Chronic Myeloid Leukemia and Myeloproliferative Neoplasms in … · ©2011 MFMER | 3133089-1 Chronic Myeloid Leukemia and Myeloproliferative Neoplasms in 2015 Rocky Mountain Blood

©2011 MFMER | 3133089-1

Chronic Myeloid Leukemia and

Myeloproliferative Neoplasms in 2015

Rocky Mountain Blood Conference April 11, 2015

Ruben A. Mesa, MD Deputy Director, Mayo Clinic Cancer Center

Professor and Chair, Division of Hematology and Medical Oncology

Disclosures:

• Research/ Clinical Trial Funding:

• Incyte, CTI, Gilead, Genentech, Promedior, NS Pharma, Celgene, Pfizer

• Consultancy:

• Novartis, Shire, AOP

MPNs and CML in 2015 Shifting Targets, Goals, and Therapies

• Are the goals of CML therapy changing?

• Early MPNs – no longer just Hydroxyurea to consider

• Evolving options for Myelofibrosis

Disease Burden in CML: Shrinking the Iceberg

www.nccn.org; accessed 11/25/14

What do Guidelines Say?

http://www.nccn.org

Effect of Early Molecular Response on Subsequent Response and Outcome

Branford S, et al, Leukemia 17(12), 2401-9, 2003 Marin D, et al, J Clin Oncol 30(3) 232-8, 2012 Hanfstein B, et al, Leukemia 26(9):2096-102, 2012

6

Months on Imatinib

% a

chie

vin

g M

MR

50

60

70

80

90

100

20

30

40

10

0

P<0.001 69%

100%

3 6 9 12 15 18 24 30 21 27

13%

>2 log reduction

1-2 log reduction

0-1 log reduction

0.0

0 1 2 3 4 5 6 7 8

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

ba

bil

ity

of

PF

S >10%

1-10% 1%

BCR-ABLIS

1%

1-10%

>10%

n

218

281 189

5Y-PFS

96%

92% 87%

p-value

n.s.

0.037

Years

Pro

ba

bil

ity

of

Su

rviv

al

Time From Onset of Imatinib Therapy (Yrs)

BCR-ABL/ABL< 9.84% 8-yr OS: 93.3%

BCR-ABL/ABL > 9.84% 8-yr OS: 56.9%

P < .001

1.0

0.8

0.6

0.4

0.2

0 0 1 3 4 5 8 7 6 2 Years

Addition of ‘CMR’ and Improvement in EFS, FFS

23 11 5 1 0 0 0

92 81 60 33 10 3 0

65 63 53 35 15 3 2

CCvR+MMR-

CCvR+MMR+CMR-

CCvR+MMR+CMR+

Number at risk

23 11 5 1 0 0 0

92 81 60 33 10 3 0

65 63 53 35 15 3 2

CCvR+MMR-

CCvR+MMR+CMR-

CCvR+MMR+CMR+

Number at risk

p = 0.00124

p < 0.0001

p < 0.0001

1.0

0.8

0.6

0.4

0.2

0.0

0 20 40 60 80 100 120 Follow-up (Months)

Eve

nt

Fre

e S

urv

iva

l

EFS

CCyR+MMR+CMR+

CCyR+MMR+CMR-

CCyR+MMR-

p = 0.0335

p < 0.0001

p < 0.0001

1.0

0.8

0.6

0.4

0.2

0.0

0 20 40 60 80 100 120 Follow-up (Months)

Fa

ilu

re F

ree

Su

rviv

al

FFS

CCyR+MMR+CMR+

CCyR+MMR+CMR-

CCyR+MMR-

EFS = event-free survival; FFS = failure-free survival. CMR Defined as undetectable BCR-ABL with a sensitivity of at least 4.7 logs on 2 consecutive analyses at least 2 months apart.

Etienne G et al. Haematologica 2014;99:458-464

©2011 MFMER | 3133089-8

Cortes et. al. ASH 2014

Final Results of Dasision Trial

Phase III Dasatinib vs. Imatinib

©2011 MFMER | 3133089-9

Lipton et. al. ASH 2014

Phase III Trial of Ponatnib Vs. Imatinib (EPIC)

CP-CML

45mg Ponatinib vs. 400mg Imatinib

Kantarjian, et al. Blood. 2012;119:1981-1987.

BCR-ABL1 TKI Associated Cardiovascular Adverse Effects

10

Cerebrovascular Disease

Coronary Heart Disease Myocardial Infarction

Pulmonary Arterial Hypertension

Venous Thrombosis Peripheral Arterial Disease

Cardiomyopathy Congestive Heart Failure

Morbidity and mortality; ? Effect on OS observations in front-line studies

? Delay/deferral of advantageous therapy both in front-line and salvage

Cardiomyocyte Injury?

