Transcript Myelodysplastic Syndromes: Principles, Practice and State

Stem Cell Mischief: Myelodysplasia and
Leukemias
John M. McCarty MD
Medical Director, BMT Program
Massey Cancer Center
Virginia Commonwealth University Medical Center
Images with Permission of L Silverman,MD
Learning Objectives:
• Understand key disease characteristics needed to
facilitate diagnosis, staging, and tailored treatment of
MDS and Acute Leukemia
• Define individualize treatment goals
• Examine new treatment approaches
• Delineate how treatment strategies fit into current
NCCN treatment algorithms
• Discuss how a comprehensive targeted treatment plan
may improve overall and transplant outcomes
ALL: Characterization
• FAB Classification based on morphology
– L1, L2, L3
• L3 contains Burkitt’s cells
• Patients evaluated by bone marrow,
cytogenetics, flow cytometry and LP
– High risk of CNS disease
– CNS can serve as a sanctuary site
ALL: Prognostic Factors
• Age: Childhood ALL better than adult ALL
– 50-75% vs 25-30% DFS at 5 years
• WBC at presentation: all ages, low WBC better
• Immunophenotype
– B cell < null < T cell<< CALLA positive
• Cytogenetics:
Philadelphia positive (t(9:22)) poor
– Low CR rates (<65%) and DFS with chemotherapy (0-15%)
• CNS involvement is worse
• Time to Response:
– 4 weeks to remission median remission 31 months
– >4 weeks to remission median remission 12 months
ALL: Treatment
• Induction chemotherapy
– Vincristine, prednisone, adriamycin, ±L-asp
• Consolidation chemotherapy (2-3 cycles)
– Cytoxan, Ara-C and Methotrexate
• Prolonged maintenance chemotherapy
– 6- mercaptopurine, MTX, thioguanine (1-2 yrs)
• CNS prophylaxis
– IT Ara-c or MTX, CNS XRT, or HD MTX/Ara-C
Indications for BMT in Acute Leukemias
• AML: Poor prognosis AML in CR1
– Autologous, but suggestion of allo better
– Syngeneic good balance of risk and relapse
– Allogeneic- From a matched family donor
• Refractory
– Obtain remission with second line/clinical trial
– Best available donor
• Relapsed AML in CR2
• Induction less important with BM blasts <20%
– Some data suggests Myelotarg prior improves relapse rates post transplant
• ALL: 20-30% adults with good prognosis= childhood ALL
– Survival improved with Matched Family donor over Autologous over Chemotherapy
– Consider for relapsed good prognosis patients
• Poor prognosis patients, especially Philadelphia +
– Best available donor
Characterizing MDS
Images with Permission of L Silverman,MD
Definition:
• A group of clonal bone marrow stem cell disorders,
characterized by hypercellular marrows, peripheral cytopenias,
and cell functional abnormalities
– Ineffective hematopoiesis
• Heterogeneity: highly variable natural history
• High mortality rate
• Unless permanent control achieved (by alloBMT) death due to
bone marrow failure, with or without conversion to AML
Kurzrock R. Semin Hematol 2002. Jul;39(3 Suppl 2):18-25.
Hamblin TJ. Epidemiology of MDS. In: Bennett JM (ed). MDS: Pathobiology and Clinical Management.
New York: Marcel Dekker Inc.; 2002.
http:// www.hmds.org.uk/mds.html
Age-related Incidence of MDS
Leukaemia Research Fund [1984-1993]
100
Rate
10
1
0.1
0.01
0
10
Males
Females
20
30
40
McNally RJQ et al. Hematological Oncology 1997. 15:173-189,
Cartwright RA,et al. Leukaemia Research Fund, 1997. http://www.lrf.org.uk
Reprinted with Permission of Leukemia Research Fund
50
60
70
80
Survival: MDS vs. Lung Cancer
IPSS
Score
0
MDS
Risk
Group
Low
Lung Cancer
Median
Survival (Yrs)
Stage
Median
Survival (Yrs)
5.7
Ia
>5
0.5-1
Int-1
3.5
IIa
2.0
1.5-2
>2
Int-2
High
1.2
0.4
IIIa
IV
1.3
0.7
Greenberg P, et al. Blood. 1997:89(6):2079-88.
