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Myelodysplasia:Myelodysplasia:Recent AdvancesRecent Advances
James M. Rossetti, D.O.James M. Rossetti, D.O.
Associate Director,Associate Director,Blood and Marrow Transplantation Blood and Marrow Transplantation
ProgramProgramWestern Pennsylvania Cancer InstituteWestern Pennsylvania Cancer Institute
Myelodysplastic SyndromesMyelodysplastic Syndromes
Incidence in U.S.Incidence in U.S.
– 15-25,000 cases per year15-25,000 cases per year
Prevalence in U.S.Prevalence in U.S.
– 55,000 cases55,000 cases
Types of MDSTypes of MDS
– 2/3 of the cases belong to the lower risk 2/3 of the cases belong to the lower risk categoriescategories
Myelodysplastic Syndromes: Myelodysplastic Syndromes: Predisposing FactorsPredisposing Factors
Unknown in more than 80% of patientsUnknown in more than 80% of patients
Older age (Median age > 60 yrs, 70% > 50 yrs)Older age (Median age > 60 yrs, 70% > 50 yrs)
Secondary MDSSecondary MDS
– Ionizing radiationIonizing radiation
– ChemotherapyChemotherapy
– Industrial chemicalsIndustrial chemicals
– Hair dyesHair dyes
Myelodysplastic SyndromesMyelodysplastic Syndromes
CLINICAL PARADOX OF
Variable cytopenias in a hypercellular bone
marrow
Myelodysplastic Syndromes:Myelodysplastic Syndromes:Dysplastic Features Dysplastic Features
Myelodysplastic Syndromes: Biologic Myelodysplastic Syndromes: Biologic Features Driving the PhenotypeFeatures Driving the Phenotype
Genetic abnormalitiesGenetic abnormalities
Epigenetic DNA modification Epigenetic DNA modification
Accelerated apoptosis Accelerated apoptosis
ProliferationProliferation
Stromal dysregulation Stromal dysregulation
Medullary angiogenesisMedullary angiogenesis
Chromosomal AbnormalityFrequency in Primary
MDS
–5/del(5q) 10%–20%
+8 10%
–7/del(7q) 5%–10%
–Y 10%
17p- 7%
del(20q) 5%
t(11q23) 5%–6%
Complex karyotypes 10%–20%Heaney ML et al. N Engl J Med. 1999;340:1649Rosenfeld C et al. Leukemia. 2000;14:2
Myelodysplastic Syndromes: Myelodysplastic Syndromes: Cytogenetic AbnormalitiesCytogenetic Abnormalities
• About half of MDS patients present with a genetic abnormality
MDS - Therapeutic ChallengeMDS - Therapeutic Challenge
IneffectiveIneffectiveHematopoiesisHematopoiesis
AMLEvolution
1976, 19821976, 1982
1997, 20011997, 2001
19971997 20032003
FABFAB
WHOWHO
IPSSIPSS IPSS-BM PathIPSS-BM Path
Evolution of MDS Classification Evolution of MDS Classification SystemsSystems
ALIPs, CD-34+ ALIPs, CD-34+ Increase risk Increase risk within IPSS within IPSS categoriescategories
Based on survival Based on survival and blast numberand blast number
Based on survival Based on survival and blast numberand blast number
Based on time to AML; Based on time to AML; % blasts, karyotype, % blasts, karyotype,
# of cytopenias# of cytopenias
FAB=French American British ClassificationWHO=World Health OrganizationIPSS=International Prognostic Scoring Systems
35 35
12
18
6
0
10
20
30
40
50
60
70
Mea
n S
urv
ival
(M
on
ths)
RA RARS CMML RAEB RAEB-t
Low Risk High Risk
RA RA (Refractory anemia) (Refractory anemia) <5% blasts<5% blasts
RARS RARS (RA with (RA with 15% 15% ringed sideroblasts)ringed sideroblasts)
CMML CMML (Chronic myelo-(Chronic myelo-monocytic leukemia)monocytic leukemia)
RAEB RAEB (RA with excess of (RA with excess of blasts) 5%–20% blastsblasts) 5%–20% blasts
RAEB-tRAEB-t (RA with excess (RA with excess of blasts in transfor-of blasts in transfor-mation) 21%–30% blastsmation) 21%–30% blasts
Bennett JM et al. Br J Haematol. 1982;51:189Gallagher A et al. Haematologica. 1997;82:191
Myelodysplastic Syndromes: Myelodysplastic Syndromes: Survival Based on FAB ClassificationSurvival Based on FAB Classification
WHO Revised MDS ClassificationWHO Revised MDS Classification
MDS/MPDMDS/MPD• CMML-1CMML-1 (<10% BM blasts)(<10% BM blasts)
• CMML-2CMML-2 (10-19% blasts)(10-19% blasts)
• CMML-Eos CMML-Eos (AEC>1500/(AEC>1500/L)L) • JMMLJMML
AML• 20% blasts
*Single lineage erythroid dysplasia.*Single lineage erythroid dysplasia.^MDS-U denotes single non-erythroid lineage dysplasia.^MDS-U denotes single non-erythroid lineage dysplasia. *Single lineage erythroid dysplasia.*Single lineage erythroid dysplasia.^MDS-U denotes single non-erythroid lineage dysplasia.^MDS-U denotes single non-erythroid lineage dysplasia.
