Research Appraisals
Evidence-based critical appraisals of the latest medical research, systematically evaluated using Oxford CEBM methodology.
Showing 6 appraisals
Blood advances
Successful gene therapy for transfusion-dependent α-thalassemia: a case report
α-Thalassemia is a severe inherited hemoglobin (Hb) disorder with limited curative options for patients with transfusion dependency, lacking suitable donors. We report, to our knowledge, the first-in-human application of lentiviral vector-mediated α-globin gene therapy in a girl aged 14 years with transfusion-dependent HbH disease (--SEA/αCSα). Autologous CD34+ hematopoietic stem and progenitor cells were mobilized, collected, and genetically modified ex vivo using the lentiviral vector (Lenti-HBA) to restore α-globin expression, then reinfused after busulfan conditioning. The patient achieved engraftment within 3 weeks and started to be free of transfusions from the fourth week onward. In the last year of follow-up (months 12-24), the average Hb level remained at ∼90 g/L without transfusion support, with HbA accounting for >85% of total Hb. Vector copy numbers were stable, and no evidence of clonal dominance, insertional mutagenesis, or replication-competent lentivirus was detected. Adverse events (AEs) were limited to expected busulfan-related toxicities, including grade 2 menstrual irregularity and ovarian failure (serious AE). Despite cessation of chelation therapy, iron overload progressed minimally, and no cardiac iron deposition occurred. Immune recovery, growth, and development were preserved. This case demonstrates the feasibility, safety, and durable efficacy of lentiviral α-globin gene therapy as a potential curative treatment for transfusion-dependent α-thalassemia. This trial was registered at www.clinicaltrials.gov as NCT05851105.
29 July 2026
Read appraisal →Blood advances
I-STRONG: an integrative, multicomponent treatment approach for chronic pain in pediatric sickle cell disease
Chronic pain affects ∼20% of adolescents living with sickle cell disease (SCD). There is a critical unmet need for evidence-based interdisciplinary approaches for chronic SCD pain treatment. We aimed to (1) use community engagement to adapt an integrative multicomponent treatment program designed to meet the unique needs of chronic SCD pain (ie, Integrative Strong Body and Mind Training [I-STRONG] for SCD), and (2) optimize feasibility and acceptability of I-STRONG through a proof-of-concept trial. Modifications to an existing cognitive behavioral therapy (CBT) and neuromuscular treatment program for chronic widespread pain were informed by semistructured qualitative interviews with adolescents (aged 12-18 years) with chronic SCD pain (n = 12) and their caregivers (n = 12), community advisory boards, and interdisciplinary experts to develop I-STRONG. I-STRONG is a virtual 8-week, 16-session, group intervention combining CBT and neuromuscular exercise training, co-led by experts in psychology and physical therapy. A pilot clinical trial of I-STRONG (n = 12 adolescents; n = 9 caregivers) was conducted to iteratively optimize intervention feasibility and acceptability. Community engagement strategies informed systematic adaptations for access, engagement, relevance, satisfaction, and sense of belonging to meet the unique needs of youth experiencing chronic SCD pain. Pilot testing demonstrated high levels of feasibility (95% completion, 97% intervention fidelity, 92% retention), moderate to high acceptability, and safety. Over 82% of adolescents reported improvements in pain after treatment and at 3-month follow-up. Preliminary evidence suggests that I-STRONG is a promising approach for management of chronic pain in pediatric SCD. A planned multicenter, randomized controlled trial will evaluate I-STRONG's efficacy for pain reduction. This trial was registered at www.clinicaltrials.gov as #NCT06110754.
14 July 2026
Read appraisal →Neurology
Hematopoietic Stem Cell Transplant and Brain Volume Changes in Adults With Sickle Cell Disease
BACKGROUND AND OBJECTIVES: Adults with sickle cell disease (SCD) are at risk of decline in brain health and cognition, even without clinical stroke. SCD-related changes on MRI include brain atrophy and T2 fluid attenuated inversion recovery (FLAIR) white matter hyperintensity (WMH) growth. Hematopoietic stem cell transplant (HSCT) can be curative, but conditioning regimens risk new complications, particularly for adults with accumulated organ damage. We tested whether successful HSCT for adults with SCD was associated with reduced brain atrophy or WMH growth. METHODS: In this cohort study, adults with severe SCD underwent HSCT as part of 5 research protocols at the National Institutes of Health Clinical Center, including autologous gene therapy, HLA-matched donor HSCs, and haploidentical HSCs. Serial brain MRI scans acquired before and after transplant for up to 12 years included 3D T1-weighted and axial FLAIR sequences. Longitudinal brain volumes, segmented using FreeSurfer and corrected for total intracranial volume (TICV), were used to measure brain parenchymal fraction (BPF). A deep learning algorithm segmented WMH volumes from FLAIR sequences. Volumes were log2-transformed as a percentage of TICV. We tested whether HSCT success (persistent engraftment vs graft failure) or change in hemoglobin (Hb) (post-pre-HSCT) was associated with the rate of brain atrophy or WMH growth using mixed-effects linear regression. Random effects included scanner, participant intercept, and slope, while fixed effects included age and sex. RESULTS: Seventy-seven participants (mean age 32 ± 9 years, 43% female) who underwent HSCT were followed for a median 5.3 years (interquartile range [IQR] = 4.6). For 65 participants with successful HSCT, BPF declined nonsignificantly (-0.055%/year; 95% CI -0.12, 0.006; p = 0.08). Twelve participants with graft failure had a 7-fold greater BPF decline (-0.42%/year; 95% CI -0.57, -0.26; p < 0.001; group difference p < 0.001). A smaller change in Hb after HSCT was associated with steeper BPF decline (0.035%/year per unit Hb; 95% CI 0.017, 0.053; interaction p < 0.001). WMH growth was similar in both groups (0.038% vs 0.030% per year; interaction p = 0.50) and was associated with older age and baseline WMHs, but not treatment success. DISCUSSION: Successful HSCT was associated with preserved brain volume, but not WMH growth, another brain health biomarker. Whether these HSCT-related brain structural changes translate to cognitive preservation remains to be determined. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT02140554 registered 2014-05-14, first enrollment February 2015; ClinicalTrials.gov NCT00061568; registered 2004-07-16, first enrollment July 2004; ClinicalTrials.gov NCT02105766; registered 2014-04-01, first enrollment April 2014; ClinicalTrials.gov NCT03077542; registered 2017-03-10, first enrollment April 2017; ClinicalTrials.gov NCT00977691; registered 2009-12-14, first enrollment December 2009. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in adults with sickle cell disease, successful hematopoietic stem cell transplant is associated with slower declines in BPFs over a median period of 5 years, compared with patients with transplant failure.
