Elara: A Phase 2 Trial Investigating The Efficacy And Safety Of Tisagenlecleucel In Adult Patients With Refractory/Relapsed Follicular Lymphoma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149492/1/hon6_2632.pd

Deferasirox significantly reduces liver iron concentration in non-transfusion-dependent thalassemia patients with iron overload : results from the 1-year randomized, double-blind, placebo-controlled phase II THALASSA Study

Background: Patients with thalassemic syndromes who require occasional or no blood transfusions are still at risk of iron overload (primarily from increased intestinal iron absorption caused by ineffective erythropoiesis) and associated serious complications. Iron chelation therapy (ICT) is the only option for decreasing iron burden, as phlebotomy is contraindicated due to anemia. The THALASSA 1-yr, randomized, double-blind, placebo-controlled study assessed efficacy and safety of deferasirox (DFX; Exjade\uae, once-daily oral iron chelator) in iron-overloaded patients with non-transfusion-dependent thalassemia (NTDT). Methods: NTDT patients aged 6510 yrs with liver iron concentration (LIC) 655 mg Fe/g dry weight (dw) and serum ferritin (SF) >300 ng/mL were enrolled and randomized 2:1:2:1 to starting doses of DFX/placebo 5 mg/kg/day or DFX/placebo 10 mg/kg/day. Patient inclusion/exclusion criteria were reported previously (Taher et al. Blood 2009;114(22):abst 5111). DFX dose could be doubled at 24 wks in patients with insufficient response (LIC >7 mg Fe/g dw and reduction <15% compared to baseline [BL]). The primary efficacy endpoint was change in LIC from BL to 1 yr calculated as least squares mean (LSM) based on ANCOVA adjusted for BL LIC. Other endpoints included change from BL in SF (LSM for quarterly SF changes), patients with LIC decrease 653 mg Fe/g dw or 6530% from BL and DFX safety. Results: 166 patients with \u3b2-thalassemia intermedia (n=95), \u3b1-thalassemia (n=22) or HbE/\u3b2-thalassemia (n=49) were randomized to starting DFX doses of 5 mg/kg/day (n=55) or matching placebo (n=28) and 10 mg/kg/day (n=55) or matching placebo (n=28). After 24 wks, 48.8% of all patients had a dose increase (47.3 and 45.5% in the DFX 5 and 10 mg/kg/day groups, respectively) resulting in an average actual dose (mean \ub1 SD) of 5.6 \ub1 1.4 and 11.5 \ub1 2.9 mg/kg/day, respectively. At 1 year, LIC significantly decreased by \u20131.95 mg Fe/g dw (95% CI: \u20132.94, \u20130.96; BL: 13.11) and \u20133.80 mg Fe/g dw (95% CI: \u20134.76, \u20132.85; BL: 14.56) in the DFX 5 and 10 mg/kg/day groups, compared with an increase of 0.38 mg Fe/g dw (95% CI: \u20130.59, 1.34; BL: 15.94) in the placebo (Figure 1A); the difference between DFX 5 and 10 mg/kg/day groups vs placebo was significant (\u20132.33 mg Fe/g dw, P=0.001 and \u20134.18 mg Fe/g dw, P<0.001, respectively). At 1 yr, the percentage of patients with LIC decrease 653 mg Fe/g dw from BL was greater in the DFX 5 and 10 mg/kg/day cohorts (32.7% and 56.4%) compared to placebo (10.7%). In addition, more patients in DFX 5 and 10 mg/kg/day cohorts achieved LIC reduction 6530% from BL (25.5% and 49.1%) compared to placebo (1.8%). Mean serum ferritin significantly decreased at 1 yr: \u2013121 ng/mL (95% CI: \u2013203, \u201338) and \u2013222 ng/mL (95% CI: \u2013304, \u2013140) for DFX 5 and 10 mg/kg/day groups (Figure 1B) while there was an increase in the placebo (115 ng/mL: 95% CI: 33, 196); difference vs placebo was significant (\u2013235 ng/mL, P<0.001 and \u2013337 ng/mL, P<0.001 for DFX 5 and 10 mg/kg/day, respectively). 148 (89.2%) patients completed 1 yr. In the placebo, DFX 5 and 10 mg/kg/day groups 8.9, 12.7 and 10.9% of patients discontinued, most commonly due to AEs (1.8, 3.6 and 5.5%, respectively). In addition, 1 patient (1.8%) in the placebo arm discontinued due to an abnormal lab value (low hemoglobin). Overall AE rates were 80.4, 76.4 and 78.2% in the placebo, DFX 5 and 10 mg/kg/day groups, respectively. The most common investigator-assessed drug-related AEs in the overall placebo (n=56), DFX 5 and 10 mg/kg/day groups, respectively, were nausea (7.1, 5.5 and 7.3%), rash (1.8, 3.6 and 9.1%), diarrhea (1.8, 0 and 9.1%), headache (3.6, 3.6 and 1.8%) and upper abdominal pain (0, 3.6 and 1.8%). Serious AEs were reported in 14.3, 12.7 and 16.4% of patients in the placebo, DFX 5 and 10 mg/kg/day groups, respectively. 3 (5.5%) DFX-treated patients (DFX 10 mg/kg/day) had 2 consecutive serum creatinine level increases >33% above BL and >upper limit of normal (ULN). 1 patient in the placebo group had an ALT increase >5 x ULN and >2 x BL and 2 patients had an AST increase to >5 x ULN and > 2 x BL, 1 in the DFX 10 mg/kg/day and 1 in the placebo group. Conclusions: This first randomized, placebo-controlled study evaluating ICT in NTDT patients confirms that these patients have high LIC despite moderately elevated SF, thus highlighting the need for ICT. Compared to placebo, 1-year DFX at starting doses of 5 and 10 mg/kg/day escalated to 10 and 20 mg/kg/day significantly reduced LIC and SF, along with a similar frequency of overall AE

