recent advances in mds
TRANSCRIPT
RECENT ADVANCES IN MDS
DR. R. RAJKUMAR M.D. , D.M CONSULTANT MEDICAL ONCOLOGIST GURU HOSPITAL
AGENDA
New biological developments
Risk assessment and prognostic factors
New therapeutic options
MYELODYSPLASTIC SYNDROMES A group of malignant hematopoietic disorders
characterized by[1]
– Bone marrow failure with resultant cytopeniaand related complications
– Macrocytic anemia is most common presentation
– Dysplastic cytologic morphology is the hallmark ofthe disease
– Tendency to progress to AML
Overall incidence 3.7-4.8/100,000[2]
– ≈ 10,000/yr in United States (true estimates ≈ 37,000-48,000)
– Median age: 70 yrs; incidence: 34-47/100,000 > 75 yrs[3]
1. Bennett J, et al. The myelodysplastic syndromes. In: Abeloff MD, et al, editors. Clinical oncology. New York NY: Churchill Livingstone; 2004. pp. 2849-2881. 2. SEER data 2000-2009. 3. SEER 18 Data. 2000-2009.
MDS EPIDEMIOLOGY
Overall incidence: 4.4 per 100,000
Inci
denc
e R
ate
(per
100
,000
)
Age at Diagnosis (Yrs)SEER Cancer Statistics Review 1975-2008. Section 30, myelodysplastic syndromes (MDS), chronic myeloproliferative disorders (CMD), and chronic myelomonocytic leukemia (CMML).
0
10
20
30
40
50
< 40 40-49 50-59 60-69 70-79 ≥ 80
0.2 0.8 2.5
9.2
27.1
49.8
FemalesMalesOverall
DIAGNOSIS OF MDS The most common presentation is cytopenia
Diagnosis requires
– Peripheral blood examination
– Bone marrow aspirate and biopsy
– Cytogenetic studies
The diagnosis requires demonstration of dysplastic features in 1 or more cell line
Bennett J, et al. The myelodysplastic syndromes. In: Abeloff MD, et al, editors. Clinical oncology. New York, NY: Churchill Livingstone; 2004. pp. 2849-2881.
Presence of refractory cytopenia without morphologic features and the following cytogenetic abnormalities considered “presumptive evidence” of MDS
Balancedt(11;16)(q23;p13.3)
t(3;21)(q26.2;q22.1)
t(1;3)(p36.3;q21.1)
t(2;11)(p21;q23)
inv(3)(q21q26.2)
t(6;9)(p23;q34)
Unbalanced
-7 or del(7q)
-5 or del(5q)
i(17q) or t(17p)
-13 or del(13q)
del(11q)
del(12p) or t(12p)
del(9q)
idic(X)(q13)
Other
Complex karyotype (≥ 3 abnormalities either balanced or
unbalanced)
Vardiman JW, et al. Blood. 2009;114:937-951.
WHO Revisions 2008: MDS Cytogenetic Minimal Criteria
IPSS Is Most Common Tool for Risk Stratification of MDS
Score Value
Prognostic variable 0 0.5 1.0 1.5 2.0
Bone marrow blasts < 5% 5% to 10% -- 11% to 20% 21% to 30%
Karyotype* Good Intermediate Poor -- --
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; platelets < 100,000/L.
Greenberg P, et al. Blood. 1997;89:2079-2088.
Total Score
0 0.5 1.0 1.5 2.0 2.5
Risk Low Intermediate I Intermediate II High
Median survival, yrs 5.7 3.5 1.2 0.4
Revised IPSS MDS Cytogenetic Scoring System
*Data from patients in this IWG-PM database, multivariate analysis (n = 7012).†Data from Schanz, et al (n = 2754).
Prognostic Subgroups, %
Cytogenetic Abnormalities
Median Survival,*
Yrs
Median AML Evolution,25%,* Yrs
HROS/AML*
HROS/AML†
Very good (4%*/3%†)
-Y, del(11q) 5.4 NR 0.7/0.4 0.5/0.5
Good (72%*/66%†)
Normal, del(5q), del(12p), del(20q), double including del(5q)
4.8 9.4 1/1 1/1
Intermediate (13%*/19%†)
del(7q), +8, +19, i(17q), any other single or
doubleindependent clones
2.7 2.5 1.5/1.8 1.6/2.2
Poor (4%*/5%†)
-7, inv(3)/t(3q)/del(3q), double including
-7/del(7q),complex: 3 abnormalities
1.5 1.7 2.3/2.3 2.6/3.4
Very poor (7%*/7%†)
Complex: >3 abnormalities
0.7 0.7 3.8/3.6 4.2/4.9
Greenberg PL, et al. Blood. 2012;120:2454-2465.
