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Slide 1
NIH Support of Research in Hematopoietic Stem Cell
TransplantationNational Cancer Advisory Board Meeting
February 4, 2009
Roy S. Wu, Ph.D.Chief
CGCB/CTEP/DCTD/NCI
Slide 2
Background• HCT – Curative therapy for malignant and non-
malignant hematological diseases: many are rare • No equivalent of big pharma HCT in the private
sector• Large federal investment to make HCT available
through the C. W. Bill Young Cell Transplantation Program and the National Cord Blood Inventory (Public Law 109-219)
• NCI has supported BMT research successfully– Nobel Prize for Dr. Donnell Thomas– GM Prize for Dr. George Santos
Slide 3
Clinical BMT Funding by NIH(2008)
MECHANISM NCI Total dollars (#)
NHLBI Total dollars (#)
NCI + NHLBI (+NIAID +NCMHD)
R grants 3,134,000 (9) 4,332,000 (10) 0
P01/U19/U54 37,401,000 (14) 11,363,000 (6) 0
U01 (BMT CTN) 0 0 10,031,000
U24 (CIBMTR) 0 0 3,083,000
Slide 4
From the bench to the bedside
Clinical Research Change in Practice –Better Outcomes
Basic Science/Animal Model Research
Phase I Phase II Phase III
PO1, RO1 Support
Preclinical Research
UO1 – BMT CTN
U24 – CIBMTR
Slide 5
Presentations• Current use and outcomes of HCT - Dennis
Confer, Chief Medical Officer, National Marrow Donor Program
• Health Resources and Services Administration (HRSA) support of HCT – Robert Baitty, Director, Blood Stem Cell Transplantation Program, Division of Transplantation, HRSA
• BMT CTN and CIBMTR: National networks for multicenter HCT research – Mary Horowitz, Scientific Director, Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin
Slide 6
Worldwide Growth and Development of Hematopoietic Cell Transplantation
Dennis L. Confer, M.D.Chief Medical Officer, NMDP
February 4, 2009
Slide 7
Annual Numbers of Blood and Marrow Transplantations, 1970-2006 - Worldwide -
0
5,000
10,000
15,000
20,000
25,000
30,000
35,000
40,000
1970 1975 1980 1985 1990 1995 2000 2005
Year
AllogeneicAutologous
Nu
mb
er o
f Tr
ansp
lan
ts
Slide 8
0
500
1,000
1,500
2,000
2,500
3,000
3,500
4,000
4,500
5,000
5,500
MultipleMy eloma
NHL AML HodgkinDisease
ALL MDS/MPD CML AplasticAnemia
Other Leuk OtherCancer
Non-MaligDisease
Tra
nspl
an
ts
Allogeneic (Total N~8,150)Autologous (Total N~11,500)
Indications for Hematopoietic Stem Cell Transplantation in North America
Slide 90
1000020000
3000040000
5000060000
7000080000
90000100000
TestisSarcomas
LarynxCervix
EsophagusLiverBrain
StomachOvary
# of HCTPancreas
Heme** Where HCT is considered good 1st
or 2nd line therapy
Annual Numbers of HCTs vs Numbers of Other Selected Malignancies
Slide 10
Current Annual Activity Estimates– Worldwide –
• Autologous transplants exceed 27,000• Allogeneic transplants exceed 22,000
– More than half of allogeneic transplants use unrelated donor products
– More than 14 million adult donors are registered worldwide
– The world’s inventory of unrelated donor (i.e., public) umbilical cord blood units exceeds 400,000
Slide 11
National Marrow Donor Program Adult Donors & Cord Blood Units – Jan, 2009
1,000,0002,000,0003,000,0004,000,0005,000,0006,000,0007,000,0008,000,0009,000,000
10,000,000
1988 1993 1998 2003 2008
Adu
lt D
onor
s
010,00020,00030,00040,00050,00060,00070,00080,00090,000100,000
Cor
d B
lood
Uni
ts
1,000,0002,000,0003,000,0004,000,0005,000,0006,000,0007,000,0008,000,0009,000,000
10,000,000
1988 1993 1998 2003 2008
Adu
lt D
onor
s
010,00020,00030,00040,00050,00060,00070,00080,00090,000100,000
Cor
d B
lood
Uni
ts
Adult Donors7,435,426
CBUs94,604
Slide 12
NMDP Transplants Facilitatedby Fiscal Year 1987–2008
0
500
1000
1500
2000
2500
3000
3500
4000
450019
87
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
Year of Transplant
Num
ber o
f Tra
nspl
ants
Cord blood
Peripheral blood stem cells
Bone marrow
Slide 13
NMDP Recipients >55 Years of Age
0.0%
2.5%
5.0%
7.5%
10.0%
12.5%
15.0%
17.5%
20.0%
22.5%
25.0%
27.5%
30.0%
1991-1994
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
Year of Transplants
Perc
enta
ge o
f Firs
t NM
DP
Tran
spla
nts
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
Num
ber o
f Tra
nspl
ants
Percentage
Number
Slide 14
Is There Evidence of Improved Results?
