The Year's Best in Sickle Cell Disease

In 2016, after completion of a landmark randomized controlled trial, a paradigm shift has occurred for primary stroke prevention in children with sickle cell anemia. The Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea (TWiTCH) trial was a multicenter, open-label, phase III, noninferiority trial published in 2016. Eligibility for the trial included children with sickle cell disease (SCD) with abnormal TCD flow velocities (≥ 200 cm/s), but no severe vasculopathy based on magnetic resonance angiography (MRA) of the brain — a group believed to be at a lower risk for an initial stroke. Participants were randomly assigned to continue standard transfusions or hydroxyurea therapy at maximum tolerated dose (MTD) for 24 months. The primary outcome measure was TCD measurements throughout the trial. During interim analysis, noninferiority was demonstrated based on TCD measurements (p=8.82 × 10^-16).

The impact of the TWITCH trial cannot be overstated. From the point of view of a student with SCD with an elevated TCD measurement, the results are life changing. Instead of coming to the hematology office for for monthly blood transfusion therapy, indefinitely, the student can be switched to a daily medication, hydroxyurea. The new therapy will only require a routine office visit of 30 minutes every two to three months, compared to a three- to six-hour visit each month.

As expected in any randomized controlled trial, some limitations in the trial design have been noted, including the lack of a long-term follow-up to ensure the efficacy of hydroxyurea for stroke prevention because the follow up-period in the trial was less than 24 months.¹  Additionally, participants randomly assigned to receive hydroxyurea therapy had a median six-month overlap of receiving both blood transfusions and hydroxyurea. Further, despite common perception, the primary endpoint of the trial, TCD measurements, are not predictive of future strokes while receiving therapy. Among the participants of the Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) trial, which had a mean follow-up of 2.4 years of blood transfusion therapy, 21 percent had TCD velocities that remained in the abnormal range (≥ 200 cm/s).²  Therefore, TCD measurements have only been proven predictive of strokes when not receiving therapy, and TCD measurements have not proven to have any predictive utility while receiving blood transfusion therapy.

Despite the inherent limitations of the TWiTCH Trial, all observational studies to date have shown that hydroxyurea therapy significantly decreases TCD measurements. In pooled analysis of the seven studies documenting TCD measurement before and after hydroxyurea therapy, the average drop in TCD measurement was 25 cm/s. The results of the TWiTCH trial, coupled with the composite of the observational studies demonstrating that hydroxyurea therapy significantly lowers TCD measurements, make a strong casefor the benefit of hydroxyurea therapy in lowering previously elevated TCD measurements.

With regard to treatment for primary stroke prevention, questions still remain. The trial looked at both hydroxyurea and blood transfusion therapy in children with elevated TCD measurement and without severe cerebral vasculopathy based on magnetic resonance angiography of the brain.³ Thus families of such children are unsure as to whether the results are applicable to their situation. Unfortunately, while receiving blood transfusion therapy, the TCD measurement will not reveal whether the child will have an ongoing stroke risk.²  The inability to further stratify the subgroup of children with SCD into the high-risk and low-risk groups based on TCD values after treatment or the presence of severe intracranial vasculopathy is challenging because the incidence rate of strokes with regular blood transfusion therapy is very low (< 1 event per 100 patient years).⁴  Another lingering question is the efficacy of hydroxyurea in preventing strokes in children with both elevated TCD measurements and silent strokes treated, the group most likely to have strokes when not treated.⁵  The Silent Infarct Transfusion Trial excluded those children with elevated TCD measurements and silent strokes, thus not providing any information on this high-risk group.⁶  Given the small proportion of children with elevated TCD measurements and silent strokes (probably less than 5%), a randomized controlled trial is not likely to occur. Ultimately, for these small group of children with poorly defined, but definitive increased initial and recurrent stroke risks, including those with hemoglobin SC disease with prior strokes, multicenter learning collaboratives will need to be considered because there are simply not enough data or clinical experience to make evidence-based decisions on management.⁷ 

For individuals with sickle cell trait, 2016 saw the completion of a landmark study describing the risk of death and exertional rhabdomyolysis during extreme exercise routines. After universal precautions were undertaken to prevent heat-related injury for all Army recruits during basic training, there was no increased rate of exercise-associated death in those with sickle cell trait compared with controls matched on race without sickle cell trait (hazard ratio, 0.99; 95% CI, 0.46-2.13; p=0.97). However, for those with sickle cell trait, there was an increase in the risk of exertional rhabdomyolysis that was statistically significant (hazard ratio, 1.54; 95% CI, 1.12-2.12; p=0.008).⁸ 

The results from Dr. D. Alan Nelson and colleagues⁷  highlights the now clear supercilious National Collegiate Athletic Association (NCAA) edict that all college football players must be screened for sickle cell trait or sign a document relieving the university and NCAA of any liability if an adverse event occurs. In light of the landmark study, there is clear evidence that after universal precautions, individuals with sickle cell trait participating in rigorous training, do not have an excessive risk of death, and are at no greater risk of exertional rhabdomyolysis than those with a body mass index (BMI) greater than 30 compared with a BMI less than 25, or those on an antipsychotic agent. Based on the strength of this large observational study, the hematology and public health communities now have a new challenge: determining whether the essential components of the Army’s universal precaution strategy can be applied to the majority of high school and college athletes. The SCD community looks forward to the NCAA updating their well-intentioned, but misguided strategy of targeting individuals with sickle cell trait to prevent future injury.

Potentially, a new therapy will be available for the prevention of vaso-occlusive pain episodes in adults with SCD. For the first time since the U.S. Food and Drug Agency (FDA) approval of hydroxyurea therapy for prevention of pain episodes in SCD, a clinical trial has provided favorable evidence that a second agent, crizanlizumab, an antibody against the adhesion molecule P-selectin, may prevent pain episodes. In a double-blind, randomized, placebo-controlled phase II trial, participants who received crizanlizumab intravenously 15 times throughout the course of a year had a 45 percent decline in the rate of pain when compared to placebo. The SCD community anxiously awaits the outcome as to whether the FDA will approve crizanlizumab — only the second drug for preventing pain in SCD in more than 20 years.