Revised IPSS: Prognostic Score Values and Risk Categories/Scores
Greenberg PL, et al. Blood. 2012;120:2454-2465.
Score Value
Prognostic Variable 0 0.5 1.0 1.5 2.0 3.0 4.0
Cytogenetics Very good
-- Good -- Intermediate Poor Very poor
BM blast, % ≤ 2 -- > 2 to < 5 -- 5-10 > 10 --
Hemoglobin, g/dL ≥ 10 -- 8 to < 10 <8 ___ ___ ___
Platelets, x 109/L ≥ 100 50 to < 100 < 50 ___ ___ ___ ___
ANC, x 109/L ≥ 0.8 < 0.8 -- ___ ___ ___ ___
Risk Score
Very low ≤ 1.5
Low > 1.5 to 3
Intermediate > 3.0 to 4.5
High > 4.5 to 6.0
Very high > 6
Revised IPSS: Survival by Risk Category
Greenberg PL, et al. Blood. 2012;120:2454-2465.
Pro
port
ion
of P
atie
nts
Aliv
e
0
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 10 12
Very lowLowIntermediateHighVery high
Median Survival, years (95% CI)
8.8 (7.8-9.9)
5.3 (5.1-5.7)
3.0 (2.7-3.3)1.6 (1.5-1.7)0.8 (0.7-0.8)
Topic 2: Treatment Options for Lower-Risk MDS
Primary endpoint: transfusion independence
Secondary endpoints: duration of TI, cytogenetic response, minor erythroid response, pathologic response, safety
MDS-003: Lenalidomide in MDS With 5q Deletion Study Design
RESPONSE
REG ISTER
Lenalidomide10 mg PO x 21 days
Eligibility IPSS diagnosed
low/int 1 MDS del(5q31) ≥ 2 U RBC/8 wks Platelets > 50,000/µL ANC > 500/µL
Yes Continue
No Off study
Wk
Lenalidomide10 mg/day PO
0 4 8 12 16 20 24
List AF, et al. N Engl J Med. 2006;355:1456-1465.
MDS-003: Response to Lenalidomide Therapy
Erythroid Response
TI
99/148(67%)
112/148(76%)
TI + Minor
Cytogenetic Response
List AF, et al. N Engl J Med. 2006;355:1456-1465.
Res
pons
e (%
)
0
20
40
70
80
100
Res
pons
e (%
)
0
20
40
70
80
100
CCR CCR + PR
38/85(45%)
62/85(73%)
Median Hb increase: 5.4 g/dL Time to response: 4.6 wks Duration of response: > 2 yrs
Primary endpoint: TI, Hb response
Secondary endpoints: cytogenetic response, safety
MDS-002: Phase II Study of Lenalidomide in RBC-Dependent Non-del(5q) MDS
Lenalidomide10 mg PO x 21 days
Eligibility IPSS diagnosed
low/int-1 MDS w/o del(5q) abnormality
≥ 2 U RBC/8 wks Platelets > 50,000/µL ANC > 500/µL
Yes Continue
No Off study
Wk
Lenalidomide10 mg/day PO
0 4 8 12 16 20 24Dose reduction
5 mg QD5 mg QOD
Raza A, et al. Blood. 2008;111:86-93.
RESPONSE
REG ISTER
Res
pons
e (%
)
0
20
40
70
80
100
Res
pons
e (%
)
0
20
40
70
80
100
MDS-002: Response to Lenalidomide Therapy
CCR CCR + PR
4/47(9%)
9/47(19%)
Erythroid Response Cytogenetic Response
TI TI + Minor
56/214(26%)
93/214(43%)
Median Hb increase: 3.2 g/dL Time to response: 4.8 wks Median duration of response:
41 wks
Raza A, et al. Blood. 2008;111:86-93.
Azacitidine Treatment for Low- or Intermediate 1–Risk MDS Pyrimidine nucleoside analogue of cytidine
Approved for use in MDS of the following subtypes
– Refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions)
– Refractory anemia with excess blasts
– Refractory anemia with excess blasts in transformation
– Chromic myelomonocytic leukemia
Causes hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow
5-2-2: 75 mg/m2
5-2-5: 50 mg/m2
5: 75 mg/m2
x 6 IWG2000 HI
12 CyclesAZA x 5 days
q4-6 wks
Study Design (N = 151)
Lyons RM, et al. J Clin Oncol. 2009;27:1850-1856.