Predisposition:
Acquired:
Heritable:
Senescence
Constitutional genetic disorders
Mutagen/Genotoxic Stress
 Trisomy 8 mosaicism
 Familial monosomy 7
 Therapeutic
alkylators, Topo-II agents,
Neurofibromatosis 1
-emitters (32P), autoSCT
Embryonal dysgenesis (del12p)
 Environmental/occupational
(benzene)
Congenital Neutropenia
 Tobacco
DNA repair deficiencies
Aplastic anemia
 Fanconi anemia, AT, Bloom syndrome
PNH
Pharmacogenomic polymorphisms
 Kostmann, Schwachman-Diamond
(GSTq1-null)
List AF, et al. The Myelodysplastic Syndromes. In: Wintrobe’s Hematology 2003.
Clinical Overlap / Associations:
•
•
•
•
•
AML
Aplastic anemia
Myeloproliferative disease
LGL leukemia
Autoimmune diseases
PNH
MDS
AML
AA
PRCA
LGL
MPD
With Permission of J Maciejewski,M.D. Taussig Cancer Center/ Cleveland Clinic Foundation
With Permission of American College of Physicians from Young NS. Ann Intern Med. 2002 Apr 2;136(7):534-46
(ACP not responsible for accuracy of figure translation).
Diagnosis and Classification:
Images with Permission of L Silverman,MD
Basic Diagnostic Evaluation:
• Peripheral blood counts + reticulocyte count
• Bone marrow biopsy and aspiration
– Cytogenetics
• Auxiliary tests
– FISH
– Flow cytometry in indeterminate cases
– Iron saturation, ferritin
– B12, folate levels
– EPO level
http:// www.NCCN.org MDS Guidelines
http://www.hmds.org.uk/mds.html
Establish diagnosis
Assess
– FAB/WHO classification
– IPSS score (if applicable)
WHO Reclassification of FAB MDS
Subtypes
MDS (FAB)
MDS (WHO)
Refractory Anemia (RA) <5% Blasts
Refractory Anemia (RA)
Refractory cytopenias with
multilineage dysplasia (RCMD)
MDS-Unclassified (MDS-U)
MDS with isolated del(5q) 5q minus
syndrome
RA with ?15% ringed sideroblasts
Refractory Anemia with ringed
sideroblasts (RARS)
Refractory cytopenias with
multilineage dysplasia and ringed
sideroblasts (RCMD-RS)
RA with excess blasts (RAEB): 520% blasts
RA with excess blasts-I (RAEB-I) 610% blasts RA with excess blasts-II
(RAEB-II) 11-20% blasts
RA with excess blasts in
transformation (RAEB-t): 21-30%
blasts
Acute myeloid leukemia
IPSS Score
Prediction of Survival
Prediction of AML
WIPSS Score
Prediction of Survival
Prediction of AML
Time dynamic risk assessment
Uses WHO diagnoses
Accounts for transfuion need
MDS Treatment
Images with Permission of L Silverman,MD
Goals of Therapy
• PROLONG SURVIVAL
• Select Therapy best suited for the individual
• Minimize toxicity
• Improve blood counts
– Decrease transfusion
– Decrease infections
• Improve quality of life
Cheson BD, et al. Blood 2000. 96:3671-4.
http:// www.NCCN.org MDS Guidelines
Best Supportive Care
Images with Permission of L Silverman,MD
49
Transfusion Dependence:
Impact on Survival*
Survival Time, mo
*Cumulative probability of survival among 374 patients with MDS. Once a regular need for blood transfusion developed,
patients had a significantly lower probability of survival (hazard ratio for death, 1.58; P = .005).
