Efficacy and Safety of Pegylated Interferon Alpha-2a in Patients with Essential Thrombocythemia (ET) and Polycythemia vera (PV): Results after a Median

7-year Follow-up of a Phase 2 Study

Srdan Verstovsek, MD, PhDProfessor,Department of Leukemia,The University of Texas MD Anderson Cancer Center

PEG-IFN2a in ET-PV. Background

• Pegylated Interferon - long half-life,

weekly schedule

• Lower toxicity and discontinuation rate

• High hematologic response rate in ET / PV

• Better disease-free survival (?)

• Relatively short follow-up

PEG-IFN2a in ET-PV. Patient Characteristics

N=83 N (%) ; Median [range]

• Age, years 53 [19-78]

• Time from Dx to study entry, months 42 [1-350]

• Molecular status: JAK2 + 63 (76)

CARL + 8 (10)

MPL + 3 (3)

Triple negative 9 (11)

• Abnormal karyotype 6 (7)

• Splenomegaly 35 / 81 (43)

• Symptoms 43 (52)

• Untreated (cytoreductive therapy) 31 (37)

PEG-IFN2a in ET-PV. Design and Current Status

N (%) ; Median [range]

Follow Up, months 83 [8-107+]

Rx duration, months 87 [58-107+]

Initial dose - weekly SQ: 450-360 mcg 6 (7)

270 mcg 19 (23)

180 mcg 26 (31)

90 mcg 32 (39)

Current Status: Off study 51 (61)

On study: 32 (39)

On active therapy 24 (75)

On hold 8 (25)

PEG-IFN2a in ET-PV. Hematologic Response

N (%) ; Median [range]

HR / CHR 66 (80) / 62 (76)

Time to response, months 4 [0.1-57]

Response duration, months 66 [2-101+]

Current: HR 26 / 66 (39)

CHR 25 / 62 (40)

PEG-IFN2a in ET-PV. Molecular Response in JAK2 V617F+ (N=55)

N (%)

Best Current

CMR - undetectable JAK2 10 (18) 9 (16)

PMR - > 50% ↓ JAK2 20 (36) 6 (11)

mMR - 20-50% ↓ JAK2 5 (9) 10 (18)

Overall MR 35 (63) 25 (45)

PEG-IFN2a in ET-PV. Molecular Response in JAK2 V617F+ (N=55)

Median [range] ; months

Duration

CMR - undetectable JAK2 69 [11-95]

PMR - > 50% ↓ JAK2 49 [11-78]

mMR - 20-50% ↓ JAK2 18 [6-58]

Overall MR 53 [6-95+]

PEG-IFN2a in ET-PV. Molecular Response in JAK2 V617F+(N=55)

0 1 2 2 4 3 6 4 8 6 0 7 2 8 4

2 0

4 0

6 0

8 0

1 0 0

J A K 2 V 6 1 7 F m u ta tio n a lle le b u rd e n ~ t im e ~ re s p o n s e

 

m M R

C M R

P M R

Me

dia

n J

AK

2 a

lle

le b

urd

en

(%

)

N o o f e v a lu a b le p a t ie n ts o n th e ra p y

C M R 1 0 1 0 5 5 7 6 7 7

P M R 2 0 1 5 1 0 9 1 3 8 1 0 9

m M R 4 3 3 2 1 1 2 3

m o n th s

0 10 20 30 40 50 60 70 80 90

autoimmune*

hypothyroidism

skin

respiratory

infection / fever

LFT elevation

psychiatric

neurologic

gastrointestinal

musculoskeletal

Percent (pts with AE) Any Grade

> G3*CNS vasculitis, hepatitis, SLE, Sjogren syndrome & dermatitis

PEG-IFN2a in ET-PV. Adverse Events

PEG-IFN2a in ET-PV. Toxicity Decreases Over Time

3 6 9 1 2 2 4 3 6 4 8 6 0 7 2 8 4

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

1 4 0

1 6 0

1 8 0

% o

f p

ts w

ith

to

xic

ity

M o n th s

M e d ia n d o s e

m c g / w e e k

N o o f p a t ie n ts w ith to x ic ity

H 3 1 3 0 3 1 2 7 2 7 1 9 1 1 9 8 6

n H 6 8 6 3 5 9 4 6 3 7 2 6 2 2 1 4 1 3 1 3

N o o f p a t ie n ts o n th e ra p y

A L L 8 3 8 1 7 6 7 1 6 4 5 4 5 0 4 9 4 1 3 3

N o n H e m .

to x .

H e m a t.

to x .

PEG-IFN2a in ET-PV. Vascular Events

N (%) ; median [range]

•Thromboembolic 8 (10) ; 3 provoked

Venous: PE, DVT, stroke 5 (6)

Arterial: thrombosis 3 (3)

•Bleeding: stroke 1 (1)

•Time to event, mos 38 [14-60]

•Patients in CHR 5 / 9 (56)

PEG-IFN2a in ET-PV. Transformation (MF/AML)

Pts TTT Signs of transformation Status FU after T.

