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Updates in Sickle Cell Disease: Expanding Treatment Options and Optimizing Outcomes (Monograph)

Sickle cell disease (SCD) is an inherited group of blood disorders that is caused by an abnormal production of sickle hemoglobin (HbS). It is the most common inherited blood disorder in the United States with a global impact that affects millions.¹ Although the exact number of Americans who live with SCD is unknown, it is estimated that approximately 100,000 Americans have SCD with its greatest prevalence among Black Americans and Hispanic Americans.¹ SCD occurs 1 in every 365 Black American and 1 in every 16,300 Hispanic American births.² SCD may also affect people of Middle Eastern, Southern European, or Asian Indian descent.³

GENOTYPES OF SCD

SCD is comprised of a group of four main genotypes: HbSS, HbSC, HbS β⁺-thalassemia, and HbS β⁰-thalassemia.⁴ HbSS is the most common genotype, and it occurs when a sickle cell gene S is inherited from each parent to form hemoglobin (Hb) with 2 abnormal genes. HbSS is one of the most severe forms of SCD and patients experience more hemolysis, lower Hb levels, and carry a higher risk of complications such as vaso-occlusive crises and stroke when compared to other genotypes.^4-6 HbSC is the second most common form of SCD and occurs when a child inherits 2 abnormal Hb genes, sickle cell S and HbC.⁴ HbSC is the least severe form of SCD.

β-thalassemia is another type of anemia. HbS β-thalassemia occurs when a child inherits a sickle cell gene S from 1 parent and a β-thalassemia gene from the other parent. There are 2 types of HbS β-thalassemia, zero (0) and plus (+). HbS β⁰-thalassemia is clinically similar to HbSS; therefore, it is one of the more severe types of SCD. Both HbSS and HbS β⁰-thalassemia are referred to as sickle cell anemia.³ Patients with HbS β⁰-thalassemia are at an increased risk for acute chest syndrome (ACS) and pulmonary hypertension when compared to other genotypes.^7,8

PATHOPHYSIOLOGY OF SICKLE CELL ANEMIA

SCD occurs as a result of a mutation on the β-globin gene at the sixth position in which valine replaces glutamic acid.⁹ This mutation leads to the formation of HbS ,which carries less oxygen than that of normal Hb; as a result, the lifespan of Hb is reduced from 120 days to 10-20 days.¹⁰ This leads to hemolysis and subsequent anemia in sickle cell patients. In the setting of reduced oxygenation and viability, Hb undergoes polymerization and forms into long, sickled-shaped fiber known as HbS.¹¹ This in turn reduces deformability and damages the cell membrane making it difficult for HbS to pass through blood vessels. It is this restrictive blood flow through the microvasculature that leads to vaso-occlusion and end-organ damage seen in SCD. The damaged membrane of HbS creates a rigid surface that causes vasculature damage and increases its adherence to endothelium to form a vaso-occlusion. Chronic inflammation occurs within the vasculature due to a constant release of multiple blood cells (ie, macrophages, mast cells, platelets), their adhesion to endothelium, a reduction in nitric oxide, and a subsequent release of proinflammatory cytokines that further complicate the clinical picture and can lead to hypoxia, tissue damage, and thrombosis.^9,11,12

ACS and vaso-occlusive crisis (VOC) are the most common complications associated with SCD, with VOC accounting for 96% of hospitalizations among patients with SCD.^3,13 VOC is characterized by a sudden onset of excruciating pain commonly in the back, chest, and extremities and is therefore also referred to as pain crises. Unfortunately, most patients will experience a VOC within their lifetime. Other complications include stroke, pulmonary hypertension, acute kidney injury, and splenic sequestration that also occur as a result of vaso-occlusion, chronic inflammation, and ischemia.³

MORBIDITY AND MORTALITY ASSOCIATED WITH SCD

The average life expectancy for a patient with SCD is about 2 to 3 decades less than that of an American without SCD.³ These unfortunate outcomes are a direct result of the cumbersome burden of acute complications that occur in patients with SCD. Acute complications such as VOC, stroke, infection, and pulmonary disease increases a patient’s risk of death.¹⁴ Although younger patients are more prone to death that is related to an acute complication, newborn screenings to determine early diagnosis of SCD, prophylactic blood transfusions to prevent stroke and VOC, and pneumococcal vaccines to prevent infection have reduced the risk of death among children with SCD.^3,14 Between 1979 and 2017, the average median age at death for a patient with SCD increased from 28 to 43 years and is likely a consequence of such proactive measures.¹⁴ Although life expectancy nearly doubled in patients with SCD, adults still experience an increase in acute complications as they age and are more likely to die from a chronic complication related to SCD.¹⁴

