Medical Advisory Board Research Articles

892. Determination of the Unavailability of Alternative Antiretroviral Formulations

BackgroundMany pediatric and some adult people living with HIV (PLWH) are unable to swallow tablets and require alternative antiretroviral formulations (ARVF) such as liquids, chewable tablets, or powders for suspension. A growing number of issues with the timely procurement of alternative ARVF have been reported; the full scope of this problem is unknown. Without access to appropriate treatment, PLWH are at increased risk of poor disease outcomes. This study’s objective was to determine the scope of availability issues of ARVF and its potential impact on patient care.MethodsAn online survey invitation was sent to members of AAHIVM and the ACCP HIV PRN. Data collection included provider demographics, number of issues related to ARVF availability, time spent procuring ARVFs, and identification of unavailable formulations. To determine potential impact on clinical care and cost of care the time required to resolve shortages was summarized. ResultsThe analyzable sample was 154, a majority of whom were pharmacists or physicians (n=132, 85.7%; Figure 1), in a clinical role (n=134, 87.0%), and serve pregnant patients (n=121, 79.2%). 85 (55.2%) practice at sites that provide care to > 300 PLWH, 81 (52.6%) practice at sites that did not serve pediatric patients. 525 instances of gaps in care due to ARVF unavailability were reported. In 283 instances, a more complex regimen was prescribed due to first-choice ARVF unavailability. Providers also reported 186 situations in which a less optimal regimen was used and 140 cases of treatment delays. The average time spent to resolve such issues was 2.7 hrs (CI: 1.3 – 4.2). The longest time reported was 72 hrs; most providers spent 1 hr or less. The most common unavailable ARVF were branded ritonavir 80 mg/mL solution (n=12), zidovudine 50 mg/5 mL syrup (n=11), raltegravir 100 mg chewable tablets (n=11), and raltegravir 100 mg granules for suspension (n=10). Branded nevirapine 50 mg/5 mL suspension (n=7) and generic nevirapine 50mg/5ml powder for suspension (n=11) were also reported more frequently.Distribution of Respondents by Provider Type ConclusionOur report suggests the unavailability of alternative ARVF has the potential to significantly impact patient care. Further research is needed to identify the root causes of this problem to determine specific solutions.Disclosures Milena M. Murray, PharmD, MSc, BCIDP, AAHIVP, Merck (Speaker’s Bureau)Theratechnologies (Other Financial or Material Support, Medical Advisory Board) Eric Farmer, PharmD, BCPS, AAHIVP, TheraTechnologies, Inc (Other Financial or Material Support, Medical Advisory Board)

Functional Immune Tolerance Induced By Sequential Hematopoietic Stem Cell-Solid Organ Transplantation

Solid organ transplantation (SOT) treats over 1500 children/year in the US. While short-term outcomes have improved, long-term outcomes still remain poor. With the rare exception of monozygotic twins as donors, recipients require lifelong immunosuppression with its accompanying toxicities, the risk of nonadherence, and chronic rejection. Further, up to half of recipients require a second transplant.We have pioneered translational approaches that abrogate rejection and the need for post-transplant immunosuppression. Previous attempts in adult patients utilizing allogeneic hematopoietic stem cell transplantation (HSCT) to eliminate the need for post-SOT immunosuppression in non-histocompatible kidney transplant (KT) recipients have failed(Lowsky R, BMT 2019). The establishment of mixed lymphoid chimerism has permitted a reduction in the number of immunosuppressive drugs needed, but not their discontinuation, whereas complete donor engraftment after HSCT has resulted in fatal graft-versus-host disease in some patients (Leventhal JR, Eur J Pediatr 2000). The use of HSCT to eliminate the need for immunosuppression following pediatric KT has not been evaluated. We have pioneered sequential haploidentical HSCT followed by KT in three patients with Schimke immuno-osseous dysplasia (SIOD) to abrogate kidney rejection and the need for post-transplant immunosuppression.SIOD is a monogenic disorder with progressive nephropathy correctable by KT and a T-cell immunodeficiency curable by HSCT. All three patients received αβT-cell/CD19 B-cell depleted HSCT (αβhaplo-HSCT) from a parent prior to a KT from the same parental donor. The pre-HSCT reduced intensity preparative regimen consisted of fludarabine (a starting dose of 1 mg/kg x 4 days, which was adjusted based on AUC), total body irradiation (TBI) 200 cGy, cyclophosphamide 1200 mg/m 2, anti-thymocyte globulin (ATG) thymoglobulin® 7.5 mg/kg, and rituximab 200 mg/m 2. Immunosuppressive drugs were not prophylactically administered after HSCT. After confirmation of full donor lymphoid chimerism post-HSCT, the patients received a living donor KT from their parental HSCT donor. Post-KT immunosuppression included intraoperative methylprednisolone and post-operative low-dose oral prednisone (0.5 mg/kg/day with taper) and tacrolimus (target serum level of 3-5 ng/ml) to reduce potential reperfusion inflammation. All immunosuppressive drugs were tapered off by Day +30 post-KT. To demonstrate functional tolerance after KT, Mixed Lymphocyte Cultures (MLC) were performed between peripheral blood mononuclear cells (PBMC) and patient/parent-derived irradiated EBV transformed lymphoblastoid cells lines (EBV-LCL) as stimulators (Figure 1). PBMC were isolated from SIOD patients (n=3) by Ficoll Hypaque separation and were labelled with Invitrogen™ CellTrace Violet Proliferation Kit (CTV). EBV-LCL were established from SIOD patients, parents and healthy donors. The assay was performed in round bottom microtiter plates with 100,000 labelled PBMC as responder cells (R) and 50,000 irradiated (30gy) EBV-LCL in RPMI medium with 10% fetal calf serum. Cells were harvested on Day 6, and T-cell proliferation determined by CTV expression of CD3+ T cells using a Novocyte Penteon flow cytometer (Agilent).Donor-derived T cells isolated from the peripheral blood of all three recipients > 1-year post-HSCT/KT, did not respond to the donor cells, while they did proliferate to the non-donor parental and control cells (Fig. 1). These results demonstrate that post-HSCT/KT the circulating donor-derived T cells are functionally tolerant to the transplanted kidney and, therefore, are unable to mediate graft rejection even in the absence of immune suppression. We have achieved two goals: first, ablating the recipient immune system before HSCT we safely established a new donor-derived immune system - that could also, if required, cure a patient's underlying disease- and, second, functional tolerance to the transplanted kidney.At 12 to 24 months after KT, all patients have full donor lymphoid and myeloid chimerism, normal renal function without immunosuppression, MLC demonstrated tolerance towards donor cells, and normal proliferative responses to non-donor parental cells. These findings suggest that the combination of αβhaplo-HSCT and SOT could be extended to other solid transplantation like liver and small intestine. [Display omitted] DisclosuresBertaina: Cellevolve Bio: Membership on an entity's Board of Directors or advisory committees; Neovii: Membership on an entity's Board of Directors or advisory committees; AdicetBio: Membership on an entity's Board of Directors or advisory committees. Shah: OrchardTherapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Dr. Shah currently serves on the medical advisory board for Orchard Therapeutics . Parkman: Jasper Biotech: Consultancy.

