S106: LONG-TERM FOLLOW-UP OF BETA-THALASSEMIA PATIENTS TREATED WITH HEMATOPOIETIC STEM CELL GENE THERAPY
Sarah MarktelSamantha ScaramuzzaFabio GiglioMaria Pia CicaleseMaria Rosa LidonniciClaudia RossiValeria CalbiNicoletta MaseraEmanuela D’AngeloN. MirraRaffaella OrigaImmacolata TartaglioneSilverio PerrottaGianluca ViarengoLuca SantoleriRaffaella MilaniSalvatore GattilloAndrea CalabriaEugenio MontiniGiovanna GraziadeiLuigi NaldiniMaria Domenica CappelliniAlessandro AiutiFabio CiceriGiuliana Ferrari
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Background: Transfusion-dependent ß-thalassemia (TDT) is a disorder due to mutations in the gene encoding the ß-globin chain causing a reduced or absent production of haemoglobin A leading to severe anaemia and lifelong transfusion dependence. Gene therapy has now been accepted as a possible alternative cure to allogeneic bone marrow (BM) transplantation. Aims: We developed a gene therapy approach based on autologous mobilized hematopoietic stem cell transduced by lentiviral vector, expressing human ß-globin gene, administered by intrabone injection, following a myeloablative conditioning (NCT02453477). Methods and Results: Nine patients with severe TDT with different genotypes have been treated with a drug product with a median cell dose of 19.5x106 CD34+ cells/kg, a transduction efficiency from 38 to 77% and a median vector copy number/genome (VCN) in bulk CD34+ cells of 0.9 (range: 0.7–1.5). Overall, gene therapy was generally well-tolerated with no adverse events related to the investigational product. No severe infectious-related adverse events were reported, except for those related to neutropenia as expected after myeloablative conditioning. Polyclonal vector integrations profiles with no evidence of clonal dominance have been detected in all patients with the expected genomic distribution for lentiviral vectors. Clinical outcome showed a reduction of transfusion requirement both in frequency and volume in adult patients up to more than 50%. Among the pediatric patients, 4 out of 6 discontinued transfusions shortly after gene therapy and are transfusion-independent at the last follow-up (up to 75 months). A robust and persistent engraftment was observed in 7 out of 9 patients, with a marking of BM progenitors that, in engrafted patients, ranged between 25.3 and 79.8% and with a median VCN in CD34+ cells of 0.53 (range: 0.34–2.21). As a relevant target for transgene expression, BM erythroid cells were stably marked (VCN range 0.3 - 2.5). Summary and Conclusions: A longer follow-up will provide further results on long-term clinical efficacy and safety of this approach. References 1. Marktel et al, Nat Med 2019; 25(2):234Keywords:
Hematopoietic stem cell
Detection of neutropenia depends on the white cell count and the differential count, both of which involve considerable error. Pathogenetically, neutropenia can be attributed one of the following mechanisms: insufficient (or inefficient) formation, enhanced destruction or utilization, or--rarely--shift to the marginal pool. Isolated neutropenia should be distinguished from neutropenia combined with anemia and/or thrombocytopenia. The latter is usually due to bone marrow failure, whereas the former depends on peripheral mechanisms. Drug induced neutropenia may appear either as unforeseen acute agranulocytosis (aminophenazone type), depending on preceding sensitization, or as a slowly developing, dose-dependent cytopenia. Gradually developing neutropenia is an early stage of a general disease (collagen diseases, leukemia and other neoplasias, infections).
