CIBMTR 2008From the Past to the FutureFrom the Past to the Future

DBV06_1.ppt

A Short History of BMT in Humans

1957-Thomas Safe infusion of marrow into humans

1959-Mathé1959-MathéFirst bone marrow transplants for radiation accident victims.

1958-DaussetFirst HLA antigen described (A2)

1963-MathéFirst successful complete engraftment and survival p gof over 1 year, description of acute and chronic GVHD in men

1968-van Rood/TerasakiMode n HLA se ologic t ping a ailable Modern HLA serologic typing available Secondary disease-runting syndrome-GVHD

1968-Good First successful HLA matched sibling transplant for First successful HLA-matched sibling transplant for SCID

COMPENDIUM OF HUMAN BONE MARROW TRANSPLANTATIONS

MM Bortin, Transplantation, 1970

Establishment of the International Bone Marrow Transplant RegistryBone Marrow Transplant Registry

1972

Forerunner - 1970Founders: Bach, van Bekkum, Bergan, Fahey Good Levey Mathé Fahey, Good, Levey, Mathé, Rogentine, Santos, ThomasVoluntary reporting of transplant outcomestransplant outcomes

Mortimer M. BortinScientific Director,IBMTR 1972-1991

A Short History of BMT in Humans

1972-ThomasFirst successful BMT for severe aplastic anemiaFirst successful BMT for severe aplastic anemia.

1977-ThomasFirst 100 BMTs for refractory acute leukemia: 13 long t i 70% lterm survivors; 70% relapse

1980-2006Improvements in supportive carep ppImprovements in GVHD prophylaxisAutotransplants, unrelated donor transplantsPe iphe al blood stem cells co d blood cellsPeripheral blood stem cells, cord blood cellsNon ablative conditioning

The National Marrow Donor Program

Established in 1986 when U S government Established in 1986 when U.S. government appropriated funds to establish the National Bone Marrow Donor Registry (Donor Panel) g y ( )In 1988 U.S. Organ Transplant Amendments Act mandated collecting outcome data (Scientific Registry); also collects donor outcomes1st t l t f ilit t d i 19871st transplant facilitated in 1987

DBV06_24.ppt

NMDP Vision –10,000 Unrelated Donor Transplants by 2015

(At Current Growth Rates Will Exceed This Target)

3500

4000

4500

ants

Bone marrow

Peripheral blood stem cells

2000

2500

3000

of T

rans

pla

Cord blood

1000

1500

2000

Num

ber o

0

500

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

8 Pr

oj20

08

Year of Transplant

Annual Numbers of Blood and Marrow Transplantations,

1970-2006- Worldwide -

40,000

30,000

35,000Allogeneic

Autologous

nts

20,000

25,000

f Tra

nsp

lan

10,000

15,000

Nu

mb

er

of

0

5,000

N

1970 1975 1980 1985 1990 1995 2000 2005

Year

Annual Numbers of HCTs vs Numbers of Other Selected Numbers of Other Selected

MalignanciesHeme*

OHCT

PancreasHeme

* Where HCT is considered good 1st

or 2nd line therapy

BrainStomach

Ovary or 2 line therapy

CervixEsophagus

Liver

TestisSarcomas

Larynx

010

000

2000

030

000

4000

050

000

6000

070

000

8000

090

000

1000

00

Testis

ESTIMATED PERCENT OF ELIGIBLE CANDIDATES RECEIVING TRANSPLANTS BY

AGE IN U.S.

