Current Active Trials: Status, & prospects

Claire HarrisonGuy’s and St Thomas’ Hospitals London, UK

Current Active Trials: Status, & prospects

• PV and ET– Interferon (still)– Ruxolitinib

• MF– JAK inhibitor– Combinations– Non-­‐JAKi based therapies

• Stem cell niche• Rare MPN– 8p11 Rearranged myeloid and lymphoid disorders– Aggressive systemic mastocytosis

MPD-­‐RC 112 Study Schema

Rand

omized

1:1

• WHO 2008 ET/PV

• High Risk• >60 years

• Thrombosis

• thrombocytosis

• Symptomatic spleen

• Uncontrolled CV risk factor

• Dx <5 years• Treatment naïve

PEGn=36

HUn=39

n=168

INTERIM

ANAL

YSIS

Planned analysis

75 subjects treated for 1 year

Modified protocol to include final analysis to be

completed once all subjects enrolled for 1 year (n=168)

[anticipated date of 6/30/2017]

HUn=86

PEGn=82

Mascarenas etal ASH 2016

Overall Response Rates at 12 Months by Treatment Arm – INTERIM ANALYSIS

HU(n=39)

PEG(n=36)

P value

PRn (%)

CRn (%)

ORRn (%)

PRn (%)

CRn (%)

ORRn (%)

Entire cohort (n=75) 14 (36)

13 (33)

27(69)

19 (53)

10 (28)

29 (81)

0.6*

ET (n=31) 4/16(25)

7/16(44)

11/16 (69)

6/15 (40)

6/15 (40)

12/15 (80)

0.8

PV (n=44) 10/23 (44)

6/23 (26)

16/23 (70)

13/21 (62)

4/21(19)

17/21 (81)

0.6

* CR comparison based on z-­‐test; did not cross stopping boundary

Complete Histopathologic Bone Marrow Response at 12 months by Blinded Central Review

HU PEG

ET+PV 8/22 2/24

ET 5/10 2/10

PV 3/12 0/14

Histopathology Criteria? Normalized BM

cellularity ? < grade 2 reticulin

fibrosis

? ET: Disappearance of MK hyperplasia, & abnormal MK histotopography

? PV: Disappearance of trilineage hyperplasia

Baseli

ne

12 m

onths

Baseli

ne

12 m

onths

0

20

40

60

Varia

nt A

llele

Fre

quen

cy (V

AF)

HUPEG

19.7%8.3%

18.8%8.4%

Molecular Response by Treatment arm after 12 months of therapy

Change in JAK2V617F burden 2009 ELN Molecular Response Category

*CR defined as < LOD for NGS assay of 3%

*

HU PEG

0

50

100

Pro

porti

on o

f Pat

ient

s

PRCR

NR22%

28%

50%

14%

32%

54%

N=22N=19

Naïve patients in need of cytoreduction

HU pre-­‐treated (<3yrs and not full responders)

Stratified Random-­‐ization by

Age, prev. HU,prev. TE

Ropeginterferon

Hydroxyurea

Up to 3-­‐5 years treatmentEligible PV patient population per WHO2008 criteria

12 months treatment

Efficacy analysis*)

Ropeg-­‐interferon

BAT

Efficacy analysis**)

Expected outcome: *) non-­‐inferiority: Hematologic Response **) benefit: durable Hematologic Response, PFS, PV symptom relief

Ropeginterferon alfa-­‐2b phase III : PROUD/CONTI-­‐PV

Gisslinger etal ASH 2016

Complete Hematologic Response at 12 months

à non-­‐inferiority is demonstrated, p=0.0028

AOP2014 HU Difference % (95% CI)

P-­‐value *)

Complete hematologicresponse rate (ITT) 43.1% 45.6% -­‐2.5

(-­‐14.9 to 9.9) 0.0028

Responding patients/n 53/123 57/125

Complete hematologicresponse rate (PP) 44.3% 46.5% -­‐2.2

(-­‐15.2 to 10.7) 0.0036

Responding patients/n 50/113 53/114

*) Non-­‐inferiority margin 20.0%

Adverse Events of Special Interest

AESIAOP2014 (n=127)

n (%)HU (n=127)

n (%)P-­‐value*

Endocrine disorders* 4 (3.1%) 1 (0.8%) n.s.

