It’s time to look beyond immunosuppression...It’s time to look beyond immunosuppression Israeli...
Transcript of It’s time to look beyond immunosuppression...It’s time to look beyond immunosuppression Israeli...
Phillip Scheinberg, MDHead, Division of Hematology
Hospital A Beneficência Portuguesa
São Paulo, Brazil
It’s time to look beyond immunosuppression
Israeli Society of HematologyKfar Blum, Israel
September 6th, 2019
Disclosures
Novartis – Speaker, Advisory
Pfizer - Speaker
2
Aplastic anemia is characterized by the destruction of bone marrow
3 AA, aplastic anemia
Risk factors for acquired AA
N Engl J Med 379: 1643, 2018
SEVERE APLASTIC ANEMIA (SAA)
green (BODIPY) = lipid
red = CD34
blue (DAPI) = cells
Years
65432100
60
80
20
40
Utah, extrapolated severe
Surv
ivin
g, %
Utah, total (n = 99)
Camitta et al, Blood 1979; 53:504
Williams et al, Sem Hematol 1973; 10:195
AA Study Group (n =
63)
Mortality 80-90% at 1-2 years
Most patients <35 y/o
Severity Criteria (two of three):
platelets <20K/uL
reticulocytes <1% (60K/uL)
ANC <500/uL
Super-severe: ANC <200/uL
Bone marrow failure syndromes
AA, aplastic anaemia; AML, acute myeloid leukaemia; DKC, dyskeratosis congenita;DM, diabetes mellitus; IBD, irritable bowel syndrome; LGL, large granular lymphocytic leukaemia;MDS, myelodysplastic syndromes; MS, multiple sclerosis; PNH, paroxysmal nocturnal haemoglobinuria; SDS, Shwachman–Diamond syndrome
SDS
DKC
LGL
AA
AA/PNHPNH
MDSHypocellular
MDS
AML
Autoimmune
diseases:
MS, IBD,
uveitis, DM
type 1 etc
6
Bone marrow destruction is stimulated by an immune-mediated
attack on HSCs
1. Young NS & Maciejewski J. N Engl J Med 1997;336:1365–1372; 2. Young NS et al. Curr Opin Hematol 2008;15:162–168; 3. University of Minnesota Medical Center, Fairview, https://www.fairview.org/HealthLibrary/Article/40317
CD, cluster of differentiation; HSC, hematopoietic stem cell; IFN, interferon; IRF, interferon regulatory factor; NO, nitric oxide; NOS, nitric oxide synthase;
TNF, tumor necrosis factor
Proposed pathophysiology of AA1
An immune response, led by an expanded cytotoxic T-cell population, targets HSCs
and progenitor cells2
Directed at CD34+ cells2
T cells induce apoptosis and hematopoietic failure2
Healthy bone marrow3
Aplastic bone marrow3
7
Clinical manifestations of AA
8
1. Brodsky RA & Jones RJ. Lancet 2005;365:1647–1656; 2 Young NS & Kaufman DW . Hematologica 2008;93:489–492; 3. Killick SB et al. Br J Haematol 2016;172:187–207; 4. Marsh JCW et al. Br J Haematol 2009;147:43–70; 5. Silva RF. J Bras Pneumol 2010;36:142–147
AA can manifest abruptly or over a number of weeks/months,1
with a biphasic age of onset2,3
Typical signs and symptoms include: anemia, skin or mucosal hemorrhage (petechiae), visual disturbance due to retinal hemorrhage, infections1,4,5
Severe AA (SAA):
• Bone marrow cellularity equal to 25% of the normal control, or 25–50% of the normal control with <30% residual HSCs3
AND two of the following peripheral blood criteria:3
• Neutrophil count: <0.5×109/L
• Platelet count: <20×109/L
• Reticulocyte count: <20×109/L
Petechial rash
What are the treatment options for SAA?
