Myelodysplastic Syndromes: Tailoring Treatment to Optimize Patient Outcomes

1
Myelodysplastic Syndromes Tailoring Treatment to
Optimize Patient Outcomes
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2
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3
Faculty

• David P. Steensma, MD, FACPAssociate Professor
  of MedicineHarvard Medical SchoolAdult Leukemia
  ProgramDana-Farber Cancer InstituteBoston,
  Massachusetts
• Disclosure
• David P. Steensma, MD, FACP, has no significant
  financial relationships to disclose.

4
Topics/Outline

• Initial Evaluation, Diagnosis, and Classification
  of MDS
• MDS Classification and Prognosis
• MDS Therapy Supportive Care
• MDS Therapy Hypomethylating Agents
• MDS Therapy Lenalidomide
• Conclusions

5
Initial Evaluation, Diagnosis, and Classification
of MDS
6
Whole Genome Sequencing in MDS
Bone marrow sample
Comparison of single-nucleotide variants
between tumor cells and germline control
Skin biopsy
Sequencing to at least 30 x haploid coverage
Single-Nucleotide Variant Hierarchy
Tier 1 Changes in coding regions of annotated
genes, consensus splice-sites, or RNA genes
(including miRNAs) Tier 2 Changes in conserved
regions of the genome (regulatory potential)
Tier 3 Changes in nonrepetitive regions of the
genome Tier 4 Changes in the remainder of the
genome
7
The Cardinal Features of MDS
Patients
Previous chemotherapy (alkylators, topoisomerase
II inhibitors)
Previous radiation exposure
Median age 70-75 yrs
Disease features
1/2 of patients have abnormal chromosomes,
usually numeric anomalies
gt 95 of patients have cytopenias, most commonly
anemia
Bone marrow usually hypercellular, cells look
abnormal (dysplastic), blasts may be increased
Infection, bleeding,complications of anemia (50)
Preleukemia
Clinicalcourse
Death from other causes (25)
AML (25)
8
Recurrent Gene Mutations or Rearrangements in MDS
Cytogenetic Abnormality Estimated Frequency in MDS, Gene(s) Involved
Unbalanced
-5 or del(5q) 10 40 in t-MDS Candidates include RPS14, EGR1, miR-145, miR-146a SPARC, CDC25C, and others
-7 or del(7q) 10 50 in t-MDS Unknown
i(17q) or t(17p) 3-5 TP53
-13 or del(13q) 3 Unknown
del(11q) 3 Unknown possibly MLL or CBL in some cases
del(12p) or t(12p) ETV6 (in some cases)
Balanced
t(1116)(q23p13.3) 3 in t-MDS MLL, CREBBP
t(321)(q26.2q22.1) 2 in t-MDS MDS1-EVI1, RUNX1
t(69)(p23q34) lt 1 DEK-NUP214
t(211)(p21q23) lt 1 miR-125b-1
Inv(3)(q21q26.2) lt 1 MDS1-EVI1, RPN1
t(13)(p35.3q21.2) lt 1 PRDM16, MDS1-EVI1
Davids MS, et al. Cancer Biol Ther.
201010309-319.
9
TET2 Mutations in MDS OS and Leukemia-Free
Survival
OS
Leukemia-Free Survival
1.0
1.0
Mutated (n 21)
0.9
0.9
Mutated (n 21)
0.8
0.8
0.7
0.7
0.6
0.6
Wild type (n 67)
Proportion Remaining Alive
Proportion Without Leukemia
P .005
0.5
0.5
0.4
0.4
P .035
Wild type (n 67)
0.3
0.3
0.2
0.2
0.1
0.1
0
0
0
6
12
18
24
30
36
42
48
54
60
0
6
12
18
24
30
36
Mos Since Diagnosis
Mos Since Diagnosis
Patients at Risk, n Mos Since Diagnosis Mos Since Diagnosis Mos Since Diagnosis Mos Since Diagnosis
Patients at Risk, n 0 12 24 36
Mutated 21 15 12 11
Wild type 67 30 14 7
Patients at Risk, n Mos Since Diagnosis Mos Since Diagnosis Mos Since Diagnosis Mos Since Diagnosis Mos Since Diagnosis Mos Since Diagnosis
Patients at Risk, n 0 12 24 36 48 60
Mutated 21 16 12 11 8 3
Wild type 67 38 14 8 4 2
Kosmider O, et al. Blood. 20091143285-3291.
10
EZH2 Mutations in MDS OS and PFS
OS
PFS
OS
Unmutated MDS/MPN (n 115)Mutated MDS/MPN (n
19)
Unmutated MDS/MPN (n 115)Mutated MDS/MPN (n
19)
Mutation negative (n 182)Heterozygous mutation
(n 22)Homozygous mutation (n 10)
100
100
100
75
75
75
50
Patients Without Progression ()
50
50
Patients Remaining Alive ()
P .089(het vs hom)
Patients Remaining Alive ()
P .0006
P .044
25
25
25
0
0
0
0
24
48
72
96
120
0
24
48
72
96
120
0
24
48
72
96
120
Mos After Diagnosis
Mos After Diagnosis
