Università degli Studi “ La Sapienza” Roma , Istituto di Ematologia

Presentazione sul tema: "Università degli Studi “ La Sapienza” Roma , Istituto di Ematologia"— Transcript della presentazione:

1 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 M. Martelli Università degli Studi “ La Sapienza” Roma , Istituto di Ematologia

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

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5 Questions to expert panel
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? 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 Survival comparison according to IPI score
PMLBCL DLBCL Abou-Elella A. et al: JCO 1990

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

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

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

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

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

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

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 MACOP-B plus radiotherapy as first line therapy for PMLBCL with sclerosis : a clinical study on 92 patients ( ) Patients 92 Age (mean age) 33 (range 15-61) Sex (M/F) 24/68 Stage II 72 (78%) IIE-IV 20 (22%) B symptoms 43 (47%) Increased LDH values 68 (74%) Bulky mass at presentation 81 (88%) Superior vena cava syndrome 47 (51%) Low risk patients (IPI=0-1) 52 (56%) High risk patients (IPI=2-3) 40 (44%) 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 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 Martelli M , Finolezzi E et al. SIE 2005 EHA 2005

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 DLCL= 576 pts CHOP x 4 CHOP x 4 + IFRT
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-EFS 5-OS > 70 5y-OS CHOP 68 72 62 70 CHOP +RT 66 60 58 P value n.s 0.01 Fillet et al ASH 2005

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

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

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 Probability of survival
Rituximab plus CHOP for DLBCL in British Columbia: PFS by treatment era 1.0 0.8 0.6 0.4 0.2 Post-rituximab Probability of survival Pre-rituximab p=0.0009 Years Sehn LH, et al. J Clin Oncol 2005;23:5027–33

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

30 Time to Treatment Failure
50 45 40 35 30 25 20 15 10 5 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 0.0 R-CHEMO (n=413) 79.9% 60.8% p = Probability CHEMO (n=410) Months Preunduschuh et al ASCO 2005

31 Overall Survival R-CHEMO CHEMO 95% p=0.00 02 86% Probability
50 45 40 35 30 25 20 15 10 5 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 0.0 Months Probability R-CHEMO CHEMO p= 86% Lymphoma-associated deaths: CHEMO: 42 R-CHEMO: 13 median observation time: 23 months MInT June 05

32 Time to Treatment Failure
CHOP vs R-CHOP 1.0 .9 82.9% R-CHOP(n=197) .8 p < .7 55.3% CHOP (n=197) Probability .6 .5 .4 .3 .2 .1 0.0 5 10 15 20 25 30 35 40 45 50 Months MInT June2005

33 Time to Treatment Failure
CHOP vs. CHOEP 1.0 .9 .8 65.1% .7 CHOEP (n=180) Probability .6 CHOP (n=187) .5 55.3% .4 .3 .2 p = 0.04 .1 0.0 5 10 15 20 25 30 35 40 45 50 Months MInT June2005

34 Time to Treatment Failure
CHOP vs. CHOEP R-CHOP vs. R-CHOEP 1.0 1.0 82.9% .9 R-CHOP (n=197) .9 .8 65.1% .8 80.4% .7 CHOEP (n=180) .7 Probability .6 Probability .6 CHOP (n=187) .5 55.3% .5 R-CHOEP (n=181) .4 .4 .3 .3 .2 .2 p = 0.04 p = 0.67 .1 .1 0.0 0.0 5 10 15 20 25 30 35 40 45 50 5 10 15 20 25 30 35 40 45 50 Months Months MInT June2005

35 Progress in the treatment of Young good-prognosis DLBCL
R-CHOP (2006) CHOEP ( ) CHOP-21 ( ) % Surviving 40 20 1 2 3 4 M O N T H S

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

37 Dose-Adjusted EPOCH-R
Treatment mg/m 2 /day Days Infusional Agents Etoposide 50 0.4 (No cap) Days 1,2, 3, 4 Vincristine Doxorubicin 10 Bolus Agents Cycle 21 Days for 6-8 cycles Days 1, 2, 3, 4 Prednisone 60 BID Cyclophosphamide 750 Day 5 Biologic Agents Rituximab Day 1 Filgrastim (g/kg) Days 6  ANC recovery NO RADIATION ADMINISTERED Dunleavy et al ASH 2005