1. Marsh JCW et al. Br J Haematol 2009;147:43–70;2. Bacigalupo A et al. Int J Hematol 2016;104:168–174
BMT, bone marrow transplant; HSCT, hematopoietic stem cell transplant; IST, immunosuppressive therapy
SAA1
Age
>40 years<40 years
Yes No
ISTHSCT
Matched family donor available
Unrelated & alternative BMT/other treatments
Failure/relapse in
one-third of patients
No matched family donor or patients ≥40 yearsHSCT is potentially curative,
but is not appropriate or
available for all patients2
9
IST is an effective treatment for patients ineligible for HSCT
10Young NS et al. Blood 2006;108:2509–2519 EGBMT, European Group for Bone Marrow Transplantation;
NIH, National Institute of Health
Response
N=63
N=120
N=104
N=114
N=100
N=84
Survival
at 15 years
49%
at 3 years
96%
at 4 years
88%
at 4 years
87%
at 5 years
87%
at 11 years
58%
0 10 20 30 40 50 60 70 80 90 100
Germany
EGMBT
Germany/Austria
Japan
NIH
Iran
Proportion of patients achieving a response (%)
EGBMT
Factors limiting successful treatment with IST
Severe stem cell deficit
Autoreactive cells not responsive to immunosuppressants
Unresponsiveness
Continuing ‘subclinical’ immune destruction of stem cells
Hematopoietic exhaustion
Relapse
Pre-existent clones?
Genomic instability
Evolution
11
Alternative directions in the initial treatment of AA
1. Tichelli A et al. Blood 2011;117:4434–4441; 2. Scheinberg P et al. Br J Haematol 2006;133:606–611;3. Scheinberg P et al. Haematologica 2009;94:348–354; 4. Scheinberg P et al. Am J Hematol 2014;89:571–574;5. Scheinberg P et al. N Engl J Med 2011;365:430–438; 6. Scheinberg P et al. Blood 2012;119:345–354
CSA, cyclosporine A; hATG, horse anti-thymocyte globulin; rATG, rabbit anti-thymocyte globulin
Granulocyte colony-stimulating factor (Neupogen)1
Mycophenolate mofetil (104 patients)2
Rapamycin (sirolimus) (77 patients)3
CSA taper (102 patients)4
Add to hATG + CSA platform
Augment initial lymphocytotoxicity
No improvement
compared with
standard
hATG/CSA
Delays, but does not prevent relapse
136 patients
Cyclophosphamide
hATG
rATG5
Alemtuzumab6
12
Post-treatment absolute lymphocyte count following IST in SAA (median + interquartile range)
Scheinberg P et al. Blood 2007;109:3219–3224; Scheinberg P et al. Blood 2012;119:345–354
13
Time (days)
AL
C/µ
L
1 2 4 8 16 64 25632 128
0
500
1000
1500
2000
2500 hATG
rATG
In a randomized trial in SAA, overall survival was greater with
hATG than with rATG
14Scheinberg P et al. N Engl J Med 2011;365:430–438
Su
rviv
al
(%)
0
20
40
60
80
100
2000150010005000
Days
hATG
rATG
P=0.04
10
1
23
12
39
34
60
60
hATG
rATG
Censored for stem cell transplantation Not censored for stem cell transplantation
Su
rviv
al
(%)
0
20
40
60
80
100
2000150010005000
Days
hATG
rATG
P=0.008
12
6
27
22
44
41
60
60
hATG
rATG
Median follow-up, all patients = 839 days (range, 2–1852)
Median follow-up, surviving patients = 891 days (range, 185–1852)
rATG is inferior to hATG in first-line treatment of SAA, as indicated by
hematologic response and survival
