Hydroxyurea Therapy for Sickle Cell Disorders in Childhood: Adherence to Therapy Transforms Lives and Needs to be the Focus - the Experience of Alder Hey Children's Hospital
Authors: Smith Louise , Phillips Kate L E , Keenan Russell D 
Published: October 2019

Abstract
Following Baby HUG trial results and other recent publications it is recommended by US evidence based guidance (NHLBI, 2014) that all children with sickle cell disorders be offered Hydroxyurea/Hydroxycarbamide (HU) therapy from 9 months. In the UK this is generally not the practice and there remains great reluctance to use HU. Only a minority of patients in the UK are offered HU therapy and many have never heard of it. There is no information at all on HU on the national UK Sickle Cell Society website.
Here, we present the experience of our first 37 patients on HU therapy over a total of 975 patient months, specifically the effects of good adherence to HU therapy. Our target was to aim for daily doses of 35mg/kg. 10 patients were identified as poor adherers based on parent admission and failure to collect prescriptions regularly enough to maintain daily dosing, all other patients were considered to have good adherence.
Doses actually achieved in patients who had been on therapy for more than 6 months had a mean of 28.5mg/kg. Overall, haemoglobin (Hb) level increased post-HU treatment to 92.0g/L from 80.6g/L, while reticulocytes decreased from 335.4 x109/L to 127.6 x109/L (n=37; p <0.0001 in both cases). 2 patients had minor transient cytopenia which recovered quickly without the need for dose reduction. In those patients with doses <26mg/kg, HbF was 20.4% as compared to 29.2% in those on doses >26mg/kg (p =0.0151). This suggests we have not reached the maximum tolerated dose in some patients and could continue to push doses higher with the benefit of improving HbF levels further.
In 27 patients, who say that they are adhering to daily HU therapy and are collecting prescriptions regularly, HbF was 30.6%, significantly higher than the 14.9% recorded in the poor adherer group (p <0.0001; Figure 1A). In good adherers who had been on therapy for more than 6 months, 5/24 achieved HbF of >40% and had HbS levels approaching trait. No patient failed to respond as measured by rise in HbF or reduction in crisis symptoms and only 4/24 failed to achieved HbF of >20%, but still had excellent increases from pre-HU therapy. 3 of these 4 have not reached their maximum dose yet and we will be increasing the HU further. In good adherers, Hb increased to 95.8 g/L compared to 84.8g/L in poor adherers (p =0.0380; Figure 1B) and reticulocytes reduced to 102 x109/L in good adherers compared to 176 x109/L in poor adherers (p =0.0034; Figure 1C). 19/24 good adherers achieved normal reticulocyte counts.
The experience has been overwhelmingly positive and patients and families lives are being transformed in practice. With good adherence to HU therapy, no patient failed to respond either in haematological parameters or clinical symptoms. Good adherers now have fewer admissions to hospital; 0.90 days/patient/year compared to poor adherers 6.3 days/patient/year (p <0.0001) and there is an obvious improvement in growth of patients once they are established on therapy. We now have many children who have forgotten what sickle pain feels like, and enjoy improved school attendance and more active lives. Some patients even play competitive sports including cross country running, which was unheard of before HU therapy. No patient had to discontinue therapy due to any toxicity. No patient developed a high transcranial Doppler or proteinuria, and in two patients who had proteinuria at commencement of HU therapy, this has resolved. HU therapy has been so successful that we now have only one patient with sickle cell disease in our practice of 70 patients who is on a transfusion programme.
Our next goals are to expand the HU programme to the rest of our patients and to increase the speed at which we achieve maximum tolerated doses. Our focus can then be on initiatives to improve adherence since our data indicate that adherence to therapy is critical. With good HU therapy adherence no patient failed to respond and therefore we envisage a minor role for transfusion programmes and BMT in the future. Our goal is also to disseminate this overwhelmingly positive experience to treating professionals, patients and families in the UK with Sickle Cell Disorder.
Figure 1. Figure 1.

Disclosures
No relevant conflicts of interest to declare.