Harris N, et al. Harris N, et al. J Clin OncolJ Clin Oncol 1999;17:3835. 1999;17:3835. Harris N, et al. Harris N, et al. J Clin OncolJ Clin Oncol 1999;17:3835. 1999;17:3835.
MDS• RA - RA*
- RCMD• RSA - RARS
- RCMD-RS• 5q- Syndrome • RAEB-1 (5-9% BM blasts)• RAEB-2 (10-19%;Auer rods)• MDS-U^
Score Value
Prognostic Variable 0 0.5 1.0 1.5 2.0
Bone marrow blasts (%) <5 5–10 – 11–20 21–30
Karyotype* Good Intermediate Poor –
Number of cytopenias** 0/1 2/3 – – –
*Good = normal, -Y, del(5q), del(20q); Intermediate = other karyotypic abnormalities; Poor = complex (3 abnormalities) or chromosome 7 abnormalities
**Hb <10 g/dL; ANC <1800/L; platelet count <100,000/L
Greenberg PL et al. Blood. 1997;89:2079
IPSS:IPSS:International Prognostic Scoring SystemInternational Prognostic Scoring System
•All 3 prognostic variables required to generate IPSS score
Parameter Low Int-1 Int-2 High
Score 0 0.5–1.0 1.5–2.0 2.5
Median survival, yr5.7 3.5 1.2 0.4
25% AML evolution, median, yr 9.4 3.3 1.1 0.2
Greenberg PL et al. Blood. 1997;89:2079
Survival and Evolution to AML by Survival and Evolution to AML by IPSSIPSS
•From diagnosis in untreated patients
FAB versus IPSSFAB versus IPSS
List A, Molldrem J, Sanders, J. Prognosis and treatment of myelodysplastic syndromes. Slide show presented at: Annual Meeting of the American Society of Clinical Oncology; June 5, 2004; New Orleans, La. Slide 11.
Cytogenetic abnormalities found
in 24% of RA and 29% of RARS patients
Outcomes of Allogeneic Stem Cell Outcomes of Allogeneic Stem Cell Transplant in Patients With MDSTransplant in Patients With MDS
Only curative therapy is high-dose Only curative therapy is high-dose chemotherapy with allogeneic BMT chemotherapy with allogeneic BMT
Up to 50% cure rate Up to 50% cure rate
Morbidity and mortality increases with ageMorbidity and mortality increases with age
Allogeneic SCT appropriate for fewer than Allogeneic SCT appropriate for fewer than 5% of MDS patients5% of MDS patients
Non-ablative SCT increasingly an option Non-ablative SCT increasingly an option (?)(?)
Allogeneic Stem Cell Transplantation for MDS: Allogeneic Stem Cell Transplantation for MDS: Approximation of Life Expectancy (Years)Approximation of Life Expectancy (Years)
Immediate Immediate TransplantTransplant
Transplant Transplant in 2 Yearsin 2 Years
Transplant at Transplant at ProgressionProgression
LowLow 6.516.51 6.866.86 7.217.21
Int-Int-11
4.614.61 4.744.74 5.165.16
Int-Int-22
4.934.93 3.213.21 2.842.84
HighHigh 3.203.20 2.752.75 2.752.75
From Cutler C, et al. A Decision Analysis of Allogeneic Bone Marrow Transplantation for Myelodysplastic Syndromes: Delayed Transplantation for Low Risk Myelodysplasia is Associated with Improved Outcome. Blood 2004- 1st Ed Publication. Prepublished online March 23, 2004; D01.1182/Blood-2004-01-0338.Copyright American Society of Hematology, used with Permission.
Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.
Cutler, C. S. et al. Blood 2004;104:579-585
Allogeneic Stem Cell Transplantation for MDS
PR
OB
AB
ILIT
Y, %
100
0
20
40
60
80
YEARS
0 1 2 3 4 65
SURVIVAL AFTER MYELOABLATIVE TRANSPLANTS FOR MYELODYSPLASTIC SYNDROMES, 1996-2001, Age > 20 Years
Unrelated, RA/RARS (N = 92)
Unrelated, RAEB/RAEB-T/CMML (N = 257)
HLA-identical sibling, RA/RARS (N = 254)
HLA-identical sibling, RAEB/RAEB-T/CMML (N = 648)
Cheson BD et al. Blood. 2000;96:3671
International Working Group International Working Group Criteria: Hematologic ImprovementCriteria: Hematologic Improvement
Erythroid response, if Hgb <11 g/dLErythroid response, if Hgb <11 g/dL– Major: Rise by >2; transfusion independenceMajor: Rise by >2; transfusion independence
– Minor: Rise by 1–2; reduce transfusion dependence Minor: Rise by 1–2; reduce transfusion dependence by 50%by 50%
Platelet response, if <100,000/Platelet response, if <100,000/LL– Major: Rise by >30k; transfusion independenceMajor: Rise by >30k; transfusion independence
– Minor: Rise by 50% (at least 10,000/Minor: Rise by 50% (at least 10,000/L)L)
Neutrophil response, if ANC <1500/Neutrophil response, if ANC <1500/LL– Major: Rise by 100% or Major: Rise by 100% or 500/500/LL
– Minor: Rise by 100% but <500/Minor: Rise by 100% but <500/LL