>65y

“Cured” by available front-line therapy

Allo

ISH00_11.ppt

N = 100,000Auto

Probability of Survival after Transplantation, 2000-20032000-2003

- by Donor Type -

100 100

80

90

70

80

90

70Auto (N = 25,689)

abili

ty,

%

60

50

70

60

50

70

HLA-sib (N = 16 789)

( , )

Proba

20

40

30

20

40

30

HLA sib (N = 16,789)

URD (N = 11,127)

00

20

10

0

20

10

2 63

Zw08_8.ppt

Years0 1 2 653 4

Probability of long-term survival among patients alive and in remission among patients alive and in remission

at 5 years after HCT for CML

1.0

0.8

ab

ilit

y

0.6

0.8

Sib + CP1Other donor + CP1Sib + Not CP1O h d N CP1

Pro

ba

0.4

Other donor + Not CP1

7 9 20135 6 8 1711 191512 1610 18140.0

0.2

7 9 20135

Years

6 8 1711 191512 1610 1814

LTO06_11.ppt

Despite dramatic advances in the use Despite dramatic advances in the use and success of BMT over the past 3 decades,

Fewer than half of the patients needing a transplant actually get onea transplant actually get oneOnly about half of patients who get a transplant become long-term survivorsp gAbout half of survivors have chronic health problems that continue for years p yafter transplantation

To Change This, We Need the Data FromGood Clinical Research

ImpairedHealth

Basic Human Clinical Clinical Practice and Basic Biomedical Research

Studies of Safety/Efficacy

Science and

Knowledge

Clinical Practice and Health Decision

Making

ImprovedEffecti eness Quality/ ImprovedOutcomes

Effectiveness vs. Efficacy

Q y/Access

Improvement

From: Sung et al. Central challenges facing the national clinical research enterprise. JAMA 2003;289:1278-87.

Commonly Accepted Hierarchy of y p yEvidence of Efficacy/Effectiveness

Experimental trialsExperimental trialsRandomized controlled trialsNon-randomized controlled trials

Observational studiesOutcomes registriesControlled cohort studiesControlled cohort studiesCase-control studiesCross-sectional studiesEcologic and historical (before-after) studies Uncontrolled case seriesCase reports

Observational Databases and Outcomes RegistriesOutcomes Registries

Observational database - Information on persons treated under ordinary circumstances, such that management of patients is determined by the caregiver and patient together and not by a specific protocol.

Outcomes registry – organized system using g y g y gobservational methods to collect uniform data to evaluate specified outcomes for a population defined by a particular condition or exposure/procedure that y p p pserves predetermined scientific, clinical or policy purposes

To be useful, an outcomes registry must be:, g yRepresentativeHave large numbersA tAccurateBe analyzed appropriately

95% CONFIDENCE INTERVALS FOR SAMPLES DRAWN FROM A POPULATION RECEIVING

A TREATMENT PRODUCING 50% SURVIVAL

%

100

LIT

Y,

%

50

70% Publish

RO

BA

BI 50

40% Don’t publish

PR

0

TCP99_30.ppt

SAMPLE SIZE, N

0 20 30 40 50 60 70 80 90 10010 300200

CENTER FOR INTERNATIONAL BLOOD AND MARROW TRANSPLANT

RESEARCH – the oldest outcomes registry in BMT

A research affiliation between:

IBMTR: established as voluntary organization in 1972

U.S. National Marrow Donor Program (NMDP)-Outcomes Registry: established to assess outcome of unrelated donor transplants in 1987

July 2004

CIBMTRNumber of Cases Registered,

1984-2007

195,000210,000225,000240,000255,000

Autologous

Allogeneic

>400 transplant centers>80% of HCTs in N America

120 000135,000150,000165,000180,000195,000

spla

nts

>80% of HCTs in N America

60,00075,00090,000

105,000120,000

Tra

ns

015,00030,00045,000

'84 '86 '88 '90 '92 '94 '96 '98 '00 '02 '04 '06'84 '86 '88 '90 '92 '94 '96 '98 '00 '02 '04 '06

Year

Mmh07_2.ppt

Data Quality – Partnership between centers and Statistical Center

Data collection: Committed transplant center CRPs

centers and Statistical Center

Committed transplant center CRPsStatistical Center liaisonsOn line resourcesOn-line resourcesTraining opportunities MentorshipMentorship

Quality control: Computerized error checksComputerized error checksContinuous process improvement

