Management of anemia with erythropoiesis stimulating agents
Disclosures
Speakers bureau
AMGEN, Janssen Cilag, Vifor
Advisory boards
Vifor, Sandoz, Janssen-Cilag, AMGEN
Anemia ­ often present before diagnosis
Prevalence increases with age
Blood donors before diagnosis of MM
Frequency of anemia in patients with MM
95,0%
90,3%
Age
84,9%
85,0%
79,4%
75,0%
65,0%
60,0%
55,0%
18 - 49
4
50 - 59
5
60 - 69
6
> 70
Edgren et al. In J Cancer 2010
Birgegard et al Eur J Heamatol 2006
Investigation of patients with anemia
Exclude/diagnose
Vitamin B12 and folate deficiency
Iron deficiency
Severe infection
Hemolysis
Blood loss
Bone marrow insufficiency
DIC
Congenital anemia
Distinguish between anemia of myeloma and
chemotherapy associated anemia.
Consider that MDS may occur concomitantly
with myeloma
`Anemia of myeloma' ­ usually multifactorial in pathogenesis
Decreased oxygen delivery to the kidneys
Peritubular interstitial cells
Sense O2
Pro-erythroblasts in
Hypoxia induces
Bone marrow
erythropoietin (EPO)
reduced EPO production
Reduced EPO sensitivity
Shortened red cell survival
Inadequate iron supply
Important causes of anemia in multiple myeloma
· Inflammatory cytokines (e.g. IL-1, TNF, IFN-) and hepcidin
induction ­ impaired iron utilisation
· Erythropoeitin production
· Number of erythroid precursors
· Sensitivity of erythroid precursors towards erythropoietin
· Fas-L and TRAIL induced apoptosis of erythroid precursors
· Decreased osteoblast-induced stimulation of hematopoiesis
· Others
­ Renal insufficiency
­ Infection
­ Chemotherapy
­ Hypervolemia
­ Bone marrow infiltration
­ Hemolysis
Indications for use erythropoietins and for RBC transfusions
Consider ESAs
chemotherapy induced anemia
,chronic` anemia of myeloma
symptoms from anemia (Hb <11g/dl) or if Hb <10g/dl)
Consider RBC transfusions
symptomatic patients with Hb <8g/dl
in case rapid symptom improvement important
refractory to ESAs
Treatment Options for Anemia
Blood Transfusions
Erythropoietins
Different indications, benefits and risks
Hb <8g/dl
Hb <11g/dl or <10g/dl
Immediate increase in Hb
Slow increase in Hb
Short effect
Long term effect
Several risks including VTE,
risk for thromboembolic
infections, induction of
complications
lymphomas, and increased
risk for mortality in non-approved
mortality
indications
Treatment Options
Hb (g/dl)
16
Erythropoiesis Stimulating Substances (ESAs)
14
12
10
Red Cell Transfusions
8
6
01
24 6
8
10 12 14 16
8 20 22 24
Dose and duration of ESA therapy
12
11
(g/dl)
10
Erythropoietin 40.000 U/week or 10.000 TIW
Darbopoetin 500µg every 3 weeks or 150µg/week
9
Hemoglobin
Dose increments usually not effective
Discontinue treatment in non-responders after 6-8
weeks
8
Recommendations for ESA therapy
Recom-
FDA
EMA
ASH/ASCO
NCCN
EORTC
mendation
Initiation
< 10g/dl
10g/dl
<10g/d
11g/dl or 2g
11g/dl
of ESA
below
therapy
baseline
Target Hb
Treat to a
<12g/dl
Lowest
Not stated
12-13g/dl
level
level to
concentration
avoid RBC
to avoid RBC
transfusions
transfusions,
reduce ESA
dose when Hb
exceeds 1g/dl in
any 2 week
period
Suppleme
Not stated
Not stated
Iron repletion
Consider iv.
Address
ntary
when indicated
iron* when
functional
therapy
TSAT <20%
iron
and ferritin
deficiency
800µg/l
with iv iron
*with erythropoetic therapy
Iron deficiency by ISS stage in multiple myeloma
AID
FID
ISS Stage
TSAT <20%,
TSAT <20%,
No ID
Total
Ferritin
Ferritin
<30µg/l
>30µg/l
I
2 (4.8%)
10 (24.3%)
29 (70.7%)
41
II + III
7 (6.7%)
37 (35.6%)
60 (57.6%)
104
Total
9 (6.2%)
47 (32.4%)
89 (61.3%)
145
AID: Absolute iron deficiency
FID: Functional iron deficiency
Ludwig H, unpublished
Epoetin beta and Intravenous Iron Sucrose
vs. Epoetin beta (30.000 U once Weekly) only
65 Patients with MM, NHL, CLL ± iron sucrose (Venofer®) 100mg/week x6, followed by
100mg biweekly (until week 14)
Hedenus M et al. Leukemia 2007;21:627-632
Intravenous iron
Iv. iron may be considered with erythropoietins
in patients with anemia and functional iron
deficiency:
TSAT <20%, Ferritin <800µg/l
Benefits of ESA therapy
60-70% of patients will respond
good risk patients more likely to respond
in aggressive disease response rate may be as low as
35%
Reduction in transfusion need by ~> 70%
Improved QoL in responders
Response rate can be increased with iv. iron
Risks of ESA therapy
Increased TVT/PE rate (HR: 1.65) in cancer patients
Risk higher in patients
treated with IMiDs
on high dose dexamethasone
with additional risk factors for TVT/PE
receiving RBC transfusions
No increased risk in some studies (VISTA, Lonial,
Katodritou)
Stimulation of malignant growth?
ESAs and survial
Author
Nature of study
Impact on OS
Österborg et al. 2006
Prospective,
None
randomized,
unplanned analysis
Baz et al., 2006
Retrospective
OS
Kadotitrou et al., 2008
Retrospective
OS
Richardson et al., 2011
Retrospective
None
ESA treatment did not impair OS, RBC transfusions were
associated with shortened OS (retrospective analysis)
ESA + VMP
ESA - VMP
RBC + VMP
RBC- VMP
ESA ­ MP
ESA + MP
RBC+ MP
RBC- MP
Retrospective analysis of the VISTA study
Richardson et al., Br. J. Heamatology 2011
Management of anemia with erythropoietins
Chemotherapy associated anemia
Chronic anemia of myeloma
Hb 10g/dl
symptomatic from anemia
Hb >10 g/dl, without
Hb <11g/dl
symptoms
Start ESAs
Start ESAs
no therapy
Erythropoietin 40.000 once weeky or 10.000 TIW
Dose escalation not
Darbopoetin 500µg, q 3 weeks, or 150µg once weekly
recommended
If no response after 6-8
Improvement of symptoms
weeks ­ stopp therapy
RBC transfusions avoided
Hb between 11-12 g/dl
In patients with functional
iron deficiency (TSAT
<20%, ferritin<800µg/l)
Halt therapy, restart when symptoms
consider iv. iron
reccur or Hb <11g/dl