Bluebird Bio Research Articles

Long-Term Clinical Outcomes of Lentiglobin Gene Therapy for Transfusion-Dependent β-Thalassemia in the Northstar (HGB-204) Study

Long-Term Clinical Outcomes of Lentiglobin Gene Therapy for Transfusion-Dependent β-Thalassemia in the Northstar (HGB-204) Study

Real-World Clinical Burden of Sickle Cell Disease in the US Community-Practice Setting: A Single-Center Experience from the Foundation for Sickle Cell Disease Research

Background Sickle cell disease (SCD) is a progressively debilitating monogenic disease characterized by unpredictable, acute, life-threatening episodes and chronic complications such as hemolytic anemia and end-organ damage. It presents with a range of severity resulting in significant morbidity, poor quality of life, and early mortality. Real-world data on treatments and clinical outcomes for patients (pts) with SCD are limited, particularly in the community clinical care setting. The objectives of this retrospective real-world study were to characterize clinical manifestations and management of pts with SCD treated at the Foundation for Sickle Cell Disease Research (FSCDR). Methods A retrospective longitudinal analysis of an electronic health records (EHR) database from the FSCDR, which captured laboratory testing, treatments, and records on outpatient, emergency, and inpatient visits, was conducted. All unique pts with SCD assigned a medical record number in the EHR (N=172) were considered. Data from external records were manually entered into the EHR to supplement the EHR database. To address limitations of a real-world database, medical records for all pts included were manually reviewed and validation was performed on 10% of the sample. Pt demographics, clinical characteristics, hydroxyurea (HU) treatment (as captured by prescriptions and usage notes), administration of red blood cell transfusions, vaso-occlusive crisis (VOC) events and acute chest syndrome (ACS) (based on physician assessment) were described. Annual VOC rates were summarized by dividing the number of events by the total follow-up duration in years. Results In total, 122 pts with SCD were included. Twenty-three pts were excluded as they were not actively seeking care and/or had no relevant clinical data from 01/01/15-07/19/19. Data for 27 pts <22 years of age were unavailable at time of analysis (results of this cohort will be included in the presentation). Among all pts, 76 (62.3%) were female and 118 (96.7%) were Black or African American. The mean age at time of analysis was 39.1 (standard deviation [SD] 12.3) years with 9 (7.4%) 22-24 year-olds, 67 (54.9%) 25-40 year-olds, 35 (28.7%) 41-55 year-olds, and 11 (9.0%) ≥ 56 year-olds. The most common genotypes were HbSS (77.0%) and HbSC (17.2%). Over a mean follow-up period of 2.9 (interquartile range: 2.0, 4.4) years, 27 (22.1%) pts were treated with HU and 66 (54.1%) pts received transfusions, of which 1 (1.5%) pt chronically received episodic transfusions (i.e., continuous monthly transfusions for ≥ 6 months). The mean total hemoglobin (Hb) was 8.3 (SD 1.7) for HbSS pts and 10.9 (SD 1.5) for HbSC pts. Among pts who never received HU or transfusions during follow-up, mean Hb was 9.4 (SD 1.7) for HbSS pts and 11.4 (SD 1.6) for HbSC pts. Among pts who ever received HU or transfusions, mean Hb was 7.7 (SD 1.3) for HbSS pts and 10.3 (SD 1.1) for HbSC pts. Eleven (9.0%) pts had ≥ 1 ACS whereas 97 (79.5%) pts had ≥ 1 VOC event. ACS and VOC events occurred mostly in pts 25-55 years of age (ACS: 9 [81.8%] pts aged 25-40 years and 2 [18.2%] pts aged 41-55 years; VOC: 54 [55.7%] pts aged 25-40 years and 29 [29.9%] pts aged 41-55 years). Annual rates of VOC are described in Figure 1. Conclusions This is one of the first studies to describe clinical characteristics and management of pts with SCD in a community practice setting. Higher Hb levels among pts who never vs ever received HU or transfusions during follow-up may be a reflection of who were selected for treatment and additional studies to take into account timing of treatment and Hb assessments and confounding factors need to be conducted. The study found high VOC rates particularly among pts aged ≤ 40 years. Lower VOC rates among older pts do not necessarily indicate less severe disease. One potential reason for lower VOC rates among older pts with SCD is that cumulative exposure to ischemia-related tissue injury and resulting end organ damage may decrease VOC-related pain over time. Further investigation to elucidate the rate of VOC decline observed in older pts is needed, including looking at underlying health and end organ damage. While limitations are inherent in real-world studies, these findings underlie the ability to and importance of studying SCD management and clinical outcomes in community care settings. This study highlights the clinical burden of SCD and possibly higher than expected unmet need in this community setting. Disclosures Bronté-Hall: bluebird bio: Research Funding. Huynh:bluebird bio: Research Funding. Puri-Sharma:bluebird bio: Employment. Chang:bluebird bio: Research Funding. Chawla:bluebird bio: Employment. Signorovitch:bluebird bio: Research Funding.

Routine Management, Healthcare Resource Use and Patient/Caregiver-Reported Outcomes of Patients with Transfusion-Dependent β-Thalassaemia in the United Kingdom: A Mixed Methods Observational Study

Routine Management, Healthcare Resource Use and Patient/Caregiver-Reported Outcomes of Patients with Transfusion-Dependent β-Thalassaemia in the United Kingdom: A Mixed Methods Observational Study

Updated Results from an Ongoing Phase 1 Clinical Study of bb21217 Anti-Bcma CAR T Cell Therapy

Updated Results from an Ongoing Phase 1 Clinical Study of bb21217 Anti-Bcma CAR T Cell Therapy

Clinical Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Transfusion-Dependent β-Thalassemia Treated at the Bambino Gesù Children's Hospital, Rome, Italy