Endothelial Dysfunction? Atherosclerosis?



Endothelial Dysfunction?

Platelet dysfunction? Prothrombotic state?

• Fatigue • Musculoskeletal Sx / Cramping • Exercise-Induced Symptoms

Other:

36mo: 61%

0

20

40

60

80

100

0 6 12 18 24 30 36 42

Su

rviv

al w

ith

ou

t M

MR

loss

%

Months since 2G-TKI discontinuation

12 mo: 61.1% (95% CI: 45.6-76.6)

Survival without loss of MMR: ~60% Success

Rea D, et al. Blood (ASH) 2012: Abstract 916

Rousselot P et al., J Clin Oncol. 2014 Feb 10;32(5):424-30

Ross DM et al. Blood. 2013 Jul 25;122(4):515-22

AUSTRALASIAN CML8

STOP 2G TKI A-STIM

Stable cCMR before stop Unstable cCMR before stop

Mo

lecu

lar

Re

lap

se-

Fre

e S

urv

iva

l (%

)

100

80

60

40

20

0 12 24 36 48 60 72 84

Time (months)

A-STIM

Paradise Lost, Regained?

Cumulative incidence of regained MR4.5 in A-STIM retreated pts after loss of MMR

Months

Perc

en

t C

MR

4.5

0 12 24 360

20

40

60

80

100

• Median time to regain deep molecular remission: 7.3 mo • One patient with CML>15y experienced lymphoid blast crisis 8.5 mo from regained

MMR after restarting imatinib

. Rousselot P et al., J Clin Oncol. 2014 Feb 10;32(5):424-30.

Pe

rce

nt

MR

4.5

What Should We Expect From MPN Therapy? Top 10 ways we better match therapy and patients

10. Understand that not all MPN patients are impacted the same

©2011 MFMER | 3133089-13

Assessing MPN Burden WHO Diagnosis Does Not Tell Whole Story

©2011 MFMER | 3133089-14

MPN Symptoms

• MF>PV>ET

• Multifactorial

• Some ET/PV > MF

• Cytoreductive rx

frequently not effective

Vascular Events

• PV/ET > MF

• Counts matter

• Can be

unrecognized

Progression

• PV/ET to MF

• PV/ET to AML

• MF to AML

• ? 2nd MDS

Cytopenias

• MF> ET/PV

• Anemia

• MF 75%

• TX Dep 25%

• TPN 30%

Splenomegaly

• MF> ET/PV

• Pain not always

a function of

size

Baseline Health AGE/ Medicines Comorbidities



9. Understand the spectrum of symptoms MPN patients face

©2011 MFMER | 3133089-15

Evolution of MPN Symptom Assessment Tools

MF–SAF

2009

(19 items)

MF-SAF 2.0

(7 items 2011)

JCO 2012

Brief Fatigue

Inventory

(BFI) – 9 Items

Spleen Sx

4 Items

Constitutional Sx

5 Items

QOL 1 Item

Vascular and Ψ Sx

9 Items MPN–SAF

2011

(27 items)

Blood 2011

MPN-SAF TSS

(10 items 2012)

JCO 2013

MPN-SAF Languages

• English

• French

• German

• Spanish

• Dutch

• Swedish

• Italian

• Portuguese

• Mandarin

• Japanese

• Hebrew

0%

20%

40%

60%

80%

100%

Wo

rst

fati

gue

(o

ne

-ite

m B

FI)

Earl

y sa

tiet

y

Ab

do

min

al d

isco

mfo

rt

Inac

tivi

ty

Co

nce

ntr

atio

n

Nig

ht

swe

ats

Itch

ing

Bo

ne

pai

n

Feve

r

We

igh

t lo

ss

ET (N=874)

PV (N=729)

MF (N=486)

MPN Total (N=2089)

Pre

vale

nce

of

Sym

pto

ms

(%)

Symptoms from 2089 MPN Patients Using the MPN-SAF TSS (MPN10)

MPN QOL - ISG




8. Understand impact of symptom clusters, and gender effect on MPN patients

©2011 MFMER | 3133089-18

Quartile 1 (Q1): 0-24% Quartile 2 (Q2): 25-49%

Quartile 3 (Q3): 50-74% Quartile 4 (Q4): 75-

100%

Percentile MPN-SAF TSS

Q1

TSS <8

Q2

TSS 8 -17

Q3

TSS 18 - 31

Q4

TSS >32

MPN Symptom Burden by Quartiles 1858 MPN-SAF Respondents

Scherber et.al.

