MARIO PETRINI Ematologia PISA UO Ematologia - Pisa

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1 I LINFOMI NON HODGKIN A BASSO GRADO DI MALIGNITA PESCARA 2008 linfomi mantellari MARIO PETRINI Ematologia PISA

2 Mantle Cell Lymphoma Typical (Classic) small to medium-sized Ly with scanty cytoplasm, irregular nuclei, condensed chromatin. Rarely round nuclei (mimicking CLL), or abundant pale cytoplasm (mimicking Marginal Zone Lymphoma) Cytology Blastoid (Blastic) Classic Blastoid Variant: medium-sized Ly with scanty cytoplasm and round nuclei with finely dispersed chromatin and high mitotic index Pleomorphic Blastoid Variant: heterogeneous large cells with irregular cleaved nuclei, finely dispersed chromatin, small distinct nucleoli

3 Mantle Cell Lymphoma - Morphology 3-26% 28-78% 13-39% Architectural Patterns in nodes

4 Mantle Cell Lymphoma - Immunophenotype Monoclonal B cell expressing CD19+ CD20+ CD22+ CD79a+ intense surface immunoglobulin IgM (± IgD) more λ light chain than κ light chain CD5+ (11% -) -CD 10 CD43+ -CD 23 -BCL 6

5 Mantle Cell Lymphoma / CD5 negative Positive t(11;14) by fluorescence in situ hybridization from a CD5- mantle cell lymphoma. Note 1 green, 1 red, and 2 orange fusion signals. The fusion signals indicate the presence of the t(11;14) translocation.

6 Mantle Cell Lymphoma Molecular Biology CDK (Cyclin Dependent Kinase) Cell cycle POSITIVE regulators Cyclin D1 CDK4 Retinoblastoma Protein Phosphorilation Cyclin/CDK complex Release of Transcription factor E2F Cell-cycle progression in S phase

7 Rosenwald et al. Cancer Cell. 2003;3:

8 Rosenwald et al. Cancer Cell. 2003;3: KI-67 results are parallel Other prognostics: Stage, IPI, blastoid morphol.

9 MCL - PFS according to RAF1 expression

10 MCL - PFS according to MYC expression

11 MCL - PFS according to RAF1 expression 19 pz con MCL

12 MCL - PFS according to RAF1 expression Leuk Res. 2007;31:

13 A New Prognostic Index (MIPI) for Patients with AdvancedStage Mantle Cell Lymphoma IPI FLIPI MIPI (età, EGOG, LDH, GB) MIPI b ( + Ki 67%) Based on data of 455 patients with advanced stage MCL from three randomized trials Hoster E, GLSG & European MCL Network.Blood First Edition Paper, prepublished online October 25, 2007

14 INITIAL OBSERVATION WITHOUT THERAPY IN PATIENTS WITH ASYMPTOMATIC, NEWLY DIAGNOSED MANTLE CELL LYMPHOMA (MCL) P. Martin1 Lugano 2008

15 Mantle Cell Lymphoma Treatment: Conventional Chemotherapy G. Lenz, M. Dreyling, W. Hiddemann Ann Hematol 2004

16 Mantle Cell Lymphoma Treatment: Rituximab Romaguera et al, Blood, 2001: R-Hyper-CVAD in 75 MCL pts < 66 years > 66 years R-Hyper-CVAD Hyper-CVAD +ABMT R-Hyper-CVAD Hyper-CVAD +ABMT CR 89% 100% 90% 70% 2-year FFS 84% 75% 60% 41% 2-year OS 87% 96% 96% 77%

17 German Low Grade Lymphoma Study Group: R-CHOP significantly improves response and time to treatment failure but not long-term outcome in untreated MCL Time to treatment failure Overall survival P=.0131 Lenz, G. et al. J Clin Oncol; 23: Copyright American Society of Clinical Oncology

18 Mantle Cell Lymphoma Treatment: SCT

19 Mantle Cell Lymphoma Treatment: SCT 79% 89% 18% 42%

20 Mantle Cell Lymphoma Treatment: SCT

21 MCL - PFS according to FCGR3A genotype

22 MCL - PFS according to FCGR2A genotype

23 Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG) Forstpointner et Al BLOOD, 2006; 108: 4003