β-thalassemia is one of the most common monogenic blood disorders worldwide, and is highly prevalent in Mediterranean countries. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been the only curative treatment for transfusion-dependent β-thalassemia (TDT; the most severe disease form) for many years, but it is limited by donor availability and has a significant risk of morbidity and mortality. We conducted a chart review of patients with β-thalassemia who underwent allo-HSCT (N=80) at the Bambino Gesù Children's Hospital, Rome, Italy, between March 2011 and August 2018. Median (range) age at allo-HSCT was 5.5 (0.3-20.0) years [<12 years: n=70 (87.5%), ≥12-18 years: n=7 (8.8%), ≥18 years: n=3 (3.8%)] and all patients but one had TDT [n=79 (98.8%)]. Prior to allo-HSCT, patients received a median (range) of 17.4 (4-52) transfusions per year (n=64) and had a median (range) serum ferritin concentration of 1217 (135-9123) ng/mL and a median (interquartile range) hemoglobin level of 10.3 (9.3-11.4) g/dL. All patients had received regular iron chelation therapy prior to transplantation. In total, 18 (22.5%), 28 (35.0%), and 34 (42.5%) patients received allo-HSCT from human leukocyte antigen (HLA)-identical sibling donors, HLA-haploidentical donors, and unrelated donors (fully matched donor: n=28, donor with a single HLA disparity: n=6), respectively. Of these donors, 42 (52.5%) were carriers for thalassemia-associated mutations. In total, 53 (66.3%) donors and 35 (43.8%) recipients were cytomegalovirus-positive. Bone marrow was the stem cell source in 51 cases (63.8%), while 28 patients received an alphabeta T-cell depleted peripheral blood haploidentical HSCT (35.0%); the remaining child (1.3%) received both bone marrow and cord blood from the same related donor. All patients continued to receive transfusions immediately after allo-HSCT; however, only 7 (8.8%) received a transfusion in the 3 to 12-month post-transplantation period (2 due to underlying disease; 5 due to other reasons including GI bleeding). Median (range) time to reach transfusion-free status was 3.8 (1.1-47.8) weeks. Median (interquartile range) hemoglobin levels at 6 and 12 months after allo-HSCT were 10.9 (10.2-11.9) and 11.9 (10.6-13.0) g/dL, respectively. The cumulative incidences of primary and secondary graft failure were 10.0% and 12.5% at 24 months (HLA-identical donor: 0% and 11.1%, haploidentical donor: 17.9% and 3.6%, unrelated donor: 8.8% and 20.6%). Eleven out of 14 patients experiencing graft failure were successfully rescued with a second allograft, while 2 patients were not retransplanted due to parental decision and 1 patient died after the engraftment of the second allograft. Eight patients developed grade II-IV acute graft-versus-host disease (GVHD) and one patient developed moderate chronic GVHD. Cumulative incidence rates of grades II-IV and III-IV acute GVHD were 12.7% and 8.0% at 24 months (HLA-identical donor: 0% and 0%, haploidentical donor: 7.3% and 0%, unrelated donor: 23.8% and 18.8%). Three patients (3.8%) died of transplant-related causes (1 case each of hemophagocytic lymphohistiocytosis, sepsis, and multi-organ failure [the patient receiving the second allograft]) with a median (range) time from transplantation to death of 8.7 (3.7-11.0) months. Of these patients, all had been transplanted from an unrelated donor and 2 had reached sustained full-donor chimerism. The probability of overall and event-free (event defined as either death or primary/secondary graft failure) survival was 96.2% and 81.2% at 24 months (HLA-identical sibling donor: 100% and 88.9%, haploidentical donor: 100% and 78.6%, unrelated donor: 91.2% and 79.4%). The probability of thalassemia-free survival (event defined as either death or primary/secondary graft failure not rescued by a second allograft) was 93.7% at 24 months (HLA-identical sibling donor: 100%, haploidentical donor: 92.9%, unrelated donor: 91.2%). In this large single-center cohort of children with predominantly TDT, allo-HSCT led to beneficial outcomes for most patients, resulting in the discontinuation of transfusions with 93.7% of patients being thalassemia-free. Nevertheless, HSCT is still associated with GVHD, graft failure, and mortality, and only 22.5% of patients had an HLA-identical sibling donor, illustrating a key limitation of allo-HSCT. Emerging research is addressing such barriers to treatment. Disclosures Merli: Novartis: Honoraria; Sobi: Consultancy; Amgen: Honoraria; Bellicum: Consultancy. Algeri:Miltenyi: Honoraria; Atara Biotherapeutics: Consultancy, Honoraria; Bluebird bio: Consultancy, Honoraria. Gruppioni:Bluebird bio: Employment, Equity Ownership. Kommera:Bluebird bio: Employment, Equity Ownership. Maa:Bluebird bio: Employment, Equity Ownership. Locatelli:Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria.

Markers of Initial and Long-Term Responses to Idecabtagene Vicleucel (Ide-Cel; bb2121) in the CRB-401 Study in Relapsed/Refractory Multiple Myeloma

†These authors contributed equally. Introduction Ide-cel, an anti-BCMA CAR T cell therapy, has demonstrated promising efficacy in the phase I CRB-401 trial in relapsed/refractory multiple myeloma (MM) (objective response rate, 85%; median progression-free survival [PFS], 11.8 months [95% CI: 6.2, 17.8]), but a subset of patients failed to respond and the duration of response varied across patients (Raje et al, N Engl J Med. 2019). A systematic examination of patient, product, and post-infusion correlates of overall and long-term response could offer biological insight into heterogeneous efficacy as well as provide biomarkers to guide post-CAR T disease management and future CAR T manufacturing and patient enrollment efforts. Soluble BCMA was of particular interest due to its expression on malignant and healthy plasma cells and its role as a composite measure of disease burden in MM. Methods We performed a retrospective analysis of 33 patients from the phase I CRB-401 study of ide-cel. The concentrations of ten immune-related factors in the blood (GMCSF, IFN-γ, IL-10, IL-1b, IL-2, IL-6, IL-8, MCP-1, TNF-α) and soluble BCMA were measured by ELISA before and after infusion with ide-cel along with 290 ide-cel CAR T-cell drug product attributes measured by flow cytometry and immunoassays. The absolute concentrations and fold-changes from baseline were assessed for correlation with overall and long-term response using univariate and multivariate (random forests) approaches. Results Several CAR T-cell drug product covariates nominally associated with longer PFS included reduced senescence phenotype in CD4 CAR T-cells and increased IL-2 and TNF-α production (P < 0.05). Pre-infusion levels of soluble BCMA correlated with serum monoclonal protein (M-protein) levels in 20 of 33 patients for whom M-protein levels were measurable (ρ = .49; P = 0.03) and with concentrations of the involved free light chain (ρ = .59; P = 0.005) in 23 of 33 patients with measurable levels. Our investigation of soluble BCMA levels in patients achieving a partial response (PR) or better confirmed significant decreases in soluble BCMA levels relative to nonresponders (NR) as early as seven days post-infusion (median reduction of 50% for ≥ PR vs. median increase of 27% for NR, P = 0.02). The fold-change in soluble BCMA 1 month after infusion stratified patients who achieved a PR or better from those who did not (P = 0.0001). Notably, patients who maintained a response to ide-cel for ≥ 18 months (M18 R) experienced a greater depth of clearance of soluble BCMA at month 2 (median concentration of 1835 ng/L for M18 R vs. 6299 ng/L for M18 NR, P = 0.002). The induction of IL-6 and TNF-α in blood on days 1-9 post-infusion was also higher in patients with a PR or better in response to ide-cel (e.g. IL-6 median fold change increase at day 2 of 2.9 for ≥ PR vs. 0.7 for NR, P = 0.001), consistent with an active inflammatory response and higher levels of CAR T expansion. Conclusions These data from CRB-401 identify candidate drug product attributes and soluble factors that correlate with response to ide-cel and potentially MM-directed cellular therapies in general. These data suggest that changes in soluble BCMA may be a robust biomarker of both early and durable responses to ide-cel and the depth of clearance of soluble BCMA at 2 months post-infusion may identify patients at risk of progression before standard markers of myeloma progression have emerged. Further molecular characterization of drug product attributes, including CyTOF and RNA sequencing, is ongoing to identify additional biomarkers associated with clinical outcomes following ide-cel treatment. These data will help inform future strategies to improve the efficacy of ide-cel and validation in a larger cohort is ongoing. Disclosures Thompson: Celgene Corporation: Employment, Equity Ownership. Jiang:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Campbell:Celgene Corporation: Employment, Equity Ownership. Fuller:Celgene Corporation: Employment, Equity Ownership. Kaiser:Celgene Corporation: Employment. Mashadi-Hossein:Celgene Corporation: Employment, Equity Ownership. Rytlewski:Adaptive Biotechnologies: Equity Ownership; Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Martin:Celgene Corporation: Employment, Equity Ownership. Finney:bluebird bio Inc.: Employment. Kleinsteuber:bluebird bio Inc.: Employment, Equity Ownership. Alonzo:bluebird bio Inc.: Employment, Equity Ownership. Pandya:bluebird bio Inc.: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees. Raje:Merck: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Celgene Corporation: Consultancy; Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy. Munshi:Celgene: Consultancy; Oncopep: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Abbvie: Consultancy; Adaptive: Consultancy. Hause:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. OffLabel Disclosure: ide-cel /bb2121 is an investigational agent and not yet approved in the US