With a prolonged life expectancy that increases the risk of complications as they age, sickle cell patients utilize a great deal of both inpatient and outpatient resources for disease management. VOC is the most common indication for inpatient hospitalizations. The average length of hospital stay for sickle cell patients is 5 days and approximately 33% of patients require readmission within 30 days of discharge.¹³ Hospitalizations related to SCD impose an estimated economic burden of $800 million annually and is likely a consequence of a high frequency in VOC events.¹³ Recurrent hospitalizations, doctors’ visits, medication utilization, and loss of productivity are all factors that reduce quality of life and have a negative impact on the productivity of sickle cell patients.^15,16 Therefore, advancement in therapies used to management SCD are crucial for reducing complications, increasing life expectancy, and improving the quality of life of sickle cell patients. Hydroxyurea and blood transfusions has been the sole maintenance treatment options for many years. But with recent approval of novel agents L-glutamine, voxelotor, and crizanlizumab—each targeting different areas in the cascade of events that lead to complications associated with SCD—more options are now available for the prevention of these complications.

MAINTENANCE TREATMENT WITH HYDROXYUREA

For the past 2 decades, hydroxyurea has been the golden standard for the management of patients with SCD. Fetal hemoglobin (HbF) is a form of Hb that is primarily found in fetal red blood cells (RBCs) that inhibits polymerization of HbS.¹⁷ Polymerization is heavily dependent on the concentration of HbS within a RBC and when other forms of Hb are present, less polymerization occurs.¹⁷ Hydroxyurea is an antineoplastic that works by increasing HbF to inhibit polymerization to prevent sickling of Hb.¹⁸ Hydroxyurea was approved by the US Food and Drug Administration (FDA) in 1998 to reduce the frequency of pain crisis and the need for blood transfusion within sickle cell patients.^18,19 It is clinically indicated in patients with 3 or more moderate-to-severe pain crises within 12 months, a previous history of stroke, a contraindication to chronic blood transfusions, a history of ACS or symptomatic anemia, in all infants and children 9 months or older regardless of clinical severity, and if SCD interferes with daily activities and quality of life.³

Hydroxyurea is dosed at 15 mg/kg/day unless the creatine clearance (CrCl) is <30 mL/min, then the patient should be started at a dose of 7.5 mg/kg/day.^11,19 The dose is then titrated by 2.5 mg/kg/day every 2 weeks until a maximal tolerated dose is obtained, which should not exceed 35 mg/kg/day.^11,18 The most common adverse effect associated with hydroxyurea use is myelosuppression and as a result, patients on hydroxyurea therapy must commit to regular laboratory testing to monitor complete blood count (CBC). Dose titrations are guided by the CBC and is then titrated until a maximal tolerated dose is achieved. A maximum tolerated dose is defined as a dose that maintains the following blood cell count range: neutrophils 2000-2500 mm³, platelets 80,000-95,000 mm³, Hb 4.5-5.3 g/dL, and reticulocytes 80,000-95,000 mm³.¹¹ If a patient’s blood count falls below the given threshold, hydroxyurea is discontinued until the blood counts recover and is restarted at a lower dose. CBC is monitored every 2 weeks during the first 12 weeks, monthly for 4 months, every 3 months for 1 year, and then every 3 to 6 months thereafter. HbF levels should be monitored every 3 to 4 months to monitor for efficacy.¹¹

Hydroxyurea has been proven to be effective in reducing complications such as VOC and ACS in patients with SCD and has been the only treatment option available for the prevention of complications associated with SCD for over 20 years.²⁰ The MSH trial (Multicenter Study of Hydroxyurea in Sickle Cell Anemia) reported a 44% reduction (P < .001) in VOC.²⁰ Hydroxyurea was also shown to reduce hospitalizations, prolong the duration between crisis, and reduce the need for blood transfusions. Hydroxyurea is effective in managing SCD and has been shown to reduce the risk of mortality by 40% in patients who are maintained on tolerable doses long term.²¹ Despite its proven benefit, there is hesitancy surrounding the use of hydroxyurea. In addition to myelosuppression, which requires frequent monitoring year-round, other adverse effects may include nausea, anorexia, decreased libido, priapism, and skin and nail changes. Hydroxyurea can also cause embryo-fetal toxicity and should not be used in patients who plan on becoming pregnant. There is also a risk for malignancy (ie, leukemia, skin cancer) with use of hydroxyurea, although sufficient data has yet to confirm this risk.¹¹