From Cazzola and Malcovati. N Engl J Med. 2005;352:536-538, with permission.
Best Supportive Care: Transfusions/GF
Transfusions
Chelation for >25 U; >15-20 in RARS
NCCN: Regular Ferritin monitoring; Goal <1000
Weekly dosing not indicated. GCSF helpful in poor
EPO responders with lowest levels (<250)
Anemia
41% RR, Median Duration 23 mo
PRBC <=2U/mo a/w increased OS (HR .57)
No effect on leukemia transformation
RARS response 3-4 mo vs. 6-8 weeks
No role for ESA if EPO >500
Consider immunesuppression therapy
CSF support improves ANC (75% patients), but has
no impact on overall survival.
Thrombocytopenia
25-50% of patients.
Most Thrombopoietic agents have no significant impact
on transfusion needs: TPO, MGDF, & IL-11
Gordon MS. Semin Hematol. 1999 Oct;36(4 Suppl 6):21-4.
Tricot GJ, et al. Semin Oncol. 1987 Dec;14(4):444-53.
Blinder VS et al. Curr Hematol Rep. 2003 Nov;2(6):453-8.
Hellstrom-Lindberg E. Curr Hematol Rep. 2003 Mar;2(2):122-9.
Hellstrom-Lindgerg E. Br J Haematol. 2003; 120(6):1037-46.
ROMBOPLASTIM (NPLATE) CURRENTLY UNDER
STUDY AT MASSEY CANCER
Chemotherapy as BSC
• No benefit of low-dose Ara-C (LDAC) vs. observation or
other chemotherapy (Mylotarg®)
• Role for standard AML-type chemotherapy only in
patients age <60 with normal cytogenetics and no history
of abnormal blood counts
• Role for chemotherapy in patients destined for transplant
– Cytoreduction role prior to reduced intensity transplants (RIT)
• Other patients should be referred for clinical trials or
considered for newer agents
PHASE I TRIAL OF FLAVOPIRIDOL/SAHA FOR RELAPSED,
REFRACTORY RAEB-2 OR ACUTE LEUKEMIA ONGOING
AT MASSEY CANCER CENTER
Miller KB, et al. Annals Hematology 1992. 65: 162-8.
Latagliata R, et al. Leuk Res. 1995 Mar;19(3):213-7.
Best Supportive Care: Chemotherapy
1.0
Era
Total
1980s 162
1990s 307
Survival Probability
0.8
Fail
155
246
CR Rates in HR-MDS
Rx
Pts
CR
IA
101
58%
FA
116
48%
TA
90
54%
0.6
0.4
0.2
0.0
0
50
100 150 200 260 310 360 410 460 520
Weeks
With Permission of E Estey, MD
Newer Approaches: Tailoring
Therapy
Images with Permission of L Silverman,MD
Immunotherapy (IP): Identify
Responding Subsets
Rationale:
Supportive
Evidence:
A subset of MDS patients have a component of immune
attack contributing to their cytopenias
In four studies, 29% (34/115) response to equine ATG.
Rabbit ATG: RR 42%. 75% responders durable response
(median 31.5 months).
Poor survival in IPSS Int-2 and High categories
HLA-DR-15-positive
Candidates:
RA (<5% blasts)
Age <60
Brief transfusion history
Trisomy 8 abnormality
Normal cytogenetics
IPSS Low/Int-1
Marrow cellularity <30%
CURRENT TRIAL OF THYMOGLOBULIN FOR IPSS
LOW/INT-1 AT MASSEY CANCER CENTER
Killick GS et al. Br J Haematol 2003: 120:679.
Lim ZY et al Leukemia 2007: 21, 1436-1441
55
Lenalidomide in 5q Deletion:
Phase II Study Design
Eligibility: del(5q); IPSS low or Int-1; platelets > 50K/mm3;
neutrophils > 500/mm3; transfusion dependent
YES
Eligible
Patients
R
e
g
i
s
t
e
r
Week: 0
R
e
s
p
o
n
s
e
10 mg po x 21
10 mg po qd
4
List et al NEJM 2006; 355;14 1456-1464.
