hematopoietic stem cell transplantation (hct) for mds
TRANSCRIPT
Jdr10_1.ppt
Hematopoietic Stem Cell Transplantation (HCT)
for MDS
Mary M. Horowitz, MD, MS
Indications for Hematopoietic Stem Cell Transplants in the United States
0
500
1,000
1,500
2,000
2,500
3,000
3,500
4,000
4,500
5,000
5,500
Multiple
Myeloma
NHL AML HD ALL MDS Aplastic
Anemia
CML Other
Leuk
Non-
Malig
Disease
Other
Cancer
Allogeneic (Total N=7,012)
Autologous (Total N=9,778)
Num
ber
of
Tra
nspla
nts
MDS is 3rd most common indication for allogeneic HCT
Years
0 2 6 1 3 4 5
HCT is a Curative Therapy for MDS: Probability of Survival after Allogeneic
Transplants for MDS, 2000-2009
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40
60
80
100
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30
50
70
90
0
20
40
60
80
100
10
30
50
70
90
Pro
bability o
f Surv
ival, %
P < 0.0001
Early, sibling donor (N=667)
Early, unrelated donor (N=752)
Advanced, sibling donor (N=1,188)
Advanced, unrelated donor (N=1,400)
Indications for Hematopoietic Stem Cell Transplants in the United States
0
500
1,000
1,500
2,000
2,500
3,000
3,500
4,000
4,500
5,000
5,500
Multiple
Myeloma
NHL AML HD ALL MDS Aplastic
Anemia
CML Other
Leuk
Non-
Malig
Disease
Other
Cancer
Allogeneic (Total N=7,012)
Autologous (Total N=9,778)
Num
ber
of
Tra
nspla
nts
MDS is 3rd most common indication for allogeneic HCT – but <10% of MDS patients undergo HCT
Patients Receiving HCT for MDS in the U.S. 2010-2011
Related Donor
Unrelated Donor
Total
Number 515 806 1321
Median age (range)
57y (1-74y)
57y (1-75y)
57y (1-75y)
<60y 66% 62% 62%
60-64y 21% 20% 21%
65+y 13% 18% 17%
AGE DISTRIBUTION OF PATIENTS WITH MDS
0%
5%
10%
15%
20%
25% Patients with MDS
Patients transplanted for MDS
PROPORTION OF PATIENTS WITH MDS TRANSPLANTED – BY AGE
0%
10%
20%
30%
40%
50%
60%
70%
80%
Does Age Matter?
Life Expectancy
Average life expectancy for:
Newborn ~ 76 years
50 year old ~ 30 years (80)
55 year old ~ 25 years (80)
60 year old ~ 22 years (82)
65 year old ~ 18 years (83)
70 year old ~ 14 years (84)
75 year old ~ 10 years (85)
Life Expectancy, years
AGE Normal IPSS-R Very Low
IPSS-R Low
IPSS-R Inter-mediate
IPSS-R High
IPSS-R Very High
50y 30 >13 9 5 2 1
55y 25 >13 9 5 2 1
60y 22 10 6 3 2 1
65y 18 10 6 3 2 1
70y 14 7 5 3 2 1
75y 10 7 5 3 2 1
TRANSPLANT-RELATED MORTALITY BY AGE
0
5
10
15
20
25
30
35
40
45
30-39y 40-49y 50-59y 60-69y
TRANSPLANT-RELATED MORTALITY BY AGE Standard vs Reduced Intensity Conditioning
0
5
10
15
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25
30
35
40
45
30-39y 40-49y 50-59y 60-69y
Standard NST
EBMT Study of HCT for Patients 50+ years with MDS or sAML
1,333 patients, transplanted 1998 - 2006
Median age: 56y (range 50-74y)
884 50-60 (median 54)
449 >60 (median 63)
Donor type
811 HLA-matched sibs
409 matched unrelated donors
113 mismatched unrelated donors
Conditioning
500 Myeloablative/ 833 Reduced Intensity
Lim et al, J Clin Oncol 2010
Relative Risk of Outcomes by Age (>60 versus 50-60)
0.00
0.20
0.40
0.60
0.80
1.00
1.20
1.40
1.60
TRM Relapse Mortality
50-60 >60
TRM
36% 39%
Relapse
32% 41%
Survival 34% 24%
CIBMTR Study of Transplants for Patients with AML or MDS
1,080 patients, transplanted 1995 – 2005
545 AML CR1
535 MDS
4 age groups considered:
40–54 years
55–59 years
60–64 years
65+ years
All received reduced intensity conditioning
McClune et al, J Clin Oncol 2010
40–54 55–59 60–64 65-78