Stenosis Outcome at 1 and 3 Years after Transplantation Vs Standard-Care in Children with Sickle-Cell Anemia and Abnormal Transcranial Doppler with Stroke or No-Stroke History

The presence of cerebral macrovasculopathy as detected by transcranial Doppler (TCD) exposes children with sickle cell anemia (SCA) to a high risk of stroke, preventable by chronic transfusion or stem cell transplantation (SCT). However, long-term outcomes of stenosis have not been well described. The Drepagreffe trial (NCT01340404) was a prospective trial comparing cerebral vasculopathy outcome after SCT vs standard-care in children with abnormal TCD with or without stroke history. Results from the whole population have recently been reported (Bernaudin et al, JAMA 2019). The decrease in velocities was significantly higher after SCT than standard-care (p<0.001) at 1 and 3-year, but the stenosis score was not different between both treatment groups. The aim of the present study was to determine stenosis outcome as a function of stroke or no-stroke history in both treatment groups using detailed post-hoc analysis. Sixty-seven SCA-children on chronic transfusion for abnormal-TCD history were enrolled (Dec-2010/June-2013) in this prospective trial with two treatment groups defined by the random-availability of having a matched-sibling donor (MSD). Thirty-two with MSD were transplanted while 35 without MSD were maintained on chronic transfusion for at least one-year and eventually switched to hydroxyurea thereafter if no stenosis and normalized velocities. Cerebral and cervical magnetic-resonance angiography (MRA) was systematically performed at enrollment, and 1- and 3-year post-enrollment. Stenosis was defined as a narrowing ≥25%. The MRA stenosis-score, was calculated as the weighted sum of the scores in the 8 assessed cerebral arteries (right and left middle cerebral (MCA), anterior (ACA), internal carotid (ICA) and extracranial internal carotid arteries (eICA)), with 0 = stenosis, 1 = mild stenosis (25-49%), 2 = moderate stenosis (50-74%), 3 = severe stenosis (75-99%), and 4 = occlusion. All 67 patients were alive at 3-year, and the 32 transplanted patients successfully engrafted. No stroke or recurrence occurred during the follow-up. No chronic-GVHD was observed. Among the 7 patients with stroke-history, all had stenosis at enrollment and the stenosis score increased in the 4 transplanted patients, but always in the arteries with previous stenosis and those feeding ischemic territories, while stenosis score remained mostly stable in the 3 patients maintained on chronic transfusion,. However, the difference between treatment groups was not significant (p=0.057). Among the 60 stroke-free patients at enrollment, 28 with MSD were transplanted while 32 without MSD were maintained on chronic transfusion. At enrollment, 28 patients (14 patients in each treatment group) had stenosis. At 1-year, 9 patients in the SCT group had stenosis, whereas in the transfusion/standard-care group, 10 had stenosis. At 3-year, 5 patients in the SCT group had stenosis, while 10 still had stenosis in the standard-care group. Moreover, 2 patients, who had no stenosis at enrollment, developed one stenosis between 1 and 3-year, despite chronic transfusion in one case and after switch to hydroxyurea in the other. In another patient, stenosis had disappeared on chronic transfusion at 1-year, although it reappeared at 3-year after a switch to hydroxyurea. In the SCT group, no worsening of stenosis was observed, and stenosis improved in 13/14 and was stable in one; in contrast, worsening of stenosis score was observed in the standard-care group in 6 patients on chronic transfusion (p=0.035), The stenosis-score between enrollment and 3-year improved more significantly in the SCT group (mean (SD): -1.39 (2.47)) than in the standard care group (-0.06 (1.18)); (p=0.012). Conclusions: This prospective trial reporting the outcome of stenosis in stroke and stroke-free SCA-patients with a history of abnormal-TCD shows a trend to worsening of the stenosis-score after SCT in stroke-patients, but no stroke recurrence; in contrast, in stroke-free patients, stenosis outcome was significantly better after SCT and with better prevention of stenosis occurrence than on standard care. These results support early recommendation of SCT in children with a history of abnormal-TCD and an MSD. Figure Disclosures Verlhac: Addmedica, Paris: Other: Financial Support; Bluebird Bio: Consultancy. Brousse:bluebird bio: Consultancy; Add medica: Consultancy. De Montalembert:Addmedica: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees. Thuret:BlueBird bio: Other: investigators for clinical trials, participation on scientific/medical advisory board; Celgene: Other: investigators for clinical trials, participation on scientific/medical advisory board; Novartis: Other: investigators for clinical trials, participation on scientific/medical advisory board; Apopharma: Consultancy. Bernaudin:GBT: Membership on an entity's Board of Directors or advisory committees; AddMedica: Honoraria, Other: Help for travel to meeting; BlueBirdBio: Consultancy.

