Introduction Despite advances in allogeneic hematopoietic cell transplantation (HCT) for sickle cell disease (SCD), graft failure (GF) remains a significant post-HCT complication. Clinical outcomes of SCD patients who experience GF and have undergone a 2nd HCT have not been characterized to date. Objective The primary objective was to estimate the 2-year overall survival (OS) (from time of GF) in patients with SCD who did or did not undergo a 2nd HCT. Secondary objectives included estimating the 2-year event-free survival (events: death, GF, 3rd HCT, CD34 boost, donor lymphocyte infusion) among 2nd HCT recipients and identification of risk factors impacting OS and EFS in this population. Methods This was a multicenter retrospective study wherein data were obtained from 30 centers across the USA, Brazil, and Saudi Arabia. Children and adults with SCD who experienced GF post-HCT from 1999-2024 were eligible. Time-to-event data were analyzed using Kaplan-Meier estimates, and univariate analysis was used to determine risk factors associated with outcomes. Results A total of 124 patients (n=67 males) with a median age of 14.6 years (range 1.3-43.9 years) at their first HCT were included. Of these, 78 (63%) proceeded to a 2nd therapy (2nd HCT or unconditioned CD34 boost) and 46 (37%) received neither (no therapy) (Figure 1). Pre-1st HCT, the two groups were similar. The majority (≥90%) had HbSS genotype, with a performance score of ≥ 90. Nearly half (49%) had history of cerebrovascular disease, 53% were on chronic transfusions, and 25% had red cell alloantibodies. First HCT characteristics are shown in Table 1a. The 2-year OS of the entire cohort was 79.2% (95% CI 70.5%-85.6%) with no difference between the no therapy vs second therapy groups (81% vs 77.4% p =0.6). Clinical outcomes (Table 1a-1b): In the no therapy group, at last follow-up, there were 8 deaths (17.5%) and 3 second neoplasms (6.5%). Unconditioned CD34+ boosts recipients were excluded from 2nd HCT analysis. In the 2nd HCT group, the median age at HCT was 15.4 years (range: 1.5-53.5 years) and median inter-HCT interval was 8.8 months (range: 1-177 months). Two patients who developed MDS following GF after 1st HCT received a 2nd HCT. The incidence of grade I-IV acute, any chronic graft versus host disease, and GF were 20.5%, 12.3%, 26%, respectively. At last follow-up there were 16 deaths (22%), and two patients (2.7%) developed second neoplasms. The 2-year OS and EFS were 81.4% and 67.9%, respectively (Figure 2a). Univariate analysis showed no association between inter-HCT interval, donor type, HCT year, or conditioning intensity on OS or EFS except for an inter-HCT interval <3 months associated with significantly reduced EFS (30.8%; 95% CI: 9.5%-55.4%; p= 0.006) (Figure 2b). Conclusion Second allogeneic HCT, though a viable salvage option for patients with SCD experiencing GF, requires careful timing and patient selection to optimize outcomes.

