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ABSTRACT
Introduction
Sickle cell disease (SCD) is an inherited disorder characterised by polymerisation of deoxygenated haemoglobin S and microvascular obstruction. The cardinal feature is generalised pain referred to as vaso-occlusive crises (VOC), multi-organ damage and premature death. SCD is the most prevalent inherited life-threatening disorders in the world and over 85% of world’s 400,000 annual births occur low-and-middle-income countries. Hydroxyurea remained the only approved disease modifying therapy (1998) until the FDA approved L-glutamine (2017), Crizanlizumab and Voxelotor (2019) and gene therapies (Exa-cel and Lovo-cel, 2023).
Areas covered
Clinical trials performed in the last 10 years (November 2013 – November 2023) were selected for the review. They were divided according to the mechanisms of drug action. The following pubmed central search terms [sickle cell disease] or [sickle cell anaemia] Hydroxycarbamide/ Hydroxyurea, L-Glutamine, Voxelotor, Crizanlizumab, Mitapivat, Etavopivat, gene therapy, haematopoietic stem cell transplantation, and combination therapy.
Expert opinion
We recommend future trials of combination therapies for specific complications such as VOCs, chronic pain and renal impairment as well as personalised medicine approach based on phenotype and patient characteristics. Following recent approval of gene therapy for SCD, the challenge is addressing the role of shared decision-making with families, global access and affordability.
Article highlights
Sickle cell disease (SCD) is a multi-organ disease with a reduced life expectancy.
Hydroxyurea is effective and safe in adults and children with sickle cell disease.
Recently FDA approved novel treatments include Crizanlizumab, Voxelotor and L-glutamine and the prospects for drug combination therapies are required.
Various agents in the pipeline of development include phase 2/3 trials of second-generation anti-sickling agents, pyruvate kinase activators and complement inhibitors.
December 2023 the FDA landmark approval of gene therapies is welcome development for SCD.
Treatments for SCD are not globally available for patients due to costs and health care structure differences.
Our expert opinion is that it is now time to undertake clinical trials for combination of approved and pipeline therapies based on mechanisms of actions and effectiveness for optimal patient benefits.
List of abbreviations
| DFS | = | disease-free survival |
| DNMT1 | = | DNA methyltransferase 1 |
| EMA | = | European Medicine Association |
| FDA | = | Food and Drug Administration |
| GVHD | = | graft versus host disease |
| HbF | = | hemoglobin F |
| HbS | = | hemoglobin S |
| HDAC | = | histone deacetylase |
| HSCT | = | hemopoeitic stem cell transplantation |
| HU | = | hydroxyurea |
| IV | = | intravenous |
| MRD | = | matched related donor |
| MTD | = | maximum tolerated dose |
| OS | = | overall survival |
| PDE9 | = | phosphodiesterase-9 |
| RBC | = | red blood cell |
| RIC | = | reduced intensity non-myeloablative conditioning |
| SCD | = | sickle cell disease |
| TCD | = | transcranial Doppler |
| THU | = | Tetrahydrouridine |
| TRM | = | treatment-related mortality |
| UK | = | United Kingdom |
| U.S.A. | = | United States of America |
| VOC | = | vaso-occlusive crises |
Declaration of interest
S Lugthart received funding to attend international conferences; Pfizer (2023), Vertex (2023), GBT (2022) and Novartis (2021). Consultancy work: Sanius Health, UK (2023). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.