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SAN DIEGO -- Kids with sickle cell disease who underwent allogeneic stem cell transplantation (allo-SCT) had fewer serious disease complications along with better quality-of-life and cognitive outcomes a decade later, updated findings from a French trial showed.

The prospective study involved 67 children with a history of abnormal cerebral velocities receiving blood transfusions for their disease. At 10 years, patients with a matched sibling donor who underwent allo-SCT had lower mean rates of hospitalization and vaso-occlusive crises (VOCs) compared with kids without a donor receiving standard care (chronic transfusion or hydroxyurea):

• Hospitalizations: 0.2 vs 6.1, respectively (P<0.001)
• Days in hospital: 0.9 vs 30 (P<0.001)
• VOCs: 0 vs 3.8 (P<0.001)

Children in the allo-SCT group also had a lower incidence of silent cerebral infarcts -- a sign of increased sickle cell severity -- along with improvements in social and physical functioning domains and in working memory and processing speed on cognitive tests, reported Françoise Bernaudin, MD, of Hôpital Intercommunal de Créteil and Université Paris-Est in France.

"This confirms the importance of complete suppression of sickle cell erythropoiesis by allogeneic transplantation, and that transplantation is more effective than hydroxyurea or chronic transfusion," she said during a press briefing here at the American Society of Hematology annual meeting.

The new findings should encourage allo-SCT for sickle cell disease in children with a matched sibling donor and abnormal cerebral velocities or severe baseline hemolytic anemia, a known risk factor for cerebral vasculopathy or crisis despite hydroxyurea treatment, Bernaudin added.

Abnormally high cerebral arterial velocities are a common complication of the inherited disease and an indicator of the presence of stenosis, a narrowing of the arteries that reduces oxygen to the brain. Detected on brain scans, cerebral arterial velocities have been linked with a higher risk of stroke and cognitive problems.

"This study provides much-needed additional evidence in favor of transplant for children with severe manifestations of sickle cell anemia," said YunZu Michele Wang, MD, of City of Hope National Medical Center/City of Hope Children's Cancer Center in Duarte, California, who was not involved in the study. "The 10-year follow-up in this study is notable, as were the improvements in cognitive performance, quality of life, and primary prevention of silent cerebral infarcts."

At 10 years, only one patient in the allo-SCT group developed stenosis as compared with seven in the standard-care group (P=0.043), and transplanted patients also had reduced stenosis scores, said Bernaudin. Additionally, no new silent cerebral infarcts occurred in the transplant group versus five in the standard-care group, while four existing silent cerebral infarcts became no longer visible after transplant compared with one in the standard-care group (P=0.01).

Transplant is beneficial earlier in life, Wang told MedPage Today, but carries potential short- and long-term side effects. To balance out the risks and benefits, she said, transplant is typically indicated only for children with severe manifestations of sickle cell anemia, which can include frequent VOCs, silent cerebral infarcts, or stroke.

"Transplant is a tough process for anyone to go through, but particularly for children, especially if they don't understand why all of these things are happening to them," said Wang. She noted that a whole team at her center works with young pediatric patients, and their families to help them prepare for what to expect, including missing months of school and losing their hair.

"Unfortunately, the chemotherapy to prepare someone for a transplant can also impact their future fertility potential, so we also discuss what fertility preservation modalities are feasible," she said. "On the other hand, transplant earlier in life can be beneficial, before more significant organ damage has occurred as a result of the sickle cell disease, which will complicate the transplant and recovery."

Bernaudin presented data on , a follow-up to , a French multicenter, prospective trial that was the first to compare allo-SCT with standard of care for children with sickle cell disease.

The cohort included 67 children enrolled from December 2010 through June 2013, including seven with a history of stroke. Children ranged in age from 5 to 15 years, had a history of abnormal cerebral velocities (detected by Doppler ultrasound), were on long-term chronic transfusion therapy, and had at least one sibling without sickle cell disease.

In total, 32 patients had a matched sibling donor, parental consent, and underwent allo-SCT with a myeloablative conditioning regimen consisting of busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin. Patients in the control arm did not have a matched donor and continued on chronic transfusion therapy for at least a year but were switched to hydroxyurea if their cerebral arterial velocities normalized and they had no stenosis.

showed that allo-SCT was associated with lower transcranial Doppler velocities at 1 year. At 3 years, there was no significant difference between the two groups when it came to the incidence of silent cerebral infarcts or measures of cognitive performance, said Bernaudin, but quality of life on physical and school performance were better in the transplant group.

Researchers continued follow-up with study participants beyond that point with clinical evaluations, cerebral scans, and using tools to assess quality of life and cognitive function.

The 10-year study included data on all 67 patients; no deaths occurred in either group and there were no new strokes, including among those with a stroke history who were kept on a long-term erythrocytapheresis program.

Differences in cognition remained high among the patients with a history of stroke, with a full-scale IQ difference of 57.8 points versus 87.8 among siblings (P=0.006). As such, subsequent analyses focused on the 60 patients without a history of stroke.

Among the stroke-free subset, the allo-SCT group had higher scores on the Working Memory Index (89.6 vs 80.5, P=0.021) and Processing Speed Index (96.5 vs 83.7, P=0.35), while no significant differences were observed on measures of verbal comprehension, perceptual reasoning, full-scale IQ, or emotional quality of life.

Researchers also observed higher scores on physical, school, and social functioning domains at 10 years.

Hemoglobin A levels were significantly higher in the allo-SCT group at 10 years, while leukocytes, neutrophils, platelets, bilirubin, reticulocytes, lactate dehydrogenase, and transaminase levels were lower.

In the standard-care group, 23 patients achieved normalized velocities with no stenosis with chronic transfusion therapy and were switched to hydroxyurea (though seven reverted back to transfusions at some point). The mean number of VOCs were higher for those switched to hydroxyurea compared with patients who stayed on chronic transfusion therapy (4.3 vs 0.8, P=0.007).

Additionally, three patients in the standard-care group underwent a haploidentical SCT, with mild chronic graft-versus-host disease occurring in one patient.

"While the standard of care is a matched sibling transplant, unfortunately many patients do not have an HLA-matched sibling donor available, so we have to turn to donor registries or use a haploidentical parent or sibling," said Wang. "Advances in the last decade including improved graft-versus-host disease prevention and treatment modalities, such as the use of abatacept and post-transplant cyclophosphamide, have made these procedures safer and less toxic, but doesn't make the risk zero, so families often still are hesitant to move forward, which is understandable."

"Hopefully, more studies like these come out and provide more reassurance that it's worth it," she added.

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