8
12
16
20
24
Continue
Dose Reduction
5 mg qd
5 mg qod
NO
Off study
56
Lenalidomide: Efficacy
All Patients
del(5q)
10 mg qd
(N = 103)
10 mg qd x 21 d
(n = 45)
Erythroid response (intent-to-treat analysis; n = 148)*
TI (≥ 8 wk)
Minor (≥ 50% decrease in transfusions)
TI + minor
70 (68%)
25 (56%)
9 (8%)
6 (13%)
79 (77%)
31 (69%)
Total erythroid response
110 (74%)
Median time to response
4.5 wk (3.6–5.3)
Median Hgb increase
5.2 g/dL (1.1–11.4)
Median duration of transfusion independence
Cytogenetic response (n = 111 evaluable)
Complexity
5q- only
5q- plus one
5q- plus two
3.6 (2.3–6.1)
n
64
CyResponse
77%
15
67%
6
50%
52.3 wk
75 (68%)
CcyR
45%
40%
50%
57
Lenalidomide:
Adverse Events (N = 148)
All Grades, %
≥ Grade 3, %
Thrombocytopenia
(62)
(50)
Neutropenia
(59)
(53)
Pruritus
(42)
(2)
Rash
(36)
(7)
Diarrhea
(49)
(3)
Fatigue
(31)
(5)
All Patients del(5q)
Dose modifications
118 (80)
Final dose (5 mg qd or qod)
108 (72)
Discontinuation due to AEs
32 (22)
Deaths on study
10 (7)
Suspected drug-related by
investigator
3 (1.4)
AEs = adverse events.
Revlimid [package insert]. Celgene; 2005.
Lenalidomide (Revlimid). Briefing Document NDA 21-880. ODAC Meeting; September 14, 2005.
FDA. Lenalidomide (Revlimid). Briefing Document NDA 21-880. ODAC Meeting; August 11, 2005.
59
Revlimid in non-5q MDS patients
• 214 patients with > 2 years followup
• 78% Low/Int I
– 26% response to RBC TI (median 4.8 weeks)
• Duration 41 weeks (8-136.4)
• Median hgb rise 3.2 g/dl
• 17% had 50%reduction in PRBC needs
– Overall RBC TI RR 43%
• TI occurred in non-5q without clonal suppression
• Response seen in patients >2U PRBC/mo
• “Revlimid restores erythropoietic activity to the
MDS clone”
Raza et al Blood Epub Sept 24 2007
DNA Methyltransferase Inhibitors
(MTIs)
Images with Permission of L Silverman,MD
Mechanism of Action
DNMTs
Images with Permission of L Silverman,MD
Azacitidine
5-azacytidine
Decitabine
5-aza-2’-deoxycytidine
RNA
DNA
Methyltransferase Inhibitor (MTI) Induced DNA
Hypomethylation and Gene Activation
A:T
A:T
C:G
G:C
DMT
mC
AZA
•
•
•
•
C:G
G:C
DAC C : G
:G
G : Cm
D
M Az
T
DMT
G:C
Azacitidine (AZA) is incorporated into DNA in lieu of cytosine residue
Inactivates DMT
Leads to formation of newly synthesized DNA with unmethylated cytosine residues
Results in hypomethylation and transcription of previously quiescent genes
Silverman L. The Oncologist 2001. 6 (S5): 8-14.
Permission from The Oncologist, AlphaMed Press.
