Sickle cell disease (SCD) causes significant pain and other complications among approximately 100,000 U.S. residents and conveys a median life expectancy of 43 years (J Hematol Oncol 2022;15[1]:20). Despite those sobering statistics, pharmacists can still make a difference by educating patients about the importance of drug adherence, the pros and cons of newer therapies, and how to navigate drug coverage hassles before they interrupt or delay care, experts said.
Such help is sorely needed. “This is a really hard disease on your body, on your quality of life,” Marilyn Bulloch, PharmD, BCPS, FCCM, SPP, noted during the American Pharmacists Association (APhA) 2023 Annual Meeting and Exposition, in Phoenix. SCD is most common in people with African, South American, Caribbean, Central American, Saudi Arabian, Indian or Mediterranean ancestry. The inherited disease is characterized by defective hemoglobin and gives rise to sickle-shaped red blood cells. “The sickle cell looks like the crescent moon compared with a normal red blood cell, which has more of that ‘jelly donut-like’ appearance,” said Dr. Bulloch, an associate clinical professor of pharmacy practice and the director of strategic operations at the Auburn University Harrison College of Pharmacy, in Alabama. “These sickles themselves hurt [the patient] when they hit the side of the blood vessels, but they also stick to each other, and they stick to platelets and leukocytes and all of that can clog things up, cause ischemia and further exacerbate the pain.”
SCD can give rise to numerous complications, including stroke, anemia, kidney disease, venous thromboembolism, acute chest syndrome (ACS), avascular aseptic necrosis, gallstones, fatigue, recurrent leg ulcers, fertility challenges, depression and anxiety. “The list goes on and on and on,” Dr. Bulloch said. Many of these complications are related to vaso-occlusive crises (VOC), which can be triggered by infection, cold or windy weather, heightened air pressure, or dehydration (J Hematol Onco 2022;15:20; PLoS One 2022;17:e0265342; Blood Adv 2020;4:1554-1588).
Current clinical guidelines focus primarily on treating acute or chronic complications of SCD and include recommendations from the American Society of Hematology (ASH) and National Heart, Lung and Blood Institute (NHLBI). “But ideally we would like to keep [patients] from going into these vaso-occlusive crises to begin with, even if they’re faced with triggers,” Dr. Bulloch said. The best way to do that, she said, is with the four disease-modifying drugs available in the United States, three of which were approved since 2017 (see literature box).
Disease-Modifying Options
Hydroxyurea
The first SCD treatment to secure FDA approval, in 1998, was hydroxyurea. It prevents red blood cells from sickling by boosting production of non-defective fetal hemoglobin. Hydroxyurea also decreases white blood cells and platelets, which reduces inflammation. The drug also can reduce VOCs, hospitalizations, and the need for blood transfusions, but may cause neutropenia, thrombocytopenia and nausea, Dr. Bulloch said.
Titilope Fasipe, MD, PhD, a co-director of the Sickle Cell Program and an assistant professor in the Department of Pediatrics, Section of Hematology-Oncology, at Texas Children’s Hospital and Baylor College of Medicine, in Houston, described this mainstay of SCD treatment as “an amazing find.”
“It reduced hospitalizations, it reduced mortality; everything bad in sickle cell [disease], it seems to make better,” said Dr. Fasipe, who was not involved with the APhA2023 presentation. But “it doesn’t cure the disease.” Some patients express hesitancy to take hydroxyurea because it was initially developed to treat cancer, which raised their concerns over adverse effects, and “then also because the medical community has a long history of mistrust with minority populations, and sickle cell [disease] predominantly affects Black and other minority populations,” Dr. Fasipe said. “But the proof is definitely in the pudding with this one; it has a great track record.”
Hydroxyurea has the most consistent data showing benefits in laboratory and clinical outcomes, and the most evidence for reducing ACS incidence, Dr. Bulloch said, and generally should remain the first-line option for treating SCD. The benefits of hydroxyurea are sustained with long-term use, but the drug must be monitored for safety and, if possible, should be stopped if a pregnancy is planned or identified. “The big thing for us as pharmacists to take home is that you need to be on the max tolerated dose for at least six months before you can say the patient failed it,” Dr. Bulloch added.
