Myeloproliferative Neoplasms [email protected]
TOPICS
• Have we learnt anything new from targeted NGS?
• IFN and its use in PV and ET
• MAJIC
• Management of MF JAK inhibition and beyond
• Blast phase MPN predisposition, outcome and treatment
• Mastocytosis
Clinical context:
• A 46 year old male presents with fatigue and palpable spleen.
• WBC 11.3, Hb 170g/l, PCV 0.49, Platelets 670
• JAK2 V617F positive
PV
ET
PV
mPV
ET
Pre
PMF
PMF OvertPMF
Pre/early
PMFPre
PMF
Changes to the WHO diagnostic criteria & recognised entities
Design of NGS study
Molecular follow-up
Last sample
Screening of mutations
in 51 genes
PV n= 63
ET n= 37
PV n=43
ET n=27
MF n=18
AML n=12
Directed study of specific mutations to
determine clonal evolution
Diagnosis
Selection of 100 patients:
Molecular monitoring> 10 years or
Disease progression
First sample
Myelofibrotic transformation
p <0.0001
Persistently high or progressive increase of JAK2 VAF
Persistently low JAK2 VAF
Probability of MF transformation according to JAK2V617F allele burden pattern
Events/total Probability at 10 years
Persistently low 2/84 1.5%
Persistently high or progressive
increase
19/52 22%
Multivariate analysis of risk factors for MF transformation
HR (95%CI) p
Age > 65 years 2.1 (0.8-5.4) 0.2
Diagnosis (PV or ET) 0.9 (0.3-2.9) 0.9
JAK2 allele burden 13.7 (2.9-64.4) 0.001
Probability of AML transformation according to specific mutations at 1st
sample
AML/total mutated p
SRSF2 3/4 <0.001
DNMT3A 2/7 0.002
IDH 1/2 2/3 <0.001
RUNX1 2/4 <0.001
Probability of AML transformation according to the presence of any
mutation at 1st sample
AML/total Probability at 10 years
No mutation at 1st simple 2/65 1.8 %
Any mutation at 1st sample 10/35 12.4%
Multivariate analysis of risk factors for progression to AML
HR (95%CI) p
Age > 65 years 3 (0.7-12.6) 0.13
Leukemogenic agents 1.6 (0.3-7.6) 0.53
Mutation at 1st sample 7.6 (1.6-35.9) 0.01
NGS ET/PV conclusions
• JAK2 VAF which increases or is persistently high correlates with risk of MF
• Mutations in other genes are involved with progression to AML but not to MF
• Non-driver mutations are found more frequently on patients with high or persistently high JAK2 VAF
Back to the case:
• A 46 year old male presents with fatigue and palpable spleen.
• WBC 11.3, Hb 170g/l, PCV 0.49, Platelets 670
• JAK2 V617F positive
• He has abdominal pain and imaging shows a portal vein thrombosis he is anticoagulatedbut needs cytoreductive treatment…
Rx of ET/PVHU vs IFN for first line: background
• Optimal management of “High Risk” ET and PV remains unknown– Mascarenhas J et al. Haematologica. 2014. 99(6):945-9.
• HU therapy associated with reduction in thrombotic risk – Fruchtman SM et al. Semin Hematol. 1997. 34(1):17-231997
– Harrison CN et al. N Engl J Med. 2005 . 353(1):33-45
• Concern regarding leukemogenic potential of HU not corroborated by most studies– Kiladjian JJ et al. J Clin Oncol. 2011. 29(29):3907-13
– Finazzi et al. Blood. 2005. 105(7):2664-70
– Tefferi et al. Leukemia. 2013. 7(9):1874-81.
• IFN-α therapy associated with hematologic ORR >75% and CMR 15-20% in phase II trials– Quintás-Cardama A et al. J Clin Oncol. 2009 . 27(32):5418-24.; Blood. 2013. 122(6):893-901.
– Kiladjian JJ et al. Blood. 2008. 112(8):3065-7
Interim Analysis of the Myeloproliferative Disorders Research Consortium (MPD-RC) 112 Global Phase III Trial of Front Line Pegylated Interferon Alpha-2a Vs. Hydroxyurea in High Risk
Polycythemia Vera and Essential Thrombocythemia(NCT01258856)
John O. Mascarenhas, MD, MS1, Josef T. Prchal, MD2, Alessandro Rambaldi, MD3, Ruben A. Mesa, MD4, Dmitriy Berenzon, MD5*, Abdulraheem Yacoub, MD6, Claire N. Harrison, DM, FRCP, FRCPath7, Mary Frances McMullin, MD8, Alessandro M.
