutropenia (FN) management. The influence of site size on CPG-inconsistent care delivery, and association between patient outcomes and CPG-inconsistent care were described. METHODS: This retrospective, multicenter study included patients less than 21 years old with cancer who were at high risk of poor FN outcomes and were previously enrolled to a Children's Oncology Group (COG) study at participating National Cancer Institute Community Oncology Research Program (NCORP) institutions from January 2014 through December 2015. Patients were randomly selected for chart review by participating sites from a COG-generated list. Care delivered in each episode was adjudicated (CPG-consistent or CPG-inconsistent) against each of five selected recommendations. RESULTS: A total of 107 patients from 22 sites, representing 157 FN episodes, were included. The most common CPG-inconsistent care delivered was omission of pulmonary computerized tomography in patients with persistent FN (60.3%). Of 74 episodes where assessment of four (episodes without persistent FN) or five (episodes with persistent FN) recommendations was possible, CPG-inconsistent care was delivered with respect to at least one recommendation in 63 (85%) episodes. Site size was not associated with CPG-inconsistent care delivery. No statistically significant association between CPG-inconsistent care and fever recurrence was observed. CONCLUSIONS: In this cohort of pediatric patients at high risk of poor FN outcomes, CPG-inconsistent care was common. Opportunities to optimize resource stewardship by boosting supportive care CPG implementation are highlighted.

The promise of novel treatments for severe chronic neutropenia.

INTRODUCTION: Severe chronic neutropenia, i.e. absolute neutrophil count (ANC) less than 0.5 × 109/L, is a serious health problem because it predisposes patients to recurrent bacterial infections. Management radically changed with the discovery that granulocyte colony-stimulating factor (G-CSF) could be used to effectively treat most patients; therapy required regular subcutaneous injections. In the early days of G-CSF therapy, there were concerns that it might somehow overstimulate the bone marrow and cause myelodysplasia (MDS) or acute myeloid leukemia (AML). Detailed research records from the Severe Chronic Neutropenia International Registry (SCNIR) indicate that this is a relatively low-risk event. The research records suggest that certain patient groups are primarily at risk. Presently, allogeneic hematopoietic stem cell therapy serves as an alternate form of therapy. AREAS COVERED: Due to these concerns and the desire for an easy-to-take oral alternative, several new treatments are under investigation. These treatments include neutrophil elastase inhibitors, SGLT-2 inhibitors, mavorixafor - an oral CXCR4 inhibitor, gene therapy, and gene editing. EXPERT OPINION: All of these alternatives to G-CSF are promising. The risks, relative benefits, and costs are yet to be determined.

Neutropenia: A Brief Review.

Neutropenia is one of the most common abnormalities on complete blood count encountered in pediatric clinical practice. It causes anxiety in the pediatric clinician as well as in the patient and their family. Neutropenia can be inherited or acquired. Acquired neutropenia is much more common than inherited neutropenia. Acquired neutropenia self-resolves after the offending cause is removed, and therefore, most acquired neutropenia can be managed by primary care physicians, unless they are associated with severe infections. In contrast, inherited neutropenia needs to be managed in collaboration with the hematologist. [Pediatr Ann. 2023;52(6):e238-e241.].

Child and family perceptions of satisfaction with neutropenia management in pediatric acute myeloid leukemia.

PURPOSE: Chemotherapy for pediatric acute myeloid leukemia (AML) is very intensive and many, but not all centers, require extended hospitalization until neutrophil recovery. Child and family preferences, beliefs, and experiences around hospitalization have not been systematically assessed. PATIENTS AND METHODS: We recruited children with AML and their parents from nine pediatric cancer centers across the United States for a qualitative interview about their experiences of neutropenia management. Interviews were analyzed using a conventional content analysis approach. RESULTS: Of 116 eligible individuals, 86 (74.1%) agreed to participate. Interviews were conducted with 32 children and 54 parents from 57 families. Of these 57 families, 39 were cared for as inpatients and 18 were managed as outpatients. A very high proportion of respondents in both groups reported satisfaction with the discharge management strategy recommended by the treating institution: 86% (57 individuals) of respondents who experienced inpatient management and 85% (17 individuals) of respondents who experienced outpatient management expressed satisfaction. Respondent perceptions associated with satisfaction related to safety (access to emergency interventions, infection risk, close monitoring) and psychosocial concerns (family separation, low morale, social support). Respondents believed it could not be assumed that all children would have the same experience due to varied life circumstances. CONCLUSION: Children with AML and their parents express a very high degree of satisfaction with the discharge strategy recommended by their treating institution. Respondents saw a nuanced tradeoff between patient safety and psychosocial concerns that was mediated by a child's life circumstances.