38 PMBCL: effect of Rituximab in 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-FFS 3y-OS 3y-LSS 3y-EFS CHOP 51 66 R-CHOP 95 96 100 91 P value P= 0.001 P=0.03 P=0.008 P=0.003 Vassilakopoulos et al, et al ASH 2005, EHA 2006

40 R-M/VACOP-B +IFRT: prospective study in 40 patients with PMBCL
Staging TAC/PET 1°Rest. (TAC/PET) 2°Rest.(TAC/PET) 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 M / VACOP-B Rituximab 18 3°Rest.TAC/PET IFRT- 30 Gy

41 Response evaluation Results of Restaging 1 Results of Restaging 2
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%)

42 R- M/VACOP-B +IFRT: a prospective study in 40 pts
Progression Free Survival 78% Martelli M. on behalf of IIL: EHA 2006

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 PML restaging after CHT – Residual mass negative complete response

45 IMMAGINI PET-TC 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 Tot pts DLBCL = 59 PMBCL = 31 Popat et al. J.Clin..Oncol 1998

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
Midollo Osseo Sangue, linfa Utilizzando come bersaglio l’antigene CD20 nella RIT, si colpiscono le cellule B ma non le cellule staminali né le plasmacellule. Il CD20 è espresso sulla superficie delle cellule B normali mature e in più del 90% delle neoplasie a cellule B.16 La continuità della linea cellulare è mantenuta dopo la RIT dal momento che il CD20 non è espresso dalle cellule staminali ematopoietiche pluripotenti e dai progenitori delle cellule B.17 16. Press OW. Radiolabeled antibody therapy of B-cell lymphomas. Semin Oncol 1999; 26: 5 (suppl 14): 17. Wood AM. Rituximab: an innovative therapy for non-hodgkin lymphoma. Am J Health Sys Pharm 2001; 58: Cellula staminale pluripotente Cellula staminale linfoide Cellula pre-B Cellula B Cellula B attivata Plasma cellula CD20 Press OW, Semin Oncol 1999; 265 (suppl 14): 58-65

61 Il CD20 è il bersaglio ideale per la radioimmunoterapia
Cellula B maligna Antigene CD20: - Bersaglio comprovato per i linfomi - Espresso solo dalla linea cellulare B - Non è modulato dal legame con l’anticorpo Antigene CD20 Zevalin® Il CD20 è il bersaglio ideale per le terapie dei LNH a cellule B perché è un antigene specifico delle cellule B, rimane legato alle cellule e non viene modulato dal legame con l’anticorpo.17 L’antigene CD20 è una proteina di superficie cellulare espressa a livelli relativamente alti sulle cellule dei LNH, ma non sulle cellule ematopoietiche e sulle plasmacellule mature.17,18 Gli anticorpi monoclonali diretti contro il CD20 hanno dimostrato di essere in grado di riconoscere le cellule B dei LNH.17 Il CD20 non è presente nella circolazione ematica come proteina libera che potrebbe influenzare la terapia con anticorpi, né viene rilasciato dalla superficie cellulare.17 Zevalin®, costituito da un anticorpo monoclonale anti-CD20 coniugato con il radioisotopo ittrio-90 (90Y), veicola particelle radioattive sulla superficie delle cellule tumorali, offrendo un approccio terapeutico innovativo per il trattamento dei LNH.18 Wood AM. Rituximab: an innovative therapy for non-Hodgkin’s lymphoma. Am J Health Sys Pharm 2001; 58: Krasner C. Zevalin tm: 90Yttrium labeled anti-CD20 monoclonal antibody for treatment of non-Hodgking’s lymphoma. Curr Pharma Biotech 2001; 2: 90Y Ibritumomab Tiuxetano Wood AM, Am J Health Sys Pharm 2001; 58: Krasner C, Curr Pharma Biotech 2001; 2:

62 Bexxar® (I-131- Tositomomab) RIT
I Tositumomab Murine anti-CD20 131-Iodine T1/2 = 193 hours Inpatient administration Beta emission 90 = 0.8 mm Gamma emission