Introduction Sickle cell disease (SCD) causes progressive organ damage and reduced life expectancy. Hematopoietic cell transplantation (HCT) using a matched sibling donor (MSD) is an established curative therapy for SCD. Myeloablative conditioning (MAC) has been recommended for pediatric MSD HCT for SCD. However, given the serious toxicity of MAC, reduced intensity conditioning (RIC) has instead been adopted by some centers. Nonmyeloablative (NMA) conditioning using alemtuzumab, 300 cGy total body irradiation (TBI), and sirolimus has been shown to have favorable outcomes in adults with SCD, but pediatric data are limited. Objective To compare toxicity and outcomes of MAC, RIC, and NMA conditioning in pediatric MSD HCT for SCD. Methods This was a retrospective cohort study of patients who underwent MSD HCT for SCD at one center from 2012-2025. Patients with <1 year of follow-up were excluded. MAC patients received busulfan-based regimens. RIC patients received alemtuzumab, fludarabine, melphalan, ± thiotepa. NMA patients were enrolled on clinical trial NCT03587272. Dosing in regimens are included in table 1. Graft failure was defined as donor myeloid chimerism <10%. Cure was defined as donor myeloid chimerism >30% and hemoglobin S% <50%. Results Eight-eight patients were included: 50 MAC, 10 RIC, and 28 NMA. NMA patients were older, but otherwise similar. Compared to MAC and RIC, NMA patients required markedly less supportive care post-HCT: none required patient-controlled analgesia or total parental nutrition during engraftment, transfusion requirements were lower, and hospitalization time was decreased (MAC 45 and RIC 54.5 vs. NMA15 days, (p<0.0001). Mortality occurred only in the MAC group (4/50, 8%). No NMA patients developed acute grade II-IV GVHD or chronic GVHD, versus 10-30% with MAC and RIC. While donor myeloid chimerism at 1-year was lower in the NMA group compared to the MAC group (100%), NMA median donor chimerism was strong at 99%. Graft failure with return of sickle hematopoiesis only occurred in one patient (NMA), but 8 patients (4 RIC and 4 NMA) elected to undergo reduced toxicity second HCT for dropping donor myeloid chimerism to prevent secondary graft failure. Measures of cardiac and pulmonary function (EF and FEV1) at 1-year post-HCT were similar across groups, while ovarian reserve at last evaluation was significantly better in the NMA group (MAC 0.01 and RIC 0.22 vs NMA 1 ng/mL, p<0.0001). At last follow-up (median time 4 years, range 1-10 years) 46/50 (92%) MAC, 10/10 (100%) RIC, and 27/28 (96.4%) NMA patients were alive and cured of SCD. Conclusion In pediatric MSD HCT for SCD, NMA conditioning with alemtuzumab, low-dose TBI, and sirolimus effectively decreases toxicity compared to MAC and RIC, with comparable cure rates. Although some patients require second HCT for declining chimerism, overall outcomes support NMA as a viable option for children and adolescents with SCD.

Abstract HLA-identical sibling donor hematopoietic cell transplant (HCT) is an established curative therapy for sickle cell disease (SCD). Although myeloablative HCT conditioning achieves a high event-free survival (EFS) in children, it carries substantial toxicity, including risks of graft-versus-host disease (GVHD), transplant-related mortality, and infertility. Nonmyeloablative conditioning with alemtuzumab, 300 cGy total body irradiation, and sirolimus has demonstrated tolerability as a curative approach in adults with SCD. We conducted a multicenter, prospective clinical trial to evaluate this regimen in children and adolescents with SCD. Thirty-eight patients (aged 2.9-21.9 years; median age, 13.5 years) underwent HCT. All achieved initial engraftment; however, 7 patients (18.4%) experienced secondary graft failure between day +39 and day +391 with autologous hematologic reconstitution. One additional patient received an unconditioned second HCT. At 2 years after HCT, overall survival was 100%, and EFS was 78.9%. Among patients with engraftment, 2-year median donor myeloid chimerism was 95%, and T-cell chimerism was 75%. No patients developed acute or chronic GVHD. The median number of platelet transfusions received was 0 (interquartile range, 0-3). Patient-reported health-related quality of life remained stable early after HCT and significantly improved at 1 year. After year 2, 3 additional patients received a reduced-intensity second HCT to avert secondary graft failure. Although regimen modifications are needed to reduce graft failure risk, this nonmyeloablative approach offers a relatively low-toxicity curative option for children with SCD who have an HLA-identical sibling donor. This trial was registered at www.clinicaltrials.gov as NCT03587272.

Background Children with sickle cell disease (SCD) remain at risk for invasive pneumococcal disease (IPD) because of impaired splenic function and increased susceptibility to encapsulated bacteria. Data describing IPD after allogeneic hematopoietic cell transplantation (HCT) for SCD are limited.Methods We conducted a multicenter retrospective cohort study of children and young adults with SCD undergoing first allogeneic HCT at two participating Sickle Cell Transplant Advocacy and Research (STAR) centers. IPD occurring within 365 days after HCT was identified through registry data, microbiologic culture review, and supplemental chart review.Results Among 182 patients undergoing HCT, three developed IPD within the first year after transplant. All cases presented with sepsis and bacteremia; one patient also developed meningitis and died of septic shock. IPD occurred between 7 and 365 days after HCT. None of the patients had received post-transplant pneumococcal vaccination before IPD diagnosis. Serotype data were unavailable for all cases.Conclusion In this multicenter cohort of patients with SCD undergoing allogeneic HCT, IPD was uncommon but clinically severe, including late infections occurring nearly one year after transplantation. Prospective studies evaluating immune recovery, splenic function, pneumococcal vaccination practices, and long-term infectious outcomes are needed to better define persistent susceptibility to invasive pneumococcal disease after HCT in patients with SCD.