Mos After Diagnosis
Ernst T, et al. Nat Genet. 201042722-726.
11
IDH1 Mutations in MDS OS and PFS
OS
PFS
100
100
IDH1 wild type (n 146)
IDH1 wild type (n 146)
IDH1 mutated (n 7)
75
75
IDH1 mutated (n 7)
Patients Remaining Alive ()
50
Patients Without Event ()
50
25
25
P .002
P .02
0
0
0
2
6
8
10
12
4
0
2
6
8
10
12
4
Yrs
Yrs
Thol F, et al. Haematologica. 2010951668-1674.
12
MDS Classification and Prognosis
13
The Evolving Classification of MDS
Refractory anemia (1938)
1976 French-American-British (FAB) Cooperative
Group Leukemia Classification
1982 French-American-British (FAB) MDS
Classification
Preleukemic anemia (1949/1953)
2 dysmyelopoietic categories RAEB, CMML
5 MDS categories Added RA, RARS, RAEB-t
Idiopathic acquired sideroblastic anemia (1956)
Preleukemia
2008 4th World Health Organization
(WHO) Classification of Tumours of Haematopoietic
and Lymphoid Tissues
1999 (draft)/2001 (final) 3rd World Health
Organization (WHO) Classification of Tumours of
Haematopoietic and Lymphoid Tissues
8 MDS categories Added RCMD, RCMD-RS, 5q-,
MDS-U Divided RAEB -gt RAEB-1 and RAEB-2 Moved
CMML Eliminated RAEB-t
9 MDS categories Added RN, RT (with RA, comprise
RCUD) Merged RCMD RCMD-RS -gt RCMD Refined
MDS-U
14
MDS Classification Systems
FAB WHO 2000 WHO 2008 Dysplasia Blast Percent (BM/PB)
Refractory anemia Refractory anemia MDS unclassified RCMD del(5q) RCUD Refractory anemia Refractory neutropenia Refractory thrombocytopenia RCMD Isolated del(5q) MDS unclassified Erythroid Nonerythroid Nonerythroid Erythroid with other Erythroid with megakaryocytic Unilineage with pancytopenia or RCMD/RCUD with 1 PB blasts All less than 5/1 or less
RARS RARS RCMD-RS RARS RCMD-RS Erythroid only Erythroid plus other (all gt 15 ringed sideroblasts) Less than 5/less than 1
RAEB RAEB-1 RAEB-2 RAEB-1 RAEB-2 1 or more lineage 1 or more lineage 5-9/2-4 10-19/5-19 with or without Auer rods
RAEB in transformation Acute myeloid leukemia Acute myeloid leukemia Myeloid with or without other 20 or more/--
CMML MDS/MPD CMML JMML Atypical CML MDS/MPD unclassified MDS/myeloproliferative neoplasm CMML JMML BCR/ABL-negative CML MDS/MPD unclassified Variable greater than 1 x 109/L monocytosis All less than 20/--
Komrokji RS, et al. Hematol Oncol Clin North
Amer. 201024443-457.
15
WHO MDS Categories (2008)
Name Abbreviation Key Feature Patients,
Refractory cytopenia, with unlineage, dysplasia RA Anemia and erythroid dysplasia 10
Refractory cytopenia, with unlineage, dysplasia RN Neutropenia and granulocytic dysplasia lt 1
Refractory cytopenia, with unlineage, dysplasia RT Thrombocytopenia and megak. dysplasia lt 1
Refractory anemia with ring sideroblasts RARS 15 ring sideroblasts 5
5q- syndrome del(5q) Isolated 5q31 deletion, anemia, hypolobated megakaryocytes 5
Refractory cytopenia with multilineage dysplasia RCMD Multilineage dysplasia with gt 1 cytopenia With or without ring sideroblasts 20
Refractory anemia with excess blasts, type 1 RAEB-1 5 to 9 blasts 20
Refractory anemia with excess blasts, type 2 RAEB-2 10 to 19 blasts Auer rods 20
Unclassifiable MDS-U Does not fit other categories 10
Childhood MDS RCC Often hypocellular pancytopenia Rare
WHO classification of tumours of haematopoietic
and lymphoid tissues, 4th edition. 2008.
16
1997 IPSS Version 1.0
Score Score Score Score Score
Prognostic variable 0 0.5 1.0 1.5 2.0
Marrow blasts, lt 5 5-10 -- 11-20 21-30
Karyotype class Good Intermediate Poor -- --
Cytopenias, n 0 or 1 2 or 3 -- -- --
Karyotypes good normal, -Y, del(5q) alone,
del(20q) alone poor chromosome 7 abnormalities
or complex intermediate other
karyotypes. Cytopenias Hb lt 10 g/dL, ANC lt
1800/uL, platelets lt 100,000/uL. 20 or more
blasts now considered AML but was still MDS at
the time this system was developed.
Greenberg P, et al. Blood. 1997892079-2089
correction 1998911100.
17
Limitations of the 1997 IPSS