1-year survival for a defined subset of patients evaluated over time– Restricted to patients <50 years age– Myeloablative regimens only– Acute leukemias in any remission– Chronic Myelogenous Leukemia– Myelodysplastic Syndromes – RA or RARS only
Analysis completed in mid-2007– 6,450 recipients through December 31, 2005– Adjusted for recipient age, sex, race, CMV status, BMI,
disease type, stage, risk and duration, performance score, coexisting disease
Slide 15
Adjusted 1-year Survivals over Time– 1988 through 2005 –
0%10%20%30%40%50%60%70%80%
1988 - 90
199119921993199419951996199719981999200020012002200320042005
Adjusted Survival
Sur
viva
l at
1 Ye
ar
Slide 16
Survivals over Time: Unrelated vs. Related Donors
0%10%20%30%40%50%60%70%80%
1988 - 90
199119921993199419951996199719981999200020012002200320042005
Adjusted SurvivalSibling DonorS
urvi
val a
t 1
Year
Slide 17
SUMMARY
• Worldwide numbers of Autologous and Allogeneic HCTs continue to increase and the potential for further growth is high
• More than half of allogeneic transplants utilize unrelated donor products
• Outcomes with related donors and unrelated donors have improved over time and are comparable
• Continued clinical research is necessary to optimize outcomes
Slide 18
HRSA’s Role in Blood & Marrow Transplantation
NCAB February 4, 2009Robert L. Baitty, MPP
Director, Blood Stem Cell Transplantation Program, Division of Transplantation, Health Resources & Services Administration (HRSA)
Slide 19
National Bone Marrow Donor Registry• Purpose: Facilitate unrelated donor transplantation• Preceded by National Organ Transplant Act-1984• Registry established-1986
– Navy grant (potential role in a marrow toxic event)– Oversight by NIH/NHLBI as a research activity
• Oversight transferred to HRSA-1994• Operated by the National Marrow Donor Program
since inception under HHS contracts– HHS and Navy have provided significant financial
support to the Registry over 20+ years
Slide 20
• Reauthorization Act of 1998: – Increase number of minorities in the Registry– Provide patient advocacy services– Quality standards and procedures– Collection of outcomes data on transplants facilitated
by the Registry (unrelated-donor transplants)– Transplant center-specific survival analyses
• Aid transplant center quality improvement • Provide patients and referring physicians with data to
help guide choice of transplant center
The Registry, cont’d
Slide 21
Stem Cell Therapeutics and Research Act of 2005 (Public Law 109-129)• Exciting opportunity to expand access to HCT• Aims to increase:
– number of blood stem cell transplants using unrelated adult donor sources or umbilical cord blood grafts
– Number of cord blood units available for research• Establishes National Cord Blood Inventory
– target of banking 150,000 new units of umbilical cord blood – Authorized at $15 million/year– FY 2009 Continuing Resolution funding ~$8.8 million
• Establishes C.W. Bill Young Cell Transplantation Program– Successor to the National Bone Marrow Donor Registry– Authorized at $38 million/year– FY 2009 Continuing Resolution funding ~$23.5 million
Slide 22
Establishes:• Secretary’s Advisory Council on Blood Stem Cell
Transplantation• Bone Marrow Coordinating Center to identify, match,
and facilitate the distribution of adult blood stem cells to patients
• Cord Blood Coordinating Center to identify, match, and facilitate the distribution of umbilical cord blood to patients
• Single Point of Access through which patients and physicians can electronically search for and gain access to all blood stem cell graft sources
• Patient Advocacy and Case Managementservices independent of other services provided by the Program
Stem Cell Therapeutics and Research Act of 2005, cont.