63 Choice of Isotope The higher beta energy and longer path length of yttrium-90 (90Y) make it a superior isotope for radioimmunotherapy (RIT) 90Y 131I 90Y is a pure, high-energy, beta-emitting isotope that does not emit gamma rays. It delivers 2.3 MeV of particle energy, with a path length (90) of 5.3 mm.1 In contrast, 131I, another radioisotope frequently used in radiotherapy, emits both gamma rays (0.364 MeV) and beta particles (0.6 MeV), with a particle path length (90) of 0.8 mm.1 The beta energy of 131I is lower than that of 90Y, and has a shorter path length. The beta particle path length of 131I is equivalent to approximately 20 cell diameters, whereas the path length of beta emissions from 90Y is equivalent to 100–250 cell diameters.2,3 The gamma radiation from 131I enables direct imaging of the radioisotope in the body, but also necessitates special radiation isolation protocols to minimise the risk of radiation exposure to others.4 1. Kuzel TM, Rosen ST. Radioimmunotherapy of lymphomas and leukemias. In: Henkin RE, Boles MA, Dillehay GL, et al. eds. Nuclear Medicine. Vol. 1. St Louis, MO:Mosby-Year Book Inc;1996:594. 2. Zelenetz AD. Radioimmunotherapy for lymphoma. Curr Opin Oncol 1999;11:375–380. 3. Wiseman GA, White CA, Witzig TE, et al. Radioimmunotherapy of relapsed non- Hodgkin’s lymphoma with Zevalin, a 90Y-labeled anti-CD20 monoclonal antibody. Clin Cancer Res 1999;5(Suppl):3281s–3286s. 4. Press OW. Radiolabeled antibody therapy of B-cell lymphomas. Semin Oncol 1999;26(5 Suppl 14):58–65.

64 Radioterapia esterna vs radioimmunoterapia
La radioimmunoterapia (RIT) colpisce tutte le sedi di malattia (conosciute e non) con ridotta esposizione dei tessuti sani rispetto alla radioterapia esterna. La radioterapia esterna (a fasci) irradia le sedi conosciute di malattia con dosi alte per brevi periodi di tempo, intervallati da ore o giorni.14 Come risultato, le sedi remote di malattia non sono irradiate e una estesa porzione di tessuto sano è esposta alle radiazioni. Al contrario, la RIT è in grado di irradiare sia le sedi note sia le sedi sconosciute di malattia, con un’esposizione minima dei tessuti sani. Una volta che l’anticorpo monoclonale si è legato alla cellula tumorale, la radiazione è emessa continuativamente per giorni o settimane in relazione al tempo di decadimento dell’isotopo legato all’anticorpo.14 Solo nel 10-20% dei pazienti la diagnosi di LNH indolente viene effettuata in stadi molto precoci che rispondono alla radioterapia esterna a fasci.12 14. Press OW. Physics for practitioners: the use of radiolabeled monoclonal antibodies in B-cell non-Hodgkin’s lymphoma. Semin Hematol 2000; 37 (4, suppl 7): 2-8. 12. Vose JM. Classification and clinical course of low-grade non-Hodgkin’s lymphomas with overview of therapy. Ann Oncol 1996; 7 (suppl 6): S13-S19.

65 Il trattamento con radioimmunoterapia richiede competenze coordinate multidisciplinari
Haematology Oncology Nuclear medicine Patient Key Point: Zevalin® administration and management is greatly facilitated by a well-trained multidisciplinary team familiar with the prescribing information instructions. Zevalin® crosses the boundaries of expertise. Collaboration between departments should start early. The involvement of a specialized radiopharmacy department may not apply in some centres. Radio- pharmacy Nursing Radiation safety

66 La radioimmunoterapia nel trattamento del LNH
Anticorpo nudo Razionale per l’uso 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 - L’esposizione alle radiazioni dei tessuti sani è limitata Zevalin® 90Y 90Y Zevalin® è un trattamento radioimmunoterapico che combina la specificità di legame di un anticorpo monoclonale anti-CD20 alla citotossicità della radiazione dell’ittrio-90. 90Y