L-glutamine
L-glutamine oral powder (Endari, Emmaus Medical Inc.) was approved in 2017 to reduce the acute complications of SCD in adult and children aged 5 years and older. The mechanism of how this amino acid treats SCD is uncertain, Dr. Bulloch said, although it may protect red blood cells against oxidative damage. L-glutamine can be taken with or without hydroxyurea. Side effects include gastrointestinal (GI) upset, headache, cough, noncardiac chest pain and fatigue, but L-glutamine is generally well tolerated. Clinical trial and real-world data suggest that L-glutamine reduces VOCs and hospital stays; one trial showed that patients who received L-glutamine experienced fewer pain crises (median three vs. four over 48 weeks; P=0.005) and hospitalizations (median two vs. three; P=0.005) than those in the placebo group over 48 weeks, while an observational study demonstrated that after commencing L-glutamine, patients had significantly fewer pain crises and hospitalizations (median change from 3.0 to 0.0; P<0.00001) over 72 weeks (N Engl J Med 2018;379[3]:226-235; Front Med [Lausanne] 2022;9:931925). The studies also indicate that L-glutamine improves hemoglobin concentration and other laboratory values; decreases ACS incidence and inpatient days; extends time between pain crises; and may reduce the need for transfusions.
Oral L-glutamine may be an alternative for patients unable to tolerate hydroxyurea. “This monoclonal antibody might be a good add-on therapy for people who are adherent [to hydroxyurea], but they’re still having a lot of those pain crises every year,” Dr. Bulloch said.
Dr. Fasipe commented that a longer observation period is needed to determine the extent to which L-glutamine influences SCD. However, she said, “for those that find it helpful, it’s a low-risk drug to take.”
Voxelotor
Voxelotor (Oxbryta, Pfizer) received accelerated FDA approval in 2019 for adults and pediatric patients aged 12 years and older, and in 2021 for children aged 4 to 11 years. “It’s thought to be the first drug to really target the pathophysiology of sickle cell disease,” Dr. Bulloch said. “It increases the oxygen affinity of hemoglobin, and the thought is as long as oxygen is more drawn to this hemoglobin, it’s not going to sickle … and then you won’t have the vaso-occlusion crisis to begin with.” Supporting this idea, voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis in the trial that led to the drug’s approval (51% of patients in the voxelotor group experienced a hemoglobin response, vs. 7% in the placebo group) (N Engl J Med 2019;381[6]:509-519).
Voxelotor can be given with or without hydroxyurea. The drug may cause side effects that include headache, GI upset and fatigue, but overall “it’s been well tolerated in clinical trials,” Dr. Bulloch said. Real-world data indicate that voxelotor improves hemoglobin concentration and other laboratory values, and reduced mean VOC-related hospitalizations and inpatient days by, respectively, 34% and 30% (Expert Rev Hematol 2022;15[2]:167-173). Furthermore, voxelotor may reduce VOCs, increase opioid-free days and promote healing of leg ulcers (Am J Hematol 2021;96[4]:E126-E128), although more data are needed to confirm this, Dr. Bulloch said. The drug can be considered in SCD patients with low baseline hemoglobin or symptoms of chronic anemia.
Crizanlizumab-tmca
Crizanlizumab-tmca (Adakveo, Novartis), a monoclonal antibody that was approved in 2019 to reduce VOC frequency in patients 16 years and older, is administered as an IV infusion with or without hydroxyurea. It decreases adhesion of sickled red blood cells, platelets and neutrophils to endothelial surfaces and each other. Crizanlizumab-tmca may be beneficial in patients who cannot take daily therapy or who have frequent VOCs, Dr. Bulloch said.
Data that supported the approval suggested that crizanlizumab-tmca decreases the occurrence of, and extends the time between, VOCs (annual VOC rate: 1.63 vs. 2.98 in placebo group, P=0.01; 36% vs. 17% did not experience VOC; time to first VOC from randomization 4.1 vs. 1.4 months) (N Engl J Med 2017;376[5]:429-439). The most common adverse reactions (>10%) were nausea, arthralgia, back pain and pyrexia.
