Novel use of a midline catheter for therapeutic and donor apheresis in children and adults.

BACKGROUND: Apheresis procedures require adequate vascular access to achieve optimal inlet flow rates. While central lines provide such access, their placement and use are associated with risks; some of these risks are minimized if peripheral intravenous access can be established. However, peripheral intravenous access is associated with challenges in the pediatric setting. Research indicates that midline catheters reduce the use of CVADs and their associated risks. The use of midline catheters for apheresis has been reported recently in adults, but no studies have been published on their use in children. Thus, the purpose of this study was to evaluate the use of midline catheters for apheresis in the pediatric setting. METHODS: A retrospective observational study was conducted to evaluate the safety and efficacy of midline catheters in subjects who underwent apheresis at a pediatric hospital from April 2018 to August 2020. Demographic data, clinical data (diagnosis, procedure, catheter size, body mass), and outcome data (inlet flow rate, total blood volume [TBV] processed, procedure time, and cell counts) were collected. RESULTS: Eighteen subjects received a total of 100 midline catheters for 73 apheresis procedures. Inlet flow rates ranged from 45 to 80 mL/min, TBV ranged from 2872 to 20 000 mL, and procedure time ranged from 1.25 to 7 hours. Inlet flow rates met or exceeded the recommended inlet flow rates for apheresis in children and adults (P < .0001). No adverse events occurred. CONCLUSION: Midline catheters provide safe and effective vascular access for apheresis. Future research should include younger patients with lower body mass.

Transfusion practices and complications in thalassemia.

BACKGROUND: The severe forms of thalassemia are the most common inherited anemias managed with regular blood transfusion therapy. Transfusion policies and complications are critical to quality of life and survival, but there is a lack of standardized care. STUDY DESIGN AND METHODS: A survey of 58 items was completed in 2016 by 11 centers in California, Washington, Oregon, Nevada, and Arizona providing long-term care for thalassemia. The questionnaire addressed demographic information, transfusion practices and complications, and educational needs. RESULTS: The centers followed 717 patients with ß-thalassemia (314, 43.8%) or α-thalassemia (394, 55%). One-third (34.7%) of patients were transfusion-dependent. Indications and goals of transfusion therapy differed between centers. Prestorage leukoreduction was universal, while routine irradiation of units was limited to one site. Red blood cell antigen phenotype was determined before the first transfusion and patients received Rh/Kell-matched units. However, more than half of the transfused patients had received blood at multiple hospitals within or outside the United States. Alloantibodies were seen in 16.9% of transfused group, but management of such patients was variable. Unusual or emerging transfusion-transmitted pathogens were not observed. Multiple educational needs were recognized, with iron overload as the biggest challenge; the approach to iron chelation varied within the group. CONCLUSION: This study identified many patients not included in earlier surveys limited to major national centers, suggesting that the thalassemia population in the United States is vastly underestimated. Lack of evidence-based guidelines is a barrier to optimal care, which should be addressed through regional consortia of thalassemia centers.

Unrelated Hematopoietic Cell Transplantation in a Patient with Combined Immunodeficiency with Granulomatous Disease and Autoimmunity Secondary to RAG Deficiency.

The use of HLA-identical hematopoietic stem cell transplantation (HSCT) demonstrates overall survival rates greater than 75 % for T-B-NK+ severe combined immunodeficiency secondary to pathogenic mutation of recombinase activating genes 1 and 2 (RAG1/2). Limited data exist regarding the use of HSCT in patients with hypomorphic RAG variants marked by greater preservation of RAG activity and associated phenotypes such as granulomatous disease in combination with autoimmunity. We describe a 17-year-old with combined immunodeficiency and immune dysregulation characterized by granulomatous lung disease and autoimmunity secondary to compound heterozygous RAG mutations. A myeloablative reduced toxicity HSCT was completed using an unrelated bone marrow donor. With the increasing cases of immune dysregulation being discovered with hypomorphic RAG variants, the use of HSCT may advance to the forefront of treatment. This case serves to discuss indications of HSCT, approaches to preparative therapy, and the potential complications in this growing cohort of patients with immune dysregulation and RAG deficiency.

Successful treatment of secondary graft failure following unrelated cord blood transplant with hematopoietic growth factors in a pediatric patient with Fanconi anemia.

Graft failure following allogeneic HCT in Fanconi anemia is associated with significant mortality. Retransplantation may be considered; however, the limited toxicity profile of HGFs also makes them an option for the treatment of graft failure. We describe a five-yr-old female diagnosed with Fanconi anemia and marrow failure treated with HCT. The course was complicated by secondary graft failure treated successfully with HGFs including G-CSF, EPO, and romiplostim. The outcome could be related to the intervention, but could also be the natural course of recovery, including recovering from a recent CMV infection treated with ganciclovir. We found the use of HGFs to be an effective and safe alternative to the potential complications as well as morbidity and mortality associated with the use of retransplantation.

