myelodysplastic syndromes · add: mds(del5q): isolated or with one add chrom abnormality, excl...
TRANSCRIPT
-
Myelodysplastic Syndromes
diagnostics
prognostics
emerging treatment strategies in lower risk disease
Arjan A. van de Loosdrecht Department of Hematology
VU University Medical Center
VU-Institute of Cancer and Immunology (V-ICI)
Cancer Center Amsterdam (CCA)
Amsterdam, The Netherlands
Nederlands Hematologie Congres 2016
Papendal
Vrijdag 22-1-2016
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Steensma DP, et al., Blood 2015;126:9-16; Malcovati L, et al., ASH 2015: pp 299-307 (educational)
Cytopenia + mutation – dysplasia = WHAT?
-
Incidence of MDS in the Netherlands A
SR
/ 1
00,0
00
Year of diagnosis
0,0
1,0
2,0
3,0
0,3 2,0 7,2
20,5
32,1
0,0
10,0
20,0
30,0
40,0
-
Relative survival of MDS in the Netherlands
RSR: relative survival rate
0%
20%
40%
60%
80%
100%
RS
R
Year Of Diagnosis
1-year RSR
3-year RSR
5-year RSR
0%
20%
40%
60%
80%
100%
0 1 2 3 4 5 6 7 8 9 10
RS
R
Time From Diagnosis (years)
2001-2005
2006-2010
A B
0%
20%
40%
60%
80%
100%
RS
R
Year Of Diagnosis
1-year RSR
3-year RSR
5-year RSR
0%
20%
40%
60%
80%
100%
0 1 2 3 4 5 6 7 8 9 10
RS
R
Time From Diagnosis (years)
2001-2005
2006-2010
A B
Relative survival is the observed patient survival corrected for the
expected survival of comparable group from the general population
Dinmohamed AG et al., Eur J Cancer 2014;50:1004-12
-
Diagnostic tool Diagnostic value Priority
Peripheral blood
smear
• Evaluation of dysplasia in one or more cell lines
• Enumeration of blasts Mandatory
Bone marrow
aspirate
• Evaluation of dysplasia in one or more
myeloid cell lines
• Enumeration of blasts
• Enumeration of ring sideroblasts
Mandatory
Bone marrow biopsy • Assessment of cellularity, CD34+ cells, and fibrosis Mandatory
Cytogenetic
analysis
• Detection of acquired clonal chromosomal
abnormalities that can allow a conclusive diagnosis
and also prognostic assessment
Mandatory
FISH
• Detection of targeted chromosomal abnormalities
in interphase nuclei following failure of standard G-
banding
Recommended
Flow cytometry
immunophenotype
• Detection of abnormalities in erythroid,
immature myeloid, maturing granulocytes,
monocytes, immature lymphoid compartments
Recommended*
If according to
ELN guidelines
SNP-array
• Detection of chromosomal defects at a high
resolution in combination with metaphase
cytogenetics
Suggested (likely to
become a
diagnostic tool in
the near future)
Mutation analysis of
candidate genes
• Detection of somatic mutations that can allow
a conclusive diagnosis and also reliable
prognostic evaluation
Suggested (likely
to become a
diagnostic tool in
the near future)
Diagnostic approach to MDS 2016 Dutch/EU guidelines
Malcovati L, et al., ELN guidelines. Blood 2013;122:2943-64; Greenberg P et al., J Nat Compr Netw
Canc 2013;11:838-74; *Westers TM, et al., Leukemia 2012;26:1730-41
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WHO2016:
reclassifying Myelodysplastic Syndromes
MDS with single lineage dysplasia (MDS-SLD)
MDS with multilineage dysplasia (MDS-MLD)
MDS with single lineage dyplasia and RS (MDS-RS-SLD)
MDS with multilineage dysplasia and RS (MDS-RS-MLD)
MDS with excess blasts-1 (MDS-EB1)
MDS with excess blasts-2 (MDS-EB2)
Arber DA and Hasserjian RP. Hematology 2015;294-298; educational session
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WHO2016:
reclassifying MDS: comments
Morphology:
no changes
– dysplasia cut-off levels remains 10% in all lineages
– blast cell counts by cytology [no FCM]
– due to IPSS-R push towards counts of
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WHO2016:
reclassifying MDS: comments
