Abstract

Introduction

Chronic transfusion therapy is the standard of care for children with sickle cell anemia (SCA) and abnormal transcranial Doppler velocities. Although effective, monthly transfusions are costly, inconvenient, and produce iron overload in the liver and extrahepatic organs. The TWiTCH study (ClinicalTrials.gov NCT01425307) is a randomized clinical trial to determine whether hydroxyurea therapy leads to comparable time averaged TCD velocities as conventional transfusion therapy, while reducing somatic iron stores. We report baseline data on iron burden in the spleen, pancreas, and kidneys from the TWiTCH cohort.

Methods

Pediatric patients from 22 centers underwent screening R2* assessment of the liver, spleen, pancreas, and kidneys. All sites used a 1.5 Tesla magnet, torso phased array coils, and a multiple echo gradient echo sequence with a minimum echo time ≤1.3 ms. Images were analyzed centrally at Children’s Hospital Los Angeles; core laboratory staff were blinded to patient, site, and visit data. Raw R2* values were used as iron surrogates for spleen, pancreas, and kidney. All statistics were performed by the TWiTCH Data Coordinating Center.

Results

A total of 113/159 enrolled patients (mean age 8.8 ± 6.3 years) successfully completed baseline abdominal R2* assessment (Table 1). Patients had received chronic transfusions for 4.2 ± 2.4 years and iron chelation for 3.2 ± 2.2 years. Serum ferritin values ranged from 191 to 10593 ng/ml (2655.6 ± 1668.1 ng/ml). All subjects had liver iron detectable by R2*, with 51.3% having liver iron concentration (LIC) >7 mg/g, and 13.3% >15 mg/g of dry weight. Splenic R2* could be assessed in 80/113 (71%) subjects, with the remainder having surgical splenectomy or autoinfarction. Splenic R2* revealed splenic tissue was comparable to liver tissue containing on average 13.1 mg Fe/g of dry weight. Pancreas R2* was greater than the upper limits of normal in 39.3% but no values exceeded 100 Hz (the level associated with pancreas dysfunction, pituitary iron accumulation, and cardiac iron deposition in thalassemia patients). LIC was the only significant predictor of pancreas R2* (r2 = 0.06, p=0.001). Kidney R2* was above the upper limits of normal in 79.5% of the patients and demonstrated preferential cortical distribution. Kidney R2* positively correlated with lactate dehydrogenase levels (p < 0.001), positive correlated with LIC R2* (p=0.005) and negatively correlated with hemoglobin level(p = 0.01) with a combined r2 of 0.29. No association was found with total bilirubin or reticulocyte count.

Table 1
ParameterNormal RangeAverageSt DevRange% abnormal
LIC by R2* < 1.3 mg/g 8.8 6.4 1.5-38.6 100% 
Spleen R2* < 35 Hz 515.3 399.3 51.5-1782.3 100% 
Pancreas R2* < 28.1 Hz 28.9 9.2 19.0-73.9 39.3% 
Kidney R2* < 32 Hz 79.3 57.9 13.3-292.6 79.5% 
ParameterNormal RangeAverageSt DevRange% abnormal
LIC by R2* < 1.3 mg/g 8.8 6.4 1.5-38.6 100% 
Spleen R2* < 35 Hz 515.3 399.3 51.5-1782.3 100% 
Pancreas R2* < 28.1 Hz 28.9 9.2 19.0-73.9 39.3% 
Kidney R2* < 32 Hz 79.3 57.9 13.3-292.6 79.5% 
Discussion

This represents the first multicenter study documenting the prevalence and extent of extrahepatic iron deposition in children with SCA receiving chronic transfusions. Splenic iron deposition was common but uncorrelated with LIC,, suggesting different kinetics of iron loading transport. Clinically-significant pancreatic iron deposition was not observed. Renal R2* tracked with intravascular hemolysis markers, rather than LIC or ferritin, consistent with tubular uptake of filtered cell-free hemoglobin. Overall, chronically transfused children with SCA have greater splenic and renal iron deposition, but much milder pancreatic iron overload, than that observed in transfused thalassemia patients.

Disclosures:

Wood:Novartis: Honoraria; Apopharma: Honoraria, Patents & Royalties; Shire: Consultancy, Research Funding. Off Label Use: Hydroxyurea is FDA-approved for use in adults but not children. Thompson:Amgen: Research Funding; Eli Lilly: Research Funding; Glaxo Smith Kline: Research Funding; ApoPharma: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; bluebird bio: Research Funding.

Author notes

*

Asterisk with author names denotes non-ASH members.