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Dalla terapia ad alte dosi alla talidomide e agli inibitori del proteasoma: una storia terapeutica in evoluzione Roma, 3 febbraio 2006 Targeted therapies.

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Presentazione sul tema: "Dalla terapia ad alte dosi alla talidomide e agli inibitori del proteasoma: una storia terapeutica in evoluzione Roma, 3 febbraio 2006 Targeted therapies."— Transcript della presentazione:

1 Dalla terapia ad alte dosi alla talidomide e agli inibitori del proteasoma: una storia terapeutica in evoluzione Roma, 3 febbraio 2006 Targeted therapies nella pratica clinica delle neoplasie ematologiche - Mieloma multiplo DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Maria Teresa Ambrosini

2 MM* (all 3 criteria required) Monoclonal plasma cells in the bone marrow 10% and/or presence of a biopsy-proven plasmacytoma Monoclonal protein present in the serum and/or urine Myeloma-related organ dysfunction (1 or more) (C)Calcium elevation in the blood (serum calcium >10.5 mg/L or upper limit of normal) (R)Renal insufficiency (serum creatinine >2 mg/dL) (A)Anemia (hemoglobin 10.5 mg/L or upper limit of normal) (R)Renal insufficiency (serum creatinine >2 mg/dL) (A)Anemia (hemoglobin <10 g/dL or 2g

3 Melphalan and Prednisone (MP) Conventional chemotherapy in use for over 40 years Conventional chemotherapy in use for over 40 years Partial Response: 50-60% Partial Response: 50-60% Complete Response 1% Complete Response 1% Median Overall Survival 3 years Median Overall Survival 3 years Equivalent mortality and survival between MP and combination chemotherapy Equivalent mortality and survival between MP and combination chemotherapy Myeloma Trialists' Collaborative Group. J Clin Oncol. 1998;16:3832 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

4 DOSE RESPONSE Melphalan dose-response curve DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

5 High dose Melphalan with Autologous Stem Cell Transplantation Complete Response rate increased from 1 - 3% to % Complete Response rate increased from 1 - 3% to % Remission extended from 18 to 30 months Remission extended from 18 to 30 months Overall survival doubled from 30 to 60 months Overall survival doubled from 30 to 60 months DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

6 Randomized studies: High Dose Therapy versus Standard Chemotherapy 1. Attal M et al. N Engl J Med. 1996;335:91 2. Child JA et al. N Engl J Med. 2003;348: P=0.03 Conventional Transplant Overall Survival (%) Treatment (mo) IFM90 1 Transplant Conventional Treatment (mo) Overall Survival (%) P = MRC7 2 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

7 For Newly Diagnosed MM Attal M et al. N Engl J Med. 2003;349:2495 Cavo M et al. Hematol J 2003;4 abstract P Fermand JP et al. Blood. 2001;98 abstract #3387 Sonneveld P et al. Blood. 2004;104 abstract #948 Single vs Double ASCT 24110Double No difference Single Cavo et al No difference Median EFS (mo) 3799Double Single Sonneveld et al (HOVON 24) No difference 4294Single Fermand et al Double Double Single Attal et al Median OS (mo) CR (%)nASCT Study P=NS P<0.05 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY P=NS P=0.002 P=0.02P=NS P=0.03 P=0.01

8 Multiple Myeloma Survival % Median survival = 3-5-years DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

9 Multiple Myeloma SEED DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY SOIL

10 Bruno B et al. Lancet Oncology 2003;4:379 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

11 Bruno B et al. Lancet Oncology 2003;4:379 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

12 Thalidomide Precise mechanism of action not yet understood Precise mechanism of action not yet understood Multiple actions: antiangiogenic effects that provide the rationale for its use in MM antiangiogenic effects that provide the rationale for its use in MM immunomodulatory effect immunomodulatory effect apoptotic effect apoptotic effect Thalidomide was first shown to be effective as a single agent in patiens with relapsed and refractory disease Thalidomide was first shown to be effective as a single agent in patiens with relapsed and refractory disease (Singhal S (Singhal S et al. N Engl J Med. 1999;341:1565) Numerous subsequent studies have confirmed its efficacy with a response rate of 30% alone, 50% when used in combination with dexamethasone and 70% with chemotherapy. Numerous subsequent studies have confirmed its efficacy with a response rate of 30% alone, 50% when used in combination with dexamethasone and 70% with chemotherapy. DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

