Real-Life Decisions
An Interactive Case-Based Symposium on the
Management of Multiple Myeloma, Myelodysplastic
Syndromes and Acute Myeloid Leukemias
Friday, December 3, 2010
6:30 PM – 9:00 PM
Orlando, Florida
Moderator
Neil Love, MD
Faculty
William I Bensinger, MD
Pierre Fenaux, MD
B Douglas Smith, MD
Morie A Gertz, MD
Ravi Vij, MD
Farhad Ravandi, MD
Copyright © 2011 Research To Practice. All rights reserved.
Agenda
CASE 1: Multiple Myeloma (MM) in the Nontransplant Setting
Dr Harwin
CASE 2: Biomarker-Guided Treatment for MDS
Dr Schwartz
CASE 3: Risk- and Age-Stratified Treatment for AML
Dr Schwartz
CASE 4: MM in the Transplant-Eligible Patient
Dr Fishkin
CASE 5: Chronic Myelomonocytic Leukemia (CMML)
Dr Harwin
CASE 6: Therapeutic Alternatives for Newly Diagnosed APL
Dr Fishkin
Panel Discussion and Response to Audience Questions
Copyright © 2011 Research To Practice. All rights reserved.
Community Oncologist Participants
Paul A S Fishkin, MD
William N Harwin, MD
Michael A Schwartz, MD
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Audience members, please remember
to take survey and ask questions
Copyright © 2011 Research To Practice. All rights reserved.
Case 1: Dr Harwin (Discussant: Dr Bensinger)
• 75 yo man: PMH – MGUS and chronic bronchiectasis
• 2/09 – Mild anemia, no bone lesions, bone marrow
50% plasma cells  no active therapy
• 1/10 – Progressive anemia, M-spike to 3.9 g/dL and
back pain  solitary osteolytic lesion with
compression fracture at T7
• Vertebroplasty/biopsy showed plasmacytoma
• Repeat bone marrow: Cytogenetics = t(11;14)
Copyright © 2011 Research To Practice. All rights reserved.
Case 1 continued:
• Started on lenalidomide/dexamethasone (Rd) and
zoledronic acid
• Completed six cycles of Rd  Len-maintenance
(15 mg 3wk on, 1wk off) plus monthly bisphosphonate
• M-spike down to 1.0 g/dL and Hgb stable
• Referred to tertiary center for consideration of
transplant  considered not eligible due to chronic
lung disease
Copyright © 2011 Research To Practice. All rights reserved.
Real-Life Decisions
An Interactive Case-Based Symposium on the
Management of Multiple Myeloma, Myelodysplastic
Syndromes and Acute Myeloid Leukemias
Friday, December 3, 2010
6:30 PM – 9:00 PM
Orlando, Florida
Moderator
Neil Love, MD
Faculty
William I Bensinger, MD
Pierre Fenaux, MD
B Douglas Smith, MD
Morie A Gertz, MD
Ravi Vij, MD
Farhad Ravandi, MD
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Management of Myeloma in Older Patients
Presented by: Dr. William Bensinger, MD
Professor of Medicine, University of Washington
Member, Fred Hutchison Cancer Research Center
Genetic Classification of MM
Genetics
Hyperdiploid
t(11;14)
t(6;14)
t(14;16)
t(14;20)
t(4;14)
Del(17p)
Fonseca, Cancer Research 2004
Incidence
Del 13
Prognosis
45%
-
fair
15%
-
fair
10%
++
poor
15-20%
+++
poor
Initial Approach to Treatment of MM
Clearly not a transplant
candidate
Potential transplant
candidate
MPT,
clinical trial
Non-alkylator based
induction, clinical trial
MPV and Len/Dex are
additional options. Other options
are under investigation.
Stem cell harvest
Drugs for Myeloma
Class
Steroids
Drugs
IMiDs
Dexamethasone,
prednisone
Cyclophosphamide,
melphalan, bendamustine
Doxorubicin, liposomal
doxorubicin
Thalidomide, lenalidomide
Proteosome inhibitors
Bortezomib
Alkylators
Anthracyclines
VMP vs. MP
VISTA: Phase III
Randomized, international phase 3 study: VMP vs MP in previously
untreated MM patients, not candidates for SCT
► Endpoints: Primary: TTP; Secondary: CR rate, ORR, TTR, DOR, PFS, TNT,
OS, QoL
► Study Schema:
ARM A (VMP)
R
A
N
D
O
M
I
Z
E
VMP: 6-week cycles: Cycles 1-4
Bortezomib 1.3mg/m2 days 1, 4, 8, 11, 22, 25, 29, 32;
Melphalan 9mg/m2 and prednisone 60mg/m2 days 1-4
Followed by 6-week cycles: Cycles 5-9
Bortezomib 1.3mg/m2 days 1, 8, 22, 29; Melphalan
9mg/m2 and prednisone 60mg/m2 once daily on days 1–4
Assessment of Efficacy
and Safety
Max of 9 cycles (total 54 weeks) in both Arms
ARM B (MP)
MP: 6-week cycles: Cycles 1-9
Melphalan 9mg/m2 and prednisone 60mg/m2 days 1-4
Mateos MV et al. J Clin Oncol 2010;28(13):2259-66.
VMP vs. MP
Overall Survival (OS)*
Median
OS
Hazard
MP
VMP
Ratio
(n=233) (n=178)
(95% CI)
p-value
0.688
Not
45.0 mos
0.021
reached (0.500-0.948)
Median Follow Up: 36.7 months
*OS for patients randomly assigned to VMP or MP who had received
subsequent therapy by data cutoff for the present analysis.
Mateos MV et al. J Clin Oncol 2010;28(13):2259-66.
Thal-Dex vs. MP
PFS
MP
(n=141)
Median PFS
Thal-Dex
(n=142)
49.4 mos 41.5 mos
Median Follow Up: 28.1 months
Dex dose 320 mg/cycle
Ludwig H et al. Proc ASH 2007;Abstract 529.
p-value
0.024
MPT vs. MP in Patients >75 years
►IFM 01-01 randomized, double blind study
►N=232
►median age 78.5 yrs
►Thal 100mg/d x 72 weeks, no VTE
prophylaxis
►MP q6wks X 12
Hulin C et al. J Clin Oncol 2009;27(22):3664-70.
MP vs. MPT in Patients >75 Years of Age:
PR
VGPR
CR
100
90
Patients (%)
80
70
P< 0.001
60
62%
50
40
30
31%
20
10
0
21%
1%
7%
7%
MP
MPT
Hulin C et al. J Clin Oncol 2009;27(22):3664-70.
MP vs. MPT in Newly Diagnosed
MM Patients Aged >75 Years: PFS and OS
MP
(n=116)
MPT
(n=113)
p-value
Median OS
29.1 mos 44.0 mos
0.028
Median PFS
18.5 mos 24.1 mos
0.001
Median Follow Up: 47.5 months
Hulin C et al. J Clin Oncol 2009;27(22):3664-70.
E4A03: Phase III Trial of Lenalidomide Plus
High- Vs. Low-Dose Dexamethasone
Newly diagnosed MM,
Age 35-87 years (median age 66 years)
(N=445)
HiDex
LoDex
Lenalidomide 25 mg days 1-21
Dexamethasone 40 mg
days 1-4, 9-12, 17-20
28-day cycle (N=223)
x4
<PR
Thal/Dex
4 cycles
Lenalidomide 25 mg days 1-21
Dexamethasone 40 mg
days 1, 8, 15, 22
28-day cycle (N=222)
CR/nCR
CR/PR/SD
Rajkumar SV et al. Lancet Oncol 2010;11(1):29-37.
SCT
Landmark Analysis
Median Follow up: 36 months
431 Patients Alive
at 4 cycles
Off therapy
@ 4 cycles
N=183
No transplant
N=93
(Median Age 68)
Primary therapy
beyond 4 cycles
N=248
Transplant
N=90
(Median Age 57)
Rajkumar SV et al. Lancet Oncol 2010;11(1):29-37.
Rd
N=140
(Median Age 66)
RD
N=108
(Median Age 65)
Landmark Analysis
Median Follow up: 36 months
431 Patients Alive
at 4 cycles
Off therapy
@ 4 cycles
N=183
No transplant
N=93
(Median Age 68)
Primary therapy
beyond 4 cycles
N=248
Transplant
N=90
(Median Age 57)
Rd
N=140
(Median Age 66)
RD
N=108
(Median Age 65)
3-yr OS rate = 79%
Rajkumar SV et al. Lancet Oncol 2010;11(1):29-37.
VMPT->VT maint vs. VMP->no maint
VMPT → VT Hazard pVMP
(n=257)
(n=254)
ratio value
Median time to next
therapy (TTNT)
Not
reached
Not
reached
TTNT (3-year rate)
60%
72%
Not
reached
Not
reached
87%
89%
Median OS*
3-year OS rate
Median Follow Up: 23.2 months
Palumbo A et al. J Clin Oncol 2010;28(34):5101-9.