ASH 2013

ET (N=775)

PV (N=654)

MF (N=423)

Q1 – 30% Q2 – 26% Q3 – 24% Q4 – 20%

Q1 – 17% Q2 – 21% Q3 – 26% Q4 – 36%

Q1 – 25% Q2 – 23% Q3 – 26% Q4 – 26%

Parameter P value of Comparison

Age 0.24

Gender F>M <0.001

MPN Diagnosis <0.001

Subtype of MF 0.86

IPSET (ET Risk) 0.18

PV Risk (PV) 0.30

DIPSS (MF Risk) <0.001

©2014 MFMER | slide-21

Results

• Higher mean age than females (mean 60.7

yrs [SD 12.6] vs 59.3 yrs [SD 14.4]; p=0.02)

• Higher rate of requirement for red blood

cell transfusion (7% vs 5%, p=0.02)

• Higher mean white blood cell count (mean

9.5x109/L [SD 8.2 x109/L] vs mean 8.5 x109/L

[SD 6.1x109/L]; p=0.004)

• Lower rate of thrombocytopenia (8% vs 14%,

p<0.001).

• Higher TSS (adjusted mean 23.9 vs 20.6;

p<0.001)

• Higher symptom scores for 15/18 items

• Prominent symptoms: fatigue, bone pain,

abdominal discomfort, and microvascular

related

Females Males

Higher levels of fatigue

• Younger

• Lower red blood counts

• Lower transfusion rates

More Abdominal Symptoms

• Male=female abdominal thrombosis rates

Microvascular symptoms

• Previous reports show more macrovascular symptoms

Higher Symptom Scores

• Individual SS and TSS

• Male=female QOL score

Females demonstrate…





7. Understand the complex issue of MPN fatigue, and possible mood disorders

©2011 MFMER | 3133089-22

MPN “Fatigue” Project 2014 Collaborative Internet Based Trial with MPN Forum

©2011 MFMER | 3133089-23 ©2011 MFMER | 3133089-23

ANY MPN Patient • Survey online

• MPN Forum

• MPN Advocacy

• MPN Research

Foundation

• CMPD Ed

Foundation

Regis

ter/

Onlin

e C

onsent

Online 70 Item Survey

• Demographics

• MPN History

• MPN-SAF (MPN10)

• Brief fatigue inventory (BFI)

• Profile of mood states (POMS-Short)

• Patient Health Questionnaire (PHQ-2)

• Mental Health Inventory (MHI-5)

1788 MPN patients/ 1676 Eval.

ET 33%, PV 39%, MF 25%

68% Female, median age 59.

MPN10 Score average 28.4

(range 0-83)

Higher BFI, MPN-SAF,

MPN10 scores all correlated

with increased depressive

symptoms (p<0.0001)

23% high likelihood of depression

(≥ 3 on PHQ-2)

Prior diagnosis depression (32%),

anxiety (29%), stress (26%), grief

(15%)

22% on therapy for mood disorder

in last 6 months

Patients Psych Comorbidity MPN Correlation

Scherber R et al. 2014, ASH: abstract 3173


MPN Fatigue Project

• Three part project:

Evaluate

strategies to reduce fatigue burden

PHASE I

Determine strategy

efficacy and comorbidites

PHASE II

Home-based prospective

online trial to employ fatigue-related

interventions

PHASE III

N=1748 MPN pts (718 PV, 625 ET, 420 MF, 29 other)


Fatigue Project Strategies To Cope with Fatigue Related to MPN

BFI - Mean (SD), N YES

BFI - Mean (SD), N NO

Δ 95% CI P

Postponing non-essential activities

5.0 (2.1), 981 3.2 (2.3), 365 1.8 (1.6, 2.1) <.0001

Setting priorities 4.9 (2.1), 1015 3.3 (2.4), 353 1.6 (1.3, 1.9) <.0001

Medication psychostimulants 5.8 (2.0), 110 4.4 (2.3), 1253 1.4 (1.0, 1.8) <.0001

Antidepressants 5.5 (2.0), 320 4.2 (2.3), 1050 1.3 (1.1, 1.6) <.0001

Delegation 5.0 (2.2), 682 3.9 (2.4), 655 1.1 (0.8, 1.3) <.0001

Scheduling of activities to times of peak energy

4.9 (2.1), 827 3.8 (2.4), 528 1.1 (0.8, 1.3) <.0001

Naps 4.8 (2.3), 942 3.7 (2.3), 415 1.1 (0.8, 1.3) <.0001

Labor-saving devices 5.1 (2.1), 493 4.1 (2.4), 838 1 (0.8, 1.2) <.0001

Structured daily routines 5.0 (2.2), 706 4.0 (2.3), 635 1 (0.8, 1.2) <.0001

Socializing with family or friends 4.8 (2.2), 853 3.9 (2.5), 487 1 (0.7, 1.2) <.0001

