Lyfgenia (lovotibeglogene autotemcel) / bluebird bio - LARVOL DELTA

REFRAMING PAIN AND VOES AFTER TRANSFORMATIVE THERAPIES FOR SICKLE CELL DISEASE: INSIGHTS FROM GENE THERAPY WITH LOVOTIBEGLOGENE AUTOTEMCEL (EBMT 2026) - P, P1/2, P3 | "Most individuals treated with lovo-cel or allo-HSCT became VOE-free; however, a minority continued to experience acute pain not consistent with traditional VOE. People with acute pain post-treatment need recognition, validation, and counseling; with a focus on long-term management. Improved classification frameworks are needed to optimize long-term approaches to pain management."

Gene therapy • Addiction (Opioid and Alcohol) • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Graft versus Host Disease • Hematological Disorders • Immunology • Inflammation • Pain • Sickle Cell Disease

BRIDGING READINESS AND REALITY: U.S. PEDIATRIC HEMATOLOGISTS' PERSPECTIVES ON GENE THERAPY FOR SICKLE CELL DISEASE IN THE POST-APPROVAL ERA (EBMT 2026) - "Confidence was lowest regarding long-term risks (busulfan toxicity, clonal hematopoiesis, secondary malignancies) and mechanistic differences between Casgevy and Lyfgenia.Insurance approval emerged as the most cited determinant of whether a patient would be referred (72%), ahead of disease severity, caregiver readiness, or institutional infrastructure. U.S. pediatric hematologists are enthusiastic about GT for SCD, but implementation is constrained by inconsistent referral practices, limited product-specific knowledge, and payer-driven access barriers. As GT expands globally, these findings offer both contrast and guidance for European systems. While Europe's nationalized health models may mitigate some structural hurdles, the variability in provider knowledge, absence of unified SDM protocols, and need for long-term safety data are universal concerns."

Clinical • Gene therapy • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Pediatrics • Sickle Cell Disease

A Population Health-Based Approach to Inform the Provisioning of Gene Therapies for Severe Sickle Anemia in a Large, Vertically Integrated, Value-Based Health Care System. (TCT-ASTCT-CIBMTR 2026) - "Objectives: We describe a population based approach to the identification and care navigation of severe sickle cell patients in collaboration with contracted centers of excellence to provision access to gene therapies (Lyfgenia & Casgevy). Providing access to gene therapy for severe sickle cell patients in a vertically integrated health system requires a data informed, multidisciplinary team. Future refinement of our workflow will be to include patient care experience feedback and to focus on patients aged 12-18yrs who may reap the benefits of gene theapy earlier and decrease the expected marked increase in complications and health care cost as they become adolescent/young adults. 1 ."

Clinical • Gene therapy • Anemia • Autoimmune Hepatitis • Gene Therapies • Hematological Disorders • Hepatology • Immunology • Infertility • Inflammation • Sexual Disorders • Sickle Cell Disease

Outcomes of Gene Therapy and Allogeneic Hematopoietic Cell Transplantation for Sickle Cell Disease: A Single-Center Retrospective Analysis (TCT-ASTCT-CIBMTR 2026) - "14 pts with sickle cell anemia (SCA) underwent 15 cellular therapies at our center, including 7 GT (lovo-cel via HGB-206/210 trials) and 8 alloHCT (3 haploidentical donors (haplo) and 5 matched-related donor (MRD))...Graft failure occurred in 2 alloHCT compared to 0 in GT, both in pts who received non-myeloablative conditioning (alemtuzumab/total body irradiation) for MRD alloHCT with 1 patient then proceeding to a second MRD alloHCT...Gene therapy and allogeneic cell transplantation offer durable engraftment and hemoglobin S suppression in sickle cell anemia. Survival, hospital length-of-stay, and infectious complications were similar between treatment groups in our study."

