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

https://www.fairview.org/HealthLibrary/Article/40317

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



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


Group 1


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


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


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


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


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


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


N = 92

Cumulative incidence of clonal evolution


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

http://www.medicines.org.uk/EMC/medicine/22949/SPC/Revolade/

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


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.

Centro Oncológico BP

Beneficência Portuguesa

Hospital BP Mirante

[email protected]

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