Support groups 5.3 (2.1), 296 4.3 (2.3), 1066 1 (0.8, 1.3) <.0001

Pacing 4.9 (2.1), 772 4.0 (2.4), 580 0.9 (0.7, 1.2) <.0001

Reading 4.8 (2.2), 820 3.9 (2.4), 523 0.9 (0.6, 1.1) <.0001

Sleep therapy 5.3 (2.1), 117 4.4 (2.3), 1237 0.9 (0.5, 1.4) <.0001

Music 4.9 (2.2), 618 4.1 (2.3), 722 0.8 (0.5, 1.0) <.0001

Church or spiritual activities 4.9 (2.1), 485 4.2 (2.4), 841 0.8 (0.5, 1.0) <.0001

Nutrition 4.8 (2.2), 876 4.0 (2.4), 499 0.8 (0.5, 1.1) <.0001

Steroids 5.3 (2.0), 75 4.5 (2.3), 1282 0.8 (0.3, 1.4) 0.003

Meditation, quiet time, or cognitive re-framing

4.9 (2.2), 555 4.2 (2.4), 822 0.7 (0.4, 0.9) <.0001

New activities/ diversions 4.8 (2.3), 476 4.3 (2.3), 857 0.5 (0.2, 0.7) 0.0003

Relaxation, including yoga 4.7 (2.3), 572 4.3 (2.4), 821 0.4 (0.1, 0.6) 0.005

Walking/sitting in a natural environment

4.6 (2.2), 891 4.3 (2.5), 477 0.2 (-0.02, 0.5) 0.1

Gardening 4.6 (2.3), 585 4.4 (2.4), 788 0.1 (-0.1, 0.4) 0.3

Volunteer activities 4.5 (2.3), 430 4.5 (2.3), 937 0.1 (-0.2, 0.3) 0.7

Exercise 4.4 (2.3), 1009 4.7 (2.5), 377 -0.4 (-0.6, -0.1) 0.01

Postponing non-essential activities

Setting priorities

Medication Psychostimulants

Antidepressants

Exercise

MPN Patient Burden- Disease Impact 2014 Landmark Study

©2011 MFMER | 3133089-26 ©2011 MFMER | 3133089-26

ANY MPN Patient • Survey online

• MPN Forum

• MPN Advocacy

• MPN Research

Foundation

• CMPD Ed

Foundation

Regis

ter/

Onlin

e C

onsent

Online Survey

• Demographics

• MPN History

• MPN-SAF (MPN10)

• Impact on QoL

• Impact on Employment

• Impact on ADLs

• 813 MPN Patients

• MF (207)/ PV (380),

ET (226)

• INT/ High Risk

• MF (94%)

• PV (78%)

• ET (74%)

• ≥ 1 sick day in last month

• MF (33%), PV (23%),

ET (22%)

• ≥ 1 cancelled activity in last

month

• MF (46%), PV (35%),

• ET (34%)

• Anxious about their MPN

• MF (91%)

• PV (78%)

• ET (74%)

• MPN Symptoms decrease my

QoL

• MF (81%)

• PV (66%)

• ET (57%)

Patients Symptom Burden Impact

Mesa R et al. 2014, ASH: abstract 3183






6. Understand complex assessment of MPN “risk”, and comorbidities

©2011 MFMER | 3133089-27

Evolving MPN prognostic scales

Tefferi Leuk 2014

Passamonti Blood 2012

Passamonti Blood 2010

a 10% weight loss over prior 6 months, night sweats, unexplained fever.

IPSET

(ET—3 groups)

Survival

thrombosis risk

PV

Risk (4 groups)

Survival

leukemia rates

DIPSS

(PMF—4 groups)

Survival

Age, years ≥ 60 (2 pts) vs < 60 ≥ 67 (5 pts)

57-66 (2 pts), < 60 (0)

