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Azienda Ospedaliera S. Maria di Terni S.C. Oncoematologia-autotrapianto, Direttore Prof. A.M. Liberati Terapia della malattia fludarabina-resistente: ruolo.

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Presentazione sul tema: "Azienda Ospedaliera S. Maria di Terni S.C. Oncoematologia-autotrapianto, Direttore Prof. A.M. Liberati Terapia della malattia fludarabina-resistente: ruolo."— Transcript della presentazione:

1 Azienda Ospedaliera S. Maria di Terni S.C. Oncoematologia-autotrapianto, Direttore Prof. A.M. Liberati Terapia della malattia fludarabina-resistente: ruolo delle mutazioni di TP53 Università degli studi di Perugia Facoltà di Medicina e Chirurgia Marco Gunnellini

2 CLL outcome Doner et Al. N Engl J Med, 2000; 343: Del (17p) patients outcome is worse than others cytogentic abnormalities AbnormalitiesN(%)Median TTFMedian OS Del(17p)7932 Del(11q) q Trisomy Normal Del(13q) p<0,001

3 CLL guidelines

4 Multidrug-resistent CLL Grever et Al; J Clin Oncol, 2007; 25: Prospective clinical studies Fludarabine Fludarabine plus Cyclophosphamide 235 pts. PFS p=0,0006

5 CLL guidelines

6 Median PFS = 30,3 mesi 3-ys OS = 96% Role of Steroids Castro et Al, Leukemia, 2009; 23: Castro et Al, Leukemia, 2008; 22: chemotherapy-naive pts ORR= 96% (27/28) CR= 32% (9/28) MRD negative = 22% (2/9) MRD positive = 78% (7/9) 30 mg 3 times weekly RR = 83%

7 CLL guidelines

8 Role of Alemtuzumab Hillmen et Al, J Clin Oncol, 2007; 25: CAM 307: Alemtuzumab vs Chlorambucil

9 Role of Alemtuzumab Cortelezzi et Al; Leukemia, 2009; 1-7 Reduced-dose Alemtuzumab Relapse in 61,5% of CR

10 Combination therapy Pettitt et Al, Leukemia, 2006; 20: 1441–5 CAM-PRED 3 pre-treated pts (3-6, median 3 previous agents) 2 untreated pts substantial lymphadenopathy p53 abnormalities ORR= 100% CR= 60% (3/5 pts) (40% MDR negative) 1 relapsed after 1 year PR= 40% (2/5 pts) (20% nPR) early relapse (4-6 months) CAM-PRED regimen appears to be a highly effective treatment option for CLL patients with p53 defects HDMP regression of bulky lymphadenopathy Alemtuzumab eradication from the blood and bone marrow.

11 Role of Alemtuzumab Stilgenbauer et Al, J Clin Oncol, 2009; 27: (30%) del(17p) 20 (19%) del(11q) Alemtuzumab SC in heavily pre-treated 106 pts (1-10, median 3 previous agents) CLL2H Study - GCLLSG ORR = 34% (only 4% of CR) PFS = 7,7 months OS = 19,1 months del(11q) ORR = 30% PFS = 9 months OS = 22,7 months del(17p) ORR = 39% PFS = 5,8 months OS = 18,3 months Altough Alemtuzumab is efficacious in inducing remissions in fludarabine-refractory CLL, the disease will eventually relapse and progress. Currently the only potentially curative therapy for fludarabine-refractory CLL is allo-SCT

12 CLL guidelines R-CHOP CFAR R-Hyper-CVAD OFAR Alemtuzumab + Rituximab

13 Role of Allo-SCT Schetelig et Al; J Clin Oncol, 2008; 26: (98%) Fludarabine 19 (43%) Alemtuzumab 13 (30%) Auto-SCT Median 3 pre-treatment (range 2-7) ORR = 84% PFS 3ys = 44% OS 3ys = 37% Early death in 2/44 (5%) Allogenic SCT in pre-treated 44 del(17p) pts Graft-versus-leukemia effects may overcome the negative prognostic impact of 17p deletions in CLL

14 Novel therapy Byrd et Al; Blood, 2007; 109: Flavopiridol in refractory, high-risk CLL PR= 40% PR= 52% PR= 33% Hyperacute Tumor Lysis Syndrome 6 pts (14%) 30 mg/m mg/m 2 40 mg/m mg/m 2 30 mg/m mg/m 2 n= 20 n= 3 n= 19 PR tot = 45% PR 17p- = 42% No CR Median PFS for responders 13 months

