Transcript Slide 1

Non-Responders to Iron
Chelation Therapy
John B. Porter, MA, MD, FRCP
Professor, Department of Haematology
University College London
London, United Kingdom
Kai-Hsin Lin, MD
Professor of Paediatrics
National Taiwan University Hospital
Taipei, Taiwan
The Non-Responder
John B. Porter, MA, MD, FRCP
2
What Does “Non-Responder” Mean?
• Balance
– Failure to balance transfusional iron input with excretion?
– Failure to excrete more iron than transfusional iron input?
• Ferritin
– Failure to decrease serum ferritin?
– Failure to control serum ferritin (or LIC) to target levels?
• Myocardial iron (T2*)
– Failure to control T2*?
– Failure to improve T2* if abnormal?
3
What Information Do We Need to Predict
“Response Rate” with a Chelation Regimen?
• The average change of a given measure in a
group of patients does NOT tell you the
probability of response in an individual
• This can only be predicted when the
proportion of patients showing the desired
effect is shown
4
What Evidence Do We Have About the
Percentage of Patients Who “Respond” to
Different Regimens?
• With desferrioxamine monotherapy
• With deferiprone monotherapy
• With combination therapy of the above
• With deferasirox monotherapy
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“Non-Response”
to Desferrioxamine (DFO)
% Responders to Desferrioxamine
Iron Balance SC 5x/Week
% of Patients in Negative Balance
Dose
mg/kg
Low
Transfusion
<0.3 mg/kg/d
Medium
Transfusion
0.3–0.5 mg/kg/d
High
Transfusion
>0.5 mg/kg/d
25 – <35
17
43
17
35 – <50
76
75
52
≥50
100
86
89
Cohen AR, et al. Blood. 2008;111:583-587.
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Responders to Desferrioxamine
Average Response with Serum Ferritin
• At 30 mg/kg
– Negative iron balance at transfusion rate of 22.2 mg/d
(0.44 mg/kg/d), only if iron stores >4g (LIC >8mg/g wt)
• At 40 mg/kg
– Negative iron balance at transfusion rate of 26.7 mg/d
(0.53 mg/kg/d), if body iron >2g (LIC 4 mg/g dw)
• At 50 mg/kg
– Negative iron balance at transfusion rate of 31.1 mg/d
(0.62 mg/kg/d), if body iron >2g (LIC 4 mg/g dw)
Fischer R, et al. Br J Haematol. 2003;121:938–948.
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Non-Responders to Desferrioxamine
Monotherapy Conclusions
• 35 mg/kg (dose used in several comparative studies) unlikely to
induce negative iron balance unless transfusion rate is low
• If poor response (LIC or ferritin), consider increasing dose or
frequency (but max 40 kg/mg in children)
• As iron load falls, chelation will be less efficient and larger doses
will be required to achieve the same response rate (especially
<2g, LIC<3.8mg/g dw)
• However, this is not practical with DFO because of risk
of toxicity
“Non–Responders”
to Deferiprone (DFP)
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Mean Iron Balance with Deferiprone
Linked to Degree of Iron Load
Changes in LIC by SQUID over 2 y at 75 mg/kg
• Low LIC (<1500 µg/g wet wt)
– Negative balance in 24% (13/54)
• At higher LICs (>1500 µg/g wet wt)
– Negative balance in 50% (12/24)
Fischer R, et al. Br J Haematol. 2003;121:938–948.
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LIC Responders to Deferiprone
Effects of Transfusion Rate and Iron Stores
• At low transfusion rate (22.2 mg/d)
– At 75mg/kg negative iron balance only if iron stores >2g
• Intermediate transfusion rate (26.7 mg/d)
– 75 mg/kg insufficient at any level of iron loading
– 100 mg/kg negative iron balance if body iron >2g
• At high transfusion rate (31.1 mg/d)
– 75mg/kg, negative iron balance only if body iron >3g
Fischer R, et al. Br J Haematol. 2003;121:938–948.
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Does Ferritin Response Rate Parallel the
LIC Response with Deferiprone
Monotherapy?
13
Ferritin vs LIC
Percent Responders to DFP Monotherapy
• Population and treatment
– Italian poor compliers with DFO
– 29 patients at 70 mg/kg
• Response by LIC
– 6/20 (30%) responders
– 70% non-responders
• Response by ferritin
– 24/29 (83%) responders
– 17% non-responders
Mazza A, et al. Haematologica. 1998;83:496-501.
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Responders to DFP
Serum Ferritin vs SQUID LIC stores
Changes in ferritin and stores (LIC + spleen )
by SQUID over 2 yrs
• Correlation between changes in ferritin and
changes in iron stores
• BUT whereas 43% (23/54) of patients show
decrease in ferritin
• Only 24% (13/54) show decrease in iron stores
Fischer R, et al. Br J Haematol. 2003;121:938-948.