≥ 65 (1 pt) vs < 65

Leukocytes ≥ 11 (1 pt) vs

< 11 x 109/L

≥ 15 (1 point) vs

< 15 x 109/L

> 25 (1 pt) vs

≤ 25 x 109/L

Hemoglobin < 10 (2 pts) vs

≥ 10 g/dL

Constitutional

symptoms

Presenta (1pt) vs

absent

Blasts ≥ 1% (1pt) vs < 1%

Prior thrombosis Yes (1 point) vs No Yes (1 Point) vs No

Risk group point

cutoffs

0; 1-2; 3-4 pts 0; 1-2; 3; 4 pts 0; 1-2; 3-4; ≥ 4 pts

Monitoring MPNs

MIPSS: Molecular International Prognostic Score System

Weighted value

1.5

0.5

0.5

1.0

1.5

0.5

0.5

0.5

MULTIVARIATE ANALYSIS

Variables HR (95% CI) P

Age >60yrs 3.8 (2.60-5.51) <0.0001

Hb <100g/L 1.4 (1.01-1.99) 0.04

Constitutional Symptoms 1.5 .(1.13-2.16) 0.007

PLT <200x109/L 2.5 (1.77-3.42) <0.0001

Triple Negativity 3.9 (2.20-6.80) <0.0001

JAK2/MPL mutation 1.8 (1.11-2.90) 0.016

ASXL1 mutation 1.4 (1.06-1.99) 0.02

SRSF2 mutation 1.7 (1.08-2.58) 0.02

Vannucchi et. al. ASH 2014

Development of the MIPSS Score in the Learning Cohort

Int-1

Low Int-2

High

Risk category

Score % of pts

OS (y) HR

Low 0-0.5 27 26.4 1

Int-1 1-1.5 14 9.7 4.7

Int-2 2-3.5 46 6.4 9.9

High >4 13 1.9 36.5

P < .001


IPSS - LOW IPSS - INT-1 IPSS - INT-2

P= .005

23.4y 17.7y 4.5y

Low 24.9y < Int-1 17.7y < Int-2 6.2y

> Low 15.3y > Int-1 8.1y > Int-2 1.9y

MIPSS

P= .040 P= < .001

*, IPSS Median Survival

* * *

Estimated

§

§

§

§

MIPSS Permits to Refine Prognostic Stratification Within the IPSS Categories


FATIGUE Trial – Co-morbidities in 1676 MPN Patients

Scherber

et. al.

ASH 2014







5. Understand new response criteria, and need for their validation

©2011 MFMER | 3133089-33

©2011 MFMER | 3133089-34

Response Criteria for MPNs 2014 (All ≥ 12 Weeks) ET/PV – ELN (Barosi et. al. Blood 2013) MF – IWG-MRT (Tefferi et. al. Blood 2013)

ET

PV

MF

Complete

Remission

Partial

Remission

Clinical

Improvement Other

N.B. ET/PV – Progression is MF/MDS/ or AML

MF – Progression based on spleen growth or AML

• Resolve ET Signs

• ≥ 10 pt. MPN10

• Near normal counts

• No Prog. or Vascular

• BM rem & ≤Gr 1 MF

• Resolve ET Signs

• ≥ 10 pt. MPN10



Peripheral Blood

Granulocytes

• CR – Eradicated

mutation

• PR - ≥50% ,

≥ 20% baseline

• Resolve MF Signs

• Resolve MF sympts



Like MF CR but

• Hb (between 85 and

100 g/L)

• PLT (between 50-100

x 10(9)/L)

• Anemia (2g/dl or T.I.)

• Spleen (Based on BL)

• Symptoms (≥ 50%)

• Molecular (ET/PV

Criteria)

• Cytogenetic

• CR – Normal

• PR - ≥ 50%

• Resolve PV Signs

• ≥ 10 pt. MPN10




• Resolve PV Signs

• ≥ 10 pt. MPN10



Peripheral Blood

Granulocytes

• CR – Eradicated

mutation

• PR - ≥50% ,

≥ 20% baseline

©2011 MFMER | 3133089-35

“Clinically Meaningful” – What is Valid?

(Example – Spleen Reduction)

> 50% reduction of Palpable Length

IWG-MRT

2006

Blood 2006

> 35% Volume Reduction by MRI

COMFORT

1 & 2

NEJM 2012

> 10% Volume Reduction by MRI

- Better Survival and PGIC

Pooled

CI/CII

Blood 2013








4. Optimizing the timing and utilization of stem cell transplant

©2011 MFMER | 3133089-36

Stem Cell Transplant Use in MPNs

©2011 MFMER | 3133089-37

Baseline Assumptions/ Caveats

• SCT almost exclusively for MF/ MPN-BP

• In MF evolving risk/benefit analysis for use

“Problematic”

MF

& SCT

Eligible

Allo SCT

Question 1

Timing?

• Urgent

• Delayed

• Never

Question 2

Pre Transplant Therapy?

• JAK Inhibition?

• Cytoreduction?

• Iron chelation?

Question 3

Post Transplant Therapy?

• JAK Inhibition?

• Interferon?

• other?