No. of Patients
208 146 126 55
Advanced MDS *
57% 64% 64% 57%
Int/High Risk Cytogenetics
52% 55% 54% 48%
tMDS 21% 23% 21% 22%
Patient Characteristics—MDS
* RAEB, RAEB-T, CMML or ≥ 5% blasts
40–54 55–59 60–64 65-78
No. of Patients
208 146 126 55
Median Age 50y 57y 62y 67y
KPS <80% 13% 13% 13% 19%
Unrelated donor
57% 62% 58% 73%
Patient Characteristics—MDS
Transplant Outcomes
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Non-engraftment Acute GVHD Chronic GVHD
40-54y
55-59y
60-64y
65+y
Transplant-related Mortality and Relapse after HCT in patients 40+ years receiving reduced
intensity conditioning, 1995-2005, by age
Tp08_10.ppt
0 1 3 4
100
0
20
40
60
80
90
10
30
50
70
2
Years
Transplant-related Mortality
65+ yrs
60-64 yrs
55-59 yrs
40-54 yrs
p=0.66
Years
0 1 3 4
0
100
20
40
60
80
90
10
30
50
70
2
Relapse
40-54 yrs
60-64 yrs
55-59 yrs
p=0.87
65+ yrs
MDS-free survival of patients 40+ years receiving allogeneic HCT for MDS with reduced
intensity conditioning, 1995-2005
Prob
ab
ilit
y,
%
Months
0 12 24 60 48 36
100
0
20
40
60
80
90
10
30
50
70
0
100
20
40
60
80
90
10
30
50
70
Tp08_5.ppt
40-54 yrs
55-59 yrs
60-64 yrs
65+ yrs
p=0.84
Overall survival of patients 40+ years receiving allogeneic HCT for MDS with reduced intensity
conditioning, 1995-2005
Prob
ab
ilit
y,
%
Months
0 12 24 60 48 36
100
0
20
40
60
80
90
10
30
50
70
0
100
20
40
60
80
90
10
30
50
70
Tp08_3.ppt
40-54 yrs
55-59 yrs
60-64 yrs
65+ yrs
p=0.37
Years
0 1 3 4
0
100
20
40
60
80
90
10
30
50
70
2 0 1 3 4
100
0
20
40
60
80
90
10
30
50
70
2
Years
MDS-free survival of patients 40+ years receiving nonmyeloablative allogeneic HSCT
for MDS, 1995-2005, by age and status
Tp08_12.ppt
Late MDS Early MDS
60-64 yrs
40-54 yrs
55-59 yrs
60-64 yrs
65+ yrs
40-54 yrs
55-59 yrs
65+ yrs
Log-rank p=0.378 Log-rank p=0.307
What Factors Do Influence Transplant Outcomes?
Lim, et al:
Advanced disease stage: 1.55, p<0.01 Poor risk cytogenetics: 1.73, p<0.01 McClune, et al:
KPS <80: 1.63, p=0.001 Poor risk cytogenetics: 1.22, p=.1* Mismatched donor: 1.85, p=0.005
* Significant for DFS
MULTIVARIATE ANALYSIS OF FACTORS ASSOCIATED WITH
SURVIVAL
IPSS at diagnosis
Low-risk 1.00 Int-1 1.02 (0.69-1.51) 0.89 Int-2 1.44 (0.97-2.14) 0.06 High-risk 1.78 (1.08-2.95) 0.02 Also, KPS, Donor type
MULTIVARIATE ANALYSIS OF FACTORS ASSOCIATED WITH SURVIVAL IN MORE
RECENT COHORT: Saber, et al. Abstract #355
Monday morning, B312-B313a
Sorror HCT-CI Hematopoietic Cell Transplantation-specific
Comorbidity Index (Blood 2005) Comorbidities HCT-CI Score
Lung 2-3
Liver 1-3
Heart valve 3
Prior solid tumor (not skin) 3
Kidney 2
Peptic ulcer 2
Rheumatologic 2
Infection 1
Heart 1
Cerebrovascular 1
Inflammatory Bowel Disease 1
Obesity 1
Diabetes 1
Psychiatric 1
Survival by Sorror HCT-CI
N=177 N=67
Sorror et al, Blood 2007;110:4606
HCT-CI is independent of Age and KPS (Multivariate Analysis of Survival)
Risk Factor HR p
HCT-CI
>3 vs 0-2 1.97 0.002
Age
> 50 vs < 50 yrs 1.99 0.006
KPS
<80% vs >80% 1.42 0.045
Sorror et al, Cancer 2008; 112: 1992
*other factors not shown
Iron Overload – A Problem for Transfusion-Dependent MDS Patients
Alessandrio, et al. Haematologica 2010: Study of 357 patients transplanted for MDS in 1997-2007: Significant effect of transfusion-dependence and ferritin levels in patients receiving myeloablative conditioning
Conditioning Regimens
Should all older patients receive reduced intensity conditioning?