Psychiatric disorders** 2 (1.6%) 0 (0.0%) n.s.

Cardiac/Vascular disorders*** 4 (3.1%) 2 (1.6%) n.s.

Tissue disorders**** 2 (1.6%) 0 (0.0%) n.s.

* Autoimmune thyroiditis, Hypo-­‐/Hyperthyroidism** Anxiety, Depression, Mood altered*** Major cardio-­‐vascular events within different System organ classes (cardiac failure, thrombotic event, stroke)**** Rheumatoid arthritis, psoriasis

* Fisher‘s exact tests. significantn.s. not significant (p>0.05)

Is there a difference in the long term?

Oral presentation on Sunday am regarding molecular responses in the PROUD PV study

Evolution of JAK2 vs. TET2 variants

JAK2 before IFN

JAK2 after IFN

TET2 before IFN

TET2 after IFN

0

10

20

30

40

50

60

70

80

90

100

UPN #1

UPN #2

UPN #3

UPN #4

UPN #5

Courtesy of Kiladjian & partly in Kiladjian et al., Leukemia. 2010 Aug;;24(8):1519-­23.

Therapeutic impact of the mutational profile

PEG-­IFN2a transformation to MF/AML still occurs

0 4 0 8 0 1 2 0 1 6 0 2 0 00

1 0

2 0

3 0

4 0

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

m on th s

Cumulative Probability (%)

P E GC on tro l

N a t r isk P EG 8 3 8 3 7 5 4 6 2 5 1 4C on 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 )

Masarova Lancet hematology 2017

What about JAK inhibition?

JAK inhibition in PV:

• Ruxolitinib approved in HU resistant/intolerant PVAfter RESPONSE and RESPONSE 2 trials

• …….BUT no conclusive data regarding impact upon thrombosis or transformation.

88 www.thelancet.com/oncology Vol 18 January 2017

Articles

Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b studyFrancesco Passamonti, Martin Griesshammer, Francesca Palandri, Miklos Egyed, Giulia Benevolo, Timothy Devos, Jeannie Callum, Alessandro M Vannucchi, Serdar Sivgin, Caroline Bensasson, Mahmudul Khan, Nadjat Mounedji, Guray Saydam

SummaryBackground In the pivotal RESPONSE study, ruxolitinib, a Janus kinase (JAK)1 and JAK2 inhibitor, was superior to best available therapy at controlling haematocrit and improving splenomegaly and symptoms in patients with polycythaemia vera with splenomegaly who were inadequately controlled with hydroxyurea. In this study, we assessed the effi cacy and safety of ruxolitinib in controlling disease in patients with polycythaemia vera without splenomegaly who need second-line therapy.

Methods RESPONSE-2 is a randomised, open-label, phase 3b study assessing ruxolitinib versus best available therapy in patients with polycythaemia vera done in 48 hospitals or clinics across 12 countries in Asia, Australia, Europe, and North America. Eligible patients (aged ≥18 years) with polycythaemia vera, no palpable splenomegaly, and hydroxyurea resistance or intolerance were stratifi ed by their hydroxyurea therapy status (resistance vs intolerance) and randomly assigned (1:1) by an interactive response technology provider using a validated system to receive either oral ruxolitinib 10 mg twice daily or investigator-selected best available therapy (hydroxyurea [at the maximum tolerated dose], interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or no cytoreductive treatment). Investigators and patients were not masked to treatment assignment; however, the study sponsor was masked to treatment assignment until database lock. The primary endpoint was the proportion of patients achieving haematocrit control at week 28. Analyses were done according to an intention-to-treat principle, including data from all patients randomly assigned to treatment. This study is registered with ClinicalTrials.gov (NCT02038036) and is ongoing but not recruiting patients.