Gene therapy • Retrospective data • Addiction (Opioid and Alcohol) • Chronic Graft versus Host Disease • Chronic Myeloid Leukemia • Gene Therapies • Genetic Disorders • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Mucositis • Neutropenia • Retinal Disorders • Septic Shock • Sickle Cell Disease • Transplantation

Venous Thromboembolism in Recipients of Ex-Vivo Gene Therapy for Adolescent, Young Adult Patients with Sickle Cell Disease (TCT-ASTCT-CIBMTR 2026) - "3 out of 5 recipients undergoing Lovotibeglogene autotemcel gene therapy developed VTE at various time points of their gene therapy journey before infusion of the gene modified cells... This report demonstrates potential benefit for instituting prophylactic anticoagulation in patients undergoing ex-vivo gene therapy for SCD. Given the baseline hypercoagulable state of SCD patients, this case series demonstrates that the added risk of central line placement may warrant consideration of prophylactic anticoagulation and proposal of an algorithm including anti-coagulant medication selection for decision making in these patients. 1."

Gene therapy • Preclinical • Cardiovascular • Gene Therapies • Genetic Disorders • Hematological Disorders • Infectious Disease • Respiratory Diseases • Sickle Cell Disease • Venous Thromboembolism • CD34 • SCD

Accelerating Access to Gene Therapy: Lessons from Commercial Implementation in Sickle Cell Disease and Transfusion-Dependent Thalassemia (TCT-ASTCT-CIBMTR 2026) - "With >700 patient-years of follow-up, beti-cel (Zynteglo; US approval Aug-2022) and lovo-cel (Lyfgenia; US approval Dec-2023) are now in routine use. This real-world analysis is the first to show that national-scale delivery of commercial gene therapy is feasible within a coordinated ecosystem. Coverage policies indicate broad access across public and private payers. These findings offer a functioning model for gene therapy implementation."

Gene therapy • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Challenges in molecular test interpretation in patients with prior gene therapy for beta-thalassemia and sickle cell disease: one laboratory's experience (ACMG 2026) - "Similarly, for Case 2, the clinician confirmed this individual received lovo-cel gene therapy for SCD...Case 2: MPS detected the HbS HBB variant, consistent with SCD, at VAF between the established heterozygous and homozygous ranges; the p.Thr88Gln variant was detected at VAF below the heterozygous range. MLPA detected copy number gain involving HBB , presumably from increased gene therapy vector copy number."

Clinical • Gene therapy • Beta-Thalassemia • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • HBB

CRISPR-Cas editing technologies for viral-mediated gene therapies of human diseases: Mechanisms, progress, and challenges. (PubMed, Mol Ther Nucleic Acids) - "Since then, the US FDA has approved nearly 30 new viral gene therapy programs, with notable examples including Zolgensma, Spinraza, Hemgenix, Zynteglo, Lyfgenia, Kymriah, Skysona, and Tecelra...In this review, we examine the range of these therapeutics and their viral carriers, focusing primarily on LVs and AAVs. We provide a snapshot of the current status of the field and highlight some of the current challenges in the clinical application of gene therapy, with particular emphasis on viral CRISPR-Cas-based technologies and their future potential."

Journal • Review • Gene Therapies • Genetic Disorders

Clinical data comparison for FDA-approved gene therapies in sickle cell disease. (PubMed, Exp Biol Med (Maywood)) - "In December 2023, the U.S. FDA approved two autologous gene therapies, lovo-cel (bluebird bio) and exa-cel (Vertex/CRISPR Therapeutics), offering potentially transformative outcomes...Mobilization of hematopoietic stem cells (HSCs) with single-agent plerixafor proved challenging in both trials, with most participants requiring multiple mobilization and apheresis cycles...However, differences in trial populations, cell collection logistics, and manufacturing have important implications for real-world applications. Continued long-term follow-up and the establishment of standardized post-treatment registries will be critical to fully assess durability, monitor late effects, and inform patient selection."

Clinical data • FDA event • Journal • Cardiovascular • Gene Therapies • Genetic Disorders • Hematological Disorders • Pediatrics • Sickle Cell Disease • Transplantation

An automated platform for lentiviral transduction for HSC gene therapy promotes fitness of hematopoietic stem cells combined with higher transduction efficiency (ASH 2025) - "Although therapies for HSC gene therapy have been recently approved (Zynteglo™, Lyfgenia™ and Casgevy®), still certain challenges remain associated with high costs, scalability and safety related to leukemic events. Notably, low-density lipoprotein receptor (LDL-R), the cellular receptor that serves for the recognition by the VSV glycoprotein, was accordingly upregulated in cells processed on the CliniMACS Prodigy. These results suggest that the CliniMACS Prodigy promotes higher stemness or better fitness of HSCs while simultaneously allowing for higher transduction efficiencies due to downregulation of immune related pathways and upregulation of cholesterol and sterol binding."

