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What is next:
SymposiumJAK2 Inhibition in Myelofibrosis:What Can We Expect in the Clinic?
4‐5 May 2012Lisbon, Portugal
What is next:
Emerging JAK2 inhibitor combination
studies
Alessandro M. Vannucchi
Section of Hematology,
University of Florence, Italy
www.progettoagimm.it
Reasons for performing combination
trials with JAK2 inhibitors
• To increase the benefits seen with JAK2 inhibitors
(splenomegaly, symptoms) as well as to bring additional
benefits (anemia, BM fibrosis, clone)
• To reduce unwanted side effects (anemia,
thrombocytopenia) yet maintaining clinical benefits
• To facilitate stem cell transplantation
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Reasons for performing combination
trials with JAK2 inhibitors
• To increase the benefits seen with JAK2 inhibitors
(splenomegaly, symptoms) as well as to bring additional
benefits (anemia, BM fibrosis, clone)
• To reduce unwanted side effects (anemia,
thrombocytopenia) yet maintaining clinical benefits
• To facilitate stem cell transplantation
Drugs of Potential Interest for Combination Studies with JAK2 inhibitors
Class MoleculeIn vitro study
Clinical trial
Selected Referencesy
ImmunomodulatorsPomalidomide Tefferi et al. JCO2009;27:4563‐9.
Lenalidomide Mesa et al. Blood 2010;116:4436‐8
mTOR inhibitors Everolimus Guglielmelli et al . Blood 2011;118:2069‐76
Hypomethylating agents
Azacitidine Mesa et al. Leukemia 2009; 23:180‐2
Decitabine Danilov et al. BJH 2009; 145:131‐2
Givinostat Rambaldi et al BJH 2010; 150:446 55Histone deacethylase inhibitors
Givinostat Rambaldi et al. BJH 2010; 150:446‐55
Panobinostat De Angelo et al (ASH annual Meeting Abstract). 2010;276
InterferonsInterferon alpha
Ianotto JC, BJH 2009;146:317‐21Silver RT, Blood 2011; 117:6669‐72Gowin K, Haematologica 2012, online
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Increased down‐regulation of JAK2 signaling with a
combination of JAK2 inhibitor and HDACi
• TG101209• Panobinostat
Wang Y et al. Blood 2009;114:5024‐5033
Combined Effects of Ruxolitinib and Panobinostat in an
in vivo model of JAK2V617F mutated MPNVehicle PAN 4 mg/kg PAN 8 mg/kg PAN 12 mg/kg
10
RUX 60 mg/kg RUX 60 mg/kg +PAN 4 mg/kg
RUX 60 mg/kg +PAN 8 mg/kg
RUX 60 mg/kg +PAN 12 mg/kg
8
6
4
2
% ofcontrol 11% *20% *27% *100%
% ofcontrol 3% *† ‡15% *†22% *40% *
* P < 0.05 vs. vehicle control; † P < 0.05 vs. ruxolitinib; ‡ P < 0.05 vs .panobinostat at same dose
• Enhanced efficacy was observed with a combination of RUX and PAN
• There was no major change in tolerability, as assessed by body weight, between panobinostat alone or in combination with ruxolitinib
Baffert et al, manuscript in preparation
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A Phase 1b, open‐label, multi‐center, single arm, dose
finding study to assess safety and pharmacokinetics of
h l b f b d l bthe oral combination of panobinostat and ruxolitinib
in patients with primary myelofibrosis (PMF), post‐
polycythemia vera‐myelofibrosis (PPV‐MF) or post‐
essential thrombocythemia‐myelofibrosis (PET‐MF)
LBH589X2106
Combination Trial of Ruxolitininb with Panobinostat
• Primary Objective: to evaluate the clinical‐pathological response
• Secondary Objectives: assessment of biological response including
measurement of histone acetylation, JAK2V617F allele burden, bone
Dose Level Ruxolitinib Panobinostat
1 10 mg BID 10 mg TIW QOW
2 10 mg BID 10 mg TIW QW
3 15 mg BID 10 mg TIW QOW
4 15 BID 10 TIW QW
y
marrow cellularity, histopathology and fibrosis.
