Acute Lymphoblastic Leukemia in Childhood

Transcription

1 Acute Lymphoblastic Leukemia in Childhood Marie-Françoise Dresse Hemato-oncology Paediatric Unit Citadelle Hospital University of Liege -ULg EORTC Children Leukemia Group 1

2 Introduction Acute lymphoblastic leukemia is characterised by the clonal expansion of immature lymphoid progenitors cells Heterogeneous disease with respect to clinical features, genetics and response to therapy -Major prognostic factors : age and white cell count, and response to therapy -Outcome for children is better than for adults -Specific genetic abnormalities are important prognostic Pic incidence is among children aged 3-5 years (7 fold more prevalent) Therefore most genetic studies are focussed on children 2

3 Childhood Leukemia ibiincidence of Leukemia in childhood 30 million/children/year Annually in Belgium :

4 EORTC-CLG Gent Lille Antwerp Brussels Leuven Liège Montegnée Reims Caen Paris R Debré Strasbourg Poitiers Besançon Porto Lyon Grenoble Toulouse Montpellier Nice 4

5 Belgian Cancer Registry 2013 Leukemia in children and Adolescents Period leukemiain Belgium 500 in children ( 0-14 years) 125 in teenagers ( years) 5

6 LLA and LMA in children Age specific incidence rates 6

7 Leukemia Survival in Belgium Period LLA OS at 5 years 86% (n= 500) Children ( 1-14 years) : 90 % Teenagers ( years ) 68 % Infants ( < 1 year ): 60 % LMA OS at 5 years 60 % (n=99) 7

8 Model for Leukemogenesisin Children Environmental factors Genetic factors 8

9 Environmental Risk Factors in Childhood Leukemia Ionisant Radiation : established role Electromagnetic fields low frequency : possible Pesticides : possible Benzene : probable Formaldehyde : possible PCB :probable Paternal tabagism: probable Maternal Tabagism: possible 9

10 M.Greaves(UK) propose the following hypothesis An inadequate priming of the immune system Children who face a narrower range of antigens in young childhood and thus remain immunologically more naive for a longer period of time, may be more susceptible to leukemogenesisin their maturing B-cell compartment Malignant progression of a preleukemiaclone to occur as part of an abnormal immune response to common infectious agent during delayed exposure 10

11 A meta-analysis of the association between day-care attendance and childhood acute lymphoblastic leukemia The most conclusive epidemiological studies have been based on the day-care attendance in early life as a parameter for early and broad exposure to common infections The vast majority of these studies have found a protective role for early institutional day care Urayama K Y et al. Int. J. Epidemiol. 2010;39:

12 LeukemiaRisk Factors First Hits-The germ lines Increased occurrence is associated with some genetic conditions Down Syndrome 20 fold-increased risk Bloom syndrome Fanconi Anaemia Ataxia-Telangiectasia all DNA repair disorders ( up to 100-fold increased risk) 12

13 Acute lymphoblastic Leukemiain children Most common cancer in children Successful treatment of ALL with an overall survival rate of 85% - Optimal use of existing antileukemia agents - Improved supportive care -More precise stratification risk to modulate the intensity of therapy on the risk of treatment failure 13

14 ALL in children Improvement in DFS in consecutive studies Pui et al, NEJM

15 EFS LLA CHILDREN EORTC Overall Logrank test: p= : EFS B-lineage ALL pts 8 Nov :17 0 (years) O N Number of patients at risk : Rand Trt S PRED DEXA 15

16 EFS by gender EORTC : EFS 12 Nov : Overall Logrank test: p= (years) O N Number of patients at risk : sex male female 16

17 Pediatric Leukemia Principles of Therapy Intensification of systemic therapy CNS treatment Risk stratification Supportive care 17

18 ALL in children Intensification Chemotherapy Pre-phase : sensitivity to steroids? Induction : sensitivity to chemotherapy? Consolidation CNS prophylaxis (IT chemo) Re-induction Maintenance 18

19 LLA Children Treatment BFM Backbone ( low and average Risk) I C CNS RI Maintenance VCR PDN/DEX DNR/ADR CY ASP Idem + MTX Ara-C MTX (IV) et (IT) 6-MP VCR PDN/DEX DNR/ADR CY ASP 6-MP + MTX Reinduction ( VCR + Dexa 2 years 19

20 CNS disease In the 60 s not recognized as a major point in the treatment % relapse in CNS after hematological remission was obtained First breakthrough ( St. Jude Hospital- Memphis) in CNS Disease : «Preventive» radiotherapy 20

21 Treatment of childhood ALL THE CNS Sanctuary CNS treatment for all patients 21

22 CNS disease Late effects of this CNS radiotherapy however were detrimental in young children Neurocognitive dysfunctions Endocrine problems ( growth, obesity) Secondary malignancies ( up to 40% after 40 years) Chemotherapy pro treatment Better classification of CNS disease 22