Additional new concepts:
Add: SF3B1 mutation and RS 50% erythroid precursors
Add: Familial myeloid neoplasms with germ line mutations
(TERT, GATA2)
Arber DA and Hasserjian RP. Hematology 2015;294-298; educational session
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WHO-2016 role of FCM: iMDSflow recommendations Discussion slides regarding clinical needs
• Diagnostics:
– Non-conclusive cases by morphology/cytogenetics
– Unilineage versus multilineage dysplasia (vs WHO criteria)
– IDUS/ICUS/CHIP/CCUS
– MDS-U vs RA vs RARS
– CMML and monocytic leukemias
– PB blast count/aberrancies in MDS +/- sF
– Diagnostic scores i.e. Ogata score vs complex score vs ABC score
– Integrated diagnostics
Cremers EMP, et al., Eur J Cancer 2015;54:49-56
Westers TM, et al., Leukemia 2012;26:1730-41; Porwit A, et al., Leukemia 2014:28:1793-98
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Validation of the integrated flowcytometric (iFC)
diagnostic algorithm in a prospective clinical trial (HOVON89)
Diagnostic score
-
Specificity: 95%
Sensitivity: 80%
By FCM dysplasia
in myeloid / erythroid lineage
Cremers EMP et al., 2015 (submitted);
Loosdrecht AA van de, Westers TM. J Nat Compr Cancer Netw 2013;11:892-902;
Westers TM, et al., Leukemia 2012;26:1730-41; Porwit A, et al., Leukemia 2014:28:1793-98
Validation of FCM acc. to integrated Flow Score within
a prospective clinial trial: HOVON 89 (n=174)
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Integrated Flow Score:
inconclusive by cytomorphology/Cytogenetics
Cremers EMP et al., Eur J Cancer 2015;54:49-56
iFS VUmc
sensitivity MDS-CM: 61%
specificity (PaCo): 95%
MDS in follow-up by CM
2.6% (3/114) (based on DysM by CM)
25% (2/8) (reactive/fe-def/drug-induced)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
??
CM? CG-FC+
CM ? CG-FC-/+
CM? CG-FC-
n= 379 total: cytopenia
n = 218 diagnosis MDS/non-MDS)
n = 161 CM/CG inconclusive
7%
t=0 FC-analyse
Ogata score
+ myelomonocytoid
FU 122/161
C
B
A
-
Prognostic
variable
0 0.5 1 1.5 2 3 4
Cytogenetics Very Good Good Int Poor Very Poor
BM Blast % ≤2% >2-10
%
Hemoglobin
g/dl; mmol/l
≥10
≥6.2
8-
-
Revised International Prognostic Scoring System (IPSS-Revised)
for MDS: clinical heterogeneity
Greenberg P, et al., Blood 2012;120:2454-65; Van
Spronsen M.F., et al., Eur J Cancer 2014;50:3198-3205
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very good
n=81
(2.8%)
single:
del(11q)
-Y
OS
60.8 months
HR
0.5 (0.3-0.7)
good
n=1809
(65.7%)
single:
normal
del(5q)
del(12p)
del(20q)
two:
del(5q)
and others
OS
48.6 months
HR
1.0 (0.9-1.1)
intermediate
n=529
(19.2%)
single:
del(7q)
+8
i(17q)
+19
other unrel
clones
two:
w/o
del(5q)/
del(7q)
OS
26 months
HR
1.6 (1.4-1.8)
poor
n=148
(5.4%)
single:
inv(3)/t(3q)/
del(3q)
-7
two:
del(7q)
and others
complex:
3
OS
15.8 months
HR
2.6 (2.1-3.2)
very poor
n=187
(6.8%)
complex:
>3
OS
5.9 months
HR
4.2 (3.4-5.2)
Cytogenetic Score within the IPSS-R
Schanz J, et al., J Clin Oncol. 2012 Mar 10;30(8):820-9. Greenberg PL, et al., Blood 2012:120;2454-2465
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Prognostic classification of rare abnormailties
into the IPSS-R: n = 7245
del(3p)
-13/13q-
very good
-X
-21
good
any balanced translocation
+1/+1q/dup1q intermediate
der(1;7)
-9/9q-/9p-
-18/18q- poor
+21
very poor
Haase D and Schanz J, ASH2015;
presented with permission for Dutch
Educational program 2015-16
-
78
22
74
26
52
48
36
64
83
17
65
35
59
41
42
58
0
20
40
60
80
100
18-5
9 ye
ars
60-6
9 ye
ars
70-7
9 ye
ars
80 yea
rs
18-5
9 ye
ars
60-6
9 ye
ars
70-7
9 ye
ars
80 yea
rs
Age at diagnosis Age at diagnosis
MDS CMML
No cytogenetics performed Cytogenetics performed
% o
