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2/26/2018

Introduction to
Myeloproliferative Neoplasms
(MPNs)
Post-ASH 2017 Wrap-Up
Naveen Pemmaraju, M.D.
Associate Professor

Department of Leukemia
University of Texas
MD Anderson Cancer Center
Houston, Texas, USA

Disclosures
• Research support, honorarium, consulting:
– Incyte
– Novartis
– Stemline
– Cellectis
– LFB

– Grant Funding: Affymetrix, Stemline
– Abbvie
– Samus

Overview/Objectives
• Introduction to MPN/MF
• ASH 2017 Wrap-Up: Clinical trials
• Translational Focus: Bench to Bedside and Back to
the Bench
• MPN: Symptom Burden: Why it Matters

1

2/26/2018

“Some Speculations on the
myeloproliferative syndromes”
William Dameshek
(1900-1966)

www.hematology.org (ASH website)

• “It is possible that these various conditions—
'myeloproliferative disorders'—are all…variable
manifestations of proliferative activity of the bone
marrow cells, perhaps due to a hitherto
undiscovered stimulus.”—William Dameshek, 1951,
Blood

Natural History of MPNs

courtesy Dr Ruben Mesa, MD, Mayo Clinic

Overt PMF
Post ET/PV MF
PV
ET
Early PMF
Short term: Vascular
events

Progressive
constitutional
symptoms

Progressive
organomegaly/EMH

Progressive
cytopenias

Leukemic
transformation

Lead time: Typically
years (>10)
to 

Time: Variable 3-5
years common

Premature
death

CP1266735-1

JAK2 V617F


Constitutively active
kinase



Over-signals via STAT,
ERK, MAP kinase,
RAS pathways



Autonomous growth,
cell survival &
differentiation



Slide courtesy of Alison Moliterno, MD, Johns Hopkins
Hospital

JAK2
V617F

p p

2

2/26/2018

CALR
• Chromosome 19p13.3
– Exon 9 of CALR (insertions or deletions)

• Calreticulin= protein Ca++binding fucntion or the
Endoplasmic reticulum
• Also found in nucleus; possible role transcription
regulation
• Klampfel et al NEJM 2013: CALR in 25% pts with
JAK2 negative ET, and in 35% in JAK2 negative MF
Klampfl T et al. N Engl J Med 2013;369:2379-2390.

Heterogeneous clinical outcomes in MF
Survival by PMF-PS
1
.9
.8
Probability

.7
.6
.5
.4
.3
.2
.1
0
0

24

48

72

96

120 144 168 192 216 240 264 288
Months

95% CI

95% CI

95% CI

PMF-PS = 0

PMF-PS = 1

PMF-PS = 2

95% CI
PMF-PS = 3

Cervantes et al., Blood 2009;113:2895-2901

Slide Courtesy: S. Verstovsek

3

2/26/2018

MF: Risk Stratification:
Poor prognostic variables
•
•
•
•
•

Age >65 y
Presence of Constitutional symptoms
Hgb <10
WBC >25
Circulating blasts cells ≥1%

• P values were all <0.001
• 1054 pts at 7 centers

Cervantes et al, Blood 2009;113:2895-2901

MF-New Prognostic Scoring
System
#factors Patients
%

Med
survival
(months)

Deaths
%

Low

0

22

135

32

Int-1

1

29

95

50

Int-2

2

28

48

71

High

>3

21

27

73

Cervantes et al, Blood
2009;113:2895-2901

Cervantes

et al, Blood
2009;113:2895-2901

4

2/26/2018

MF: Further scoring systems
•

DIPSS (dynamic)—Mayo (Blood 2010;115)
– Modified IPSS to be able to calculate over time: all 1 pt except Hb
(2 points)
– Age >65

– WBC >25K
– Hb <10: 2 points
– Circulating blasts greater than or equal to 1%
– Constitutional sxs
•

DIPSS Plus—adds 3 new factors, each 1 point (Mayo, 2011 JCO)
– Unfavorable karyotype
– Plt count <100K

– Transfusion need

Kaplan-Meier estimate of blast phase–free survival in primary myelofibrosis according to the
DIPSS. Risk categories were according to the score obtained anytime during follow-up.

Francesco Passamonti et al. Blood 2010;116:2857-2858

©2010 by American Society of Hematology

Fig 3 Survival data of 793 patients with primary myelofibrosis evaluated at time of their first Mayo Clinic referral and stratified by their Dynamic International Prognostic Scoring System
(DIPSS) + karyotype + platelet count + transfusion status prognostic scores. Low risk, zero adverse points; n = 66; median survival, approximately 185 months. Intermediate-1 risk, one
adverse point; n = 174; median survival, approximately 78 months. Intermediate-2 risk, two or three adverse points; n = 360; median survival, approximately 35 months. High risk, four to
six adverse points; n = 193; median survival, approximately 16 months. Scale for DIPSS: high risk, three adverse points; intermediate-2, two adverse points; intermediate-1, unfavorable
karyotype, platelets < 100 x 109/L, and transfusion need, one adverse point.