Vannucchi, MD, PhD9, Joanne C Ewing, PhD, BMBS, BSc, FRPATH,10*, Casey L O'Connell, M.D.11, Jean-Jacques Kiladjian, MD, PhD12, Adam Mead, MD, PhD13*, Elliott F. Winton, MD14, David S. Leibowitz, MD15, Valerio De Stefano16*, Murat O. Arcasoy,
MD17, Craig M. Kessler, MD18, Rosalind Catchatorian19*, Damiano Rondelli, MD20, Richard T. Silver, MD21, Ellen K. Ritchie, MD22, Arnon Nagler23, Marina Kremyanskaya, MD PhD24, Richard F. Schlenk, MD25, Rona Singer Weinberg, PhD26, Mohamed E Salama, M.D.27, Gianni Tognoni28*, Giuseppe Prosperini28*, Alessandra Di Lelio28*, Eliseo Serone28*, Lorenzo Marfisi28*, Jill Kleczko1*, Heidi
E. Kosiorek, MS29*, Tiziano Barbui, MD30*, Amylou C. Dueck, PhD29 and Ronald Hoffman31
1Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY; 2Division of Hematology, University of Utah, Salt Lake City, UT; 3Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII and University of Milan, Bergamo, Italy; 4Mayo Clinic, Scottsdale, AZ; 5Comprehensive Cancer Center, Wake
Forest School of Medicine, WINSTON SALEM, NC; 6University of Kansas Cancer Center, Westwood, KS; 7Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom; 8Queen's University Belfast, Belfast, United Kingdom; 9Azienda Ospedaliera-Universitaria Careggi, Florence, Italy; 10Heart of England NHS Foundation Trust,
Birmingham, United Kingdom; 11Norris Comprehensive Cancer Center, Jane Anne Nohl Division of Hematology, University of Southern California, Los Angeles, CA; 12Hôpital Saint-Louis and Paris Diderot University, Paris, France; 13MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United
Kingdom; 14Winship Cancer Institute of Emory University, Atlanta, GA; 15Palo Alto Medical Foundation, Palo Alto, CA; 16Università Cattolica del Sacro Cuore Rome, Italy; 17Duke University Health System, Durham, NC; 18Georgetown University Med. Ctr., Washington, DC; 19John.H.Stroger hospital, chicago; 20Division of Hematology/Oncology,
University of Illinois at Chicago, Chicago, IL; 21Department of Hematology/Medical Oncology, Weill Cornell Medicine, New York, NY; 22Weill Cornell Medical College, New York, NY; 23Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel; 24The Myeloproliferative Research Consortium, The myeloproliferative Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY; 25University Hospital of Ulm, Ulm, Germany; 26New York Blood Center, New York, NY; 27Department of Pathology, University of Utah, Salt Lake City, UT; 28Istituto di RicercheFarmacologiche Mario Negri, Milan, Italy; 29Mayo Clinic Cancer Center, Phoenix, AZ; 30Research Foundation (FROM) Hospital Papa Giovanni XXIII, Bergamo, Italy; 31Division of
Hematology and Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
MPD-RC 112 Study Schema
Ran
do
miz
ed
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
INTE
RIM
A
NA
LYSI
S
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
Baseline characteristics of first 75 patients on the MPD-RC 112 trial
* Based on t-test for continuous variables and z-test for binary variables.
HU (n=39) PEG (n=36) Total (n=75) P Value*
Age, years median (range) 66 (28-85) 56 (20-71) 61 (20-85) <0.001
Gender, Female 19 (49%) 16 (44%) 35 (47%) 0.71
MPN subtype, ET/PV 16 (41%) /23 (59%) 15 (42%)/21 (58%) 31 (41%) /44 (59%) 0.95
JAK2V617F 36 (92%) 32 (89%) 68 (91%) 0.51
ECOG PS, 0 34 (87%) 29 (81%) 63 (84%) 0.44
Age >60 years 27 (69%) 15 (42%) 42 (56%) 0.02
History of venous thrombosis 6 (15%) 5 (14%) 11 (15%) 0.86
History of arterial thrombosis 4 (10%) 9 (25%) 13 (17%) 0.09
Cardiovascular risk factors 25 (64%) 16 (44%) 41 (55%) 0.09
Palpable spleen 10 (26%) 7 (19%) 17 (23%) 0.52
Spleen length by palpation (cm below left costal margin)
1.5 (0-10) 1.0 (0-10) 1.3 (0-10) 0.52
Spleen length by ultrasound (cm) 12.4 (0-18) 13.0 (0-20.2) 12.6 (0-20.2) 0.90
Leukocytes (x 109/L) 10.3 (4.8-20.0) 8.1 (4.0-23.4) 9.3 (4.0-23.4) 0.43
Hemoglobin (g/dL) 14.1 (12.1-22.4) 14.4 (11.3-16.6) 14.4 (11.3-16.6) 0.17
Hematocrit (%) 45.7 (36.2-70.2) 43.9 (33.5-60.7) 45.0 (33.5 -70.2) 0.33
Platelets (x 109/L) 615 (142-1444) 538 (112-1382) 592 (112-1444) 0.24
Number of patients with any grade AEs regardless of attribution occurring in ≥15% of patients in either arm
Adverse Event HU (n=36) PEG (n=36) P Value*
Abdominal pain 2 (6%) 7 (19%) 0.07
Anemia 6 (17%) 7 (19%) 0.76
Depression - 10 (28%) <0.001
Diarrhea 5 (14%) 7 (19%) 0.53
Dyspnea 1 (3%) 7 (19%) 0.02
Fatigue 10 (28%) 18 (50%) 0.05
Flu-like symptoms 1 (3%) 12 (33%) <0.001
Headache 4 (11%) 7 (19%) 0.33
Injection site reaction - 9 (25%) 0.001
Leukopenia 3 (8%) 8 (22%) 0.10
Nausea 7 (19%) 7 (19%) 0.99
Pain 9 (25%) 11 (31%) 0.60
Pruritus 3 (8%) 10 (28%) 0.03
Thrombocytopenia 7 (19%) 6 (17%) 0.76
Overall (grade 1+) 32 (89%) 36 (100%) 0.04
Overall (grade 3+) 5 (14%) 17 (47%) 0.002
* Based on z-test for all AEs.
