Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.
Sickle cell disease (SCD) is a rare genetic hematological disorder in which sickle-shaped red blood cells (RBCs) disrupt blood flow in the small vessels.1,2 Vaso-occlusive events perturb the blood flow, causing painful episodes of ischemia and inflammation.2 In addition to painful crises, anemia and severe infection are commonly associated with SCD.1 Penicillin prophylaxis can, however, reduce the rate of invasive pneumococcal disease.3
Managing Pain Crises
Pain crises in SCD can last for days or weeks (acute pain) or continue over time (chronic pain). Prevention is the best approach to pain management in SCD. Patients with SCD may implement a few simple actions focused on prevention; these include drinking plenty of water, exercising, and avoiding exposure to extreme temperature changes and high altitudes.4 Painful crises can be managed with pain medication, such as nonsteroidal anti-inflammatory drugs; however, a few patients will require opioid treatment or hospitalization to treat severe episodes.1,4
More than 90% of adult patients with SCD receive at least one transfusion in their lifetime.2 RBCs may be transfused without the removal of blood from the patient, or the patient’s blood may be replaced with blood from a donor.3
Blood transfusions make it possible to manage acute conditions—immediately improving blood flow, increasing the oxygen-carrying capacity of the blood, and preventing possible complications of SCD.2,3 Clinical indications for blood transfusions include severe anemia, acute organ damage, and presurgical prophylaxis.2 Chronic transfusions may attenuate the long-term complications of SCD by replacing abnormal RBCs with normal cells and reducing the production of sickled RBCs. Prevention of stroke is a frequent clinical indication for chronic transfusions.2
Several risks are associated with transfusion therapy. Blood-borne pathogens, including hepatitis B virus, hepatitis C virus, and HIV may be transmitted despite significant improvements in screening methods. Alloimmunization may develop as a consequence of incompatibility between donor and recipients. Hemosiderosis, which can result in fatal complications, may develop in patients who regularly receive transfusions.2
Stem Cell Transplant
Stem cell transplant is the only curative therapeutic approach in SCD. This treatment can be undertaken when a donor is available and when the benefits of the procedure outweigh the risks involved in a hematopoietic transplant, such as rejection and intracranial hemorrhage.3,5 Available drug therapies with lower risks for toxicity and mortality should be evaluated before stem cell transplant is considered.2
The overall survival rate of patients with SCD who receive a bone marrow or cord blood stem cell transplant from an HLA-matched sibling donor is approximately 90%; the survival rate of those who receive a peripheral blood stem cell transplant is lower.2 Stem cell transplant has been most successful in children who have fully matched sibling donors and who have undergone myeloablative conditioning.2 Vaso-occlusive events, acute chest syndrome, stroke, and progression of cerebrovascular disease can be prevented in patients undergoing transplant.2
Hydroxyurea was the first treatment approved by the US Food and Drug Administration (FDA) for patients with SCD. This drug, an inhibitor of the ribonucleoside diphosphate reductase enzyme, has been used primarily for treating myeloproliferative diseases.5 Hydroxyurea increase the level of fetal hemoglobin (HbF) and decreases hemoglobin S (HbS) polymerization. Additionally, hydroxyurea reduces the number of leukocytes, platelets, and reticulocytes while also modifying the expression of adhesion molecules and consequently cellular adhesion and inflammation.5 The administration of hydroxyurea is well tolerated, with few short-term side effects observed.2
In 2017, Endari (L-glutamine) was approved by the FDA for the treatment of patients with SCD at least 5 years old to reduce complications associated with the disease. L-glutamine is used in SCD to reduce oxidative stress, which may decrease hemolysis and painful vaso-occlusive events.6
Adakveo® (crizanlizumab-tmca) and Oxbryta® (voxelotor) were approved by the FDA in 2019.7,8 Adakveo is a monoclonal antibody that prevents vaso-occlusive crises by binding to P-selectin and disrupting the interactions among endothelial cells, platelets, leukocytes, and RBCs.9 Adakveo is recommended for patients aged 16 years and older. It can cause adverse effects, such as infusion-related reactions and in the long term immunogenicity may reduce the effectiveness of the treatment.10 Oxbryta, an inhibitor of HbS polymerization, is indicated for patients at least 12 years of age. Oxbryta increases the affinity of hemoglobin for oxygen, stabilizing RBCs and preventing HbS polymerization.11 Patients not responding to standard treatment with hydroxyurea may benefit from this treatment.12
Gene-modifying therapies may be used to replace the defective beta-globin gene, increase HbF production, or reactivate silenced gamma-globin genes. Several clinical trials for adult patients (NCT02186418, NCT02247843, NCT02140554) are currently ongoing.3
1. Sickle cell disease. National Organization for Rare Disorders (NORD). Accessed November 17, 2021.
2. Ware RE, de Montalembert M, Tshilolo L, Abboud MR. Sickle cell disease. Lancet. 2017;390(10091):311-323. doi:10.1016/S0140-6736(17)30193-9
3. Meier ER. Treatment options for sickle cell disease. Pediatr Clin North Am. 2018;65(3):427-443. doi:10.1016/j.pcl.2018.01.005
4. Complications and treatments of sickle cell disease. Centers for Disease and Control Prevention. Accessed November 17, 2021.
5. Kapoor S, Little JA, Pecker LH. Advances in the treatment of sickle cell disease. Mayo Clin Proc. 2018;93(12):1810-1824. doi:10.1016/j.mayocp.2018.08.001
6. Endari. Prescribing information. Emmaus Medical; 2020. Accessed November 17, 2021.
8. Lehrer-Graiwer J, Yokoshima L, Tong B, Love TW. Accelerated approval of Oxbryta® (voxelotor): a case study on novel endpoint selection in sickle cell disease. Contemp Clin Trials. 2020;98:106161. doi:10.1016/j.cct.2020.106161
9. Darbari DS, Sheehan VA, Ballas SK. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management. Eur J Haematol. 2020;105(3):237-246. doi:10.1111/ejh.13430
10. Adakveo. Highlights of prescribing information. Novartis; 2021. Accessed November 17, 2021.
11. Oxbryta. Package insert. Global Blood Therapeutics; 2021. Accessed November 17, 2021.
12. Ali MA, Ahmad A, Chaudry H, et al. Efficacy and safety of recently approved drugs for sickle cell disease: a review of clinical trials. Exp Hematol. 2020;92:11-18.e1. doi:10.1016/j.exphem.2020.08.008
Reviewed by Kyle Habet, MD, on 11/30/2021.