Published in: Naseema Gangat; Domenica Caramazza; Rakhee Vaidya; Geeta George; Kebede Begna; Susan Schwager; Daniel Van Dyke; Curtis Hanson; Wenting Wu; Animesh
Pardanani; Francisco Cervantes; Francesco Passamonti; Ayalew Tefferi; JCO 2011, 29, 392-397.
DOI: 10.1200/JCO.2010.32.2446
Copyright © 2010

5

2/26/2018

Kaplan-Meier analysis of survival of PMF patients stratified according to their driver mutation.

Elisa Rumi et al. Blood 2014;124:1062-1069

©2014 by American Society of Hematology

ASH 2017: MIPSS70
• ASH 2017: Abstract 200 MIPSS70: MutationEnhanced Prognostic System for Transplant Age
Patients with Primary Myelofibrosis
– Alessandro M. Vannucchi, MD1, et al, ASH 2017
•

MVA for OS:

•

1)Anemia Hb <10

•

2)WBC >25K

•

3)plts <100

•

4)circulating blasts ≥ 2%

•

5)BM fibrosis ≥ 2

•

6)Constitutional sxs

•

7)absence of CALR Type 1mutation

•

8)Presence of HR molecular mutation [ASXL1; EZH2; SRSF2; IDH1/2]

•

9)Presence of two or more HR molecular mutations

Guglielmelli P et al JCO
2017; 36: 310-318;

Fig A1. Overall survival (OS) in (A) learning and (B) validation cohorts by the MIPSS70 prognostic scoring system risk classification in all age–inclusive cohorts. OS in (C) learning and (D)
validation cohorts by the MIPSS70-plus prognostic scoring system risk classification in all age–inclusive cohorts. Appendix Table A2 lists details.

Published in: Paola Guglielmelli; Terra L. Lasho; Giada Rotunno; Mythri Mudireddy; Carmela Mannarelli; Maura Nicolosi; Annalisa Pacilli; Animesh Pardanani; Elisa Rumi; Vittorio Rosti;
Curtis A. Hanson; Francesco Mannelli; Rhett P. Ketterling; Naseema Gangat; Alessandro Rambaldi; Francesco Passamonti; Giovanni Barosi; Tiziano Barbui; Mario Cazzola; Alessandro
M. Vannucchi; Ayalew Tefferi; JCO 2018, 36, 310-318.
DOI: 10.1200/JCO.2017.76.4886
Copyright © 2017 American Society of Clinical Oncology

6

2/26/2018

Fig A2. Leukemia-free survival (LFS) in (A) learning and (B) validation cohorts by the MIPSS70 prognostic scoring system risk classification. LFS in (C) learning and (D) validation cohorts
by the MIPSS70-plus prognostic scoring system risk classification. Appendix Table A3 lists details.
Published in: Paola Guglielmelli; Terra L. Lasho; Giada Rotunno; Mythri Mudireddy; Carmela Mannarelli; Maura Nicolosi; Annalisa Pacilli; Animesh Pardanani; Elisa Rumi; Vittorio Rosti;
Curtis A. Hanson; Francesco Mannelli; Rhett P. Ketterling; Naseema Gangat; Alessandro Rambaldi; Francesco Passamonti; Giovanni Barosi; Tiziano Barbui; Mario Cazzola; Alessandro
M. Vannucchi; Ayalew Tefferi; JCO 2018, 36, 310-318.
DOI: 10.1200/JCO.2017.76.4886
Copyright © 2017 American Society of Clinical Oncology

WHO 2016
• New categories/items to note:
• SM: now its own separate myeloid neoplasm outside of
MPN
• Creation of new “pre-fibrotic MF” (ET/MF)
• Lowering of PV Hb threshold
• CALR
• CSF3R

Symptom Burden in MF: Total Symptom
Score (MPN-TSS)
•
•
•
•
•
•
•
•
•
•

Fatigue
Early Satiety
Abdominal discomfort
Inactivity
Concentration problems
Night Sweats
Pruritis
Bone pain
Fever
Weight loss
Emmanuel/Mesa JCO 2012, Mesa et al Cancer 2007,
Geyer/Mesa Blood 2014

7

2/26/2018

#MPNSM: An ongoing Twitter
conversation about MPNs
•

Inspired by: CTO (based on #hcsm & #btsm) (Katz et al Disease-Specific hashtags
for online communication about cancer care - JCO. 2015;33 suppl abstr 6520); and
for hematology specific influence, #mmsm

•

Founder of #MPNSM Twitter community : Naveen Pemmaraju, MD @doctorpemm
–
With key co-founders: @mtmdphd, @Vikas_Gupta_1, @mpdrc

