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: ielsg@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.

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 !!!!