Gene therapy • IO biomarker • Dyslipidemia • Gene Therapies • Immunology • Infectious Disease • CD34 • TLR8

Non-genotoxic conditioning to increase donor chimerism levels in a mismatched murine transplant model for sickle cell disease (ASH 2025) - "The recently FDA-approved gene therapies Lyfgenia and Casgevy also employ MAC...We first investigated theefficiency of CD45- and CD117-sap as conditioning agents compared to classical total body irradiation(TBI) and busulfan. Our base conditioning regimen also included post-transplant cyclophosphamide (PT-Cy) and sirolimus...HPLC analysis at 20 weeks post-HCT showed that recipients conditioned with CD117-sapexhibited donor-derived Hb, while recipients conditioned with 200cGy TBI showed mixed donor/recipientHb. Furthermore, BM analysis at 24 weeks post-HCT also showed a significant increase in the frequenciesof donor-derived short- (52.50±5.67% vs 4.80±2.40%, p=0.0010) and long-term (43.28±5.79% vs0.79±0.79%, p=0.0016) hematopoietic stem cells in CD117-sap conditioned recipients, which furtherconfirms the successful long-term engraftment of CD117-sap conditioned recipients.In summary, CD117-sap, in combination with anti-thy1.2, PT-Cy, and sirolimus, is..."

Preclinical • Anemia • Gene Therapies • Genetic Disorders • Hematological Malignancies • Sickle Cell Disease • Transplantation • KIT • PTPRC • THY1

Accelerating access to gene therapy: Lessons from commercial implementation in sickle cell disease and transfusion-dependent thalassemia (ASH 2025) - "With >700 patient-years of follow-up in clinical trials, Zynteglo (approved Aug 2022 for thalassemia) and Lyfgenia (approvedDec 2023 for sickle cell disease) are now in real-world use in the United States. This real-world analysis is the first to characterize commercial gene therapy implementation,demonstrating scalable delivery and accelerated access over time. Cross-program learning andcentralized support enabled faster treatment across a national network. With published payer coveragefor >250M lives – without a single ultimate denial – these findings offer a functioning model for genetherapy implementation."

Gene therapy • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Provider practices and preparedness for gene therapy in pediatric sickle cell disease: A national survey of pediatric hematologists (ASH 2025) - "In 2023, the FDA approvedtwo autologous gene therapies for patients ≥12 years old with recurrent vaso-occlusive crises (VOCs):lovotibeglogene autotemcel (Bluebird Bio) and exagamglogene autotemcel (Vertex/CRISPR Therapeutics).Despite their promise, integration into routine care remains challenging due to strict trial criteria andlimited implementation guidance. This national survey highlights substantial variability in gene therapy referral practices forpediatric sickle cell disease, particularly in cases involving neurologic complications and across differentprovider types. While hematologists with a SCD-focused practice reported greater comfort with GTcounseling, they were less likely to recommend GT in certain high-risk scenarios. These findingsemphasize the urgent need for standardized, evidence-based guidelines and targeted provider educationto ensure equitable access and appropriate integration of GT into pediatric SCD care."

Clinical • Gene therapy • Bone Marrow Transplantation • Cardiovascular • Gene Therapies • Genetic Disorders • Pediatrics • Sickle Cell Disease

Engineered extracellular vesicles for In Vivo gene therapy in sickle cell disease (ASH 2025) - "In2023, the FDA approved two gene therapies for SCD: Casgevy and Lyfgenia. Our innovative approach has the potential to serve as a foundationaltechnology for a safer, more accessible, and non-viral gene therapy applicable to a broad range ofgenetic disorders. The successful completion of this project will generate critical proof-of-concept dataand enable us to pursue further translational development for in vivo gene therapy for SCD."

