M. Martelli

1
Diagnostic and therapeutic burning questions on
lymphoproliferative diseases
Rieti 27-29 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

4
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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 91027-1029, 1998
11
PMBCL MACOP-B IFRT is an effective therapy
Martelli et al Annals of Oncology 91027-1029,
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
PMBCL a clinical study of 89 patients treated
with MACOP-B and IFRT
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
N
MACOP / VACOP-B
CHOP
Todeschini et al B.J.Cancer 2004
18
PMLBCL prognostic factors

• PSgt2, 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 ( 1994-2004)

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 (IPI0-1) 52 (56)
High risk patients (IPI2-3) 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) 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
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
Chemoradiotherapy compared to Chemotherapy alone
in elderly DLCL
Results of the LNH93-4 GELA Study.
DLCL 576 pts gt60 stage I-II IPI0
CHOP x 4 (277 pts)
CHOP x 4 IFRT (299 pts)
5y-EFS 5-OS 5y-EFS gt 70 5y-OS gt 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
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
IFRT
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
Rituximab plus CHOP for DLBCL
in British Columbia PFS by treatment era
1.0 0.8 0.6 0.4 0.2 0
Post-rituximab
Probability of survival
Pre-rituximab
p0.0009
0 1 2 3 4
Years
Sehn LH, et al. J Clin Oncol 200523502733
29
Chemo (n410)
R-Chemo (n413)
CHOEP-21 44 44 CHOP-21 48 48
MACOP-B 4 4 PMitCEBO 4 4
30
R-CHEMO (n413)
79.9
p 0. 00 0 0 00 00 7
60.8
Probability
CHEMO (n410)
Months
Preunduschuh et al
ASCO 2005
31
Overall Survival
95
p0.00 02
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
82.9
.9
R-CHOP(n197)
.8
p lt 0. 00 00 00 05
.7
55.3
CHOP (n197)
.6
Probability
.5
.4
.3
.2
.1
0.0
50
45
40
35
30
25
20
15
10
5
0
Months
MInT June2005
33
Time to Treatment Failure
CHOP vs. CHOEP
1.0
.9
65.1
.8
.7
CHOEP (n180)
.6
Probability
CHOP (n187)
55.3
.5
.4
.3
.2
p 0.04
.1
0.0
50
45
40
35
30
25
20
15
10
5
0
Months
MInT June2005
34
Time to Treatment Failure
R-CHOP vs. R-CHOEP
CHOP vs. CHOEP
1.0
1.0
82.9
R-CHOP (n197)
.9
.9
65.1
.8
.8
80.4
.7
.7
CHOEP (n180)
.6
.6
Probability
Probability
CHOP (n187)
55.3
.5
.5
R-CHOEP (n181)
.4
.4
.3
.3
.2
.2
p 0.67
p 0.04
.1
.1
0.0
0.0
50
45
40
35
30
25
20
15
10
5
0
50
45
40
35
30
25
20
15
10
5
0
Months
Months
MInT June2005
35
R-CHOP (2006)
CHOEP (2001-2003)
CHOP-21 (1975-2001)
Surviving
40
20
0
0
1
2
3
4
M O N T H S
36
The Vancouver ExperienceSavage et al. 9-ICML,
Lugano 2005
37
Dose-Adjusted EPOCH-R
Dose
Treatment
2
mg/m
/day
Days
Infusional Agents
50
Etoposide
0.4 (No cap)
Days 1,2, 3, 4
Vincristine
10
Doxorubicin
Bolus Agents
Cycle 21 Days for 6-8 cycles
Days 1, 2, 3, 4
60 BID
Prednisone
Day 5
750
Cyclophosphamide
Biologic Agents
Rituximab 375
Day 1
Filgrastim 5 (?g/kg)
Days 6 ? ANC recovery
NO RADIATION ADMINISTERED
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-FFS 3y-OS 3y-LSS 3y-EFS
CHOP 51 66 66 51
R-CHOP 95 96 100 91
P value P 0.001 P0.03 P0.008 P0.003
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
1Rest. (TAC/PET)
2Rest.(TAC/PET)
1
2
3
4
5
6
7
8
9
10
11
12
2
3
4
1
5
6
M / VACOP-B