However, recent developments have raised doubts about the efficacy of crizanlizumab-tmca. On Aug. 3, the European Commission revoked the conditional marketing authorization for crizanlizumab-tmca, in accordance with a recommendation from the European Medicines Agency’s Committee for Medicinal Products for Human Use. Although there were no safety concerns with the drug, preliminary data from a phase 3 clinical trial failed to demonstrate that crizanlizumab-tmca was superior to a placebo in annual VOCs leading to a healthcare visit; these results were inconsistent with previous findings from a phase 2 clinical trial and open-label study data.
In a July 7 statement, the Sickle Cell Disease Association of America’s Medical and Research Advisory Committee urged the FDA “to keep crizanlizumab available for use in the U.S. while it awaits more detailed examination of the data so that individuals with sickle cell disease can benefit from this treatment.”
Barriers to Treatment
Hydroxyurea has a major advantage over other SCD treatments: its longer availability in the market (Blood Rev 2022;53:100925). “Hydroxyurea has a report card, meaning that it has many research trials under its name and years and years of research,” Dr. Fasipe said. “These new drugs just need the same thing; we need more ... research to help us understand which patients each drug may work best in.” To help patients understand the new therapies, she recommended a fact sheet from the Sickle Cell Disease Coalition.
There are additional barriers that stand between patients and effective SCD management. “You can make a drug; that does not mean people have access to it,” Dr. Fasipe commented. The newer therapies—crizanlizumab-tmca, voxelotor and L-glutamine—must be procured through specialty pharmacies and may be less affordable for patients than hydroxyurea. (For a 2020 analysis on SCD treatments, the Institute for Clinical and Economic Review assumed a wholesale acquisition cost [WAC] per package/vial for hydroxyurea of $88.10 for 100 capsules. The annual WACs for crizanlizumab-tmca, voxelotor, and L-glutamine were, respectively, $132,000, $127,000, and $40,540). Additionally, insurance companies sometimes require patients to “fail” on one SCD therapy before trying another. “With sickle cell disease, these four drugs do not work in the same way,” Dr. Fasipe said. “So they should not be step therapy to each other. They should not be compared apples-to-apples.” For this complicated disease, many patients would likely benefit from taking several medications.
“If you live in a rural community, or you don’t live close to a sickle cell center that sees a lot of patients with sickle cell [disease], your doctor may not even tell you about the drugs because they may not even know about them,” Dr. Fasipe added.
In addition to patient access, another potential issue is adherence. “None of these medications will work if patients don’t take them,” Dr. Bulloch said. “Especially in your younger patients, the ones that are just out of high school, [or in their] early twenties, we have got to stress adherence with them every time that they pick up that prescription.”
Other Options
Beyond disease-modifying medications for managing SCD, another treatment option is hematopoietic cell transplantation (Hematol Oncol Clin North Am 2022;36[6]:1313-1335). This approach, with multiple trials sponsored by the NHLBI, is currently the only cure for SCD, with more than 1,200 cases reported since 1984. For SCD, a cure involves the reversal of acute complications of the disease, said Courtney Fitzhugh, MD, the chief of the NHLBI’s Laboratory of Early Sickle Mortality Prevention. “So, if a patient’s symptoms are recurrent pain crises/acute chest syndrome, those go away. Anemia and evidence of hemolysis in the blood resolves,” she said. “And the red blood cells are the same as the donor; if the donor has normal hemoglobin, the patient does.” If the donor has sickle cell trait (a single copy of the defective gene that typically causes no medical issues), the patient does as well. Additionally, Dr. Fitzhugh said, after the procedure there are no sickle cells circulating in the patient’s blood.
However, transplantation comes with risks that include secondary neoplasms, graft-versus-host disease and treatment failure, and it is limited by the availability of human leukocyte antigen-matched sibling donors (J Clin Oncol 2023;41[12]:2227-2237).
Several strategies are available to minimize these difficulties. To decrease the incidence of post-transplant leukemia, Dr. Fitzhugh said, recently practitioners have shifted from mixed to complete donor chimerism (in which the recipient’s hematopoietic cells are entirely derived from the donor, rather than being a mix of host and donor cells).