• Not validated in numerous patient subsets
• Secondary MDS
• CMML with WBC gt 12 x 109/L
• Previously treated patients
• Children
• Limited number of karyotypes
• Only 3 categories
• Many common karyotypes omitted
• Does not account for molecular heterogeneity
• Problems with blast counting
• Uses obsolete 30 blast cutoff
• Overemphasizes blasts vs karyotype

• Omits validated prognostically relevant
  information
• LDH
• Mutations (eg, TP53, TET2)
• Performance score
• Marrow fibrosis, ALIP
• Absolute lymphocyte count

18
M. D. Anderson Cancer Center Risk Model Accounts
for Events Not in the IPSS
Prognostic Factor Points (0-17)
Performance score 2 2
Age, yrs
60-64 1
65 2
Platelets x 109/L
lt 30 3
30-49 2
50-199 1
Hemoglobin lt 12 g/dL 2
Bone marrow blasts,
5-10 1
11-29 2
White blood count 20 x 109/L 2
Karyotype chromosome 7 abnormality or complex ( 3 abnormalities) 3
Previous transfusion 1
Kantarjian H, et al. Cancer. 2008113135-1361.
19
M. D. Anderson Cancer Center Risk Model Survival
by Prognostic Scores
Score Patients, n () Survival Survival Survival
Score Patients, n () Median, Mos At 3 Yrs, At 6 Yrs,
Low
0-4 157 (16) 54 63 38
Intermediate-1 Intermediate-1
5 111 (12) 30 40 14
6 116 (12) 23 29 14
Intermediate-2 Intermediate-2
7 127 (13) 14 19 8
8 106 (11) 13 13 4
High
9 97 (10) 10 10 2
10 244 (25) 5 2 0
Kantarjian H, et al. Cancer. 2008113135-1361.
20
M. D. Anderson Cancer Center MDS Risk Model OS
1.0
Median Survival, MosLow 54
Intermediate-1 25 Intermediate-2 14 High
6
0.8
0.6
Proportion Surviving
0.4
0.2
0
0
24
48
72
96
Mos From Referral
Also validated in secondary MDS, CMML, and
postdiagnosis/treatment.
Kantarjian H, et al. Cancer. 2008113135-1361.
21
MDACC MDS Risk Model Applied to 1503 Mayo Clinic
Patients
1.0
LowIntermediate-1Intermediate-2High
0.9
0.8
0.7
0.6
Surviving
0.5
0.4
0.3
0.2
0.1
0
20
40
60
80
100
120
140
160
180
Mos to Death
Patients seen between 1995 and 2007 complete
follow-up to death in 74.
Hugo S, et al. ASH 2009. Abstract 3814.
22
2012 Revised IPSS

• IPSS revisions intended to incorporate larger
  cytogenetic subgroups, fine-tune their prognostic
  effect, analyze depth of cytopenias, and provide
  better prognostic ability
• Analysis based on 2902 patients with primary MDS
  or oligoblastic AML after MDS
• New IPSS-R cytogenetic prognostic subgroups

Prognostic Subgroup Cytogenetic Abnormality Median OS, Mos Median Time to AML, Mos
Very good del(11del(11q), -Yq), -Y 60.8 NR
Good Normal, del(20q), del(5q) alone or double, del(12p) 48.6 NR
Intermediate 8, del(7q), i(17q), 19, any other single or double, independent clones 26.0 78.0
Poor inv(3)/t(3q)/del(eq), -7, double including del(7q), complex (3) 15.8 21.0
Very poor complex ( 3) 5.9 8.2
Schanz J, et al. J Clin Oncol. 201230820-829.
23
IPSS-R Effect of Cytogenetics on OS and
Transformation to AML
OS (n 1893)
Transformation to AML (n 1691)
Better
Worse
Lower
Higher
Normal
Normal
1.00 (reference)
1.00 (reference)
del(11q)
0.43
del(11q)
0.40
0.46
-Y
-Y
0.46
del(12p)
2.47
del(12p)
0.56
1.39
del(20q)
0.62
del(20q)
2.70
19
19
0.80
0.96
0.91
del(5q)
del(5q)
i(17q)
1.69
i(17q)
1.14
1.56
1.17
Double 5
Double 5
1.19
1.21
del(7q)
del(7q)
7.83
1.23
der(3)
der(3)
1.45
1.95
Any 1
Any 1
1.50
Ind. clones
3.33
Ind. clones
2.95
1.75
8
8
2.01
1.75
Double
Double
1.86
1.83
-7
-7
3.03
2.77
Double 7
Double 7
4.94
3.61
Complex 3
Complex 3
5.11
4.14
Complex gt 3
Complex gt 3
0.01
1
10
0.1
1
10
0.1
HR (95 CI)
HR (95 CI)
Schanz J, et al. J Clin Oncol. 201230820-829.
24
IPSS-R OS and Transformation to AML by Risk Group
OS
Transformation to AML
Very good (n 81 events 34) Good (n 1809
events 890) Intermediate (n 529 events
312) Poor (n 148 events 109) Very poor (n
187 events 158) Log-rank P lt .001
Very good (n 72 events 6) Good (n 1611
events 284) Intermediate (n 457 events
145) Poor (n 129 events 56) Very poor (n
167 events 47) Log-rank P lt .001
1.0
1.0
0.8
0.8
0.6
0.6
Fraction Survival
Fraction AML-Free Survival
0.4
0.4
0.2
0.2
0
0
350
50
100
150
200
250
300
350
50
100
150
200
250
300
0
0
Mos
Mos
Schanz J, et al. J Clin Oncol. 201230820-829.
25
MDS Therapy Supportive Care (Hematopoietic
Growth Factors, Iron Chelation)
26
Has Supportive Care for MDS Improved Over Time?
Unfortunately, Not . . .
1.0
Yr of Diagnosis
1970-19751975-1980 1980-1985 1985-1990 1990-1995
1995-2000 2000-2005
0.8
Dusseldorf registry survival data (N 3058
2449 received BSC only)
0.6
Cumulative Survival
0.4
0.2
P .5742
0
0
100
200
300
400
Survival in Mos
Nachtkamp K, et al. Leuk Res. 2009331024-1028.
27
Erythropoiesis-Stimulating Agents in MDS