Lentiviral Mediated Gene Therapy for Pyruvate Kinase Deficiency: Interim Results of a Global Phase 1 Study for Adult and Pediatric Patients

▪Background: Pyruvate kinase deficiency (PKD) is a rare inherited hemolytic anemia caused by mutations in the PKLR gene resulting in decreased red cell pyruvate kinase activity and impaired erythrocyte metabolism. Manifestations include anemia, reticulocytosis, splenomegaly and iron overload, and may be life-threatening in severely affected individuals. PKD represents a significant unmet medical need as current treatments are palliative and limited to blood transfusions, chelation therapy, and splenectomy which are associated with significant side effects. Preclinical studies in a clinically relevant PKD murine model have demonstrated that infusion of gene-modified Lin− bone marrow (BM) cells may ameliorate PKD phenotype. Based on compelling preclinical data, a global Phase 1 clinical trial RP-L301-0119 (NCT04105166) is underway to evaluate the feasibility and safety of lentiviral mediated gene therapy in adult and pediatric subjects with severe PKD.Methods: Six adult and pediatric patients with severe PKD (defined as severe and/or transfusion-dependent anemia despite prior splenectomy) will be enrolled. Peripheral blood (PB) hematopoietic stem cells (HSCs) are collected on 2 consecutive days via apheresis after mobilization with granulocyte-colony stimulating factor (G-CSF) and plerixafor. HSCs are enriched, transduced with PGK-coRPK-WPRE lentiviral vector (LV), and cryopreserved. Following release testing of the investigational product (IP), RP-L301, myeloablative therapeutic drug monitoring (TDM) busulfan is administered over 4 days. RP-L301 is then thawed and infused. Patients are followed for safety assessments, including replication competent lentivirus (RCL) and insertion site analysis (ISA), and for efficacy parameters including PB and BM genetic correction, decrease in transfusion requirements, clinically significant improvement in anemia, and reduction of hemolysis for 2 years post-infusion.Results: As of May 2021, 2 adult patients with severe anemia have received RP-L301. Patient 1 (age 31 years) received 3.9x106 CD34+ cells/kg with mean vector copy number (VCN) of 2.73. Patient 2 (age 47 years) received 2.4x106 CD34+ cells/kg with mean VCN of 2.08. Despite baseline hemoglobin (Hb) levels in the 7.0-7.5 g/dL range, both patients displayed normal-range hemoglobin (Hb), improved hemolysis markers, and have required no red blood cell transfusions post-engraftment at 9- and 6- months follow-up. Both report improved quality of life. PB mononuclear cell VCNs for both patients were >2.0 at last evaluated timepoint (6- and 3-months post-treatment, respectively). No serious adverse events have been attributed to RP-L301. Updated safety and efficacy data will be presented.Conclusions: Hematopoietic stem cell mobilization using G-CSF and plerixafor is feasible and effective in adult PKD patients. RP-L301 was successfully manufactured to meet the required specifications for the Phase 1 clinical study and administered without short-term infusion related complications. Efficacy was demonstrated by normalized Hb associated with engraftment confirmed by PB and BM VCN. DisclosuresShah: OrchardTherapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Dr. Shah currently serves on the medical advisory board for Orchard Therapeutics . Navarro: Rocket Pharmaceuticals, Inc.: Current equity holder in publicly-traded company, Other: Dr. Navarro has licensed medicinal products and receives research funding and equity from Rocket Pharmaceuticals, Inc., Patents & Royalties, Research Funding. Sevilla: Miltenyi: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Rocket Pharmaceuticals, Inc.: Consultancy, Other: J.Sevilla is an inventor on patents on lentiviral vectors filed by CIEMAT, CIBERER and Fundación Jiménez Díaz, and may be entitled to receive financial benefits from the licensing of such patents.; SOBI: Consultancy. Glader: Agios: Consultancy. Quintana Bustamante: Rocket Pharmaceuticals, Inc.: Current equity holder in publicly-traded company. Beard: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Law: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Zeini: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Choi: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Nicoletti: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Rao: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Bueren: Rocket Pharmaceuticals, Inc.: Consultancy, Other: J.Bueren is an inventor on patents on lentiviral vectors filed by CIEMAT, CIBERER and Fundación Jiménez Díaz, may be entitled to receive financial benefits from the licensing of such patents and receives funding for research., Patents & Royalties, Research Funding. Schwartz: Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Segovia: Rocket Pharmaceuticals, Inc.: Consultancy, Research Funding.