Status of 75 Subjects at Time of Interim Analysis (12 months)
HU(n=39)
PEG(n=36)
On Therapy 29/39 33/36
Never Initiated Therapy 3/39 0/36
Adverse Event 1/39 1/36
Physician Decision 0/39 1/36
Pt Withdrawal 5/39 1/36
Non-Compliance 1/39 0/39
Overall Response Rates at 12 Months by Treatment Arm
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 megakaryocyte hyperplasia, and abnormal megakaryocyte histotopography
PV: Disappearance of trilineage hyperplasia
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
portio
n o
f P
atients
PR
CR
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 development: PROUD/CONTI-PV
Primary objective
Demonstration of non-inferiority of Ropeginterferon vs. HU
• 12 month response rate
Complete Hematologic Response (+/-spleen response)
• Hct, Plt, WBC in range (ELN criteria)
• No phlebotomy within preceding 3 months
• Spleen size (by central MRI)
Exposure to study drugs
AOP2014
Median plateau dose 450µg
Reached from week 28
Dose reduction due to AE32
(25.2%)
12 month discontinuation rate 16.5%
Week in the study (Visit)
D0
(V1)
W2
(V2)
W4
(V3)
W6
(V4)
W8
(V5)
W10
(V6)
W12
(V7)
-A
W14
(V8)
W16
(V9)
W18
(V10
)
W20
(V11
)
W22
(V12
)
W24
(V13
)
W26
(V14
)-A
W28
(V15
)
W30
(V16
)
W32
(V17
)
W34
(V18
)
W36
(V19
)
W38
(V20
)
W40
(V21
)-A
W42
(V22
)
W44
(V23
)
W46
(V24
)
W48
(V25
)
W50
(V26
)
W52
(EOT)
-A
0
500
1000
1500
2000
2500
3000
HU
do
se [
mg
]
|
N 127 124 119 120 119 121 117 119 117 114 112 114 113 113 114 115 114 113 115 115 111 109 110 110 107 107
Week in the study (Visit)
D0
(V1)
W2
(V2)
W4
(V3)
W6
(V4)
W8
(V5)
W10
(V6)
W12
(V7)
-A
W14
(V8)
W16
(V9)
W18
(V10
)
W20
(V11
)
W22
(V12
)
W24
(V13
)
W26
(V14
)-A
W28
(V15
)
W30
(V16
)
W32
(V17
)
W34
(V18
)
W36
(V19
)
W38
(V20
)
W40
(V21
)-A
W42
(V22
)
W44
(V23
)
W46
(V24
)
W48
(V25
)
W50
(V26
)
W52
(EOT)
-A
0
100
200
300
400
500
AO
P2014 d
ose [
ug
]
|
N 115 111 115 115 115 113 114 114 112 110 110 109 107 109 105 103 105 106 104 105 104 101 99 101 99 97 97
HU
Median plateau dose 1250mg
Reached from week 8
Dose reduction due to AE 65 (51.2%)
12 month discontinuation rate 12.6%
Complete Hematologic Response at 12 months
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%
All grade AEs in >10% of patients in either treatment arm
Adverse Event
AOP2014 (n=127)n (%)
HU (n=127)n (%)
P-value*
Anaemia 8 (6.3%) 31 (24.4%) p<0.01
Leukopenia 11 (8.7%) 27 (21.3%) p<0.01
Thrombocytopenia 19 (15.0%) 36 (28.3%) p<0.01
Nausea 3 (2.4%) 15 (11.8%) p<0.01
Fatigue 16 (12.6%) 17 (13.4%) n.s. (p>0.05)
GGT increased 18 (14.2%) 1 (0.8%) p<0.01
Number of patients with any treatment-emergent eventregardless of relationship to study drug and intensity
* Fisher‘s exact testn.s. not significant
Adverse Events of Special Interest
AESI
AOP2014 (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)
Secondary related malignancies during PROUD/CONTI
AOP2014 (n=127) HU (n=127)
Total number 2nd related malignancies
0 5
during PROUD n/a Basal cell carcinomaBasal cell carcinoma
during CONTI n/a Malignant melanomaAcute leukemiaAcute leukemia
Summary
• Both treatments achieved robust hematologic control from week 12 on.