Cytopenia
Leukopenia
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Objective:To investigate the prevalence, genotype and clinic characterization of childrenαβ-thalassemia in Guangdong province. Methods:The DNA samples of 286β-thalassemias diagnosed by reverse dot blot (RDB ) were analyzed by Gap-PCR for α-thalassemia 1 gene and α-thalassemia 2 gene.Results:Of 286 β-thalassemias, 25 were detected to be combined with α-thalassemia, among which 14 were detected to be combined withα-thalassemia 1 gene and 10 were detected to be combined with α-thalassemia 2 gene. 18 cases of β-thalassemia minor were detected to be combined with α-thalassemia, 7 cases of β-thalassemia major were detected to be combined with α-thalassemia. The prevalences were 8.74%, 4.89%, 3.85%, 8.74% and 8.75%, respetively. β-thalassemia major accounted for 28.0 % in 25 cases of childrenαβ-thalassemia. The children of β-thalassemia minor combined withα-thalassemia had no remarkable clinic characterization. The chidren of β-thalassemia major combined with α-thalassemia had obvious clinic characterization such as anaemia and splenohepatomegalia and were detected to be β-thalassemia intermedius type. Conclusion: The prevalence of αβ-thalassemia in Guangdong province is relatively frequent. The genotypes of αβ-thalassemia are associated with the phenotypes. It is very important to investigate the genotype of αβ-thalassemia for guiding the nursing, health care, therapy, marriage and procreation of thalassemia children.
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Abstract Neutropenia is a decrease in the number of neutrophilic leucocytes in the blood. Neutropenia is defined as an absolute neutrophil count or ANC (total white blood cells per litre multiplied by the percentage of neutrophils) more than two standard deviations below the normal mean. The ANC is usually more than 2.0 × 10 9 L −1 . Neutropenia is graded as mild, moderate or severe; severe is less than 0.5 × 10 9 L −1 . Severe neutropenia predisposes to a high risk of bacterial and fungal infections. Neutropenia occurs both as an acquired and as an inherited disorder. Drugs and autoimmune diseases are the common causes of acquired neutropenia. There are many hereditary causes of neutropenia; all of these are rare conditions, but some are quite severe. Proper treatment depends on understanding the cause of neutropenia and its expected duration. Short periods of neutropenia can be managed with careful observation or antibiotics. Patients with severe chronic neutropenia benefit from long‐term treatment with granulocyte colony‐stimulating factor (G‐CSF). Key Concepts Neutrophils are critical for normal defence from infections by bacteria on body surfaces. Blood neutrophil levels below normal, that is, neutropenia, predispose to bacterial and fungal infections. The bone marrow produces neutrophils from haematopoietic stem cells through an orderly process that takes about 10–14 days. Neutropenia is usually due to acquired or intrinsic/hereditary disorders affecting bone marrow production of these cells. When neutrophil production is interrupted by drugs or diseases recovery often takes several days. The risk of infection in patients with neutropenia depends on the severity of neutropenia and its duration. With a brief period, that is, 1–3 days, the risk is relatively low. Severe neutropenia lasting longer is associated with a steadily increasing risk of severe infection and even death. Proper management of neutropenia requires understanding its cause and the expected duration of neutropenia. When it is due to drugs, either cancer chemotherapy or as an idiosyncratic reaction to other drugs, the duration is usually relatively brief and can be managed with observation or antibiotics. Neutropenia lasting more than about 5–7 days and more chronic neutropenia predispose patients to a much higher risk of bacterial and fungal infections. These patients benefit from treatment with granulocyte colony‐stimulating factor (G‐CSF). It is now possible to identify the genetic cause for severe chronic neutropenia in many patients through deoxyribonucleic acid (DNA) sequencing studies. Understanding of the molecular and cellular basis for these disorders is growing rapidly.
Congenital Neutropenia
Absolute neutrophil count
Leukopenia
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Not uncommonly, during the course of a workup for fever, the pediatrician will find that a patient has neutropenia. Neutropenia is defined as an absolute decrease in the number of circulating neutrophils in the blood. The lower limit for normal neutrophil counts is 1000/mm3 in infants between 2 weeks and 1 year of age; after infancy the corresponding value is 1500/mm3. Blacks have lower neutrophil counts, and the lower limit is 100 to 200/mm3 less than those cited for whites. These lower counts probably reflect a relative decrease in the storage pool of the bone marrow. CLASSIFICATION OF NEUTROPENIA Neutropenia can be classified as mild (neutrophil counts of 1000 to 1500/mm3), moderate (neutrophil counts of 500 to 1000/mm3), or severe (neutrophil counts less than 200/mm3). This stratification is useful in predicting risk of infection, but it provides no etiologic information. On the other hand, it is useful to classify patients as having an abnormality either in production or in destruction of neutrophils, because each of these processes is now frequently amenable to distinct therapies if needed. Susceptibility to bacterial infection, even in the face of severe neutropenia, is variable. Most patients with chronic neutropenia do not experience as many serious infections as those patients receiving cancer chemotherapy or those infected with human immunodeficiency virus who develop comparable degrees of neutropenia.
