Cerebrovascular events in sickle cell‐beta thalassemia treated with hydroxyurea: A single center prospective survey in adult Italians

Abstract

Stroke is a common cause of morbidity and mortality in sickle cell disease (SCD) and silent cerebral infarction is the most common form of neurologic injury. The frequency and risk factors for new silent cerebral infarction are incompletely understood. Moreover, no recommended treatment has been established. Although hydroxyurea (HU) is recommended for SCD, concerns remain regarding its role in the prevention of cerebrovascular events, including silent cerebral infarction. A single center population of 104 Italian patients with HbS-ß thalassemia treated with HU has been followed for a mean of 11 years. Clinical evaluation and brain imaging by Magnetic Resonance Imaging were done before and during HU treatment. During follow-up, the number of sickle cell crises (86%, 7.8 6 6.9 vs. 1.2 6 0.5 per year, P < 0.0001), hospitalizations (2.5 6 2.9 vs. 0.3 6 1.5 per year, P < 0.0001), and days in the hospital (22.4 6 21.9 vs. 0.361.5 per year, P < 0.0001) decreased significantly and HbF increased from a mean of 8-20.8%. Cerebral infarcts occurred in 37.5% of patients. Among these, 6.7% had overt strokes, while 30% had new or progressive silent cerebral infarction. Stroke and silent cerebral infarction were not related to clinical hematologic or HbF response to HU. These findings suggest that in adults, HU treatment does not prevent new cerebrovascular events or the progression of existent silent cerebral infarcts in HbS-b thalassemia. A major benefit of HU is the increase in HbF; the association of high HbF and reduced cerebrovascular disease has been weak. New treatment strategies should be developed for the prevention of sickle cerebrovascular disease. Am. J. Hematol. 88:E261-E264,

Low and fixed dose of hydroxyurea is effective and safe in patients with HbSβ+ thalassemia with IVS1‐5(G→C) mutation

“…In the present study, the response for VOC in all patients was 98.7%, which is similar to that of the study from Greece [8]. In a study from Italy on 104 adult patients with HbSb-thalassemia, the overall response for VOC was 86% [9]. The primary objective of this Italian study was to evaluate the effectiveness of HU in preventing stroke and silent cerebral infarction.…”

Breakthrough: new guidance for silent cerebral ischemia and infarction in sickle cell disease

“…Two studies provide evidence that chronic transfusions may decrease the frequency of new SCI in patients with prior stroke or abnormal transcranial Doppler (TCD) velocities. However, there is also evidence that chronic transfusions for first overt stroke may not prevent SCI, 25 hydroxyurea may not prevent SCI, 26 and that SCI still occurs frequently despite intensification of medical therapy for SCD. 3 The results of the recently completed SIT trial were not published at the time this chapter was written, so no comments about the findings can be made here.…”

Update on the use of hydroxyurea therapy in sickle cell disease

“…Evidence from cohort studies of patients from Greece and Italy with HbSb 1 -thalassemia extend the findings for SCA to this population; however, the recommendation to use hydroxyurea is weak based on a relatively small sample size compared with data on SCA. 30,36 Furthermore, in the Greek cohort, the majority of patients had the IVSI-110 mutation, which is associated with more severe disease than those of African ancestry with HbSb 1 -thalassemia. 36 The recommendation to use hydroxyurea treatment in asymptomatic children with SCA is based on secondary outcomes of BABY HUG and safety data from previously reported and currently cited studies.…”

“…21 In adults with HbSb 0 -and HbSb 1 -thalassemia, new ischemic neurologic events occurred on hydroxyurea despite effectively reducing VOC and hospitalizations ( Table 2). 30 Hydroxyurea compared with placebo did not prevent early evidence of renal or splenic dysfunction in toddlers aged 9 to 18 months (Table 1), 15 but observational studies in children aged 9 months to 20 years noted significant improvement in splenic uptake, glomerular filtration rate, renal hypertrophy, ability to concentrate urine, microalbuminuria, and retinopathy. 16,22,23,26,33 Toxicity Leukopenia, neutropenia, and thrombocytopenia were the most frequently reported side effects of hydroxyurea.…”

“…Thirteen studies 6, [21][22][23][24][25][26][27][28][29][30][31][32] indicated a goal to increase to maximum tolerated dose (limited by mild myelosuppression), 5 studies increased until clinical or laboratory improvement was observed, [33][34][35][36][37] and 5 studies used fixed dosing at 10 or 20 mg/kg per day. 15,[38][39][40][41] When stated, all studies used a maximum dose of 30 to 35 mg/kg per day.…”