CIBMTR Study of Conditioning Regimen Intensity in HCT for
Leukemia and MDS Luger, et al. BMT 2012
HLA-identical sibling or URD HCT for AML or MDS, reported to the CIBMTR, 1997-2004
5,179 patients
Age 18-70 years; 503 60-70
Conditioning Regimen Intensity: CIBMTR Categories*
Myeloablative: Cy/TBI (n=1635), Bu/Cy (n=1575)
TBI 500 cGy, or 800 cGy fx (n=144)
Mel 150 mg/m2 (n=57)
Bu 9 mg/kg (n=320)
Reduced-intensity (RIC): TBI 500 cGy, or 800 cGy fx (n=149)
Mel 150 mg/m2 (n=378)
Bu 9 mg/kg (n=514)
Non-myeloablative (NST): TBI 200 cGy (n=34), Flu/TBI 200 cGy (n=245)
Flu/Cy (n=128)
*Consensus criteria CIBMTR Regimen Related Toxicity Working Committee
Adjusted Probability of Overall Survival
Wsp08_18.ppt
Ad
just
ed P
rob
ab
ilit
y, %
Years
0 1 2 5 4 3
100
0
20
40
60
80
90
10
30
50
70
Myeloablative (N = 3,731)
RIC BM (N = 273)
RIC PB (N = 768)
NST (N = 407)
NST vs Myeloablative, p 0.01
NST vs RIC PB, p=0.02
CIBMTR Study of Conditioning Regimen Intensity in HCT for
Leukemia and MDS Luger, et al. BMT 2012
HLA-identical sibling or URD HCT for AML or MDS, reported to the CIBMTR, 1997-2004
5,179 patients
Age 18-70 years; 503 60-70 years
Myeloablative: 3721 patients – only 3% were 60-70 years
Age and Prevalence of Comorbidities
Sorror et al, Blood 2007;110:4606
> 3
1-2
0
BMT CTN 0901: A Randomized, Multi-Center, Phase III Study of Allogeneic Stem Cell Transplantation Comparing Regimen Intensity in Patients with Myelodysplastic Syndrome or Acute Myeloid Leukemia
BMT CTN 0901
Advanced MDS/ AML< 5% blasts
18 Month Overall Survival
Patients randomized
RIC regimens1
Bu/Flu2
Flu/Mel
MAC Regimens Bu/Flu Bu/Cy Cy/TBI
GVHD
Prophylaxis
per
Institutional
practice
1Bu <9mg/kg PO or IV
equivalent, Mel
<150mg/m2 2 IV or PO Bu
3T-replete bone
marrow or peripheral
blood.
Centers choose one
myeloablative and one
reduced intensity
regimen for each
patient before
randomization
Eligibility: Inclusion Criteria
Age ≤ 65 yrs
AML or MDS <5% bone marrow blasts
Available HLA-matched related or matched unrelated donor (8/8 or 7/8)
Peripheral blood or bone marrow stem cells
Statistical Considerations
Superiority trial to test a difference of 15% in 18 mo OS.