• ESAs remain the standard of care and are commonly
  prescribed, although not FDA approved, for MDS
• NCCN guidelines ESAs remain frontline treatment
  for anemia in IPSS low/intermediate-1 MDS1
• 2008 survey (N 359) 55 of patients had used
  ESAs2
• Medicare survey 45 of patients had used growth
  factors3
• FDA clarified in 2010 that ESA APPRISE REMS does
  not apply to MDS4

1. NCCN. Clinical practice guidelines in
oncology MDS. v.1.2012. 2. Steensma DP, et al.
Leuk Res. 200832691-698. 3. Goldberg SL, et al.
ASH 2008. Abstract 636. 4. ASH Newsroom.
Available at http//www.hematology.org/News/2010/
5024.aspx.
28
Treatment in US Patients With MDS Analysis of 6
Surveys (N 4514)
ESA (Darbepoetin and/or Erythropoietin)
58
55 to 63
Azacitidine
16
11 to 15
G-CSF, GM-CSF, or Peg-filgrastim
10
8 to 11
Lenalidomide
8
1 to 9
Decitabine
2
Recently diagnosed patients (proportion)Establish
ed patients (range across 6 surveys)
0 to 4
1
Thalidomide
2 to 5
70
0
10
30
40
50
60
20
Patients ()
Surveys conducted between June 2005 and January
2007.
Sekeres M, et al. J Natl Cancer Inst.
20081001542-1551.
29
Meta-analysis ESAs and Mortality in Patients
With Cancer

• N 13,933 patients in 53 trials individual
  patient data systematic review
• ESAs increased mortality during active study
  period (cHR 1.17 95 CI 1.06-1.30)
• ESAs worsened overall survival (cHR 1.06 95
  CI 1.00-1.12)
• In 10,441 patients on 38 chemotherapy trials,
  trend seen toward worse survival with ESAs for
  mortality during active study period (cHR 1.10
  95 CI 0.98-1.24)

Bohlius J, et al. Lancet. 20093731532-1542.
30
Addition of EPO to G-CSF Improved OS, But No
Effect on AML Transformation
OS
EPO-G treatedUntreated
1.0
0.8
HR 0.61(95 CI 0.44-0.83P .002)
0.6
Probability of OS

• Analysis of 3 phase II Nordic group trials of
  patients who received EPO (N 121)
• Control group who received no EPO (N 237)
• ESA exposure 39 erythroid RR
• HR for death 0.61 (P .002)

0.4
0.2
0
2
4
6
8
10
12
14
16
Yrs
1.0
Free of AML
EPO-G treatedUntreated
0.8
0.6
Probability of Freedom of AML
HR 0.89(95 CI 0.52-1.52P .66)
0.4
0.2
0
2
4
6
8
10
12
14
16
Yrs
Jädersten M, et al J Clin Oncol.
2008263607-3613.
31
EPO G-CSF Improves OS in MDS Comparison of GFM
and IMRAW Cohorts
OS by Cohort
OS by Matched Pair Analysis
100
100
80
80
60
OS ()
40
GFMIMRAW
60
20
OS ()
40
0
GFMIMRAW
0
1
6
8
9
10
2
3
4
5
7
Yrs Since Diagnosis or rEPO Treatment
20
OS by Response to EPO
100
0
80
0
1
2
3
4
5
60
Yrs Since Diagnosis or rEPO Treatment
OS ()
40
EPO responseEPO no responseIMRAW

