Corso nazionale SIE di aggiornamento in ematologia clinica. Il trapianto allogenico nella LLC

Transcription

1 Corso nazionale SIE di aggiornamento in ematologia clinica Il trapianto allogenico nella LLC Bolzano, giugno 2009 Francesco Zaja - Clinica Ematologica, Udine

2 Curative strategy for CLL Induction Flu-CYT + Rituximab PCR- PCR+ Consolidation Campath-1H PCR- PCR+ Eradication Transplant M. Keating

3 GITMO Trapianto Allogenico Numero Trapianti per principali Patologie (N= 1467) Attività 2008 LY ST MDS/MPS IE AA ID Thal AD MM/PCD LMA 3% LMC LLC LLA n=393 n=275 n=41 n=26 n=78 n=188 n=12 n=256 n=26 n=56 n=3 n=66 n=1 Leucemia Mieloide Acuta Leucemia Linfatica Cronica MielMult/Plasmacell Tumori Solidi Errori genetici Immunodeficienze AD Leucemia Linfatica Acuta Leucemia Mieloide Cronica Linfomi MDS/MPS Anemia Aplastica Talassemia

4 Epidemiologia CLL La più frequente forma leucemica dell adulto (25% delle leucemie) Incidenza pari a 2-6 x abitanti anno (paesi occidentali), ma 13 x abitanti anno a 65 anni e circa 30 x abitanti anno dopo i 70 anni Età mediana di insorgenza 65 anni M/F: 2/1 30% dei pazienti ha un età < 60 anni 10-15% dei pazienti ha un età < 50 anni

5 Rationale of SCT in CLL CLL in relapsed/advanced stage or with high risk features: - poor prognosis - conventional therapies not curative Potentially curative in CLL: - Stem cell source free of tumour contamination - Graft vs leukemia effect

6 Who are poor risk patients?

7 Outcome of conventional salvage for fludarabine-refractory CLL Source n Salvage OS Keating, L&L various 10 mo O'Brien, JCO FC 12 mo Keating, Blood Campath iv 16 mo Stilgenbauer, ASH Campath sc 17 mo

8 Prognostic impact of FISH karyotype in CLL Survival from Time of Diagnosis (n=325) q- 17p q- single Overall survival of CLL patients by FISH karyotype Survival in Months Döhner, NEJM 2000

9 Sopravvivenza mediana dei pz con LLC in rapporto allo stato mutazionale IgV H ed espressione ZAP-70 Hamblin et al Blood 1999 Crespo et al, 2003

10 Definition of poor risk patients for therapeutic purpose NR or early relapse (within 12 months) after purine analogue containing therapy Relapse within 24 months from ASCT p53 deletion/mutation requiring therapy Dreger et al Leukemia 2007 (EBMT consensus)

11 Probability of survival after autologous and HLA-identical sibling SCT for CLL, Probability of Survival, % CONV (N=382) Autotransplant (N=394) RIC (N=529) P< Years CIBMTR

12 PFS after auto-sct in CLL: retrospective studies Esteve 2001 Gribben Allo 42% (±9) Probability n = 124 Auto 24% (±7) n = Years n = 25 TCD

13 Allo-SCT in CLL: key issues 1. Does GVL activity in CLL exist? 2. What is the success rate of SCT (disease control vs. toxicity)? 3. Is it effective in high-risk disease? 4. Indications for allo-sct in CLL? Dreger et al Leukemia 2007 (EBMT consensus)

14 1. Does GVL activity in CLL exist?

15 Evidence for GVL in CLL: relapse rate Few late relapses after allo-sct in contrast to auto-sct (Esteve 01) MRD kinetics correlate to immune intervention (Ritgen 04) Esteve Allo 42% (±9) auto 0.4 Probability Auto 24% (±7) n = 124 n = Years allo

16 Evidence for GVL in CLL: detrimental effect of TCD PFS: auto vs. TCD-alloSCT n = 137 n = 25 Gribben et al 2005

17 Evidence for GVL in CLL: beneficial effect of DLI 1 x 10 7 CD4+ cells/kg or 3 x 10 7 CD4+ cells/kg 6/7patients responded to DLI Gribben et al 2005

18 Evidence for GVL in CLL: favorable effect of cgvhd Dreger, Leukemia 03; Ritgen, Leukemia 08; Schetelig, JCO 08; Corradini, Haematologica 09 h t i w t n e c r e P o i s s e r g o r p Dreger et al. Leukemia 2003 cgvhd always absent after cgvhd onset Months from SCT

19 Evidence for GVL in CLL: favorable effect of cgvhd Higher incidence of PCR negativity in patients with cgvhd (75% vs 46%) 2. in PCR neg pts with a delayed clearance of MRD, the onset of GvHD preceded the achievement of molecular remission; 3. overall GvHD was more frequent in patients who did not relapse (p=0.04): the crude incidence of grade 2-4 acute and chronic GvHD was 22% in relapsed and and 70% in not relapsed patients. Corradini, Haematologica 2009

20 CLL3x: m (sib) p# start of cgvhd Chimerism CSA -180 SCT BLOOD 2004;104:2600

21 Does GVL activity in CLL exist? Yes

22 2. What is the success rate of SCT (disease control vs. toxicity)?