Its adverse-effect profile, presumed risk of cancer, and teratogenic effects are common limitations for use of hydroxyurea. In a survey study, more than 20% of patients refused use of hydroxyurea due to fear of side effects, cancer risk, their unwillingness to take medications, frequency of blood draws required for monitoring, and a personal disbelief in efficacy.²² An evaluation of sickle cell patients within the Maryland Medicaid database revealed that 85.9% of recipients with SCD had never had a prescription claim filed for hydroxyurea, and those with at least 1 claim had minimal refill history.²³ Compliance is a major concern in the management of sickle cell patients, and noncompliance is associated with poorer outcomes, increased complications, and a poor quality of life.²⁴ Provider hesitancy to prescribe hydroxyurea due to risk of cancer and fear of noncompliance with use and laboratory monitoring also impacts use among sickle cell patients.²⁵

In addition to hesitancy and compliance issues, patients who do use hydroxyurea still experience complications while on therapy. There has been a desperate need for therapeutic options that will reduce or prevent breakthrough complications, are equally effective to that of hydroxyurea, less toxic, and convenient for long-term use. With the recent approvals of L-glutamine, voxelotor, and crizanlizumab, newer therapeutic options have been developed to bridge gaps in therapy.^26-28 These drugs (TABLE 1) have the potential for use as monotherapy or in combination with hydroxyurea to reduce complications, hospitalizations, and the need for blood transfusions among patients with SCD.

NOVEL AGENTS FOR THE MANAGEMENT OF SCD

L-glutamine (Endari)

L-glutamine was the first drug approved in almost 2 decades to help manage SCD in patients with frequent VOC. In 2017, L-glutamine was approved for use in patients ≥5 years of age with 2 or more VOC a year.²⁶ L-glutamine is an amino acid that is used to prevent oxidative damage in sickled RBCs. Oxidative stress plays a key role in the development of SCD and the complications associated with it. L-glutamine acts as a precursor to antioxidants—nicotinamide adenine dinucleotide (NAD) and its reduced form NADH.^29,30  NAD and NADH both help maintain redox balance within RBCs to prevent cell damage; however, this ratio is reduced in sickled RBCs, making them more prone to damage. As a result, sickled RBCs consume triple the amount of L-glutamine than normal RBCs to maintain intracellular levels of NAD.²⁹ L-glutamine works by increasing the NAD redox ratio to reduce sickling of blood cells and its adhesion to endothelium.^30,31

L-glutamine is a weight-based oral formulation that is dosed twice daily.³² Patients who weigh <30 kg, between 30 kg and 65 kg, and who are more than 65 kg should be dosed at 5 g/kg/dose, 10 g/kg/dose, and 15 g/kg/dose, respectively. L-glutamine is formulated in 5-gram powder packets that must be mixed in a cold or room temperature beverage, apple sauce, or yogurt. There are no contraindications with use and no dose adjustments are required in patients with renal or hepatic impairment.³²

L-glutamine provides an additional treatment option for patients who suffer from frequent VOC. In a phase 3 trial, L-glutamine was shown to significantly reduce the number of pain crises by 25% (P = .005) and hospitalizations by 33% (P = .005) compared to placebo.²⁶ It was also found to reduce the incidence of ACS and shorten length of hospital stay.²⁶ Approximately 66% of patients used hydroxyurea within the study period with no reported differences in outcomes between patients who did or did not use hydroxyurea. L-glutamine did not affect Hb, hematocrit, or reticulocyte count; therefore, its clinical use would be more beneficial in the prevention of VOC. The most common adverse events associated with its use are constipation, nausea, headache, and pain in the abdomen, extremities, and/or back. L-glutamine should not be used in women who are pregnant and/or nursing since both populations have not been evaluated for use.³²

Voxelotor (Oxbryta)

Voxelotor is a polymerization inhibitor that inhibits the initial process in the downstream of events that leads to the development of SCD. By increasing Hb oxygen affinity, voxelotor works by inhibiting polymerization, which in turn will improve deformability and reduce hemolysis, anemia, VOC, and other complications associated with SCD.^27,33 In 2019, voxelotor was approved for use in sickle cell patients ≥12 years of age to reduce hemolysis and anemia.^27,34

A dose of 1500 mg by mouth daily is recommended for patients, with a dose adjustment to 1000 mg by mouth once daily for patients with severe hepatic impairment.³⁴ If used concomitantly with a moderate-to-strong CYP 3A4 inhibitor, it is recommended that the dose be adjusted to 1000 mg and to 2500 mg for moderate or strong inducers. Voxelotor increases the concentration of midazolam and should be avoided or used with caution. Voxelotor can be used with or without hydroxyurea and should not be cut, crushed, or chewed.³⁴

