Can we alter MPN evolution

with IFN therapy?

J.J. Kiladjian, MD, PhD,Clinical Investigation Center,

Saint-Louis Hospital and Paris Diderot University

Natural history of MPN

Current data of IFN in MPN

Clinical trials of pegylated IFNs in MPNs

• High rates of hematological response

• Good tolerance

• Molecular responses

0 6 12 18 24 30 36

020

4060

8010

0

Months

% V

617F

45%

22%

5% 3%

48%

21%

18 mos

Quintas Cardama et al, JCO, 2009Kiladjian et al, Blood, 2008 Them et al, Am J Hematol, 2015

M0 M12 M24 M36 M48 M60 M72

50%

100%

0

%V

617

F

PVN1 study – Long term Molecular response

%V617F M0 M12 M24 M36 M48 M60 M72

Median 45% 25% 5% 5% 10% 6% 5%

Range 10 - 100 0 - 60 0 - 50 0 - 40 0 - 40 0 - 45 0 - 45

0

10

20

30

40

50

60

%C

ALR

Months

0

10

20

30

40

50

60

%C

ALR

Months

0

10

20

30

40

50

60

%C

ALR

Months

IFNa Aspirin Hydroxyurea

b e fo r e a f te r

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

% C

AL

R

****

1 s t s a m p le 2 n d s a m p le

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

% C

AL

R

N S

b e fo r e a f te r

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

% C

AL

R

N S

CALR mutant allele burden evolution

IFN alpha – Histological response

Larsen et al., Ann Hem, 2008

Silver, Leukemia, 2009

IFN alpha – Histological response in PVN1

UPN 1

UPN 2

UPN 3

x10 x20 reticulin (x10)

IFN discontinuation and outcome

PVN1 study – peg-IFNα-2a discontinuation

• Causes of peg-IFNα-2a discontinuation

– 14 (38%) for hematol. CR

– 10 (27%) for toxicity

Fatigue (n= 2)

Depression (n= 1)

Auto-antibodies (n=2)

Thyroiditis (n= 1)

Arthralgia (n= 1)

Neutropenia (n= 1)

Neuropathy gr. 2 (n= 1)

LFTs elevation gr. 2 (n=1)

0

2

4

6

8

10

12

14

16

18

1 2 3 4 5 6 7 8

No

of

pat

ien

ts

years

toxicity MF/AML Loss of Resp., NR others

MD Anderson - FU: 83 months

Impact of molecular response on clinical outcomes

Kiladjian et al., ASH 2016

• Single center study of outcome of MPN patients treated with IFN after discontinuation (whichever the cause)

• Endpoints (competing risk) :

• hematological relapse

• thrombosis

• hematological transformation

• EFS

• Predictive factors

Impact of molecular response on clinical outcomes

Kiladjian et al., ASH 2016

• Since 2000, 333 MPN patients received IFNa

• 149 stops

• 78 PV, 61 ET, 10 MF

• Reason for IFN start: age: 50 %, resistance / intoleranceprevious therapy: 27%, pregnancy n = 4

• Median Age 49.5 years

• Time between MPN diagnosis and IFN: 2 years

• 64 (43 %) had a history of thrombosis

Impact of molecular response on clinical outcomes

Kiladjian et al., ASH 2016

• 123 JAK2V617F+, 15 CALR, 5 MPL & 1 JAK2 exon 12, 5 triple-neg.

• 47 tested by NGS: 15 additional mutations

• IFN response : CHR in 123 (83%), PR in 16, failure in 10 pts

• Reasons for stopping:

• Toxicity : 79 (53%)

• Prolonged CHR: 52 (35%)

• Median time on IFN : 28.3 months

Impact of molecular response on clinical outcomes

Influence of JAK2V617 allele burden

on the predicted probability of

persistent complete hematological response

without cytoreductive therapy

JAK2 End IFN (%)

Prob

abilit

y of C

HR

0 20 40 60 80 100

00.2

0.40.6

0.81.0

Kiladjian et al., ASH 2016

Impact of molecular response on clinical outcomes

Kiladjian et al., ASH 2016

Months post IFN start

Eve

nt-

Fre

e s

urv

iva

l

0 20 40 60 80 100 120 140 160 180 200

0.0

0.2

0.4

0.6

0.8

1.0

149 142 126 93 59 32 18 4 2

Model HR (95%CI) P-value

%JAK2V617F at IFN stop (for a 10% difference)

1.4 (1.18-1.60) <0.0001

Time since diagnosis(for a 2-year difference)

1.2 (1.05-1.46) 0.011

EFS: Thrombosis, transformation, death

• 5-year EFS: 92% (95%CI, 87-97) • 10-year EFS: 72% (95%CI, 62-84)

Selective impact of IFN

AOP2014 / P1101 vs. JAK2V617F

• AOP2014/P1101 specifically targets JAK2V617Ferythroïd progenitors in vitro

0

20

40

60

80

100

treatment

% r

es

idu

al c

olo

nie

s/u

ntr

ea

ted

co

nd

itio

n **

******

***

AOP 0,5ug/ml with Epo

AOP 0,5ug/ml w/o Epo

AOP 2ug/ml with Epo

AOP 2ug/ml w/o Epo

0

20

40

60

80

100

untreated AOP0,5µg/ml

AOP2µg/ml

0%

20%

40%

60%

80%

100%

untreated AOP 0,5µg/ml AOP 2µg/ml

V617F/V617F

V617F/WT

WT/WT

AOP2014 / P1101 vs. JAK2V617F

• In vivo: PROUD-PV cohort

• 13 (of 257) patients randomized in France (5 AOP2014, 8 HU)

• Evolution of %JAK2V617F:

0%

10%

20%

30%

40%

50%

60%

0 6 12

AOP2014/P1101

HU

AOP2014 / P1101 vs. JAK2V617F

• In vivo: PROUD-PV cohort

• BM progenitors could be studied in 10/13 French pts, 3 treated with AOP2014 and 7 with HU

• ratio of the proportions of EECs after and before treatment

AOP2014 / P1101 vs. JAK2V617F

• In vivo: PROUD-PV cohort

• BM progenitors could be studied in 10/13 French pts, 3 treated with AOP2014 and 7 with HU

• ratio of mutant to wild-type JAK2 colonies was determined in cultured progenitors obtained before and 1 year after treatment initiation

AOP2014 / P1101 vs. JAK2V617F

• In vivo: PROUD-PV cohort

• BM progenitors could be studied in 10/13 French pts, 3 treated with AOP2014 and 7 with HU

• ratio of mutant to wild-type JAK2 colonies was determined in cultured progenitors obtained before and 1 year after treatment initiation

20%

40%

60%

80%

100%

0 6 12

AOP2014/P1101

HU

Conclusion

• IFN alpha is the only drug able to induce significant rates of clinical, hematological, histopathological and molecular responses in MPN patients

• Reducing the mutant allele burden could translate in higher probability of:

remaining in complete hematological response without therapy

longer event free survival

• Early treatment with IFN could also be a key factor to alter disease evolution