•

First tweet: @doctorpemm [Aug 2014]but #mpnsm did not really take off as a
regular hashtag until Dec’14-Jan’15: during/after #ASH15 meeting

•

As of Sept,13,2015: For #MPNSM, According to @symplur @healthcarehashtags
project: Jan’15-Sept’15
Pemmaraju N, e t al Current Hematologic
–
2013 tweets from 285 participants
Malignancy Reports10(4), 413-420. 9/28/15 online
Pemmaraju N, et al Curr Hematol Malig Rep. 2016
–
Resulting in: 4,049,415 impressions
Aug 4. [Epub ahead of print]

•

Brings together, in real-time: investigators/researchers, MPN healthcare providers,
patients, advocates, organizations for discussion of basic science, translational, and
clinical topics in MPNs
Slide: courtesy Mike Thompson, MD, PhD
#EBMT16

22

Thank you
• Please email me npemmaraju@mdanderson.org or
call me 713-792-4956 if you have any questions
• #MPNSM: Twitter/social media
• Thank you to Dr Serge Verstovsek, our chief of
MPNs, research RNs, and MPN team at MDACC

8

2/26/2018

Beyond single-agent JAK inhibitors:
New therapies and combinations
from ASH 2017
Aaron T. Gerds, MD, MS
Assistant Professor of Medicine
Hematology and Medical Oncology
@AaronGerds

Leukemia & Myeloid Disorders
Program

Beyond single-agent JAK inhibitors –
ASH 2017
• New drugs
•
•
•
•
•
•
•

Givinostat
LCL-161
Glasdegib
Sotatercept
Idasanutlin
Alisertib
SL-401

Abstract No.

Comments

253/1648
256
258
255
254
1631
2908

HDACi, CR/PR 86% (ITT, n=30) in PV
Oral Smac Mimetic, ORR 30% in MF
Modest symptom and spleen reduction in MF
New “ESA,” activin receptor IIA ligand trap
MDM2 inhibitor, in PV/ET, Ph1 study
Aurora kinase inhibitor
Recombinant IL-3 fused to diphtheria toxin

1632
4179
1649

Modest benefit over single-agent ruxolitinib
No clear benefit over single-agent ruxolitinib
AP/BP, ORR 33% (2 of 6 evaluable patients)

321/323/320
4197

Front-line and beyond, Ropeginterferon ⍺-2b
Wernicke’s exposé from JAKARTA studies

• Combination therapy

• Pracinostat + ruxolitinib
• Vismodegib + ruxolitinib
• Azacitidine + ruxolitinib

• Old is new again!
• Interferons
• Fedratinib

@AaronGerds

SOTATERCEPT (ACE-011) ALONE AND WITH
RUXOLITINIB IN PATIENTS WITH MPNASSOCIATED MYELOFIBROSIS (MF) AND ANEMIA
Prithviraj Bose, Naval G. Daver, Naveen Pemmaraju, Elias J. Jabbour, Zeev Estrov, Allison M. Pike,
Julie Huynh-Lu, Madeleine Nguyen-Cao, Xuemei Wang, Lingsha Zhou, Sherry Pierce, Hagop M.
Kantarjian, and Srdan Verstovsek

Slide courtesy of Prithviraj Bose

Supported by Celgene Corporation

1

2/26/2018

Sotatercept
Phase II Study Design
• MF with Hgb <10 g/dL x ≥ 84 days
• 2 cohorts:

• Sotatercept alone q3 wk
• Sotatercept q3 wk in patients on
stable dose of ruxolitinib

• Response (on study x ≥ 84 days):
• Anemic patients: ≥1.5 g/dL ↑ from
baseline x ≥ 84 d
• Tx-dependent patients: transfusion
independence per 2013 IWG-MRT
criteria

Sotatercept/Luspatercept responsive

Suragani RN, et al. Nat Med. 2014 Apr;20(4):408-14
Bose P, et al. Blood. 2017 Dec;130(supp1):225

Variable

Value/Category

Sotatercept (n=24)

Sotatercpt + Rux (n=11)

Median age (range)

years

66.5 (47-84)

68 (57 – 84)

Diagnosis

PMF

20

9

Post-ET/PV MF

4

2

Sex

Male

14

7

Median baseline hemoglobin (range)

g/dl

7.5 (4.7 – 8.7)

7.2 (4.6 – 9.1)

Driver mutation

JAK2

16

8

CALR

3

2

MPL

3

1

Triple negative

1, CALR mutation status unknown in 1

0

Karyotype

Abnormal

8, insufficient metaphases in 1

6

DIPSS category

Intermediate-2

19

7

High

5

4

MF-2

8

5

MF-3

16

5

Splenomegaly

Present

13

11

Previously treated

Yes

19

Median rux dose (range)

mg PO BID

Bone marrow fibrosis grade

Bose P, et al. Blood. 2017 Dec;130(supp1):225

10 (5-20)