USB1 is a miRNA deadenylase that regulates hematopoietic development.

Mutations in the 3' to 5' RNA exonuclease USB1 cause hematopoietic failure in poikiloderma with neutropenia (PN). Although USB1 is known to regulate U6 small nuclear RNA maturation, the molecular mechanism underlying PN remains undetermined, as pre-mRNA splicing is unaffected in patients. We generated human embryonic stem cells harboring the PN-associated mutation c.531_delA in USB1 and show that this mutation impairs human hematopoiesis. Dysregulated microRNA (miRNA) levels in USB1 mutants during blood development contribute to hematopoietic failure, because of a failure to remove 3'-end adenylated tails added by PAPD5/7. Modulation of miRNA 3'-end adenylation through genetic or chemical inhibition of PAPD5/7 rescues hematopoiesis in USB1 mutants. This work shows that USB1 acts as a miRNA deadenylase and suggests PAPD5/7 inhibition as a potential therapy for PN.

The essentials of acute oncology.

The general medical physician will often encounter patients who develop acute complications of their cancer diagnosis or anti-cancer treatment. Here we provide an overview of emergency solid tumour oncology to guide the initial management of these patients.

How are granulocytes for transfusion best used? The past, the present and the future.

Granulocyte transfusions continue to be used in clinical practice, predominantly for treatment of refractory infection in the setting of severe neutropenia. There is biological plausibility for effectiveness in these patients with deficiencies of neutrophils, either as a consequence of disease or treatment. However, there is a chequered history of conducting and completing interventional trials to define optimal use, and many uncertainties remain regarding schedule and dose. Practice and clinical studies are severely limited by the short shelf life and viability of current products, which often restricts the timely access to granulocyte transfusions. In the future, methods are needed to optimise donor-derived granulocyte products. Options include use of manufactured neutrophils, expanded and engineered from stem cells. Further possibilities include manipulation of neutrophils to enhance their function and/or longevity. Granulocyte transfusions contain a heterogeneous mix of cells, and there is additional interest in how these transfusions may have immunomodulatory effects, including for potential uses as adjuncts for anti-cancer effects.

How I manage inpatient consultations for quantitative neutrophil abnormalities in adults.

Neutrophilia and neutropenia commonly lead to inpatient hematology consultation. Quantitative neutrophil abnormalities have a broad differential and include diagnoses that are important to recognize because they may be associated with increased mortality. Neutrophilia can reflect etiologies such as infection, medications, inflammation, splenectomy, and congenital disorders. Neutropenia can arise from infection, medications, autoimmune destruction, sequestration, nutritional deficiency, malignancy, and congenital neutropenia syndromes. In the evaluation of all abnormalities of neutrophil number, the timing of the change, and the patient's historical neutrophil count are crucial.

Neutropenia in Preterm Infants.

BACKGROUND: The non-specific and antigen-specific components of host defense mechanisms are subject to the adaptation process in the neonate; however, the neutrophil quantitative and qualitative deficiency is one of the most significant causative factors of neonatal-increased vulnerability to infection. OBJECTIVE: To review the incidence and outcome of neutropenia of unknown cause in preterm infants. RESULTS: The incidence of early and late-onset idiopathic neutropenia of prematurity is significant. CONCLUSION: The low neutrophil counts respond quickly to G-CSF treatment; however, due to the low probability of septic complications, particularly in the late-onset neutropenia, a deep diagnostic approach and the potential hematopoietic growth factor treatment should be limited to the severe cases, such as a neutrophil count <500/µL, lasting for more than 2 days.

Diagnosis and management of isolated neutropenia: A survey of pediatric hematologist oncologists.