15Marsh JC et al. Blood 2012;119:5391–5396 CR, complete response; PR, partial response
Phase II pilot study of
rATG + CSAN=35
Retrospective matched comparison
(pair matched) with hATG + CSAN=105
CR: 23% PR: 37% CR: 44% PR: 23%
Pro
po
rtio
n s
urv
ivin
g
hATG; n=105
rATG; n=35
0 133.3 266.7 400.0 666.7 800533.3
Days from ATG
P=0.009
Overall survival for all patients
0
0.2
0.6
0.8
1.0
0.4
86%
68%
Pro
po
rtio
n s
urv
ivin
g hATG
rATG
Days from ATG
P=0.002
Transplant-free survival for all patients: transplant
is considered an event
0
0.2
0.6
0.8
1.0
0.4
76%
52%
0 133.3 266.7 400.0 666.7 800533.3
Study
(Year)
H-ATG
(N)
R-ATG
(N)
H-ATG
Resp
R-ATG
RespDesign
Zheng
(2006)47 (LG) 32 (Fr) 79% 53%
Prospective,
randomized
Atta
(2010)42 (LG)
29 (Thymo)60% 35% Retrospective
Afable
(2011)
67
(ATGAM)
20 (Thymo)58% 45% Retrospective
Scheinberg
(2011)
60
(ATGAM)60 (Thymo) 68% 37%
Prospective,
randomized
Marsh
(2012)105 (LG) 35 (Thymo) 67% 40%
Prospective
Shin (2013) 46 (LG) 53 (Thymo) 39% 45%Retrospective
Yoshimii (2013) 96 (LG) 32 (Thymo) 65% 34% Retrospective
Vallejo (2015) 62 (LG) 162 (Thymo) 66% 63% Retrospective
Studies comparing horse and rabbit ATGas first therapy in SAA
Exp Hematol. 2006;34(7):826-831 N Engl J Med. 2011;365(5):430-438Blood 121: 860, 2013
Ann Hematol. 2010;89(9):851-859Blood 119: 5391, 2012
Haematologica 96:1269, 2011 Ann Hematol 92: 817, 2013Ann Hematol 2015 epub
* Only complete manuscripts shown that include a comparative analysis between the 2 ATG formulations are shown. Abstracts are not included.
rATG or alemtuzumab are options for patients after
failure of hATG
Treatment arm (N=54) Overall response
Rabbit ATG (N=27), n (%) 9 (35)
Alemtuzumab (N=27), n (%) 10 (37)
Scheinberg P, et al. Blood 2012;119:345–354
One-third of patients with refractory SAA respond to second
immunosuppression following initial horse ATG
Salvage rate after initial rabbit ATG failure is low
Scheinberg P et al. Blood 2012;119:345–354; Scheinberg P et al. Am J Hematol 2014;89:467–469; Clé DV et al. Haematologica 2015;100:e345–e347
Salvage therapy Overall response
Horse ATG (N=19), n (%) 4 (21)
Alemtuzumab (N=13), n (%) 1 (8)
Rabbit ATG (N=32), n (%) 7 (22)
Treatment options for a patient with refractory SAA in 2010
Matched related
Alternative donor
HSCT
rATG + CSA
Treatment
options
hATG + CSA
Alemtuzumab
CSA
monotherapy
Androgens*
*
* Off label
30-40% pf patients
attain hematologic
response at 6
months
?????
Telomeropathy
5-10% TRM
20-30% aGVHD
30-40% cGVHD
Br J Haematol 133: 622, 2006
Blood 119: 345, 2012
Am J Haematol 89: 467, 2014
Br J Haematol 107: 330, 1999
Blood 149: 1428, 2017
Blood 120: 1185, 2012
N Engl J Med 374: 1922, 2016
Factors limiting successful treatment with IST
Severe stem cell deficit
Autoreactive cells not responsive to immunosuppressants
Unresponsiveness
Continuing ‘subclinical’ immune destruction of stem cells
Hematopoietic exhaustion
Relapse
Pre-existent clones?
Genomic instability
Evolution
21
Does failure to respond to IST reflect only residual
stem cell numbers?