Gene therapy (GT) has recently become available for sickle cell disease (SCD), but how it is being incorporated into pediatric clinical practice remains unclear. We conducted a national anonymous cross-sectional survey of board-certified or board-eligible pediatric hematology/oncology physicians caring for children with SCD. Survey domains included referral likelihood across clinical scenarios, counseling confidence, and pre-referral evaluation practices. Responses were compared by practice focus (SCD-focused, general hematology/oncology, pediatric HCT) and years in practice. Among 138 eligible respondents, willingness to discuss GT was high, particularly when families expressed interest (97.1%). Referral likelihood was highest for HbSS/HbSβ0 disease with recurrent vaso-occlusive events (85.5%), but lower for patients without recurrent events (44.2%) and for HbSC/HbSβ+ disease (46.4%). General pediatric hematology/oncology physicians were more likely than specialists to endorse referral for neurologic complications, including silent cerebral infarcts (63% vs 39%, p=0.01), despite lower confidence discussing product-specific differences (65.0% vs >95%, p<0.001). Routine α-globin testing before referral was reported by 57.2% of respondents and by 44.2% of generalists. HLA typing among patients with siblings was performed by 53.5% of generalists compared with 70.4% of SCD-focused and 91.7% of HCT physicians (p=0.004). Common barriers included insurance authorization, access to specialized centers, and uncertainty regarding long-term outcomes. Pediatric hematologists demonstrate strong engagement with GT for SCD, but variation in referral practices, counseling confidence, and pre-referral evaluation persists. Standardized referral pathways and targeted educational resources may support more consistent integration of GT into pediatric care.

BACKGROUND:Sickle cell disease (SCD) is a chronic and life-limiting hemoglobin and systemic vascular disease. While over 1000 people have undergone hematopoietic cell transplantation (HCT) over the last 40 years, long-term disease-specific and health-related quality of life data are lacking. The American Society of Hematology 2021 Guidelines for SCD emphasized the need for more detailed registry data to inform patients and providers with decision-making and practice recommendations. PROCEDURES:In January 2021, the Sickle Cell Transplant Advocacy and Research Alliance (STAR) launched Project Sickle Cure (PSC). This multi-center, prospective study of patients who have undergone HCT for SCD includes baseline demographics and SCD-specific post-HCT outcomes, serial neurocognitive testing, health-related quality of life measures, health equity evaluations, a neuroimaging bank, detailed evaluation of neurologic status pre- and post-transplant, and chronic pain evaluation. A biorepository is in the planning stage of development. RESULTS:As of November 2025, 115 participants have enrolled at 18 STAR sites with enrollment ongoing. CONCLUSIONS:PSC is a STAR prospective study which will address a major gap in our understanding of outcomes post-HCT specific to SCD. WeDecide, a larger study comparing HCT health-related quality of life outcomes to those who receive non-transplant disease modifying therapy (NT-DMT) is in development, and PSC will provide the HCT comparator data. These data will also be highly relevant as other curative and transformative therapies, such as gene therapy, become more widely used.

BACKGROUND:Children with sickle cell disease (SCD) increasingly undergo HLA-identical sibling donor hematopoietic cell transplant (HCT), yet the optimal conditioning intensity remains uncertain. Myeloablative conditioning (MAC) has been the conventional approach, but reduced-intensity conditioning (RIC) and nonmyeloablative conditioning (NMA) may achieve cure with less toxicity. OBJECTIVE:Among pediatric patients with SCD undergoing HLA-identical HCT, to compare outcomes by conditioning intensity. STUDY DESIGN:We evaluated all patients who underwent HLA-identical HCT for SCD at a single pediatric center from 2012-2025. Data were retrospectively collected for MAC and RIC recipients and prospectively collected for NMA recipients enrolled on two clinical trials (NCT03587272, NCT06358638). RESULTS:Among 91 patients studied, 50 received busulfan-based MAC, 10 received alemtuzumab/fludarabine/melphalan ± thiotepa RIC, and 31 received alemtuzumab/300 cGy total body total body irradiation (TBI) ± daratumumab NMA. Compared with MAC and RIC, NMA recipients required significantly less supportive care, including markedly less use of patient-controlled analgesia, total parenteral nutrition, transfusions, and hospitalization. No NMA recipients developed the combined graft-versus-host disease (GVHD) endpoint (acute grade 2-4 or chronic GVHD), compared with 20% of MAC and 30% of RIC recipients. Graft failure occurred in only one patient (NMA), although eight patients (4 RIC and 4 NMA) underwent successful low-toxicity second HCT for declining donor myeloid chimerism to avert secondary graft failure. All four deaths occurred in the MAC group (8%). The proportion of patients alive without SCD at last follow-up in each group was: MAC 46/50 (92%), RIC 10/10 (100%), NMA 30/31 (96.8%). Post-HCT cardiac and pulmonary function were similar across groups, while ovarian reserve measured by anti-Müllerian hormone was significantly higher after NMA. CONCLUSION:NMA conditioning with alemtuzumab and low-dose TBI substantially reduces toxicity compared with MAC and RIC. Although some patients require second HCT to improve donor engraftment, overall outcomes support this NMA approach as an option for children and adolescents with SCD.

