Sickle Cell Disease (SCD)

Sickle cell disease (SCD) is a chronic and painful condition that results in considerable morbidity and mortality secondary to ischemia-reperfusion injuries. The long-term consequences of repeated and painful vascular occlusions can predispose susceptible individuals to cerebral infarcts and cardiac, pulmonary, and renal diseases.¹ Hydroxyurea, often considered the mainstay of treatment for patients with SCD, has demonstrated efficacy for use as a monotherapeutic agent along with supportive care, which includes trigger avoidance and pain management. More recently, additional therapeutic options have been developed to aid in the treatment of individuals who are unable to take hydroxyurea or for whom hydroxyurea has been ineffective.¹

Hydroxyurea

Hydroxyurea, originally developed as an anticancer drug, was first tested in SCD in 1984. Hydroxyurea is a myelosuppressive agent that raises the level of fetal hemoglobin (HbF) while also suppresses bone marrow production of neutrophils, reticulocytes, and platelets, thus reducing inflammation. ²

A multicenter study demonstrated that hydroxyurea reduced the incidence of acute chest syndrome episodes by nearly half over a period of 2.5 years. A 40% reduction in mortality at 3-month follow-up intervals was also reported.³

Hydroxyurea ameliorates anemia and decreases hemolysis, leading to fewer vaso-occlusive events. The drug has few side effects and short term toxicities that could limit adherence and is typically well tolerated over the long term, with few sequelae or complications. Furthermore, the medication is inexpensive, administered orally, and functions as a single-agent therapy with once-daily dosing.²

Read more about Hydrea and Droxia

Blood Transfusion and Stem Cell Transplant 

Red blood cell (RBC) transfusion is commonly performed in patients with SCD for the management of acute complications and the prevention of stroke in at-risk individuals. Although effective, RBC transfusion is associated with significant costs and requires routine iron chelation therapy to minimize the risk of end organ damage from iron overload. Chronic RBC transfusions are also associated with a risk of alloimmunization.⁴

Stem cell transplantation, while a potentially curative intervention, is limited by the need for cross-matched donors and the significant risk of adverse events due to the invasiveness of the procedure.⁴

Recent Advances

Endari

In 2017, the US Food and Drug Administration (FDA) approved Endari™ (L-glutamine) for patients aged 5 and older–the first approved treatment for patients with SCD in almost 20 years.⁵

Endari increases the amount of free glutamine available to circulating sickle cells, allowing them to generate antioxidant molecules that can help neutralize oxidative stress, allowing cells to regain flexibility as they travel through capillaries and other blood vessels.⁵

The results of a phase 3 clinical trial demonstrated that patients taking Endari had a 25% reduction in pain crisis episodes and a 33% percent reduction in hospitalizations compared to those given a placebo.⁶

Read more about Endari

Adakveo and Oxbryta

In 2019, the FDA approved 2 additional therapeutics for the treatment of SCD–Adakveo^® (crizanlizumab-tmca) and Oxbryta^® (voxelotor).⁷

Adakveo, an anti-P-selectin antibody used for the treatment of vaso-occlusive crises caused by SCD, is approved for patients aged 16 years and older. Adakveo inhibits P-selectin, a protein found on the surface of endothelial cells that contributes to the adhesion of sickled RBCs to blood vessel walls, resulting in inflammation and vaso-occlusive pain crises. By inhibiting P-selectin, Adakveo limits blood vessel occlusion, inflammation, and pain and helps to maintain normal perfusion.⁸

The most common documented side effects of Adakveo include nausea, arthralgia, back pain, abdominal pain, and fever. Infusion-related reactions have also been reported.⁹

Read more about Adakveo

Oxbryta, an inhibitor of deoxygenated sickle hemoglobin polymerization, received accelerated approval from the FDA in 2019. Oxbryta’s approval followed a clinical trial that demonstrated increased hemoglobin response rates and reduced hemolysis markers in patients who received Oxbryta compared to those given a placebo, indicating disease-modifying potential.¹⁰

Oxbryta is indicated for the treatment of SCD in patients over 12 years of age. Side effects include headache, diarrhea, abdominal pain, fatigue, and fever.¹¹

Read more about Oxbryta

References

1. Fitzhugh C. Investigational therapies for sickle cell disease. UpToDate. Updated September 10, 2021. Accessed November 29, 2021. 
2. Agrawal RK, Patel RK, Shah V, Nainiwal L, Trivedi B. Hydroxyurea in sickle cell disease: drug review. Indian J Hematol Blood Transfus. 2014;30(2):91-96. doi:10.1007/s12288-013-0261-4
3. Steinberg MH, Barton F, Castro O, et al. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA. 2003;289(13):1645-1651. doi:10.1001/jama.289.13.1645
4. Neumayr LD, Hoppe CC, Brown C. Sickle cell disease: current treatment and emerging therapies. Am J Manag Care. 2019;25(18 Suppl):S335-S343.
5. Endari (L-glutamine) for sickle cell disease. Sickle Cell Disease News. Updated February 8, 2021. Accessed November 29, 2021. 
6. Niihara Y, Miller ST, Kanter J, et al. A phase 3 trial of L-glutamine in sickle cell disease. N Engl J Med. 2018;379(3):226-235. doi:10.1056/NEJMoa1715971
7. Sickle cell disease. National Organization for Rare Disorders (NORD). Accessed November 29, 2021. 
8. Adakveo (crizanlizumab). Sickle Cell Disease News. Updated December 14, 2019. Accessed November 29, 2021. 
9. Adakveo. Package insert. Novartis; 2021. Accessed November 29, 2021.
10. Vichinsky E, Hoppe CC, Ataga KI, et al.; HOPE Trial Investigators. A phase 3 randomized trial of voxelotor in sickle cell disease. N Engl J Med. 2019;381(6):509-519. doi:10.1056/NEJMoa1903212
11. Oxbryta side effects center. RxList. Updated November 15, 2021. Accessed November 29, 2021.

Reviewed by Harshi Dhingra, MD, on 11/30/2021.

---

James Frederick