Voxelotor received an accelerated FDA approval following the landmark HOPE trial (Study to Evaluate the Effect of Voxelotor Administered Orally to Patients With Sickle Cell Disease), which reported a significant increase in Hb by at least 1 g/dL from baseline to week 24 in 51% and 6.5% (P < .001) of patients who received voxelotor and placebo, respectively.²⁷ At baseline these patients had at least 1 VOC within the year, Hb ≥5.5 g/dL to ≤10.5 g/dL, and 66% of patients had previously used hydroxyurea. Patients were allowed to continue use with hydroxyurea if they were stable on therapy for at least 90 days before trial enrollment. There was no significant improvement in outcomes among patients who received hydroxyurea compared to those who did not receive it. Voxelotor substantially reduced indirect bilirubin (-29.08%, P < .001) and the percentage of reticulocytes (-19.93%, P < .001) to reduce the incidence of anemia and hemolysis in sickle cell patients.²⁷ At week 24, more patients who received voxelotor (41%) had a Hb >10 g/dL when compared to placebo (9%). There was a minimal difference found in the incidence of VOC among patients who received voxelotor (2.7 events per year) when compared to placebo (3.19 events per year).²⁷

Adverse events reported include headache, diarrhea, and abdominal pain.³⁴ Theoretically, an increase in viscosity secondary to an increase in Hb and hematocrit may increase a patient’s risk of thrombosis; however, there have been no reports of thrombosis with the use of voxelotor. Severe hypersensitivity reactions have been reported after the administration of voxelotor and if it occurs, use should be discontinued indefinitely. Voxelotor has not been evaluated in pregnancy or in women who are nursing; therefore, it should not be used in pregnancy or while breastfeeding.³⁴

A 72-week follow-up analysis was performed to evaluate the long-term effects of voxelotor and reported that 89% of participants had an adjusted mean change in Hb >1 g/dL when compared to 25% of those in placebo.³⁵ Participants also had a -26.6% and -18.6% change in baseline for indirect bilirubin and reticulocyte percentage, respectively. Voxelotor has been proven to reduce the risk of anemia and hemolysis in patients with SCD and to continuously maintain its effects long term. With therapeutic efficacy within 2 weeks, voxelotor is a great option for patients with persistent anemia.³⁵

Crizanlizumab (Adakveo)

Crizanlizumab is the first once monthly infusion to be approved for use in SCD. It is a humanized immunoglobulin G2 (IgG2) kappa monoclonal antibody that inhibits P-selectin to reduce the incidence of VOC.³⁶ P-selectin is an adhesion molecule that binds leukocytes, RBCs, and platelets to endothelium, and plays a major role in the development of VOC. Crizanlizumab works by binding to P-selectin to prevent adhesion of blood cells to prevent vaso-occlusion. Crizanlizumab was approved in 2019 to reduce the frequency of VOC in patients ≥16 years of age with SCD.^28,36

Crizanlizumab is recommended at a dose of 5 mg/kg on week 0, week 2, and every 4 weeks thereafter.³⁶ Crizanlizumab is administered via intravenous (IV) infusion over 30 minutes and must be used with a 0.2-micron inline filter during administration. Infusion-related reactions may occur and guidance on therapy reinitiation is dependent on the severity of the reaction and clinical benefit versus risk of withholding use. The majority of infusion reactions usually occur with the first or second infusion, and patients commonly report pain that occurs all over the body during the infusion and within 24 hours of use of crizanlizumab. Unfortunately, there have been reports of patients who have experienced pain crises as a result of crizanlizumab use that have resulted in hospitalization.³⁶ Corticosteroids should be used cautiously and only if clinically indicated in patients being treated for an infusion-related reaction. Patients who have received corticosteroids to manage infusion-related reactions were more likely to develop complications from pain crisis such as ACS and fat embolism.³⁶

