ohio state's ash review 2017 - myeloproliferative disorders

Updates in Myeloproliferative Disorders, including Chronic Myeloid LeukemiaKatherine Walsh, MD

No conflicts of interest to discloseOff-label use: pegIFN, ruxolitinib in combination with azacitidine, investigational agents

The Ohio State University Comprehensive Cancer Center –Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Objectives

To discuss clinical updates in Philadelphia chromosome negative myeloproliferative disorders (MPDs).

To discuss clinical updates in chronic myeloid leukemia.


Single agent studies Late breaking abstract: Pacritinib (PERSIST-2)

Combination therapy studies Ruxolitinib plus additional agent

Additional abstracts of interest

MPD Updates


RESULTS OF THE PERSIST-2 PHASE 3 STUDY OF PACRITINIB (PAC) VERSUS

BEST AVAILABLE THERAPY (BAT), INCLUDING RUXOLITINIB (RUX), IN

PATIENTS WITH MYELOFIBROSIS (MF) AND PLATELET COUNTS ≤100,000/ΜL

John Mascarenhas1, Ronald Hoffman1, Moshe Talpaz2, Aaron T. Gerds3, Brady Stein4, Vikas Gupta5, Anita Szoke6, Mark Drummond7, Alexander Pristupa8, Tanya

Granston9, Robert Daly9, James P. Dean9, Suliman Al-Fayoumi9, Jennifer A. Callahan9, Jack W. Singer9, Jason Gotlib10, Catriona Jamieson11, Claire Harrison12,

Ruben Mesa13, Srdan Verstovsek14

1Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 2University of Michigan, Comprehensive Cancer Center, Ann Arbor, MI, USA; 3Cleveland Clinic, Cleveland, OH, USA; 4Northwestern University, Feinberg School of

Medicine, Chicago, IL, USA; 5Princess Margaret Cancer Center, University of Toronto, Ontario, Canada; 6Albert Szent-Györgyi Clinical Center, University of Szeged, Szeged, Hungary; 7Beatson West of Scotland Cancer Centre, Glasgow, UK; 8Ryazan’s

Clinical Hospital, Ryazan, Russia; 9CTI BioPharma Corp., Seattle, WA, USA; 10Stanford University Medical Center, Stanford, CA, USA; 11University of California-San Diego, La Jolla, CA, USA; 12Guy's and St Thomas' NHS Foundation Trust, London UK;

13Mayo Clinic, Scottsdale, AZ, USA; 14MD Anderson Cancer Center, Houston, TX, USA.

Slides provided by presenting author Dr. Mascarenhas

Background

• MF is a life-threatening hematologic malignancy characterized by splenomegaly and debilitating constitutional symptoms1-3

• ~1/4 of MF pts present with thrombocytopenia;4 platelets <50,000/µL associated with reduced QoL,1 more severe symptom burden, and shorter overall survival5

• Approved JAK1/2 inhibitor RUX reduces splenomegaly and symptoms, but is associated with dose-limiting cytopenias and not indicated for pts with platelets <50,000/µL6,7

• PAC: oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1, & CSF1R8

• PERSIST-1 trial: sustained spleen volume reduction (SVR) and symptom control with PAC vs BAT (excluding JAK2 inhibitors) in pts with MF regardless of baseline platelet count9

• PAC placed on full clinical hold by the US FDA (2/8/2016) due to concerns over interim survival results, bleeding, and cardiovascular events

1. Tefferi A, et al. Blood. 2013;122:1395-1398. 2. Mesa et al. Cancer. 2007;109:68-76. 3. Geyer HL, et al. Blood. 2014;124:3529-3537. 4. Tefferi A, et al. Mayo Clinic Proc. 2012;87:25-33. 5. Alhuraiji A, et al. J Clin Oncol. 2016;34(suppl):abstract 7068. 6. Harrison C, et al. N Engl J Med. 2012;366:787-798. 7. Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 8. Hart S, et al. Leukemia. 2011;25:1751-1759. 9. Mesa RA, et al. ASCO 2015. Abstract LBA7006.

