Download Decision Point 2 What Is the Best Next Step?

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
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.
Compliance and Survival
• Survival in thalassaemia is directly related to compliance with iron
chelation therapy1
• Projected survival is markedly improved with 100% compliance2
100
Survival (%)
90
Infusionsa/year
300–365
225–300
150–225
75–150
0–75
80
70
60
50
40
N = 257
30
Compliance, rather than LIC or
serum ferritin, predicted survival
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
aDesferrioxamine.
Time (years)
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.
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).
Garbowski M, et al. Blood. 2008;11:116.
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 1
For 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
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.
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 Most
Patient Surveys in the United Kingdom and Cyprus
60
Cyprus (N = 119)
UK (N = 129)
Patients (%)
50
40
30
20
10
0
Pump
Transfusions
Visiting Investigations
hospital
With permission from Telfer P, et al. Ann N Y Acad Sci. 2005;1054:273-282.
Other
Impact of Infusion Iron Chelation Therapy
on Patients with Iron Overload
Results from Patients and Clinician Interviews
Work:
• Work-related travel
• Ability to work late
Evening social life:
• Limits going out at
night and doing
"normal" things
• Interrupts activities
due to preparing
Self-esteem:
• Due to unsightly
bumps/bruises
• Due to inability to
do “normal”
things
Impact of ICT on patients
with iron overload
Pain at
needle site
Impact on
parent
(thalassaemia/
SCD):
• Guilt
• Stress/worry
• May impact
relationship
with child
Sex life:
• Pump inhibits sexual
activity
• May inhibit development
of intimate relationships
Sleep
disturbance:
• Specific to
those with oldstyle pump:
noise keeps
them awake
• Have to sleep
on opposite
side, which may
interrupt sleep
• Pain may also
disrupt sleep
Abbreviation: ICT, iron chelation therapy; SCD, sickle cell disease.
With permission from Abetz L, et al. Health Qual Life Outcomes. 2006;4:73.
Emotional well-being:
• Depression
• Anger
• Frustration
• Sadness
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
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.
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
Start of Noncompliance
3500
50
3000
Ferritin ng/mL
2500
2000
30
1500
20
1000
10
500
0
0
0
3
6
9
12
15
Months
18
21
24
T2* ms; LIC Fe g/dw
40
Ferritin ng/mL
LIC Fe g/dw
T2* ms
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
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
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
Counseling Intervention
Start of Noncompliance
3500
50
3000
Ferritin ng/mL
2500
2000
30
1500
20
1000
10
500
0
0
0
3
6
9
12
15
Months
18
21
24
T2* ms; LIC Fe g/dw
40
Ferritin ng/mL
LIC Fe g/dw
T2* ms
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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