• Non-inferiority of Ropeginterferon vs. HU demonstrated:12 month Complete Hematologic Response: 43.1 vs. 45.6% (p=0.0028).
• Safety and tolerability of Ropeginterferon showed benefits over HU.
• Five related secondary malignancies appeared in the HU cohort (long-term).
Back to the clinical case:
• The patient has hydroxycarbamide, he does well on therapy for 5 years but then becomes neutropenic on doses required to control his platelet count…
• What about second line therapy?
C. HARRISON1, A. MEAD2, S.FOX3, A.PANCHAL3, C.YAP3, A.HOULTON3, S.ALIMAN1, J. EWING4, M.WOOD5, F.CHEN6, J.COPPELL7, N.PANOSKALTSIS8, S. KNAPPER9, S. ALI10, A. HAMBLIN11, R.SCHERBER12, H.GEYER13, A. SCOTCH13, A.DUECK14, N. CROSS15, R.MESA13 and M. MCMULLIN 16
1Guy's and St Thomas' NHS Foundation Trust, London, 2Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, 3Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, 4Heart of England NHS Foundation Trust, Birmingham, United Kingdom, 5Colchester Hospital University NHS Foundation Trust, Colchester, 6Centre for Clinical Haematology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, 7Royal Devon and Exeter NHS Foundation Trust, Exeter, 8Department of Haematology, London North West Healthcare NHS Trust, London, 9Department of Hematology, Cardiff University, Cardiff, United Kingdom, 10 Castle Hill Hospital, Hull, United Kingdom, 11 NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom, 12Department of Hematology and Oncology, Oregon Health and Sciences University, Portland, 13 Mayo Clinic, Scottsdale, United States, 14 Division of Health Sciences Research, Mayo Clinic, Scottsdale, United States, 15 Faculty of Medicine, University of Southampton, Southampton, United Kingdom, 16Department of Hematology, Belfast City Hospital, Belfast, United Kingdom.
INTRODUCTION• Essential Thrombocythemia (ET) is a myeloproliferative neoplasm (MPN)
characterised by a thrombocytosis associated with an increased risk of arterial and venous thrombosis, major hemorrhage, & in the longer term, transformation to myelofibrosis (MF) or leukemia.
• Hydroxycarbamide (HC) is commonly used to reduce the platelet count but approximately 20% of patients will become resistant or intolerant to HC , and have been shown to have a worse prognosis1.
• Ruxolitinib (RUX), a Janus kinase (JAK) 1 & 2 inhibitor has significant clinical benefits in MF2 & those patients with Polycythaemia Vera who are resistant or intolerant to HC3.
• We conducted a randomized, phase II, trial (MAJIC) of RUX vs Best Available Therapy (BAT) in patients with ET who were resistant or intolerant to HC.
CONCLUSIONSWe report primary results from the ET arm of the MAJIC study, the first randomized study of RUX in ET, 110 patients were eligible for the mITT analysis.
• HC resistant/intolerant ET is clinically & molecularly diverse.
• We confirm that these patients are at high risk of thrombosis & transformation as suggested in prior retrospective studies.
