1 La LAL del adulto tiene mal pronóstico PETHEMA LAL infantilPETHEMA LAL Adulto 15% 25%

2 Aclaramiento ER y pronóstico en LAL adulto JM Ribera et al, ASH 2009, oral presentation Bassan R, et al. Blood 2009; 113: 4153-4162

4 AL in AYA. Retrospective comparative studies “Pediatric” vs “adult” treatments Country ProtocolAge NCR(%) 5yr.EFS(%) USA CCG(P) 16-21 197 96 64 CALGB(A)16-21 124 93 38 France FRALLE93(P) 15-20 77 94 67 LALA94 (A)15-20 100 83 41 Holland DCOG (P)15-18 47 98 69 HOVON (A)15-20 44 91 34 UK ALL97 (P)15-17 61 98 66 UKALLXII(A) 67 94 49 Italy AIEOP (P)14-18 150 94 80 GIMEMA (A) 95 89 71(2yr) Sweden NOPHO-92(P)10-18 144 99 66 Adult (A)15-25 99 90 42 Finland NOPHO (P)10-25 128 96 67 ALL (A) 97 97 60 Reviewed in: Ribera JM. Hematol Oncol Clin North Am 2009; 23:1033-42

5 Major differences in pediatric vs. adult protocols Higher dose of essential drugs –Up to 3x vinca alkaloids –Up to 5x prednisolone –Up to 20x asparaginase Less use of myelosuppressive drugs –eg, anthracyclines, cyclophosphamide, cytarabine Less use of BMT –BMT only recommended by pediatricians for very high-risk ALL Less delays between therapy elements –Time to treatment following initial CR was 2 days in pediatric practice vs. 7 days in adult practice (P =.002)

6 Prospective studies on therapy of ALL in AYA Group-ProtocolAge NCR(%) EFS (%) DFCI 91-01,95-0115-18 51 94 78 GRAALL-03*15-45 172 95 58 PETHEMA ALL96**15-18 35 94 60 19-30 46 100 63 DFCI18-50 74 82 72 Toronto-Modified DFCI18-60 85 89 71 FRALLE 93 HR-derived***18-55 40 90 72 (OS) Toronto-Modified DFCI****17-64 32 84 83 (OS) *Increase of 8.6-fold, 3.7-fold and 16-fold in cumulated doses of PDN, VCR and L-ASP compared to ALL-94 protocol. Better results in patients up to 45 yr ** No differences between adolescents and young adults ***Better results in patients up to 40 yr **** Only T-ALL Reviewed in: Ribera JM. Hematol Oncol Clin North Am 2009; 23:1033-42

7 Ribera, JM. et al. J Clin Oncol 2008; 26:1843-1849 PETHEMA ALL-96 Adolescents 15-18 yr. Young adults: 19-30 yr.

8 LAL riesgo estándar. PETHEMA RI-08

9 Huguet, F. et al. J Clin Oncol; 27:911-918 2009 How far can we go with pediatric protocols?

10 LAL riesgo elevado, Ph-negativa Edad >30 a, leucocitos >30x10 9 /L, t(4;11) Respuesta lenta al tratamiento LAL riesgo elevado, Ph-negativa Edad >30 a, leucocitos >30x10 9 /L, t(4;11) Respuesta lenta al tratamiento Quimioterapia Trasplante progenitores hematopoyéticos

11 Study Year n AgeDrugs CR rate GMALL 02/84 1993 56228V,P,A,D,C, AC,M,MP 75% FGTALL 1993 572n.r.V,P,D/R,C, [AM,AC] 76% MRC XA 1997 618>15V,P,A,D82% PETHEMA 1998 10820V,P,D,A,C86% CALGB 1998 19835V,P,D,A,C85% MDACC 2000 20439V,DX,A,D,C91% GMALL 05/93 2001116335V,P,D,A,C,AC,MP83% Lombardia 2001 12135V,P,A,[C]84% Sweden 2002 15342V,BX, HDAC,C,D,AM 86% GIMEMA 2002 79428V,P,A,D,C [HDAC,Mi]82% PETHEMA/ALL-93 2005 22227V,P,D,A,C82% MRC/ECOG 20051521

12 ADULT ALL (n=4687) CHILDREN ALL (n=2126) CR1 (2739)45+/-1 CR2 (1023)26+/-2 ADV (925)11+/-1 Outcome after alloHSCT from for ALL: ALWP registry 1994 - 2008 HLA-identical sibling (N=4687) Matched unrelated donor (N=2332) 41+/-2CR1 (1000) 26+/-2CR2 (784) 9+/-1ADV (548)

