Background/Objectives: Transfusion-dependent β-thalassaemia (TDT) is a lifelong condition requiring coordinated multidisciplinary care. In France, where the disease is rare, transition from pediatric to adult care remains poorly structured, potentially compromising adherence and long-term outcomes. Methods: This national retrospective study evaluated current transition practices and their clinical impact among young adults with TDT. Patients aged 20-25 years in December 2022 were identified from the national NaThalY registry. Those diagnosed and managed in France before age 15 were included. Clinical data were collected for the two years preceding and following transition. Transition practices were assessed using a standardized questionnaire sent to pediatric centers. Results: Thirty-four patients were included (mean transition age: 19 years). The rate of response to the questionnaire was 90.5%, with feedback from 19 centers. Only one-third of centers offered joint pediatric-adult consultations, and one-quarter provided transition-focused education. No written transition protocols were reported. Mean pre-transfusion hemoglobin levels were significantly lower after the transition (8.5 vs. 8.0 g/dL; p = 0.01). Ferritin levels showed a non-significant increase, with no statistically significant changes observed in hepatic or cardiac iron concentrations. Conclusions: This study demonstrates marked heterogeneity and limited formalization of transition practices in France. Development of structured, standardized transition pathways is urgently needed to ensure continuity of care and optimal disease management in adults with TDT.

Management of cerebral vasculopathy in sickle cell anemia (SCA) includes standard-care, that is, chronic transfusion (CT) or hydroxyurea, and hematopoietic cell transplantation (HCT). DREPAGREFFE-1 (December 2010/June 2013), a French multicenter trial, was the first prospective trial comparing standard-care to match sibling donor (MSD)-HCT in 67 (35F/32M) SCA children (5-15 year) on CT for abnormal time-averaged mean maximum velocities (TAMMV ≥ 200 cm/s). Seven had a stroke history. We reported that MSD-HCT reduced the highest TAMMVs at 1- and 3-year (p < 0.001) and improved quality of life (QoL) for physical and school functioning. In stroke-free patients, the 3-year stenosis score was lower (p = 0.010). Nevertheless, no significant difference was observed for silent cerebral infarcts (SCI) and cognitive performance. This prompted us to initiate DREPAGREFFE-2 to reevaluate the outcomes at 10 years (September 2022/August 2024) with the same 67 SCA children. No death or stroke occurred in either arm. No rejection or chronic-GvHD arose in the MSD-HCT group (n = 32). In the standard-care group (n = 35), 16 were on hydroxyurea, and 16 on CT at Year 10, and 3 received haploidentical-HCT. After MSD-HCT, the QoL was better, even for social functioning, and the number of hospitalizations, hospitalized days (p < 0.001), and crises (p = 0.001) was lower than on standard-care. In stroke-free patients, stenosis (p = 0.027) and SCI scores (p = 0.041) decreased significantly more after MSD-HCT than on standard-care; working memory (p = 0.016) and processing speed (p = 0.011) improved significantly after MSD-HCT, but worsened on standard-care. These effects were not previously detected with shorter follow-up. This supports earlier consideration of HCT for SCA children with MSD to preserve neurologic function and QoL for a more productive future.

ABSTRACT:Betibeglogene autotemcel (beti-cel) gene therapy for transfusion-dependent β-thalassemia (TDT) involves autologous transplantation of hematopoietic stem and progenitor cells transduced with a modified β-globin gene to produce functional adult hemoglobin (Hb) containing βA-T87Q-globin (HbAT87Q). Sixty-three participants with TDT (median age, 17 years [range, 4-35]) received beti-cel in phase 1/2 (n = 22) or phase 3 (n = 41) studies and enrolled in the long-term follow-up LTF-303 study (median follow-up, 5.9 years [range, 2.9-10.1]). Manufacturing refinements in phase 3 increased transduction efficiency, resulting in higher drug product vector copy number and HbAT87Q levels, which translated into higher Hb and transfusion independence (TI) rates than in phase 1/2. TI was achieved by 15 of 22 (68.2%) phase 1/2 participants (median weighted average Hb during TI, 10.2 g/dL) and 37 of 41 (90.2%) of phase 3 participants (median, 11.2 g/dL), and was sustained through last follow-up. Treatment efficacy was similar across ages and TDT genotypes. Among participants achieving TI, 38 of 52 (73%) had discontinued iron chelation at last follow-up, with no increase in liver iron concentration. Markers of ineffective erythropoiesis, including serum transferrin receptor and erythropoietin, improved with restoration of iron homeostasis. Health-related quality-of-life assessment scores showed durable improvements. No malignancies, insertional oncogenesis, or vector-derived replication-competent lentivirus were reported. These findings establish beti-cel as a durable, 1-time therapy that achieves TI, restores iron balance, and improves quality of life, offering a potentially curative treatment option for people with TDT. This trial was registered at www.clinicaltrials.gov as NCT02633943.

