Terapia della LAL dell adulto guidata dalla valutazione molecolare della malattia minima residua

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1 Terapia della LAL dell adulto guidata dalla valutazione molecolare della malattia minima residua SIES Verona, R Bassan Nthern Italy Leukemia Group (NILG) Kaplan-Meier survival estimates, by etablasti standard risk (>0% curable) high risk (30%) very high risk (<0%) P=0.000 commonly used risk facts (age,, WB, time to R, PDN response, immunophenotype, cytogenetics) age <3 and blasts < (N 7) 0.7 age >3 blasts > (N 3) 0.9 age >3 and blasts > (N 93) years Survival of 710 remission s out of 83 total s with B-/T-precurs ALL (median age 3 years, range 1-7), registered since 1979 into NILG (Nthern Italy Leukemia Group) database risk facts (f relapse) Risk stratification criteria in recent European trials URRENT RISK MODELS Risk lass therapy GIMEMA (09/0) GMALL* (07/03) GRAALL (0) NILG* (09/00, 10/07) PALG (/07)* PETHEMA* (AR-03) DO NOT SUPPORT OPTIMAL RISK-ORIENTED THERAPY MINIMAL RESIDUAL DISEASE (one gets all) SR (0-6%) HT HR (3-70%) ST Non-HR/VHR -negative WB >30 (B-Lin) NS+ D10- togenetics PPR Late R -positive Non-VHR -negative Non-VHR -positive WB <0 PGR No late R Ph(t(;11)/t(1;19)- -negative WB >0 PPR Late R t(;11)/t(1;19)+ -positive WB <30 (B-Lin) EGIL BII-III, T-III No late R Ph/t(;11)- -negative WB >30 (B-Lin) Late R EGIL B-I, T-I-II- IVt(;11)+ SR -positive Age <3 WB <30 EGIL BII-III, T-III No late R Ph/t(;11)- -negative Age >3 WB >30 EGIL BI, T-I-II-IV No late R t(;11)+ SR -positive Non-HR -negative Age >30 WB > Late R t(;11) -positive IMPROVED PROGNOSTI LASSIFIATION FOR BETTER TREATMENT DESIGN VHR (0-0%) Ph+ Ph+ Ph+ Adv. cytogenetics EGIL TI-II-IV WB >100 Ph+ Ph+ * ientates postremission therapy 1

2 1-3 1 persistence relapse 3 clearing -based clinical trial (PROSPETIVE) Overt ALL risk of relapse Individual approach to risk-adapted therapy HT f neg ST f pos, taking the risk of TRM about 0% 10-1 R (RQ-PR) concept of molecular R (Rm) concept of molecular relapse comparison of therapeutic elements molr 10-3 cure possible IND ONSOLIDATION MAINTENANE time -based risk stratification in adult ALL risk model probe(s) Patients Time-points ut-point onsequence GMALL SR Ind/cons, 10 - Stop Rx in - (Blood 006) d1-1 mos. ( probes) ST in + started 1999 NILG SR, HR Ind/cons, <10 -/- Maint in - (Blood 009) 10- wks. (1 probe) ST in + started 000 Phase A V,A,P (Y), x R N S W1 W W10 W16 W w10 f retrospective crelations * *blood stem cells and HD- MTX/ HD- MTX/ V,P NEG Phase B (Risk-iented) NEG=SR POS=HR w 16- f prospective risk model POS VHR Ph/t(;11)+ allogeneic ST Ph+: imatinib jan 03

3 risk model probe(s) Phase A V,A,P (Y), x R 3 N S Risk-specific therapy - -1 * -3 Phase A V,P (Risk-iented) *blood stem cells W1 w 16- f prospective risk model - / SR W16 1st yr nd yr = daily 6-MP, weekly MTX = triple IT W + / HR 10- w10 f retrospective crelations Maintenance NEG=SR POS=HR W10 W moniting moniting:: 6, 1, mos mos.. Phase B Phase B 10- NEG retrospective analysis on w10 ST (HLA id. sibling sibling/mud) /MUD) 10- POS 10- (1, 3: 3: Mel Mel,, 6MP, 6MP, VP16; VP16 ;, : : HD-MTX HD- MTX;; HD-Ara-) HD-Ara-) Hypercycles MEL, 6MP, VP16 MEL, 6MP, VP16 = autologous blood D3+ cells (1-x106/kg, purged purged), ), Rituximab if D0+ plus Maintenance VHR Ph/t(;11)+ allogeneic ST Ph+: imatinib jan 03 Identification and production of case-specific probes 7 (6.%) (7.9%) HR-B HR-T (19.3%) 37 (13.%) -Omo-heteroduplex clonality test VHR Ph+ t(;11)+ 68 (.3%) 0 (7.1%) 3-Sequence Undefined (T) (B) WB <30, EGIL BII-III (T) WB <100, EGIL T-III nonadverse cytogenetics, R cycle 1 *HR non-sr, adverse cytogenetics: -7, +8, del6q, low hypo, near tr, t(8;1), complex X Five s block weeks X (1.8%) *SR PR... weeks 1-Rearrangement PR Panel (16-1) Risk stratification* SR-B SR-T PR H0 PR 3 H0 PR 38 (16-66) 16 (8.%) PR 1 Age M H0 total pts. on NILG Trial 09/00 study rept, Blood 009 (mimimum FUP 1 yr) H0 N = 370 N = 80 weeks -Patient-specific primer design -Primer sensitivity test at different temperatures Dx weeks 3

