Management

This is aimed at avoiding factors that may precipitate a crisis and maintenance of the steady state. As a general point, early diagnosis, penicillin prophylaxis, blood transfusion, transcranial Doppler imaging, hydroxyurea, and haematopoietic stem-cell transplantation can all dramatically improve survival and quality of life for patients with sickle cell disease (1). Treatment is required when crises occur for the control of pain, the maintenance of hydration and correction of anaemia. This also involves: (2)

• educating patients, parents and carers on
  • how to manage uncomplicated problems at home
  • how to recognise the onset of serious complications so that the patient could be admitted to a hospital immediately
• good nutrition with regular supplements of folic acid especially during pregnancy
  • all women with sickle cell disease should be advised to take a supplement of 5 mg folic acid per day (3)
• antibiotic prophylaxis and vaccination
• prompt treatment of any infection
• management of pain at home (2)
• maintain adequate fluid intake
• avoidance situation which might precipitate sickling e.g. – dehydration, acidosis, cold
• prevention of vascular stasis, e.g. tight clothing
• malaria prophylaxis
  • Falciparum malaria is believed to precipitate sickle cell crisis and to increase the risk of death in children with sickle cell anaemia; therefore, regular chemoprophylaxis with antimalarial drugs is advocated by consensus (4)
• monitoring the of frequency of acute complication
• early recognition and prevention of chronic complications e.g. – cerebrovascular disease, pulmonary hypertension
• providing psychological therapy to patients (2)

Specific therapy used in sickle cell disease includes:

• hydroxycarbamide (hydroxyurea) - there is evidence this can ameliorate the course of sickle cell anaemia in some adults (5). In the short term, hydroxycarbamide has been shown to decrease the frequency of pain episodes, reduce transfusion requirements, and decrease the risk of acute chest syndrome (6)
• transfusion therapy (7)
  • is an essential and life-saving therapy for some acute complications of SCD
  • has been shown to reduce the risk of chronic progressive organ damage in the case of ischaemic stroke
  • it is a common prophylactic treatment, repeated simple transfusion is used to maintain HbS below 30% (8)
• bone marrow/stem-cell transplantation. (9)

(Crizanlizumab, a monoclonal antibody targeting P-selectin, was approved for prevention of sickle cell crises by NICE in 2021 but the MHRA revoked its UK marketing authorisation in 2024, following the results of the STAND trial, which failed to demonstrate efficacy over placebo. It is no longer available for use in the UK. (10) )

Note

Casgevy® (exagamglogene autotemcel) was licensed by the MHRA in 2023, and is the first clinically-available gene therapy for sickle cell disease. This is a gene-editing therapy that will be offered to about 50 patients a year on the NHS in England, in specialist centres in London, Manchester and Birmingham to people aged 12 and over who get recurrent sickle cell crises and who cannot find a donor for a stem cell transplant. (11)

With Casgevy, the patient’s blood stem cells are edited in a way that makes them produce high levels of foetal haemoglobin, which is produced during foetal development and binds to oxygen more strongly than adult haemoglobin. It is a multi-step process.

As a first step, patients receive blood transfusions, which help minimize the number of sickle cells in circulation. Usually, this can be done on an outpatient basis and takes multiple transfusions over a period of two months or so. Next, they stay in the hospital for a week to have their stem cells collected.

In the laboratory, a gene-editing tool called Crispr is used that allows a specific gene to be pinpointed and very precise editing to take place. This can take up to four to six months.

However, instead of directly editing a faulty gene, Casgevy takes advantage of a process that happens when babies are in the womb, where they make red blood cells with foetal haemoglobin (a key protein that carries oxygen). This switches to the adult form once they are born.

Crucially foetal haemoglobin is not affected by sickle cell disease, so Crispr acts by dampening down the "switch" that makes the body produce the adult form.

Patients have to undergo "conditioning" chemotherapy to make sure their bodies are ready to accept the edited stem cells.

Modified stem cells are then transfused back into the body, where they multiply and increase the production of stable, well-functioning red cells. The patient typically remains in hospital for a month while these cells begin to take hold, and the immune system starts to show signs that it is coming back in a robust way

The full treatment must be considered carefully - it can involve lengthy stays in hospital and may have side effects, including headaches and bleeding problems.

Casgevy was studied in a multicentre trial involving adult and adolescent patients with a history of sickle cell crises and over 90% reached the goal of having no pain episodes for at least one year during the two-year follow-up period. Trials are ongoing.

This therapy has already been approved for transfusion-dependent beta thalassemia and is being given to patients in other countries such as France, Germany and Italy.

Reference

1. Piel FB, Steinberg MH, Rees DC; Sickle Cell Disease. N Engl J Med. 2017 Apr 20;376(16):1561-1573.
2. NICE. Sickle cell disease. Quality standard QS58. Published April 2014
3. Oteng-Ntim E, Pavord S, Howard R, et al; Management of sickle cell disease in pregnancy. A British Society for Haematology Guideline. Br J Haematol. 2021 Sep;194(6):980-995
4. Aneni EC, Hamer DH, Gill CJ; Systematic review of current and emerging strategies for reducing morbidity from malaria in sickle cell disease. Trop Med Int Health. 2013 Mar;18(3):313-27.
5. Ballas SK, Bauserman RL, McCarthy WF, et al; Hydroxyurea and Acute Painful Crises in Sickle Cell Anemia: Effects on Hospital hospital length of stay and opioid utilization during hospitalization, outpatient acute care contacts, and at home. J Pain Symptom Manage. 2010 Sep 21.
6. Rankine-Mullings AE, Nevitt SJ. Hydroxyurea (hydroxycarbamide) for sickle cell disease. Cochrane Database Syst Rev. 2022 Sep 1;9(9):CD002202.
7. Chou ST; Transfusion therapy for sickle cell disease: a balancing act. Hematology Am Soc Hematol Educ Program. 2013;2013:439-46.
8. DeBaun MR, Jordan LC, King AA, et al. American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults. Blood Adv. 2020 Apr 28;4(8):1554-88.
9. Kanter J, Liem RI, Bernaudin F, et al. American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation. Blood Adv. 2021 Sep 28;5(18):3668-89.
10. Brousse V, Makani J, Rees DC; Management of sickle cell disease in the community. BMJ. 2014 Mar 10;348:g1765.
11. ADAKVEO (crizanlizumab): revocation of UK marketing authorisation due to lack of therapeutic efficacy as determined by MHRA. Novartis, 10th Jan 2024.
12. MHRA authorises world-first gene therapy that aims to cure sickle-cell disease and transfusion-dependent β-thalassemia. Medicines and Healthcare products Regulatory Agency, 16 November 2023.