Deferasirox Continues to Reduce Iron Overload in Non-Transfusion-Dependent Thalassemia: A One-Year, Open-Label Extension to a One-Year, Randomized, Double-Blind, Placebo-Controlled Study (THALASSA)
Authors: Taher Ali T , Porter John B , Viprakasit Vip , Kattamis Antonis , Chuncharunee Suporn , Sutcharitchan Pranee , Siritanaratkul Noppadol , Galanello Renzo , Karakas Zeynep , Lawniczek Tomasz , Habr Dany , Ros Jacqueline , Zhu Zewen , Cappellini M Domenica 
Published: October 2019

Abstract
Abstract 3258

Background:
Despite receiving occasional/no blood transfusions, non-transfusion-dependent thalassemia (NTDT) patients (eg β-thalassemia intermedia, mild/moderate HbE/β-thalassemia, α-thalassemia [HbH disease]) are at risk of iron overload, mainly due to increased intestinal iron absorption. The THALASSA 1-year randomized core study assessing deferasirox for investigational use in NTDT showed deferasirox superiority in reducing iron overload with a similar frequency of overall adverse events (AEs) compared with placebo (PBO). This 1-year extension evaluates continued efficacy/safety of deferasirox in patients receiving deferasirox in the core as well as patients receiving PBO who switched to deferasirox.

Methods:
Study design/inclusion-exclusion criteria have been described (Taher et al. Blood 2012). In the prospective, open-label, 1-year extension, patients whose LIC decreased ≥30% vs baseline (BL) continued at the same dose received at core end of study (EOS). Patients with LIC 3–15 or >15 mg Fe/g dw received deferasirox 10 or 20 mg/kg/day in the extension, respectively. After 6 months extension, patients with LIC <3 mg Fe/g dw at month 18 interrupted treatment; patients with LIC >7 mg Fe/g dw at month 18 and with LIC reduction <15% compared with core EOS received dose escalation up to a max of 20 mg/kg/day provided no safety issues. If serum ferritin fell <100 ng/mL, drug was withheld. Primary efficacy endpoint was number of patients with LIC <5 mg Fe/g dw by extension end. “Deferasirox” patients refer to combined core + extension. Patients treated with PBO during the core who had the option to enter the extension and be treated with deferasirox are referred to as “PBO/DFX” patients.

Results:
166 patients enrolled in the core study (deferasirox: 110; PBO: 56). 133/148 who completed the core entered the extension (deferasirox: 85; 48 PBO/DFX); 15 did not enrol in the extension (mainly due to extension amendment not approved when patients reached core EOS [n=8] and not interested in continuing [n=5]). 130 patients (84 [98.8%] deferasirox; 46 [95.8%] PBO/DFX) completed the extension; 1 patient discontinued in the deferasirox group (due to AE), 2 patients discontinued in the PBO/DFX group (due to AE [n=1], local admin problem [n=1]). Mean actual deferasirox dose was 9.8 ± 3.6 mg/kg/day (median 9.5) in core + extension; 12.6 ± 4.5 mg/kg/day (median 10.8) in the extension (n=82) and 13.7 ± 4.6 mg/kg/day (median 14.0) in patients who crossed over from PBO to deferasirox in the extension, notably higher than those continuing on deferasirox (Figure).

Deferasirox group (core + extension n=110)
Mean absolute change in LIC from BL to month 24 was –7.14 mg Fe/g dw (Figure). By EOS, 43 (39.1%), 18 (16.4%) and 80 (72.7%) patients achieved a LIC<5, <3 and LIC decrease ≥3 mg Fe/g dw, respectively. In patients with BL LIC>7 mg Fe/g dw, 51/92 (55.4%) achieved LIC ≤7 at EOS. Median change in serum ferritin from BL to EOS was –450 ng/mL. Most common AEs regardless of study drug relationship: upper respiratory tract infection (20.9%), pyrexia (17.3%), diarrhea (13.6%), headache and nausea (both 12.7%), upper abdominal pain, anemia and gastroenteritis (11.8%); serious AEs (>2%): gastroenteritis (6.4%), pyrexia (3.6%), anemia (2.7%). 5 (4.5%) patients had serum creatinine increases >33% above BL and above ULN at ≥2 consecutive visits. One patient had ALT increase >5 × ULN and >2 × BL.

PBO/DFX group (core + extension n=56)
21 (37.5%), 6 (10.7%) and 36 (66.1%) patients achieved LIC<5, <3 and LIC decrease ≥3 mg Fe/g dw, respectively. In patients with BL LIC>7 mg Fe/g dw, 17/42 (40.5%) achieved LIC ≤7 at EOS. Patients who crossed over from PBO to deferasirox entered the extension with a higher extension BL LIC than those continuing on deferasirox. Most common AEs regardless of study drug relationship: pyrexia (26.8%), upper respiratory tract infection (25.0%), diarrhea, headache, nausea (21.4%), abdominal pain (16.1%), vomiting, cough (14.3%).

Conclusions:
In iron-overloaded NTDT patients treated with deferasirox in the core study, LIC continued to decrease in the extension with 39.1% and 16.4% of patients reaching LIC <5 and <3 mg Fe/g dw, respectively, over 2 years. In patients originally randomized to PBO, whose LIC had increased by core EOS, LIC decreased with deferasirox in the extension. Data confirm deferasirox efficacy in reducing iron overload in NTDT, with a safety profile over 2 years consistent with that in the core study.

Disclosures:
Taher: Novartis: Honoraria, Research Funding. Off Label Use: Exjade is indicated for the treatment of chronic iron overload due to frequent blood transfusions. This abstract describes off-label use of Exjade in patients with non-transfusion-dependent thalassemia syndromes with iron overload. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Viprakasit:GPO, Thailand: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kattamis:Novartis: Honoraria, Research Funding, Speakers Bureau. Chuncharunee:Novartis: Research Funding. Sutcharitchan:Novartis: Research Funding. Siritanaratkul:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Galanello:Ferrokin: Research Funding; Apopharma: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Karakas:Novartis: Honoraria. Lawniczek:Novartis: Employment. Habr:Novartis: Employment. Ros:Novartis: Employment. Zhu:Novartis: Employment. Cappellini:Novartis: Speakers Bureau.