• Major erythroid response in GFM 40
• HR for death 0.43 (P lt .001)

20
P lt .001
0
0
1
6
8
9
10
2
3
4
5
7
Yrs Since Diagnosis or rEPO Treatment
Park S, et al. Blood. 2008111574-582.
32
E1996 Phase III Trial of EPO G-CSF No
Difference in OS
OS by Treatment
1.0
0.9
Supportive care EPO 150 µ/kg/day
0.8
0.7
0.6
Probability
0.5
0.4
0.3
0.2
Log-rank P .28
0.1
0
120
0
10
20
30
40
50
60
70
80
90
100
110
Mo
Treatment, nSupportive care EPO 150 µ/kg/day
Total5753
Fail4838
CNSR915
Median3137
Crossover at Month 4 meant survival difference
would have to be very large to be observed
Greenberg PL, et al. Blood. 20091142393-2400.
33
E1996 Phase III Trial of EPO G-CSF Time to
Leukemic Transformation
1.0
0.9
0.8
0.7
Supportive care EPO 150 µ/kg/day
0.6
Probability of Leukemic Transformation
0.5
0.4
0.3
0.2
Log-rank P 0.83
0.1
0
120
0
10
20
30
40
50
60
70
80
90
100
110
Mo
Total5753
Fail64
CNSR5149
Median NR NR
Treatment, nSupportive care EPO 150 µ/kg/day
Only 10 events
Greenberg PL, et al. Blood. 20091142393-2400.
34
EPO-ANE-3018 Phase III Study of 2 Epoetin Alfa
Levels vs Placebo

• Study closed early in 2009 due to low accrual (lt
  30 patients accrued)

Wk 48
Epoetin alfa 40,000 IU SC weekly
Patients with IPSS low or intermediate-1 MDS, Hb
lt 10 g/dL, not transfusion dependent (Planned N
450)
Epoetin alfa 80,000 IU SC weekly
4.5 yrs of follow-up
Placebo SC weekly
Clinicaltrials.gov. NCT00695396.
35
The Risk of Transfusion Dependence in MDS
Transfusion independent
100
90
Transfusion dependent

• Cumulative probability of survival among 374 MDS
  patients in Pavia, Italy, 1992-2002
• Transfusion HR for death 1.58 (P .005)

80
70
60
50
Patients Surviving ()
40
30
20
10
0
140
20
40
60
80
100
120
Mos From Diagnosis
Cazzola M, et al. N Engl J Med. 2005352536-538.
36
Phase III EPIC Trial Deferasirox Chelation With
Guided Dose Titration

• Open-label prospective trial (N 1744) initial
  dose of deferasirox based on iron intake from
  blood transfusions, then subsequent doses
  titrated according to serum ferritin trends and
  safety markers
• Indications thalassemia (n 1115), MDS (n
  341), aplastic anemia (n 116), sickle cell
  disease (n 80), and other anemias (n 92)
• Treatment
• lt 2-4 pRBC units/mo 10 mg/day
• 2-4 pRBC units/mo 20 mg/kg/day
• gt 2-4 pRBC units/mo 30 mg/kg/day
• Primary endpoint change in serum ferritin from
  baseline after 52 wks

Cappellini MD, et al. Haematologica.
201095557-566.
37
EPIC Trial Mean Deferasirox Dose and Median
Change in Serum Ferritin

• Deferasirox titration effective at reducing
  ferritin in iron-overloaded, regularly transfused
  patients

Serum ferritinDeferasirox dose
1000
45
1000
45
All patients
lt 20 mg/kg/day
40
40
500
500
30
30
0
0
30
30
-500
-500
25
25
20
20
-1000
-1000
15
15
-1500
-1500
10
10
Mean transfusional iron intake0.41 mg/kg/day
Mean transfusional iron intake0.36 mg/kg/day
-2000
-2000
5
5
-2500
0
-2500
0
01744
31571
61511
91439
121387
0604
3504
6459
9426
12401
Median Change From Baseline in Serum Ferritin
(ng/mL)
n
Mean Deferasirox Dose (mg/kg/day)
n
Mean Deferasirox Dose (mg/kg/day)
Median Change From Baseline in Serum Ferritin
(ng/mL)
1000
45
1000
45
20 - lt 30 mg/kg/day
30 mg/kg/day
40
40
500
500
30
30
0
0
30
30
-500
-500
25
25
20
20
-1000
-1000
15
15
-1500
-1500
10
10
Mean transfusional iron intake0.44 mg/kg/day
Mean transfusional iron intake0.37 mg/kg/day
-2000
-2000
5
5
-2500
0
-2500
0
0981
3920
6908
9875
12847
0150
3147
6144
9138
12139
n
n
Mos
Mos
Cappellini MD, et al. Haematologica.
201095557-566.
38
US03 Phase II Trial Deferasirox in Lower-Risk
Transfusion-Dependent MDS

