Cappellini and colleagues1 recently published the results of the first large, randomized phase 3 trial comparing deferoxamine (DFO) and deferasirox, a trial designed to demonstrate the efficacy of deferasirox in regularly transfused patients with β-thalassemia. The efficacy of a drug is its ability to produce a specific effect in a specific patient population. Effectiveness is a measure of efficacy in the “real world,” outside the bounds of a randomized clinical trial; it explores compliance, generalizability, and external validity.2 DFO is efficacious, but its effectiveness is limited mainly by poor compliance. It is anticipated that deferasirox, as a once-daily oral medication, might exhibit improved effectiveness over DFO.
In the trial by Capellini and colleagues, when the primary end-point analysis failed to prove noninferiority despite adequate power, the data were reanalyzed using a nonprespecified subgroup analysis to show noninferiority in those patients with baseline liver iron concentrations of 7 mg Fe/g dry weight (dw) or higher dosed with 20 to 30 mg/kg deferasirox, thereby retrospectively excluding approximately 30% of the patients randomized to the deferasirox arm. The reported tolerability and safety data, on the other hand, take into account the entire patient population randomized to take deferasirox, not the nonprespecified subgroup, in which noninferiority to DFO was demonstrated. In order to provide a better understanding of the potential effectiveness of deferasirox, it would be helpful to report the compliance, tolerability, and adverse event rate data stratified by dose.
Deferasirox (ICL670) is clinically effective and generally well tolerated, and demonstrates dose-responsiveness
As Martin and Arcasoy observed, noninferiority to deferoxamine (DFO) was demonstrated in patients with baseline liver iron concentrations (LICs) of 7 mg Fe/g dry weight or greater (71% of the deferasirox-treated population), who were assigned doses of 20 or 30 mg/kg per day. We agree it is useful to determine both the efficacy and effectiveness of deferasirox and to review tolerability and safety data by dose.
It is generally recognized that randomized, controlled clinical trials are inadequate to measure “real-world” compliance and that drug counts do not effectively measure compliance. We collected actual feedback from patients by measuring satisfaction with and convenience of treatment. Significantly more patients receiving deferasirox, all of whom had previous experience with DFO, were satisfied with treatment and found it to be more convenient than DFO.1 Patients also found that deferasirox had less effect on daily life, and many more patients were willing to continue deferasirox after the end of the study; similar results have been observed in patients with sickle cell disease.2 These results could provide important information for clinical practice. Superior satisfaction with and convenience of deferasirox therapy versus DFO may translate into actual patient compliance and may therefore increase the effectiveness of chelation therapy, optimizing the outcome of iron-overloaded, transfusion-dependent patients.
Deferasirox treatment was generally well tolerated in patients aged 2 years and older. Dose adjustments/interruptions (36.8% versus 33.1%, respectively) and discontinuations (5.7% versus 4.1%, respectively) were similar with deferasirox and DFO (Table 1). We note that adjustments in the groups given 5 or 10 mg/kg per day were primarily due to insufficient dosing rather than safety concerns (87.5% and 42.7%, respectively).
Tolerability and safety parameters, stratified by dose
. | . | Initial deferasirox dose, mg/kg/d . | . | . | . | |||
|---|---|---|---|---|---|---|---|---|
. | Total . | 5 . | 10 . | 20 . | 30 . | |||
| Total no. of patients | 296 | 15 | 78 | 84 | 119 | |||
| Mean dose ± SD, mg/kg/d | 19.9 ± 8.3 | 6.2 ± 1.6 | 10.2 ± 1.2 | 19.4 ± 1.7 | 28.2 ± 3.5 | |||
| Dose adjustments, no. of patients (%) | 109 (36.8) | 8 (53.3) | 24 (30.8) | 28 (33.3) | 49 (41.2) | |||
| Discontinuations, no. of patients (%) | 17 (5.7) | 0 (0) | 8 (10.3) | 3 (3.6) | 6 (5.0) | |||
| GI events, no. of patients (%)* | 45 (15.2) | 1 (6.7) | 9 (11.5) | 12 (14.3) | 23 (19.3) | |||
| Skin rash, no. of patients (%)† | 32 (10.8) | 0 (0) | 8 (10.3) | 7 (8.3) | 17 (14.3) | |||
| Nonprogressive creatinine increases, no. of patients (%)† | 113 (38.3) | 1 (6.7) | 15 (19.2) | 33 (39.3) | 64 (53.8) | |||
| Increases above ULN, no. of patients (%) | 7 (2.4) | 0 (0) | 0 (0) | 3 (3.6) | 4 (3.4) | |||
. | . | Initial deferasirox dose, mg/kg/d . | . | . | . | |||
|---|---|---|---|---|---|---|---|---|
. | Total . | 5 . | 10 . | 20 . | 30 . | |||
| Total no. of patients | 296 | 15 | 78 | 84 | 119 | |||
| Mean dose ± SD, mg/kg/d | 19.9 ± 8.3 | 6.2 ± 1.6 | 10.2 ± 1.2 | 19.4 ± 1.7 | 28.2 ± 3.5 | |||
| Dose adjustments, no. of patients (%) | 109 (36.8) | 8 (53.3) | 24 (30.8) | 28 (33.3) | 49 (41.2) | |||
| Discontinuations, no. of patients (%) | 17 (5.7) | 0 (0) | 8 (10.3) | 3 (3.6) | 6 (5.0) | |||
| GI events, no. of patients (%)* | 45 (15.2) | 1 (6.7) | 9 (11.5) | 12 (14.3) | 23 (19.3) | |||
| Skin rash, no. of patients (%)† | 32 (10.8) | 0 (0) | 8 (10.3) | 7 (8.3) | 17 (14.3) | |||
| Nonprogressive creatinine increases, no. of patients (%)† | 113 (38.3) | 1 (6.7) | 15 (19.2) | 33 (39.3) | 64 (53.8) | |||
| Increases above ULN, no. of patients (%) | 7 (2.4) | 0 (0) | 0 (0) | 3 (3.6) | 4 (3.4) | |||
ULN indicates upper limit of normal.
Drug-related AEs only.
All AEs, irrespective of relationship to study drug.
The most common deferasirox-related adverse events (AEs) were mild to moderate transient gastrointestinal (GI) events. Skin rash and mild, nonprogressive dose-dependent serum creatinine increases were also observed in deferasirox-treated patients (Table 1). Regarding the creatinine increases, it is possible that the glomerular filtration rate is reset as observed with other drugs such as ACE (angiotensin converting enzyme) inhibitors.3 Preliminary analyses indicate that the volume of blood transfused is inversely related to nonprogressive creatinine increases; further analyses to fully evaluate this relationship are ongoing.
A clear dose response was observed with no reduction in efficiency, indicating that the dose of deferasirox can be tailored for each patient depending on her or his need (ie, maintenance or reduction of body iron levels). We note that the response to deferasirox is not only influenced by dose but also by the rate of transfusional iron intake.4,5 This factor must also be considered when defining the therapeutic dose for a patient.
In closing, deferasirox doses of at least 30 mg/kg per day are generally well tolerated in β-thalassemia patients as young as 2 years. The overall discontinuation rate with deferasirox was low, and most reported AEs were transient and managed by dose modification or comedication. It is thought that, in clinical practice, the low discontinuation rate will be reproduced, and that the greater satisfaction and convenience compared with DFO will translate into improved patient compliance. This should lead to increased effectiveness compared with current chelation therapy.
Correspondence: Maria Domenica Cappellini, Università di Milano, Via f Sforza 35, Fondazione Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena IRCCS, 20122 Milan, Italy; e-mail: maria.cappellini@unimi.it.
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