i linfomi non-hodgkin: ruolo degli anticorpi radiomarcati · linfomi follicolari? migliorare la...
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Dr.Umberto VitoloSCDO Ematologia 2
Azienda Ospedaliera-UniversitariaSan Giovanni Battista Torino
I Linfomi non-Hodgkin:I Linfomi non-Hodgkin:Ruolo degli anticorpiRuolo degli anticorpi
radiomarcatiradiomarcati
Pre-dose + Zevalin®
Anti-CD20 anticorpo freddo*(Rituximab 250 mg/m2)
giorni 81 2 3 4 5 6 7
Seguito da 90Y-Zevalin®
(15 MBq/kg BW;dose max 1200 MBq)
*Dose of cold anti-CD20 monoclonal antibody to*Dose of cold anti-CD20 monoclonal antibody tooptimize biodistribution of Zevalinoptimize biodistribution of Zevalin® ® BW, bodyBW, bodyweightweight Zevalin® Summary of Product Characteristics (SmPC), EMEA 2004
Prima pre-dose
Anti-CD20 anticorpo freddo*(Rituximab 250 mg/m2)
Zevalin®: schema di trattamentoZevalin®: schema di trattamento
9
o o
Ruolo degli anticorpi radiomarcatiRuolo degli anticorpi radiomarcati
Linfomi Follicolari in recidivaLinfomi Follicolari in recidiva
Linfomi follicolari come consolidamento della rispostaLinfomi follicolari come consolidamento della risposta
In indicazione approvataIn indicazione approvata
In sperimentazione avanzataIn sperimentazione avanzata Linfomi Follicolari in prima linea single agentLinfomi Follicolari in prima linea single agent
Linfomi follicolari o aggressivi in recidiva comeLinfomi follicolari o aggressivi in recidiva come
potenziamento del condizionamento pre trapiantopotenziamento del condizionamento pre trapianto
9090Y-ibritumomab tiuxetan:Y-ibritumomab tiuxetan:indicazioni approvate nella EUindicazioni approvate nella EU
““Trattamento di pazienti adulti con LinfomaTrattamento di pazienti adulti con Linfomafollicolare a cellule B CD20+ resistenti ofollicolare a cellule B CD20+ resistenti o
ricaduti dopo Rituximabricaduti dopo Rituximab”” Gennaio 2004
““Consolidamento della risposta dopoConsolidamento della risposta dopochemioterapia di prima linea nei pazienti adultichemioterapia di prima linea nei pazienti adulti
con Linfoma follicolare a cellule B CD20+. Ilcon Linfoma follicolare a cellule B CD20+. Ilbeneficio nei pazienti pretrattati con Rituximabbeneficio nei pazienti pretrattati con Rituximab
non è dimostratonon è dimostrato”” Marzo 2008
Months
15.0
24.7
15.0
0 5 10 15 20 25
TTP in CR/CRu
10.6
13.4
13.2
10.2
10.1TTP in allpatients
TTP inresponders
TTP infollicularhistology
ZevalinZevalin®: ®: 73 patients73 patients
Rituximab: 70 patientsRituximab: 70 patients
Gordon et al. Clin Lymphoma 2004;5:98-101
Phase III Trial: Zevalin® Increases TTPPhase III Trial: Zevalin® Increases TTPMedian follow-up 44 monthsMedian follow-up 44 months
0%
10%
20%
30%
40%
50%
60%
70%
80%
OR CR
428 pz: R-CHOP x 6-8 vs CHOP x 6-8428 pz: R-CHOP x 6-8 vs CHOP x 6-8Hiddemann W et al: Blood 2005Hiddemann W et al: Blood 2005
R-CHOP
CHOP