13 Thalidomide/dexamethasone combination Cavo Blood 2005 Ludwig ASH 2005 Rajkumar JCO 2006 Study DVT (15), constipation (9), infections (4), neuropathy (4), deaths (6) 76%13%100 (*) ToxicityCR+PRCR/nCRNo DVT (20),neuropathy (7), skin rash (4), deaths (6) 63%4% (CR)103 (*) DVT (5), neuropathy (15), skin rash (7) 52%22% 60 (*) (*) in untreated patients (°) in relapsed patients Palumbo Hematol J 2004 DVT (2), neuropathy( 20), confusion (8), skin rash (4) 52%na120 (°) na 55% neuropathy, confusion, constipation, sonnolence Dimopoulos Ann Oncol (°) DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

14 Thalidomide/Dexamethasone vs Dexamethasone in Newly Diagnosed Multiple Myeloma Phase III Clinical Trial, newly diagnosed MM for whom stem cell transplantation was considerate appropriate Phase III Clinical Trial, newly diagnosed MM for whom stem cell transplantation was considerate appropriate Thalidomide 200 mg daily p.o. + Dexamethasone 40 mg p.o. on days 1-4, 9-12, or Dexamethasone alone Thalidomide 200 mg daily p.o. + Dexamethasone 40 mg p.o. on days 1-4, 9-12, or Dexamethasone alone Every 4 week Every 4 week Rajkumar SV et al. J Clin Oncol 2006;24:1 Endpoint Dex (n=100) Thal/Dex (n=99) 42 Disease progression within first 4 mo, % 1.1 Median time to response, mo 41 (41)62 (63) Response rate, n (%)* *Best response within 4 courses DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

15 Thalidomide/Dexamethasone vs Dexamethasone: Drug-Related Adverse Events Dex, n (%) (n=102) Thal/Dex, n (%) (n=102)Drug-Related Adverse Event 21 (21)46 (45)Total 18 (18)35 (34)Any toxicity grade 4 4 (4)7 (7)Neuropathy grade 3 0 (0)1 (1)Sinus bradycardia grade 3 0 (0)4 (4)Rash grade 3 3 (3)17 (17)DVT grade 3 Deaths within 4 cycles: Thal/Dex, 7%; Dex, 11% Rajkumar SV et al. J Clin Oncol 2006;24:1 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

16 Thalidomide Chemotherapy combinations (*) in untreated patients (°) in relapsed patients DVT (4), neutropenia (6), thrombocytopenia (6), constipation (4), neuropathy (2) 64%10% T-VAD (*) Vcr + Adria + Dex + THAL 39 Zervas Ann Oncol 2004 Death (4), DVT (17), infection (11), neuropathy(31) 76%28% MPT MPT (*) M + P + THAL 129 Palumbo ASH % CR+PR32% na CR/nCRToxicityRegimenNoStudy Infections (6), Neuropathy (2), constipation (7) CTD (°) Cy + Dex + THAL 22 Garcia-Sanz Hemat J 2002 Schutt Eur J Haematol T-VED (*) Vcr + Epir + Dex +THAL 19% 80% DVT (8), neutropenia (10), infection (7), neuropathy (20) Offidani Haematologica DVd-T (°) Vcr+AdriaLipo + Dex + THAL 76% DVT (6),neutropenia (8), constipation (1), neuropathy (1) DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

17 Thalidomide With Melphalan and Prednisone in Elderly Patients With MM MPT Arm (Median age 72) Melphalan, 4 mg/m 2 (7 days/mo) Prednisone, 40 mg/m 2 (7 days/mo) Thalidomide, 100 mg/d (continuously)* (n=129) MP Arm (Median age 72) Melphalan, 4 mg/m 2 (7 days/mo) Prednisone, 40 mg/m 2 (7 days/mo) (n=126) 6 courses 6 courses Newly diagnosed MM patients, aged >65 yr (n=255 as of 3/05) *Thalidomide dose reduced to 50% if grade 2 toxicity. Follow-up 6 mos. Palumbo A et al. Blood. 2005;106: abstract #779 Phase III Randomized Controlled Trial DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