Cheson BD et al. Blood. 2000;96:3671
International Working Group:International Working Group:Response Criteria in MDSResponse Criteria in MDS
CR: duration CR: duration 2 months2 months– BM: <5% blasts; no dysplasia; normal maturationBM: <5% blasts; no dysplasia; normal maturation
– Blood: Hgb >11 g/dL; ANC >1500/Blood: Hgb >11 g/dL; ANC >1500/L; platelets L; platelets >100,000/>100,000/L; no blasts; no dysplasiaL; no blasts; no dysplasia
PR: same as for CR, except blast decrease by PR: same as for CR, except blast decrease by >50% or lower FAB >50% or lower FAB
Stable disease (SD): no progression for Stable disease (SD): no progression for 2 months2 months
Progressive disease (PD)Progressive disease (PD)
Survival Rates Before (1980s) andAfter (1990s) the Use of Chemotherapy
With Permission of E Estey, MD
1.0
0.8
0.6
0.4
0.2
0.00 50 100 150 200 260 310 360 410 460 520
Weeks
Su
rviv
al
Pro
bab
ilit
yEra Total Fail1980s162 1551990s307 246
Erythropoietin for MDSErythropoietin for MDS
EPO response rate 15-20%EPO response rate 15-20%
Best if EPO level < 200-500 U/lBest if EPO level < 200-500 U/l
Dose 10,000 u/day (or 40,000 u twice a Dose 10,000 u/day (or 40,000 u twice a week)week)
Best responses in low grade MDSBest responses in low grade MDS
Hellstrom-Lindberg, 1995
Darbepoetin Alfa for MDSDarbepoetin Alfa for MDS
May induce response in EPO non-respondersMay induce response in EPO non-responders
Low EPO level may not be as important (?)Low EPO level may not be as important (?)
Newer studies suggest higher doses more Newer studies suggest higher doses more effectiveeffective
EPO + G-CSF for MDSEPO + G-CSF for MDS
Higher responses to EPO + G-CSF (reduced Higher responses to EPO + G-CSF (reduced caspase induced apoptosis)caspase induced apoptosis)
Synergy as late addition of G-CSF converts Synergy as late addition of G-CSF converts non-responders to PR and CRnon-responders to PR and CR
RA, RARS, RAEB – 38% RRRA, RARS, RAEB – 38% RR
Duration 24 monthsDuration 24 months
Hellstrom-Lindberg, 1998
Predictive ModelPredictive Model
British Journal of Hematology, 2003
Epo + G-CSF Epo + G-CSF Synergy Synergy
81 year old female diagnosed with MDS-RARS in 6/94:
56789
101112131415
Jul-9
4
Jan-
95
Jul-9
5
Jan-
96
Jul-9
6
Jan-
97
Jul-9
7
Jan-
98
Jul-9
8
Jan-
99
Jul-9
9
Jan-
00
Jul-0
0
Jan-
01
Jul-0
1
Jan-
02
Jul-0
2
Jan-
03
Jul-0
3
Jan-
04
Epo Epo + G-CSF
Bimonthly PRBC Transfusions
Hg
b (
G/D
L)
Strategies Directed at the BM Strategies Directed at the BM MicroenvironmentMicroenvironment
Immunomodulatory (ATG, Immunomodulatory (ATG, cyclosporine)cyclosporine)
Anti-TNFAnti-TNF
Antiangiogenic (VEGF-A)Antiangiogenic (VEGF-A)
Cytoprotective (amifostine)Cytoprotective (amifostine)
Immunosuppressive Therapy for Immunosuppressive Therapy for MDSMDS
ATG ATG steroids steroids cyclosporine: cyclosporine:
• 40 – 70% responses in hypoplastic MDS40 – 70% responses in hypoplastic MDS
• Responses greatest in younger patients, Responses greatest in younger patients, shorter duration, and HLA DRB1*15shorter duration, and HLA DRB1*15
• Responses 5 years or moreResponses 5 years or more
Thalidomide in MDSThalidomide in MDS
AnticytokineAnticytokine
AntiangiogenicAntiangiogenic
Immune modulatorImmune modulator
ThalidomideThalidomide
16/83 (19%) RBC transfusion responders16/83 (19%) RBC transfusion responders
Rare responders in WBC or PLTRare responders in WBC or PLT
Intolerant of > 200mg/dayIntolerant of > 200mg/day
16 weeks to respond (12-20)16 weeks to respond (12-20)
Response was 29% in patients completing Response was 29% in patients completing 12 weeks of therapy12 weeks of therapy
Phase II Trial
Raza, 2001
Survival in days
1400120010008006004002000-200
Cu
m S
urv
ival
1.2
1.0
.8
.6
.4
.2
Response Code
Responders
Responders-alive
Non-responders
Non-responders-alive
Median non-responders = 317 daysMedian responders = none reached P =< 0.0005
Survival Curve: Survival Curve: After Starting Treatment With ThalidomideAfter Starting Treatment With Thalidomide
ThalidomideThalidomide
SedationSedation
ConstipationConstipation
NeuropathyNeuropathy
Major Side Effects
Revlimid (lenalidomide)Revlimid (lenalidomide)
