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

Transcription

1 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, PhD Professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center

2 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

3 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: JAK (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)

4 PEG-IFN2a in ET-PV. Design and Current Status N (%) ; Median [range] Follow Up, months 83 [8-107+] Rx duration, months 87 [ ] Initial dose - weekly SQ: 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)

5 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)

6 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 % JAK2 5 (9) 10 (18) Overall MR 35 (63) 25 (45)

7 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 % JAK2 18 [6-58] Overall MR 53 [6-95+]

8 M e d ia n J A K 2 a lle le b u r d e n (% ) PEG-IFN2a in ET-PV. Molecular Response in JAK2 V617F+(N=55) J A K 2 V F m u ta tio n a lle le b u rd e n ~ tim e ~ r e s p o n s e C M R P M R m M R m o n th s N o o f e v a lu a b le p a tie n ts o n th e ra p y C M R P M R m M R

9 PEG-IFN2a in ET-PV. Adverse Events musculoskeletal gastrointestinal neurologic psychiatric LFT elevation infection / fever respiratory skin hypothyroidism autoimmune* Percent (pts with AE) Any Grade > G3 *CNS vasculitis, hepatitis, SLE, Sjogren syndrome & dermatitis

10 % o f p ts w ith to x ic ity PEG-IFN2a in ET-PV. Toxicity Decreases Over Time M o n th s N o o f p a tie n ts w ith to x ic ity H n H N o o f p a tie n ts o n th e ra p y A L L M e d ia n d o s e m c g / w e e k N o n H e m. to x. H e m a t. to x.

11 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)

12 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 F ET 53 symp., spleen, blasts, LDH D: stroke 36 36F PV 61 symp., anemia, spleen, blasts A: JAK+LEN F PV 40 symp., anemia, spleen A: OBS / CML F ET 62 symp., anemia, spleen, blasts A: OBS F PV 10 symp., anemia, spleen A: CR / SCT F 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

13 P r o b a b ility o f s u r v iv a l (% ) PEG-IFN2a in ET-PV. Overall Survival O v e r a ll s u r v iv a l Median OS = not reached N o o f ris k m o n th s

14 C u m u la tiv e P ro b a b ility (% ) PEG-IFN2a in ET-PV. Transformation MF/AML T ra n s fo rm a tio n to M F / A M L p = (H R 1.3 3, 9 5 % C I ) P E G C o n tro l m o n th s N a t ris k P E G C o n tro l

15 PEG-IFN2a in ET-PV. Therapy Discontinuation, Reasons Off: N=51 (61%) On Hold: N=8 Toxicity - G (10) 3 - G (12) 2 Vascular events 7 (14) -- Progression to MF/AML 7 (14) -- Loss of response/nr 3 (6) -- Others - Motor vehicle accident 1 (2) -- * Not related to therapy or disease - Lost to Follow up 3 (6) -- - Death* 3 (6) -- - Other malignancy 2 (4) -- - Financial 7 (14) 3

16 No of patients PEG-IFN2a in ET-PV. Discontinuation Over Time years ON study, No toxicity MF/AML Loss of Resp., NR others

17 PEG-IFN2a in ET-PV. Patient disposition Hematologic responders, N=66 On study, N=32 HR=19 On therapy: N=24 On hold: N=8 >90 mcg / week: N= 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

18 PEG-IFN2a in ET-PV. Patient disposition Hematologic responders, N=66 On study, N=32 HR=19 Off study, N=34 HR=7 (PEG- IFN2a) On therapy: N=24 On hold: N=8 >90 mcg / week: N= 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

19 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)

20 Histomorphological responses after therapy with pegylated interferon α-2a in patients with essential thrombocythemia (ET) and polycythemia vera (PV)

21 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 CMR b 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

22 Histomorphological responses after therapy with pegylated interferon 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.