HSCT remains the only cure for patients with transfusion-dependent thalassemia until gene therapy strategies are proven to be safe

Oikonomopoulou, Christina; Goussetis, Evgenios

doi:10.1038/s41409-021-01461-0

Cited by 13 publications

(11 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite that HSCT from a matched family or unrelated donor, may offer a successful therapy for selected young TM patients who have no secondary organ damage due to iron overload, the risks of death and serious toxic effects are still high for the majority of the remaining patients [7,[173][174][175][176][177]. Further improvements on safety in HSCT transplantation and the introduction of safe gene therapy may offer a…”

Section: Future Prospects Including Transplantation and Gene Therapiesmentioning

confidence: 99%

“…Iron overload damage: DF, L1 and DFRA. Various combinations of all three drugs from young age [29,30] Growth retardation and arrested puberty in young TM patients [50][51][52][53][54][55][56][57][58] In males: Delayed puberty and hypogonadotrophic hypogonadism Intramuscular depot-testosterone Intramuscular testosterone esters or topical testosterone gel [120][121][122][123][124][125][126][127][128] Pubertal arrest [161][162][163][164][165][166][167][168][169][170] In complete treatment for TM patients [7,[173][174][175][176][177][178][179].…”

Section: Endocrine Glandsmentioning

confidence: 99%

“…There is increasing interest as well as many clinical trials in progress over the last 2 to 3 years concerning gene therapy and its comparison with allogeneic HSCT, both of which can potentially offer complete therapy for TM patients [6][7][8][173][174][175][176][177][178][179][180]. The risk/benefit assessment of these two HSCT methods and their comparison with the standard therapy of regular RBC transfusion and chelation therapy are likely to be the subject of future investigations.…”

Section: Endocrine Glandsmentioning

confidence: 99%

“…Allogeneic HSCT in TM from human leukocyte antigen (HLA) matched siblings or unrelated bone marrow donors was initiated 40 years ago and is estimated to have been used so far in about 4000 TM patients worldwide [6][7][8][173][174][175][176][177]181]. This therapeutic method is subject to suitable donor availability and offers the complete treatment of TM especially for young TM children.…”

Section: Endocrine Glandsmentioning

confidence: 99%

See 3 more Smart Citations

Benefits and Risks in Polypathology and Polypharmacotherapy Challenges in the Era of the Transition of Thalassaemia from a Fatal to a Chronic or Curable Disease

Kolnagou¹,

Kleanthous²,

Kontoghiorghes³

2022

Front. Biosci. (Elite Ed)

View full text Add to dashboard Cite

Beta thalassaemia major (TM), a potentially fatal haemoglobinopathy, has transformed from a fatal to a chronic disease in the last 30 years following the introduction of effective, personalised iron chelation protocols, in particular the use of oral deferiprone, which is most effective in the removal of excess iron from the heart. This transition in TM has been achieved by the accessibility to combination therapy with the other chelating drugs deferoxamine and deferasirox but also therapeutic advances in the treatment of related co-morbidities. The transition and design of effective personalised chelation protocols was facilitated by the development of new non-invasive diagnostic techniques for monitoring iron removal such as MRI T2*. Despite this progress, the transition in TM is mainly observed in developed countries, but not globally. Similarly, potential cures of TM with haemopoietic stem cell transplantation and gene therapy are available to selected TM patients but potentially carry high risk of toxicity. A global strategy is required for the transition efforts to become available for all TM patients worldwide. The same strategy could also benefit many other categories of transfusional iron loaded patients including other thalassaemias, sickle cell anaemia, myelodysplasia and leukaemia patients.

show abstract

Section: Future Prospects Including Transplantation and Gene Therapiesmentioning

confidence: 99%

Section: Endocrine Glandsmentioning

confidence: 99%

Section: Endocrine Glandsmentioning

confidence: 99%

Section: Endocrine Glandsmentioning

confidence: 99%

See 2 more Smart Citations

Benefits and Risks in Polypathology and Polypharmacotherapy Challenges in the Era of the Transition of Thalassaemia from a Fatal to a Chronic or Curable Disease

Kolnagou¹,

Kleanthous²,

Kontoghiorghes³

2022

Front. Biosci. (Elite Ed)

View full text Add to dashboard Cite

show abstract

“…Fortunately, the transplantation procedure has been extensively studied and successfully applied for the last four decades. Moreover, genetic therapies are becoming available in clinical trial settings, increasing the likelihood of further improvement in life expectancy [72].…”

Section: Supplementary Materialsmentioning

confidence: 99%

Conditioning Regimens in Patients with β-Thalassemia Who Underwent Hematopoietic Stem Cell Transplantation: A Scoping Review