0.58
0.007
0.92
0.77
MRC Myeloma IX—
Analysis Schematic for ZOL vs CLO
N = 1,960
Patients with newly
diagnosed MM
(stage I, II, III)
R
A
N
D
O
M
I
Z
A
T
I
O
N
Zoledronic acid (4 mga IV q 3-4 wk) +
intensive or non-intensive chemotherapy
(n = 981)
Treatment continued at least
until disease progression
Clodronate (1,600 mg/d PO) +
intensive or non-intensive chemotherapy
(n = 979)
Endpoints (ZOL vs CLO)
Primary: PFS, OS, and ORR
Secondary: Time to first SRE, SRE incidence, and Safety
Abbreviations: CLO, clodronate; IV, intravenous; MM, multiple myeloma; ORR, overall response rate; OS, overall survival,
PFS, progression-free survival; PO, oral; SRE, skeletal-related event; ZOL, zoledronic acid.
a Dose-adjusted for patients with impaired renal function, per the prescribing information.
With permission, Morgan G et al. Proc ASCO 2010;Abstract 8021.
MRC Myeloma IX —
ZOL Significantly Reduced SREs vs CLOa
24% relative
reduction
P = .0004
Abbreviations: CLO, clodronate; SRE, skeletal-related event; ZOL, zoledronic acid.
a SREs were defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or
surgery to bone lesions or the appearance of new osteolytic bone lesions.
With permission, Morgan G et al. Proc ASCO 2010;Abstract 8021.
MRC Myeloma IX —
ZOL Improved OS vs CLO After Adjustment for SREsa
• Is the observed OS ↑ with ZOL because of SRE prevention, or does it
represent an anti-myeloma effect?
• Exploratory analysis that adjusted for SREs
• ZOL reduced the risk of death by 15% vs CLO (HR = 0.850; P = .0178)
P value
15%
.0178
0.850
OS
0
Risk
reduction
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
Hazard ratio (ZOL versus CLO)
In favor of ZOL
1.8
2
In favor of CLO
Abbreviations: CLO, clodronate; HR, hazard ratio; OS, overall survival; SRE, skeletal-related event; ZOL, zoledronic acid.
a Time
to first SRE was included as a time-dependent covariate in an exploratory Cox model examining OS.
With permission, Morgan G et al. Proc ASCO 2010;Abstract 8021.
Conclusions
►75 year old man h/o MGUS with symptomatic
MM, co-morbidities, no high risk features
MPV, MPT, Rd are all acceptable induction
therapies
Maintenance improved PFS in some trials; no clear
survival benefits in current trials
Compelling evidence for benefits of zoledronate for
both skeletal disease and survival
Real-Life Decisions
An Interactive Case-Based Symposium on the
Management of Multiple Myeloma, Myelodysplastic
Syndromes and Acute Myeloid Leukemias
Friday, December 3, 2010
6:30 PM – 9:00 PM
Orlando, Florida
Moderator
Neil Love, MD
Faculty
William I Bensinger, MD
Pierre Fenaux, MD
B Douglas Smith, MD
Morie A Gertz, MD
Ravi Vij, MD
Farhad Ravandi, MD
Copyright © 2011 Research To Practice. All rights reserved.
Life Expectancy in Older Men According to
Health Status
88
Age = 70
82.4
90.8
Age = 80
86.7
76.7
70
75
83.3
80
85
90
95
80
85
90
89.2
84.3
Age = 75
92.9
Age = 85
79.9
75
80
95
89.7
87.2
85
90
95
85
Life expectancy, years
Top 25th percentile (healthy)
90
95
Life expectancy, years
50th percentile (median)
Lowest 25th percentile (frail)
Walter LC, Covinsky KE. JAMA 2001;285:2750-6.
Copyright © 2011 Research To Practice, All rights reserved.
(117)
(42)
(38)
(12)
(1)
(69)
(54)
(33)
(23)
(6)
(6)
(15)
(5)
Case 2: Dr Schwartz (Discussant: Dr Fenaux)
• 71 yo man: PMH – Diabetes
• 10/09 – Pancytopenia (ANC <1, platelets 63,000/µL,
Hgb 8.8 g/dL)
• Bone marrow hypercellular, dysplastic changes,
trisomy 8 and <5% blasts
• IPSS 1.0 = Intermediate-1 MDS
• Patient is completely asymptomatic
• Started on azacitidine 75mg/m2/day SQ x 7 days
(M-Sun) on q4 week intervals
Copyright © 2011 Research To Practice. All rights reserved.
Case 2 continued:
• Well-tolerated – mild nausea and slight pain at
injection site
• Difficulty with transportation to clinic  treatment
interval stretch to 5 weeks for C5, 6 weeks for C6
• Lab values normalized post C6, but patient did not
return to clinic for 4 mos
• 10/10 – Follow-up visit, asymptomatic but declining
blood counts and repeat biopsy MDS with trisomy 8
Copyright © 2011 Research To Practice. All rights reserved.
Real-Life Decisions
An Interactive Case-Based Symposium on the
Management of Multiple Myeloma, Myelodysplastic
Syndromes and Acute Myeloid Leukemias
Friday, December 3, 2010
6:30 PM – 9:00 PM
Orlando, Florida
Moderator
Neil Love, MD
Faculty
William I Bensinger, MD
Pierre Fenaux, MD
B Douglas Smith, MD
Morie A Gertz, MD
Ravi Vij, MD
Farhad Ravandi, MD
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Real-Life Decisions
An Interactive Case-Based Symposium on the
Management of Multiple Myeloma, Myelodysplastic
Syndromes and Acute Myeloid Leukemias
Friday, December 3, 2010
6:30 PM – 9:00 PM
Orlando, Florida
Moderator
Neil Love, MD
Faculty
William I Bensinger, MD
Pierre Fenaux, MD
B Douglas Smith, MD
Morie A Gertz, MD
Ravi Vij, MD
Farhad Ravandi, MD
Copyright © 2011 Research To Practice. All rights reserved.
Current Treatment of MDS
Pierre Fenaux
Hôpital Avicenne
Paris 13 University
Inserm U 848
France
ASH « super Friday » 2010
Cytogenetic Abnormalities
in MDS
No. of
patients
(%)
–Y
17
(2)
del(5q)
48
(6)
Normal
48
9
(60)
del(20q)
16
(2)
Misc. single
74
(9)
+8
38
(5)
Double
29
(3)
Misc. double
14
(2)
Chrom 7
abn
10
(1)
Misc.
complex
15
(2)
Complex
66
(8)
Complex
–Y
del(5q)
Misc. complex
Chrom 7 abn
Misc. double
Double
+8
Misc. single
del(20q)
Greenberg P et al. Blood. 1997;89:2079-2088.
Normal
MDS:
« Higher » vs « Lower » Risk
• Higher Risk
– IPSS intermediate-2 or high
• Lower Risk
– IPSS low or intermediate-1
Treatment Objectives
•
•
•
•
Delay disease progression
Prolong survival
Improve blood cytopenias
Improve quality of life
Treatment of Anemia in
Lower Risk MDS
• First-Line Treatment
– ESAs (EPO and darbepoetin)
– Lenalidomide (del 5q)
• Second-Line Treatment
–
–
–
–
Immunosuppression (ATG+/- ciclo)
Thalidomide
Lenalidomide (non del 5q)
Hypomethylating agents
National Comprehensive Cancer Network, v2.2011.
Erythroid Response to Lenalidomide in
Lower Risk MDS with or without del 5q
MDS with del 5q
deletion1
(n = 148)
MDS without del 5q2
(n = 214)
67%
26%
9%
17%
Total transfusion
response
76%
43%
Median time to transfusion
independence (range)
4.6 weeks (1-49)
4.8 weeks (1-39)
Erythroid response
Transfusion
independence
≥50% decrease in
number of
transfusions
1 List
A et al. N Engl J Med 2006;355(14):1456-65; 2 Raza A et al. Blood 2008;111(1):86-93.
Treatment of Higher Risk MDS
• Allogeneic stem cell transplantation
• Chemotherapy (intensive or not)
• Hypomethylating agents
Phase III Trial: Efficacy of Azacitidine (AZA)
vs Conventional Care Regimens (CCR) in the
Treatment of Higher-Risk Myelodysplastic Syndromes
AZA 75 mg/m2/d x 7 d q28 d
Screening/Central
Pathology Review
Investigator CCR
Tx Selection
Randomization
CCR
• Best Supportive Care (BSC) or
• Low Dose Ara-C (LDAC,
20 mg/m2/d x 14 d q28-42 d) or
• Intensive Chemo (7 + 3)
BSC was included with each arm
Tx continued until unacceptable toxicity or AML transformation or disease progression
Fenaux P et al. Lancet Oncol 2009;10:223-32.
Primary Endpoint: Median Overall Survival
— AZA vs CCR (ITT Population)
Log-Rank p = 0.0001
HR = 0.58 [95% CI: 0.43, 0.77]
Deaths: AZA = 82, CCR = 113
Difference: 9.4 months
Proportion Surviving
1.0
0.9
0.8
0.7
50.8%
24.4 months
0.6
0.5
0.4
15 months
26.2%
AZA
0.3
CCR
0.2
0.1
0.0
0
5
10
15
20
25
30
35
40
Time (months) from Randomization
Reprinted from the Lancet Oncology Vol. 10, Fenaux P et al. Efficacy of azacitidine compared with that of conventional
care regimens in the treatment of higher-risk myelodysplastic syndromes: A randomised, open-label, phase III
study, pp223-232. Copyright 2009, with permission from Elsevier.
