Response to hydroxyurea among <scp>K</scp>uwaiti patients with sickle cell disease and elevated baseline <scp>H</scp>b<scp>F</scp> levels
Authors: Adekunle Adekile, Stephan Menzel, Renu Gupta, Sondus Al‐Sharida, Asma Farag, Mohammad Haider, Nagihan Akbulut, Nada Mustafa, Swee Lay Thein
Journal: American Journal of Hematology (2015)

The only currently FDA-approved drug for sickle cell disease (SCD) is hydroxyurea (HU), a ribonucleotide reductase inhibitor, associated with induction of HbF. In addition, it affects the RBC membrane, numbers of circulating leucocytes and platelets, and the expression of adhesion molecules 1. However there is considerable variability in the degree of clinical and HbF response to HU, and several genetic polymorphisms have been implicated. Genome-wide association studies (GWAS) have identified three major quantitative trait loci (QTL) in association with HbF expression in normal populations and in those with β-thalassemia or SCD. These are Xmn-1-HBG2 (rs7482144) on chromosome 11, BCL11A on chromosome 2p16 and HBS1L-MYB intergenic polymorphisms (HMIP) on chromosome 6q23 2, 3. It appears that these variants also influence HbF levels following HU therapy in SCD patients. While the role of C→T substitution at Xmn-1-HBG2 is well recognized in SCD patients with the Arab/India (AI) haplotype, the roles of the other two QTL have not been studied in Arab patients especially in relation to HU therapy. There are concerns about the safety of HU in SCD patients with the AI haplotype because of potential osteonecrosis of the femoral head (ONFH), consequent upon increased hematocrit (Hct) levels and blood viscosity 4. It was also not certain what degree of HbF response to expect given their elevated baseline levels. The present study documents the clinical, radiological (MRI of the hip), and laboratory responses among a group of 38 Kuwaiti patients (aged 3–20 years, mean 11.1 ± 4.5) with SCD—22 (57.9%) HbSS, 10 (26.3%) HbSβ0 thal, 3 (7.9%) HbSD, and 3 (7.9%) HbSβ+ thal—who had been on hydroxyurea for 1–15 years and investigates the influence of Xmn1-HBG2, BCL11A, and HMIP QTL on the observed HbF response. The indication for HU was frequent severe vaso-occlusive crisis in 35 (92.1%), previous stroke in 2 (5.3%), and severe anemia in 1 (2.6%). The two patients with previous stroke had been on regular blood transfusions for about 2 years before switching to HU. The drug was well tolerated in all patients with no major adverse effects. All the patients but two had significant subjective improvement in general well being. Pre-HU, 13 (35.1%) patients required ≥3 blood transfusions for acute anemic episodes, while post-HU, there was only one incident requiring transfusion. Six (16.2%) had one or two episodes of acute chest syndrome pre-HU, while post-HU there has been only one mild episode. There were significant increases in the Hb, hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and HbF and significant decreases in the reticulocyte count, and lactate dehydrogenase (LDH) (P < 0.05) in the whole group, while the decrease in the total bilirubin level was not significant. The breakdown among the SS and Sβ0-thal groups were similar especially in the Hb, Hct, WBC, and HbF levels pre- and post-HU (Table 1). In the whole group, there was a strongly-significant positive correlation between the pre- and post-HU HbF levels (r = 0.6, P <00.1); 92.1% had increases of at least 10% over the baseline, pre-HU level, while 52.6% had >50%. The most impressive increase was >400% over the baseline in the Sβ0-thal patient. In two patients (1 each of SS and Sβ0), HbF increased to a level of >40% of total hemoglobin, which has been sustained for 3 and 7 years, respectively. The mean absolute increase of HbF pre- and post-HU (ΔHbF) in the whole group was 8.7 ± 7.4%. The difference in the ΔHbF between the SS (7.4 ± 6.2) and the Sβ0thal (13.5 ± 7.3%) patients was significant (P<0.05). The Sβ+ and the SD patients had significantly lower mean ΔHbF of 4.0 ± 1.6 and 3.3 ± 1.5%, respectively. The patients, who were homozygous for the T allele of the Xmn-1-HBG2 C→T polymorphism, had significantly higher pre- (P < 0.001) and post-HU (P < 0.05) HbF levels. The mean ΔHbF values were 10.0 ± 5.2, 8.2 ± 7.5, and 8.6 ± 7.2% in the CC, CT, and TT groups, respectively. The differences did not reach statistical significance. Carriers of the C allele in BCL11A rs11886868, T allele in HMIP rs9376090, C allele in rs9399137, and the A in rs9402686 had higher mean pre-HU HbF values, the differences were not significant compared to those with the wild-type alleles. The alleles also did not show any influence on the post-HU HbF levels. Similarly, a recent study from Saudi Arabia found little or no influence of BCL11A and HIMP alleles on HbF levels in their SCD patients 5. Twenty-five patients had pre- and post-HU MRI of the hips; 17 (68.0%) had normal pre-HU images while 8 (32.0%) had varying degrees of ONFH, 5 of which were bilateral. Post-HU, of the 17 that were initially normal, 15 (88.2%) remained unchanged, while 2 (11.8%) developed unilateral ONFH. Of the eight that had lesions in the initial MRI, six (75%) remained static while three (25%) had progressed with more florid lesions. This rate of progression and incidence of new cases are less much than has been reported in a previous study of Kuwaiti SCD patients, not on HU, over a similar span of time 6. Kuwaiti Arab patients with high baseline HbF levels respond well to HU and the subsequent HbF levels reached are influenced by Xmn-1-HBG2, but not BCL11A and HIMP polymorphisms. The impressive responses are similar in SS and Sβ0 thal patients, while those with SD and Sβ+ thal may have a blunted response. There is no evidence that HU promotes osteonecrosis in our patients; to the contrary, it may be protective. Larger studies are needed to validate these findings. Adekunle Adekile,1* Stephan Menzel,2 Renu Gupta,3,4 Sondus Al-Sharida,4Asmaa Farag Azab,4 Mohammad Haider,1 Nagihan Akbulut,5 Nada Mustafa,1 and Swee Lay Thein2 1Department of Pediatrics, Kuwait University, Kuwait City, Kuwait; 2Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom; 3Department of Radiology, Kuwait University, Kuwait City, Kuwait; 4Pediatric Hematology Unit, Mubarak Al-Kabeer Hospital, Kuwait; 5Advanced Technology Company, Kuwait