NIH halts pediatric sickle cell study

The NIH’s National Heart, Lung, and Blood Institute (NHLBI) halted a clinical trial evaluating a new approach to reduce the risk of recurrent stroke in children with sickle cell anemia and iron overload because of evidence that the new treatment was unlikely to prove better than the existing treatment.

The Stroke With Transfusions Changing to Hydroxyurea, or SWiTCH trial, tested hydroxyurea use in 133 participants between the ages of 5 and 18 who had already experienced a stroke.

All of the study patients had been receiving the standard treatment of blood transfusions for at least 18 months and high levels of iron before entering the study.

The study tested whether the drug hydroxyurea, known to prevent complications of sickle cell disease in adults, was as effective as transfusions, the standard therapy, in reducing the risk of recurrent strokes.

Study researchers concluded that hydroxyurea was not as effective blood transfusions, and the treatment may have put younger patients at increased risk for stroke.

The study also compared two approaches to remove excess iron, a consequence of regular blood transfusions. Participants who continued to receive transfusion therapy were given the standard oral iron-removal drug deferasirox, and participants who were switched to hydroxyurea underwent regular phlebotomy to eliminate excess iron that had accumulated from their earlier transfusions.

The researchers noted that phlebotomy did not reduce liver iron better than deferasirox therapy.

Thee study’s independent Data and Safety Monitoring Board (DSMB) noted that no strokes occurred in the 66 participants who received the standard therapy of blood transfusions and deferasirox, while seven strokes occurred in the group of 67 participants who received hydroxyurea with phlebotomy.

DSMB members cited concerns about the medication’s lack of benefit, and recommended shutting down the study, researchers said in a press release.

NHLBI-supported research has shown that hydroxyurea helps prevent pain crises, a common complication of the disease, and some lung complications in adults. Preliminary studies have suggested that hydroxyurea might also help reduce the risk of stroke recurrence in children with sickle cell disease. Patients currently taking hydroxyurea should continue taking the treatment as prescribed and should talk to their primary care provider if they have any concerns, the study researchers advised.

The study was scheduled to run at 28 researcher sites until 2012. Rho Inc. of Chapel Hill, N.C., served as the SWiTCH statistics and data management center. Researchers are expected to analyze and publish the final data in the coming months.

There have been very few randomized controlled studies examining the use of hydroxyurea in pediatric sickle cell anemia. The first one was the BABY HUG study. In that study, a fixed dose of hydroxyurea was used in infants. The authors published the rationale for the study earlier this year; wherein, the authors will use maintenance of renal function and liver/spleen function as measured by scans to determine drug efficacy. The results of the trial will be published in the near future.

In relationship to the NIH publication, there was a pilot study indicating that hydroxyurea may be an acceptable alternative to transfusion for secondary stroke prophylaxis. Those pilot data were published in 2004. In 2007, a further study, headed by Russell Ware, MD, showed that hydroxyurea therapy lowers transcranial Doppler flow velocities in children with sickle cell anemia.

Therefore, it was reasonable to do this randomized, controlled trial. To the NIH's credit, they appropriately stopped this study when it appeared that patients getting hydroxyurea suffered strokes. Seven strokes occurred in a group of 67 participants who received hydroxyurea with phlebotomy compared to 66 participants who received only blood transfusions with deferasirox without suffering strokes.

I commend the oversight committee in stopping the trial, but it raises the issue: What kind of alternative can be found to replace blood transfusions with all of its potential problems including iron overload? This doesn't negate the need - and I believe a randomized, controlled trial has been established in sickle cell patients with findings of high velocity by transcranial doppler who have not had a primary stroke, which compares hydroxyurea in patients to blood transfusions. We will have to wait and see whether the drug is efficacious in this situation.

In this trial, it would appear that once damage has occurred in central nervous system, it isn't warranted to replace blood transfusions with oral medication.

– Laurence Boxer, MD
HemOnc Today Editorial Board member

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