Characterization of the Severe Phenotype of Pyruvate Kinase Deficiency

Background: Pyruvate kinase deficiency (PKD) is the most common cause of chronic hereditary non-spherocytic hemolytic anemia. The spectrum of disease in PKD is broad, ranging from an incidentally discovered mild anemia to a severe transfusion-dependent anemia. Splenectomy partially ameliorates the anemia and reduces the transfusion burden in the majority of patients. Because hemoglobin poorly correlates with symptoms in PKD, transfusion requirements are typically used clinically to classify disease severity with those who are regularly transfused despite splenectomy recognized as the most severely affected subgroup. Aim: To compare demographics, complications, and laboratory results between the most severely-affected PKD patients (those that are splenectomized and regularly transfused) with non-regularly transfused splenectomized PKD patients. Methods: After ethics committee approval, patients were enrolled on the PKD Natural History Study, a prospective 30 site international study. All patients had molecularly confirmed PKD. Only splenectomized patients were included in the analysis. Transfusion frequency was observed over a 3-year period. Patients were divided into two groups based on transfusion frequency: the severe phenotype group was defined as those who receive regular transfusions (≥6 discrete red cell transfusion episodes per year) and the control group did not receive regular transfusions. Phenotype stability over the 3-year period was also assessed. Results: 154 splenectomized patients with PKD were included: 30 patients in the severe PKD phenotype group and 124 patients in the comparison PKD group. Results of the analysis comparing the two groups are described in the Table. Severely affected patients were more likely to be female (77% versus 51%, p=0.013), older at the time of splenectomy (median age: 5 versus 3.6, p=0.011), have iron overload (93% vs. 51%, p<0.0001), have received chelation therapy (90% vs. 42%, p<0.0001), and had more lifetime transfusions (median: 77 versus 15, p<0.0001). Rates of other PKD complications including pulmonary hypertension, extramedullary hematopoiesis, liver cirrhosis, endocrinopathy, and bone fracture appear similar between the two groups. Laboratory values, including hemoglobin, total bilirubin, normalized PK enzyme activity, and median absolute reticulocyte count appear similar between the two groups. The underlying genetic mutation patterns (missense mutations versus non-missense mutations) were also similar between the groups. Phenotype stability over time was highly variable: of the patients with a severe phenotype at enrollment, 62% had a severe phenotype during the first follow-up year and 39% had a severe phenotype at the second follow-up year. Conclusions: Patients with PKD who are regularly transfused despite splenectomy appeared to have similar rates of PKD-associated complications (except for iron overload) and similar relevant laboratory values and genotypes when compared to those who are not regularly transfused after splenectomy. The similarity observed between severe phenotype patients and comparison patients with PKD may result from a protective effect of transfusion (e.g. reduction of bone fractures and extramedullary hematopoiesis) or could suggest transfusion-dependence is an artificial signifier of disease severity, reflective of provider practices and patient symptoms rather than an actual distinct phenotype. Transfusion requirements in severe PKD appear to fluctuate significantly over time. Disclosures Al-Samkari: Dova: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Moderna: Consultancy. van Beers:RR Mechatronics: Research Funding; Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding. Barcellini:Agios: Consultancy, Other: Advisory board; Apellis: Consultancy; Incyte: Consultancy, Other: Advisory board; Bioverativ: Consultancy, Other: Advisory board; Novartis: Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau. Eber:Agios Pharmaceuticals, Inc.: Consultancy. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chonat:Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Kuo:Pfizer: Consultancy; Novartis: Consultancy, Honoraria; Celgene: Consultancy; Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy. Despotovic:Dova: Honoraria; Novartis: Research Funding; Amgen: Research Funding. Kwiatkowski:Celgene: Consultancy; Terumo: Research Funding; Apopharma: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Imara: Consultancy; Novartis: Research Funding. Thompson:Baxalta: Research Funding; Novartis: Consultancy, Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Rothman:Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Verhovsek:Sickle Cell Awareness Group of Ontario: Membership on an entity's Board of Directors or advisory committees; Sickle Cell Disease Association of Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding; Canadian Haemoglobinopathy Association: Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy. Kunz:Novartis: Membership on an entity's Board of Directors or advisory committees. Sheth:CRSPR/Vertex: Other: Clinical Trial Steering committee; Apopharma: Other: Clinical trial DSMB; Celgene: Consultancy. London:United Therapeutics: Consultancy; ArQule, Inc: Consultancy. Grace:Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Pyruvate Kinase (PK) Protein and Enzyme Levels in the Diagnosis and Clinical Phenotype of PK Deficiency

Background: Pyruvate Kinase (PK) deficiency is caused by mutations in the PKLR gene leading to chronic hereditary non-spherocytic hemolytic anemia. Diagnostic evaluation can be challenging with falsely normal PK enzyme activity levels in chronically transfused patients, in those with profound reticulocytosis, or in patients with mutations with unusual biochemical properties. Genetic testing can also be complex, as up to 20% of affected patients have new PKLR variants and up to 10% of patients have variants not routinely detected through exon sequencing. The phenotypic spectrum is broad, and biomarkers of clinical severity would be helpful for both prognosis and monitoring. Aims: To describe the correlation of PK enzyme activity, red cell PK (PK-R) protein level, and red cell metabolites [adenosine triphosphate (ATP), 2,3-diphosphoglycerate (2,3-DPG)] with clinical phenotype. To estimate the sensitivity of PK enzyme activity to diagnose PK deficiency in a cohort of patients with genetically confirmed PK deficiency. Methods: Blood samples were collected from a subset of 41 patients enrolled in the PK Deficiency Natural History Study, all with two confirmed PKLR mutations and no red cell transfusions for ≥3 months prior to the blood sample. PK and hexokinase (HK) enzyme activity testing were performed using standard biochemical assays (Beutler 1985) at the Stanford Red Blood Cell Special Studies Laboratory (normal ranges: PK activity: 3.2-6.5 EU/gm Hb, HK activity: 0.14-0.37 EU/gm Hb). Baseline PK-R protein was quantitated by antibody-based capture and detection using a Meso Scale assay and the signal normalized to a control sample without PK deficiency. ATP and 2,3-DPG concentrations (μg/ml) in blood were analyzed using qualified tandem mass spectrometry methods and then normalized for individual hemoglobin (Hb) values (ATP and 2,3-DPG concentrations were converted to g/dL and divided by Hb (g/dL)). Spearman correlation coefficients were calculated to estimate the correlation between continuous variables, and Wilcoxon rank-sum testing was used to assess the association of continuous and binary variables. Results: The median age was 25.3 years (range 1.4-60.4) and 80% of patients were splenectomized (Table). The mean PK enzyme activity level was 1.1 EU/gm Hb with 90% (37/41) of patients with low PK activity. Normal PK activity was observed in 4 patients, 3 of whom had high HK activity and a low PK/HK ratio (normal mean PK/HK ratio 15.6, range: 8.7-22.5), with a sensitivity of 98% (40/41) when both PK activity and PK/HK ratio were used together. There were no correlations between PK enzyme activity and clinical severity indicators, including transfusion status (p=0.3), splenectomy status (p=0.4), or post-splenectomy Hb (r=0.109). Normalized ATP levels were significantly correlated with normalized 2,3-DPG levels (r=0.93) and higher in ever transfused (median=0.0022, range=0.0011-0.0029) compared with never transfused patients (median=0.0012 , range=0.0008-0.0020), (p=0.004). PK-R protein level was inversely correlated with the total number of transfusions prior to enrollment (r= -0.53) and was higher in never transfused (median=40.1%, range=9.8-73.9%) compared with ever transfused patients (median=7.7%, range=0.4%-15.1%), (p=0.0014). Conclusions: In this cohort with a molecularly confirmed diagnosis, PK deficiency was detected by enzyme testing with 98% sensitivity by utilizing both the PK activity and the PK/HK ratio. Although these assays cannot distinguish between heterozygotes and affected patients, the combination of PK activity and the PK/HK ratio is useful as a screening test to determine which patients require genetic testing. There was no correlation between PK enzyme activity and clinical phenotype. PK-R protein and ATP levels were inversely correlated with clinical severity and may be a helpful marker of disease phenotype. Disclosures Al-Samkari: Agios: Consultancy, Research Funding; Moderna: Consultancy; Dova: Consultancy, Research Funding. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chonat:Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Thompson:bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Kuo:Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Rothman:Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Kwiatkowski:Celgene: Consultancy; Terumo: Research Funding; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy. Kung:Agios Pharmaceuticals, Inc: Employment, Other: Stakeholder. Kosinski:Agios Pharmaceuticals, Inc: Employment, Other: Stakeholder. London:United Therapeutics: Consultancy; ArQule, Inc: Consultancy. Grace:Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Mitapivat (AG-348), an Oral PK-R Activator, in Adults with Non-Transfusion Dependent Thalassemia: A Phase 2, Open-Label, Multicenter Study in Progress

