Publication Only: Sickle cell disease
Sickle cell disease (SCD) is a severe inherited hemoglobinopathy, characterized by hemolysis, vaso-occlusive crisis (VOC) and progressive organ damage resulting in poor quality of life and reduced life expectancy. While improvements in supportive care, use of blood transfusion and hydroxyurea have resulted in better survival in SCD children, adult SCD patients still have progressive complications resulting in increased morbidity and mortality.Allogeneic stem cell transplantation is currently the only curative treatment option for SCD. However, in adults, myeloablative conditioning is associated with significant toxicity, primarily due to cumulative organ damage. Matched sibling donor (MSD) transplantation with non-myeloablative conditioning (alemtuzumab + 3 Gy total body irradiation (TBI)) and using peripheral blood stem cells has shown promising results in adult SCD patients. In patients treated with this regimen the SCD phenotype resolved with only mild transplantation-related complications, but no reports of graft-versus-host disease (GvHD). However, a large part of these patients did not reach complete donor chimerism and graft failure rates of 8-13% have been reported with this regimen. Seeking improvement in engraftment and donor chimerism, we added 3 months of preconditioning with azathioprine and hydroxyurea prior to alemtuzumab/TBI conditioning.
To evaluate engraftment, myeloid and CD3 T-cell donor chimerism and SCD phenotype after MSD allogeneic stem cell transplantation with azathioprine/hydroxyurea preconditioning and non-myeloablative conditioning in adult SCD patients.
Adult SCD patients with complications refractory to standard care who had an HLA-identical sibling donor were eligible for this treatment. After 3 months of azathioprine 150 mg qd and hydroxyurea 25 mg/kg qd, erythrocyte exchange transfusion was performed on day -10, aiming for HbS <30%. The alemtuzumab/TBI conditioning started on day -7, as described by Hsieh et al (N Engl J Med, 2009). GvHD prophylaxis consisted of sirolimus. Data regarding SCD phenotype, donor chimerism and transplantation-related complications were collected prospectively.
Data of 4 transplanted patients are described here and results of 3 recently transplanted patients will be available for presentation. All 4 patients had successful engraftment. Three patients reached a donor myeloid chimerism of 100% at 1 month and remained stable in the following months (Figure). Patient #4 reached a donor myeloid chimerism of 69% at 1 month which increased to 75% at 3 months. CD3 T-cell chimerism was 79%, 48%, 70% and 23% in patients #1, 2, 3 and 4 respectively, and increased further over time. The percentages of donor myeloid and T-cell chimerism are higher than previously reported with alemtuzumab/TBI only. All patients had a corrected SCD phenotype with normalized Hb levels at 3 months (mean ± SD 9,7 ± 1,2 g/dL to 12,7 ± 1,3 g/dL) with no reports of VOC. Importantly, there was no evidence of GvHD. Treatment-related complications were mTOR inhibitor-associated stomatitis (n = 3) responding well to local steroids, mild arthralgia (n = 2), and progression of preexistent chronic kidney injury in patient #3.
Azathioprine/hydroxyurea preconditioning prior to alemtuzumab/TBI is well tolerated and in this small series of patients resulted in excellent donor chimerism and resolution of SCD. Longer term results of a larger cohort need to be awaited to determine the place of azathioprine/ hydroxyurea preconditioning in the setting of non-myeloablative MSD transplantation.