Editorial introductions

Editorial introductions

Activity Participation in the Pediatric Skeletal Dysplasia Population

<h3>Research Objectives</h3> To investigate activities children with skeletal dysplasia participate.To identify activities with the greatest and lowest participation rates among children with skeletal dysplasia .To investigate participation patterns among children with skeletal dysplasia. <h3>Design</h3> Children with skeletal dysplasia were asked to complete the Children's Assessment of Participation and Enjoyment (CAPE) survey during visits July 2014-June 2019. Demographic information and use of assistive devices was collected retrospectively. <h3>Setting</h3> City-based ambulatory orthopedic hospital. <h3>Participants</h3> Sixty-six children (38 females, 28 males) average age 11.5+/-4.21 years participated. Twenty-three (35%) were at least 13 years old, 43 (65%) were younger than 13. Thirty-two had average stature for age, 34 had short stature. There were 21 different skeletal dysplasia diagnoses among the participants. Fifteen children (23%) used assistive devices. Thirty-six children identified as white, 10 as black, 9 as Hispanic, 9 as Asian, 2 as other. <h3>Interventions</h3> CAPE was validated in Ontario, Canada for children (ages 6-21) with or without disabilities. <h3>Main Outcome Measures</h3> CAPE measures children participation of 55 informal and formal activities of five activity types: recreational, active-physical, social, skill-based, and self-improvement. <h3>Results</h3> Children participated in an average of 27.6+/-9.21 activities (overall diversity scores) out of 55 individual activities. CAPE diversity responses for each domain were used to compare the degree of activity involvement. Intensity and enjoyment were calculated. Chi-square analyses were conducted to analyze responses by each individual item. Paired t-tests were used to compare variation across population demographics. All statistical analysis was conducted using SPSS 22 for Windows. <h3>Conclusions</h3> Children with skeletal dysplasia participate in a wide variety of activities. Greatest participation was in social activities, lowest in physical activities. Use of assistive devices did not affect participation; there were no participation differences between genders. No study has previously evaluated the participation activities in this population. <h3>Author(s) Disclosures</h3> Dr. Cathleen Raggio received consulting fees from Alexion Pharmaceuticals, Ascendis and Biomarin. She was on speaker's bureau for Alexion Pharmaceuticals and Medical Advisory Board for Osteogenesis Imperfecta Foundation. Erin Carter on Medical Advisory Board for Little People of America, Inc.

Barth Syndrome Foundation: From humble beginnings to becoming an integral partner.

Barth Syndrome Foundation: From humble beginnings to becoming an integral partner.

Safety and Efficacy of Veverimer in Acidotic Patients With CKD and Heart Failure

Safety and Efficacy of Veverimer in Acidotic Patients With CKD and Heart Failure

No Evident Systemic Terminal Complement Pathway Activation in Hidradenitis Suppurativa

No Evident Systemic Terminal Complement Pathway Activation in Hidradenitis Suppurativa

Impact of Humoral Immunogenicity (Anti-mCAR19 Antibodies) on CTL019 Cellular Kinetics, Efficacy, and Safety

Background: The humoral immunogenicity of CAR19, a chimeric antigen receptor with a murine scFV domain developed for treatment with CTL019 (tisagenlecleucel) in relapsed/refractory (R/R) pediatric and young adult acute lymphoblastic leukemia (ALL), was evaluated in 2 studies (ELIANA [NCT02435849]; ENSIGN [NCT02228096]). To date, little is known about the presence and impact of preexisting or treatment-induced anti-murine (m)CAR19 antibodies in patients treated with CAR T-cell therapy.Methods: Anti-mCAR19 antibodies were measured in patients from ELIANA and ENSIGN trials before and after CTL019 infusion to evaluate the impact of anti-mCAR19 antibodies on cellular kinetics, efficacy, and safety. Data were pooled from ELIANA (n = 68) and ENSIGN (n = 29). Anti-mCAR19 antibodies were captured by mCAR19-transfected Jurkat cells and wild-type Jurkat cells. Following incubation and washing, an R-phycoerythrin (PE)-labeled anti-IgG/M F(ab')2 fragment was added for detection of anti-mCAR19 antibodies using flow cytometry and reported as median fluorescence intensity (MFI). Exploratory assay development included assessment of whether the presence of immunoglobulins after IVIG therapy in clinical samples would interfere with the anti-mCAR19 antibody assay. Impact of preexisting immunogenicity, as detected by MFI levels, was evaluated using cellular kinetic, efficacy, and safety endpoints. The impact of treatment-induced immunogenicity (defined as having an increase in anti-mCAR19 antibody levels over baseline) was assessed by calculating the fold change between preexisting (ie, baseline) levels and postinfusion levels.Results: Approximately 90% of patients displayed preexisting anti-mCAR19 antibodies; a similar incidence was detected in healthy volunteer samples, as observed during assay development. Approximately 35% of patients developed treatment-induced anti-mCAR19 antibodies. No apparent relationship between CTL019 expansion (AUC0-28d) and preexisting or treatment-induced anti-mCAR19 antibodies was identified (r2 < 0.001 and r2 = 0.006, respectively); similar results were seen for Cmax (Figure 1a). Presence of anti-mCAR19 after infusion did not appear to influence the persistence of transgene or day 28 response (Figure 1b). Kaplan-Meier curves showed that the presence of preexisting and treatment-induced anti-mCAR19 antibodies did not appear to impact the duration of response or event-free survival (Figure 1c). Strip plots showed consistent levels of preexisting and treatment-induced anti-mCAR19 antibodies across patients with safety events (grade 0/1/2/3/4), including CRS, neutropenia, thrombocytopenia, and neurological events. There was no apparent relationship between treatment- induced anti-mCAR19 antibodies with B-cell recovery categories (recovery ≤ 3 months, > 3 months and ≤ 6 months, > 6 months, and ongoing sustained B-cell aplasia). There was also no association in patients at the time of B-cell recovery with the presence of treatment-induced anti-mCAR19 antibodies following CTL019 infusion. B-cell aplasia requiring immunoglobulin replacement therapy (IVIG) occurred following CTL019 in the majority of patients. The CTL019 concentration time profiles for patients with treatment-induced anti-mCAR19 antibodies were categorized by the time following IVIG administration (within 1 week, 2 weeks, or > 3 weeks of IVIG administration). The results revealed no impact of the time at which IVIG was administered on the in vivo expansion and persistence of the transgene.Conclusions: We report the first comprehensive assessment of the impact of anti-mCAR antibodies on clinically relevant endpoints for CAR therapy. Determination of immunogenicity is an important endpoint required by health authorities for biologic drugs, and these analyses demonstrate the importance of characterizing the impact on clinical endpoints for CAR therapies. These analyses in patients with pediatric R/R ALL revealed a surprisingly high frequency of baseline anti-mCAR19 antibodies and showed that the presence of preexisting and treatment-induced anti-mCAR19 antibodies did not impact the cellular kinetics, safety, and efficacy of CTL019. Cell-mediated immunity studies are ongoing. [Display omitted] DisclosuresMueller:Novartis Pharmaceuticals Corporation: Employment. Waldron:Novartis Pharmaceuticals Corporation: Employment. Sickert:Novartis Institutes for BioMedical Research: Employment. Grupp:University of Pennsylvania: Patents & Royalties; Novartis Pharmaceuticals Corporation: Consultancy, Other: grant; Adaptimmune: Consultancy; Jazz Pharmaceuticals: Consultancy. Maude:Novartis Pharmaceuticals: Consultancy, Other: Medical Advisory Boards. Levine:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Laetsch:Novartis Pharmaceuticals Corporation: Consultancy. Pulsipher:Novartis Pharmaceuticals Corporation: Consultancy, Other: Phase II steering committee; Chimerix: Other: Advisory board Dec 2015; Jazz Pharmaceuticals: Other: advisory board, education; CSL Behring: Other: advisory board Feb 2017; Adaptive: Other: Advisory board 6/17. Boyer:Novartis Pharmaceuticals Corporation: Honoraria. August:Novartis Pharmaceuticals Corporation: Consultancy. Awasthi:Novartis Pharmaceuticals Corporation: Employment. Levine:GE Healthcare: Consultancy; Novartis Pharmaceuticals Corporation: Patents & Royalties, Research Funding; Brammer Bio: Consultancy; Tmunity Therapeutics: Equity Ownership, Research Funding. June:WIRB/Copernicus Group: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celldex: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Design: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis: Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Research Funding. Taran:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Wood:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Myers:Novartis Pharmaceuticals Corporation: Consultancy.