Encouraging early response rates in low-Encouraging early response rates in low-grade MDS: 10 –40% CR + PRgrade MDS: 10 –40% CR + PR
Largely devoid of thalidomide side effectsLargely devoid of thalidomide side effects
Like thalidomide, mainly erythroid Like thalidomide, mainly erythroid responsesresponses
Well tolerated, but thrombocytopenia is Well tolerated, but thrombocytopenia is dose limitingdose limiting
5q- Syndrome: A Subset of MDS5q- Syndrome: A Subset of MDS
Isolated chromosome 5q deletionIsolated chromosome 5q deletion
Hematologic featuresHematologic features
– Refractory anemiaRefractory anemia
– Mild leukopeniaMild leukopenia
– Atypical megakaryocytes, normal to elevated Atypical megakaryocytes, normal to elevated plateletsplatelets
– Transfusion dependenceTransfusion dependence
– Extended survival with low frequency of AML Extended survival with low frequency of AML transformationtransformation
Revlimid (lenalidomide)Revlimid (lenalidomide)5q- Syndrome5q- Syndrome
Very high response rateVery high response rate
10/12 reversed the cytogenetic abnormality10/12 reversed the cytogenetic abnormality
Now more than 70 patients treated – many with Now more than 70 patients treated – many with excellent responsesexcellent responses
May see an early aplastic phase during treatmentMay see an early aplastic phase during treatment
Recently FDA approved for low-risk MDS patients Recently FDA approved for low-risk MDS patients with transfusion dependence and 5q-with transfusion dependence and 5q-
ADVERSE EVENTS MDS-003 (5q-) MDS-002 (non-5q-)
Neutropenia 57.0% 24.0%
Thrombocytopenia 58.0% 19.0%
Pruritis 32.0% 21.0%
Rash 28.0% 22.0%
Diarrhea 24.0% 13.0%
Fatigue 12.0% 12.0%
Constipation NR 14.0%
PATIENT DEATHS
Deaths 15 (10.1%) 20 (9.3%)
Suspected drug related by investigator
2 (1.4%) 2 (0.9%)
Lenalidomide Phase II ExperienceLenalidomide Phase II Experience
List. ASCO 2005 Plenary Session. Celgene data on file.List. ASCO 2005 Plenary Session. Celgene data on file.
AngiogenesisAngiogenesis• VEGF suppresionVEGF suppresion• COX-2 repressionCOX-2 repression• Endothelial apoptosisEndothelial apoptosis
AngiogenesisAngiogenesis• VEGF suppresionVEGF suppresion• COX-2 repressionCOX-2 repression• Endothelial apoptosisEndothelial apoptosis
DifferentiationDifferentiation • G1 arrest (p21,p27)G1 arrest (p21,p27)• SMRT corepressor-P SMRT corepressor-P • Histone acetylationHistone acetylation• DNA-MT inhibitionDNA-MT inhibition
DifferentiationDifferentiation • G1 arrest (p21,p27)G1 arrest (p21,p27)• SMRT corepressor-P SMRT corepressor-P • Histone acetylationHistone acetylation• DNA-MT inhibitionDNA-MT inhibition
ApoptosisApoptosis • NF-B inhibition • Bcl-2 downregulation• Microtubule disruption • Caspase activation
ApoptosisApoptosis • NF-B inhibition • Bcl-2 downregulation• Microtubule disruption • Caspase activation
TRISENOXTRISENOX®® (arsenic trioxide) (arsenic trioxide) Mechanisms of ActionMechanisms of Action
Study DesignStudy Design
• Multi-center, open-label, 2-stageMulti-center, open-label, 2-stage
• Two patient cohortsTwo patient cohorts− Lower-risk MDS (IPSS Risk Category Low or Int-1)Lower-risk MDS (IPSS Risk Category Low or Int-1)
− Higher-risk MDS (IPSS Risk Category Int-2 or High) Higher-risk MDS (IPSS Risk Category Int-2 or High)
• 4-week cycles4-week cycles− ATO given 5 days per week for 2 weeks ATO given 5 days per week for 2 weeks
followed by 2 weeks with no dosingfollowed by 2 weeks with no dosing
• ATO 0.25 mg/kg/dose given as a 1 to 2 hour IV ATO 0.25 mg/kg/dose given as a 1 to 2 hour IV infusioninfusion
Disease Response SummaryDisease Response Summary
Patients with Response (as defined in the IWG Patients with Response (as defined in the IWG Criteria): Criteria):
Lower RiskLower RiskHigher RiskHigher RiskPatientsPatients PatientsPatients
Complete RemissionComplete Remission 00 11Hematologic ResponseHematologic Response 6633Stable DiseaseStable Disease 1111 44Progressive DiseaseProgressive Disease 00 55
Total (CR + HR)Total (CR + HR) 6 (35%) 4 (31%) 6 (35%) 4 (31%)
List A et al. List A et al. 7th Intl Symposium on MDS. 7th Intl Symposium on MDS. 2003;Abstract 112179.2003;Abstract 112179.