On-site auditsOn site audits

NAM04_8.ppt

STATISTICAL SUPPORT

Led by John Klein, PhD – fellow of the American Statistical Association and elected member of the

l lInternational Statistical Society

4 Other PhD statisticians

10 MS l l t ti ti i10 MS level statisticians

7 MD-MS faculty

A ti f t ti ti l th d l Active program of statistical methodology research specifically focused on transplant outcomes outco es

Scientific oversight through scientific Working and Advisory committees

B d ti i ti b i tifi itBroad participation by scientific community

CIBMTR Studies – Partnership of St ti ti i d Cli i l S i ti tStatisticians and Clinical ScientistsClinicians: diagnose and treat patientsCl d f d l l lClinician-scientists: define and solve clinical problemsBiostatisticians: ensure quantitative and Biostatisticians: ensure quantitative and reproducible dataClinician-scientists + biostatisticians: create a study design that effectively answer clinical questionObservational studies like clinical trials must be Observational studies, like clinical trials, must be planned and executed well - with pre-specified hypotheses and considerations of power, bias

d i t d iand appropriate design

CIBMTR PRODUCTIVITY

American Society of Hematology2006: 12 studies presented2007: 20 studies presented2008: 24 studies to be presented

BMT Tandem meetingsBMT Tandem meetings2007: 5 studies presented2008: 6 studies presented2009 10 t di l d f b i i2009: 10 studies planned for submission

Publications:2006: 20 peer-reviewed publications2007: 32 peer-reviewed publications2008: 36 accepted or in press; 10 under review

ENT04_16.ppt

OTHER OUTCOMES REGISTRIESOTHER OUTCOMES REGISTRIES

BMTNational: Japan, Canada, Germany, France, many others International: A i P ifi BMT G E Asian-Pacific BMT Group; European Group for Blood and Marrow Transplantation; Eurocord

OtherSociety of Thoracic Surgeons, Scientific R i t f S lid O T l t Registry for Solid Organ Transplants, Cystic Fibrosis, others

OUTCOMES REGISTRIES - A NEW ERA?

Sophisticated (computationally ( p ydemanding) statistical tools for data sharing and data sharing and analysisGrowing

f happreciation of the power of analyzing large datasetsgHas led to a hunger for data on part of many users

Greatly enhanced many userscomputing power

EVERYBODY WANTS DATAEVERYBODY WANTS DATA

PolicyyMed/Scientific Makers/Community Payors Patient

Assess trends + ++ +

A l ffiAnalyze efficacy +++ ++ +++

Advance strategies +++ + +

Allocate resources + +++ +

TCP99_4.ppt

Structure of the C.W. Bill Young Cell Transplantation Program

AdvisoryDepartment of Advisory Council

HRSA/Division of

pHealth and Human

Services

Transplantation NMDP

Accrediting Organizations

Infrastructure

Cord Blood Banks

Cord Blood Coordinating

Center

Stem Cell Therapeutic Outcomes Database

Bone Marrow Coordinating

Center

Public Interface

CIBMTRSingle Point of Access /

Office of

T l ReferringHRSA ContractO i ti

CIBMTRPatient Advocacy

Transplant Centers

Referring Physicians

Organizations

Other New Organizations or

Relationships

Patients

Under the Contract, SCTOD will-Collect data (and specimens)Collect data (and specimens)

ALL allogeneic hematopoietic cell transplants (HCTs) with a recipient or donor from the U.S.Related donor-recipient repositoryRelated donor-recipient repositoryOther cellular therapiesQuality of life dataSecure efficient electronic data capture systemSecure, efficient electronic data capture system

Analyze dataCenter-specific outcomes for U.S. transplant centersPe fo m anal ses of optimal si e fo the ad lt dono egist Perform analyses of optimal size for the adult donor registry and cord blood unit inventoryConduct and support other research using the data collected under the contractunder the contract

Disseminate dataWithin the ProgramTo the scientific and medical communityTo the scientific and medical communityTo patients, families and the public