4 MOLEULAR PROBES AT DIAGNOSIS Study flow Excluded 7 (9.7%) ED 8 insufficient 19 Probe search 3 (90.3%) 1 found 138 (.%) found 8 (33.%) no probe 30 (1%) Probe sensitivity >10-9. % Probe type IgH 18.% Ig-kappa.% TRD 18.% TRB 7.8% TRG.% BR-ABL 19.8% MLL-AF 6.% EA-PBX1 1.6% SIL-TAL1 0.3% 88% pre Day Week ST toxicity relapse completed: Phase A: (n=3) (n=16) (n=) n=1/36 (60.%) Phase B: Study n=11/1 (78.8%) no probe no sampling neg (n = 3) (n = 7) (n = 8) u/k SR (n = 10) 1 3 HD 6 HD7 8 H Diagnosis R (n = 36) 1 8 TP TP TP maintenance (non-vhr) allogeneic pos ST (n = ) u/k (no don) HR/VHR (n = 0) H/ H/ H/ % 66.7% H/ R R R R maintenance P= Details-I DFS by Details-II (ST/H-auto) 8 (-) NR/0.7 failed 1 (.1%) 30 (u/k) 1.77 y/0.37 failed 17 (6.6%) (+) 1.16 y/0.1 failed 37 (68.%) analysis time mos. BM relapse in pts. with >1 sensitive probe(s) (>10 - ) Kaplan-Meier survival estimate - N = 0.78 no remission death

5 Effects of clinical risk class and no. of molecular markers B Kaplan-Meier survival estimates, by internaz DFS VHR (n = ) HR (n = 18) SR (n = 3) Kaplan-Meier survival estimates, by n_sonde DFS markers (n = 8) 1 marker (n = 30) ST and H/-auto in + s (DFS) Kaplan-Meier survival estimates, by allo_iper A (ST H/-auto better) Kaplan-Meier survival estimates, by allo_iper H/ (n = 1) ST (n = ) ST H/ (n = 36) rest (n = 18) P =.0000 umulative Survival Kaplan-Meier survival estimates, by fupmrd_allo_iper ( conversion) neg (n = 16) pos (n = 8) P =.06 B (both effective) umulative incidence + ST H/ conversion and relapse following ST. H/-auto + (N = 8) 3 (37.%) ST H/ H/ - (N = 16) 3 (18.7%) P= umulative survival NONRELAPSE MORTALITY (Phase B, relapsed. pts. excluded) ST (N = 1) 11 (6.8%) H/-auto (N = 19), (1%) HT (N = ), (0%) months months

6 w10 response relation between TP1 and risk model TP1 TP-3 model -NEG -POS No. ative Low pos (<10-) Positive (87.%) 7 (3.8%) 3 (7.7%) 6 (1.8%) 9 (6.%) 36 (9.3%) -1 probe(s) P.001 Phase A V,A,P (), IT N S * W10 W TP1 n eg (n = 36) TP1 p os, WB 30 (n = 7) V,P W16 NEW STUDY V,A,D x,, IT R, A, 6MP, HDltMTX A W comparison of therapeutic elements (increased neg rate) early ST if w10 >10- TP1 p os 10- (n = ) P =.0000 (B-precurs) 0.0 umulative Survival TP1 p os < 10- (n = 0) R Kaplan-Meier survival estimates, by mrdtp1b_wbc TP1 n eg (n = ) 0.00 umulative Survival DFS 3 *blood stem cells W1 Kaplan-Meier survival estimates, by tpuno_3gruppi TP1 p os, WB > 30 (n = 1) P = onclusions pediatrictype 8 Bergamo T Intermesoli E Oldani F Delaini O Spinelli M Tosi B Peruta S Salmoiraghi A Rambaldi Brescia G Rossi E Blenghi lineagetargeted HD MTX + HD Ara- Bolzano P Fabris I avattoni V assibba S telazzo Vicenza E Di Bona Venezia T hisesi P Polistena A Scattolin Noale A Pcellini Monza Minotto E Pogliani E Terruzzi Gambacti Gambacti-- Passerini Varese L ampiotti L Appio uneo A Gallamini D Mattei Firenze A Bosi F Mannelli G Gianfaldoni Milano OM G Lambertenghi Lambertenghi-- Deliliers agliari A telezzi E Angelucci A Gardellini Romani Milano HSR F iceri M Tassara M Bernardi remona S Mandi M Tajana Palermo M Musso A rescimanno Alessandria A Levis F Salvi Tino U Vitolo E Audisio F Marmont SM Imbaro ( risud risud)) R Marchioli A Masciulli Nthern Italy Leukemia Group ladies: Silvia, Vittia, Barbara, Orietta, Manuela 6