Embed Size (px)
Citation preview
11
Emerging Therapies Emerging Therapies in MDS: A Focus on in MDS: A Focus on EpigeneticsEpigenetics
Click to edit Master subtitle styleClick to edit Master subtitle style
22
Myelodysplastic Syndrome (MDS) Myelodysplastic Syndrome (MDS) EpidemiologyEpidemiology
10,000-15,000 estimated new cases/year in US (adults)10,000-15,000 estimated new cases/year in US (adults) More common than acute myeloid leukemia (AML)More common than acute myeloid leukemia (AML)
– 8,000 new cases/year in US8,000 new cases/year in US Predominantly a disease of the elderlyPredominantly a disease of the elderly
– Median age > 60Median age > 60
– Incidence greater in men than in womenIncidence greater in men than in women
– Incidence increases with age Incidence increases with age Median survival 3 months to 6 years depending on risk Median survival 3 months to 6 years depending on risk
categorycategory
Myelodysplastic syndromes detailed guide. American Cancer Society. Available at www.cancer.org. Accessed 6/20/06. Xie Y, et al. Cancer. 2003;97(9):2229-35; American Cancer Society, www.cancer.org; Aplastic Anemia and MDS International Foundation, www.aamds.org; Kurzrock R. Semin Hematol. 2002;39(3 Suppl 2):18-25; Steensma DP, Tefferi A. Leuk Res. 2003;27(2):95-120. Greenberg P, et al. Blood. 1997;89:2079-88.
33
Risk Factors for MDSRisk Factors for MDS
Greatest risk factor appears to be advancing ageGreatest risk factor appears to be advancing age– 80%80%90% of all patients with these disorders > than 60 years90% of all patients with these disorders > than 60 years
Previous cancer therapyPrevious cancer therapy– Mechlorethamine, procarbazine, chlorambucil, etoposide, Mechlorethamine, procarbazine, chlorambucil, etoposide,
teniposide (with or without concomitant radiation therapy) teniposide (with or without concomitant radiation therapy) and other chemotherapy agentsand other chemotherapy agents
Exposure to environmental toxinsExposure to environmental toxins– Benzene, organic solvents, pesticides, radiationBenzene, organic solvents, pesticides, radiation
Tobacco smokeTobacco smoke Cigarette smokingCigarette smoking Congenital disordersCongenital disorders Familial disorderFamilial disorder Male sexMale sexMyelodysplastic syndromes detailed guide. American Cancer Society. Available at www.cancer.org; accessed 6/20/06.Frogge MH, et al. CE monograph published by Oncology Education Services, Inc. Pittsburgh, PA, 2005. List AF, et al. Hematology. 2004;297-317.
44
Symptoms of MDSSymptoms of MDS
Many patients have no apparent symptoms, but are diagnosed after routine Many patients have no apparent symptoms, but are diagnosed after routine laboratory tests uncover abnormalities in the circulating blood cellslaboratory tests uncover abnormalities in the circulating blood cells
Fatigue is the most common symptom of MDS Fatigue is the most common symptom of MDS Early symptoms of MDS may include:Early symptoms of MDS may include:
– BruisingBruising– Increased bleeding (ie, nose and gum bleeds)Increased bleeding (ie, nose and gum bleeds)– RashRash– Shortness of breathShortness of breath– Rapid heart rateRapid heart rate– Weight lossWeight loss– FeverFever– Loss of appetiteLoss of appetite
None of these symptoms are specific to MDS, and may be attributable to other None of these symptoms are specific to MDS, and may be attributable to other conditionsconditions
Myelodysplastic syndromes detailed guide. American Cancer Society. Available at www.cancer.org. Accessed 6/20/06.Frogge MH, et al. CE monograph published by Oncology Education Services, Inc, Pittsburgh, PA, 2005.
55
Diagnosis of MDSDiagnosis of MDS
Key FeaturesKey Features Evidence of ineffective hematopoiesis (anemia, Evidence of ineffective hematopoiesis (anemia,
neutropenia, thrombocytopenia)neutropenia, thrombocytopenia) Hypercellular marrow (rarely, hypocellular Hypercellular marrow (rarely, hypocellular
marrow)marrow) Evidence of dysplasia by bone marrow Evidence of dysplasia by bone marrow
examination – typically in more than one lineageexamination – typically in more than one lineage
List AF, et al. Hematology. 2004;297-317.Myelodysplastic syndromes detailed guide. American Cancer Society. Available at www.cancer.org. Accessed 6/20/06.
66
MDS ClassificationMDS Classification
French-American-British (FAB)French-American-British (FAB) World Health Organization (WHO)World Health Organization (WHO) International Prognostic Scoring System (IPSS)International Prognostic Scoring System (IPSS)
Bennett J, et al. Br J Haematol. 1982;51:189-99.Harris N, et al. Ann Oncol. 1999;10:1419-32.Greenberg P, et al. Blood. 1997;89:2079-88.
77
MDS FAB (French-American- MDS FAB (French-American- British) Classification British) Classification
Category
% Blasts in Bone Marrow
Survival in
Months
RARA (Refractory anemia) (Refractory anemia)
RARSRARS (Refractory anemia with ringed sideroblasts) (Refractory anemia with ringed sideroblasts)
RAEBRAEB (Refractory anemia with excess blasts) (Refractory anemia with excess blasts)
RAEB-TRAEB-T (Refractory anemia with excess blasts in (Refractory anemia with excess blasts in transformation) transformation)
CMMoLCMMoL (Chronic myelomonocytic leukemia) (Chronic myelomonocytic leukemia)
< 5%< 5%
< 5%< 5%
5-20%5-20%
21-30%21-30%
1-20%1-20%
19–6419–64
21–7621–76
7–157–15
5–125–12
8–60+8–60+
List AF, et al. The myelodysplastic syndromes. In: Wintrobe’s Hematology 2003.Bennett J, et al. Br J Haematol. 1982;51:189-99.
88
MDS World Health Organization MDS World Health Organization (WHO) Classification(WHO) Classification
Revised MDS classification proposed in 2000Revised MDS classification proposed in 2000 Changes included:Changes included:
– Eliminated RAEB-TEliminated RAEB-T– Redefined AML as Redefined AML as 20% blasts 20% blasts– Recognize prognostic impact of multilineage Recognize prognostic impact of multilineage
dysplasia in RA and RARS and isolated interstitial dysplasia in RA and RARS and isolated interstitial deletion of chromosome 5qdeletion of chromosome 5q
– CMMoL = Myelodysplastic/myeloproliferative CMMoL = Myelodysplastic/myeloproliferative disorderdisorder
May provide more uniform and accurate prognostic dataMay provide more uniform and accurate prognostic dataSteensma DP, et al. Leuk Res. 2003;27:95-120.Harris N, Jaffe E, Diebold J, et al. Ann Oncol. 1999;10:1419-32.