(n = 50)
(n = 51)
(n = 50)
Eligibility All FAB Cytopenia ECOG PS: 0-3
Randomized Phase II Study of Alternative Azacitidine Dose Schedules
Topic 3: Treatment Options for High-Risk MDS
SCTcandidate
No donor
Allogeneicdonor
Azanucleosides
Investigational
SCTFavorable
Unfavorable
Treatment Algorithm 2013: Intermediate 2–/High-Risk MDS
Field T, et al. Mediterr J Hematol Infect Dis. 2010;2:e2010019. Adapted from NCCN. Clinical practice guidelines in oncology. MDS. v.2.2013.
Approximate Life Expectancy After Ablative Allogeneic TransplantationRisk Group, Yrs
Transplantation at Diagnosis
Transplantation at Yr 2
Transplantation at Progression
Low 6.51 6.86 7.21
Int 1 4.61 4.74 5.16
Int 2 4.93 3.21 2.84
High 3.20 2.75 2.75
Cutler C, et al. Blood. 2004;104:579-585.
Median age: 42 yrs
Data precede all FDA-approved drugs for MDS
Pre-Transplantation Chemotherapy as a Bridge to Transplantation Retrospective data[1,2]
– No benefit from induction chemotherapy prior to transplantation
– No survival benefit from azacitidine over chemotherapy prior to transplantation
– Caveats: 1) data from 1990s, 2) retrospective, 3) poor description of chemotherapies used
– Improved survival in those achieving CR before transplantation
Feasibility data[3-5]
– Feasible to give azacitidine or decitabine before transplantation
– Rapid donor cell engraftment
Prospective clinical trials needed
1. Nakai K, et al. Leukemia. 2005;19:396-401. 2. Damaj G, et al. J Clin Oncol. 2012;30:4533-4540.3. De Padua Silva L, et al. Bone Marrow Transplant. 2009;43:839-843. 4. Cogle CR, et al. Clin Adv Hematol Oncol. 2010;8:40-46. 5. Field T, et al. Bone Marrow Transplant. 2010;45:255-260.
Azacitidine + BSC (75 mg/m2/day x 7 days SC q28 days)
Stratified by FAB: RAEB, RAEB-T IPSS: int 2, high
(n = 179)
(n = 179)
Treatment continued until unacceptable toxicity or AML transformation or disease progression
CCR
RANDOMIZE
Physician choice of 1 of 3 CCRs
1. BSC only
2. LDAC (20 mg/m2/day SC x 14 day q28-42 days)
3. 7 + 3 chemotherapy (induction + 1-2 consolidation cycles)
Fenaux P, et al. Lancet Oncol. 2009;10:223-232.
AZA-001: Trial Design
0
1.0
5 10 15 20 25 30 35 40Mos From Randomization
00.10.20.30.40.50.60.70.80.9
Pro
port
ion
Sur
vivi
ng
CCRAzacitidine
HR: 0.58 (95% CI: 0.43-0.77; log-rank P = .0001)
24.5 mos
15.0 mos
Fenaux P, et al. Lancet Oncol. 2009;10:223-232.
AZA-001 Trial: Azacitidine SignificantlyImproves OS
EORTC-06011 Decitabine Phase III Trial: Study DesignEORTC-06011 Decitabine Phase III Trial: Study Design Open-label, multicenter, 1:1 randomized study
IPSS: int-1, -2, and high-risk MDS; ≥ 60 yrs (n = 223)
Primary endpoint: survival
Stratification Cytogenics
risk group IPSS Primary vs
secondary Study center
RANDOMIZE
Decitabine 15 mg/m2 IV x 4 hrs q8h x 3 days q6w
(max 8 cycles) (n = 119)
Best Supportive Care(n = 114)
Response assessment q2 cycles; HI, CR, PR, and SD continue for up to 8 cyclesException: CR—2 additional cycles.
Lübbert M, et al. J Clin Oncol. 2011;29:1987-1996.
20 mg/m2/day IV recommended in PI
EORTC-06011: OS With Decitabine Treatment
Lübbert M, et al. J Clin Oncol. 2011;29:1987-1996.
