Haemophilia patients with inhibitors can develop bleeding episodes, which are refractory to monotherapy with either recombinant factor VIIa (rFVIIa) or activated prothrombin complex concentrates (APCC). Management of such bleeds is often difficult. We previously reported the safety of using a combination of rFVIIa and APCC given in sequential fashion. In this report, we update our experience with sequential therapy. A retrospective review of medical records was conducted including all reports of sequential therapy defined as receiving both rFVIIa and APCC within 6 h. Data extracted included demographic data, treatment prior to and following hospital admission, clinical data including type and location of bleed, response to therapy, physical examination and laboratory data. In addition, for some patients, thromboelastography was performed to document the effect of sequential therapy on clot formation characteristics. Four patients comprising 35 admissions, 209 hospital days and 115 days of sequential therapy were included in the updated dataset. No patient developed thrombosis or overt disseminated intravascular coagulation (DIC) although elevations in the D-dimer above 5 microg mL(-1) were noted in 42% of the courses that lasted >3 days. Efficacy is suggested by the fact that patients had resolution of their bleeds after a median of 3 days of sequential therapy after failing to respond to a median of 3 days of monotherapy. Thromboelastography demonstrated an additive effect. Sequential therapy is a safe, potentially efficacious approach in the management of refractory bleeding episodes in patients with haemophilia and inhibitors.

BACKGROUNDBetibeglogene autotemcel (beti-cel) gene therapy for transfusion-dependent β-thalassemia contains autologous CD34+ hematopoietic stem cells and progenitor cells transduced with the BB305 lentiviral vector encoding the β-globin (β A-T87Q ) gene. METHODSIn this open-label, phase 3 study, we evaluated the efficacy and safety of beti-cel in adult and pediatric patients with transfusion-dependent β-thalassemia and a non-β 0 /β 0 genotype. Patients underwent myeloablation with busulfan (with doses adjusted on the basis of pharmacokinetic analysis) and received beti-cel intravenously. The primary end point was transfusion independence (i.e., a weighted average hemoglobin level of ≥9 g per deciliter without red-cell transfusions for ≥12 months). RESULTSA total of 23 patients were enrolled and received treatment, with a median followup of 29.5 months (range, 13.0 to 48.2). Transfusion independence occurred in 20 of 22 patients who could be evaluated (91%), including 6 of 7 patients (86%) who were younger than 12 years of age. The average hemoglobin level during transfusion independence was 11.7 g per deciliter (range, 9.5 to 12.8). Twelve months after beti-cel infusion, the median level of gene therapy-derived adult hemoglobin (HbA) with a T87Q amino acid substitution (HbA T87Q ) was 8.7 g per deciliter (range, 5.2 to 10.6) in patients who had transfusion independence. The safety profile of beti-cel was consistent with that of busulfan-based myeloablation. Four patients had at least one adverse event that was considered by the investigators to be related or possibly related to beti-cel; all events were nonserious except for thrombocytopenia (in 1 patient). No cases of cancer were observed. CONCLUSIONSTreatment with beti-cel resulted in a sustained HbA T87Q level and a total hemoglobin level that was high enough to enable transfusion independence in most patients with a non-β 0 /β 0 genotype, including those younger than 12 years of age. (Funded by Bluebird Bio; HGB-207 ClinicalTrials.gov number, NCT02906202.

Patients with haemophilia and inhibitors have bleeding episodes that can be refractory to home therapy with either activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (rFVIIa). Sequential therapy with these products has not been widely used because of concern regarding the possibility of thrombosis. This report describes the results of a retrospective chart review of five hospitalized children with severe haemophilia and inhibitors who have been treated with sequential doses of APCC and rFVIIa for refractory bleeding. These patients all had failed home therapy with APCC and rFVIIa alone. A total of 20 admissions were documented covering 170 hospital days, including 91 days of combination therapy. While being closely monitored in the hospital, they received alternating doses of APCC and rFVIIa every 6 h. Anywhere from one to three doses of rFVIIa were given every 2 h between APCC doses. Doses of APCC ranged from 35 to 80 U kg(-1) dose(-1), and doses of rFVIIa ranged from 80 to 225 mcg kg(-1) dose(-1). There was no clinical or laboratory evidence of thrombosis, thrombocytopenia, or disseminated intravascular coagulation (DIC). We found the combination of these factors to be safe and effective for patients with refractory bleeds. However, we recommend this aggressive therapy only in the inpatient setting with careful monitoring of the physical examination and frequent laboratory screening to assess for thrombosis and DIC, and without the concurrent use of antifibrinolytic medications.

