The Role of Outcomes Registries in Blood and Marrow

The Role of Outcomes Registries in
Blood and Marrow Transplantation
Mary M Horowitz, MD, MS
Cape Town, South Africa
November 2014
Worldwide Network for Blood and Marrow Transplantation
A Little History…….
Reported Human Bone Marrow
Transplants, 1958-1968
70
BMTs
60
Transplants
50
40
30
20
?
10
0
1958
1959
1960
1961
1962
1963
1964
1965
1966
1967
1968
Years
Bortin, Transplantation, 1970
(Source: Transplantation 1970,9:572) Mmh09_9.ppt
2
Transplant Activity Worldwide
1968-2014
Autologous
Allogeneic
40000
Transplants
35000
30000
25000
20000
15000
International
Bone Marrow
Transplant
Registry
Established
10000
5000
0
'68 '70 '72 '74 '76 '78 '80 '82 '84 '86 '88 '90 '92 '94 '96 '98 '00 '02 '04 '06 '08 '10 '12
3
In the Beginning……
First Advisory Committee of
the International Bone
Marrow Transplant Registry
Dirk van Bekkum
Don Thomas
George Mathe
Bob Good
George Santos
Mort Bortin
Fritz Bach
JJ Bergan, JL Fahey,
Bob Levey, GN Rogentine
4
OUTCOMES REGISTRIES – A Part of the HCT Community
Since the “Beginning” and Continuing to Grow
40000
35000
Transplants
30000
25000
20000
15000
10000
5000
IBMTR– 1970; EBMT - 1974
National: US, Japan, Germany,
France, etc – 1980s-90s
International: Asian-Pacific BMT
Group; Eastern Mediterranean
BMT Group; Eurocord – 1990s2000s; LABMT - emerging
NMDP
Established
IBMTR
Established
NMDP &
IBMTR join to
form CIBMTR
0
'68 '70 '72 '74 '76 '78 '80 '82 '84 '86 '88 '90 '92 '94 '96 '98 '00 '02 '04 '06 '08 '10 '12
5
First 200 Patients Reported to IBMTR
1968-73, 11 Countries, 35 Centers
82 with Malignancy; 108 with SCID/Marrow Failure
USA
France
Netherlands
Switzerland
Canada
United Kingdom
Denmark
Germany
Italy
Australia
Hungary
International Bone Marrow Transplant
Registry - 1985
1970 - 1985
• 200 centers
• 1,000 transplants
• 35 publications
Mortimer M. Bortin, MD
Scientific Director
Al Rimm, PhD
Statistician
D’Etta Waldoch
Sharon Nell
Diane Knudsen
Data Management
Karen Gurgul
Admin. Assistant
7
Key Contributions
Transplants Can Be Done Safely and Can Cure
•
Bortin MM, Rimm AA. ACS-NIH organ transplant registry. 2nd scientific report.
JAMA. 1972
• Bortin MM, Buckner CD. Major complications of marrow harvesting for
transplantation. Experimental Hematology. 1983
Disease Specific Outcomes
•
•
•
•
•
Bortin MM, Rimm AA. Severe combined immunodeficiency disease:
characterization of the disease and results of transplantation. Transplantation
Proceedings. 1977
Bortin MM, Rimm AA. Bone marrow transplantation for acute myeloblastic
leukemia. JAMA. 1978.
Bortin MM, Rimm AA. Allogeneic bone marrow transplantation for of 144
patients with severe aplastic anemia. JAMA. 1981
Gale RP, Kersey JH, Bortin MM, Dicke KA, Good RA, Zwaan FE, Rimm AA.
Bone-marrow transplantation for acute lymphoblastic leukaemia. Lancet.
1983.
Speck B, Bortin MM, Champlin RE, Goldman JM, et al. Allogeneic bonemarrow transplantation for chronic myelogenous leukaemia. Lancet. 1984
8
Key Contributions
Risk Factors
• Bortin MM, Rimm AA. Factors influencing success and failure of
human marrow transplantation: a review from the International Bone
Marrow Transplant Registry. Experimental Hematology Today. 1979
• Bortin MM, Kay HEM, Gale RP, Rimm AA. Factors associated with
interstitial pneumonitis after bone-marrow transplantation for acute
leukaemia. Lancet. 1982
• Bortin MM, Gale RP, Kay HEM, Rimm AA. Bone marrow transplantation
for acute myelogenous leukemia. Factors associated with early
mortality. JAMA. 1983
HLA Associations
• Rimm AA, Bortin MM. HLA antigens and SCID. Lancet. 1977
• D'Amaro JD, van Rood JJ, Rimm AA, Bortin MM. HLA associations in
Italian and non-Italian Caucasoid aplastic anaemia patients. Tissue
Antigens. 1983
• D'Amaro JD, van Rood JJ, Bach FH, Rimm AA, Bortin MM. HLA C
associations with acute leukaemia. Lancet. 1984
9
Why are Large Registries Still Necessary? SMALL NUMBERS
Annual Numbers of HCTs vs Numbers of Selected Cancers in the US
Breast
Pancreas
HCT
Ovary
Stomach
Brain
Liver
Sarcomas
0
50000
100000
150000
200000
10
Distribution of Allotransplant Volumes Among 162
US Centers Reporting Data to CIBMTR in 2012
2% 8%
19%
52%
<200
100-199
19%
50-99
31-49
<30
Individual transplant centers treat relatively few
patients and these patients are heterogeneous in
many factors that affect outcomes
11
95% Confidence Intervals for Samples Drawn from a
Population Receiving a Treatment Producing 50% Survival
Probability, %
100
70% Publish
50
40% Don’t publish
0
0
10
20
30
40
50
60
70
80
90
100 200
300
Sample Size, N
12
CIBMTR 420,000 Cases Registered,
1985-2013 > 900 Publications
Allogeneic
Autologous
Cumulative Total
450000
Health Services Research
Transplants
400000
QOL, Long-term Follow-up
350000
Immunobiology*
300000
Multicenter Clinical Trials
250000
200000
Technology Assessment
150000
*NMDP Repository Specimens for >33,000
donor-recipient pairs.