9 June 2026
Read appraisal →The New England journal of medicine
Base Editing of HBG1 and HBG2 Promoters for Sickle Cell Disease
BACKGROUND: Sickle cell disease is characterized by chronic hemolytic anemia and recurrent severe vaso-occlusive crises. Ristoglogene autogetemcel (risto-cel) includes autologous CD34+ hematopoietic stem and progenitor cells that have been base-edited to target the HBG1 and HBG2 promoters and inhibit BCL11A binding without altering BCL11A expression, yielding a switch in hemoglobin production from sickle hemoglobin (HbS) to antisickling fetal hemoglobin (HbF). METHODS: In this phase 1-2 study, we enrolled patients 12 to 35 years of age with sickle cell disease who had had at least four severe vaso-occlusive crises in the 2 years before enrollment. After myeloablative conditioning with pharmacokinetically guided administration of busulfan, patients received a single infusion of risto-cel (at a dose of ≥3.0×106 viable CD34+ cells per kilogram of body weight). The primary efficacy end point was freedom from severe vaso-occlusive crises for 12 consecutive months, starting later than 60 days after the last red-cell transfusion. This interim analysis was unplanned; here, we describe safety, editing, engraftment, and hemoglobin production and the number of severe vaso-occlusive crises starting later than 60 days after the last red-cell transfusion. RESULTS: A total of 31 patients received risto-cel and were followed for a mean of 6.6 months (range, 0.3 to 20.4). A median of one cycle (range, one to five) was required for stem-cell collection. Neutrophil engraftment occurred at a median of 17.5 days, and platelet engraftment at a median of 19 days. One patient died from idiopathic pneumonia syndrome. All 31 patients had at least one adverse event, 27 (87%) had an adverse event of grade 3 or higher, and 12 (39%) had a serious adverse event. At 6 months, the mean fraction of on-target edited alleles in peripheral blood was 67.4%, the mean HbF as a fraction of total hemoglobin was more than 60%, and the HbS as a fraction of total hemoglobin was less than 40% (among 13 patients); these levels were maintained throughout follow-up. No investigator-reported severe vaso-occlusive crises occurred later than 60 days after the last red-cell transfusion. CONCLUSIONS: Treatment with risto-cel was followed by rapid engraftment and durable expression of HbF and reduction in HbS. These data support further investigation of risto-cel to treat sickle cell disease. (Funded by Beam Therapeutics; BEACON ClinicalTrials.gov number, NCT05456880.).
12 May 2026
Read appraisal →Blood
Long-term efficacy and safety results of betibeglogene autotemcel gene therapy for transfusion-dependent β-thalassemia.
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.
11 May 2026
Read appraisal →Hematology (Amsterdam, Netherlands)
Machine learning in the prediction of liver iron concentration and iron chelation therapy adjustment
OBJECTIVES: Iron chelation therapy titration is managed by hematologists who monitor iron levels and adjust medication dosages to achieve patient outcomes. This study developed a machine learning (ML) algorithm to predict the liver iron concentration (LIC) and chelation therapy adjustments. METHODS: This retrospective, single-centre cohort study included adult patients who underwent FerriScan MRI to obtain LIC for chelation therapy monitoring. Using an XgBoost-based ML framework, the proximal-time model (PTM) utilised clinical/drug, laboratory and MRI data features from one visit prior to the target visit, whereas the all-time model (ATM) utilised the data from all prior visits. RESULTS: 94 patients with 892 consecutive visits between January 2008 and November 2018 were included in this study. We assessed the prediction capabilities of the PTM and ATM in LIC, changes to chelation drug type and dosage changes. The PTM model was superior to the ATM model in all the experiments. When drug features were excluded, the CLICT model for predicting patient iron overload status improved to an AUROC of 0.83 [95% CI 0.75-0.91] for PTM; compared to an AUROC of 0.73 [95% CI 0.66-0.80] when drug features were included.For predicting changes in chelation type, the CLICT model showed AUROC of 0.83 [95% CIs 0.77-0.89] for PTM. There is high concordance of the agreement of hematologists with ML in not changing the chelation drug type. DISCUSSION/CONCLUSION: The ML model is a step toward creating a clinical decision support system tool for the prediction of LIC and iron chelation therapy adjustment in patients with haemoglobinopathies or hemolytic anemias.
5 Apr 2026
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