Study 9221: A Randomized Phase III Trial
of SC VIDAZA® in MDS
R
A
Stratify:
• RA
• RARS
• RAEB
• RAEB-T
• CMMoL
N
D
Supportive
Care* Alone
(Observation)
Exit
No
criteria
Yes
O
Continue until
endpoint +
VIDAZA
(Dose as
below)
M
I
Z
E
Response
S
•
S
Continue
Rx
E
VIDAZA 75 mg/m2/d SC
X 7 days every 28 d x 4 cycles
BM
Day
A
0
BM
29
57
S
No Response
S
•
Off study
BM
85
113
*Transfusions and antibiotics used as needed; hematopoietic growth factors were prohibited
Silverman L. Oncologist. 2001;6:8-14; Silverman LR, et al. J Clin Oncol. 2002;20:2429-2440.
BM=bone marrow.
66
Study 9221: Response Rates*
VIDAZA® SC
N=89
Observation
Before Cross
Over N=83
N (%)
N (%)
P Value
14 (15.7)
0 (0.0)
<0.0001
CR
5 (5.6)
0 (0.0)
0.06
PR
9 (10.1)
0 (0.0)
--
Response
Overall (CR + PR)
Approximately 24% of VIDAZA patients who did not meet the criteria of PR
or better were considered improved
*Excludes patients with adjudicated baseline diagnosis of AML
CR=complete response; PR=partial response.
67
• In the pivotal study, 92.9% of
responding patients achieved
initial positive effect* by the
end of 6 treatment cycles
• Responders received a mean
duration of 18.2 months of
VIDAZA® therapy
• Treatment may be continued as
long as the patient continues to
benefit
% Responding Patients (CR + PR)
Achieving Initial Positive Effect (N=14)
Study 9221: Duration of Therapy
*Initial positive effect was defined as the
first day of achievement of target for 4 weeks
for at least 1 cell line abnormality
Celgene Corporation, Data on File.
92.9%
42.9
28.6
21.4
7.1
2
3-4
5-6
>6
Number of Cycles
69
Study 9221: RBC Transfusion
Independence
• Median duration of transfusion
independence was estimated as
330 days for VIDAZA®
responders
• Median time to transfusion
independence was ~2.5 months
Higher-risk patients are RAEB, RAEB-T, and
CMMoL.
RBC=red blood cell.
Celgene Corporation, Data on File.
Transfusion-Independent Patients (%)
• Benefit extended across all MDS
subtypes
0%
Supportive
Care
N=56
44%
42.5%
(29/66)
(17/40)
VIDAZA
All Patients
N=66
VIDAZA
Higher Risk
N=40
RBC Transfusion Dependent at Baseline
70
• 87% (13/15) were
higher risk
• Median time to
transfusion
independence was ~2
months
Transfusion-Independent Patients (%)
Study 9221:
Platelet Transfusion Independence
53%
(8/15)
46%
(6/13)
0%
Higher-risk patients are RAEB, RAEB-T, and
CMMoL.
Supportive
Care
N=12
VIDAZA®
All Patients
N=15
VIDAZA®
Higher Risk
N=13
Platelet Transfusion Dependent at Baseline
Celgene Corporation, Data on File.
71
AZA-001: Trial Design
Physician Choice of 1 of 3
Conventional Care Regimens
2. LDAC or
(20 mg/m2/d SC x 14d q 28-42d)
3. 7+3 chemotherapy (Induction + 1
or 2 consolidation cycles)
RANDOMIZE
1. BSC only or
VIDAZA® + BSC
(75 mg/m2/d x 7d SC q28d)
N=179
Stratify:
•FAB = RAEB, RAEB-T
•IPSS = INT-2, High
CCR
N=179
Treatment continued until unacceptable toxicity or AML transformation or
disease progression
AML=acute myeloid leukemia; BSC=best supportive care; CCR=conventional care regimen;
IPSS=international prognostic scoring system; LDAC=low-dose Ara-C.
72
Proportion Surviving
AZA-001 Trial: VIDAZA® Significantly
Improves Overall Survival (OS)
Log-rank P=0.0001
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
HR=0.58 (95% CI: 0.43-0.77)
24.5 months
15 months
VIDAZA
CCR
0
5
10
15
20
25
30
35
40
Time (months) From Randomization
CI=confidence interval; HR=hazard ratio; ITT=intent-to-treat.