Prognostic factors
100000
50000 Descriptive
0
'85
'87
'89
'91
'93
'95
'97
'99
'01
'03
'05
'07
'09
'11
'13
Years
13
The Value of Outcome Registries: Identifying
patients most likely to benefit from BMT
100
Probability of Overall Survival
after HCT for AML not in Remission
by CIBMTR Risk Score
Probability, %
80
60
Risk score = 0, N = 148, 42% (39-50)
40
Risk score = 1, N = 326, 27% (23-33%)
Risk score = 2, N = 342, 15%(11-19%)
20
Risk score = 3, N = 321, 6%(3-9%)
0
0
1
2
Years
3
Duval, JCO, 2010
14
The Value of Outcomes Registries:
Evaluating Graft Sources
15
The Value of Outcomes Registries: Changing
Practice - US Cord Blood Transplants, 1990-2011
500
Children
400
350
300
250
200
150
100
50
0
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
Number of transplants
450
Adults
16
The Value of Outcome Registries:
Understanding the Influence of HLA
8/8 Match
6/8 Match
1.0
1.0
Early Disease Stage
0.9
1.0
Intermediate Disease Stage
0.9
0.8
0.7
0.7
0.7
0.6
0.6
0.6
0.4
Survival
0.8
0.5
0.5
0.4
0.5
0.4
0.3
0.3
0.3
0.2
0.2
0.2
0.1
0.1
0.1
0.0
0.0
0
12
24
36
48
Months after transplant
60
Advanced Disease Stage
0.9
0.8
Survival
Survival
7/8 Match
0.0
0
12
24
36
48
Months after transplant
60
0
12
24
36
48
Months after transplant
S. Lee, et al. Blood 2007 Showed impact of single allele mismatch at A,
B, C and DRB1: changed the paradigm for selecting adult donors
17
60
Survival After Unrelated Donor Transplantation
Age <50 years, myeloablative conditioning, acute leukemia in remission or MDS
100
90
Adjusted 1-year Overall Survival
Probability, %
80
70
60
50
40
30
20
10
Odds of 1-year survival increased by 8% per year
(95% CI, 7-9%) on average between 1990 and 2011
0
Year of Transplant
18
Adjusted Probability of Survival After
Transplantation for AML, 2002-2006
Probability of Survival, %
100
100
90
90
80
80
70
70
60
60
HLA-id Sib (N=624)
50
50
7/8 MUD (N=406)
40
30
40
30
8/8 MUD (N=1,193)
20
20
10
10
0
0
0
6
12
18
24
30
36
Months
19
Early and ongoing collaboration with cooperative groups to
synergize and avoid duplication (intensified since 2005)
NMDP
EMMES
CIBMTR
BMT CTN
Total Subjects =
450
1,050
1,625
2,150
2,625
3,050
3,450
4,300
7,000
DCC
2001 2002
Developed
Infrastructure
2003
2004
2005
2006
2007
2008
2009
2010
2011
1301
1203
1102
+ 1304
1205
1204
1202
1101 Haplo vs. UCB
0903 Allo HIV+
2012
2013
9 trials this grant cycle
0903: Allo for HIV-malignancy
1101: Haplo vs Double Cord
1202: Biomarker collection
1204: RIC for HLH
1102: BMT vs Chemo for MDS
1205: Patient-friendly Consent
1304: Early vs Late BMT for MM
1203: GVHD proph in RIC BMT
1301: CNI-free GVHD proph (soon)
2014
0901 Full vs. RIC - MDS/AML
+
0804 High Risk CLL
0902 Stress Mgmt
0803 HIV+ Lymphoma
ECOG
CALBG
BMT CTN
Steering
Committee
SWOG
COG
0805 Ph+ ALL
+
0702 PIII Myeloma Follow-on
0801 P II/III CGVHD Treatment
0802 PIII AGVHD Treatment
0701 PII NST for NHL
0604 PII DCB in Adult
0603 PII Haplo in Adult
= Enrollment/follow-up complete
= Enrollment complete; ongoing F/U
= Enrollment on-going
+
0403 PIII Etanercept for IPS
+
+
PUBLICATIONS
(closed early)
0704 PIII MM maintenance
0502 PII NST for AML >60y
0402 PIII GVHD prophylaxis
0501 III Single vs. Double CBT
Primary Outcome
0301 PII Unrelated Tx for aplastic anemia
0401 PIII BEAM vs BEAM-Bexxar for Lymphoma
Safety, Secondary
Outcome, or Design
Submitted,
Primary Outcome
0601 PII Sickle Cell NST
0703 PII HD
0302 PII AGVHD therapy
0303 PII T-depleted HCT for AML
0202 PIII follicular NHL
(closed early)
0201 PIII Unrelated PBSC vs. Marrow
0101 PIII Vori vs. Fluconazole
0102 PIII Myeloma Tandem HCT
20
The Value of Global Outcome Registries:
Understanding Late Effects
www.ebmt.org
21
The Value of Outcome Registries:
Influencing National Public Policy
• Most US patients 65+ years have health
insurance through Medicare which did not
cover BMT for MDS
