Received: October 15, 2018
Accepted: September 15, 2018
Mediterr J Hematol Infect Dis 2018, 10(1): e2018066 DOI 10.4084/MJHID.2018.066
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incorporates a broad clinical spectrum characterized by decreased or
absent production of normal hemoglobin leading to decreased red blood
cell survival and ineffective erythropoiesis. Chronic iron overload
remains an inevitable complication resulting from regular blood
transfusions (transfusion-dependent) and/or increased iron absorption
(mainly non-transfusion-dependent thalassemia), requiring adequate
treatment to prevent the significant associated morbidity and
mortality. Iron chelation therapy has become a cornerstone in the
management of thalassemia patients, leading to improvements in their
outcome and quality of life. Deferasirox (DFX), an oral iron chelating
agent, is approved for use in transfusion dependent and
non-transfusion-dependent thalassemia and has shown excellent efficacy
in this setting. We herein present an updated review of the role of
deferasirox in thalassemia, exploring over a decade of experience,
which has documented its effectiveness and convenience; in addition to
its manageable safety profile.
Pathophysiology of IOL in Thalassemia
Diagnosis and Quantification of IOL
Pharmacokinetics of DFX
Evidence in TDT
Monotherapy. DFX at 20 mg/kg/d had shown similar efficacy to DFO at 40 mg/kg/d in reducing LIC. The prospective ESCALTOR trial reported sustained reduction in LPI levels in a group of β- thalassemia patients with significant IOL with a mean decrease in LIC by 3.8 mg iron/g dw, and SF by 517 ng/ml.[30,36] Two-year treatment with DFX leads to a reduction of iron levels in those whose baseline LIC ≥7 mg iron/g dw while maintaining iron levels in those with baseline LIC < 7 mg/g dw. An initial phase II trial in pediatric patients with TDT had shown that low doses of DFX were associated with limited efficacy. These results were also replicated in a large randomized phase III study including 586 pediatric and adult patients with β-thalassemia who achieved a significant reduction in SF and LIC with DFX at doses of 20-30 mg/kg/d, while doses of 10 mg/kg/d showed inadequate efficacy in regularly transfused patients. Sustained improvements in iron burden were noted with follow up to 5 years, where 83% achieved SF ≤2500 ng/ml, 47.3% of patients reaching SF≤1000 ng/ml after 4 years, with more than half of patients receiving a final dose of DFX ≥25 mg/kg/d during the extension period. While doses of 20 mg/kg/d have maintained an LIC below 7 mg/g dw, higher doses of around 30 mg/kg/d have been required to achieve a net reduction in iron levels in those with LIC ≥ 7 mg/g dw.[40,41] This large prospective trial included 1115 patients with β-thalassemia and showed a statistically significant decrease in SF with DFX therapy. In addition, it indicated the need to choose a starting dose that correlates with the patient’s transfusion requirements, and that needs to be titrated in a timely manner. At least three years of DFX lead to reversal or stabilization of liver fibrosis in TDT patients showing evidence of IOL. A systematic review and meta-analysis including 1520 patients with TDT also showed increases in SF at lower DFX doses, but no significant difference in the change in SF with DFX at 30 mg/kg as compared to DFO. JaiSwal et al. later reported a significant mean reduction in SF of 1207.11 ng/ml (32.38% decrease) after 12 months therapy with DFX at a mean dose of 38 mg/kg/d in 45 heavily transfused thalassemia patients. A prospective observational study including 176 patients with TDT (total 267), reported long-term results in pediatric patients treated with DFX and documented a decrease in median SF of 575 ng/ml after five years of DFX therapy with a mean dose of 25.8 mg/kg/d. A Cochrane review reported by Bollig et al. indicated similar efficacy of DFX as compared to DFO (depending on the ratio of DFX to DFO dose, generally showing similar results at a mean ratio of 1 mg of DFX to 1.8 mg of DFO).