f p
atie
nts
78
22
74
26
52
48
36
64
83
17
65
35
59
41
42
58
0
20
40
60
80
100
18-5
9 ye
ars
60-6
9 ye
ars
70-7
9 ye
ars
80 yea
rs
18-5
9 ye
ars
60-6
9 ye
ars
70-7
9 ye
ars
80 yea
rs
Age at diagnosis Age at diagnosis
MDS CMML
No cytogenetics performed Cytogenetics performed
78
22
74
26
52
48
36
64
83
17
65
35
59
41
42
58
0
20
40
60
80
100
18-5
9 ye
ars
60-6
9 ye
ars
70-7
9 ye
ars
80 yea
rs
18-5
9 ye
ars
60-6
9 ye
ars
70-7
9 ye
ars
80 yea
rs
Age at diagnosis Age at diagnosis
MDS CMML
No cytogenetics performed Cytogenetics performed
0% 25% 50% 75% 100%
Very low
Low
Intermediate
High
Very high
Percent of patients
Low Int-1 Int-2 High
IPSS
IPS
S-R
Prognostication of MDS in daily practice Results from the Dutch PHAROS MDS registry
Dinmohamed AG, et al., 2016 (submitted)
Dinmohamed AG et al. Leukemia. 29: 2449-2451 (2015)
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Alhan C, et al., Leukemia 2015; Oct 27. doi: 10.1038/leu.2015.295. [Epub ahead of print]
Haferlach T, et al., Leukemia 2014;28:241-7
Emerging prognostic models in MDS:
FCM and molecular abnormalities
IPSS-R low
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Outcomes After An MDS Diagnosis: kindly provided by DP Steensma (Leuk Lymphoma 2016:57;17-22)
If the ~32,000/yr MDS patients diagnosed in the U.S. were represented as 100 people…
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6 will undergo allogeneic transplant: 2 will be cured, 3 will relapse and die, 1 will die of complications
7 will die of anemia-related complications (CVA, MI etc)
27 will progress to AML and die
26 will die of unrelated causes (e.g., geriatric conditions)
2 die of iron overload 12 will die of hemorrhage
20 will die of infection
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What are the major needs in MDS
• Optimizing geriatric assessment in (EU/ELN MDS-Right
HORIZON2020)
• Optimizing supportive care (infection/bleeding/iron)
• Development of new targeted therapies in mds
– ESA refractory lower risk MDS (HOVON/HOVON-associated
studies)
• Identification of the poor prognostic lower risk patients (HOVON and
(EU/ELN MDS-Right HORIZON2020)
• Understanding mechanisms of resistance to ESA/IMiDs and
epigenetic therapies
• Understanding mechanisms of transformation to AML
• Incorporation of alloTx in MDS
– Minimizing risk of TRM/relapse post alloTx in MDS
MDS-F symposium 2015; ASH2015 educational session; oral and poster ASH2015
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What are the current and emerging new clinical trial
options in low/high risk MDS?
Lower risk
• IMiDs (lenalidomide) (HOVON89)
• IRAK-1 inhibition (Pacritinib) (HOVON)
• Toll-like receptor inhibition (OPN-301)
• Oral Azacitidine (MDS-003) (NL)
• Luspatercept (NL)
• Telomerase Inhibition (Imetelstat) (NL)
Higher risk
• Genomic annotations: IDH1, IDH2, RAS, FLT3
• Anti-PD1/PDL1 combinations +/- HMA (NL)
• Rigosertib (PI3k/PLK1 inhibitor) (under evaluation in NL)
• (oral) second generation hypomethylating agents
• Decitabine +/- ibrutinib (HOVON135)
MDS-F sympoisum 2015; ASH2015 educational session; oral and poster ASH2015
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Therapeutic options for lower IPSS risk MDS:
ELN/Dutch guidelines (update 2016 expected)
Low IPSS risk
Symptomatic anaemia asymptomatic cytopenia
Immunosuppressive therapy with ATG
Watchful-waiting RBC transfusion and ICT
Age < 60 years, BM blasts
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KM plot of the time to first post-ESA transfusion for ESA-treated patients that did not have any
transfusions prior to ESA treatment stratified by whether the patient was defined as a responder or not.
