1. Noncompliance with Iron Chelation Therapy in an Adolescent with Thalassaemia Major
Adlette C. Inati, MD
Head, Division of Pediatric Hematology-Oncology Medical Director Children's Center for Cancer and Blood Diseases Rafik Hariri University Hospital Beirut, Lebanon 1

2. Background Information
In thalassaemia major,chelation therapy is recommended in patients1
With serum ferritin >1000 ng/mL, or
Who have received >10–20 blood transfusions, or
Who have an elevated liver iron concentration (level D)
Compliance with chelation therapy and adequate dose titration are crucial factors in achieving prolonged patient survival1
The probability of survival to at least 25 years of age in poorly chelated patients was just one third that of well chelated patients2
1. Thalassaemia International Federation. Guidelines for the clinical management of thalassaemia. 2nd ed. Nicosia, Cyprus; Brittenham GM, et al. N Engl J Med. 1994;331:

3. Compliance and Survival
Survival in thalassaemia is directly related to compliance with iron chelation therapy1
Projected survival is markedly improved with 100% compliance2
100 90
Infusionsa/year 80
300–365
225–300 70
150–225
Survival (%) 60
75–150
0–75 50 40
N = 257 30
Compliance, rather than LIC or serum ferritin, predicted survival 20 10 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
aDesferrioxamine.
Abbreviation: LIC, liver iron concentration.
1. Gabutti V, et al. Acta Haematol. 1996;95: Delea TE, et al. Pharmacoeconomics. 2007;25: Graphic with permission from Gabutti V, et al. Acta Haematol. 1996;95:26-36.
Time (years)

4. Impact of Compliance, Ferritin and LIC on Long-Term Trends in Myocardial T2* with Deferasirox
33 transfusion-dependent patients with thalassaemia or rare anaemias, age range 7–51 years
mT2* and T2* liver iron concentration (LIC) assessments repeated with a median interval of 14 months (3.6 occasions per patient) while receiving deferasirox
Factors associated with trends in mT2* = compliance, LIC, and ferritin
Compliance <90% (more than 3 daily doses missed per month) was associated with decrease in mT2*
Whereas compliance ≥90% was associated with an increase in mT2* (P = .0001).
Compliance calculated from the % of intended doses that were missed over the period of observation, assessed from patient interviews conducted on monthly visits. Longitudinal control of LIC and ferritin may also be important to reducing the risk of myocardial iron loading in patients receiving long-term deferasiox treatment
Garbowski M, et al. Blood. 2008;11:116.

5. Patient Presentation
Patient is now a 16-year-old boy with thalassaemia major diagnosed at age 6 months
Treated with packed red blood cell transfusion every 3–4 weeks since diagnosis
At age 3 years, his laboratory values were as follows
LIC 12 mg Fe/g dry weight
Serum ferritin 3000 ng/mL
T2* 40 ms

6. Decision Point 1 For the Patient at Age 3 Years, What Was the Best Next Step?
Start patient on desferrioxamine
b. Start patient on deferasirox
c. Start patient on deferiprone
d. Continue with transfusions but wait to start iron chelation therapy

7. Decision Point 1 For the Patient at Age 3 Years, What Was the Best Next Step?
a. Start patient on desferrioxamine
CORRECT: Until recently, desferrioxamine has been the gold standard and the only approved chelator for thalassaemia.
b. Start patient on deferasirox
INCORRECT: 13 years ago, when this patient needed chelation, deferasirox was not available. If he were treated now, deferasirox would also be a correct choice.
c. Start patient on deferiprone
INCORRECT: Deferiprone is not approved for the initial treatment of iron overload in patients with thalassaemia major, but for cases when desferrioxamine therapy is inadequate or contraindicated.
d. Continue with transfusions but wait to start iron chelation therapy
INCORRECT: As indicated by the very high serum ferritin level and LIC, the patient has significant iron overload, which necessitates immediate chelation.

8. Case Continues Patient started on desferrioxamine at age 3 years
In recent years, patient was often noncompliant with desferrioxamine therapy
He complained of local pain at site of injection and was concerned about carrying a pump and not being accepted by peers
All attempts by parents and thalassaemia team to convince him to be compliant were unsuccessful
He decided to stop desferrioxamine altogether

9. What Patients Dislike Most Patient Surveys in the United Kingdom and Cyprus60
Cyprus (N = 119) 50
UK (N = 129) 40
Patients (%) 30 20 10
Pump
Transfusions
Visiting hospital
Investigations
Other
With permission from Telfer P, et al. Ann N Y Acad Sci. 2005;1054:

10. Impact of ICT on patients with iron overload
Impact of Infusion Iron Chelation Therapy on Patients with Iron Overload
Results from Patients and Clinician Interviews
Impact of ICT on patients with iron overload
Sex life:
Pump inhibits sexual activity
May inhibit development of intimate relationships
Work:
Work-related travel
Ability to work late
Pain at needle site
Evening social life:
Limits going out at night and doing "normal" things
Interrupts activities due to preparing
Sleep disturbance:
Specific to those with old-style pump: noise keeps them awake
Have to sleep on opposite side, which may interrupt sleep
Pain may also disrupt sleep
Emotional well-being:
Depression
Anger
Frustration
Sadness
Impact on parent
(thalassaemia/
SCD):
Guilt
Stress/worry
May impact relationship with child
Self-esteem:
Due to unsightly bumps/bruises
Due to inability to do “normal” things
Abbreviation: ICT, iron chelation therapy; SCD, sickle cell disease.
With permission from Abetz L, et al. Health Qual Life Outcomes. 2006;4:73.
This patients noncompliance with DFO is no surprise because the impact of ICT on patients with iron overload is profound and may be greatest for adolescents and young adults as this patient. It affects every aspects of patients’ lives from their work, social life, sex life, emotional wellbeing and sleeping abilities. On top of that, the pain at the needle site. However the highest impact is on patients self esteem and their image as perceived by peers. The impact on parents is of paramount importance: feelings of guilt,.and Can be intense and may result in a disturbed parent child. Because of all these issues, patients are less likely to adhere or continue recommended treatment regimens and this may result in severe morbidity and early mortality

11. Decision Point 2 What Is the Best Next Step?
a. Let patient have a drug holiday, then restart desferrioxamine
b. Start patient on deferiprone
c. Start patient on deferasirox
d. Let patient have a transfusion and drug holiday

12. Decision Point 2 What Is the Best Next Step?
a. Let patient have a drug holiday, then restart desferrioxamine
INCORRECT: Patient will continue to accumulate iron, which will be toxic to his organs, from ongoing transfusions.
b. Start patient on deferiprone
INCORRECT: Deferiprone is indicated when desferrioxamine therapy is inadequate or contraindicated.
c. Start patient on deferasirox
CORRECT: Patient’s compliance is expected to increase with a once-daily oral drug, and the efficacy and safety of deferasirox in thalassaemia has been well documented.
d. Let patient have a transfusion and drug holiday
INCORRECT: This would deprive the patient of recommended medical treatment and increase disease complications.

13. Case Continues
Patient was started on deferasirox 30 mg/kg/day with good tolerance
Serum ferritin levels and LIC decreased over the next 12 months on deferasirox
After 12 months, serum ferritin level started to increase
No changes in other clinical parameters, such as markers of inflammation or infection or in patient’s transfusion requirement, were observed

14. Start of Noncompliance
Patient Trends in Serum Ferritin, LIC, and T2* Deferasirox 30 mg/kg/day
Start of Noncompliance

15. Decision Point 3 What Is the Best Next Step?
a. Increase dose of deferasirox
b. Question the patient about compliance
c. Switch to deferiprone
d. Add deferiprone to the treatment regimen

16. Decision Point 3 What Is the Best Next Step?
a. Increase dose of deferasirox
INCORRECT: This patient is receiving recommended dose of deferasirox and there is no indication to increase the dose.
b. Question the patient about compliance
CORRECT: Even with oral drugs, patients may be noncompliant.
c. Switch to deferiprone
INCORRECT: Deferiprone is used in cases when desferrioxamine therapy is inadequate or contraindicated.
d. Add deferiprone to the treatment regimen
INCORRECT: To date, there are no data on combining any other chelator with deferasirox

17. Reasons for Noncompliance Associated with Deferasirox
Forgetting to take the drug
Undesirable drug-related side effects
Cost of drug
Ignorance among parents/patients about morbidity and mortality associated with untreated iron overload

18. Case Continues The patient was asked about his compliance
He admitted to forgetting to take some pills and, on occasion, had also not taken the prescribed deferasirox dose due to high drug cost and concern about possible side effects
Lack of compliance with deferasirox treatment may explain the increase in serum ferritin levels after month 12
Counseling on the importance of compliance and taking the medication as directed was provided

19. Outcomes
Patient continued on deferasirox 30 mg/kg/day and was fully compliant with the regimen
Serum ferritin levels and LIC steadily decreased
T2* continued normal at normal level
At month 24, serum ferritin levels had decreased to 1300 ng/mL and LIC was 3.5 mg Fe/g dw
No further adverse events or abnormal laboratory values were observed

20. Start of Noncompliance
Patient Trends in Serum Ferritin, LIC, and T2* Deferasirox 30 mg/kg/day
Counseling Intervention
Start of Noncompliance

21. Conclusions
Iron chelation therapy is a safe and effective way to manage iron overload in patients with thalassaemia
Survival in thalassaemia is directly related to compliance with iron chelation therapy
Physicians need to stress to their patients the importance of full compliance with therapy if iron burden is to be reduced
Patients must take their assigned dose on a daily basis as directed and dose should be reviewed regularly at 3- to 6-month intervals
Dose adjusted according to trends in serum ferritin levels
Compliance remains a challenge for all forms of medical therapy, including oral therapies
The first thing to suspect if drug does not seem to be working is that the patient is not taking it!

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