18 MPT in Elderly Patients With MM: Response NS6480OS at 36 mo < Median EFS, mo < CR + nCR 4560PR MP, % (n=126) <0.001 P value 16CR 76ORR 12nCR MPT, % (n=129) Response Palumbo A et al. Blood. 2005;106: abstract#779 PR (>50%), nCR (IF+), CR (IF-) DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

19 Thromboembolism in MPT-Treated Elderly Patients Reduced With Prophylaxis Arterial occlusion Pulmonary thromboembolism DVT With Prophylaxis (n=64) No Prophylaxis (n=65) Adverse Event Incidence, % More DVT with MPT than with MP (P=0.003)More DVT with MPT than with MP (P=0.003) DVT prophylaxis: enoxaparin, 0.4 mL/day for 4 monthsDVT prophylaxis: enoxaparin, 0.4 mL/day for 4 months Palumbo A et al. Blood. 2005;106:abstract #779 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

20 MP vs MP-Thal and MP vs Mel100 in Newly Diagnosed MM Patients Aged 65–75 Years Response MP (n=191) MP-Thal (n=124) MEL100 (n=121) PFS17,127,619 OS30,3> 5538,6 3 nd planned interim analysis 5/2005; median follow-up time = 32.2 months Facon T et al. Blood. 2005;106 abstract#780 IFM Trial Response to Treatment* DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Random MP MP + THAL 2 VAD CTX 3g/mq MEL100 MEL courses

21 Maintenance With Thalidomide after ASCT No maintenance Pamidronate, 90 mg/mo Pamidronate, 90 mg/mo Thalidomide, 100 mg/day Attal M et al. Blood. 2005;106 abstract #1148 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY EndpointNo maintenancePamThal/PamP Value Patients, n yr EFS, % yr OS, %867886ns ASCT (MEL140 MEL200) as front line therapy Month 3 after 2 ASCT, if no progression Random

22 CC5013 is more potent and less toxic than the parent compound CC5013 is more potent and less toxic than the parent compound Induces apoptosis in MM cells Induces apoptosis in MM cells Decreases binding of MM cells to bone marrow stromal cells Decreases binding of MM cells to bone marrow stromal cells –Inhibits cytokine production (IL-6, VEGF, TNF-alfa) –Blocks angiogenesis Thalidomide Analog; REVLIMID (CC5013) DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

23 Phase III Trial of Lenalidomide/Dex in Relapsed or Refractory MM Lenalidomide 25 mg d 1–21 Placebo d 22–28 Dex 40 mg, d 1–4, 9–12, 17–20 Placebo d 1–28 Dex 40 mg, d 1–4, 9–12, 17–20 Same, except Dex d 1–4 4 COURSES 4 COURSES CONTINUE UNTIL PD International MM-010 (51 Centers Europe/Australia/Israel): Dimopoulos (351 patients) Primary endpoint: TTP (by Bladé criteria) Secondary endpoints: OS, RR, safety, 1 st skeletal-related event, PS Inclusion criteria 3 prior therapies No Dex resistance Normal liver/renal function Dimopoulous M et al. Blood. 2005;106 abstract #6 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

24 Phase III Trial of Lenalidomide/Dex in Relapsed or Refractory MM EndpointLenalidomide/ Dex Placebo/DexP value Time To Progression 13 mo 5,1 mo < Overall Response Rate 58%22%<0.001 An independent commettee closed the study: Revlimid superior to Dex Dimopoulous M et al. Blood. 2005;106 abstract #6 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

25 Bortezomib Bruno B et al. Lancet Oncology 2004 The Proteasome: A Target for Novel Therapies

26 APEX : Treatment plan 273 treatment days 280 treatment days 1.3 mg/m 2 IV push Days 1, 4, 8, 11 Q3W cycle 8 cycles 1.3 mg/m 2 IV push Days 1, 8, 15, 22 Q5W cycle 4 cycles 3 cycles 5 cycles 40 mg po Days 1–4, 9–12, 17–20 Q5W cycle 40 mg po Days 1–4 Q4W cycle Randomization Bortezomib Dexamethasone Induction Maintenance Richardson et al. N Engl J Med 2005;352:2487 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