Secondary Endpoints:
IWG (2000) CR, PR and HI
Response
Overall (CR+PR)
CR
PR
IWG HI
Major+Minor
AZA
N=179
(%)
CCR
N=179
(%)
P-Value
AZA vs
CCR
29
17
12
12
8
4
0.0001
0.02
0.009
49
29
<0.0001
Fenaux P et al. Lancet Oncol 2009;10:223-32.
Median Overall Survival Per
Frequent Cytogenetic Abnormality
AZA
Karyotype
CCR
Patient n°
Median OS
Patient n°
Median OS
HR
- 7/ 7q- not complex
16
24.5
11
8.1
0.33
- complex
14
5.3
16
3.9
0.45
+8
- not complex
16
26.3
12
8.7
0.20
- complex
9
17.3
9
4.9
0.44
Mufti GJ et al. Proc ASH 2009;Abstract 1755.
Azacitidine in Higher Risk MDS
• Works slowly
• Survival improvement may require a
large number of cycles
• Survival improvement for all responses
(including « HI »)
• Prophylactic measures for side effects?
– cytopenias
EORTC Trial: Decitabine versus BSC in
Higher Risk MDS (Lubbert, 2010)
Decitabine
BSC
HR,
p-value
Median
PFS (mos)
6.6
3
0.68, 0.004
Median OS
(mos)
10.1
8.5
0.88, 0.38
PFS = progression free survival, OS = overall survival, BSC = best supportive care
Wijermans P et al. Proc ASH 2008. Abstract 226
Decitabine Alternate Schedules
5 day IV
(20 mg/m2/d)
(n = 64)
5 day SC
(n = 14)
10 day IV
(n = 17)
CR
25 (39%)
3 (21%)
4 (24%)
Median number of
courses (range)
5 (1–18)
8 (1–17)
9 (1–15)
Median days to
subsequent cycle
35
35
40
Courses requiring
hospitalization
50 (12%)
14 (14%)
23 (23%)
Parameter
Kantarjian, et al. Blood 2007;109:52–7
A Scoring System for Higher-Risk MDS
Treated with Azacitidine
Risk factor
Point
PS
0-1
0
2+
1
Karyotype:
FAV
0
INT
1
UNFAV
2
Transfusions
0-3 RBC units/8 weeks
0
> 3 RBC units/8 weeks
1
PB blasts
absent
0
present
1
Itzykson R et al. Blood 2010. [Epub ahead of print]
ATU
Initial cohort
AZA-001
Validation cohort
At risk
Median
OS
2-year OS
[95% CI]
Low
30 (12%)
NR
80% [63-96]
Int
182 (70%)
15.0
31% [24-39]
High
48 (19%)
6.1
0
Itzykson R et al. Blood 2010. [Epub ahead of print]
At risk
Median
OS
2-year OS
[95% CI]
Low
27 (17%)
NR
83% [68-98]
Int
120 (73%)
20.8
48% [37-58]
High
16 (10%)
14.4
20% [0.2-50]
Second-Line Treatment After
Failure of Hypomethylating Agents
• Median survival after failure of azacitidine:
6 months (Prébet, ASH 2010)
• Treatment ?
– Clofarabine
– ON 01910 Na
– Allogeneic SCT
Hypomethylating Agents in
Lower Risk MDS
• Silverman (2002), Wijermans (2005)
Lyons (2007)
– Patients generally resistant to EPO
– 35–40% HI-E, generally with transfusion
independence
• Italian group experience
(Musto, Cancer 2010)
– 63 patients, generally resistant to EPO
– 41% erythroid responses
Alternative Regimens of AZA
Phase II, prospective, multicenter,
randomized, open-label, 3-arm trial
Screening
Cycle 1-6
AZA 5-2-2
75 mg/m2 SC
Day -21 to -1
AZA 5-2-5
50 mg/m2 SC
AZA 5
75 mg/m2 SC
q 28 or 42 days
AZA 5
75 mg/m2 SC
Initial
Randomization
Repeat cycle
every 28 days
Lyons RM et al. J Clin Oncol 2009;27(11):1850-56.
Maintenance
Randomization
Groupe Francophone
des Myélodysplasies
• Activates clinical trials in MDS (35 centers in France and
Belgium + (recently) Switzerland, Tunisia)
• Website: www.gfmgroup.org
• Online registry of French MDS cases
• Close cooperation with:
- a patient support group
- the International MDS Foundation
- the European Leukemia Net
Real-Life Decisions
An Interactive Case-Based Symposium on the
Management of Multiple Myeloma, Myelodysplastic
Syndromes and Acute Myeloid Leukemias
Friday, December 3, 2010
6:30 PM – 9:00 PM
Orlando, Florida
Moderator
Neil Love, MD
Faculty
William I Bensinger, MD
Pierre Fenaux, MD
B Douglas Smith, MD
Morie A Gertz, MD
Ravi Vij, MD
Farhad Ravandi, MD
Copyright © 2011 Research To Practice. All rights reserved.
Case 3: Dr Schwartz (Discussant: Dr Smith)
• 72 yo man: PMH – CAD, but PS0
• 12/09: High fever, obtunded, LP-negative,
pancytopenia
• Bone marrow = 24% blasts, hypocellular, CD33+,
monosomy 11, MML gene rearrangement
• Inpatient tx: Azacitidine 75mg/m2/day x 7 days plus
gemtuzumab 3 mg/m2 on day 8
Copyright © 2011 Research To Practice. All rights reserved.
Case 3 continued:
• Repeat bone marrow day 22 = hypocellular with
<10% blasts
• Discharged home
• 2nd cycle azacitidine/gemtuzumab outpatient 
blood counts and bone marrow normalized
• Maintenance – 4 cycles azacitidine alone
• In remission
Copyright © 2011 Research To Practice. All rights reserved.
Real-Life Decisions
An Interactive Case-Based Symposium on the
Management of Multiple Myeloma, Myelodysplastic
Syndromes and Acute Myeloid Leukemias
Friday, December 3, 2010
6:30 PM – 9:00 PM
Orlando, Florida
Moderator
Neil Love, MD
Faculty
William I Bensinger, MD
Pierre Fenaux, MD
B Douglas Smith, MD
Morie A Gertz, MD
Ravi Vij, MD
Farhad Ravandi, MD
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Real-Life Decisions
An Interactive Case-Based Symposium on the
Management of Multiple Myeloma, Myelodysplastic
Syndromes and Acute Myeloid Leukemias
Friday, December 3, 2010
6:30 PM – 9:00 PM
Orlando, Florida
Moderator
Neil Love, MD
Faculty
William I Bensinger, MD
Pierre Fenaux, MD
B Douglas Smith, MD
Morie A Gertz, MD
Ravi Vij, MD
Farhad Ravandi, MD
Copyright © 2011 Research To Practice. All rights reserved.
Management Strategies for Elderly
Patients with AML
B. Douglas Smith, MD
Associate Professor, Oncology
Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins
Elderly AML:
Limited Improvements in Outcome
Younger
Older
• Supportive care
• Supportive care
• Risk-adapted therapy
• Intensifying therapy
ACUTE MYELOID LEUKEMIA
Question #1: When is one really OLD?
Age ≥ 60 Years = Independent Risk Factor:
Analysis From the German AMLCG 99 Study
< 60
Years
(n=1137)
≥ 60
Years
(n=1367)
P Value
sAML
17%
29%
< .0001
Unfavorable Cytogenetics
23%
29%
.0004
Favorable Cytogenetics
12%
4%
< .0001
nl Cyto, NPM mut, ITD wt
34%
26%
< .009
Median WBC/mL
12.600
7.360
< .0001
Median LDH U/L
413
340
< .0001
CR Rate
70%
54%
< .001
Early and Hypoplastic Death
12%
16%
< .001
Persistent Leukemia
18%
30%
< .001
Patient Characteristics
Buchner, T et al. ASH 2008, Abstract 555
Age ≥ 60 Years = Independent Risk Factor:
Analysis From the German AMLCG 99 Study
Overall
Survival
Relapse Rate
Unfavorable Cytogenetics
2.17
2.08
Age ≥ 60 Years (all patients)
1.96
2.04
Age ≥ 60 Years (nl cytogenetics)
2.0
2.0
LDH > 700 U/L
1.32
1.41
Multivariate Analysis
Buchner, T et al. ASH 2008, Abstract 555
ACUTE MYELOID LEUKEMIA
Question #2: Is your “old” pt ready for
intensive induction chemotherapy?
“FIT” vs “UNFIT”?
Choosing Patients Wisely
• Age = continuous variable
• Organ Function:
• renal (cytarabine)
• cardiac (anthracyclines)
• History of previous chemotherapy
• Performance status
• nutritional parameters
• Family / social support
ACUTE MYELOID LEUKEMIA
Question #3: Is your “old” pt ready for
intensive induction chemotherapy?
Wild card = is the AML the problem?
ACUTE MYELOID LEUKEMIA
Question #4: When is the AML
really OLD?
AML: TWO Diseases
60 years ??
De novo
AML
“MDS/AML”
?
