TMO em Crianças Avanços no Transplante da Leucemia ... Encontro SBTMO - 201… · Biology and clinical application of CAR T cells for B cell malignancies Int J Hematol (2016) 104:6–17

TMO em Crianças

Avanços no Transplante da Leucemia Linfóide Aguda

Maria Lucia M. Lee

Biology and clinical application of CAR T cells for B cellmalignancies

Int J Hematol (2016) 104:6–17

SNC

Citocinas

ÍNDICES DE REMISSÃO: 95 – 98% SLE : 76 – 87 % SG : 85 - 90%

Cenário Atual da LLA Pediátrica

JCO 2015

Masculino, 4 anos Masc, 6a5m

• LI : 7500/mm3

• SNC 1

• IF: LLA comum

• Cariótipo: 46 , XY

• BM : bcr-abl p 190 : neg

ETV6 – RUN X1 : neg

Protocolo IC BFM 2002 - RI

D8: < 1000 bl/mm3

D15 : MO – M1

D 33 : MO – M1

Recidiva Mo Isolada: 7 meses pós FT

6 irmãos não compatíveis

• LI: 3400/mm3

• SNC 1

• IF: LLA pré B

• Cariótipo e BM: não avaliáveis

• Protocolo IC BFM 2002 – RS

• D8 : > 1000bl/mm3- AR

• D15 : M0 M3

• D33: MO 27% blastos – TMO?

• D64: MO M1

• CONDUTA: TMO NA? Filho único

Quando Indicar TMO ?

“HSCT should therefore be considered for patients in whom this procedure is likely to result in superior long term disease free survival (DFS) when compared with

other therapeutic modalities"Principles and Practice

of Pediatric Oncology, 6th edition

TMO em LLA Pediátrica

PRIMEIRA REMISSÃO

• Falha Indutória

• Lactentes

• Ph+

• Hipodiploides

• ETP

• DRM Positiva final indução

RECAÍDAS

• Muito Precoces

• Precoces

• Tardias ?

• Mo isoladas

• Mo combinadas

• Extramedulares ?

• LLA – T extramedularisolada?

FALHA INDUTORIA GRUPO ALTÍSSIMO RISCO

98%

2%

95 %

< 5%

1a Remissão: de quem estamos falando?

INDICAÇÕES EM PRIMEIRA REMISSÃO

INDICAÇÃO

Particularidades da doença

Particularidades

do

paciente

Modalidade do TMO

Particularidadesda avaliação da

resposta

• 3a,masc, LI: 3400/mm3

• SNC 1

• IF: LLA pré B


• Protocolo IC BFM 2002 – RS

• D8 : > 1000bl/mm3- AR

• D15 : M0 M3


• D64: MO M1

• CONDUTA: TMO NA? Filho único

1a Remissão: de quem estamos falando?

95%

5%

SUBGRUPO PACIENTES

ALTÍSSIMO RISCO

De quem estamos falando?

Carrol WL, 2005

Blood. 2007;109:926-935

Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the

Pediatric Oncology Group (POG) and Children’s Cancer Group (CCG)Kirk R. Schultz, D. Jeanette Pullen, Harland N. Sather et al

Falha IndutóriaHipodiploidia < 44 crPh+/bcr-abl

Near-haploid and low-hypodiploid acute lymphoblastic leukemia:two distinct subtypes with consistently poor prognosis

• Cariótipo < 40 cromossomos, distribuição bimodal

• Near haploide : 24 – 30 cr ( media 5a)

• Low hipodiploide : 31 – 39 cr ( em crianças necessita de investigação mut p 53 familiar)( media 11, 5 a)

• Alterações nas vias RAS, TK, RB1, IKZF3, IKZF2

• “It is not clear whether hematopoietic stem cell transplantation in CR1 is beneficial in near-haploid and low hypodiploid ALL."

Blood. 2017;129(4)

Transplant Outcomes for Children with Hypodiploid AcuteLymphoblastic Leukemia

Biol Blood Marrow Transplant. 2015 ; 21(7)

Outcome of children with hypodiploid ALL treated with risk-directed therapy based on MRD levels

Blood 2015;126

Estudos Total 15 e Total 16 : 2,2% Hipodiploide

20 pacientes : Todos alcançaram RCCDRM NEG no D29 : 14/20,13 QT INTENSIVA : SLE 85%1 – TMO alo : óbito por toxic

> 0,01% : 6/20 pts ( 1com DRM > 1%)

Coustan-Smith et al, Lancet Oncol 2009

Early T-cell precursor leukaemia: a subtype of very high-riskacute lymphoblastic leukaemia ( 11 -12% população pediátrica)

SG SLE Falha ind ou rec

SJRH

AEIOP

Outcome for children and young people with Early T-cell precursor acute lymphoblastic leukaemia treated on a

contemporary protocol, UKALL 2003

British Journal of Haematology 2014; 166

35 pts = 16% grupo T

Outcome for children and young people with Early T-cell precursor acute lymphoblastic leukaemia treated on a

contemporary protocol, UKALL 2003

British Journal of Haematology 2014; 166

De quem estamos falando ?

