Pediatric Ph + ALL. Andrea Biondi, MD on behalf of the I-BFM EsPhALL group

Transcription

1 The EsPhALL experience for the treatment t t of Pediatric Ph + ALL Andrea Biondi, MD on behalf of the I-BFM EsPhALL group Clinica Pediatrica, Centro M.Tettamanti and Dipartimento di Scienze della Salute, Università Milano-Bicocca, Italy abiondi.unimib@gmail.com

2 I-BFM EsPhALL study EsPhALL Chair: A.Biondi & M.Schrappe National EsPhALL Groups: AIEOP (M.Aricò); BFM-A (G.Mann); BFM- G (M.Schrappe) ; COALL (G. Escherich); CPH (J.Stary) ; DCOG (R.Pieters); FRALLE (V.Gandemer); HKSG (C.Kong) MRC (V.Saha); NOPHO (A.Castors); M.Campbell (PINDA-Chile). Trial Data Center: M.G.Valsecchi Paola De Lorenzo Giovanna Lucchini Statistician 2

3 I-BFM EsPhALL study design Biondi A. et al Lancet Oncology, 2012

4 Overall outcome ility Probab Median follow up: 37 months (2 79) 0.2 EFS Survival 62 events (45 relapses) 44 deaths Months from start EsPhALL EsPhALL 174 * pts. AIEOP-BFM pts. Ponte di Legno 610 pts. 3-year EFS (SE) 62.4 (4.0) 51.9 (7.0) 40.1 (2.0) 3-year Survival (SE) 75.4 (3.5) 66.6 (5.5) 55.3 (2.0)

5 EsPhALL Historical comparison: SCT N Historical cohort (EsPhALL groups) HSCT in TRM HSCT CR1 in CR1 N EsPhALL HSCT in CR1 TRM HSCT in CR1 overall (61%) 25 (14%) (77%) 12 (9%) Poor Risk (67%) 6 (14%) (84%) 6 (10%) ER by PB 15 7 (47%) 3 (42%) (82%) 4 (13%) ER by BM (73%) 3 (8%) (85%) 2 (9%) Good Risk (58%) 17 (15%) (77%) 5(7%) ER=early response 5

6 Conclusions and Perspectives The addition of IM to intensive BFM-type chemotherapy regimens seems to convey an advantage: 10% (ITT) and 20% ( as treated ) in long-term DFS in GR patients. The PR group treated with IM had improved EFS and OS as compared to historical controls (more than 20%). IM was generally well tolerated on top of intensive BFM-type chemotherapy with a reassuring safety profile. In Dec randomization i was closed due to external evidence (COG results (AALL0031). The ongoing Amendedstudy will allow to test whether continuous exposure to IM (as in COG) will further improve results. 6

7 Outline MRD Timepoints 1a 1 1b (7) (8) SCT Induction I B H R 1' H R 2' H R 3' II cranial RT II IMATINIB 300 mg/m 2 /d G- CSF BM sampling

8 Recruitment observed expected (in 3 years) Ph+ALL 01Jan Dec Diagnosis before amend. approval 35 - BMS CA (AIEOP+MRC) 8 - Eligibility ibilit not evaluable 5 - Not eligible pts. 3 - On study patients t Good Risk 63 (61.8%) 60.8% Poor Risk 39 (38.2%) 39.2% With 135 pts. by the end of 2013: 80% power to detect 14% difference from the baseline 3-year EFS of 60%. 8

9 CR1 achievement Good Risk: by definition, pts. with early response and CR1 Poor Risk: amended d closed EsPhALL N=39 EsPhALL N=70 Early response 0 4 Too early for CR1 3 0 CR1 achievement at end of Induction 35 (97%) 35 (50%) after Protocol IB 1 (3%) 28 (40%) after HR1 Block - 5 (7%) after HR2 Block - 2 (3%) 9