Background: Thalassemia is a group of inherited blood disorders in which genetic mutation(s) in the α- and/or β-globin locus lead to excess precipitation of β- or α-globin, respectively, and compromised red blood cell (RBC) survival. The condition is characterized by ineffective erythropoiesis and peripheral hemolysis, with resultant anemia. Adenosine triphosphate (ATP) supply appears to be insufficient in thalassemic RBCs to maintain RBC membrane fitness and clearance of globin precipitates. Mitapivat (AG-348) is an oral, small-molecule, allosteric activator of the RBC-specific form of pyruvate kinase (PK-R). PK-R is a key enzyme for maintaining energy homeostasis in RBCs, as they rely almost exclusively on the process of glycolysis to generate ATP. In healthy adults, mitapivat activates wild-type PK-R and increases ATP levels in RBCs. In adults with PK deficiency who were not regularly transfused, oral mitapivat was well tolerated and induced rapid, durable hemoglobin (Hb) increases (NCT02476916). In the Hbbth/3+ mouse model of β-thalassemia, mitapivat increased ATP levels; reduced markers of ineffective erythropoiesis; and improved anemia, RBC survival, and indices of iron overload. These data support the hypothesis that increased ATP synthesis mediated via PK-R activation by mitapivat may improve the survival of thalassemic RBCs in the bone marrow and/or peripheral circulation, and thus represents a novel mechanism to treat patients with thalassemia. Here we present the design of a phase 2, open-label study designed to test this hypothesis and assess the proof of concept of mitapivat in patients with thalassemia. Methods: This phase 2, multicenter, open-label study (NCT03692052) is evaluating the efficacy, safety, pharmacokinetics, and pharmacodynamics of mitapivat in adults with non-transfusion-dependent thalassemia (NTDT). Four sites in North America and the United Kingdom are enrolling patients. The study consists of a 24-week core period followed by a 2-year extension period (Figure). Approximately 17 subjects with NTDT, i.e., β-thalassemia with or without α-globin gene mutations, HbE β-thalassemia, or α-thalassemia (HbH disease), will be enrolled. Non-transfusion dependence is defined as ≤5 units of RBCs transfused in the preceding 24 weeks and no transfusions in the 8 weeks prior to the first day of study drug. The hemoglobin inclusion criterion is ≤10.0 g/dL, which was increased from ≤9.0 g/dL in a recent protocol amendment to better reflect the clinical representation in the NTDT patient population. All eligible patients will receive an initial mitapivat dose of 50 mg twice daily (BID). At the week 6 visit the dose may be increased to 100 mg BID, depending on safety and Hb response. The primary endpoint is the proportion of subjects who achieve an Hb response, defined as an increase in Hb of ≥1.0 g/dL from baseline at any time between week 4 and week 12 (inclusive). Key secondary and exploratory endpoints include changes in Hb and markers of hemolysis; hematopoietic activity; iron metabolism and iron overload; and assessments of safety and pharmacokinetics. The study is currently enrolling. Figure Disclosures Kuo: Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Layton:Cerus Corporation: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Uhlig:Agios: Employment, Equity Ownership. Lynch:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Vichinsky:GBT: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Agios: Consultancy, Research Funding; bluebird bio: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Long-Term Outcome of Children with Acute Leukemia (AL) Given Alphabeta T and B-Cell Depleted HLA-Haploidentical Hematopoietic Stem Cell Transplantation (TBdepl-haploHSCT)

Background: TBdepl-haploHSCT is a suitable option for children with AL in need of an allograft, lacking an HLA-compatible donor. We previously published promising results in a cohort of 80 children with AL, given this type of allograft (Locatelli et al., Blood 2017), demonstrating a low incidence of acute and chronic graft-versus-host disease (GvHD) and low non-relapse mortality (NRM), translating into a final outcome comparable to that of patients transplanted from an HLA-compatible donor. We present the long-term follow-up analysis of this study (NCT01810120), now including 134 patients, with a minimum observation time of 100 days after the allograft. Patients and methods: Between October 2010 and April 2019, 134 children with AL in morphological complete remission (CR) received TBdepl-haploHSCT from an HLA-partially matched relative (a parent in 97% of cases) at Ospedale Pediatrico Bambino Gesù in Rome, Italy. All patients were prepared to the allograft using a fully-myeloablative conditioning regimen including a combination of cytotoxic drugs and/or total body irradiation (TBI). Anti-T-lymphocyte globulin (ATLG) was used before transplantation (12 mg/kg total dose, from days -5 to day -3) to modulate bi-directional donor/recipient alloreactivity. Rituximab (200 mg/sqm) was administered on day -1 to prevent post-transplantation EBV-induced lymphoproliferative disorders (PTLD). No patient received any post-transplant GvHD prophylaxis. Results: Characteristics of patients enrolled in the study are shown in Table 1. Median follow-up of surviving patients is 60 months (range: 3 months - 8.7 years). Only 3 patients did not achieve engraftment (all affected by acute myeloid leukemia and who did not receive TBI during conditioning regimen); median time to neutrophil and platelet recovery was 13 (range 9-22) and 11 (range 8-23) days, respectively. Cumulative incidence of grade II-III acute GvHD was 16.5% (95% CI 9.9-22.6). One patient developed gut GvHD, while for all other patients skin was the sole organ involved; no case of grade IV GvHD was recorded. Eight out of the 123 patients at risk developed chronic GvHD, in all cases of limited severity, the cumulative incidence of this complication being 7.6% (95% CI 2.3-12.6). Six patients died for transplant-related complications (2 because of idiopathic pneumonitis and 1 each of disseminated adenovirus infection, cardiac insufficiency, combined CMV/rhinovirus pneumonia and sepsis from Pseudomonas aeruginosa), the 5-year cumulative incidence of NRM being 4.5% (95% CI, 1.8-9.0). Since 25 patients relapsed at a median time of 173 days (range 59-1012) after HSCT, the 5-year cumulative incidence of relapse is 21.1% (95% CI, 14.2-29.1). The 5-year probability of overall and leukemia-free survival (LFS) were 74.6 (95% CI 65.1 -71.9) and 74.4% (95% CI 65.4-81.4) (Figure 1A), respectively. Use of TBI during the preparative regimen, age at transplant above the median value (Figure 1B) and disease status at transplantation (CR1 and CR2, Figure 1C) were associated with better patient's outcome, because of a reduced incidence of relapse (Figure 1D for TBI). All these 3 factors remained statistically significant in multivariable analysis for LFS: hazard ratio (HR) for TBI was 0.16 (95% CI, 0.06- 0.37, p<0.001, HR for age at HSCT was 0.27 (95% CI, 0.11-0.65, p=0.003), while that for disease status was 0.49 (95% CI, 0.26-0.91, p=0.02), respectively. The 5-year GvHD/relapse-free survival was 69.9% (95% CI 60.8-77.3). The median CD3+ cell count on day +30, +90, +180 and +360 were 187, 215, 660 and 1260/mcl, respectively. Conclusions: These data confirm in a larger population and with a longer follow-up that TBdepl-haploHSCT is a safe and effective transplant option, being associated with a low risk of both NRM and acute/chronic GvHD, resulting into a 5-year LFS comparable or even better with that reported in studies using either an HLA-identical sibling or an unrelated volunteer as donor. In particular, the low incidence of chronic GvHD preserves a good quality of life in patients with long life-expectancy. Leukemia recurrence represents the main cause of treatment failure and strategies based either on the use of a titrated number of donor T cells transduced with a safety switch or ex-vivo depleted of the alloreactive component could further improve patient's outcome. Figure 1 Disclosures Merli: Novartis: Honoraria; Sobi: Consultancy; Amgen: Honoraria; Bellicum: Consultancy. Algeri:Miltenyi: Honoraria; Atara Biotherapeutics: Consultancy, Honoraria; Bluebird bio: Consultancy, Honoraria. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Comorbidities and Complications in Adults with Pyruvate Kinase Deficiency