BACKGROUND: Isolated neutropenia is a common referral to pediatric hematology oncology (PHO) physicians. There are no established consensus guidelines in the diagnosis and management of patients with isolated, asymptomatic, and incidentally discovered neutropenia. METHODS: A survey was distributed to PHO physicians on the American Society of Pediatric Hematology Oncology member discussion page to determine the common diagnostic and management decisions regarding patients with isolated neutropenia and to explore beliefs regarding the term "benign ethnic neutropenia." RESULTS: One hundred twenty-six PHO attending physicians completed the survey. The most common tests reportedly ordered for this patient population included complete blood cell count (CBC) (98%), peripheral smear (75%), antineutrophil antibody testing (29%), and immunoglobulins (24%). Providers were more likely to order an antineutrophil antibody in toddlers (p = .0085), and antinuclear antibody (ANA) panels in adolescents (p < .001). Half of providers do not request additional CBCs prior to their initial consultation, and most suggest referring patients with mild neutropenia after confirming a declining absolute neutrophil count (ANC) (51%). The three most important factors influencing ongoing follow-up included: history of recurrent/severe infections (98%), family history of blood disorders (98%), and more severe/progressively worsening neutropenia (97%). Seventy percent of respondents have diagnosed patients with "benign ethnic neutropenia," and 75% support replacement of the term to "typical neutrophil count with Fy(a-/b-) status," if confirmed with red cell phenotyping. CONCLUSION: We identified practice patterns of PHO physicians for the diagnosis and management of patients referred for asymptomatic and isolated neutropenia. These data provide the framework to conduct cost-effectiveness studies.

Genetics of severe congenital neutropenia as a gateway to personalized therapy.

Severe congenital neutropenias (SCNs) are rare diseases, and to date about 30 subtypes have been described according to their genetic causes. Standard care aims to prevent infections and limit the risk of leukemic transformation; however, several subtypes may have additional organ dysfunction(s), requiring specialized care. Granulocyte colony-stimulating factor and hematopoietic stem cell transplantation are now the bedrock of standard care. Better understanding of SCN mechanisms now offers the possibility of adapted therapy for some entities. An inhibitor of sodium glucose cotransporter, an antidiabetic drug, may attenuate glycogen storage disease type Ib and glucose-6-phosphatase catalytic subunit 3 neutropenias by clearing 1,5-anhydroglucitol, the precursor of the phosphate ester responsible for these SCNs. Chemokine receptor CXCR4 inhibitors contribute to reversing the leukocyte defect in warts, hypoglobulinemia, infections, and myelokathexis syndrome. All these new approaches use oral drugs, which notably improve quality of life. Additionally, improved research into clonal evolution has highlighted some ways to potentially prevent leukemia, such as stimulating somatic genetic rescue, a physiological process that might limit the risk of leukemic transformation.

Invasive Pulmonary Aspergillosis Successfully Treated with Granulocyte Transfusions Followed by Hematopoietic Stem Cell Transplantation in a Patient with Severe Childhood Aplastic Anemia.

Granulocyte transfusions (GTX) have been used in patients with neutropenia or neutropenia associated with invasive fungal infection. An 11-year-old girl with severe aplastic anemia (SAA) received immunosuppressive therapy (IST) with rabbit antithymocyte globulin, cyclosporine, and granulocyte colony-stimulating factor. However, IST was not effective and her condition became complicated with life-threatening invasive pulmonary aspergillosis. Owing to the necessity for early neutrophil recovery to resolve the infection, GTX were performed, followed by bone marrow transplantation (BMT) from her mother with human leukocyte antigen-B locus mismatch. Her dyspnea improved and she eventually became afebrile after the initiation of GTX. Despite engraftment failure following BMT, successful engraftment was achieved by salvage therapy with peripheral blood stem cell transplantation. Chest computed tomography scan obtained 4 months after BMT revealed marked improvement in pneumonia. The current case illustrates that GTX may be useful in controlling invasive fungal infections before hematopoietic stem cell transplantation in patients with SAA.

New approaches to management of fever and neutropenia in high-risk patients.

