LLA: Esperienza Pediatrica

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1 Società Italiana di Ematologia Convegno Interregionale SIE Le malattie Linfoproliferative Acute e croniche LLA: Esperienza Pediatrica Dott. Simone Cesaro Oncoematologia Pediatrica Azienda Ospedaliera Universitaria Integrata Verona Padova, 12 maggio 2011 Auditorium San Gaetano Via Altinate, 72

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3 Evoluzione dell AIEOP Anni Anni 90 Creazione della rete dei centri Condivisione protocolli Dimostrazione di capacità di lavoro associativo Creazione del Registro Centralizzazione diagnostica e biol. mol. Sviluppo protocolli europei/internazionali anche materiali biologici Anni 2000 Sviluppo MRD nella stratificazione pazienti Sviluppo studi complessi in accordo (nonostante) la normativa CEE su sperimentazioni cliniche

4 LLA Studi AIEOP Studi AIEOP-FM Total therapy studies Year N patients N induction failures(%) 45 (5.0) 12 (1.9) 19 (4.8) 38 (3.2) 27 (1.6) Induction deaths Resistant a (%) 25 (3) 8 (1) 14 (3.5) 22 (2) 15 (0.8) N relapses (%) 346 (38) 207 (33) 115 (29) 312 (26) N second malignant neoplasm (%) 8 (0.9) 2 (0.3) 2 (0.5) 6 (0.5) N death in remission (%) 30 (3.3) 10 (1.6) 7 (1.8) 23 (1.9) 398 (23) 5 (0.3) 27 (1.6) 10-year cumulative risk of death in remission 3.2% 1.6% 1.3% 1.9% 1.6% 10-year event-free survival 52.8% 63.0% 64.8% 68.4% 71.7% 10-year overall survival 63.8% 74.9% 74.3% 76.9% 82.4% Conter Conter et et al al Leukemia Leukemia

5 ALL-FM backbone: Induction therapy (Protocol I) PRED p.o. 60mg/m 2 /d Protocollo Ia VCR i.v. 1.5mg/m 2 DNR p.i. (1h) 30mg/m 2 L-ASP (E.coli) p.i. (1h) U/m 2 Protocollo Ib CPM p.i. (1h) 1000mg/m 2 ARA-Ci.v. 75mg/m 2 /d 6-MP p.o. (28 d) 60mg/m 2 /d MTX i.th. Day

6 Consolidation M MTX-IT MTX-IT MTX-IT MTX-IT 6-MP MP 25 mg/m 2 /day, per os HD MTX 2000 mg or 5000 mg/m 2, i.v./24 h + Folinic acid at 7.5 mg/m 2 at 42, 48, & 54 hrs after HD MTX

7 Re-induction-Protocol II M L-ASP ADM ADM ADM ADM MTX-IT MTX-IT VCR VCR VCR VCR CPM ARA-C ARA-C DXM 6-TG DXM 10 mg/m 2 L-Asp10,000 U/m 2 CPM 1000mg/m 2 VCR 1.5 mg/m 2 ADM 30mg/m 2 6TG 60 mg/m 2 ARA-C 75mg/m 2

8 Maintenance M MTX-IT MTX 6-MP 30 weeks MP 50 mg/m 2 /day, per os MTX 20 mg/m 2, i.m. or os, weekly IT-MTX every 6 or 8 weeks

9 Quesiti a cui i successivi trial AIEOP hanno cercato di rispondere negli anni 9 E posssibile ridurre la dose-intensity nei pazienti a rischio standard? Quale vantaggio dall uso di HD-dose L-Asp (20 x UI/m2/sett)? Utile l inserimento di pulses con VCR-Dexa nel mantenimento? Utile l intensificazione mediante terapia a blocchi negli alti rischi? Per tutti: Inserimento di un criterio di risposta rapida nella stratificazione dei pazienti: PGR vs PPR al g. + 7

10 A I E O P A L L 9 1 study SR 24.5% PDN Ia M 2 gr II R 1 A 6-MP+MTX 6-MP+MTX+HD-L-Asp w IR PDN Ia + Ib 59.2% M 5 gr 1 13 R 2 A II II+HD-L-Asp x MP+MTX 105 w HR 16.3% SR IR HR PDN Ia MP+MTX Age >1 <15 yrs; R.F. <0.8; PGR; non-t/non-; CR d +42; no t(9;22)/no t(4;11); no CNS disease Age <15 yrs; R.I. >0.8 <1.7; PGR; non-; CR d +42; no t(9;22)/no t(4;11); no CNS disease or R.F. <0.8 and T-immunology or age <1 yr Age < 15; R.F. > 1.7; PPR; non-; t(9;22); t(4;11); no CR at d +42; no CNS disease Gy w M = 6-MP+MTX (2/5 gr/sqm) HD-L-Asp = 25,000 U/sqm IT MTX TIT G-CSF

