The Year's Best in Sickle Cell Disease for 2017

For decades, patients with sickle-cell disease (SCD) have not benefited from the novel approaches being used in malignant neoplastic conditions. Lately, however, there are hints that this seems to be changing. Data from the phase II trial using the anti-P-selectin antibody crizanlizumab for the prevention of acute vaso-occlusive pain events in SCD were presented last winter, opening the door to alternative strategies for decreasing vaso-occlusive pain events in individuals with SCD.¹  This double-blind, randomized, placebo-controlled phase II trial assigned participants aged 16 to 65 years to either low-dose intravenous crizanlizumab (2.5 mg/kg), high-dose intravenous crizanlizumab (5.0 mg/kg), or placebo, administered over 30 minutes, 14 times thoughout the course of one year. The aim was to determine which arm best reduced the annual rate of acute pain episodes, as well as to understand the annual rate of days hospitalized, time to first and second acute pain episodes, and annual rate of other acute vaso-occlusive events including, but not limited to, priapism and acute chest syndrome. A 43 percent relative risk reduction in annual acute pain episodes (1.63 vs. 2.98) occurred when comparing the high-dose crizanlizumab and placebo treatment groups (p=0.01). Not only did the therapy decrease the annual acute pain episode rate, but the high dose of crizanlizumab also delayed the first and second acute pain episodes when compared with placebo (first episode, 4.07 months vs. 1.38 months, p=0.001; second episode, 10.32 months vs. 5.09 months, p=0.02; respectively). Equally important was the absence of any increase in adverse event rates between the high-dose and placebo treatment groups. Although the SCD community is anxiously awaiting the initiation of a phase III trial, positive clinical endpoint results were highly compelling, and the conduct and completion of the trial has significantly changed patient-oriented research for SCD in two major ways.

First, targeted anti-inflammatory therapy can decrease the rate of acute vaso-occlusive pain events. In this case, anti-P-selectin, an adhesion molecule that facilitates cell-to-cell interactions of red blood cells, endothelial cells, white blood cells, and platelets, may decrease the incidence rate of acute vaso-occlusive pain events. It has been known for some time that anti-inflammatory strategies may be helpful with this condition.^2,3  In two trials, intravenous corticosteroids were compared to placebo and demonstrated that steroid treatment dramatically hastened recovery to baseline for both acute pain episodes and acute chest syndrome. However, the use of corticosteroids has been met with tempered enthusiasm because of the high rate of rebound acute vaso-occlusive pain events temporarily associated with their use. The results of the crizanlizumab phase II trial provide new and important evidence that targeted anti-inflammatory therapies might prove effective in decreasing the symptoms associated with the disease.

A second victory was a logistical one. The trial was large (60 international sites participated), and accrual was completed rapidly, at just 18 months. The fact that any large multicenter international trial, let alone a trial for a rare disease, can be completed in 18 months is a testimony to the supporting organization, allocated resources, leadership, and the participants who agreed to volunteer for the trial. Important lessons can be learned for future SCD trials from the successful implementation and completion of this international randomized controlled trial.

Of course, the enthusiasm for the new treatment must be tempered a bit because the trial did not include children, the treatment requires intravenous administration, and the durability of the therapy and long-term sequelae of treatment are unknown facts. Further, the study generalizability, and the potential cost and infrastructure required for administration of the therapy are likely limited to high-resource settings with health insurance coverage of the therapy. However, the future looks bright for targeted anti-inflammatory strategies as an alternative therapy to prevent SCD complications.

A second groundbreaking SCD research discovery occurred in 2017, namely the use of gene therapy to cure a child with severe SCD.⁴  Gene therapy, though very early in development, provides optimism for a definitive cure for all affected individuals, not just those with sibling-matched hematopoietic stem cell transplant donors.

A third development in SCD in 2017 was a U.S. Food and Drug Administration (FDA) press release describing the approval of once-a-day oral L-glutamine for prevention of acute vas-occlusive pain events.⁵  The FDA approval was based on a randomized double-blind placebo controlled trial comparing once daily orally administered L-glutamine to placebo in 230 participants (5 to 58 years old) with sickle cell anemia or sickle β⁰-thalassemia for 48 weeks followed by three weeks of drug tapering. The results indicated a statistically significant decrease in acute vaso-occlusive episodes, fewer pain-associated hospitalizations and a lower incidence of acute chest syndrome. The adverse event rates were low and only 2.7 percent of the treatment group were compelled to stop the study drug due to adverse reactions. L-glutamine is only the second FDA-approved drug, after hydroxyurea, approved to prevent acute vaso-occlusive pain, and the first FDA-approved drug for children with SCD older than five years of age.

In summary, due to landmark clinical research completed in 2017, the SCD community should be cautiously optimistic about new treatment options with targeted anti-inflammation therapies, gene therapy for curing the disease, and a new FDA-approved drug to prevent vaso-occlusive events in children and adults. Given the nonoverlapping mechanism of action of the current FDA-approved therapies (hydroxyurea and L-glutamine) coupled with targeted anti-inflammatory therapies, we can envision the next generation of randomized controlled trials in SCD, including combination therapies of these agents, in 2018 and beyond.