Age
** Courtesy of Dr. Mark Levis
“MDS/AML” is more likely to have:
- poor risk cytogenetics
- antecedent marrow disorder
- MDR1 overexpression
Prognostic Factors in AML
•
•
•
•
•
•
CYTOGENETICS
Molecular Mutations
WBC @ presentation
Preceding MDS
CD34 expression
MDR1 phenotype
•
•
•
•
•
Age
Performance status
Secondary AML
Extramedullary AML
Failure to achieve CR
Molecular Mutations in AML
• FLT3
• FLT3/ITD mutation
• FLT3/D835 mutation
Currently available
• NPM1 mutation
•
•
•
•
Kit mutations
CEBPa
WT-1
BAALC
The Future???
Arriving SOON…
TET2 – impacts methylation status of cytosine…
Jankowska, Ko, Huang, et al. ASH 2010, Abstract 1, Plenary Session
Prognostic Factors in AML
•
•
•
•
•
•
CYTOGENETICS
Molecular Mutations
WBC @ presentation
Preceding MDS
CD34 expression
MDR1 phenotype
•
•
•
•
•
Age
Performance status
Secondary AML ??
Extramedullary AML
Failure to achieve CR
What should this tell us AND what should we do?
#1 Our patient is NOT likely to respond to traditional cytotoxics…
#2 Start a direct dialog with your pt and consider a clinical trial…
ACUTE MYELOID LEUKEMIA
Question #5: Are there better cytotoxic
agents for older patients with AML?
GOAL = increase induction success?
Decrease toxicity? Improve survival?
Clinical Trials in Older Adults with AML
STUDY
AGE (YRS)
CR(%)
OVERALL
SURVIVAL
(MONTHS)
ECOG 1490.
Rowe
1995
64
52
7.8
CALGB 8923.
Stone
1995
69
52
9.6
SWOG 9031.
Godwin
1998
68
45
8.5
HOVON AML 9.
Löwenberg
1998
68
42
9.5
MRC AML 11.
Goldstone
2001
66
55
10% - 5 yrs
CALGB 9720.
Baer
2002
70
46
10
SWOG 9333.
Anderson
2002
68
43
9
ECOG 3993.
Rowe
2004
68
42
7.5
2009
66
59
16%- 4 yrs
German AML Coop Group Büchner
Induction Death
~
Disease-Free Survival ~
15 – 20%
6 – 9 months
What’s New ASH 2010: AML Novel RX
Monday, Dec 6, 4:30pm – 6pm, room 311 ABCD
•
Abstract #655: Phase 2B Randomized Study of CPX-351 Vs. Cytarabine (CYT) + Daunorubicin
(DNR) (7+3 Regimen) In Newly Diagnosed AML Patients Aged 60-75. Jeffery E. Lancet, MD, et al
•
Abstract #656: Phase I Study to Assess the Safety and Tolerability of AZD1152 In Combination with
Low Dose Cytosine Arabinoside In Patients with Acute Myeloid Leukemia (AML). Hagop M.
Kantarjian, MD, et al
•
Abstract #657: A Multi-Center, Open-Label, Phase I Study of Single Agent RG7112, A First in Class
p53-MDM2 Antagonist, In Patients with Relapsed/Refractory Acute Myeloid and Lymphoid
Leukemias (AML/ALL) and Refractory Chronic Lymphocytic Leukemia/Small Cell Lymphocytic
Lymphomas (CLL/SCLL). Michael Andreeff, MD, PhD, et al
•
Abstract #658: The Novel, Investigational NEDD8-Activating Enzyme Inhibitor MLN4924 In Adult
Patients with Acute Myeloid Leukemia (AML) or High-Grade Myelodysplastic Syndromes (MDS): A
Phase 1 Study. Ronan T. Swords, MD, MRCPI, FRCPath, et al
•
Abstract #659: Anti-Leukemic Activity of PIK-75, a P13-Kinase p110a Selective Inhibitor, In Acute
Myeloid Leukemia. François Vergez, et al
•
Abstract #660: Terminal Differentiation of FLT3/ITD AML Blasts In Patients Treated with the FLT3
Inhibitor AC220. Mark J. Levis, MD, PhD, et al
CPX-351 Randomized Phase II Study 204:
Newly Diagnosed AML, Elderly Patients
• Liposomal formulation
• Ara-C + daunorubicin
• (fixed molar ratio = 5:1)
• Taken up in whole by cell
• preferential = bone marrow
• Phase IIB, Elderly AML
•
•
•
•
Age btwn 60-74, non-favorable risk, “fit” for chemo
2 to 1 randomization = CPX-351 (100 u/m2 IV d 1,3,5) vs “7 + 3”
1˚ endpoint: % CR
2˚ endpoints: CR duration, EFS, survival at 12 mos, rate of SCT
and mortality (30, 60, 90 d)
Lancet J, et al. ASH 2009, Abstract 1033
CPX-351 Phase II: Interim Data
Clinical Response and Toxicity
Response:
CPX-351 (n = 57)
7+3 (n = 28)
CRm
23 (40%)
CRi
12 (21%)
3 (11%)
TOTAL
35 (61%)
14 (50%)
Lancet J, et al. ASH 2009, Abstract 1033
11 (39%)
CPX-351 Phase II: Interim Data
Clinical Response and Toxicity
Response:
CPX-351 (n = 57)
7+3 (n = 28)
CRm
23 (40%)
11 (39%)
CRi
12 (21%)
3 (11%)
TOTAL
35 (61%)
14 (50%)
</- 30 days
3 (5.3%)
1 (3.6%)
31-60 days
0 (0%)
0 (0%)
61-90 days
2 (3.5%)
1 (3.6%)
5 (8.8%)
2 (7.2%)
Mortality:
TOTAL
Lancet, et al. ASH 2009
ACUTE MYELOID LEUKEMIA
Question #6: NON-cytotoxic agents for
older patients with AML?
GOAL = stabilize marrow function?
Decrease toxicity? Improve survival?
DNA Methyltransferase Inhibitors
•
Abstract #1063: Decitabine for Older AML Patients: An Effective Therapy Associated with Short
Hospitalization and No Invasive Fungal Infection (G. Ansstas, MD, W. Touma, MD, C. Adeimy,
MD, G. Feng, P. Westevelt, MD, PhD, C. Abboud, MD, G. Uy, MD, K. Stockerl-Goldstein, MD, A.
Cashen, MD, J. DiPersio, MD, PhD, and R.Vij, MBBS, MD)
•
PLAN: Elderly AML pts
Decitabine 20 mg/m2 IV daily x 5 days every 28 days
•
45 pts enrolled median age 71 (range 61-83) years
•
Best response to therapy: CR/CRi = 13 (29%) SD/PR = 22 (49%) Progression = 10 (22%)
•
OVERALL SURVIVAL:
CR/CRi = 18.9 mos SD/PR = 7.3 mos Progression = 1.9 mos
•
Abstract #2181: 5-AZA to Treat AML In Elderly or Frail Patients: A Phase II Study (SAKK 30/07).
J. Passweg, MD, MS, T. Pabst, S. Blum, M. Bargetzi, H. Sun, D. Heim, MD, G. Stussi, MD, M.
Gregor, L. Leoncini, S. Meyer-Monard, MD, P. Brauchli, and Y. Chaladon, MD
•
PLAN: Elderly AML pts (PS</= 3) Azacitidine 100 mg/m2 SQ daily x 5 every 28 days
•
45 pts enrolled median age 74 (range 55-86) years >78% with PS 0 or 1
•
17 pts remain on study (authors concluded “feasible strategy” – updating outcomes)
•
28 pts stopped early – reasons: progression, NR, toxicity, pt choice, infection, death (8)
ACUTE MYELOID LEUKEMIA
Question #7: Can we extend our
patients’ remissions?
Maintenance strategies?
Potential Maintenance Regimens in AML
AFTER OPTIMAL CONSOLIDATION
•
Low-dose cytarabine
•
Farnesyltransferase inhibitors
•
Hypomethylating agents
•
Gemtuzumab ozogamicin
•
Lenalidomide
•
Tyrosine kinase inhibitors: FLT3-ITD
•
Interferon
•
IL – 2
•
IL – 2 + Histamine
•
Immunomodulation / vaccines
ACUTE MYELOID LEUKEMIA
Question #8: How are we going to
make the next big discovery?
What’s New ASH 2010 – Elderly AML
Monday, Dec 6, 10:30am – noon, room 311 ABCD
•
Abstract #331: Ph II Study of Bortezomib + Daunorubicin and Ara-C Induction and Dose Escalation
of Bortezomib with Intermed-Dose Ara-C Consolidation Rx for Pts with Previously Untreated AML
Age 60-75 Years: Cancer and Leukemia Group B (CALGB) Study 10502
•
Abstract #332: A Ph II Study of Lenalidomide for Previously Untreated Deletion (del) 5q AML Pts
Age 60 or Older Who Are Not Candidates for Remission Induction Chemotherapy (SWOG S0605)
•
Abstract #333: Sorafenib In Combo with Induction and Consolidation Rx Elderly AML Pts: Results
From a Randomized, Placebo-Controlled Ph II Trial
•
Abstract #334: Induction Rx in Elderly Pts w/AML: Random Comparison of Intermed-Dose Ara-C +
Mitoxantrone vs Standard-Dose Ara-C + Dauno in 492 AML Pts >60 Years – the SAL 60+ Trial
•
Abstract #335: Induction Rx by Ara-C + Dauno vs Ara-C + Gemtuz: Interim Analysis of a
Randomized Phase II Trial of the SAL In Elderly Pts with AML
•
Abstract #336: Frontline Rx for Older Pts with AML: Clofarabine + LD Ara-C Induction Followed by
Prolonged Consolidation with Clofarabine Plus LD Ara-C Alternating with Decitabine
Real-Life Decisions
An Interactive Case-Based Symposium on the
Management of Multiple Myeloma, Myelodysplastic
Syndromes and Acute Myeloid Leukemias
Friday, December 3, 2010
6:30 PM – 9:00 PM
Orlando, Florida
Moderator
Neil Love, MD
Faculty
William I Bensinger, MD
Pierre Fenaux, MD
B Douglas Smith, MD
Morie A Gertz, MD
Ravi Vij, MD
Farhad Ravandi, MD
Copyright © 2011 Research To Practice. All rights reserved.
