Successfully reported this slideshow.
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 re...
MDS EPIDEMIOLOGY
 Overall incidence: 4.4 per 100,000

49.8

50
Overall

40

Males

Females
27.1

30
20
9.2
10
0.2
0

0.8
...
DIAGNOSIS OF MDS
 The most common presentation is cytopenia
 Diagnosis requires

– Peripheral blood examination
– Bone m...
WHO Revisions 2008: MDS Cytogenetic
Minimal Criteria
 Presence of refractory cytopenia without morphologic features and t...
IPSS Is Most Common Tool for Risk
Stratification of MDS
Score Value
Prognostic variable

0

0.5

1.0

1.5

2.0

Bone marro...
Revised IPSS MDS Cytogenetic Scoring
System
Cytogenetic
Abnormalities

Median
Survival,*
Yrs

Median AML
Evolution,
25%,* ...
Revised IPSS: Prognostic Score Values
and Risk Categories/Scores
Score Value
Prognostic
Variable

0

0.5

Cytogenetics

Ve...
Revised IPSS: Survival by Risk Category
Very low
Low
Intermediate
High
Very high

Proportion of Patients Alive

1.0
0.8
0....
Topic 2: Treatment Options for
Lower-Risk MDS
MDS-003: Lenalidomide in MDS With 5q
Deletion Study Design
Eligibility
 IPSS diagnosed
low/int 1 MDS
 del(5q31)
 ≥ 2 U ...
MDS-003: Response to Lenalidomide
Therapy

Response (%)

80

Erythroid Response

99/148
(67%)

112/148
(76%)

100

Cytogen...
MDS-002: Phase II Study of Lenalidomide
in RBC-Dependent Non-del(5q) MDS
Eligibility
 IPSS diagnosed
low/int-1 MDS w/o
de...
MDS-002: Response to Lenalidomide
Therapy
Erythroid Response

Response (%)

Cytogenetic Response

 Median Hb increase: 3....
Azacitidine Treatment for Low- or
Intermediate 1–Risk MDS
 Pyrimidine nucleoside analogue of cytidine

 Approved for use...
Randomized Phase II Study of Alternative
Azacitidine Dose Schedules
Study Design (N = 151)
5-2-2: 75 mg/m2
Eligibility
 A...
Topic 3: Treatment Options for
High-Risk MDS
Treatment Algorithm 2013:
Intermediate 2–/High-Risk MDS
Favorable

SCT

Allogeneic
donor
Unfavorable

SCT
candidate
No don...
Approximate Life Expectancy After
Ablative Allogeneic Transplantation
Risk
Group, Yrs
Low
Int 1
Int 2
High

Transplantatio...
Pre-Transplantation Chemotherapy as a
Bridge to Transplantation


Retrospective data[1,2]
– No benefit from induction che...
AZA-001: Trial Design
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...
Proportion Surviving

AZA-001 Trial: Azacitidine Significantly
Improves OS
HR: 0.58 (95% CI: 0.43-0.77;
log-rank P = .0001...
EORTC-06011 Decitabine Phase III Trial:
Study Design


Open-label, multicenter, 1:1 randomized study



IPSS: int-1, -2,...
EORTC-06011: OS With Decitabine
Treatment
1.0
BSC
Decitabine
Log-rank test P = .38

OS (%)

80
60
40
20
0
0
Pts at Risk, n...
Salvage Therapy After Azacitidine Failure:
GFM and AZA001 Studies
Type of
Salvage

Investigational

OS (%)

25

0
0

165

...
Selected Novel Agents Under Investigation
Agent

Patient Population

Response

Higher-risk MDS
(n = 58)

ORR: IV-15 41%; I...
Combination Therapy: Lenalidomide +
Azacitidine in Higher-Risk MDS
 Multicenter, single-arm open-label phase II continuat...
Lenalidomide + Azacitidine in Patients
With Higher-Risk MDS: Results
 Median CR duration: 17+ mos
(range: 3-39+)