• August 2010: Medicare, in part because of
existing CIBMTR data, decided it would cover
costs of BMT but ONLY if patients enrolled in
an IRB-approved study that will provide CMS
with data to determine the value of the
procedure in the Medicare population
• CIBMTR used its infrastructure to open a
study using EXISTING data collection
mechanisms (minimal additional work of
transplant centers)
22
US Allogeneic Transplants for MDS
in patients older than 65, 2005 - 2013
250
200
150
100
50
0
2005
2006
2007
2008
2009
2010
2011
2012
2013
23
The Value of Global Outcome Registries: Understanding
Trends in Use, Practice and Outcomes
Low
middle
high income
24
The Value of Global Outcomes Registries: Understanding
Macro-Economic Influences on Survival Globally
LEUKEMIA-FREE SURVIVAL
1.0
0.9
0.8
Probability
0.7
0.6
0.5
Association of Human
Development Index with rates
and outcomes of hematopoietic
stem cell transplantation for
patients with acute leukemia
(Giebel at al, Blood 2010)
0.4
1st percentile
2nd percentile
3rd percentile
4th percentile
5th percentile
0.3
0.2
0.1
0.0
0
1
2
3
4
5
6
7
8
Years after allo-HSCT
25
Why Should a Registry
be Considered When BMT is Just
Developing in a Country or a Region?
Because to Develop a Therapy Effectively,
We Need DATA
• Assessment – identify the most important
problems and most promising solutions
• Analysis - determine efficacy – overall and
for specific subgroups/regions; monitor longterm outcomes
• Advancing best practices - Optimize
treatment strategies/improve outcome in the
real world with real resource constraints
• Allocation of resources – research and
clinical care
27
Data Are Needed:
• At the center level
– Quality improvement
– Understanding costs and resource needs (and
making the case for them to hospital and local
authorities)
– Scientific study
• At the national level
– Understanding access, costs and resource needs
(and making the case for them)
– To advance best practices
28
Data Are Needed:
• At the regional level
– Facilitate research relevant to regional issues
– The process of sharing data also creates
opportunities for professional, educational and
scientific collaboration in a community that faces
similar challenges and affords the potential for
sharing expertise and resources
• At the global level
– To understand differences and commonalities in
access, practice and outcomes
– To advance the science and practice of HCT
– To communicate with regulatory and funding
bodies about needs
29
It is Important to Incorporate Careful Data
Collection and Analysis Early
• Because building a culture of evaluating and
understanding outcomes is critical for
– effective quality management systems to improve
patient care
– building an effective clinical research infrastructure to
improve patient care
• When numbers of transplants in individual
centers and countries are small, sharing data
allows examination of important issues with
greater power
30
An African Registry Could Offer Some Unique
Contributions to Global Understanding of BMT
• High prevalence of non-malignant hematopoietic
disorders
– Development and evaluation of regimens that ensure
engraftment and minimize GVHD
– Studies of BMT vs non-BMT therapy; HLA-id sib vs
haplo or other alternative graft sources
• Extremely diverse distribution of HLA and other
genetic determinants of outcomes – insight into
permissive vs non-permissive
matches/variations
• Examination of cost-effective approaches to both
autologous and allogeneic BMT
31
Levels of Data Collection
Start small but plan for growth:
What are the most important
questions to answer in the next
3-5 years? 5-10 years? 10-15 years?
TED/MED-A
level data
Comprehensive Data
(CRF/MED B)
Basic
Outcome
Data
Simple
Activity
Data
32
Thank You
If you want to go
fast, go alone; if
you want to go
far, go with
others.