• Molecular responses were limited to RUX & for the first time we demonstrate such responses may correlate with symptom improvement but not always with progression events
RESULTSSymptoms• Mean MPN-10 TSS for early satiety, itching, & weight loss during the first 12 months
were all significantly lower for RUX vs BAT (all p<0.05). • Patients who achieved a CHR had significantly better TSS, fatigue, inactivity,
concentration problems & MDASI symptom interference (all p<0.05) at baseline vsthose without; however, scores during treatment did not appear to difer
Adverse Events• Anemia, thrombocytopenia and infections occurred more frequent in RUX patients
(Grade 3 or 4 anemia in 19% & 0% for RUX arm vs 0% (both grades) for BAT arm; grade 3 or 4 thrombocytopenia in 5.2% & 1.7% of RUX vs 0% (both grades) of BAT patients and grade 3 or 4 infections in 10.3% of RUX patients vs 3.6% BAT arm)
• There were 2 non treatment related deaths in each arm• Multivariable analysis revealed that only baseline Hb ≤100g/dl was significant for the
occurrence of grade 3+ anemia (OR [95% CI]=0.17 [0.04, 0.72]). • No risk factors for thrombocytopenia were identifiedClinical course• Transformations to post-ET MF occurred in 8 RUX vs 3 BAT treated patients, 1 RUX
patient developed acute myeloid leukemia. • Transformation to PET-MF only occurred in patients with baseline WBC <10x109/L• 9 patients (15.5%) patients on RUX experienced 10 thrombotic events compared to 5
patients (8.9%) experiencing 5 events on BAT.• Hemorrhagic events were 1 (1.7%) vs 5 (8.9%) for RUX and BAT patients respectively Allele burden and molecular response• Assays for JAK2 V617F were performed independently in 3 centres• Allele burden for both patient groups was defined* at baseline and 12 months (Figure
1)• Notably, MRs only occurred with RUX treatment. One complete response (12 – 0%) and
one partial was observed in the JAK2 V617F group, while 2 complete (39 – 0%** & 34 –0%) and 1 partial (65 – 9%) occurred in the CALR group
• No pattern of MR or progression with C/PHR or transformation could be identified; however 1 patient who transformed to PET MF had a complete MR
* Comparisons of mean scores longitudinally employed linear mixed models using all available data during the first 12 months of the study. A mixed model was used to compare each outcome during the initial 12-month treatment period (starting at the Month 2 assessment and ending at the Month 12 assessment) between patients with (N=4) and without (N=44) molecular response on the Ruxolitinib arm. In addition to the molecular response (yes v no) covariate, each model included a continuous covariate for the baseline value of the outcome and used the planned month of assessment as the categorical time value. An unstructured covariance structure was used. Results are displayed above
** This patient progressed to PET MF
METHODS• Patients with high-risk ET who fulfilled ELN criteria for HC resistance/intolerance
were recruited over 30 months (2012-2015), stratified by JAK2V617F status & randomized to receive 25mg bd of RUX or BAT, 20mg bd in patients with platelets xxxxxx.
• Post-ET MF was excluded at trial entry. • Patients eligible for the modified intention to treat (mITT) analysis were those who
commenced study treatment & received at least one response assessment. • JAK2/CALR/MPL allele burdens were assessed via Q-PCR analysis at baseline & 4
monthly. • Patient reported outcome & quality of life were assessed using EQ5D, MDASI & MPN
Symptom Assessment Form (MPN10). Symptom response was defined as ≥ 50% reduction in MPN10 total symptom score (TSS) & compared between arms using a linear mixed model of post-baseline scores through month 12 adjusting for baseline.
ACKNOWLEDGEMENTSThis trial is funded by Bloodwise under the Trials Acceleration Programme (TAP). An unrestricted educational grant was provided to support the trial & adjunctive science by Novartis. Ruxolitinib provided free of charge by Novartis. The support and time of participating patients and their families is gratefully acknowledged.
OBJECTIVES• To evaluate the activity & safety of RUX treatment of patients with ET who met the
modified European LeukemiaNet (ELN) criteria for resistance or intolerance to HC4. • The primary end-point was the rate of achievement of complete hematological
response within 1 year (according to ELN guidelines5).• Secondary endpoints included partial hematological response, safety,
thrombosis/hemorrhage (adjudicated by central review), progression free survival (including transformation), molecular response (MR) & symptom/quality of life assessment.
REFERENCES1 - Hernandez-Boluda, J-C et al. Clinical Evaluation of the European LeukemiaNet criteria for clinicohaematological response and resistance3/intolerance to hydroxycarbamide is essential thrombocythaemia. Br J Haematol 2011; 152(1); 81-882 - Vannucchi, A-M et al. A pooled analysis of overall survival in COMFORT-1 and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis. Haematologica, 2015. 100(9): p. 1139-453 - Vannucchi, A-M et al. Ruxolitinib versus standard therapy for the treatment of polycythaemia vera. NEJM 2015; 372(5): p. 426-35.4 - Barosi, G., et al. A unified definition of clinical resistance/intolerance to hydroxyurea in essential thrombocythemia: results of a consensus process by an international working group. Leukemia, 2007. 21(2): p. 277-80. 5 - Barosi, G., et al. Response criteria for essential thrombocythemia and polycythemia vera: result of a European LeukemiaNetconsensus conference. Blood, 2009. 113(20): p. 4829-33.