73
AZA-001 Trial: Survival Results
• VIDAZA® provided a significantly improved OS compared
with CCR in the ITT population (log-rank P=0.0001)
• VIDAZA median OS was 24.5 months compared with 15
months for CCR
• VIDAZA 2-year OS was 51% compared with 26% for
CCR (24.6% difference, 95% CI, 13.1-36.1)
• The relative risk of death was 0.58 (95% CI: 0.43-0.77)
indicating a 42% less risk for the VIDAZA group relative
to the CCR group
– More deaths were observed on CCR (113) compared with VIDAZA
(82)
74
AZA-001: Survival Across Subgroups
Favors VIDAZA®
ITT Subgroups
Favors CCR
Total - Event / N
ITT
195 / 358
AGE: <65
≥65
45 / 100
150 / 258
50 / 87
≥75
FAB: RAEB
RAEB-T
FAB: Other
WHO: RAEB-1
RAEB-2
WHO: Other
IPSS: INT-2
High
IPSS: Other
IPSS Cytogenetic: Good
Intermediate
Poor
IPSS Cytopenias: 0/1
2/3
BM Blasts: ≥5% to <11%
≥11% to <21%
≥21% to <31%
Celgene Corporation, Data on File.
95 / 207
80 / 123
20 / 28
15 / 31
102 / 193
78 / 134
71 / 146
98 / 167
26 / 45
80 / 167
38 / 76
67 / 100
20 / 53
167 / 290
34 / 61
98 / 192
58 / 99
0.125
0.250
0.500
1
2
4
75
AZA-001 Trial: IWG Response Rates
Response (%)
Overall (CR + PR)
CR
PR
Celgene Corporation, Data on File.
VIDAZA®
N=179
CCR
N=179
29
17
12
12
8
4
76
AZA-001 Trial: Treatment Cycles
• Per study design, treat with VIDAZA® for at least 6 cycles, and maintain treatment until
disease progression occurs to maximize patient outcomes
Treatment
Median # Cycles (Range)
VIDAZA
9 (1-39)
BSC Only*
7 (1-26)
LDAC
7+3 Chemotherapy
4.5 (1-15)
1 (1-3)†
• Treatment continued until unacceptable toxicity or AML transformation or
disease progression
*One cycle of therapy = 28 days
†Induction + 1 or 2 consolidation cycles
Celgene Corporation, Data on File.
80
Percent
AZA-001: First Occurrence of Treatment
Emergent Hematologic AEs* with VIDAZA®
Cycles 1-2
Cycles 3-4
Cycles 5-6
Cycles 7-12
Cycles 13-24
Thrombocytopenia
95 (54.3%)
8 (5.4%)
6 (4.6%)
6 (5.6%)
5 (8.9%)
Neutropenia
88 (50.3%)
16 (10.9%)
2 (1.5%)
7 (6.5%)
2 (3.6%)
Anemia
57 (32.6%)
11 (7.5%)
9 (6.9%)
8 (7.5%)
4 (7.1%)
*All grades
Celgene Corporation, Data on File.
81
AZA-001: Rate of Infection Requiring IV
Antimicrobials per Patient-Year
Rate per Patient-Year
0.24
0.16
VIDAZA®
CCR
A 33% reduction (HR, 0.67; 95% CI: 0.35-1.20)
Celgene Corporation, Data on File.
82
83
Decitabine Phase III MDS Trial Study
Design
• Open-label, multicenter, 1:1 randomized study
• IPSS: Int-1, Int-2, and high-risk MDS patients eligible
• Primary end points: response, time to AML/death
– IWG response criteria utilized for assessment
Eligible
patients
(n = 170)
R
A
N
D
O
M
I
Z
E
D
Stratification
- IPSS
-Type of MDS
(primary or
secondary)
Saba et al. Presented at: ASCO 2005 Annual Meeting. Abstract 6543.
