M. MartelliM. Martelli
Università degli Studi “ La Sapienza” Università degli Studi “ La Sapienza” Roma , Istituto di EmatologiaRoma , Istituto di Ematologia
Diagnostic and therapeutic burning questions on lymphoproliferative diseases Rieti 27-29 Ottobre 2006
Linfomi primitivi del mediastino:
Dalla chemioradioterapia convenzionale alleattuali possibilità di integrazione dellachemioterapia con anticorpi radiomarcati
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 !!!!!!!
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
• 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
PMBCL: a clinic study of 43 patients treated with CAP/BOP from the Nebraska Lymphoma Study Group
Abou-Elella A. et al: JCO 1990
PMLBCL DLBCL
Survival comparison according to IPI score
Abou-Elella A. et al: JCO 1990
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
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
Primary mediastinal large B-cell lymphoma
Annals of Oncology 9:1027-1029, 1998
PMBCL: MACOP-B + IFRT is an effective therapy
Martelli et al: Annals of Oncology 9:1027-1029, 1998
Blood 94 (10):3289, 1999Blood 94 (10):3289, 1999
Zinzani P.L, Martelli M, Magagnoli M, et al. Blood, 1999
PMBCL : MACOP-B + mediastinal IFRT in 50 pts
Relapse Free Survival
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
Zinzani P.L, Martelli M, Bertini M, et al. Haematologica 2002
Primary mediastinal large B-cell lymphoma
Zinzani P.L, Martelli M, Bertini M, et al. Haematologica, 2002
PMBCL: IELSG retrospective study in 426 patients
PMBCL: retrospective multicentre Italian study in 138 pts
Todeschini et al B.J.Cancer 2004
NMACOP / VACOP-B
CHOP
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.
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%)
MACOP-B plus radiotherapy as first line therapy for PMLBCL with sclerosis : a clinical study on 92 patients ( 1994-2004)
Finolezzi E, Natalino F, Martelli M. et al. SIE 2005 EHA 2005
Results
After MACOP-B CR/CRu PR NR Death toxic
72 (78%)18 (20%) 1 (1%)1 (1%)
After RT CR/CRu PR NR
78 (91%)3 (3%)5 (6%)
Relapses(median follow-up of 58 months)
9 (12%)
overall survival
0
10
20
30
40
50
60
70
80
90
100
0 20 40 60 80 100 120 140 160 180
months
%
88%
Martelli M , Finolezzi E et al. SIE 2005 EHA 2005
progression free survival
0
10
20
30
40
50
60
70
80
90
100
0 50 100 150 200
months
%
85%
Martelli M , Finolezzi E et al. SIE 2005 EHA 2005
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)
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 5y-EFS
> 70
5y-OS
> 70
CHOP 68 72 62 70
CHOP +RT 66 68 60 58
P value n.s n.s n.s 0.01
Fillet et al ASH 2005
Zinzani P.L, Martelli M, Magagnoli M, et al. Blood, 1999
PMBCL : MACOP-B + mediastinal IFRT in 50 pts
PMBCL: role of mediastinal IFRT in a retrospective study
Todeschini et al B.J.Cancer 2004
IFRT
NO-IFRT
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
Rituximab plus CHOP for DLBCL in British Columbia: PFS by treatment era
1.0
0.8
0.6
0.4
0.2
0
Years
Pro
bab
ilit
y o
f su
rviv
al
0 1 2 3 4
Post-rituximab
Pre-rituximab
p=0.0009
Sehn LH, et al. J Clin Oncol 2005;23:5027–33
CHOEP-21 44% 44%
CHOP-21 48% 48%
MACOP-B 4% 4%
PMitCEBO 4% 4%
ChemotherapyChemo (n=410)
R-Chemo
(n=413)
Preunduschuh et al ASCO 2005
Months
Pro
bab
ility
79.9%