10 Overall outcome (5.5) PROBABIL LITY (6.1) Survival EFS YEARS FROM DX Pts at risk amended EsPhALL closed EsPhALL N. pts. N. events (relapses) 2-year EFS (SE) N. deaths 2-year Survival (SE) (10) 64.8 (6.1) (5.5) (45) 64.8 (3.9) (3.6) 10

11 SCT in CR1 Good Risk Poor Risk Overall Pts. in CR Early failures ^ (deaths CCR) 4(4) 2(2) 6(6) Too early for SCT^ Evaluable for post-cr1 treat. 48 (100%) 30 (100%) 78 (100%) SCT CR1 21 (44%) 19 (63%) 40 (51%) events (deaths CCR) 4(3) 11 (6) 15 (9) Chemotherapy only 27 (56%) 11 (37%) 38 (49%) events (deaths CCR) 2 (0) 2 (0) 4 (0) ^ within median time to SCT CR1 (5 months from CR1) SCT in CR1 in closed EsPhALL: 69/90 (77%) Good Risk, 59/70 (84%) Poor Risk 11

12 COG EsPhALL/BMS CA MRD Timepoints determining SCT allocation SCT G-CSF Induction I B H R 1' H R 2' H R 3' II II Maintenance cranial RT (CNS3 only) W. DASATINIB 60 mg/m 2 /d To SCT if To SCT if End-IB MRD > 0.05%, or End-IB MRD % and end HR3 is positive at any level

13 COG EsPhALL/BMS CA International Collaborative Study (COG/EsPhALL) Co-Chairs Biondi and Hunger Sponsored by Bristol Myers Squibb (BMS) Dasatinib 60 mg/m 2 (starts day 15 Ia)+ EsPhALL chemo backbone Several changes to backbone including cxrt for CNS3 only and split dose Dex (d ) in protocol II Indication for SCT based on MRD response (assessed primarily il by PCR for IgH/TCR) End of IB End of HR3 consolidation block

14 AALL1122/CA : Current Status t (5/16/13) Opened to accrual: February 2012 Goal accrual: 75 treated patients Current status: 55 patients enrolled 3 screen failures 51 pts treated with 47 on treatment (37 US, 8 Italy, 5 UK, 1 Canada) E t ill l t l i f ll 2013 Expect will complete accrual in fall 2013 (4-5 pt entries/month)

15 Successor COG/EsPhALL Ph + ALL Study Working group has been meeting by phone/in-person for past year COG: Stephen Hunger, Mignon Loh, Kirk Schultz, Lewis Silverman, Mini Devidas EsPhALL/I-BFM: Andrea Biondi, Martin Schrappe, Vaskar Saha, Michel Zwan, Maria Grazia Valsecchi

16 Chemotherapy Backbone: Current Proposal All patients enroll at Day 15 of Induction IA (?Day 8 if feasible), begin TKI Patients continue therapy through IB phase as per current EsPhALL backbone Use MRD response end IB to stratify pts as good/poor risk Good risk: (MRD <10-3 ; ~80-85%?) Randomized to current EsPhALL backbone vs. more standard BFM/COG backbone + continued TKI; test for erosion in EFS Compare MRD at start and end protocol II to make sure no early signs of MRD difference between study arms High risk: (MRD 10-3 ; ~15-20%?) Non-randomly assigned to current EsPhALL backbone + continue TKI with SCT following HR3; expect vast majority of pts to be MRD negative by end HR3 based on data from current EsPhALL study

17 Expanded International Collaboration Interest in having more countries enroll on trial 2012 SIOP meeting: drug availability and resources in other countries may limit feasiblity (eg, may not be possible to get trial TKI) Current thought: Main trial with COG, EsPhALL (now including Spain), and likely Japan Hope to develop a parallel trial for other study groups within ALL-IC BFM family and beyond using imatinib ib Same risk stratification? Same chemo backbone randomization or non-random pilot of less intensive arm Objective: Determine feasibility of this approach in expanded international setting; additional data on TKI + less intensive chemo backbone? Role of SCT

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