TMO em Crianças Avanços no Transplante da Leucemia Linfóide Aguda

Transcrição

1 TMO em Crianças Avanços no Transplante da Leucemia Linfóide Aguda Maria Lucia M. Lee

2 Biology and clinical application of CAR T cells for B cell malignancies Citocinas SNC Int J Hematol (2016) 104:6 17

3 Cenário Atual da LLA Pediátrica ÍNDICES DE REMISSÃO: 95 98% SLE : % SG : 85-90% JCO 2015

4 Masculino, 4 anos 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 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 RI D8: < 1000 bl/mm3 D15 : MO M1 D 33 : MO M1 Recidiva Mo Isolada: 7 meses pós FT 6 irmãos não compatíveis

5 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" of Pediatric Oncology, 6th edition Principles and Practice

6 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 extramedular isolada?

7 1a Remissão: de quem estamos falando? FALHA INDUTORIA 2% GRUPO ALTÍSSIMO RISCO < 5% 98% 95 %

8 INDICAÇÕES EM PRIMEIRA REMISSÃO Particularidades da doença Particularidades da avaliação da resposta INDICAÇÃO Particularidades do paciente Modalidade do TMO 3a,masc, 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

9 1a Remissão: de quem estamos falando? SUBGRUPO PACIENTES 5% ALTÍSSIMO RISCO 95%

10 Carrol WL, 2005 De quem estamos falando?

11 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 Indutória Hipodiploidia < 44 cr Ph+/bcr-abl Blood. 2007;109:

12 Near-haploid and low-hypodiploid acute lymphoblastic leukemia: two distinct subtypes with consistently poor prognosis Cariótipo < 40 cromossomos, distribuição bimodal Near haploide : cr ( media 5a) Low hipodiploide : 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)

13 Transplant Outcomes for Children with Hypodiploid Acute Lymphoblastic Leukemia Biol Blood Marrow Transplant ; 21(7)

14 Outcome of children with hypodiploid ALL treated with risk-directed therapy based on MRD levels Estudos Total 15 e Total 16 : 2,2% Hipodiploide 20 pacientes : Todos alcançaram RCC DRM NEG no D29 : 14/20, 13 QT INTENSIVA : SLE 85% 1 TMO alo : óbito por toxic > 0,01% : 6/20 pts ( 1com DRM > 1%) Blood 2015;126

15 Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia ( 11-12% população pediátrica) SJRH SG SLE Falha ind ou rec AEIOP Coustan-Smith et al, Lancet Oncol 2009

16 Outcome for children and young people with Early T-cell precursor acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL pts = 16% grupo T British Journal of Haematology 2014; 166

17 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

18 De quem estamos falando? Falha Indutória 2% 98%

19 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; cooperative study groups between 1985 and pts 1041 ( 2,4%) "Pediatric ALL with induction failure is highly heterogeneous."

20 Outcomes after Induction Failure in Childhood Acute Lymphoblastic Leukemia 624 pts N Engl J Med 2012;366

21 Outcomes after Induction Failure in Childhood Acute Lymphoblastic Leukemia 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." N Engl J Med 2012;366

22 N Engl J Med 2012;366 Outcomes after Induction Failure in Childhood Acute Lymphoblastic Leukemia Pacientes LLA pb sem rg MLL > 6 anos

23 Outcomes after Induction Failure in Childhood Acute Lymphoblastic Leukemia Pacientes com LLA T N Engl J Med 2012;366

24 Doença Residual Miníma é o mais importante determinante prognóstico? Estudos Total XIIIA e XIII St. Jude: Impacto da DRM no final indução Coustan-Smith. Blood 96 (8): , 2000

25 Doença Residual Miníma é o mais importante determinante prognóstico?

26 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 April ; 16(4)

27 Inc acum recidiva SLE Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study 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%) TP1 <10-4 TP1 >10-4 MAS TP2 <10-3 >10-3 (TP2) Conter et al. Blood 15(16), 2010

28 Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study Blood DRM em TP2 x Recidiva MRD < 10-4 em TP1 e TP2 MRD + em TP1 ou TP2 MAS TP2 < 10-3 MRD > 10-3 em TP2

29 ESTUDOS NOPHO ALL-92 and ALL-2000 Leukemia (2010) 24,

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

31 Childhood high-risk acute lymphoblastic leukemia in first remission: results after chemotherapy or transplant from the AIEOP ALL 2000 study Grupo 3 : DRM TP2 10-2, FI D33, t (4;11) e PRP SLD QUIMIO: 54,7% TMO 1 RC : 50,5% SG QUIMIO: 54,7% TMO 1 RC : 50,5% BLOOD ; 123 ( 10 )

32 Childhood high-risk acute lymphoblastic leukemia in first remission: results after chemotherapy or transplant from the AIEOP ALL 2000 study Grupo 2: DRM TP ou t (4;11) e BRP SLD QUIMIO: 47,2% TMO 1 RC : 51,1% SG QUIMIO: 59,3% TMO 1 RC : 59,3%

33 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.