@AaronGerds

Summary of results
Sotatercept (n=18 evaluable)

Sotatercept + Rux(n=10 evaluable)

• 40% response (7/18); 3/11
transfusion-dependent

• 30% response (3/10); 0/4 transfusiondependent

• Median time to response 7d (1-22d)

• Responses began at 7, 14 and 140 d

• Median response duration 12 (5-24+)
months

• Response durations of 3+, 4+ and 15+
months

• Multiple drug holds in 3 patients due
to Hgb levels ≥11.5 g/dl

• Multiple drug holds in 1 patient due to
Hgb levels ≥11.5 g/dl

• 1.5 g/dl ↑ in Hgb from baseline in 1
additional patient (s/p 3 cycles)

Bose P, et al. Blood. 2017 Dec;130(supp1):225

2

2/26/2018

MEAN HEMOGLOBIN OVER TIME IN RESPONDERS (N=10)

Slide courtesy of
Prithviraj Bose

Sotatercept in MF

ADVERSE EVENTS POSSIBLY RELATED TO
SOTATERCEPT (N = 35)
Adverse event

Grade

No. of patients

Hypertension

3

3

2

2

3

1

2

1

1

1

Elevated UMACR

1

2

Limb edema

1

1

Headache (in the context
of HTN)

2

1

1

1

Nausea

1

1

Pain (joints/muscle)

Slide courtesy of
Prithviraj Bose

Comclusions
• Sotatercept effective for MPN-associated anemia
• Planned enrollment 60 subjects

• Multi-center phase 2 trial of luspatercept in MF open
• ClinicalTrials.gov Identifier: NCT03194542

Bose P, et al. Blood. 2017 Dec;130(supp1):225

@AaronGerds

3

2/26/2018

Open Label Phase I Study of Single Agent Oral RG7388
(idasanutlin) in Patients with Polycythemia Vera and
Essential Thrombocythemia

Mascarenhas J1, Lu M1, Virtgaym E1, Kosiorek H 2, Stal M1, Sandy L1, Orellana A1,
Xia L1, Rampal R3, Kremyanskaya M1, Petersen B4, Dueck A 2, Hoffman R1

1

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
Mayo Clinic Scottsdale, Scottsdale, Arizona
Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York
4 Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New
York 10029
2
3

Slide courtesy of John Mascarenhas

Background: P53/MDM2
• P53 regulates cell cycle, apoptosis, DNA repair, and senescence
• Wild type P53 seen in chronic phase MPN and mutated P53 in advanced phase
• Down regulation of P53 by MDM2 overexpression
•
•
•
•

Promotes proteosomal degradation
Inhibits P53 transcription
Inhibits transactivation
Facilitates export from nucleus

• Nutlins Block the MDM2:P53 interaction and activate the p53 pathway

Nakatake M et al. Oncogene. (2012); Cassinat and Kiladjian Blood (2012); Shangary and Wang. Clin Cancer
Res. (2008); Lu and Hoffman Oncotarget (2012).
Slide courtesy of John Mascarenhas

Study Schema and Design
• 2 dose cohorts evaluated
• 100 mg daily, days 1-5
• 150 mg daily, days 1-5

• DLT is defined as:

• non-hematologic AE of
G3+
• hematologic AE of G2+
thrombocytopenia, G3+
neutropenia, or G3+
anemia

• Dosing after cycle 3
dependent on attaining
HCT >42% and/or PLT
>400K at Day 1

Slide courtesy of John
Mascarenhas

4

2/26/2018

Baseline Demographics
Diagnosis
Essential Thrombocythemia
Polycythemia Vera
Age, median (years)
Gender, female
Disease duration, mos
(prior to study)
Previous thrombosis
Prior hydroxyurea therapy
Spleen length by palpation, median (cm)
Leukocytes , median (x109/L)

100 mg
(N=6)

150 mg
(N=6)

Total
(N=12)

1 (16.7%)

0 (0.0%)

1 (8.3%)

5 (83.3%)

6 (100.0%)

11 (91.6%)

62 (32-83)

63 (48-68)

63.5 (32-83)

5 (83.3%)

2 (33.3%)

41.6

65.4

43.9

(14.9-80.1)

(21.0-154.3)

(14.9-154.3)

3 (50.0%)

0 (0.0%)

3 (25.0%)

7 (58.3%)

5 (83.3%)

5 (83.3%)

10 (83.3%)

1.0 (1.0-7.0)

2.5(0.0-18.0)

1.0 (0.0-18.0)

10.3

12.2

Hemoglobin, median (g/dL)

(4.9-15.9)
13.4

(7.4-28.3)
13.7

(4.9-28.3)
13.6

Hematocrit , median (%)