99
MDS International Prognostic MDS International Prognostic Scoring System (IPSS)Scoring System (IPSS)
The first comprehensive prognostic scoring The first comprehensive prognostic scoring system adoptedsystem adopted
Patients are stratified into four well-defined Patients are stratified into four well-defined risk groups according to survival and AML risk groups according to survival and AML transformationtransformation
Scoring system based on percentage of bone Scoring system based on percentage of bone marrow blasts, karyotype, and cytopeniasmarrow blasts, karyotype, and cytopenias
Greenberg P, et al. Blood. 1997:89(6):2079-88.
1010
MDS Subtypes IPSSMDS Subtypes IPSS
Greenberg P, et al. Blood.1997:89(6):2079-88.
*Good: Normal, -Y, del(5q), del(20q); Poor: Complex(>3abnl) or Chr 7 abnl; Intermediate: All others.
Score
Prognostic Variable 0 0.5 1.0 1.5 2.0
Bone marrow blast (%)Bone marrow blast (%)
Karyotype*Karyotype*
CytopeniasCytopenias
< 5< 5
GoodGood
0/10/1
5-105-10
IntermediateIntermediate
2/32/3
––
PoorPoor
11-2011-20 21-3021-30
Prognosis Score IPSS Subgroup
Median AML Transformation
(yrs)Median Survival
(yrs)
00
0.5-1.00.5-1.0
1.5-2.01.5-2.0
>2.5>2.5
LowLow
Intermediate-1Intermediate-1
Intermediate-2Intermediate-2
HighHigh
9.49.4
3.33.3
1.11.1
0.20.2
5.75.7
3.53.5
1.21.2
0.40.4
1111
Causes of Death in MDSCauses of Death in MDS
Greenberg P, et al. Blood. 1997;89:2079-2088.
No. of Patients Who:
SubgroupsNo. of
Patients Died (%)Died With
Leukemia (%)Died Without Leukemia (%)
LowLow 235235 113 (48)113 (48) 22 (19)22 (19) 91 (81)91 (81)
Int-1Int-1 295295 181 (61)181 (61) 55 (30)55 (30) 126 (70)126 (70)
Int-2Int-2 171171 147 (86)147 (86) 49 (33)49 (33) 98 (67)98 (67)
HighHigh 5858 51 (88)51 (88) 23 (45)23 (45) 28 (55)28 (55)
TotalTotal 759759 492 (65)492 (65) 149 (30)149 (30) 343 (70)343 (70)
1212
Goals of Therapy in MDSGoals of Therapy in MDS
Select the therapy best suited for the individualSelect the therapy best suited for the individual– Performance status, disease classification, IPSS Performance status, disease classification, IPSS
score (cytogenetics, cytopenias, BM blasts), and score (cytogenetics, cytopenias, BM blasts), and treatment tolerancetreatment tolerance
Low/Int-1 IPSS: Improve blood counts (decrease Low/Int-1 IPSS: Improve blood counts (decrease transfusions and infections)transfusions and infections)
Improve quality of lifeImprove quality of life Int-2/high-risk IPSS: Prolong survival and delay Int-2/high-risk IPSS: Prolong survival and delay
leukemic progressionleukemic progression– Possible cure of diseasePossible cure of disease
List AF, et al. Hematology (Am Soc Hematol Educ Program). 2004;297-317. Cheson BD, et al. Blood. 2000:96:3671. NCCN Myelodysplastic Panel Members. Available at: http://www.nccn.org/professionals/physician_gls/PDF/mds.pdf
1313
MDS TreatmentsMDS Treatments
Best supportive careBest supportive care– Transfusions (RBCs, platelets)Transfusions (RBCs, platelets)– Chelation therapyChelation therapy– Colony-stimulating factors (EPO Colony-stimulating factors (EPO ±± G-CSF or G-CSF or
GM-CSF)GM-CSF) ChemotherapyChemotherapy Anti-thymocyte globulin (ATG) ± cyclosporin in patients with hypocellular Anti-thymocyte globulin (ATG) ± cyclosporin in patients with hypocellular
MDSMDS Stem cell transplantStem cell transplant
– Best candidates are younger patients with low % blasts and preserved Best candidates are younger patients with low % blasts and preserved platelet countsplatelet counts11
– Median age at transplant (IBMTR data) = 38 yrs oldMedian age at transplant (IBMTR data) = 38 yrs old11
Hypomethylating agentsHypomethylating agents Immunomodulatory drugsImmunomodulatory drugs Other novel agentsOther novel agents
– HDAC inhibitors, farnesyl transferase inhibitors etc.HDAC inhibitors, farnesyl transferase inhibitors etc.
1Sierra J, et al. Blood. 2002;100:1997-2004.
1414
IPSS CATEGORY Treatment
Low,INT-1
Supportivecare
Anemia
Serum Epo> 500 mU/ml
Thrombocytopenia,neutropenia
Clinicallysignificantcytopenia(s)
Serum Epo≤ 500 mU/ml
HLADR-15 +
HLADR-15 -
Epoetin alfa(EPO)± G-CSF
Noresponse
Azacitidine/DecitabineorClinical trial
Noresponse
Clinicaltrial
AntithymocyteGlobulin (ATG),Cyclosporin A
Azacitidine/DecitabineorClinical trial
Noresponse
Noresponse
Clinicaltrial
Azacitidine/Decitabine
Noresponse
ATGorClinical trial
NCCN Guidelines-Low RiskNCCN Guidelines-Low Risk
National Comprehensive Cancer Network (NCCN) guidelines v.4.2006. For more information see: http://www.nccn.org.
del(5q) Lenalidomide No response
Follow appropriate pathway below
1515
INT-2,HIGH
Not intensivetherapy candidate
IntensivetherapyCandidate*
Donoravailable
Yes
No
Hemopoietic stem celltransplant (HSCT)
High intensity therapyr
orSupportive care
Azacitidine/DecitabineorClinical trialorSupportive care
*Based on age, performance status and absence of major comorbid medical conditions that would preclude high dose therapy. National Comprehensive Cancer Network (NCCN) guidelines v.4.2006.
High-Intensity Therapy:• Clinical Trials (preferred)
• Investigational therapy preferred.• Standard induction therapy if investigational
protocol unavailable or as a bridge to HSCT.(See text for more detail)
• Hemopoietic stem cell transplant (HSCT)• allogeneic-matched sibling including standard
and (experimental) reduced intensity preparativeapproaches or matched unrelated donor (MUD)
IPSS CATEGORY TreatmentTreatment
NCCN Guidelines-High RiskNCCN Guidelines-High Risk
1616
Overview of Overview of Epigenetics and Its Epigenetics and Its Role in MDSRole in MDS
1717
SAM SAH
NH2
H
N
NO H
Cytosine
NH2
CH3
N
NO H
5-Methyl-Cytosine
MTASE
Cytosine DNA MethylationCytosine DNA Methylation
SAM = S-adenosyl methionine; SAH = S-adenosyl homocysteine. www.mdanderson.org/leukemia/methylation.
