La presentazione è in caricamento. Aspetta per favore

La presentazione è in caricamento. Aspetta per favore

M. Martelli M. Martelli Università degli Studi La Sapienza Roma, Istituto di Ematologia Diagnostic and therapeutic burning questions on lymphoproliferative.

Presentazioni simili


Presentazione sul tema: "M. Martelli M. Martelli Università degli Studi La Sapienza Roma, Istituto di Ematologia Diagnostic and therapeutic burning questions on lymphoproliferative."— Transcript della presentazione:

1 M. Martelli M. Martelli Università degli Studi La Sapienza Roma, Istituto di Ematologia Diagnostic and therapeutic burning questions on lymphoproliferative diseases Rieti Ottobre 2006 Linfomi primitivi del mediastino: Dalla chemioradioterapia convenzionale alle attuali possibilità di integrazione della chemioterapia con anticorpi radiomarcati

2 Background Particular clinical and pathological entity in the REAL/WHO classification. Female predominance with median age less than 30 years. Predominat or exclusive mediastinal involvement. Bulky mediastinal mass invading adjacent organs (lung, vena cava, pleura, pericardium and chest wall) producing vena cava compression. May be hematological emergency !!!!!!!

3 Primary Mediastinal B Cell Lymphoma (PMBCL) Patients were defined as having PMLBL (Hamlin 2004 ASH) if they showed all the following: –a clonal lymphoid proliferation with a DLBC centroblastic or immunoblastic histology –a mediastinal mass greater than 5 cm with or without contiguous extranodal or supraclavicular involvement –no detectable extramediastinal mass greater in size than the primary mediastinal lesion

4

5 Which is the appropriate first-line therapy? More intensive weekly third generation regimens as M/VACOP-B improves outcome over CHOP or CHOP like regimens ? Which patients are candidate to local radiotherapy and which modality is recommended? Questions to expert panel Linee guida SIE, SIES, GITMO per i LNH extranodali

6 PMBCL: a clinic study of 43 patients treated with CAP/BOP from the Nebraska Lymphoma Study Group Abou-Elella A. et al: JCO 1990

7 PMLBCLDLBCL Survival comparison according to IPI score Abou-Elella A. et al: JCO 1990

8 PMBCL: Italian prospective study in 21 pts Todeschini et al. J.Clin. Oncol. 8 (5),804-8,1990 All patients Treated with MACOP-B +/- RT

9 Stage II DLBCL with sclerosis treated with MACOP-B 1= PMBL without sclerosis (25 pts) 2= DLCL no mediastinum (38 pts) 3= PMBL with sclerosis (18 pts) 3yrs OS PMBL with sclerosis = 73% Bertini M. et al Ann.Oncol 1991

10 Primary mediastinal large B-cell lymphoma Annals of Oncology 9: , 1998

11 PMBCL: MACOP-B + IFRT is an effective therapy Martelli et al: Annals of Oncology 9: , 1998

12 Blood 94 (10):3289, 1999

13 Zinzani P.L, Martelli M, Magagnoli M, et al. Blood, 1999 PMBCL : MACOP-B + mediastinal IFRT in 50 pts Relapse Free Survival

14 Zinzani P.L, Martelli M, De Renzo A, et al. Haematologica, 2001 PMBCL: a clinical study of 89 patients treated with MACOP-B and IFRT Overall survival Relapse Free Survival

15 Zinzani P.L, Martelli M, Bertini M, et al. Haematologica 2002 Primary mediastinal large B-cell lymphoma

16 Zinzani P.L, Martelli M, Bertini M, et al. Haematologica, 2002 PMBCL: IELSG retrospective study in 426 patients

17 PMBCL: retrospective multicentre Italian study in 138 pts Todeschini et al B.J.Cancer 2004 N MACOP / VACOP-B CHOP

18 PMLBCL prognostic factors PS>2, increased LDH, pleuro-pericardial effusion, IPI ? Early response to initial therapy Extranodal disease (kidney,ovary,CNS,liver). Decrease of dose intensity Residual mass TC positive.