Adapted from Young NS et al. Hematology Am Soc Hematol Educ Program 2013;76–81
Probability
of failure
Probability
of recovery
Patients
Stem cell number
Lower limit of
accurate in vitro
assays
(Correlation with blood counts, age)
22
TPO, acting through TPO-R, is essential for normal
thrombopoiesis1
1. Kaushansky K. Stem Cells 1997;15:15–97; 2. Jacobsen SE et al. Stem Cells 1996(Suppl. 1);173–180; 3. Yoshihara H et al. Cell Stem Cell 2007;1:685–697; 4. Alexander WS et al. Blood 1996;87:2162–2170; 5. Qian H et al. Cell Stem Cell 2007;1:671–684; 6. Ballmaier M et al. Ann NY Acad Sci 2003;996:17–25; 7. Robb L et al. Cytokine 2007;26:6715–6723
TPO-R is expressed on HSCs and early progenitor cells
– TPO may act at multiple levels to stimulate hematopoiesis2
TPO expands HSCs defined phenotypically and functionally in vitro3
c-Mpl and TPO knockout mice have reduced HSCs4,5
CAMT patients (c-Mpl loss of function mutations) develop multi-lineage marrow failure6
HSC
CLPCMP
MEP GM TNK BCP
EP
B
cellsNK cells
T cells
Neutrophils,
Eosinophils
Monocytes
Erythrocytes
Platelets
MP GP TCP NKPMkP
M-CSF G-CSF
IL-5
SCF
IL-7
IL-2IL-15
IL-4
TPO
EPO
TPO EPOIL-7
IL-2
IL-7
IL-15
IL-7GM-CSF
IL-3
SCF
TPO
SCF
TPOIL-7
IL-7
Multipotent stem cell
Primitive
progenitor cells
Committed
precursor cells
Lineage
committed cells
Self-
renewal
TPO: role in hematopoiesis7
TPO, thrombopoietin; TPO-R, thrombopoietin receptor23
Refractory SAA is defined as lack of response with persistence of severe pancytopenia at 6 months after one course of IST1
• Approximately one-third of patients withSAA fail to respond to IST2
HSCT should be considered if pancytopenia persists 6 months after IST3
• First choice in older and younger patients: Matched sibling donor HSCT3
• Unrelated donor HSCT may be considered in younger patients3
Treatment of refractory SAA
1Marsh JC & Kulasekararaj AG. Blood 2013;122:3561–3567; 2Young NS et al. Blood 2006;108:2509–2519; 3Scheinberg P. Hematology 2012;2012:292–300; 4Valdez JM et al. Clin Infect Dis2011;52:726–735 HSCT, Haematopoietic stem cell transplantation
Five-year survival of patients with IST-refractory SAA has improved
over time, but is still below that observed for HSCT4
Su
rviv
al p
rob
ab
ilit
y24
Group 1: Patients treated from 1989 to 1996
Group 2: Patients treated from 1996 to 2002
Group 3: Patients treated from 2002 to 2008
0
0.2
0.4
0.6
0.8
1.0
Time (years)
Group 3
5-year survival = 57%
P<0.001
Non-responders to IST (N=174)
Group 2
5-year survival = 35%
Group 1
5-year survival = 23%
0 2 4 6 8
Serum TPO levels are markedly elevated in patients with AA
Emmons RV et al. Blood 1996;87:4068–4071; Feng X et al. Haematologica 2011;96:602–606 HC, healthy control; ITP, immune thrombocytopenia; MDS, myelodysplastic syndrome
TP
O level (p
g/m
L)1
2500
SAA ITP
2000
1500
1000
500
0
TP
O level (p
g/m
L)2
10,000
1000
100
SAA MDS HC
P<0.001
P<0.001 P<0.05
25
Orally administered nonpeptide
Interacts in the transmembrane domain of TPO receptor
FDA approval in 2008 for treatment of chronic ITP
FDA approval 2014 in 2nd line SAA
EMA approval 2015 in 2nd line SAA
FDA approval 2018 in 1st line SAA + IST
Synthetic thrombopoietin (TPO) receptor agonist (TPO-RA)