Decitabine + supportive care
15 mg/m2 over 3 h q 8 h x 3 d q 6 wk
(N = 89)
Supportive care
ABX, GFs, and/or transfusions
(N = 81)
84
Decitabine Phase III MDS Trial: Efficacy
Decitabine
(n = 89)
Supportive Care
(n = 81)
17
0
CR, %
9
0
PR, %
8
0
Hematologic improvement (IWG), %
13
7
Median time to response (CR + PR), mo
3.2
N/A
Overall response (IWG criteria), %*
(2–5.5)
Median duration of response (CR + PR)
9.5
N/A
(4.7–12.4)
Median time to AML/death,* mo†
*P < .001 from 2-sided Fisher’s exact test.
†P = .16 by log-rank test.
Kantarjian Cancer 2006;1 106;1794-80
12.1
7.8
85
Decitabine Phase III MDS Trial: Adverse
Events
Decitabine, %
(n = 83)*
Supportive Care, %
(n = 81)
Grade 3
Grade 4
Grade 3
Grade 4
Neutropenia
10
77
25
25
Thrombocytopenia
22
63
27
16
Anemia
11
1
14
1
Febrile neutropenia
17
6
4
0
Pneumonia
13
2
7
2
Median number of courses: 3
52% received >3 courses
26% received >6 courses
Approved Decitabine Dose and
Administration
Three
Consecutive
Hospital
Days
Cycle
15 mg/m2
3-hour
8 hours
15 mg/m2
3-hour
8 hours
15 mg/m2
3-hour
8 hours
20 mg/m2
x5 days
4-week cycle
•Alternative schedule vs historical intensive chemo (IC)
•Survival advantage for DAC over IC
•22 months vs 12 months
•Three large Phase II and III studies have failed to meet primary
Survival endpoint
What Drug, What Patient?
• Transfusion/CSF support: RARS, EPO for low serum
EPO levels at dx
– EPO/G if <2U PRBC/mo
• IP therapy- +8, hypoplastic, IPSS low, minimal
transfusion burden
• Revlimid: 5q- cytogenetics, IPSS low/int-1, RBC
response only
– Best if <4 PRBC/8 weeks
• Trisenox: Low IPSS risk patients failing prior
therapy- third line drug
• Dacogen: possibly as bridge for secondary AML
• Vidaza: All FAB types, including CMML, all IPSS
scores, use early when intervention required
– Maintenance concept- able to use indefinitely
Bone Marrow Transplantation
Images with Permission of L Silverman,MD
Remission Durability Requires Stem Cell
Directed Therapy
Low Quality
MDS
Stem Cell
Relapse
Chemotherapy
Non-dividing
MDS cells
Remission
Stem Cell -Directed
Therapy
Approximation of Life Expectancy
(Years)
Immediate
Transplant
Transplant in
2 Years
Transplant 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
From Cutler C, et al. A Decision Analysis of Allogenetic Bone Marrow Transplantation for Myelodysplastic Syndromes: Delayed
Transplantation for Low Risk Myelodysplasia is Associated with Improved Outcome. Blood 2004- 1st Ed Publication. Prepublished
online March 23, 2004; D01.1182/Blood-2004-01-0338.
Copyright American Society of Hematology, used with Permission.
Relapse and Relapse-free Survival (tBUCY):
IPSS Score
Relapse
IPSS >2 (N=8)/ H
IPSS 1.5-2 (N=24)/ I-2
IPSS 5-1 (N=54)/ I-1
IPSS 0 (N=16)/ L
80
60
Overall Survival
40
20
0
0
1
2
3
4
5
Years from Transplant
6
7
Relapse-free Survival (%)
Relapse (CI%)
100
100
80
60
40
20
IPSS 0 (N=16)/ L
IPSS 5-1 (N=54)/ I-1
IPSS 1.5-2 (N=24)/ I-2
IPSS >2 (N=8)/ H
0
0
1
2
3
4
5
6
Years from Transplant
From Deeg J, et al. Conditioning with Targeted Busulfan and Cyclophosphamide for Hemopoitic
Stem Cell Transplantation from Related and Unrelated Donors in Patients with MDS. Blood 2002. 100:1201-7.
