Chelation Choices and Iron Burden Among Patients with Thalassemia in the 21st Century: a Report From the Thalassemia Clinical Research Network (TCRN) Longitudinal Cohort.
Authors: Kwiatkowski Janet L , Kim Hae-Young , Thompson Alexis A. , Quinn Charles T. , Mueller Brigitta U , Odame Isaac , Giardina Patricia J , Vichinsky Elliott P , Boudreaux Jeanne , Porter John B , Coates Thomas , Olivieri Nancy F , Neufeld Ellis J 
Published: October 2019

Abstract
Abstract 4056
Poster Board III-991

BACKGROUND
Survival in thalassemia is strongly influenced by iron burden and adherence to chelation therapy. Deferoxamine (DFO) is an effective chelator, in use since the 1970s, but the parenteral mode of administration hinders adherence. Deferasirox (DFX), taken orally, became commercially available in the US in Jan. 2006, and deferiprone (DFP) is only available in North America (N.A.) through research or compassionate use. The impact of expanded chelation options on iron burden in thalassemia patients has not been studied. The goals of this study were to assess the chelator choices among patients with thalassemia and to compare efficacy and treatment adherence among chelators.

METHODS
The TCRN is a NHLBI-sponsored clinical trial network of Thalassemia Centers in N. A. and London, U.K. The Thalassemia Longitudinal Cohort (TLC) study of the TCRN was launched in 2006. Baseline data collection included a five-year retrospective component, with clinical, radiographic, and laboratory data from 2002 onward. This is followed by annual prospective data collection thereafter. The current analyses include data from the retrospective portion through baseline assessment. The dates of data collection span the initiation of DFX, first in clinical trials and then in routine clinical use.

RESULTS
Of the 404 enrolled subjects, 317 had ever received chelation therapy. Mean age was 21.2 ± 12.1y, and 46.4% were male. Genotype distribution included beta-thal major (79.2%), beta-thal intermedia (6.6%), chronically transfused HbE-beta-thal (9.5%), Hb E-beta-thal, not chronically transfused (1.6%), chronically transfused alpha-thal syndromes (2.3%), and other (1%). The median ferritin level was 1431 ng/mL (range, 122-23712 ng/mL) and mean liver iron content (LIC) was 10.8 mg/g dw (0.3-43.3 mg/g dw). Current choices are: DFO (27%), DFX (58%), DFP (1%), combination DFO+DFP (5%), DFO+DFX (3%), and no chelation (7%). Among chelated patients, 65 (21%, mean age 19.1y) chose to continue DFO and never used DFX, while 192 (61%, mean age 21.9y) have taken DFX (p=0.1). The mean current doses of DFO and DFX were 39 mg/kg/day and 25 mg/kg/day, respectively. Compared to those who switched to DFX, patients who continued DFO had lower initial ferritin levels (1499 DFO v. 2144 ng/mL DFX, p=0.02), but similar LICs (14.1 v 13.9 mg/g dw, p=0.9). Reasons for switching to DFX included: participation in clinical trials before 2006 (26%), commercial availability of drug (27%), patient/family preference (22%), high iron burden (15%), and other (10%). Conversely, 32 subjects who tried DFX switched back to DFO for the following reasons: patient/family preference (38%), high iron burden on DFX (16%), renal dysfunction (6%), elevated alanine aminotransferase (3%), and other (37%). Over the 5-year period, patients currently receiving DFX had a significant reduction in LIC (13.3 to 10.9 mg/g dw, p=0.02) and a trend towards reduction in ferritin level (2198 to 2027 ng/mL, p=0.06), while those receiving DFO had no significant change in LIC (12.2 to 10.4 mg/g dw. P=0.17) but had a significant decrease in ferritin levels (1881 to 1516 ng/mL, p=0.04). Self-reported treatment adherence was higher in the DFX group than in the DFO group, with 89% compared with 76.5% reporting adherence at least 75% of the time (p=0.02). Twenty-seven percent of patients on DFO at study entry and 30% of patients on DFX have ferritin >2500 ng/mL and/or LIC >15 mg/g d.w., indices of inadequate chelation.

CONCLUSIONS
DFX is currently the predominant chelator choice among patients with thalassemia in the TCRN. LIC appeared to improve among patients who have switched to DFX between 2002 and baseline TLC studies in 2007-2009, although ferritin remained stable. In the same time period, for DFO treated patients, ferritin significantly decreased but the LIC did not change. Nevertheless, the final LIC was similar between DFO and DFX treated groups. Inadequate control of iron burden was observed in a significant subset of patients receiving either chelator; thus, close monitoring of iron burden and encouragement and support of adherence are essential.

Disclosures:
Thompson: Novartis: Consultancy, Honoraria. Mueller:Novartis: Site principal investigator. Odame:Novartis: Consultancy, Speakers Bureau. Giardina:Novartis: Research Funding. Vichinsky:Novartis: Consultancy, Research Funding. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Coates:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Neufeld:Novartis: Research Funding.