Absolute neutrophil count
Abnormality
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Heterozygote advantage
Beta thalassemia
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Wiskott-Aldrich syndrome (WAS), an X-linked primary immunodeficiency disease (PID) with unique and characteristic features, had been considered to be a good candidate for gene therapy. In 2010, hematopoietic stem cell (HSC) gene therapy, using a retroviral vector, was performed for WAS patients; however, concerns remain regarding the long-term safety of this therapy as several patients with PID developed myeloproliferative diseases due to insertional mutagenesis related to HSC gene therapy using retroviral vectors. Aiuti et al. first reported HSC gene therapy for WAS using a lentiviral vector and compared the safety and efficacy of the two therapies in the context of the same disease background. They undertook a detailed study of the vector integration sites and concluded that lentiviral HSC gene therapy was safer than retroviral gene therapy.
Hematopoietic stem cell
Wiskott–Aldrich syndrome
Primary Immunodeficiency
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Background: Benign (ethnic) neutropenia (BN) is an inherited condition, common in many parts of the world, and often undiagnosed. It should be differentiated from other types of neutropenia which increase the risk of infections.
Objective: We aimed to ascertain the frequency of neutropenia in patients from a population (citizens of the United Arab Emirates) with a known high frequency of BN (10.7%) to assess how often clinicians might be compelled to differentiate benign neutropenia from other types of neutropenia.
Methodology: Study subjects were 27,392 Emirati inpatients and outpatients of all ages in a general hospital. They had 55,935 absolute neutrophil counts (ANC). Patients were defined to have neutropenia if the ANC was <1.5x109/L. The frequency of neutropenia was analyzed against several relevant variables.
Results: Among patients who had one test, the overall frequency of neutropenia (5.3%) was half that in a healthy population (10.7%) in earlier study (p < 0.0001). The prevalence of neutropenia was lower in hospitalized (3.5%, 132/3,769) than in non-hospitalized (9.2%, 510/5,570) patients (p<0.0001), where it was similar (p=0.13) to that in the general population (10.7%, 110/1032). While none of the 282 pregnant women at the time of delivery had neutropenia, it was most common among pediatric outpatients (15.1%, 75/497). Neutropenia was more frequent in patients who had more ANC determinations: one test, 5.3%; two tests, 7.8%; three and more tests, 12.4% (p<0.00001).
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Summary Neutropenia is linked to the development of invasive candidiasis/candidaemia, for which micafungin has demonstrated efficacy, but evidence in patients with neutropenia is limited. The aim of this study was to evaluate the efficacy of micafungin for the treatment of invasive candidiasis/candidaemia in patients with neutropenia (<500 neutrophils/μL) and without neutropenia. This pooled, post hoc analysis of 2 Phase 3 trials compared micafungin 100 mg/d (adults) and 2 mg/kg/d (paediatrics) with L‐AmB 3 mg/kg/d ( NCT 00106288) and micafungin 100 mg/d and 150 mg/d with caspofungin 70 mg/d followed by 50 mg/d (adults) ( NCT 00105144); treatment duration 2‐4 weeks (≤8 weeks for chronic disseminated candidiasis). Effects of neutropenia duration and Candida spp. on efficacy outcomes (treatment success, clinical and mycological response) were examined. Of 685 patients, 77 had neutropenia. The most common infection in patients with/without neutropenia was due to C. tropicalis (31/77) and C. albicans (295/608) respectively. Overall success was numerically lower in patients with vs without neutropenia (63.6% vs 72.9%). Clinical and mycological response was similar between groups. Neutropenia duration or Candida spp. did not impact micafungin's overall success rate. This analysis supports evidence that micafungin is effective against invasive candidiasis/candidaemia in patients with neutropenia, irrespective of neutropenia duration or Candida spp., although overall success may be lower than in patients without neutropenia.