3. Optimizing the utilization of current available agents

©2011 MFMER | 3133089-38

Primary Commercially Available MPN Drugs 2015

ET

PV

MF

Hydroxyurea Interferon/

Peg -INF Anagrelide Ruxolitinib

XXX XX

XXX X X X

X

XX XX XXX

XX

X

EXPERIMENTAL – OFF LABEL – PHASE III DATA

Management of PV-ET

• ALL PV Patients

• Maintain HCT <45% Men, 42% Women

• Low Dose ASA

• Aggressive control of CV risk factors

• Cytoreduction

• High Risk or

• Intol to Phlebotomy, Increasing Spleen, Severe Sx

Plt >1500 x 10(9)/L, or prog WBC

• Medications • Hydroxyurea or Interferon alpha as Front line (or second)

• Busulfan, pipobroman, P-32 as second line

Barbui T, et. al. LeukemiaNET Consensus Guidelines. JCO 2011;29:761-770

Risk of the Primary End Point in prespecified subgroups

Barbui et. NEJM 2013

©2011 MFMER | 3133089-42

Interferons in MPNs – Evolving Footprint

Peginterferon alpha-2a

Pegasys (Roche/ Genentech)

Pegylated P Interferon alpha-2b

AOP 2014 P1101

(AOP/ Pharmessentia)

MPD – RC 112

PEG INF vs HU

(Front Line)

High Risk ET/PV NCT01258856

MPD-RC 111

PEG INF

(2nd Line)

High Risk ET/PV - SVT NCT01259817

PROUD - PV

AOP2014/P1101 vs HU

(Front Line)

High Risk PV NCT01949805

JAK Inhibitors and Status of Development Myelofibrosis as lead indications

0 1 2 3 4

AZD1280

XL019

CEP 701

Fedratininb (SAR302503)

INCB039110 (JAK1)

NS-018

BMS-911543

LY2784544

Momelotinib (CYT387)

Pacritinib (SB1518)

Ruxolitinib (FDA Approved)

©2011 MFMER | 3133089-43

No Longer in Development

For MPNs

* Now Testing

in PV

*

*

*

*

©2011 MFMER | 3133089-44

Ruxolitinib (Single Agent) in Myelofibrosis

COMFORT 1 COMFORT 2

Verstovsek, Mesa, Gotlib et. al. NEJM 2012;366(9):799-807

Harrison, Kiladjian, Kathrin et.al. NEJM 2012;366(9):787-798

©2011 MFMER | 3133089-45

Ruxolitinib (Single Agent) in Polycythemia Vera

BAT

Week 32

(Primary analysis)

Week 80

n = 110

n = 112

Crossover to

ruxolitinib

•Resistance to

or intolerance

of HU (modified

ELN criteria)

•Phlebotomy

requirement

•Splenomegaly

Pre-randomization

(Day −28 to Day −1)

Hct 40%-45%

Ra

nd

om

ize

d (

1:1

)

Extended

Treatment

Phase Ruxolitinib

10 mg BID

Week 208

Week 208

Vannucchi et. al. NEJM In Press

Compared to Best Alternative Therapy Ruxolitinib (post HU) in PV

1. Superior control of hematocrit

2. Superior reduction in splenomegaly

3. Superior reduction in PV related symptoms

4. Trend for less thrombotic events

Change in Symptoms on RESPONSE Trial

in PV

46

Median Percentage Changes From Baseline at Week 32 in

Individual MPN-SAF Symptom Scores

−100.0 −99.5 −94.9 −93.9

−80.2

−65.9 −64.1 −61.1

−51.5 −49.6 −44.0 −41.8

−37.1

0.0

−4.4

3.9

−2.1

0.0 7.9

1.4 5.0

0.4

11.1

−4.2

16.7 10.9

15.7 17.2

-120

-100

-80

-60

-40

-20

0

20

40

Me

dia

n C

ha

ng

e F

rom

Ba

se

lin

e, %

Rux BAT

Impro

vem

ent

−120

−100

−80

−60

−40

−20

0

20

40

Mesa. et. al. ASH 2014

Proposed Algorithm of Therapy of ET/PV in 2015

Diagnosis of PV or ET

Front Line Cytoreduction HU, or HU vs INF Clinical Trial

JAK2 Inhibitor (Experimental Indication)

• Ruxolitinib

• Other Clinical Trial JAK2 Inhib

Consider Ruxolitinib (PV)/ ET ( 2nd line or Trial) or INF (Trial)/HU if not previously received