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Ferritin Response with
Long-Term Deferiprone
58 Patients in total treated with DFP
• Continued treatment (n = 26) • Discontinued (n = 25a)
– Mean treatment duration
– Mean treatment
39.4 months
duration 18.7 months
– Non-response 61%
– Non-response 72%
– 8/26 (31%) remain
– 20/25 (80%) remain
>2500 µg/L
>2500 µg/L
aIncluding
5 deaths.
Hoffbrand AV, et al. Blood. 1998;91:295-300.
Ferritin Response Rates to DFP
by Starting Ferritins
• 151 patients completing 3 years of therapy
• Mean serum ferritin level declined from 2579 ng/mL at
baseline to 2320 ng/ml at 3 years (P = 0.01)
• If initial ferritin levels higher than 2500 ng/mL, the ferritin
level declined significantly
• If initial values <2500 ng/mL, the mean ferritin level did not
change significantly
• Overall, 18% passed to a more severe class of ferritin
Ceci A, et al. Br J Haematol. 2002;118:330-336.
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Long-Term Ferritin Response to DFP
What Factors Affect Response Rate?
58 patients on DFP at least 3 years DFP 75 mg/kg/d
• At baseline
– Group 1 (n = 8):
– Group 2 (n = 21):
– Group 3 (n = 29):
Ferritin <2000
Ferritin 2000-4000
Ferritin >4000
• Overall response at 3 years
– 29% patients showed rise in serum ferritin
– 52% remained stable
– 19% showed decline
– Group 1: Significant ferritin increase (7/8 increased) (88% non-responders)
– Group 2: Significant ferritin increase (19/21 increased) (90% nonresponders)
– Group 3: 8/29 decreased (ie, responded); (75% non-responders)
Goel H, et al. Hematology. 2008;13:77-82.
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Non-Responders to DFP Monotherapy
Conclusions
• Highly variable reports of response rates - likely due to
- Variations in baseline iron stores1,2
- Variations in transfusion rates3
- Variations in metabolism UGT1A64
- Variable follow-up time
• More non-responders with LIC than ferritin, why?
- Hypothesis
Greater ferritin response than LIC3,5 response because
 Ferritin changes reflect macrophage (RE) iron changes
 RE iron mobilised more rapidly than hepatocellular iron
 Because DFP inactivated by glucuronidation iron binding site in hepatocytes
• Practical point
- Ferritin changes may not fully reflect iron balance
- May explain late rise in ferritin observed by several groups
Abbreviation: RE, reticuloendothelial.
1. Ceci A, et al. Br J Haematol. 2002;118:330–336. 2. Goel H, at al. Hematology. 2008;13:77-82. 3. Fischer R, et al.
Br J Haematol. 2003;121:938–948. 4. Haverfield, Blood. 2005 106: Abstract 2703. 5. Mazza A, et al. Haematologica.
1998;83:496-501.
.
Responders to Combined DFP + DFO
Iron Balance (LIC)
DFP Monotherapy
Decrease in 5/12
Non-response 58%
Baseline
12 months
With permission from Aydinok Y, et al. Haematologica. 2007;92:1599-1606.
Combination Therapy
Decrease in 7/8
Non-response 13%
Baseline
12 months
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Responders to Combined DFP + DFO
Serum Ferritin
• Effect of deferiprone (75 mg/kg/d) + DFO (2 g/d
twice weekly) on serum ferritin levels
• Iron intake reported in each patient (mean
0.31mg/kg/d, n = 11)
• 9/11 decreased ferritin
• In 2/11 no decrease (iron intake 0.39 and 0.30 mg/kg/d)
Mourad FH, et al. Br J Haematol. 2003;121:187-189.
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“Non-Responders”
to Deferasirox
(DFX)
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Change in LIC by Deferasirox Dose and
Ongoing Transfusion Burden
% of Patients in Negative Balance
Dose
mg/kg
Low
Transfusion
<0.3 mg/kg/d
Medium
Transfusion
0.3-0.5 mg/kg/d
High
Transfusion
>0.5 mg/kg/d
10
29
14
0
20
76
55
47
30
96
83
82
Cohen AR, et al. Blood. 2008;111:583-587.
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Pharmacokinetics of Deferasirox in Patients
with Adequate/Inadequate Response
• 10 transfused patients with inadequate response
(rising ferritin or rising LIC) on >30 mg/kg per day
vs 5 control transfusion-dependent patients with
adequate response
• Compared to controls, patients with inadequate
had significantly lower systemic drug exposure
(P <.00001)
Chirnomas D, et al. Blood. 2009;114:4009-4013.