60.8% p = 0. 00 0 0 00 00 7
50454035302520151050
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.10.0
R-CHEMO(n=413)
CHEMO(n=410)
Time to Treatment Failure
Overall Survival
median observation time: 23 months
50454035302520151050
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.10.0
Months
Pro
bab
ility
R-CHEMO
CHEMO
95%
86%p=0.00 02
MInT June 05
Lymphoma-associated deaths:CHEMO: 42R-CHEMO: 13
MInT June2005
50454035302520151050
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.10.0
Months
Pro
bab
ility
R-CHOP(n=197)
CHOP (n=197)
82.9%
55.3%
p < 0. 00 00 00 05
Time to Treatment Failure
CHOP vs R-CHOP
MInT June2005
Time to Treatment Failure
CHOP vs. CHOEP
50454035302520151050
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
CHOP(n=187)
CHOEP(n=180)
55.3%
65.1%
p = 0.04
Months
Pro
bab
ility
MInT June2005
Time to Treatment Failure
CHOP vs. CHOEP R-CHOP vs. R-CHOEP
50454035302520151050
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
55.3%
65.1%
p = 0.04
Months
Pro
bab
ility
Months
Pro
bab
ility
50454035302520151050
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
R-CHOEP(n=181)
80.4%
82.9%
p = 0.67
CHOP(n=187)
CHOEP(n=180)
R-CHOP(n=197)
0
20
40
0 1 2 3 4
CHOP-21(1975-2001)
CHOEP(2001-2003)
R-CHOP(2006)
% S
urv
ivin
g
M O N T H S
Progress in the treatment of Young good-prognosis DLBCL
The Vancouver ExperienceSavage et al. 9-ICML, Lugano 2005
Dosemg/m2/day
EtoposideVincristineDoxorubicin
CyclophosphamidePrednisone
Cycle 21 Daysfor 6-8 cycles
500.4 (No cap) 10
75060 BID
Days 1,2, 3, 4
Day 5Days 1, 2, 3, 4
Treatment Days
Infusional Agents
Bolus Agents
Biologic AgentsRituximab 375 Day 1
Dose-Adjusted EPOCH-R
NO RADIATION ADMINISTERED
Filgrastim 5 (g/kg) Days 6 ANC recovery
Dunleavy et al ASH 2005
PMBCL: effect of Rituximab in DA-EPOCH
DA-EPOCH DA-EPOCH-R
Perc
ent
0
20
100
80
60
40
Years on Study 1 2
PFS: 64%
5 6 7
Median Follow-up: 8.5 years
83 4 9 10
OS: 79%
Patients accrued: 14
Perc
ent
0
20
100
80
60
40
Months on Study 12 24
PFS: 93% and OS:100%
36 48 60
Median Follow-up: 36 months
72
Patients accrued: 18
Dunleavy et al ASH 2005
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 66 51
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
R-M/VACOP-B +IFRT: prospective study in
40 patients with PMBCL
1°Rest. (TAC/PET) 2°Rest.(TAC/PET)
1 2 3 4 5 6 7 8 9 10 11 12
2 3 4
18 3°Rest.TAC/PET
M / VACOP-B
Rituximab
IFRT- 30 Gy
1 5 6
StagingTAC/PET
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 2Complete 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
0 6 12 18 24 30 36 42 48
Months
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Pro
ba
bil
ity
Disease free survivalProgression Free Survival
R- M/VACOP-B +IFRT: a prospective study in 40 pts
Martelli M. on behalf of IIL: EHA 2006
78%
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
PML restaging after CHT – Residual mass negative complete response
IMMAGINI PET-TC
IMMAGINI PET-TC
PML restaging after CHT – Residual mass positive
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.
RegistrationPatients 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 www.iilinf.it 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: +41 91 811 91 82 E-mail: [email protected]
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.
