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. 2024 May;59(5):587-596.
doi: 10.1038/s41409-024-02219-0. Epub 2024 Feb 7.

Finding a balance in reduced toxicity hematopoietic stem cell transplantation for thalassemia: role of infused CD3+ cell count and immunosuppression

Barbara Meissner  1 , Peter Lang  2 , Peter Bader  3 , Manfred Hoenig  4 , Ingo Müller  5 , Roland Meisel  6 , Johann Greil  7 , Martin G Sauer  8 , Markus Metzler  9 , Selim Corbacioglu  10 , Birgit Burkhardt  11 , Matthias Wölfl  12 , Brigitte Strahm  13 , Kinan Kafa  14 , Oliver Basu  15 , Holger N Lode  16 , Bernd Gruhn  17 , Holger Cario  4 , Ann-Kathrin Ozga  18 , Martin Zimmermann  8 , Andrea Jarisch #  3 , Rita Beier #  8
Affiliations

Finding a balance in reduced toxicity hematopoietic stem cell transplantation for thalassemia: role of infused CD3+ cell count and immunosuppression

Barbara Meissner et al. Bone Marrow Transplant. 2024 May.

Abstract

We performed a retrospective analysis on 124 patients with transfusion-dependent thalassemia who were registered in the German pediatric registry for stem cell transplantation. All patients underwent first allogeneic hematopoietic stem cell transplantation (HSCT) between 2011 and 2020 and belonged mainly to Pesaro risk class 1-2. Four-year overall (OS) and thalassemia-free survival (TFS) were 94.5% ± 2.9% and 88.0% ± 3.4% after treosulfan-fludarabine-thiotepa- and 96.9% ± 3.1% (P = 0.763) and 96.9% ± 3.1% (P = 0.155) after busulfan-fludarabine-based conditioning. Mixed chimerism below 75% occurred predominantly in treosulfan-based regimens (27.5% versus 6.2%). OS and TFS did not differ significantly between matched sibling, other matched family and matched unrelated donor (UD) HSCTs (OS: 100.0%, 100.0%, 96.3% ± 3.6%; TFS: 96.5% ± 2.4%, 90.0% ± 9.5%, 88.9% ± 6.0%). However, mismatched UD-HSCTs performed less favorable (OS: 84.7% ± 7.3% (P = 0.029); TFS: 79.9% ± 7.4% (P = 0.082)). We generated a scoring system reflecting the risk to develop mixed chimerism in our cohort. The main risk-reducing factors were a high CD3+ cell count (≥6 × 107/kg) in the graft, busulfan-conditioning, pre-conditioning therapy and low-targeted ciclosporin A trough levels. Acute GvHD grade III-IV in treosulfan-based concepts predominantly occurred in patients with UD and reduced GvHD prophylaxis but not in the context of high CD3+ cell doses. Taken together, this information might be used to develop more risk-adapted HSCT regimens for thalassemia patients.

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Conflict of interest statement

PB declares research grants from Neovii, Riemser, Medac, and Bristol Myer Squibb (BMS) (to Institution); membership in advisory boards for Novartis, Cellgene, Amgen, Medac, Servier (personal and to Institution); received speaker fees from Miltenyi, Jazz, Riemser, Novartis, and Amgen (to institution); and declares a patent and royalties from Medac. RM reports research support from and cooperation with Jazz, Miltenyi Biotech, Neovii, Novartis, Celgene BMS, Gilead/KITE, CRISPR Therapeutics and Vertex Pharmaceuticals. MW received Honoria from Amgen Research, Munich, Germany. BG received honoria from Amgen GmbH, EUSA Pharma GmbH, medac GmbH, Novartis Pharma GmbH; and reports membership on an entity’s Board of Directors or advisory committees for Amgen GmbH, EUSA Pharma GmbH. HC received consultancy fees and honoraria from Novartis, GBT (Pfizer), Vertex, Bluebird Bio, Agios, BMS (Celgene) and Chiesi. AJ declares speakers fees from Novartis and advisory board participation with Bluebird Bio and Novartis. RB received speaker’s fees from Medac. The remaining authors declare no competing financial interests.

Figures

Fig. 1
Fig. 1. Outcome according to donor and lowest chimerism in relation to CD3+ cell count in the entire cohort.
a–c Presentation of OS, TFS and TGFS according to donor groups. (a) OS (b) TFS and (c) TGFS. MFD matched family donor other than sibling, MSD matched sibling donor, MUD matched unrelated donor 10/10, MMUD mismatched unrelated donor 9/10. d–f Relationship of lowest donor chimerism (percentage of donor cells) and CD3+ cell count in the graft. In 99 patients with available CD3+ cell count, the relationship of lowest donor chimerism and CD3+ cell count in the graft (x107/kg body weight) is depicted with the specification of (d) donor (e) graft source (f) acute GvHD. MFD matched family donor other than sibling, MSD matched sibling donor, MUD matched unrelated donor 10/10, MMUD mismatched unrelated donor 9/10, PBSC peripheral blood stem cells, TCD ex vivo T-cell depletion.
See this image and copyright information in PMC

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