34 Recidivas : o que considerar? Muito Precoces Precoces Tardias? Mo isoladas Mo combinadas Extramedulares? LLA T extramedular isolada?

35 Fatores Prognósticos na Recidiva TEMPO DA 1ª RCC SÍTIO DA RECAIDA FENÓTIPO BLASTO

36 Estudo RECAÍDA 15 St JUDE

37 Factors Influencing Survival After Relapse From Acute Lymphoblastic Leukemia: A Children's Oncology Group Study RECAIDA ISOLADA MO x TEMPO > 36 m Sobrevida : 43% Sobrevida : 18,4 % < 18 m Sobrevida : 11,5 % Leukemia 2008;14:

38 Factors Influencing Survival After Relapse From Acute Lymphoblastic Leukemia: A Children's Oncology Group Study RECAIDA MO COMBINADA x TEMPO > 36 mo Sobrevida : 60,3% Sobrevida: 39,8% < 18 mo Sobrevida: 11,6% Leukemia 2008;14:

39 Factors Influencing Survival After Relapse From Acute Lymphoblastic Leukemia: A Children's Oncology Group Study RECAIDA ISOLADA SNC x TEMPO >36 mo Sobrevida: 78,2% Sobrevida: 68% < 18 mo Sobrevida: 43,5% Leukemia 2008;14:

40 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 SLE x Tempo /Sítio recaída J Clin Oncol 2006 ; 24

41 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 SLE x Risco Inicial J Clin Oncol 2006 ; 24

42 Outcome After Relapse Among Children With Standard- Risk Acute Lymphoblastic Leukemia: Children s Oncology Group Study CCG-1952 Recaida Medular Isolada J Clin Oncol 2007;25:

43 Transplant Outcomes for Children with T-Cell Acute Lymphoblastic Leukemia in Second Remission: A Report of the CIBMTR Numero de Pacientes: 229 Número de Centros: 99 Idade: mediana 10 a ( 2 18) Biol Blood Marrow Transplant December ; 21(12): SLD Extra Mo 56 % x 35 % Rec Mo Rec Extra Mo 15% x 45% Rec Mo

44 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 :

45 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

46 Excellent prognosis of late relapses of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia: lessons from the FRALLE 93 Protocol Recidivas tardias: frequentes Haematologica 2012

47 Prognostic Value of Minimal Residual Disease Quantification Before Allogeneic Stem-Cell Transplantation in Relapsed Childhood Acute Lymphoblastic Leukemia: The ALL-REZ BFM Study Group Pacientes em Primeira ou Segunda Recidiva Clin Oncol 2008 ; 27:

48 Prognostic Value of Minimal Residual Disease Quantification Before Allogeneic Stem-Cell Transplantation in Relapsed Childhood Acute Lymphoblastic Leukemia: The ALL-REZ BFM Study Group 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)

49 Prognostic Value of Minimal Residual Disease Quantification Before Allogeneic Stem-Cell Transplantation in Relapsed Childhood Acute Lymphoblastic Leukemia: The ALL-REZ BFM Study Group Grupo Alto risco/ 3 RCC Clin Oncol 2008 ; 27:

50 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 DRM < 10-3 DRM > 10-3 Clin Oncol 2013; 31

51 Outcome of pediatric acute lymphoblastic leukemia with very late relapse: a retrospective analysis by the Tokyo Children s Cancer Study Group (TCCSG) Int J Hematol (2015) 101:52 57

52 Outcome of pediatric acute lymphoblastic leukemia with very late relapse: a retrospective analysis by the Tokyo Children s Cancer Study Group (TCCSG) our results demonstrated that the risk of second 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

53 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)

54 Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia J Clin Oncol 2016; 34 RCC após 2 ciclos: 39% pts

55 CASO 1 LI: 3400/mm3, 4 anos SNC 1 IF: LLA pré B Cariótipo e BM: não avaliáveis Protocolo BFM IC 2002 RS D8 : > 1000bl/mm3- AR D15 : M0 M3 D33: MO 27% blastos TMO? 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 : neg Protocolo IC BFM RI D8: < 1000 bl/mm3 D15 : MO M1 D 33 : MO M1 Recidiva Mo Isolada: 7 meses pós FT 6 irmãos não compatíveis Refratariedade

56 OBRIGADA!