Thalassaemia: Advances in conventional transplantation and gene therapy

Updates regarding gene therapy and conventional transplantations in patients with thalassaemia were discussed by Prof. Josu de la Fuente (Imperial College London, UK). His talk included the importance of age for transplant outcomes, the feasibility of haploidentical transplantation, and the rise of gene therapies.

“Thalassaemia is a complex systemic disorder,” said Prof. de la Fuente at the start of his presentation [1]. “α/β globin-chain imbalance leads to ineffective erythropoiesis, iron overload, and anaemia, resulting in marrow expansion, bone disease, organ damage, gall stones, and other manifestations.” Prof. de la Fuente stressed that there is still a need for better therapies to treat patients with thalassaemia.

Conventional transplantation

Transplantation improves the quality of life for patients with transfusion-dependent thalassaemia (TDT) in terms of role limitation, bodily pain, and emotional functioning, except for those who develop chronic graft-versus-host disease (GvHD) [2]. “Expanded ineffective haemopoiesis is a risk factor for graft failure in patients with thalassaemia,” continued Prof. de la Fuente [1]. Strategies to deal with this situation are hyper-transfusions, suppression of endogenous haemopoiesis with hydroxycarbamide and azathioprine, or the addition of thiotepa, particularly in young patients [3].

Fludarabine and beyond

“Next, fludarabine-based regimens have enabled unrelated donor transplantation for patients with TDT,” said Prof. de la Fuente [1,4]. Also, a recent sibling bone marrow transplantation study (n=58) showed that the addition of serotherapy to fludarabine, treosulfan, and thiotepa (FTT) led to a low graft failure rate (3.4%), a 5-year overall survival rate of 96.6%, a median time to neutrophil engraftment of 12 days, a median time to cessation of immunosuppression of 170 days, and an acute GvHD grade II-IV rate of 13.8% [1]. “Less than 2% of the patients needed any treatment beyond 18 months,” added Prof. de la Fuente.

The importance of age

Subsequently, Prof. de la Fuente showed 2 studies that demonstrated that age is the most important indicator for bone marrow transplantation outcomes, with the best results observed in patients up to 13 years of age [5]. “Thus, transplantation should be part of the treatment algorithm at an early point, probably before the age of 6 years,” emphasised Prof. de la Fuente [1,6].

Post-transplantation cyclophosphamide

Importantly, graft failure rate and mortality are somewhat higher in mismatched donors [6,7]. The administration of post-transplantation cyclophosphamide (PTCy) may address this issue. This strategy enables reduced intensity conditioning (RIC) haploidentical transplantation and long-term engraftment in patients with thalassaemia [8]. Furthermore, pharmacologic pretransplant immunosuppression (PTIS) and abatacept reduce graft failure and improve the outcomes in mismatched patients receiving PTCy [9,10].

Gene therapies

“An alternative solution for obtaining a cure for patients with TDT is the use of corrected autologous cells by means of gene addition or gene editing strategies,” explained Prof. de la Fuente. Treatment with betibeglogene autotemcel (beti-cel) in patients with thalassaemia did not lead to treatment-related adverse events 2 years post-infusion or vector-derived replication of the competent lentivirus. Also, 90% of the patients who have completed the phase 3 LTF-303 trial (n=10) achieved transfusion independence after a median follow-up of 26.1 months [11].

Finally, all patients with thalassaemia who were infused with the gene-editing therapy exa-cel (n=44) achieved neutrophil engraftment and platelet engraftment, in a median time of 29.0 and 43.5 months, respectively. Also, 42 out of 44 treated patients are transfusion-free, with durations between 0.8 and 36.2 months [12]. “The safety profile of exa-cel is consistent with that of busulfan myeloablation and autologous HSCT,” added Prof. de la Fuente.

In conclusion, age is the most important determinant in transplant outcomes, indicating that early transplantation is crucial in patients with thalassaemia. Also, transplantation with unrelated donors and siblings lead to equal long-term outcomes in most patients. Next, haploidentical transplantation is feasible, addressing poor donor availability. Finally, strategies are emerging where a corrected form of a patient’s stem cells may offer a solution for their disease.

1. De la Fuente J. Thalassaemia: advances in conventional transplantation & gene therapy. E03-03, European Society for Blood and Marrow Transplantation (EBMT) 49^th Annual Meeting, 23–26 April 2023, Paris, France.
2. La Nasa G, et al. 2013;122(13):2262–2270.
3. Lucarelli G, et al. Blood Rev. 2008;22(2):53–63.
4. Bernardo ME, et al. Blood. 2012;120(2):473–476.
5. Baronciani D, et al. BMT. 2016;51(4).
6. Li C, et al. Blood Advances. 2019;3(17):2562–2570.
7. Lüftinger R, et al. Ann Hematol. 2022;101(3):655–665.
8. De la Fuente J, et al. Biol Blood Marrow Transplant. 2019 Jun;25(6):1197–1209.
9. Jaiswal SR, et al. BBMT. 202026(8):1469-1476
10. Anurathapan U, et al. BBMT. 2020;26(6):1106-1112
11. Locatelli F, et al. N Engl J Med 2022; 386:415–427.
12. Frangoul H, et al. N Engl J Med 2021;384(3):252–260.

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Posted on 15 June, 202322 February, 2024