27 APEX: Outcome Time to progression (n = 669) 1-year survival (n = 669) EndpointBortezomibDexamethasone Time To Progression 6,2 mo 3,5 mo Overall 1yr 80%66% Richardson et al. N Engl J Med 2005;352:2487 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

28 APEX: response rates (CR, PR) Median time to response (TTR) 43 days in both arms Duration of response Bortezomib 8.0 months Dexamethasone 5.6 months Median follow-up ~8.3 months <1% nCR 25% PR 16% PR 7% nCR 6% CR Bortezomib Dexamethasone Response (%) 38% 18% P< <1% CR Richardson et al. N Engl J Med 2005;352:2487 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

29 APEX: Treatment-emergent grade 3 AEs reported by 5% of patients Patients % Thrombocytopenia Neutropenia Anemia Peripheral neuropathy Diarrhea Fatigue Dyspnea Pneumonia Hyperglycemia Bortezomib (n = 331) (n = 332) Dexamethasone (n = 332) Richardson et al. N Engl J Med 2005;352:2487 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

30 Bortezomib alone and in combination with Dexamethasone for untreated MM Treatment Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 of 21-day cycle Dexamethasone 40 mg P.O. on days 1, 2, 4, 5, 8, 9, 11, 12 added if

31 PAD combination therapy (bortezomib (PS-341), Adriamycin and Dexamethasone) for untreated MM Oakervee et al. Br J of Haematology 2005;129:755 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Treatment Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 of 21-day cycle Dexamethasone 40 mg on days 1-4, 8-11, during cycle 1, days 1-4 cycles 2-4 Doxorubicine 0 - 4,5 – 9 mg/mq on days %ORR 33%PR 33%VGPR 5%nCR24%CR Response Rate:

32 VTD (VELCADE ®, Thalidomide, Dexamethasone) as Primary Therapy for Newly-Diagnosed MM Treatment: Bortezomib 1.0 to 1.9 mg/m 2 days 1, 4, 8, 11 q 28 days Bortezomib 1.0 to 1.9 mg/m 2 days 1, 4, 8, 11 q 28 days Thalidomide mg each evening Thalidomide mg each evening Dexamethasone 20 mg/m 2 days 1-4, 9-12, q 28 days Dexamethasone 20 mg/m 2 days 1-4, 9-12, q 28 days 28- day treatment cycle, 2 cycles Institutional experience of 36 patients –92% Response rate (CR+PR) –PBSC easily collected Wang et al. Blood 2005;106 Abstract#784 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

33 A phase I/II study of Bortezomib plus Melphalan and Prednisone (V-MP) in Elderly Untreated MM patients Mateos et al. Blood 2005;106 Abstract#786 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY Treatment V-MP 9 courses Four 6-week courses Melphalan p.o. 9 mg/m2 on days 1-4, Prednisone p.o. 60 mg mg/m2 on days 1-4 VELCADE i.v 1,3 mg/m2 days 1, 4, 8, 11, 22, 25, 29, and 32 Five 5-week courses Melphalan p.o. 9 mg/m2 on days 1-4, Prednisone p.o. 60 mg mg/m2 on days 1-4 VELCADE i.v 1,3 mg/m2 days 1, 8, 22, and 29

34 V-MP: Response Rates (N=53) After 1st cycle 0% 10% 20% 30% 40% 50% 60% 70% CR IF-CR IF+PR 72% 6%2% 64% Best response (median 3 cycles) 10% 20% 30% 40% 50% 60% 70% 85% 0% CR IF- CR IF+ PRMRSD 28% 11% 45% 3% 13 % Mateos et al. Blood 2005;106 Abstract#786 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

35 V-MP: Conclusions High Response Rate High Response Rate Manageable toxicities: Manageable toxicities: –Neutropenia and thrombocytopenia were the only Gr3 events Basis for VISTA Phase III trial (n=680): VMP vs MP Basis for VISTA Phase III trial (n=680): VMP vs MP DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

36 HOW TO IMPROVE VMP ? V-MPT Bortezomib + Melphalan + Prednisone + Thalidomide DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

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38 Protocol GIMEMA-MM DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY A PHASE III, MULTI-CENTER, RANDOMIZED OPEN LABEL STUDY OF VELCADE, MELPHALAN, PREDNISONE AND THALIDOMIDE (V-MPT) Versus VELCADE, MELPHALAN, PREDNISONE (V-MP) IN ELDERLY UNTREATED MULTIPLE MYELOMA PATIENTS