Comorbidities and Complications in Adults with Pyruvate Kinase Deficiency

Preliminary Results of a Phase 1/2 Clinical Study of Zinc Finger Nuclease-Mediated Editing of BCL11A in Autologous Hematopoietic Stem Cells for Transfusion-Dependent Beta Thalassemia

Introduction: Persistently high fetal hemoglobin (HbF) expression can ameliorate severe transfusion-dependent beta thalassemia (TDT). BCL11A, a master regulator of the fetal-to-adult hemoglobin switch, is a rational gene-editing target in beta globinopathies. In pre-clinical studies with human hematopoietic stem cells (HSC), zinc finger nuclease (ZFN)-mediated disruption of the GATA-binding region of the intronic erythroid-specific enhancer (BCL11A ESE) increased endogenous HbF production in erythroid cells while allowing healthy, multi-lineage hematopoiesis. Though allogeneic hematopoietic stem cell transplantation (HSCT) can be curative in TDT, its application is partly limited by donor availability. Autologous transplantation using ex vivo gene-modified HSCs (HSCGT) can circumvent this, and lentiviral vector-mediated beta globin gene addition studies have shown efficacy in TDT. However, the long-term safety of random lentiviral genomic integration in HSCs is uncertain. ST-400 is an investigational cell therapy comprised of autologous CD34+ cells that have undergone high-precision, ZFN-mediated ex vivo editing at BCL11A ESE. The aim of this study is to induce HbF expression in edited erythroid cells. We hypothesized that HSCGT with ST-400 is safe and effective in TDT. Methods: The Thales trial (NCT03432364) is a Phase I/II study of the safety, tolerability and efficacy of ST-400 in adult patients with TDT, defined as undergoing ≥8 annual packed red blood cell transfusion episodes for at least 2 consecutive years before enrollment. After routine leukapheresis following mobilization with G-CSF and plerixafor, autologous collections are enriched for CD34+ cells and transfected with mRNA encoding ZFNs with binding sites flanking the GATA-binding region of BCL11A ESE. ST-400 product is infused following myeloablative busulfan conditioning. The trial will enroll 6 patients who are monitored for safety and efficacy for 3 years post-infusion. Results: Three patients have completed ST-400 manufacturing, and two have been infused. Patient 1 (β0/β0 genotype) received an ST-400 dose of 6.1 x 106 cells/kg. The patient experienced a serious adverse event (SAE) of hypersensitivity during ST-400 infusion considered to be related to the product cryoprotectant, DMSO, that resolved by the end of infusion. The patient had prompt hematopoietic reconstitution (ANC recovery day +14; platelet recovery day +24), with increasing HbF fraction that contributed to stable total hemoglobin. After being free from PRBC transfusions for 6 weeks, the patient has since required intermittent PRBC transfusions. At last follow-up, on-target DNA insertions-deletions (indels) at BCL11A ESE were present in peripheral blood mononuclear cells (PBMCs), and HbF levels remain elevated at 6 months post-infusion. Patient 2 (homozygous for the severe β+ IVS-I-5 G>C mutation) received an ST-400 dose of 4.5 x 106 cells/kg. There was prompt hematopoietic reconstitution (ANC recovery day +15; platelet recovery day +29) with on-target indels detected in PBMCs at last follow-up, and rising HbF levels observed through 90 days post-infusion. Longer follow-up will be required to assess the clinical significance of these early results. Patient 3 (β0/β+ genotype including the severe IVS-II-654 C>T mutation) has completed ST-400 manufacturing. Besides the SAE reported for Patient 1, no other SAEs related to ST-400 have been reported and other AEs have been consistent with myeloablation. No clonal hematopoiesis has been observed. Conclusions: ST-400 is an ex vivo, ZFN-edited autologous HSC product for increased erythroid HbF expression in TDT. Two infused patients had rapid hematopoietic reconstitution following myeloablative conditioning, and both have elevated HbF levels following HSCGT. These data are preliminary, and additional patients and longer follow-up will be required to understand the safety and efficacy of this therapy. Disclosures Smith: Amgen: Research Funding; Jazz Pharmaceuticals: Research Funding. Schiller:Agios: Research Funding, Speakers Bureau; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Amgen: Other, Research Funding; Daiichi Sankyo: Research Funding; Constellation Pharmaceutical: Research Funding; Celgene: Research Funding, Speakers Bureau; Bristol Myer Squibb: Research Funding; Biomed Valley Discoveries: Research Funding; Astellas: Research Funding. Vercellotti:Mitobridge, an Astellas Company: Consultancy, Research Funding. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Terumo: Research Funding; Novartis: Research Funding; Apopharma: Research Funding; Imara: Consultancy; Celgene: Consultancy. Williams:bluebird bio: Patents & Royalties: License of certain IP relevant to hemoglobinopathies to bluebird bio. Potential for future royalty/milestone income., Research Funding; Orchard Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Co-founder, Patents & Royalties: Potential for future royalty/milestone income, X-SCID., Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Alerion Biosciences: Other: Co-founder. Miller:Sangamo Therapeutics: Employment, Equity Ownership. Woolfson:Sangamo Therapeutics: Employment, Equity Ownership. Walters:Editas Medicine: Consultancy; TruCode: Consultancy; AllCells, Inc: Consultancy. OffLabel Disclosure: busulfan: used for myeloablation prior to infusing the investigational autologous HSPC product (ST-400) plerixafor: used with G-CSF to enhance mobilization of autologous HSPC for collection via leukapheresis. Autologous HSPC then undergo ex vivo manufacturing to generate the investigational product (ST-400)