Eltrombopag
27
Eltrombopag 50 mg daily
(25 mg Japan)
Dose escalation
every 2 weeks to 150 mg
daily
(100 mg Japan)
Hematologic response
after 3-4 months
Continue eltrombopaguntil robust response or no further
improvement
(extension study)
Hematologic Response Criteria
• Platelets: >20K/uL increase, or transfusion-independence
• RBCs: >1.5 g/dL increase in Hb, or least 50% transfusion reduction
• ANC: >100% increase if severe neutropenia, or >500/uL increase
• SAA with plts < 30K/uL
• Refractory to IST
ELTROMBOPAG FOR REFRACTORY APLASTIC ANEMIA
Treatment plan
Eltrombopag
TPO-RAs, such as eltrombopag, are potent stimulators of
hematopoiesis
1. Erickson-Miller CL et al. Stem Cells 2009;27:424–430 28
TPO-RA, thrombopoietin receptor agonist
Small molecule, non-peptide
TPO-RA1
Binds to the transmembrane
domain of TPO-R and does not
compete for binding with TPO1
Currently approved for the
treatment of refractory AA
patients
Eltrombopag and AA
Olnes MJ et al. N Engl J Med 2012;367:11–19; Desmond R et al. Blood 2014;123:1818–1825
40% (17/43)
response rate
Durable tri- and
bilineage responses
Transfusion
independenceWell-tolerated
Platelet increases after eltrombopag
Olnes MJ et al. N Engl J Med 2012;367:11–19
Platelet counts in the 9 patients who met the criteria for a platelet response at 12 weeks or later
BL 3 6 9 12 15 18 21 24 27 30
Median platelet increase 39×109/L (at censure)
Pla
tele
ts
10
9/L
0
20
40
60
80
100
120
140
1 2 3 4 5 6 7 8 9 10 11
Pt 1
Pt 2
Pt 4
Pt 5
Pt 12
Pt 13
Pt 22
Pt 25
Pt 26
Months
BL 3 6 9 12 15 18 21 24 27 30
0
20
40
60
80
100
120
140
Hemoglobin increases after eltrombopag
Olnes MJ et al. N Engl J Med 2012;367:11–19
Hemoglobin responses in 6 patients who met the criteria for a hemoglobinresponse at 12 weeks or later
Median hemoglobin increase 3.8 g/dL (range 1.5–8.2
g/dL)
He
mo
glo
bin
, gr
/dL
6789
1011121314151617
1 2 3 4 5 6 7 8 9 10 11
Pt 1
Pt 2
Pt 4
Pt 5
Pt 13
Pt 25
Months
BL 3 6 9 12 15 18 21 24 27 30
Hem
og
lob
in (
g/d
L)
17
16
15
14
13
12
11
10
9
8
7
6
Neutrophil increases after eltrombopag
Olnes MJ et al. N Engl J Med 2012;367:11–19
ANC, absolute neutrophil countNeutrophil responses in 9 patients who met the criteria for a neutrophil
response at 12 weeks or later
Median ANC increase 590109/L (460–990109/L)
BL 3 6 9 12 15 18 21 24 27 30
Ab
solu
te n
eutr
op
hil
count 10
9/L
Months
0
1
2
3
4
5
6
1 2 3 4 5 6 7 8 9 10 11
Pt 1
Pt 2
Pt 4
Pt 5
Pt 12
Pt 13
Pt 20
Pt 24BL 3 6 9 12 15 18 21 24 27 30
BONE MARROW CELLULARITY AT ONE YEARIN FOUR RESPONDING PATIENTS
Pre-treatment Post-treatment Pre-treatment Post-treatment
Pre-treatment Post-treatment Post-treatmentPre-treatment
Olnes MJ et al. N Engl J Med 2012;367:11–19
Eltrombopag
Eltrombopag in refractory AA
Desmond R et al. Blood 2014;123:1818–182534
AE, adverse event
Hematologic response rates (n=17/43) observed in refractory
SAA patients40%
Trilineage responses observed in 7/17 patients at follow-up3
4
7
22
Platelets
Neutrophils
Hemoglobin
Five patients tapered off drug following robust response
– median duration without drug: 13 months
Reversible transaminitis was the only dose-limiting AE
Robust responders – can eltrombopag be stopped?