In the SUSTAIN trial (Study to Assess Safety and Impact of SELG1 With or Without Hydroxyurea Therapy in Sickle Cell Disease Patients With Pain Crises), crizanlizumab 5 mg/kg (high dose), crizanlizumab 2.5 mg/kg (low dose), and placebo were compared to evaluate efficacy in reducing the incidence of VOC.²⁸ Unfortunately, the pharmacokinetic profile of low-dose crizanlizumab failed to provide sufficient blockage of P-selectin, and as a result, there was minimal effect in reducing pain crises when compared to placebo (18% vs 17%). Therefore, the 5 mg/kg dose was FDA approved for use. Crizanlizumab has been proven to reduce the incidence of VOC, increase the likelihood of patients being VOC free, and prolong the time between crises. The annual incidence of VOC was reduced by 45.3% (P = .01) in patients with at least 2 pain crises a year, and patients with 5 to 10 pain crises per year at baseline were found to have a greater reduction in VOC events than those who experienced 2 to 4 pain crises per year (63% vs 43%).²⁸ Crizanlizumab not only reduced the incidence of VOC, but it also caused 36% of the patients who received crizanlizumab to become free of any VOC during the treatment period. Reduction in VOC events were observed across all genotypes. Patients without previous use of hydroxyurea at baseline were found to have a 50% reduction in pain crises, while those who used hydroxyurea had a 32.1% reduction.²⁸ Crizanlizumab was also shown to shorten length of hospital stay (4 days vs 6.87 days per year) and prolong the time between the first (4.07 vs 1.38 months) and second (10.32 vs 5.09 months) occurrence of a pain crisis when compared to placebo.²⁸

Crizanlizumab has a clean safety profile when compared to that of hydroxyurea.^11,20,28,36 The most common adverse events reported were nausea, arthralgia, back pain, abdominal pain, and pyrexia.^28,36 There are no contraindications with use; however, patients who are pregnant or nursing should not use crizanlizumab.³⁶

With the ability to almost eradicate the reoccurrence of pain crises among patients who previously had a higher frequency of crises and with a greater efficacy as monotherapy, crizanlizumab may become the agent of choice for use as an alternative to hydroxyurea. Crizanlizumab is presently being studied in 3 different clinical trials to further improve outcomes among patients with SCD. The STAND trial is currently studying the efficacy and safety of crizanlizumab (5 mg/kg and 7.5 mg/kg) compared to placebo in sickle cell patients >12 years of age.³⁷ This would shed light on whether higher dosing could further reduce pain crises and other secondary outcomes evaluated in SUSTAIN. It would also lower the age limit to 12 years of age, which would make this drug a viable option to more children at a younger age. Crizanlizumab is also being studied to determine the percent change in the incidence of priapism in male patients (SPARTAN trial) and its effects on renal function in patients age >16 years of age with sickle cell nephropathy (STEADFAST trial).^38,39

ADVANCES IN THERAPEUTIC OPTIONS

Hematopoietic Stem Cell Transplantation

SCD is a debilitating disease with a multitude of complications that drastically impact patients over their lifespan. The ultimate treatment goal for SCD is curative therapy; however ,there is only 1 treatment that has been shown to cure SCD. Hematopoietic stem cell transplantation (HSCT) has an 86% cure rate and is usually reserved for patients with severe disease.^40,41 Myelosuppressive drugs are used to remove the patient’s blood cells to replace them with donor stem cells from the bone marrow, peripheral blood, or umbilical cord to perform a HSCT. One of the major limitations against widespread use of HSCT is the need for a matched donor since the risk of morbidity, mortality, and graft-versus-host disease (GVHD) is high in its absence. As a result, researchers are investigating new therapies and procedures that will prevent complications or cure patients of SCD.

Gene Therapy

Advances in gene therapy are being investigated to identify alternative therapies that will provide a cure for SCD with minimal toxicity. Gene therapy is a disease-modifying treatment option that edits or adds to sickle cell genes to prevent complications and may ultimately cure SCD. This innovative approach uses the patient’s own blood to cure their disease by adding normal genetic material to or editing genetically mutated β-globin genes with normal genetic material to reverse the mutation.^42,43

There are 3 gene-editing systems being studied to correct the mutation of the sickle cell β-globin gene: zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats (CRISPR) or CRISPR-associated protein 9.⁴³ Gene-editing trials are in the early preclinical phases and may be a promising future for the cure of SCD.