Cardiac dysfunction causes morbidity and mortality in sickle cell disease (SCD). Allogeneic hematopoietic cell transplantation (HCT) is the most common curative option, yet its impact on long-term cardiac function is not well defined in multicenter cohorts. After our Sickle cell Transplant Advocacy and Research (STAR) retrospective registry analysis on long-term organ function, we sought to complete more detailed cardiac function analysis and determine predictors of dysfunction.This retrospective cohort study of pediatric patients (pts) with SCD post-HCT with pre- and post-HCT echocardiograms (echo) in the STAR registry (Figure 1). Additional echo data was extracted from source documents and linked to existing data. Cardiac dysfunction was defined as ejection fraction (EF) <55% or shortening fraction (SF) <28%. Data were summarized as median (IQR) or N (%). Linear mixed effect models were used to compare pre- to post-HCT data, accounting for within-pt clustering. Associations between risk factors and cardiac dysfunction were assessed using Firth logistic regression.Within 228 pts (Table), age at HCT was 8.8 years (yrs), and most pts received matched related donor (MRD; 75%) bone marrow (76%) after myeloablative conditioning (MAC; 76%). Engraftment was prompt, with most pts remaining alive and free from severe graft-versus-host disease (GVHD) or rejection. At 3.4 yrs (2.2, 6.3) post-HCT, while EF significantly decreased, SF was stable (Figure 2A). Left ventricular (LV) size and function significantly decreased (Figures 2B-C). Mitral and tricuspid valve (MV, TV) flow significantly decreased (Figure 2D), as did tricuspid regurgitant jet velocity (TRJV; Figure 2A). While most (93%) remained free of cardiac dysfunction, significantly more pts had low EF (1.6%→6.7%, p=0.008) or SF (0.9%→4.1%, p=0.022) post-HCT. Controlling for MAC and cytoxan (Cy) dose, male sex was significantly associated with post-HCT cardiac dysfunction and age <6 yrs was protective.In pediatric SCD, HCT is associated with favorable reverse remodeling and reduced pulmonary pressures, but with a modest EF decrease. Early HCT appears protective and male sex increases risk. Longer follow-up is needed to clarify durability and clinical significance of these findings. Additional analyses of predictors for diastolic dysfunction are planned.

Patients with sickle cell disease (SCD) commonly receive red blood cell (RBC) transfusions and can become RBC alloimmunized. This study was designed to investigate if RBC alloimmunization before hematopoietic cell transplant (HCT) was associated with post-HCT outcomes and transfusion support using the multicenter Sickle cell Transplant Advocacy and Research (STAR) retrospective registry. From a cohort of 229 pediatric patients with SCD who underwent human leukocyte antigen (HLA)-matched related donor HCT with myeloablative or reduced intensity conditioning, 40 patients (17%) were RBC alloimmunized pre-HCT. The RBC alloimmunized group had a significantly higher incidence of grade III-IV acute graft-versus-host disease (GVHD) (15% vs. 3.7%, p = 0.013), which remained significant (OR 4.22, 95% CI, 1.19, 14.3; p = 0.027) when controlling for pre-HCT RBC transfusion burden and conditioning intensity. Graft failure occurred in 10% of RBC alloimmunized patients compared with 2.6% of non-alloimmunized patients, p = 0.052. Patients with RBC alloimmunization had lower 5-year severe GVHD-free, rejection-free survival (69% vs. 88%, p = 0.004), which remained significant when controlling for age. Post-HCT patients received a median 3 RBC units (IQR 2, 6) and 11 platelet transfusions (IQR 7, 19). Pre-HCT RBC alloimmunization was associated with a greater requirement for post-HCT platelet transfusions, but not post-HCT RBC units transfused. We postulate that the observed associations of pre-HCT RBC alloimmunization with severe acute GVHD and post-HCT platelet transfusion burden are due to inherent immunologic characteristics that render patients at increased risk of developing multiple immune-mediated complications.