• N 173 patients with IPSS low to intermediate-1
  risk, serum ferritin 1000 µg/L, and 20 units
  RBC with ongoing need for transfusions
• Treatment deferasirox 20 mg/kg/day with dose
  escalation to 40 mg/kg

Serum Ferritin Levels
Labile Plasma Iron Levels
3500
1.2
P .6063
3000
1.0
P lt .001
P lt .001
2500
0.8
2000
Median Serum Ferritin (µg/L)
Threshold of normal LPI(lt 0.5 µmol/L)
0.6
Mean LPI (µmol/L)
1500
1000
0.4
500
0.2
0
0
Baseline
13
37
53
Wks
Baseline
13
25
49
37
Pts at Risk, nMedian change from baseline (µg/L)
Wks
Pts at Risk, n
95
94-48
90-574
91-561
68
47
47
37
43
List AF, et al. J Clin Oncol. 2012302134-2139.
39
TELESTO MDS Event-Free Survival With Iron
Chelation Therapy for Up to 5 Yrs
Deferasirox (n 420) 10 mg/kg/day (1st 2 wks) 20
mg/kg/day (Wks 2-12) Up to 40 mg/kg/day (after 12
wks)
Screening 1 mo
Patients with low or int-1 risk MDS, serum
ferritin gt 1000 µg/L and lt 3500 µg/L (Planned N
630)
4 yrs
1 yr
2 yrs
3 yrs
5 yrs
Placebo (n 210) 10 mg/kg/day (1st 2 wks) 20
mg/kg/day (Wks 2-12) Up to 40 mg/kg/day (after 12
wks)
IA
IA
Expected end of study
54 chance to stop the trial depending on interim
analysis results
Randomization (21 Deferasirox/Placebo)
Interim analysis at 50 of primary composite
events ( 3 yrs) at 75 of primary
composite events ( 4 yrs)
ClinicalTrials.gov. NCT00940602.
40
Other Iron Chelation Agents Deferiprone and
Deferoxamine

• Deferiprone
• Available in Canada and Europe not approved in
  US
• Study of dosing strategies in 292 patients with
  MDS and other transfusion-dependent diseases1
• Mean change in serum ferritin over study period
  increased by 2200 µg/L for intermittent and
  concurrent dosing, decreased by 1100 µg/L with
  daily dosing
• Deferoxamine
• Study of weight-based dosing 5 MDS, 1
  ß-thalassemia2
• Mean serum ferritin 2.086 µg/L at baseline vs
  879 µg/L at end of study

1. Takatoku M, et al. Eur J Haematol.
200778487-494. 2. Cermak J. Hemoglobin.
200630105-112.
41
Romiplostim Efficacy, Safety in Patients With
Low and Intermediate-1 MDS
Event or Response Patients Receiving Azacitidine1 Patients Receiving Azacitidine1 Patients Receiving Lenalidomide2 Patients Receiving Lenalidomide2 Patients Receiving Lenalidomide2 Patients Receiving Lenalidomide2 No Previous Treatment3
Event or Response Romiplostim 750 µg (n 14) Placebo (n 13) Romiplostim 500 µg (n 14) Romiplostim 750 µg (n 13) Romiplostim 750 µg (n 13) Placebo (n 12) Romiplostim (n 44)
Clinically significant thrombocytopenic events, n () 10 (71) 11 (85) 4 (29) 7 (54) 7 (54) 8 (67) Not reported
Incidence of bleeding events, n () 7 (50) 7 (54) Not reported Not reported Not reported Not reported 23 (52)
Incidence of platelet transfusions, n () 5 (36) 9 (69) 1 (7) 4 (31) 3 (25) 3 (25) 30 (68)
Platelet response Higher platelet nadir Fewer LEN dose reductions Fewer LEN dose reductions 41 (93)
1. Kantarjian HM, et al. Blood.
20101163163-3170. 2. Lyons et al. ASH 2009.
Abstract 1770. 3. Kantarjian HM, et al. J Clin
Oncol. 201028437-444.
42
MDS Therapy Hypomethylating Agents(Demethylatin
g Agents, Epigenetic Drugs, DNMT1 Inhibitors)
43
Standard of Care for Higher-Risk MDS Current
NCCN Guidelines (v.1.2012)

• Allogeneic HSCT, preferably from a HLA-matched
  sibling, or
• Azacitidine 75 mg/m2/day SC x 7 consecutive days
  every 4 wks
• Improves survival compared with conventional
  (mostly supportive) care, based on AZA-001 data
• Alternatives
• Decitabine 20 mg/m2/day IV x 5 consecutive days
  every 4 wks
• Azacitidine IV, or using weekend-sparing
  schedules
• Decitabine 15 mg/m2/dose IV, given every 8 hrs x
  9 doses (total dose/cycle 135 mg/m2)

NCCN. Clinical Practice Guidelines in Oncology
MDS. v.1.2012.
44
AZA-001 Trial Azacitidine SignificantlyImproves
OS
HR 0.58 (95 CI 0.43-0.77 log-rank P .0001)
1.0
0.9
0.8
0.7
0.6
0.5
Proportion Surviving
24.5 mos
0.4
15.0 mos
0.3
Azacitidine
0.2
CCR
0.1
0
0
5
10
15
20
25
30
35
40
Mos From Randomization
Fenaux P, et al. Lancet Oncol. 200910223-232.
45
. . . Were 4.4 of the Way There!