Desmond R et al. Blood 2014;123:1818–1825
Definition of response
>50×109/L >10g/dL >1×109/L
Platelets Hemoglobin Neutrophils
Dose by 50%
Counts remain above
limits for 8 weeks
Discontinue drug and monitor
>8 weeks
35
Eltrombopag
Clonal evolution (n=8/43) in refractory AA on eltrombopag
Desmond R et al. Blood 2014;123:1818–182536 *mild dyserythropoeisis
Subject (age) Responder Baseline DysplasiaClone Time on drug (months)
7 (60)
8 (18)
19 (20)
31 (41)
36 (23)
42 (17)
-7[20]
+8[9]/46XX[11]
46XY[20]
46XY
No metaphases
46XY[20]
46XX[6]
46XY[20]
-7[5]t(1;16) [3]/46XY[12]
+21(3)/46XY(17) and
-7[2]/46XY[19]
-7[5],XY[15]
+1,der(1;7) [4]/46XY[16]
3
3
3
3 and
6
3
3
*
26 (67)
32 (66)
46XY[20]
46XY[20]
del(13)[19]/46XY[1]
46XYdel13q[2]/46XY[18]
13
9
*
Recent data suggest the incidence of high-risk clonal evolution during
eltrombopag treatment may be comparable to historical controls
37
1. Winkler et al. Blood 133: 2575, 2019 (NCT01891994); 2. Olnes MJ et al. N Engl J Med 2012;367:11–19; 3. Desmond R et al. Blood 2014;123:1818–1825
39 patients enrolled in a Phase II study of eltrombopag in refractory AA1 (150 mg fixed)
1
Primary endpoint: hematologic
response at 6 months
2
Secondary endpoints: hematologic response at
3 months and rate of clonal evolution
49% (n=19/39) of patients attained
hematologic response at 6 months
36% (n=14/39) of patients achieved a
hematologic response at 3 months
15% (n=6/39) of patients developed cytogenetic
abnormalities, in line with previous studies of
eltrombopag2,3
A pooled analysis including patients (n=83) from previous studies1–3 suggested that the frequency of
high-risk clonal evolution 24 months post-eltrombopag may be comparable to historical controls
72% (n=13/18) of patients continuing
in an extension arm discontinued for
robust response
Eltrombopag remains efficacious in ‘real-world’ clinical practice
38Ann Hematol. 2019 Jun;98(6):1341-1350 Blood 2018 132:1304
Hematological response was observed in 64.6% of patients (19.5% CR, 28% PR, 17.1% minimal)
Eltrombopag for the Treatment of Aplastic Anemia in Europe
AE 31%
Severe AE
uncommon (9%)
2 discontinuations
due to AE
143 SAA
patients
122
refractory to
IST
21 relapsedEltrombopag:
median duration
at least 2mo
Median f/u 14 mo
Eltrombopag:
median duration
at least 2 mo
Median survival not
reached (1 yr surv
88%)
2 cases of MDS
No strong
predictors of
response
39Ann Hematol. 2019 Jun;98(6):1341-1350 Blood 2018 132:1304
Pattern of eltrombopag usage
40Ann Hematol. 2019 Jun;98(6):1341-1350 Blood 2018 132:1304
Pattern of eltrombopag usage
41Ann Hematol. 2019 Jun;98(6):1341-1350 Blood 2018 132:1304
Pattern of eltrombopag usage
Treatment options for a patient with refractory SAA in 2019
Matched related
Alternative donor
HSCT
rATG + CSA
Treatment
options
hATG + CSA
Alemtuzumab
Androgens*
*
* Off label
Telomeropathy
Br J Haematol 133: 622, 2006
Blood 119: 345, 2012
Am J Haematol 89: 467, 2014
Br J Haematol 107: 330, 1999
Blood 149: 1428, 2017
Blood 120: 1185, 2012
N Engl J Med 374: 1922, 2016
Eltrombopag
Eltrombopag
??
Eltrombopag possible mechanisms of action
43
Effects on HSCs- HSC stimulation- HSC maintenance
- Bypass IFNg mediated HSC inhibition
Promote tolerance
- delay macrophage activity- impairment of dendritic cell maturation- increase in regulatory B cells- increase in regulatory T cells
Immunomodulation- decrease in IFNg release- decrease in TNFa release- increase in TGFb release
Iron chelation- cellular iron mobilization- decrease in iron overload- possible benefit in hematopoiesis
BONE MARROW ANALYSIS
Townsley DM, et al. NEJM 2017; 376:1540-50.