CHALLENGE OF THE NEW ERA

Accommodate the many demands for d t i th t t th d f ll data in a way that meets the needs of all users (including the SCTOD, research programs of CIBMTR local research programs of CIBMTR, local research needs), ensures quality, is maximally efficient and minimizes demands on transplant centers

Previous Data FlowPrevious Data Flow

N USEBMT

Registration NMDP Report

Non-US;US Related; Auto

US Unrelated

Voluntary Mandatory

EBMT

MED-A

(TED/MED-A) Forms

IBMTR MED B IBMTR Report Form

d

MED-B

MKE MSPConcatenated File

First Step - DEVELOPING INTERNATIONAL CONSENSUS ON

Expanded

INTERNATIONAL CONSENSUS ON DATA COLLECTION

pTransplant Essential Data (TED) Form -

ASBMTFACTEBMTAPBMTAPBMTCord Blood BanksNIH CIBMTR Report

Forms –harmonized IBMTR d

NIHHRSAConsumers and Providers IBMTR and

NMDP forms

Providers

Second Step – Implement Electronic Data p pCollection System: FormsNet2.0TM

Electronic data entry system to Electronic data entry system to collect all data on TED and Report forms Report forms Web-based High level of securityHigh level of securityGradual launch starting December 2007December 2007

Current Data FlowCurrent Data Flow

Non-US; US Related; EBMT Non-US;US Auto

US Related; Unrelated

Voluntary Mandatory

EBMT

ExpandedMED A

FormsNet

Expanded TED

CIBMTR

MED-A

MED B

Conversion

Report Forms

Voluntary

MED-B

Single CIBMTRDatabase (Research Database)

Eurocord

AP BMT Ad hoc

Group

Next Step – Improve the Electronic p pData Collection System

Multiple features plannedReal-time forms due reportsError / range checking on entryReport generation (including p g ( guniform RFI)Downloadable data (eventually)

Long-term solution – Electronic i ti d t b AGNIScommunication among databases: AGNIS

NIH-funded project to facilitate sharing of BMT NIH funded project to facilitate sharing of BMT outcomes data – without requiring adoption of any specific database or data entry systemBased upon data standards established by U.S. National Cancer Institute’s caDSR and CaBIG i f t tinfrastructure

Goal: allow centers to submit data from home-grown or commercially available local databases grown or commercially available local databases directly to CIBMTR without manual re-entry

CIBMTRCB

Bank

Transplant Center

Bank

APBMT AGNISSecure communication

protocols

Eurocord

protocols

EBMT

Transplant

Center

www.agnis.netOpen source software

Future Data Flow

Non-US;US Auto

US Related; Unrelated

FormsNetTM

or AGNISEBMT

Transplant Essential D t F

Voluntary Mandatory-SCTOD

EurocordData Form

CIBMTR R t FAPBMT Report Forms

Voluntary

APBMT

CIBMTRResearch Database

Other research partners

AGNIS

MULTIPLE DATA USES –Collect once, use often,

From the Transplant Center Perspective

Clinical trial data

Data for local uses

TED/SCTOD Data

Report Form/Research Data

TED/SCTOD Data

2000 State of Science Symposium #1 sets scientific agenda for 2001-2007 7 focus areas for HCT trials

2007 State of Science Symposium #2 sets scientific agenda for 2008-2012+ 12 Working Committees

1. Expanding donor/graft source 5. Decrease infections2. Reduce regimen related toxicity 6. Improve late effects/QOL3 GVHD ti /th 7 R di ( dd d b St i

11 high priority trials – 4 in development (anticipated open date):Maintenance vs consol vs 2nd Tx for MM – 0702 (2009)C l i i f i hibit f CGVHD 0801 (2009)

Collectively Administer

DCC

R S P3. GVHD prevention/therapy 7. Rare diseases (added by Steering 4. Decrease relapse Committee and 2005 RFA