β-thalassemia is a globally distributed hereditary red blood cell disorder. Up to now, clinical management of transfusion-dependent β-thalassemia (TDT) patients is still based on chronic transfusion combined with iron chelation therapy. Allogeneic hematopoietic cell transplantation potentially provides a cure, but few patients have an HLA-identical sibling, and optimal results are reported in patients ≤ 14 years. The European Hematology Association (EHA), through the EHA Scientific Working Group on Red Cells/Iron and the European Bone Marrow Transplantation (EBMT) group, has updated a 2021 EHA decision-making algorithm on evidence and expert consensus with the aim of identifying which patients with TDT could benefit from gene therapy (GT). Indeed, it is important to establish the patient setting for whom it is a priority, particularly in the early phase of real-world use outside experimental trials. Moreover, actual price, limited availability, and resource disposal constitute a further indication of a rational and progressive approach to this innovative treatment. In this expert consensus document, different clinical scenarios have been considered and analyzed for the possible impact on treatment outcome. This expert opinion provides dynamic, updatable, priority-based guidance for physicians taking care of TDT patients.

Gene therapy has emerged as a promising curative treatment for β-hemoglobinopathies, the most common genetic disorders worldwide. However, current approved approaches still have some limitations in terms of safety and efficacy. Here, we used highly processive adenine base editor (ABE) variants to precisely correct some of the most prevalent and severe β-thalassemia–causing mutations in the β-globin–encoding HBB gene, including CD39 and IVS2-1, using NRCH-ABE8e and SpRY-ABE8e, respectively. More than 90% of editing of hematopoietic stem and progenitor cells (HSPCs) led to improved β-globin expression in their erythroid progeny and persistent correction of both β-thalassemia and sickle cell–β-thalassemia phenotypes. The safety of this strategy was confirmed in HSPCs in vitro and in vivo through the absence of gene dysregulation and any meaningful impact on the DNA mutational burden, RNA deamination, β-globin gene locus integrity, and the clonality of the HSPC graft, as assessed by RNA sequencing, whole-exome sequencing, long-read sequencing, and human HSPC transplantation in immunodeficient mice. Overall, these preclinical studies suggest that base editing–mediated gene correction may be a safe and effective strategy for treating β-hemoglobinopathies.

Gene therapy has emerged as a promising curative treatment for β-hemoglobinopathies, the most common genetic disorders worldwide. However, current approved approaches still have some limitations in terms of safety and efficacy. Here, we used highly processive adenine base editors (ABE) variants to precisely correct some of the most prevalent and severe β-thalassemia-causing mutations in the β-globin gene. Efficient editing of hematopoietic stem/progenitor cells (HSPCs) led to potent β-globin expression in their erythroid progeny and persistent correction of both β-thalassemia and sickle cell-β-thalassemia phenotypes. Safety of this strategy was confirmed in HSPCs in vitro and in vivo by the absence of gene dysregulation or any meaningful impact on the DNA mutational burden, the RNA deamination level, the β-globin gene locus integrity and the clonality of the HSPC graft. Overall, base editing-mediated gene correction is a safe and effective strategy for treating β-hemoglobinopathies. One sentence summary Preclinical safety and efficacy studies of a new gene therapy approach for patients with severe β-hemoglobinopathies. ### Competing Interest Statement Giulia Hardouin and Annarita Miccio are the inventors of two patents describing base editing approaches for beta-thalassemia (PCT/EP2023/062468: Correction of the CD39 betathalassemic mutation with base editing approach, PCT/EP2023/070283: Correction of the IVS2-1 beta-thalassemic mutation with base editing approach). All other authors declare no competing interests. Agence Nationale de la Recherche, https://ror.org/00rbzpz17, ANR-10-IAHU-01 European Research Council, 865797 European Commission, 101057659 Telethon SR-Tiget Core Grant, NA Filière MCGRE, NA