Rituximab
18
3Rest.TAC/PET
IFRT- 30 Gy
41
Response evaluation
Results of Restaging 1
Complete Response (CR/CRu) Complete Response (CR/CRu) 20/40 (50)
Partial Response (PR) Partial Response (PR) 19/40 (47)
Not Response (NR) Not Response (NR) 1/40 (3)
Results of Restaging 2
Complete Response (CR/CRu) Complete Response (CR/CRu) 29/40 (73)
Partial Response (PR) 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
IMMAGINI PET-TC
PML restaging after CHT Residual mass
negative
complete response
45
IMMAGINI PET-TC
PML restaging after CHT Residual mass
positive
46
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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 Secon
dary 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 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 [phone] E-mail
ielsg_at_ticino.com 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. 90 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
Overall Survival
Event Free-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 massTC/PET response after chemotherapy

58
PMBCL conclusions and open questions

• Better prognosis with weekly III generation
  regimens
• Benefit of Rituximab plus chemotherapy
• Residual massTC/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 massTC/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
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 lanticorpo

Antigene CD20
Zevalin
90Y
Ibritumomab
Tiuxetano
Wood AM, Am J Health Sys Pharm 2001 58
215-229 Krasner C, Curr Pharma Biotech 2001 2
341-349
62
Bexxar (I-131- Tositomomab) RIT
I-131 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)

131I
90Y
64
Radioterapia esterna vs radioimmunoterapia
Radioterapia esterna
Radioimmunoterapia
65
Il trattamento con radioimmunoterapia richiede
competenze coordinate multidisciplinari
Haematology Oncology
Nuclearmedicine
Patient
Radio-pharmacy
Nursing
Radiationsafety
66
La radioimmunoterapia nel trattamento del LNH
Anticorpo nudo

• 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

Zevalin
90Y
90Y
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 BWmax
dose 1200 MBq)
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
p 0.002
OR
CRu
p 0.04
CR
100
80
80
56
60
Patients ()
4
40
4
20
30
16
0
Zevalin (n 73)
Rituximab(n 70)
Witzig et al. J Clin Oncol 2002 2024532463
69
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70
90Y Ibritumomab Tiuxetano in seconda linea nel
DLBCL Risultati
R-chemio (B)
Chemioterapia (A)
Parametri
Ricaduti gt1 anno (n 19)
Ricaduti 1 anno
(n 4)
n 5
Refrattari (n 17)
58 12 (36) 3 (9) 4 (12)
40 2 (20) 2 (20)
20 1 (4) 2 (8) 2 (8)
53 7 (22) 1 (3) 9 (28)
ORR CR CRu PR
Morschhauser F, et al. Blood. 200410441a.
Abstract 130.
71
Studio di Fase II in pazienti anziani con DLCBL
allesordio CHOP e 90Y Ibritumomab Tiuxetano
sequenziali - Bologna
90Y Ibritumomab tiuxetano 6-10 settimane dopo CHOP
CHOP (21) x 6 cicli
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 69 settimane dopo
R-CHOP
Ristadiazione tra il ciclo 4 e 5
Ristadiazione 45 settimane dopo R-CHOP
Ristadiazione 1213 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)
CR/CRu
R-CHOP (21) x 8
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-BEAMStudy design
R
RZ
PBSC
PBSC
BEAM
d-21
d-14
from d-7 to d-2
d 0
d14
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 ANClt0.5x109/L on
d14
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 lt 50
77
Salvage treatment plus Z-BEAM-ASCT in PMBCL
relapse / refractory to standard first line
therapy.
Z-BEAM ASCT
R-IEV/ DHAP/ ICE
CR/PR

• End point primario Relapse Free Survival

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