Slide 23
• Stem Cell Therapeutic Outcomes Database to collect basic scientific data on transplant recipients – Scope expanded to include both related and unrelated
donor transplants– Limited data set for each patient– Operational research to evaluate Program– Annual center-specific outcomes analysis
• More comprehensive research data on HCT collected through other mechanisms– Program depends on more comprehensive data
and research to further the field of allogeneic transplantation and improve patient outcomes
Stem Cell Therapeutics and Research Act of 2005, cont.
Slide 24
C.W. Bill Young Cell Transplantation Program: Contracting Structure
Office of Patient Advocacy
Single Point of Access
Cord Blood Coordinatin
g Center
SCTOutcomes Database
Bone Marrow
Coordinating Center
Center for International Blood and Marrow Transplant Research (CIBMTR)
at the Medical College of Wisconsin
National Marrow Donor Program (NMDP)
HRSA Support of SCTOD2006 $4.002007 $2.242008 $3.68Total $9.92No $ for data submission
Slide 25BUS06_1.ppt
Multicenter Networks for HCT Research:
CIBMTR and BMT CTN
Mary M. Horowitz, MD, MSMedical College of Wisconsin
Slide 26
The CIBMTR Grew Out of Two Important Collaborative Efforts in HCT
An affiliation of National Marrow Donor Program (NMDP) International Bone Marrow Transplant
Registry (IBMTR) at the Medical College of Wisconsin Voluntary outcomes registry established
in 1970 (2 years after the first successful HCTs) at a time when there were ~ 12 transplant centers, < 50 transplants a year worldwide
Established CIBMTR in July 2004 to support clinical research in HCT & related fields
Slide 27
IBMTR – 1985 (year of first major NIH funding)
Mortimer M. Bortin, MD
Scientific Director
Al Rimm, PhDStatistician
D’Etta WaldochSharon Nell
Diane Knudsen Data
Management
Karen GurgulAdministrative
Asst
1970-1985:•200 centers•1,000 transplants•35 publications
Location of Centers Participating in the CIBMTR, 2009
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135 staff including, 5 PhD statisticians, 11 MS statisticians, 10 MD-MS faculty; Active program of statistical methodology research specifically focused on transplant outcomes in addition to supporting clinical studies Slide 29
Slide 29
015,00030,00045,00060,00075,00090,000
105,000120,000135,000150,000165,000180,000195,000210,000225,000240,000
'84 '86 '88 '90 '92 '94 '96 '98 '00 '02 '04 '06
Year
Tran
spla
nts
CIBMTR Observational Database (415 publications)
Descriptive
Technology Assessment
Prognostic factors
Immunobiology*
Multicenter Clinical Trials
QOL, Long-term Follow-up
*NMDP Repository -Established 1988
Specimens for >13,000 unrelated donor-recip pairs
>14,000 samples distributedpast 2 yrs
415 publications
*SCTOD Repository –Related donor-recipient pairs
Pilot project in selected centers
Slide 30
Current/Future Data Flow
Transplant Essential Data Form
ComprehensiveReport Forms
Single CIBMTRDatabase (Research Database)
Non-US;US Auto
US Related*; Unrelated**
Voluntary Mandatory
Voluntary
EBMT
ExpandedMED-A
MED-B
Eurocord
AP BMT Group
*Donor outcomes routinely collected**Donor outcomes to be collected on subset
SCTOD
AGNIS – A Growable Network Information System: Collaboration
with NIH Bioinformatics
Slide 31
Acute Leukemia Chronic Leukemia Lymphoma Plasma Cell Disorders Solid Tumors Pediatric Cancer Non-Malignant Marrow
Disorders Immune Deficiencies /
Inborn Errors Autoimmune Diseases
Graft Sources/Manipulation GVHD Late Effects & QOL Immunobiology Infection / Immune
Reconstitution Regimen-related Toxicity Emerging Cellular Therapies Health Services &
Psychosocial Issues Donor Health & Safety International Studies
WORKING COMMITTEES
Slide 32
CIBMTR PUBLICATIONS
1993-1997
1998-2002
2003-2007*
Peer-reviewed pubs
34 66 115
# Different authors
177 295 403
# Different Institutions
98 158 216
*34 publications in 2008
Slide 33