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
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
High dose Chemotherapy and ASCT for relapsed and refractoryDLBCL. Favorable outcome for PMBCL
Popat et al. J.Clin..Oncol 1998
Tot. 90 pts
DLBCL = 59PMBCL = 31
PMBCL: outcome following High-Dose Chemotherapy and ASCT retrospective analysis in 35 patients with PMBCL
Sehn et al Blood 1998
PMBCL: outcome following High-Dose Chemotherapy and ASCT by disease status at transplantation
Sehn et al Blood 1998
PMBCL: long-term results from MSKCC
Event Free-Survival Overall Survival
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
PMBCL: conclusions and open questions
• Better prognosis with weekly III generation regimens
• Benefit of Rituximab plus chemotherapy
• Residual mass:TC/PET response after chemotherapy
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
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
Espressione del CD20 nello sviluppo delle cellule B
Espressione del CD20 nello sviluppo delle cellule B
Cellula staminale
pluripotente
Cellula staminale linfoide
Cellula pre-B
Cellula B Cellula B attivata
Plasma cellula
Midollo Osseo Sangue, linfa
CD20
Press OW, Semin Oncol 1999; 265 (suppl 14): 58-65
Il CD20 è il bersaglio ideale per la radioimmunoterapia 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 l’anticorpo
90Y
Cellula B maligna
AntigeneCD20
IbritumomabTiuxetano
Zevalin®
Wood AM, Am J Health Sys Pharm 2001; 58: 215-229Krasner C, Curr Pharma Biotech 2001; 2: 341-349
BexxarBexxar® (I-131- Tositomomab) RIT (I-131- Tositomomab) RIT
131-Iodine•T1/2 = 193 hours•Inpatient administration•Beta emission 90 = 0.8 mm•Gamma emission
I-131 I-131 TositumomabTositumomabMurine anti-Murine anti-CD20CD20
90Y 131I
Choice of Isotope• The higher beta energy and longer path length of
yttrium-90 (90Y) make it a superior isotope for radioimmunotherapy (RIT)
Radioterapia esterna vs radioimmunoterapia Radioterapia esterna vs radioimmunoterapia
Radioterapia esterna Radioimmunoterapia
Il trattamento con radioimmunoterapia richiede competenze coordinate multidisciplinari
Patient
Haematology
OncologyNuclear
medicine
Rad
io-
ph
armacy
Radiationsafety
Nu
rsin
g
La radioimmunoterapia nel trattamento del LNHLa radioimmunoterapia nel trattamento del LNH
90Y
90Y
90Y
Anticorpo nudo
Zevalin®
• 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: Treatment schema
Cold anti-CD20 antibody*(Rituximab 250 mg/m2)
Cold anti-CD20 antibody*(Rituximab 250 mg/m2)
First pre-dose Pre-dose + Zevalin®
Day 81 2 3 4 5 6 7
Followed by90Y-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 weightZevalin® Summary of Product Characteristics (SmPC), EMEA 2004
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)
1630
0
20
40
60
80
100
Patients Patients (%)(%)
p = 0.002
p = 0.04
80
56
OR
CR
4
CRu
4
Morschhauser F, et al. Blood. 2004;104:41a. Abstract 130.
58%
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%)
2 (8%)
53%
7 (22%)
1 (3%)
9 (28%)
ORR
CR
CRu
PR
n = 5
Refrattari
(n = 17)
90Y Ibritumomab Tiuxetano in seconda linea nel DLBCL: Risultati
Studio di Fase II in pazienti anziani con DLCBL all’esordio : CHOP e 90Y Ibritumomab
Tiuxetano sequenziali - Bologna
CHOP (21) x 6 cicli90Y Ibritumomab tiuxetano6-10 settimane dopo CHOP
Ristadiazione 4-6 settimane dopo CHOP
20 pazienti arruolati
Studio di Fase II in pazienti anziani ad alto rischio con DLBCL non trattato : R-CHOP e
90Y Ibritumomab Tiuxetano sequenziali
Hamlin et al. Hamlin et al. BloodBlood. 2005; 106 (11). Abstract 926.. 2005; 106 (11). Abstract 926.
R-CHOP (21) 6 cicli + darbepoetin
Ristadiazione tra
il ciclo 4 e 5
Ristadiazione4–5 settimanedopo R-CHOP
Ristadiazione12–13 settimane
dopo RIT
9090Y Ibritumomab tiuxetanoY Ibritumomab tiuxetano6–9 settimane dopo R-CHOP
Fase III nel DLBCL in pazienti anziani non trattati: Studio randomizzato con 90Y Ibritumomab Tiuxetano vs osservazione dopo CHOP-R
CR/CRu
90Y 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
RandomizzazioneRandomizzazione
(Inizio dello studio)(Inizio dello studio)
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
d-21 d-14 from d-7 to d-2
d 0 d+14
R R+Z BEAM PBSC PBSC*
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-6-5-4-3; Melphalan 140 mg/m2 d-2
PBSC: CD34+5x106/kg
PBSC*: additional infusion if ANC<0.5x109/L on d+14
Z-BEAM:Study design
Morra et al : Intergruppo Italiano Linfomi
PMBCL early non response MACOP-B + IEV+ Z-BEAM
R-MACOP-B x 6 cicli R-IEV x 2 Z-BEAM
PR < 50 %
PSCT
Salvage treatment plus Z-BEAM-ASCT in PMBCL relapse / refractory to standard first line therapy.
CR/PRZ-BEAM
ASCT
• End point primario: Relapse Free Survival
R-IEV/ DHAP/ ICE
Verso una cura dei Linfomi
ChemioterapiaChemioterapia + IFRT+ MoAbs + radioimmunotherapy?
90Y
Grazie per l’attenzione !!!!
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