Efficacy and safety of eculizumab in children and adolescents with paroxysmal nocturnal hemoglobinuria.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is rare in children, but represents a similarly serious and chronic condition as in adults. Children with PNH frequently experience complications of chronic hemolysis, recurrent thrombosis, marrow failure, serious infections, abdominal pain, chronic fatigue, and decreased quality of life with reduced survival. The terminal complement inhibitor eculizumab is proven to be effective and safe in adults and approved by the FDA for treatment of PNH. PROCEDURE: This 12-week, open-label, multi-center phase I/II study evaluated pharmacokinetics, pharmacodynamics, efficacy, and safety in seven children with PNH 11-17 years of age. Eculizumab was intravenously administered at 600 mg weekly for 4 weeks, 900 mg in week 5, and 900 mg every 2 weeks thereafter (http://clinicaltrials.gov NCT00867932). RESULTS: Eculizumab therapy resulted in complete and sustained inhibition of hemolysis in all participants with a reduction of lactate dehydrogenase to normal levels. All hematological parameters stabilized. No definitive, study drug-related adverse events were observed. Only one severe SAE of hospitalization due to aplastic anemia occurred, which was not study drug-related. CONCLUSION: Eculizumab appears to be a safe and effective therapy for children with PNH.

Successful cord blood transplantation in a patient with malignant infantile osteopetrosis and hemophilia.

MIOP is a congenital disorder of osteoclast differentiation or dysfunction. Inadequate bone resorption by osteoclasts results in a spectrum of complications including hypocalcemia, osteosclerosis, marrow failure, extramedullary hematopoiesis, hydrocephalus, visual deficits, and eventual mortality. Early diagnosis and timely HCT is a recommended treatment approach for select patients prior to the development of end-organ damage. A comorbid bleeding disorder presents a unique challenge in the setting of MIOP and cord blood HCT given the additional risk factors for bleeding including delayed engraftment, a high risk of developing sinusoidal obstruction syndrome, and potential need for emergent invasive procedures. To our knowledge, this is the first report of a patient with an autosomal recessive form of MIOP who successfully underwent a cord blood HCT complicated by the presence of mild hemophilia A and HCT-related complications including delayed engraftment, sinusoidal obstruction syndrome, and need for multiple invasive procedures (e.g., ventriculostomy, tracheostomy) without clinically significant bleeding. Given the underlying diagnosis of MIOP and need for HCT, the challenge of mitigating the significant risk of bleeding in a patient with a comorbid bleeding disorder is discussed.

Successful autologous cord blood transplantation in a child with acquired severe aplastic anemia.

Over 400 cases of pediatric SAA occur annually in the United States. A growing number of children with SAA may have had their stem cells harvested through cord blood collection. We describe a nine-yr-old male with SAA treated successfully with an autologous cord blood transplant following immunoablative chemotherapy. With the increasing number of people cryopreserving autologous cord blood, the use of autologous cord blood in the treatment of SAA might be considered as initial therapy. This case serves to discuss approaches to preparative therapy as well as the potential complications in this growing cohort of patients.

Unrelated hematopoietic stem cell transplantation in a patient with congenital dyserythropoietic anemia and iron overload.

CDA is a heterogeneous group of disorders that result in morphologically abnormal erythroid maturation and ineffective erythropoiesis. Curative therapy for CDA focuses on the use of HSCT using fully matched sibling donors. This is the first report of a Type II CDA patient with severe iron overload who was successfully treated with HSCT using a HLA-matched unrelated donor after aggressive chelation therapy. Given the challenges of HSCT in any patient with CDA and severe iron overload, the role of novel approaches to iron chelation and HSCT is discussed.

Inflammatory polyps following successful HLA-matched cord blood transplantation in a patient with X-linked lymphoproliferative syndrome.

Gastrointestinal complications following HSCT are numerous and include a variety of issues resulting in hepatic, biliary, pancreatic, and intestinal compromise. In the context of an underlying state of immune dysregulation, novel complications may arise including autoimmunity. To our knowledge, this is the first report of a patient with XLP who was successfully treated with HSCT using an HLA-matched unrelated cord blood unit that was complicated by the development of inflammatory polyps of the colon. Given the underlying diagnosis of XLP and its associated immune dysregulation, the challenge of understanding unique gastrointestinal manifestations of autoimmunity following HSCT is discussed.

Hemophilia - Impact of Recent Advances on Management.