Advances in the addition of genetically modified genes to the hematopoietic stem cells of sickle cell patients are currently being studied in humans; therefore, they are a step ahead of gene-editing systems.⁴⁴ Gene-addition therapy uses a viral vector to transfer functional β-globin genes back into hematopoietic stem cells to produce normal functioning blood cells.⁴² This in turn will prevent the downstream of events that lead to complications associated with SCD and may someday cure patients of SCD. Because gene therapy is using the patient’s own genes, this procedure eliminates the need to find a donor match and reduces the risk of GVHD.⁴⁴

A phase 1 trial is underway to evaluate primary engraftment following the transduction of CD34+ cells using a BCH-BB694 lentiviral vector that will encode short hairpin RNA (shRNA) to target BCL11A mRNA to increase HbF levels in patients with SCD.⁴⁴ HbF must be widely distributed to inhibit HbS polymerization and a HbF concentration level of at least 20% must be maintained to reduce complications associated with SCD.⁴⁵ Of the 6 patients who were enrolled and followed for a median of 18 months, all achieved induction of HbF, with some patients reporting a reduction in complications associated with SCD. This study is scheduled to be completed by February 2023; therefore, final results are forthcoming. Gene therapy through reversal of HbS back to HbF via gene modification is a remarkable discovery and will be a profound advancement in preventing complications associated with SCD. Gene therapy is the key to opening the door of additional curative opportunities for patients with SCD.

Anti-inflammatory Agents

The expression of invariant natural killer T cells (iNKT) causes the release of proinflammatory markers that leads to tissue damage and ultimately vaso-occlusion due its negative effects on the endothelium.⁴⁶ Sickle cell patients have elevated levels of iNKT cells, and by inhibiting these cells, its proinflammatory effects can be muted. Regadenoson, which is an adenosine A2A receptor agonist that reduces inflammation by preventing the activation of iNKT cells, was studied in sickle cell patients to evaluate the rate of reduction in VOC. ⁴⁷ Unfortunately, regadenoson failed to reduce the activation of iNKT cells or show benefit in reducing VOC.⁴⁷ Another iNKT inhibitor, NKTT120, is being studied to evaluate its effects on VOC. NKTT120 is a humanized IgG1k monoclonal antibody that works to reduce systemic inflammation and VOC by depleting iNKT. During an open-label study, NKTT120 was found to rapidly deplete iNKT cells without serious adverse effects. This drug will require additional investigation since some participants still experienced VOC.⁴⁸

Pyruvate Kinase (PKR) Activators

FT-4202 is an oral investigational drug being studied in preclinical trials to evaluate its effect on hemolysis and polymerization of HbS. In sickle cell patients, 2,3-diphosphoglycerate (2,3-DPG) reduces oxygen affinity to deoxygenate HbS, which in turn will increase polymerization and sickling of HgS.⁴⁹ FT-4202 is a PKR activator that decreased levels of 2,3-DPG to improve oxygen affinity to prevent sickling of Hb. In mice that received FT-4202, there was a reported reduction in sickling of Hb, a 30% increase in Hb levels (+1.7 g/dL), and improved deformability of Hb.⁴⁹ FT-4202 is a hopeful therapeutic option that would target a key pathway to prevent complications associated with SCD.

DEVELOPING A THERAPEUTIC PLAN

Currently, hydroxyurea remains the drug of choice for reducing complications associated with SCD. Blood transfusions are recommended to reduce the risk of stroke and to treat anemia caused by hemolysis. The last guideline update was in 2014; therefore, official guidance for use of recently approved drugs have not been provided outside of clinical trials.³

With new therapeutic options available, pharmacists can now use a customized approach to tailor therapy to a patient’s individual needs, risk of complications, and their likelihood of compliance using a specific therapy.⁴³ For patients at an increased risk of VOC, hydroxyurea in addition to L-glutamine or crizanlizumab are viable options to significantly reduce VOC. Crizanlizumab monotherapy may be best suited for patients with a frequent history of VOC. In patients at an increased risk for anemia or those who require frequent blood transfusions, voxelotor may be an option to reduce hemolysis and anemia, although it should be noted that its actual benefit in the reduction of VOC is minimal. Adherence and compliance remain a persistent issue among patients with SCD; therefore, crizanlizumab may be better suited to improve adherence with its once monthly administration, nontoxic adverse-effect profile, and infrequent requirement of laboratory monitoring. L-glutamine would likely not be the best option for patients with adherence issues since it is administered twice daily and patients may have to take multiple packets per dose, depending on their weight.

CONCLUSION

Hydroxyurea has remained the mainstay of therapy for SCD for over 2 decades. The groundbreaking results of the MSH trial provided a viable treatment option for sickle cell patients that could reduce morbidity and mortality during a time period for which not many therapeutic options were available. As the sole option for therapy outside of blood transfusions, patients with SCD were met at a crossroad to choose between adverse effects, fetal risk, and concerns of cancer versus a shorter life expectancy plagued with frequent life-threatening complications. Unfortunately, many patients have chosen to not receive treatment with hydroxyurea, which has led to poor outcomes and mortality. The recent approval of 3 novel agents with fairly decent adverse-effect profiles, no requirements for laboratory monitoring, limited toxicities, and convenient dosing provides a glimpse of hope for patients who are hesitant to use hydroxyurea. Gene therapy and targeted therapy are the future of treatment advances in SCD that may ameliorate or prevent complications associated with SCD.