Study DesignStudy Design
• European multicenter, open-label, 2-stageEuropean multicenter, open-label, 2-stage
• Two patient cohortsTwo patient cohorts
− Lower-risk MDS (IPSS Risk Category Low or Int-1)Lower-risk MDS (IPSS Risk Category Low or Int-1)
− Higher-risk MDS (IPSS Risk Category Int-2 or High) Higher-risk MDS (IPSS Risk Category Int-2 or High)
• 16-week cycles16-week cycles
− ATO given 5 days for 1 week, followed by 2 doses/week ATO given 5 days for 1 week, followed by 2 doses/week for at least 15 weeksfor at least 15 weeks
• ATO 0.30 mg/kg/dose given as a 1 to 2 hour IV infusion ATO 0.30 mg/kg/dose given as a 1 to 2 hour IV infusion (loading), followed by 0.25 mg/kg/dose twice weekly(loading), followed by 0.25 mg/kg/dose twice weekly
ConclusionsConclusions
• There were hematologic responses in 9 of 37 There were hematologic responses in 9 of 37 (24%) evaluable MDS patients(24%) evaluable MDS patients
• Treatment led to transfusion independence or Treatment led to transfusion independence or decreased transfusion requirements in 6 patientsdecreased transfusion requirements in 6 patients
• Some platelet and WBC respondersSome platelet and WBC responders
• Twenty-three additional patients (62%) Twenty-three additional patients (62%) maintained stable diseasemaintained stable disease
• Responses seen within 8 to 12 weeks of therapyResponses seen within 8 to 12 weeks of therapy
• Responses were durable, lasting up to 300+ days Responses were durable, lasting up to 300+ days (range 90-300+ days)(range 90-300+ days)
Epigenetic Gene Silencing • DNA hypermethylation - Promoter, global DNA
hypermethylation common in MDS
Therapeutic Strategy• DNA methyltransferase inhibitors (eg, azacitidine,
decitabine) promote hypomethylation of DNA, allowing
expression of previously silenced genes
Myelodysplastic Syndromes: Myelodysplastic Syndromes: Epigenetic DNA ModificationsEpigenetic DNA Modifications
Decitabine Phase III Trial:Decitabine Phase III Trial:Study DesignStudy Design
Open-label, multicenter, 1:1 randomized study in U.S. and Open-label, multicenter, 1:1 randomized study in U.S. and CanadaCanada
Int-1, Int-2 and High Risk MDS patients eligibleInt-1, Int-2 and High Risk MDS patients eligible Primary Endpoints: Response, Time to AML/deathPrimary Endpoints: Response, Time to AML/death
Decitabine + Supportive Care*15mg/m2/q8h x 3days q6wks
(N=89)
Supportive Care*ABX, GFs and/or Transfusions
(N=81)
Stratification
- IPSS- Prior chemo- Type of MDS- Site
EligiblePatients(n=170)
RANDOMIZED
Saba et al. Proc ASCO. 2005; Poster Presentation.
Decitabine Phase III Trial:Decitabine Phase III Trial:ResultsResults
Decitabine(n=81)
Supportive Care (n=81)
Overall Response (IWG)* 17% 0%
Complete Response 9% 0%
Partial Response 8% 0%
Hematologic Improvement (IWG) 13% 7%
Median Time to Response 89d (55-153) N/A
Median Duration of Response 266d (131-346) N/A
Median Time to AML/Death** 12.1 months 7.8 months
*p<0.01**p=0.16
Saba et al. Proc ASCO. 2005; Poster Presentation.
Decitabine Phase III Trial:Decitabine Phase III Trial:Adverse EventsAdverse Events
- Major grade 3/4 adverse event: Febrile neutropenia
Decitabine(n=83)
Supportive Care
(n=81)
Grade 3 Grade 4 Grade 3 Grade 4
Neutropenia 10% 77% 25% 25%
Thrombocytopenia 22% 63% 27% 16%
Anemia 11% 1% 14% 1%
Febrile neutropenia 17% 6% 4% 0%
Pneumonia 13% 2% 7% 2%
Saba et al. Proc ASCO. 2005; Poster Presentation.
* Minimum duration of supportive care = 4 months unless transform to AML; death or plts≤ 20 x 109/L at week 8 or later
QOL – Quality of Life AssessmentM = Bone Marrow Aza C – Azacitidine S.C.
MM M
0 5729 113
1) Supportive Care*
QOL QOL QOL
RA
RARS
RAEB
RAEB-T
CMML
Stratify
Randomize
2) Aza C 75mg/m2/d x 7 days q28
ExitCriteria
No Continue untilEndpoint
Yes Aza C(dose as per arm #2)
ASSESS
Response- Continue Rx
No Response- Off Study
Day
CALGB 9221CALGB 9221A Randomized Phase III Controlled Trial of SubcutaneousA Randomized Phase III Controlled Trial of SubcutaneousAzacitidine in Myelodysplastic SyndromesAzacitidine in Myelodysplastic Syndromes
Silverman L. The Oncologist 2001. 6 (S5): 8-14.Silverman L, et al. J Clin Oncol 2002. 18:2414-26.Kornblith AB, et al. J Clin Oncol 2002. 18:2427-39
Transformation toTransformation to
TreatmentTreatment ResponseResponse Time to leukemia or death* AML as 1Time to leukemia or death* AML as 1stst eventevent
Aza C Aza C CR = 7%CR = 7% 21 months21 months 15%15%(n = 99)(n = 99) PR = 16%PR = 16%
Improved = 37%Improved = 37%(Overall = 60%)(Overall = 60%)
Supportive care Supportive care CR = 0%CR = 0% 13 months13 months 38%38%(n = 92) (n = 92) PR = 0%PR = 0%
Improved = 5%Improved = 5%(Overall = 5%)(Overall = 5%)
Quality of life significantly improved with treatment: fatigue (P = 0.001), dyspnea (P = 0.0014), physical functioning (P = 0.0002), positive affect (P = 0.0077), and psychological distress (P = 0.015)
Silverman LR et al. J Clin Oncol. 2002;20:2429
CALGB Trial of Azacitidine vs. Supportive CareCALGB Trial of Azacitidine vs. Supportive Care
*Not IWG Criteria of Response; Cross-over design did not allow proof of survival advantage.