Abstract Introduction: Sickle cell disease (SCD) is a severe, life-limiting genetic disorder affecting over 100,000 individuals in the U.S. While allogeneic hematopoietic stem cell transplantation from an HLA-matched donor remains the only established cure, most patients lack a suitable donor. In 2023, the FDA approved two 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 and limited implementation guidance. We sought to assess provider knowledge, referral patterns, and comfort discussing gene therapy (GT) to guide equitable adoption across pediatric SCD practices. Method: We distributed a 35-question REDCap survey to pediatric hematology providers in North America. Eligible participants were board-eligible/certified pediatric hematologists who care for individuals with SCD. The study was approved by the IRB of Baylor College of Medicine. This interim analysis includes responses collected from June 6 to July 24, 2025. Stratified analyses based on provider practice type, clinical experience, and SCD center volume were conducted using two-sided t-tests. Results: In addition to posting the survey link on the American Society of Pediatric Hematology and Oncology (ASPHO) Hemoglobinopathy Special Interest Group discussion board and ASPHO Clinical Forum, we distributed email invitations to approximately 500 pediatric hematology/oncology providers identified through pediatric hematology directories. A total of 102 providers who met inclusion criteria completed the survey, yielding a response rate of ~20%. We captured a representative sample of pediatric hematologists caring for individuals with SCD and pediatric SCD centers across the United States and Canada. Practice types included general hematology/oncology (38.3%), SCD-focused (47.1%), and HSCT-focused (14.7%). Clinical experience ranged from <10 years (31.4%) to >20 years (29.4%). Practice sizes ranged from centers caring for <100 (22.5%), 100–400 (36.3%), and >400 (41.2%) individuals with SCD. Most providers (91.6%) reported they would likely discuss GT with patients lacking a matched donor who either had recurrent VOCs or expressed interest. However, only 40% were likely to discuss GT in the absence of VOCs. Stratification revealed that SCD-focused providers were significantly less likely than generalists to recommend GT for patients with prior SCD related neurological complications including: prior stroke (44.8% vs. 69.2%, p=0.028); CNS vasculopathy (39.6% vs. 69.2%, p=0.005); abnormal TCD (60.4% vs. 74.4%, p=0.1). Comfort with gene therapy-related discussions also varied significantly. SCD focused hematologists reported significantly greater comfort with GT counseling including: initiating conversations (100% vs. 76.9%, p=0.002); differentiating products (97.9% vs. 30.8%, p<0.001); discussing risks/benefits (97.9% vs. 51.3%, p<0.001). Physicians were also asked whether, based on currently available information, they would be inclined to recommend one gene therapy product over another when referring patients. Among respondents, 26.7% of HSCT-focused providers indicated they would make such a recommendation, compared to 12.5% of SCD-focused providers and 7.7% of general hematology/oncology providers. Notably, all who expressed a preference favored exagamglogene autotemcel over lovotibeglogene autotemcel, citing concerns about insertional mutagenesis and secondary malignancies, a preference for gene-editing approaches, and considerations related to cost. Conclusions: This national survey highlights substantial variability in gene therapy referral practices for pediatric sickle cell disease, particularly in cases involving neurologic complications and across different provider types. While hematologists with a SCD-focused practice reported greater comfort with GT counseling, they were less likely to recommend GT in certain high-risk scenarios. These findings emphasize the urgent need for standardized, evidence-based guidelines and targeted provider education to ensure equitable access and appropriate integration of GT into pediatric SCD care.