State of the art as first line treatment in advancedState of the art as first line treatment in advancedstage FL: Rituximab + any chemotherapystage FL: Rituximab + any chemotherapy
0 20 40 5060
1.00
0.75
0.50
0.25
0
Prog
ress
ion-
free
surv
ival
201 pz FL: R-MCP x 8 vs MCP x 8201 pz FL: R-MCP x 8 vs MCP x 8Herold M et al: ASH 2004Herold M et al: ASH 2004
MCPMCPmedian 19.7 monthsmedian 19.7 months
R-MCP median not reachedR-MCP median not reached(88.5% at 19.7 months)(88.5% at 19.7 months)
R-CVP:mediana 32 mesi
CVP: mediana 15 mesi
321 pz: R-CVP x 8 vs CVP x 8321 pz: R-CVP x 8 vs CVP x 8Marcus R et al: Blood 2005Marcus R et al: Blood 2005
63%63%
78%78%100
75
50
25
0
Rituximab +Rituximab +CHVP/IFNCHVP/IFN
CHVP/IFNCHVP/IFN
Log-rankp=0.0031
358 pz: R-CHVP x 6 + IFN vs CHVP x 6 + IFN358 pz: R-CHVP x 6 + IFN vs CHVP x 6 + IFNSalles G et al: ASH 2005Salles G et al: ASH 2005
IIL-FOLL05: Linfoma Follicolare inIIL-FOLL05: Linfoma Follicolare instadio II-IVstadio II-IV
R-CVP x 3
R-FM x 3
RANDOM
CRPR
R-CHOP x 3 R-CHOP x 3 + 2 R
R-FM x 3 + 2 R
R-CVP x 5
RESTAGING
Quale è la miglior chemioterapia inQuale è la miglior chemioterapia inassociazione al Rituximab?associazione al Rituximab?
Persistance of high risk patients according to FLIPIin Rituximab-CHOP era (Buske et al, Blood 2006)
Good
Intermediate
Poor
MORTALITY ACCORDING TO FLIPP INDEX
Survival probability
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months
0 12 24 36 48 60 72 84
COME è possibile migliorare lCOME è possibile migliorare l’’outcome deioutcome deilinfomi follicolari?linfomi follicolari?
Migliorare la qualità della risposta:Migliorare la qualità della risposta:Risposta MolecolareRisposta Molecolare
Migliorare le percentuali diMigliorare le percentuali diRemissione CompletaRemissione Completa
Aumentare lAumentare l’’efficacia terapeuticaefficacia terapeuticariducendo la tossicità eriducendo la tossicità e
aumentando la possibilità diaumentando la possibilità ditrattamento anche nelltrattamento anche nell’’anzianoanziano
Treatment of NHL: Consolidation options
Chemo + rituximab CRCRPRPR
90Y-ibritumomab tiuxetan
ASCT
No treatment
RituximabRituximab
Poor risk
Relapse, refractoryRelapse, refractoryUpfront lineUpfront lineB-cell lymphomaB-cell lymphoma
Radiommunotherapy: rationale asRadiommunotherapy: rationale asconsolidation after first line R-chemotherapyconsolidation after first line R-chemotherapy
Reduced toxicity and increased efficacyReduced toxicity and increased efficacy
RIT may overcome Rituximab resistanceRIT may overcome Rituximab resistance((131131I Tositumobab ORR 65% Horning JCO 2005; 90YI Tositumobab ORR 65% Horning JCO 2005; 90YIbritumobab ORR 74%-83% Witzig JCO 2002, OguraIbritumobab ORR 74%-83% Witzig JCO 2002, OguraASH 2006)ASH 2006)
Can radioimmunotherapy eliminate residual disease inpatients achieving a first-line response?