Case 4: Dr Fishkin (Discussant: Dr Gertz)
• 54 yo woman with pneumococcal sepsis and
pancytopenia
• Persistent serum protein elevation, SPEP with
IFE = 9.5 g/dL IgG kappa
• ß2-microglobulin 4.6 mg/L
• Bone marrow = plasma cells, normal cytogenetics
• Enrolled in clinical trial: SWOG S0777
RVd vs Rd
Copyright © 2011 Research To Practice. All rights reserved.
Case 4 continued:
• Randomized to RVd
• Toxicity  dose reduced x 2 and D/C after
completing 4 cycles:
Neuropathy with Bell’s palsy
↓ Na and ↓K
Skin toxicity (lower extremity ulcer)
• VGPR, stem cells collected and stored
• Maintenance lenalidomide 10 mg/day
Copyright © 2011 Research To Practice. All rights reserved.
Real-Life Decisions
An Interactive Case-Based Symposium on the
Management of Multiple Myeloma, Myelodysplastic
Syndromes and Acute Myeloid Leukemias
Friday, December 3, 2010
6:30 PM – 9:00 PM
Orlando, Florida
Moderator
Neil Love, MD
Faculty
William I Bensinger, MD
Pierre Fenaux, MD
B Douglas Smith, MD
Morie A Gertz, MD
Ravi Vij, MD
Farhad Ravandi, MD
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Myeloma – Managing Younger Patients
MA Gertz MD MACP
Chair Medicine Mayo Rochester
Scottsdale, Arizona
Rochester, Minnesota
Jacksonville, Florida
Real-Life Decisions
An Interactive Case-Based Symposium on the
Management of Multiple Myeloma, Myelodysplastic
Syndromes and Acute Myeloid Leukemias
Friday, December 3, 2010
6:30 PM – 9:00 PM
Orlando, Florida
Moderator
Neil Love, MD
Faculty
William I Bensinger, MD
Pierre Fenaux, MD
B Douglas Smith, MD
Morie A Gertz, MD
Ravi Vij, MD
Farhad Ravandi, MD
Copyright © 2011 Research To Practice. All rights reserved.
mSMART 2.0: Classification of Active MM
High-Risk 20%
 FISH
 Del 17p
 t(14;16)
 t(14;20)
 GEP
High risk
signature
Intermediate-Risk 20%
 FISH
 t(4;14)*
 Cytogenetic
deletion 13 or
hypodiploidy
Standard-Risk 60%**
All others including:
 Hyperdiploid
 t(11;14)***
 t(6;14)
 PCLI >3%
* Prognosis is worse when associated with high beta 2 M and anemia.
** LDH > ULN and beta 2 M > 5.5 in standard risk may indicate worse prognosis.
*** t(11;14) is associated with plasma cell leukemia.
Kumar SK et al. Mayo Clin Proc 2009;84(12):1095-110. Revised and updated June 2010.
How to Treat Standard Risk Disease
Standard-Risk
All others including:
 Hyperdiploid
 t(11;14)
 t(6;14)
Mayo Clinic OS at 5 years is 60%
(for 210 standard risk patients) in
new drug era.
Reproduced with permission from Kapoor S et al. Mayo Clin Proc 2010;85(6):532-7. Quadrant
HealthCom Inc.
How to Treat Standard Risk Disease
Standard-Risk
All others including:
 Hyperdiploid
 t(11;14)
 t(6;14)
80% OS at 5 years in 150 transplant eligible
standard risk patients treated
with RD, CRD or CBD +/- HDM.
Reproduced with permission from Kapoor S et al. Mayo Clin Proc 2010;85(6):532-7. Quadrant
HealthCom Inc.
mSMART – Off-Study
Transplant Eligible
High Risk
Intermediate Risk
Standard Risk
Experimental therapy
Induction with bortezomib
based regimen
4 cycles of Rda or
bortezomib based regimen
Collect stem cells
Collect stem cellsb
If not available,
then consider…
Standard
risk
approach
Allogeneic
approach
Intermediate
risk
approach
Autologous stem cell
transplant (ASCT)
Autologous stem cell
transplant (ASCT)
Continue
Rdc
Consider 2nd ASCT if not
in CR
Bortezomib based maintenance
for minimum of 1 year
Consider lenalidomide
maintenance
a
Bortezomib containing regimens preferred in renal failure or if rapid response needed
If age >65 years or ≥4 cycles of Rd consider G-CSF plus cyclophosphamide or plerixafor
c Continuing Rd is option for patients responding and with low toxicities; Dex is usually discontinued after first year
b
Kumar et al. Mayo Clin Proc 2009 84(12):1095-110. v6 Revised and updated: Dec 2009
Transplant for Standard Risk Disease?
Reproduced with permission of The American Society of Hematology from "How I treat multiple myeloma in younger
Transplant for Standard Risk Disease?
Reproduced with permission of The American Society of Hematology from "How I treat multiple myeloma in younger
Efficacy of Lenalidomide, Bortezomib
and Dexamethasone (RVD): A Phase 1/2 Study
in Newly Diagnosed Myeloma
Response
All Patients (N = 66)
≥ PR
100%
≥
VGPR
67%
Phase 2 Population
(N = 35)*
100%
74%
CR +
nCR
40%
CR
29%
57%
37%
Estimated 18-Month Survival (with/without transplantation)
Progression-free survival
75%
Overall survival
97%
*Bortezomib 1.3 mg/m2, lenalidomide 25 mg, dexamethasone 20 mg
Richardson PG et al. Blood 2010;116(5):679-86.
Select Adverse Events with Lenalidomide,
Bortezomib and Dexamethasone (RVD):
A Phase 1/2 Study in Newly Diagnosed Myeloma
All
Grades
80%
Grade 3/4
2%
Fatigue
64%
3%
Neuropathic pain
32%
3%
Motor neuropathy
18%
2%
Lymphopenia
14%
14%
Thrombosis/embolism
6%
5%
Sensory neuropathy
Richardson PG et al. Blood 2010;116(5):679-86.
Maintenance therapy with thalidomide
after ASCT
N
Initial
dose, mg
Maintenance versus no
maintenance
CR, %
EFS or
PFS, %
OS, %
Barlogie et al.1 668
400
64 vs 43 5-year EFS 8-year OS
56 vs 45
57 vs 44
Attal et al.2
597
400
67 vs 55* 3-year EFS 4-year OS
52 vs 36
87 vs 77
Spencer et al.3
243
200
63 vs 40* 3-year PFS 3-year OS
42 vs 23
86 vs 75
* CR + VGPR rates.
1
Barlogie B et al. Blood 2008;112(8):3115-21. 2 Attal M et al. Blood 2006;108(10):3289-94.
3 Spencer A et al. J Clin Oncol 2009;27(11):1788-93.
CALGB-100104:
Median TTP: Not yet reached
Median TTP 25.5 mo
Median follow up from ASCT is 12 months
With permission, McCarthy PL et al. Proc ASCO 2010;Abstract 8017.
CALGB-100104:
Once again availability
of len in the placebo
arm at prog is critical
There is not long enough follow-up to determine if there is a
difference in OS; 11 deaths in lenalidomide arm and 17
deaths in the placebo arm (p<0.2)
With permission, McCarthy PL et al. Proc ASCO 2010;Abstract 8017.
Results
• Stratification by beta-2 microglobulin and previous
thalidomide or lenalidomide exposure during induction
demonstrated a benefit for lenalidomide over placebo in
each stratification.
• The study was un-blinded in December 2009 allowing
patients (with physician support) to cross over to openlabel lenalidomide.
• 77 of 89 eligible placebo patients have started
lenalidomide therapy.
McCarthy PL et al. Proc ASCO 2010;Abstract 8017.
IFM 2005-02: Study design
Phase III randomized, placebo-controlled trial
N = 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008
Patients < 65 years, with non-progressive disease,  6
months after ASCT in first line
Randomization: stratified according to beta-2m, del13, VGPR
Consolidation:
Lenalidomide alone 25 mg/day p.o.
days 1-21 of every 28 days for 2 months
Arm A =
Placebo
Arm B =
Lenalidomide
(N=307)
until relapse
(N=307)
10-15 mg/d until relapse
Primary endpoint: PFS.