Management of Coagulopathy Associated with CTL019 CAR T-Cell Therapy

Introduction: CTL019 (tisagenlecleucel) is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that has demonstrated high durable response rates and a manageable safety profile in pediatric/young adult patients (pts) with relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). CTL019-associated cytokine-release syndrome (CRS), a systemic inflammatory response caused by elevated serum cytokine levels, occurred in 81% of pts treated in 2 multicenter trials (Maude et al, Haematologica . 2017;120(s2): [abstract P517]). Coagulopathy has been associated with CRS and macrophage activation syndrome (MAS) in previous reports of CTL019 from a single-center US study, and similar coagulopathy has been reported in cases of MAS/hemophagocytic lymphohistiocytosis associated with other events such as infections or chemotherapy. Here, we outline the treatment guidelines established and US and global multicenter experience with CTL019-associated coagulopathy in 97 pts treated with CTL019.Methods: Pooled data from 2 single-arm, multicenter phase II trials of CTL019 in pediatric/young adult pts with r/r B-ALL (ELIANA, NCT02435849 and ENSIGN, NCT02228096) were used to further characterize coagulopathy during CTL019-associated CRS.Results: Maximal grades 1-2, 3, and 4 CRS occurred in 36, 19, and 24 pts, respectively. Median lowest fibrinogen levels were 3.5 g/L and 3.3 g/L in pts with maximal grade 1-2 and 3 CRS, respectively, while median lowest fibrinogen level in pts with maximal grade 4 CRS was 1.2 g/L. 3%, 11%, and 25% of pts with maximal grades 1-2, 3, and 4 CRS, respectively, had lowest reported fibrinogen levels of ≥ 1 to < 1.5 g/L. Very low fibrinogen levels (<1 g/L) were observed in 33% of pts with maximal grade 4 CRS, with 2 pts having unmeasurable levels of fibrinogen, but not in any pt with maximal grade 1-3 CRS. Very low fibrinogen levels (<1 g/L) could occur before maximal CRS grade (n=1), during maximal CRS grade (n=6), or at the time of CRS improvement (n=1). Near the time of very low fibrinogen levels (<1 g/L) onset, only 1 pt had concurrent grade 3 increased INR and aPTT; the other 7 pts had grade 0-2 increased INR and aPTT.Given that hypofibrinogenemia was the most notable coagulopathy, cryoprecipitate was the mainstay of treatment in the US. In addition, administration of large volumes of fresh frozen plasma can be problematic in pts with CRS, fluid overload, and capillary leak. Guidelines for fibrinogen concentrate (FC) use were developed for the ELIANA global trial for CTL019-associated coagulopathy since cryoprecipitate is not readily available in Japan and some European countries. FC was available at 7/25 sites and administered to 3/7 pts with grade 4 CRS, and none of 8 pts with grades 1-3 CRS, out of 20 infused pts. Cryoprecipitate was available in 18/25 sites and administered to 12/17 pts with grade 4 CRS, 2/15 pts with grade 3 CRS, and none of 32 pts with grades 1-2 CRS, out of 77 infused pts.In pediatric pts with r/r B-ALL, the risk of bleeding from CTL019-associated hypofibrinogenemia can be increased by co-morbid thrombocytopenia and the use of anticoagulants, including those used in veno-venous hemofiltration (CVVH). Within 1 day of onset of very low fibrinogen levels (<1 g/L), 5/8 pts had concurrent grade 3 or 4 decreased platelets. 1 fatal case (1/97 infused pts=1%) of intra-parenchymal cranial hemorrhage was seen during resolving CRS with grade 3 hypofibrinogenemia, ongoing thrombocytopenia, and CVVH with citrate.Conclusions: Clinical recommendations and guidelines were developed for the use of FC and cryoprecipitate for the treatment of CTL019-associated coagulopathy with hypofibrinogenemia. During CTL019-associated coagulopathy, fibrinogen levels were disproportionately low as compared with INR/PTT. Hypofibrinogenemia was observed more frequently in pts with higher CRS grades, could be seen either during or when CRS was improving or resolution, and was effectively managed by FC or cryoprecipitate replacement. Rarely, fatal bleeding can be seen. Frequent monitoring of fibrinogen, INR/PTT, platelets, and signs of clinical bleeding, as well as appropriate fibrinogen replacement are needed in pts with grade 3 and 4 CRS associated with CAR T-cell therapies. DisclosuresBüchner:Novartis Pharmaceuticals Corporation: Consultancy; Pfizer: Consultancy. Grupp:Novartis Pharmaceuticals Corporation: Consultancy, Other: grant; Jazz Pharmaceuticals: Consultancy; Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties. Maude:Novartis Pharmaceuticals: Consultancy, Other: Medical Advisory Boards. Hiramatsu:Novartis Pharmaceuticals Corporation: Other: Clinical trials . Wood:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Awasthi:Novartis Pharmaceuticals Corporation: Employment. Yi:Novartis Pharmaceuticals Corporation: Employment.