Shipley et al. Proc ASCO 2005.abst 6577
Settimane 1 3 4 5 8 11 16 -18
R Zevalin®R R R CHOP (or CVP)
R
2
CHOP (or CVP)
R CHOP (or CVP)
R
0
10
20
30
40
50
60
70CR%CR%
CHOP-R ZEVALIN
28%
67%
First-line treatment in FL: Consolidation radiolabelledimmunotherapy after R-chemotherapy
•• Patients: Patients: 42 Previously untreated follicular lymphoma (grades 142 Previously untreated follicular lymphoma (grades 1––3,3,stages IIstages II––IV), Stage IV 60%IV), Stage IV 60%
•• Treatment: Treatment: weekly rituximab x 4, followed by 3 weekly rituximab x 4, followed by 3 courses of R-CHOP*-21,courses of R-CHOP*-21,Responders with < 25% BM involvement received ZevalinResponders with < 25% BM involvement received Zevalin®® consolidation, consolidation,5 weeks after last dose of CHOP-R5 weeks after last dose of CHOP-R
Response; Response; final restaging performed 12 weeksafter Zevalin® administration
Shipley et al. JCO 23: 2005 (abst 6577)
Months
100%
80%
60%
40%
20%
0%
0 3 6 9 12 15 18 21 24 27 30 33 36
Results Total Fail 2yrEFS 40 5 85OS 40 2 95
OS
EFS
First line treatment in Follicular Lymphoma:consolidation RIT after R-chemotherapy
FIT Study Schema
ZevalinZevalin(n = 208)(n = 208)
Rituximab 250 mg/mRituximab 250 mg/m22
IV Day -7 and Day 0 +IV Day -7 and Day 0 +Zevalin 14.8 MBq/kgZevalin 14.8 MBq/kg
(maximum 1184(maximum 1184MBq/kg) Day 0MBq/kg) Day 0
First-line therapywith CVP, CHOP-like,
fludarabinecombinations,
chlorambucil, orrituximab combination
INDUCTION
CONSOLIDATION
No furtherNo furthertreatmenttreatment(n=206)(n=206)
NRPD
CR/CRCR/CRu or PRu or PR
No inclusion
RANDOMIZATION
CONTROLCONTROL
Start of study
FIT: 90Y-Ibritumomab as ConsolidationTherapy in FL (cont’d)
Hagenbeek A, et al. ASH 2007. Abstract 643.
PR to CR/CRu Conversion
Ibritumomab (n = 208)Ibritumomab (n = 208) Observation (n = 206)Observation (n = 206)
CHOP-Like
First-Line Regimen
Overall Chlorambucil CVP/COP CHOP FludarabineCombination
RituximabCombination
77.284.6
72.7 75.6 76.9
100
71.4
17.57.7 10.3
25
0 0
41.7
020406080
100
Perc
enta
ge o
f Pat
ient
s
P < .001 P < .001P < .001 P < .001 P < .005
P < .05
P < .34
FIT Primary Endpoint:Median PFS in All Patients*
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48 54 60 66
PFS, Time From Randomization (months)
Pro
po
rtio
n R
em
ain
ing
Pro
gre
ssio
n F
ree (
%)
Log-rankP<0.0001HR 0.463
Zevalin: median 37 monthsn=208
Control: median 13.5 monthsn=206
*Median observation period was 3.5 years.
PFS in Patients With CR/CRuAfter First-line Therapy
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48 54 60 66
PFS, Time From Randomization (months)
Pro
po
rtio
n R
em
ain
ing
Pro
gre
ssio
n F
ree (
%)
Log-rankP=0.01
HR 0.609Zevalin: median 54.6 mon=107
Control: median 29.9 mon=109
PFS in Patients With PRAfter First-line Therapy
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48 54 60 66
PFS, Time From Randomization (months)
Pro
po
rtio
n R
em
ain
ing
Pro
gre
ssio
n F
ree (
%)
Control: median 6.3 mon=97
Log-rankP<0.0001HR 0.304
Zevalin: median 29.7 mon=101
90% of Patients Converted From PCR+Status to PCR- (in blood) After Zevalin
Consolidation
No. of patients converting from bcl-2 PCR+(after remission-induction treatment)to PCR- status post-randomization
Control, n/N*(%)
Zevalin, n/N*(%)
Blood 21/59 (36) 61/68 (90)
*Patients with PCR+ status at randomization and who have had at least 1 post-randomization PCR assessment; all other patients were either PCR- at
randomization or lacked a second assessment.