Drs. Thompson and Kwiatkowski contributed equally. Introduction: Beti-cel gene therapy is a one-time treatment for transfusion-dependent β-thalassemia (TDT) that adds functional copies of the β-globin gene (βT87Q) to address the underlying cause of disease. Here, we report long-term outcomes of participants treated with beti-cel with up to 10 years of follow-up. Methods: After completion of a 2-year phase 1/2 (HGB-204 [NCT01745120]; HGB-205 [NCT02151526]) or phase 3 (HGB-207 [NCT02906202]; HGB-212 [NCT03207009]) beti-cel parent study, treated participants were eligible for the long-term, 13-year follow-up study LTF-303 (NCT02633943). Clinical efficacy, iron homeostasis, health-related quality of life (HRQOL), and safety are reported through last follow-up visit. Key outcomes were also examined by genotype (β0/β0 vs non-β0/β0) and by participant age at enrollment (pediatric: <12 years; adolescent: ≥12 years to <18 years; adult: ≥18 years). Results:As of Feb 2024, 63 participants (median [range] age: 17 [4-35] years) had received beti-cel and subsequently enrolled in LTF-303 (median [range] follow-up: 71.2 [34.5-121.4] months); 2 participants had 10 years of follow-up, 51 (81.0%) participants had at least 5 years of follow-up, and 1 participant withdrew consent after 39 months of follow-up due to personal reasons. Peripheral blood vector copy number (PB VCN) and HbAT87Q levels were stable by month 6 after infusion, sustained across studies up to 10 years, and were higher in phase 3 versus phase 1/2 studies following beti-cel drug product manufacturing optimization, which is similar to the commercial process. At last follow-up, median (range) PB VCN was 0.4 (0.1-4.9) c/dg and 1.6 (0.1-4.8) c/dg in phase 1/2 and phase 3, respectively. Among participants who achieved transfusion independence (TI) in phase 1/2 studies (15/22 [68.2%]), median (range) HbAT87Q was 7.6 (3.9-10.8) g/dL and weighted average hemoglobin (Hb) during TI was 10.24 (9.1-13.1) g/dL. In phase 3 studies, 37/41 (90.2%) participants achieved TI, median (range) HbAT87Q was 9.8 (5.1-14.3) g/dL, and weighted average Hb during TI was 11.24 (9.8-13.9) g/dL. Transduction efficiency, pharmacodynamics, TI rate, and weighted average Hb were similar across genotypes and ages. While iron overload management was at the physician's discretion, 28/37 (78.4%) phase 3 participants who achieved TI are no longer receiving iron-chelation therapy, and of those 28, 22 (78.6%) had liver iron concentration (LIC) <5 mg Fe/g dry weight (dw). Among phase 1/2 and phase 3 participants who achieved and maintained TI and had baseline data, median (range) change from baseline in serum ferritin at month 24 was -907.9 (-5014 to 5539) ng/mL (n=51). At month 60, median (range) change from baseline in serum ferritin and LIC were -1951.0 (-7079 to 1345) ng/mL (n=39) and -2.2 (-20.6 to 9.6) mg Fe/g dw (n=30), respectively, indicating improvement in iron overload. Cardiac T2* remained stable and was >20 msec at last follow-up in all participants who achieved TI, including 2 participants with cardiac T2* ≤20 msec at baseline. Among participants who achieved TI and had HRQOL data, clinically meaningful improvements were reported in Short Form-36 Health Survey Questionnaire (SF-36) scores at month 24 for the mental component summary and at month 36 for physical component summary (mean score increase >2). Participants had sustained SF-36 physical and emotional scores above the normative population mean (50) at month 60. Clinically meaningful improvements in Pediatric Quality of Life Inventory total scores were reported at month 36, and scores remained above the normative population mean (81) at month 60. All 26 participants who achieved TI and completed a questionnaire reported an overall benefit with beti-cel. No beti-cel-related serious adverse events were reported >2 years after infusion through last follow-up. No malignancies, insertional oncogenesis, or vector-derived replication-competent lentivirus were reported. Conclusion: These data provide evidence of the sustained favorable benefit-risk profile of gene addition therapy with beti-cel in participants with TDT and will inform real-world treatment decisions.Beti-cel is a potentially curative gene addition therapy for patients with TDT across genotypes and ages through achievement of durable TI, normal or near-normal Hb, and a favorable long-term safety profile with up to 10 years of follow-up.

Forty-two questions were evaluated concerning management of emergencies and critical illnesses in paediatric and adult patients with sickle cell disease. The assessment covered the following areas: patient referral, vaso-occlusive crisis, acute chest syndrome, transfusion therapy, and priapism. The patient referral category included guidelines for admission to intensive care unit and management at specialized reference centers. The vaso-occlusive crisis topic encompassed pain management, hydration, incentive spirometry, and target oxygen saturation levels. For acute chest syndrome, the focus areas included imaging techniques such as lung ultrasound, computed tomography scans, and echocardiography; treatment with systemic corticosteroids; non-invasive ventilation; prophylactic and therapeutic anticoagulation; and procalcitonin and antibiotic therapy. The section on transfusion therapy addressed indications and methods of transfusion, as well as the diagnosis and prediction of delayed hemolytic transfusion reactions. A total of 45 recommendations were proposed, including 14 specific to adults, 13 specific to pediatrics, and 18 applicable to both adults and children, along with three therapeutic algorithms. The Grade of Recommendation Assessment, Development, and Evaluation (GRADE) methodology was adhered to throughout the process. Sixteen recommendations were based on a low level of evidence (GRADE 2+ or 2−), while 26 were based on evidence that could not be classified under the GRADE system and were therefore considered expert opinions. Finally, for three aspects of sickle cell disease management, the experts concluded that no reliable recommendations could be made based on the current state of knowledge. The recommendations and therapeutic algorithms received strong agreement from the experts.

