SBTMO REUNIÃO EDUCACIONAL

REGIONAL

HIGHLIGHTS TANDEM 2018

UNRELATED DONORS

LUIS FERNANDO BOUZAS

Increase in annual number of transplants

performed in the US

2

Increase number of allogeneic

transplants in patients older than 60y

^Transplants for AML, ALL, NHL, Hodgkin Disease,

Multiple Myeloma9

Cost and Morbidity of Alternative

Donor OptionsMarcelo C Pasquini, MD, MS

BMT Tandem Meetings – 2018

WBMT Session

@mpasca

Current options – Universal Donor Era

11

HLA-matched

Sibling

Graft Type

Conditioning Intensity

Conditioning Type

GVHD Prophylaxis

UCB

Cell Dose

HLA matching

Conditioning Intensity

Conditioning Type

GVHD Prophylaxis

Unrelated

HLA matching

Gender, ABO, CMV, HLA DP

Graft Type

Conditioning Intensity

Conditioning Type

GVHD Prophylaxis

Related

Sib, parents, children

Graft Type

Conditioning Intensity

Conditioning Type

GVHD Prophylaxis

Transplant Options – Not Applicable to all

12

Regional

Center

Patient

Have we reached the HCT Promised

Land? No…

• Despite improvements in supportive care, transplant recipients are at risk of significant and life long complications.

• HCT in US had the highest increase of inpatient costs from 2004-2007* and continues to grow.

• Increase in cost of medications used in transplantation. – Conditioning chemotherapy shortages with more

expensive replacements

– New drugs use for supportive care and treatment of complications.

*AHRQ HCUP Stats Brief 82, Dec 2009 13

Date of download:

mm/dd/yyyy

Copyright © 2012 American Medical

Association. All rights reserved.Copyright © 2016 American Medical

Association. All rights reserved.

From: US Spending on Personal Health Care and Public Health, 1996-2013

JAMA. 2016;316(24):2627-2646. doi:10.1001/jama.2016.16885

Dangerous Combination of Factors

• Expanding number of transplant – increase

baseline costs Unsustainable model

• Transplant in the context of treatment of

cancer

– HCT is no longer the most expensive treatment…

Consequences:

• Increase in costs can limit access to

transplant.

15

Healthcare (or HCT) Costs – US

Direct Costs

Indirect CostsHOSPITAL/CENTER/

PROVIDERS

Charges

Adjudicated Costs

Total Costs

PATIENT

Margin

Negotiation

Deductibles, Out-of-pocket

Courtesy of Navneet S. Majhail, MD @BldCancerDoc

Costs of HCTUsing Hospital Billing Data

• Single center study (N=294), allogeneic HCT

• Costs from day -30 to +100 (excluding MD costs)

• Median costs by conditioning (excl graft acq)

- Myeloablative = $137,112

- Non-myeloablative = $84,824

• Median costs by graft source (excl graft acq)

- Umbilical cord blood = $137,564

- Sibling donor = $83,583

• Cost predictors

- HCT type, complications and length of hospital

stay

NS Majhail et al, Biol Blood Marrow Transplant, 2009

US HCT Median Costs using Claims

Database – 2010 -2013 (N=1,562)

Broder M. S et al American Health and Drug Benefits, October 2017 18

Costs: Pediatric > Adults HCT

Post Transplant Out of Pocket Expenses

• Costs involved with maintenance medications, visit, travel, lodging, among others.

• Variable co-payments plans in the US can result in costs close to $5,000 in the first few months of HCT.

• In the event of complications the costs are incremental (new medication, rehabilitation, other).

• Financial toxicity higher morbidity.