Findings Between March 25, 2014, and Feb 11, 2015, of 173 patients assessed for eligibility, 74 patients were randomly assigned to receive ruxolitinib and 75 to receive best available therapy. At randomisation, best available therapy included hydroxyurea (37 [49%] of 75 in the best available therapy group), interferon or pegylated interferon (ten [13%] of 75), pipobroman (fi ve [7%] of 75), lenalidomide (one [1%] of 75), no treatment (21 [28%] of 75), and other (one [1%] of 75). Haematocrit control was achieved in 46 (62%) of 74 ruxolitinib-treated patients versus 14 (19%) of 75 patients who received best available therapy (odds ratio 7·28 [95% CI 3·43–15·45]; p<0·0001). The most frequent haematological adverse events of any grade were anaemia (ten [14%] of 74 in the ruxolitinib group vs two [3%] of 75 in the best available therapy group) and thrombocytopenia (two [3%] vs six [8%]). No cases of grade 3–4 anaemia or thrombocytopenia occurred with ruxolitinib; one patient (1%) reported grade 3–4 anaemia and three patients (4%) reported grade 3–4 thrombocytopenia in the group receiving best available therapy. Frequent grade 3–4 non-haematological adverse events were hypertension (fi ve [7%] of 74 vs three [4%] of 75) and pruritus (0 of 74 vs two [3%] of 75). Serious adverse events occurring in more than 2% of patients in either group, irrespective of cause, included thrombocytopenia (none in the ruxolitinib group vs two [3%] of 75 in the best available therapy group) and angina pectoris (two [3%] of 74 in the ruxolitinib group vs none in the best available therapy group). Two deaths occurred, both in the best available therapy group.

Interpretation RESPONSE-2 met its primary endpoint. The fi ndings of this study indicate that ruxolitinib could be considered a standard of care for second-line therapy in this post-hydroxyurea patient population.

Funding Novartis.

IntroductionPolycythaemia vera is a myeloproliferative neoplasm characterised by clonal stem-cell proliferation of erythroid, myeloid, and megakaryocytic cell lines.1,2 Most patients have an activating Janus kinase 2 (JAK2) mutation (JAK2 Val617Phe or exon 12 mutation), leading to an overactive JAK–STAT signalling pathway,

unregulated myeloid cell proliferation, and imbalances in cytokine production.1,3 Polycythaemia vera is characterised by erythrocytosis, with an associated increase in white blood cell and platelet counts in about 40% of patients.4 Patients with polycythaemia vera are at high risk of vascular complications, which are associated with advanced age, history of thrombosis, and leukocytosis,5

Lancet Oncol 2017; 18: 88–99

Published OnlineDecember 1, 2016

http://dx.doi.org/10.1016/S1470-2045(16)30558-7

See Comment page 9

Department of Hematology, University of Insubria, Varese,

Italy (Prof F Passamonti MD); Department of Hematology,

Oncology, Hemostaseology and Palliative Care,

Johannes Wesling Clinic, Minden, Germany

(Prof M Griesshammer MD); Department of Hematology/

Oncology, Seràgnoli Institute of Hematology, Bologna

University School of Medicine, Bologna, Italy (F Palandri MD);

Hematology Department of Somogy County, Kaposi Mor

Teaching Hospital, Kaposvar, Hungary

(Prof M Egyed MD, PhD); Department of Hematology,

Città della Salute e della Scienza di Torino, Turin, Italy

(G Benevolo MD); Laboratory of Experimental Transplantation,

Department of Microbiology and Immunology and

Department of Hematology, University Hospitals Leuven, KU Leuven, Leuven, Belgium

(Prof T Devos MD); Department of Transfusion Medicine and

Tissue Banks, Sunnybrook Health Sciences Centre,

Toronto, ON, Canada (J Callum FRCPC); Department

of Experimental and Clinical Medicine, Center for Research

and Innovation of Myeloproliferative Neoplasms,

AOU Careggi, University of Florence, Florence, Italy

(Prof A M Vannucchi MD); Department of Hematology,

Dedeman Stem Cell Transplantation Hospital,

Erciyes University, Kayseri, Turkey (S Sivgin MD);

Department of Clinical Research (C Bensasson PhD) and

Department of Biostatistics (M Khan PhD), Novartis

original article

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 372;5 nejm.org january 29, 2015426

Ruxolitinib versus Standard Therapy for the Treatment of Polycythemia Vera

Alessandro M. Vannucchi, M.D., Jean Jacques Kiladjian, M.D., Ph.D., Martin Griesshammer, M.D., Tamas Masszi, M.D., Ph.D., Simon Durrant, M.D.,

Francesco Passamonti, M.D., Claire N. Harrison, D.M., Fabrizio Pane, M.D., Pierre Zachee, M.D., Ph.D., Ruben Mesa, M.D., Shui He, Ph.D., Mark M. Jones, M.D., William Garrett, M.B.A., Jingjin Li, Ph.D.,

Ulrich Pirron, Ph.D., Dany Habr, M.D., and Srdan Verstovsek, M.D., Ph.D.

