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