Farnia S et al BBMT 2017 19

SO

CIE

TY

Healthcare (or HCT) Costs – US

Direct Costs

Indirect CostsHOSPITAL/CENTER/

PROVIDERS

Charges

Adjudicated Costs

Total Costs

PATIENT

Margin

Negotiation

Deductibles, Out-of-pocket

Courtesy of Navneet S. Majhail, MD @BldCancerDoc

HCT Costs and the Tip of the Iceberg

Cliché

21

Added/Unpredictable CostsOverall Costs

Estimated Costs

Prolonged Hospitalization

ICU care

Out of pocket expenses

GVHD

Graft Failure

Relapse and treatment

Second Transplant

Cellular Therapies

Transplant procedure

Hospitalization

Standard medications

Haploidentical HCT Recipients in the

US, by Graft Type

22

Asad Bashey et al; JCO 2017, 35, 3002-3009.

PB vs. BM in Haplo with PtCY

Acute GVHD

Chronic GVHD

UCB vs. Haplo: Cost Considerations

UCB Haplo

Predictable

“extra” costs

Graft acquisition

Hospital LOS

Desensitization

for DSA

Unpredictable

“extra” costs

Graft failure

Complications,

GVHD

Graft failure

Complications,

GVHD

What is the solution(s)?

• Advance the field:

– Best option to a specific patient considering all

other center and regional factors.

– Minimize all expected morbidities

• Bring cost “front and center”

– Understand all determinants of costs.

– Include financial toxicity among complications

from therapy.

– This needs to influence clinical decision making.

25

Choosing Wisely for HCT

Don’t use PBSC for SAA when a BM donor is available

Don’t use > 2mg/kg/day methylpredinisolone (or equivalent) for initial aGVHD treatment

Don’t use 2 UCB for standard of care HCT when a single UCB is available

Don’t routinely use PBSC for MURD with MAC and standard GVHD prophy when a BM donor is available

Don’t routinely use IG replacement in adults after HCT in the absence of recurrent infections

Bhella S et al BBMT 2017 26

Conclusion

• Advances in the HCT field allow access to a larger number of patients.

• Increasing costs are an ongoing threat to access worldwide.

• Further reducing transplant related morbidities is critical to minimize livelong costs.

• Ongoing review of practices that reduce cost without impact on safety or effectiveness of HCT is really important for the field.

27

Acknowledgements

• Navneet Majhail, MD

• J. Doug Rizzo, MD

• Bronwen Shaw, MD

• Mary Eapen, MD

• Marcelo Pasquini, MD

28

How the best donor can improve outcomes of transplantation?

How can regional haplotype frequencies influence the success of finding the best Unrelated UCB or volunteer Donor?

Luis Fernando BouzasNational Cancer institute Brazil

Number of HLA Alleles – described 08/2013

http://www.ebi.ac.uk/ipd/imgt/hla/stats.html

Brazil► Continental country

► Geopolitically divided in 5 Regions by IBGE – Brazilian Institute of Geography and Statistics

North

Northeast

Central-west

Southeast

South

► Color/Race categories:

White

Brown (mestizos /mulatos)

Black

Yellow (East Asian phenotype)

Indigenous (Native American)

Brazilian Program - HSCT

• Etnic constitution of Brazilian population:

– Highly mixed

– Intense genetic diversity in the population

– Difficulty for compatible donor search.

Donors

Donors

Donors

PATIENTS

► REDOME – Volunteer Donor Registry

Established in 1993 at F. PróSangue / SP;

Transfered to INCA / Rio de Janeiro in 1999;

New administration after 2003/2004

► BrasilCord – Public CBB Network

Established in 2004

RENACORD – CBB Registry

►Banks + Cellular Processing/Criobiology Labs

► REREME – Receptors Registry

Established after 2006

0

500.000

1.000.000

1.500.000

2.000.000

2.500.000

3.000.000

3.500.000

4.000.000

4.500.000

0

100.000

200.000

300.000

400.000

500.000

600.000

700.000

800.000

Até1999

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

Donors per year Total donors

Limit to free registration)