67 Zevalin: Treatment schema
First pre-dose Pre-dose + Zevalin® Cold anti-CD20 antibody* (Rituximab 250 mg/m2) Cold anti-CD20 antibody* (Rituximab 250 mg/m2) Followed by 90Y-Zevalin® (15 or 11 MBq/kg BW; max dose 1200 MBq) Key Point: The Zevalin® therapeutic regimen is completed in 7 days, with two hospital visits. Day 1 – intravenous infusion of dose of cold anti-CD20 monoclonal antibody (rituximab 250 mg/m2). Day 8 – second intravenous infusion of dose of cold anti-CD20 followed by intravenous infusion of Zevalin®. Dosage of Zevalin® is conveniently based on body weight (BW) and platelet count:1 15 MBq/kg BW in patients with a platelet count  cells/µl 11 MBq/kg BW with a platelet count –< cells/µl Maximum dose is 1200 MBq. Determination of whole-body clearance is not required as there is little interpatient variability and the urinary excretion is low and stable (7% of radioactivity in the first week).2 General performance of dosimetry is not recommended.1 Dosimetry in clinical trials showed there to be no correlation between toxicity and dosimetry, and all values remained well below the thresholds of 400 cGY (bone marrow) and 2000 cGY (other organs).2,3 1. Zevalin Summary of Product Characteristics (SmPC), EMEA 2004. 2. Wagner HN Jr, Wiseman GA, Marcus CS et al. Administration guidelines for radioimmunotherapy of non-Hodgkin’s lymphoma with 90Y-labeled anti-CD20 monoclonal antibody. J Nucl Med 2002;43:267–272. 3. Wiseman GA, Kornmehl E, Leigh B et al. Radiation dosimetry results and safety correlations from 90Y-ibritumomab tiuxetan radioimmunotherapy for relapsed or refractory non-Hodgkin’s lymphoma: combined data from 4 clinical trials. J Nucl Med. 2003;44:465–474. Day 1 2 3 4 5 6 7 8 *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*
OR p = 0.002 CRu p = 0.04 CR 100 80 80 56 60 Patients (%) The ORR based on the International Workshop NHL response criteria was 80% in the Zevalin® arm and 56% in the rituximab arm (p = 0.002).1 The CR rate was 30% in the Zevalin® arm and 16% in the rituximab arm.1 1. Witzig TE, Gordon LI, Cabanillas F, et al. Randomised controlled trials of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular or transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol 2002;20:2453–2463. 4 40 4 20 30 16 Zevalin® (n = 73) Rituximab (n = 70) * Witzig et al. J Clin Oncol 2002; 20:2453–2463

69

70 Ricaduti >1 anno (n = 19)
90Y Ibritumomab Tiuxetano in seconda linea nel DLBCL: Risultati Parametri Chemioterapia (A) R-chemio (B) Refrattari (n = 17) Ricaduti ≤1 anno (n = 4) Ricaduti >1 anno (n = 19) n = 5 ORR CR CRu PR 53% 7 (22%) 1 (3%) 9 (28%) 40% 2 (20%) – 58% 12 (36%) 3 (9%) 4 (12%) 20% 1 (4%) 2 (8%) Results 103 pts were evaluable for efficacy and 104 for safety An ORR of 44% was observed in the entire study population In Group A, the ORR was 52% in stratum 1, 40% in stratum 2, and 58% in stratum 3 In Group B, in which 37% of patients were refractory to CHOP-rituximab, the ORR was 19% The median PFS was 5.9, 2.3, and 6.2 months in strata 1, 2, and 3 of Group A, respectively; the median PFS for Group B was 1.6 months Median OS in Group A was 22.4 months in stratum 3 and has not yet been reached at a maximum follow-up time of 32 months in strata 1 & 2. Median OS was 4.5 months for Group B Morschhauser F, et al. Blood. 2004;104:41a. Abstract 130.

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

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

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

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 Z-BEAM:Study design R R+Z BEAM PBSC PBSC* R: rituximab 250 mg/m2
from d-7 to d-2 d 0 d+14 R: rituximab 250 mg/m2 Z: 90Y-ibritumomab tiuxetan 0.4 mCi/kg BEAM: BCNU 300 mg/m2 d-7; Etoposide 100 mg/m2/12h and Ara-C 400 mg/m2 d ; Melphalan 140 mg/m2 d-2 PBSC: CD34+5x106/kg PBSC*: additional infusion if ANC<0.5x109/L on d+14 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 2 Z-BEAM PSCT PR < 50 %

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

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