Correlation between Treatment Outcomes, Baseline Characteristics and Molecular Responses in the MAJIC Study which compared Ruxolitinib to Best Available Therapy in Essential Thrombocythemia
RELATIONSHIP DISCLOSURES:
C. Harrison: Consultancy, Honoraria, travel, accommodation, expenses, research funding and Speakers Bureau from Novartis; Honoraria and Speakers bureau from Shire; Honoraria and Speakers Bureau from Gilead, Consultancy Honoraria and Speakers Bureau from Baxaltra; Honoraria and Speakers Bureau from Incyte Corporation, A. Mead: Honoraria, Research Funding and Speakers Bureau from Novartis, S. Fox: There are no relationships to disclose, A. Panchal: There are no relationships to disclose, C. Yap: There
are no relationships to disclose, A. Houlton: There are no relationships to disclose, S. Aliman: Institutional funding and grant for international conference from Novartis, J. Ewing: There are no relationships to disclose, M. Wood: There are no relationships to disclose, F. Chen: Advisory Board from Novartis, J. Coppell: Travel, accommodation and conference attendance from Novartis, N. Panoskaltsis: There are no relationships to disclose, S. Knapper: Research funding from ONO Pharmaceuticals; Honoraria, travel and
expenses for international conferences from Novartis , S. Ali: Honoraria, conference sponsorship and advisory board meetings from Novartis, A. Hamblin: Advisory Board from Novartis, R. Scherber: There are no relationships to disclose, H. Geyer: There are no relationships to disclose, A. Scotch: There are no relationships to disclose, A. Dueck: Honoraria from Bayer, N. Cross: Consultancy, honoraria, research funding and speakers bureau from Novartis, R. Mesa: Consultancy from Novartis; Consultancy from Ariad;
Consultancy from Galena: Research funding from Incyte; Research funding from Gilead: Research funding from CTI; Research funding from Promedior; Research funding from Celgene, M. McMullin: Honoratia and speakers bureau from Novartis
RESULTSMolecular response and symptom/QoL improvement• Baseline symptoms & QOL were not associated with JAK2, CALR, nor MPL status
(Table 1).• Within RUX, baseline symptoms & QOL did not predict MR.• There was a higher symptom response rate (2/4 [50%] vs 9/30 [30%]) overall for
patients with MR.
ScaleEstimate
SEMixed Model P
ScaleEstimate
SEMixed Model P
MPN-10 TSS -6.21 4.35 0.16 MDASI Symptom Interference
-0.75 0.88 0.40
MPN-10 Fatigue -2.53 0.83 0.005
MPN-10 Early satiety
-1.90 0.74 0.01 MDASI REM -0.76 0.88 0.39
MPN-10 Abdominal discomfort
-1.90 0.80 0.02 EQ5D Index 0.09 0.06 0.16
MPN-10 Inactivity
-0.92 1.22 0.45 EQ5D Mobility -0.23 0.29 0.42
MPN-10 Concentration problems
-1.40 0.92 0.14 EQ5D Self-care -0.05 0.15 0.73
MPN-10 Night sweats
0.51 1.09 0.64 EQ5D Usual activities
-0.36 0.36 0.32
MPN-10 Itching -0.14 0.75 0.86 EQ5D Pain/discomfort
-0.24 0.31 0.44
MPN-10 Bone pain
0.08 0.67 0.90 EQ5D Anxiety/depression
-0.09 0.31 0.77
MDASI Symptom Severity
-0.64 0.56 0.26 EQ5D Health status 4.27 8.16 0.60
Figure 1. Molecular characterisation of MAJIC study patients at baseline and 12 months
RESULTSPatientsOverall 116 patients were recruited, 110 were eligible for mITT analysis, 58 (52%) & 52 (48%) in RUX & BAT arms respectively, comprising 44 males, 66 females, median age 64.2ys, who were resistant (24.5%), intolerant (51.8%) or both (22.7%) to HC.
OutcomesResponse• The primary end point complete hematological response, (CHR) was achieved in 27
(46.6%) of the patients in the RUX arm vs 23 (44.2%) in the BAT arm (p= 0.81). • Partial response occurred in 26 (44.8%) RUX arm & 27 (51.9%) BAT arm. • A non pre-specified multivariate analysis to assess baseline factors influencing CHR
(modelled for: treatment received, HC resistance or intolerance, white cell count, platelets, Hb & JAK2/ CALR status) did not reveal any statistically significant findings.
Table 1. Correlation between molecular response and symptom/ QoL improvement
n = 6
n = 26
n = 20
n = 17
n = 3
n = 2
CONCLUSIONSWe report primary results from the ET arm of the MAJIC study, the first randomized study of RUX in ET, 110 patients were eligible for the mITT analysis.
•HC resistant/intolerant ET is clinically & molecularly diverse.
•We confirm that these patients are at high risk of thrombosis & transformation as suggested in prior retrospective studies.
•Molecular responses were limited to RUX & for the first time we demonstrate such responses may correlate with symptom improvement but not always with progression
Myelofibrosis
• Our patient develops myelofibrosis and takes ruxolitinib..
• What is the latest data regarding outcomes with this drug versus others?