Key Eligibility Criteria

• Primary/ secondary MF

• Platelets ≤100,000/µL,

• Prior JAK2 inhibitors allowed

1:1:

1 R

ando

miz

atio

n(N

= 3

11)

BAT (including RUX)

PAC400 mg QD

PAC200 mg BID

PERSIST-2 Phase 3 Study Design

• In PK simulations, PAC 200 mg BID was predicted to have higher Cmin and lower Cmax than PAC 400 QD

• Crossover from BAT allowed after progression (any time) or at Wk 24

• Study Objectives:• Primary: efficacy of pooled QD and BID PAC vs BAT• Secondary: efficacy of QD PAC or BID PAC separately vs BAT

PK, pharmacokinetics; PPV, post-polycythemia; PET, post-essential thrombocythemia.

Co-Primary Endpoints (Wk 24)

% of pts achieving≥35% SVR

and% of pts achieving

≥50% reduction in TSS*

Co-Primary Endpoints (Wk 24)

% of pts achieving≥35% SVR

and% of pts achieving

≥50% reduction in TSS**TSS, total symptom score by MPN-SAF 2.0

Patient Demographics (ITT Efficacy Population*)

CharacteristicPAC QD

n=75PAC BID

n=74BATn=72

Median age, yrs (range)≥65 yrs, n (%)

69 (39-85)53 (71)

67 (39-85)46 (62)

69 (32-83)51 (71)

Male, n (%) 38 (51) 48 (65) 39 (54)ECOG PS, n (%)

0-12-3

57 (76)17 (23)

65 (88)8 (11)

54 (75)15 (21)

MF diagnosis, n (%)PrimaryPPVPET

46 (61)16 (21)13 (17)

55 (74)14 (19)5 (7)

43 (60)16 (22)13 (18)

DIPSS risk category, n (%)Int-1Int-2High

13 (17)40 (53)22 (29)

14 (19)38 (51)22 (30)

13 (18)37 (51)22 (31)

JAK2V617F positive, n (%) 60 (80) 59 (80) 51 (71)*Included all pts with randomization date that allowed them to contribute data for a wk 24 endpoint (pts randomized prior to September 7, 2015; ≥ 22 wks prior to clinical hold)

Patient Demographics (Cont’d)(ITT Efficacy Population)

CharacteristicPAC QD

n=75PAC BID

n=74BATn=72

Median spleen length by physical exam, cm (range) 13 (3-33) 15 (5-32) 13 (2-34)

Platelet count <50,000/µL, n (%) 38 (51) 31 (42) 32 (44)

Hemoglobin <10 g/dL, n (%) 45 (60) 44 (59) 41 (57)

Peripheral blasts category, n (%)0-<1%≥1%0-<5%≥5%Missing

41 (55)30 (40)62 (83)9 (12)4 (5)

38 (51)30 (41)61 (82)7 (9)6 (8)

36 (50)31 (43)60 (83)7 (10)5 (7)

White blood cell category, n (%)>25 x 109/L≤25 x 109/L

15 (20.0)60 (80.0)

17 (23)57 (77)

14 (19)58 (81)

Received prior RUX, n (%) 31 (41.3) 31 (42) 33 (46)

Efficacy: Analysis by ArmRUX (n=22)Other (n=28)

RUX (n=22)Other (n=29)

14.7%* 21.6%* 2.8%

17.3% 32.4%* 13.9%

Most Common TEAEs (≥10%)