Ruolo degli anticorpi radiomarcatiRuolo degli anticorpi radiomarcati
Linfomi Follicolari in recidivaLinfomi Follicolari in recidiva
Linfomi follicolari come consolidamento della rispostaLinfomi follicolari come consolidamento della risposta
In indicazione approvataIn indicazione approvata
In sperimentazione avanzataIn sperimentazione avanzata Linfomi Follicolari in prima linea single agentLinfomi Follicolari in prima linea single agent
Linfomi follicolari o aggressivi in recidiva comeLinfomi follicolari o aggressivi in recidiva come
potenziamento del condizionamento pre trapiantopotenziamento del condizionamento pre trapianto
First-line radioimmunotherapy•• Single course of Single course of 131131I-tositumomabI-tositumomab
–– 76 patients, stage III/IV FL76 patients, stage III/IV FL
•• ORR 95%, CR rate 75%ORR 95%, CR rate 75%•• 8-year PFS is 50%8-year PFS is 50%
•• Among CRsAmong CRs–– molecular CRs in 80% of evaluable patientsmolecular CRs in 80% of evaluable patients–– patients with molecular CR had better PFS than patientspatients with molecular CR had better PFS than patients
remaining PCR+remaining PCR+
•• No cases of MDS or AMLNo cases of MDS or AML–– Median follow-up 8 yearsMedian follow-up 8 years
Kaminski, et al. ASCO 2007 Abstract 8033; Kaminski et al. N Engl J Med 2005;352:441-9
ORRCR/CRu
0%10%20%30%40%50%60%70%80%90%
100% 95%
75%
Kaminski MS, et al. N Engl J Med. 2005; 352: 441–449.
0
Surv
ival
(%)
Years after Dosimetric Dose
20
40
60
80
100
01 2 3 4 5 6 7 8
Overall SurvivalProgression-free Survival
0Prog
ress
ion-
free
Sur
viva
l (%
)Years after Dosimetric Dose
20
40
60
80
100
01 2 3 4 5 6 7 8
Complete Responders(57/76 = 75%)Partial Responders(15/76 = 20%)
PFS and OS (All 75 Patients) PFS for Responders
131I Tositumomab alone as first line treatment in131I Tositumomab alone as first line treatment infollicular lymphomafollicular lymphoma
Phase II study of 90Y Ibritumomab Tiuxetan (Zevalin®) inPhase II study of 90Y Ibritumomab Tiuxetan (Zevalin®) inpatients with untreated Follicular Non Hodgkinpatients with untreated Follicular Non Hodgkin‘‘s Lymphomas Lymphoma
Principal Investigator: AM Carella, GenovaParticipating centers: PL Zinzani, Bologna; E Morra, Milano; M Lazzarino,Pavia; M Petrini, Pisa; Cascavilla, San Giovanni Rotondo; U Vitolo, Torino
PLANNEDPLANNEDENROLLEMENT:ENROLLEMENT:
50 PATIENTS50 PATIENTS
Witzig et al. J Clin Oncol 2003;21:1263–1270
Platelets = 50 000ANC = 1000
Platelets (103/µl)
Study week
0
4
8
12
16
0 2 4 6 8 10 12 140
50
100
150
200
250
300
350
400
450Absolute neutrophil countHaemoglobin Platelets
Hb = 10
Haemoglobin (g/dl)
ANC(103/µl)
9090Y-ibritumomab tiuxetan safety:Y-ibritumomab tiuxetan safety:Kinetics of median blood countsKinetics of median blood counts
68%59%70%Thrombocytopenia grade III/IV
68%47%66%Neutropenia grade III/IV
Patients≥70 years
(n=40)
Patients60-69 years
(n=58)
Patients<60 years (n=113)
Pooled analysis of four registrational studies
(n=211)
Schilder RJ et al. J Clin Oncol 200; 23(16S):575s, abstr 6562
0
20
40
60
80
100
<60 years 60-69 years ≥70 years
Res
pons
e ra
te (%
)
PR
CR/CRu7871
80
35 3338
0
2
4
6
8
10
Median duration of response
Mon
ths
12
9.9
11
9.4<60 years
60-69 years
≥70 years