23 19
30
8 7
1517
10
6
1
2
4
0
10
20
30
40
50Complete Response
Partial Response
Major Hematologic Improvement
Response Rates (CR + PR + Major HI) Using Response Rates (CR + PR + Major HI) Using IWG IWG MDS Response Criteria by StudyMDS Response Criteria by Study
Per
cen
t o
f P
atie
nts
8421Azacitidine
N=48
9221Azacitidine
N=99
9221Supportive care only
N=41
8921Azacitidine
N=70
9221Azacitidine after
Supportive careN=51
IV SC
4036
41
7
18
Silverman et. al. ASH Meeting Dec 9-13, 2005. Abstract 2526 and Poster Presentation.
Time to AML TransformationTime to AML TransformationP
rob
ab
ilit
y of
Pro
bab
ilit
y of
Rem
ain
ing
Eve
nt-
Fre
eR
em
ain
ing
Eve
nt-
Fre
e
0.00.0
0.20.2
0.40.4
0.60.6
0.80.8
1.01.0
00 66 1212 1818 2424 3030 3636 4242 4848 5454
AzacitidineAzacitidineSupportive CareSupportive Care
MonthsMonths
++++++++
++
++++
++++++ ++++ ++++
++++++
++++
++++++++++++
++
++++ ++++++ ++++++++++
++++++++
++++++++++
++++++++
++++++
p=0.007
Silverman L, et al. Randomized Controlled Trial of Azacitidine in Patients with MDS: A Study of the CALGB
J Clin Oncol 2002. 18:2414-26. Reprinted with permission from the American Society of Clinical Oncology.
Survival: Landmark AnalysisSurvival: Landmark Analysis
0 12 24 30 42 546 18 36 48
Pro
bab
ilit
y of
Su
rviv
al
0.0
0.2
0.4
0.6
0.8
1.0
Months
AzacitidineSupportive Care
p=0.1
0.0
0.2
0.4
0.6
0.8
1.0
Pro
bab
ilit
y of
Su
rviv
al
Months from 6-month Landmark
Induction AzacitidineCrossed before 6 monthsDid not cross before 6 months
0 10 20 30 40 505 15 25 35 45
p=0.03
Silverman L, et al. Randomized Controlled Trial of Azacitidine in Patients with MDS: A Study of the CALGB
J Clin Oncol 2002. 18:2414-26. Reprinted with permission from the American Society of Clinical Oncology.
Time to Death or AML Transformation in RAEB Time to Death or AML Transformation in RAEB and RAEB-T Patients ≥ 65 Years of Ageand RAEB-T Patients ≥ 65 Years of Age
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 20 40 60 80 100Time (28 day months)
Pro
port
ion
Su
rviv
ing
Log-rank P=0.008Hazard ratio (HR)=0.52 (95% CI: 0.32,
0.85)
24% difference (95% CI: 5%, 43%)2
9.9 month difference (95% CI: 1.5, 15.5)1
• 48% less risk of death or AML
• 92% prolongation to death or AML
Azacitidine (N=31)Supportive care (N=37)
24
1 Hodges, Lehmann. Ann Math Statistics. 1963;34:598-6112 Greenwood M. The Natural Duration of Cancer. 1926.
Silverman et. al. ASH Meeting Dec 9-13, 2005. Abstract 2524 and Poster Presentation.
Median Survival:Median Survival:FAB-based Risk GroupsFAB-based Risk Groups
Median Survival - FAB risk groups
19.5
34.7
9.0
13.2
0
5
10
15
20
25
30
35
40
High-Risk Low-Risk
Mo
nth
s
VIDAZA
Observationp=0.0043
p=0.0820
Similar findings for Predicted Survival Risk Groups.
Leukopenia: 43% (43 Pts)Leukopenia: 43% (43 Pts)
Neutropenia: 58%Neutropenia: 58%
Thrombocytopenia: 52% (51 Pts)Thrombocytopenia: 52% (51 Pts)
Erythema at Injection Site: 35%Erythema at Injection Site: 35%
N&V: 4% (6 Pts)N&V: 4% (6 Pts)**
Treatment Related Mortality: <1%Treatment Related Mortality: <1% (4 Pts- 3 (4 Pts- 3 Infections) Infections)
No DiarrheaNo Diarrhea**, Elevated Transaminases, Elevated Transaminases
Adverse EventsAdverse Events
Silverman LR, et. al. Silverman LR, et. al. J Clin OncolJ Clin Oncol 2002;20:2429-40. 2002;20:2429-40. Silverman L. Silverman L. Cancer MedicineCancer Medicine. 2000a; Edition 5:1931-. 2000a; Edition 5:1931-46.46.Silverman L, et. al. Silverman L, et. al. Cancer Inves.Cancer Inves. 1999;17(Suppl):4-5: 1999;17(Suppl):4-5:[5a].[5a].Silverman LR, et. al. Silverman LR, et. al. Proc Am Soc Clin OncolProc Am Soc Clin Oncol 1998;17:53a.1998;17:53a.
*Pertains only to adverse events with CALGB 9221.