Deferasirox effectively reduces iron overload in non-transfusion-dependent thalassemia (NTDT) patients: 1-year extension results from the THALASSA study

Patients with non-transfusion-dependent thalassemia (NTDT) often develop iron overload that requires chelation to levels below the threshold associated with complications. This can take several years in patients with high iron burden, highlighting the value of long-term chelation data. Here, we report the 1-year extension of the THALASSA trial assessing deferasirox in NTDT; patients continued with deferasirox or crossed from placebo to deferasirox. Of 133 patients entering extension, 130 completed. Liver iron concentration (LIC) continued to decrease with deferasirox over 2 years; mean change was -7.14 mg Fe/g dry weight (dw) (mean dose 9.8 ± 3.6 mg/kg/day). In patients originally randomized to placebo, whose LIC had increased by the end of the core study, LIC decreased in the extension with deferasirox with a mean change of -6.66 mg Fe/g dw (baseline to month 24; mean dose in extension 13.7 ± 4.6 mg/kg/day). Of 166 patients enrolled, 64 (38.6 %) and 24 (14.5 %) patients achieved LIC &lt;5 and &lt;3 mg Fe/g dw by the end of the study, respectively. Mean LIC reduction was greatest in patients with the highest pretreatment LIC. Deferasirox progressively decreases iron overload over 2 years in NTDT patients with both low and high LIC. Safety profile of deferasirox over 2 years was consistent with that in the core study. © 2013 The Author(s)

Deferasirox reduces iron overload significantly in nontransfusion-dependent thalassemia : 1-year results from a prospective, randomized, double-blind, placebo-controlled study

Nontransfusion-dependent thalassemia (NTDT) patients may develop iron overload and its associated complications despite receiving only occasional or no transfusions. The present 1-year, randomized, double-blind, placebo-controlled THALASSA (Assessment of Exjade in Nontransfusion-Dependent Thalassemia) trial assessed the efficacy and safety of deferasirox in iron-overloaded NTDT patients. A total of 166 patients were randomized in a 2:1:2:1 ratio to starting doses of 5 or 10 mg/kg/d of deferasirox or placebo. The means \ub1 SD of the actual deferasirox doses received over the duration of the study in the 5 and 10 mg/kg/d starting dose cohorts were 5.7 \ub1 1.4 and 11.5 \ub1 2.9 mg/kg/d, respectively. At 1 year, the liver iron concentration (LIC) decreased significantly compared with placebo (least-squares mean [LSM] \ub1 SEM, -2.33 \ub1 0.7 mg Fe/g dry weight [dw], P = .001, and -4.18 \ub1 0.69 mg Fe/g dw, P < .001) for the 5 and 10 mg/kg/d deferasirox groups, respectively (baseline values [means \ub1 SD], 13.11 \ub1 7.29 and 14.56 \ub1 7.92 mg Fe/g dw, respectively). Similarly, serum ferritin decreased significantly compared with placebo by LSM -235 and -337 ng/mL for the deferasirox 5 and 10 mg/kg/d groups, respectively (P < .001). In the placebo patients, LIC and serum ferritin increased from baseline by 0.38 mg Fe/g dw and 115 ng/mL (LSM), respectively. The most common drug-related adverse events were nausea (n = 11; 6.6%), rash (n = 8; 4.8%), and diarrhea (n = 6; 3.6%). This is the first randomized study showing that iron chelation with deferasirox significantly reduces iron overload in NTDT patients with a frequency of overall adverse events similar to placeb