Transcript Indications for Successful Iron Overload Treatment and

Indications for Successful Iron
Overload Treatment and
Monitoring: Myelodysplastic
Syndromes
Norbert Gattermann, MD, PhD
Professor
Department of Haematology, Oncology
Heinrich-Heine-University
Dusseldorf, Germany
MDS—Treatment Options
Low risk
Prognostic
group
High risk
´

Best supportive care, including iron chelation

Growth factors

Immunosuppressive treatment

Differentiation induction

Farnesyltransferase inhibitors

Arsenic trioxide

Thalidomide/lenalidomide

Epigenetic treatment (eg. 5-aza cytidine, 5-aza2'-deoxycytidine)

Low-dose chemotherapy

Intensive chemotherapy

Allogeneic stem cell transplantation
Anaemia in Patients with MDS
• ~80% of patients with MDS
have a haemoglobin
<10 g/dL at diagnosis
• The majority become
transfusion-dependent
Sanz GF, et al. Blood. 1989;74:395.
200–250 mg
iron
Ineffective Erythropoiesis in MDS
Duodenum
Unrestrained
intestinal
iron absorption
Suppressed
hepcidin
expression
in the liver
Increased
GDF15
in the serum
Liver
Normal
daily iron
uptake
~ 1 mg
Other cells in
the body
Urine, faeces,
nails, hair, skin
Erythroblasts
Ineffective
erythropoiesis
Courtesy of Dr. N. Gattermann.
Daily losses
~ 1 mg
Transferrin
Haemoglobin
(1.7–2.4 g)
Macrophages
(0.5–1.5 g)
Blood losses
(eg, menstrual)
MDS—Serum Ferritin at Diagnosis
8000
7794
Serum Ferritin (ng/mL)
6980
6000
5000
4176
3839
4000
3526
2000
2500
2284
1980
1800
1500
1290
2555
2283
2000
1749
2980
2690
1830
1590
2000
2500
2136
2000
1309
0
RA
Data on file: Düsseldorf MDS Registry.
Courtesy of Dr. U. Germing.
RARS
RAEB
RAEB-T
CMML
(n = 650)
Transfusion Requirements
• Moderate transfusion requirement
2 units/month
24 units/year
~ 100 units/4 years
• High transfusion requirement
4 units/month
48 units/year
~ 100 units/2 years
• 100 units: ≥ 20 g iron
• Normal body iron: 3–4 g
Survival Disadvantage for
Transfusion-Dependent MDS Patients
Cazzola M, et al. N Engl J Med. 2005;352:536.
Transfusion Dependency—A Risk Factor
Independent of Cytogenetic Risk Group
Not transfusion dependent
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0 20 40 60 80 100 120
Intermediate
0 20 40 60 80 100 120
Months
*Only isolated del 5q.
Malcovati L, et al. J Clin Oncol. 2005;23:7594.
Cumulative Proportion Surviving
Favourable*
Cumulative Proportion Surviving
Cumulative Proportion Surviving
Transfusion dependent
Poor
0 20 40 60 80 100 120
Complications of Iron Overload



Heart
 Heart failure, arrhythmias
Liver
 Fibrosis, cirrhosis, cancer
Endocrine tissues
 Diabetes mellitus
Clinical Consequences of Acquired
Transfusional Iron Overload in Adults
15 Nonthalassaemic Patients