Assess Symptom Quartile

by MPN 10

Q1:TSS <8

Q2:TSS 8-17

Q3:TSS 18-31

Q4:TSS ≥32

Decide on need for concurrent cytoreduction based on Risk and Symptoms

YES NO

Monitor for symptom burden, vascular events,

progression

Worsening symptom burden Vascular event, progression Phlebotomy intolerance

Worsening symptom burden Vascular event, progression HU Resistance/ Intolerance

Assess MPN Risk Score (Table 1) & Assess MPN Symptoms (MPN 10)

Control of Hematocrit (<45%) in PV (? In ET) Low dose aspirin in appropriate patients

Diagnosis of MPN-MF (Primary, Post ET or Post PV Myelofibrosis)

Calculate DIPSS MF Score & Assess MPN Symptoms (MPN 10)

Low Risk Med S = 185m

Symptom Q1-Q2

Low Risk Med S <185m

Symptom Q3-Q4

Intermediate to High Risk Med S = 16m (H), 35m (Int 2), 78 (Int 1)

Assess role and timing of ALLO SCT (Donor, Risk, Candidate) ALLO – Urgent, Delayed, Never

Observation vs INF (Trial)

Possible Role Of JAK2 Inhib (Trial) or INF

(Trial)

Proceed to ALLO

(Possible JAK2 Inhib Prior)

(Trial)

N.B. Consider Rx for Prevention of

Vascular Events in Appropriate Patients (Aspirin & Cytoreduction)

JAK2 Inhibitors

• Ruxolitinib (Jakafi/Jakavi)

(Approved for MF)

• Clinical Trial JAK2 Inhib

Anemia Rx • Clinical Trials • IMID/ Androgens/ EPO • Splenectomy

Symptom Quartiles by MPN 10

Q1:TSS <8 Q3:TSS 18-31

Q2:TSS 8-17 Q4:TSS ≥32

Proposed Algorithm of Therapy of MPN-MF in 2015

Urgent ALLO

JAK2 Inhibitor* *Unless anemia/ cytopenias main

problem

Delayed/Never ALLO

Clinical Trials • Ruxo Combination • Non Ruxo JAK2 • New Targets

JAK2 Single Agent Failure Refractory Cytopenias










2. Thoughtful analysis of combination MPN therapeutic approaches

©2011 MFMER | 3133089-49

Myelofibrosis – Rx Opportunities

©2011 MFMER | 3133089-50 Time

Clinical Status

Dx of MF

MF on

JAK

Inhibitor

Spleen

MF Symptoms

Survival

Fibrosis

Anemia/

Thrombocytopenia

Molecular

Response

©2011 MFMER | 3133089-51

LANDSCAPE MPN Clinical Trials 2015

ET/PV Single Agent MF Combination MF

Rux Plus -

PEG INF vs HU

MPD-RC 112

NCT01258856

PEG INF (2nd Line)

NCT01259817

P1101 vs HU (PV)

AOP

NCT01949805

Ruxolitinib (PV)

Response 1,2

Relief Trials

Momelotinib

NCT01998828

Givinostat (HDAC)

NCT0190432

Pacritinib v BAT

(PERSIST1-PH III)

NCT01773187

Pacritinib v. BAT

(PERSIST2- PH III)

NCT02055781

Momelotinib v. Rux

(PH III)

NCT01969838

Momelotinib vs.

BAT (PH III)

NCT012101268

NS-018 (PH II)

NCT01423851

PRM-151

NCT01981850

Panobinostat

NCT01693601

NCT01433445

BKM 120 (Pi3K)

NCT01730248

LDE 225 (HH)

NCT01787552

Lenalidomide

NCT013575140

Pomalidomide

NCT01644110

Danazol

NCT01732445

Azacitidine

NCT01787487

Decitibine

NCT02076191

PF04449913 (Smo)

NCT02226172

Imetelstat

Different phenotypes in setting of JAK inhibition

Primary anemia phenotype

Proliferative phenotype

Good ruxolitinib response

Ruxolitinib response with anemia a problem

©2011 MFMER | 3133089-52

SPLN SX

Anemia/Cytope

nias

SPLN SX

Anemia/Cyt

openias

SPLN SX Anemia/C

ytopenias

SPLN SX

Anemia/Cyt

openias

SPLN SX

Anemia/Cyt

openias

SPLN SX

Anemia/Cytopen

ias

MPN Patient Supportive and Survivorship Care

Wellness

MPN

Post Therapy

Care MPN

Deficit/ Therapy Recovery

Care










2. Thoughtful analysis of combination MPN therapeutic approaches

1. Never lose the forest through the trees

©2011 MFMER | 3133089-54

Medicine Wheel of Health “Integrative Medicine”

Being a Blood Disease Survivor Top 10 List

10. Learn about your disease

9. Make friends with facing a similar challenge

8. Be your own best advocate

7. Capture what is discussed at doctors visits (friends/ recorder)

6. Take care of your caregiver

5. Take care of the rest of your health

4. Eat in a healthy way (most of the time)

3. Exercise

2. Live every moment

1. Focus on relationships

©2011 MFMER | 3133089-56

Quotes from Erma Bombeck Written as she was dying from Cancer

• If I had my life to live over I would…

• Have gone to bed when I was sick instead of pretending the earth would go into a holding pattern if I weren’t there for a day

I would have...