19 Patients92 Age (mean age)33 (range 15-61) Sex (M/F)24/68 Stage II72 (78%) IIE-IV20 (22%) B symptoms43 (47%) Increased LDH values68 (74%) Bulky mass at presentation81 (88%) Superior vena cava syndrome47 (51%) Low risk patients (IPI=0-1)52 (56%) High risk patients (IPI=2-3)40 (44%) MACOP-B plus radiotherapy as first line therapy for PMLBCL with sclerosis : a clinical study on 92 patients ( ) Finolezzi E, Natalino F, Martelli M. et al. SIE 2005 EHA 2005

20 Results After MACOP-B CR/CRu PR NR Death toxic 72 (78%) 18 (20%) 1 (1%) After RT CR/CRu PR NR 78 (91%) 3 (3%) 5 (6%) Relapses ( median follow-up of 58 months) 9 (12%)

21 Martelli M, Finolezzi E et al. SIE 2005 EHA 2005

22

23 DLBCL: role of consolidation radiation therapy In a randomized study ( level 1+) the use of consolidation IFRT on bulky sites of disease was compared to no further treatment The IFRT produced a better control of disease, reduced significantly relapses on site of bulky and improves PFS and OS. ( Aviles 1994). Two prospective trials (level 2+) confirmed that IFRT significantly reduced local relapses in patients with bulky disease improving PFS and OS. (Schlembach 2000, Ferreri 2000). Two retrospective studies (level 2-) patients treated with CHT + IFRT showed a significantly reduction of recurrence on site of bulky disease compared to CHT alone. (Wilder 2001, Fuller 1995)

24 Chemoradiotherapy compared to Chemotherapy alone in elderly DLCL: Results of the LNH93-4 GELA Study. DLCL= 576 pts >60 stage I-II IPI=0 CHOP x 4 (277 pts) CHOP x 4 + IFRT (299 pts) 5y-EFS5-OS5y-EFS > 70 5y-OS > 70 CHOP CHOP +RT P value n.s 0.01 Fillet et al ASH 2005

25 Zinzani P.L, Martelli M, Magagnoli M, et al. Blood, 1999 PMBCL : MACOP-B + mediastinal IFRT in 50 pts

26 PMBCL: role of mediastinal IFRT in a retrospective study Todeschini et al B.J.Cancer 2004 IFRT NO-IFRT

27 Raccomandazioni (2) The recommended first-line therapy is a chemotherapy and radiotherapy association (grade B). An antracycline-based chemotherapy with CHOP, MACOP-B or VACOP-B is recommended (grade B). Mediastinal RT should start within 8 weeks from the last dose of chemotherapy. A dose of at least 30 Gy should be delivered to the original tumor volume. (grade B) Linee guida SIE, SIES, GITMO per i LNH extranodali

28 Rituximab plus CHOP for DLBCL in British Columbia: PFS by treatment era Years Probability of survival Post-rituximab Pre-rituximab p= Sehn LH, et al. J Clin Oncol 2005;23:5027–33

29 CHOEP-2144%44% CHOP-2148%48% MACOP-B 4% 4% PMitCEBO 4% 4% Chemotherapy Chemo (n=410) R-Chemo (n=413)

30 Preunduschuh et al ASCO 2005 Months Probability 79.9% 60.8% p = R-CHEMO (n=413) CHEMO (n=410) Time to Treatment Failure

31 Overall Survival median observation time: 23 months 95% 86% p= MInT June 05 Lymphoma-associated deaths: CHEMO: 42 R-CHEMO:13

32 MInT June Months Probability R-CHOP (n=197) CHOP (n=197) 82.9% 55.3% p < Time to Treatment Failure CHOP vs R-CHOP

33 MInT June2005 Time to Treatment Failure CHOP vs. CHOEP CHOP ( n=187) CHOEP (n=180) 55.3% 65.1% p = 0.04 Months Probability

34 MInT June2005 Time to Treatment Failure CHOP vs. CHOEP R-CHOP vs. R-CHOEP % 65.1% p = 0.04 Months Probability Months Probability R-CHOEP (n=181) 80.4% 82.9% p = 0.67 CHOP ( n=187) CHOEP (n=180) R-CHOP (n=197)