REFERENCES

1. Hassell KL. Population estimates of sickle cell disease in the U.S. Am J Prev Med. 201;38(4 suppl):S512-S521.
2. Data & statistics on sickle cell disease. https://www.cdc.gov/ncbddd/sicklecell/data.html. Accessed August 6, 2021.
3. National Heart, Lung, and Blood Institute (NHLBI). Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014. Bethesda, MD: National Institutes of Health (NIH); 2014. https://www.nhlbi.nih.gov/health-topics/evidence-based-management-sickle-cell-disease. Accessed August 9, 2021.
4. Saraf S, Moloki RE, Nouraie M, et al. Differences in clinical and genotypic presentation of sickle cell disease around the world. Paediatr Respir Rev. 2014;15(1):4-12.
5. Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease. Rates and risk factors. N Engl J Med. 1991;325(1):11-16.
6. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood. 1998;91(1):288-294.
7. Castro O, Brambilla DJ, Thorington B, et al. The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease. Blood. 1994;84(2):643-649.
8. Taylor JG, Ackah D, Cobb C, et al. Mutations and polymorphisms in hemoglobin genes and the risk of pulmonary hypertension and death in sickle cell disease. Am J Hematol. 2008;83(1):6-14.
9. Ballas SK. The evolving pharmacotherapeutic landscape for the treatment of sickle cell disease. Mediterr J Hematol Infect Dis. 2020,12(1):e2020010.
10. Sickle cell disease. MedlinePlus. https://medlineplus.gov/sicklecelldisease.html. Accessed August 10, 2021.
11. Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med. 2008;358(13):1362-1369.
12. Darbari D, 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.
13. Statistical Brief #251. Characteristics of inpatient hospital stays involving sickle cell disease, 2000-2016. Healthcare Cost and Utilization Project (HCUP). September 2019. https://www.hcup-us.ahrq.gov/reports/statbriefs/sb251-Sickle-Cell-Disease-Stays-2016.jsp. Accessed August 10, 2021.
14. Payne AB, Mehal JM, Chapman C, et al. Trends in sickle cell disease-related mortality in the United States, 1979 to 2017. Ann Emerg Med. 2020;76(3S):S28-S36.
15. Campbell A, Cong Z, Agodoa I, et al. The economic burden of end-organ damage among Medicaid patients with sickle cell disease in the United States: a population-based longitudinal claims study. J Manag Care Spec Pharm. 2020;26(9):1121-1129.
16. Brandow A, Panepinto J. Hydroxyurea use in sickle cell disease: the battle with low rates of prescription, poor patient compliance, and fears of toxicities and side effects. Expert Rev Hematol. 2010;3(3):255-260.
17. Steinberg M, Chui DHK, Dover GJ, et al. Fetal hemoglobin in sickle cell anemia: a glass half full? Blood. 2014;123(4):481-485.
18. Droxia (hydroxyurea) prescribing information. Princeton, NJ: Bristol-Myers Squibb Company; December 2019.
19. Ault A. US FDA approves first drug for sickle cell anaemia. Lancet. 1998;351(9105):P809.
20. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med. 1995;332(20):1317-1322.
21. Steinberg MH, McCarthy WF, Castro O, et al. The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: a 17.5-year follow-up. Am J Hematol. 2010;85(6):403-408.
22. Brandow AM, Jirovec DL, Panepinto JA. Hydroxyurea in children with sickle cell disease: practice patterns and barriers to utilization. Am J Hematol. 2010;85(8):611-613.
23. Lanzkron S, Haywood C Jr, Segal JB, Dover GJ. Hospitalization rates and costs of care of patients with sickle-cell anemia in the state of Maryland in the era of hydroxyurea. Am J Hematol. 2006;81:927-932.
24. Alberts N, Badawy SM, Hodges J, et al. Development of the InCharge Health mobile app to improve adherence to hydroxyurea in patients with sickle cell disease: user centered design approach. JMIR Mhealth Uhealth. 2020;8(5)e14884.
25. Lanzkron S, Haywood C Jr, Hassell KL, Rand C. Provider barriers to hydroxyurea use in adults with sickle cell disease: a survey of the Sickle Cell Disease Adult Provider Network. J Natl Med Assoc. 2008;100(8):968-973.
