StemCell Therapy

Lynne D. Neumayr, MD; Carolyn C. Hoppe, MD, MPH; Clark Brown, MD, PhD

2 decades; in 2017, L-glutamine oral powder was approved for the prevention of the acute complications of SCD. During the last several years there has been a dramatic increase in research into treatments that address distinct elements of SCD pathophysiology and even new curative approaches that provide new hope to patients and physicians for a clinically consequential disease that has long been neglected.

Am J Manag Care. 2019;25:-S0

For author information and disclosures, see end of text.

Background

Sickle cell disease (SCD) is a common, severe disorder that includes congenital hemolytic anemias caused by inherited point mutations in the -globin gene.1 These mutations result in abnormal hemoglobin polymerization, which leads to a cascade of physiologic consequences, including erythrocyte rigidity, vaso-occlusion, chronic anemia, hemolysis, and vasculopathy.1 This change in the behavior of hemoglobin has profound clinical consequences, including recurrent pain episodes (known as sickle cellrelated pain crises or vaso-occlusive crises), hemolytic anemia, multiorgan dysfunction, and premature death.1 Newborn screening, early immunization, and prophylactic penicillin treatment in infants and children, as well as comprehensive management for pain and disease complications, have improved outcomes in these patients; however, the average life expectancy of a patient with SCD remains only about 40 to 50 years.2,3

Globally, it is expected that approximately 306,000 people are born every year with SCD; an estimated 79% of these births occur in sub-Saharan Africa. In the United States, approximately 100,000 people are living with SCD, including approximately 1 in 365 African Americans and 1 in 16,300 Hispanic Americans.4,5

The impact of SCD on patient quality of life (QOL) has been estimated to be greater than that of cystic fibrosis and similar to that of patients undergoing hemodialysis, which is widely recognized as having a severe impact on QOL.6 Impairments are seen across functional and QOL domains and are particularly profound in terms of pain, fatigue, and physical function.7,8

Management of SCD can be intensive, time-consuming, and costly, particularly in patients with recurrent acute pain episodes. On average, patients with SCD experience approximately 3 vaso-occlusive crises each year, of which at least 1 requires inpatient treatment and 1 requires emergency department management without admission.9 Among patients who require admission, the median length of stay is approximately 6 days.9 More than 90% of acute hospital admissions for patients with SCD are due to severe and unpredictable pain crises, and these crises are responsible for 85% of all acute medical care for these patients.10 Estimates of the lifetime care costs for SCD vary dramatically based on underlying assumptions, from approximately $500,000 to nearly $9 million.11,12

Few options are currently available for the management of SCD. Hydroxyurea, which until recently was the only FDA-approved drug for adults with severe SCD genotypes (and is also used off-label for adults with less severe genotypes and children ages 9 months to 2 years), improves the course of SCD and results in substantial cost savings.13,14 Unfortunately, hydroxyurea is underutilized and treatment adherence is poor for a variety of reasons.15 Recently, L-glutamine became the second drug approved for SCD in the United States.16

Red blood cell (RBC) transfusion is common in patients with SCD for the management of acute complications, and regular or chronic transfusion regimens are used for stroke prevention in at-risk patients. Despite being effective for the management of both acute and chronic complications of SCD,1 transfusion is associated with annual costs exceeding $60,000; it requires routine, costly iron chelation therapy to prevent liver and other organ damage as a result of iron overload; and it is associated with the risk of alloimmunization.12,17 Stem cell transplantation, while potentially curative, is limited by a scarcity of matched donors and the risks for adverse events (AEs) and death.18 Currently under investigation are novel gene therapies that offer considerable hope for a more broadly applicable curative therapy.

This review will first examine our current understanding of the pathogenesis of SCD and explore the broad range of clinical manifestations of this disease. It will then focus on the relatively limited current therapeutic options, recent clinical trials, and near-term therapies for the chronic and acute management of the disease.