100

CR...
SWOG-S1117: North American Intergroup
Randomized Phase II MDS/CMML Trial
AZA
(n = 80)
Higher-risk
MDS (IPSS
> 1.5 or
blast...
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Recent advances in mds
Upcoming SlideShare
Loading in …5
×

Recent advances in mds

466 views

Published on

  • Be the first to comment

  • Be the first to like this

Recent advances in mds

  1. 1. RECENT ADVANCES IN MDS DR. R. RAJKUMAR M.D. , D.M CONSULTANT MEDICAL ONCOLOGIST GURU HOSPITAL
  2. 2. AGENDA  New biological developments  Risk assessment and prognostic factors  New therapeutic options
  3. 3. MYELODYSPLASTIC SYNDROMES  A group of malignant hematopoietic disorders characterized by[1] – Bone marrow failure with resultant cytopenia and related complications – Macrocytic anemia is most common presentation – Dysplastic cytologic morphology is the hallmark of the 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.
  4. 4. MDS EPIDEMIOLOGY  Overall incidence: 4.4 per 100,000 49.8 50 Overall 40 Males Females 27.1 30 20 9.2 10 0.2 0 0.8 < 40 40-49 2.5 50-59 60-69 Age at Diagnosis (Yrs) 70-79 ≥ 80 SEER Cancer Statistics Review 1975-2008. Section 30, myelodysplastic syndromes (MDS), chronic myeloproliferative disorders (CMD), and chronic myelomonocytic leukemia (CMML).
  5. 5. 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.
  6. 6. WHO Revisions 2008: MDS Cytogenetic Minimal Criteria  Presence of refractory cytopenia without morphologic features and the following cytogenetic abnormalities considered ―presumptive evidence‖ of MDS Unbalanced Balanced Other -7 or del(7q) t(11;16)(q23;p13.3) -5 or del(5q) t(3;21)(q26.2;q22.1) i(17q) or t(17p) t(1;3)(p36.3;q21.1) Complex karyotype (≥ 3 abnormalities either balanced or unbalanced) -13 or del(13q) del(11q) del(12p) or t(12p) del(9q) t(2;11)(p21;q23) inv(3)(q21q26.2) t(6;9)(p23;q34) idic(X)(q13) Vardiman JW, et al. Blood. 2009;114:937-951.
  7. 7. 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 -- -- -- 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 *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.
  8. 8. Revised IPSS MDS Cytogenetic Scoring System Cytogenetic Abnormalities Median Survival,* Yrs Median AML Evolution, 25%,* Yrs HR OS/AML* HR OS/AML† -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 double independent 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 Prognostic Subgroups, % Very good (4%*/3%†) *Data from patients in this IWG-PM database, multivariate analysis (n = 7012). †Data from Schanz, et al (n = 2754). Greenberg PL, et al. Blood. 2012;120:2454-2465.
  9. 9. Revised IPSS: Prognostic Score Values and Risk Categories/Scores Score Value Prognostic Variable 0 0.5 Cytogenetics Very good -- BM blast, % ≤2 -- Hemoglobin, g/dL ≥ 10 -- ≥ 100 50 to < 100 ≥ 0.8 < 0.8 Platelets, x 109/L 1.0 Good > 2 to < 5 8 to < 10 < 50 1.5 2.0 3.0 4.0 Intermediate Poor Very poor 5-10 > 10 Risk <8 ___ ___ Score ___ Very low ___ ___ ≤ ___ 1.5 ___ --- -- Greenberg PL, et al. Blood. 2012;120:2454-2465. ___ ___ Intermediate > ___ to 4.5 3.0 ___ > 4.5 to 6.0 Very high -- > 1.5 to 3 High ANC, x 109/L Low >6