BACKGROUND:Sickle cell disease (SCD) predisposes children to bacterial infections, particularly invasive pneumococcal disease. Pneumococcal immunization associated with antibiotic prophylaxis reduced the incidence of invasive pneumococcal disease in these patients. However, the risk remains higher than in the general population. Our main objective was to describe the features of pneumococcal meningitis and estimate the case-fatality rate in children with SCD. The secondary objective was to assess serotype distribution and resistance patterns and the proportion of cases related to vaccine failure. METHODS:This nationwide multicenter observational study was conducted in France between 2001 and 2021. All cases of pneumococcal meningitis in children with SCD < 18 years old from the French National Registry of Pediatric Pneumococcal Meningitis were included. RESULTS:Of 2145 pneumococcal meningitis, 25 cases (1.2%, 95% CI: 0.8-1.7) occurred in children with SCD [mean age = 4.6 years (±4)], with a high case-fatality rate (28%, n = 7, 95% CI: 10.4-45.6). Nonvaccine serotypes were predominant (n = 15, 65%, 95% CI: 45.8-84.7) over vaccine serotypes (n = 8, 35%, 95% CI: 15.3-54.3). One case of vaccine failure (4%, n = 1/23) and 2 breakthrough cases (n = 2/23, 9%) were observed. Penicillin-non-susceptible Streptococcus pneumoniae strains were identified in 39% (n = 7). CONCLUSIONS:The occurrence of pneumococcal meningitis in children with SCD during the pneumococcal conjugate vaccines era was associated with a high case-fatality rate and a predominance of nonvaccine serotypes. The implementation of new serotype-expanded PCV may have a potentially positive impact on this vulnerable population.

Background Transfusion-dependent f3-thalassaemia (TDT) is a severe disease, resulting in lifelong blood transfusions, iron overload, and associated complications. Betibeglogene autotemcel (beti-cel) gene therapy uses autologous haematopoietic stem and progenitor cells (HSPCs) transduced with BB305 lentiviral vector to enable transfusion independence. Methods HGB-212 was a non-randomised, multicentre, single-arm, open-label, phase 3 study of beti-cel in patients with TDT conducted at eight centres in France, Germany, Greece, Italy, the UK, and the USA. Patients with f30/f30, f30/ f3 +IVS-I- 110 , or f3 +IVS-I- 110 /f3 +IVS-I- 110 genotypes, clinically stable TDT, and a transfusion history of at least 100 mL/kg per year of packed red blood cells (pRBCs) or at least eight transfusions of pRBCs per year in the 2 years before enrolment were eligible for participation. After undergoing HSPC mobilisation and busulfan-based, pharmacokinetic-adjusted myeloablative conditioning, patients were infused with beti-cel and followed up for 24 months. The primary efficacy outcome was transfusion independence, defined as weighted average haemoglobin level of 9 g/dL or above without pRBC transfusions for 12 or more months. The primary outcome was measured in all patients who received an infusion of beti-cel (transplant population); safety was evaluated in all patients who initiated study treatment (intention-to-treat population). Patients were eligible to enrol in the ongoing 13-year long-term follow-up study (for a total of 15 years), LTF-303 (registered at ClinicalTrials.gov, NCT02633943). This trial, HGB-212, was registered at ClinicalTrials.gov (NCT03207009), and is complete. Findings From June 8, 2017, to March 12, 2020, 20 patients were screened for eligibility. One patient was ineligible and one withdrew consent before HSPC mobilisation and myeloablative conditioning. Of the 18 patients who received beti-cel, ten (56%) were male and eight (44%) were female; 13 (72%) were younger than 18 years at the time of informed consent, and five (28%) were older than 18 years. 12 (67%) patients had f30/f30 genotypes, three (17%) had f30/ f3 +IVS-I- 110 , and three (17%) had f3 +IVS-I- 110 /f3 +IVS-I- 110 . As of Jan 30, 2023, all patients enrolled in the long-term follow-up study and the median follow-up was 479 months (range 238-590). All 18 patients were evaluable for transfusion independence, with 16 (89%) of 18 reaching and maintaining transfusion independence to last follow=up (estimated effect size 899% [95% CI 653-986]). All patients had at least one adverse event after beti-cel infusion. There were no serious adverse events considered to be related to beti-cel, and no deaths. Interpretation These data demonstrate that beti-cel can allow patients with genotypes that cause severe f3-thalassaemia (f30/f30, f3 0 /f3 +IVS-I- 110 , or f3 +IVS-I- 110 /f3 +IVS-I- 110 ) to reach transfusion independence. Beti-cel offers the potential to attain near- normal haemoglobin levels for those with severe forms of TDT, and a potentially curative option without the risks and limitations of allogeneic HSPC transplantation. Patients are being followed up for a total of 15 years to assess the durability of transfusion independence and long-term safety profile of beti-cel.

