Como transplantar na LLA

Fábio Kerbauy

Leucemia Linfoblástica Aguda

https://seer.cancer.gov/statfacts/html/alyl.html

Classificação WHO - 2016

Roberts KG, et al. N Engl J Med. 2014;371:1005-1015.

Children

(1-15 Yrs of Age)

Adolescents

(16-20 Yrs of Age)

Young Adults

(21-39 Yrs of Age)

Ph-like.

BCR-ABL1.

ETV6-RUNX1

4.2%

1.5%4.1% 8.2%

7.3%

15.1%

14.6%

11.9%

33.0%

5.1%

10.7%

3.7%

5.9%

20.6%

38.0%

10.2%4.5%

1.3%5.4%

22.0%

15.5%

27.4%23.2%

1.8%

3.0% 1.8%

Hyperdiploid

TCF3-PBX1

ERG

MLL.

Hypodiploid.

Other

Classificação WHO por faixa etária

Study Year N Median Age (Range) SCT CR Rate Early Death Survival

CALGB 9111, USA5 1998 198 35 (16–83) Ph+ 85% 8% 40% (3 y)

LALA 87, France1 2000 572 33 (15–60) PO 76% 9% 27% (10 y)

NILG 08/96, Italy7 2001 121 35 (15–74) PR 84% 8% 48% (5 y)

GMALL 05/93, Germany8 2001 1163 35 (15–65) PR 83% n.r. 35% (5 y)

JALSG-ALL93, Japan2 2002 263 31 (15–59) PO 78% 6% 30% (6 y)

UCLA, USA9 2002 84 27 (16–59) PR 93% 1% 47% (5 y)

Sweden10 2002 153 42 (16–82) PR 75% n.r. 28% (5 y)

GIMEMA 0288, Italy12 2002 767 28 (12–60) — 82% 11% 27% (9 y)

MD Anderson, USA6 2004 288 40 (15–92) Ph+ 92% 5% 38% (5 y)

EORTC ALL-3, Europe3 2004 340 33 (14–79) PO 74% n.r. 36%*(6 y)

LALA 94, France11 2004 922 33 (15–55) PR 84% 5% 36% (5 y)

GOELAL02, France13 2004 198 33 (15–59) HR 86% 2% 41% (6 y)

MRC XII/ECOG, UK-USA4 2005 1521 15–59 PO 91% n.r. 38% (5 y)

GIMEMA 0496, Italy14 2005 450 16–60 n.r. 80% n.r. 33% (5 y)

Pethema ALL-93, Spain15 2005 222 27 (15–50) HR 82% 6% 34% (5 y)

LLA – Indução/Consolidação/Manutenção

LLA Adulto – Fatores de risco

ESMO- Hoelzer D. et al. Annals of Oncol. 2016

MRC UKALL XII/ECOG E2993

Goldstone AH, et al. Blood. 2008;111(4):1827-34

Standard risk patients, <40y

Meta analysis Acute Leukemia Stem Cell Transplantation Trialists' Collaborative Group

13 studies, N=2962, excluding Ph+

Gupta V. Blood. 2013 Jan 10;121(2):339-50

Regimes padrão ouro até início do século

• Berlin-Frankfurt Münster (GM ALL)[1]

• CALGB (88-11, 91-11, 93-11, 95-11[2]

• Hyper-CVAD[3]

• Linker[4]

• Medical Research Council trials[5]

• LALA-87 trial[6]

1. Gökbuget N, et al. Hematol Oncol Clin North Am. 2000;14:1307-1325. 2. Larson RA. Hematol Oncol Clin

North Am. 2000;14:1367-1379. 3. Garcia-Manero G, et al. Hematol Oncol Clin North Am. 2000;14:1381-1396.

4. Linker C, et al. J Clin Oncol. 2002; 20:2464-2471. 5. Durrant IJ, et al. Hematol Oncol Clin North Am.

2000;14:1327-1352. 6. Thiebaut A, et al. Hematol Oncol Clin North Am. 2000;14:1353-1366.