Randomized Controlled Trial of the Efficacy and Safety of Deferiprone in Iron-Overloaded Patients with Sickle Cell Disease or Other Anemias

Randomized Controlled Trial of the Efficacy and Safety of Deferiprone in Iron-Overloaded Patients with Sickle Cell Disease or Other Anemias

Crizanlizumab Treatment Is Associated with Clinically Significant Reductions in Hospitalization in Patients with Sickle Cell Disease: Results from the Sustain Study

Background: Sickle cell disease (SCD) is characterized by the presence of sickle hemoglobin (HbS), chronic hemolysis, recurrent pain episodes called vaso-occlusive crises (VOCs), multiorgan dysfunction and early death. VOCs decrease quality of life, are the main cause of healthcare encounters in SCD, and increase the risk of death. New therapies that reduce SCD hospitalizations are desirable given the potential to impact healthcare utilization, but also to reduce disease burden and decrease mortality and morbidity. The SUSTAIN study (Ataga et al. NEJM 2017), was a Phase 2, multicenter, randomized, placebo-controlled, double-blind, 12-month study to assess safety and efficacy of crizanlizumab (2.5 and 5 mg/kg) with or without hydroxyurea therapy, in patients with SCD and a history of 2-10 VOCs in the previous 12 months (NCT01895361). The primary efficacy endpoint was annual rate of SCD-related pain crises (VOCs) leading to healthcare visit. The key secondary endpoint was annual rate of days hospitalized, regardless of cause. There was a statistically significant 45.3% reduction in median annual rate of VOCs leading to healthcare visit with crizanlizumab 5 mg/kg compared with placebo (1.63 vs 2.98 VOCs/year, P=0.01). There was a 41.8% reduction in median rate of days hospitalized with crizanlizumab 5 mg/kg compared with placebo (4.00 vs 6.87 days/year). Although this difference was not statistically significant (P=0.45), it appears to be clinically relevant. Methods: A post-hoc analysis of the SUSTAIN data was performed to better characterize the difference in the annual rate of days hospitalized between the crizanlizumab 5 mg/kg and placebo arms, and to compare the distribution of hospitalizations and time to first hospitalization. Results: As illustrated in Figure 1, a greater proportion of patients in the crizanlizumab arm (46%) were not hospitalized during the trial period (up to end of treatment) than in the placebo arm (35%). Correspondingly, the percentage of patients with ≥1 hospitalization was lower in the crizanlizumab (54%) than the placebo arm (65%). In addition, a trend for delayed time to first hospitalization shown in Figure 1 was further explored with a Kaplan-Meier (KM) analysis (Figure 2). Figure 2 shows clear separation of the curves, evident from Month 1 of treatment. The median time to first hospitalization was greater with crizanlizumab 5 mg/kg than with placebo (6.3 vs 3.2 months; hazard ratio [HR] 0.683 [95% CI 0.437-1.066]). The apparent improvement in time to first hospitalization is consistent with previously published SUSTAIN results regarding median time to first VOC leading to healthcare visit. Patients treated with crizanlizumab 5 mg/kg were found to experience a longer median time to first VOC leading to healthcare visit than patients on placebo (4.07 vs 1.38 months; HR 0.50 [95% CI 0.33-0.74]). Conclusions: The primary SUSTAIN results showed that crizanlizumab reduced VOCs leading to a healthcare visit. This analysis demonstrates additional positive trends associated with crizanlizumab treatment compared to placebo, regarding the percentage of patients with no hospitalizations and a delayed time to first hospitalization. Together, these findings provide further evidence that crizanlizumab may have a beneficial impact on reducing hospitalizations. Disclosures Ataga: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Emmaus Life Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Modus Therapeutics: Honoraria. Kutlar:Micelle Biopharma: Other: DSMB Chair; Novartis: Consultancy; Global Blood Therapeutics, Inc. (GBT): Research Funding; Novo Nordisk: Research Funding; Bluebird Bio: Other: DSMB Member. DeBonnett:Novartis Pharmaceuticals Corporation: Employment. Lincy:NOVARTIS PHARMA AG: Employment. Kanter:Novartis: Consultancy, Honoraria; Imara: Consultancy; Sangamo: Consultancy, Honoraria; Modus: Consultancy, Honoraria; Guidepoint Global: Consultancy; GLG: Consultancy; Cowen: Consultancy; Jeffries: Consultancy; Medscape: Honoraria; Rockpointe: Honoraria; Peerview: Honoraria; SCDAA: Membership on an entity's Board of Directors or advisory committees; NHLBI: Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy.

Academic, Phase I/II Trial on T Cells Expressing a Second Generation, CD19-Specific Chimeric Antigen Receptor (CAR) and Inducible Caspase 9 Safety Switch for the Treatment of B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) and B-Cell Non-Hodgkin Lymphoma (B-NHL) in Children

