Background: Hydroxyurea (HU) therapy in children with sickle cell disease (SCD) produces positive hematological and clinical improvements similar to those seen in adults. Increases in HbF levels while receiving HU therapy, reported in pediatric studies varies from a low of 10%-15% to a high that occasionally exceeds 40% (Ware et al. 2011). Approximately 30% of sickle cell disease patients co-inherit α-thalassemia and prior studies have demonstrated conflicting results with regard to its impact on response to HU. Vasavda et al. reported a significantly blunted clinical and laboratory response to HU treatment in adult patients who carried the α-globin gene deletion (Vasavda et al. 2008 & 2012). A more recent report by Darbari et al. analyzed data from the adult MSH cohort and reported a smaller interaction of change in %HbF in patients with α-globin deletion; however these results did not achieve statistical significance (Darbari et al. 2014). Two pediatric studies have evaluated the impact of α- thalassemia on HU response in SCD. A recent analysis of the BABY HUG data, looking at the effect of genetic modifiers of SCD on HU treatment in a cohort of very young patients, found a significant laboratory as well as a clinical response to HU in SCD infants regardless of α-thalassemia status (Sheehan et al. 2013). Ware et al. reported on the association of α-thalassemia status with MTD (maximum tolerated dose) %HbF level (HUSTLE data) (Ware et al. 2011). They showed that α-thalassemia status had no significant association with MTD HbF, but did not report on the clinical efficacy or change in %HbF. While our study examines a similar age cohort as the HUSTLE study, the effect of α-thalassemia status is assessed in the context of routine clinical care. Patients in this cohort were not treated at MTD (maximum tolerated dose), but based on clinical response. We further evaluate the magnitude of reduction in vaso-occlusive events and examine the effect of older age within the pediatric cohort.

Methods: This is a retrospective, single institution study. Patients with SCD were included if they were between the ages of 5 and 21, on HU treatment for at least 6 months, had been genotyped for α-thalassemia, and had data on % HbF prior to, and during HU therapy. For both pre and post HU periods, the extreme values were taken (minimum and maximum) so as to capture the maximum effect possible from the HU therapy and minimize the impact of variable adherence. Other parameters that were assessed included hemoglobin, MCV, WBC, ANC and reticulocyte count, HU dose and number of vaso-occlusive pain events.

Results: 36 patients without α-thalassemia trait and 26 patients that were heterozygous for the trait were eligible for inclusion. Analysis of the entire cohort revealed no difference in the increase in HbF% between the two groups (Table 1, p=0.3). Surprisingly a greater reduction in vaso-occlusive events in patients with α-thalassemia was seen (p=0.03). Of note, patients that were > 12, and had α-thalassemia trait, had a blunted response with regard to change in HbF% (12.5 +/- 5.4) versus those without the mutation (18.9 +/- 7.1, p=0.02). In these patients that were > 12 years old, this was associated with a loss of the clinical advantage with no statistical difference in the reduction of vaso-occlusive events (p=0.08).

Conclusions: Young patients with α-thalassemia trait have an equivalent hematologic response and better clinical response to HU than patients without α-thalassemia. In contrast, patients 12-21 years of age with α-thalassemia have a blunted hematologic response to HU when not treated at MTD. Increasing HU dose to MTD may be more important in older patients with alpha thalassemia.

Table 1:

Delta HbF% and VOC rate on HU in SCD patients with and without α-thalassemia trait

VariablesAgeαα/α-αα/ααP-value
Change in %HbF 5-21 12.5 (+/- 8.4) 9.9 (+/- 6.3) 0.3 
Mean (+SD) 12-21 12.5 (+/- 5.4) 18.9 (+/- 7.1) 0.02 
VOC rate on HU 5-21 0 (0-1.3) 1 (0-2.8) 0.03 
Median (25-75 percentile) 12-21 0 (0-2) 1 (1-5) 0.08 
VariablesAgeαα/α-αα/ααP-value
Change in %HbF 5-21 12.5 (+/- 8.4) 9.9 (+/- 6.3) 0.3 
Mean (+SD) 12-21 12.5 (+/- 5.4) 18.9 (+/- 7.1) 0.02 
VOC rate on HU 5-21 0 (0-1.3) 1 (0-2.8) 0.03 
Median (25-75 percentile) 12-21 0 (0-2) 1 (1-5) 0.08 

Disclosures

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.