Sickle cell disease (SCD) has long been marked by few drug treatment options, but increased efforts by researchers, organizations including the American Society of Hematology (ASH), and pharmaceutical companies to prioritize SCD research has led to the development of a number of novel therapies.
Until recently, patients with SCD had only one therapy, hydroxyurea, which was approved by the FDA in 1998. A myelosuppressive agent, hydroxyurea was, until 2017, the only effective drug to reduce the painful and frequent vaso-occlusive crises associated with SCD.
"The key therapy for the majority of patients [with SCD] is hydroxyurea," said Sophie Lanzkron, MD, of Johns Hopkins Medicine in Baltimore. "It's been around a long time, but has a lot of negative connotations associated with it, although there isn't a lot of evidence to support that."
Consequently, it has been underused in clinical practice.
In a in the American Journal of Hematology, Amanda Brandow, MD, of Children's Hospital Wisconsin in Milwaukee, and colleagues, surveyed 350 members of the American Society of Pediatric Hematology/Oncology and found that of those members providing SCD care, only 9% had >50% of their patients on hydroxyurea, while 10% had <10% on the drug.
The main reason given by providers for not prescribing hydroxyurea had to do with patient compliance. The most common reasons for patient refusal to take the drug were fear of cancer (51%), other side effects (62%), an unwillingness to take medication (49%) or deal with laboratory monitoring (28%), and a belief that it simply wouldn't work (17%).
"A lot of work on both ends is necessary to get patients to understand the benefits of hydroxyurea, and providers to use it correctly," said Lanzkron.
Because it presently is the major drug therapy for treating SCD, sickle cell experts are looking for ways to optimize it's use. ASH has made optimizing the use of existing therapies
For example, many providers "don't know how to use hydroxyurea properly," said Lanzkron. "They put people on a certain dose, and they never escalate the dose. So, we have to try to get providers to understand that they have to push this therapy in order to get it to work for people."
Results of the found that rather than calculating a standard dose of hydroxyurea based on a patient's weight, a dose-escalation approach to determine the maximum tolerated dose reduced hospitalizations among SCD patients to less than one a year, rather than four to six annually.
In 2017, L-glutamine became the second drug therapy approved for use in SCD when it was approved by the FDA, based on a phase III trial that found its use resulted in a decrease in the median frequency of sickle cell crises, and a reduction in the mean frequency of hospitalizations.
"They saw about a 25% reduction [in sickle cell crises]," said John J. Strouse, MD, PhD, of Duke University School of Medicine in Durham, N.C. "And a little bit more than half of the people in that study were already on hydroxyurea. There was also a suggestion of reduction -- but not statistically significant -- for acute chest syndrome, which is the second most common sickle cell complication that brings people to the hospital."
"I use L-glutamine in patients that cannot tolerate hydroxyurea," Strouse said. "Or, I will add it to hydroxyurea if their response is inadequate to hydroxyurea alone."
As for new sickle cell research, Strouse expressed excitement for three areas of therapy. "The first is the expansion of options in curative therapies, which would include gene editing and gene addition technologies," he said. "The one that's furthest along in clinical development is LentiGlobin [BB305], which is a gene addition where they have a lentiviral vector that puts in a modified hemoglobin that is anti-sickling."
In a 2017 article, Jean-Antoine Ribeil, MD, PhD, of the Reference Centre for Sickle Cell Disease, Necker Children's Hospital in Paris, described how a teenager with the βS/βS genotype of SCD, who had a history of numerous vaso-occlusive crises, completely responded to an infusion of LentiGlobin.
According to Ribeil and colleagues, 15 months after transplantation, the boy experienced no SCD-related events or hospitalizations.
"This is a space with a lot of products under development, and one that everyone is excited about," said Strouse.
A second noteworthy therapy is crizanlizumab (SEG101), an anti P-selectin antibody (Novartis). In a , researchers reported that SCD patients undergoing therapy with crizanlizumab, significantly lowered their rate of sickle-cell related pain compared with placebo.
Finally, "Another phase III study I'm excited about is voxelotor, which increases the affinity of hemoglobin for oxygen, and by that, helps prevent it from sickling," Strouse said.
At ASH 2018, researchers announced updated safety and efficacy results from the of voxelotor in patients, ages ≥12 with SCD. Preliminary results from the study demonstrated "rapid, robust, and sustained improvements in hemoglobin levels and measures of hemolysis with a favorable safety and tolerability profile."
Researchers found that 65% of patients taking voxelotor 1500 mg and 33% of patients taking voxelotor 900 mg achieved a greater than 1 g/dL increase in hemoglobin at 24 weeks vs 10% of patients taking placebo.
"It's really an exciting time to be part of the sickle cell world in looking at therapies that are coming down the pipeline," said Lanzkron. "New ways of doing transplants, gene therapy, new drugs working in different ways we haven't thought of before to decrease sickling. There's a lot of industry excitement about participating in looking for new therapies that didn't exist before."