1818
MM MMMM
MMMMMMMMMMMMMMMMMM
Expressed (or ready for expression)Expressed (or ready for expression)
SilencedSilencedImprinted genes, Inactive XImprinted genes, Inactive X
Ectopically Silenced Genes (e.g. tumor suppressor genes)Ectopically Silenced Genes (e.g. tumor suppressor genes)
Hypermethylation and SilencingHypermethylation and Silencing
Courtesy of Issa, JP
1919
Tumor Suppressor Gene Tumor Suppressor Gene MethylationMethylation
p15p15INK4bINK4b
– Inhibitor of the cyclin-dependent kinases Inhibitor of the cyclin-dependent kinases CDK4 and CDK6 CDK4 and CDK6
– Plays a role in transforming growth factor-Plays a role in transforming growth factor- (TGF- (TGF-)-mediated growth inhibition )-mediated growth inhibition
– Inactivated by hypermethylation in Inactivated by hypermethylation in hematopoietic neoplasms (AML, ALL, MDS, hematopoietic neoplasms (AML, ALL, MDS, and Burkitt’s lymphoma)and Burkitt’s lymphoma)
Quesnel, et al. Blood. 1998;91:2985.
2020
0
20
40
60
80
100
0 20 40 60 80 100 120 140
t (months)
p s
urv
ival
Association Between Survival and Association Between Survival and p15 Methylation Status in MDSp15 Methylation Status in MDS
Quesnel B, et al. Blood. 1998;91:2985-90.
Methylated
Unmethylated
P = .049
2121
Hypomethylating Hypomethylating AgentsAgents
2222
Hypomethylating Cytosine Hypomethylating Cytosine AnalogsAnalogs
Santini V, et al. Ann Intern Med. 2001;134(7):573-86.
N O
NH2
N
N O
NH2
NCH3
N O
NH2
NN
Ribose
N O
NH2
NN
Deoxyribose
5-aza-cytidine 5-aza-2′-deoxycytidine5-methyl-cytosineCytosine
(azacitidine) (decitabine)
2323
How Hypomethylating AgentsHow Hypomethylating Agents WorkWork
Act as cytosine nucleoside analogs that reverse Act as cytosine nucleoside analogs that reverse aberrant DNA methylationaberrant DNA methylation
Incorporate into DNA and trap DNA-Incorporate into DNA and trap DNA-methyltransferase, depleting cells of DNA-methyltransferase, depleting cells of DNA-methyltransferasemethyltransferase
Decitabine contains deoxyribose and is incorporated Decitabine contains deoxyribose and is incorporated into DNA while azacitidine, which contains ribose, is into DNA while azacitidine, which contains ribose, is incorporated into both RNA and DNAincorporated into both RNA and DNA
– 10-20% azacitidine incorporation into DNA10-20% azacitidine incorporation into DNA
Leone G, et al. Haematologica. 2002;87:1324-41; Kuykendall JR. The Annals of Pharmacotherapy.2005;39:1700-1709.
2424
Mechanism of Epigenetic TherapyMechanism of Epigenetic Therapy
STOP
Fully methylated DNA
Silencing
DNAreplication Mtase
Epigenetic Therapy
STOP
MaintainedSilencing
Fully methylated DNA
Unmethylated DNA
Reactivated GeneExpression
Hemi-methylated DNA
CH3
CH3CH3CH3
CH3
CH 3
CH 3
CH 3
CH3 CH3 CH
3CH
3
CH3
CH3CH3CH3
CH3
CH 3
CH 3
CH 3
CH3 CH3 CH
3CH
3
CH 3
CH 3
CH 3
CH3 CH
3
CH3
CH3 CH3 CH3 CH3 CH3 CH3
CH3 CH3 CH3 CH3 CH3CH3
Differentiation - Apoptosis - Senescence - Enhanced Immune Response
Courtesy of Issa JP.
2525
Phase 3 Clinical Phase 3 Clinical Experience with Experience with Decitabine in Advanced Decitabine in Advanced MDSMDS
2626
Decitabine Phase 3 Decitabine Phase 3 Study Design (D-0007)Study Design (D-0007)
Open-label, 1:1 randomized, multicenter study in US and CAOpen-label, 1:1 randomized, multicenter study in US and CA Schedule: 3-hour infusion of 15 mg/mSchedule: 3-hour infusion of 15 mg/m22 q 8 hrs x 3 days q 8 hrs x 3 days
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
*Antibiotics, growth factors, and/or transfusions.Kantarjian , et al. Cancer. 2006;106:1794-1803.
2727
Decitabine Phase 3Decitabine Phase 3Patient Eligibility and Study Design Patient Eligibility and Study Design
Patient populationPatient population– de novo or secondary MDSde novo or secondary MDS– IPSS IPSS 0.5; all FAB subgroups 0.5; all FAB subgroups
Primary endpointsPrimary endpoints– Overall response rate (CR + PR), IWG criteria Overall response rate (CR + PR), IWG criteria – Time to AML transformation or deathTime to AML transformation or death
In the primary endpoint analysis, a In the primary endpoint analysis, a PP value less than .024 value less than .024 was required to achieve statistical significancewas required to achieve statistical significance
Secondary endpointsSecondary endpoints– Duration of response, cytogenetic response rate, transfusion Duration of response, cytogenetic response rate, transfusion
requirements, QOL, survival, febrile neutropenia, toxicityrequirements, QOL, survival, febrile neutropenia, toxicity
Kantarjian HM, et al. Cancer. 2006;106:1794-1803.
2828
Decitabine Phase 3 Decitabine Phase 3 IWG Response Criteria IWG Response Criteria
Independent review of bone marrow and best response Independent review of bone marrow and best response Complete response (CR) Complete response (CR)
– <5% blasts in bone marrow <5% blasts in bone marrow
– Hgb Hgb 11, ANC 11, ANC 1500, platelets > 100,000, no blasts 1500, platelets > 100,000, no blasts
– No dysplasia No dysplasia
– No transfusions or growth factorsNo transfusions or growth factors
– Minimum duration 8 weeks Minimum duration 8 weeks Partial response (PR) Partial response (PR)
– 50% decrease in marrow blasts50% decrease in marrow blasts
– Other response criteria same as CROther response criteria same as CRIWG = international working group; Hgb = hemoglobin; ANC = absolute neutrophil count.Kantarjian HM, et al. Cancer. 2006;106:1794-1803.Cheson BD. Blood. 2000;96:3671-74.
2929
Decitabine Phase 3 Decitabine Phase 3 Demographics (ITT Population)Demographics (ITT Population)
Parameters
Decitabine
n = 89 (%)
Supportive Care
n = 81 (%)
Sex (male)Sex (male) 59 (66)59 (66) 57 (70)57 (70)
Median Age Median Age 70 70 7070
Median Time From Diagnosis (months)Median Time From Diagnosis (months) 7.37.3 8.88.8
Type of MDSType of MDS
De novoDe novo
SecondarySecondary77 (87)77 (87)
12 (13)12 (13)
70 (86)70 (86)
11 (14)11 (14)
Previous MDS TherapyPrevious MDS Therapy 20 (22)20 (22) 16 (20)16 (20)
IPSSIPSS
High risk High risk
Intermediate-2Intermediate-2
Intermediate-1 Intermediate-1
23 (26)23 (26)
38 (43)38 (43)
28 (31)28 (31)
21 (26)21 (26)
36 (44)36 (44)
24 (30)24 (30)
ITT = intent to treat.ITT = intent to treat.Kantarjian HM, et al. Kantarjian HM, et al. CancerCancer. 2006;106:1794-1803.. 2006;106:1794-1803.
