Center for International Blood and

Marrow Transplant Research

(CIBMTR): Outcomes Database

and Research Organization for the

Advancement of the Transplant

Field Marcelo C. Pasquini, MD MS

2015 Joint Annual Congress of the

Hematology Society of Taiwan and Taiwan

Society of Blood and Marrow

Transplantation-

Taipei, April 2015

Outline

• CIBMTR: from a transplant registry to a

comprehensive research organization

• Outcomes database :

– Impact of research on practice

• Transplant Center performance

• Clinical Trials: BMT CTN

• Worldwide Collaboration: WBMT

2

What is a Registry?

• Organized system that uses observational study

methods to collect uniform data to evaluate

specified outcomes for a population defined by a

particular disease, condition or exposure that that

serves one or more predetermined scientific,

clinical, or policy purposes – US Agency for

Healthcare Research and Quality

– Provides “real world” assessments of diseases

and their treatments

DBV06_64.ppt

Why Are Registries Important in BMT?

1. Small numbers

2. Many important clinical issues cannot be addressed in

randomized trials

3. Few trials can be done – we need to select and design

them carefully

4. BMT has the potential for late effects – requires long-

term monitoring

5. National funding and regulatory bodies want increasing

amounts of data on efficacy and quality

6. Issues of cost and access need to be addressed

BMT’s Biggest Statistical Challenge: Small Numbers

Annual Numbers of HCTs vs Numbers of Selected

Cancers in the US

0 50000 100000 150000 200000

Sarcomas

Liver

Brain

Stomach

Ovary

HCT

Pancreas

Breast

5

Distribution of Allotransplant Volumes Among 162

US Centers Reporting Data to CIBMTR in 2012

2% 8%

19%

19%

52%

<200

100-199

50-99

31-49

<30

Individual transplant centers treat relatively few patients and these patients are heterogeneous in many factors that affect outcomes

6

95% Confidence Intervals for Samples Drawn from a

Population Receiving a Treatment Producing 50% Survival

Sample Size, N

0 20 30 40 50 60 70 80 90 100 10

Pro

babili

ty,

%

0

50

100

300 200

70% Publish

40% Don’t publish

7

(Source: Transplantation 1970,9:572) Mmh09_9.ppt

Tra

nsp

lan

ts

Years

0

10

20

30

40

50

60

70

1958 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968

BMTs

Reported Human Bone Marrow Transplants, 1958-1968

?

A Little History…….

Bortin, Transplantation, 1970

8

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

10

11

NMDP/Be

The Match

Medical

College of

Wisconsin

A research collaboration

between NMDP/Be The Match

and Medical College of

Wisconsin

CIBMTR Number of Patients Registered,

1984-2013

0

50000

100000

150000

200000

250000

300000

350000

400000

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

20

11

2012

2013

Allogeneic Autologous Cumulative Total

12

Data for 2013 incomplete

OUTCOMES REGISTRIES – A Part of the HCT

Community Since the “Beginning” and Continuing to Grow

0

5000

10000

15000

20000

25000

30000

35000

40000

'68 '70 '72 '74 '76 '78 '80 '82 '84 '86 '88 '90 '92 '94 '96 '98 '00 '02 '04 '06 '08 '10 '12

CIBMTR

Established

IBMTR– 1970; EBMT - 1974 National: US, Japan, Germany, France, etc – 1980s-90s International: Asian-Pacific BMT Group; Eastern Mediterranean BMT Group; Eurocord – 1990s-2000s

IBMTR

Established

NMDP

Established

BMT CTN

Funded

Tra

nspla

nts

13

Indications for Hematopoietic Stem Cell

Transplants in the US, 2012

0

1000

2000

3000

4000

5000

6000

7000

Myeloma/ PCD

AML ALL CML NHL HD MDS/MPD CLL Aplastic Anemia

Other Non-Malig

Dis

Other Cancer

Allogeneic (Total N=7,554) Autologous (Total N=11,145)

14

Nu

mb

er

of T

ran

sp

lan

ts

15

CIBMTR Scientific Activities

Observational Research

Clinical Outcomes

Prospective Clinical Trial

Support

Statistical Methodology

Immunobiology

Health Services

BMT CTN

RCI BMT

Bioinformatics

BMT CTN = Blood and Marrow Transplant Clinical Trials Network

RCI BMT = Resource for Clinical Investigations in Blood and Marrow Transplant

CIBMTR,

1985-2013 > 900 Publications

0

50000

100000

150000

200000

250000

300000

350000

400000

450000

'85 '87 '89 '91 '93 '95 '97 '99 '01 '03 '05 '07 '09 '11 '13

Allogeneic Autologous Cumulative Total

Health Services Research

16

Tra

nsp

lan

ts

Years

QOL, Long-term Follow-up

Multicenter Clinical Trials

Immunobiology*

Technology Assessment

Prognostic factors

Descriptive

*NMDP Repository - Specimens for >33,000 donor-recipient pairs.

