Learning to Modify the Chronic Neurologic Burden of Sickle Cell Anemia

Posted by • August 20th, 2014

The patient sitting in front of you is a smiling, well-adjusted 6-year old boy.  He has a supportive family, eats a healthy diet, and is physically active.  What if, despite all of this, you knew that he had more than a 30 percent chance of developing a condition that would hamper his educational attainment?  Every day, pediatricians caring for children with sickle cell anemia are faced with this reality: around 37% of patients with sickle cell disease develop silent cerebral infarcts during childhood, which place them at significantly increased risk for poor academic achievement, cognitive deficits and strokes.

In this week’s NEJM, the Silent Cerebral Infarct Transfusion (SIT) Trial examines whether regular blood transfusions in children with known silent cerebral infarcts can reduce recurrent cerebral infarcts.  This multi-center, randomized control trial recruited children aged 5 to 15 years with hemoglobin SS or hemoglobin Sβ0 thalassemia, and a silent infarct on screening head MRI.

Study participants were randomized to receive monthly transfusion to maintain target hemoglobin greater than 9g/dL and a percentage of hemoglobin S less than or equal to 30% of their total hemoglobin.  The primary endpoint was infarct recurrence, defined as presence of a new infarct or enlargement of a previously noted infarct on the brain MRI performed at study exit.  Additionally, SIT monitored cognitive outcomes and safety outcomes, including transfusion reaction occurrence, ferritin levels, development of alloantibodies, and need for permanent central venous catheter access.

Of the 196 children who met study entry criteria, 99 were assigned to the transfusion group and 97 were assigned to the observation group.  After a mean follow-up of about 3 years, the incidence rate of infarct recurrence was 4.8 per 100 person years in the observation group versus 2.0 per 100 person years in the transfusion group ( p=0.04).  The number needed to treat was 13.

There was no significant difference in measured cognitive outcomes between the two groups. Patients in the transfusion group had a five-fold higher rate of blood-transfusion reactions and fourteen-fold higher rate of elevated ferritin levels (greater than 1500ng/mL).  Additionally, 11 patients in the transfusion group required tunneled venous catheter placement, and 4 patients in the transfusion group developed alloantibodies, compared with 0 patients for both outcomes in the observation group.

So does the SIT trial prove that transfusion for secondary prevention of silent infarcts in children with sickle cell anemia is ready for prime time?  While they represent an important realization—the chronic neurologic burden of sickle cell anemia may be modifiable—SIT’s encouraging results should be viewed in the context of treatment risks and implementation uncertainties.

In his accompanying editorial, Dr. Martin Steinberg states, “The study raises important questions for pediatricians and especially for internists who see these patients after many years of treatment, when untoward consequences of chronic transfusion can be present.”  For patients undergoing transfusion for secondary prevention we will need long-term mitigation strategies for alloimmunization, complications of permanent central venous catheter access, and iron overload.  We also lack clarity on the most appropriate duration of transfusion therapy and on whether transfusion strategies can have meaningful effects on longitudinal neurocognitive function.

Despite these concerns, Dr. Steinberg’s commentary remains hopeful about the promise of future long-term implementation trials.  As NEJM Deputy Editor Dan Longo adds, “Other methods of suppressing sickle globin gene expression are on the horizon; however, for the time being, transfusion appears to be capable of halving the neurologic consequences of sickle cell disease.  The late effects of transfusion are either rare (alloimmunization) or treatable (iron overload).  The same cannot be said for strokes.”

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