CharacteristicPAC QDn=104

PAC BIDn=106

BATn=98

Pts with ≥1 TEAE 104 (100) 100 (94) 87 (89)Diarrhea 70 (67) 51 (48) 15 (15)Nausea 39 (38) 34 (32) 11 (11)Thrombocytopenia 34 (33) 36 (34) 23 (23)Anemia 29 (28) 25 (24) 15 (15)Vomiting 22 (21) 20 (19) 5 (5)Fatigue 18 (17) 18 (17) 16 (16)Peripheral edema 14 (13) 21 (20) 15 (15)Dizziness 15 (14) 16 (15) 5 (5)Abdominal pain 20 (19) 10 (9) 19 (19)Pyrexia 11 (11) 16 (15) 3 (3)Decreased appetite 13 (13) 13 (12) 11 (11)Epistaxis 11 (11) 13 (12) 13 (13)Constipation 15 (14) 8 (8) 6 (6)Insomnia 12 (12) 10 (9) 4 (4)Pruritus 10 (10) 11 (10) 6 (6)Cough 11 (11) 9 (8) 10 (10)Dyspnea 9 (9) 11 (10) 9 (9)Upper respiratory tract infection 8 (8) 11 (10) 6 (6)

Characteristic

PAC QDn=104

PAC BIDn=106

BATn=98

Pts with ≥1 TEAE 104 (100) 100 (94) 87 (89)

Diarrhea 70 (67) 51 (48) 15 (15)

Nausea 39 (38) 34 (32) 11 (11)

Thrombocytopenia 34 (33) 36 (34) 23 (23)

Anemia 29 (28) 25 (24) 15 (15)

Vomiting 22 (21) 20 (19) 5 (5)

Conclusions

Despite study truncation due to the clinical hold:

• PAC (QD+BID) was significantly more effective than BAT (including RUX) for SVR (p=0.001) and trended toward improved TSS (p=0.079)

• PAC BID appeared more effective than PAC QD versus BAT for SVR and TSS

• SVR and TSS responses to PAC BID were consistent across demographic and disease risk characteristics

• PAC BID appeared to have a better benefit/risk profile than BAT, which included RUX

RUXOLITINIB IN COMBINATION WITH 5-AZACYTIDINE AS THERAPY FOR PATIENTS WITH MYELOFIBROSIS

Naval Daver, Jorge Cortes, Naveen Pemmaraju, Elias Jabbour, Prithviraj Bose, Linghsa Zhou, Sherry Pierce, Stephanie Van Derbur, Gautam Borthakur, Zeev Estrov,

Guillermo Garcia-Manero, Hagop Kantarjian, Srdan Verstovsek

Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Slides provided by presenter Dr. Daver

• Ruxolitinib 15-20 mg PO BID (cycles 1-3)

• Azacytidine 25 mg/m2 IV daily x 5 days (starting cycle 4 day 1)

• Azacytidine could be increased to 50mg/m2 and 75 mg/m2

• Cycles repeated every 4-6 weeks13

Rux + Aza in MF: Design

Rux + Aza in MF: Response Criteria IWG-MRT 2013

14

CI (clinical improvement) definitions:

• CI Spleen (palpation): Baseline >10 cm, decreases by ≥50%, Baseline 5-10 cm, becomes non-palpable Baseline <5 cm, not eligible

•CI Total symptom score (TSS): >50% reduction in MPN-SAF

•CI Hb:•Transfusion independent: > 20 g/dL improvement•Transfusion dependent: becomes independent

All CI must be maintained > 12 weeks

Tefferi et al., Blood 2013

IWG-MRT 2013 response N (%)Objective response 28 (72)

Partial Remission 2 (7)CI spleen + TSS 7 (25)CI TSS + Hb 2 (7)CI spleen; CR cyto [1 PR Jak2] 2 (7)CI TSS; CR cyto 1 (4)CI spleen+TSS+PR Jak2/ PR Jak2 2 (7)CI TSS only/ CI spleen only 8 (28)/ 4(14)

No IWG response 11 (28)

Rux + Aza in MF: IWG-MRT Responses (N=39)

15

Rux + Aza in MF: Conclusion

16

• Rux with Aza feasible and promising:IWG response = 72%; >50% spleen reduction at 24 wks = 48%; Overall >50% spleen reduction = 79%.