PURPOSE OF REVIEW: Patients receiving treatment for acute leukaemia and haematopoietic cell transplantation (HCT) have prolonged neutropenia and are at high risk of neutropenic fever, with bacterial and particularly invasive fungal infections as feared complications, possessing potentially serious consequences including intensive care admission and mortality. Concerns for these serious complications often lead to long durations of broad-spectrum antimicrobial therapy and escalation to even broader therapy if fever persists. Further, the default approach is to continue neutropenic fever therapy until count recovery, leaving many patients who have long defervesced on prolonged antibiotics. RECENT FINDINGS: This article details recent progress in this field with particular emphasis on early discontinuation studies in resolved neutropenic fever and improved imaging techniques for the investigation of those with persistent neutropenic fever. Recent randomized controlled trials have shown that early cessation of empiric neutropenic fever therapy is well tolerated in acute leukaemia and autologous HCT patients who are clinically stable and afebrile for 72 h. Delineation of the best approach to cessation (timing and/or use of fluoroquinolone prophylaxis) and whether this approach is well tolerated in the higher risk allogeneic HCT setting is still required. Recent RCT data demonstrate utility of FDG-PET/CT to guide management and rationalize antimicrobial therapy in high-risk patient groups with persistent neutropenic fever. SUMMARY: Acute leukaemic and autologous HCT patients with resolved neutropenic fever prior to count recovery can have empiric therapy safely discontinued or de-escalated. There is an emerging role of FDG-PET/CT to support decision-making about antibiotic and antifungal use in high-risk persistent/recurrent neutropenic fever patients.

Transfusable neutrophil progenitors as cellular therapy for the prevention of invasive fungal infections.

The use of mature neutrophil (granulocyte) transfusions for the treatment of neutropenic patients with invasive fungal infections (IFIs) has been the focus of multiple clinical trials. Despite these efforts, the transfusion of mature neutrophils has resulted in limited clinical benefit, likely owing to problems of insufficient numbers and the very short lifespan of these donor cells. In this report, we employed a system of conditionally immortalized murine neutrophil progenitors that are capable of continuous expansion, allowing for the generation of unlimited numbers of homogenous granulocyte-macrophage progenitors (GMPs). These GMPs were assayed in vivo to demonstrate their effect on survival in 2 models of IFI: candidemia and pulmonary aspergillosis. Mature neutrophils derived from GMPs executed all cardinal functions of neutrophils. Transfused GMPs homed to the bone marrow and spleen, where they completed normal differentiation to mature neutrophils. These neutrophils were capable of homing and extravasation in response to inflammatory stimuli using a sterile peritoneal challenge model. Furthermore, conditionally immortalized GMP transfusions significantly improved survival in models of candidemia and pulmonary aspergillosis. These data confirm the therapeutic benefit of prophylactic GMP transfusions in the setting of neutropenia and encourage development of progenitor cellular therapies for the management of fungal disease in high-risk patients.

Adult Evans' Syndrome.

Evans syndrome (ES) is a rare immune disorder defined as the simultaneous or sequential occurrence in a single patient of immune thrombocytopenia (ITP) and warm autoimmune hemolytic anemia (wAIHA) ± autoimmune neutropenia (AIN). ES represents approximately 5% to 10% of all wAIHA and 2%-5% of all ITP cases in adults and its mortality rate is high. When ITP and wAIHA occurred concomitantly, other differential diagnoses must be ruled out. ES can be primary or secondary and isolated or associated with another underlying disorder and secondary ES. The management of ES is mostly empirical with a low level of evidence. This review reports some new insights on this rare disease and provides some practical tools for the diagnosis and management of adult ES.

Diagnosis and management of neutropenia in children: The approach of the Study Group on Neutropenia and Marrow Failure Syndromes of the Pediatric Italian Hemato-Oncology Association (Associazione Italiana Emato-Oncologia Pediatrica - AIEOP).

Neutropenia refers to a group of diseases characterized by a reduction in neutrophil levels below the recommended age threshold. The present study aimed to review the diagnosis and management of neutropenia, including a diagnostic toolkit and candidate underlying genes. This study also aimed to review the progress toward the definition of autoimmune and idiopathic neutropenia rising in infancy or in late childhood but without remission, and provide suggestions for efficient diagnostics, including indications for the bone marrow and genetic testing. The management and treatment protocols for common and unique presentations are also reviewed, providing evidence tailored to a single patient.