DFX has also been effective in the management of cardiac siderosis. Wood et al. have reported an improvement in myocardial T2* in patients with severe cardiac siderosis treated for 18 months with DFX at doses up to 40 mg/kg/d (13 patients). DFX also led to normalization of cardiac T2* in 68% of patients with a baseline level of 10-20 ms, and sustained improvements with prolonged duration of therapy. The phase II CORDELIA trial documented non-inferiority of DFX compared to DFO in the management of β-thalassemia major asymptomatic patients with cardiac IOL (T2* 6-20 ms), with a 12% increase in the geometric mean (Gmean ) myocardial T2*. On the other hand, the MILE study has shown that DFX at similar doses lead to a 10% relative improvement in myocardial T2*, with the most significant results noted in those with moderate cardiac siderosis and those with lower baseline LIC, while no significant changes were reported in cases of severe cardiac iron deposition. Greater improvement in LIC and myocardial T2* were noted with higher doses of DFX (above 30 mg/kg/d). This study also showed statistically significant improvement in LIC, specifically those with baseline LIC ≥7 mg/g dw, with a statistically insignificant reduction in SF, and no major safety concerns. DFX has also resulted in the greatest improvement in the prevalence of endocrinopathy, in addition to a significant improvement noted on bone mineral density evaluation as compared to DFO, DFP and DFO combined with DFP in a retrospective study.
Safety of DFX
Less common AEs include ocular and visual disturbances, cytopenia, and Fanconi syndrome. For pediatric patients, Vichinsky et al. reported AEs with suspected relation to DFX in 39.1% of patients with nine patients having a serious AE (3.4%), with a gradual decline in the incidence of AEs over time. Osborne et al. recently reported the utilization and safety of DFX using an observational post-marketing study conducted in England. Beta-thalassemia was the second most frequent reason for prescribing DFX (26 patients; 21.3%), and increased creatinine was noted in only two patients out of 122 (1.6%). The EPIC trial had reported a 0.6% of proteinuria after 1-year follow up. Bayhana et al later evaluated the prevalence and need for monitoring of proteinuria in thalassemia patients on DFX therapy, where a retrospective single center analysis including 37 total patients (36 with thalassemia major), reported proteinuria in 7 patients (18.9%) at a mean follow up of 44 months, all of which resolved with follow up. This analysis identified younger age (below 23) and higher doses of DFX (above 29 mg/kg/d) as risk factors for the development of proteinuria. A retrospective chart review recently reported safety data for prolonged follow-up periods reaching 13 years, including 282 patients, with no significant or persistent nephrotoxicity noted and only non-progressive and reversible increases in creatinine.
DFO and DFX
DFP and DFX
DFX in the Post-transplantation Setting
DFX in NTDT
Guidelines with specific indications/thresholds have been established to determine the appropriate time for initiation, dose escalation, and termination of ICT in NTDT patients. DFX with an initial starting dose of 10 mg/kg/d should be started in patients ≥10 years of age if their LIC ≥ 5 mg iron/g dw, or if their SF concentration was found to be ≥ 800 μg/L (if LIC is not available due to MRI unavailability). To monitor iron levels, LIC should be repeated six months after therapy initiation, with follow up every 6–12 months, and SF levels should be measured every three months. If LIC levels at six months are still greater than 7 mg/g dw (or SF >1500 μg/L only if LIC is unavailable) with less than 15% reduction in baseline values, dose escalation should be considered up to 20 mg/kg/d. DFX therapy can be safely discontinued when patients reach an LIC value of 3 mg/g dry weight (or SF level of 300 μg/L only if LIC is unavailable). In the realm of NTDT, it is recommended to intensify ICT if the LIC after six months of treatment >7 mg/g dw, SF >1500–2000 ng/mL or in case of <15% decrease from baseline. Indications to stop ICT in NTDT include a SF < 300 ng/mL and/or LIC < 3 mg/g dry wt. liver.