DREPAGREFFE-1 (NCT01340404), was the first prospective trial comparing allogeneic stem cell transplantation (alloSCT) to standard-of-care (SoC) in children with sickle cell anemia (SCA). This French multicenter trial was defined by the random-availability of a matched-sibling donor (MSD). Inclusion criteria were SS/Sb0 children (5-15yr) placed on long-term chronic-transfusion (CT) for a history of abnormal cerebral arterial velocities (TAMMV≥200 cm/sec), with at least one non-SCA sibling, and parents accepting HLA-typing and alloSCT if an MSD was available.Sixty-seven children (35F/32M), including 7 with stroke-history, were enrolled (Dec-2010/June-2013). Children with MSD (n=32) were transplanted, while those without (n=35) were maintained on CT for at least one year and then switched to hydroxyurea (HU) if normalized TAMMVs and no stenosis. Results at 1 and 3 years were reported (Bernaudin et al JAMA. 2019;321(3); Verlhac et al Br J Haematol. 2021;193(1)). As a reminder, comparing alloSCT vs. SoC at 1 yr, the highest TAMMVs (primary outcome) were significantly lower after alloSCT than under SoC (difference -40.8 cm/s; [95%CI:-62.9;-18.6]; P<.001). At 3 years, the highest TAMMVs were lower, the proportion of patients with normalized-TAMMVs was higher, the stenosis score in stroke-free patients was lower, and the quality of life (QoL) was better for physical and school functioning. Nevertheless, no significant difference in ischemic lesions and cognitive performance was observed.DREPAGREFFE-2 trial (NCT 05053932), supported by ABM and Pfizer, aimed to reevaluate at 10yr the 67 SCA-children (Sept-2022/Aug-2024) to test whether the differences in cognitive performance and ischemic lesions had changed significantly. Events and treatment changes since Year 3 were routinely recorded. Clinical evaluation, routine biological check-up, Intracranial and cervical-color Doppler-ultrasound, cerebral MRI/MRA/neck-MRA were performed. Non-opposition consent was required for cognitive testing (WISC-V and WAIS-IV), biological research, and QoL (PedsQLTM) assessment. Death and stroke did not occur in either arm.In the alloSCT arm (n=32), follow-up ended at 7.0 and 7.9 years for 2 children with full donor-chimerism and no chGvHD, due to return to Africa and UK. At 10yr, median (range) donor-chimerism was 92.5% (19%-100%) and no chGvHD was observed.In the SoC arm (n=35), 23 patients with normalized velocities and no stenosis under CT were switched to HU. At 10yr, 17 are still on HU, 15 are on CT, and 3 had related haploIdentical-SCT at 6.7, 7.2 and 9.3yr post-enrollment. They are well, one having only mild chGvHD. Two patients still on CT for stroke-history did not give consent for research analyses.Including the 3 haplo-SCT with the alloSCT-arm for analysis at 10yr, Hb and HbA% were higher while HbS%, Retic., WBC, neutro, bilirubin, LDH, and ferritin were lower in the alloSCT vs. SoC arm (P<.001 for all).Available mean (SD) QoL at 10yr in alloSCT (n=25) vs. SoC (n=28) was not different for emotional but higher for physical (84.0 (16.3) vs 76.4 (11.2); P=.013), school (72.6 (17.2) vs 61.4 (14.7);P=.016) and even social functioning (93.8 (10.7) vs. 86.4 (12.9); P=.003).MRI/MRA and cognitive performance data were only analyzed in stroke-free patients. At enrollment (T0), silent cerebral infarcts (SCI) were present in 6/31 in the SoC-arm and 12/28 in the alloSCT arm. At 10yr, 5 additional patients had developed SCI in the SoC arm, but none did in the alloSCT, while SCI were either no more visible or <3mm in 1 (SoC) and 4 patients (alloSCT) (P=.010). Comparing alloSCT (n=24) to SoC (n=21), cognitive testing showed no difference in verbal comprehension and perceptual reasoning index, while the mean (SD) working memory index (WMI) was higher (89.6 (11.8) vs 80.5 (10.8); P=.021) with a digit span of 8.4 (1.9) vs. 6.7 (1.8)(P=.005), the processing speed index (PSI) was higher (96.5 (21.9) vs. 83.7 (14.4);P=.035) with a symbol search of 9.3 (2.0) vs. 7.3 (2.9)(P=.021), respectively. Compared to T0, mean (SD) WMI and PSI at 10yr improved, although not significantly, in transplanted patients [+5.8 (15.6) vs. +9.0 (25.4)] but not in the SoC arm [-2.0 (15.7) and +0.6 (19.7)].Thus, this first prospective comparative trial demonstrates that differences between alloSCT and SoC changed significantly at 10yr with alloSCT providing better primary prevention of SCI, social QoL, working memory and processing speed