Secondary endpoints: CR rate, TTP, OS, feasibility of long-term lenalidomide…
Attal M et al. Proc ASCO 2010;Abstract 8018.
IFM = Intergroupe Francophone du Myélome.
1.00
0.75
IFM 2005-02: PFS from randomization
0.25
0.50
Len
Placebo
0.00
P < 10-7
0
6
12
18
24
Placebo
With permission, Attal M et al. Proc ASCO 2010;Abstract 8018.
30
36
Lenalidomide
IFM 2005-02: First Interim Analysis
(Cutoff date 4th September 2009)
 Maintenance therapy with lenalidomide:
• Is well tolerated:
 Low discontinuation rate due to SAE (A = 4% vs B = 6%, NS)
 No increased incidence of DVT or peripheral neuropathy
• Is superior to placebo:
 54% reduction in risk of progression (p < 10-7)
In all stratified subgroups (VGPR, beta-2m, del13)
 A longer follow-up is required to appreciate the
impact of lenalidomide on OS (Final analysis:
8/2010)
Attal M et al. Proc ASCO 2010;Abstract 8018.
Conclusions
• SCT remains an important regimen capable
of improving depth of response beyond that
achievable with novel agents alone.
• All patients fit for transplantation should
have stem cells collected followed by a
frank discussion of the pros & cons of early
vs delayed transplant.
• Maintenance lengthens PFS; impact on OS
unknown.
Real-Life Decisions
An Interactive Case-Based Symposium on the
Management of Multiple Myeloma, Myelodysplastic
Syndromes and Acute Myeloid Leukemias
Friday, December 3, 2010
6:30 PM – 9:00 PM
Orlando, Florida
Moderator
Neil Love, MD
Faculty
William I Bensinger, MD
Pierre Fenaux, MD
B Douglas Smith, MD
Morie A Gertz, MD
Ravi Vij, MD
Farhad Ravandi, MD
Copyright © 2011 Research To Practice. All rights reserved.
Case 5: Dr Harwin (Discussant: Dr Vij)
• 60 yo man: PMH – Pancreas NET since 1997
surgery, radioactive lutecium and temozolomide/
capecitabine
• Rising WBC to 50,000/mm3 while on chemotherapy
• 4/10: Bone marrow = 15% blasts, monosomy 7,
negative for bcr-abl
• Referred to tertiary center for diagnostic consult –
CMML-2
Copyright © 2011 Research To Practice. All rights reserved.
Case 5 continued:
• Azacitidine 75 mg/m2/day IV x 7 days (M-Sat,+M)
on q 4 week intervals
• Bone marrow after C5 = normocellular marrow,
2% blasts, monosomy 7
• WBC: 4,400/mm3, Hgb: 9.9 g/dL, platelets
107,000/µL
• Feeling well, continues on azacitidine
Copyright © 2011 Research To Practice. All rights reserved.
Real-Life Decisions
An Interactive Case-Based Symposium on the
Management of Multiple Myeloma, Myelodysplastic
Syndromes and Acute Myeloid Leukemias
Friday, December 3, 2010
6:30 PM – 9:00 PM
Orlando, Florida
Moderator
Neil Love, MD
Faculty
William I Bensinger, MD
Pierre Fenaux, MD
B Douglas Smith, MD
Morie A Gertz, MD
Ravi Vij, MD
Farhad Ravandi, MD
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
Chronic Myelomonocytic
Leukemia (CMML)
Ravi Vij MD
Associate Professor
Section of BMT and Leukemia
Washington University School of Medicine
St Louis, MO
CMML
•
•
•
•
Affects 3 out of 100,000 individuals in the US/year.
75% are > 60 years at diagnosis.
Incidence in males is 2X females.
The defining features of CMML are:
– Absolute monocytosis >1X109/l, increased numbers of monocytes in
bone marrow, and a variable degree of dysplasia in all three
lineages.
– Myeloblasts and promonocytes comprise < 5% of nucleated cells in
peripheral blood and < 20% in bone marrow.
• 50% of patients present with an elevated white cell count >13K,
hepatomegaly and splenomegaly, the myeloproliferative form of the
disease.
• Patients lacking these features are considered to have the
myelodysplastic form of the disease.
www.leukemia-lymphoma.org, November 2010; www.atlasgeneticsoncology.org, November 2010.
Biology of CMML
• Overall 20-30% of cases show cytogenetic abnormalities.
• These include: numerical and structural abnormalities +8,del(20q),
-7,del(11q).
• Rarely translocations have been identified in CMML.
– Cases associated with eosinophilia commonly show t(5;12)(q33;13) which fuses TEL to
the platelet-derived growth factor receptor (PDGFbR) (about 2-5% of all CMML cases).
– Fusions of the Huntington interacting protein 1(HIP1) gene to PDGFbR have also been
described in CMML associated with t(5;7)(q33;q11.2).
– Occasional cases of therapy-associated CMML are associated with the
t(11;16)(q23;p13) which fuses MLL to CBP.
– Rare reports of CMML associated with t(1;13)(p36;q21),t(7;11)(p15;p15) and
t(8;9)(p11;q34) have been reported.
• Targeted next generation sequencing detected frequent mutations in
TET2,CBL,RAS and RUNX1,EZH2,ASXL1,IDH1,IDH2,NPM1.
www.atlasgeneticsoncology.org, November 2010.
FAB Classification
Blasts, %
MDS
Subtype
BM
RA
PB
Ringed
Sideroblasts
Monocytosis
(>1000/µL)
<5
<1
<15%
No
RARS
<5
<1
>15%
No
CMML
5-20
<5
Variable
Yes
RAEB
5-20
<5
Variable
No
RAEB-t*
21-30
>5
Variable
Variable
*With or without Auer rods.
FAB = French-American-British; BM = bone marrow; PB = peripheral blood; RA = refractory anemia;
RARS = RA with ringed sideroblasts; CMML = chronic myelomonocytic leukemia; RAEB = RA with
excessive blasts; RAEB-t = RAEB in transformation.
Bennett. Br J Haematol. 1982;82:358.
FAB Categories: Patient Distribution
and Estimated Survival
12 mo
CMML
16%
6 mo
RAEB-t
9%
RAEB
23%
18 mo
35 mo
RA
28%
RARS
24%
35 mo
Bennett JM et al. Br J Haematol. 1982;51:189
Gallagher A et al. Haematologica. 1997;82:191
WHO-Revised MDS
Classification
• RA
MDS/MPD
MDS*
• CMML-1 (<10% BM blasts)
• CMML-2 (10-19% blasts)
• CMML-Eos (AEC >1500/L)
• JMML
- RA
- RCMD
• RSA - RARS
- RCMD-RS
• RAEB-1 (5%-9% BM blasts)
• RAEB-2 (10%-19%  Auer rods)
• 5q– syndrome
• MDS-U
AML
• 20% blasts
*Single-lineage erythroid dysplasia.
WHO = World Health Organization;
MPD = myeloproliferative disease; Eos = eosinophils;
AEC = absolute blood eosinophil count; JMML = juvenile
myelomonocytic leukemia.
Harris et al. J Clin Oncol. 1999;17:3835.
International Prognostic Scoring System
All 3 prognostic variables required to generate IPSS score
Score Value
Prognostic variable
Bone marrow blasts (%)
Karyotype*
Number of cytopenias**
0
0.5
1.0
1.5
2.0
<5
5–10
–
11–20
21–30
Good
Intermediate
Poor
–
0/1
2/3
–
–
*Good = normal, -Y, del(5q), del(20q); Intermediate = other karyotypic abnormalities;
Poor = complex (3 abnormalities) or chromosome 7 abnormalities
**Hgb <10 g/dL; ANC <1800/L; platelet count <100,000/L
Greenberg P et al. Blood. 1997;89:2079
–
MDS: IPSS Risk* Categories
Numeric Score
IPSS Risk Category
0
Low
0.5–1.0
Int-1
1.5–2.0
Int-2
2.5
High
High
8%
Int-2 Risk
22%
Low Risk
31%
Int-1 Risk
39%
*Estimated survival and risk of AML transformation
Greenberg P et al. Blood. 1997;89:2079
Prognostic parameters for CMML
Kaplan-Meier survival curves of CMML
patients (n = 212) according to the MD
Anderson Prognostic Score.
Kaplan-Meier survival curves of CMML
patients (n = 212) according
to the Dusseldorf score.
Reproduced with permission of The American Society of Hematology from "New prognostic parameters for
chronic myelomonocytic leukemia?” Germing et al. Blood 2002;100(2):731-2. Permission conveyed
through Copyright Clearance Center, Inc.
Goals of Therapy in MDS
•
•
•
•
Select the therapy best suited for the individual
– Performance status, disease classification, IPSS score
(cytogenetics, cytopenias, BM blasts), and treatment
tolerance
Low/Int-1 IPSS: Improve blood counts (decrease transfusions
and infections)
Improve quality of life
Int-2/high-risk IPSS: Prolong survival and delay leukemic
progression
– Possible cure of disease
List AF, et al. Hematology (Am Soc Hematol Educ Program). 2004;297-317. Cheson BD, et al. Blood.