Gene therapy • Preclinical • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • CD63

Differing Definitions of Vaso-Occlusion in Clinical Studies of Sickle Cell Disease Can Result in Differing Outcomes (ASH 2023) - " We reviewed completed and ongoing clinical trials and published articles using endpoints assessing the reduction or elimination of vaso-occlusive crisis/events, including trials of (i) exagamglogene autotemcel (exa-cel, CRISPR/Cas-9 based genome editing treatment), (ii) lovotibeglogene autotemcel (lovo-cel, gene addition therapy), (iii) L-glutamine, (iv) voxelotor, (v) hydroxyurea (HU) and (vi) crizanlizumab. Requirements for health care facility visits in the definitions of severe VOC (exa-cel), VOC, and SCPC were more broadly inclusive and include events that would not be counted in the definitions of severe VOE (lovo-cel) or painful crisis. Clinically, support for this observation comes from our analysis of exa-cel SCD pivotal clinical trial data using these different definitions, which showed the number of patients free from vaso-occlusive episodes changed depending on the definition of vaso-occlusion employed. These results show differences in vaso-occlusion..."

Clinical • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Efficacy, Safety, and Health-Related Quality of Life (HRQOL) in Patients with Sickle Cell Disease (SCD) Who Have Received Lovotibeglogene Autotemcel (Lovo-cel) Gene Therapy: Up to 60 Months of Follow-up (ASH 2023) - P, P1/2, P3 | "Patients with SCD and recurrent severe vaso-occlusive events (VOEs) or history of overt stroke underwent plerixafor mobilization and apheresis followed by myeloablative busulfan conditioning and lovo-cel infusion. One-time treatment with lovo-cel resulted in sustained HbAT87Q production and near-complete resolution of VOEs and severe VOEs up to 18 months post treatment; the safety profile was consistent with underlying SCD and myeloablative conditioning. Patients reported sustained improvements in pain intensity, pain interference, and fatigue. Ongoing long-term follow-up will continue to provide important information on efficacy, safety, and patient experience post lovo-cel treatment."

Clinical • Gene therapy • HEOR • Cardiovascular • Dental Disorders • Fatigue • Gene Therapies • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Hepatology • Mood Disorders • Myelodysplastic Syndrome • Neuralgia • Oncology • Pain • Pediatrics • Psychiatry • Sickle Cell Disease • Stomatitis • Thrombocytopenia

Gene Therapies for Hemoglobinopathies: Efficacy, Cell Collection & Transfusion Support. (PubMed, Transfus Med Rev) - "The U.S. Food and Drug Administration (FDA) has approved GTs for both SCD and TDT: lovotibeglogene autotemcel (Lyfgenia) and exagamglogene autotemcel (Casgevy) in 2023 for SCD and betibeglogene autotemcel (Zynteglo) in 2022 and exagamglogene autotemcel (Casgevy) in 2024 for TDT. This article appraises the studies the FDA approvals were based upon, with comments on transfusion and stem collection regimens. The latter aspects highlighting variability in practice and the need for additional studies to optimize pretransfusion regimens and the collection process for successful GT."

Journal • Beta-Thalassemia • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Graft versus Host Disease • Hematological Disorders • Immunology • Sickle Cell Disease • Transplantation

Transformative Therapies for Sickle Cell Disease: A Global Stakeholder Perception Study on Advanced Cell Therapies (ASH 2024) - "Exagamglogene autotemcel(EA) was the preferred gene therapy (20%), followed by lovotibeglogene autotemcel(L) (16.7%), 63.3%had no preference. It highlights fertility preservation, access to QTC, risk of secondary malignancy and cost barriers critical factors in patient selection. Future research should focus on expanding the donor pool for HSCT, gathering long-term data on GT's safety and efficacy, and developing strategies to alleviate the financial burden associated with these TT."

Clinical • Metastases • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Graft versus Host Disease • Hematological Disorders • Immunology • Pediatrics • Sickle Cell Disease

Maximizing Safety and Efficacy in Hematopoietic Stem Cell Gene Therapy (ASH 2024) - "Hematopoietic stem cell (HSC) gene therapy has been recently successfully employed for certain rare blood disorders including hemoglobinopathies, which resulted even in marketing authorizations such as Lyfgenia™ and Casgevy™. Based on these results, we propose a combined strategy of transduction enhancers on the automated platform to achieve significantly higher transduction efficiency. Ongoing experiments investigate the mechanisms involved in better performance of lentiviral transduction on the automated platform with molecular analysis via Next Generation Sequencing (NGS) and respective bioinformatics analysis."