Log-rank test p=0.0011
Time to first post-ESA transfusion: Transfusion Naive
patients; all ESA treated
EU-MDS registry 2015 (submitted; presented with permission)
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HOVON89: Epo refr/TD non-del(5q) low risk MDS:
preliminary conclusions/perspectives
• HOVON89:
– closed august 12, 2015
– Target number of patients n=200 is reached
– No safety/no efficacy issues in interim analysis (n=100/FU 10
month)
– DB closed April 1, 2016:
• ASH2016 1st clinical data to be presented
• Add-on studies:
– Molecular profile follows expected mutations in lower risk MDS
– Validations of FCM: specificity 95%; sensitivity 85%
– Association studies between FCM and Mol. Mutations ongoing
– MDS/Niche studies ongoing
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A phase II, multicentre, randomised, open-label comparative study evaluating the efficacy
of LEN with or without EPO in patients with RBC-TD lower-risk MDS without chromosome
5 abnormalities who are resistant to ESAs (NCT01718379*)/GFM-len-epo-08)
Key eligibility criteria
•Patients with de novo MDS or IPSS low- or int-1-risk MDS
•RBC-TD anaemia
•Resistance or loss of response to a previous treatment with epoetin alpha/beta
(60,000 IU/week) or darbepoetin (>250µg/week), administered for ≥12 weeks
•ECOG performance status ≤2
N=132
Randomisation
Arm A 4 cycles of lenalidomide 10mg p.o.
once daily d1–21/28-day cycle
Arm B 4 cycles of lenalidomide
10mg p.o. once daily on d1–21/28-day
cycle
EPO 60,000 IU/week
Continue treatment until disease
progression
Responders
(IMG 2006 criteria)
Responders
(IMG 2006 criteria)
Toma A, et al., Leukemia 2015; Oct 26 [epub ahead of print]
Primary endpoint: erythroid response rate after 4 courses (IMG 2006 criteria)
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HI-E and RBC-TI in patients who received at least 4 cycles (n= 99)
LEN + EPO
N = 50
LEN
N = 49
HI-E 52% 30.6% RR = 1.7, p= 0.03
RBC-TI 32% 18.4% RR = 1.7, p= 0.12
HI-E and RBC-TI in the ITT population (n=129)
LEN + EPO
N = 65
LEN
N = 64
HI-E 40 % 23.4 % RR1.7; p= 0.043
RBC-TI 24.6 % 14.1 % RR1.7; p= 0.13
Toma A, et al., Leukemia 2015; Oct 26 [epub ahead of print]
A phase II, multicentre, randomised, open-label comparative study evaluating the efficacy
of LEN with or without EPO in patients with RBC-TD lower-risk MDS without chromosome
5 abnormalities who are resistant to ESAs (NCT01718379*)/GFM-len-epo-08)
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MDS-005: phase III trial of LEN vs placebo in patients
with lower-risk RBC-TD MDS without del(5q)
*≥2 units packed RBCs/28 days in the 112 days prior to randomisation; †≥40,000 units/week
rhEPO for 8 weeks, equivalent dose of darbopoetin, or serum EPO >500mU/mL; ‡5mg for
patients with creatinine clearance 40–60mL/min; §≥5 years from randomisation
ESA = erythropoietin-stimulating agent; QD = daily; SPM = second primary malignancy
Santini V, et al. Oral presentation at
ASH 2014. Abstract 409
Phase III, randomised, multicentre, placebo-controlled study assessing the efficacy and safety of LEN
in patients with lower-risk RBC-TD MDS without del(5q) who are unresponsive/refractory to ESAs
Inclusion criteria
•IPSS low-/
int-1-risk
•Non-del(5q)
•RBC-TD*
•Unresponsive/
refractory to
ESAs†
Long-term
follow-up§
•OS
•AML progression
•Subsequent MDS
treatment
•SPMs 2:1
random
isation
Day 1
68 a
ssessm
ent
Discontinue
treatment
Continue treatment
until erythroid relapse
or disease
progression
LEN 10mg