3030
Decitabine Phase 3 Decitabine Phase 3 Response to Decitabine (ITT)Response to Decitabine (ITT)
IWG Response Rate,Onset, and Duration*
Decitabine (n = 89)
Supportive Care(n = 81)
Overall Response Rate (CR+PR)Overall Response Rate (CR+PR)
Complete response (CR)Complete response (CR)
Partial response (PR)Partial response (PR)
Hematologic improvement (HI)Hematologic improvement (HI)
15 (17%)15 (17%)††
8 (9%)8 (9%)
7 (8%)7 (8%)
12 (13%)12 (13%)
0 (0%)0 (0%)
0 (0%)0 (0%)
0 (0%)0 (0%)
6 (7%)6 (7%)
††P value < .001 from two-sided Fisher’s exact test
Onset and Duration of Response (Months) Onset and Duration of Response (Months)
Median time to response (CR+PR)Median time to response (CR+PR)
Median duration of response (CR+PR)Median duration of response (CR+PR)
3.3 (2.0 – 9.7)3.3 (2.0 – 9.7)
10.3 (4.1 - 13.9)10.3 (4.1 - 13.9)‡‡
N/AN/A
Best response observed after 2 cycles (median number of cycles = 3)*Cheson BD. Blood. 2000 96:3671-74.Kantarjian HM, et al. Cancer. 2006;106:1794-1803.‡‡For patients with a confirmed date of progression.
3131
Response in Patients Response in Patients with AML at Baselinewith AML at Baseline
*IWG AML Response Criteria. †One patient was a CRi (morphologic complete remission with incomplete blood count recovery). Cheson et al. J Clin Oncol. 2003;21:4642-49; Kantarjian HM, et al. Cancer. 2006;106:1794-1803; Data on File, MGI PHARMA.
Decitabine
n = 9 (%)
Supportive Care
n = 3 (%)
Overall Overall Response*Response*
5 (56)5 (56)
3 (33)3 (33)
2 (22)2 (22)
Complete Complete ResponseResponse††
0 (0)0 (0)
0 (0)0 (0)
Partial ResponsePartial Response 0 (0)0 (0)
3232
Decitabine Phase 3 Decitabine Phase 3 Median Time to AML or DeathMedian Time to AML or Death
MDS GroupDecitabine
Months (range)Supportive Care Months (range)
Log-rankP Value
All PatientsAll Patients12.1 (0.312.1 (0.3**-22.3)-22.3)
n = 89n = 89
7.8 (0.3-21.07.8 (0.3-21.0**))
n = 81n = 81.160.160
Treatment Treatment NaiveNaive
12.3 (0.312.3 (0.3**-20.1-20.1**))
n = 69n = 69
7.3 (0.3-21.07.3 (0.3-21.0**))
n = 65n = 65.082.082
Int-2/ Int-2/
High RiskHigh Risk
12.0 (0.412.0 (0.4**-22.3)-22.3)
n = 61n = 61
6.8 (0.3-21.06.8 (0.3-21.0**))
n = 57n = 57.028.028
High RiskHigh Risk9.3 (0.49.3 (0.4**-19.9)-19.9)
n = 23n = 23
2.8 (0.3-13.5)2.8 (0.3-13.5)
n = 21n = 21.010.010
**Censored data.Kantarjian HM, et al. Cancer. 2006;106:1794-1803; Data on File, MGI PHARMA.
3333
Decitabine Phase 3 Decitabine Phase 3 Survival by Response Survival by Response
0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800
Days
0
10
20
30
40
50
60
70
80
90
100
Pe
rce
nt
Aliv
e
Analyzed population = All patients
Nonresponders (N=155)
Responders (N=15)
Kantarjian HM, et al. Cancer. 2006;106:1794-1803.
P = .007
3434
Decitabine Phase 3 Decitabine Phase 3 Cytogenetic EvaluationsCytogenetic Evaluations
Patients Evaluable for Cytogenetic Evaluations
Decitabinen = 26 (%)
Supportive Care
n = 21 (%)
Cytogenetic responsesCytogenetic responses
Major ResponseMajor Response
Minor ResponseMinor Response
9* (35)9* (35)
1 (4)1 (4)
2 (10)2 (10)
––
*1 additional patient who was randomized to supportive care crossed over to decitabine and had a major cytogenetic response and clinical CR.Kantarjian HM, et al. Cancer. 2006;106:1794-1803.
3535
Decitabine Phase 3: Percent of Patients Decitabine Phase 3: Percent of Patients RBC Transfusion-Free Per CycleRBC Transfusion-Free Per Cycle
% o
f P
atie
nts
RB
C
Tra
nsf
usi
on
-Fre
e
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6
DecitabineSupportive Care
Note: Last cycles less than 35 days long with 0 transfusions are not considered in this analysis. Kantarjian HM, et al. Cancer. 2006;106:1794-1803.
Decitabine N= 89 83 64 44 37 26 23 Supportive Care N= 81 75 63 40 28 23 15
3636
Quality of Life MeasureQuality of Life Measure Percent Change from Baseline for Percent Change from Baseline for Global Health StatusGlobal Health Status
-25
-15
-5
5
15
25
35
45
% Change From Baseline*
*
Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6
* P < .05 Decitabine
Supportive Care
Kantarjian HM, et al. Kantarjian HM, et al. CancerCancer. 2006;106:1794-1803.. 2006;106:1794-1803.
3737
Decitabine Phase 3 Decitabine Phase 3 Adverse Events (>10% Incidence)Adverse Events (>10% Incidence)
Decitabine
(n = 83)*
Supportive Care
(n = 81)
Grade 3 Grade 4 Grade 3 Grade 4
Hematologic
Neutropenia 10% 77% 25% 25%
Thrombocytopenia 22% 63% 27% 16%
Anemia 11% 1% 14% 1%
Febrile neutropenia 17% 6% 4% 0%
Nonhematologic
Pneumonia 13% 2% 7% 2%
Kantarjian et al. Cancer. 2006;106:1794-1803.*Exposed to decitabine.
3838
Decitabine Phase 3 Decitabine Phase 3 Summary and ConclusionsSummary and Conclusions
Decitabine therapy was superior to supportive care Decitabine therapy was superior to supportive care – Response rate 17% (CR 9%, PR 8%)Response rate 17% (CR 9%, PR 8%)– Durable responses (median 10.3 months) Durable responses (median 10.3 months) – Responders remained or became transfusion Responders remained or became transfusion
independent and symptoms improvedindependent and symptoms improved Delayed time to AML progression or death Delayed time to AML progression or death Responders had longer survival Responders had longer survival
– 24 months responders vs 14 months in non-24 months responders vs 14 months in non-responders (responders (P = P = .007).007)
Well tolerated with manageable toxicity profile Well tolerated with manageable toxicity profile
Kantarjian et al. Kantarjian et al. CancerCancer. 2006;106:1794-1803.. 2006;106:1794-1803.