Plan accrual of 356 patients
178 per arm
Actual vs Projected Accrual
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100
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300
350
400 Ju
n-1
1
Sep-1
1
Dec-1
1
Mar-
12
Jun-1
2
Sep-1
2
Dec-1
2
Mar-
13
Jun-1
3
Sep-1
3
Dec-1
3
Mar-
14
Jun-1
4
Sep-1
4
Dec-1
4
Mar-
15
Jun-1
5
Sep-1
5
Projected
Actual
THE DECISION – Whether and When
SU
RV
IV
AL,
%
TIME
Factors to Consider: Effect on Life Expectancy
AGE Normal IPSS-R Very Low
IPSS-R Low
IPSS-R Inter-mediate
IPSS-R High
IPSS-R Very High
50y 30 >13 9 5 2 1
55y 25 >13 9 5 2 1
60y 22 10 6 3 2 1
65y 18 10 6 3 2 1
70y 14 7 5 3 2 1
75y 10 7 5 3 2 1
Factors to Consider: Effect on Life Expectancy
AGE Normal IPSS-R Very Low
IPSS-R Low
IPSS-R Inter-mediate
IPSS-R High
IPSS-R Very High
50y 30 ? -21 -25 -28 -29
55y 25 ? -16 -20 -23 -24
60y 22 -12 -16 -19 -20 -59
65y 18 -8 -12 -15 -16 -17
70y 14 -7 -9 -11 -12 -13
75y 10 -3 -5 -7 -8 -9
THE DECISION – Whether and When
SU
RV
IV
AL,
%
TIME
THE DECISION S
UR
VIV
AL,
%
TIME
THE DECISION S
UR
VIV
AL,
%
TIME
Factors to Consider
Effect on non-HCT outcome
Effect on HCT outcome
Older age (after 40) (up to 70)
High HCT-CI
Low KPS ?
High IPSS
Mismatched donor
Treatment-related MDS
Hypomethyl failure ?
Decision Analysis: Life Expectancy Estimate (Years) After Allogeneic HCT for MDS in Patients <60y
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
Cutler C, et al. Blood 2004;104:579.
Decision Analysis: Life Expectancy Estimate (Years) After Allogeneic HCT for MDS in Patients 60-70
IPSS Outcome Non-HCT Early HCT
Low/Int-1 LE 77 mo 48 mo
QALE 46 mo 44 mo
Int-2/High LE 28 mo 38 mo
QALE 15 mo 35 mo
J. Koreth, et al. ASH 2011
THE DECISION – Whether and When
SU
RV
IV
AL,
%
TIME
THE DECISION
MDS04_3.ppt
SU
RV
IV
AL,
%
TIME
Factors to Consider
Effect on non-HCT outcome
Effect on HCT outcome
Older age (after 40) (up to 70)
High HCT-CI
Low KPS ?
High IPSS
Mismatched donor
Treatment related
Hypomethyl failure ?
Cohort Comparison: HCT vs Azacitidine for MDS in Patients 60-70
HCT: 103 Patients receiving HCT in German MDS and Transplant Study Groups, Fred Hutchinson
AZA: 75 Patients in a French cohort who did not have a donor or were not considered for HCT because of guidelines that preclude offering HCT to patients older than 60 years
Platzbecker, et al. BBMT 2012
Cohort Comparison: HCT vs Azacitidine for MDS in Pts 60-70
AZA – At Dx
HCT – At Dx
AZA – At Rx
HCT – At Rx
Age 65 63 66 64
FAB RAEB RAEB-T AML CMML
80% 15% 0% 5%
73% 16% 0% 12%
60% 28% 9% 3%
40% 10% 42% 9%
IPSS Int-1 Int-2 High AML Unk
19% 40% 31% 0 11%
19% 35% 30% 0 16%
5% 39% 49% 0 7%
9% 22% 18% 42% 9%
Poor risk cytog. 31% 24% 43% 27%
Platzbecker, et al. BBMT 2012
Cohort Comparison: HCT vs Azacitidine for MDS in Pts 60-70
AZA HCT
NRM @ 2 years 34% 33%
Relapse/Prog @ 2 years
52% 30%
Survival @ 2 years 23% 39%
Survival @ 5 years NA 35%
Platzbecker, et al. BBMT 2012
BMT CTN 1102:
Multi-Center Phase III Trial Comparing Reduced
Intensity Allogeneic Hematopoietic Cell Transplant
to Hypomethylating Therapy or Best Supportive Care
in Patients Age 50 or Older with Intermediate-2 and
High Risk Myelodysplastic Syndrome
Co-chairs
Corey Cutler, Dana Farber Cancer Institute
Ryotaro Nakamura, City of Hope Cancer Center
Primary Objective
- Compare the three-year overall survival probabilities
between the two study arms using an intent-to-treat
analysis
Arm 1: RIC alloHCT
Arm 2: Non-Transplant Therapy / Best Supportive Care
Secondary Objectives
- Compare leukemia-free survival (LFS) at 3 years from
enrollment
- Compare QOL measures between treatment arms
Study Objectives
Basic Design
Eligibility:
De novo MDS with CURRENT or PRIOR
Intermediate-2 / High-risk IPSS Score
Aged 50-75 years
