Adult ALL: NILG experience

Transcription

1 Adult ALL: NILG experience R Bassan USC Ematologia, Ospedali Riuniti, Bergamo SIE Interregionale, Padova

2 Now and then

3 Northern Italy Leukemia Group Prospective clinical trials 09/00 10/07 Northern NHL 2002 B (EWALL) EWALL DepoCyte EWALL Ph1 Blinotumomab (EWALL) CLO-CY (GIMEMA) 10/07 ext. GIMEMA 10/07 ext. GIMEMA T-ALL/LL Italy Leukemia Group GIMEMA

4 Towards 50% survival at 5 years PROGNOSIS AND TREATMENT - risk subsets and MRD - risk-adapted SCT - post-sct therapy - targeted therapy and new drugs - better use of old drugs PEDIATRIC-TYPE APPROACH NICHE PROBLEMS - CNS relapse - molecular relapse - treatment-related mortality (TRM)

5 Enrollment to NILG protocols for acute lymphoid malignancies 106 B-ALL Burkitt N= Precursor B/T ALL GMALL NHL-2002 MRD / Risk-Oriented Programs N9 (2000-7) N10 (2008-) Ph+ 100 (pilot) Ph- 304 LBL 30

6 Burkitt leukemia/lymphoma Treatment Schema (GMALL B-2002, EWALL) Age <55 Age >55 no cycle C (HD-AraC), MTX g/m 2

7 Patients N. 106 HIV+ 16 (15%) Age, median[range] > 55 years 47 [17-78] 33 (31%) PS (ECOG): 0-2 / > 2 / Unk. 88 / 15 / 3 B-ALL 50 (47%) Burkitt lymphoma stage III/IV 30 (28%) Extranodal involvement 36 (64%)

8 Ph+ ALL Moderate-intensity chemo plus imatinib to optimize induction results Standard chemo CR 33/41 (80%) Standard chemo/im CR 16/20 (80%) De-intensified chemo/im CR 55/55 (100%) without L-ASP single IDR dose Pre-phase PDN dd -5 to -1 CY dd -3 to -1 Ph/BCR-ABL C1 IM dd 1-28 VCR dd 1,8,15,22 IDR d 1 DEX dd 1-5, 15-9

9 Improved survival (imatinib group) Higher CR rate Lower early relapse rate PCR negative (40%) More transplants Kaplan-Meier survival estimates, by stisino_invert P =.009 Overall survival IM + (n 59) IM - (n 35) SCT = 39/54 in CR1 (72%) SCT = 15/28 in CR1 (54%) years

10 An MRD-guided strategy in ALL Improves risk stratification To decide for SCT Abrogates remission mortality (TRM) In MRD-neg receiving chemo Highlights role of SCT In MRD-pos (accepting TRM, 15%-35%)

11 Risk stratification VERY HIGH Ph+ t(4;11)+ HIGH risk B-cell precursor WBC >30, Pro-B phenotype (EGIL B-I) Late CR Adverse cytogenetics [-7, +8, del6q, t(8;14), low hypo/near tripl, complex] T-cell precursor WBC >100 Pro/pre/mature-T phenotype (EGIL T-I/II/IV) Late CR Adverse cytogenetics STANDARD risk None of the above SCT MRD study to decide between chemo and SCT

12 Simplified, two-step prospective MRD analysis for treatment decisions in SR and HR adult ALL (Protocol N-9) pt sib HLA pt 1 (PHASE A) CR donor search Ph/t(4;11)+ to SCT a.s.a.p 2 (PHASE B) MRD neg MRD neg MRD u/k SR maintenance pre Diagnosis Day Week C1 C2 C3 HD4 TP Treatment elements H R PDN-CY MRD 10 H C5 C6 TP HD7 IDR, VCR, ASP, PDN (ind( ind); IDR, VCR, CY, DXM (cons( cons) HD MTX-AraC Cranial RTR registered Blood stem cell harvest / reinfusion TP C8 <10-4 neg > pos MRD MRD pos MRD pos MRD u/k HR =MRD neg =MRD pos maintenance or allogeneic SCT (no donor) H/C 1 H/C 2 H/C 3 H/C 4 R R R R maintenance 6MP-MTX for 2 yy V-P alternating monthly with CY-AraC (1st y) HD 6MP-VP-mel (( autograft) HD MTX-Ara-C ( autograft)

13 MRD study *1-2 sensitive molecular probe(s) at diagnosis (> ) Pts CR, no. (%) Early SCT Relapse Off study Phase A Completed MRD study* (85%) 16 (6.7%) 37 (15.6%) 6 (2.5%) 178 (75.1%) 134 (75.2%) MRD-pos MRD-neg 59 (44%) 75 (56%)

14 Therapeutic use of MRD Chemotherapy MRD-neg SR (n 75) 45 (60%) HR (n 56) 28 (50%) Realization 92% SCT MRD-pos SR (n 75) 30 (40%) HR (n 56) 28 (50%) Realization 71%

15 The facts MRD study applicable to 75% of patients Simplified two-step analysis (w16-22) MRD-guided therapy: Most MRD-neg curable by CHT (survival 74%) No TRM Relapse risk MRD monitoring One half of MRD-pos curable by SCT (survival 49%) TRM Relapse risk MRD monitoring Molecular relapse Detection and therapy