98%

2%

Falha Indutória

Outcomes after Induction Failure in Childhood Acute Lymphoblastic Leukemia

Martin Schrappe, M.D., Stephen P. Hunger, M.D., Ching-Hon Pui, M.D.,et al.

N Engl J Med 2012;366

14 cooperative study groups between 1985 and 2000

44.017 pts – 1041 ( 2,4%)

"Pediatric ALL with induction failure is highly heterogeneous."



624 pts


Pacientes LLA pB sem rg MLL < 6 anos


" our analysis showed no benefit of allogeneic transplantation in patients younger than 6 years of age who had precursor B-cell ALL and induction failure and no high-risk cytogenetic features ."


Pacientes LLA pB sem rg MLL > 6 anos



Pacientes com LLA T


Doença Residual Miníma é o mais importantedeterminante prognóstico?

Coustan-Smith. Blood 96 (8): 2691-6, 2000

Estudos Total XIIIA e XIII St. Jude:Impacto da DRM no final indução

Doença Residual Miníma é o mais importante determinante prognóstico?

Clinical Utility of Sequential Minimal Residual Disease Measurements in the Context of Risk-based Therapy in Childhood Acute Lymphoblastic Leukemia:

a Prospective Study St. Jude Total Therapy XV study

GRUPO LOW RISK

DRM D19 < 1% DRM D19 ≥ 1%

Lancet Oncol. 2015 April ; 16(4)

Molecular response to treatment redefines all prognostic factors in childrenand adolescents with B-cell precursor acute lymphoblastic leukemia:

results in 3184 patients of the AIEOP-BFM ALL 2000 study

TP1 <10-4

>10-3 (TP2)

TP1 >10-4 MAS TP2 <10-3

MRD Estratificação Risco • SR = MRD NEG no D33 e 78

( 42%)• RI= >10-4(TP1) <10-3 (TP2) (51,7% )• HR = MRD > 10-³ no D78

( 6%)

SLE

Conter et al. Blood 15(16), 2010

Inc

acu

mre

cid

iva

Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study

Blood. 2011

MRD < 10-4 em TP1 e TP2

MRD > 10-3 em TP2

MRD + em TP1 ou TP2 MASTP2 < 10-3

DRM em TP2 x Recidiva

ESTUDOS NOPHO ALL-92 and ALL-2000

Leukemia (2010) 24, 345–35

Childhood high-risk acute lymphoblastic leukemia in first remission: results after chemotherapy or transplant from the

AIEOP ALL 2000 study Estimates of EFS in 312 children with HR- ALL by HR criteria

(hierarchical order).

BLOOD. 2014 ; 123 ( 10 )Critérios Grupo Alto Risco: DRM ≥ 10 -3 no D78 ( HR MRD), D33 falha indutória, t( 4;11), PRP

Grupo 3 : DRM TP2 ≥ 10 -2, FI D33, t (4;11) e PRP

SG QUIMIO: 54,7% TMO 1 RC : 50,5% SLD QUIMIO: 54,7% TMO 1 RC : 50,5%


AIEOP ALL 2000 study

BLOOD. 2014 ; 123 ( 10 )

Grupo 2: DRM TP2 ≥ 10 3 ou t (4;11) e BRP


AIEOP ALL 2000 study

SLD QUIMIO: 47,2% TMO 1 RC : 51,1% SG QUIMIO: 59,3% TMO 1 RC : 59,3%

TMO nas Recidivas

• 15 - 20% ainda recidivam

• 9 casos/milhão/ano

• Considerada ainda a principal causa de morte

associada ao cancer infantil

• Número significativo ocorre em pacientes que

não são caracterizados inicialmente com

aspectos desfavoráveis.

Recidivas : o que considerar?

• Muito Precoces

• Precoces

• Tardias ?

• Mo isoladas

• Mo combinadas

• Extramedulares ?

• LLA – T extramedular isolada?

Fatores Prognósticos na Recidiva

TEMPO DA 1ª RCC

FENÓTIPO

BLASTO

SÍTIO DA RECAIDA

Estudo RECAÍDA 15 St JUDE

Factors Influencing Survival After Relapse From Acute

Lymphoblastic Leukemia: A Children's Oncology Group Study

RECAIDA ISOLADA MO x TEMPO

Leukemia 2008;14:2142-50

> 36 mSobrevida : 43%

Sobrevida : 18,4 %

< 18 mSobrevida : 11,5 %



RECAIDA MO COMBINADA x TEMPO

> 36 mo

Sobrevida :

60,3%

< 18 mo

Sobrevida: 11,6%

Leukemia 2008;14:2142-50

Sobrevida:

39,8%



RECAIDA ISOLADA SNC x TEMPO

>36 moSobrevida: 78,2%

< 18 moSobrevida: 43,5%

Leukemia 2008;14:2142-50

Sobrevida: 68%

Pathways Through Relapses and Deaths of Children With Acute Lymphoblastic Leukemia: Role of Allogeneic Stem Cell Transplantation in