39 Combinations therapies in Multiple Myeloma Bortezomib + Thalidomide +/- cytotoxic drugs M-COMPONENT induction High-dose relapse remission DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

40 Take home message Combinations increase response rate Frontline therapy + New Drugs DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

41 GIMEMA: Italian Myeloma Network 1. ALESSANDRIALevis, Baraldi 2. ANCONALeoni, Offidani 3. AOSTADi Vito 4. ASCOLI PICENOGalieni, Bigazzi 5. ASTIScassa, Campa 6. AVELLINOCantore, Volpe 7. AVIANOTirelli, Rupolo 8. BARIDammacco, Lauta 9. BARILiso 10. BERGAMOBarbui, Galli 11. BIELLATonso 12. Cavo, Tosi 12. BOLOGNACavo, Tosi 13. BOLZANOPescosta 14. BRAVanni, Stefani 15. BRESCIARossi, Crippa 16. CAGLIARIAngelucci, Carubelli 17. CAGLIARIMantovani 18. CAMPOBASSOStorti 19. CANDIOLOAglietta, Capaldi 20. CATANIAGiustolisi,Di Raimondo 21. CATANZAROPiro 22. CATTOLICAPasquini 23. CESENAGuardigni 24. CHIOGGIABattista 25. CIRIE'Freilone, Beggiatto 26. COSENZAMorabito 27. CREMONAPassalacqua, Morandi 28. CREMONAMorandi 29. CUNEOGallamini, Grasso 30. FIRENZEBosi/Nozzoli 31. FOGGIAFerrandina 32. FOGGIAMonaco 33. FORLIAmadori, Gentilini 34. GALLARATECiambelli 35. GENOVAGobbi, Canepa 36. GENOVACarella 37. LATINAZapone 38. LECCEPavone 39. MATERACiancio 40. MESSINABrugiatelli, Mamone 41. MESSINAMusolino 42. MILANOCorradini, Montefusco 43. MILANOMorra 44. MILANOBregni 45. MODENANarni 46. MONTEFIASC.Montanaro, Niscola 49. MONZAPogliani, Rossini 50. NAPOLIRotoli,Catalano 51. NAPOLIFerrara 52. NOCERA INF.DArco, Califano 53. NOVARAGaidano, Rossi 54. NUOROLatte, Palmas 55. ORBASSANOSaglio, Guglielmelli 56. PADOVASemenzato, Zambello 57. PALERMO Mirto, Cangialosi 58. PARMARizzoli, Giuliani 59. PAVIALazzarino, Corso 60. PERUGIALiberati, Nunzi 61. PESAROVisani, Leopardi 62. PESCARAFioritoni, Spadano 63. PIACENZACavanna, Lazzaro 64. PINEROLOGriso 65. PISA Petrini/Benedetti 66. POTENZA Ricciuti, Vertone 67. RAVENNA Zaccaria, Molinari 68. REGGIO CAL. Nobile, Callea 69. REGGIO EMILIA Gugliotta,Masini 70. RIMINI Pasquini, Fattori 71. ROMA Annino, Bongarzoni 72. ROMA Andriani 73. ROMA 1 Foà, Petrucci 74. ROMA Cattolica Leone, De Stefano 75. ROMA R.Elena Petti, Pisani 76. ROMA S. Camillo Majolino, De Rosa 77. ROMA T. Vergata Amadori, Caravita, i 78. ROZZANO Santoro, Nozza 79. S. G. ROTONDO Musto, Merla 80. SASSARI Longinotti, Dore 81. SIENA Lauria, Gozzetti 82. TARANTO Mazza, Casulli 83. TORINO 1 Boccadoro, Palumbo 84. TORINO 2 Gallo, Pregno 85. TORINO MAURIZ. Poccardi, Gottardi 86. TORINO S. VITO Marinone, Ficara 87. TREVISO Foscolo, Gherlinzoni 88. TRIESTE De Sabbata 89. UDINE Fanin, Patriarca 90. VARESE Pinotti 91. VENEZIA Chisesi 92. VERBANIA Montanara, Luraschi 93. VERONA Pizzolo, Meneghini 94. VICENZA Rodeghiero, Elice


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