23 Risk groups EORTC Very low risk Average risk low B lineage Average risk high B lineage Average risk high T lineage Very high risk Diagnostic biological criteria Response criteria 23

24 EFS by Risk group EORTC : EFS 12 Nov : Overall Wald test: p< (df=3) 10 0 (years) O N Number of patients at risk : Risk Group (d VLR AR AR VHRInitial 24

25 OS by Risk group EORTC : OS 8 Nov : Overall Wald test: p< (df=3) 0 (years) O N Number of patients at risk : Risk Group (d VLR AR AR VHRInitial 25

26 Risk Group EORTC CLG anno 2013 Very Low Risk VLR B-cell lineage ALL 13% With a leucocyte count < /L AND age > 1 year * and <10 year AND absence of CNS/gonadal involvement AND absence of VHR features** AND DI > 1.16 and < 1.50, and chrom. number Or DI > 1.16 and <1.50, and chrom. number is unknown Or chrom. number 54-66; and DI is not assessed *<1 year old : Interfant Protocol-Intercontinental study * *Including Response criteria 26

27 EFS from evaluation of response by WBC ( 10 9/l ) 58951: EFS 12 Nov : Overall Wald test: p< (df=3) 0 (years) O N Number of patients at risk : WBC (x109/l) < < < >=100 27

28 58951: EFS 12 Nov : AGE Overall Logrank test: p= (years) O N Number of patients at risk : Age (yrs) < <1 or >=10 28

29 Outcome according to ploidy modal number cut-off 54 and : EFS Succesful karyotype 99% 2 May : % 80% Overall Wald test: p= (df=2) (years) O N Number of patients at risk : Modal nb chromosomes: 87 patients (19.5%) chromosomes: 258 patients (58%) >=58 58 chromosomes: 101 patients (23%) 29

30 Outcome according to ploidy ploidy by DI cut-off 1.16 and 1.24 Overall Wald test: p= (df=2) 58951: EFS Succesful karyotype 4 May :40 95% 90% 83% cut-off DI modal number chromosomes chromosomes 0 (years) O N Number of patients at risk : dnai3c < < >=

31 Risk Group EORTC CLG anno 2013 VHR group : B or T lineage ALL 16%16 with t(9;22) or bcr/abl* OR t(4;11)/mll AF4 OR 11q23/MLL rearrangement (t9;11),t(10/11),t(6/11),t(11;19) OR near haploidy( <34 chrom. or DI <0.67) OR hypodiploid(35-43 chrom. or DI >0.67 and <0.94)(or near triploidy) OR iamp21 OR AR 2 with CNS involvement *specific recommendations 31

32 Risk Group EORTC CLG anno 2013 VHR group : Réponse criteria 16%16 OR Poor response to the prephase OR failure to achieve CR OR MDR according to EORTC CLG denominators ( >10-2 ) at evaluation of IA OR MDR > 10 3 at the end of IB Down s syndrome with VHR are allocated to the AR1 group 32

33 58951: EFS 12 Nov : Response to prephase Overall Logrank test: p< (years) O N Number of patients at risk : response to pr < >=

34 Overall Wald test: p< (df=4) 58951: DFS from CR Succesful MRD evaluation (years) O N Number of patients at risk : vhr55c No VHR Nov :11 PoorResp OtherInitial NoCRIa MRDd35+ 34

35 Risk Group EORTC CLG anno 2013 Average Risk Low-AR1 57% Good response to prephase and who are neither VLR nor VHR B-cell -lineage ALL With WBC< ç /L And no CNS involvement And no gonadal involvement 35

36 Risk Group Average Risk High -AR2 - B B-cell lineage ALL with WBC > /L or CNS involvement or gonadal involvement and absence of VHR features Average Risk High -AR2 - T T-cell lineage ALL whatever WBC or with CNS or gonadal involvement and absence of VHR features 6% 8% 36

37 EFS by B ALL EORTC Overall Logrank test: p= : EFS B-lineage ALL pts 8 Nov :17 0 (years) O N Number of patients at risk : Rand Trt S PRED DEXA 37

38 EFS by T ALL EORTC Overall Logrank test: p= : EFS T-lineage ALL 8 Nov :24 0 (years) O N Number of patients at risk : Rand Trt S PRED DEXA 38

39 INDICATIONS Allo BMT in ALL -Non CR after IA -VHR patients with Poor PrephaseResponse (PPR) and MRD 10-2 after IA -MRD 10-2 after IB/IB Augmented -Hypodiploidy<44 chromosomes -Duplication of an hypodiploidclone (pseudo-tripoidy) -MLL rearranged and Poor PrephaseResponse (PPR) -MLL rearranged and NCI HR criteria 39

40 Genetic abnormalities ALL Childhood 75 to 80 % Primary genetic abnormalities identified by Standard chromosomal and molecular genetic analysis Virtually all cases with the addition of genome-wide analyses 40