New administration

4.210.421

684.156

330.360

Probability to find a compatible donor (6x6) at

REDOME National patient in low resolution

0%

10%

20%

30%

40%

50%

60%

70%

80%

2002 2003 2004 2005 2006 2007 2008 2009

Ano

% d

e r

ecep

to

res c

om

6 x

6

PROBABILIDADE DE UM DOADOR IDÊNTICO

TAMANHO DO REGISTRO

Müller, CR

REDOME

Alemanha

Comparison w/ German Registry

2002 - 2009

REDOME and RENACORD Data Analisys

in order to supply donors for patients

included in REREME for URD search

Luis Fernando da Silva Bouzas

INSTITUTO NACIONAL DE CÂNCER

Post Graduation Programm in ONCOLOGY

2011 - 2014

Objectives

► The Registry Evolution after first 10 years

► Donor characteristics

► Capacity to supply donors for patients registered for URD search

► HLA Allele and Haplotype Frequencies Analisys

REDOME (volunteer donors)

REREME (receptors)

Method

► Comparison of Haplotypes frequencies REDOME (donors) x REREME (receptors);

► Most frequent alleles and haplotypes in the population and the rare present only in REREME (receptors);

► Evaluate the geografic Alleles and Haplotypes origin ---- plan the Brazilian Program and Registry growth;

► Actions to reduce the lack of a suitable unrelated donor for HSCT for all patients.

Analisys

Allelic Groups

►HLA – A (n=21)

►HLA – B (n=36)

►HLA – DRB1 (n=13)

Alleles HLA-A*02, A*24, HLA-B*44, B*35,

HLA-DRB1*01, DRB1*04, DRB1*07, DRB1*11, DRB1*13 e

DRB1*15

present in ALL Data Base, with Highest frequencies.

Most Frequent Alleles

ALELOS MAIS FREQUENTES (%)

Alelo REDOME RENACORD REREME

A*02 25,8% 25,7% 25,5%

A*24 9,9% 9,9% 10,1%

A*03 9,4% 9,2% 8,7%

A*01 9,1% 9,7% 9,1%

B*44 10,8% 10,8% 10,8%

B*35 12,3% 12,3% 11,4%

DRB1*01 10,2% 10,2% 9,6%

DRB1*04 11,9% 11,9% 12,7%

DRB1*07 12,9% 12,9% 12,8%

DRB1*11 14% 14% 12,1%

DRB1*13 14% 14% 12,8%

DRB1*15 9,7% 9,7% 10,9%

Less Frequent AllelesALELOS MENOS FREQUENTES (%)

Alelo REDOME RENACORD REREME

A*34 0,75% 0,6% 0,9%

A*36 0,53% 0,39% 0,6%

A*43 0% 0% 0,03%

A*66 0,9% 1,2% 1,1%

A*69 0,2% 0,3% 0,3%

A*80 0,2% 0,1% 0,2%

B*46 0,1% 0,2% 0,1%

B*47 0,2% 0,2% 0,3%

B*48 0,5% 0,5% 0,6%

B*54 0,2% 0,2% 0,1%

B*56 0,5% 0,5% 0,3%

B*59 0,06% 0,06% 0,03%

B*67 0,06% 0,06% 0,05%

B*73 0,2% 0,1% 0,1%

B*78 0,06% 0,06% 0,09%

B*81 0,4% 0,4% 0,5%

B*82 0,02% 0,02% 0,03%

B*83 0% 0% 0%

ALELO

FREQUÊNCIA

REDOME/REREME

(%)

ORIGEM

A*11 5,3 / 5,4 Ásia / Oceania

A*23 4,9 / 5,2 África

A*30 5,1 / 5,9 Norte da África / Europa Mediterrânea

A*31 4,5 / 4,3 Japão e tríplice fronteira

A*69 0,2 / 0,3 Disseminado com baixa freqüência

B*13 2,1 / 1,6 Ásia / Oceania

B*37 1,0 / 0,9 Disseminado com baixa freqüência

B*40 4,4 / 4,6 Ásia/Oceania(Costa Pacífico) /Américas (Costa do Pacífico)

