Granulocyte transfusions in severe aplastic anemia.

Patients with severe aplastic anemia (SAA) are at high risk for morbidity and mortality due to severe infections. We aimed to characterize the role of granulocyte transfusion (GT) in SAA. Primary outcomes were survival from first GT, including overall survival (OS) at last follow up, survival to discharge, and receipt of HSCT. Secondary outcomes included evaluation of clinical response at 7 and 30 days after GT initiation based on a clinical scoring system incorporating microbiological and radiographic response. Twenty-eight SAA patients underwent 30 GT courses with a per-dose median of 1.28 x 109 granulocyte cells/kilogram (range 0.45-4.52 x 109). OS from initial GT to median last follow up (551 days) was 50%, with 39% (11/28) alive at last follow up. Sixty-four percent (18/28) of all patients survived to hospital discharge. Patients with complete, partial, or stable response at 30 days had significantly improved OS compared to non-responders (p=0.0004). Eighty-six percent (18/21) of patients awaiting HSCT during GT underwent transplant and 62% (13/21) survived to post-HSCT discharge. Sex, type of infection, or percentage of days with absolute neutrophil count > 0.2x109/L during GT course were not predictive of survival (p=0.52, p=0.7, p=0.28). Nine of 28 (32%) patients developed new or increased human leukocyte antigen (HLA) alloimmunization during their GT course. GTs in SAA may impact survival in those with improvement or stabilization of their underlying infection. Alloimmunization can occur and OS in this population remains poor, but GTs may be a useful tool to bridge patients to curative treatment with HSCT.

Clinical Impact of a Standardized Risk-Stratified Thromboprophylaxis Protocol for Multisystem Inflammatory Syndrome in Children.

OBJECTIVE: To evaluate the clinical impact of an institutional thromboprophylaxis protocol in patients with multisystem inflammatory syndrome in children (MIS-C), who are at increased risk for thromboembolism (TE). STUDY DESIGN: We conducted a single-center retrospective cohort study of children less than 18 years between March 2020 and December 2021. Eligible patients were confirmed with MIS-C and were managed with a standardized multidisciplinary treatment approach that included a thromboprophylaxis protocol to guide and unify clinical practice. For high-risk patients, prophylactic dose enoxaparin (target anti-Factor Xa 0.1-0.3 U/mL) was added. In high-risk patients with TE risk factors persistent at hospital discharge, thromboprophylaxis was prescribed for an additional 30 days. RESULTS: Of 135 patients with MIS-C, 124 (92%) required intensive care unit stay and 64 (47%) required a central venous catheter for a median duration of 5 days (IQR, 4-7). Prophylactic dose enoxaparin was initiated in 116 out of 121 patients (96%) deemed high-risk per our protocol at a median of 1 day after admission [IQR, 0-3] achieving target levels at a median of 1 day [IQR, 1-2]. The median initial anti-Factor Xa level was 0.13 u/mL [IQR, 0.05-0.19]. One patient (0.7%) developed symptomatic noncatheter related superficial vein thrombosis requiring therapeutic anticoagulation. Thromboprophylaxis was extended for 30 days after discharge in 108 out of 135 patients (80%). Bleeding events occurred in 5 patients during hospitalization (4.2%). All bleeding events were clinically relevant nonmajor bleeding. There were no deaths. CONCLUSIONS: Implementation of an institutional standardized thromboprophylaxis protocol in MIS-C was feasible and led to timely initiation of prophylactic anticoagulation and low rates of TEs and bleeding complications.

GATA2 Deficiency: Predisposition to Myeloid Malignancy and Hematopoietic Cell Transplantation.

PURPOSE OF REVIEW: GATA2 deficiency is a haploinsufficiency syndrome associated with a wide spectrum of disease, including severe monocytopenia and B and NK lymphopenia, predisposition to myeloid malignancies, human papillomavirus infections, and infections with opportunistic organisms, particularly nontuberculous mycobacteria, herpes virus, and certain fungi. GATA2 mutations have variable penetrance and expressivity with imperfect genotype-phenotype correlations. However, approximately 75% of patients will develop a myeloid neoplasm at some point. Allogeneic hematopoietic cell transplantation (HCT) is the only currently available curative therapy. Here, we review the clinical manifestations of GATA2 deficiency, characterization of the hematologic abnormalities and progression to myeloid malignancy, and current HCT practices and outcomes. RECENT FINDINGS: Cytogenetic abnormalities are common with high rates of trisomy 8, monosomy 7, and unbalanced translocation der(1;7) and may suggest an underlying GATA2 deficiency in patients presenting with myelodysplastic syndrome (MDS). Mutations in ASXL1 and STAG2 are the most frequently encountered somatic mutations and are associated with lower survival probability. A recent report of 59 patients with GATA2 deficiency who underwent allogenic HCT with myeloablative, busulfan-based conditioning and post-transplant cyclophosphamide reported excellent overall and event-free survival of 85% and 82% with reversal of disease phenotype and low rates of graft versus host disease. Allogeneic HCT with myeloablative conditioning results in disease correction and should be considered for patients with a history of recurrent, disfiguring and/or severe infections, organ dysfunction, MDS with cytogenetic abnormalities, high-risk somatic mutations or transfusion dependence, or myeloid progression. Improved genotype/phenotype correlations are needed to allow for greater predictive capabilities.

Clinical outcomes and immune responses to SARS-CoV-2 vaccination in severe aplastic anaemia.

Patients with severe aplastic anaemia (SAA) are often not vaccinated against viruses due to concerns of ineffective protective antibody response and potential for pathogenic global immune system activation, leading to relapse. We evaluated the impact of COVID-19 vaccination on haematological indices and disease status and characterized the humoural and cellular responses to vaccination in 50 SAA patients, who were previously treated with immunosuppressive therapy (IST). There was no significant difference in haemoglobin (p = 0.52), platelet count (p = 0.67), absolute lymphocyte (p = 0.42) and neutrophil (p = 0.98) counts prior to and after completion of vaccination series. Relapse after vaccination, defined as a progressive decline in counts requiring treatment, occurred in three patients (6%). Humoural response was detectable in 90% (28/31) of cases by reduction in an in-vitro Angiotensin II Converting Enzyme (ACE2) binding and neutralization assay, even in patients receiving ciclosporin (10/11, 90.1%). Comparison of spike-specific T-cell responses in 27 SAA patients and 10 control subjects revealed qualitatively similar CD4+ Th1-dominant responses to vaccination. There was no difference in CD4+ (p = 0.77) or CD8+ (p = 0.74) T-cell responses between patients on or off ciclosporin therapy at the time of vaccination. Our data highlight appropriate humoural and cellular responses in SAA previously treated with IST and true relapse after vaccination is rare.