Noncompliance with Iron Chelation Therapy in an Adolescent with

Thalassaemia Major

Adlette C. Inati, MD

Head, Division of Pediatric Hematology-OncologyMedical Director

Children's Center for Cancer and Blood DiseasesRafik Hariri University Hospital

Beirut, Lebanon

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. 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.

Compliance and Survival• Survival in thalassaemia is directly related to compliance with iron

chelation therapy1

• Projected survival is markedly improved with 100% compliance2

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.

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.

Su

rviv

al (

%)

Time (years)

0

60

80

50

40

30

20

10

70

90

100

0 282624222018161412108642 30 32 34 36 38 40

300–365225–300150–22575–1500–75

Infusionsa/year

Compliance, rather than LIC or serum ferritin, predicted survival

N = 257N = 257

Impact of Compliance, Ferritin and LIC on Long-Term Trends in Myocardial T2* with

Deferasirox

Garbowski M, et al. Blood. 2008;11:116.Garbowski M, et al. Blood. 2008;11:116.

• 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).

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

Decision Point 1For the Patient at Age 3 Years, What Was the

Best Next Step?a. 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

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.

Decision Point 1For the Patient at Age 3 Years, What Was the

Best Next Step?

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

What Patients Dislike MostPatient Surveys in the United Kingdom and Cyprus

Pat

ien

ts (

%)

0

10

20

30

40

50

60

Pump Transfusions Visiting hospital

Investigations Other

With permission from Telfer P, et al. Ann N Y Acad Sci. 2005;1054:273-282.With permission from Telfer P, et al. Ann N Y Acad Sci. 2005;1054:273-282.

Cyprus (N = 119)Cyprus (N = 119)

UK (N = 129)UK (N = 129)

Impact of Infusion Iron Chelation Therapy on Patients with Iron Overload

Results from Patients and Clinician Interviews

Impact of ICT on patients with iron overloadWork:Work:

• Work-related travelWork-related travel• Ability to work lateAbility to work late

Self-esteem:Self-esteem:• Due to unsightly Due to unsightly bumps/bruisesbumps/bruises

• Due to inability to Due to inability to do “normal” do “normal” thingsthings

Evening social life:Evening social life:• Limits going out at Limits going out at night and doing night and doing "normal" things"normal" things

• Interrupts activities Interrupts activities due to preparingdue to preparing Impact on Impact on

parentparent(thalassaemia/(thalassaemia/SCD):SCD):• GuiltGuilt• Stress/worryStress/worry• May impact May impact relationship relationship with childwith child

Sleep Sleep disturbance:disturbance:

• Specific to Specific to those with old-those with old-style pump: style pump: noise keeps noise keeps them awakethem awake

• Have to sleep Have to sleep on opposite on opposite side, which may side, which may interrupt sleepinterrupt sleep

• Pain may also Pain may also disrupt sleepdisrupt sleep

Sex life:Sex life:• Pump inhibits sexual Pump inhibits sexual activityactivity

• May inhibit development May inhibit development of intimate relationshipsof intimate relationships

Emotional well-being:Emotional well-being:• DepressionDepression• AngerAnger• FrustrationFrustration• SadnessSadness

Pain at Pain at needle siteneedle site

Abbreviation: ICT, iron chelation therapy; SCD, sickle cell disease.With permission from Abetz L, et al. Health Qual Life Outcomes. 2006;4:73.Abbreviation: ICT, iron chelation therapy; SCD, sickle cell disease.With permission from Abetz L, et al. Health Qual Life Outcomes. 2006;4:73.

Decision Point 2What 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

Decision Point 2What 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.

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

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

0

500

1000

1500

2000

2500

3000

3500

0 3 6 9 12 15 18 21 24

Months

Ferritin ng/mL

0

10

20

30

40

50

T2* ms; LIC Fe g/dw

Ferritin ng/mLLIC Fe g/dwT2* ms

Start of Noncompliance

Decision Point 3What 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

Decision Point 3What 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

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

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

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

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

0

500

1000

1500

2000

2500

3000

3500

0 3 6 9 12 15 18 21 24

Months

Ferritin ng/mL

0

10

20

30

40

50

T2* ms; LIC Fe g/dw

Ferritin ng/mLLIC Fe g/dwT2* ms

Start of Noncompliance

Counseling Intervention

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!

Thank you for participating

in this webcast

Please remember to take the posttest

QuickTime™ and a decompressor

are needed to see this picture.