Transcript Document

MDS Recent Developments:
Disease Status and Treatment
• Classification: marrow blasts, chromosomes, CBC;
age, RBC transfusion need
• Treatment options: ‘Low risk’ patients
–
–
–
–
Anemia: Epo, darbepoetin (Aranesp)
5q-: lenalidomide (Revlimid)
Int-1/young/HLADR15: ATG
RBC transfusions >20: Iron chelation (Exjade)
• Treatment options: ‘High risk’ patients
– Azacytidine (Vidaza), decitabine (Dacogen)
– High intensity: HSC transplant
Myeloid Clonal Hemopathies:
Evolutions
WPSS: WHO-Based Prognostic
Scoring System
Malcovati et al, ASH 05, #788
Points
WHO subtype
Transfusion
requirement
IPSS Cytogenetic
Risk
0
1
2
3
RA,
RARS,
5q-
RCMD,
RCMDRS
RAEB-I
RAEB-II
None
Regular
-
-
Good
Int.
Poor
-
*Defined as1ery 8 weeks
Mt al. Blood. 2005;106:232a [abstract 788]
Survival Based on WPSS
Malcovati et al, ASH 05, #788
L et al. Blood. 2005;106:232a [abstract 788]
WPSS for MDS: Clinical Outcomes
Malcovati et al, ASH 12/05 #788a
Risk / Score
Survival
AML evolution
Very Low / 0
11.3 yr
7%@10yr
Low / 1
5.3
-
Intermediate/2
3.7
-
High / 3-4
1.6
-
Very High / 5-6
0.7
50%@8mo
MDS: RBC Transfusion Impact on
Clinical Outcomes
Malcovati et al, ASH 12/05, #791a
Condition
Transfusion dependence
Transfusion burden
Iron overload
_______________
_
*RA,RARS,5q-, RCMD
**RA,RARS
Significant Effects
Survival*, LFS*; Nonleukemic mortality*(cardiac)
“
Survival**
THERAPEUTIC OPTIONS IN
MDS
•
•
•
•
•
•
•
Supportive Care
Hemopoietic Growth Factors (HGFs)
Biologic Response Modifiers (BRMs)
Low Intensity Chemotherapy (LICT)
High Intensity Chemotherapy
HSCT--Standard, Non-myeloablative
Combinations
THERAPEUTIC OPTIONS IN
Low Risk MDS: Low intensity
• Supportive Care: antibiotics, txns, iron chelation
• HGFs: EPO/darbepoetin, G-CSF, GM-CSF, (TPO)
• BRMs: ATG, cyclosporine, lenalidomide, danazol,
bevacizumab, -TNF
• LICT:azacytidine, decitabine, HDACi, tipifarnib (FTI);
imatinib [for t(5q) CMML]
• Combinations
• Clinical trial (eg, Scio469/-p38,…)
Darbepoetin treatment of
anemia in MDS (12+ wks)
Pts (Low/Int-1)
Dose,g/wk sc
HI-Erythroid
Major/Minor
HI-E w/ GCSF
HI-E maintained
*Blood 2004,
**Brit J Hem 2004:
Mannoni +*
Musto +**
40 (36)
300
60%
47/13%
25% (2/8 pts)
14/16 pts
37 (33)
150
40%
35/5%
-13/17 pts
ASH abstract # 69
128, 204
15
50
Thalassemia major:
transfusion without chelation
40
10
Homozygous
hemochromatosis
30
20
5
Threshold for cardiac disease and early death
Increased Risk of Complications
Heterozygote
10
• Optimal level in chelated patients
0
0
Normal
0
10
20
30
Age, years
From Olivieri NF et al, Blood 89:739, 1997
40
50
Hepatic iron, mg/g of liver, dry weight
Liver iron, mg/g of liver, wet weight
Correlation of LIC with Prognosis in
Thalassemia and Hemochromatosis
NCCN MDS Questionnaire:
Iron Chelation Practices
80
70
60
50
40
30
20
10
0
Low/Int-1
Int-2/ High
Sx Anemia
Sx Anemia, Txn, Chelation
Sx Anemia, Txn
‘Should be’ Chelated
Potential Impediments/Enhancers for
Iron Chelation



Drug tolerance
Evidence of clinical need
Evidence of clinical efficacy
-- eg, cardiac, hematologic function


Altered quality of life
Cost
Iron Chelation Agents
Agent
Route
t1/2
Schedule
Clearance
Toxicity
8–24 hr
x5–7d/wk
Renal &
hepatic
Infusion site &
allergic rxns,
ocular, auditory
hours
Desferal® --deferoxamine
SQ, IV
0.5
Ferriprox® deferiprone, L1
Oral
2–3
3x/d
Renal
Neutropenia,
agranulocytosis,
nausea/vomiting,
arthropathy
Exjade® deferasirox,
ICL670
Oral
12–16
1x/d
Hepatobiliary
Transient
nausea,
diarrhea, rash
Thal major Liver Iron Content:
ICL670 vs Deferoxamine
ICL670 10
Change in LIC, mg/g dry weight
5
Time on study, months
ICL670 20
4
3
3
6
9
2
1
0
-1
-2
-3
-4
-5
Mean ± SD; LIC using SQUID
Cappellini M, et al, Presented at: World Congress on Iron Metabolism
16th Annual Meeting of the International BioIron Society 2003
12
Deferoxamine 40
Liver iron content using MRI-R2
measurements
b-Thal
Hepatitis
LIC=0.6 mg/g
LIC=13.4 mg/g
Hemochromatosis
LIC=7.7 mg/g
b-Thal/Hb E
LIC=24.5 mg/g
St Pierre et al, Blood 105: 855, 2005.