Targetting CD38 in T Cell Acute Lymphoblastic Leukemia

Targeted immunotherapy has become a promising emerging therapeutic strategy for many cancers. No safe and effective immunotherapies have been developed for T-cell acute lymphoblastic leukemia (T-ALL). CD38 is a transmembrane glycoprotein found on the cell surface of activated T cells, terminally differentiated B cells, but relatively low levels on normal lymphoid and myeloid cells. Daratumumab (Janssen Biotech, Inc.) is a human monoclonal antibody that binds to CD38 and is used in the treatment of refractory multiple myeloma (MM).To ensure CD38 is a relevant target in T-ALL, we evaluated CD38 expression by flow cytometry from 21 patients with T-ALL (10 early T-cell precursor (ETP) and 11 non-ETP) at diagnosis and after induction chemotherapy. CD38 was expressed in all samples and surface expression did not change after induction (mean CD38 mean fluorescence intensity (MFI) at diagnosis vs end-of-induction: 3.27 log vs 3.19 (p = 0.25). Similarly, we evaluated CD38 expression of 15 primary T-ALL xenograft samples (7 ETP and 8 non-ETP T-ALL), and only 1 sample demonstrated low CD38 expression. In contrast, we evaluated CD38 expression in 10 patients with de novo B-ALL at diagnosis and found CD38 expression was significantly decreased after induction therapy (5351 vs. 723, p-0.002). Therefore we hypothesized that targeting CD38 with daratumumab would be effective against T-ALL.We xenografted primary ALL blasts from 15 different patients, including 7 with ETP-ALL and 8 with non-ETP T-ALL. Mice were randomized to daratumumab (200 μg /mouse intraperitoneally weekly) vs isotype control (200 μg/mouse; 5 mice per arm for each sample) after they developed >1% peripheral blood (pb) blasts by FACS. Disease burden was assessed by FACS enumeration of pb blasts weekly and splenic blasts at sacrifice.We demonstrate striking efficacy of daratumumab monotherapy in 6 of 7 ETP-ALL samples with significant reduction of pb and splenic blasts. Mice treated with high disease burden from 5 of the 8 non-ETP T-ALL samples were moribund immediately after daratumumab injection, presumably from tumor lysis. Autopsy performed on moribund compared to isotype-treated animals did not reveal embolism. We repeated the experiments in the 8 non-ETP T-ALL samples and the one ETP sample that did not respond when treated at high disease burden. For these experiments, we treated the mice after injection but before detectable pb blasts (termed low disease burden). Using this approach, daratumumab was effective in 7 of 8 non-ETP ALL samples and the one ETP sample that was non-responsive when treated at high disease burden. In summary, we found dara monotherapy was effective in patient-derived xneograft models developed from 14 of 15 patients with T-ALL.The 1 T-ALL sample that did not respond to daratumumab, was the only sample with low CD38 expression. Therefore we hypothesize that the clinical benefit from daratumumab reflects the level of CD38 expression. In myeloid and MM cells, low dose all-trans retinoic acid (ATRA) significantly upregulates CD38 expression. We have similarly tested T-ALL cell lines across a broad range of ATRA doses, however ATRA has no effect on CD38 expression on T-ALL cells. Experiments are ongoing to evaluate alternative agents such as interferon to upregulate CD38 and CRISPR/Cas9 to knock-out CD38.In summary, we found daratumumab is a highly effective novel monotherapy for T-ALL in preclinical models. Based on this work, we are planning to open a multi-institutional early phase clinical trial for children and young adults with relapsed and refractory T-ALL. DisclosuresMaude:Novartis Pharmaceuticals: Consultancy, Other: Medical Advisory Boards. Grupp:Novartis Pharmaceuticals Corporation: Consultancy, Other: grant; Adaptimmune: Consultancy; Jazz Pharmaceuticals: Consultancy; University of Pennsylvania: Patents & Royalties.

Pharmacokinetics and Pharmacodynamics of Tocilizumab for the Management of Cytokine Release Syndrome (CRS) in Pediatric and Young Adult Patients with Relapsed/Refractory (R/R) B-Cell Acute Lymphoblastic Leukemia (B-ALL) Treated with CAR T-Cell Therapy, CTL019