Rates of Bleeding and Infection in Patients Rates of Bleeding and Infection in Patients Treated with Azacitidine vs. Supportive Care: Treated with Azacitidine vs. Supportive Care: CALGB 9221CALGB 9221
Number of PatientsNumber of Patients (number of patients per patient-year of exposure)(number of patients per patient-year of exposure)
AzacitidineAzacitidine Supportive CareSupportive Care
All PatientsAll Patients N=150N=150 N=92N=92
Infections - Infections - TotalTotal
89 (0.64)89 (0.64) 41 (0.95)41 (0.95)
Bleeding - TotalBleeding - Total 77 (0.56)77 (0.56) 26 (0.60)26 (0.60)
Patients with Patients with RAEB & RAEB-RAEB & RAEB-t t 65 years 65 years N=51N=51 N=37N=37
Infection - TotalInfection - Total 31 (0.38)31 (0.38) 19 (0.76)19 (0.76)
Bleeding - TotalBleeding - Total 26 (0.32)26 (0.32) 11 (0.44)11 (0.44)
Silverman et. al. ASH Meeting Dec 9-13, 2005. Abstract 2525 and Poster Presentation.
5-aza in MDS-RA5-aza in MDS-RAPlatelet ResponsePlatelet Response
15 Eligible
Major Response = 47%
aTTR = 3 cycles
aRD = 17 cycles+ (2 – 68)
aTTR = average time to responseaRD = average response duration
0
1,000
2,000
3,000
4,000
5,000
6,000
7,000
1 2 3 4 5 6 7 8 9 10 11 12 13
Azacitidine Cycles 1-13
WBCANC
5-aza in RARS
5-aza in MDS5-aza in MDS
0
5
10
15
20
25
30
35
40
45
50
55
60
RA RARS RAEB CMML RAEB-T Total
ResponseCRPR
Resp
on
se (
%)
5-aza in MDS: CMML5-aza in MDS: CMML
CMMLCMML
(MDS)(MDS)
CMMLCMML
(MPD)(MPD)
NN 66 1818
CRCR 33%33% 33%33%
PRPR 0%0% 22%22%
Time to ResponseTime to Response 11 22
Response DurationResponse Duration 13+13+ 7+7+
Times to First Response and from First Response Times to First Response and from First Response to Best Response Using IWG MDS Response to Best Response Using IWG MDS Response CriteriaCriteria
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Time to First Response (CR, PR, HI [n=114])
Time From First Responseto Best Response (CR, PR [n=36])
Time (cycles)
Cu
mu
lati
ve P
rob
ab
ilit
y
Silverman et. al. ASH Meeting Dec 9-13, 2005. Abstract 2526 and Poster Presentation.
G-CSF Increases Hematological Response G-CSF Increases Hematological Response Among Patients with MDS Treated with Among Patients with MDS Treated with
AzacitidineAzacitidine
Retrospective review of 86 MDS patients treated with Retrospective review of 86 MDS patients treated with Azacitidine (avg 10.8 cycles)Azacitidine (avg 10.8 cycles)
49 also received EPO, G-CSF or both, 37 did not49 also received EPO, G-CSF or both, 37 did not
2 groups did not differ in number of cycles of aza 2 groups did not differ in number of cycles of aza received or FAB MDS subtypereceived or FAB MDS subtype
The addition of G-CSF improved overall hematological The addition of G-CSF improved overall hematological response, erythroid and platelet response response, erythroid and platelet response
Rossetti et al. Blood 2006;108(11):A4868.Rossetti et al. Blood 2006;108(11):A4868.
G-CSF Increases Hematological Response G-CSF Increases Hematological Response Among Patients with MDS Treated with Among Patients with MDS Treated with
AzacitidineAzacitidine
TreatmentTreatment Overall Hematological Overall Hematological ResponseResponse
P -P -valuevalue
Aza AloneAza Alone 51% (19/37)51% (19/37)
Aza + EPOAza + EPO 50% (6/12)50% (6/12) P=.09P=.09
Aza + G-CSF +/- Aza + G-CSF +/- EPOEPO
84% (31/37)84% (31/37)
Aza without G-CSFAza without G-CSF 51% (25/49)51% (25/49) P=.003P=.003
Rossetti et al. Blood 2006;108(11):A4868.Rossetti et al. Blood 2006;108(11):A4868.
Azacitidine Survival StudyAzacitidine Survival Study
Azacitidine Survival Trial Study DesignAzacitidine Survival Trial Study Design
Open label, randomized, parallel-groupOpen label, randomized, parallel-group
Patient Population: Patient Population:
– MDS with RAEB or RAEB-tMDS with RAEB or RAEB-t
– IPSS score INT-2 or HighIPSS score INT-2 or High
Status: Status:
– 358 enrolled (354 planned)- enrollment complete Aug 358 enrolled (354 planned)- enrollment complete Aug 7, 2006. 7, 2006. 112 investigators in 15 countries.112 investigators in 15 countries.
Azacitidine Survival StudyAzacitidine Survival Study
Survival Study DesignSurvival Study Design
Azacitidine 75 mg/mAzacitidine 75 mg/m22 x 7 days x 7 daysEvery 28 daysEvery 28 days
Standard of care optionsStandard of care optionsconsist of:consist of:1. Best supportive care1. Best supportive care2. Low-dose Ara-C2. Low-dose Ara-C3. Standard chemotherapy3. Standard chemotherapy
Patient randomized.Patient randomized.
BSC included in BSC included in both arms.both arms.