•Burned the pink candle sculpted like a rose before it melted in storage

I would have...

•Sat on the lawn with my grass stains

I would have...

•Talked less and listened more

I would have...

• Invited friends over to dinner even if the carpet was stained or the sofa faded

I would have...

•Shared more of the responsibility carried by my husband

I would have...

•Never have insisted the car windows be rolled up on a summer day because my hair had just been teased and sprayed

I would have...

•Don’t worry about who doesn’t like you, who has more or who is doing what. Instead, cherish the relationships we have with those who do love us.

I would have...

•Never have bought anything just because it was practical, wouldn’t show soil, or was guaranteed to last a lifetime

I would have...

• Instead of wishing away nine months of pregnancy, I’d have cherished every moment and realized that the wonderment growing inside me was the only chance in life to assist God in a miracle

I would have...

•Taken the time to listen to my grandfather ramble about his youth

I would have...

•Cried and laughed less while watching TV and more while watching life

I would have...

•But mostly, given another shot at life, I would seize every minute… look at it and really see it… live it and never give it back. Stop sweating the small stuff.

©2011 MFMER | 3133089-70

©2011 MFMER | 3133089-72

Acknowledgements Argentina

Ana Clara Kneese, MD

Federico Sackmann, MD

Australia

David M Ross MBBS, PhD

Cecily Forsyth

John Seymour, MBBS, PhD

Karen Hall, MD

Kate Burbury MD

Tam Constantine, MD

Canada

Lynda Foltz, MD

Vikas Gupta, MD

China

Hsin-An Hou, MD

Huan-Chau Lin,

MD Hung Chang, MD

Ming-Shen Dai, MD

Yuan-Bin Yu, MD

Yung-Chen Su, MD

Zhijian Xiao, MD

Denmark

Christen Lykkegaard Andersen, MD

Hans Hasselbalch, MD

France

Brigitte Dupriez, MD

Jean-Jacques Kiladjian, MD

Jean-Loup Demory MD

Magali Demilly, PhD

Germany

Heike L. Pahl, PhD

Ireland

Mary Francis McMullen, MD

Israel

Martin Ellis, MD

Italy

Alessandro M. Vannucchi, MD

Francesco Passamonti, MD

Giovanni Barosi, MD

Tiziano Barbui, MD

Netherlands

Harry Schouten, MD, PhD

Jan Jacques Michiels, MD

Karin Klauke, MD

Peter te Boekhorst, MD

Sonja Zweegman, MD PhD

Stephanie Slot, MD

Suzan Commandeur, MD

New Zealand

Hilary Blacklock, MD

Panama

Francis Guerra, MD

Singapore

Wee Joo Chng, MB ChB

Spain

Ana Kerguelen Fuentes, MD

Carlos Besses, MD

Francisco Cervantes, MD

Dolores Fernandez-Casados

Sweden

Andreasson Bjorn, MD

Elisabeth Ejerblad, MD

Gunnar Birgegard, MD

Jan Samuelsson, MD

Johanna Ablesson, MD

Peter Johansson, MD

UK

Anthony Green, MD

Claire N. Harrison, MD

Deepti Radia, MD

Uruguay

Pablo Muxi, MD

USA

Alison Moliterno, MD

Brady Stein, MD MHS

Casey O'Connell

Catriona Jamieson

Daniel Rubin, ND

Elizabth Hexner

Hala Simm

Jason Gotlib, MD

Jeff Sloan, PhD

Jessica Altman, MD

Joseph Prchal, MD

Kimberly Hickman

Martin Tallman, MD

Mike Boxer, MD

Olatoyosi Odenike, MD

Richard T Silver, MD

Ross Levine, MD

Soo Jin Kim

Srdan Verstovsek, MD

©2011 MFMER | 3133089-73

Thanks to MPN Patients, and their loved ones,

for Their Contributions to MPN Research

Courtesy of C. Harrison and UK MPN Patient

Documents

Chronic Myeloid Leukemia and Myeloproliferative Neoplasms in … · ©2011 MFMER | 3133089-1 Chronic Myeloid Leukemia and Myeloproliferative Neoplasms in 2015 Rocky Mountain Blood