11 AIEOP ALL 91 study (no. of pts = 1194)

12 A I E O P A L L 9 1 study Standard risk group SR 24.5% PDN Ia M 2 gr II A 6-MP+MTX 6-MP+MTX+HD-L-Asp w IT MTX TIT Stratification criteria: Age >1 <15 yrs; R.F. <0.8; PGR; non-t/non-; CR d +42; no t(9;22)/no t(4;11); no CNS disease 490 patients eligible for random assignment 355 (72.4%) were randomly assigned (178 YES-ASP and 177 NO-ASP)

13 IDH (Italy-Dutch-Hungary) IDH (Italy-Dutch-Hungary) ALL 91 Standard Risk Protocol Analysis by randomized treatment ANALYSIS by randomized treatment (ITT) D F S YES ASP178 pts22 events NO ASP177 pts36 events log-rank test: p-value=0.03 (one-tailed) Years from randomization 87.5(2.5) 78.7(3.4) Pession et al. J Clin Oncol. 2005; 23(28):

14 Conclusioni 1) L omissione del protocollo I si associa ad un aumento di recidive midollari 2) La somministrazione protratta di HD-L-ASP compensa questo svantaggio 3) L HD-L-ASP può avere un ruolo nel migliorare la prognosi per trattamenti con Minore dose-intensity

15 A I E O P A L L 9 1 study Intermediate risk group IR PDN Ia + Ib 59.2% M 5 gr 1 13 R 2 A II II+HD-L-Asp x20 6-MP+MTX IT MTX TIT Stratification criteria: Age <15 yrs; R.I. >0.8 <1.7; PGR; non-; CR d +42; no t(9;22)/no t(4;11); no CNS disease or R.F. <0.8 and T-immunology or age <1 yr 610 pazienti 322 no HD-L-ASP 288 HD-L-ASP

16 AIEOP ALL 91 Intermediate Risk DFS according to treatment arm C. Rizzari et al. JCO 19: , 2001

17 Conclusioni Nessun vantaggio nell uso dell HD-L-ASP (E. Chrysanthemi) nella reinduzione e mantenimento in pazienti trattati secondo uno schema intensivo FM Altri risultati (insoddisfacenti): 1) Gruppo IR con T-LLA, G > , PGR (no RTC): 10y-EFS = 7% 2) Gruppo HR: 10y-EFS = 38%

18 A I E O P A L L 9 5 SR 8% PDN Ia No DNM M 2 gr II 6-MP+MTX w IR 77% PDN Ia + Ib M 2*gr II *5 gr for T-ALL or CNS/testis involvement R A 30 6-MP+MTX 6-MP+MTX+VCR/DXM pulses w HR 15% PDN Ia + Ib II 18Gy Interim II 6-MP+MTX+VCR/PDN pulses 105 w SR IR HR Age >1 <6 yrs; WC<20,000/cmm; DNA Ind >1.16 <1.6; PGR; non-t/non-; CR d +42; no t(9;22); no CNS or testis involvement Patients not eligible for SR or HR groups Age <1 and t(4;11) or CD10 negative; PPR; no CR at d +42; t(9;22) M = RT: 6-MP+MTX (2 gr/sqm) 18 or 24 Gy in <20% pts IT MTX TIT TIT+VCR/DXM pulse G-CSF

19 Event-free survival (EFS), survival and cumulative incidence of isolated or any central nervous system (CNS) relapse in 1743 patients of Study 95

20 Randomized I-FM-SG ALL IR 95 study VCR-DXM pulses (repeated 6 times) Arm A VCR DXM MTX 6-MP R Arm MTX 6-MP days

21 I-FM-SG ALL IR 95 Study: DFS by intention-to-treat I-FM-SG ALL IR Study 2622 patients 508 events by intention to treat 2622 patients events D F S 79.5(1.2) 77.4(1.5) 79.0(1.2) 78.3(1.3) 0.6 YES P 1327 pts 254 events(240 relapses) NO P 1295 pts 254 events(240 relapses) log-rank test: p-value=0.67 median follo-wp: 4.6 years YEARS FROM RANDOMIZATION 6 7

22 AIEOP ALL HR 91 vs PDN Ia Gy 6-MP+MTX PPR t(9;22) age <1 and t(4;11) or CD10 negative; no CR after IA (< 15% of the overall population) 9503 PDN Ia + Ib II 18Gy Interim II 6-MP+MTX+ VCR/DXM pulses

23 AIEOP 95 High Risk 244 patients SURVIVAL EFS 10 yrs Prob. 102 deaths 57.6%(3.2) 118 events 51%(3.2) YEARS FROM DIAGNOSIS CORS - Feb 2006

24 Event-free survival (SE) of children with high-risk ALL who were PPR or PPR-only, treated in the AIEOP-ALL95 and AIEOP-ALL91 studies. PPR-only is the subgroup of PPR patients who achieved CR and were negative for t(9;22) and t(4;11) translocation Aricò M et al. lood 2002;100:

25 LLA 2000 Stratification criteria: - prednisone response day +8 - t(4;11) translocation - t(9;22) translocation - day +33 bone marrow - PCR MRD based study

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27 AIEOP-FM 2000 by first random 3655 patients N. pts N. rel. DXM PDN D. IND D.CCR SMN DXM 35 36(9) 16 PDN 15 29(11) 14 5 yrs Cum. Incidence 10.5%(0.8) 16.4%(1) % M CNS Test Oth DXM PDN p-value< YEARS FROM DIAGNOSIS Apr 2008