Introduction: Beti-cel is an approved, one-time gene therapy treatment for adult and pediatric patients with TDT. Beti-cel consists of autologous hematopoietic stem and progenitor cells transduced with the BB305 lentiviral vector encoding a modified β-globin gene (β A-T87Q), which produces functional hemoglobin (Hb) and addresses the underlying genetic cause of TDT. While transfusion independence (TI) remains a critical component for assessing patient response to gene therapy, other measures, including markers of iron overload, are important for evaluating the impact of therapy and management of disease burden over time. Previously, we demonstrated that iron markers stabilized in patients who achieved TI and stopped chelation therapy. Here, we report iron management outcomes in patients who completed either a phase 1/2 or phase 3 beti-cel parent study and subsequently enrolled in the long-term follow-up study. Methods: Patients with TDT who completed a parent beti-cel study (phase 1/2 studies: HGB-204 [NCT01745120]; HGB-205 [NCT02151526]; phase 3 studies: HGB-207 [NCT02906202]; HGB-212 [NCT03207009]) could enroll in a long-term study (LTF-303 [NCT02633943]) for up to an additional 13 years of follow-up. In these studies, TI was defined as a weighted average Hb ≥9 g/dL without packed red blood cell transfusions for ≥12 months. Iron removal therapy was at the discretion of the treating physician. Liver and cardiac magnetic resonance imaging evaluated liver iron concentration (LIC) and cardiac T2*; serum ferritin and transferrin receptor (TfR) were assessed at regular intervals according to protocol. Results:As of January 30, 2023, 63 patients received beti-cel; median (range) follow-up was 60.1 (23.8-109.5) months. In phase 3 studies, 37/41 (90%) patients achieved TI and maintained TI through the last follow-up, which was 5+ years for 10 patients ( Figure 1). In phase 1/2 studies, 15/22 (68%) patients achieved TI; 14 of these patients maintained TI through the last follow-up, which was up to 9 years. One patient no longer meets protocol-defined TI as a result of Hb level <9g/dL at year 6 due to acute health events unrelated to β-thalassemia, which were not attributed to loss of beti-cel treatment effect. In total, 51 patients across phase 1/2 and 3 studies achieved and maintained TI through last follow-up with 35/51 (69%) patients off chelation. Thirty of 51 patients had an LIC measurement at month 48. Of these 30 patients, 21 had an LIC <5 mg/g at month 48 post infusion. Among these 21 patients, 5 never restarted chelation after infusion (2 received phlebotomy only), 11 restarted chelation and then were able to discontinue after iron stores normalized (1 also received phlebotomy), and 5 continue to receive chelation (none had phlebotomy). The other 9 patients who had an LIC measurement at month 48 had an iron burden ≥5 mg/g. All 9 of these patients restarted chelation; 4 were able to discontinue (2 had phlebotomy) and 5 continue to receive chelation (1 had phlebotomy). Analysis of iron marker stabilization after discontinuation of chelation will be presented. The median (range) change from baseline in LIC levels at month 48 was -3.9 (-22.3 to 10.5) mg Fe/g dry weight; the median (range) change from baseline in serum ferritin was -2119.0 (-7211 to 3889) pmoL/L. Reductions from baseline in serum TfR were observed at month 36; cardiac T2* remained stable at month 48 ( Table 1). Safety of beti-cel treatment largely reflected the known side effects of hematopoietic stem cell collection and the busulfan conditioning regimen. Conclusion: In this analysis with up to 9 years of follow up, patients treated with beti-cel who achieved TI also demonstrated sustained improvements in iron burden, and the majority of patients were able to stop chelation. Collectively, these results demonstrate the long-term durability and stability of response after beti-cel gene therapy in patients with TDT.

