Efficacy, safety and cost of emicizumab prophylaxis in haemophilia A patients with inhibitors: A nationwide observational study in Taiwan.

INTRODUCTION: Emicizumab mimicking the cofactor function of activated factor VIII (FVIII) restores haemostasis. METHODS: This nationwide observational study aimed to retrospectively investigate efficacy, safety, and cost in 1 year before and up to 3 years after emicizumab prophylaxis for haemophilia A (HA) patients with FVIII inhibitors. RESULTS AND DISCUSSION: A total of 39 severe HA patients with a median age of 23.0 years were enrolled. The median historical peak FVIII inhibitor titre was 174.2 BU/mL with an interquartile range of 56.5-578.8 BU/mL. The median annualized bleeding rate reduced from 24 to 0 events in the first year after emicizumab prophylaxis (p < .01) and sustained in the second and third years. The median annualized joint bleeding rate reduced to 0 and maintained up to 3 years (p < .01). Twenty-seven patients (69.2%) had target joints before emicizumab prophylaxis and only seven patients (17.9%) of them had target joints after prophylaxis. Medical costs, including cost of haemostatic therapy, frequency of outpatient department visits, emergency room visits and hospital admission, were significantly reduced after emicizumab prophylaxis (p < .01). FVIII inhibitor titre decreased after emicizumab prophylaxis. Overall, three (7.7%) patients experienced 202 grade 1 drug-related adverse events after emicizumab prophylaxis. No serious adverse events were reported during emicizumab prophylaxis period. The adherence to emicizumab prophylaxis was 100% up to 3 years. CONCLUSIONS: HA patients with FVIII inhibitors treated with emicizumab prophylaxis resulted in a significant reduction in treated bleeds and associated costs. No new safety events were observed.

Lymphocyte disturbance and functional assessment of the [Asp521Asn] ZAP70 mutation.

Activated zeta-chain-associated protein kinase 70 (ZAP70) phosphorylates the TCRαß:CD3:zeta complex to diversify and amplify TCR signaling. Patients with ZAP70 mutations can present with phenotypes of immune dysregulation as well as infection. We identified the first Taiwanese boy with the [Asp521Asn] ZAP70 mutation who presented with recurrent pneumonia, inflammatory bowel disease-like diarrhea, transient hematuria and autoimmune hepatitis. He had isolated CD8 lymphopenia, eosinophilia, hypogammaglobulinemia, and impaired lymphocyte proliferation. Downstream CD3/CD28 signaling, phosphorylation of AKT, ZAP70 and Ca2+ influx were decreased in [Asp521Asn] ZAP70 lymphocytes. Immunophenotyping analysis revealed expansion of transitional B and CD21-low B cells, Th2-skewing T follicular helper cells, but lower Treg cells. The Asp521Asn-ZAP70 hindered TCR-CD3 downstream phosphorylation and disturbed lymphocyte subgroup "profiles" leading to autoimmunity/autoinflammation. Further large-scale studies are warranted to clarify this lymphocyte disturbance. The prognosis significantly depends on hematopoietic stem cell transplantation, but not the genotype, the presence of opportunistic infections or immune dysregulation.

Assessment of Platelet Activation and Immature Platelet Fraction as Predictors of Platelet Engraftment After Hematopoietic Stem Cell Transplantation.

Delayed platelet engraftment is a well-known complication of umbilical cord blood transplantation (CBT). Megakaryocytes derived from cord blood (CB) in vitro are smaller than megakaryocytes derived from bone marrow (BM) in adults. A small megakaryocyte size might contribute to delayed megakaryocytic maturation. This study included 37 patients undergoing hematopoietic stem cell transplantation (HSCT) at Chang Gung Children's Hospital between July 2011 and June 2013. Blood samples were obtained at different times: preconditioning and post-HSCT days 56 and 97. To test whether platelet activation persists posttransplantation, two commonly used platelet activation marker antibodies, CD62P (P-selectin) and CD42b, were evaluated using whole blood flow cytometry, combining thiazole orange and anti-CD41a staining, to assess reticulated platelets. Serial peripheral blood (PB) samples were obtained posttransplantation from patients undergoing CBT (CBT group; n = 15) and mobilized peripheral blood transplantation (PBT group; n = 22). Platelet activation in the postengraftment samples was considerably higher in the PBT group than the CBT group. Moreover, immature platelet fractions (IPF) were higher in the CBT group. Our results emphasize the role of IPF for dynamic prediction of platelet engraftment in CBT.

Clinical aspects, immunologic assessment, and genetic analysis in Taiwanese children with hemophagocytic lymphohistiocytosis.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by immune disturbance associated with certain genetic defects. This study aimed to define the clinical spectrum, immunology, and candidate genes in HLH in Taiwanese patients. PATIENTS AND METHODS: The medical records of children who met the updated diagnostic criteria and had confirmed hemophagocytosis by bone marrow aspiration between 1992 and 2007 were retrospectively evaluated. The clinical course and prognosis were analyzed. Quantitative immunoglobulin, lymphocyte subsets, cytotoxicity to K562 cells, intracellular natural killer perforin expression, and candidate genes including SH2D1A, PFR1, Mun13-4, and STX11 genes were also investigated. RESULTS: Thirty-two patients (16 male) were evaluated during the 15-year period. The underlying diseases were acute lymphoblastic leukemia, systemic lupus erythematosus, natural killer malignancy, juvenile idiopathic arthritis, and Chediak-Higashi syndrome. Epstein-Barr virus (EBV)-associated HLH was present in 12 patients, 6 of whom died, while 12 of 20 non-EBV-associated patients died despite aggressive polychemotherapy. Extreme immunoglobulin values occurred in 3 fatal cases. There was decreasing percentage of CD4, CD1656, and B-memory cells and increasing CD8, activated lymphocyte, and T-memory cells among the patients. Cytotoxicity in 14 patients and intracellular perforin expression in 13 were diminished but restored to borderline normal range during the convalescent stage. None of the mutations of SH2D1A, PFR1, Mun13-4, and STX11 genes were found. CONCLUSIONS: In the treatment of Taiwanese HLH patients, aggressive chemotherapy in EBV-associated patients and stem cell transplantation in non-EBV-associated patients are recommended to improve survival. Individualized immune dysregulation instead of the well-known candidate genetic mutations can explain the genetic variation in our cohort.