1st NIH

Funding for

IBMTR

NMDP

Established

BMT CTN

Funded

NMDP &

IBMTR join to

form CIBMTR

Have These Studies Made A

Difference?

The Value of CIBMTR: Identifying patients

most likely to benefit from BMT

Duval, JCO, 2010

100

0

20

40

60

80

Pro

babili

ty,

%

Years

0 1 3 2

Risk score = 0, N = 148, 42% (39-50)

Risk score = 1, N = 326, 27% (23-33%)

Risk score = 2, N = 342, 15%(11-19%)

Risk score = 3, N = 321, 6%(3-9%)

Probability of Overall Survival after HCT for AML not in Remission

by CIBMTR Risk Score

Vh09_25.ppt

The Value of CIBMTR: Evaluating Graft

Sources

The Value of CIBMTR: Changing Practice US

Cord Blood Transplants, 1990-2011

0

50

100

150

200

250

300

350

400

450

500 1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

Num

ber

of

transpla

nts

Adults Children

The Value of CIBMTR: Understanding the

Influence of HLA 8/8 Match 7/8 Match 6/8 Match

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

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 12 24 36 48 60

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 12 24 36 48 60

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 12 24 36 48 60

Su

rviv

al

Early Disease Stage Intermediate Disease Stage Advanced Disease Stage

Su

rviv

al

Su

rviv

al

Months after transplant Months after transplant Months after transplant

Survival After Unrelated Donor Transplantation Age <50 years, myeloablative conditioning, acute leukemia in

remission or MDS

Odds of 1-year survival increased by 8% per year

(95% CI, 7-9%) on average between 1990 and 2011

0

10

20

30

40

50

60

70

80

90

100

Prob

ab

ilit

y,

%

Year of Transplant

Adjusted 1-year Overall Survival

Adjusted Probability of After Transplantation

for AML, 2002-2006

Prob

ab

ilit

y o

f S

urviv

al,

%

Months

0 6 12 36 24 18

100

0

20

40

60

80

90

10

30

50

70

0

100

20

40

60

80

90

10

30

50

70

30

HLA-id Sib (N=624)

8/8 MUD (N=1,193)

7/8 MUD (N=406)

AML11_12.ppt

The Value of CIBMTR: Understanding Effect of

Allele-level Matching at A, B, C, DRB1

in Cord Blood Transplantation

Eapen, Blood, 2013

100

0

20

40

60

80

Incid

ence, %

Years

0 1 3 2

6/8 (26%)

4/8 (37%)

5/8 (34%)

3/8 (41%)

7/8 (26%)

8/8 (9%)

P < 0.001 Likely to change the

paradigm for cord

selection

Long-term Survival after HCT • CIBMTR study of 10,632 allogeneic HCT recipients surviving ≥ 2

years in remission (median followup 9 years)

25

Overall survival Non-relapse mortality

J Wingard et al, JCO 2011 ; 29: 2230

Rizzo JD, Curtis RE et al CIBMTR 2008

The Value of CIBMTR:

Understanding Long-term Outcomes

0%

3%

6%

9%

12%

15%

0 5 10 15 20 25

Cumulative Incidence

Upper Confidence Limit

Lower Confidence Limit

Cum

ula

tive I

ncid

ence

Years

1%

2.2%

3.3%

0

Pro

babili

ty,

%

Overall Survival Comparison of Haplo with post Cy to match unrelated Donor HCT

Years Years

Myeloablative 100

0

20

40

60

80

0 1 3 2

HR 0.93 (95% CI 0.70 – 1.22), p=0.58

MUD 50% (47-53)

HAPLO 45% (36-54)

0

100

20

40

60

80

1 3 2

Reduced Intensity

HR 1.06 (95% CI 0.79 – 1.43), p=0.70

HAPLO 46% (35-56)

MUD 44% (40-47)

Adjusted for age, DRI, secondary AML

Ciurea S. et al, ASH 2014

The Value of CIBMTR: Understanding

and Improving Health Care Delivery

Accrediting Organizations

Advisory Council

Cord Blood Banks

Cord Blood Coordinating

Center

Outcomes Database

Bone Marrow Coordinating

Center

Blood Stem Cell Single Point of Access

Access Point for Stem Cell Sources

Patient Advocacy Services

HRSA/Division of Transplantation

Department of Health and Human

Services

Transplant Centers

Patients

Referring Physicians

Infrastructure

Public Interface

= HRSA Contract Organizations

= Other New Organizations or Relationships

Assembly10_2.ppt

Stem Cell Therapeutic and Research Act of 2005:

C. W. Bill Young Program Structure

The Value of CIBMTR:

Center-Specific Outcomes Adjusted Survival Rates for Transplant Centers with

11–20 Transplants

Adjusted Survival with 95% Confidence Interval

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

305

1

310

1

312

2

407

5

425

2

436

2

441

1

443

2

448

5

481

4

513

4

580

5

582

5

589

4

593

4

Transplant Center Code and Risk Score

Ad

juste

d S

urv

ival

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

The Value of CIBMTR: Facilitating

Transplants for Myelodysplasia (MDS) • Most patients 65+ years have health insurance

through Medicare which did not cover BMT for MDS

• August 2010: Medicare 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 leveraged existing infrastructure to propose a study using EXISTING data collection mechanisms and CIBMTR observational protocol (already IRB approved at US centers)

US Allogeneic Transplants for MDS in

patients older than 65, 2005 - 2013

0

50

100

150

200

250

2005 2006 2007 2008 2009 2010 2011 2012 2013

31

Joshua, Cancer, 2010

Relative Rate of HCT in the US

Caucasians vs. African-Americans

Overall Autologous HLA-identical Unrelated

HCT HCT Sib HCT Donor HCT

P<0.0001

1.35

1.45 1.40

Od

ds R

atio

0.00

1.00

1.50

2.00

2.50

0.50

P<0.0001

1.19

1.30 1.24

P<0.0001

1.46

1.74 1.59

P<0.0001

1.75

2.33

2.02

Odds Ratio

95% CI

BLOOD AND MARROW TRANSPLANT CLINICAL TRIALS NETWORK

A national clinical trials network

Established Sept 2001 Re-competed July 2010

Funded through 2017

Goals:

Evaluate promising BMT therapies and novel cell products in high quality multicenter studies

Improve safety and efficacy of BMT and cellular therapy

Enhance understanding of the biology and effectiveness of BMT

34

BMT CTN Centers

>115 centers have enrolled >7,500 patients since 2003

= Core Centers

= PBMTC Centers

= Affiliate Centers

35

2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

SWOG COG

ECOG CALBG BMT CTN Steering

Committee

Early and ongoing collaboration with cooperative groups to synergize and avoid duplication (intensified since 2005)

Developed Infrastructure

2001 2002

CIB

MT

R

EM

ME

S

NM

DP

DCC

BMT CTN

PUBLICATIONS Primary Outcome

Safety, Secondary

Outcome, or Design

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)

= Enrollment/follow-up complete

= Enrollment complete; ongoing F/U

= Enrollment on-going

0101 PIII Vori vs. Fluconazole

0201 PIII Unrelated PBSC vs. Marrow

0102 PIII Myeloma Tandem HCT

0202 PIII follicular NHL (closed early)

0301 PII Unrelated Tx for aplastic anemia

0302 PII AGVHD therapy

0303 PII T-depleted HCT for AML

0401 PIII BEAM vs BEAM-Bexxar for Lymphoma

0402 PIII GVHD prophylaxis

0403 PIII Etanercept for IPS (closed early)

0601 PII Sickle Cell NST

0603 PII Haplo in Adult

0604 PII DCB in Adult

0701 PII NST for NHL

0702 PIII Myeloma Follow-on

0703 PII HD

0704 PIII MM maintenance

0801 P II/III CGVHD Treatment

0803 HIV+ Lymphoma

0804 High Risk CLL

0902 Stress Mgmt

0903 Allo HIV+

0501 III Single vs. Double CBT

0502 PII NST for AML >60y

0802 PIII AGVHD Treatment

1101 Haplo vs. UCB

0805 Ph+ ALL

1202

1204

1205

1304

1102

0901 Full vs. RIC - MDS/AML

1301 1203

+

+

+

+

+

+

34 Trials Opened

(8 currently open)

28 BMT CTN-led

6 NCI Group-led (+)

Total Subjects = 450 1,050 1,625 2,150 2,625 3,050 3,450 4,300 7,000 7,500

www.bmtctn.net

How Can Registries facilitate clinical

trials?