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Objective:To investigate the prevalence and genotype distribution of α β-thalassemia by using molecular detection and haematological methods.Methods:396 cases with screening positive in thalassemia were given gene diagnosis of α-thalassemia and β-thalassemia by gap-PCR and reverse dot blot hybridization.Results:There were 109 cases of α-thalassemia,115 cases of β-thalassemia and 26 cases of α β-thalassemia,which is 18.44% of α β-thalassemia in β-thalassemia.There were 7 geneypes in α β-thalassemia,involving 5 β-thalassemia geneypes and 2 α-thalassemia geneypes.No significant differences were found between β-thalassemia and α β-thalassemia in some RBC parameters.Conclusion:The incidence of α β-thalassem is frequent.The hematological analysis can not give specificity for diagnosing α β-thalassemia.Patients with screening positive in β thalassemia should be given gene diagnosis of α and β thalassemia.It is more useful for genetic counselling and prenatal diagnosis of this disease.
Beta thalassemia
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A: Neutropenia is defined as a neutrophil count of less than 1,000 cells/mm3 (normal: 2,500 to 6,000 cells/mm3). Infection risk increases as the neutrophil count decreases. Less than 500 cells/mm3 is considered profound neutropenia; these patients have the highest risk of infection.Figure: Q: How do I best care for a patient with neutropenia?Neutropenia can be caused by either the lack of progenitor myeloid cell production in the bone marrow or the destruction of neutrophils elsewhere in the body. Blood disorders; tumors, such as acute leukemias, lymphomas, and aplastic anemia; and chemotherapy, radiation, and biotherapy agents are direct causes of neutropenia. Some medications, such as antiepileptics and antipsychotics, can also cause neutropenia. Medication-related neutropenia may resolve over time when the medication is discontinued or the dosage reduced. Neutropenia is an expected adverse reaction of cancer treatment and is usually reversible. However, treatment may be seriously compromised by profound neutropenia. If left untreated, the consequences of neutropenia can be sepsis, prolonged hospitalization, and even death from infection. Most patients recover neutrophil counts in a predictable way, either from cancer treatment discontinuation or from treatment of the disease that's causing the neutropenia. But the longer neutropenia lasts, the greater the risk of infection. For some patients, growth factors are an option to increase neutrophil counts and decrease the length of time they're especially vulnerable to infection. A patient with neutropenia may or may not have typical signs and symptoms of infection. Know which patients are at risk for neutropenia and assess and monitor them carefully. All wounds and catheters require careful monitoring because they're frequent sources of infection, but remain alert to subtle changes as well. Patients may complain of not feeling well, dizziness, increased fatigue, sore throat, difficulty swallowing, and urinary or bowel changes—all signs that can herald infection. Febrile neutropenia requires immediate action, so notify the healthcare provider at once. Be prepared for blood and urine cultures to be collected, and for empirical antibiotics to be started. A delay in treatment can increase the incidence of sepsis in neutropenic patients. Teach patients to: avoid exposure to sick individuals and those who've recently received live vaccines wash any fruits and vegetables carefully wash their hands often, especially before eating and after toileting immediately report a fever greater than 100.4° F (38° C) to their healthcare provider report headache, facial tenderness, sore throat, mouth sores, fatigue, or pain with or without fever report any symptoms of infection, such as tenderness, erythema, or discharge at any wound or I.V. site report any bowel or bladder changes or vaginal discharge or itching. Careful teaching will help protect patients both in the hospital and when they return home.
Absolute neutrophil count
Aplastic anemia
Leukopenia
Discontinuation
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