R2- LIC (mg Fe/g dry tissue)
Liver iron content:
MRI-R2 vs Liver Biopsy
n = 105
40
r = 0.98 p < 0.0001
30
20
10
0
0
10
20
30
40
Biopsy LIC (mg Fe/g dry tissue)
St Pierre et al, Blood 2004
St Pierre et al, Blood 105: 855, 2005.
Iron chelation effects of 1-year deferasirox
treatment: LIC
Int’l Novartis Study 108: Greenberg et al, Blood 106 (#11,Suppl):757a, 2005
β-thalassemia
DBA
MDS
Other
anemias
(n=76)
(n=26)
(n=28)
(n=17)
Change in LIC (mg Fe/g dw)
0
-2
-4
-6
-8
-10
-12
-14
Iron chelation effects over 1-year
deferasirox treatment: Serum ferritin
Int’l Novartis Study108: Greenberg et al, Blood 106 (#11,Suppl):757a, 2005
β-thalassemia
DBA
MDS
Other
anemias
(n=30)
(n=47)
(n=22)
Change in serum ferritin (ng/mL)
0
-500
-1000
-1500
-2000
-2500
(n=85)
Effects of deferasirox dose and iron intake
on changes in LIC over 1 year
Int’l Novartis Study 108: Greenberg et al, Blood 106 (#11,Suppl):757a, 2005
Iron intake
(mg/kg/day)
Change in LIC (mg/Fe/g dw)
15
2
5
<0.3
10 2
0.3–0.5
15 20 4
>0.5
2
1
29 48
5
10
20
Initial deferasirox dose (mg/kg/day)
10
5
0
-5
-10
-15
-20
30
9 Patient numbers
Lenalidomide/Revlimid
(CC5013): Pleiotropic Effects
• Induced TNF, IL1b, IL2, IL6 production
• VEGF production/angiogenesis
• Precursor cell adhesion to marrow stroma
• Precursor cell apoptosis
• Responsiveness of Epo receptor
Lenalidomide Treatment of MDS
List et al, New Eng J Med 352: 549, 2005
43 anemic patients (75% RBC Txn dependent):
RA 20, RARS 13, RAEB 8, RAEBT 1,CMML 1
Low/Int-1 38, Int-2/High 5
Cytogenetics: Abnormal 20 (12 5q-), 23 Normal
Prior failed therapy: Epo 77%, thalidomide 30%
Dose, po: 10-25 mg/d or 10mg 21/28d x 2-4+ months
Lenalidomide Treatment of MDS
List et al. N Engl J Med 352:549, 2005
Erythroid responses (IWG criteria):
24/43 pts (56%), 20 major
RA 75%, RARS 46%, RAEB/RAEBT 33%
5q- 83%, Normal cyto 57%, Other abn cyto 12%
Low/Int-1 61%, Int-2/High 20%
Response duration: 20+(10–27) month median
Cytogenetic responses (5q-): 10/12 (9 complete)
Adverse events: Dose-related myelosuppression 58%
thrombocytopenia 74%, neutropenia 65%,
3 deaths ‘unrelated to drug’
List et al. Treatment of 5q- MDS patients with lenalidomide, ASCO 5/05
List et al. Treatment of 5q- MDS patients with lenalidomide, ASCO 5/05
List et al. Treatment of 5q- MDS patients with lenalidomide, ASCO 5/05
List et al. Treatment of 5q- MDS patients with lenalidomide, ASCO 5/05
A Predictive Score for Response
to Immunosuppression
Patient’s Age in Years + Duration
of RCTD in Months
DR15-negative
patients
DR15-positive
patients
58
>72
50-58
64-72
<50
<64
Predicted Probability
of Response
Low
Intermediate
High
RCTD = red-cell transfusion dependence
Saunthararajah Y et al. Blood. 2003;102:3025-7
(0-40%)
(41-70%)
(71-100%)
Immunosuppressive Treatment in IPSS
Intermediate-1 MDS Patients: ATG±CSA
(Sloand et al, ASH ‘05 abstract #2519)
Features
Patients
Response
High Prob’y
46 (55%)
70%
Low Prob’y
38 (45%)
0
84
38%
≤60 yo
51 (54%)
55%
>60 yo
42 (46%)
10%
93
34%
Total
Total
Decitabine Phase III Study
Saba et al, J Clin Onc 23:570s, 2005

Open-label, 1:1 randomized, multi-center
study in the US and Canada
Decitabine + Supportive Care*
(n = 89)
R
A
Eligible
Patients N
(n = 170) D
O
M
I
Z
E
D
Stratification
• IPSS Classification
• Prior Chemotherapy
• Study Center
Supportive Care*
(n = 81)
. 2005;23(suppl 16S):570 Abstract 6543..