From Azienda Ospedaliera–Universitaria Careggi, University of Florence, Florence (A.M.V.), Ospedale di Circolo e Fondazi-one Macchi, Varese (F. Passamonti), and University of Naples Federico II, Naples (F. Pane) — all in Italy; Hôpital Saint-Louis et Université Paris Diderot, Paris ( J.J.K.); Johannes Wesling Clinic, Min-den, Germany (M.G.); St. István and St. László Hospital and Semmelweis Univer-sity, Budapest, Hungary (T.M.); Royal Brisbane and Women’s Hospital, Bris-bane, QLD, Australia (S.D.); Guy’s and St. Thomas’ NHS Foundation Trust, Lon-don (C.N.H.); Ziekenhuis Netwerk Ant-werpen Stuivenberg, Antwerp, Belgium (P.Z.); Mayo Clinic Cancer Center, Scotts-dale, AZ (R.M.); Incyte, Wilmington, DE (S.H., M.M.J., W.G.); Novartis Pharma-ceuticals, East Hanover, NJ ( J.L., D.H.); Novartis Pharma, Basel, Switzerland (U.P.); and University of Texas M.D. An-derson Cancer Center, Houston (S.V.). Address reprint requests to Dr. Vannucchi at Laboratorio Congiunto Malattie Mielo-proliferative, Azienda Ospedaliera–Uni-versitaria Careggi, University of Florence, Largo Brambilla 3, 50134 Florence, Italy, or at amvannucchi@unifi.it.

This article was updated on January 29, 2015, at NEJM.org.

N Engl J Med 2015;372:426-35.DOI: 10.1056/NEJMoa1409002Copyright © 2015 Massachusetts Medical Society.

A BS TR AC T

BackgroundRuxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea.

MethodsWe randomly assigned phlebotomy-dependent patients with splenomegaly, in a 1:1 ratio, to receive ruxolitinib (110 patients) or standard therapy (112 patients). The primary end point was both hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32, as assessed by means of imaging.

ResultsThe primary end point was achieved in 21% of the patients in the ruxolitinib group versus 1% of those in the standard-therapy group (P<0.001). Hematocrit control was achieved in 60% of patients receiving ruxolitinib and 20% of those receiving stan-dard therapy; 38% and 1% of patients in the two groups, respectively, had at least a 35% reduction in spleen volume. A complete hematologic remission was achieved in 24% of patients in the ruxolitinib group and 9% of those in the standard-therapy group (P = 0.003); 49% versus 5% had at least a 50% reduction in the total symptom score at week 32. In the ruxolitinib group, grade 3 or 4 anemia occurred in 2% of patients, and grade 3 or 4 thrombocytopenia occurred in 5%; the corresponding percentages in the standard-therapy group were 0% and 4%. Herpes zoster infection was reported in 6% of patients in the ruxolitinib group and 0% of those in the stan-dard-therapy group (grade 1 or 2 in all cases). Thromboembolic events occurred in one patient receiving ruxolitinib and in six patients receiving standard therapy.

ConclusionsIn patients who had an inadequate response to or had unacceptable side effects from hydroxyurea, ruxolitinib was superior to standard therapy in controlling the hematocrit, reducing the spleen volume, and improving symptoms associated with polycythemia vera. (Funded by Incyte and others; RESPONSE ClinicalTrials.gov number, NCT01243944.)

The New England Journal of Medicine Downloaded from nejm.org on March 24, 2017. For personal use only. No other uses without permission.

Copyright © 2015 Massachusetts Medical Society. All rights reserved.