26. 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.
27. Vichinsky E, Hoppe CC, Ataga KI, et al. A phase 3 randomized trial of voxelotor in sickle cell disease. N Engl J Med. 2019;381(6):509-519.
28. Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017;365(5):429-439.
29. Niihara Y, Zerez CR, Akiyama DS, Tanaka KR. Increased red cell glutamine availability in sickle cell anemia: demonstration of increased active transport, affinity, and increased glutamate level in intact red cells. J Lab Clin Med. 1997;130(1):83-90.
30. Niihara Y, Zerez CR, Akiyama DS, Tanaka KR. Oral L-glutamine therapy for sickle cell anemia: I. Subjective clinical improvement and favorable change in red cell NAD redox potential. Am J Hematol. 1998;58(2):117-21.
31. Antwi-Boasiako C, Dankwah GB, Aryee R, et al. Oxidative profile of patient with sickle cell disease. Med Sci (Basel). 2019;7(2):17.
32. Endari (L-glutamine) prescribing information. Torrance, CA: Emmaus Medical, Inc; 2017.
33. Glaros AK, Razvi R, Shah N, Zaidi AU. Voxelotor: alteration of sickle cell disease pathophysiology by a first-in-class polymerization inhibitor. Ther Adv Hematol. 2021;12:20406207211001136.
34. Oxbryta (voxelotor) prescribing information. South San Francisco, CA: Global Blood Therapeutics, Inc; January 2021.
35. Howard J, Ataga KI, Brown RC, et al. Efficacy and safety of voxelotor in adolescents and adults with sickle cell disease: HOPE trial 72-week analysis. Blood. 2020;136(suppl 1):19.
36. Adakveo (crizanlizumab) prescribing information. East Hanover, NJ: Novartis Pharmaceuticals; July 2021.
37. Novartis Pharmaceuticals. Study of two doses of crizanlizumab versus placebo in adolescent and adult sickle cell disease patients (STAND). ClinicalTrials.gov: Identifier https://clinicaltrials.gov/ct2/show/NCT03814746. Accessed August 20, 2021.
38. Novartis Pharmaceuticals. A study to evaluate the safety and efficacy of crizanlizumab in sickle cell disease related priapism (SPARTAN). ClinicalTrials.gov Identifier: https://clinicaltrials.gov/ct2/show/NCT03938454. Accessed August 20, 2021.
39. Novartis Pharmaceuticals. A study exploring the effect of crizanlizumab on kidney function in patients with chronic kidney disease caused by sickle cell disease (STEADFAST). ClinicalTrials.gov Identifier: https://clinicaltrials.gov/ct2/show/NCT04053764. Accessed August 20, 2021.
40. Hsieh MM, Fitzhugh CD, Weitzel RP, et al. Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype. JAMA. 2014;312(1):48-56.
41. Shenoy S. Hematopoietic stem-cell transplantation for sickle cell disease: current evidence and opinions. Ther Adv Hematol. 2013;4(5)335-344.
42. Osunkwo I, Osunkwo I, Manwani D, Kanter J. Current and novel therapies for the prevention of vaso-occlusive crisis in sickle cell disease. Ther Adv Hematol. 2020;11:2040620720955000.
43. Gardner RV. Sickle cell disease: advances in treatment. Ochsner J. 2018;18(4):377-389.
44. Esrick EB, Lehmann LE, Biffi A, et al. Post-transcriptional genetic silencing of BCLA11A to treat sickle cell disease. N Engl J Med. 2021;384(3):205-215.
45. Powars DR, Weiss JN, Chan LS, Schroeder WA. Is there a threshold level of fetal hemoglobin that ameliorates morbidity in sickle cell anemia? Blood. 1984;63:921-926.
46. Field JJ, Nathan DG, Linden J. Targeting iNKT cells for the treatment of sickle cell disease. Clin Immunol. 2011;140(2):177-183.
47. Field JJ, Majerus E, Gordeuk VR, et al. Randomized phase 2 trial of regadenoson for treatment of acute vaso-occlusive crises in sickle cell disease. Blood Adv. 2017;1(20):1645-1649.
48. Field JJ, Majerus E, Ataga KI, et al. NNKTT120, an anti-iNKT cell monoclonal antibody, produces rapid and sustained iNKT cell depletion in adults with sickle cell disease. PLoS One. 2017;12(2):e0171067.
49. Shrestha A, Chi M, Wagner K, et al. FT-4202, an oral PKR activator, has potent antisickling effects and improves RBC survival and Hb levels in SCA mice. Blood Adv. 2021;5(9)2385-2390.

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