Background: ELIANA (NCT02435849) is a pivotal multicenter study to test the efficacy of CTL019 (tisagenlecleucel; anti-CD19 CAR-T) in children and young adult patients (pts) with relapsed/refractory B-ALL. Tocilizumab (toci) has been used for the management of moderate/severe (grade 3/4) CRS in ≈ 38% of pts treated with CTL019 (Buechner J et al, EHA 2017) at the same doses used in approved non-oncologic pediatric indications (<30 kg received 12 mg/kg and ≥30 kg received 8 mg/kg [800 mg max dose]). CRS onset generally occurred at a median of 3 days (range 1-22 days) after CTL019 infusion, requiring administration of 1-3 doses of toci in some patients per the Penn CRS treatment algorithm. Toci is a humanized mAb that binds to and blocks IL-6 receptor (IL-6R) signaling. The pharmacokinetics (PK) and pharmacodynamics (PD) of toci in pediatric B-ALL patients with CAR-associated CRS has not previously been described.Objectives: To characterize the PK/PD of toci for the management of CRS following CTL019 infusion in B-ALL in the ELIANA study. To describe the impact of toci on CTL019 cellular kinetics and expansion.Methods: Pharmacokinetics of toci and pharmacodynamics of soluble IL-6R (sIL-6R) concentrations (conc) were determined from serum and quantified using validated assays to provide mechanistic support for the use of toci in the management of CRS in B-ALL. Maximum toci conc (Cmax) was derived using non-compartmental methods and compared with levels in approved indications. sIL-6R, proinflammatory cytokines and time to CRS resolution were characterized to describe the pharmacodynamic effects of toci. Summary statistics and graphical analyses of CTL019 exposure by number of toci doses were performed for patients that responded to CTL019 infusion to describe the impact of toci on CTL019 expansion and persistence.Results: A total of 28 out of 58 pts with CRS received their first dose of toci at a median of 5 days (range 1-18) after CRS onset. 17 pts received 1 IV dose of toci; 8 pts 2 doses; 3 pts 3 doses. First dose of toci ranged from 6.9 to 12 mg/kg; second dose of toci ranged from 8 to 12 mg/kg. Following the first and second dose of toci, the mean Cmax (SD) were ≈ 111 (30.6) µg/mL and 265 (376) µg/mL, respectively (Table 1). Individual patient PK/PD concentration-time profiles in B-ALL, show increased sIL-6R after the first toci dose that remained elevated following the second dose (Figure 2). The median time to CRS resolution (including fever resolution) was 5 days (range, 2-29 days) after toci administration. CRS onset coincided with CTL019 expansion, and was followed by a peak in serum cytokines, including IL-6. Maximal expansion of the CTL019 transgene (determined by qPCR) was 159% higher in patients treated with toci (n=14) compared with patients that did not receive toci (n=28) demonstrating tocilizumab does not negatively impact expansion (Figure 3).Conclusions: Toci administration resulted in resolution of CRS symptoms within a median of 5 days after administration. Notably, levels of toci achieved in B-ALL were similar to levels published in pediatric non-oncologic indications [tocilizumab label], resulting in concentration- and time-dependent increases in sIL-6R. CTL019 transgene expanded and persisted following tocilizumab administration. Together these data support the use of toci for the management of CRS, showing the compound to be 1) pharmacologically active, 2) able to achieve levels consistent with those achieved in other disorders in spite of CRS and 3) able to be given without impairing CTL019 expansion. [Display omitted] DisclosuresLee:Novartis Pharmaceuticals Corporation: Other: Post-Doctoral Fellow; The State University of New Jersey: Other: Post doctoral fellow. Bittencourt:Novartis Pharmaceuticals Corporation: Consultancy; Amgen Inc.: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Travel Grant. Rives:Novartis Pharmaceuticals Corporation: Consultancy; Jazz Pharmaceutical: Other: Travel expenses; Shire: Consultancy. Boyer:Novartis Pharmaceuticals Corporation: Honoraria. Pulsipher:Adaptive: Other: Advisory board 6/17; CSL Behring: Other: advisory board Feb 2017; Jazz Pharmaceuticals: Other: advisory board, education; Chimerix: Other: Advisory board Dec 2015; Novartis Pharmaceuticals Corporation: Consultancy, Other: Phase II steering committee. Jaitner:Novartis Pharma AG: Employment. Yi:Novartis Pharmaceuticals Corporation: Employment. Lund:Novartis Pharmaceuticals Corporation: Employment. Leung:Novartis Pharmaceuticals Corporation: Employment. Awasthi:Novartis Pharmaceuticals Corporation: Employment. Wood:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Maude:Novartis Pharmaceuticals: Consultancy, Other: Medical Advisory Boards. Grupp:Novartis Pharmaceuticals Corporation: Consultancy, Other: grant; Adaptimmune: Consultancy; Jazz Pharmaceuticals: Consultancy; University of Pennsylvania: Patents & Royalties. Mueller:Novartis Pharmaceuticals Corporation: Employment.

Durable Remissions with Humanized CD19-Targeted Chimeric Antigen Receptor (CAR)-Modified T Cells in CAR-Naive and CAR-Exposed Children and Young Adults with Relapsed/Refractory Acute Lymphoblastic Leukemia

BackgroundChimeric antigen receptor (CAR)-modified T cells targeting CD19 can induce potent and sustained responses in children with relapsed/refractory acute lymphoblastic leukemia (ALL). We previously demonstrated durable remissions with the CD19-targeted CAR T cell product CTL019; however, a subset of patients has limited persistence, which can increase the risk of relapse. Most CAR single chain variable fragment (scFv) domains, including that of CTL019, are of murine origin; therefore, anti-mouse reactivity is one potential cause of immune-mediated rejection that may be overcome by fully human or humanized CAR designs. We developed a humanized anti-CD19 scFv domain and now report on treatment with humanized CD19-directed CAR T cells (CTL119).DesignA pilot/phase 1 study of CTL119 enrolled children and young adults with relapsed/refractory B-ALL or lymphoblastic lymphoma (B-LL) with or without prior exposure to a CAR T cell product in retreatment and CAR-naive cohorts, respectively. Patients in the retreatment cohort were eligible if they met 1 of 3 criteria: 1) CD19+ relapse 2) no response or 3) early B cell recovery indicating poor persistence of CAR T cells. Patient-derived T cells were transduced ex vivo with a lentiviral vector encoding the CAR composed of CD3z, 4-1BB, and humanized anti-CD19 scFv domains and activated/expanded with anti-CD3/CD28 beads. Patients received lymphodepletion with cyclophosphamide and fludarabine 1 week prior to infusion with CTL119.ResultsThirty-eight children and young adults (2-24 yr) with B-ALL (n=37) and B-LL (n=1) were infused with CTL119 in 2 cohorts: CAR-naive (n=22) and retreatment (n=16). Indications included primary refractory disease (n=4), first relapse (n=9), second or greater relapse (n=25), relapse after prior allogeneic stem cell transplant (SCT, n=22), CNS disease (n=7), and other extramedullary disease (n=6). Sixteen patients with prior exposure to murine-derived CD19-specific CAR-modified T cells (CTL019, n=10; other, n=6) were retreated for B cell recovery (n=5), CD19+ relapse (n=10), or no response to prior CAR T cells (n=1). Two retreatment patients previously received 2 different CAR T cell products.At assessment 1 month after infusion, 22/22 (100%) CAR-naive patients were in complete remission. Multiparameter flow cytometry for minimal residual disease (MRD) was negative at a detection level of 0.01% in all responding patients. Four patients relapsed 3-9 months after infusion, 2 CD19+, 2 CD19-. Median follow-up was 14 mo. RFS in responding patients was 86% (95% CI: 63, 95) at 6 months and 82% (95% CI: 58, 93) at 12 months, with 3/22 (14%) proceeding to SCT in remission.In the retreatment cohort, 9/16 (56%) patients achieved a complete response (CR), defined as morphologic remission with B cell aplasia. Refractory disease showed reduced CD19 expression in 3 non-responding patients. MRD was negative in 7/9 responding patients and positive in 2 patients, who progressed to CD19+ relapse at 1.6 and 3 mo. Median follow-up was 13 months. Relapse-free survival (RFS) in responding patients was 67% (95% CI: 28, 88) at 6 months and 56% (95% CI: 20, 80) at 12 months.B cell aplasia, a functional marker of CD19-targeted CAR T cell persistence, continued for 6 months or more in 15/26 patients with adequate follow-up: 13/17 CAR-naive, 2/9 retreatment. Cytokine release syndrome (CRS) was observed in 34/38 patients and mild in most patients (grade 1, n=6; grade 2, n=23). Four patients experienced grade 3 CRS requiring supplemental oxygen and/or low-dose vasopressor support and 1 experienced grade 4 CRS requiring high-dose vasopressor and ventilatory support. Neurologic toxicity included encephalopathy (n=5) and seizure (n=5) and was fully reversible.ConclusionIn the first study of humanized anti-CD19 CAR T cells, CTL119 induced CR in 100% of patients with no prior CAR T cell exposure, with a 12-mo RFS of 82%. In the retreatment setting, 56% of patients with poor or transient response to prior murine CD19-directed CAR T cells achieved CR. CTL119 can induce durable remissions without further therapy in children and young adults with relapsed/refractory B-ALL. DisclosuresMaude:Novartis Pharmaceuticals: Consultancy, Other: Medical Advisory Boards. Brogdon:Novartis: Employment. Young:Novartis: Research Funding. Levine:Tmunity Therapeutics: Equity Ownership, Research Funding; Novartis Pharmaceuticals Corporation: Patents & Royalties, Research Funding; Brammer Bio: Consultancy; GE Healthcare: Consultancy. Frey:Novartis: Research Funding. Porter:Genentech/Roche: Employment, Other: Family member employment, stock ownship - family member; Incyte: Honoraria; Immunovative Therapies: Other: Member DSMB; Servier: Honoraria, Other: Travel reimbursement; Novartis: Honoraria, Patents & Royalties, Research Funding. Lacey:Novartis: Research Funding; Genentech: Honoraria. Melenhorst:Novartis: Research Funding. June:Novartis: Patents & Royalties, Research Funding; Celldex: Honoraria, Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Equity Ownership, Research Funding; WIRB/Copernicus Group: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Design: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Grupp:Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties; Jazz Pharmaceuticals: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Other: grant.