B*41 2,0 / 1,2 República Checa / Norte da África

B*49 3,3 / 3,0 Europa Ocidental / América do Sul

B*53 2,3 / 2,6 África / afro-americanos

DRB1*01 10,2 / 9,6 Europa Ocidental

DRB1*03 9,2 / 9,9 Europa Ocidental / Irã

DRB1*09 1,5 / 1,9 Ásia / Oceania

DRB1*13 14,0 / 12,8 Europa / Ásia

DRB1*16 3,7 / 3,3 Brasil (índios guaranis)

Geografic Origin of Rare Alleles identified in REREME

www.allelefrequencies.net (ASHI)

REDOME (May /2012 – Feb 2013)

►Race

►Age

►Gender

►Region/State

►Place of birth

►Comparison w/ Last Pop. Survey

REDOME (2013)

Results

Epidemiologic Data

Total = 3.093.847 donors

16.602

105.943

2.681 3.391

0

100000

200000

300000

400000

500000

600000

700000

<18 anos 18 - 19

anos

20 - 24

anos

25 - 29

anos

30 - 34

anos

35 - 39

anos

40 - 44

anos

45 - 49

anos

50 - 54

anos

55 - 59

anos

60 - 69

anos

>69 anos

REDOME (Age)(3.093.847 donors)

2013

Comparison REDOME 2013 X Census

2010

Age

586017

117442

1346790

274005392731 376862

0

200000

400000

600000

800000

1000000

1200000

1400000

NÃO

INFORMADO

AMARELA BRANCA INDIGENA PARDA PRETA

REDOME Race /Color self informed(3.093.847 doadores)

Comparison REDOME 2013 X Census 2010

Race

1,7%

2,5%

1,7%

0,8%

1,2%

51%

49%

REDOME x CENSO 2010

1,43 %

0,91%

1,94 %

2,82 %

1,98 %

MAY

2012APRIL

2014

American and German Registry

► NMDP – 6 957 831 doadores

(BMDW 27/05/2013)

► EUA população – 316 266 000 inhab

(US Census Bureau)

► EUA pop 15 to 54 yo – 170 768 000 inhab

(US Census Bureau)

► NMDP represents 2,19 % american pop. and 4,07% 15 to 54 yo pop.

► DKMS (Germany) – 4 955 663 donors

► German population – 81 843 743 inhab

(Eurostat)

► Registry represents 6,05 % german pop.

4,07% 15 a 54 yo

6,05 %

Tabela 1. Nº de doadores cadastrados no REDOME

Descrição Quantidade %

REDOME 4.182.569 100%

REGIÃO NORTE 284.411 6,80%

AC 5.256 0,13%

AM 30.624 0,73%

AP 25.033 0,60%

PA 93.591 2,24%

RO 88.176 2,11%

RR 7.706 0,18%

TO 34.025 0,81%

REGIÃO SUDESTE 1.875.150 44,83%

ES 125.473 3,00%

MG 453.242 10,84%

RJ 207.830 4,97%

SP 1.088.605 26,03%

REGIÃO SUL 944.462 22,58%

PR 455.150 10,88%

RS 317.478 7,59%

SC 171.834 4,11%

REGIÃO CENTRO-OESTE

371.991 8,89%

DF 44.298 1,06%

GO 141.566 3,38%

MS 128.608 3,07%

MT 57.519 1,38%

REGIÃO NORDESTE

691.660 16,54%

AL 37.546 0,90%

BA 127.892 3,06%

CE 160.501 3,84%

MA 18.717 0,45%

PB 60.543 1,45%

PE 114.657 2,74%

PI 77.418 1,85%

RN 65.255 1,56%

SE 29.131 0,70%

NÃO IDENTIFICADO

14.895 0,36%

2016 – Comparison REDOME x Brazilian Population

Tabela 2. Representatividade percentual da população brasileira no REDOME.