16 Blinotumomab Breakthrough therapy for MRD-pos NILG & GIMEMA centers activated

17 Aims of N-10 (pilot, randomized phase II, N=100) Treatment phase Intervention Objective CR induction (5-drug) Intensive prephase (PDN-CY) Dexamethasone blocks % CR 90+ Postremission therapy Pediatric-type (x3 [modified AIEOP-BFM]) Lineage-targeted MTX (x3): 5 g/m 2 (T) 70 micromol/l 2.5 g/m 2 (B) 35 micromol/l Improved MRD response, w10-22 (MRD and risk-oriented strategy) CNS prophylaxis Random : Triple IT (x12) vs IT DepoCyte* (B: x6; T: x8) Radiation-free *Safety & efficacy

18 NILG 10/07 (Ph-( ALL) IT DepoCyte 50 mg TIT VCR, DX/PDN, ASP, IDR, CY, Ara-C, 6MP Standard dose, pediatric-derived (p/d) Pre-phase (PDN, CY) M/A M/Asp MTX 2.5 g/m 2 (B),5 g/m 2 (T) ARAC 2 g/m 2 x4 MTX 2.5 g/m 2, 5 g/m 2 (T) ASP 10,000/m 2 x2 T T ind p/d M/A* p/d M/Asp p/d M/A re *stem cell apheresis Week Risk stratification MRD TP1 SR*/HR * B: WBC <30, EGIL B-II/III, CR <4 wk T: WBC <100, EGIL T-III, CR <4 wk B: WBC , EGIL B-I, late CR T: late CR VHR # TP2 early allo-sct (RD, URD, cord) TP3 early allo-sct TP2 MRD > TP4 MRD+ allo-sct (or auto [MEL200] + maint.) # t(4;11)/abn q23/+8/- /+8/-7/ 7/low-hypo/near tripl/del6q/t(8;14)/ /del6q/t(8;14)/complex WBC >100, EGIL T-I/II/IV IV MRD- maintenance

19 N-10: interim analysis (EHA 10) CR rate 95% Improved early survival in HR subsets Will develop into a NILG/GIMEMA project

20 Induction of early MRD response (w10) after 8 treatment weeks in T-ALL * * * * CR recovery d 0 pre-phase response (PB) d 28 induction response (BM) MRD TP1 d 70 early consolidation response (BM) MRD TP2 pre-phase & cycle 1 (weeks 1-4) cycle 2 (weeks 5-7) cycle 3 (weeks 8-10) =CY, 300 mg/m 2 /d x3 =PDN, 20 mg/m 2 /bd x5 * =I.T. therapy (Random: TIT vs DepoCyte) =VCR (2 mg weekly x4) * =I.T. therapy =IDR (12 mg/m 2 ) =HD-MTX (5 g/m 2 [24-h inf.], 1.5 g if >55 y) =IDR (12 mg/m 2 /d x2) =CY (1000 mg/m 2 ) =HD-AraC (2 g/m 2 /bd x2) =DEX (5 mg/m 2 /bd x5) =ASP (3000 IU/m 2 /d x6) =AraC (75 mg/m 2 /d x4) modulated =6MP (60 mg/m 2 /d x14) by WBC =DEX (5 mg/m 2 /bd x5)

21 Improved early results in adult T-ALL (updated feb 2011)

22 Higher-dose MTX infusions (5 g/m 2 ) Targeting MTX ~65 micromol/l MTX plasma levels at 8-h and 24-h from 37 blocks administered to 19 patients (micromol/l): 8-h, mean: 78.1 [21.6] median: 75 [44-120] 24-h, mean: 76.9 [22.5] median 84 [ ] Extrahematologic grade III-IV toxicity hepatic 5.4% gastrointestinal 8% metabolic 2.7%

23 Lymphoblastic lymphoma (N = 30) CT-guided early mediastinal irradiation (CT/PET?) RTR not needed in chemo-responsive patients CR with chemo 62% 90% CR with chemo + RTR 28% Mediastinal relapse 7% (nonirradiated) MRD study Reveals disseminated/resistant subclinical disease (SCT) MRD-neg for chemo

24 GIMEMA STUDY PROTOCOL A comprehensive treatment strategy for adult T-lymphoblastic leukemia and lymphoma: use of computed/positron emission tomography and study of minimal residual disease for risk-adapted mediastinal irradiation and stem cell transplantation Northern Italy Leukemia Group

25 Therapy of T-lymphoblastic lymphoma Probe 1: VgIII/Jg (10-5 ) (LN) Probe 2: VgI/Jg (10-5 ) (LN) neg neg neg neg off therapy (2+ yy)

26 Perspectives* Chance of cure 50%-85% Burkitt/B-ALL Ph+ (SCT) Ph- MRD- T-ALL (preliminar) LBL Most critical areas t(4;11) Ph+ (no SCT) Ph- MRD+ The elderly (>60 yy) Concept of molecular remission/relapse *multicenter setting, survival rates at 5 years

27 NILG-ALL - acknowledgements 2011 (in press)