Topic: 27. Thalassemias Background: Endocrinopathies remain the main complication of iron overload in Transfusion Dependent Thalassemia (TDT), hypogonadism, generally due to oxidative stress related pituitary damage, being the most frequent and often the earliest manifestation. A well-managed chelation therapy initiated during infancy reduces the risk of pubertal delay and hypogonadism. Few data about the current pubertal development of TDT patients receiving DFX are available in literature. Aims: The aim of this national study was to evaluate pubertal development and hypogonadism in TDT adolescents and young adults included in the French National Thalassemia Registry (NaThalY) who received oral chelation with DFX. Methods: This retrospective study concerned all TDT patients included in the national registry (HSCT recipients excluded) who received DFX for at least three years before puberty. Patients were born between 1997 (maximum age of 10 years when DFX was marketed in 2007) and 2009 (evaluable for puberty in 2022). Delayed puberty was defined as lack of testicular development at 14 years old in boys and absence of thelarche at 13 years old in girls. Simple delayed puberty was defined as puberty with a delayed onset but then proceeding normally without the need for any treatment to achieve full pubertal development and hypogonadism as insufficient synthesis of sexual hormones. Results: Fifty patients fulfilled inclusion criteria. Their median age at evaluation was 18 years (range 13-24) and 25 patients (50%) were male. The median duration of DFX chelation before puberty was 7 years (3 -12). 80% of patients were born in France. Regular transfusion regimen and chelation therapy were initiated early, at 1.3 years (0.2-4) and 3 years (1-6) respectively. The median age at puberty onset was 14 years in males and 12 years in females with a median age at first menstruation of 13.5 years (Table). Ten patients (20%) had pubertal development anomalies or hypogonadism. Six patients had simple pubertal delay (n=5) or a transient arrest of puberty with a spontaneous favorable outcome (n=1). One patient developed persistent primary amenorrhea despite a one-year estrogen-progestogen hormone therapy and three others had early secondary amenorrhea: one had a severe chronic iron overload, the second received hormone replacement therapy for a central and peripheral hypogonadism with premature ovarian insufficiency and the third patient had secondary amenorrhea just after a normal pregnancy (the only pregnancy registered in the cohort) currently under investigation. These 10 patients (median age of 20.5 years, range 16-24) had all a beta0/0 genotype and 7/10 experienced a history of severe iron overload (Serum ferritin > 2500 ug/L or liver iron concentration > 15 mg/g). Nonetheless the duration of DFX before puberty and the age at the start of chelation were similar to the other 40 patients with no delay in puberty onset. The final height reached in 35 patients was slightly reduced (-0.7 DS) with a median pubertal growth spurt (difference between final height and prepubertal height) of 18 cm in girls and 21.5 cm in boys. Summary/Conclusion: In adolescents and young adults starting chelation therapy early and receiving before puberty a median of 7 years of DFX, the residual frequency of pubertal anomalies or hypogonadism was of 20% half of them presenting a simple pubertal delay. A pubertal growth spurt was observed leading to a final height only mildly reduced. Specialized follow-up of puberty even in the absence of abnormality is mandatory in TDT children. In the next years the frequency of hypogonadism in young adults could be also assessed.Keywords: Iron overload, Blood transfusion, Iron chelation, beta thalassemia

Introduction: Beti-cel gene therapy addresses the underlying cause of transfusion-dependent β-thalassemia (TDT) by adding functional copies of a modified β-globin gene to autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) via a third-generation, self-inactivating lentiviral vector (LVV), BB305, which produces functional adult hemoglobin (Hb), HbA T87Q, in red blood cells (RBCs). Here, we report efficacy, safety, and quality of life (QOL) data from adult and pediatric patients treated with beti-cel who were followed for up to 9 years after treatment. These outcomes may inform patient selection for real-world treatment with beti-cel. Methods: Patients with TDT who completed either a phase 1/2 (HGB-204 [NCT01745120]; HGB-205 [NCT02151526]) or phase 3 (HGB-207 [NCT02906202]; HGB-212 [NCT03207009]) beti-cel parent study and subsequently participated in the long-term, 13-year follow-up study LTF-303 (NCT02633943) were included in this analysis. Analyses were performed with data collected through January 30, 2023. Efficacy (including transfusion independence [TI], defined as a weighted average Hb ≥9 g/dL without packed RBC transfusions for ≥12 months) and safety are reported through last follow-up. QOL data are reported for studies HGB-204, HGB-207, and HGB-212 through month 36. Statistical analyses were conducted to examine key outcomes in subgroups based on patient age at enrollment (pediatric: <18 years; adult: ≥18 years). Results:As of January 30, 2023, 63 patients (median [range] age: 17 [4-35] years) had received beti-cel in a phase 1/2 or 3 study and enrolled in LTF-303, with a median (range) follow-up of 60.1 (23.8-109.5) months. Phase 3 studies used the commercial drug product manufacturing process. Ninety percent (37/41) of phase 3 patients achieved and maintained TI through last follow-up (up to 6 years; Table 1). TI rates by study, genotype, and age for phase 3 patients are also presented in Table 1. In phase 1/2 studies that used an older drug manufacturing process, 68.2% (15/22) of patients achieved TI; 14 of these patients sustained TI through last follow-up (up to 9 years). One patient no longer meets protocol-defined TI as a result of Hb level <9g/dL at year 6 due to acute health events unrelated to β-thalassemia, which were not attributed to loss of beti-cel treatment effect. Approximately 80% of pediatric and adult patients required only one mobilization cycle to achieve the drug product dose. The median percentage of drug product cells transduced with the BB305 LVV was comparable between adult and pediatric populations (78% and 80%, respectively), as were the month 6 median peripheral blood vector copy number (1.4 c/dg and 1.1 c/dg) and HbA T87Q (9.4 g/dL and 8.3 g/dL). Adult patients reported improvements in QOL up to month 36 as assessed by the Short Form-36 Health Survey Questionnaire mental and physical component summary scores, Functional Assessment of Cancer Therapy, and EuroQol ( Table 2). Pediatric Quality of Life Inventory scores will be reported at the time of presentation. Overall, 19% (12/63) of patients experienced ≥1 beti-cel-related adverse event (AE); the most common beti-cel-related AEs (occurring in ≥3 patients) were abdominal pain (experienced in 5/63 [7.9%] patients) and thrombocytopenia (3/63 [4.8%] patients). Five patients experienced serious veno-occlusive liver disease; all 5 received defibrotide and recovered. No malignancies, insertional oncogenesis, or vector-derived replication-competent lentivirus were reported. Age subgroup safety analysis as of last follow-up will be reported in the final presentation. Conclusion: Beti-cel is a potentially curative gene therapy for patients with TDT across ages and genotypes through achievement of TI and normal or near-normal Hb. These data will inform real-world beti-cel treatment decisions for patients with TDT and providers.