  10. 10. Revised IPSS: Survival by Risk Category Very low Low Intermediate High Very high Proportion of Patients Alive 1.0 0.8 0.6 Median Survival, years (95% CI) 0.4 8.8 (7.8-9.9) 0.2 5.3 (5.1-5.7) 0 3.0 (2.7-3.3) 1.6 (1.5-1.7) 0.8 (0.7-0.8) 0 2 4 Greenberg PL, et al. Blood. 2012;120:2454-2465. 6 8 10 12
  11. 11. Topic 2: Treatment Options for Lower-Risk MDS
  12. 12. MDS-003: Lenalidomide in MDS With 5q Deletion Study Design Eligibility  IPSS diagnosed low/int 1 MDS  del(5q31)  ≥ 2 U RBC/8 wks  Platelets > 50,000/µL  ANC > 500/µL Wk R E G I S T E R 0 R E S P O N S E Lenalidomide 10 mg/day PO Lenalidomide 10 mg PO x 21 days 4 8 12 16 20 Yes No Continue Off study 24  Primary endpoint: transfusion independence  Secondary endpoints: duration of TI, cytogenetic response, minor erythroid response, pathologic response, safety List AF, et al. N Engl J Med. 2006;355:1456-1465.
  13. 13. MDS-003: Response to Lenalidomide Therapy Response (%) 80 Erythroid Response 99/148 (67%) 112/148 (76%) 100 Cytogenetic Response  Median Hb increase: 5.4 g/dL 62/85 80  Time to response: 4.6 wks (73%)  Duration of response: > 2 yrs Response (%) 100 70 40 70 38/85 (45%) 40 20 20 0 0 TI TI + Minor List AF, et al. N Engl J Med. 2006;355:1456-1465. CCR CCR + PR
  14. 14. MDS-002: Phase II Study of Lenalidomide in RBC-Dependent Non-del(5q) MDS Eligibility  IPSS diagnosed low/int-1 MDS w/o del(5q) abnormality  ≥ 2 U RBC/8 wks  Platelets > 50,000/µL  ANC > 500/µL Wk R E G I S T E R 0 R E S P O N S E Lenalidomide 10 mg/day PO Lenalidomide 10 mg PO x 21 days 4 8 12 16 20  Primary endpoint: TI, Hb response  Secondary endpoints: cytogenetic response, safety Raza A, et al. Blood. 2008;111:86-93. 24 Yes No Continue Off study Dose reduction 5 mg QD 5 mg QOD
  15. 15. MDS-002: Response to Lenalidomide Therapy Erythroid Response Response (%) Cytogenetic Response  Median Hb increase: 3.2 g/dL  Time to response: 4.8 wks 80  Median duration of response: 41 wks 80 70 40 100 93/214 (43%) 56/214 (26%) Response (%) 100 70 40 20 20 0 0 TI TI + Minor Raza A, et al. Blood. 2008;111:86-93. 4/47 (9%) CCR 9/47 (19%) CCR + PR
  16. 16. 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
  17. 17. Randomized Phase II Study of Alternative Azacitidine Dose Schedules Study Design (N = 151) 5-2-2: 75 mg/m2 Eligibility  All FAB  Cytopenia  ECOG PS: 0-3 (n = 50) x6 5-2-5: 50 mg/m2 (n = 51) 5: 75 mg/m2 (n = 50) Lyons RM, et al. J Clin Oncol. 2009;27:1850-1856. IWG 2000 HI 12 Cycles AZA x 5 days q4-6 wks
  18. 18. Topic 3: Treatment Options for High-Risk MDS
  19. 19. Treatment Algorithm 2013: Intermediate 2–/High-Risk MDS Favorable SCT Allogeneic donor Unfavorable SCT candidate No donor Azanucleosides Investigational Field T, et al. Mediterr J Hematol Infect Dis. 2010;2:e2010019. Adapted from NCCN. Clinical practice guidelines in oncology. MDS. v.2.2013.
  20. 20. Approximate Life Expectancy After Ablative Allogeneic Transplantation Risk Group, Yrs Low Int 1 Int 2 High Transplantation at Diagnosis 6.51 4.61 4.93 3.20 Transplantation at Yr 2 6.86 4.74 3.21 2.75 Transplantation at Progression 7.21 5.16 2.84 2.75  Median age: 42 yrs  Data precede all FDA-approved drugs for MDS Cutler C, et al. Blood. 2004;104:579-585.
  21. 21. 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.