Ruxolitinib + PanobinostatN = 48 (max)
• ≥18 years of age• Int‐2/High risk PMF or Post PV/ET MF or pts with MF in accelerated phase
A
S
S
E
S
S
Progressive DiseaseOffstudy
Toxicity Off study or dose
difi ti4 15 mg BID 10 mg TIW QW
5 15 mg BID 15 mg TIW QOW
6 15 mg BID 15 mg TIW QW
7 20mg BID 15 mg TIW QOW
8 20 mg BID 15 mg TIW QW
accelerated phase• ANC ≥1 x 109/L• Platelets ≥75 x 109/L• ECOG PS ≤3• Adequate cardiac function
3+3 DESIGNTreatment duration = 28 days
M
E
N
T
modification
Continue until next dosage cohort is completed
Participating Country: USAPrincipal Investigator: John Mascarenhas, MD
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Combination Trial of Ruxolitinib and Lenalidomide
(NCT01375140)
• Sponsored by MDACC, PI S. Verstovsek
• Primary Outcome: the rate of IWG‐defined responses after 3
cycles
• Projected enrolment: 49 subjects
• Treatment: Ruxolitinib 15 mg BID + Lenalidomide 5 mg/day d1‐
21 P d i dd d i l 4 6 i f21. Prednisone added in cycles 4‐6 in case of no response
• Ongoing, 20 patients enrolled till now.
Combination Trial of Ruxolitinib with peg Interferon‐alpha2a
Efficacy reported (variably)
Silver RT, Blood 2011; 117:6669‐72
Efficacy reported (variably)
against splenomegaly, anemia,
V617F allele burden and bone
marrow morphology
Iannotto JC, BJH 2009; 146:317‐21Gowin K, Haematologica 2012, online
A Phase 1/2 dose finding study to assess safety and
pharmacokinetics of the combination of Ruxolitinib and peg‐
interferon alpha‐2a in patients with PMF, PPV‐MF or PET‐MF
(PI, J.J. Kiladjian: France)
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A Phase I/II trial of Everolimus in Myelofibrosis
• Phase I (n=9), Phase II at MTD (10 mg/die; n=30), 4‐months
• Responses (ITT):
• EUMNET: overall 60%, Major 27%, Moderate 23%, Minor 10%; No response 40%
ll• IWG‐MRT: overall 23%, PR 3%, CI 20%, SD 77%
CR= 69%
Guglielmelli P et al. Blood 2011;118:2069‐2076
CR=80%
A phase 1/2 study of combination therapy of Ruxolitinib and EVErolimus in patients with primary an post‐PV/ET MYelofibrosis
(REVEMY study)• Primary Objective: evaluate the safety, efficacy, and MTD of Ruxolitinib combined with
Everolimus in patients with PMF and PPV/PET‐MF
• Secondary Objectives: effects of the treatment on normalization of abnormal peripheral blood cell count; changes in V617F or MPL allelic burden in mutated patients
Dose Level Ruxolitinib Everolimus
1 5 mg BID 2.5 mg QD
2 10 mg BID 5 mg QD
3 15 mg BID 7.5 mg QD
Ruxolitinib + Everolimus
N = 12 (Phase 1)*N = 20 (Phase 2)• Primary myelofibrosis
(WHO 2008)• PPV-/PET-MF (IWG-MRT
criteria)• Intermediate-2/high risk or
Intermediate-1 with constitutional symptomsS l l (≥5 f
A
S
S
E
S
S
M
Progressive Disease Off Study
Toxicity (off study or dose modification)
3 + 3 Design
3 15 mg BID 7.5 mg QD
4 20 mg BID 7.5 mg QD
• Splenomegaly (≥5 cm from the right costal margin)
• Platelets >100 x 109/L; ANC ≥1 x 109/L
Treatment duration = 28 days
E
N
T
Participating Country: ItalyPrincipal Investigator: Alessandro M Vannucchi
FPFV = May 2012
Continue until next dosage cohort is completed
*12 patients enrolled with 12 additional patients if necessary for DLT estimationANC, absolute neutrophil count; MTD, maximum tolerated dose
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Reasons for performing combination
trials with JAK2 inhibitors
• To increase the benefits seen with JAK2 inhibitors
(splenomegaly, symptoms) as well as to bring additional
benefits (anemia, BM fibrosis, clone)
• To reduce unwanted side effects (anemia,
thrombocytopenia) yet maintaining clinical benefits
• To facilitate stem cell transplantation
Anemia During Ruxolitinib Treatment
Ruxolitinib Comparator
G3 G4 Tot G3 G4 Tot
COMFORT‐I
Hb 34.2 11.0 44.2 15.9 3.3 19.2
COMFORT‐IICOMFORT II
Hb 34 8 42 21 10 31
(% of patients)
Verstovsek S et al. NEJM 2012; 366:799‐807. Harrison C et al. NEJM 2012; 366:787‐98
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Development of Anemia Does not Affect Responseto Ruxolitinib Treatment
Verstovsek S et al. NEJM 2012; 366:799‐807.