ResultsResults
Median survival: Median survival:
– 24.4 months for Azacitidine vs 15 months for 24.4 months for Azacitidine vs 15 months for conventional care regimens (p-value = 0.0001)conventional care regimens (p-value = 0.0001)
– 9.4 months median survival benefit for patients 9.4 months median survival benefit for patients on azacitidine compared to CCRon azacitidine compared to CCR
Aza extends overall survival by 74%Aza extends overall survival by 74%
– HR = 0.58 (95% CI: 0.43-0.77) HR = 0.58 (95% CI: 0.43-0.77)
Two-year survival rate: Two-year survival rate:
– 50.8% for azacitidine vs 26.2% for CCR (p < 50.8% for azacitidine vs 26.2% for CCR (p < 0.0001)0.0001)
Treatment AlgorithmTreatment Algorithm
SCT Candidate
Yes No
Int-2/High Low/Int-1 Int-2/High
AlloSCT EPO/G-CSF MTIs Thalidomide
MTIs Revlimid (5q-)
No Response
Clinical Trial (HDAC, FTI)
? MTIs
? MTIs
Maintenance Azacitidine Post Allo-SCT in Maintenance Azacitidine Post Allo-SCT in AML & High-Risk MDS: Dose/Schedule AML & High-Risk MDS: Dose/Schedule StudyStudy
5Unrelated7Related
Donor HLA Compatibility8Refractory disease4In remission
Disease Status at Time of Transplant
4Patients with MDS
8Patients with AML
56 (25-66) yearsMedian Age (Range)
Evaluable PatientsEvaluable Patients(n = 12)(n = 12)
Soriano et al. Blood 2006;108(11):A3668.
Maintenance Azacitidine post Allo-SCT in Maintenance Azacitidine post Allo-SCT in AML & High-Risk MDS: Dose/Schedule AML & High-Risk MDS: Dose/Schedule StudyStudy
At a median follow-up of 5 months post Allo-SCT, At a median follow-up of 5 months post Allo-SCT, no pts had relapsedno pts had relapsed
No drug-related induction of GVHD was observedNo drug-related induction of GVHD was observed
All pts were 100% donor chimeras at azacitidine All pts were 100% donor chimeras at azacitidine initiationinitiation
At 8 mg/mAt 8 mg/m2 2 /day, azacitidine produced detectable /day, azacitidine produced detectable hypomethylationhypomethylation
Soriano et al. Blood 2006;108(11):A3668.
32
2130
8
4
12
11
7
0
8
0
10
20
30
40
50 Complete Response
Partial Response
Hematologic Improvement
Perc
en
t of
Pati
en
ts
8421Azacitidine
N=25
9221Azacitidine
as Randomized
N=27
9221Supportive
care N=12
8921Azacitidine
N=28
9221Azacitidine
after Supportive care
N=13IV SC
Response Rates (CR + PR + HI) for WHO AML Response Rates (CR + PR + HI) for WHO AML Patients Using MDS Response Criteria by StudyPatients Using MDS Response Criteria by Study
48
32
37
16
Silverman et. al. ASH Meeting Dec 9-13, 2005. Abstract 1848 and Poster Presentation.
5-aza in AML5-aza in AML(( 20% BM blasts) 20% BM blasts)
0
5
10
15
20
25
30
CR PR SD
Perc
en
t
15 patients, mean age = 68 yrs
Azacitidine in AML: WPCIAzacitidine in AML: WPCI(WHO Criteria)(WHO Criteria)
N = 20
Mean age = 68 yrs (44-80)
CR = 4 (20%)
PR = 5 (25%)
HI = 3 (15%)
ORR = 60%
5-aza in AML5-aza in AML(BM blast count (BM blast count 30%)30%)
N = 4
Mean age = 75 yrs (68-79)
Avg. survival = 13.5 months
CR = 25%
PR = 50%
0
5
10
15
20
25
CR PR SD NR
5-aza in AML: Survival5-aza in AML: SurvivalM
on
ths
Average survival in responders = 15+ months (All with PS ≤ 1 while being
treated)
o = Taken to HSCT
+ = Mean
Azacitidine + Gemtuzumab as Induction Azacitidine + Gemtuzumab as Induction and Consolidation in High-Risk MDS and and Consolidation in High-Risk MDS and AMLAML
10 of 13 (77%) patients achieved a CR10 of 13 (77%) patients achieved a CR
Reductions in BM & peripheral blasts observed in Reductions in BM & peripheral blasts observed in all patientsall patients
10 of 13 pts required 2 courses of induction therapy10 of 13 pts required 2 courses of induction therapy
12 of 13 pts were treated in an outpatient setting 12 of 13 pts were treated in an outpatient setting
6 of 13 pts required no hospitalization6 of 13 pts required no hospitalization
7 of 13 pts hospitalized (median: 16 days [range: 4-7 of 13 pts hospitalized (median: 16 days [range: 4-47])47])
Nand et al. Blood 2006;108(11):A1981
0 2 4 6 8 10 12 14 16 18
Months
0
.1
.2
.3
.4
.5
.6
.7
.8
.9
1.0
Cu
mu
lativ
e S
urvi
val
Nand et al. Blood 2006;108(11):A1981
Azacitidine + Gemtuzumab as Induction and Azacitidine + Gemtuzumab as Induction and Consolidation in High-Risk MDS and AMLConsolidation in High-Risk MDS and AML
Thank YouThank You
