Efficacy and Safety of Deferasirox Across Underlying Non-Transfusion-Dependent Thalassemia Syndromes: 1-Year Results from the Thetis Study

Background: THALASSA demonstrated consistent efficacy and safety of iron chelation therapy with deferasirox (Exjade^®) across underlying non-transfusion-dependent thalassemia syndromes: β thalassemia intermedia (β TI), Hb E/β thalassemia and α thalassemia (Hb H disease); Taher et al AJH 2013;88:503–506. THETIS added to this evidence by investigating a broader patient population (including non-transfusion-dependent congenital anemias and those treated with concomitant medications [eg hydroxyurea]) and by evaluating early escalation with higher deferasirox doses (LIC; max: 30 mg/kg/day) according to baseline liver iron concentration. Here, we report 1-year efficacy and safety findings from THETIS by underlying non-transfusion-dependent anemia.

Methods: Patients aged ≥10 years with iron overload (LIC ≥5 mg Fe/g dry weight [dw]) and serum ferritin (SF) ≥300 ng/mL were enrolled. Exclusion criteria included: blood transfusions within 6 months of study enrollment or anticipated regular transfusions (unplanned transfusions allowed); Hb S/β thalassemia; active hepatitis B/C; cirrhosis; history of clinically relevant ocular and/or auditory toxicity; on two consecutive measurements: alanine aminotransferase (ALT) >5× the upper limit of normal (ULN), serum creatinine (SCr) >ULN, creatinine clearance (CrCl) ≤40 mL/min, or urine protein/urine creatinine ratio (UPCR) >1.0 mg/mg. All patients started deferasirox at 10 mg/kg/day. At week 4, deferasirox was increased according to baseline LIC (LIC >15, 20 mg/kg/day; LIC >7–≤15, 15 mg/kg/day; LIC ≥5–≤7, 10 mg/kg/day). At week 24, deferasirox was adjusted further: LIC >15, +5–10 mg/kg/day (max 30 mg/kg/day); LIC >7–≤15, +5 mg/kg/day (max 20 mg/kg/day); LIC ≥3–≤7, same dose. If LIC <3 or SF <300, therapy was held and restarted at the previously effective dose when LIC ≥5 and SF ≥300 (max 10 mg/kg/day). This analysis evaluated absolute change in LIC and SF from baseline to week 52 by underlying non-transfusion-dependent anemia.

Results: 134 patients with β TI (n=69), Hb H disease (n=40), Hb E/β thalassemia (n=24) and congenital dyserythropoietic anemia (n=1) were enrolled. 39 (56.5%) patients with β TI, 12 (30.0%) with Hb H disease, 12 (50.0%) with Hb E/β thalassemia and 1 (100.0%) with congenital dyserythropoietic anemia received previous chelation therapy. Most patients received prior transfusion therapy: 57 (82.6%) β TI, 36 (90.0%) Hb H disease, 21 (87.5%) Hb E/β thalassemia and 1 (100.0%) congenital dyserythropoietic anemia. Mean actual daily deferasirox dose ± SD over 1 year (including dose adjustments) was: β TI 15.25 ± 5.64 mg/kg/day; Hb H disease 14.34 ± 5.37 mg/kg/day; Hb E/β thalassemia 13.74 ± 5.34 mg/kg/day; congenital dyserythropoietic anemia 14.71 mg/kg/day. Baseline LIC and SF were similar across the different underlying non-transfusion-dependent anemias (Table). Mean LIC ± SD decreased significantly from baseline to week 52 in underlying non-transfusion-dependent thalassemias (Table; Figure). Additionally, median (range) SF decreased in all underlying anemias from baseline to week 52 (Table).

Adverse events (AEs) regardless of study drug relationship were reported in similar proportions of β TI (54 [78.3%]) and Hb E/β thalassemia patients (19 [79.2%]), and in a smaller proportion of patients with Hb H disease (23 [57.5%]). The most common AEs were infections and infestations recorded in 40 patients (26 [37.7%] β TI; 6 [15.0%] Hb H disease; 7 [29.2%] Hb E/β thalassemia; 1 [100%] congenital dyserythropoietic anemia) and gastrointestinal disorders recorded in 38 patients (27 [39.1%]; 6 [15.0%]; 5 [20.8%], respectively). Laboratory investigation AEs (including shifts in ALT, SCr, CrCl and UPCR from baseline) showed similar relative frequencies as the total AE profile across underlying anemias, and were reported in 15 (21.7%) β TI, 5 (12.5%) Hb H disease and 7 (29.2%) Hb E/β thalassemia patients.

Conclusions: Deferasirox at 10 mg/kg/day escalated to a maximum of 30 mg/kg/day resulted in clinically relevant reductions in LIC and SF that were similar across β TI, Hb H disease and Hb E/β thalassemia. The safety profile was consistent across underlying anemias and similar to THALASSA. Patients with Hb H disease appeared to have moderately better LIC and SF reduction and fewer AEs. These results support application of this dosing algorithm across patients with various underlying non-transfusion-dependent congenital anemias.