Calcineurin-free inhibitors for CGVHD – 0801 (2009)Reduced intensity tx for CLL – 0804/CALGB lead (2009)Chemo vs HCT for Ph+ALL – 0805/SWOG lead (2009)Note: See Appendix G of July 2008 Progress Report for list of all

high-priority trials

2001 2002 2006 2007 2008 20102003 2004 2005 2011 20122009BMT CTN

Foundation

CIBM

TREM

MES

NMDP

N of pts = 440 1,058 1,615 2,090 [2,500] [3,000] [3,600] [4,200]Early and ongoing collaboration with cooperative groups to synergize and avoid duplication (intensified since 2005)

2001 2002

• Governance and leadership• Established 16 Core Centers• Manual of Policies/procedures• Electronic data capture system

P i i b d l

0601 PII Sickle Cell NST0703 PII Hodgkin Disease

0603 PII Double CB in Adults0604 PII Haplo in Adults

0701 PII NST for NHLOther trials to be opened in 2009 or later:0602 Systemic Sclerosis allo-NMT (2009)0802 Phase III MMF for Acute GVHD (2009)0803 Allo-HCT in HIV with malignancies (2010)

0704 PIII MM maintenance

ECOG CALBGBMT CTNSteering

• Per patient reimbursement model• Websites for members & public

0402 PIII GVHD prophylaxis

0403 PIII Etanercept for IPS

0501 III Single vs Double CBT0502 PII NST for AML >60y

SWOG COG

SteeringComm 0301 PII Unrelated Tx for aplastic anemia

0303 PII T-depleted HCT for AML0401 PIII BEAM vs BEAM-Bexxar for Lymphoma

p p y

0302 PII AGVHD therapy0202 PIII follicular NHL (closed early)

= Enrollment completeE ll i

LEGENDS

0202 PIII follicular NHL (closed early)

0102 PIII Myeloma Tandem HCT0101 PIII Vori vs Fluconazole

0201 PIII Unrelated PBSC vs Marrow

TRIALS OPEN FOR ENROLLMENT, 2001-2008

= Enrollment on-going= Cumulative actual

[projected] accrual= Coop group collaboration

(see color key above)Figure 1

BMT CTN MONTHLY ACCRUAL All ProtocolsAll Protocols

70 3000

50

602500

MonthlyCumulative

40

50

1500

2000

20

30

1000

0

10

0

500

0

Nov-0

3Fe

b-04

May-0

4Au

g-04

Nov-0

4Fe

b-05

May-0

5Au

g-05

Nov-0

5Fe

b-06

May-0

6Au

g-06

Nov-0

6Fe

b-07

May-0

7Au

g-07

Nov-0

7Fe

b-08

May-0

8Au

g-08

0

CHALLENGE: Integrate data collection procedures for CIBMTR SCTOD BMT CTNCIBMTR, SCTOD, BMT CTN, ……….

Clinical trial data

Data for local uses

TED/SCTOD Data

Report Form/Research Data

TED/SCTOD Data

PARTNERSHIPSPARTNERSHIPS

Sharing data on transplants using U.S. donors but done outside the U Sdonors but done outside the U.S.

EBMT, Eurocord/Netcord, Asian-Pacific BMT Group Japanese BMT GroupsBMT Group, Japanese BMT Groups

Collecting data on outcome of cellular therapies for emerging indicationstherapies for emerging indications

CCTRN, SCCT, PACT, ISCT, EBMTCollaboration on observational and Collaboration on observational and interventional studies

Prediction is a hazardous business…

“Airplanes have “640,000 bytes of no military value.”

- Marshal Foch

memory ought to be enough for anybody.”

- Bill Gates, 1981

BUTBUT………….

Use of BMT will continue to growCIBMTR will continue to grow

h ll d l hTogether we will develop systems that will allow us to accommodate an ever-increasing body of data and facilitate g ycollaboration in a way that can answer important questionsUltimatel t ansplant o tcomes ill be Ultimately, transplant outcomes will be improved through these efforts