• Population: Patients with high risk Polycythaemia vera(PV) or Essential Thrombocythaemia (ET) who are intolerant or resistant to Hydroxycarbamide

• Aim: To investigate and evaluate the safety and activity (in terms of complete haematological response within one year) of Ruxolitinib in the treatment of patients with PV or ET who have met criteria for resistance or intolerance of hydroxycarbamide (HC) therapy

• Patients are randomised to ruxolitinibor BAT

MAJ C

Bloodwise Harrison etal EHA & ASH 2016

Rates of CR/PR at one year similar

More discontinuations with ruxolitinib

3.8%

51.9%

44.2%

6.8%

46.5% 46.5%

0

10

20

30

40

50

60

70

80

90

100

NR PR CR

% of p

atients

Response category

BAT

Rux

Table2.Overviewofdiscontinuationspertreatmentarm

Rux BAT Total

Lackofefficacy 15 1 16Transformation 9 3 12Toxicity 6 1 7Other 3 3 6Consent 1 0 1Death* 1 2 3Total 35 10 45

MAJ C ET

Equivalent outcome for composite end point of

transformation, thrombosis and haemorrhage

………………unpublished data

logrank P = .080.5

0.6

0.7

0.8

0.9

1.0

Survival Probability

0 1 2 3 4Time from Randomsation in years

Trt = Best Available Therapy Trt = Ruxolitinib

Thromboembolic event free Survival by Treatment

logrank P = .10.5

0.6

0.7

0.8

0.9

1.0

Survival Probability

0 1 2 3 4Time from Randomsation in years

Trt = Best Available Therapy Trt = Ruxolitinib

Haemorrhagic event free Survival by Treatment

logrank P = .34

0.5

0.6

0.7

0.8

0.9

1.0

Survival Probability

0 1 2 3 4Time from Randomsation in years

Trt = Best Available Therapy Trt = Ruxolitinib

Time to first Event by Treatment MAJ C ET

PV and ET: What might we do in the future?

• More individualised therapy

• Combinations of ruxolitinib and pegasys?

• Ruxolitinib earlier in PV – first line study MITHRIDATES in UK and France supported by Novartis and MPN voice..

Surviv

al free of venous throm

bosis

0.6

0.7

0.8

0.9

1.0

0.6

0.7

0.8

0.9

1.0

96 94 74 53 35 15

166 164 118 73 46 14

84 84 64 47 27 11

168 164 115 78 50 14

Surviv

al free of m

yelo

fib

rosis

96 95 75 52 34 15

166 165 120 75 48 14

84 84 62 44 24 9

163 114 78 49 14

Time after trial entry (yrs)

0 1 2 3 4 5

Time after trial entry (yrs)

0 1 2 3 4 5

HU, JAK2

HU, CALR

AG, JAK2

AG, CALR

HU, JAK2

HU, CALR

AG, JAK2

AG, CALR

168

p=1.0

p=0.36

CALR, HU JAK2, HU

CALR, AG JAK2, AG

CALR, HU JAK2, HU

CALR, AG JAK2, AG

ET -­‐Does treatment with HU or Ag alter adverse outcomes associated with molecular status?

(unpublished data from PT-­‐1, Nangalia EHA 2016)

Myelofibrosis CALR ANAGRELIDE

Surviv

al free of venous throm

bosis

0.6

0.7

0.8

0.9

1.0

96 94 74 53 35 15

166 164 118 73 46 14

84 84 64 47 27 11

168 164 115 78 50 14

Time after trial entry (yrs)

0 1 2 3 4 5

HU, JAK2

HU, CALR

AG, JAK2

AG, CALR

CALR, HU JAK2, HU

CALR, AG JAK2, AG

ET -­‐Does treatment with HU or Ag alter adverse outcomes associated with molecular status?

(unpublished data from PT-­‐1, Nangalia EHA 2016)

Venous thrombosis

JAK2 HU

Emerging therapies for MPN• PV and ET– Interferon (still)– Ruxolitinib

• MF– JAK inhibitor– Combinations– Non-­‐JAKi based therapies

• Stem cell niche• Rare MPN– 8p11 Rearranged myeloid and lymphoid disorders– Aggressive systemic mastocytosis

Benefits of Ruxolitinib in a COMFORT-­II patient

êSpleen

éQoL

22

BEFORE AFTER 72 wks

“……This drug gave me my life, back I can work and enjoy life…….”

ReTHINK: prevention study in early MF

Objectives & Study design

Ruxolitinib 10 mg bid

Placebo

IPSS Low-­risk MF Patients

Spleen ≤ 5 cm below LCMHMR+ (ASXL1, EZH2, SRSF2 or IDHI1/2)

N = 320

1:1

Screening Treatment Phase

PFS1*

Ruxolitinib 15/20 mg bid

Ruxolitinib 15/20 mg bid

PFS2

Survival Follow up

Primary Objective : Progression-­free survival

Secondary Objectives :Time to progression in spleen/symptoms, Safety, Overall Survival,

Study stopped April 2017………………….