Model of IFNγ-mediated bone marrow failure
signaling inhibition by TPO:IFNγ heterodimers in human HSPCs
Alvarado LJ et al. Blood 2017;130:4;Image courtesy of A Larochelle
45
HSPCs, hematopoietic stem progenitor cells; IFNγ, interferon gamma
HSPC survival/proliferation
Signaling
IFNɣ
TPO c-MPL
Heteromers
+ Signaling
Signaling
c-MPL
Signaling
Eltrombopag
IFNɣ
+
HSPC survival/proliferation
Eltrombopag
TPO IFNγ occludes TPO:c-MPL
low-affinity site
IFNγ
TPO
c-MPL
Romiplostim
Patients may become refractory to IST, requiring efficacious
second-line treatments: Romiplostim
Lee JW et al. Blood 2016;128:abst 391046
URTI, upper respiratory tract infection
Interim analysis: no dose-dependent AEs; commonly occurring AEs included URTI, fatigue,
transfusion reaction, myalgia and dyspepsia
In an ongoing, dose-finding study of romiplostim in refractory AA:
During 52 weeks of treatment, 33.3% (n=11/33) of patients achieved a trilineage response at least once
Baseline dose
group (µg/kg)
Platelet response after
8 weeks treatment
1
3
6
10
33.3% (n=3/9)
70.0% (n=7/10)
No response (n=0/14)
• 1/14 responded (10 prior ATG, 8 prior Epag)
• median max dose 9.4 ug/kg (6-12)
• median Tx duratoin 6 months (2-21)
Insights into SAA pathophysiology
Stem cell number
Probability
of failure
Probability
of recovery
Eltrombopag therapy
Immune attack
Patients
Eltrombopag as first line option in SAA
Townsley DM et al. N Engl J Med 2017;376:1540–1550
hATG
Day 1–
4
Eltrombopag 150 mg*
Day 14 to 6 months
Hematologic response
Eltrombopag 150 mg*
Day 14 to 3 months
CSA×6 months
Cohort 1
5-year
follow-up
Eltrombopag 150 mg**
Day 1 to 6 months
3 months 6 months
Cohort 2
Cohort 3
Primary endpoints: Complete response (CR) rate at 6 months and safetySecondary endpoints: Overall response (OR), partial response (PR), survival, clonal evolution and relapse
CR = ANC ≥1109/L, hemoglobin ≥10 g/dL and platelets ≥100109/L
PR = Blood counts no longer meeting criteria for SAA or CR
* Dose in Japan is 75 mg
** Day 1 not approved in Japan
Eltrombopag as a first-line treatment option for SAA
1. Townsley DM et al. N Engl J Med 2017;376:1540–1550;2. Scheinberg P et al. Haematologica 2009;94:348–354; 3. Scheinberg P et al. N Engl J Med 2011;365:430–438
8087
9487
3326
58
3947
61
35
48
0
10
20
30
40
50
60
70
80
90
100
Cohort 1(N=30)
Cohort 2(N=31)
Cohort 3(N=31)
All cohorts(N=92)
He
ma
tolo
gic
re
sp
on
se
ra
te (
%)
OR CR PR
Hematologic response at 6 months1
Historical IST hematologic response at 6 months: OR ~60–70%; CR ~10%2,3
77 77
8780
1726
48
30
6052
39
50
0
10
20
30
40
50
60
70
80
90
100
Cohort 1(N=30)
Cohort 2(N=31)
Cohort 3(N=31)
All cohorts(N=92)
He
ma
tolo
gic
re
sp
on
se
ra
te (
%)
OR CR PR
Hematologic response at 3 months1
Eltrombopag added to IST and overall survival
Townsley DM, Scheinberg P,et al. N Engl J Med 2017;376:1540–1550
Censored for HSCT Not censored for HSCT
Time (days)
Median follow-up 18 months
(range 1 – 42 months)
99%
0 500 1000 1500
0
50
100
Surv
ival (
%)
97%
Time (days)
0 500 1000 1500
0
50
100
One (1) death on study:
Thymoma with paraneoplastic encephalopathy
Two (2) deaths after HSCT
MDS/AML: HSCT relapsed AML
Relapsed aplastic anemia: HSCT GVHD
Clonal evolution in upfront SAA on eltrombopag
Dumitriu B et al. Blood 2015;125:706–709; Townsley DM et al. Blood 2015;126:LBA-2, oral presentation at ASH 2015
VAF, variant allele frequency
Age