• Well tolerated: only one patient off study due to cytopenia

• Encouraging improvement in BM fibrosis, needs sequential confirmation

• Patients being followed for hemoglobin, OS, JAK2 allele and fibrosis.


Additional Abstracts of Interest

17

PV/ET PROUD-PV [Abstract 475]: Ropeginterferon α-2b

(longer-acting pegIFN non-inferior to HU MPD-RC 112 (PV/ET) [Abstract 478: pegIFN-α (PEG)

vs HU, similar efficacy but more SE [Abstract 479]

Myelofibrosis Momelotinib [Abstract 1123]: JAK1/2 inhibitor Improved anemia (20% durable), but 50% toxicity

including peripheral neuropathy Ruxolitinib + PI3K inhibitor [Abstract 1125]: In patients with lost/sub-optimal response to ruxolitinib

Sotatercept [Abstract 478]: BlocksTGF-ß Small sample size, 4 patients with anemia response


TKI Discontinuation: Imatinib: EURO-SKI Nilotinib: Nilst, ENESTop Dasatinib: D-STOP

Definitions: MR3 = <0.1% on IS (MMR) MR4 = <0.01% on IS MR4.5 = <0.0032% on IS

CML Updates:

After Stopping Imatinib Treatment of CML: No Differences in Molecular Relapse-Free Survival

Between Patients with Prior 4.5 Log Reduction (MR4.5) but Detectable and Patients with

Undetectable Disease in the EURO-SKI Trial

Markus Pfirrmann for all project partnersE-mail: [email protected]

San Diego, 5th December 2016

Slides provided by presenter Dr. Pfirrmann

Study outline of EURO-SKI

20

Follow‐up

RQ‐PCR RQ‐PCRevery 3rd month

Screening phase

(confirmationof MR4 incentral lab)

Stop TKIInformedconsent

Year 1 Year 2 Year 3

MR4

≥ 1 year

q4w q6w

≤ 6 weeks

Patients included between May 2012 and December 2014

TKI treatment ≥ 3 years

Relapse:Loss of MMR

MMR: 3‐log reduction of BCR‐ABL1

Results presented by Richter et al., EHA meeting 2016

21

Molecular relapse-free survival

Molecular relapse-free survival, MRFSMol

. rel

apse

-free

sur

viva

l

Months MRFS, % 95%-C.I.6 62 59-6712 56 52-59

24 52 48-56

36 49 44-53

n=750 (of 868) patients fulfilling inclusion criteria

What are prognostic factors for remaining in molecular relapse-free survival 6 months after TKI-stop?

Results at 6 months for all patients available

Months since discontinuation of TKI


Cessation of Tyrosine Kinase Inhibitors Treatment in Chronic Myeloid Leukemia Patients with Deep Molecular Response: Results of the Euro-Ski Trial Francois-xavier Mahon et al,, Johan Richter, MD,

Joelle Guilhot, PhD, Henrik Hjorth-Hansen, MD, PhD, Antonio Almeida, MD, PhD, Jeroen J.W.M. JWM Janssen, MD, Jiri Mayer, Kimmo Porkka, MD, PhD, Panayiotis Panayiotidis, MD, PhD, Ulla Stromberg, MD PhD, Marc G Berger, MD, PhD, Professor, Joanna Diamond, Hans Ehrencrona, MD, PhD, Veli Kairisto, Katerina Machova Polakova, Martin C. Mueller, Prof., Satu Mustjoki, MD, PhD, Andreas Hochhaus, MD, Markus Pfirrmann, PhD and Susanne Saussele, MD

22


EURO-SKI Results: Imatinib Subgroup

821 patients enrolled on study 448 treated with imatinib

Predictors of sustained MMR at 6 months: Treatment duration with imatinib and MR4 duration

prior to the stop (p<0.001)

Conclusion: Stopping TKI therapy appears feasible and safe in this large cohort study.