Adherence to ICT
DFO therapy, owing largely to its cumbersome administration, has a detrimental impact on multiple areas of patients’ lives, including their emotional well-being, physical functioning, self- esteem, among others. Treatment with DFO is demanding. The drug has poor oral bioavailability and a short plasma half-life. Therefore, slow subcutaneous infusions are necessary 3–7 times weekly. Because of injection-site reactions and pain, the administration is inconvenient, and the necessary equipment is not available in many countries. These factors lead to poor compliance, which in turn leads to increased mortality. Treatment satisfaction and adherence are generally greater with oral ICT than with parenteral infusion. One study showed that adherence to oral DFX monotherapy was significantly higher than DFO infusion (96% vs. 92%; p<0.001). Adherence to oral DFX on DFO/DFX combination therapy was lower than that of monotherapy (90% vs. 96%; p<0.001). Adherence to DFO infusion on DFO/DFP combination therapy was non- significantly lower than that of monotherapy or DFO/DFX combination therapy (88% vs. 92%; p=0.25). Adherence did not significantly change over follow-up period except that an increase in adherence was seen after a change in chelation from DFO infusion to oral DFX (p=0.03, paired t- test). In a qualitative examination of the reported patient adherence over time after this iron chelator change, no evidence of a ‘honeymoon’ phase was seen, with temporary high adherence to the new chelator. In an open-ended comment section, many participants commented on the benefits of oral chelation and their improved adherence.
Another study by Cappellini et al., compared patient-reported outcomes (PROs) during receipt of DFO infusions or once-daily DFX oral therapy. PRO questionnaires were completed by patients, their parents or legal guardian at different time points: baseline, week 4, week 24, and end of study (EOS). Patients assessed their satisfaction level with study treatment (very satisfied, satisfied, neutral, dissatisfied, or very dissatisfied) and rated its convenience. At baseline, 289 and 282 patients in the DFX and DFO groups, respectively, had previous experience with DFO (7 and 8 patients, respectively were DFO-naïve); of these patients, 45.3% and 45.0%, respectively, reported that they were very satisfied or satisfied with DFO treatment, while 32.5% and 33.0% reported being dissatisfied or very dissatisfied. There were no significant differences in the satisfaction ratings between the groups at baseline. At week 4, week 24, and EOS, significantly more patients receiving DFX reported being very satisfied or satisfied with treatment compared with those receiving DFO (92.0% vs 50.4% and 89.6% vs 44.0%, respectively; P < 0.001). At each time point, more patients receiving DFO reported being dissatisfied or very dissatisfied with treatment compared with those receiving DFX (28.0% vs. 0.7% and 31.2% vs. 2.4%). When considering only those patients who responded to the question at EOS, the overall proportion of patients who were satisfied with treatment was 88.8% (246/277) for DFX and 40.5% (109/269) for DFO. Results of this study suggested that DFX had a positive impact on patients' daily lives. A recent Cochrane review exploring the interventions needed for improving adherence to ICT in patients with thalassemia or sickle cell disease concluded that real-life data is required to assess specific adherence strategies and thus make recommendations in this setting.
Recent Advances in ICT
DFX film coated tablet (FCT)
The open-label, phase II ECLIPSE study evaluated the overall safety profile, as measured by the frequency and severity of AEs and changes in laboratory values, and the pharmacokinetics (PK), and PROs of DFX FCT and DT formulations in patients aged ≥10 years with TDT or very-low-, low-, or intermediate-risk MDS, requiring ICT. The overall incidence of AEs was similar between treatments, but there were fewer serious AEs with FCT. FCT recipients consistently reported better adherence, greater satisfaction, and fewer concerns, with a safety profile consistent with the known DT formulation. Taking the dose conversion factor into account, which was required because the two formulations have differing bioavailability, patients received similar mean doses of the active ingredient in DFX. However, at the end of the 24-week trial period, FCT patients had a higher observed median absolute reduction in SF from baseline, suggesting a possible association between the treatment arm and observed efficacy. A potential explanatory factor of this difference in efficacy could be better treatment adherence among the patients receiving FCT compared with DT. These findings suggest a preference in favor of the new formulation, with better patient satisfaction and adherence translating into reduced IOL-related complications.
Table 1 includes significant trials evaluating DFX in TDT and NTDT, and figure 1A and B includes recommendations regarding chelation with DFX and suggested monitoring and/or adjustments.
|Table 1. Significant trials evaluating DFX in TDT and NTDT.|
|Figure 1A. DFX in thalassemia.|
|Figure 1B. Monitoring for and managing adverse events with DFX.|
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