Nordic Data Pathways Through Relapses and Deaths of Children With Acute Lymphoblastic Leukemia: Role of Allogeneic Stem- Cell Transplantation in

Nordic Data

J Clin Oncol 2006 ; 24

SLE x Tempo /Sítio recaída

Pathways Through Relapses and Deaths of Children With Acute Lymphoblastic Leukemia: Role of Allogeneic Stem Cell Transplantation

in Nordic Data Pathways Through Relapses and Deaths of Children With Acute Lymphoblastic Leukemia: Role of Allogeneic Stem- Cell Transplantation

in Nordic Data

J Clin Oncol 2006 ; 24

SLE x Risco Inicial

Outcome After Relapse Among Children With Standard-Risk Acute Lymphoblastic Leukemia: Children’s Oncology

Group Study CCG-1952

J Clin Oncol 2007;25:5800-5807

Recaida Medular Isolada

Transplant Outcomes for Children with T-Cell Acute Lymphoblastic Leukemia in Second Remission: A Report of the CIBMTR

Biol Blood Marrow Transplant. 2015 December ; 21(12):

Rec Extra Mo 15% x 45% Rec Mo SLD Extra Mo 56 % x 35 % Rec Mo

Numero de Pacientes: 229Número de Centros: 99Idade: mediana 10 a ( 2 – 18)

Results of Trial ALL-REZ BFM 90

A: Rec MO Precoce ( isolada/comb.)

B:Rec. MO Tardia

C:Rec. Extra Mo Isolada

PPG: Rec MO muito precoce ou T .

Muito Precoce: Dentro de 18 meses após Dx

Precoce: Após 18 meses do Dx e menos 6 meses após término Tto.

Tardia: Após 6 meses término Tto.

J Clin Oncol 2010 28:2339-2347.

Excellent prognosis of late relapses of ETV6/RUNX1-positive

childhood acute lymphoblastic leukemia: lessons from the

FRALLE 93 Protocol

43/713 ETV6/RUNX1 –

recidivaram ( 19,4%)

Haematologica 2012

Excellent prognosis of late relapses of ETV6/RUNX1-positive

childhood acute lymphoblastic leukemia: lessons from the

FRALLE 93 Protocol

Recidivas tardias:

frequentes

Haematologica 2012

Prognostic Value of Minimal Residual Disease Quantification Before Allogeneic Stem-Cell Transplantation in Relapsed Childhood Acute

Lymphoblastic Leukemia: The ALL-REZ BFM Study Group

Clin Oncol 2008 ; 27:377-384

Pacientes em Primeira ou Segunda Recidiva



• Nas Recidivas Risco Intermediário: Recidivas Mo de pB combinadas precoces ou > 6 m FT; • Mo tardia de pB• Extra Mo isoladas muito precoces ( pB ou T)



Clin Oncol 2008 ; 27:377-384

Grupo Alto risco/ 3 RCC

Use of Allogeneic Hematopoietic Stem-Cell Transplantation Based on Minimal Residual Disease Response Improves Outcomes for Children With Relapsed

Acute Lymphoblastic Leukemia in the Intermediate-Risk Group

Clin Oncol 2013; 31

DRM < 10 -3

DRM > 10-3

Outcome of pediatric acute lymphoblastic leukemia with very laterelapse: a retrospective analysis by the Tokyo Children’s Cancer

Study Group (TCCSG)

Int J Hematol (2015) 101:52–57

Outcome of pediatric acute lymphoblastic leukemia with very laterelapse: a retrospective analysis by the Tokyo Children’s Cancer

Study Group (TCCSG)

“our results demonstrated that the risk ofsecond relapse in very late relapsed ALL was lower than that of late relapsed ALL, and suggested that these patients should be treated without allogeneic HSCT even when first relapse occurs in the bone marrow."

Int J Hematol (2015) 101:52–57

Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia

J Clin Oncol 2016; 34

Dose I ciclo : 5/15 μ/m2 ( 70 pts)Idade: mediana 8a ( <1 – 17)

RCC após 2 ciclos: 39% pts

Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia

J Clin Oncol 2016; 34

CASO 1

• LI: 3400/mm3, 4 anos

• SNC 1

• IF: LLA pré B


• Protocolo BFM IC 2002 – RS

• D8 : > 1000bl/mm3- AR

• D15 : M0 M3


• D64: MO M1

• CONDUTA: Completou tratamento, FT em 1RCC – 8 anos

• LI : 7500/mm3, 6a 5m• SNC 1• IF: LLA comum• Cariótipo: 46 , XY• BM : bcr-abl p 190 : neg

ETV6 – RUN X1 : negProtocolo IC BFM 2002 - RID8: < 1000 bl/mm3D15 : MO – M1D 33 : MO – M1Recidiva Mo Isolada: 7 meses pós FT6 irmãos não compatíveis –

Refratariedade

OBRIGADA [email protected]

Documents

TMO em Crianças Avanços no Transplante da Leucemia ... Encontro SBTMO - 201… · Biology and clinical application of CAR T cells for B cell malignancies Int J Hematol (2016) 104:6–17