All with anaemias requiring transfusions
Iron loading present <4 years in 14 patients
Liver biopsy in 10 patients contained 7–25 times
normal amount of iron; focal portal fibrosis typical
All patients had glucose intolerance with significantly
reduced insulin output
Pituitary ACTH reserve limited in 10 of 12 patients;
that of gonadotropin in 5 of 13
Schaefer AI, et al. N Engl J Med. 1981;304:319.
Cardiac Consequences of Acquired
Transfusional Iron Overload in Adults
15 Nonthalassaemic Patients
• Noninvasive cardiac studies demonstrated left
ventricular dysfunction in the most heavily transfused
patients and frequently showed supraventricular
arrhythmias
• Clinical heart failure and ventricular arrhythmias
occurred only in the presence of coronary artery
disease
• It is difficult to separate the relative contributions of
myocardial iron deposition and chronic anaemia in
the development of functional abnormalities in
patients with transfusion-dependent anaemia
Schaefer AI, et al. N Engl J Med. 1981;304:319.
Contributing Factors to Cardiac
Disease in Chronically Transfused
Patients with MDS
Age
Coronary artery disease
Chronic anaemia
Myocardial iron deposition?
Patients with Cardiac Iron (%)
Relation of Cardiac Iron Deposits
to Amount of Blood Transfused
100
90
131 transfused adult patients
• 101 leukaemias
• 30 other anaemias
80
70
60
50
40
30
20
10
0
0–25
26–50
51–75
76–100
101–200
Units of Blood Transfused
Buja LM, Roberts WC. Am J Med. 1971;51:209.
201–300
Iron in the Heart
Aetiology and Clinical Significance
•
Grossly visible cardiac iron deposits (CID) are always associated with
cardiac dysfunction and usually chronic heart failure
•
Extensive CID occur in patients who receive >100 units of blood unless
bleeding diatheses coexist
•
Patients with chronic anaemia and hepatic cirrhosis who receive
<100 units of blood also may have extensive CID
•
CID initially occur in ventricular myocardium, and are usually
more extensive in ventricular than atrial myocardium
•
CID are always more extensive in working than in
conducting myocardium
•
Supraventricular arrhythmias correlate with the extent of CID
in atrial myocardium
Buja LM, Roberts WC. Am J Med. 1971;51:209.
MRI Detection of
Cardiac Iron Overload in MDS
Patients with T2* <20 ms
Proportion of
MDS Patients
Average No. of
PRC Units
Transfused
Serum Ferritin
(mean; ng/mL)
Average
Hepatic T2*
(ms)
Glanville J, et al.1
3/7
208
5865
1.4
Chacko J, et al.2
1/11
116
4400
1.5
Konen E, et al.
1/10
50
4250
2–3
1. Glanville J, et al. Blood. 2006;108:Abstract 1553. 2. Chacko J, et al. Br J Haematol. 2007;138:587. 3.
Konen E, et al. Am J Hematol. 2007;82:1013.
WHO Classification of MDS—Patients in the
Düsseldorf Registry (%)
%
MDS
Blood
Bone marrow
3.7
5q– syndrome
• Anaemia
• Blasts <5%
• Platelets normal to increased
• Megakaryocytes normal to increased
• Blasts <5%
• No Auer rods
• Isolated del(5q)
8.8
RA
• Anaemia
• Blasts ≤1%
• Dyserythropoiesis only
• Blasts <5%
• Ringed sideroblasts <15%
7.8
RARS
• Anaemia
• Blasts ≤1%
• Dyserythropoiesis only
• Blasts <5%
• Ringed sideroblasts <15%
31.0
RCMD
• Cytopaenia of ≥2 lineages
• Blasts ≤1%
• Monocytes <1000/µL
• >10% of cells per lineage dysplastic
• No Auer rods
• Blasts <5%
• Ringed sideroblasts <15%
15.4
RCMD-RS
• Cytopaenia of ≥2 lineages
• Blasts ≤ 1%
• Monocytes <1000/µL
• >10% of cells per lineage dysplastic
• No Auer rods
• Blasts <5%
• Ringed sideroblasts ≥15%
15.0
RAEB I
• Cytopaenia of ≥2 lineages
• PB blasts ≤5%
• Monocytes <1000/µL
• Uni-linear or multi-linear dysplasia
• No Auer rods
• Blasts 5%–9%
18.3
RAEB II
• Cytopaenia of ≥2 lineages
• PB blasts ≤19%
• ± Auer rods
• Uni-linear or multi-linear dysplasia
• ± Auer rods
• Blasts 10%–19%
Courtesy of Dr. U. Germing.
Cumulative Survival of MDS Patients
According to WHO Type
Cumulative Proportion Surviving
Düsseldorf MDS Registry, n = 1598
P <.00005
1.0
.8
5q- syndrom
.6
.4
RCMD
RA
RARS
.2
RAEB II
0.0
0
24
RAEB I
48
72
RSCMD
96
120
144
168
Months
Gattermann N. Hematol Oncol Clin North Am. 2005;19(suppl 1):S13.
192
216
240
264
288
312
336
Survival of RCMD+RSCMD Patients
According to IPSS
Düsseldorf MDS Registry
MDS Type
RA
No.
IPSS Score
Median survival
(months)
131
RARS RCMD RSCMD
RAEBI
RAEBII
5q-
211
41
146
420
247
200
Low
36%
Int-1
50%
Int-2
13%
High
1%
62
36
12
7
RCMD = refractory cytopaenia with multilineage dysplasia; RSCMD = refractory sideroblastic cytopaenia with multilineage dysplasia;
IPSS = International Prognostic Scoring System; RA = refractory anaemia; RARS = refractory anaemia with ringed sideroblasts;
RAEB = refractory anaemia with excess blasts.
Courtesy of Dr. U. Germing.
Requirement for Iron Chelator Therapy
in MDS Patients
Crude Estimate
Median survival
~ 20% of MDS patients
(RA+RARS)
~ 15% of MDS patients
(RCMD±RS)
5–6 years
5–6
years
36% low-risk
~ 20% of MDS patients
(RCMD±RS)
years
Courtesy of Dr. U. Germing.
50% int-1
3
Iron overload in MDS—Consensus Meeting