23

Treatment >5.8 years ≤ 5.8 years MMR at 6 months 65.5% 42.6%


Norimitsu Kadowaki, MD, PhD, Tatsuya Kawaguchi, MD, PhD, Junya Kuroda, MD, PhD, Hirohisa Nakamae, MD, PhD, Itaru Matsumura, MD, PhD, Toshihiro Miyamoto, MD, PhD, Jun Ishikawa, MD, PhD, Koji Nagafuji, MD, PhD, Yutaka Imamura, MD, PhD, Hirohito Yamazaki, Mototsugu Shimokawa, PhD, Koichi Akashi, MD, PhD and Yuzuru Kanakura, MD, PhD

Discontinuation of Nilotinib in Patients with Chronic Myeloid Leukemia Who Have Maintained Deep Molecular Responses for at Least 2 Years: A Multicenter Phase 2 Stop Nilotinib (Nilst) Trial

24


Consolidation with 2 years of nilotinib Primary

endpoint: MR4.5 at 1 year = 58.9% Longer duration

of therapy pre-stop did not correlate with maintenance of response

Nilst Trial: n=90 patients, MR4.5

26

Treatment-Free Remission in Patients With Chronic Myeloid Leukemia in Chronic Phase According to Reasons for Switching From Imatinib to Nilotinib:

Subgroup Analysis From ENESTopTimothy P. Hughes, Carla Boquimpani, Naoto Takahashi, Noam Benyamini,

Nelma Cristina D. Clementino, Vasily Shuvaev, Sikander Ailawadhi, Jeffrey H. Lipton, Anna G. Turkina, Beatriz Moiraghi, Franck E. Nicolini,

Jolanta Dengler, Tomasz Sacha, Dong-Wook Kim, Rafik Fellague-Chebra, Sandip Acharya, Nancy Krunic, Yu Jin, François-Xavier Mahon

Slides provided by presenter Dr. Hughes

27

ENESTop: Ongoing Single-Arm, Phase 2 Study• Adults with CML-CP• ≥ 3 years of TKI

therapy (first imatinib for > 4 weeks, then nilotinib for ≥ 2 years)

• No documented MR4.5

at time of switch to nilotinib

• Achieved MR4.5 on nilotinib

• Adults with CML-CP• ≥ 3 years of TKI

therapy (first imatinib for > 4 weeks, then nilotinib for ≥ 2 years)

• No documented MR4.5

at time of switch to nilotinib

• Achieved MR4.5 on nilotinib

Nilotinib consolidation

phase (52 weeks)

Nilotinib consolidation

phase (52 weeks)

TFR phase (up to 192 weeks after last patient entered TFR phase)

TFR phase (up to 192 weeks after last patient entered TFR phase)

RQ-PCR every 12 weeks

Enro

llEn

roll

No confirmeda loss of MR4.5

TFR-2 phase(up to 192 weeks after last patient

entered TFR phase)

TFR-2 phase(up to 192 weeks after last patient

entered TFR phase)

Nilotinib treatmentreinitiation

phase

Nilotinib treatmentreinitiation

phase

Nilotinib continuation

phasec

(52 weeks)

Nilotinib continuation

phasec

(52 weeks)

No confirmeda

loss of MR4.5

Criteria for reinitiating nilotinib:

• Loss of MMRor

• Confirmedb loss of MR4

Confirmeda

loss of MR4.5

1st year: RQ-PCR every 4 weeks2nd year: RQ-PCR every 6 weeks

Thereafter: RQ-PCR every 12 weeks

MR4.5, BCR-ABL1IS ≤ 0.0032%; RQ-PCR, real-time quantitative polymerase chain reaction.a Confirmed loss of MR4.5 was defined as BCR-ABL1IS > 0.0032%, confirmed in a second assessment within 4 weeks.b Confirmed loss of MR4 was defined as BCR-ABL1IS > 0.01%, confirmed in a second assessment within 4 weeks.c Patients with confirmed loss of MR4.5 during the continuation phase continued nilotinib treatment in the prolonged continuation phase until 192 weeks after the last patient entered the TFR phase or until discontinuation due to unacceptable toxicity, disease progression, investigator discretion, or withdrawal of consent.