15 Basso Rischio: assenza delle caratteristiche dellalto rischio FLU 30mg/mq/ev+ Cy 250 mg/mq/ev gg 1,2,3 (4 cicli) RC,RP FLU+Cy (2 cicli) Alemtuzumab 30mg/w (6+6 w) RP,RC, RC-cy, RC- mol MS-PM Watch&Wait Off-Study MS-PM Alto Rischio: del17p in >20%, del11q + IgVH germline o ZAP70+ >10% o CD38+ >7% IgVH germline (o mutated VH3-21) + (almeno 2) ZAP70+ >10%, CD38+ >7%, del6q o tri12. FLU 30mg/mq/ev+ Campath1H 30 mg ev gg 1,2,3 (4 cicli) RC, RC-cy, b-RP nb-RP, MS, PM no donor donor RC-mol W&W alemtuzumabAutoBEAM Mini Allo Fam Off-Study No CS Si CS (Thio/CTX/Flu) Mobilizzazione CSP Ara-C(800 mg/mq/12h x 3 gg)+G-CSF (multicenter, < 60 years, advanced/progressive CLL) GIMEMA LLC0405

16 Ongoing Study IdentificationDrugsPhaseState NCT Iodine-131 Anti-B1 AntibodyInot recruiting NCT Dasatinib plus LenalidomideI/IIrecruiting NCT Allo-SCTI/IInot recruiting NCT Alemtuzumab plus HDMPIInot yet recruiting NCT HDMP plus RituximabIInot recruiting NCT Alemtuzumab plus Rituximab plus GM-CSF IIrecruiting NCT RC plus vaccine therapyIInot recruiting NCT Alemtuzumab plus RituximabIInot recruiting NCT CFARIInot recruiting NCT Rituximab plus Fludarabine (early vs delayed treatment) IIIrecruiting

17 Take-home message An optimal treatment of del(17p) B-CLL still awaits to be defined Del(17p) B-CLL results in poor response to fludarabine and rituximab Alemtuzumab with or without HDMP can partially overcome p53-dependent resistance but duration of responses is short New agents and more effective regimens are in pre-clinical or early clinical study in del(17p) CLL patients Allogeneic HCT has the potential to induce long term disease-free survival in patients with 17p– CLL but prospective confirmation is needed

18 Grazie per lattenzione Terapia della malattia fludarabina-resistente: ruolo delle mutazioni di TP53 Marco Gunnellini

19

20 Multidrug-resistent CLL Pettitt et Al, Br J Haematol 1999:;106: Sturm et Al, Cell Death Differ 2003; 10: In-vitro studies P= 0.03 P< Fludarabine γ-radiation p53 mutated cases conserve response to steroids, anthracyclines and vincristine P=

21 Multidrug-resistent CLL Byrd et Al, J Clin Oncol 2006; 24: Valganon et Al, Br J Haematol 2005; 129: 53-9 Retrospective clinical studies Fludarabine plus Rituximab 88 pts Fludarabine Significant correlation between non-response to treatment and the presence of p53 aberrations (P=0.0065) 54 pts

22 Multidrug-resistent CLL Tam et Al; Blood, 2009; 114: Retrospective clinical studies p=0,001

23 Role of Steroids Thornton et Al, Ann Hematol, 2003; 82: pre-treated pts (1-6, median 3 previous agents) HDMP can induce regression of bulky lymphadenopathy in CLL patients with p53 abnormalities Pts with p53 losses still fared worse than those with normal p53

24 Role of Alemtuzumab Stilgenbauer et Al, Blood, 2004;104: a (29%) del(17p) 13 (29%) del(11q) 27 (59%) V H um Heavily pre-treated (1-7, median 4 previous agents) Alemtuzumab SC in heavily pre-treated 46 pts Early stop of treatment for toxicity in 13/46 (28%) pts del(17p) del(11q) ORR = 36% PFS = 9,7 months OS = 13,1 months PD in 9/46 (20%)

25 Role of Alemtuzumab Lozanski et Al; Blood, 2004; 103: (42%) p53 mutation or del(17p) Heavily pre-treated (1-12, median 3 previous agents) 81% Fludarabine Cytogenetic screening of all B-CLL patients at diagnosis can avoid administration of ineffective therapy for this disease Alemtuzumab in heavily pre-treated 36 pts ORR 11 (31%)

26 Role of Alemtuzumab Osuji et Al; Blood, 2004; a (30%) del(17p) Heavily pre-treated (1-11, median 4 previous agents) 92% Fludarabine 8% ASCT Alemtuzumab in heavily pre-treated 23 pts Toxicity in 10/23 (43%) pts: 4 asymptomatic CMV reactivation 4 cytopenias with infection 1 anorexia 1 death for pulmonary CMV

27 Novel therapy DrugsPhaseReferences OFARI/IITsimberidou et Al., J Clin Oncol, 2008; 26: LenalidomideIIFerrajoli et Al.; Blood, 2008; 111: GossypolPre-clinicBalakrishnan et A.; Blood, 2008; 112: ABT-737Pre-clinicPaoluzzi et Al.; Blood, 2008; 112: microRNA106 b activators Pre-clinicSampath et Al.; Blood, 2008; PMID CD40L gene- therapy Pre-clinicKato et Al.; J Clin Invest, 1998; 101: Kipps; ASCO EDUCATIONAL BOOK.2009; 2009:


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