28 AIEOP-FM 2000 by first random 3655 patients S 0.6 F E 0.4 DXM PDN 0.2 N. pts N. events yrs EFS 84.5%(0.9) 80.3%(1) p-value= YEARS FROM DIAGNOSIS 4 5 Apr 2008

29 AIEOP-FM 2000 T ALL - PGR - by first random 275 patients N. pts N. rel. DXM PDN D. IND D.CCR SMN DXM 3 1(0) 2 PDN 1 2(1) 3 p-value= yrs Cum. Incidence 6%(2) 17.5%(3.2) % M CNS Test Oth DXM PDN YEARS FROM DIAGNOSIS Apr 2008

30 1.0 AIEOP-FM 2000 T ALL - PGR - by first random 275 patients 0.8 S F E DXM PDN p-value=0.01 N. pts N. events 5 yrs EFS %(2.6) %(3.5) YEARS FROM DIAGNOSIS Apr 2008

31 1.0 AIEOP-FM 2000 T ALL - PGR - by first random 275 patients l a v i v r u S DXM PDN p-value=0.02 N. pts N. deaths 5 yrs Survival %(2.3) %(3.3) YEARS FROM DIAGNOSIS Apr 2008

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33 AIEOP + ALL-FM 2000, EFS (5 years) SR: 2nd Randomization (as treated) Patient enrollment AIEOP: 09/00 07/06 FM: 07/00 06/06 (Status April 07) dsmc0407.tab 26APR07 P , SE= , SE=0.02 Log-Rank p = years Prot. III adm. (N=587, 35 events) Prot. II adm. (N=575, 16 events)

34 dsmc0407.tab 26APR07 P AIEOP + ALL-FM 2000, EFS (5 years) MR: 2nd Randomization (ITT) Log-Rank p = , SE= , SE=0.02 Patient enrollment AIEOP: 09/00 07/06 FM: 07/00 06/06 (Status April 07) years 2x Prot. III (N=1022, 117 events) Prot. II (N=1018, 117 events)

35 dsmc0407.tab 26APR07 P AIEOP + ALL-FM 2000 EFS (5 years) HR (w/o CR/AL pos.) 2nd Randomization (ITT) Log-Rank p =.57 Patient enrollment AIEOP: 09/00 07/06 FM: 07/00 06/06 (Status April 07) years Prot. III 0.68, SE=0.04 (N=267, 69 events) Prot. II AIEOP 0.63, SE=0.05 (N=136, 42 events) Prot. II FM 0.67, SE=0.05 (N=143, 37 events)

36 Trial 2009 of the AIEOP-FM group Italia Austria Germania Svizzera Australia Republica ceca Israele Nuovi criteri di stratificazione Intensificazione del trattamento in LLA MR e HR con Peg-Lasp

37 Prednisone poor-response Non-remission on day 33 CR/AL-positive # MLL/AF4-positive Hypodiploidy PCR-MRD-HR AIEOP-FM ALL 2009 High Risk Criteria PCR-MRD-MR SER (Slow Early Responders) = < 10-3 gg FCM-MRD in M on day 15 >10% # only if not treated in EsPhALL

38 Conclusioni La prognosi delle LLA pediatriche è migliorata in 40 anni diagnostica avanzata (citometria a flusso, biologia molecolare) stratificazione più adeguata maggiore dose-intensity migliore terapia di supporto Gli studi AIEOP rappresentano una modello di strategia vincente nella lotta contro le neoplasie - x Sinergia di gruppo - x Coordinamento delle risorse - x Obiettivi assistenziali associati a ricerca clinica L AIEOP è impegnata ora a mantenere e migliorare gli standard raggiunti a fronte delle difficoltà presenti regolamentazione studi clinici, contrazione di risorse contrazione personale piani di programmazione sanitaria

39 Nessun conflitto di interessi da dichiarare Grazie al Dott. Valentino Conter, ergamo Responsabile Scientifico Protocollo AIEOP LLA 2009

40 1.0 AIEOP-FM 2000 T ALL - PPR - by first random 144 patients 0.8 S F E DXM PDN p-value=0.61 N. pts N. events 5 yrs EFS %(5.8) %(5.8) YEARS FROM DIAGNOSIS Apr 2008

41 Chemo vs. Allo-SCT for children with HR-ALL in CR Comparison by genetic randomization-an international study HR definition: Induction Failure t(9;22) t(4;11) PPR+T/WC>100K alduzzi et al Lancet 2005

42 63% 45% 49% vs. 34% 34% 10% vs 9% Estimates of Disease-Free Survival y treatment assigned Estimates of cumulative incidence of relapse and death, by treatment assigned alduzzi et al Lancet 2005

43 I-FM-SG ALL IR 95 Study I-FM-SG ALL IR 95 Study Randomization by country No. Argentina 197 Austria 112 Chile 249 Czech Republic 86 EORTC 80 Germany 1011 Hungary 120 Italy 767 TOTAL 2622