• Life Expectancy in MDS

40
Higher-risk MDS treated with supportive care
35
Higher-risk MDS treated with azacitidine
30
25
IPSS low-risk MDS
Remaining Life Expectancy (Yrs)
20
Healthy man
15
Healthy woman
10
5
0
45 Yrs of Age
65 Yrs of Age
Fenaux P, et al. Lancet Oncol. 200910223-232.
Greenberg P, et al. Blood. 1997892079-2089US
Department of Health and Human Services data.
46
Phase III EORTC 06011 LD Decitabine vs BSC in
Elderly, Int- or High-Risk MDS
Stratified by IPSS score, primary vs secondary
disease, cytogenetic risk, study center
Stop at 2 cycles beyond CR or max of 8 cycles
Decitabine 15 mg/m2 IV over 4 hrs q8h x 9 q6w (n
119)
Patients with intermediate- or high-risk MDS or
CMML, 60 yrs of age or older, 11 to 20 blasts
or lt 11 with poor cytogenetics or 21 to 30
with stable disease for 1 mo (N 233)
Best Supportive Care (n 114)

• Primary endpoint OS

Lübbert M, et al. J Clin Oncol. 2011291987-1996.
47
Phase III Study of LD Decitabine vs BSC in
Elderly, Int- or High-Risk MDS Results

• No difference in median OS 10.1 mos for
  decitabine vs 8.5 mos for supportive care (P
  .38)
• Responses in treatment arm (IWG 2000 criteria)
  34
• 13 CR, 6 PR, 15 HI
• Median time to best response 3.8 mos
• Median time to CR 5.8 mos PR 2.9 mos HI 3.8
  mos
• No difference in progression to AML 8.8 mos for
  decitabine vs 6.1 mos for supportive care (P
  .24)
• Modestly but significantly improved median PFS
  (including higher-risk MDS) 6.6 mos for
  decitabine vs 3.0 mos for supportive care (P
  .004)
• Median cycles of decitabine 4
• 2 cycles 38
• Compare with a median of 9 cycles in AZA-001 study

Lübbert M, et al. J Clin Oncol. 2011291987-1996.
48
LD Decitabine vs BSC in Elderly, Int- or
High-Risk MDS Why No OS Improvement?

• Not optimal decitabine schedule (3-day inpatient
  vs 5-day outpatient treatment)
• Small numbers of cycles
• 40 received 2 cycles or less
• Median of 4 cycles vs 9 cycles in AZA-001
• Higher-risk patient group
• Control arm lived median of 15 mos in AZA-001 vs
  8.5 mos in EORTC study
• Different drugs

Lübbert M, et al. J Clin Oncol. 2011291987-1996.
49
Phase II Trial of Azacitidine Entinostat in MDS
and AML With Myelodysplasia

• US Leukemia Intergroup Trial E1905

Azacitidine 50 mg/m2/day for 10 days of 28-day
cycle Entinostat 4 mg/m2/day on Days 3, 10 of
azacitidine treatment
Patients with MDS or AML with myelodysplasia-relat
ed changes (N 136)
Maximum 24 cycles
Azacitidine 50 mg/m2/day for 10 days of 28-day
cycle
After 6 cycles, treatment extended up to 24
cycles in patients with clinical response (CR,
PR, or HI) by International Working Group
criteria.
Prebet TP, et al. ASH 2010. Abstract 601.
50
Response and Toxicity With Entinostat
Azacitidine vs Azacitidine Alone1
100

• Median follow-up 17 mos
• Median cycles 6 (range 1-24)
• Azacitidine entinostat did not increase
  trilineage response vs azacitidine alone 24 vs
  31
• No difference in median time to response or
  median OS between arms
• Higher rate of toxicity with azacitidine
  entinostat
• Grade 4 platelet disorders 63 vs 46 (P .07)

HI
Trilineage HI
80
PR
CR
60
Patients With Response ()
40
12
19
10
20
10
TR 31
9
TR 24
7
12
7
0
Azacitidine Entinostat
Azacitidine

• 10-day duration of azacitidine appeared to
  increase TR vs 7-day treatment (cross-study
  comparison)
• 31 vs 15 in CALGB 92212,3