• 69F ET 36 symp., anemia, blasts A: JAK+DAC 28+

• 58F ET 53 symp., spleen, blasts, LDH D: stroke 36

• 36F PV 61 symp., anemia, spleen, blasts A: JAK+LEN 18+

• 53F PV 40 symp., anemia, spleen A: OBS / CML 20+

• 59F ET 62 symp., anemia, spleen, blasts A: OBS 84+

• 62F PV 10 symp., anemia, spleen A: CR / SCT 59+

• 66F PV 18 anemia, blasts D:unk (CR) 24 BM fibrosis of G 2-3 or 3-4 in All pts, Time to transformation (TTT) & FU in months,

* pts in CHR prior Transformation

PEG-IFN2a in ET-PV. Overall Survival

0 4 0 8 0 1 2 0 1 6 0 2 0 0 2 4 0 2 8 0

0

2 0

4 0

6 0

8 0

1 0 0

O v e r a l l s u rv iv a l

m o n th s

Pro

ba

bil

ity

of

su

rviv

al

(%)

N o o f r is k

8 3 8 3 7 9 4 8 2 6 1 6 9 6

Median OS = not reached

PEG-IFN2a in ET-PV. Transformation MF/AML

0 4 0 8 0 1 2 0 1 6 0 2 0 0

0

1 0

2 0

3 0

4 0

T ra n s fo rm a tio n to M F / A M L

m o n th s

Cu

mu

lati

ve

Pro

ba

bil

ity

(%

)

P E G

C o n tro l

N a t r is k

P E G 8 3 8 3 7 5 4 6 2 5 1 4

C o n tro l 3 5 2 2 2 4 1 5 9 9 7 6 2 3 5

p = 0 .4 9 (H R 1 .3 3 ,

9 5 % C I 0 .5 8 -1 .7 2 )

PEG-IFN2a in ET-PV. Therapy Discontinuation, Reasons

Off: N=51 (61%) On Hold: N=8

• Toxicity - G 1-2 8 (10) 3

- G 3-4 10 (12) 2

• Vascular events 7 (14) --

• Progression to MF/AML 7 (14) --

• Loss of response/NR 3 (6) --

• Others - Motor vehicle accident 1 (2) --

- Lost to Follow up 3 (6) --

- Death* 3 (6) --

- Other malignancy 2 (4) --

- Financial 7 (14) 3

* Not related to therapy or disease

PEG-IFN2a in ET-PV. Discontinuation Over Time

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

ON study, No 67 61 58 54 50 47 39 32

PEG-IFN2a in ET-PV. Patient disposition –Hematologic responders, N=66

>90 mcg / week: N=6

45 - 90 mcg / week: N=4

90 mcg / every 2 weeks: N=4

45 mcg / every 2-6 weeks: N=10

Died: N=11

ON study, N=3

All unrelated

On hold:

N=8

On therapy:

N=24

On study, N=32

HR=19

PEG-IFN2a in ET-PV. Patient disposition –Hematologic responders, N=66

On study, N=32

HR=19

>90 mcg / week: N=6

45 - 90 mcg / week: N=4

90 mcg / every 2 weeks: N=4

45 mcg / every 2-6 weeks: N=10

Died: N=11

ON study, N=3

All unrelated

On hold:

N=8

On therapy:

N=24

Off study, N=34

HR=7 (PEG-

IFN2a)

PEG-IFN2a in ET-PV. Clinical Conclusions

• Effective Rx

HR 80%, CHR 76%-- response duration 66 months

> 60% MR-- duration 53 months

• Toxicity continues over time

• Discontinuation ~ 61% (35% for toxicity)

• Rx failures occur (vascular events &

progression)

Histomorphological responses after therapy withpegylated interferon α-2a in patients with

essential thrombocythemia (ET) and polycythemia vera (PV)

Patients with BM assessment stratified by response Characteristics BM-NR, n=29 BM-PR, n=16 BM-CR, n=13

PV/ET, No. 15/14 5/11 7/6

Molecular status, No. 22 JAK2

1 CALR

6 TN

9 JAK2

5 CALR

2 MPL

11 JAK2

2 TN

HR, No. (%) 26 (90) 15 (94) 13 (100)

Duration of HR, months (range) 50 (10-98) 69 (17-96) 87 (59-101)a

MR, No. (%), type* 11 (50)

2 CMR

7 PMR

2 mMR

8 (89)

6 PMR

2 mMR

10 (91)

7 CMRb

3 PMR

Duration of treatment, months

(range)

75 (25-205) 85 (77-107) 83 (15-101)c

Total follow-up, months (range) 81 (36-105) 94 (67-107) 93 (83-106)

On study at last follow-up, No. (%) 10 (35) 13 (81) 9 (69)d

Abbr.: a-d statistically significant results; BM-NR = BM no-response; BM-PR = BM partial response; BM-CR = BM complete response; RX = treatment; DX = diagnosis; TN = triple negative; HR = hematologic response; MR = molecular response; CMR-PMR-MMR = complete- partial-minor molecular response; *only in JAK2V617F mutation positive patients

Histomorphological responses after therapy with pegylatedinterferon α-2a in patients with essential

thrombocythemia (ET) and polycythemia vera (PV)

CONCLUSION

Morphological BM responses can occur in ET/PV patients treated with PEG-IFN-a-2a, and generally correlate with more durable treatment benefit. Complete BM responses may be seen or sustained even after treatment discontinuation. However, no uniform correlation between hematologic, morphological and molecular response was found.