9090Y-ibritumomab tiuxetan:Y-ibritumomab tiuxetan:efficacy and safety in geriatric patientsefficacy and safety in geriatric patients
746 patients 746 patients from registration and compassionate use trials,from registration and compassionate use trials,19961996––20022002
Median 3 prior therapies (0Median 3 prior therapies (0––9+) with a m9+) with a median follow-up of 4.4 yearsedian follow-up of 4.4 years–– 19 cases of t-MDS or t-AML reported (crude rate 2.5%)19 cases of t-MDS or t-AML reported (crude rate 2.5%)
•• 11 cases in registration trials11 cases in registration trials•• 8 cases in compassionate-use trial8 cases in compassionate-use trial
Annualized rateAnnualized rate–– 0.3% after diagnosis of NHL0.3% after diagnosis of NHL–– 0.7% after 90Y-ibritumomab tiuxetan0.7% after 90Y-ibritumomab tiuxetan
Cytogenetic aberrationsCytogenetic aberrations–– Multiple, commonly on chromosomes 5 and 7Multiple, commonly on chromosomes 5 and 7
Cox regression analysisCox regression analysis–– Previous treatment with fludarabine significant risk factor forPrevious treatment with fludarabine significant risk factor for
MDS or AML (HR 3.5; 95% CI, 1.4 to 8.8; p= .006) along with boneMDS or AML (HR 3.5; 95% CI, 1.4 to 8.8; p= .006) along with bonemarrow involvementmarrow involvement
Czuczman et al, J Clin Oncol 2007; 25: 4285-92
9090Y-ibritumomab tiuxetan long term toxicity:Y-ibritumomab tiuxetan long term toxicity:treatment related myelodysplastic syndrometreatment related myelodysplastic syndrome
9090Y-ibritumomab tiuxetan long term toxicity:Y-ibritumomab tiuxetan long term toxicity:treatment related myelodysplastic syndrometreatment related myelodysplastic syndrome
Cumulative incidence of treatment related MDS and AML
Czuczman et al, J Clin Oncol 2007; 25: 4285-92
The finding of abnormalities of chromosome 5 and/or 7 in patientswith secondary MDS or AML after 90Y-ibritumomab tiuxetansuggests an association with previous exposure to chemotherapy.
Interestingly, no cases of MDS/AML have developed in a group of76 patients receiving 131I-tositumomab as single agent first-linetherapy with a median follow-up of almost 8 years.
According to these data, the incidence of MDS and AML isconsistent with that expected in NHL after conventionalchemotherapy and does not appear to be increased after 90Y-ibritumomab tiuxetan.
Panel discussion: response assessment, follow-up, long Panel discussion: response assessment, follow-up, longterm safetyterm safety
Italian Society of Hematology
Consensus Conference on the use of Consensus Conference on the use of9090YY-ibritumomab tiuxetan therapy in clinical practice-ibritumomab tiuxetan therapy in clinical practice
Refractory DLBCL: HDC + ASCT Refractory DLBCL: HDC + ASCT
100
80
60
40
20
01086420
31%
11%11%
P=0.02
REFRACTORYREFRACTORY
CHEMOSENSITIVE
Event-Free SurvivalEvent-Free Survival
Martelli M et al, EBMT 2001Martelli M et al, EBMT 2001
Progression-free survival CRProgression-free survival CRcompared to PRcompared to PR
Zelenetz et al, Ann Oncol 2003Zelenetz et al, Ann Oncol 2003
aa-IPI predicts Autologous Stem Cellaa-IPI predicts Autologous Stem CellTransplantation Outcome for patients withTransplantation Outcome for patients with
relapsed or primary refractory DLBCL.relapsed or primary refractory DLBCL.