Introduction: Hematopoietic Cell Transplant (HCT) using a HLA-haploidentical donor greatly expands access to curative therapy for patients with sickle cell disease (SCD). Historically haploidentical HCT for SCD has been complicated by a high incidence of graft failure. Testing that could identify patients at risk of graft failure could be an important clinical tool. We investigated a novel HLA-specific Flow cytometry-based Assay (HFA) to evaluate lymphocyte donor chimerism as a potential predictive indicator of engraftment outcomes. Objective: In the BMT CTN 1507 multicenter study (NCT#03263559) evaluating haploidentical HCT for severe SCD using reduced intensity conditioning with post-HCT cyclophosphamide, we sought to quantify donor T-cell and Natural Killer (NK) cell populations utilizing HFA and compare these results to clinical chimerism testing. Methods: Peripheral blood mononuclear cells (PBMCs) were collected and analyzed from patients pre-transplants, day +28, day +100, day +180, and day +365. Donors were also analyzed when available. All samples were evaluated for donor HLA detection by assessing the single-allele HLA mismatch between the haploidentical donor and the patient based on the high-resolution HLA typing. Donor HLA detection was further supported by an HFA assay that utilizes cell surface markers (CD3, CD56 and HLA antibodies targeting a donor or patient specific HLA for each case) for lymphocyte donor chimerism. Results/Discussion: In the adult stratum of the BMT CTN 1507 clinical trial, research samples for HFA testing were available for 33 of the 42 transplanted patients. Clinically 32/33 (97.0%) analyzed patients had sustained donor engraftment at 1-year post-HCT and all of these patients also had evidence of donor engraftment on HFA testing. The one patient with secondary graft failure was diagnosed with graft failure at day +82. Importantly for this patient on day +28 the HFA testing showed only 7.7% T-cell and 2.8% NK cell donor chimerism, whereas clinical whole blood donor chimerism at this time was 96.0%. In addition, one other patient had low (<15%) lymphocyte donor chimerism at day +28 with HFA testing that declined with time. With clinical chimerism testing this patient initially had stable, strong donor engraftment (100% myeloid donor chimerism at day +100 and +180) but then had a notable decline in myeloid donor chimerism of 84.0% at day +365 to 47% at day +730. In both the two patients with problematic donor engraftment, the HFA assay was able to indicate the risk of graft failure at an earlier timepoint than observed clinically. Overall, we observed the lowest lymphocyte donor chimerism for T and NK-cell (84.3 ± 19.4% and 89.0% ± 17.6% respectively) on day+28. Further post-HCT, donor chimerism on HFA testing increases with the highest chimerism at day +365 and similar results to clinical chimerism testing. At day +365 there is low inter-individual variability as compared to earlier timepoints with lymphocyte donor chimerism remaining consistently high above 95% for most patients. The overall median in both lymphocyte lineage exceeds 95% in all evaluated timepoints. Conclusion: Our lymphocyte donor chimerism results using a novel HFA confirms the strong donor engraftment observed clinically for almost all adult patients transplanted on BMT CTN 1507. HFA testing identified the few patients with problematic donor engraftment before they were diagnosed with secondary graft failure or had a serious decline in donor myeloid engraftment. The assay provides a rapid, phenotypically resolved, predictive measure of donor derived lymphocyte reconstitution. HFA testing may serve as valuable supporting data to current clinical monitoring and enable early intervention for patients that are risk for graft failure.

Allogeneic hematopoietic cell transplantation (HCT) provides a curative option for patients with hemoglobinopathies by establishing donor-derived hematopoiesis. However, outcomes are compromised by toxicities and graft-versus-host disease (GVHD), particularly in patients older than 13 years undergoing HCT from unrelated donors. To evaluate the safety and benefit of extended duration (until day +365) abatacept incorporated into GVHD prophylaxis compared to standard prophylaxis that included prednisone in children and adolescents with hemoglobinopathy undergoing HCT from related and unrelated donors. Forty patients with hemoglobinopathy received reduced intensity conditioning and prednisone-inclusive GVHD prophylaxis. Donors were matched siblings or matched/mismatched unrelated donors. Outcomes were compared with 20 subsequent patients who received extended duration abatacept instead of prednisone and targeted lower tacrolimus levels. The incidence of posterior reversible encephalopathy syndrome (PRES) was 17% with prednisone and 0% with abatacept. Acute grade 3 to 4 GVHD occurred in 28% of patients who received prednisone and in 0% that received abatacept (P = .011). Among patients who received prednisone, chronic GVHD (cGVHD) was observed in 2.5% (mild), 5% (moderate), and 30% (severe) of cases. In contrast, abatacept recipients experienced cGVHD at rates of 25% (mild), 5% (moderate), and 5% (severe). Skin/oral involvement was most common in patients with cGVHD who received abatacept. Post-transplant immune reconstitution patterns were similar in both groups. Infection in the presence of GVHD and systemic immune suppression intensification was the primary cause of mortality in patients who received prednisone. The only death in the abatacept group was a patient with primary graft rejection that died after a subsequent transplant. Two patients in the abatacept group developed EBV-associated lymphadenopathy that responded to rituximab. Overall survival and event-free survival were 87% and 80% with prednisone. The corresponding numbers were 95% and 90%, respectively, with abatacept, despite a higher proportion of recipients at risk for poor outcomes (older age, mismatched grafts) in the abatacept group. Including extended duration abatacept and eliminating prednisone as GVHD prophylaxis was safe, effective in eliminating PRES, and reducing the incidence and severity of acute and cGVHD in children, yielding similar outcomes after matched sibling and unrelated donor HCT.

