Abstract

Introduction

Hydroxyurea (HU) therapy ameliorates the morbidity associated with Sickle cell anemia (SCA). HU is typically escalated to maximum tolerated doses (MTD) for treatment of SCA patients. Monitoring HU for toxicity poses potential challenges in low resource settings. We have previously reported the safety and efficacy of fixed low dose HU at 10mg/kg body weight ( Jain et al 2013). We studied the long term safety and efficacy of low dose HU in pediatric patients with SCA.

Methods

Long term observational follow up of 40 young Indian SCA patients was carried out for a period of 10 years in a single tertiary care center in central India. The number of clinical events including vasocclusive crises, acute chest syndrome, stroke, sequestration crises, avascular bone necrosis in the entire cohort was assessed prior to starting HU and subsequently every 3 months. Laboratory parameters including hemoglobin levels, Hb F levels, mean corpuscular volume, mean corpuscular hemoglobin concentration were also followed up over the same time period.

Results

The total number of patients in this study was 40 (17 females & 23 males). Mean age was 12.95 years ± 9.62. All patients had HbSS. There was an increase in mean hemoglobin, HbF, MCV and MCH over time in the patient population ( Table 1). There was a decrease in the mean number of hospitalizations, vasocclusive crises, acute chest syndromes, stroke and severe anemia ( Table 2). HU was well tolerated with minimal hematological or other toxicity (Table3). Patients who experienced transient hematological, liver or renal toxicity were able to resume HU at the same dose. HU was permanently discontinued in 2 patients who had manifestations of HIV/AIDS. HU was temporarily interrupted in one patient who was receiving treatment for tuberculosis and in one patient for the duration of a normal pregnancy. There was one death attributable to severe septicemia without evidence of neutropenia after 2 years follow up. There were 3 subjects who were lost to follow up, one after 2 years follow up and remaining 2 after 5 years of follow up. Of note, patients had a high HbF level at baseline. High HbF levels at baseline, the variable relationship of HbF to disease severity and amelioration of disease in Indian patients with high HbF has been previously reported ( Jain et al 2012, Patel et al 2012, Italia et al 2009).

Table 1.

Mean value ± S.D of Hematological parameters for patients on long term HU(n= no.of patients)

Lab parameters Baseline (n=40) 6 months(n=40) 24 months(n=38) 60 months(n=36) 120 months(n=36) 
Hb F 18.44 ± 10.53 21.35 ± 9.63 21.08 ± 8.56 21.92 ± 8.95 22.15 ± 8.74 
Hb (gm %) 8.94 ± 1.82 9.29 ± 1.63 9.83 ± 1.74 9.74 ± 1.61 9.76 ± 1.53 
MCV (fl) 89.27 ± 10.98 92.89 ± 10.49 93.31 ± 11.33 93.39 ± 10.39 93.36 ± 10.41 
MCH 29.65 ± 4.46 31.11 ± 4.18 31.16 ± 4.30 30.88 ± 3.84 31.31 ± 4.15 
Lab parameters Baseline (n=40) 6 months(n=40) 24 months(n=38) 60 months(n=36) 120 months(n=36) 
Hb F 18.44 ± 10.53 21.35 ± 9.63 21.08 ± 8.56 21.92 ± 8.95 22.15 ± 8.74 
Hb (gm %) 8.94 ± 1.82 9.29 ± 1.63 9.83 ± 1.74 9.74 ± 1.61 9.76 ± 1.53 
MCV (fl) 89.27 ± 10.98 92.89 ± 10.49 93.31 ± 11.33 93.39 ± 10.39 93.36 ± 10.41 
MCH 29.65 ± 4.46 31.11 ± 4.18 31.16 ± 4.30 30.88 ± 3.84 31.31 ± 4.15 
Table 2.

Mean number of clinical events per year ± S.D in the entire cohort

Clinical parameters Baseline (n=40) 1 year(n=40) 5 years(n=36) 10 years(n=36) 
Hospitalizations 18.34 ± 17.33 2.82 ± 1.25 2.27 ± 2.06 2.72 ± 2.37 
Vasocclusive crises 13.07 ± 18.53 1.45 ± 0.87 1.65 ± 1.58 1.82 ± 1.81 
Severe anemia 4.35 ± 4.31 0.65 ± 0.72 0.58 ± 0.84 0.62 ± 0.83 
Stroke 0.075 ± 0.26 
Sequestration crises 0.075 ± 0.26 
Chest syndrome 0.075 ± 0.26 0.025 ± 0.158 0.025 ± 0.158 
Avascular Necrosis 0.075 ± 0.26 0.025 ± 0.158 
Clinical parameters Baseline (n=40) 1 year(n=40) 5 years(n=36) 10 years(n=36) 
Hospitalizations 18.34 ± 17.33 2.82 ± 1.25 2.27 ± 2.06 2.72 ± 2.37 
Vasocclusive crises 13.07 ± 18.53 1.45 ± 0.87 1.65 ± 1.58 1.82 ± 1.81 
Severe anemia 4.35 ± 4.31 0.65 ± 0.72 0.58 ± 0.84 0.62 ± 0.83 
Stroke 0.075 ± 0.26 
Sequestration crises 0.075 ± 0.26 
Chest syndrome 0.075 ± 0.26 0.025 ± 0.158 0.025 ± 0.158 
Avascular Necrosis 0.075 ± 0.26 0.025 ± 0.158 
Table 3.

Toxicity Associated with HU During Study Period of 10 years

Toxicity No. of episodes No. of patients 
ANC < 500x109/L 
ANC 500-1500 x109/L 
Thrombocytopenia (<80  x109/L ) 
ALT (> 2 times upper limit of normal) 
Creatinine (> upper limit of normal) 
Reticulocytopenia (Absolute Reticulocyte Count < 80 x1012/L) 
Hyperpigmentation 
Toxicity No. of episodes No. of patients 
ANC < 500x109/L 
ANC 500-1500 x109/L 
Thrombocytopenia (<80  x109/L ) 
ALT (> 2 times upper limit of normal) 
Creatinine (> upper limit of normal) 
Reticulocytopenia (Absolute Reticulocyte Count < 80 x1012/L) 
Hyperpigmentation 
Conclusions

Low fixed dose HU is well tolerated and is efficacious in reducing incidence of VOC, hospitalizations, severe anemia, stroke and acute chest syndrome. Low fixed dose HU may be advantageous in low resource settings because of lower toxicity and consequently less need for monitoring. There is a need for multi-center randomized comparisons of low fixed dose HU with conventional escalation of HU dose to MTD.

Disclosures:

Krishnamurti:GlycoMimetics, Inc.: Research Funding.

Author notes

*

Asterisk with author names denotes non-ASH members.