3939
Decitabine Exposure in Decitabine Exposure in Phase 2 and 3 StudiesPhase 2 and 3 Studies
Multiple cycles of decitabine therapy may be Multiple cycles of decitabine therapy may be required for optimal responserequired for optimal response
Phase 2 Phase 391-01 95-11 97-19 D-0007D-0007
N 29 66 87 89
ORR (CR + PR) 13 (45%) 17 (26%) 23 (26%) 15 (17%)
CR 8 (28%) 14 (21%) 19 (22%) 8 (9%)
PR 5 (17%) 3 (5%) 4 (5%) 7 (8%)
Median # cycles 44 44 44 33
Saba HI, et al. Saba HI, et al. BloodBlood . 2005;106:706a [abstract 2515]. Kantarjian HM, et al. . 2005;106:706a [abstract 2515]. Kantarjian HM, et al. CancerCancer. 2006;106:1794-1803. Saba HI, et al. . 2006;106:1794-1803. Saba HI, et al. Semin Semin HematolHematol. 2005;42(3 suppl 2): S23-S31. Wijermans PW, et al. . 2005;42(3 suppl 2): S23-S31. Wijermans PW, et al. LeukemiaLeukemia. 1997;11:1-5. Wijermans PW, et al. . 1997;11:1-5. Wijermans PW, et al. J Clin OncolJ Clin Oncol..2000;18:956-962.2000;18:956-962.
4040
Alternative Dosing Alternative Dosing with Decitabinewith Decitabine
4141
Decitabine Reduced-Dose Schedule Decitabine Reduced-Dose Schedule (100 mg/m(100 mg/m22/course): 3-Arm Dosing Study/course): 3-Arm Dosing Study
3 decitabine treatment arms:3 decitabine treatment arms:– 10 mg/m10 mg/m22 IV over 1 hr daily x 10 days IV over 1 hr daily x 10 days– 20 mg/m20 mg/m22 IV over 1 hr daily x 5 days IV over 1 hr daily x 5 days – 20 mg/m20 mg/m22 SQ (10 mg SQ BID) daily x 5 days SQ (10 mg SQ BID) daily x 5 days
Preferential randomization to arm with higher CR started after 45Preferential randomization to arm with higher CR started after 45 thth patientpatient
Courses were given every 4 weeksCourses were given every 4 weeks Total = 100 mg/mTotal = 100 mg/m22/course (75% of phase 3 MDS trial dose)/course (75% of phase 3 MDS trial dose) Study groupStudy group
– 95 patients treated (77 MDS, 18 CMML)95 patients treated (77 MDS, 18 CMML)– 65% patients Int-2/High Risk65% patients Int-2/High Risk– 69% male, 65% were 69% male, 65% were 60 yrs of age 60 yrs of age
SQ = subcutaneous; CR = complete response.Kantarjian H, et al. Blood. 2006;108(in press). First Edition Paper, prepublished online Aug 1, 2006; DOI 10.1182/blood-2006-05-021162.
4242
3-Arm Dosing Study: 3-Arm Dosing Study: Overall ResponseOverall Response
Response n = 95 (%)
Complete Response (CR)Complete Response (CR) 32 (34)32 (34)
Partial Response (PR)Partial Response (PR) 1 (1)1 (1)
Marrow CRMarrow CR 10 (11)10 (11)
Marrow CR + other HIMarrow CR + other HI 13 (14)13 (14)
Hematologic Improvement (HI)Hematologic Improvement (HI) 13 (14)13 (14)
Single lineageSingle lineage 9 (9)9 (9)
2 or 3 lineage2 or 3 lineage 4 (4)4 (4)
Objective ResponseObjective Response 69 (72%)69 (72%)
Kantarjian H, et al. Blood. 2006;108(in press). First Edition Paper, prepublished online Aug 1, 2006; DOI 10.1182/blood-2006-05-021162.
4343
Comparison of outcome and side Comparison of outcome and side effects by dose scheduleeffects by dose schedule
Parameter 5 Day IV 5 Day SQ 10 Day IV
nn 6464 1414 1717
4 (24)4 (24)
99
Median duration of therapy in Median duration of therapy in mos (range)mos (range)
5.4 (1.0 – 20.4+)5.4 (1.0 – 20.4+) 9.7 (0.5 – 22.9+)9.7 (0.5 – 22.9+) 10.8 (1.9 – 17.7+)10.8 (1.9 – 17.7+)
Median days to granulocytes Median days to granulocytes recovery*recovery*
2424 1414 2727
Median days to platelet Median days to platelet recoveryrecovery†† 2020 3131 2727
Median days to delivery of Median days to delivery of subsequent coursessubsequent courses
3535 3535 4040
No. courses requiring No. courses requiring hospitalization (%)hospitalization (%)
50 (12)50 (12) 14 (14)14 (14) 23 (23)23 (23)
CR / treated (%)CR / treated (%) 25 (39)25 (39) 3 (21)3 (21)
Median no. coursesMedian no. courses 5 5 8 8
*To 10o 1099/L or above/L or above; †To 50 x 10To 50 x 1099/L or above/L or above; Kantarjian H, et al. Blood. 2006;108(in press). First Edition Paper, prepublished online Aug 1, 2006; DOI 10.1182/blood-2006-05-021162.
4444
3-Arm Dosing Study Data3-Arm Dosing Study DataSummarySummary
Low-dose schedules of decitabine have significant activityLow-dose schedules of decitabine have significant activity– 34% complete response rate* and a 73% objective response 34% complete response rate* and a 73% objective response
raterate†† across all 3 arms across all 3 arms The optimal dose was 20 mg/mThe optimal dose was 20 mg/m22 IV x 5 days (CR = 39%) IV x 5 days (CR = 39%) Primary toxicity across all arms was myelosuppressionPrimary toxicity across all arms was myelosuppression
– Lower frequency vs. higher dose regimenLower frequency vs. higher dose regimen The dose of 10 mg/mThe dose of 10 mg/m22 IV x 10 days was associated with higher IV x 10 days was associated with higher
incidence of myelosuppression and hospitalizationincidence of myelosuppression and hospitalization A dose schedule of 20 mg/mA dose schedule of 20 mg/m22 IV x 5 days represents an excellent IV x 5 days represents an excellent
therapeutic option and offers an alternative dosing scheduletherapeutic option and offers an alternative dosing schedule
*Response criteria for CR and PR were as for AML but required response durability for at least 4 weeks (PR also requiring that blasts decrease by >50%). †CR + PR + marrow CR + HI.Kantarjian H, et al. Blood. 2006;108(in press). First Edition Paper, prepublished online Aug 1, 2006; DOI 10.1182/blood-2006-05-021162.
