Deferasirox maintained34,39 or improved35,36 cardiacfunction (ie, LVEF) in these trials. However, appropriatedoses are needed to have an impact on cardiac iron,with doses of 30 mg/kg/day to 40 mg/kg/day shown toreduce cardiac iron, and with doses of 20 mg/kg/day to30 mg/kg/day shown to prevent myocardial ironaccumulation.

Ongoing Clinical Trials
Studies are ongoing to determine long-term benefits andrisks of deferasirox. In 2009, the safety profile of deferasiroxin patients with beta-thalassemia (n=951), MDS (n=584),and other anemias (n=263) was characterized in a 1-yearstudy of pooled data that emphasized renal safety. Resultssuggest deferasirox may be used in patients with a baselinecreatinine clearance of >60 mL/minute, while individualswith a creatinine clearance of 40 mL/min to <60 mL/minneed close monitoring, and those with a creatinine clearanceof <40 mL/min should not receive deferasirox. Inpatients with MDS and liver iron overload, alanine aminotransferaseand aspartate aminotransferase levels decreasedfrom baseline over the study year, indicating iron chelationtherapy improves these markers of liver function.41


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Two observational studies of deferasirox were conductedin 167 patients with MDS: 123 individuals who werechelation-naïve and 44 individuals who had received chelation(80% with deferoxamine) for a median of 2 years(range: 0.3–16.4 years). Those who were chelation-naïvehad a high baseline median serum ferritin level of2679 ng/mL (range, 184 ng/m–16,500 ng/m) at studyentry, indicating that iron chelation therapy was startedrelatively late in this population. Those who had receivedchelation with deferoxamine prior to the study had a medianserum ferritin of 2442 ng/mL (range, 521 ng/mL–8565 ng/mL), suggesting that deferoxamine therapy wassuboptimal in most patients.42 After 1 year of treatmentwith deferasirox, however, serum ferritin levels decreasedsignificantly—by 662 ng/mL in the chelation-naïve populationand by 716 ng/mL in those previously chelated. Inpatients with MDS with transfusion-dependent iron overload,deferasirox substantially reduced serum ferritin levels,indicating that deferasirox was a viable daily treatmentoption. Deferasirox was also safe. The most common drug-relatedadverse events were diarrhea, nausea, and rash.42

A phase II open-label trial (lasting 1 year followed by a2-year extension phase) was conducted to evaluate longtermsafety and tolerability of deferasirox in 83 patientswith low or Int-1 IPSS-risk MDS. Mean age was 68 years(range, 21-90 years) and mean serum ferritin level was3312.7 mcg/L. Despite ongoing transfusion therapy (meanrate of 3.6 units/month), 31 of 50 patients who completed2 years of treatment with deferasirox had a decrease inserum ferritin of at least 200 mcg/L (mean decrease:1088 mcg/L). To determine whether decreases in serumferritin correlate with clinical benefits, a large, prospective,

TABLE 4. Monitoring Treatment With Deferasirox

TEST  FREQUENCY
Complete blood count Monthly or more frequently if patient is at increased risk of complications (eg, preexisting kidney condition, elderly, has multiple medical conditions, or is taking medication that may affect organs)
Serum ferritin Monthly, with dose adjustment based on 3 to 6 month trends
Serum creatinine and creatinine clearance 2 times prior to therapy and monthly thereafter; in patients with underlying renal impairment or risk factors for renal impairment, monitor creatinine and/or creatinine clearance weekly for the first month, then monthly thereafter
Proteinuria Monthly
Liver function (serum transaminase and
bilirubin)
Prior to initiation of therapy; every 2 weeks during the first month; and monthly thereafter
Auditory and ophthalmic Testing recommended prior to therapy and yearly thereafter

Source: Exjade.21

randomized, controlled trial in low and Int-1 MDS patientsis currently enrolling participants.43