0
1.0
0
20
40
60
80
OS
(%
)
6 12 18 24 30 36Mos
Pts at Risk, nBSCDecitabine
7183
3853
2224
1015
64
BSCDecitabine
Log-rank test P = .38
Type of Salvage
N ORR Median OS, Mos
Unknown 165 NA 3.6
Best supportive care 122 NA 4.1
Low-dose chemotherapy 32 0/18 7.3
Intensive chemotherapy 35 3/22 8.9*
Investigational therapy 44 4/36 13.2*†
Allogeneic transplantation 37 13/19 19.5*†
Prébet T, et al. J Clin Oncol. 2011;29:3332-3327.
*Log-rank comparison of BSC vs intensive CT (P = .04), investigational therapy (P < .001), or alloSCT (P < .001). †Comparison of intensive CT vs investigational therapy (P = .05), intensive CT vs ASCT (P = .008), or IT vs ASCT (P = .09).
Salvage Therapy After Azacitidine Failure: GFM and AZA001 Studies
100
75
50
25
00 365 730 1095 1460
OS
(%
)
Days Since AZA Failure
Investigational
Allo-SCT
Selected Novel Agents Under Investigation
Agent Patient Population Response
Clofarabine[1] Higher-risk MDS (n = 58)
ORR: IV-15 41%; IV-30 29%Median OS with response: 13.4 mos
Median OS: 7.4 mos
Oral azacitidine[2] MDS, CMML, AML (n = 41)
ORR (previous treated): 35% (6/17)ORR (tx naive): 73% (11/15)
Rigosertib[3] MDS (n = 60)HMA failure (n = 39)
31% (16/51) ≥ 50% blast decrease Median OS with response: 11 mos
Sapcitabine[4] Phase I refractory AML/MDS(n = 47)
Objective Response: 28%
Erlotinib[5] HMA failure higher-risk MDS (n = 35)
ORR (evaluable): 19% (5/26)Median OS with response: 16.8 mos
Median OS: 6.8 mos
Dasatinib[6] HMA failure higher-risk MDS, CMML, AML
(n = 18)
ORR: 16.7%
1. Faderl S, et. al. Cancer. 2012;118:722-728. 2. Garcia-Manero G, et al. J Clin Oncol. 2011;29:2521-2527. 3. Raza, et al. ASH 2011. Abstract 3822. 4. Kantarjian H, et al. J Clin Oncol. 2010;28:285-291. 5. Komrokji R, et al. ASH 2011. Abstract 1714. 6. Vu D, et al. Leuk Res. 2013;37:300-304.
Combination Therapy: Lenalidomide + Azacitidine in Higher-Risk MDS Multicenter, single-arm open-label phase II continuation study (N = 36)
Patient eligibility
– Higher-risk MDS: CMML-2, RAEB-1 or -2, IPSS intermediate 2 or high (score ≥ 1.5), or revised IPSS score 4 or 5
– No previous treatment with lenalidomide or azacitidine
Maximum of seven 28-day treatment cycles administered
– Lenalidomide 10 mg on Days 1-21
– Azacitidine 75 mg/m2 on Days 1-5
– After 7 cycles, patients could continue azacitidine monotherapy off study
Median patient follow-up: 12 mos (range: 3-55)
Sekeres MA, et al. Blood. 2012;120:4945-4951.
Lenalidomide + Azacitidine in Patients With Higher-Risk MDS: Results
Median CR duration: 17+ mos (range: 3-39+)
Median OS among CR: 37+ mos (range: 7-55+)
8 patients evolved to AML at median of 18 mos after CR
Treatment well tolerated; FN was most common grade 3/4 AE (22%)
Randomized trial planned to compare azacitidine vs lenalidomide/azacitidine vs azacitidine/vorinostat in higher-risk MDS
0
10
20
30
40
50
60
70
80
90
100
Lenalidomide/Azacitidine
(N = 36)
Res
pons
e R
ate
(%)
CR
Hematologic improvement
44
28
Sekeres MA, et al. Blood. 2012;120:4945-4951.
AZA(n = 80)
AZA + Lenalidomide(n = 80)
AZA + Vorinostat(n = 80)
Higher-risk MDS (IPSS
> 1.5 or blasts > 5%)
SWOG-S1117: North American Intergroup Randomized Phase II MDS/CMML Trial
Groups: SWOG, ECOG,CALGB, NCICTotal sample size: 240Primary objective: 20%improvement of RR based on 2006 IWG CriteriaSecondary objectives: OS,RFS, LFSPower 81%, alpha 0.05 for each combo arm vs AZAAnticipated time: 2.5 yrs
Clinicaltrials.gov. NCT01522976