ASH Clinical News October 2017 | Page 26

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PAPER SPOTLIGHT

Hydroxyurea Is Safe , Efficacious in Children With SCA Living in Malaria- Endemic Sub-Saharan Africa

In vitro and animal studies suggest that hydroxyurea – one of two treatments approved by the U . S . Food and Drug Administration for the treatment of sickle cell anemia ( SCA ) – could increase the incidence and severity of malarial infection . This complicates the recommendation to use hydroxyurea in malariaendemic sub-Saharan Africa , where the vast majority of children with SCA are born .
In a study published in Blood , Robert O . Opoka , MBChB , MMed , of the Department of Paediatrics and Child Health at Makerere University in Kampala , Uganda , and co-authors shared results from a study of children with SCA living in sub-Saharan Africa in which these children were randomized to receive hydroxyurea or placebo . They found that hydroxyurea treatment did not lead to an increased in severe malarial infections , or adverse events ( AEs ) in patients , “ but optimal dosing and monitoring regimens for Africa remain undefined .”
The prospective , double-blind , randomized NOHARM ( Novel use Of Hydroxyurea in an African Region with Malaria ) study included 207 children ( 1-3.99 years of age ) who were treated at Mulago Hospital Sickle Cell Clinic in Kampala , Uganda , between September 24 , 2014 , and October 2 , 2015 , and lived within 31 miles of the clinic . Patients were excluded if they weighed < 11 pounds , had severe malnutrition or a known chronic medical condition , were already receiving hydroxyurea at the time of enrollment , or had received a blood transfusion in the previous 30 days .
Children were randomized 1:1 to receive 12 months of treatment with either :
• hydroxyurea 20 ± 2.5 mg / kg once-daily ( n = 104 ; mean age = 2.2 years ; standard deviation [ SD ] = 0.9 )
• placebo ( n = 103 ; mean age = 2.3 years ; SD = 0.9 )
Dose adjustments were allowed based on weight gain and hematologic toxicities .
Patients had 10 scheduled visits during the study treatment period to measure complete blood counts with leukocyte differential and absolute reticulocyte count , as well as blood chemistries . Patients with malaria ( defined as an axillary temperature ≥99.5 degrees Fahrenheit ) were treated with parenteral artesunate , followed by oral artemether-lumefantrine if hospitalized or oral artemetherlumefantrine alone if not hospitalized .
During the 12-month treatment period , malaria testing was performed for 235 episodes of fever , with only 12 confirmed episodes of malaria . The incidence of malaria ( primary endpoint ) did not differ between the two treatment groups : 0.05 episodes per child , per year in the hydroxyurea group ( 95 % CI 0.02-0.13 ) versus 0.07 episodes per child , per year in the placebo group ( 95 % CI 0.03-0.16 ), for a nonsignificant incidence rate ratio of 0.7 ( 95 % CI 0.2-2.7 ; p = 0.61 ).
Three children in the hydroxyurea cohort had five malaria episodes and seven children in the placebo cohort had seven malaria episodes .
Six of the total of 12 malaria episodes were severe and required hospitalization related to hemoglobin concentration < 5 g / dL ( n = 2 ), impaired consciousness ( n = 1 ), hemoglobin concentration < 5 g / dL and impaired consciousness ( n = 1 ), or an inability to take oral medication ( n = 2 ). Four malaria episodes had concomitant clinical AEs , including vasoocclusive crisis ( VOC ; n = 3 ) and acute chest syndrome / pneumonia ( n = 1 ). Two malaria episodes had concomitant serious AEs , including splenic sequestration ( n = 1 ) and bacteremia ( n = 1 ).
All patients with malaria recovered from the disease ; however , three patients died because of presumed sepsis ( n = 2 ; one in each treatment group ) or sudden death from an unknown cause ( n = 1 ; hydroxyurea cohort ). Five patients withdrew from the study .
A composite endpoint of SCArelated clinical outcomes ( including VOC , dactylitis , acute chest syndrome , splenic sequestration , and blood transfusion ) occurred in 45 percent of those treated with hydroxyurea , compared with 69 percent treated with placebo ( p = 0.001 ).
Serious AEs ( defined as death , acute life-threatening event , or hospitalization for more than 7 days ) occurred in six patients in each treatment cohort . ( See TABLE 1 for other AE outcomes .)
The results “ suggest that hydroxyurea should be strongly considered as an important therapeutic option for young children with SCA living in malaria-endemic areas ,” the authors concluded .
Because the overall rate of malaria was low – “ perhaps reflecting excellent adherence to malaria prophylaxis ,” the authors wrote – the results may not be generalizable to “ children with SCA not on malaria prophylaxis and / or not using insecticide-treated bed nets .” The authors also noted that risks of hydroxyurea “ may differ in areas of higher malaria transmission , and genetic or environmental factors in other areas could affect risk of hydroxyurea toxicity or malariahydroxyurea interactions .”
“ Outcomes were excellent … with a safe and relatively easily administered fixed dose ( 20 mg / kg ), so it will be important to investigate how treatment benefits and risks differ with different dosing schemes of hydroxyurea for children with SCA living in malaria-endemic areas ,” the authors concluded . The researchers plan to compare the effects of early initiation with longer-term effects of the drug in future studies .
Addmedica donated both hydroxyurea and placebo for the study . The authors report no conflicts .
REFERENCE
Opoka RO , Ndugwa CM , Latham TS , et al . Novel use of hydroxyurea in an African region with malaria ( NOHARM ): a randomized controlled trial . Blood . 2017 . [ Epub ahead of print ]
TABLE 1 . Adverse Events ( AEs ) in the NOHARM Population
Hydroxyurea ( n = 104 ) Placebo ( n = 103 ) p Value Serious AEs Events Participants Events Participants Bacteremia / sepsis 2 2 2 2 1.0 Acute chest syndrome / pneumonia 1 1 2 2 0.62 Vaso-occlusive crisis 0 0 1 1 0.5 Acute splenic sequestration 2 2 0 0 0.5 Anemia 0 0 1 1 0.5 Sudden death 1 1 0 0 1.0 SCA-related events ( composite ) 47 71 0.001
Dose-limiting toxicities Anemia
6
4
8
8
0.36
Reticulocytopenia
1
1
5
5
0.12
Neutropenia
2
2
0
0
0.5
Thrombocytopenia
12
11
4
4
0.11
SCA = sickle cell anemia
24 ASH Clinical News October 2017