• Leveraged CIBMTR outcomes registry for

trial design,

• Assessing reasonable effect size

• Realistic estimation of center- based accrual

• Enhancing accrual – during the trial

• Assisting with data collection: Paradigm for

increasing trial efficiency with real time

population data

37

Approaches

Etanercept

All disease

status

80% PBSC

MA

URD

Pentostatin

/ATG

All

80% BM

MA

URD

PostCy

All

BM

MA

MRD/URD

TCD

Early

PBSC

MA

MRD/URD

Bortezomib

Early

PBSC

RIC

URD

Maraviroc

All

PBSC

RIC

URD

• Six strategies with “promising” results in single center trial

• Major differences:

• Disease status, graft source,

conditioning regimen intensity and donor type N=74 N=66 N=117 N=291 N=44 N=33

Benchmark Analysis Done Using CIBMTR

Tacrolimus+MTX Data as Control

Control FK+

MTX

A B C D E F

AGVHD 3-4

1.00 0.86 0.50* 0.90 0.31* 0.48 0.91

CGVHD 1.00 1.50 0.60* 0.24* 0.10* 0.73 0.29*

Survival 1.00 0.85 0.69* 1.07 0.68* 0.53* 0.80

GVHD- free surv

1.00 1.01 0.73* 1.07 0.29* 0.68* 0.65*

DFS 1.00 0.92 0.65* 1.21 0.66* 0.67 1.20

39

BMT CNT 1203: Study Outline

18-75y

Malignant Diseases

Matched donor

RIC

Tac/MTX/

Bortezomib

Tac/Cy/MMF

Tac/MTX/

Maraviroc

Tac/MTX

Control

(CIBMTR)

• 3 arm Phase II trial with a contemporary control

• Primary endpoint: GFRS

– Baseline rate of 23% based on benchmark analysis

• 90 patients/arm compared to 270 controls (CIBMTR)

Clinical Trials vs. Retrospective

Studies

41

Overall Survival from Randomization

Intent-to-treat analysis

Anasetti et al NEJM 2012; BMT CTN 0201 42

100

0

20

40

60

80

Pro

babili

ty,

%

Months

2-year point P value = 0.288

PBSC (n=278)

Marrow (n=273)

0 12 36 24 30 18 6

51%

46%

Adjusted Probability of Overall Survival After

Unrelated HCT by Graft Type

Eapen, BBMT, 2007 43

100

0

20

40

60

80

Pro

babili

ty,

%

Months

0 12 36 24

PBSC (n=274) 31% @ 3 yrs

Marrow (n=618) 32% @ 3 yrs

Bone Marrow vs Peripheral Blood

Observational vs Randomized Trial Results

CIBMTR

Observational

Study

(Eapen, 2007)

BMT CTN

Randomized Trial

(Anasetti, 2012 )

BM PB BM PB

Number of

patients

586 331 278 273

Survival 33% 32% 48% 52%

Acute GVHD 45% 58% 46% 47%

Chronic GVHD 42% 56% 41% 53%

Cost Not so much A lot 44

WBMT Global Survey Update

Helen Baldomero

WBMT meeti ng Cape Town

November 2014

Worldwide Network for Blood and Marrow Transplantation NGO in official relations with World Health Organization

Transplant Type by Region: 2012

Main indication Allogeneic HSCT Autologous HSCT Total

Europe 13 271 18 836 32 107 (49%)

The Americas 8 399 10 969 19 368 (30%)

South East Asia / Western Pacific

7 522 4 373 11 895 (19%)

Eastern Mediterranean / Africa

1 185 875 2 060 (2%)

Total 30 77 (46%) 35 053 65 430

Increase in reported HSCT since 2006: 40% (allogeneic: 49%, autologous: 34%)

74 reporting countries

1 497 contributing teams

Worldwide Network for Blood and Marrow Transplantation NGO in official relations with World Health Organization HB: Nov 2014

Preliminary data

WBMT Global Survey 2006-2012

Worldwide Network for Blood and Marrow Transplantation NGO in official relations with World Health Organization HB: Nov 2014

0

10000

20000

30000

40000

2006 2007 2008 2009 2010 2011 2012

H

S

C

T

Autologous Allogeneic

Preliminary data

1200

1250

1300

1350

1400

1450

1500

1550

2006 2007 2008 2009 2010 2011 2012

Reporting teams

Increase in the numbers of transplants and reporting teams

Hong Kong Singapore

0 or no report

1 - 10

11 - 50

51 - 250

> 250

Transplant Rates per 10 million population

Allogeneic HSCT in 2012

Worldwide Network for Blood and Marrow Transplantation NGO in official relations with World Health Organization HB: Nov 2014

Preliminary data

WBMT Global Survey 2012

Conclusions

• Transplant database can impact and

advance the field

• Demonstrates real life practices

• Assists in clinical trial development

• Access to care and other aspects of care

delivery.

• Data collection needs to be part of day to

day transplant practices.

Thank you (謝謝) for your attention

50