(12.8-15.6)
41.5

(12.3-14.7)
43.0

(12.3-15.6)
42.3

(38.3-46.7)
443.5

(40.7-47.8)
412.0

(38.3-47.8)
443.5

(118.0-1339.0)
252.0

(153.0-700.0)
252.0

(118.0-1339.0)
252.0

(184.0-370.0)
23.7

(177.0-616.0)
63.7

(177.0-616.0)
40.6

(5.3-69.3)

(6.3-88.6)

(5.3-88.6)

Platelets median, (x

109/L)

LDH median, (U/L)
JAK2V617F Variant Allele Frequency,
median (%)

11.3

Slide courtesy of
John Mascarenhas

TEAE occurring in at least 2 patients regardless of attribution
100 mg (n=6)

150 mg (n=6)

Grade 3

Grade 1/2

5 (83.3%)

1 (16.7%)

4 (66.7%)

Headache

4 (66.7%)

1 (16.7%)

1 (16.7%)

6 (50%)

Dry skin

2 (33.3%)

2 (33.3%)

4 (33.3%)

Pain

1 (16.7%)

1 (16.7%)

3 (25%)

Arthralgia

1 (16.7%)

Grade 3

Total (n=12)

Grade 1/2
Fatigue

10 (91.7%)

3 (50%)

Dizziness

Any grade

3 (25%)

3 (50%)

3 (25%)
2 (33.3%)

Atrial
fibrillation

2 (16.7%)

Cough

2 (33.3%)

2 (16.7%)

Decreased
appetite

1 (16.7%)

1 (16.7%)

2 (16.7%)

Epistaxis

1 (16.7%)

1 (16.7%)

2 (16.7%)

Flushing

2 (33.3%)

Jaw pain

2 (33.3%)

Oropharyngeal
pain

1 (16.7%)

1 (16.7%)

2 (16.7%)

URI

1 (16.7%)

1 (16.7%)

2 (16.7%)

Weight gain

1 (16.7%)

1 (16.7%)

2 (16.7%)

• 3 patients had grade 3 nonhematologic AE (all at 100 mg)
• Pt #1 – grade 3 fatigue
• Pt #2 – grade 3 headache
• Pt #3 – grade 3 pain

• No grade 4 non-hematologic
adverse events at either dose
level noted
• No hematologic AE of any grade
noted

2 (16.7%)
2 (16.7%)

Slide courtesy of
John Mascarenhas

Focus on Gastrointestinal TEAE
(regardless of attribution)
100 mg (n=6)

Grade 1/2

Grade 3

150 mg (n=6)

Grade 1/2

Grade 3

Total (n=12)

Any grade

Constipation

6 (100%)

4 (66.7%)

Nausea

5 (83.3%)

4 (66.7%)

9 (75%)

Diarrhea

5 (83.3%)

3 (50%)

8 (66.7%)

Dyspepsia

4 (33.3%)

3 (16.7%)

7 (58.3%)

Abdominal
pain

4 (66.7%)

1 (16.7%)

5 (41.7%)

Anorexia

2 (33.3%)

2 (33.3%)

4 (33%)

Vomiting

3 (50%)

10 (91.7%)

• No G3/4 GI TEAE
were observed
• GI prophylaxis:
• Ondansetron
• Lorazepam
• Decadron

• Constipation
likely due to 5ht3 antagonist

3 (25%)

Abdominal
distension

2 (33.3%)

1 (16.7%)

Dysgeusia

1 (16.7%)

2 (33.3%)

3 (25%)
3 (25%)

Flatulence

1 (16.7%)

1 (16.7%)

2 (16.7%)

Slide courtesy of John Mascarenhas

5

2/26/2018

Responses by 2013 ELN-IWG1 criteria
By 6 cycles of therapy with idasanutlin monotherapy in PART A and combination pegylated interferon-α in PART B

Not
evaluable
(NE)

No
response
(NR)

Partial
Response
(PR)

Complete
Response
(CR)

Overall
Response
(PR+CR)

PART A (n=12)

1#

4

3*

4

7 (58%)

PART B (n=4)^

1+

1

1

1

2 (50%)

PART A + PART B ORR 9 (75%)
• # not evaluable due to patient decision to withdraw from study after 4 cycles due to GI toxicity
• *Residual splenomegaly likely due to known portal vein thrombosis, likely a CR (n=1)
• ^4 subjects from PART A that had NR continued on to PART B combination idasanutlin + interferon-α
• + not yet completed cycle 7

Slide courtesy of John Mascarenhas

1Barosi

et al Blood 2013

Maximum Total Symptom Score (TSS) response on study
1

Baseline TSS
8

8

14

12

42

42

66

8

50

2

6

1

13

32

7

2

2
3

3
3

4
6

2

Slide courtesy of John Mascarenhas

Driver mutation responses with idasanutlin therapy
Median % reduction -43%
(range -91.9% to +60.3%)