23 Survival After SCT Auto 63% (±7) Allo 56% (±7) Probability days CONV allo-trm: 31% Years Esteve et al, ASH 2001 Auto=124 (28 dead) Allo=46 (20 dead)

24 CONV Allo-SCT with in CLL Dreger et al. Leukemia 07

25 EBMT survey on RIC allografting for CLL: Treatment-related mortality (n=77) M R T 100 t n e c r e P % (9;27) Months from SCT Dreger et al Leukemia 2003

26 RIC allo-sct: CLL-specific trials Study Seattle GCTSG CLL3X n TRM 22%(2y) 15%(5y) 7%(3y) OS 60%(2y) 69%(5y) 75%(3y) REL 18%(2y) 30%(5y) 24%(3y) REL >2y F/U (mo) Sorror JCO 2005; GCLLSG 2005; Schetelig JCO 2003, 2005

27 Allo-SCT in CLL (EBMT): Population-matched analysis - 73 RIC cases (survey), 82 MC cases (registry) - matched for age, donor, remission status, sex - by serial Cox modeling - RIC reduces TRM (HR 0.4; p 0.025) - RIC increases relapse (HR 2.7; p 0.054) (?) - no influence on EFS and OS Prospective controlled studies are needed! Dreger et al Leukemia 2005

28 RIC allo-sct on CLL: MRD vs. MUD Study Seattle CLL3X MRD MUD MRD MUD n TRM (2y) 22% 20% 0% 14% OS (2y) 56% 74% 87% 77% REL (2y) 34% 5% 13% 23% GCLLSG 2005; Sorror JCO 2005

29 RIC allo-sct in CLL: results from the GCLLSG CLL3X trial f - n o i s s e r g o r p % Molecular response 50% of the pts with high-risk CLL Prognostic impact of MRD negativity at +12 month CLL3X: PFS according to MRD negativity (n=26) MRD neg at 12 mo not MRD neg at 12 mo HR 0.06; p Months post SCT Percent TRM CLL3X: TRM 11% (0, 23%) Months from allo-sct Ritgen et al Leukemia 2008

30 Role of molecular response at + 6 month after RIC allo-sct in CLL: p=0.012 p=0.031 Corradini et al Haematologica 2009

31 What is the success rate of SCT (disease control vs. toxicity)? Allo SCT active Molecular remission RIC associated with reduced TRM

32 3. Is it effective in high-risk disease?

33 RIC allo-sct in CLL: impact of 17p- 44 patients from EBMT database ( ) median age: 54 years (35-64) 60% fludarabine refractory status at SCT: 14% CR, 39% PR, 48% SD/PD 24 sibling / 20 alternative donor 89% RIC agvhd grade 2-4: 43% extensive cgvhd: 53% Schetelig, JCO 2008

34 RIC allo-sct in CLL: impact of 17p3-year OS 44% 3-year PFS 37% 3-year relapse 30% 3-year TRM 32% Schetelig et al JCO 2008

35 d e s p a l e r % CLL3X: Relapse incidence by FISH karyotype (n=42) del 11q- / del 17p- other Months post SCT Dreger 2005

36 RIC allo-sct in CLL: Impact of poor-risk factors Other adverse prognostic factors like VH gene mutational status or ZAP-70 espression seem to have no major influence on the outcome after allogeneic SCT. Ritgen, Blood 2004; Moreno, JCO 2005 (VH gene); Caballero, Clin Cancer Res 2005; Khouri, BJH 2007 (ZAP-70)

37 Is it effective in high-risk disease? Yes. Allo SCT has the potential to induce long-term DFS in patients with 17p-CLL. Detrimental effect of TCD.

38 4. Indications for allo-sct in CLL?

39 EBMT guidelines for SCT in CLL Allo-SCT in poor-risk CLL including: Fludarabine resistence non response or early relapse (<12 months) after purine analogue-based tx Relapse <24 months after purine analogue combinations or auto-sct (+ high risk genetics) p53 mutation with treatment indication Auto-SCT indicated in clinical trial only. Dreger et al. Leukemia 07 (EBMT consensus panel)

40 Criteri di eleggibilità per ricerca MUD. Standard IBMDR maggio 09 Patologia Categoria A Categoria B Categoria C comprovata sperimentale senza indicazione LNH/LLC Ricaduto/resistente all autologo e/o polichemioterapia di età 65 anni Frontline Linfomi aggressivi in franca progressione Pazienti anni: Nell ambito di protocolli clinici Specifica richiesto al registro

41 Allo SCT in CLL - - CONV RIC PRO vs CONS + +

42 Proposal for allosct in poor risk CLL Good disease control Older Comorbidities Refractory Younger (???) No comorbidities RIC CONV

43 Richter s syndrome patients with CLL/SLL ( , MDACC) 204 patients (5.1%): possible RS 148 patients (3.7%): biopsy proven RS 20 patients underwent allosct AM Tsimberidou et al. JCO 2006

44 Patients who received allosct as postremission therapy had longer survival than patients who achieved remission and received no additional therapy or patients who underwent allo or autosct as salvage therapy (P =.019). AM Tsimberidou et al. JCO 2006

45