1. Prebet TP, et al. ASH 2010. Abstract 601. 2.
Silverman LR, et al. J Clin Oncol.
2002202429-2440. 3. Silverman LR, et al. J Clin
Oncol. 2006243895-3903.
51
Why Do Some Patients Not Respond to
Hypomethylating Agents?
10
1000
R 0.44P lt .11
R 0.89P lt .001
100
1
IC50 of Cytarabine (nM)
10
IC50 of AZA (µM)
0.1
1
0.01
0.1
0.001
0.01
0.1
1
10
100
0.001
0.01
0.1
1
10
100
IC50 of DAC µM
IC50 of DAC µM
Decitabine sensitivity in 14 cell lines (7
leukemia) correlates with cytarabine sensitivity
Decitabine correlates more poorly with
azacitidine sensitivity
Qin T, et al. Blood. 2009113659-657.
52
Decitabine Mechanism of Action
Decitabine (5-aza-2-dC)
Extracellular fluid
hENT1
hENT2
Equilibrative nucleoside transporters
Cytoplasm
Deoxycytidine kinase
Cytidine deaminase
Rate limiting step
5-aza-2-dCMP
5-aza-2-dU
dCMP kinase
dCMP deaminase
5-aza-2-dCDP
5-aza-2-dUMP
NDP kinase
5-aza-2-dCTP

• Azacitidine metabolism uses UCK instead of dCK
• Correlates of decitabine resistance1
• Low hENT1/2 expression
• Low dCK (transfection of dCK restores
  sensitivity)
• High cytidine deaminase

1. Qin T, et al. Blood. 2009113659-657.
53
Hypomethylating Agents Unanswered Questions

• Relative merits of azacitidine vs decitabine
• Role for 1 hypomethylating agent when the other
  has failed
• Is there a survival advantage when decitabine is
  administered using current common practice (ie,
  5-day regimen, more cycles)?
• Optimal dose/schedule
• What to do once patient achieves CR (ie,
  maintenance dosing question need for maintenance
  seems to be established)
• What to do in patients without a response
• Molecular predictors of response
• Use in combination therapies
• Actual mechanism of action

54
MDS TherapyLenalidomide
55
Lenalidomide Development History in MDS
Patients with transfusion dependence ( 4 units
pRBCs/8 wks),platelets gt 50 x 109/L, ANC gt
500/mm3
MDS-0011 N 43 Phase I/II initiated Feb 2002
del(5q)
Non-del(5q)
MDS-0032 N 148 Phase II initiated July 2003
MDS-0023 N 214 Phase II initiated July 2003
Transfusion independent 67Median DOR gt 2
yrsCCyR 45
Transfusion independent 26Median DOR 41
wksCCyR 9
1. List A, et al. N Engl J Med. 2005352549-557.
2. List A, et al. N Engl J Med.
20063551456-1465. 3. Raza A, et al. Blood.
200811186-93
56
MDS-004 Phase III Placebo-Controlled Study of 2
Lenalidomide Doses in del(5q)
Lenalidomide PO 10 mg/day for 21 days of each
28-day cycle
Response

• Eligibility
• IPSS low/int-1
• Del(5q31)
• Transfusion dependent
• Lenalidomide naive
• (N 205)

Continue for 52 wks
A R S E S S E P S O S N S E
Lenalidomide PO 5 mg/day for 28 days of each
28-day cycle

• Stratified by
• IPSS
• Complexity

Open-label treatment
Placebo
No response
(Not included inefficacy analysis)
Double blind
Wk
0
4
8
12
16

• Crossover at Wk 16
• Primary endpoint transfusion independence 26
  wks
• Secondary endpoints duration of transfusion
  independence, progression to AML, adverse events

Fenaux P, et al. Blood. 20111183765-3776.
57
MDS-004 Transfusion Independence
Outcome ITT Population ITT Population ITT Population Confirmed Low/Int-1 Confirmed Low/Int-1 Confirmed Low/Int-1
Outcome Placebo(n 51) LEN5 mg(n 46) LEN10 mg(n 41) Placebo(n 51) LEN5 mg(n 46) LEN10 mg(n 41)
Transfusion independence (8 wks), 1 7.5 47.8 60.9 7.8 51.1 61.0
Transfusion independence (26 wks), 1 6 41 56 5.9 (1.2-16.12) 42.6 (28.3-567.8) 56.1 (39.7-71.5)
Median rise in hemoglobin, g/dL2 2.3 5.1 6.3 2.3 5.1 6.3
P lt .001 vs placebo. P lt .05 vs placebo.
1. Fenaux P, et al. ASH 2009. Abstract 944.2.
Fenaux P, et al. Blood. 20111183765-3776.
58
Conclusions

• MDS pathobiology likely to be complex
• New cytogenetic risk modeling ongoing
• IPSS has been revised
• Growth factors effective for lower-risk patients
  but safety still uncertain
• Iron chelation improves numbers but unclear if
  patient outcomes better
• Hypomethylating agents can improve survival

59
Go Online for More CCO Coverage of MDS!

• Interactive Decision Support Tool Treatment
  Recommendations for Patients With Myelodysplastic
  Syndromes
• This tool provides expert recommendations for
  the treatment of MDS in a variety of clinical
  scenarios

• clinicaloptions.com/oncology