Limitations of Ruxolitinib in MF…….

• Response criteria a challenge in trials and real life practice

• Criteria for loss of response heterogeneous in trials & do not exist for standard practice• Mechanism of resistance undefined

• Anaemia and thrombocytopenia can limit effective dosing• Infections may be problematic

• Some potential signal for cancer – skin SCC in RESPONSE study (PV patients often heavily pre-­treated with HU)• Lack of current credible benefit intervention in asymptomatic low-­risk patients• Median duration of response 3-­4 years in clinical trials

JAK Inhibitors and Status of Development:

No longer in developmentfor MPNs

25

Pacritinib: on clinical hold Feb 2016Positive data for both PERSIST-­1 –May 2015PERSIST-­2 – ASH 2016Hold lifted further trial planned

Wernicke’s encephalopathy an

uncommon complication

Recently published JAKARTA 2

Momelotinib: SIMPLIFY 1 and 2 trials to be presented at ASCO. Mixed results, drug future uncertain

Entering MF studies in UK alone or in

combination with ruxolitinib

Combinations….. Many ??? HOW TO MEASURES SUCCESS

26

RUX-PAN RUX-LDE RUX-BKMnaive

RUX-BKMpretreat

SpleenResponse(at24w)

56.5% 44.4% 45.5% 22.2%

Meanspleenreduc/onat24w

41.7% 30.8% 38.8% 26.5%

Adverseevents

• Diarrhea: 68%, 18%

gradoe3/4

• Astenia :50%, 12%

grade 3/4

• Fa9gue: 29%, 6%

grade 3/4

• Raised CK 37%,

18,5% grade 3/4

• Myalgia:29,6%, 7,4%

grade 3/4

• Diarrhea: 25,9%,

3,7% grade 3/4

• Fa9gue: 25,9%; 0

grade 3/4

• Anxiety 15,9%, 4,8% grade 3-4

• Depression: 14,3%, 3,2% grade

3/4

• Iperglycemia: 12,7%; 3,2%

grade 3/4

Ruxoli/nibCombina/ons

Kiladjian; et al, ASH 2014

Durrant; et al, ASH 2014

Gupta et al, ASH 2014

•  Combina9ons

27

Developmentofresistancetoruxoli/nib

28

JAK/STATpathwayalonedoesnotexplainthefullspectrumofMPN-associatedabnormali/es

Vainchenker W, Kralovics R. Blood 2017;129:667-679

Abnormal Intracellular signaling and epigene9c regula9on contribute to MPN pathogenesis

•  Combina9ons

Emerging therapies for MPN• PV and ET– Interferon (still)– Ruxolitinib

• MF– JAK inhibitor– Combinations– Non-­‐JAKi based therapies

• Stem cell niche• Rare MPN– 8p11 Rearranged myeloid and lymphoid disorders– Aggressive systemic mastocytosis

Factors of interest in the stem cell niche

Arranz et al (2014) Nature, 512:78–81

NESTIN POSITIVE CELLS

ESTROGEN SIGNALLING

Article

Estrogen Signaling Selectively Induces Apoptosis ofHematopoietic Progenitors and Myeloid Neoplasmswithout Harming Steady-State Hematopoiesis

Graphical Abstract

HighlightsHematopoietic stem andmultipotent progenitor cells (MPPs) ex-

press ERa

ERa activation induces apoptosis of MPPs and proliferation of

LT-HSCs

Tamoxifen blocks JAK2V617F-induced myeloproliferative

neoplasia in mice

Tamoxifen enhances chemotherapy response of MLL-AF9-

induced leukemias

Authors

Abel Sanchez-Aguilera, Lorena Arranz, ...,

Jurg Schwaller, Simon Mendez-Ferrer

Correspondenceabel.sanchez-aguilera@cnic.es (A.S.-A.),smendez@cnic.es (S.M.-F.)

In BriefIn mice, activation of estrogen receptor

(ER) signaling induces apoptosis in multi-

potent hematopoietic progenitors but in-

duces proliferation and compromises

function of HSCs in a reversible manner.

