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

0 1 2 3

WHO subtype RA, RARS,

5q-

RCMD, RCMD-

RS

RAEB-I RAEB-II

Transfusion requirement

None Regular - -

IPSS Cytogenetic Risk

Good Int. Poor -

*Defined as1ery 8 weeksMt 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 OutcomesMalcovati 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 Significant Effects

Transfusion dependence Survival*, LFS*; Non-leukemic mortality*(cardiac)

Transfusion burden “

Iron overload

________________ Survival**

*RA,RARS,5q-, RCMD

**RA,RARS

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)

Mannoni +* Musto +**

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:

40 (36)

300

60%

47/13%

25% (2/8 pts)

14/16 ptsASH abstract # 69

128, 204

37 (33)

150

40%

35/5%

--

13/17 pts

Correlation of LIC with Prognosis in Thalassemia and

HemochromatosisL

iver

ir

on

, m

g/g

of

live

r, w

et w

eig

ht

Hep

atic

iro

n,

mg

/g o

f li

ver,

dry

wei

gh

t

From Olivieri NF et al, Blood 89:739, 1997

15

10

5

0

50

40

30

20

10

00 10 20 30 40 50

Age, years

Thalassemia major: transfusion without chelation

Homozygous hemochromatosis

Threshold for cardiac disease and early death

Heterozygote

Normal

Increased Risk of Complications

• Optimal level in chelated patients

NCCN MDS Questionnaire: Iron Chelation Practices

Sx Anemia

Sx Anemia, Txn

Sx Anemia, Txn, Chelation

‘Should be’ Chelated

0

10

20

30

40

50

60

70

80

Low/Int-1 Int-2/ High

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

hours

Schedule Clearance Toxicity

Desferal® --- deferoxamine

SQ, IV 0.5 8–24 hrx5–7d/wk

Renal & hepatic

Infusion site & allergic rxns,

ocular, auditory

Ferriprox® - deferiprone, L1

Oral 2–3 3x/d Renal Neutropenia, agranulocytosis, nausea/vomiting,

arthropathy

Exjade® - deferasirox,

ICL670

Oral 12–16 1x/d Hepato-biliary

Transient nausea,

diarrhea, rash

Mean ± SD; LIC using SQUIDCappellini M, et al, Presented at: World Congress on Iron Metabolism16th Annual Meeting of the International BioIron Society 2003

Ch

ang

e i

n L

IC,

mg

/g d

ry w

eig

ht

3 6 9 12

Time on study, months

-5

-4

-3

-2

-1

0

1

2

3

4

5

Deferoxamine 40

ICL670 10

ICL670 20

Thal major Liver Iron Content: ICL670 vs Deferoxamine

Liver iron content using MRI-R2 measurements

LIC=0.6 mg/g

LIC=7.7 mg/g

LIC=13.4 mg/g

LIC=24.5 mg/g

Hepatitis

Hemochromatosis

-Thal

-Thal/Hb E

St Pierre et al, Blood 105: 855, 2005.

St Pierre et al, Blood 2004

0 10 20

Biopsy LIC (mg Fe/g dry tissue)

30 40

40

30

20

10

0

R2-

LIC

(m

g F

e/g

dry

tis

sue) n = 105

r = 0.98 p < 0.0001

Liver iron content: MRI-R2 vs Liver Biopsy

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

-14

-12

-10

-8

-6

-4

-2

0_-thalassemia DBA MDS

Otheranemias

Change in LIC (mg Fe/g

dw)

(n=76) (n=26) (n=28) (n=17)

Iron chelation effects over 1-year deferasirox treatment: Serum ferritin

Int’l Novartis Study108: Greenberg et al, Blood 106 (#11,Suppl):757a, 2005

-2500

-2000

-1500

-1000

-500

0_-thalassemia DBA MDS

Otheranemias

Change in serum ferritin (

ng/mL

)

(n=85) (n=30) (n=47) (n=22)

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

Change in LIC (mg/Fe/g

dw

)

-20

-15

-10

-5

0

5

10

15

5 10 20 30

Initial deferasirox dose (mg/kg/day)

Patient numbers2 2 1 5 10 2 15 20 4 29 48 9

<0.3 0.3 –0.5 >0.5Iron intake

(mg/kg/day)

Lenalidomide/Revlimid (CC5013): Pleiotropic Effects

• Induced TNF, IL1, IL2, IL6 production

• VEGF production/angiogenesis

• Precursor cell adhesion to marrow stroma

• Precursor cell apoptosis

• Responsiveness of Epo receptor

Lenalidomide Treatment of MDSList 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 5Cytogenetics: Abnormal 20 (12 5q-), 23 NormalPrior failed therapy: Epo 77%, thalidomide 30%Dose, po: 10-25 mg/d or 10mg 21/28d x 2-4+ months

Lenalidomide Treatment of MDSList 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 medianCytogenetic 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

58

50-58

<50

>72

64-72

<64

Low (0-40%)

Intermediate (41-70%)

High (71-100%)

Predicted Probability of Response

Patient’s Age in Years + Duration of RCTD in Months

DR15-positive patients

DR15-negative patients

RCTD = red-cell transfusion dependence

Saunthararajah Y et al. Blood. 2003;102:3025-7

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

Total 84 38%

≤60 yo 51 (54%) 55%

>60 yo 42 (46%) 10%

Total 93 34%

Decitabine Phase III StudySaba et al, J Clin Onc 23:570s, 2005

Open-label, 1:1 randomized, multi-center Open-label, 1:1 randomized, multi-center study in the US and Canada study in the US and Canada

Eligible Patients (n = 170)

Decitabine + Supportive Care* Decitabine + Supportive Care* (n = 89)(n = 89)

RANDOMIZED

Supportive Care*Supportive Care*(n = 81) (n = 81)

Stratification• IPSS Classification• Prior Chemotherapy• Study Center

Study D-0007Study D-0007. 2005;23(suppl 16S):570 Abstract 6543..

Response to Decitabine in Subgroups

Overall Response Rate (CR+PR)

Decitabine(n = 89)

Supportive Care

(n = 81)

IPSS subgroupsIntermediate-1Intermediate-2High Risk

14%18%17%

0%0%0%

Prior MDS Therapy Yes

No15%17%

0%0%

De novo MDS Yes

No17%16%

0%0% Study D-0007

MDS: Therapeutically targeted subtypes

• RARS• 5q-• Hypoplastic/PNH or

HLA-DR15+• CMML w/ t(5q31-33)/

PDGFR gene rearrang’t

• GCSF + Epo• Lenalidomide• Immunosuppression

(ATG, CSA)• Imatinib

Reproduced with permission from the National Comprehensive Cancer Network. © 2006 National Comprehensive Cancer Network.

NCCN MEMBER INSTITUTIONS

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

• Lenalidomide* -VEGF McAb*• Darbepoetin +/- GCSF• Scio-469/-p38• 5-Azacytidine• HSC Transplant• Tipifarnib (Zarnestra)*• ATG, CSA• Exjade (oral iron chelator)• Tipifarnib (Zarnestra)*

* = recently completed trials

• Low risk MDS

• High risk MDS

• AML post-MDS• Hypoplastic MDS• MDS, Iron overload• CMML/UMPD