4545
Phase 3 Clinical Phase 3 Clinical Experience with Experience with Azacitidine in MDSAzacitidine in MDS
4646
Azacitidine Phase 3 Azacitidine Phase 3 Study Design (CALGB 9221)Study Design (CALGB 9221)
RRAANNDDOOMMIIZZEEDD
Supportive Care
Eligible Patients(n = 191)
ASSESS
HI: Continue
Azacitidine+
SupportiveCare
NR: Off study
CR: 3 Cycles
Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
SC: Pts worseningazacitidine
Randomized, crossover trial Schedule: 75 mg/m2/day SQ x 7 days q 28 days
(n = 92)
(n = 99)
4747
Azacitidine Phase 3 Azacitidine Phase 3 Patient Eligibility and Study DesignPatient Eligibility and Study Design
Patient populationPatient population– FAB classification for MDSFAB classification for MDS– Symptomatic cytopenia requiring active therapySymptomatic cytopenia requiring active therapy– Cancer-free for 3 years with no radiation or Cancer-free for 3 years with no radiation or
chemotherapy for 6 previous monthschemotherapy for 6 previous months EndpointsEndpoints
– Analysis of response (CR, PR, improved)Analysis of response (CR, PR, improved)– Time to treatment failureTime to treatment failure– Effects on RBC and plateletsEffects on RBC and platelets– Quality of lifeQuality of life– Overall survivalOverall survival
Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
4848
Azacitidine Phase 3 Azacitidine Phase 3 Response CriteriaResponse Criteria
Complete response (CR)Complete response (CR)– Normal bone marrow or < 5% blasts in the bone marrowNormal bone marrow or < 5% blasts in the bone marrow– Normal peripheral blood countsNormal peripheral blood counts– No blastsNo blasts– No transfusionsNo transfusions
Partial response (PR)Partial response (PR)– ≤ ≤ 50% initial bone marrow blasts50% initial bone marrow blasts– Trilineage responseTrilineage response– No blastsNo blasts– No transfusionsNo transfusions
ImprovedImproved– Monolineage or bilineage responseMonolineage or bilineage response– Transfusions ≤ 50% of baselineTransfusions ≤ 50% of baseline
Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
4949
Azacitidine Phase 3 Azacitidine Phase 3 Demographics (ITT Population)Demographics (ITT Population)
Parameters
Azacitidine
n = 99 (%)
Supportive Care
n = 92 (%)
Sex (male)Sex (male) 72 (73)72 (73) 60 (65)60 (65)
Median Age Median Age 69 69 6767
Median Time From Diagnosis (days)Median Time From Diagnosis (days) 7777 8787
Previous MDS therapyPrevious MDS therapy 16 (16)16 (16) 17 (18)17 (18)
FABFAB
RARA
RARSRARS
RAEB RAEB
RAEB-TRAEB-T
CMMoLCMMoL
Other*Other*
17 (17)17 (17)
5 (5)5 (5)
32 (32)32 (32)
27 (27)27 (27)
7 (7)7 (7)
11 (11)11 (11)
20 (22)20 (22)
3 (3)3 (3)
34 (37)34 (37)
18 (20)18 (20)
7 (8)7 (8)
10 (11)10 (11)
Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
*Includes 19 AML, one classifiable acute leukemia, and one undefined MDS.
5050
Azacitidine Phase 3Azacitidine Phase 3Response RatesResponse Rates
Azacitidine(n = 99)
Supportive Care
(n = 92)
Overall Response (CR + PR)
Complete response
Partial response
Hematologic improvement
16 (16.2%)*
6 (6.1%)
10 (10.1%)
19 (19%)
0%
0%
0%
6%
*P < .0001 (CR + PR)
Median Duration of Response (CR + PR + improved) (months)
15† N/A
†95% CI, 11 to 20 months
Kaminskas E.Kaminskas E. Clin Cancer Res. Clin Cancer Res. 2005;11:3604-82005;11:3604-8. . Silverman LR, et al.Silverman LR, et al. J Clin Oncol. J Clin Oncol. 2002;20:2429-40.2002;20:2429-40.
5151
Azacitidine Phase 3 Azacitidine Phase 3 Duration of ResponseDuration of Response
Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
Median duration of response (CR + PR + improved) = 15 months (95% CI, 11- 20 months)
AzacitidineSupportive Care
1.0
0.8
0.6
0.4
0.2
0.00 6 12 18 24 30 36 42
Pro
bab
ilit
y o
f C
on
tin
uin
g i
n R
emis
sio
n
MonthsNumber of Patients at Risk
Azacitidine 60 51 34 25 15 8 2 1
Observation 5 1 1 1 1 0 0 0
5252
Azacitidine Phase 3 Azacitidine Phase 3 Time to AML Transformation or DeathTime to AML Transformation or Death
Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
Median time to AML or death: azacitidine – 21 months (95% CI, 16-27 months) and supportive care – 12 months (95% CI, 8-15 months)
1.0
0.8
0.6
0.4
0.2
0.00 6 12 18 24 30 36 42
Pro
bab
ilit
y o
f R
emai
nin
g E
ven
t-F
ree
Months
48 54
AzacitidineSupportive Care
Azacitidine 89 69 55 39 28 16 9 2 0 0
1 1Observation 82 51 38 22 15 10 8 3
Number of Patients at Risk
P = .007
5353
Azacitidine Phase 3 Azacitidine Phase 3 Effects on RBC and PlateletsEffects on RBC and Platelets
RBC transfusions decreased over the course of RBC transfusions decreased over the course of the study with azacitidine treatment the study with azacitidine treatment –– transfusions remained stable or increased on transfusions remained stable or increased on supportive caresupportive care
Patients treated with azacitidine:Patients treated with azacitidine:– 51% had an RBC lineage response51% had an RBC lineage response– 47% had a platelet lineage response47% had a platelet lineage response
– 41% had a WBC lineage response41% had a WBC lineage response
Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
5454
Azacitidine Phase 3 Azacitidine Phase 3 Quality of LifeQuality of Life
Azacitidine patients had significantly greater Azacitidine patients had significantly greater improvement over time in: fatigue (improvement over time in: fatigue (PP = .001), = .001), physical functioning (physical functioning (PP = .002), dyspnea ( = .002), dyspnea (PP = .0014), = .0014), psychosocial distress (psychosocial distress (PP = .015), and positive affect = .015), and positive affect ((PP = .0077) = .0077)
Patients on supportive care experienced declining Patients on supportive care experienced declining QOL, but significant improvements were noted in QOL, but significant improvements were noted in fatigue (fatigue (PP = .0001), physical functioning ( = .0001), physical functioning (PP = .004), = .004), dyspnea (dyspnea (PP = .0002), and general well-being ( = .0002), and general well-being (PP = .016) after crossover to azacitidine treatment= .016) after crossover to azacitidine treatment
Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
5555
Azacitidine Phase 3 Azacitidine Phase 3 Overall SurvivalOverall Survival
Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
Median survival: azacitidine – 20 months (95% CI, 16-26 months) and supportive care – 14 months (95% CI, 12-14 months)
1.0
0.8
0.6
0.4
0.2
0.00 6 12 18 24 30 36 42
Pro
bab
ilit
y o
f S
urv
ival
Months
48 54
AzacitidineSupportive Care
Azacitidine 99 82 71 52 42 30 21 11 2 0
2 1Observation 92 73 58 38 25 19 12 6
Number of Patients at Risk
P = .10
5656
Azacitidine Phase 3 Azacitidine Phase 3 Adverse EventsAdverse Events
For azacitidine patients, the most common For azacitidine patients, the most common treatment-related toxicity was myelosuppressiontreatment-related toxicity was myelosuppression– Grade 3 or 4 leukopenia = 43%Grade 3 or 4 leukopenia = 43%– Grade 3 or 4 granulocytopenia = 58%Grade 3 or 4 granulocytopenia = 58%– Grade 3 or 4 thrombocytopenia = 52%Grade 3 or 4 thrombocytopenia = 52%
Toxicity was transient – recovery by the next Toxicity was transient – recovery by the next treatment cycletreatment cycle
Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
5757
Azacitidine Phase 3 Azacitidine Phase 3 Summary and ConclusionsSummary and Conclusions
Responses occurred in 35% of patients treated with Responses occurred in 35% of patients treated with azacitidine (6% CR, 10% PR, 19% improved) compared azacitidine (6% CR, 10% PR, 19% improved) compared with 5% (improved) of supportive care patientswith 5% (improved) of supportive care patients
Median time to AML or death was significantly Median time to AML or death was significantly increased with azacitidine treatment (21 months increased with azacitidine treatment (21 months compared with 13 months for supportive care)compared with 13 months for supportive care)
Survival increased with azacitidine treatment (20 Survival increased with azacitidine treatment (20 months compared with 14 months for supportive care)months compared with 14 months for supportive care)
Significant improvements in QOL criteria were notedSignificant improvements in QOL criteria were noted
Kaminskas E. Clin Cancer Res. 2005;11:3604-8; Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
5858
Comparison of Decitabine/D-0007 and Comparison of Decitabine/D-0007 and Azacitidine/9221 Phase 3 TrialsAzacitidine/9221 Phase 3 Trials
1Kantarjian et al. Cancer. 2006;106:1794-1803.; 2Silverman LR, et al. J Clin Oncol. 2002;20:2429-40; 3Kaminskas E. Clin Cancer Res. 2005;11:3604-8; 4Cheson BD. Blood. 2000;96:3671-74. NA = Not available.
Parameters
Decitabine
D-00071
Azacitidine
CALGB 92212,3
Crossover
Response Criteria
< 5%
IWG4
53%
CALGB
% of IPSS Int-2/High
% of prior therapy
Median duration of MDS (months)
Median number of treatment cycles
69
22
7.3
3
NA
16
2.8
9
Response Rates CR + PR = 15 (16.9%)CR + PR = 15 (16.9%)
CR = 8 (9.0%)CR = 8 (9.0%)
PR = 7 (7.8%)PR = 7 (7.8%)
CR + PR = 14 (16.2%)
CR = 6 (6.1%)
PR = 10 (10.1%)
Differences in study design make it difficult to compare efficacy
5959
Alternative Dosing Alternative Dosing with Azacitidinewith Azacitidine
6060
Azacitidine Alternative Dosing Schedules Azacitidine Alternative Dosing Schedules 3-Arm Dosing Study3-Arm Dosing Study
Phase 2, multicenter, randomized, open-label trialPhase 2, multicenter, randomized, open-label trial Objective: treatment response in schedules that do not Objective: treatment response in schedules that do not
require weekend injectionsrequire weekend injections 3 azacitidine treatment arms:3 azacitidine treatment arms:
– 75 mg/m75 mg/m22/day x 5 days, followed by 2 days of no /day x 5 days, followed by 2 days of no treatment, followed by 75 mg/mtreatment, followed by 75 mg/m22/day x 2 days/day x 2 days
– 50 mg/m50 mg/m22/day x 5 days, followed by 2 days of no /day x 5 days, followed by 2 days of no treatment, followed by 50 mg/mtreatment, followed by 50 mg/m22/day x 5 days/day x 5 days
– 75 mg/m75 mg/m22/day x 5 days /day x 5 days Eligible patients must have a life expectancy of Eligible patients must have a life expectancy of 7 months 7 months
and ECOG grade of 0-3and ECOG grade of 0-3 FAB classification of RA, RARS, RAEB, RAEB-T, CMMLFAB classification of RA, RARS, RAEB, RAEB-T, CMML
Anthony S, et al. J Clin Oncol. 2006;24(abstr 6574).
6161
3-Arm Dosing Study Data3-Arm Dosing Study DataSummary of Preliminary ResultsSummary of Preliminary Results
75 patients were randomized at the time of 75 patients were randomized at the time of presentation; 49 were evaluablepresentation; 49 were evaluable
61% male, median age 74.5 yrs61% male, median age 74.5 yrs RA and RARS were the most common subtypesRA and RARS were the most common subtypes Of 24 patients RBC transfusion dependent at baseline, Of 24 patients RBC transfusion dependent at baseline,
13 (54%) became independent13 (54%) became independent– AZA 5-2-2: 8/14 (57%)AZA 5-2-2: 8/14 (57%)– AZA 5-2-5: 3/5 (60%)AZA 5-2-5: 3/5 (60%)– AZA 5: 2/5 (40%)AZA 5: 2/5 (40%)
2 patients were platelet transfusion dependent at 2 patients were platelet transfusion dependent at baseline; both became independentbaseline; both became independent
Anthony S, et al. J Clin Oncol. 2006;24(abstr 6574).
6262
Considerations Considerations When Using When Using Hypomethylating Hypomethylating AgentsAgents
6363
Azacitidine for Injectable Azacitidine for Injectable SuspensionSuspension
IndicationsIndications– For treatment of the following MDS subtypes: RA, RARS,* For treatment of the following MDS subtypes: RA, RARS,*
RAEB, RAEB-T, and CMMoLRAEB, RAEB-T, and CMMoL Preparation Preparation
– Cytotoxic drug, caution should be used in handlingCytotoxic drug, caution should be used in handling StabilityStability
– Reconstituted azacitidine may be stored for up Reconstituted azacitidine may be stored for up to 1 hour at 25to 1 hour at 25C or up to 8 hours between 2C or up to 8 hours between 2 and 8 and 8CC
*If accompanied by neutropenia or thrombocytopenia or requiring transfusions. Vidaza [package Insert]. Boulder, CO: Pharmion Company; 2004.