Clinical • Gene therapy • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • CD34

Multi-Disciplinary Care Model for Transition and Re-Transition after Gene Therapy in Sickle Cell Disease (ASH 2024) - "This led to the Food and Drug Administration (FDA) approval of the lentiviral-based gene addition product (lovotibeglogene autotemcel) and CRISPR-Cas9 based gene editing product (exagamglogene autotemcel) for patients with SCD above 12 years of age. Our team's collaborative approach to SCD care with sickle cell specialists, transplant team and other care providers and CBO continues into the long term follow up period, including ongoing supportive services for both patients and their families. Conclusion : As newer therapies are developed and approved for transformative SCD care, development of a transitional model with early engagement of an interdisciplinary team is critical for empowering sickle cell warriors and for their successful transition back into the community."

Gene therapy • Bone Marrow Transplantation • Fatigue • Gene Therapies • Genetic Disorders • Hematological Disorders • Mood Disorders • Psychiatry • Sickle Cell Disease

Participants with a History of Stroke in Lovotibeglogene Autotemcel (Lovo-cel) Clinical Trials (ASH 2024) - P, P1/2, P3 | "Longer follow-up will be required to understand the impact on neurovasculature and risk of stroke recurrence. These data will help inform real-world lovo-cel treatment recommendations and decisions for those with SCD and their care providers."

Clinical • Cardiovascular • Genetic Disorders • Hematological Disorders • Ischemic stroke • Sickle Cell Disease • Vascular Neurology

An Update on Lovotibeglogene Autotemcel (Lovo-cel) Clinical Trials for Sickle Cell Disease (SCD) and Analysis of Early Predictors of Response to Lovo-Cel (ASH 2024) - P, P1/2, P3 | "Conclusions : One-time lovo-cel treatment results in sustained HbAT87Q production and eliminated VOEs and sVOEs in a majority of participants. Models developed in this post hoc analysis enable prediction of the likelihood of VOE-CR and sVOE-CR using measurements as early as 6 mo post treatment."

Clinical • Genetic Disorders • Hematological Disorders • Pediatrics • Sickle Cell Disease

Ernest Beutler Lecture and Prize (ASH 2024) - "In the last year, both globin gene addition (lovo-cel) and CRISPR gene editing (exa-cel) therapies received FDA approval. Dr. John Tisdale will summarize recent advances in ex vivo modification of hematopoietic stem cells for both lentiviral gene and CRISPR gene editing therapies for the hemoglobin disorders, concentrating on clinical parameters and prospects for improving preconditioning and moving toward strategies that would allow application without the need for hospitalization and intensive supportive care."

Beta-Thalassemia • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • BCL11A

Maximizing safety and efficacy in hematopoietic stem cell gene therapy (ESGCT 2024) - "Hematopoietic stem cell (HSC) gene therapy has been recently successfully employed for certain rare blood disorders including hemoglobinopathies, which resulted even in marketing authorizations such as Lyfgenia™ and Casgevy™. Based on these results, we propose a combined strategy of transduction enhancers on the automated platform to achieve significantly higher transduction efficiency. Ongoing experiments investigate the mechanisms involved in better performance of lentiviral transduction on the automated platform with molecular analysis via Next Generation Sequencing (NGS) and respective bioinformatics analysis."

Clinical • Gene therapy • Gene Therapies • Hematological Disorders • Sickle Cell Disease • CD34

Sickle Cell Disease and Gene Therapy Among African Americans: A Dilemma and Challenge. (PubMed, J Racial Ethn Health Disparities) - "Although the US Food and Drug Administration's recently approved groundbreaking base editing gene therapies of Casgevy and Lyfgenia have been declared promising in treating SCD, uptake for the therapies has been low. Though the treatment of SCD through gene therapy has sparked some excitement in the African American community, it is also causing a dilemma and challenges. This paper documents the dilemma and challenges associated with gene therapy among the African American SCD community and what can be done to address them."

Journal • Review • Cardiovascular • Gene Therapies • Genetic Disorders • Heart Failure • Hematological Disorders • Pain • Sickle Cell Disease