BackgroundRelated human leukocyte antigen (HLA)-haploidentical bone marrow transplantation (BMT) with posttransplant cyclophosphamide may be curative for sickle cell disease. However, graft failure, severe graft-versus-host disease (GVHD), infections, and mortality remain a concern. We evaluated a novel conditioning regimen followed by related HLA-haploidentical BMT in adults with sickle cell disease.MethodsIn a phase 2, open-label, single-arm, multicenter study, 54 eligible participants from 19 U.S. centers were enrolled. Of these, 42 (78%) received transplantation with conditioning including antithymocyte globulin, fludarabine, cyclophosphamide, thiotepa, and total body irradiation. GVHD prophylaxis included posttransplant cyclophosphamide, mycophenolate mofetil, and sirolimus. The primary outcome was event-free survival at 2 years, while secondary outcomes included overall survival and other transplant-related end points.ResultsThe median age at enrollment was 22.8 years (range, 15.5 to 43.2), and the median follow-up period was 37.2 months (range, 20.4 to 56.4). The 2-year event-free and overall survival rates were 88.0% (95% confidence interval [CI], 73.5 to 94.8%) and 95.0% (95% CI, 81.5 to 98.7%), respectively. Two participants experienced primary and another secondary graft failure. The incidence of grade-3-to-4 acute GVHD at day 100 was 4.8% (95% CI, 0.9 to 14.4%), while the 2-year chronic GVHD rate was 22.4% (95% CI, 10.9 to 36.4%). Two of the four reported deaths were due to early infectious complications.ConclusionsHLA-haploidentical BMT is an accessible and potentially curative therapy for adults with sickle cell disease. Adverse events were those anticipated from this procedure, including GVHD. (Funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; BMT CTN 1507; ClinicalTrials.gov number, NCT03263559) In this phase 2, open-label, single-arm study, adults with sickle cell disease were treated with a modified conditioning regimen involving thymoglobulin, thiotepa, cyclophosphamide, and fludarabine followed by haploidentical bone marrow transplantation and graft-versus-host disease prophylaxis. The primary outcome was 2-year posttransplant event-free survival. After a median follow-up period of 37.2 months, the 2-year event-free and overall survival rates were 88.0% (95% CI, 73.5 to 94.8%) and 95.0% (95% CI, 81.5 to 98.7%), respectively.

Background: The advent of autologous gene modified cell therapies to treat monogenic disorders has been a major step forward for the field of hematopoietic stem cell transplantation (HCT) and cellular therapies. The need for disease-specific conditioning to enable these products to provide a potential cure has required extrapolation from experience in myeloablative and non-myeloablative HCT for these disorders. Methods: In this manuscript, we review the current datasets and clinical experience using different conditioning regimens for autologous gene therapies in hemoglobinopathies, metabolic and lysosomal disorders, inborn errors of immunity (IEI) and bone marrow failure (BMF) syndromes. Results: The disease specific and unique conditioning requirements of each disorder are considered in order to achieve maximal benefit while minimizing associated toxicities. Conclusions: Standardized recommendations based on these data are made for each set of disorders to harmonize treatment. Future directions and the possibility of non-genotoxic conditioning regimens for autologous gene therapies are also discussed. Ethical Statement: The authors followed all relevant ethical considerations in writing this manuscript. (c) 2024 International Society for Cell & Gene Therapy. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)