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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