The document discusses recent advances in myelodysplastic syndromes (MDS), including new risk stratification models, prognostic factors, and therapeutic options for lower-risk and higher-risk MDS such as lenalidomide for lower-risk MDS and azacitidine or allogeneic stem cell transplantation for higher-risk MDS. Clinical trials demonstrate that lenalidomide provides significant erythroid responses in lower-risk MDS patients with or without del5q abnormalities, while azacitidine improves overall survival compared
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International Journal of Engineering Research and Applications (IJERA) is an open access online peer reviewed international journal that publishes research and review articles in the fields of Computer Science, Neural Networks, Electrical Engineering, Software Engineering, Information Technology, Mechanical Engineering, Chemical Engineering, Plastic Engineering, Food Technology, Textile Engineering, Nano Technology & science, Power Electronics, Electronics & Communication Engineering, Computational mathematics, Image processing, Civil Engineering, Structural Engineering, Environmental Engineering, VLSI Testing & Low Power VLSI Design etc.
Dr. Feroze Momin presents Chronic Lymphocytic Leukemia - Review and new Insights.
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Dr. Feroze Momin presents Chronic Lymphocytic Leukemia - Review and new Insights.
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1. RECENT ADVANCES IN MDS
DR. R. RAJKUMAR M.D. , D.M
CONSULTANT MEDICAL ONCOLOGIST
GURU HOSPITAL
2. AGENDA
New biological developments
Risk assessment and prognostic
factors
New therapeutic options
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.
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. 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. 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.
9.
10.
11. 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.
12. 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
13. 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
16. 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.
17. 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
18. 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
19. 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
20. 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
21. 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
23. 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.
24. 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.
25. 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.
26. 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)
27. 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
28. 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.
29. 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
30. 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.
31. 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.
32. 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.
33. 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
34. 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
Editor's Notes
MDS, myelodysplastic syndromes; WHO, World Health Organization.
AZA, azacitidine; ECOG PS, Eastern Cooperative Oncology Group Performance Status; FAB, French-American-British classification; IWG 2000 HI, International Working Group 2000 hematologic improvement.
FDA, US Food and Drug Administration; Int, intermediate; MDS, myelodysplastic syndromes.
AML, acute myeloid leukemia; BSC, best supportive care; CCR, conventional care regimens; FAB, French-American-British classification; Int, intermediate; IPSS, International Prognostic Scoring System; LDAC, low-dose Ara-C; RAEB, refractory anemia with excess blasts; RAEB-T; refractory anemia with excess blasts in transformation; SC, subcutaneous.
CCR, conventional care regimens.
EORTC, European Organisation for Research and Treatment of Cancer; HI, hematologic improvement; Int, intermediate; IPSS, international Prognostic Scoring System; IV, intravenous; MDS, myelodysplastic syndromes; q8h, every 8 hours; q6w, every 6 weeks
AZA, azacitidine; CALGB, Cancer and Leukemia Group B; CMML, chronic myelomonocytic leukemia; ECOG, Eastern Cooperative Oncology Group; IWG Working Group; NCIC, National Cancer Institute of Canada; SWOG Southwest Oncology Group.