Copyright American Society of Hematology, used with Permission.
7
Additional Risk Factors
• Cytogenetics as risk factor for relapse
– Complex cytogenetics 83% relapse at 7 years
– IPSS cytogenetic risk:
• Good
• Intermediate
• Poor
Sutton et al Blood 1996, 88:358
Nevill et al Blood 1997;89:2578
Guardiola Blood 2002;99:4370
EFS 51% relapse 19%
EFS 40% relapse 12%
EFS 6% relapse 82%
94
Pretransplant Cytoreductive
Chemotherapy
• Yacoub-Agha: allotransplant for tMDS (31) or tAML (39)
– 33 patients received IC prior to BMT
• 24 patients in CR vs 46 with active disease
– IC to CR reduced relapse risk in advanced or high-risk
cytogenetics
• De Witte: patients obtaining CR with IC pre-transplant
improved overall survival and EFS (EBMT Registry data)
• IC to CR essential in patients receiving AuBMT
• Ho, de Lima conclude IC to CR improves survival in RIT
• Cermak: transplantation with untreated RAEB increases TRM
• Questions
– IC to CR or stable disease allows more effective GV-MDS?
– Does prior IC add to TRM?
Yacoub-Agha et al. Blood. 2000;18:963-971.
De Witte et al. Br J Haematol. 1990;74:151-155.
– Is Azacytidine effective pre-transplant?
Ho et al. Blood. 2004;104:1616-1623.
De Lima et al. Blood. 2004;104:865-872.
Results Azacytidine Pre-Transplant
OVERALL
MEDIAN
AGE
M:F
MEDIAN F/U
MEDIAN F/U DAYS RX PRE
POST
(ITT)
TRANSPLANT TRANSPLANT
48 (16-68)
10:15
544 (42-1554)
201 (18-552)
253 (18-1388)
4:7
544 (91-1554)
208 (166-552)
258 (18-1388)
AZACYTIDINE 52 (19-68)
FLAG
36 (16-54)
2:6
475 (42-1275)
154 (18-288)
169 (24-1183)
AZA TO FLAG
55 (37-62)
4:2
487 (250-862)
212 (181-324)
132 (69-132)
76% of all 5-Aza patients achieved CR/VGPR and proceeded to transplant
18/19 patients engrafted WBC D+16, platelets D+21
All patients 100% donor at day +30
Acceptable aGVHD II-III (10%) and expected cGVHD (37%) seen
Overall
Mortality Rate
Relapsed/
Refractory
Non-Relapse
Mortality
Transplant
Related
Mortality
OVERALL
44.0%
24.0%
20.0%
20.0%
AZACYTIDINE
36.4%
9.1%
27.3%
22.2%
FLAG
37.5%
12.5%
25.0%
28.6%
AZA TO FLAG
66.7%
66.7%
16.7%
33.3%
Developing a Treatment
Algorithm for MDS
Images with Permission of L Silverman,MD
100
Treatment Algorithm for Patients With MDS
Asymptomatic
Low/Int-1
Int-2/High
S
u
r
v
i
v
a
l
Symptomatic
Observation
Cytokine
Epo/G-CSF
B
l
a
s
t
s
5q8+
Lenalidomide
Azacitidine
Thalidomide
SCT—ablative
Investigational RIC
5/7-, 7q
Complex
Azacitidine
Investigational
Intensive chemotherapy
SCT—full ablative-RIT
RIC = reduced intensity conditioning.
From Silverman. In: Holland et al, eds. Cancer Medicine. 7th ed. BC Decker; 2006, with permission.
To view the most recent and complete
version of the NCCN Acute Leukemia and
MDS Clinical Practice Guidelines in
Oncology (Version 2.2007), go online to
www.nccn.org.