Descrição Quantidade %

BRASIL 206.741.083 2,02%

REGIÃO NORTE 17.798.866 1,60%

AC 821.840 0,64%

AM 4.026.412 0,76%

AP 789.153 3,17%

PA 8.307.420 1,13%

RO 1.795.264 4,91%

RR 518.593 1,49%

TO 1.540.184 2,21%

REGIÃO SUDESTE 86.623.950 2,16%

ES 3.987.337 3,15%

MG 21.049.563 2,15%

RJ 16.676.481 1,25%

SP 44.910.569 2,42%

REGIÃO SUL 29.513.960 3,20%

PR 11.279.095 4,04%

RS 11.308.036 2,81%

SC 6.926.829 2,48%

REGIÃO CENTRO-OESTE

15.746.845 2,36%

DF 2.999.306 1,48%

GO 6.730.803 2,10%

MS 2.695.586 4,77%

MT 3.321.150 1,73%

REGIÃO NORDESTE

57.057.462 1,21%

AL 3.365.860 1,12%

BA 15.305.001 0,84%

CE 8.992.197 1,78%

MA 6.969.141 0,27%

PB 4.008.617 1,51%

PE 9.436.262 1,22%

PI 3.215.975 2,41%

RN 3.488.910 1,87%

SE 2.275.499 1,28%

*baseado na população total estimada até

30/11/2016 (fonte: IBGE)

2016 – Comparison REDOME x Brazilian Population

Evolution - New Donors per Year and Haplotypes

Evolution – Haplotypes Cumulative Frequencies (2016)

Projection Rate - Compatibility 09x10 and Race

(Taxa de compatibilidade 09x10 projetada)

Size of the Registry

Projection Rate – 10x10 Compatibility and Race

Taxa de compatibilidade 10x10 projetada

Size of Registry

COMPATIBILITY Rate 9x10 and 10x10 /Race

Taxa de compatibilidade para 9x10 e 10x10

REDOME

Jan 2018

0

50

100

150

200

250

300

350

400

450

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

Non Related HSCT in Brazilian patients

Intl CBU

BrasilCord

International (BM/PBSC)

REDOME (BM/PBSC)

Total

95

275

33% National Donors67% International Donors

73% National Donors27% International Donors

n= 30

n= 381

83

Planning and Research

Summary

► 3 038 286 donors

► From 2003 – 2014

► Ethnicity self–reported (IBGE´s classification)

► Parental Pop. Portugal , Italy, Germany, France, Spain,

Sub-Saharian Africa

Peru , Chile, Mexico

Japan

► HLA – A ; -B ; -DRB1 antigenic groups

► ARLEQUIN 3,5 software

► Analisys of Variance (ANOVA)

HUMAN IMMUNOLOGY 2017

Genetic Diversity and Geo Distribution

TOP 30 Haplotypes in

REDOME

Haplotypes most frequent in REDOME:

A*01-B*08-DRB1*03 2.1%,

A*29-B*44-DRB1*07 1.4%

A*03-B*07-DRB1*15 1.0%.

Geographic Distribution and Ethnicity

CONCLUSION

► To improve assistance for receptors is important to characterize the population from Volunteer Donor Registries

►The Antigenic group and Haplotype frequency data could be helpful for recruitment strategies and planning

►Predictive algorithm could be developed to help the indication and search process.

Thank you !

Acknowledgement

•MINISTÉRIO DA SAÚDE

•INCA / SNT

•REDOME

•Brasilcord

•FUNDAÇÃO DO CÂNCER

•Blood centers

•LABs IMMUNOGENETICs

•HSCT Centers

•DONORS (National and International)

•PATIENTS and Families

•OTHER (NGOs, Private Comp, etc)

Contact : medula@inca.gov.br

lbouzas@inca.gov.br