One approach to broaden the potential pool of donors is haploidentical, or partially matched, transplantation. To this end, NHLBI-funded researchers and the Vanderbilt Global Haploidentical Learning Collaborative are developing protocols to boost success rates for haploidentical transplantation (Blood 2022;140[1]:2383-2385). “Vanderbilt’s protocol adds an additional medication [thiotepa (Tepadina, Amneal Pharmaceuticals)] that increases myelosuppression (the amount of space in the bone marrow for donor cells to engraft) and immunosuppression,” Dr. Fitzhugh explained, describing the approach as “very exciting.” However, “haploidentical transplant in general is also exciting as the efficacy and toxicity have improved substantially over the past five years.”
Clinical trials are also underway for gene therapies that could benefit SCD patients who aren’t eligible for transplantation. Among these are therapies developed by NHLBI-funded investigators, Bioverativ, bluebird bio, Editas Medicine and Vertex Pharmaceuticals. The FDA has assigned the therapies developed by Vertex Pharmaceuticals and bluebird bio Prescription Drug User Fee Action goal dates of, respectively, Dec. 8 and 20, 2023.
Supportive Care Considerations
Pain crises account for the majority of emergency room visits and hospitalizations in SCD patients, Dr. Bulloch said, but there are no reliable biomarkers to evaluate this pain. “It begins in infancy, and this is severe pain,” she said. The frequent pain associated with SCD can contribute to depression and anxiety. Furthermore, “they’re having to deal with the healthcare system that has become very cynical against people who use pain medicine.”
There are currently no analgesics that target SCD pain pathophysiology. “When we treat these patients, we do try to individualize care,” Dr. Bulloch said. “Oftentimes our first-line therapy is going to be opioids. There are some nonpharmacologic options that we can use as add-ons, but they’re never going to be used alone.” Nonpharmacologic therapies include massage, transcutaneous electrical nerve stimulation, yoga and guided relaxation.
For acute pain crises, Dr. Bulloch said, “your goal there is really to return patients to their baseline.” When it comes to chronic pain, which an estimated 30% to 40% of adolescents and adults with SCD experience (Ann Intern Med 2008;148[2]:94-101; Clin J Pain 2016;32[6]:527-533), however, “it’s important that they know that they may unfortunately never be pain-free; it’s just getting them to a pain level that they can tolerate.”
For chronic SCD pain, opioids are the first-line treatment, Dr. Bulloch said, and other treatments include serotonin and norepinephrine reuptake inhibitors such as duloxetine and milnacipran; nonsteroidal anti-inflammatory drugs (NSAIDs); vitamin D; and tricyclic antidepressants. Opioids are the first-line treatment for acute SCD pain as well, with adjuvants including NSAIDs, acetaminophen, ketamine and regional anesthesia (Blood Adv 2020;4[12]:2656-2701).
Some SCD patients may be able to manage acute pain crises at home with oral opioids, but they are the exception. “When these patients repeatedly come into the hospital since infancy, and they’re getting high doses of opioids since infancy, it makes sense that they’re going to have a higher opioid tolerance and they’re going to require higher doses” than people without SCD, Dr. Bulloch said. It’s important to tailor opioid dosing based on the patient’s baseline opioid use and history of effective therapy, develop care plans proactively with lists of medications and doses that have been effective for the patient, and educate patients on potential harms of opioid therapy, she said.
(For more on the pain management challenges faced by SCD patients, see bit.ly/3VZAX1e-SPC.)
Dr. Fasipe, who has SCD, noted that her country of birth, Nigeria, has the world’s highest rates of the disease (Pan Afr Med J 2022;41:161). “It’s a rare disease in America, but it’s not a rare disease globally,” she said. “I’ve always seen disparities with sickle cell disease; that made me very passionate about making sure we can improve lifespan, especially for children, and to make sure that they live healthy, productive [lives] and have high quality of life.”
Pharmacists can help in these efforts by educating themselves about SCD and how to manage it. “This is a disease that has faced a lot of historical injustices and disparities, and so it’s a disease that requires … champions,” Dr. Fasipe said. “Patients would love the fact that their pharmacists are empowering themselves with this information.”
Dr. Bulloch is a consultant to Alabama Medicaid and has previously received honoraria from Genentech. Dr. Fasipe reported no active financial relationships, but has served as a consultant to bluebird bio, Emmaus, Forma Therapeutics, Global Blood Therapeutics and Novartis. Dr. Fitzhugh reported no relevant financial disclosures.
This article is from the October 2023 print issue.