24 Zevalin in MCL: PFS RIT induction RIT consolidation Weigert O, Jurczak W et al. Proc Am Soc Clin Oncol 2006; 24: #7533

25 Zevalin in MCL: OS RIT induction RIT consolidation Weigert O, Jurczak W et al. Proc Am Soc Clin Oncol 2006; 24: #7533

26 E1499 Trial: R-CHOP followed by Zevalin Consolidation in 1st line MCL Phase II Study 56 Pts. eligible for treatment ORR CR/Cru 50 Pts. evaluable post R-CHOP ORR 72% (CR/CRu 14%, PR 58%); SD 26% 44 Pts. evaluable post Zevalin ORR 84% (CR 45%) Responses improved in 15/ 37 Pts. with < CR/CRu Responders (%) Conclusion Zevalin consolidation improves the number and quality of responses 0 After R-CHOP induction (n=50) After Zevalin consolidation (n=44) Smith MR et al. Proc Am Soc Clin Oncol 2006; 24: # 7503

27 Comparison of 3 Trials assessing RIT consolidation in MCL 1st and 2nd line Jurczak W. et al., Blood 2006;108:#2747

28 Z-BEAM Consolidating Remission OS by disease histology (N=41) PFS by disease histology Krishnan et al J Clin Oncol 2008;28:90 5

29 Radioimmunotherapy as an Alternative Consolidation for Mantle Cell Lymphoma (MCL) patients not Eligible for Transplant Protocols Final Analysis of Multicentre PLRG Trial with 90Y-Zevalin (90Y-ibritumomab tiuxetan) W Jurczak1, et AL Lugano 2008

30 PHASE I TRIAL OF BORTEZOMIB IN COMBINATION WITH RITUXIMABHYPERCVAD/ METHOTREXATE AND CYTARABINE FOR UNTREATEDMANTLE CELL LYMPHOMA. J. E. Romaguera et Al Lugano 2008 Bortezomib can be safely combined with R-M/A at 0.7 mg/m2, toxicity similar to prior experience with R-HyperCVAD. Accrual is ongoing. (7 Pt) BORTEZOMIB IN ASSOCIATION WITH FCM-R AS SALVAGE TREATMEN FOR PATIENTS WITH NON HODGKIN LYMPHOMA F. Zaja Lugano 2008 The results of this pilot study indicate that FCM- BR can be administered without major toxicity and with good activity in the majority of cases.

31 R-CHOP + THALIDOMIDE FOR PREVIOUSLY UNTREATED MANTLE CELL LYMPHOMA J. Drach et Al. Lugano 2008 All 10 pts experienced a response to R-CHOP-Thal (with 8 patients in CR; 4 pts were also negative by FDG-PET). DURABLE RESPONSES WITH THE ANTI-ANGIOGENIC METRONOMIC REGIMEN RT-PEPC IN RECURRENT MANTLE CELL LYMPHOMA (MCL) J. Ruan et Al. Lugano 2008 RT-PEPC has significant and durable clinical activity in MCL by targeting both tumor cells and tumor angiogenesis. LENALIDOMIDE IN COMBINATION WITH RITUXIMAB IS EFFECTIVE WITHMANAGEABLE TOXICITY IN A PHASE I/II STUDY IN RELAPSED/REFRACTORY MANTLE CELL LYMPHOMA M. Wang The MTD for Len+R in relapsed/refractory MCL was 20 mg (days 1 21 of a 28-day cycle). Early evidence of response is promising with a favorable toxicity profile at 20 mg.

32 EUROPEAN MANTLE CELL LYMPHOMA NETWORK: AN UPDATE ON CURRENT FIRST LINE TRIALS M. Dreyling et Al Lugano 2008 In MCL elderly, 302 patients are initially randomized between 8 cycles of R-CHOP or 6 cycles of R-FC (experimental arm). Patients who achieve either a PR or CR, receive subsequently either interferon maintenance (standard arm) or a single rituximab dose every 2 months. In MCL younger, 314 patients the standard arm (R-CHOP induction followed by myeloablative consolidation: 12 Gray TBI, 2x 60mg/kg cyclophosphamide) is compared to the implementation of high dose cytarabine into induction (R-CHOP/R-DHAP) and consolidation (10 Gray TBI, 4x1,5 g/m2 Ara-C, 140mg/m2 melphalan).