orally QD‡
(n=160)
Placebo
(n=79)
RBC-TI ≥8
weeks or
erythroid
response
No RBC-TI
≥8 weeks or
erythroid
response
• Primary endpoint: RBC-TI ≥8 weeks
• Secondary endpoints: RBC-TI ≥24 weeks, duration of RBC-TI, erythroid response, time to RBC-TI,
AML progression, safety
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MDS-005: phase III trial of LEN vs placebo in patients
with lower-risk RBC-TD non-del(5q) MDS
1. Santini V, et al. Poster presentation at MDSF 2015. Abstract 035
2. Santini V, et al. Oral presentation at ASH 2014. Abstract 409
3. Ebert BL, et al. PLoS Med 2008;5:e35
Rate of RBC-TI ≥8 weeks was significantly higher with LEN vs placebo in patients
with lower-risk MDS non-del(5q), with 90% of patients responding within 4 cycles
• Median duration of RBC-TI ≥8 weeks with LEN, weeks (95% CI): 32.9 (20.7–71.1)
• The Ebert signature (a collection of genes whose expression levels have previously appeared
to correlate with response)3 was not predictive of RBC-TI ≥8 weeks in this population
Time to RBC-TI ≥8 weeks in patients
responding to LEN (n=41)1,2
p
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New studies in 2016 for low/int-1 risk MDS within
HOVON/SAKK/Belgium and NMDSG
• Pacritinib in Epo/Lenalidomide refractory lower risk MDS
• (phase 2 start q2-2016)/HOVON-associated
• Pacritinib upfront in non-del5q lower risk MDS
• (HOVON 1xx; in preparation)
• MDS with RS/SF3B1: ACE536 [Luspatercept](Pharma)
• Imetelstat (telomerase inhibitor)(Pharma)
• Azacitidine oral formulation: MDS-AZA-003
• risk adapted treatment in low-int-1 risk MDS • (HOVON: concept in development)
• CMML (Ceplene/IL-2); pilot NMDSG • (HOVON associated)
-
IRAK family signalling network
Rhyasen GW and Starczynoswski DT. BJC 2015;112:232-237
-
Rhyasen GW and Starczynoswski DT. Br J Cancer 2015;112:232-237;
Rhyasen GW et al., Cancer Cell 2013;24:90-104
IRAK family signalling network in disease
-
HOVON-associated study: IRAK1 inhibitor in HOVON89
relapse/refractory patients
• Small phase-II study (pilot: n=27)
• Start q1/2 2016 [MetC approval awaiting]
• Pacritinib: Epo/Lenalidomide refractory patients/TD:
– HOVON89: off-study patients
• Primary Endpoints: HI/TI
• Secondary Endpoints: Safety/tolerability
– Time-to-HI/TI
-
Aristoteles Giagounidis1, Uwe Platzbecker2, Ulrich Germing3, Katharina Götze4, Philipp Kiewe5, Karin Tina Mayer6, Oliver Ottmann7, Markus Radsak8, Thomas Wolff9,
Detlef Haase10, Monty Hankin11, Dawn Wilson11, Xiaosha Zhang11,
Adberrahmane Laadem12, Matthew L. Sherman11, Kenneth M. Attie11
1Marien Hospital Düsseldorf, 2Universitätsklinikum Carl Gustav Carus, Dresden, 3Universitätsklinikum Düsseldorf, 4Technical University of Munich, 5Onkologischer Schwerpunkt am Oskar-Helene-Heim, Berlin, 6University Hospital
Bonn, 7Universitätsklinikum Frankfurt, Goethe Universitaet, Frankfurt/Main, 8Johannes Gutenberg-Universität,
Mainz, 9OncoResearch Lerchenfeld UG, Hamburg, 10Universitätsmedizin Göttingen, Germany; 11Acceleron
Pharma, Cambridge, MA, 12Celgene Corporation, Summit, NJ, USA
Oral presentation:
Dec 5, 2015
12:15 PM
W331, Level 3
Orange County Convention Center
Giagoundis A, et al. Luspatercept Treatment Leads to Long Term Increases in Hemoglobin and Reductions in Transfusion Burden in Patients with Low or
Intermediate-1 Risk MDS: Preliminary Results from the Phase 2 PACE-MDS Extension Study. Oral presented at: Annual Meeting and Exposition of the
American Society of Hematology 2015; December 5‒8; Orlando, FL. Abstract 92.
