Short-term safety and beneficial effects of hydroxyurea therapy in children with sickle cell disease

Abstract

Introduction: Worldwide, sickle cell disease (SCD) is the most common hemoglobinopathy among which SS pattern is more common. Although hydroxyurea (HU) is approved by the Food and Drug Administration for the treatment of recurrent moderate-to-severe painful crises in pediatric sickle cell anemia, there is a fear of toxicities. Objectives: The objectives of the study were to evaluate the short-term safety and beneficial effects of low-dose HU therapy in SCD (SS pattern) children. Materials and Methods: This prospective cohort study enrolled 40 cases of severe SCD and started HU in a fixed dose of 10 mg/kg/day. During follow-up, cases were evaluated for compliance of HU, its toxic effects and adverse events from their histories, clinical examinations, and laboratory parameters. Furthermore, beneficial effects of HU therapy were evaluated by assessing blood transfusion rate, frequency of painful events, strokes, acute chest syndrome, avascular necrosis of femur, and estimation of hemoglobin F (HbF) level after 2 years of therapy. HU was discontinued temporarily if any toxicity or minor adverse drug events occurred during therapy and was restarted at the same dose after normalization of deranged laboratory parameters. Results: The clinical adverse drug events seen were nausea (8.33%), diarrhea (2.78%), and hematuria (2.78%). The most common hematological toxicity was anemia and thrombocytopenia. Renal and hepatic toxicities were transient in nature. The mean acute painful events and blood transfusion rate reduced significantly on HU therapy. It increased Hb and HbF level significantly in SCD children. Conclusion: HU is a safe drug without significant toxicity or adverse events in a dose of 10 mg/kg/day for short duration and it is beneficial in SCD (SS pattern) children in reducing acute painful events and decrease blood transfusion rate.

A systematic review on hydroxyurea therapy for sickle cell disease in India

“…While selected 10 studies 20 , 22 - 24 , 26 , 27 , 29 , 30 , 32 , 33 assessed the efficacy/toxicity of HU therapy in SCD, two articles each were on beta-thalassaemia 21 , 28 and HbSD-Punjab 25 , 31 . Of the total 14 studies reviewed, five (35.7%) studies 20 , 22 , 27 , 29 , 31 were conducted in paediatric patients, six (42.8%) 21 , 24 , 25 , 30 , 32 , 33 in adults patients and three (21.4%) in others 26 - 28 in paediatric as well as adult patients with SCD. The duration of both observation and the follow up of patients, however, varied in the studies.…”

“…Efficacy & effectiveness of hydroxyurea (HU) : It was noted that the majority of the studies indicated the efficacy of low-dose HU therapy in reducing the frequency of pain crises, blood transfusions and hospitalization. Of the 14 studies, 12 used the fixed-dose method 20 , 22 - 26 , 28 - 33 , and two used the standard dose escalation method 21 , 27 . In the two studies that used the dose escalation method, while one study started with a low dose of 10 mg/kg/day and escalated to 15 mg/kg/day, the other one started from 15 mg/kg/day and escalated to 30 mg/kg/day 21 , 27 .…”

Hydroxyurea and blood transfusion therapy for Sickle cell disease in South Asia: inconsistent treatment of a neglected disease

“…Prevalence of allo-immunization was higher in SCD than in β-thalassaemia major Dave et al [ 56 ] A longitudinal descriptive study of patients with SCD from tribal area of Gujarat, India SCD comprehensive care programme increased the coverage of HU from 3.5 to 88%. Rate of transfusion reduced significantly after the enrolment with the programme (27.4 vs 17.8 per 100 patient years) Good quality care can be provided even for the economically deprived remote communities with SCD Somkuwar et al [ 57 ] A prospective cohort study involving Hb SS children from Maharashtra, India After the HU therapy, rate of acute pain crisis and blood transfusion reduced significantly ( p = 0.001) Low-fixed dose HU therapy is safe and effective for Indian Hb SS children Sinha et al [ 58 ] A descriptive survey which projected the blood and budgetary requirement for haemoglobinopathies in India (2017–2026) Annual requirement of blood for SCD would increase by 0.99 million units/year. Projected requirement of blood in 2026 was 9.24 million units Widespread efficient and effective preventive strategies are urgently required to cope with the sharply increasing demand of blood Jain et al [ 59 ] A prospective cohort comparison study involving Hb SS patients from Nagpur, India 26 (33%) Hb SS patients received 74 transfusions (mean 2.8 episodes/patient) Pre-transfusion Hb was below 6 g/dl in 67% of patients.…”

“…Five studies practiced HU therapy in accordance with first recommendation (Grade 1A) which is the usage of HU when adult Sickle cell anaemia (SCA) patients’ experience ≥ 3 moderate to severe pain crises in a 12-month period [ 29 – 31 , 52 , 53 ]. Seven studies practiced HU therapy in accordance with 2 nd , 3 rd and 4 th recommendations (Grade 1 B) suggesting the usage of HU when adult SCA patient has a history of ACS or symptomatic anaemia; children with SCA experience ≥ 3 moderate to severe pain crises in 12-month time period or having a history of ACS or symptomatic anaemia [ 29 – 32 , 34 , 35 , 57 ]. In addition, five studies practiced HU therapy in accordance with recommendation 6 (usage of HU in SCA patients who have a history of stroke) [ 29 , 30 , 34 , 35 , 57 ], and two studies [ 29 , 42 ] in accordance with recommendation 7 (usage of HU in adult Hb S-β+ thalassaemia patients who experience ≥ 3 pain crises in 12-month period or having a history of ACS).…”

“…Seven studies practiced HU therapy in accordance with 2 nd , 3 rd and 4 th recommendations (Grade 1 B) suggesting the usage of HU when adult SCA patient has a history of ACS or symptomatic anaemia; children with SCA experience ≥ 3 moderate to severe pain crises in 12-month time period or having a history of ACS or symptomatic anaemia [ 29 – 32 , 34 , 35 , 57 ]. In addition, five studies practiced HU therapy in accordance with recommendation 6 (usage of HU in SCA patients who have a history of stroke) [ 29 , 30 , 34 , 35 , 57 ], and two studies [ 29 , 42 ] in accordance with recommendation 7 (usage of HU in adult Hb S-β+ thalassaemia patients who experience ≥ 3 pain crises in 12-month period or having a history of ACS). Incidentally, 2 further studies reported the usage of HU in Hb S-D Punjab patients when they experience 3 or more VOC within 12-month period time [ 38 , 40 ].…”