33 BENDAMUSTINE PLUS RITUXIMAB VERSUS CHOP PLUS RITUXIMAB IN THE FIRST-LINE TREATMENT OF PATIENTS WITH INDOLENT AND MANTLE CELL LYMPHOMAS INTERIM RESULTS OF A RANDOMIZED PHASE IIISTUDY OF THE STIL (STUDY GROUP INDOLENT LYMPHOMAS, GERMANY) M. J. Rummel In this interim analysis the combination of Bendamustine plus Rituximab appears to be non-inferior to CHOP-R while showing a better tolerability profile

34 Phase II Trial of Single-Agent Temsirolimus (CCI-779) for Relapsed Mantle Cell Lymphoma Thomas E. Witzig Et Al JCO 2005

35 Phase 3 study of patients with relapsed. Refractory MCL: comparison of treatment with Temsirolimus vs investigator s choice therapy. Verhoef E.G, et Al. EHA pt 2-7 previous lines Pt treated with 175/75 mg showed longher PFS Pt treated with 175/25 mg did not significantly differ from controls. No significant improving of OS Adverese events: Thrombocytemia, anemia, neutropenia, asthenia

36 Distinct functional significance of Akt and mtor constitutive activation in mantle cell lymphoma J Dal Col et Al. Blood 2008 To assess whether the PI3-K/Akt and/or mtor signalings regulate MCL cell survival, we investigated the effects of wortmannin, SH-5 (Akt inhibitor), and rapamycin in Granta 519 and SP-53 cells.

37 Day Fludarabine 25 mg/m 2 Bortezomib 1.3 mg/m 2 Myocet 50 mg/m 2 Mabthera (cycle 2 only) 375 mg/m 2

38 Pazienti 21 Pretrattati 18 Fragili 5 Age, years median 66 range Sex Male 14 Female 7 Stage IV 15 IV ext 4 IV int 2 IPI median 3 range 2-4 No. previous CT median 3 range 0-4 ABMT yes 2 no 19 Disease status front line 5 resistant 5 relapsed 11

39 Patient No. Age at diagnoses Sex Stage IPI No. previous CT ABMT Resistant/relapsed M IV int 3 1 no relapse F IV 2 1 no relapse F IV 2 3 no resistant M IV 3 4 no resistant F IV int 3 3 no resistant F IV M IV 3 2 no resistant M IV M IV ext 3 1 no relapse F IV 2 3 no relapse M IV ext 3 3 no relapse M IV ext M IV 3 3 no relapse M IV M IV M IV 3 4 yes relapse F IV ext 3 4 no relapse M IV 3 3 no relapse F IV 3 1 no resistant M IV 2 2 no relapse M IV 3 4 yes relapse

40 ORR 57% % 14.3% 14.3% 9.5% 9.5% CR/uCR PR SD PD Mortality

41 neutropenia piastrinopenia anemia cardiotoxicity nausea diarrhea vomiting coutaneous rash FUO pneumonia death

42 Pazienti Radioimmunoterapia Pz Risposta Biol mol RIT Risposta Biol mol #1 RC JH+ BCL1- Zevalin RC JH- BCL1- #2 RP JH+ BCL1- Zevalin RP JH+ BCL1- #3 RC JH- BCL1- Zevalin RC JH- BCL1- #4 RC JH- BCL1- Zevalin RC JH- BCL1- #5 RC JH- BCL1- Zevalin RC JH- BCL1- #6 RP JH- BCL1- Zevalin RP JH- BCL1- #7 RC JH- BCL1- Zevalin RC In corso #8 RC JH- BCL1- Zevalin RC In corso

43 Pazienti Follow-up Pz EFS Biol mol Evento OS post RIT #1 7 mesi JH+ BCL1+ relapse 12 mesi #2 12 mesi JH+ BCL1- Ancora in RC 12 mesi #3 11 mesi JH- BCL1- Ancora in RC 11 mesi #4 8 mesi JH- BCL1- Ancora in RC 8 mesi #5 6 mesi JH- BCL1- Ancora in RC 6 mesi #6 6 mesi JH- BCL1- Ancora in RC 6 mesi