2000:96:3671. NCCN Myelodysplastic Panel Members. Available at:
http://www.nccn.org/professionals/physician_gls/PDF/mds.pdf
% Survival
The Decision
HCT
No HCT
Time
With Permission of C. Cutler,MD
The EBMT Experience
• 50 allogeneic transplantations from related
(n = 43) or unrelated (n =7) donors
• Median age 44 years (range 19–61)
• The 5-year estimated overall survival was 21% and the 5-year
estimated disease-free survival was 18%
• Earlier transplantation in the course of disease, male donor, use of
unmanipulated grafts, and acute GvHD favoured better DFS
• The 5-year estimated probability of relapse was 49%. The data
showed a trend for a lower relapse with acute GvHD suggesting a
graft-versus-CMML effect.
Kroger et al, British Journal of Haematology, 2002, 118, 67–73
Hypomethylating Cytosine
Analogs
NH2
NH2
NH2
NH2
CH3
N
N
N
O
N
N
N
O
N
O
Ribose
Cytosine
5-methyl-cytosine
5-aza-cytidine
(azacitidine)
Santini V, et al. Ann Intern Med. 2001;134(7):573-86.
N
N
N
O
Deoxyribose
5-aza-2′-deoxycytidine
(decitabine)
Efficacy of Azacitidine in the Treatment of
Chronic Myelomonocytic Leukemia (n = 35)
n (%)
Age (years)
Median
Range
70
33-85
Gender
M:F
19:16
Splenomegaly
Yes
13 (37.1)
Hemoglobin, g/dl
< 10.0
8 (22.9)
Platelets, X 109/L
< 50
12(13.3)
<100
19 (54.3)
•
ORR:48.6%: CR 5 (14.3%), marrow CR 4 (11.4%), PR 1 (2.9%),
HI 7 (20%)
•
The median OS was 25 months (95% CI 13.8-36.1 mo).
Teichman et al ASH 2010 Abstract # 4017
Treatment of Advanced CMML by Azacitidine in a
Compassionate Program: the GFM Experience
N = 38
• Median age was 71 y (range 50-87)
• Median interval from diagnosis to treatment: 22 months
(range 0.2-74 months).
• 20 pts (53%) responded including 9 CR, 3 marrow CR, 8 HI-E and 1 partial
remission.
• Median number of cycles of AZA to achieve best response was 4
(range 3-12).
• 9 of the 20 responders relapsed after a median of 10.6 months
(range 3-23).
• Median overall survival (OS) was 24 months in CMML compared to 7 months
in AML arising from CMML (p = 0.0081).
• Presence of splenomegaly, WBC>13 G/l, previous treatment (excluding
ESA), Sex, -7/del7q and normal karyotype had no impact on OS.
Wolfromm et al ASH 2010 Abstract # 4023
Decitabine is Effective and Safe in Patients
with Chronic Myelomonocytic Leukemia
• A subset of patients with CMML from a pivotal phase III 3-day dosing
and an open-label trial of 5-day dosing were identified
Response Rates (N=17)
n
%
7
41.1
Complete Response (CR)
3
17.6
Marrow Complete Response (mCR)
4
23.5
Hematologic Improvement (HI)
2
11.7
Overall Response Rate
(CR + mCR + PR)
• Median survival was 391 (95% CI 239, 678) days and 2 (11.7%)
patients progressed to AML.
Jabbour et al. ASH 2010 Abstract # 4032
A Phase II Study of Decitabine in
Advanced CMML
•
41 pts in 16 centers
• Median age 71 years (range 54-88)
• Seventeen pts had CMML 1 and 22 had CMML 2
• Median number of cycles was 9 (range 1-17)
• Overall Response Rate (ORR) was 38.6% with 4 (10.3%) CR, 8 (20.5%)
marrow CR and 3 (7.7%) with HI.
• Overall Survival (OS) estimate was 60% at 2 years. By comparison, in a
previous trial of HY in CMML where inclusion criteria were the same, 2 year
survival was 43% (Blood 1996 88:2480)
• The only factor associated with response to DAC was WHO subtype: CMML
2 pts showing significantly better ORR (30.8% vs 7.7% in CMML 1;
p = 0.041).There was no difference in survival between CMML 1 and 2 pts.
Braun et al ASH 2010 Abstract # 1873
Conclusions
• Allogeneic transplant is the only known curative
therapy for patients with CMML. However, few
patients are eligible for such an approach.
• DNA hypomethylating agents are a therapeutic
option that most patients can tolerate and
produce responses similar to that reported for
other FAB categories of MDS.
Case 6: Dr Fishkin (Discussant: Dr Ravandi)
• 48 yo woman with kidney stone
• Thrombocytopenia, anemia and microgranules on
pre-op evaluation
• DIC panel mildly positive
• Emergent bone marrow = t(15;17)
• Inpatient tx: Idarubicin + ATRA x 3 days
• Discharged home to complete induction outpatient
Copyright © 2011 Research To Practice. All rights reserved.
Case 6 continued:
• Completed 3 cycles of induction therapy in 6/07
• Arsenic trioxide consolidation x 2 cycles
• Maintenance with ATRA + MTX/6MP
D/C MTX/6MP after one month b/c potential to
exacerbate kidney stone disease 1 full year of
ATRA
• Remains in continuous cytogenetic and molecular
remission
Copyright © 2011 Research To Practice. All rights reserved.
Real-Life Decisions
An Interactive Case-Based Symposium on the
Management of Multiple Myeloma, Myelodysplastic
Syndromes and Acute Myeloid Leukemias
Friday, December 3, 2010
6:30 PM – 9:00 PM
Orlando, Florida
Moderator
Neil Love, MD
Faculty
William I Bensinger, MD
Pierre Fenaux, MD
B Douglas Smith, MD
Morie A Gertz, MD
Ravi Vij, MD
Farhad Ravandi, MD
Copyright © 2011 Research To Practice. All rights reserved.
Copyright © 2011 Research To Practice. All rights reserved.
ACUTE PROMYELOCYTIC
LEUKEMIA
Farhad Ravandi, MD
University of Texas – M. D.
Anderson Cancer Center
Friday, December 3, 2010
Distribution of APL Molecular Lesions
PML/RARa
t(15;17)(q22;q21)
92%
PML/RARa + insertions
4%
PML/RARa + variants
2%
PLZF/RARa
t(11;17)(q23,q21)
0.8%
NPM/RARa
t(5;17)(q35,q21)
0.2%
NuMa/RARa
t(11;17)(q13,q21)
< 0.1%
Stat5b/RARa
der(17)
< 0.1%
No RARa
Grimwade D, Lo Coco F. Leukemia. 2002;16(10):1959-1973
1%
Genetic Diagnosis
• Confirm genetic diagnosis with leukemic cells from BM
Level
Method
Chromosomal
Karyotyping
DNA
FISH
RNA
RT-PCR
Protein
a-PML mAb
Sanz MA, et al. Blood 2009;113:1875-1891
The Role of Ara-C
• Phase II, Idarubicin w/o Ara-C
• PETHEMA
° 3-yr DFS: 81% standard dose vs 90% intermediate/high-dose
• ATRA/DNR/Ara-C vs ATRA/DNR
• European APL group
° CR similar (99% vs 94%, P = 0.12)
° Relapse higher w/o Ara-C (2-yr CIR: 4.7% vs 15.9%, P = 0.011)
• ATRA /DNR/Etoposide/Ara-C vs ATRA/Idarubicin
• MRC
° No difference in CR rate (91% vs 93%)
° No difference in 4-year OS (81% vs 85%)
° ↓ myelosuppression w/o Ara-C/etoposide
Sanz MA, et al. Blood. 2004;103(4):1237-1243
Ades L, et al. J Clin Oncol. 2006;24:5703-5710
Burnett AK, et al. Blood. 2007;181a; Abstract 589
2-Yr Cumulative incidence of relapse,
EFS, and OS by Ara-C or no Ara-C
Ara-C
No Ara-C
p-value
Relapse
4.7%
15.9%
0.011
EFS
93.3%
77.2%
0.0021
OS
97.9%
89.6%
0.0066
EFS = event-free survival; OS = overall survival
Ades, L. et al. J Clin Oncol; 24:5703-5710 2006
2-Yr Cumulative incidence of relapse, EFS, and
OS of younger patients with WBC  10 x 109/L
Relapse
EFS
OS
2.9%
89%
91.9%
EFS = event-free survival; OS = overall survival
Ades, L. et al. J Clin Oncol; 24:5703-5710 2006
UK MRC AML 15: Study
Schema
MRC Arm*
Induction ADE
and ATRA (2
courses)
*MACE
and MidAC
Induction Ida
and ATRA (2
courses)
*Mitoxantrone/Ida
and ATRA (2
courses)
Pts with
APL
(N = 291)
PETHEMA Arm*
*Patients on both arms undergo second randomization
to placebo or gemtuzumab ozogamicin in CR
Burnett AK, et al. ASH 2007; Abstract 589.
Maintenance
6-mercaptopurine
Methotrexate
ATRA
UK MRC AML 15: Results
• Outcomes: MRC vs PETHEMA
– CR: 91% vs 93% (P = .5)
– OS: 81% vs 85% at 4 years (P = .10)
• Induction death: 10 patients in MRC vs 8 patients in
PETHEMA
• Resistance equal for 2 arms: 1 patient each
• Relapse similar between 2 arms: 5 patients in MRC
vs 6 patients in PETHEMA
• Death in CR higher for MRC: 11 vs 2 (P = .009)
• More transfusions, infections, hospitalizations in the
MRC arm (P < .0001)
• Better quality of life in the PETHEMA arm
Burnett AK, et al. ASH 2007; Abstract 589.