Study D-0007
Response to Decitabine in
Subgroups Supportive
Overall Response Rate
(CR+PR)
IPSS subgroups
Intermediate-1
Intermediate-2
High Risk
Prior MDS Therapy
Yes
No
De novo MDS
Yes
No
Decitabine
(n = 89)
Care
(n = 81)
14%
18%
17%
0%
0%
0%
0%
0%
15%
17%
17%
16%
0%
0% Study D-0007
MDS:
Therapeutically targeted subtypes
• RARS
• 5q• Hypoplastic/PNH or
HLA-DR15+
• CMML w/ t(5q31-33)/
PDGFRb gene rearrang’t
• GCSF + Epo
• Lenalidomide
• Immunosuppression
(ATG, CSA)
• Imatinib
NCCN MEMBER INSTITUTIONS
Reproduced with permission from the National Comprehensive Cancer Network.
© 2006 National Comprehensive Cancer Network.
MDS Mgt: Supportive care
• Transfusion support: RBCs, platelets
– CMV compatible, XRT for HSCT candidate
– Symptomatic trigger Hb level
• Antibiotics +/- GCSF
– if infections are recurrent, refractory
• Iron chelation: sc desferioxamine or oral deferasirox
(preferably) on clinical trial
– Low risk polytransfused pts:~≥20-40 RBCu
• Address Quality of Life domains
– Emotional, functional, physical, social, spiritual
(www.nccn.org/MDS v3.2006)
NCCN MDS Mgt: IPSS Low/Int-1
w/ clinically relevant cytopenia(s)
• Del(5q) abnormality
• Non-del(5q) patients w/ anemia
– sEpo <500, +RS
–
“
- RS
– sEpo >500/HLADR15+/Hypoplastic
–
“
/HLADR15• CMML w/ t(5q31-33)
• Non-responsive/progressive disease/
other cytopenias
(www.nccn.org/MDS v3.2006)
NCCN MDS Mgt: IPSS Low/Int-1
w/ clinically relevant cytopenia(s)
• Del(5q) abnormality: Lenalidomide
• Non-del(5q) w/ anemia:
– sEpo <500, +RS : Epo/Darbepoetin + GCSF
–
“
- RS : Epo/Darbepoetin -/+ GCSF
– sEpo >500/HLADR15+/Hypoplastic: ATG -/+ CSA
-
“
/HLADR15-: Azacytidine, Clinical trial
• CMML w/ t(5q31-33): Imatinib mesylate
• Non-responsive/progressive disease/other
cytopenias
– Azacytidine (Decitabine), ATG
– Clinical trial
– Consider HSCT (for Int-1; age, PS dependent)
(www.nccn.org/MDS v3.2006)
NCCN MDS Mgt:
IPSS Int-2/High
• HSCT candidate (age, PS, donor)
– Sibling, MUD HSCT: Std vs Non-myeloablative
– Azacytidine(Decitabine)/Induction chemotherapy
– Clinical trial
• Non-HSCT candidate (age, PS)
– Azacytidine(Decitabine)/Induction chemotherapy
– Clinical trial
• CMML w/ t(5q31-33): Imatinib mesylate
(www.nccn.org/MDS v3.2006)
Challenges for HSCT in MDS:
Tolerance, GVHD, Relapse
• Elderly pts: Reduced intensity HSCT
• Abnormal stroma: Block inhibitory cytokines,
immune dysregulation
• Primitive stem cells: Target mutations
• Tumor burden: Bridge to HSCT w/ targeted
chemotherapy
MDS: Directions
• Understanding biology
• Select patients for targeted therapy
– Biospecific agents-finite trials
– Low vs high intensity therapy
– Relevant drug combination trials
– Quality of life assessment
• Analyze cost/benefit ratios
MDS Recent Developments:
Disease Status and Treatment
• Classification: marrow blasts, chromosomes, CBC;
age, RBC transfusion need
• Treatment options: ‘Low risk’ patients
–
–
–
–
Anemia: Epo, darbepoetin (Aranesp)
5q-: lenalidomide (Revlimid)
Int-1/young/HLADR15: ATG
RBC transfusions >20: Iron chelation (Exjade)
• Treatment options: ‘High risk’ patients
– Azacytidine (Vidaza), decitabine (Dacogen)
– High intensity: HSC transplant
Stanford MDS Center:
Clinical
Trials
• Low risk MDS
• Lenalidomide*
•
•
•
•
•
•
•
•
High risk MDS
•
•
AML post-MDS
•
Hypoplastic MDS
•
MDS, Iron overload •
CMML/UMPD
•
-VEGF McAb*
Darbepoetin +/- GCSF
Scio-469/-p38
5-Azacytidine
HSC Transplant
Tipifarnib (Zarnestra)*
ATG, CSA
Exjade (oral iron chelator)
Tipifarnib (Zarnestra)*
* = recently completed trials