ROLE OF OBSERVATIONAL DATABASE IN CLINICAL RESEARCH
Analyze trends Descriptive studies Identify factors associated with outcome
Clinical Center-specific Socioeconomic Biologic/genomic
Assess treatments / strategies Donor selection
Study late effects Analyze access / utilization Design / Interpret / Facilitate clinical trials
Slide 34
From the bench to the bedside
Clinical Research Change in Practice –Better Outcomes
Basic Science/Animal Model Research
Phase I Phase II Phase III
PO1, RO1 Support
Preclinical Research
Slide 35
US Transplants on Cooperative Group Trials: Before the BMT CTN
0
200
400
600
800
1000
1200
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
Nu
mb
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ansp
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ts
Primarily (90%) autologous transplants Allo studies usually restricted to sibling transplants<3% of all HCTs, <1% allotransplants
Focused on comparing HCT to non-HCT therapy – rarely addressed how to improve transplant outcomes
Slide 36
Established: Sept. 2001; renewed Oct. 2006 16 Core Center cooperative agreements 1 DCC cooperative agreement:
CIBMTR with subcontracts to NMDP & EMMES Goal of the Program: Provide the infrastructure needed to allow
promising HCT therapies to be developed/evaluated in high quality multicenter studies
Slide 37
2001 2002 2006 2007 2008 20102003 2004 2005
SWOG COG
ECOG CALGBBMT CTNSteeringComm
2011
20122009BMT CTN
Foundation
Collectively Administer DCC
CIBM
TR
EMME
S
NMDP
2007 State of Science Symposium #2 Sets scientific agenda for 2008-12+
12 Working Committees
N of pts =440 1,058 1,615 2,090 2,500 [3,000] [3,600] [4,200]
• Governance and leadership• Established 16 Core Centers• Manual of Policies/procedures• Electronic data capture system• Per patient reimbursement model• Websites for members & public
1. Expanding donor/graft source 5. Decrease infections2. Reduce regimen related toxicity 6. Late effects/QOL3. GVHD prevention/therapy 7. Rare diseases 4. Decrease relapse
Early and ongoing collaboration with cooperative groups to synergize and avoid duplication (intensified since 2005)
11 high priority trials – 6 in development:1. Maint vs consol vs 2nd Tx for MM 2. Calcineurin-inhibitor-free Rx for CGVHD3. Reduced intensity tx for CLL 4. Chemo vs HCT for Ph+ ALL5. Reduced vs standard intensity conditioning6. Peritransplant QOL
2000 State of Science Symposium #1 -Set scientific agenda for 2001-07
7 focus areas for HCT trials
N of trials = 2 4 6 9 13 18 [22] [27] [32]
Slide 37
Slide 38= PBMTC Centers= Affiliate Centers= Core Centers
BMT CTN Centers, 2009>70 centers have enrolled patients since 2003~25% of enrollment is from Affiliate Centers
Slide 39
US Transplants on Cooperative Group Trials:Impact of the BMT CTN
0
200
400
600
800
1000
1200
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
Nu
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• 80% of BMT CTN transplants – allotransplants•>5% of US transplants – both auto and allo•>900 unrelated transplants (almost 10%)
Cooperative Groups
BMT CTN
Total
Slide 40
Clinical Research
Basic Biomedical Research
Human Studies of
Safety/Efficacy
Clinical Science
and Knowledge
Clinical Practice and Health Decision
Making
Improved Health
From: Sung et al. Central challenges facing the national clinical research enterprise. JAMA 2003;289:1278-87.
Effectiveness vs. Efficacy
Quality/Access
Improvement
ImpairedHealth
Slide 41
DHHS Support for Clinical Research in HCT: Roles of BMT CTN and CIBMTR
Basic Biomedical Research –new HCT
drugs,strategies
Human Studies of Safety/Efficacy
Clinical Science
and Knowledge
Clinical Practice and Health Decision
Making – Optimal HCT Treatment
Improved Health-more
successful transplant
s
Effectiveness vs. Efficacy –who should vs does
get HCT and why?
Quality/Access
Improvement
ImpairedHealth - low access, poor
HCT outcomes