6464
Decitabine for InjectionDecitabine for Injection
IndicationsIndications– Previously treated and untreated, de novo and secondary MDS of all French-Previously treated and untreated, de novo and secondary MDS of all French-
American-British subtypes (RA, RARS, RAEB, RAEB-T, and CMMoL) and Int-1, American-British subtypes (RA, RARS, RAEB, RAEB-T, and CMMoL) and Int-1, Int-2, and high-risk IPSS groupsInt-2, and high-risk IPSS groups
Preparation Preparation – Cytotoxic drug, caution should be used in handling Cytotoxic drug, caution should be used in handling – Aseptically reconstituted with 10 mL of Sterile Water for Injection (USP); Aseptically reconstituted with 10 mL of Sterile Water for Injection (USP);
immediately after reconstitution, the solution should be further diluted with 0.9% immediately after reconstitution, the solution should be further diluted with 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer’s injection sodium chloride injection, 5% dextrose injection, or lactated Ringer’s injection to a final drug concentration of 0.1 to a final drug concentration of 0.1 – – 1.0 mg/mL 1.0 mg/mL
StabilityStability– Unless used within 15 minutes of reconstitution, the diluted solution must be Unless used within 15 minutes of reconstitution, the diluted solution must be
prepared using cold (2°C - 8°C) infusion fluids and stored at 2°C - 8°C (36°F - prepared using cold (2°C - 8°C) infusion fluids and stored at 2°C - 8°C (36°F - 46°F) for up to 7 hours46°F) for up to 7 hours
DacogenTM [package insert]. Bloomington, Minn; MGI Pharma; 2006.
6565
Safety Considerations of Safety Considerations of Decitabine and AzacitidineDecitabine and Azacitidine
– NauseaNausea– AnemiaAnemia– ThrombocytopeniaThrombocytopenia– VomitingVomiting– PyrexiaPyrexia– LeukopeniaLeukopenia– DiarrheaDiarrhea
VidazaTM [package Insert]. Boulder, CO: Pharmion Company; 2004. DacogenTM [package insert]. Bloomington, Minn; MGI Pharma; 2006. Kantarjian HM, et al. Cancer. 2006;106:1794-1803.
– FatigueFatigue– Injection site erythemaInjection site erythema– ConstipationConstipation– NeutropeniaNeutropenia– EcchymosisEcchymosis– CoughCough– PetechiaePetechiae– HyperglycemiaHyperglycemia
Most commonly occurring adverse reactions:Most commonly occurring adverse reactions:
Patients should be premedicated for nausea and vomitingPatients should be premedicated for nausea and vomiting Blood and platelet counts should be performed at a minimum before each dosing cycle; dose adjustment or delay should be made based on Blood and platelet counts should be performed at a minimum before each dosing cycle; dose adjustment or delay should be made based on
hematology laboratory valueshematology laboratory values Consider need for early institution of growth factors and/or antimicrobial agentsConsider need for early institution of growth factors and/or antimicrobial agents
6666
Future Directions for Future Directions for Hypomethylating AgentsHypomethylating Agents
Other hematologic malignancies: AML, CMLOther hematologic malignancies: AML, CML Solid tumorsSolid tumors Further studiesFurther studies
– Alternative dose schedulesAlternative dose schedules
– Mechanisms and targetsMechanisms and targets
– Decitabine combinations with:Decitabine combinations with: Histone deacetylase inhibitorsHistone deacetylase inhibitors Colony-stimulating factorsColony-stimulating factors ImmunomodulatorsImmunomodulators
6767
Other Emerging Other Emerging Therapies in MDS: Therapies in MDS: LenalidomideLenalidomide
6868
Lenalidomide OverviewLenalidomide Overview
An immunomodulatory drug derived from thalidomide An immunomodulatory drug derived from thalidomide Encouraging data have been presented in lower risk MDS patientsEncouraging data have been presented in lower risk MDS patients Recently approved by FDA for treatment of MDS patients with Recently approved by FDA for treatment of MDS patients with
del(5q) del(5q) Careful monitoring of the patients’ blood counts during the Careful monitoring of the patients’ blood counts during the
treatment period is necessary, particularly in patients with renal treatment period is necessary, particularly in patients with renal dysfunctiondysfunction
Further studies are required to determine the efficacy of this drug Further studies are required to determine the efficacy of this drug and other agents for non-del(5q) MDS patientsand other agents for non-del(5q) MDS patients
6969
Phase 2 Trial of LenalidomidePhase 2 Trial of Lenalidomide
Study designStudy design– Multicenter phase 2 trial Multicenter phase 2 trial – Lenalidomide administered 10 mg/day for 21 days or 10 mg/dayLenalidomide administered 10 mg/day for 21 days or 10 mg/day– 148 anemic RBC transfusion-dependent MDS patients with del(5q), 148 anemic RBC transfusion-dependent MDS patients with del(5q),
with or without additional cytogenetic abnormalitieswith or without additional cytogenetic abnormalities ResultsResults
– RBC TI at 24 weeks in 67% of patients in an ITT analysisRBC TI at 24 weeks in 67% of patients in an ITT analysis– Median TI duration not reached after 104 weeks’ median follow-upMedian TI duration not reached after 104 weeks’ median follow-up– Cytogenetic responses in 73% of patients; 45% complete Cytogenetic responses in 73% of patients; 45% complete
cytogenetic responsecytogenetic response– Common adverse events (in ~50% of patients) required treatment Common adverse events (in ~50% of patients) required treatment
interruption or dose reduction for potentially serious but generally interruption or dose reduction for potentially serious but generally transient neutropenia and/or thrombocytopeniatransient neutropenia and/or thrombocytopenia
TI = transfusion independence; ITT = intention-to-treatList AF, et al. Proc ASCO. 2005;23[suppl 16S]:2S [abstract 5].
7070
SummarySummary
Hypomethylating agents: Hypomethylating agents: – Provide a new and exciting treatment option for an underserved Provide a new and exciting treatment option for an underserved
MDS populationMDS population– Offer encouraging response rates, transfusion-independence Offer encouraging response rates, transfusion-independence
(TI), and delayed time to AML or death compared with (TI), and delayed time to AML or death compared with supportive caresupportive care
– Are well tolerated with manageable adverse eventsAre well tolerated with manageable adverse events– Can be considered the treatment of choice for Int-2/high-risk Can be considered the treatment of choice for Int-2/high-risk
patients who are not transplant candidatespatients who are not transplant candidates– Future directions for hypomethylating agents include Future directions for hypomethylating agents include
alternative dosing regimens that may help to optimize responsealternative dosing regimens that may help to optimize response Lenalidomide is effective in lower-risk patients with del(5q), Lenalidomide is effective in lower-risk patients with del(5q),
inducing TI and cytogenetic responses in a high proportion of inducing TI and cytogenetic responses in a high proportion of patientspatients
7171
Program Evaluation Form Program Evaluation Form and Post Test Examand Post Test Exam
Go back to website to download and print out the post-Go back to website to download and print out the post-activity program evaluation form and post-test exam or click activity program evaluation form and post-test exam or click here: here: http://www.dwrite.com/Files/TELECONFERENCES/TELECONFERENCES3/Download%20Materials_0http://www.dwrite.com/Files/TELECONFERENCES/TELECONFERENCES3/Download%20Materials_01/Post-Activity%20Evaluation%20Form%20&%20Post-Test%20Exam.pdf1/Post-Activity%20Evaluation%20Form%20&%20Post-Test%20Exam.pdf
Return forms to address providedReturn forms to address provided Questions: Contact Andy Beloff of DesignWrite at 609-436-Questions: Contact Andy Beloff of DesignWrite at 609-436-
2412, 2412, [email protected]@dwrite.com
To receive credit for today’s program:
