Emesis and Anemia
M. DICATO
Hematology- Oncology
Centre Hospitalier
1210 Luxembourg
Dicato.mario@chl.lu
mdicato@gmail.com
Antiemetic Agents
1981: R. Gralla: Metoclopramide
1982: M. Aapro: Corticosteroids
1983: M. Dicato: Cannabis
1989: Setrons
1999: NK-1 inhibitors
NEUROTRANSMITTERS AND EMESIS
Dopamine/
DA RAs
Serotonin/
5-HT3 RAs
Histamine
Endorphins
Emetic
reflex
Substance P/
NK-1 RAs
Acetylcholine
GABA
Cannabinoids
DA = dopamine; GABA = gamma-aminobutyric acid; NK = neurokinin; RAs = receptor antagonists
5HT3-RA
Substance P (central)
Postcisplatin: Differential Involvement
of Neurotransmitters Over Time
ACUTE (Day 1)
Serotonindependent
mechanisms
(peripheral)
0
8
DELAYED (Days 2–5)
Substance P–dependent
mechanisms
(central)
12
24
Hours after cisplatin
Hesketh PJ et al Eur J Cancer 2003;39:1074–1080.
120
Gralla RJ et al. N Engl J Med 1981;305.905-909.
Natural History of Delayed
Nausea and Vomiting
Percent
with Nausea
or Vomiting
80
70
60
50
40
30
20
10
0
Vomiting
Nausea
0-24
24-48
48-72
72-96
96-120
Hours after Cisplatin
Kris MG. J Clin Oncol 1985;3:1379-1384.
Presence of acute nausea and vomiting
as a prognostic factor for delayed N/V
Percent of Patients with Delayed Symptoms
100
90
80
70
60
50
40
30
20
10
0
ACUTE
NO
ACUTE
Vomiting
ACUTE
NO
ACUTE
Nausea
IGAR. Support Care Cancer 1999;8:229-232.
Perception vs Reality
Moderately Emetogenic Chemotherapy
Percent of patients
70
60
50
40
30
20
10
0
Acute
Nausea
Acute
Vomiting
MD/RN Prediction
Grunberg SM et al. Cancer 2004;100:2261-8.
Delayed
Nausea
Delayed
Vomiting
Patient Experience
Dose-finding study of dexamethasone
Acute nausea and vomiting from HEC
• Patients: Cisplatin > 50 mg/m2 +/- others
• All received ondansetron 8 mg IV
• Randomized to receive single IV doses of DEX
Dexamethasone
4 mg
8 mg
12 mg
20 mg
N
No Emesis
No Nausea
133
136
130
131
69%
69%
79%
83%
61%
61%
67%
71%
Conclusions: Dexamethasone 20 mg should be the standard.
No difference in adverse effects.
IGAR. JCO 1998;16:2937-42.
Dose-finding study of dexamethasone
Acute nausea and vomiting from MEC
• Patients: Anthracyclines, carboplatin or
cyclophosphamide
• All received ondansetron 8 mg IV
• Randomized to receive different doses of DEX
Dexamethasone
8 mg iv
24 mg iv
8 mg iv + 4 mg x 4
N
No Emesis
No Nausea
195
195
195
89.2%
83.6%
84.6%
61.0%
56.9%
66.7%
Conclusions: Dexamethasone 8 mg iv should be the standard.
No difference in adverse effects.
IGAR. JCO 2004;22:725-9.
Setrons
Key Features of Palonosetron
•
•
•
•
•
Highly selective for 5-HT3 receptor
High binding affinity
Extended half-life (~40 hours)
Single, fixed IV dose
Prolonged duration of effect
ASCO 2011
Abstr.: 9079: Palonosetron in patients on
irinotecan and on oxaliplatin regimens in CRC
D1 Palo 2.5mg+ dex 12mg D1 Ond 16mg + dex 12mg
p
>Aug 2009
<Aug 2009
N= 305
148
157
Risk of failure
28.4%
50.3%
< 0.001
irino
28.6%
55.7%
= 0.006
oxali
28.3%
44.9%
= 0.026
Palonosetron seems to be a better setron
NK1 RA
HEC Studies: Cycle 1
Primary Endpoint: Complete Response (0-120 h)
100
p<0.001
p<0.001
p=0.003
Percentage of Patients
90
80
73%
72%
70
60
63%
61%
52%
50
43%
40
30
20
10
0
Hesketh
Poli-Bigelli
Aprepitant Regimen
Standard Regimen
Schmoll
MEC study: Cycle 1
Primary Endpoint: Complete Response (0-120 h)
100
90
Primary
Efficacy
Analysis
p<0.001
p=ns
76%
80
Aprepitant Regimen (N=433)
Standard Regimen (N=424)
Percentage of Patients
p=0.015
70
59%
60
59%
56%
51%
50
42%
40
30
20
10
0
Complete
Response
(CR)
No Vomiting
No Rescue
Therapy
Components of CR
Warr DG et al. J Clin Oncol 2005;23:2822-2830.
Sustained No Vomiting Rate
Aprepitant Regimen
Standard Regimen
80
76%
70%
67%
63%
Percentage of Patients
60
59%
48%
40
42%
39%
Log-rank test, p<0.001
20
0
1
Number at Risk:
2
3
4
Time (Cycle) since First Chemotherapy
Aprepitant Regimen
432
296
258
234
Standard Regimen
424
224
168
139
Herrstedt J et al.
Cancer 2005;
104:1548-55.
STANDARDS OF CARE
ACUTE NAUSEA AND VOMITING
Emetic risk group
Antiemetics
High
Serotonin antagonist +
dexamethasone + aprepitant
Anthracycline +
Cyclophosphamide (AC)
Serotonin antagonist +
dexamethasone + aprepitant
Moderate (other than AC)
Serotonin antagonist +
dexamethasone
Low
Dexamethasone
Minimal
No routine prophylaxis
The Antiemetic Subcommittee of MASCC. Ann Oncol 2006;17:20-28.
ESMO Minimum Clinical Recommendations. Ann Oncol: in press.
STANDARDS OF CARE
DELAYED NAUSEA AND VOMITING
Emetic risk group
Antiemetics
High
Dexamethasone + aprepitant
Anthracycline +
Cyclophosphamide (AC)
Aprepitant or dexamethasone
Moderate (other than AC)
Dexamethasone
A serotonin antagonist may
be used as an alternative
Low
No routine prophylaxis
Minimal
No routine prophylaxis
The Antiemetic Subcommittee of MASCC. Ann Oncol 2006;17:20-28.
ESMO Minimum Clinical Recommendations. Ann Oncol: in press.
Emesis: CINV (ASCO 2010, abstr. 9021)
• NK1-RAs:
– Fosaprepitant (IV) 1 day = 3 days Aprepitant (po)
– in combination ondansetron and dexa
– HEC (cispl > 70 mg/m²) (abstr 9021)
aprepitant
fosaprepitant
nr. pts
1138
1109
CR
72.3
71.9
CR delayed
72.2
74.3
no Vom
74.6
72.9
Emesis: CINV (ASCO 2010, abstr. 9020)
• Olanzapine (Zyprexa ®):
• compared to aprepitant
• 50 pts (27 O vs 23 A) in HEC (?)
• statistically not different
a) old story (?): -3 US trials (Hoosier group, 15 – 30 – 40 pts)
-1
Chinese trial (229 pts) : randomized vs pl
- no
large studies over 6-10 y period
MASCC ESMO 2010
Antiemetic Treatment
Consensus Guidelines
Emetic
Risk Group
Risk (% of
Patients)
Acute Prevention
Delayed Prevention
High/
>90%
**
5-HT3 + dex +
[fos]aprepitant
Dex+ aprepitant d2-3
Dex d4
Moderate
(AC)
Moderate
30-90%
5-HT3* + dex +
[fos]aprepitant
Palonosetron+dex
aprepitant
Low
10-30%
Single agent (dex,dopaRA No routine prophylaxis
5-HT3)
Minimal
< 10%
No routine prophylaxis
Dex days 2-3
No routine prophylaxis
*2010: if an NK1RA is not available, palonosetron is the preferred agent for AC chemotherapy
NB: OXALIPLATIN IS CONSIDERED MODERATELY EMETOGENIC
CONTROLLING CHEMOTHERAPY-INDUCED EMESIS:
PROGRESS OVER THE PAST 30 YEARS
Cisplatin (Highly Emetic)
“AC” Chemotherapy
5-day Complete Control:
100% -
85% 75%
60% 50%
75% 50% 50%
50% 25% -
0%
10%
1978
1988
No Useful Rx
HD-MCP + Dex
1998
5-HT3 + Dex + Del
2008
All + NK1
ASCO 2011
• Abstr.: 9078: Aprepitant active in biological
therapies induced severe pruritus.
N= 22 pts. Lung Ca 10, CRC 9, other 3.
Erlotinib 10, cetuximab 10, sunitinib 1,
imatinib 1.
Aprepitant 125mg on d1, 80 mg on d3-5
VAS median 8, after 1 week 1, decrease of
88%. 2 did not respond
Anemia of Cancer
Anemia: definition
Female: Hb <12g/dl
Male:
Hb <14 g/dl
Anemia: mild 12- 10
moderate 8- 10
severe 6.5- 8
life- threatening <6.5
M. Dicato
Pathogenesis of Anemia in
Malignancies
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Inadequate erythropoietin levels
 Inflammatory cytokines (e.g. IL-1, TNF, IFN-)
 Number of erythroid precursors
 Sensitivity of erythroid precursors
towards erythropoietin
Renal insufficiency
Infection
Chemoradiotherapy
Hypervolemia
Bone marrow infiltration
Bleeding
Hemolysis
Splenomegaly
Vit. B12 %, Nutritional deficits
…
M. DICATO
Signs and symptoms of anemia
CNS
• Debilitating fatigue
• Dizziness, vertigo
• Depression
• Impaired cognitive function
Gastrointestinal system
• Anorexia
• Nausea
Vascular system
• Low skin temperature
• Pallor of skin, mucous
membranes, and conjunctivae
Immune system
• Impaired T-cell and
macrophage function
Cardiorespiratory system
• Exertional dyspnea
• Tachycardia, palpitations
• Cardiac enlargement, hypertrophy
• Increased pulse pressure,
systolic ejection murmur
• Risk of life-threatening cardiac
failure
Genital tract
• Menstrual problems
• Loss of libido
Ludwig. Semin Oncol 1998;25(3 Suppl 7):2–6
Productivity of Indonesian Rubber Tappers Varies
With Hb Levels
Take-Home Pay
(Rupiahs per Week)
4000
3500
3000
2500
2000
1500
9
10
11
Basta SS, et al. Am J Clin Nutr. 1979;32:916-925.
12
Hb (g/dL)
13
14
15
Anemia is Common in Cancer Patients Receiving
Chemotherapy
75% of patients receiving chemotherapy are anaemic at baseline
or become anemic during a 6 month follow up period
% Patients Ever Anaemic
During the Survey
100
90
80
75%
70
72%
62%
60
50
40%
40
38%
30
20
10
0
CT
Combination Concomitant
CT/RT
CT/RT
No
Treatment
1145
n=
8470
1955
299
*Analysis Population: n = 14 912 / Missing data n=216
RT
1543
Ludwig EJC 2004
Major diseases linked to TNF and its family members
Autoimmune
Deficiency
Syndrome
(AIDS)
Hematopoiesis
Protection from
Bacterial inflection
Innate
Immunity
Tumor
regression
Crohn’s
disease
F5
Immune
surveillance
Systemic lupus
erythematosus
Alzheimer’s
disease
TNF
Multiple
sclerosis
Transplant
rejection
Osteoporosis/
Bone resorption
Septic
shock
Diabetes
(type II)
Lymphoproliferative
diseases
Rheumatoid
arthritis
Pulmonary
fibrosis
Heart failure
Atherosclerosis
Liver
disease
Allergic
asthma
Fever
Tumor
metastasis
Tumorigenesis
Aggarwal BB, Nature Rev Immunol. 2003 Sep;3(9):745-56
TNFa (1)
TNFa
 decrease of GATA-1 mRNA
decrease of GATA-1 protein
induces NF-kB binding activity
M. DICATO
TNFa (2)
TNFa  inhibits induction of erythroid differentiation
 inhibits expression of erythroid specific genes:
y-globin and EpoR
 affects induced transcription factor GATA-1
 Blocks binding of GATA-1 to its DNA sequence
Conclusion: TNFa acts at several levels of the regulation of
erythroid genes, in particular GATA- 1.
Inhibition of GATA-1 correlates to increased NF-kB activity
M.Dicato, L. Plawny, M. Diederich: Ann. Oncol. 2010,
Fig. 3 – Pathophysiology of anemia. Tumor cells act on erythrocytes through macrophages by cytokine release, which leads
to impaired erythropoiesis. Released cytokines can affect BFU-E and CFU-E proliferation, iron utilization and Epo
production. TNFa can also affect erythrocyte half-life. TNFa, tumor necrosis factor alpha; IFN, interferon; IL, interleukin;
BFU-E, burst-forming units-erythroid; CFU-E, colony-forming units-erythroid; Epo, erythropoietin (adapted from Ref. [68]).
b i o c h e m i c a l pharmacology xxx ( 2 0 0 9 ) xxx–xxx 5
BCP-10047; No of Pages 8
Please cite this article in press as: Buck I, M. Dicato, M. Diederich et al., Linking anemia to inflammation and cancer: The crucial
role of TNFa, BiochemPharmacol (2009), doi:10.1016/j.bcp.2008.12.018
Body Iron Regulation
Courtesy: Patrice Cacoub
Iron Cycle.
Fleming RE, Ponka P. N Engl J Med 2012;366:348-359
Fleming RE, Ponka P. N Engl J Med 2012;366:348-359
Regulation of Hepatocellular Hepcidin
Expression.
Fleming RE, Ponka P. N Engl J Med 2012;366:348-359
Fleming RE, Ponka P. N Engl J Med 2012;366:348-359
Treatment options in CIA
CIA treatment
Main advantages/ concerns
Blood transfusions
• Immediate correction of anaemia,1 however
associated risk level is still debated
Oral iron
• I.v. iron superior to oral iron1
ESA without iron
• Reduction of transfusion requirements2–4
• Improvement in QoL2–5
• 50–70% response rate2,6–8
ESA with oral iron
• Same advantages as ‘without oral iron’, however
more side effects1,5,9
ESA with i.v. iron
•
•
•
•
Increased patient response rate of up to 90%10–14
Correction of FID10–14
Reduction of transfusion requirements10
Improved QoL11
CIA, chemotherapy-induced anaemia; QoL, quality of life; FID, functional iron deficiency
1. National Comprehensive Cancer Network ® 2009; Practice guidelines in oncology V.3.2009; 2. Littlewood TJ et al. J Clin Oncol 2001;19:2865–2874; 3.
Vansteenkiste J et al. J Natl Cancer Inst 2002;94:1211–1220; 4. Bohilus J et al. J Natl Cancer Inst 2006;98:708–714; 5. Bokemeyer C et al. Eur J Cancer
2007;43:258–270; 6. Glaspy J et al. J Clin Oncol 1997;15:1218–1234; 7. Demetric GD et al. J Clin Oncol 1998;16:3412–3425; 8. Gabrilove JL et al. J Clin Oncol
2001;19:2875–2882; 9. Aapro MS & Link H. Oncologist 2008;13(Suppl 3):33–36; 10. Bastit L et al. J Clin Oncol 2008;26:1611–1618; 11. Auerbach M et al. J Clin
Oncol 2004;22:1301–1307; 12. Pedrazzoli P et al. J Clin Oncol 2008;26:1619–1625; 13. Henry DH et al. Oncologist 2007;12:231–242; 14. Hedenus M et al.
Leukemia 2007;21:627–632
RBC Transfusion
Potential risks of
red blood cell transfusions (1)
• Transfusions have well-recognized liabilities
–
–
–
–
–
–
–
Infections: HIV 1:1.000.000, others.., ? unknown…
Acute lung injury: whole blood 1:432, RBC 1:557.000
Volume overload
Acute and delayed reactions
Alloimmunization
Iron overload
Suggestions of adverse cancer-related outcomes
• Demand on blood supply would intensify
• Multiple transfusions needed to maintain Hb level
sufficient to minimize signs and symptoms of anemia
K. Nilsson et al. Arch. Surg 2007,142: 126-31
• N= 14014 pts
• Male:
transfusion
no transfusion
• Female
transfusion
no transfusion
VTE %
p
0,7
0,8
0.84
2,1
0,9
<0,001
Colorectal resection and blood transfusions:
• 0,97% of pts. developed VTE while in hospital
• increased risk of VTE in women, not in men
Blood transfusions are associated
with a high risk of thrombosis
• Red blood cell (RBC) transfusions were associated
with a high risk of venous and arterial
thrombotic events
– Patients receiving RBC transfusions
 7.2% developed venous thromboembolism
 5.2% developed arterial thromboembolism (values significantly
greater than remaining study population; p<0.001)
• RBC transfusions were associated with increased
risk of mortality in hospitalised patients with cancer
(OR, 1.34; 95% CI=1.29–1.38)
OR, odds ratio; CI, confidence interval
Khorana A et al. Arch Intern Med 2008;168:2377–2381
Red Blood Cell (RBC) Transfusion
Indications1
 Acute blood loss
– Loss of circulating blood volume
– Concentration of haemoglobin
– Further bleeding resulting from abnormal haemostasis
 Anaemia in critical care
 Perioperative transfusion
 Chronic anaemia including chemotherapy-induced anaemia
Compatibility2
 Must be ABO and Rh compatible
 Antibody detection and crossmatch required
Shelf life3
 Refrigerated red blood cells: 42 days
 Once opened: 24 hours at 1–6°C2
Administration2
 Unless otherwise indicated by the patient's clinical condition, rate
of infusion no greater than 2 mL/min for the first 15 min
 One unit usually takes 45–90 minutes to infuse
 Transfusion should not take longer than 4 hours due to risk of
bacterial proliferation at room temperature
Erythropoiesis
Stimulating Agents
Benefit of ESAs
• Decrease Rate of Transfusions
• QoL?
• Fatigue?
Fandrey /Dicato, 2009
BEST Study
• Littlewood study: subgroup of 134 patients with
breast cancer had better survival. Not a study
endpoint, not powered for statistical significance.
Hypothesis generation for a larger study
• BEST: Epo vs. Placebo qw., 939 breast cancer
patients receiving chemotherapy. Hb to be
maintained 12-14g/dl.
Terminated prematurely: Interim results at 4 mo.:
Mortality (8,7% vs 3,4%) and fatal thrombotic events
(1,1& vs 0,2%)
ODAC 2008: FDA
Study
N
1 Endpoint
ESA adverse
outcome
939
344
733
114
12 months OS
Hb
RFS,OS
PFS
↓ 12 mo OS
↓ OS
↓ RFS, OS
↓ OS
RT
ENHANCE(H/N)
DAHANCA(H/N)
351
522
LRPFS
LRC
↓ LRPFS, OS
↓ LRC, OS
No CT no RT
Can-20(NSCLC)
103(Heterogenous)
70
989
QOL
Transfusion
↓ OS
↓ OS
Chemo
BEST(breast)
161(Lymphoid)
Prepare(breast)
GOG191(cervical)
Cochrane Analysis (1)
J. Bohlius et al. Lancet, 2009, 373:1532
N= 13933 patients, 53 trials
Mortality: during study period incl. 28 days after end of
active study
Overall survival: death from any cause from
randomisation to last available follow-up
EPO receptors in cancer and noncancer patients
Figure 3. Commercial polyclonal anti-EPOR M-20 antibodies detect multiple proteins in Western blots
(left) and erroneously stain structures in EPOR knockout mice (right)
Copyright ©2008 AlphaMed Press
Fandrey, J., M. Dicato Oncologist
2008;13(Suppl 3):16-20
Pooled Analysis of
Individual Patient-Level Data
From All Randomized, Double-Blind, PlaceboControlled Trials of Darbepoetin Alfa in the
Treatment of Patients With
Chemotherapy-Induced Anemia
Heinz Ludwig, Jeffrey Crawford, Anders
Österborg, Johan Vansteenkiste, David H.
Henry, Alex Fleishman, Ken Bridges, and
John A. Glaspy
J Clin Oncol 27; published ahead of print on April 20, 2009.
Results
Percentage Event-free
Progression-free Survival (Including LTFU)
100
90
80
70
60
50
40
30
20
10
0
HR = 0.93 (95% CI: 0.84 to 1.04)
DA
Placebo
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230240
Time to Disease Progression or Death (weeks)
Patients at risk:
DA
1200 1020 401 270 191 147 121 98 84
Placebo
912 758 399 251 184 144 121 101 83
HR, hazard ratio; DA, darbepoetin alfa.
72
70
61
58
56
52
54
45
50
44
48
40
44
37
40
33
39
32
34
30
26
26
15
17
7
8
2
1
N. Engl. J. Med. 2009
Risk/ Benefit of Anemia Treatment
• VTE Risk in Anemia Treatment :
– ESAs and VTE Risk (HR: 1, 3 à 1.9 depending
on Hb level targeted (JAMA, 2008)
– TRANSFUSION and VTE Risk
( Arch Int. Med 2008 : HR: 1.34)
Epo proangiogenic effect
• In human glioma: J. Neuro-oncology 2011, 102:
51-58
• In melanoma: Int. J. Exp. Pathol. 2010, 91-495-99
Antagonistic effect of Epo(E) on treatment
with Trastuzumab(T) in Breast Cancer
• Co-expression of EpoR and EGFR-2 (Her-2) in a
significant percentage of human BC samples.
• Concurrent treatment of the cells with E and T
reduced response to T both in vitro and in vivo.
Jak-2 mediated activation of Src and of PTEN
could be a mechanism thru which E antagonizes T
and reduces clinical response.
• Retrospective study: 37 pts with both drugs
compared to 74 pts only T: better PFS and OS in
the non E group.
Cancer Cell 2010, 18: 423-35
Hematologica 2010, 95:1823
• Epo enhances pro-inflammatory activity and
function of macrophages
• Dendritic cells express Epo-R and Epo increases
survival and function
• Macrophages may produce functional EPO
• EPO may attenuate inflammatory response,
delaying appearance of TNF and decreasing IL-6 and TNF
• Macrophages can be target for EPO
• Epo improves wound healing
ASCO 2011
Abstr 9048 GELA LNH 03-6B: phase 3 : Survival effect
of Darbepoietin in DLBCL treated with immunochemotherapy R-CHOP 14 or R-CHOP 21
Median follow up 44 mo. End points PFS, DFS, OS and
Toxicity. N= 602 pts. Baseline Hb 12.3g
Darbepoietin
Conventional
Median Hb level
11.6g
10.8g
PFS at 3years
66%
58%
p
0.04
DFS
0.02
OS
0.16
VTE: Darb vs Control: 15 vs 6%
Concl.:Better PFS. First evidence of positive survival impact
of Darb in patients receiving chemotherapy for malignancy
SURVIVAL IN GELA NHL STUDY
2-year PFS and OS with/without concomitant ESA
were 61% vs. 51% (p=NS) and 74% vs. 63% (p=NS),
Delarue et al
Epoetin Alfa in Patients With AdvancedStage Hodgkin's Lymphoma: Results of
the Randomized Placebo-Controlled
GHSG HD15EPO Trial
A. Engert et al
JCO 2010, 28:2239- 45
Epo in Hodgkin Disease. A. Engert JCO 2010
ASCO 2011
• Abstr. TPS235: Sotatercept: fusion protein,
extramembranous activin receptor IIA linked
to IgG1 Fc increases release of RBC from
marrow to blood
NSCLC treated with cDDP regimen: open for
enrollment
Iron Therapy
K-M Curve of Time to Hematopoietic
Response
Auerbach M ESMO 2009
IV Iron
No IV Iron
100%
90%
Cumulative Percent
80%
70%
60%
50%
40%
30%
Time to Hematopoietic Response
K-M Median Weeks (95% CL)
No IV Iron
IV Iron
12 (10, 15)
8 (7, 9)
20%
10%
0%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
39
55
33
53
30
48
24
41
21
38
19
35
13
25
Study Week
N 116
N 122
116
121
107
117
94
107
86
103
72
94
65
83
60
74
47
62
Overview of published Studies evaluating
IV Iron and ESA in Oncology
Auerbach et al[
(n = 157)
Henry et al
(n = 187)
Hedenus et al
(n = 67)
Bastit et al
(n = 398)
Pedrazzoli et al[
(n = 149)
Treatment
arms
IV iron (TDI or
bolus) vs oral iron
v no iron
IV iron vs oral
iron v no iron
IV iron vs no iron
IV iron vs no/oral
iron
IV iron vs no iron
Inclusion
criteria, Hb
10.5 g/dL
< 11 g/dL
9-11 g/dL
< 11 g/dL
11 g/dL
Inclusion
criteria,
TSAT/SF
< 200 SF
or < 20 % TSAT
>100 SF
or > 15% TSAT
stainable iron in
bone marrow
> 10 SF and
> 15% TSAT
> 100 SF and
> 20% TSAT
IV iron
dosing
Iron dextran TDI
or 100 mg to
calculated dose
Ferric gluconate
125 mg QW for 8
weeks
Iron sucrose
100 mg QW
(Weeks 1-6)
100 mg Q2W
(Weeks 8-14)
Ferric gluconate
or iron sucrose
200 mg Q3W
Ferric gluconate
125 mg QW for
6 weeks
ESA dosing
40,000 U/week
epoetin alfa
40,000 U/week
epoetin alfa
30,000 U/week
epoetin beta
500 µg Q3W
darbepoetin alfa
150 µg QW
darbepoetin alfa
for
12 weeks
Hb
response
IV iron: 68%
Oral iron: 36%
No iron: 25%
IV iron: 73%
Oral iron: 45%
No iron: 41%
IV iron: 93%
No iron: 53%
IV iron: 86%
No/oral iron: 73%
IV iron: 77%
No iron: 62%
Percent of
patients
undergoing
transfusion
IV iron: 12%
Oral iron: 7%
No iron: 19%
Week 5 to EOTP:
IV iron: 3%
Oral iron: 8%
No iron: 11%
IV iron: 7%
No iron: 3%
Week 5 to EOTP:
IV iron: 9%
No/oral iron: 20%
IV iron: 3%
No iron: 7%
71
Conclusions
• The effects of ESA QW are enhanced in
patients receiving IV iron supplementation
– Haematopoietic response rates of patients in the
per-protocol population receiving ESA QW with
or without IV iron were 92.5% vs 70%,