CTL019 Therapy Appears Safe and Effective in Pediatric Patients with Down Syndrome with Relapsed/ Refractory (r/r) Acute Lymphoblastic Leukemia

Introduction: Children with Down syndrome have increased risk of developing leukemia. Pediatric patients with Down syndrome-associated acute lymphoblastic leukemia (DS-ALL) are known to have significant toxicities with reinduction chemotherapy and historically poor outcomes with stem cell transplant (SCT) compared to those without Down syndrome. Alternate therapies are urgently needed for this patient population. The anti-CD19 chimeric antigen receptor (CAR) T-cell therapy CTL019 has demonstrated high rates of durable complete remission and a manageable safety profile in children with r/r B-ALL treated in the multicenter ELIANA and ENSIGN trials.Methods: Pooled data from 2 single-arm, multicenter phase 2 trials of CTL019 in pediatric/young adult patients with r/r B-ALL (ELIANA, NCT02435849 and ENSIGN, NCT02228096) were used to characterize efficacy and safety of CTL019 therapy in children with DS-ALL.Results: Eight patients with DS-ALL were enrolled (data cutoff: ELIANA, 23 November 2016; ENSIGN, 1 February 2016). 7 DS-ALL patients were infused with CTL019; 1 patient died prior to infusion due to ALL progression and intracranial hemorrhage. No manufacturing issues occurred during the production of CTL019 for DS-ALL patients. 5/7 infused patients were male, 2/7 had prior SCT, and the patients' ages ranged from 6-16 years.Complete remission (CR) or CR with incomplete blood count recovery (CRi) occurred in 6/7 patients by day 28 (CR+CRi rate, 86%); the 7th patient died (cerebral hemorrhage) prior to day 28 and was not evaluable for response. Multiparameter flow cytometry was negative in bone marrow for minimal residual disease in all responding patients. Two patients have relapsed at 5 and 8 months after infusion (both CD19 negative relapses). Ongoing remissions in the 4 patients without relapse ranges from 2 to 11 months.The safety profile of CTL019 in DS-ALL (n=7) appears similar to that for patients without Down syndrome treated in the same trials (n=90). Grade 3 or 4 cytokine release syndrome occurred in 3/7 patients (43%) with Down syndrome and 44% of patients without Down syndrome. Rates of other grade 3 or 4 adverse events of special interest did not appear to favor a consistent trend between patients with and without Down syndrome (febrile neutropenia: 43% vs 36%; neurological events: 14% vs 11%; tumor lysis syndrome: 14% vs 2%). Importantly, grade 3 or 4 infections were not observed in patients with Down syndrome (0% vs 23%). One patient died after infusion due to intracranial parenchymal hemorrhage on day 15 associated with ongoing coagulopathy. Extent and timing of CTL019 expansion as well as long-term persistence of CTL019 was similar in patients with and without Down syndrome.Conclusions: This is the first analysis of CAR T-cell therapy in pediatric patients with r/r B-ALL and Down syndrome. Although experience in these patients is limited, these data suggest that toxicities appear similar to B-ALL patients without Down syndrome, rates of remission in DS-ALL are high and long-term outcomes of CTL019 therapy with sustained persistence appear promising. Further exploration of CTL019 therapy as an alternative to SCT in children with r/r DS-ALL is warranted. DisclosuresLaetsch:Novartis Pharmaceuticals Corporation: Consultancy. Maude:Novartis Pharmaceuticals: Consultancy, Other: Medical Advisory Boards. Grupp:Novartis Pharmaceuticals Corporation: Consultancy, Other: grant; Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties; Jazz Pharmaceuticals: Consultancy. Boyer:Novartis Pharmaceuticals Corporation: Honoraria. Phillips:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Pulsipher:Chimerix: Other: Advisory board Dec 2015; Jazz Pharmaceuticals: Other: advisory board, education; CSL Behring: Other: advisory board Feb 2017; Adaptive: Other: Advisory board 6/17; Novartis Pharmaceuticals Corporation: Consultancy, Other: Phase II steering committee. Bittencourt:Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Travel Grant; Amgen Inc.: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy. Wood:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Mueller:Novartis Pharmaceuticals Corporation: Employment. Weng:Novartis Pharmaceuticals Corporation: Employment. June:Immune Design: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celldex: Honoraria, Membership on an entity's Board of Directors or advisory committees; WIRB/Copernicus Group: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Research Funding. Levine:Tmunity Therapeutics: Equity Ownership, Research Funding; Novartis Pharmaceuticals Corporation: Patents & Royalties, Research Funding; Brammer Bio: Consultancy; GE Healthcare: Consultancy. Hiramatsu:Novartis Pharmaceuticals Corporation: Other: Clinical trials .