4
4

7

52%

7

82%

8

8

69%

9

4
4

12
12

3
3

9

89%

87%

2%

24%

8

8

23%

10

10

45%

6

6

36%

8

8

6%

Baseline VAF
Slide courtesy of John Mascarenhas

6

2/26/2018

Bone marrow responses with Idasanutlin therapy
A

B

Pre-treatment X100

Post-treatment X100

C

D

Pre-treatment X400

Post-treatment X400

Slide courtesy of John Mascarenhas

Conclusions
• Idasanutlin is well tolerated in patients with PV after multiple cycles of exposure and
expected GI toxicity is manageable
• No DLT was observed and 150 mg x 5 days/cycle was chosen to be RPTD
• Idasanutlin may also be safely combined with pegylated IFN to improve upon the
response (PART B)
• On target P53 pathway activation was demonstrated with idasanutlin treatment
• Normalization of the hematologic profile and improvement in symptom burden were
observed with idasanutlin monotherapy and in combination with Pegasys
• Extended treatment-free-periods are possible with idasanutlin therapy
• Bone marrow morphologic and molecular responses were attained with idasanutlin
therapy
• A global, multicenter, single arm phase II trial of idasanutlin in patients with hydroxyurea
resistant/intolerant PV is underway (ClinicalTrials.gov Identifier: NCT03287245)

Slide courtesy of John Mascarenhas

@AaronGerds

7

2/26/2018

Fedratinib clinical activity
• JAKARTA-1 (randomized placebo-controlled)
• 47% (400mg) and 50% (500mg) of patients with intermediate 2 or high
risk myelofibrosis (MF) had SRV of ≥35% at 24 weeks

• JAKARTA-2 (open-label)
• 53% of MF intermediate/high-risk patients who were resistant and 63%
of patients who were intolerant to ruxolitinib had ≥35% reduction in
spleen volume at Week 24

Pardanani A, et al. JAMA Oncol. 2015 Aug;1(5):643-51.
Harrison CN, et al. Lancet Haematol. 2017;4(7):e317-e324.

@AaronGerds

US FDA: Hold it!
• Clinical hold placed on November 15, 2013 as a result of
neurological symptoms, suggestive of Wernicke’s
encephalopathy in 8/877 patients, exposed to fedratinib

@AaronGerds

Thiamine uptake and fedratinib
• Fedratinib IC50 >300 μm against
THTr1 and THTr2
• Clinical Cmax = 3-5 μM at 400 &
500 mg doses, respectively

Thiamine (nmol/L)

End of fedratinib treatment

Patients (N)

Mean

Median

161

171

198

Normal range of thiamine levels: 74-224 nmol/L
Harrison CN, et al. Blood. 2017 Dec;130(supp1):4197

@AaronGerds

8

2/26/2018

Harrison CN, et al. Blood. 2017 Dec;130(supp1):4197

@AaronGerds

Summary
• Treatment with fedratinib did not decrease thiamine levels in
patients from the clinical trials
•

• A single confirmed case of WE from 877 treated patients
• 2 patients with unconfirmed diagnosis (symptoms and MRI findings
consistent with WE but presence of confounding abnormalities)

• Prevalence of WE in the trials was less than what has been
published for people with MPNs
• Prevalence 0.1%-0.4%
Harrison CN, et al. Blood. 2017 Dec;130(supp1):4197

@AaronGerds

Summary and Conclusions
• New, non-JAK inhibitor agents being developed
• Combination therapy remains burdened with toxicity and limited
additive benefit
• Many challenges remain
•
•
•
•
•

Separate normal biology from pathogenesis
Spectrum of fitness
Long time observation until outcome of interest (PV/ET)
“Ruxolitinib failure” not defined (MF)
Dealing with cytopenias (MF)

@AaronGerds

9

2/26/2018

Thanks!
Mikkael Sekeres, MD, MS
Jaroslaw Maciejewski, MD, PhD
Sudipto Mukherjee, MD, PhD
Yogen Saunthararajah, MD
Hetty Carraway, MD, MBA
Anjali Advani, MD
Matt Kalaycio, MD
Ronald Sobecks, MD
Betty Hamilton, MD
Aziz Nazha, MD
John Desamito, MD

Leukemia & Myeloid Disorders
Program

Tracy Cinalli, RN
Jacqui Mau, RN
Christine Cooper, RN
Mary Lynn Rush, RN
Rachael Diligente, RN
Andrea Smith, RN
Eric Parsons, RN
Samjhana Bogati, RN
Barbara Paulic, RN, NP
Raychel Berardinelli, RN, NP
Barb Tripp, RN, NP
Alicia Bitterice, RN, NP
Meghan Scully, RN, NP
Becky Habecker, BA
Chante Cavin, BA
Sarah Kaufman, BA
Dennis Kramarz, BA
Ben Pannell, BA
Allison Unger, BA
Abby Statler, MPH
Donna Abounader, BA
Abigail Snow, BA
Justine DeAngelis, BA
Oliovia Kodramaz
Caitlin Swann, PharmD