RESULTS OF THE PERSIST-2 PHASE 3 STUDY OF PACRITINIB (PAC) VERSUS
BEST AVAILABLE THERAPY (BAT), INCLUDING RUXOLITINIB (RUX), IN
PATIENTS WITH MYELOFIBROSIS (MF) AND PLATELET COUNTS ≤100,000/ΜL
John Mascarenhas1, Ronald Hoffman1, Moshe Talpaz2, Aaron T. Gerds3, Brady Stein4, Vikas Gupta5, Anita Szoke6, Mark Drummond7, Alexander Pristupa8, Tanya Granston9,
Robert Daly9, James P. Dean9, Suliman Al-Fayoumi9, Jennifer A. Callahan9, Jack W. Singer9, Jason Gotlib10, Catriona Jamieson11, Claire Harrison12,
Ruben Mesa13, Srdan Verstovsek14
1Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 2University of Michigan, Comprehensive
Cancer Center, Ann Arbor, MI, USA; 3Cleveland Clinic, Cleveland, OH, USA; 4Northwestern University, Feinberg School of
Medicine, Chicago, IL, USA; 5Princess Margaret Cancer Center, University of Toronto, Ontario, Canada; 6Albert Szent-Györgyi
Clinical Center, University of Szeged, Szeged, Hungary; 7Beatson West of Scotland Cancer Centre, Glasgow, UK; 8Ryazan’s
Clinical Hospital, Ryazan, Russia; 9CTI BioPharma Corp., Seattle, WA, USA; 10Stanford University Medical Center, Stanford, CA,
USA; 11University of California-San Diego, La Jolla, CA, USA; 12Guy's and St Thomas' NHS Foundation Trust, London UK; 13Mayo Clinic, Scottsdale, AZ, USA; 14MD Anderson Cancer Center, Houston, TX, USA.
No longer on clinical hold
Results for Phase II Clinical Trial of LCL161,a SMAC Mimetic,in Patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (post-PV MF) or Post-Essential Thrombocytosis Myelofibrosis (post-ET MF)
Naveen Pemmaraju, Bing Z Carter, Hagop Kantarjian, Jorge Cortes, Tapan Kadia, Guillermo Garcia-Manero, Courtney DiNardo, PrithvirajBose, Sherry Pierce, Lingsha Zhou, Zeev Estrov, Carla Tuttle, Karina Salinas, Po Yee Mak, Srdan VerstovsekThe University of Texas MD Anderson Cancer Center, Houston, TX
Phase 2 Study of Sotatercept (ACE-011) in MyeloproliferativeNeoplasm-Associated Myelofibrosis and Anemia
Prithviraj Bose, Naval Daver, Elias J Jabbour, Allison Pike, Kate J Newberry, Lingsha Zhou, Sherry Pierce, Xuemei Wang, Hagop M. Kantarjian, Srdan Verstovsek
Supported by Celgene Corporation
• Sotatercept (ACE-011) a soluble receptor fusion protein (activinreceptor type IIA linked to Fc fragment of human IgG1) that “traps” ligands that bind to ActIIRA, relieving blockade of terminal erythropoiesis
• Preclinically in thalassemia, Diamond-Blackfan anemia, hepcidintransgenic mice; clinically in patients with ß-thalassemia and MDS
Raftopoulos H et al. Support Care Cancer 2016. Ear J et al. Blood 2015. Langdon JM et al. Am J Hematol 2015.Dussiot M et al. Nat Med 2014. Carrancio S et al. Br J Haematol 2014. Komrokji R et al. ASH 2014. Iancu-Rubin C et al. Exp Hematol 2013.
Sotatercept in MF
Results: efficacy• 19 pts Rx: 12 at 0.75, 7 at 1 mg/kg; median # of cycles 5 (1-19)
• 5 of 14 (36%) evaluable pts have responded; all female
• 5 not evaluable: 2 too early (2 doses); 3 off after 1, 2, & 2 doses
• 13 have discontinued (5 had no response, 2 proceeded to SCT,2 had MF progression, 1 transformed to AML, 1 each withdrew consent, had unrelated medical problems and HTN)
Responses by category
Dose 0.75 mg/kg 4 of 10 (40%)
1 mg/kg 1 of 4 (25%)
Transfusiondependence
Dependent (IWG) 3 of 10 (33%)
Not dependent 2 of 4 (50%)
Gender Female 5 of 5 (100%)
Male 0 of 9 (0%)
Sotatercept in MF
61 yo F, PMF, MF2-3, type 2 CALR, TET2, IDH1 mutated, diploidDIPSS int-2, previous therapies ruxolitinib and danazol (>2 yrs)
0.75 mg/kg
Sotatercept in MF
Conclusions and future directions
• Sotatercept well-tolerated and active in patients with anemia of MF
•Accrual to a parallel cohort of patients on a stable dose of ruxolitinib is underway (0.75 mg/kg q3weeks)
Global study planned.