Luspatercept Treatment Leads to Long Term
Increases in Hemoglobin and Reductions in
Transfusion Burden in Patients with Low or
Intermediate-1 Risk MDS: Preliminary Results
from the Phase 2 PACE-MDS Extension Study
-
Luspatercept in MDS: Results
• Mean (SE) change in Hb for LTB patients
– 9 of 13 (69%) LTB patients achieved IWG HI-E response for mean Hb increase
Giagoundis A, et al. Luspatercept Treatment Leads to Long Term Increases in Hemoglobin and Reductions in Transfusion Burden in Patients with Low or
Intermediate-1 Risk MDS: Preliminary Results from the Phase 2 PACE-MDS Extension Study. Oral presented at: Annual Meeting and Exposition of the
American Society of Hematology 2015; December 5‒8; Orlando, FL. Abstract 92.
• 13 of 19 (68%) HTB patients achieved IWG HI-E response for transfusions
• 8 of 19 (42%) HTB patients achieved RBC-TI
– 3 of 3 LTB patients with 2U RBC/8 weeks achieved RBC-TI SE, standard error.
-
Luspatercept: Results
• Most patients in the extension study were RS+
• ≥ 50% patients responding to luspatercept had prior ESA
treatment or baseline EPO of ≤ 500 U/L
Giagoundis A, et al. Luspatercept Treatment Leads to Long Term Increases in Hemoglobin and Reductions in Transfusion Burden in Patients with Low or
Intermediate-1 Risk MDS: Preliminary Results from the Phase 2 PACE-MDS Extension Study. Oral presented at: Annual Meeting and Exposition of the
American Society of Hematology 2015; December 5‒8; Orlando, FL. Abstract 92.
Baseline feature, n (%) IWG HI-E
N = 32
RBC-TI ≥ 8 Weeksa
N = 22
All Patients 22 of 32 (69) 11 of 22 (50)
RS positive 21 of 29 (72) 10 of 19 (53)
Baseline EPO
< 200 U/L 16 of 20 (80) 7 of 13 (54)
200–500 U/L 5 of 7 (70) 2 of 4 (50)
> 500 U/L 1 of 5 (20) 2 of 5 (40)
Prior ESA Treatment
Yes 12 of 19 (63) 7 of 14 (50)
No 10 of 13 (77) 4 of 8 (50)
EPO, erythropoetin; ESA, erythropoetin stimulating agent; RS, ring sideroblast.
a Includes 19 HTB patients and 3 LTB patients evaluable for RBC-TI (≥ 2 units over 8 weeks).
-
CONFIDENTIAL 37
Rationale for Targeting Telomerase in MDS
• MDS patients have higher telomerase activity (TA), higher expression level of
hTERT (Telomerase reverse transcriptase) and shorter telomere length (TL)
compared to age-match normal control
• Higher TA & hTERT, shorter TL correlated to IPSS risk score in MDS
• Shortened telomeres in MDS have been associated with the disease progression
and conversion to AML
• High TA & short TL represent poor prognostic features in lower risk MDS
• MDS pts with high TA have shorter survival
• Inhibition of TA should hasten apoptosis of malignant clone
• Preliminary clinical results of imetelstat in int-1 risk MDS showed clinical benefit
(transfusion independence)
-
A Phase 2/3 Study to Evaluate the Activity of Imetelstat in TD Low
or Intermediate-1 Risk MDS who have Failed ESA Treatment
MDS
Transfusion
Dependent
Failed
ESA
• IPSS Risk: • Low
• Intermediate-1
• RBC 4 units/8w (12w pre-study)
• Pretransfusion Hb ≤9.0 g/dL
• Epo 40K qw* x8w without Hb inc ≥1.5 g/dL or RBC dec ≥4 units/8w
• Relapsed following response
• Poor candidate: sEPO>500mU/mL
38
*or equivalent agent/dose CONFIDENTIAL
-
Imetelstat (n~115) R
A
N
D
O
M
I
Z
E
2:1
Best Supportive Care (n~55)
RBC transfusions,
hematopoietic growth factors
Stratification factors:
• IPSS risk (low / intermediate-1)
• Prior lenalidomide (yes / no)
39
Imetelstat
7.5 mg/kg IV q4w x2 cycles,
escalate to 9.4 mg/kg IV q4w
based on tolerability
Study Design: Phase 2/3, Open Label, N~200
Phase 2, run-in single arm n up to 30
Phase 3 randomized 2:1, controlled
n~170
CONFIDENTIAL
-
Conclusions: MDS in 2016
• WHO2016 is coming soon
– SF3B1 is incorporated in defining MDS-RS if RS