(p=0.0033) respectively
• The safety profile of ESA QW was comparable
between study arms
Pedrazzoli P et al. J Clin Oncol 2008;26:1619–1625
IV Iron Use in Cancer Patients
• Summary of clinical findings
–
–
–
–
Generally well tolerated
Increased rate of Hb response
Reduction of RBC need
IV iron supplementation optimizes response to ESA therapy in
patients with chemotherapy induced anemia independent of Fe
parameters
• Limitations
–
–
–
–
Heterogeneous inclusion criteria
Identification of patients likely to benefit from IV iron unclear
No long-term follow-up data for IV iron in cancer patients
No data showing that the combination of an ESA with iron is safer
than ESA alone
– “IV-iron only” studies still to be performed
• Guideline Recommendations
M. DICATO
73
International guidelines
Recommendation
ESMO 2010
Initiate ESA therapy
HB <=10 with Chemo
Iron supplementation
Pts with iron deffiiciency, IV
iron leads to higher Hb
increment and reduces
RBCT
Transfusions
Iron level monitoring
Baseline and periodic, +
CRP, TFS and ferritin
Target Hb
Increase <2g or prevent
further decline
Should not exceed 12g
If Hb >12 dose adaptations
should be made
Withold at Hb>13 until it
falls <12g
Schrijvers et al, Ann Oncol 21 suppl 5, 2010
Ferric Carboxymaltose fot the Correction of Cancer_ and
Chemotherapy induced Anemia in Clinical Practice.
T. Steinmetz et al. EHA 2011, abstr. 1595
Ferric Carboxymaltose for the Correction of Cancer_ and
Chemotherapy induced Anemia in Clinical Practice.
T. Steinmetz et al. EHA 2011, abstr. 1595
Treatment options in CIA
CIA treatment
Main advantages/ concerns
Blood transfusions
• Immediate correction of anaemia,1 however
associated risk level is still debated
Oral iron
• I.v. iron superior to oral iron1
ESA without iron
• Reduction of transfusion requirements2–4
• Improvement in QoL2–5
• 50–70% response rate2,6–8
ESA with oral iron
• Same advantages as ‘without oral iron’, however
more side effects1,5,9
ESA with i.v. iron
•
•
•
•
Increased patient response rate of up to 90%10–14
Correction of FID10–14
Reduction of transfusion requirements10
Improved QoL11
CIA, chemotherapy-induced anaemia; QoL, quality of life; FID, functional iron deficiency
1. National Comprehensive Cancer Network® 2009; Practice guidelines in oncology V.3.2009; 2. Littlewood TJ et al. J Clin Oncol
2001;19:2865–2874; 3. Vansteenkiste J et al. J Natl Cancer Inst 2002;94:1211–1220; 4. Bohilus J et al. J Natl Cancer Inst 2006;98:708–
714; 5. Bokemeyer C et al. Eur J Cancer 2007;43:258–270; 6. Glaspy J et al. J Clin Oncol 1997;15:1218–1234; 7. Demetric GD et al. J
Clin Oncol 1998;16:3412–3425; 8. Gabrilove JL et al. J Clin Oncol 2001;19:2875–2882; 9. Aapro MS & Link H. Oncologist 2008;13(Suppl
3):33–36; 10. Bastit L et al. J Clin Oncol 2008;26:1611–1618; 11. Auerbach M et al. J Clin Oncol 2004;22:1301–1307; 12. Pedrazzoli P et
al. J Clin Oncol 2008;26:1619–1625; 13. Henry DH et al. Oncologist 2007;12:231–242; 14. Hedenus M et al. Leukemia 2007;21:627–632
International guidelines
Recommendation
ASH/ASCO1
EORTC2,3
Canadian4
NCCN5
Initiate ESA therapy
Hb approaching
or <10 g/dL
Symptomatic
Hb 9–11 g/dL
<11 g/dL
Consider if
Hb <11 g/dL
Consider use
with ESAs
Iron
deficiency
also present
Consider use
with ESAs
Iron
deficiency and
with ESAs
Minimal use
Minimal use
Avoid use
where
possible
Baseline and
periodic
monitoring
–
Baseline and
periodic
monitoring
Monitor TSAT
and ferritin
≥12 g/dL
≈12 g/dL
12 g/dL
<12 g/dL (?)