13 0 20 40 60 80 100 Probability, % CR1

14 Adjusted Leukemia-Free Survival an relapse in ALL Ringden O, et al. Blood. 2009;113:3110-3118

15 Role of alloHSCT for adult ALL in CR1: comparative prospective studies (donor vs. no donor) : allo > control Study n Population DFS Surv LALA-87 116 vs 141 Adult ALL 45 vs 31% 48 vs 35% in high-risk ALL 39 vs 14% 44 vs. 11% JALSG-93 34 vs 108 Adult ALL NR 46 vs 40% LALA-94 100 vs 159 High-risk ALL 45 vs 23% 51 vs 33% GOELAL02 41 vs 106 High-risk ALL 75 vs 40% 75 vs 33% EORTC 68 vs 116 Adult ALL 38 vs 36% 41 vs 39% PETHEMA 84 vs 98 High-risk ALL 40 vs 49% 37 vs 46% MRC/ECOG 443 vs 558 Adult ALL 50 vs 41% 53 vs 45% in high-risk ALL 38 vs 32% 41 vs. 35%

16 Role of alloHSCT in adult ALL (CR1): better outcome in patients with a matched-related donor (MRC UKALL XII/ECOG E2993) Goldstone et al, 2008

17 Role of alloHSCT for adult ALL in CR1: a meta-analysis of prospective trials Yanada et al, 2006

18 Role of alloHSCT for adult ALL in CR1: high-risk patients Yanada et al, 2006

19 TPH DNE. SCU frente a MO Atsuta et al. Blood 2009

20 Results of non-myeloablative SCT in adult ALL Author YearAgeNOSRELTRM (med)ALLCC R Martino et al2003502731%49%23% Arnold et al2002382218% 36%41% Gutierrez et al20071943CR230%nr21% Hamaki et al2005554340%1y50%30% Mohty et al (EBMT)2008389731%2y51%28% TOTAL23231%49%28%

21 RIC vs. mieloablativo en LAL adulto (pacientes >45 a., registro EBMT) RICMieloabl.P N97601 Edad mediana56500,0001 SP88%58%0,001 EICHa II-IV35%28%NS EICHa III-IV14%10%NS NRM a 2a.22%32%0,04 Prob. Recaída 2a.42%30%0,0007 Prob. SLE 2a*37%38%0,42 *Unico factor pronóstico: estado LAL al TPH Mothy M, 2008

22 TPH LAL adulto. Indicaciones actuales Fase y subtipoAlo DEAlo DNEAuto RC-1 - Adultos jóvenes RE NoNoNo - Riesgo elevado SiSiNo - LAL Ph+ Si*Si*No - LAL-B madura NoNoNo - LAL edad avanzada¿AIR?¿AIR?No RC>1SiSiNo

23 Risk groupPost- remission tx Thymic T-ALL with favorable markers Absence of HOX11L2 (TLX3) expression Low BAALC/ERG expression HOX11 (TLX1) high CT-based Thymic T-ALL with unfavorable markers HOX11L2 (TLX3) expression High BAALC or ERG expression Early T-ALL Mature T – ALL AlloHCT in CR1? Risk-adapted therapy in T-ALL: proposed strategy according to molecularly defined subgroups

24 Will MRD negativity stop more allografts? JM Ribera et al, ASH 2009, oral presentation Bassan R, et al. Blood 2009; 113: 4153-4162

25 LAL Ph+

26 Quimioterapia + Inhibidores de tirosincinasa de ABL + Trasplante alogénico de progenitores hematopoyéticos LAL Ph (BCR-ABL) en pacientes jóvenes

27 Approved substances and pipeline ATP-Binding T315I-Active Nonkinase Inhibition Bcr-AblAbl & Src ImatinibDasatinibMK-045717-AAG NilotinibBosutinibKW-2449HDAC INNO-406XL228DAC AT9283HHT PHA-739358

28

29 Modalidades de combinaciones a b c d Trasplante Quimioterapia Imatinib

30 Aprobación de imatinib para el tratamiento de pacientes adultos con LAL Ph+ adultos con LAL Ph+ de diagnóstico reciente, integrado con quimioterapia integrado con quimioterapia

31 Dasatinib +HyperCVAD EFS, CR duration, DFS, and OS. Ravandi F et al. Blood 2010;116:2070-2077

32

33 LAL Ph+: Imatinib. Estudios aleatorizados LAL Ph+ 15-60a R I-800-VD I-800-HiperCVAD Alo-TPH (o auto TPH si no donante y ERM

34 Ph+ ALL < 55 yr. ALL Ph-08 ALL, < 55yr Pre-phase Ph+ ALL Induction (I-600) Consolidation-1 Donor Allo SCT MRD- MRD+ Imatinib* Follow-up No donor/No allo SCT feasible Auto-SCT Imatinib+MP+MTX (up to 2-yr) *Except T315I mutation

35 Registrados 23, 13 centros Válidos 22, (97%) RC 22, (100%) Consolidación : 21 Faltan datos : 1 LAL-PH-08 Pte. inicio consolidación : 1 Alo TPH: 13 Hermano HLA-id : 3 DNE : 3 TSCU : 7 AutoTPH (No donante HLA-id. o imposibilidad AloTPH) : 0 RCC : 9 En tratamiento : 4 Recaída m.o. : 3 Fin consolidación : 4 Exitus : 1