Noncompliance with Iron Chelation Therapy in an Adolescent with Thalassaemia Major

1. Adlette C. Inati, MD Head, Division of Pediatric Hematology-OncologyMedical DirectorChildren's Center for Cancer and Blood DiseasesRafik Hariri University HospitalBeirut, Lebanon Noncompliance with Iron Chelation Therapy in an Adolescent with Thalassaemia Major

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; 2008. 2. Brittenham GM, et al. N Engl J Med. 1994;331:567-573.

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 300–365 80 225–300 70 150–225 Survival (%) 60 75–150 0–75 50 40 N = 257 Compliance, rather than LIC or serum ferritin, predicted survival 30 20 10 0 40 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 aDesferrioxamine. Abbreviation: LIC, liver iron concentration. 1. Gabutti V, et al. Acta Haematol. 1996;95:26-36. 2. Delea TE, et al. Pharmacoeconomics. 2007;25:329-342. Graphic with permission from Gabutti V, et al. Acta Haematol. 1996;95:26-36. Time (years)

4. 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). Impact of Compliance, Ferritin and LIC on Long-Term Trends in Myocardial T2* with Deferasirox 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 1For the Patient at Age 3 Years, What Was the Best Next Step?

7. Decision Point 1For the Patient at Age 3 Years, What Was the Best Next Step?

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 MostPatient Surveys in the United Kingdom and Cyprus 60 Cyprus (N = 119) UK (N = 129) 50 40 Patients (%) 30 20 10 0 Pump Transfusions Visiting hospital Investigations Other With permission from Telfer P, et al. Ann N Y Acad Sci. 2005;1054:273-282.

10. 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.

11. Decision Point 2What Is the Best Next Step?

12. Decision Point 2What Is the Best Next Step?

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

15. Decision Point 3What Is the Best Next Step?

16. Decision Point 3What Is the Best Next Step?

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. 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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