Iron supplementation
Transfusions
Iron level monitoring
Target Hb
TSAT, transferrin
Considered for
very severe
anaemia or
individual clinical
needs
1. Rizzo DJ et al. J Clin Oncol 2008;26:132–149; 2. Bokemeyer C et al. Eur J Cancer 2007;43:258–270;
3. Aapro MS & Link H. Oncologist 2008;13(Suppl 3):33–36; 4. Mikhael J et al. Curr Oncol 2007;14:209–217;
saturation
5. National Comprehensive Cancer Network® 2010; Practice guidelines in oncology V.2.2010
Biosimilars
Biosimilars (1)
For regulatory EMA to be approved:
• Active substance as suc h and in the marketed
form
• Preclinical toxicity and pharmacology
• Pharmacodynamic and pharmacokinetic
activities in man
• Clinical activity and toxicity in phase III
Biosimilars (2)
Requirements by EMA
• Phase I
• Phase III
• Follow-on for 12 months of treated patients
for possible immunogenicity
Table 2: Biosimilar
Development requirement
Biosimilar
Comparator
Quality-Manufacturing:
Demonstration of product quality
Quality-Manufacturing
Demonstration of product quality
and similarity with the original product
Préclinical
Préclinical
Pharmacodynamics (PD): in vitro & in vivo tests.
Pharmacodynamics (PD): in vitro & in vivo tests.
Toxicology: Repeated dose studies and local tolerance
Toxicology: repeated studies and local tolerance
Clinical
Clinical
Pharmacokinetics (PK) & PD
Equivalence PK & PD equivalence vs original
product
Phase II dose-response
No dose-response
Phase III study of effectiveness in each indication
Security at least 12 months (immunogenicity)
Phase III comparative study of efficacy in an
indication (if same mode of action for other
indications
Duration and cost
Security at least 12 months (immunogenicity)
Duration and cost
5-10 years
3 - 5 years
30 to 50 millions euros
Approximately one hundred million euros
NB: A comparator has 20 years of patent protection and 10 years of "data Exclusivity" therefore a
monopoly position for 10 to 15 years before a biosimilar can be registered.
Figure 2: Electrophoresis of Rhu EPO
unauthorized in Europe and not « Biosimilar »
A
B
Cathode
From Schellekens H et al. Poster ERA-EDTA Congress 2004
VII China
Ref. Eprex®
Ref. Eprex®
VII China
VI India
V Argentina
IV Argentina
IIIB Korea
IIIA Korea
IIB Korea
IIA Korea
IB Korea
IA Korea
Ref. Eprex®
Anode
Epoetine Concentration (mUI/ml)
igure 3: Pharmacokinetic profile similar to
F
the referent
Time (hours)
Binocrit® (n=37)

Comparator (n=37)

AUC 0-48h (mIUI/mL*h)
2044.9 ± 587.9

2095.0 ± 486.4

Median ± standard
deviation
Ratio : 96.9% [IC à 90% : 88.2 – 106.5%]


12
Hemoglobin concentration (g/dl)
Reticulocytes proportion (%)
igure 4: Pharmacodynamic profile similar
F
to the referent
Time (days)
AUEC Hb (g/dL*h) Median

AUEC RET (%*h) Median
Time (days)
Binocrit® (n=37)

Comparator (n=37)

0 236.6
1
1 501.05
0 457.7
1
1 634.33
Ratio Hb 98.9% [ IC à 90% : 97.7 – 100.2% ] - Ratio RET 93.4% [ IC à 90% : 88.3 – 98.8% ]

1

13

Figure 5: comparison of efficacy between
Biosimilar EPO and hemoglobin variation
Hemoglobin variation

Time (weeks)
1
17
Table 3: cost comparison between biosimilars
and comparison of EPO and GCSF
GCSF cost
EPO cost
Comparator: Filgrastim
Comparator: epoetin alpha
Neupogen 30: 119,10 euros
Eprex 30 000: 254,01 euros
Biosimilars:
Biosimilar:
Zarzio 30: 95,83 euros
Binocrit: 206,69 euros
Tevagrastim: 95,83 euros
Sources Vidal 2010.
P. Cornes, in M. Dicato Edit., Targeted Oncology, Springer UK 2011
P. Cornes, in M. Dicato Edit., Targeted Oncology, Springer UK 2011
Generic Substitution
• Highly effective: In USA each 1% increase in
generic prescribing reduces drug cost by 1.32
billion $ annually.
• In UK average cost of a generic is ¼ of the
original brand drug
• In generic substitution of the top 10
prescribed drugs in E.U. could release savings
of 20-48% to reinvest in improved patient care
Biosimilar Substitution
•
•
•
•
•
Biologic drug sales in US in 2010: >60 billion $
At present in Oncology in EU: G-CSF and Epo
Oncology McAb in 2015
Darbepoietin in 2016
Cost savings: average 20-30%
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