β-thalassemia is an haemoglobinopathy characterized by a defective synthesis of the β-globin chain. To assess the current state of health of paediatric patients with β-thalassemia, data from the French national registry regarding children born between 2005 and 2020 with β-thalassemia intermedia (TI) or major (TM) were collected. A total of 237 patients (median age 7.1 years at last visit) were analysed, of whom 156 (65.8%) were born in France and 162 (68.4%) had a TM phenotype. The probability of survival for children with TM born in France was 98.3% at 15 years. Fifty-four (22.8%) children received a haematopoietic stem cell transplant with a success rate of 88.8%. Hepatic and cardiac iron overload monitoring in non-transplanted patients showed moderate overload in 15.7% (18/115) and 7.1% (7/99) of cases, respectively, while clinical complications were found in only 4 patients with TM (hepatic in 3 cases). At last visit, mean ferritinemia was 1293 ng/ml (±759). Overall, less than 10% of children underwent splenectomy. No significant impact of the disease on growth or academic achievement was observed. Deferasirox was the main first-line chelator, prescribed in 78.2% of cases, with side effects reported in 11.7% of instances.

The use of thiotepa-treosulfan-fludarabine conditioning regimen and peripheral blood stem cell grafts is associated with improved outcomes of hematopoietic stem cell transplantation (HCT) in patients with high-risk thalassemia major. However, there remains a need to identify predictors of poor outcomes in this cohort to further optimize outcomes. The Endothelial Activation and Stress Index (EASIX) is a biomarker shown to predict survival in various settings, including graft-versus-host disease, veno-occlusive disease, and nonrelapse mortality following allogeneic HCT. In this retrospective analysis, we evaluated the role of EASIX-PreTx (measured before conditioning therapy) as a biomarker in predicting day +100 transplantation-related mortality (TRM+100) in 281 patients with thalassemia major who underwent HCT with a uniform conditioning regimen using thiotepa-treosulfan-fludarabine at our center between January 2012 and December 2019. The median patient age was 9 years (range, 1 to 25 years), and 109 (38.8%) were females. According to the Pesaro classification (with Vellore modification), 3 patients (1.1%) were class I, 34 (12.1%) were class II, 134 (47.7%) were class III low risk, and 110 (39.1%) were class III high risk. Stem cell donors were matched sibling (n = 218; 77.6%), matched related nonsibling (n = 23; 8.2%), or matched unrelated (n = 40; 14.2%). Five patients (1.8%) received a bone marrow graft, and the others received a peripheral blood stem cell graft. Thirty-eight patients (13.5%) had TRM+100. EASIX-PreTx was available for 184 patients (65.5%). The median EASIX-PreTx was significantly higher in patients with TRM+100 compared with those without TRM+100 (1.09 versus .75; P = .008). An EASIX-PreTx cutoff of .85 had 70.4% sensitivity and 62% specificity for predicting TRM+100. The TRM+100 for patients with EASIX-PreTx >.85 was significantly higher than those with EASIX <.85 (24.4% versus 7.5%; P = .003). In a uniform subgroup of class III patients undergoing allogeneic HCT (n = 156), EASIX-PreTx was an independent predictor of TRM+100.