35 CHOP-21 ( ) CHOEP ( ) R-CHOP (2006) % Surviving M O N T H S Progress in the treatment of Young good-prognosis DLBCL

36 The Vancouver Experience Savage et al. 9-ICML, Lugano 2005

37 Dose mg/m 2 /day Etoposide Vincristine Doxorubicin Cyclophosphamide Prednisone Cycle 21 Days for 6-8 cycles (No cap) BID Days 1,2, 3, 4 Day 5 Days 1, 2, 3, 4 Treatment Days Infusional Agents Bolus Agents Biologic Agents Rituximab 375 Day 1 Dose-Adjusted EPOCH-R NO RADIATION ADMINISTERED Filgrastim 5 ( g/kg) Days 6 ANC recovery Dunleavy et al ASH 2005

38 PMBCL: effect of Rituximab in DA-EPOCH DA-EPOCH DA-EPOCH-R Dunleavy et al ASH 2005

39 Rituximab-CHOP combined with mediastinal IFRT. PMBCL= 62 pts CHOP + IFRT (39 pts) R-CHOP + IFRT (23 pts) 3y-FFS3y-OS3y-LSS 3y-EFS CHOP R-CHOP P value P= P=0.03 P=0.008P=0.003 Vassilakopoulos et al, et al ASH 2005, EHA 2006

40 R-M/VACOP-B +IFRT: prospective study in 40 patients with PMBCL 1°Rest. (TAC/PET) 2°Rest.(TAC/PET) °Rest.TAC/PET M / VACOP-B Rituximab IFRT- 30 Gy 156 Staging TAC/PET

41 Results of Restaging 1 Complete Response (CR/CRu)20/40 (50%) Partial Response (PR)19/40 (47%) Not Response (NR) 1/40 (3%) Results of Restaging 2 Complete Response (CR/CRu)29/40 (73%) Partial Response (PR)11/40 (27%) Results of restaging 3 Pre-IFRT Post-IFRT Complete Response (CR/CRu)18/27 (66%) 24/27 (89%) Partial Response (PR)9/27 (34%) 3/27 (11%) Response evaluation

42 Progression Free Survival R- M/VACOP-B +IFRT: a prospective study in 40 pts Martelli M. on behalf of IIL: EHA %

43 Raccomandazioni (3) Rituximab combination with chemotherapy is highly suggested but only for patients enrolled into approved clinical trials. (grade C) Linee guida SIE, SIES, GITMO per i LNH extranodali

44 PML restaging after CHT – Residual mass negative complete response IMMAGINI PET-TC

45 PML restaging after CHT – Residual mass positive

46

47

48 Aims of the trial Primary objectives: To analyse the phenotype and molecular characteristics of Primary Mediastinal Large B-cell Lymphoma To determine the PET response rate following chemo- immunotherapy Secondary objectives: To obtain data, on a non-randomised basis, regarding the outcomes of treatment using different chemotherapy regimens. The impact of mediastinal radiotherapy depending upon the practice of the participating institutions. Progression free and overall survival will be analysed.

49 Registration Patients will be centrally registered at the IELSG Coordination and Data Management Office. Patients enrolled from IIL institutions will be centrally registered at the I.I.L Data Center, Modena: For I.I.L. centers Data Center, Modena From IIL Data Center the registration form should be submitted to IELSG Study Coordination and Data Management Office IELSG Study Coordination and Data Management Office: Fax: Patients fulfilling the eligibility criteria will then be registered and a notification sent back within 48 hours to the investigator. Treatment should start within 15 days from registration.

50 Raccomandazioni (4) Patients should receive an early evaluation with CT scan during the first courses of chemotherapy (about half of the programmed courses), in order to identify patients with inadequate response, i.e. less than partial response (grade D). Patients with an inadequate early response should be candidate to early intensification with high-dose chemotherapy (grade C). At the end of chemotherapy, patients should be evaluated with CT scan and PET, in order to assess a progression occurred in the second half of the chemotherapy period (grade D). Linee guida SIE, SIES, GITMO per i LNH extranodali

51 Raccomandazioni No definite recommendation can be currently formulated for patients without a bulky disease who achieve a PET-negative state at the end of chemotherapy: radiotherapy is less strongly recommended in such a clinical subset. Linee guida SIE, SIES, GITMO per i LNH extranodali