Pharmacokinetics of Deferasirox in Patients
with Adequate/Inadequate Response
• No differences observed between adequate
and inadequate responders in
– Cmax
– Volume of distribution/bioavailability (Vd/F)
– Elimination half-life (t½)
• Conclusion
– Bioavailability is the likely discriminant
Chirnomas D, et al. Blood. 2009;114:4009-4013.
Relationship of Ferritin to LIC Changes
with Deferasirox?
• Change in ferritin correlates with change in LIC across
diagnoses (TM n = 85, MDS n = 47, DBA n = 30, rare
anaemias n = 22)
• Intersect of correlation suggests that when no
change in ferritin, there is a fall in LIC of about 47mg/g d wt
• So when body iron falls, there may be a decrease in
LIC (negative iron balance) without a significant
change in ferritin
• Ferritin may also increase in the absence of a positive
trend in LIC
Porter J, et al. EJH. 2008;80:168-176.
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Liver Tissue Iron Scores Following
Therapy with Deferasirox
• Method
Tissue Iron Score (TIS) on liver iron biopsies
Change in score after 1 year of chelation
Change in distribution of iron after 1 year of chelation
Deferasirox n = 224, Desferrioxamine n = 230
• Results
• Fall in TIS correlated with fall in LIC
• Greater removal from hepatocellular than
macrophage compartment (cf DFO)
Porter J, et al. 10th International Conference on Thalassaemia and Haemoglobinopathies, January 7-10, 2006.
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Hepatocytic—Total Liver Iron Ratio
Reflects Tissue Distribution of Iron
LIC
8.0 mg/Fe g dw
Total, TIS
24
Hetatocyte, HIS
24
Sinusoidal, SIS
0
Portal, PIS
0
Hepatocytic:total liver iron ratio 1
LIC
9.1 mg/Fe g dw
TIS
19
HIS
3
SIS
10
PIS
6
Hepatocytic:total liver iron ratio 0.16
Prussian blue stain
Abbreviations: HIS, hepatocytic iron score; PIS, portal iron score; SIS, sinusoidal iron score; total tissue iron score.
Deugnier YM, et al. Gastroenterology.1992;102:2050–2059. Turlin B, Deugnier Y. J Clin Pathol. 1997;50:971.
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Change in Hepatocytic: Total Liver Iron Ratio
Deferasirox But Not Desferrioxamine
Showed a Tendency to Reduce
Hepatocytic:Total Liver Iron Ratio
Mean ± 95% CI
0.4
0.2
n= 6
27
86
10
9
48
83
191
0
<25
-0.2
25–<35 35–<50
≥50
DFO (mg/kg 5 days/week)
5
10
20
30
DFX (mg/kg/day)
Porter J, et al. 10th International Conference on Thalassaemia and Haemoglobinopathies, January 7-10, 2006.
Serum Ferritin
Response to Different Chelators
Hypothesis
• With DFO
– Iron removal is approximately equal in hepatocytes and RE cells
– So changes in ferritin reflect changes in LIC and RE iron
• With DFP
– Iron removal is preferential in RE cells compared with hepatocytes
– Explains why may see response with ferritin but not with LIC
– Explains late secondary resurgence of ferritin
• With DFX
– Iron is removed preferentially from hepatocytes compared with RE cells
– Body iron (LIC) may fall even though ferritin may lag
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Possible Reasons for
“Non-Response”
• The measure used may not reflect iron balance in
that individual
• The patient may have a high transfusion requirement
• The dose/frequency may be insufficient
• The patient may not be taking the treatment
regularly
• The PK and metabolism of the chelator may not be
favorable (very limited data)
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Non-Responders
Practical Questions to Ask
• How are you assessing “non-response”? Is this the
correct measure?
• How long have you been assessing response? Is it
long enough?
• Is the patient on a high, low, or average transfusion
schedule?
• Is the patient taking the prescribed dose and
frequency of chelator?