41 Frequency of specific genotypes in pediatric ALL 41

42 Cytogenetic subgroup BCP-ALL Good-risk cytogenetic abnormalities High hyperdiploid( chromosomes) t(12;21)(p13;q22)/etv6-runx1 Seen almost exclusively in young children Excellent outcome with good-risk clinical feature VLR Group ( EORTC) Therapy reduction 42

43 Cytogenetic subgroup BCP-ALL Poor-risk cytogenetic abnormalities t(9;22)(q34;q11)/bcr/abl1 Rearrangements of the MLL gene at 11q23 Hypodiploidy <44 chromosomes Including Near haploidy <30 chromosomes Low hypodiploidy(30-39) chromosomes iamp21 43

44 BCR-ABL1 in childhood ALL BCR-ABL 1 positive patients are treated with TKI s in addition to convential chemotherapy to avoid BM transplantation Outcome better higher 44

45 Cytogenetic subgroup BCP-ALL iamp21 Intriguing chromosomal aberration with gross instability of chromosome 21 Distinct cytogenetic subgroup of older children Mean age, 9 years Dismal outcome, with a high risk of both early and late relapse, when treated as Standard risk ( EFS 29%) Outcome is dramatically improved when treated on High risk regimens ( EFS 78%) 45

46 Cytogenetic subgroup BCP- ALL Association of chromosal abnormalities with age Infant (<1 year) MLL rearrangement ( t(4;11)(q21;q23) and other MLL rearrangements Young child ETV6-RUNX1 and high hyperdiploidy Exceptional in adult Age increased Incidence BCR-ABL1 increased 46

47 Cytogenetic subgroup BCP-ALL Additional genetic aberrations by Genomic studies BCR-ABL1-like ALL Specific genetic Subtype : 15 % BCP-ALL Novel high-risk subtype Exhibit a gene expression profile similar to that BCR- ABL1-positive ALL with an IKZF1 alteration 10 % of ALL children ( 25 % adult ALL) High risk of relapse independent of age, WBC, cytogenetic and MDR after remission induction Potential target therapy (Tyrosine kinase Inhibitors, TKI ) 47

48 What is on the horizon? Pediatric Cancer Genome Project Molecular Classification ALL TARGET (Therapeutically Applicable Research to Generate Effective Treatments) 48

49 MLL-rearranged infant ALL Overexpression of wild-type FLT3 FLT3 inhibitors : lestaurtinib Recently incorporated in the treatment of infants (backbone of intensive therapy by the American Children s Oncology Group (COG)) 49

50 MLL-Rearrangement The Histone methyltransferase DOT1L is required for the development and the maintenance of MLL-rearranged leukemia A selective inhibitor of DOT1L target therapy EPZ

51 Selected caracteristics with therapeutic implications Characteristics Associated features Potential therapeutic intervention Infants with rearranged MLL Hyperleukocytosis, CD10 B- cell precursor phenotype, increased CNS leukemia, poor prednisone response t(9;22)/bcr-abl1 Hyperleukocytosis, older age, precursor B-cell phenotype, poor prednisone response, IKZF1 alterations FLT3 inhibitor (eg, lestaurtinib), tyrosine kinase inhibitor (eg, sorafenib), demethylating agents (eg, 5- azacytidine, decitabine), novel nucleoside analogs(eg, clofarabine) Tyrosine kinase inhibitor (imatinib, dasatinib, nilotinib) 51

52 Running academic childhood ALL treatment programs Front line Lowrisk(20%) Average low(48%) Average high(15%) High risk(10%) Mature-B-All(3%) Infant ALL (4%) Phi+ ALL (3%) Relapse Early relapse Late relapse Extra-medullary Future Tel/AML Down ALL 52

53 Summary and Conclusions LLA in children High cure rates and large population of leukemia survivors Children ALL is a genetically heterogeneous Current spectrum of genetic abnormalities in children ALL has yielded a plethora of potential therapeutic targets Promise of personalized treatment with target agent, resulting in more effective and less toxic treatment Future novel therapies should focussed on targeting disrupted genetic pathways 53

54 References Vilmer E, Suciu S, Ferster A, Bertrand Y, Cavé H, Thyss A et al. Long Term Results of three Randomized Trials ( 58831,58832,58881) in childhood Acute Lymphoblastic Leukemia : a CLCG-EORTC Report. Leukemia 2000; 14, Ching-Hon Pui, Mary V. Relling and James R. Downing: Mechanisms of disease- Acute Lymphoblastic Leukemia-Review Article. N Engl J Med 2004;350: Pui CH and Evans WE Treatment of acute lymphoblastic leukemia. Review Article. N Engl J Med 2006; 354: Stanulla M, Schrappe M. Treatment of childhood acute lymphoblastic leukemia. Seminar Hematol 2009;46 (1):52-63 Pui Ch, Mullighan CG,Evans WE, Relling Mv. Pediatric acute lymphoblastic leukemia : where are we going and how do we get there? Blood 2012; Aug 9: 120(6) :