MANAGEMENT OF PATIENTS ONDEFERASIROX

Evidence-based guidelines for treating patients with betathalassemia,SCD, and MDS include recommendations formonitoring iron overload when they receive chronic bloodtransfusions. The National Heart, Lung and Blood Instituterecommends that even if patients with SCD receive onlyintermittent transfusions, a comprehensive program tomonitor and treat iron overload is necessary, beginningwith baseline serum ferritin testing at transfusion onset.11The National Comprehensive Cancer Network guidelinesrecommend that patients with low or Int-1 IPSS-risk MDSbe monitored after 20 or more RBC transfusions; whenongoing RBC transfusions are anticipated; and when serumferritin levels are >2500 mcg/L, with the goal of decreasingferritin levels to <1000 mcg/L. The ThalassaemiaInternational Federation recommends serum ferritin andLIC testing as iron chelation regimens are tailored to thespecific needs of individual patients.5

The goal of chelation therapy, regardless of which drug isused, is to provide the maximum therapeutic benefit withthe fewest adverse events. That is a primary reason patientsundergoing daily infusions of deferoxamine are generallyamenable to switching to oral therapy with deferasiroxtablets: studies show that, when compared with deferoxamine,deferasirox was preferred by patients because ofconvenience, no injection-site soreness or other reactionsassociated with infusion therapy, and less daily disruptionof life (more free time and greater mobility from not havingto endure lengthy daily infusions).5,44,45 In addition, patientsatisfaction is higher with deferasirox.44,46

Deferasirox dosages are initiated at 20 mg/kg per day;if the patient does not respond while adhering to andtolerating treatment, slowly titrate up in 5 mg/kg/day to10 mg/kg/day increments over 3 to 6 months accordingto serum ferritin level trends. Doses of up to 40 mg/kg areFDA approved; doses above 40 mg/kg are notrecommended. Deferasirox therapy requires close patientmonitoring, including measurement of serum creatinineand/or creatinine clearance prior to initiation of therapyand monthly thereafter (Table 4).21 Concomitant use ofdeferasirox with cholestyramine may result in a decreasein efficacy of deferasirox. For adults, reduce the daily doseof deferasirox by 10 mg/kg if a rise in serum creatinine to>33% above the average of the pretreatment measurementsis seen at two consecutive visits and cannot be attributedto other causes. For pediatric patients, reduce the dose by10 mg/kg if serum creatinine levels rise above theage-appropriate upper limit of normal at two consecutivevisits.

In clinical trials, elderly patients (eg, ≥65 years), primarilythose with MDS, had a higher frequency of adverse eventsthan younger patients.21 Therefore, elderly patients shouldbe closely monitored for early signs or symptoms of adverseevents that may require a dose adjustment. Elderly patientsare at increased risk for deferasirox toxicity due to thegreater frequency of decreased hepatic, renal, or cardiacfunction, and of concomitant disease or other drugtherapy.

TABLE 5. Management of Common Adverse EventsAssociated With Deferasirox

ADVERSE EVENT  MANAGEMENT RECOMMENDATIONS
Gastrointestinal
  • Take dose in the evening; many patients will sleep through any reactions
Diarrhea
  • Increase dietary bran and fiber
  • If lactose intolerant, avoid dairy products
  • Stay hydrated
  • Take antidiarrheal medications for up to 2 days (not recommended in pediatric patients)
Nausea/vomiting
  •  Stay hydrated (eg, electrolyte solutions)
Abdominal pain
  •  Drink small, steady amounts of clear liquids, such as electrolyte solutions
  • Avoid solid foods for first few hours after taking dose
  • Avoid narcotic pain medications and nonsteroidal anti-inflammatory drugs, such as aspirin or ibuprofen
Skin rash
  • Occurs in 8% to 10% of patients
  • Generally appears on the trunk and face within the first few weeks of starting therapy
  • Patients experience discomfort and interference with activities of daily living
  • Use OTC medications such as corticosteroids or long-acting antihistamines until rash resolves or symptoms improve
  • Rash should abate as patient stays on medication and becomes sensitized
  • If rash progresses or recurs, instruct patients to call the doctor
  • If rash is severe, consider dose interruption or adjustment

Sources: Ault1; Cappellini3; Exjade21; Pilo47; Vinchinsky.48