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The Non-Responder
Practical Things to Do
• Quantitate current transfusional iron loading rate
• Consider additional measures of “response” (e.g.,
changes in LIC)
• Carefully interview the patient about adherence
patterns
• Consider whether administration of drug is optimal
(e.g., timing of oral dose relative to food, number of
hours of DFO infusion)
• Consider whether the dose can be safely increased
• Consider alternative chelation
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Management of Non-Responders to
Iron Chelation Therapy
Kai-Hsin Lin, MD
34
Contributing Factors
in Inadequate-Responders
•
•
•
•
Poor drug compliance
Inadequate drug dose due to side effects
Poor drug efficacy
Comorbid diseases confounding the
assessment of iron overload
35
Case 1: Ms H
36
Ms. H—Treatment History
• 18-year-old female diagnosed with thalassaemia
major at age 1 year
• Received regular transfusions
– 4 units washed RBC every 2 weeks (250 cc whole blood)
• Has been receiving iron chelation therapy with
desferrioxamine since 3 years old
– Poor desferrioxamine compliance (4-5 nights per week)
due to inconvenience and discomfort
• No hepatitis B or C or diabetes mellitus
• No puberty
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Initiation of Deferasirox
• Ms. H started take deferasirox as iron
chelation therapy at 20 mg/kg/day in
Feb 2007
• Baseline assessments
– Serum ferritin: 5037 ng/mL
– AST: 19 U/L, ALT: 21 U/L
– Creatinine: 0.7 mg/dL
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Deferasirox Therapy
• Patient found once-daily oral administration of
deferasirox to be more convenient than SC or
IV desferrioxamine
• Improved drug compliance
• Improved iron chelation and reduced total
iron burden
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Deferasirox Treatment Course
Serum Ferritin (Months 1–36)
Deferasirox therapy
(mg/kg/day)
20
30
35
40
35
6000
Serum ferritin (ng/mL)
5000
4000
3000
Start
2000
1000
0
-5
Courtesy of Dr. Lin
0
5
10
15
Months
20
25
30
35
40
Poor Drug Compliance
1. Forgetting to take the drug
2. Not understanding or misinterpreting
instructions
3. Experiencing side effects (the treatment may be
perceived as worse than the disorder)
4. Disliking the drug taste or smell
5. Finding restrictions on treatment inconvenient
6. Not caring about getting better
41
Poor Injection Compliance
Two main reasons are
• Lack of disease knowledge
• Incorrect injection method
Lin SS. Presented at 12th TIF, January 7-10, 2006.
42
Serum Ferritin Level vs Injection Days
(Before & After Disease Education)
Group
Items
Experimental Group (n=20)
Average Score
Standard
Deviation
3.65
4.625
1.077
0.646
T value
P value
Control Group (n=20)
Average
Score
Standard
Deviation
3.55
3.8
T value
P value
1.731
1.399
-.773
.449
4153.7
3958.5
-.768
.452
Injection
Days
Before
After
.000
-4.791
Serum
Ferritin
Level
Before
After
8286.9
6180.8
4355.9
3868.9
.000
3.94
Lin SS. Presented at: 12th TIF, January 7-10,2006.
Courtesy of Syi Su Lin, MD
6383.2
6734.6
43
Poor Drug Compliance: Management
*Medication diary
*Family support group
*Patient peer support
group
*Disease education
*Treatment guideline
44
Courtesy of Kai-Hsin Lin, MD
Case 2: ML
45
ML: Treatment History
• 15-year-old male diagnosed with thalassaemia
major at age 8 months
• Received regular transfusions
– 2 units washed RBC every 2 weeks (250 cc whole
blood)
• Started iron chelation therapy with
desferrioxamine at age 1 year
• No hepatitic B or C or diabetes mellitus
46
Initiation of Deferasirox
• Began iron chelation therapy with deferasirox
at 20 mg/kg/day in March 2006
• Baseline assessments
– Serum ferritin: 3693 ng/mL
– AST: 24 U/L, ALT: 16 U/L
– Creatinine: 0.5 mg/dL
• Good compliance but had mild GI upset when
taking deferasirox
47
Reduced Bioavailability
• 40 mg/kg/day once-daily deferasirox only maintained total iron burden
and led to GI upset in this patient
• Bioavailability of deferasirox in this patient may be reduced, as individuals
with inadequate response to deferasirox have been found to have
significantly lower systemic drug exposure compared with those having an
adequate response1
• Reduced drug bioavailability in this patient may be the result of patient
variability in
– Oral absorption
– Distribution
– Metabolism
– Excretion
1. Chirnomas D, et al. Blood. 2009;114:4009-4013.
48
Managing Inadequate Bioavailability
In this patient, twice-daily deferasirox at the
same total dose increased bioavailability,
relieved GI upset, and further reduced total
iron burden
49
Deferasirox Treatment Course
Serum Ferritin (Months 1 - 48)
Deferasirox therapy
(mg/kg/day)
40
30
20
40 BID
7000
Serum ferritin (ng/mL)
6000
5000
4000
3000
Start
2000
1000
0
-5
0
5
10
Courtesy of Kai-Hsin Lin, MD
15
20
25
Months
30
35
40
45
50
55
50
Conclusions
• Improved medication compliance can improve the efficacy of
iron chelation therapy
– Improved treatment convenience
– Disease education
– Patient support group
• Individual bioavailability of deferasirox for iron chelation
– Identify responders versus inadequate responders
– Consider alternative regimens, such as twice-daily dosing or
deferasirox + desferrioxamine combination therapy to deal with side
effects while maintaining iron chelation efficacy
51