The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating, and categorizing indications for the evidence-based use of therapeutic apheresis (TA) in human disease. In the Ninth Edition, the JCA Special Issue Writing Committee has incorporated systematic review and evidence-based approaches in the grading of evidence and categorization of apheresis indications to make recommendations on the use of apheresis in a wide variety of diseases and conditions. This edition has largely maintained the general layout and concept of a fact sheet introduced in the Fourth Edition (2007). Each fact sheet succinctly summarizes the evidence for the use of TA in a specific disease or medical condition. The Ninth Edition of the JCA Special Issue comprises 91 fact sheets and

This survey based study describes current ECP practices. Further research to provide evidence for optimal standardization of patient qualifications, procedure parameters and product quality assessment is recommended.

Stimulated by the scientific progress in deciphering the principal elements contributing to the clinical efficacy of extracorporeal photochemotherapy (ECP), the American Council on ECP (ACE) was formed, under the auspices of the American Society for Apheresis (ASFA), to develop a field-guiding Consensus Report. ACE is composed of thirty nationally recognized ECP experts, clinically spanning cancer, transplantation, and autoimmunity and scientifically bridging immunology, bioengineering, and hematology. The two-day meeting took place in Manhattan, April 13-14, 2017, and unanimous consensus on nine pivotal points is herein reported. (1) ECP's clinical evolution must now enter a scientifically driven phase. (2) ECP is currently a bidirectional therapy, both immunizing and tolerizing simultaneously, via a single one-size-fits-all inflexible medical device. (3) To preclude inadvertent tolerization in the cancer setting, or immunization in the transplant rejection setting, polarization of ECP to either immunization or tolerization mode to match the clinical need is now possible and necessary. (4) Cutaneous T cell lymphoma (CTCL) is a genetically driven cancer, whose response to ECP is due to enhanced anti-cancer immunity. (5) ECP is a dendritic antigen-presenting cell (DC) based therapy. (6) ECP's efficacy can now be tested in a broad array of cancers. (7) ECP's capacity to tolerize to allotransplants via processing of donor leukocytes merits expedited human investigation. (8) UVA-8-MOP-impacted ECP-induced DC are potent antigen-specific tolerizing agents, while UVA-8-MOP(8-Methoxypsoralen)-spared ECP-induced DC are potent antigen-specific immunizing agents. (9) Six pilot clinical trial areas (CTCL, graft-vs.-host disease, ovarian carcinoma, anti-graft cytotoxic antibodies, pemphigus vulgaris, and haplotype mismatched stem cell transplants) are advised. ACE will be an ongoing advisory group for the field, with the goal of overseeing coordinated clinical and fundamental research efforts.

Tumor cell ploidy may be a clinically useful factor for prognostication and treatment stratification in children with MYCN-amplified, favorable-stage NB tumors.

Apheresis procedures in small children are technically challenging and require special planning with attention to extracorporeal volume. Discontinuous procedures such as extracorporeal photopheresis (ECP) require additional consideration. Alternative methods to perform ECP have been utilized in small children that require manipulation of mononuclear cells outside the standard closed-loop system. We present a safe and feasible alternative to the procedure for children who weigh less than 40 Kg, while maintaining a closed loop, sterile system utilizing the UVAR XTS device. A retrospective chart review was performed analyzing the use of fluid boluses (normal saline in those between 20 and 40 Kg, 5% albumin in those under 20 Kg) before ECP. Eleven patients underwent 334 ECP procedures for acute and chronic graft-versus-host disease (n 5 9), and for prevention of graft-versus-host disease (n 5 2). Volumes of fluid boluses were calculated based on the expected extracorporeal volume during the first draw cycle. Treatments consisted of at least three draw cycles using the 125 mL bowl. The median weight was 28.5 Kg (range 19 to 39); nine of 11 required red cell transfusions to maintain adequate hematocrit. Complications attributed to ECP included tachycardia, dizziness, nausea, and hypotension; these occurred either in combination or isolation in 31% of the procedures and resolved following additional fluid boluses. Only three (0.8%) required early photoactivation due to these complications. The median time to completion of treatment was 2 h and 58 min (range 1:30 to 5:03). ECP is well tolerated in low-weight pediatric patients if hematocrit and hydration are carefully maintained. J. Clin. Apheresis 25:63-69, 2010. V V C 2010 Wiley-Liss, Inc.