(years)Response
Time to
evolutionCytogenetics
BM
dysplasiaOutcome
68 CR 3 months46, XX,
del(13)(q12q22)[cp3]/46,XX[17] No Cytogenetics normalized
39 CR 30 months 48,XX +6 +15 [2]/46,XX[18] No Stable
64 PR 3 months45,XX,t(3;3)(q21;q26),-7[3]/ 46,
XX[17] Yes
AML/HSCT, death
(RTEL1)
72PR/
Relapse30 months 45, XY,-7[20] Yes Stable
48CR/
Relapse6 months
46,XX,del
(7)(p13p15)[3]/46,XX[19] No HSCT
61 PR 6 months 45,XX,-7[7]/46,XX[16] Yes Proceeding to HSCT
16 NR 3 months 45,XY,-7[6]/46,XY[14] NoHSCT
(RTEL1)
MDS/AML somatic gene
mutations (VAF)
none detected
DNMT3A (3%)
none detected
ASXL1 (24%)
RUNX1 (12%)
DNMT3A (15%)
none detected
none detected
Townsley DM, Scheinberg P,et al. N Engl J Med 2017;376:1540–1550
N = 92
Cumulative incidence of clonal evolution
Townsley DM, Scheinberg P,et al. N Engl J Med 2017;376:1540–1550
Treatment options for initial therapy in SAA in 2019
54
N Engl J Med 379: 1643, 2018
Avoid any dairy products, foods
or indigestion remedies,
medicines containing calcium,
aluminium, iron, magnesium,
zinc, selenium
Why? Chelator backbone to
structure of eltrombopag
Take each dose at least 2 hr
before or 4 hr after meals
Timing of eltrombopag is important to optimize outcomes
Kuter DJ. Ann Rev Med 2009;60:193–196
Structure of eltrombopag
Requirements for dose adjustments of eltrombopag
1. Gibiansky E et al. J Clin Pharmacol 2011;51:842–856; 2. Bauman JW et al. J Clin Pharmacol 2011;51:739–750;
3. Revolade (eltrombopag) summary of product characteristics revised 11/2016: http://www.medicines.org.uk/EMC/medicine/22949/SPC/Revolade/ Last accessed May 2017
East Asian patients (Japanese, Chinese, Taiwanese, Korean)
Patients have
higher plasma
eltrombopag
exposure1
Start eltrombopag at lower
dose of 25 mg daily3
Mild, moderate or severe
hepatic impairment
Plasma
concentration of
eltrombopag
increased
compared to
healthy patients2
Start eltrombopag at lower
dose of 25 mg daily3
Renal
impairment
No dose adjustment needed2,3
Closely monitor patients
Summary
57
1. Desmond R et al. Blood 2014;123:1818–1825; 2. Lee JW et al. Blood 2016;128:abst 3910;3. Townsley DM et al. N Engl J Med 2017;376:1540–1550
HSCT (if possible) and IST remain the treatment of choice for SAA
Eltrombopag represents an efficacious treatment for refractory SAA patients:1
– 40% hematological responses observed in clincial trials and in the ‘real-world’, as well as possible trilineage responses
– Thrombopoietin receptor agonists may predispose to earlier clonal evolution
Preliminary findings from an ongoing trial of romiplostim suggest this agent may also be an appealing treatment option for patients with refractory SAA2
Trials are ongoing to further determine the efficacy and safety of TPO-R agonists in refractory and also treatment naïve SAA
– More recent data show that eltrombopag is also active in the first-line treatment setting for SAA3
Eltrombopag as a first-line therapy for SAA without ATG – SOAR trial
FPFV, first patient first visit NCT02998645
FPFV May
2017
Eltrombopag 150 mg
Day 0 to 6 months*
CSA×12 months
3 months 6 months
Hematologic response
12 months
Primary endpoints: OR rate at 6 months
Secondary endpoints: OR rate at 3 and 12 months, survival and safety
Phase II, open-label, single-arm trial to assess efficacy and safety of
eltrombopag combined with CSA as first-line therapy in patients with SAA
* Not approved indication.