Tamoxifen induces apoptosis of MLL-

AF9+ blasts, improving conventional

chemotherapy, and tamoxifen alone

blocks JAK2V617F-induced myeloprolifer-

ative neoplasm by restoring normal

apoptosis levels in mutant cells.

Accession NumbersGSE62621

Sanchez-Aguilera et al., 2014, Cell Stem Cell 15, 791–804December 4, 2014 ª2014 Elsevier Inc.http://dx.doi.org/10.1016/j.stem.2014.11.002

Study open in UK to test this

1Division of Hematology, University Hospital of Basel, Basel, Switzerland;; 2Swiss Group for Clinical Cancer Research, Bern, Switzerland;; 3Division of Hematology, University Hospital Zurich, Zurich, Switzerland;; 4Center of Oncology, Hematology, & Transfusion Medicine, Cantonal Hospital of Aarau, Aarau, Switzerland;; 5University Clinic of Hematology and Central Hematology Laboratory, University Hospital Bern, Bern, Switzerland;; 6Clinic of Haematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;; 7Departement Medizin, Luzerner Kantonsspital, Luzern, Switzerland;; 8Kantonsspital Muensterlingen, Muensterlingen, CHE;; 9Cantonal Hospital Liestal, Liestal, Switzerland;; 10Institute of Pathology, University Hospital of Basel, Basel, Switzerland;; 11Stem Cell Institute and Department of Haematology, University of Cambridge, and National Health Service Blood and Transplant, Cambridge, United Kingdom;; 12Department of Biomedicine, Experimental Hematology, University Hospital Basel, Basel, Switzerland

Beatrice Drexler1, Jakob R. Passweg1, Martin Bigler2, Alexandre PA Theocharides3, Nathan Cantoni4, Peter Keller5, Georg Stuessi6, Axel Rüfer7, Rudolf A. Benz8, Geneviève Favre9, Alexandar Tzankov10, Pontus Lundberg1, Andrea Fuhrer2, Christine Biaggi2, Markus G. Manz3, Mario Bargetzi4, Simon Mendez-­Ferrer11, and Radek C. Skoda12 on behalf of the Swiss Group for Clinical Cancer Research (SAKK)

Effects of the Sympathicomimetic Agonist Mirabegron on Disease Course, Mutant Allele Burden, Marrow Fibrosis, and Nestin Positive Stem Cell Niche in Patients with JAK2-­Mutated Myeloproliferative Neoplasms: a Prospective Multicenter Phase II Trial SAKK 33/14

Myeloproliferative neoplasms (MPN) are initiated and maintained bymutated hematopoietic stem cells (HSPC). Bone marrowmesenchymal stem cells expressing the intermediate filament proteinnestin (nestin+ MSCs) that are innervated by sympathetic nerve fibersconstitute an important component of the stem cell niche and regulatenormal HSCs. These nestin+ MSCs are strongly reduced in the bonemarrow of JAK2-­V617F positive MPN patients and in mice expressingJAK2-­V617F due to damage of the sympathetic nerve fibers triggeredby cytokines from the mutant cells. In a JAK2-­V617F mouse model ofMPN, treatment with a beta-­3 sympathomimetic agonist corrected thedamage inflicted by the MPN clones on their niches and amelioratedthe MPN phenotype.1

METHODS AND PATIENT COHORT

ABSTRACT RESULTS

1.Arranz et al, Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms. Nature 512:78-­81, 2014

2.Thiele et al, European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica. 90: 1128-­1132, 2005

To test the potentially beneficial effect of beta-­3 sympathomimeticstimulation on MPN by modulating bone marrow niche cells, weperformed a phase II trial with mirabegron, a beta-­3 sympathomimeticagonist, which is approved for the treatment of patients with irritablebladder.

The primary endpoint of 50% reduction in allele burden was notreached by any of the patients, one patient achieved a 25% reductionby 24 weeks of treatment. Adverse events were mostly grade I or II onthe CTCAE scale. Three patients had grade III events: two wereconsidered to be at least possibly related to study medication. Themean blood counts were similar between start and end of thetreatment. In 20 patients bone marrow biopsy prior to and at the endof mirabegron treatment was available. In these patients an increasein the nestin+ MSCs cells from a median of 1.09 (Q1-­Q3 0.38-­3.27)/mm2 to 3.95 (Q1-­Q3 1.98-­8.79)/mm2 (p<0.0001, Wilcoxonsigned-­rank test) and a slight decrease of myelofibrosis from amedian grade of 1.00 (Q1-­Q3 0.50-­3.00) to 0.75 (Q1-­Q3 0.50-­2.00)(p=0.02), were observed (Figure 1). The mean change in the nestin+cells from baseline to week 24 was 3.52 (95% confidence interval1.65-­5.39).