52 High dose Chemotherapy and ASCT for relapsed and refractory DLBCL. Favorable outcome for PMBCL Popat et al. J.Clin..Oncol 1998 Tot. 90 pts DLBCL = 59 PMBCL = 31

53 PMBCL: outcome following High-Dose Chemotherapy and ASCT retrospective analysis in 35 patients with PMBCL Sehn et al Blood 1998

54 PMBCL: outcome following High-Dose Chemotherapy and ASCT by disease status at transplantation Sehn et al Blood 1998

55 PMBCL: long-term results from MSKCC Event Free-Survival Overall Survival

56 Raccomandazioni (6) Patients with refractory or relapsed disease should undergo rescue programs including intensive, non-cross-resistant debulkying treatment followed, in chemosensitive patients, by high-dose chemotherapy and autologous SCT (grade B). Linee guida SIE, SIES, GITMO per i LNH extranodali

57 PMBCL: conclusions and open questions Better prognosis with weekly III generation regimens Benefit of Rituximab plus chemotherapy Residual mass:TC/PET response after chemotherapy

58 PMBCL: conclusions and open questions Better prognosis with weekly III generation regimens Benefit of Rituximab plus chemotherapy Residual mass:TC/PET response after chemotherapy Role of consolidation radiotherapy (PET neg) Early HDT-ASCT in poor prognosis patients Radioimmunotherapy in refractory/relapse patients

59 PMBCL: conclusions and open questions Better prognosis with weekly III generation regimens Benefit of Rituximab plus chemotherapy Residual mass:TC/PET response after chemotherapy Role of consolidation radiotherapy (PET neg) Early HDT-ASCT in poor prognosis patients Radioimmunotherapy in refractory/relapse patients

60 Espressione del CD20 nello sviluppo delle cellule B Cellula staminale pluripotent e Cellula staminale linfoide Cellula pre-B Cellula BCellula B attivata Plasma cellula Midollo OsseoSangue, linfa CD20 Press OW, Semin Oncol 1999; 265 (suppl 14): 58-65

61 Il CD20 è il bersaglio ideale per la radioimmunoterapia Antigene CD20: - Bersaglio comprovato per i linfomi - Espresso solo dalla linea cellulare B - Non è modulato dal legame con lanticorpo 90 Y Cellula B maligna Antigene CD20 Ibritumomab Tiuxetano Zevalin ® Wood AM, Am J Health Sys Pharm 2001; 58: Krasner C, Curr Pharma Biotech 2001; 2:

62 Bexxar (I-131- Tositomomab) RIT Bexxar® (I-131- Tositomomab) RIT 131-Iodine T 1/2 = 193 hours Inpatient administration Beta emission 90 = 0.8 mm Gamma emission I-131 Tositumomab Murine anti- CD20

63 90 Y 131 I Choice of Isotope The higher beta energy and longer path length of yttrium-90 ( 90 Y) make it a superior isotope for radioimmunotherapy (RIT)

64 Radioterapia esterna vs radioimmunoterapia Radioterapia esterna Radioimmunoterapia

65 Il trattamento con radioimmunoterapia richiede competenze coordinate multidisciplinari Patient Haematology Oncology Nuclear medicine Radio- pharmacy Radiation safety Nursing

66 La radioimmunoterapia nel trattamento del LNH 90 Y Anticorpo nudo Zevalin ® Razionale per luso di Zevalin ® nel trattamento dei LNH: - Le cellule del linfoma sono radiosensibili - Zevalin ® distrugge anche le cellule tumorali non direttamente legate effetto di fuoco incrociato - È efficace nei tumori bulky o poco vascolarizzati - Più sedi di malattia possono essere trattate simultaneamente -Lesposizione alle radiazioni dei tessuti sani è limitata

67 Zevalin: Treatment schema Cold anti-CD20 antibody* (Rituximab 250 mg/m 2 ) First pre-dosePre-dose + Zevalin ® Day Followed by 90 Y-Zevalin ® (15 or 11 MBq/kg BW; max dose 1200 MBq) *Dose of cold anti-CD20 monoclonal antibody to optimize biodistribution of Zevalin ® BW, body weight Zevalin ® Summary of Product Characteristics (SmPC), EMEA 2004