The Pathogenesis of SCD

SCD is not a single disorder. Rather, it is a clinical entity that includes a number of heritable hemolytic anemias with widely variable clinical severity and life expectancy. All involve point mutations in the -globin gene, resulting in an abnormal hemoglobin referred to as hemoglobin S (HbS).19 In the most common forms of SCD, which are also the most severe, the patient inherits the sickling gene from both parents and produces HbS exclusively.19 The compound heterozygous forms of SCD are defined by the production of HbS and another abnormal -globin protein.19

The point mutation in the -globin gene results in the substitution of glutamic acid in position 6 with valine in the resulting protein.1 This small change in the amino acid sequence of hemoglobin has profound structural and functional consequences, because under low oxygen conditions, it produces a hydrophobic region in deoxygenated HbS that promotes binding between the 1 and 2 chains of 2 hemoglobin molecules, ultimately resulting in HbS polymerization into rod-shaped structures.

The polymerization of HbS changes both the shape and physical properties of RBCs, resulting in red cell dehydration, increased rigidity, and a variety of deleterious structural abnormalities, including the characteristic sickled RBCs from which the disease gets its name.20 The rigidity of deoxygenated RBCs contributes to vaso-occlusion by impeding their passage through the microcirculation.1 Repeated cycles of tissue hypoxia and reperfusion damage elicits upregulation of adhesion molecules, such as P-selectin and E-selectin, on the vascular endothelium. This promotes adherence of RBCs, white blood cells (WBCs), and platelets, further contributing to a propensity for vaso-occlusive events and a chronic inflammatory state.1,20,21

Hemolytic anemia is an important driver of the pathophysiology of SCD. The average RBC in homozygous SCD survives only approximately 10 to 20 days, compared with 120 days for normal RBCs.22 Destruction and release of the contents of RBCs into the circulation results in progressive endothelial dysfunction and proliferation, which may in part be due to scavenging of nitric oxide (a key regulator of vascular tone) by extracellular hemoglobin.20,23-25 The end result is an impaired vasodilatory response, chronic activation of endothelial cells and platelets, and an ongoing inflammatory state. Exposure of phosphatidylserine, which is normally only found on the inner surface of the RBC membrane, also occurs, and this predisposes cells to premature lysis and promotes the activation of coagulation pathways.26,27 Excess levels of adenosine, often related to stress, are also seen in SCD. Adenosine signaling contributes to the pathophysiology of SCD by stimulating the production of erythrocyte 2,3-bisphosphoglycerate, an intracellular signal that decreases oxygen binding to hemoglobin.28

Clinical Consequences of SCD

SCD is associated with a broad range of acute and chronic complications that have a profound impact on patients, their families, and society. As noted previously, patients with SCD can present with a broad range of manifestations and disease severities depending upon the underlying genetics of their disease; the discussion below primarily refers to the most common homozygous form of the disease.

Acute pain events affect approximately 60% of patients with SCD in any given year.29-31 Such events can begin as early as 6 months of age and may recur throughout the patients life. Acute pain events are responsible for more than three-quarters of hospitalizations in patients with SCD,32 and from the perspective of the patient, they are often considered the most important and disabling consequence of the disease.32,33 Many such events can be managed at home with oral analgesics, hydration, and rest; however, in some cases, patients must be administered opioids in the emergency department or hospital setting to achieve adequate pain control.34 Acute pain events are major contributors to the high healthcare utilization of many patients with SCD.32

Stroke is the most common, and most concerning, long-term risk of homozygous SCD. The risk for stroke in children with SCD is approximately 300 times higher than for children without SCD, and approximately 25% of adults with SCA will have a stroke.20,35 Silent cerebral infarcts occur in 27% of patients by age 6 years and in 37% by age 14 years; the prevalence of silent cerebral infarct in adults is less well defined, although it is likely that progressive injury occurs as patients age.36 Cognitive impairment is seen in 5 to 9 times as many patients with SCD as compared with patients without SCD, likely due to silent repetitive ischemic brain injury.29 The use of transcranial Doppler or MRI to screen patients can help to identify patients who would benefit from additional measures to decrease the frequency and severity of stroke.20

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Sickle Cell Disease: Current Treatment and Emerging Therapies - AJMC.com Managed Markets Network

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