And Our
Patients!!!
@AaronGerds

10

2/26/2018

Inflammation in MPN
Angela Fleischman M.D. Ph.D.
University of California, Irvine
Feb 26, 2018

Angela Fleischman Disclosures
• Incyte (speakers bureau)

Elevated Inflammatory Cytokines in
Many Hematologic Malignancies
CML

AML

MDS

MPN

1

2/26/2018

Elevated Inflammatory Cytokines in
MPN
MPN patients

Mouse Model

CD40
IL-2R
IL-2

MIP-1α
MIP-1β

IL-9

IL-7

TNF

VCAM-1

IFN-α
IL-11
ICAM-1

MMP-2
MMP-10

IL-8

IL-13

IL-18

IL-15

VEGF
IL-6

IL-16

IL-10
TIMP-1

IFN-γ

(Tyner et al, 2010)

IL-1α,ß

IL-12

G-CSF

(Verstovsek et al, 2010 Slezak et al, 2009,
Boissinot et al, 2010, Tefferi et al 2011)

Both mutant and wild-type cells
produce excessive inflammatory
cytokines in MPN

Wild
-type

Wild
-type

mutant

mutant

Wild
-type

Wild
-type
Wild
-type

mutant

Kleppe et al, Cancer Discovery 2015

Specific Cytokines Drive Specific
Symptoms in MPN

Geyer et. al. Mediators of Inflammation 2015

2

2/26/2018

Impact of Inflammatory Cytokines and
Chemokines in the MPNs
INF

BMP1
VCAM1

BMP6

HGF

TNF-RII
Splenomegaly

TIMP1
MIG

IL1RA

Disease
Advancement

PAL1

BMPRcp2

IL1B

TNF-1
IL-8

IL8

IL-8

TNF1

IP10

Clonal
expansion/bla
sts

TIMP1

IL17A

IL-12
Leptin

Ferritin

Symptom
Burden

TNF-RII

JAK2V617F

INF

B2MG
VCAM1

IL8

BMP7

IL12

Inferior
Survival
IL8

IL15

IL2R

Leptin
PAL1

TNFa

Tefferi et. al. J Clin Oncol. 2011 Apr 1;29(10):1356-63.
Geyer et. al. Mediators of Inflammation 2015. 1-9.

Chronic inflammation Exhausts
Blood stem cells
HSC
exhaustion

Stress
hematopoiesis

What are methods to control
inflammation?
• Prescription Medications
• Over the counter medications and
supplements
• Stress reduction/mindfulness
• Exercise
• Diet

3

2/26/2018

Inflammation as a Treatment Target in
MPNs
Understanding Our Current Therapies

• Contributes both to:
• Platelet aggregation
inhibition
• Inhibit the activity of
cyclooxygenase which
leads to the formation of
prostaglandins.

Interferon:
• Alters the inflammatory
pathway and has been
one of the only
therapeutic options which
has been able to alter the
stem cell clone

• Initially developed as an antiinflammatory in RA
• Associated with reduced
inflammatory markers
(previously described)
• Proposed to be one of the
most powerful non-steroidal
anti-inflammatories available.

Aspirin:

Ruxolitinib:

JAK usage by cytokine receptors

JAK inhibitors are anti-inflammatory drugs
From Murray P, Journal of Immunology 2007

JAK inhibitors in development for
MPN
Company

Activity

Status

Ruxolitinib (INCB18424)

Agent

Novartis/Incyte

JAK1/JAK2

FDAapproved

Fedratinib (TG101348/SAR302503)
(ON HOLD; Wernicke’s encephalopathy )

Celgene

JAK2, FLT3

Phase 3

Momelotinib (CYT387)
Gilead
(ON HOLD, failed to meet endpoint goals in phase 3)

JAK1/JAK2/
TYK2

Phase 3

Pacritinib (SB1518)
(ON HOLD, then back to dose-finding)

CTI BioPharma

JAK2, FLT3,
IRAK1

Phase 3

Lestaurtinib (CEP701)

Cephalon

JAK2/FLT3

Phase 1/2

BMS-911453

Bristol-Myers
Squibb

JAK2

Phase 1

NS-018

Nippon-Shinyaku

JAK2/Src

Phase 1/2

AZD1480 (discontinued due to neurotoxicity and
other side effects)

Astra Zeneca

JAK1/JAK2

Phase 1

Gandotinib (LY2784544)

Eli Lily

JAK2 V617F

Phase 1

INCB039110

Incyte

JAK1 (alone)

