Durable Clinical Benefits in Transfusion-Dependent Β-Thalassemia with Exagamglogene Autotemcel
Bibliographic record
Abstract
Background Exagamglogene autotemcel (exa-cel) is a cell therapy that reactivates HbF via non-viral, ex vivo CRISPR/Cas9 gene-editing at the erythroid enhancer region of BCL11A in autologous CD34 + hematopoietic stem and progenitor cells (HSPCs). Exa-cel is approved for patients aged ≥12 years (yrs) with transfusion-dependent β-thalassemia (TDT). We report data from ongoing Phase 3 CLIMB THAL-111 and CLIMB-131 trials. Methods Participants (pts; 12-35yrs) with TDT and history of ≥100mL/kg/y or ≥10units/yr RBC transfusions in 2yrs before screening were eligible. Following pharmacokinetic-adjusted busulfan myeloablation and exa-cel infusion, pts are monitored for engraftment, Hb, HbF, BCL11A -edited alleles, transfusions, and adverse events (AEs). Primary endpoint is proportion of pts achieving a maintained weighted average Hb ≥9g/dL without RBC transfusion for ≥12months (mos) after exa-cel, starting 60days after last RBC transfusion (TI12). Data reported as mean (range) unless noted. Results As of May 2024, 56 pts (21.2 [12-35] yrs), including 20 adolescents (14.8 [12-17] yrs), were infused with exa-cel following 1.3 (range 1.0-4.0) mobilization cycles and myeloablative busulfan conditioning, with a median follow-up of 34.7mos (4.5-63.8). Thirty-five (62.5%) pts had severe genotypes (β0/β0, β0/β0-like). 44/56 pts completed 2yrs of follow-up in CLIMB THAL-111 and transitioned to CLIMB-131. After exa-cel infusion, all pts engrafted neutrophils and platelets (median 29.0 [12-56] and 43.5 [20-200] days). Median duration of neutropenia was 20.5 (4-48) days and time to hospital discharge was 39.0 (23-110) days. Notably, 49/52 (94.2%) evaluable pts achieved TI12 in CLIMB THAL-111 and stopped RBC transfusion after 1.1mos (SD, 0.6). Duration of transfusion independence was 32.4 (14.3-60.8) mos. For the 3 pts who did not achieve TI12 in CLIMB-111, 2 achieved TI12 in CLIMB-131 (duration transfusion free: 23.0 and 15.7mos), while 1 stopped transfusion for 4.8mos. Mean total Hb remained at normal/near normal levels of ≥12g/dL from Month 5 onward, and mean HbF were consistently ≥11g/dL at Month 5 onward with pancellular distribution. Proportion of edited BCL11A alleles was stable in bone marrow CD34 + HSPCs and remained stable from Month 2 onward in peripheral blood mononuclear cells. Most AEs occurred within the first 6mos, with 2 pts with serious AEs (previously reported) related to exa-cel that resolved; there were no deaths, discontinuations due to AEs, or malignancies. Conclusion Durable transfusion independence was achieved in >94% of pts receiving exa-cel, with associated clinically meaningful and sustained increases in HbF and total Hb for up to 5yrs of available follow-up. Exa-cel's safety profile remains consistent with busulfan myeloablation and autologous transplantation. These findings confirm exa-cel's potential as a one-time functional cure for patients with TDT.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".