Optimizing Iron Chelation Therapy with Deferasirox for Non-Transfusion-Dependent Thalassemia Patients: 1-Year Results from the Phase IV, Open-Label Thetis Study

Background: Efficacy and safety of iron chelation with deferasirox (Exjade^®; DFX) 5 and 10 mg/kg/day (escalated to max: 20 mg/kg/day) in non-transfusion-dependent thalassemia patients, was established in the placebo-controlled, THALASSA study; Taher et al Blood 2012;120:970–977. THETIS added to this evidence by investigating a broader patient population, including non-transfusion-dependent congenital anemia patients and those treated with concomitant medications (eg hydroxyurea) and by evaluating early escalation with higher DFX doses according to liver iron concentration (LIC; max: 30 mg/kg/day).

Methods: Patients ≥10 yrs of age 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 >ULN, creatinine clearance ≤40 mL/min, or urine protein/urine creatinine ratio >1.0 mg/mg. All patients started DFX at 10 mg/kg/day. At week 4, DFX was increased according to baseline (BL) LIC: LIC >15, 20 mg/kg/day; LIC >7–≤15, 15 mg/kg/day; LIC ≥5–≤7, 10 mg/kg/day. At week 24, DFX 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 ng/mL, therapy was held and restarted at the previously effective dose when LIC ≥5 and SF ≥300 ng/mL (max 10 mg/kg/day). The primary efficacy endpoint was absolute change in LIC from BL to week 52. Secondary endpoints included absolute change in LIC from BL to week 24 and change in SF from BL to week 52.

Results: 134 patients were enrolled consisting of β thalassemia intermedia (n=69), Hb H disease (n=40), Hb E/β thalassemia (n=24) and congenital dyserythropoietic anemia (n=1) patients. Mean actual daily DFX dose ± SD over 1 yr (considering dose adjustments) was 14.70 ± 5.48 mg/kg/day. Mean LIC ± SD decreased significantly from 15.13 ± 10.72 mg Fe/g dw at BL to 8.46 ± 6.25 mg Fe/g dw at week 52 (absolute change, ‒6.68 ± 7.02 mg Fe/g dw [95% CI: –7.91, –5.45]; P<0.0001). At the last assessment, an absolute decrease in LIC of ≥3 mg Fe/g dw was observed in 86 (64.2%) patients and a ≥30% relative reduction in LIC in 81 (60.4%) patients. Reduction in LIC was greater in patients with higher BL LIC, with these patients receiving a higher than average dose (Figure). Median SF (range) decreased from 1001 (232–6638) ng/mL at BL to 669 (200–4315) ng/mL at week 52 (absolute median change, –304 [–5307 to –1669] ng/mL).

112 (83.58%) patients completed 1 yr. Patients discontinued primarily because of withdrawal of consent (n=10, personal/logistical reasons). Adverse events (AE) regardless of causality were reported in 97 (72.4%) patients and were unaffected by average dose. AEs with a suspected relationship to DFX were reported in 42 (31.3%) patients; most commonly, gastrointestinal (abdominal discomfort, diarrhea, nausea; n=6 each). One patient had a suspected drug-related serious AE (pancreatitis) that lasted 11 days; DFX was withheld for the duration, then restarted. One patient discontinued because of an AE (extramedullary hematopoiesis) and one death occurred (pneumonia leading to cardiac failure); neither suspected as drug-related. One patient had an elevated BL ALT 2×ULN that increased to >5×ULN on one occasion; BL bilirubin levels were 2×ULN and alkaline phosphatase 1.5×ULN; without dose adjustment or interruption, all parameters improved better than baseline values by week 52. No patient had two consecutive serum creatinine increases >33% above BL or >ULN. All patients with notable renal or liver laboratory values continued treatment.

Conclusions: DFX 10 mg/kg/day (escalated to max: 30 mg/kg/day) resulted in significant and clinically relevant reductions in iron overload, with a similar safety profile as reported in THALASSA (in both DFX- and placebo-treated patients). With early dose escalation at week 4 with further adjustment at week 24, patients with a higher iron burden received higher DFX doses. These results support early dose escalation of DFX to optimize chelation in more heavily iron-overloaded patients with non-transfusion-dependent anemias.