GMALL: Evolução da Sobrevida Geral

Study 03: 0.24 (N = 353)

Study 04: 0.30 (N = 593)

Study 05: 0.32 (N = 1224)

Study 06: 0.37 (N = 832)

Study 07: 0.51 (N = 1292)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Yrs

Pro

bab

ilit

y o

f S

urv

ival

LLA pediátrica: Sobrevida geral

Seminars in Hematology, Vol 50, Pui CH, Evans WE, A 50-year journey to cure childhood acute lymphoblastic leukemia, Pages 185–196,14 Copyright © 2013

LLA: Tratamento “personalisado”

Tipo Tratamento Cura, %

Burkitt’s ALLHCVAD-R x 8; ITx16;

R/O-EPOCH80-90

Ph-positive ALLHCVAD + TKI; TKI maintenance;

allo SCT in CR150+

T-cell ALL HD CTX, HD ara-C, Asp; nelarabina? 50-60

CD20-positive ALL QT + rituximab/ofatumumab 40-50

AAJ (AYA) Augmented BFM; HCVAD-R/O 60+

MRD by FCM Prognóstico; TCTH alo em RC1 --

LLA: Doença residual na semana 16 em pacientes em RC

YrsGökbuget N, et al. Blood. 2012;120:1868-1876.

P < .0001

OS

MRD < 10-4

MRD ≥ 10-4

80%

42%

(n = 384)

(n = 120)

1.0

0.8

0.6

0.4

0.2

00 1 2 3 4 5 6 7 8 9 10 11

Doença residual mínima

Bassan R et al. Blood 2009 113:4153-4162

ESMO- Hoelzer D. et al. Annals of Oncol. 2016

Tipo de doador

Kiehl, M. G. et al. J Clin Oncol; 22:2816-2825 2004

Tipo de doador

Eapen, M. et al. J Clin Oncol; 24:145-151 2006

Tipo de doador: Pediátricos – MUD x SCUP

Eapen M et. al. Lancet 2007

We´re meaking less babies… and getting older…

http://www.ibge.gov.br/apps/populacao/projecao/index.html

Brazil´s violance map

http://redome.inca.gov.br/o-redome/dados/

REDOME

Brazilina transplant network

Probability of finding a LOW RESOLUTION 6/6 matched unrelated donor from REDOME

Doador Haploidêntico (Cy pos ou ATG)

Santoro, N et al J Hematol Oncol. 2017; 10: 113

Doador Haploidêntico (Cy pos)

Srour, SA et al. BBMT. 2017

Preparative regimens

Melphalan-based40(37)Flu/Cy/TBI 32(29)Busulfan-based 9(8)TBI-based 25(23)Other 3(3)

Condicionamento – EBMT TBI x Tiotepa

Eder S et. al. Am J Hematol 2017

Efeito GVL – EBMT megafile (n=48.000)

Sobrevida global: RIC x MA (>45ª) - EBMT

Mohamad Mohty et al. Blood 2010;116:4439-4443

Nicola Gökbuget et al. Haematologica 2016;101:1524-1533

SG da LLA Ph- Recidivada

LLA Ph- Recidivada – O que fazer?

Frey NV and Luger SM et al. Blood, 2015;126:589-596

SG da LLA Ph- Recidivada Impacto do Transplante alogênico

Nicola Gökbuget et al. Haematologica 2016;101:1524-1533

Impact of drug development on SCT - ALL

EBMT activity survey. Passweg et al. BMT, 2017; 52: 191-196

Nelarabine Blinatumomab

Latin America Transplant Group: 2011

154 centers (94 centers sent reports)

Report in 2009-2012 (n= 11.519 trasplants)

Reasons for transplant in latin america

EBMT activity survey. Passweg et al. BMT, 2017; 52: 191-196

Allo (n=4486) Auto (n=7033)

Transplant rate (per 10 million population)

Jaimovich G et al. BMT, 2017; 52: 671-677

Auto Allo

N of Tx increased 30% from 2009 to 2012

Obrigado!!

fkerbauy@gmail.com@fkerbauy@fkerbauy