ATO Monotherapy in Newly
Diagnosed Patients
N
CR
%
PML-RARa
negative post-CR
%
EFS
%
OS
%
111*
86
92
64
(2-yr)
88†
(3-yr)
Mathews, et al
India
72
86
76
75
(3-yr)
86
(3-yr)
George, et al
India
11
91
100
82
(5-yr)
91
(5-yr)
Ghavamzadeh, et al
Iran
*94 of the 111 patients were newly diagnosed.
†For patients in CR.
Ghavamzadeh A, et al. Ann Oncol. 2006;17(1):131-134.
Mathews V, et al. Blood. 2006;107(7):2627-2632.
George B, et al. Leukemia. 2004;18(10):1587-1590.
ATRA/CT→ATO vs ATRA/CT in Newly Diagnosed APL
Intergroup Protocol C9710
APL
PML-RARa
confirmed by
RT-PCR
N = 481
(adults)
R
A
N
D
O
M
I
Z
E
D
ATRA
Ara-C
Daunorubicin
ATO x 2
ATRA
DNR
x2
CR
Newly
Diagnosed
ATRA
Ara-C
Daunorubicin
ATRA
DNR
x2
Induction
R
A
N
D
O
M
I
Z
E
D
Consolidation
ATRA
ATRA
6-MP
MTX
Maintenance
Agent
Induction
Consolidation
Maintenance
ATRA
45 mg/m2 , PO, d 1-CR
45 mg/m2 , PO, d 1-7
45 mg/m2 , PO, d 1-7, every other wk
Ara-C
200 mg/m2 , IV, d 3-9
DNR
50 mg/m2, IV, d 3-6
ATO
50 mg/m2, IV, d 1-3
0.15 mg/kg 5 d/week, x 5 wks
6-MP
60 mg/m2/d, PO, daily
MTX
20 mg/m2, once/week
Powell BL, et al. Blood 2010;116(19):3751-7
ATRA/CT→ATO vs ATRA/CT in Newly
Diagnosed APL EFS, ITT
Response
+ ATO
n = 244
No ATO
n = 237
P
3-year EFS
80%
63%
0.0001
3-year OS
86%
81%
0.07
Powell BL, et al. Blood 2010;116(19):3751-7
ATRA and ATO
Therapy
N
CR
%
PML-RARa
EFS/DFS/RFS
negative post-CR %
%
Hu, et al
China
85
94
NR
89
(5-yr DFS)
91
(5-yr)
Ravandi, et al
MD Anderson
82
90*
100
80
(2-yr RFS)
85
(2-yr)
Dai, et al
China
90
93
100
92
(3-yr EFS)
NR
*95% in low-risk, 81% in high-risk.
Hu J, et al. Proc Natl Acad Sci U S A. 2009;106(9):3342-3347.
Ravandi F, et al. J Clin Oncol. 2009;27(4):504-510.
Dai CW, et al. Acta Haematol. 2009;121(1):1-8.
OS
%
Randomized 3 arm study of
ATRA vs ATO vs ATRA + ATO
ATRA
ATO
ATRA + ATO
20
20
21
Age in years
(median, range)
30.5 (14 – 74)
39.5 (15 – 69)
34 (14 – 62)
WBC x 109/L
(median, range)
3.0 (1.2 – 49.4)
2.7 (0.9 – 40)
2.1 (0.5 – 52.6)
6
10
4
8
8
4
7
8
6
23 (4 -76)
27 (12 – 72)
30 (6 – 73)
19 (95)
18 (90)
20 (95.2)
40.5 (25 – 65)
31 (28 – 38)
25.5 (18 – 35)
Number
<2
2 – 10
> 10
Plt x 109/L
(median, range)
CR (%)
Median days to CR
(range)
Shen ZX, PNAS, vol. 101 | no. 15 | 5328-5335, 2004
Randomized 3 arm study of
ATRA vs ATO vs ATRA + ATO
Sample collection
ATRA
ATO
ATRA + ATO
Pretreatment
N = 19
N = 18
N = 20
4,595.6
6,655.7
5,155.3
N = 19
N = 18
N = 20
Median copy number
793.5
286.3
177.3
Median reduction fold
6.7
32.1
118.9
N = 14
N = 11
N = 14
Median copy number
71.6
41.3
15.2
Median reduction fold
369.5
521.3
800
Median copy number
After CR
After consolidation
Shen ZX, PNAS, vol. 101 | no. 15 | 5328-5335, 2004
A
DAY 1
DAY 10
BONE MARROW CR
CR
WBC <
10 x 109/l
WBC ≥
10 x 109/L
B
DAY 1
WBC <
10 x 109/l
BONE MARROW CR
CR
ATRA
ATO
WBC ≥
10 x 109/L
Ravandi, F. et al. J Clin Oncol; 27:504-510 2009
GO
CR
4
8
12
16
20
24
28
*
Time in weeks after CR
PCR *
PCR *
•If PCR is positive, it is repeated 2 to 4 weeks later and if positive again,
start GO once monthly
ATRA
ATO
Ravandi, F. et al. J Clin Oncol; 27:504-510 2009
Patients
Characteristics
Number of patients
Age in years; median, range
Age ≥ 60 (%)
Sex
Male: Female
Leukocyte count, x 109/L
Median, range
Platelet count, x 109/L
Median, range
Number
82
47,14-81
23 (28%)
44: 38
2.5, 0.4-195.0
32, 7-261
Risk category
High
Low
26
56
Cytogenetics
t(15;17)
t(15;17) + other
Other (PCR +)
Not Done (PCR +)
Insufficient (PCR +)
14
58
3
5
2
FAB Morphology
M3
M3v
70
12
PML-RARA Isoforms
Short
Long
Positive-Undefined
Not Done/Suboptimal
30
33
8
11
Ravandi, F. et al. J Clin Oncol; 27:504-510 2009
Molecular status with follow-up
Time
(months)
Patients
(n)
PCR negative
n
%
At CR
13
5
38
1-3
50
47
94
4-6
49
49
100
7-9
49
46
94*
10-12
43
41
95*
13-18
53
53
100
19-24
37
36
97*
25-36
36
35
97*
37-48
17
17
100
49-63
5
5
100
Legend – *Late PCR positive tests were seen in
3 patients with relapse as well as in 4
patients who had a transient weak positive PCR
Ravandi, F. et al. J Clin Oncol; 27:504-510 2009
Outcome: ATRA+ ATO
With permission, Ravandi F, ASH 2010; Abstract #1080
ASH 2010 APL papers
• Paper #1083: Early events excluding pts from trial enrollment – Micol
J-B, et al. 100 pts referred to single institution, 29 not enrolled, higher
WBC ≥ 10 x 109/L, lower Plt < 40 x 109/L, lower CR (79% vs. 97%),
5-year EFS (62% vs. 84%) and OS (63% vs. 85%; p = 0.03)
• Paper #872: Higher early death and lower OS in a population-based
study; Park JH, et al. 1400 and 721 pts with APL in SEER and NY State
cancer registry. ED rate 10-20% with only modest change since 1992.
Long-term survival, although improved, is less than reported in trials.
More than 25% are not cured
• Paper #506: Frontline therapy of APL by ATO; Iranian experience –
Ghavamzadeh A, et al. 197 pts with newly dx APL treated with ATO.
Induction followed by 4 courses of ATO consolidation. CR in 86% ED
and DS in 15%. DFS and OS 67%±4% and 64%±4% at 5 years,
respectively
ASH 2010 APL papers
• Paper #505: ATO consolidation for newly diagnosed APL; European
APL 2006 trial; Ades L, et al. Randomization with ATO replacing araC in pts with WBC< 10 x 109/L and with addition of ATO in pts with
WBC> 10 x 109/L. Interim analysis CR 99.3% and 100% in WBC< and
> 10 groups. Very low relapse rate after a median f/u 2 years.
• Paper # 15: Treatment of relapse of APL with ATO; European
registry – Lengfelder E, et al. 69 pts in first relapse (25 molecular, 42
hematological, 2 isolated CNS/EMD). 2nd molecular CR higher after
induction with molecular relapse than hematological; Importance of
monitoring
• Paper #13: Is ara-C required in standard risk apl; Long-term f/u of
European APL 2000 trial; Ades L, et al. 95 and 101 pts. CR in ara-C+:
99% and in no ara-C: 94%; CIR, EFS, and survival were all inferior in
no ara-C group (p = 0.013, p = 0.01, and p = 0.07, respectively)
Real-Life Decisions
An Interactive Case-Based Symposium on the
Management of Multiple Myeloma, Myelodysplastic
Syndromes and Acute Myeloid Leukemias
Friday, December 3, 2010
6:30 PM – 9:00 PM
Orlando, Florida
Moderator
Neil Love, MD
Faculty
William I Bensinger, MD
Pierre Fenaux, MD
B Douglas Smith, MD
Morie A Gertz, MD
Ravi Vij, MD
Farhad Ravandi, MD
Copyright © 2011 Research To Practice. All rights reserved.