Nagasaki, Japan, May 11, 2005
Question
Consensus
How would you define the role
of chelation therapy in MDS?
Highly likely to be clinically
important in a subgroup of patients
What does chelation therapy
need to achieve in MDS patients
with iron overload?
– Prevention of complications
– Treatment of complications
– Improvement of survival
What are the clinical
consequences
of no iron chelation?
Potential cardiac, hepatic, and
endocrine complications
In patients with MDS, when would
you assess body iron stores?
– At diagnosis
– At regular intervals (considering
transfusion rates)
Gattermann N, et al. Hematol/Oncol Clin North Am. 2005;19(suppl 1):18.
Iron overload in MDS—Consensus Meeting
Nagasaki, Japan, May 11, 2005
Question
Consensus
How frequently would you monitor
iron overload?
At least every 3 months in patients
receiving transfusion
Which tools would you use to
diagnose and monitor iron
overload?
– Serum ferritin
– Transferrin saturation
– Liver MRI
What would you use most
frequently?
Serum ferritin
When would you start chelation
therapy?
Serum ferritin >1000–2000 ng/mL
considering rate of transfusions
For how long would you continue
chelation therapy?
As long as transfusion therapy
continues (as long as iron overload
is clinically relevant)
Iron overload in MDS—Consensus Meeting
Nagasaki, Japan, May 11, 2005
Question
Consensus
What is the patient profile of who might
benefit from the treatment of iron overload ?
– Transfusion-dependent patients
– Low risk MDS: IPSS low or Int-1
– WHO-type RA and RARS and 5q– Candidates for allografting
– MDS patients with documented
stable disease
– Ferritin levels >1000–2000 ng/mL
or other evidence of significant
tissue iron overload
– Absence of comorbidities severely
limiting prognosis
NCCN Guidelines
Myelodysplastic Syndromes
• For relatively low-risk patients with excessive iron accumulation
resulting from the number of red blood cell (RBC) transfusions
received, iron chelation therapy should be instituted
• This treatment is used predominantly for patients with relatively
lower-risk MDS, whose clinical course suggests ongoing chronic
RBC transfusion need, and for those with concurrent cardiac or
hepatic dysfunction
• . . . generally administered for patients who have previously
received 20–30 units of RBCs, for whom ongoing RBC
transfusions are anticipated and for those with serum ferritin
levels >2500 µg/L
• Monitoring serum ferritin may be useful, aiming to decrease
ferritin levels to <1000 µg/L
NCCN Practice Guidelines in Oncology. V3. Myelodysplastic Syndromes. 2006.
Improved Survival in Patients with MDS
Receiving Iron Chelation Therapy
Retrospective review of 178 patients
(36 RA, 42 RARS, 28 RAEB, 16 RAEB-T or AML,
25 CMML, 31 other)
28
Ferritin ≥2000 ng/mL
22
Clinical evidence
of iron overload
18
10 No-ICT
Chelation
therapy
Median overall survival
for low or int-1 IPSS
Not reached
at 160 mo
P <.03
“Although we were not able to demonstrate
a decrease in organ dysfunction
in patients receiving ICT for MDS,
there was a significant improvement in
overall survival.
These are to our knowledge the first data
documenting improvement in clinical outcome
in patients with MDS receiving ICT.”
40 mo
(0.7–224)
Leitch H, et al. Blood. 2006;108:Abstract 249.
Iron Chelation Therapy Improves Survival in
Regularly Transfused MDS Patients—A
Prospective Analysis by the GFM
Survival Distribution Function
1.00
Median Survival: 63 months (whole group)
115 vs 51 months (P <.0001)
0.75
0.50
CT
0.25
No CT
0.00
0
50
100
150
Diagnosis to Death Time (months)
GFM = Groupe Francophone des Myelodysplasies.
Rose C, et al. Blood. 2007;110:Abstract 249.
200
250
IPSS = low
IPSS = int 1
Median: not reached
vs 69 months (P <.002)
Median: 115 vs 50 months
(P <.003)
1.00
Survival Distribution Function
Survival Distribution Function
Survival–According IPSS
Chelation therapy
0.75
0.50
No chelation therapy
0.25
1.00
0.75
Chelation therapy
0.50
No chelation therapy
0.25
0.00
0.00
0
50
100
150
200
Diagnosis to Death Time (months)
Rose C, et al. Blood. 2007:110:Abstract 249.
250
0
20
40
60
80
100
Diagnosis to Death Time (months)
120
140
The Relative Importance of Iron
Overload in MDS Morbidity
Iron chelation
Complications of
chronic anaemia
Complications of
marrow failure
Clinical
problems
in MDS
Leukaemic
transformation
Courtesy of Dr. N. Gattermann.
Problems of
aging
Comcomitant
diseases
Summary





Iron overload in MDS starts before transfusion
therapy is initiated. This is due to ineffective
erythropoiesis
The most important cause of iron overload in MDS is
chronic transfusion therapy
MDS patients with unfavorable prognosis usually do
not survive long enough to develop the clinical
consequences of iron overload
MDS patients with good prognosis (RA, RARS, 5q-)
should receive iron chelation therapy if transfusiondependent
Besides preventing iron-related organ damage, iron
chelation therapy may also improve bone marrow
function in patients with MDS