Any therapy prior to registration
KPS > 70 / ECOG ≤ 1
Donor vs. No Donor Comparison of Patients
Referred for Transplantation
Intention to Treat
No mandate of transplant or non-transplant regimen
No-Donor Determination
Follow-up for Survival, AML progression, and QOL – 3 yrs*
Screening/Study Enrollment
Donor Search (3 months)
No-Donor Arm
Donor Arm
Donor
Donor
Donor
Alternative Donor
HCT
HCT
HCT
QOL baseline
QOL 6 mos
QOL 12 mos
QOL 18 mos
QOL 24 mos
QOL 36 mos
Standard CIBMTR follow-up
Standard CIBMTR Follow-up
Standard CIBMTR Follow-up
Every 3rd month heme follow-up (contact with treating MD’s office)
Every 3rd month heme follow-up (contact with treating MD’s office)
Every 3rd month heme follow-up (contact with treating MD’s office)
Not HCT candidate
* From the time of enrollment
Study Schema
Paying for HCT for MDS in Older Patients in the US
Most people with MDS are >65 years old
Most people over 65 have health insurance through Medicare/CMS
Before 2010, CMS did not explicitly cover BMT coverage for MDS
Local decisions
Few covered
The Request - 2009
ASBMT, NMDP, ASH, ASCO and others organized a formal request for CMS to consider covering HCT for MDS
Supporting data (McClune et al, 2010; Cutler et al, 2004; others)
CMS formally accepted request
CMS held public comment periods, performs National Coverage Analysis.
Review focused on those 65 and older
Coverage with Evidence Development
CMS issued decision Aug 2010 allowing “coverage with evidence development (CED)”
Suggests insufficient evidence
“..evidence does not demonstrate that the use of HCT improves health outcomes in Medicare beneficiaries with MDS.”
“paucity of evidence regarding the use of HCT in patients with MDS who are 65 years or older”
Will cover costs of HCT if patients enrolled in a study that will provide CMS with data (“evidence”) to determine the value of the procedure in the Medicare population
To qualify for CED, a trial must address at least one of the following 3 questions
1. Prospectively, compared to Medicare beneficiaries with MDS who do not receive HCT, do Medicare beneficiaries with MDS who receive HSCT have improved outcomes?
2. Prospectively, in Medicare beneficiaries with MDS who receive HCT, how do IPSS score, patient age, cytopenias and comorbidities predict outcomes?
3. Prospectively, in Medicare beneficiaries with MDS who receive HCT, what treatment facility characteristics predict meaningful clinical improvement in outcomes?
CIBMTR Cohort Study
CIBMTR leveraged existing infrastructure to launch a study using EXISTING data collection mechanisms and CIBMTR observational protocol (already IRB approved at US centers) – opened December 2010
Will address Questions 2 and 3
Compares outcomes in patients 55-64 and 65+
Evaluate prognostic factors, including IPSS and center characteristics
Data on first 120 patients
Similar early mortality (~20%) in the 2 age groups
Atallah, et al. Poster 1983, Saturday evening
0
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2005 2006 2007 2008 2009 2010 2011 2012
Num
ber
of tr
ansp
lant
s
Related ≥ 65y
Unrelated ≥ 65y
US Allogeneic Transplants for MDS in patients older than 65, 1990-2012
Preventing Relapse
Relapse is the single most common cause of death after HCT for MDS
Strategies to prevent relapse:
Posttransplant azacytidine
Donor lymphocyte infusion
Monitoring for MRD/pre-emptive therapy
SUMMARY
HCT is a curative therapy for MDS that is under-utilized
Decisions about when and whether to apply this therapy depend on patient and disease factors predicting natural history of the MDS and the risk for transplant-related mortality
Future studies are needed to identify the patients most likely to benefit and to improve posttransplant disease control