Sotatercept in MF
Back to the clinical case:
• The patient has ruxolitinib, he does well on therapy for 5 years but over the course of 6 months loses his response and a diagnosis of secondary AML is made
P=0.391
0.0
00.2
50.5
00.7
51.0
0
Pro
bability
0 24 48 72 96 120Months
CR
non-CR
Overall Survival after allo-SCT
Risk factors HR 95%CI
Age ≥ 60 1.77 1.26-2.50
Albumin <3.0 g/dl 2.25 1.59-3.19
Del 7q 1.71 1.16-2.53
Complex karyotype 1.55 1.10-2.20
Survival after allo-SCT
Survival outcome of patients with acute myeloid leukemia transformed from myeloproliferative neoplasms
Dai Chihara1, 2, Hagop Kantarjian1, Kate Newberry1, Farhad Ravandi1, Naval Daver1, Prithviraj Bose1, Courtney D. DiNardo1, Naveen
Pemmaraju1,
Tapan Kadia1, Gautam Borthakur1, Marina Konopleva1, Guillermo Garcia-Manero1, Uday R. Popat3, Jorge E. Cortes1, Srdan Verstovsek1
P=0.422
0.0
00.2
50.5
00.7
51.0
0
Pro
bability
0 12 24 36 48 60Months
1989-2007
2007-2011
2011-2016
Overall survival
No significant improvement in survival outcome after LT from 1989 to 2016
Median OS after allo-SCT
15.3 Mo (95%CI: 6.1-29.4 Mo)
Multivariate analysis for OS
Adjusted with treatment and bone marrow
blast at the time of LT
Safety and efficacy of combined Ruxolitinib and Decitabine in patients with blast-phase MPN and
post-MPN AML: Results of a Phase I study (Myeloproliferative Diseases Research Consortium
109 trial)
Rampal R, Mascarenhas J, Kosiorek HE, Berenzon D, Hexner E, Abboud C, Tognoni G, Prosperini G, Di LelioA, Serone E, Marfisi L, Sandy L, Price L, Goldberg JD,
Levine R, Mesa R, Dueck AC, R Hoffman
Response10mg BID 15mg BID 25mg BID 50 mg BID Total
CR - - 1 (17%) 1 (17%) 2 (10%)
CRi 1 (17%) - 1 (17%) 3 (50%) 5 (24%)
PR 2 (33%) 2 (67%) 1 (17%) - 5 (24%)
NR 3 (50%) 1 (33%) 3 (50%) 2 (33%) 9 (43%)
CR/CRi 1 (17%) - 2 (33%) 4 (67%)7 (33%,
95% CI 15-57%)
Overall response rate (CR/CRi/PR)
3 (50%) 2 (67%) 3 (50%) 4 (67%)12 (57%,
95% CI 34-78%)
Survival
OS: 10.4 months (95% CI 3.3 mo - not reached).
10mg 15mg 25mg 50mg Total
Median cycles received(range)
10.5
(1-22)
4.0
(1-6)
2.0
(1-16)
2.5
(1-7)
3.0
(1-22)
And finally….
• A patient presents with pancytopenia, profound weight loss, a chronic urticarial rash, hepatosplenomegaly, there is a history of anaphylactic reactions….
Conclusions: 1• Targeted NGS of interest in prognosis for MF also
PV and ET
• IFN and its use in PV and ET, 2 studies presented.
• IFN is non-inferior, toxicity remains limiting
• HU may deliver histological & molecular responses
• Toxicity of HU differs between the studies.
• MAJIC rux in HU resistant/intolerant ET is equivalent to BAT molecular responses only on rux
Conclusions 2Management of MF JAK inhibition and beyond:
– Pooled data on survival with rux, data on titrated dose and tolerability in older patients
– Data from NS-018 and Pacritinib (now off hold)
– Sotatercept and SMAC mimetic interesting
Blast phase MPN predisposition
– In PV/ET patients high JAK allele burden may predispose to MF & epigenetic mutations to AML
Conclusions 3Blast phase MPN predisposition, outcome and treatment
– Outcomes in blast phase remain poor. In elderly patients azacytidine regime may perform better
– RUX combinations being evaluated.
Mastocytosis
– BLU-285 a CKIT mutant specific drug delivered striking responses for patients with advanced SM with minimal toxicity
MPN trial portfolio in the UK
•ET
•PT-1 low/intermediate risk
•ET and PV
•First line:
•PEGASYS vs HC MPD RC 112
•Refractory/intolerant to HU:
•MAJIC
•Response, Relief, ARD12042 –closed
•TAMARIN adding tamoxifen to HU
•MF
•ERNEST registry
•Momelolinib* vs Ruxolitinib – SIMPLIFY 1
•Second line:
•Momelotinib* vs BAT anaemic on ruxolitinib
•Pfixer Smo* vs BAT
•PERSIST 2 pacritinib* vs BAT plts < 100
•Telomerase inhibitor
•PRM-151
•TAMARIN adding tamoxifen to HU
•Combinations:
•Ruxolitinib+Pbinostat*,+BKM120*,+LDE225*
•Ruxoliitnib + LEE + PIMM
•Ruxolitinib pre BMT* study MPD RC114
All MPN: MEASURES symptom assessment
MOSAICC epidemiology
Sample banks – Nick Cross and Tony Green
MDS/AML after MPN:
Phazar ruxolitinib* + 5 azacytidine
/ data collection only (30 patients)