Endogenous Epo Levels During Ruxolitinib Treatment
Verstovsek et al. N Engl J Med. 2010; 363:1117‐27.
Erythropoietin
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Is there a Rationale for Adding Epo to Ruxolitinib?
• Strictly speaking, mutuating the experience from MDS where
endogenous EPO levels >500 U/L negatively correlated with g g y
response, NO or LITTLE
• But, anedoctal experience of 9 (+1) patients in COMFORT‐II
suggested efficacy without unwanted increase in spleen size
An open‐label, multicenter study of Ruxolitinib and
Erythropoietic Stimulating Agents for patients with PMF or
PPV‐MF or PET‐MF and anemia
(PI, H. Katrin Al‐Ali: Germany)
Pomalidomide for MF‐associated Anemia
• 5 phase I/II studies with >240 patients
• Best anemia responses at doses of 0.5 mg/day
(±prednisone)
100%
ses
(±prednisone)
• Median duration of anemia response: 16 months
• Modest activity against splenomegaly, up to 58%
platelet responses
•A placebo‐controlled, phase‐3 study (NCT01178281) 63
50%
Respons
Months
Tefferi A et al J Clin Oncol 2009; 27:4563 9; Mesa R et al Am J Hematol 2010; 85:129 30; Begna K et al
A Phase‐Ib/II Study of Ruxolitinib and Pomalidomide
Combination Therapy in Patients with Primary and Secondary
Myelofibrosis: The POMINC Study.
(PI, K. Dohner: Germany)
Tefferi A et al. J Clin Oncol 2009; 27:4563‐9; Mesa R et al. Am J Hematol 2010; 85:129‐30; Begna K et al. Leukemia 2011; 25:301‐4; Begna K et al. Am J Hematol 2011;on‐line
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Reasons for performing combination
trials with JAK2 inhibitors
• To increase the benefits seen with JAK2 inhibitors
(splenomegaly, symptoms) as well as to bring additional
benefits (anemia, BM fibrosis, clone)
• To reduce unwanted side effects (anemia,
thrombocytopenia) yet maintaining clinical benefits
• To facilitate stem cell transplantation
• Extensive splenomegaly raises concerns about excessive sequestration of
transplanted SCs as ell as increased transf sional s pport after SCT
Does Splenomegaly Negatively Affect
Hematopoietic Recovery after SCT?
transplanted SCs as well as increased transfusional support after SCT
• There is a negative correlation between time to neutrophil engraftment and
extent of splenomegaly in some1 but not all2 series
• In a study of 11 splenectomized vs
15 non‐splenectomized MF
patients there was evidence of
1 Ciurea S et al. BJH 2008; 141:80‐3; 2 Scott BL, Blood 2012; 119:2657‐64 ; 3 Li z et al., Blood 2001; 97: 2180‐1
patients there was evidence of
faster granulocyte recovery
although with no impact on
outcome3
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Splenomegaly is a Negative Risk Factor for Survival
after SCT
Risk variables
• Spleen >22 cm• Transfusions >20• Donor other thanHLA id ibliHLA‐id sibling
Low risk= 0‐1 variables
High risk= >2 variables1 Bacigalupo A, BMT 2010; 45:458‐63
• Splenectomy was protective against disease relapse (13% vs 56%
in splenectomized vs non splenectomized pts) in an Italian study1
• In a study of 31 splenectomized vs 180 non splenectomized pts pre
JAK2 Inhibitors as Part of the STC Procedure
• In a study of 31 splenectomized vs 180 non‐splenectomized pts, pre‐
HCT splenectomy was the only variable associated with reduced
mortality (HR 0.51, p=0.05) 2.
• However, the risks associated with surgery do not justify the routine
use of splenectomy unless in very selected cases
1 Bacigalupo A, BMT 2010; 45:458‐63; 2 Scott BL, Blood 2012; 119:2657‐64
Feasibility of administering Ruxolitinib with reduced intensity
conditioning (RIC) allogeneic hematopoietic cell transplantation
(RIC‐HSCT) in MF patients
(PI, V. Gupta: USA, Canada, Italy, Germany, UK, Israel)
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Combinations……..at a glance
• Ruxolitinib plus azacitidine
Low‐dose azacitidine to be added to ruxolitinib after 3 months.
(S. Verstovsek, personal communication)
• Ruxolitinib followed by decitabine in MPN‐related AML
(R.Hoffman, personal communication)(R.Hoffman, personal communication)
• Ruxolitinib and Smo inhibitors
(in preparation)