The trial consisted of mirabegron treatment with 25 mg daily duringthe first week, followed by 50 mg daily for at least 24 weeks.Patients with a cytohistologically confirmed diagnosis of MPN and aJAK2-­V617F allele burden >20% in granulocytes at study entry wereeligible, if not treated with JAK2 inhibitors or interferon. Reduction ofthe JAK2-­V617F mutant allele burden ≥50% in granulocytes wasdefined as the primary endpoint. Secondary endpoints includedchanges in blood counts or MPN related symptoms. As a side study,bone marrow biopsies were quantified for nestin+ MSCs, fibrosisand CD34+ HSPCs. N=39 patients have been accrued in 10institutions in Switzerland. Eight (21%) had ET, 22 (56%) PV, and 9(23%) PMF. N=27 (69%) were male, the median age was 62 (Q1-­Q3 53-­72) years. N=28 (72%) patients had cytoreductive treatment,the remaining patients had antiaggregation, anticoagulation, orphlebotomy.

OBJECTIVES

CONCLUSIONS

REFERENCES

Figure 2: Bone marrow histology of a patient before (week 0) and at the end of treatment (week 24) with mirabegron. Upper panel, reticulin fibers are stained black by silver impregnation (Gömöri). Lower panel, immunohistochemistry staining with a monoclonal antibody against human nestin protein. Note decrease of reticulin fibrosis and increase of nestin positive cells (brown staining) after 24 weeks of treatment. Magnification: 200x

Figure 1: Single patient evolutional curves of the nestin+ mesenchymal cells/mm2

(left panel) and grade of reticulin fibrosis according to the European consensus on grading bone marrow fibrosis2 (right panel) at study inclusion and after 24 weeks of mirabegron.

The beta-­3 sympathomimetic agonist mirabegron for 24 weeks failedto achieve the primary endpoint, i.e. to reduce the JAK2-­V617Fmutant allele burden ≥50% in patients with MPN.

A decrease of myelofibrosis and an increase in the nestin+ MSCs inbone marrow were observed.

This data suggest that mirabegron treatment can reverse the damageinflicted by the JAK2-­V617F positive MPN clone on the nestin+ stemcell niche.

Poster presented at ASH 2016

Acknowledgements:This work was supported by the Rising Tide Foundation for Clinical Cancer Research, Gateway for Cancer Research, the Swiss Cancer Research Foundation, and the Swiss State Secretariat for Education, Research and Innovation.

Mirabegron:

increased Nestin did not reduce the JAK2 allele burden

Emerging therapies for MPN

• PV and ET– Interferon (still)– Ruxolitinib

• MF– JAK inhibitor

– Combinations– Non-­JAKi based therapies

• Stem cell niche• Rare MPN– 8p11 Rearranged myeloid and lymphoid disorders

– Aggressive systemic mastocytosis

Summary ET/PV

• An accurate diagnosis is important with increased focus on the boundaries with other MPNs

• A question remains about IFN vs HU. Recent data is reassuring to patients that these agents are similar in efficacy at least in the short term.

• We might begin to use molecular information to tailor our therapies. Eg need for aspirin in CALR + ET

• & we may also use this data to risk stratify patients

• Expect the results of intermediate risk arm of PT-­‐1 and also that we will start a first-­‐line PV study this year.

Summary MF/ other rare MPN

• Better surrogate markers of response/progression are needed

• Studies are required in early phase disease• Currently no available credible second line option• Management of anemic and thrombocytopenic patients more challenging

• Novel therapies are under investigation• Midostaurin offers important responses for patients with systemic mastocytosis

• Consider trial of FGFR inhibitor in 8p11

Thanks to and acknowledgement of:GSTT MPN team and patients

UK NCRN MPN Clinical Study Group Global MPN friends and collaborators

“The real voyage of discovery consists not in seeking new landscapes but in having new eyes”

Marcel Proust