Journal article
Model-based antithymocyte globulin dosing in ex vivo CD34+ selected allogeneic haematopoietic cell transplantation: a single-centre, single-arm, phase 2 study
The Lancet. Haematology, Vol.12(12), pp.e956-e965
12/2025
DOI: 10.1016/S2352-3026(25)00293-5
PMID: 41338864
Abstract
Ex-vivo CD34+ selected allogeneic haematopoietic cell transplantation (HCT) provides favourable chronic graft-versus-host disease (GVHD)-free relapse-free survival but is limited by delayed immune reconstitution and early non-relapse mortality. High anti-thymocyte globulin (ATG) exposure after HCT has been associated with delayed CD4+ T-cell immune reconstitution, increased non-relapse mortality, and poor overall survival.
We report the final analysis of a single-centre, phase 2 trial investigating pharmacokinetic model-based ATG (targeting <20 AU × d/mL post-HCT exposure) in participants of any age undergoing ex vivo CD34+ selected allogeneic HCT after myeloablative conditioning for haematological malignancies. Two myeloablative conditioning regimens were used at the discretion of the treating physician: the chemotherapy-based regimen (target cumulative exposure of 65 mg × h/L busulfan, 140 mg/m
melphalan, and 150 mg/m
fludarabine) and a high-dose total-body irradiation-based regimen (included total-body irradiation [1375 cGy], thiotepa [10 mg/kg], and cyclophosphamide [100 mg/kg]). The primary objective was an improvement in CD4+ immune reconstitution (>50 cells per μL at two consecutive timepoints by day +100) in at least 32% of the per protocol population. This study was registered with ClinicalTrials.gov (NCT04872595) and is completed.
Between June 14, 2021, and Nov 28, 2023, we enrolled 59 participants with haematological malignancies. Among evaluable participants (n=56), the median age was 55 years (IQR 30-63), 34 (61%) were male, 22 (39%) were female, 44 (79%) had myeloid malignancies, and 44 (79%) had received chemotherapy-only myeloablative conditioning. The median estimated ATG exposure after HCT was 10 AU × d/mL (IQR 9-11). CD4+ immune reconstitution was reached in 39 (70%) of 56 participants, meeting the study's primary endpoint. The most common grade 3 or worse adverse events were infections (103 [40%] of 259 events) and oral or gastrointestinal events (44 [17%] of 259 events). Grade 5 adverse events occurred in three participants including secondary graft failure (n=1) and multi-organ failure (n=2), with a total of four treatment-related deaths among participants.
These results demonstrate that model-based ATG dosing promotes robust CD4+ immune reconstitution after ex vivo CD34+ selected allogeneic HCT, underscoring the potential of pharmacokinetically guided ATG as a strategy to optimise immune recovery in myeloablative, calcineurin inhibitor-free transplantation for haematological malignancies.
US National Cancer Institute, Memorial Sloan Kettering Cancer Center.
Details
- Title: Subtitle
- Model-based antithymocyte globulin dosing in ex vivo CD34+ selected allogeneic haematopoietic cell transplantation: a single-centre, single-arm, phase 2 study
- Creators
- Michael ScordoMiguel-Angel PeralesAudrey Mauguen - Memorial Sloan Kettering Cancer CenterAndrew Lin - Memorial Sloan Kettering Cancer CenterBinni Kunvarjee - Memorial Sloan Kettering Cancer CenterMaria Paes Pena - Memorial Sloan Kettering Cancer CenterDevin Mcavoy - Memorial Sloan Kettering Cancer CenterLinh Khanh Nguyen - Memorial Sloan Kettering Cancer CenterMolly Hogan - Memorial Sloan Kettering Cancer CenterNancy Chapman - Memorial Sloan Kettering Cancer CenterJennifer Bieler - Memorial Sloan Kettering Cancer CenterChristina Cho - Hackensack University Medical CenterBoglarka Gyurkocza - University of Washington School of MedicineAndrew C HarrisBarbara Spitzer - Hackensack University Medical CenterRichard J O'ReillyAnn A JakubowskiRichard J LinEsperanza B PapadopoulosIoannis PolitikosDoris M PonceBrian C ShafferGunjan L ShahRoni TamariSergio A GiraltJaap-Jan BoelensKevin J Curran
- Resource Type
- Journal article
- Publication Details
- The Lancet. Haematology, Vol.12(12), pp.e956-e965
- DOI
- 10.1016/S2352-3026(25)00293-5
- PMID
- 41338864
- NLM abbreviation
- Lancet Haematol
- ISSN
- 2352-3026
- eISSN
- 2352-3026
- Publisher
- ELSEVIER SCI LTD
- Grant note
- Department of Medicine at Memorial Sloan Kettering Cancer CenterNational Cancer Institute Core Grant: P30 CA008748 National Institutes of Health: P01 CA23766
This work was supported by an internal investigator-initiated grant awarded by the Department of Medicine at Memorial Sloan Kettering Cancer Center. It was also supported in part by the National Cancer Institute Core Grant (P30 CA008748) and the National Institutes of Health award number P01 CA23766. Joseph Olechnowicz at the
- Language
- English
- Date published
- 12/2025
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985090407902771
Metrics
6 Record Views