68 Zevalin ® vs Rituximab Randomised Phase III Trial in FBCL : Response Rates * * * Witzig et al. J Clin Oncol 2002; 20:2453–2463 Zevalin ® (n = 73) Rituximab (n = 70) Patients (%) p = p = OR CR 4 CRu 4

69

70 Morschhauser F, et al. Blood. 2004;104:41a. Abstract % 12 (36%) 3 (9%) 4 (12%) Ricaduti >1 anno (n = 19) 40% 2 (20%) – 2 (20%) Ricaduti 1 anno (n = 4) R-chemio (B) Chemioterapia (A) Parametri 20% 1 (4%) 2 (8%) 53% 7 (22%) 1 (3%) 9 (28%) ORR CR CRu PR n = 5 Refrattari (n = 17) 90 Y Ibritumomab Tiuxetano in seconda linea nel DLBCL: Risultati

71 Studio di Fase II in pazienti anziani con DLCBL allesordio : CHOP e 90 Y Ibritumomab Tiuxetano sequenziali - Bologna CHOP (21) x 6 cicli 90 Y Ibritumomab tiuxetano 6-10 settimane dopo CHOP Ristadiazione 4-6 settimane dopo CHOP 20 pazienti arruolati

72 Studio di Fase II in pazienti anziani ad alto rischio con DLBCL non trattato : R-CHOP e 90 Y Ibritumomab Tiuxetano sequenziali Hamlin et al. Blood. 2005; 106 (11). Abstract 926. R-CHOP (21) 6 cicli + darbepoetin Ristadiazione tra il ciclo 4 e 5 Ristadiazione 4–5 settimane dopo R-CHOP Ristadiazione 12 – 13 settimane dopo RIT 90 Y Ibritumomab tiuxetano 6–9 settimane dopo R-CHOP

73 Fase III nel DLBCL in pazienti anziani non trattati: Studio randomizzato con 90 Y Ibritumomab Tiuxetano vs osservazione dopo CHOP-R CR/CRu 90 Y ibritumomab tiuxetano (0.4 mCi/kg) Osservazione Pazienti con DLBCL, non trattati, di stadio II-IV, età 60 End point primario: Sopravvivenza globale R-CHOP (21) x 8 PI: Franck Morschhauser Randomizzazione (Inizio dello studio) (Inizio dello studio)

74 Uso di Zevalin nella terapia ad alte dosi + CSP Zevalin + CHT ad alte dosi (Z- BEAM) Zevalin in sostituzione della TBI (Z-VP16/Cy) Zevalin a dosi scalari

75 d-21d-14from d-7 to d-2d 0d+14 R R+Z BEAM PBSCPBSC* R: rituximab 250 mg/m 2 Z: 90 Y-ibritumomab tiuxetan 0.4 mCi/kg BEAM: BCNU 300 mg/m 2 d-7; Etoposide 100 mg/m 2 /12h and Ara-C 400 mg/m 2 d ; Melphalan 140 mg/m 2 d-2 PBSC: CD34+ 5x10 6 /kg PBSC*: additional infusion if ANC<0.5x10 9 /L on d+14 Z-BEAM:Study design Morra et al : Intergruppo Italiano Linfomi

76 PMBCL early non response MACOP-B + IEV+ Z-BEAM R-MACOP-B x 6 cicli R-IEV x 2Z-BEAM PR < 50 % PSCT

77 Salvage treatment plus Z-BEAM-ASCT in PMBCL relapse / refractory to standard first line therapy. CR/PR Z-BEAM ASCT End point primario: Relapse Free Survival R-IEV/ DHAP/ ICE

78 Verso una cura dei Linfomi Chemioterapia Chemioterapia + IFRT+ MoAbs + radioimmunotherapy? 90 Y Grazie per lattenzione !!!!


Scaricare ppt "M. Martelli M. Martelli Università degli Studi La Sapienza Roma, Istituto di Ematologia Diagnostic and therapeutic burning questions on lymphoproliferative."

Presentazioni simili


Annunci Google