A Prepubertal Girl with Delusions of Pregnancy.

A Prepubertal Girl with Delusions of Pregnancy.

Longitudinal Trends in Bleeding Complications on Extracorporeal Life Support (ECLS) Over the Past Two Decades – ELSO Registry Analysis

Background: The use of extracorporeal life support (ECLS) has increased worldwide over the last decade including for new emerging indications like extracorporeal cardiopulmonary resuscitation, trauma, and COVID-19. Bleeding complications remain feared and frequent, with high morbidity and increased mortality. Yet, data about trends, and in-hospital outcomes, have been poorly investigated.Methods: The Extracorporeal Life Support Organization (ELSO) Registry database was explored for patients who received veno-venous (V-V) and veno-arterial (V-A) ECLS between the years 2000 and 2020. Trends in bleeding complications and mortality were analyzed. Bleeding complications were classified according to site (gastro-intestinal, cannulation site, surgical site, pulmonary, tamponade and central nervous system) and analyzed separately. Multivariable analysis was performed to identify risk factors for bleeding complications.Results: ELSO database analysis included 53.644 patients with single ECLS runs, mean age 51.4± 15.9 years, 33.859 (64.5%) male. Study cohort included 19.748 patients cannulated for V-V ECLS and 30.696 patients for V-A ECLS. Bleeding complications were reported in 14.786 patients (27.6%) and occurred more often in V-A-modalities compared to V-V modalities (30.0% versus 21.9%, pConclusions: The steady decrease in particular cannulation and surgical site related bleeding complications over the past 20 years suggests advances in equipment development (membrane and tubes surfaces) as well as better understanding of anticoagulation management. However, the high incidence of bleeding and association with hospital mortality reinforces the need for studies to understand bleeding complications more thoroughly during ECLS.Funding Information: No funding.Declaration of Interests: Prof. Dr. Lorusso is a consultant for Medtronic, Getinge and LivaNova and medical advisory board member for EUROSETS, all unrelated to this work; all honoraria to the university for research funding. Dr. Tonna is supported by a Career Development Award from the National Institutes of Health/National Heart, Lung, And Blood Institute (K23 HL141596). Dr. Tonna received speaker fees and travel compensation from LivaNova and Philips Healthcare, unrelated to this work. Prof. Ten Cate received research support from Bayer and Pfizer, is a consultant for Alveron and stockholder with Coagulation Profile; all unrelated to this work. Prof Zoe McQuilten is supported by an Australian National Health and Medical Council (NHMRC) Investigator Grant.Other authors have no conflict of interest to declare.Ethics Approval Statement: Each institution participating in ELSO Registry approves data reported to the registry through their local institutional review board. This study involved only analysis of pre-existing de-identified data from an international registry, and as such no ethics approval was required. Similarly, no patient consent was required.

Paid platelet donors: Points to consider

Paid platelet donors: Points to consider

COVID and the Cornea: From Controversies to Consensus: Report of the Eye Bank Association of America Medical Advisory Board Policy and Position Review Subcommittee.

COVID and the Cornea: From Controversies to Consensus: Report of the Eye Bank Association of America Medical Advisory Board Policy and Position Review Subcommittee.

Extracorporeal Membrane Oxygenation in the Middle East and India During the COVID-19 Pandemic

Background: Extracorporeal membrane oxygenation (ECMO) use for severe Coronavirus disease 2019 (COVID-19) patients has evolved during the course of the pandemic. Early uncertainty regarding the role of ECMO during the current pandemic was based on the suboptimal initial experiences. However, more recent data suggests favorable outcomes in COVID-19 patients receiving ECMO support. We aimed to explore the epidemiology and outcomes of ECMO for COVID-19 related cardiopulmonary failure and evaluate outcomes of new centers versus established ones.Methods: This is a retrospective, multicenter international, observational study conducted in (19) ECMO centers in five countries from March 1, 2020, to September 30, 2020. We included 307 patients with COVID-19 who received ECMO for refractory hypoxemia and severe respiratory acidosis with or without circulatory failure. Data collection included Patients characteristics, demographic data, ECMO-related specific data, pre-ECMO patient condition, 24 hours post-ECMO initiation data, and outcome. The primary outcome is survival to home discharge. Secondary outcomes include mortality during ECMO, survival to decannulation, and outcomes stratified by center type in which patients were treated.Findings: Three hundred and seven COVID-19 patients received ECMO support during the study period. The median age was 45 years (37-52 IQR), and 81% were men. 178 (58%) patients survived ECMO, of whom 138 (45%) patients were discharged home, and 40 patients (13%) died post-ECMO decannulation while 128 patients (41.7%) died during ECMO. Patient outcomes in the new centers developed in response to the pandemic were similar to those of established centers.Interpretation: During pandemics, ECMO may provide favorable outcomes in highly select patients as resources allow. Outcomes in ECMO centers established during the pandemic were comparable to existing centers.Funding Statement: None.Declaration of Interests: Kiran Shekar acknowledges research support from the Metro North Hospital and Health Service and the Prince Charles Hospital Foundation. Dr. Brodie receives research support from ALung Technologies. He has been on the medical advisory boards for Baxter, Abiomed, Xenios, and Hemovent and is the President-Elect of the Extracorporeal Life Support Organization (ELSO). Dr. Combes reported receiving grants and personal fees from Maquet, Xenios, and Baxter and serving as the recent past president of the EuroELSO organization. Other authors have no conflict of interest.Ethics Approval Statement: After the SWAAC ELSO steering committee's authorization, IRB approval was obtained from the coordinating center King Saud Medical City in Riyadh - Saudi Arabia. The country representatives obtained IRB approval for each participating center as well.

Trends in COVID-19-related in-hospital mortality: lessons learned from nationwide samples

Trends in COVID-19-related in-hospital mortality: lessons learned from nationwide samples