Phase 2

INCB054329

Incyte

JAK1

Phase 1/2

4

2/26/2018

Rationale for JAK1 inhibitor
• Blockade of inflammatory signaling pathways
that use JAK1 while sparing
myelosuppression attributable to the
inhibition of JAK2-mediated hematopoiesis
• INCB039110 (itacitinib) is a potent and
selective inhibitor of JAK1 with low in
vitro affinity for JAK2 (>20-fold selectivity for
JAK1 over JAK2) and other members of the
JAK family (>100-fold selectivity for JAK1
over JAK3 and TYK2)

Phase II Open-Label Trial Of INCB039110, A
Selective JAK1 Inhibitor, In Patients With
Myelofibrosis
Simon two-stage design to assess the efficacy and safety of different
doses of INCB039110
83 patients evaluable for primary endpoint
10 patients in 100 mg twice-daily
42 patients in 200 mg twice-daily
31 patients in 600 mg once-daily cohorts, respectively

Inclusion criteria:
intermediate- or high-risk myelofibrosis
Plt≥50×109/L, Hgb ≥8.0 g/dL, ANC ≥1×109/L
palpable spleen or prior splenectomy
active myelofibrosis-related symptoms
Mascarenhas et al, Haematologica 2017

Phase II Open-Label Trial Of INCB039110, A
Selective JAK1 Inhibitor, In Patients With
Myelofibrosis
Primary endpoint:
• proportion of patients in each dose group with a ≥50% reduction from
baseline to week 12 in total symptom score (TSS

Secondary endpoints:
• proportion of patients with a ≥50% reduction in TSS from baseline to
week 24
• proportions of patients with a ≥35% reduction in spleen volume from
baseline to weeks 12 and 24
• percentage changes from baseline to weeks 12 and 24 in TSS and
spleen volume
• proportion of patients who exhibited a ≥50% decrease in transfusion
frequency over any 12-week period during the study
Mascarenhas et al, Haematologica 2017

5

2/26/2018

Treatment Effects on Total
Symptom Score (TSS)

Mascarenhas et al. Haematologica 2017;102:327-335

Treatment Effects on Spleen
Volume

Mascarenhas et al. Haematologica 2017;102:327-335

Effects on Blood Counts

Mascarenhas et al. Haematologica 2017;102:327-335

6

2/26/2018

Impact on plasma cytokines at
week 4
Plasma levels of a
number of key
inflammatory markers,
such as C-reactive
protein, interleukin-6,
interleukin-10, CD40
ligand, RANTES, and
vascular endothelial
growth factor,
decreased in most
patients following 4
weeks of treatment
Mascarenhas et al. Haematologica 2017;102:327-335

IRAK1 is involved in production of
inflammatory cytokines ligands to IL-1R and
TLRs

Jeoung-Eun Park et al. J Immunol 2009;182:6316-6327

Pacritinib is an IRAK1 inhibitor
Company

Activity

Status

Ruxolitinib (INCB18424)

Agent

Novartis/Incyte

JAK1/JAK2

FDAapproved

Fedratinib (TG101348/SAR302503)
(ON HOLD; Wernicke’s encephalopathy )

Celgene

JAK2, FLT3

Phase 3

Momelotinib (CYT387)
Gilead
(ON HOLD, failed to meet endpoint goals in phase 3)

JAK1/JAK2/
TYK2

Phase 3

Pacritinib (SB1518)
(ON HOLD, then back to dose-finding)

CTI BioPharma

JAK2, FLT3,
IRAK1

Phase 3

Lestaurtinib (CEP701)

Cephalon

JAK2/FLT3

Phase 1/2

BMS-911453

Bristol-Myers
Squibb

JAK2

Phase 1

NS-018

Nippon-Shinyaku

JAK2/Src

Phase 1/2

AZD1480 (discontinued due to neurotoxicity and
other side effects)

Astra Zeneca

JAK1/JAK2

Phase 1

Gandotinib (LY2784544)

Eli Lily

JAK2 V617F

Phase 1

INCB039110

Incyte

JAK1 (alone)

Phase 2

INCB054329

Incyte

JAK1

Phase 1/2

7

2/26/2018

Take Home Points
• Inflammation is high in MPN and drives
symptom burden and potentially disease
progression
• JAK inhibitors reduce inflammation
• Each JAK inhibitor has a unique spectrum
of signaling molecules which it inhibits

Thanks
UC Irvine
UT-San Antonio
Rick Van Etten
Robyn Scherber
Susan O’Brien
Ruben Mesa
Lauren Pinter Brown
Edward Nelson
Deepa Jeyakumar
Elizabeth Brem

Mayo Clinic AZ
Holly Geyer
Amylou Dueck
Jeanne Palmer
Leslie Padrnos
Heidi Kosiorek
Blake Langlais

8
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