Survival rates of children with relapsed/refractory (r/r) BCP-ALL remain unsatisfactory and little progress has been made in the past 2 decades. Similarly, relapse of childhood B-NHL is usually associated with an aggressive disease and poor outcomes. Targeted immunotherapy with T-cells genetically modified to express a CD19-directed CAR showed an unprecedented antitumor efficacy, leading to the recent FDA and EMA approval of two CD19-CAR products for treatment of BCP-ALL and B-NHL. Relevant toxicities have, however, been reported, mainly related to the development of severe Cytokine Release Syndrome (CRS) and/or of neurotoxicity. At Ospedale Pediatrico Bambino Gesù (OPBG) in Rome, we developed a clinical-grade, 2nd generation, CD19-specific CAR construct, including 4.1bb as costimulatory domain and the inducible caspase-9 safety switch (iC9-CD19-CAR), vehiculated by a retroviral vector, to conduct an academic, phase I/II clinical trial in patients (age 1-25 yrs) affected by BCP-ALL or B-NHL. We now report on the results of the phase I and of the first 8 patients treated in the phase II portion of the study, in terms of feasibility, toxicity, maximum tolerated/recommended dose (MTD/RD) and data on response rate and biological correlates. The phase I, dose-escalation portion of the study included 3 dose levels (DL), namely: DL1, 0.5×106; DL2, 1.5×106; DL3, 3.0×106 CAR+ T cells per kg of recipient body weight. In the phase II portion, patients were treated at the RD identified in the phase I, namely 3.0×106 CAR+cells/kg. All patients received a lymphodepleting regimen consisting of fludarabine and cyclophosphamide for 3 days and iC9-CD19-CAR T cells were subsequently administered as single infusion. Patients were monitored for toxicity, expansion and persistence of iC9-CD19-CAR T cells. Seventeen children were enrolled into the trial and received iC9-CD19-CAR T cells between January 2018 and June 2019. Data were analyzed as of July 20, 2019. The characteristics of the patients are detailed in table 1. The designed dose concentration was successfully produced for all the enrolled patients and we did not observe any production failure. The median transduction rate in the drug product was 54% (range 21-73), while the median vector copy number was 3.8 (range 2.8-6.2). During the phase I portion of the study, no dose limiting toxicities (DLTs) have been recorded, defining the MTD as 3.0×106 CAR+ T cells per kg of recipient body weight. The treatment was overall tolerated and all the toxicities were reversible, the most severe being grade 3-4 neutropenia, thrombocytopenia and/or anemia, occurring in 16/17 (94.1%) patients; in 13/16 patients (81.2%) the hematological toxicity developed before the infusion and persisted after the administration of CAR T cells. Cytokine release syndrome (CRS) occurred in 10/17 patients (58.8%) and was overall moderate, reaching grade 3 (Lee criteria) in one patient only. Notably, none of the patients developed neurotoxicity and no activation of the safety switch was required. All patients were assessed for response at 4 weeks from iC9-CD19-CAR T cell infusion and 13/15 (86.7%) patients with ALL achieved complete remission (CR) with negativity of minimal residual disease (MRD), including 2/3 patients receiving the DL1, 9 patients who had failed a previous allogeneic haematopoietic stem-cell transplantation (HSCT) and 6 patients that had previously received blinatumomab, as CD19-directed immunotherapy. The iC9-CD19-CAR T cells expanded in vivo and were detectable by both flow-cytometry and molecular biology in the blood (Fig.1), bone marrow and cerebrospinal fluid of the responders. One CD19-negative relapse 3 months after infusion was recorded, while 3 additional patients relapsed with CD19+ leukemia blasts. Four patients received HSCT while in CR with MRD negativity because of regrowth of normal CD19+ B cells. The 18-month probability of overall survival for the BCP-ALL cohort is 72.2% (Fig.2). One of the 2 B-NHL patients showed a partial response. Our data indicate that iC9-CD19-CAR T cell in an academic setting is feasible, safe and extremely effective in treating highly resistant/relapsed BCP-ALL. In our trial, no major or life-threatening toxicities were observed and, despite the moderate CRS recorded, high rates of CR were achieved, suggesting that the combination of a retroviral platform and 4.1bb as costimulation is able to mediate a potent antitumor effect Disclosures Merli: Amgen: Honoraria; Novartis: Honoraria; Sobi: Consultancy; Bellicum: Consultancy. Algeri:Bluebird bio: Consultancy, Honoraria; Atara Biotherapeutics: Consultancy, Honoraria; Miltenyi: Honoraria. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Evaluation of Outcomes and Quality of Care in Children with Sickle Cell Disease Diagnosed By Newborn Screening: A Real-World Nation-Wide Study in France

Background: The goals of newborn screening programs (NBS) for sickle cell disease (SCD) are to reduce early mortality and morbidity, by introducing preventive measures like penicillin prophylaxis, pneumococcal vaccines and Transcranial Doppler (TCD) screening. The main objective of this study (NCT 03119922) was to assess on a national scale and during the first 5 years residual risks of death, overt stroke and bacterial meningitis/septicemia resulting from current TCD and pneumococcal prophylactic utilization in SCD children diagnosed at birth. An additional objective was to determine the frequency of other main SCD-related events and the use of disease-modifying or curative therapy. Methods: Using the national NBS database between 2006-2010, data was collected in 2014/2015 from the patients' medical files up to the age of 5 years, and included age at first prescription of penicillin, occurrence of death/overt stroke/bacterial meningitis and septicemia, age at first transfusion (TF), use of pneumococcal vaccines/chronic transfusion program/hydroxyurea (HU)/hematopoietic stem cell transplantation (HSCT) and TCD results. Results: Out of 1792 eligible subjects, 152 (8%) were lost to follow-up. A total of 1620 patients with available follow-up data across 69 centers constituted the EVADREP cohort. Of them, 71.8% had SS or S beta°-thalassemia (SB°) while 20.3% had SC /S Beta+-thalassemia (SB+) disease, and 59.6% resided in Paris area. Overall mortality rate for all patients was 0.23/100 person-years during the 5 first years of life and probability of survival at 5 years was 98.9% (95%CI: 98.2-99.3), with 18 deaths during the study period, 12 related to SCD (11 patients SS or SB°). The probability of overt stroke at 5 years was 1.1% all in SS/SB° patients. DTC was performed in 56% and 81% of patients before 2 and 3 years of age, respectively. The probability of abnormal TCD at 5 years was 10.4%. A total of 26 patients had a severe infection (meningitis or septicemia), lethal in 8 cases and caused by a pneumococcal strain in 8 cases. More than 99% of patients were prescribed prophylactic penicillin, started at a median age of 2.2 months of life. Full pneumococcal vaccination (at least 4 PCV and one P23) was performed in only 47.4% before 3 years but the probability of receiving P23 was 90% at 5 years. At 3 years, 42.9% of the EVADREP cohort had experienced a first VOE and the probability of survival without VOE was 62.4% [60.0-64.8] at 5 years. When pooling all SCD-related events (death, stroke, severe infection, VOE, acute anemia, as well as abnormal DTC, pneumonia and/or ACS and transfusion), 58.6% of children had experienced at least one event at 3 years. The probability of survival without SCD-related events at 5 years was 10.7% [0.9-12.6] for SS/SB° patients and 46.3% (41.5-51) for SC/SB+. In sharp contrast, HU was prescribed in 13.7% and HSCT performed in 9 patients only. Vaccination and DTC coverage, use of TF program and HU were significantly higher in larger centers. Summary/Conclusion: Current residual risks of severe complications and mortality rates on a national scale are similar to those observed in SCD expert center cohorts, presumably as a result of good TCD and vaccination coverage and an easy access to health care in France. Further improvement could be achieved with better referral to centers of expertise. The burden of disease is still high and increased use of disease modifying or curative therapy should benefit more children in the future. Disclosures Brousse: Add medica: Consultancy; bluebird bio: Consultancy. Bernaudin:BlueBirdBio: Consultancy; AddMedica: Honoraria, Other: Help for travel; GBT: Membership on an entity's Board of Directors or advisory committees. de Montalembert:AddMedica: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Incidence of Vaso-Occlusive Crisis Does Not Increase with Achieving Higher Hemoglobin Levels on Voxelotor Treatment or after Discontinuation: Analyses of the HOPE Study

Incidence of Vaso-Occlusive Crisis Does Not Increase with Achieving Higher Hemoglobin Levels on Voxelotor Treatment or after Discontinuation: Analyses of the HOPE Study

Long-Term Safety and Efficacy of Mitapivat (AG-348), a Pyruvate Kinase Activator, in Patients with Pyruvate Kinase Deficiency: The DRIVE PK Study

Long-Term Safety and Efficacy of Mitapivat (AG-348), a Pyruvate Kinase Activator, in Patients with Pyruvate Kinase Deficiency: The DRIVE PK Study

Management Strategies and Satisfaction Levels in Patients with Sickle Cell Disease: Interim Results from the International Sickle Cell World Assessment Survey (SWAY)

Management Strategies and Satisfaction Levels in Patients with Sickle Cell Disease: Interim Results from the International Sickle Cell World Assessment Survey (SWAY)