  22. 22. AZA-001: Trial Design 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) Stratified by  FAB: RAEB, RAEB-T  IPSS: int 2, high Azacitidine + BSC R A N D O M I Z E (75 mg/m2/day x 7 days SC q28 days) CCR Treatment continued until unacceptable toxicity or AML transformation or disease progression Fenaux P, et al. Lancet Oncol. 2009;10:223-232. (n = 179) (n = 179)
  23. 23. Proportion Surviving AZA-001 Trial: Azacitidine Significantly Improves OS HR: 0.58 (95% CI: 0.43-0.77; log-rank P = .0001) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 24.5 mos 15.0 mos Azacitidine CCR 0 5 10 15 20 25 30 Mos From Randomization Fenaux P, et al. Lancet Oncol. 2009;10:223-232. 35 40
  24. 24. EORTC-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 R A N D O M I Z E 20 mg/m2/day IV recommended in PI 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 cycles Exception: CR—2 additional cycles. Lübbert M, et al. J Clin Oncol. 2011;29:1987-1996.
  25. 25. EORTC-06011: OS With Decitabine Treatment 1.0 BSC Decitabine Log-rank test P = .38 OS (%) 80 60 40 20 0 0 Pts at Risk, n BSC Decitabine 6 12 18 Mos 24 30 71 83 38 53 22 24 10 15 6 4 Lübbert M, et al. J Clin Oncol. 2011;29:1987-1996. 36
  26. 26. Salvage Therapy After Azacitidine Failure: GFM and AZA001 Studies Type of Salvage Investigational OS (%) 25 0 0 165 NA 3.6 122 NA 4.1 Low-dose chemotherapy 32 0/18 7.3 Intensive chemotherapy 35 3/22 8.9* 44 4/36 13.2*† Allogeneic transplantation 50 Median OS, Mos Investigational therapy Allo-SCT ORR Best supportive care 75 N Unknown 100 37 13/19 19.5*† 365 730 1095 1460 Days Since AZA Failure *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). Prébet T, et al. J Clin Oncol. 2011;29:3332-3327.
  27. 27. Selected Novel Agents Under Investigation Agent Patient Population Response Higher-risk MDS (n = 58) ORR: IV-15 41%; IV-30 29% Median OS with response: 13.4 mos Median OS: 7.4 mos MDS, CMML, AML (n = 41) ORR (previous treated): 35% (6/17) ORR (tx naive): 73% (11/15) 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 Clofarabine[1] Oral azacitidine[2] Rigosertib[3] Dasatinib[6] HMA failure higher-risk MDS, ORR: 16.7% CMML, AML (n = 18) 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.
  28. 28. 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.
  29. 29. Lenalidomide + Azacitidine in Patients With Higher-Risk MDS: Results  Median CR duration: 17+ mos (range: 3-39+) 100 CR Hematologic improvement Response Rate (%) 90 80  Median OS among CR: 37+ mos (range: 7-55+) 70 60 28 50 40 30 20 44 10 0 Lenalidomide/ Azacitidine (N = 36) Sekeres MA, et al. Blood. 2012;120:4945-4951.  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 higherrisk MDS
  30. 30. SWOG-S1117: North American Intergroup Randomized Phase II MDS/CMML Trial AZA (n = 80) Higher-risk MDS (IPSS > 1.5 or blasts > 5%) AZA + Lenalidomide (n = 80) AZA + Vorinostat (n = 80) Clinicaltrials.gov. NCT01522976 Groups: SWOG, ECOG,CALGB, NCIC Total sample size: 240 Primary objective: 20% improvement of RR based on 2006 IWG Criteria Secondary objectives: OS, RFS, LFS Power 81%, alpha 0.05 for each combo arm vs AZA Anticipated time: 2.5 yrs

×