Primary endpoint: proportion of patients in TFR (no loss of MMR, no confirmed loss of MR4, and no reinitiation of treatment) at 48 weeks after stopping nilotinib

Proportion of patients who entered the TFR phase:• Overall population: 126/163 (77%)

• Intolerance subgroup: 51/59 (86%)

• Resistance subgroup: 30/38 (79%)

• Physician preference subgroup: 45/66 (68%)

28

Time to Loss of Response in the TFR Phase by Reasons for Switch

Kaplan-Meier–estimated median duration of TFR was not reached by the data cutoff date

51:0 44:7 31:20 30:21 24:21 16:21 9:21 1:2130:0 24:6 17:13 16:14 13:14 7:14 2:14 0:1444:0 38:6 28:16 28:16 24:17 13:17 3:17 0:17

0:21

12 24 36 48 60 72 84 96

20

10

0

50

40

30

60

80

70

90

100

0

Time Since TFR, weeks

IntoleranceResistancePhysician preferenceCensored observations

Pts Evt Cen513044

211417

301627Pa

tient

s W

ithou

t Los

s of

MM

R o

rC

onfir

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MR

4 , %

IntoleranceResistance

Physician preference

At risk:Events


Discontinuation of Dasatinib after Deep Molecular Response for over 2 Years in Patients with Chronic Myelogenous Leukemia and the Unique Profiles of Lymphocyte Subsets for Successful Discontinuation: A Prospective, Multicenter Japanese Trial (D-STOP Trial)

Takashi Kumagai, MD, PhD, Chiaki Nakaseko, MD, Kaichi Nishiwaki, M.D, PhD, Chikashi Yoshida, MD, PhD, Kazuteru Ohashi, Naoki Takezako, MD, PhD, Hina Takano, M.D, PhD, Yasuji Kouzai, MD, PhD, Tadashi Murase, MD, PhD, Kosei Matsue, MD, PhD, Satoshi Morita, PhD, Prof, Junichi Sakamoto, MD, PhD, Hisashi Wakita, MD, PhD, Hisashi Sakamaki, MD, PhD and Koiti Inokuchi, MD, PhD, Prof

29


65 patients enrolled at IS <0.01%

Consolidation with dasatinib for 2 years

62.9% TFS at 12mosfeasible with relatively high TFS Unique profile of

lymphocyte subsets reported that may be able to predict successful discontinuation

D-STOP results

At 12 months


TKI Discontinuation Criteria (NCCN, 1/2017)

Chronic phase CML only Duration of treatment: At least 3 years Depth of response: stable MR4 (IS <0.01%) for at least 2

years On at least 4 tests, 3 months apart

Depth of response recommended to remain off of TKI: MR3 (IS <0.1%) Patients must have access to reliable PCR testing on the IS with

results available within 2 weeks while off of TKI Recommended monitoring while off of TKI:

MONTHLY PCR testing for the first 6 months Bimonthly for months 7-24 if MMR sustained Quarterly for months 25 and beyond as long as MMR sustained If loss of MMR at any time, prompt resumption MONTHLY

testing for the first 6 months with resistance testing if not back in MMR after resuming TKI by 6 months


MPD Summary

Current therapy updates: TKI Discontinuation: NCCN guidelines released

January 2017

Areas of ongoing and future investigation: PV/ET: pegIFN-α (PEG) Myelofibrosis: JAK2 inhibitors, combination of JAK2

inhibitors with novel agents, and development of novel agents

CML: Potential for second TKI discontinuation attempt and novel agents (ABL-001, Abstract 625)

32

ohio state's ash review 2017 - myeloproliferative disorders

Education