There have been numerous advances in the field of hemophilia management in the past decade, including long acting factor products, non-factor products, and potentially curative interventions such as gene therapy. Each of these interventions introduces exciting treatment modalities to patients with both hemophilia A and B, however they also pose a daunting array of possible management options. Adverse reactions to novel agents are being reported as more patients are treated and long-term sustainability of interventions such as gene therapy is yet to be determined. The practicing hematologist should be aware of the intricacies involved in customizing care for their individual patients and be aware of the monitoring strategies for each interventional strategy to avoid adverse events. Upfront cost vs. long term benefit should be considered as choices of treatment strategies are made, especially in resource poor countries. The goal of the newer agents is to decrease annualized bleed rates and avoid debilitating arthropathy. This article looks at current treatment models for prophylaxis and management of inhibitors, reviews the recent advances in the field (with bioengineered factor products, non-factor products and gene therapy) and summarizes the incorporation of these new interventions in the treatment plan for patients with hemophilia.

Successful correction of the human Cooley's anemia beta-thalassemia major phenotype using a lentiviral vector flanked by the chicken hypersensitive site 4 chromatin insulator.

beta-Thalassemias are the most common single-gene disorders and are potentially amenable to gene therapy. While retroviral vectors carrying the human beta-globin cassette were notoriously unstable and expressed poorly, considerable progress has now been made using lentiviral vectors (LVs), which stably transmit the beta-globin expression cassette. Mouse studies using LVs have shown correction of the beta-thalassemia-intermedia phenotype and a partial, variable correction of the mouse beta-thalassemia major phenotype, despite the use of beta-globin-hypersensitive sites that are known to result in position-independent effects. Our group used the alpha-globin-hypersensitive site in self-inactivating (SIN) LVs with long-term expression in secondary mice that resisted methylation-associated proviral silencing. However, these vectors also suffered from chromatin position effects. We therefore flanked a SIN-lentiviral vector carrying the human beta-globin expression cassette with a chromatin insulator and studied expression in bone marrow from four patients with transfusion-dependent human thalassemia major. We demonstrated normal levels of human beta-globin expression in erythroid cells produced in in vitro cultures for unilineage erythroid differentiation. There was restoration of effective erythropoiesis and reversal of the abnormally elevated apoptosis that characterizes beta-thalassemia. The gene-corrected human beta-thalassemia progenitor cells were transplanted into immune-deficient mice, where they underwent normal erythroid differentiation, expressed normal levels of human beta-globin, and displayed normal effective erythropoiesis 3-4 months after xenotransplantation. Variability of beta-globin expression in erythroid colonies derived in vitro or from xenograft bone marrow was similar to that seen in normal control subjects. Results show genetic correction of primitive human progenitor cells and normalization of the human thalassemia major phenotype.

Gene therapy for hemoglobinopathies: are we there yet?

beta-Thalassemia and sickle cell disease constitute the most common single gene defect in humans and are characterized by absent/reduced and abnormal beta-globin, respectively. Patients with these hemoglobinopathies require chronic blood transfusions and rely on bone marrow transplant for a potential cure. Gene therapy provides a viable alternative by permanent correction of the defect in hematopoietic stem cells, but it has suffered from problems of vector instability, low viral titers, and variable expression of globin genes for more than a decade. This paper reviews the field of gene therapy for hemoglobinopathies with emphasis on the complexities of the beta-globin gene and its regulation, obstacles that have impeded progress, and recent advances in vector technology that will take this field forward toward the goal of successful genetic correction of these devastating diseases.

Successful correction of the human beta-thalassemia major phenotype using a lentiviral vector.

beta-thalassemias are the most common single gene disorders and are potentially amenable to gene therapy. However, retroviral vectors carrying the human beta-globin cassette have been notoriously unstable. Recently, considerable progress has been made using lentiviral vectors, which stably transmit the beta-globin expression cassette. Thus far, mouse studies have shown correction of the beta-thalassemia intermedia phenotype and a partial, variable correction of beta-thalassemia major phenotype. We tested a lentiviral vector carrying the human beta-globin expression cassette flanked by a chromatin insulator in transfusion-dependent human thalassemia major, where it would be ultimately relevant. We demonstrated that the vector expressed normal amounts of human beta-globin in erythroid cells produced in in vitro cultures for unilineage erythroid differentiation. There was restoration of effective erythropoiesis and reversal of the abnormally elevated apoptosis that characterizes beta-thalassemia. The gene-corrected human beta-thalassemia progenitor cells were transplanted into immune-deficient mice, where they underwent normal erythroid differentiation, expressed normal levels of human beta-globin, and displayed normal effective erythropoiesis 3 to 4 months after xenotransplantation. Variability of beta-globin expression in erythroid colonies derived in vitro or from xenograft bone marrow was similar to that seen in normal controls. Our results show genetic modification of primitive progenitor cells with correction of the human thalassemia major phenotype.