Mulas

Mola

Caocci

et al. 2022

JCM

View full text Add to dashboard Cite

The success of transplant procedures in patients with beta-thalassemia major (β-thalassemia) goes hand-in-hand with improvements in disease knowledge, better supportive care, discoveries in immunogenetics, increase in stem cell sources, and enhancement of conditioning regimens. The aim of this scoping review was to report the evolution of conditioning regimes for β-thalassemia hematopoietic stem cell transplantation. We performed a systematic search for all relevant articles published before July 2021, using the following Medical Subject Headings: “bone marrow transplantation”, “stem cell transplantation”, “allogeneic”, “thalassemia”, “β-thalassemia”, and “thalassemia major”. The final analysis included 52 studies, published between 1988 and 2021, out of 3877 records. The most common conditioning regimen was a combination of busulfan and cyclophosphamide, with successive dose adjustments or remodulation based on patient characteristics. Pre-transplant treatments, reductions in cyclophosphamide dosage, or the adoption of novel agents such as treosulphan all improved overall survival and thalassemia-free survival in transplant-related mortality high-risk patients. Conditioning regimes were modulated for those without a suitable fully matched sibling or unrelated donor, with encouraging results. Hematopoietic stem cell transplantation with haploidentical donors is currently available to virtually all patients with β-thalassemia. However, disparities in outcome are still present around the world. In developing and limited-resource countries, where most diagnoses are focused, transplants are not always available. Therefore, more efforts are needed to close this treatment gap.

show abstract

Treosulfan Exposure Predicts Thalassemia‐Free Survival in Patients with Beta Thalassemia Major Undergoing Allogeneic Hematopoietic Cell Transplantation

Pai,

Mohanan,

Panetta

et al. 2023

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

A toxicity‐reduced conditioning regimen with Treosulfan, Fludarabine, and Thiotepa in patients with high‐risk β‐ thalassemia major has significantly improved HCT outcomes. However, complications resulting from regimen‐related toxicities (RRTs), mixed chimerism, and graft rejection remain a challenge. We evaluated the dose‐exposure‐response relationship of Treosulfan and its active metabolite S, S‐EBDM, in a uniform cohort of patients with β‐thalassemia major to identify whether therapeutic drug monitoring (TDM) and dose adjustment of Treosulfan is feasible. Plasma Treosulfan/S, S‐EBDM levels were measured in seventy‐seven patients using a validated LC‐MS/MS method, and the PK parameters were estimated using nlmixr2. The influence of Treosulfan & S, S‐EBDM exposure, and GSTA1/NQO1 polymorphisms on graft rejection, RRTs, chimerism status, and 1‐year Overall Survival (OS), and Thalassemia Free Survival (TFS) were assessed. We observed that Treosulfan exposure was lower in patients with graft rejection than those without (1655 vs. 2037 mg*h/L, p=0.07). Pharmacodynamic modeling analysis to identify therapeutic cut‐off revealed that Treosulfan exposure ≥1660 mg*hr/L was significantly associated with better 1‐year TFS (97% vs. 81%, p=0.02) and a trend to better 1‐year OS (90% vs. 69%, p=0.07). Further, multivariate analysis adjusting for known PreHCT risk factors also revealed Treosulfan exposure <1660mg*h/L (HR=3.23; 95% CI=1.12‐9.34; p=0.03) and GSTA1*B variant genotype (HR=3.75; 95% CI=1.04‐13.47; p=0.04) to be independent predictors for inferior 1‐year TFS. We conclude that lower Treosulfan exposure increases the risk of graft rejection and early transplant‐related mortality affecting TFS. As no RRTs were observed with increasing Treosulfan exposure, TDM‐based dose adjustment could be feasible and beneficial.

show abstract

HSCT remains the only cure for patients with transfusion-dependent thalassemia until gene therapy strategies are proven to be safe

Cited by 13 publications

References 68 publications

Benefits and Risks in Polypathology and Polypharmacotherapy Challenges in the Era of the Transition of Thalassaemia from a Fatal to a Chronic or Curable Disease

Benefits and Risks in Polypathology and Polypharmacotherapy Challenges in the Era of the Transition of Thalassaemia from a Fatal to a Chronic or Curable Disease

Conditioning Regimens in Patients with β-Thalassemia Who Underwent Hematopoietic Stem Cell Transplantation: A Scoping Review

Treosulfan Exposure Predicts Thalassemia‐Free Survival in Patients with Beta Thalassemia Major Undergoing Allogeneic Hematopoietic Cell Transplantation

Contact Info

Product

Resources

About