Hamnlin P et al, Blood 2003Hamnlin P et al, Blood 2003
PFS
InpatientInpatientOutpatientOutpatient
-14 -7 -4 -2
9090Y-ibritumomabY-ibritumomabtiuxetantiuxetan therapytherapy
0.4 mCi/Kg0.4 mCi/Kg VP/AraCVP/AraC MelMelTRANSPLANTTRANSPLANT
Close observation,Close observation,discharge upondischarge upon
blood countblood countrecoveryrecoveryClose observationClose observation
BCNUBCNU
-5 -3-6 -1 0
n = 12n = 12 Age: median 61 yrs (20-78 yrs)Age: median 61 yrs (20-78 yrs) Histology: DLCBL, MCLHistology: DLCBL, MCL
Fung H, et al. ASH 2003Fung H, et al. ASH 2003
9090Y-ibritumomab tiuxetanY-ibritumomab tiuxetan32 mCi/BEAM32 mCi/BEAM
Time to recovery: WBC 11 days,Time to recovery: WBC 11 days,platelets 11 daysplatelets 11 days
Pilot study: Combining conventional dose Z-BEAMPilot study: Combining conventional dose Z-BEAMas a conditioning regimenas a conditioning regimen
-21
RituximabRituximab250 mg/sqm250 mg/sqm
Z-BEAM in poor risk NHL patients ineligible for total-bodyZ-BEAM in poor risk NHL patients ineligible for total-bodyirradiation:irradiation:
Overall and progression-free survivalOverall and progression-free survival
89%
70%
Krishnan et al, JCO 26:90-5, 2008
n = 41n = 41 Age: median 60 yrs (19-Age: median 60 yrs (19-
78 yrs)78 yrs) Histology: Histology: DLCBLDLCBL (20), (20),
MCLMCL (13), (13), FLFL (4), (4), Transf.Transf.LNHLNH (4) (4)
90Median time torecovery: WBC 11 d(range 9-26), platelets12 d (range: 3-107)
ITALIAN EXPERIENCE:ITALIAN EXPERIENCE:BASELINE CHARACTERISTICS 53 ptsBASELINE CHARACTERISTICS 53 pts
Median age, y (range) 54 yrs (20-75)
Histology, no. (%) Follicular 16 (30%) Aggressive 37 (70%)
III-IV stage at diagnosis, no. (%) 40 (75%)
Median number of prior chemotherapy 2 (2-5)
IPI, grade 0 8 (15%) > I 45 (85%)
Bone marrow involvement at diagnosis 19 (36%)
Prior rituximab, no. (%) 48 (91%)
high risk high risk patients !!! patients !!!
By courtesy of Enzo Pavone
Status at enrollment Relapse Progression PR CR
Status at transplant Progressive disease PR RC
Median time to ASCT, months (range)
11 (21%)13 (25%)24 (45%) 5 (9%)
11 (21%)27 (51%)15 (28%)
16 (5-108)
ITALIAN EXPERIENCE:ITALIAN EXPERIENCE:BASELINE CHARACTERISTICS 53 ptsBASELINE CHARACTERISTICS 53 pts
By courtesy of Enzo Pavone
Early Response post Z-BEAM (90 days)Early Response post Z-BEAM (90 days)
CR 32 (74 %) PR 5 (11 %) PD 6 (14 %)
ORR 85%ORR 85%
RESULTSRESULTS
2 - septic shock (day +6 and +39)
1 - pneumonitis (day +22)
1 – BK viral encephalites (day +61)
1 - MOF (day +14)
Early Death before 90 daysEarly Death before 90 daysTRM all 9.3%TRM all 9.3%
TRM <65 3.4%TRM <65 3.4%(multivariate analysis)(multivariate analysis)
By courtesy of Enzo Pavone
2-Years EFS2-Years EFS
64%64%
By courtesy of Enzo Pavone
44 G. BenevoloG. Benevolo44 C. BoccominiC. Boccomini44 B. BottoB. Botto44 A. ChiappellaA. Chiappella44 L. OrsucciL. Orsucci44 P. PregnoP. Pregno
HEMATOLOGY 2- Lymphoma sectionHEMATOLOGY 2- Lymphoma sectionASO S.Giovanni Battista TorinoASO S.Giovanni Battista Torino
PATHOLOGYPATHOLOGYUniversity of Torino Prof G. InghiramiUniversity of Torino Prof G. Inghirami
44 P. Francia di CelleP. Francia di Celle44 L. GodioL. Godio44 D. NoveroD. Novero44 A. StacchiniA. Stacchini
Aknowledgments
CANCER EPIDEMIOLOGYCANCER EPIDEMIOLOGYUniversity of Torino Prof F. MerlettiUniversity of Torino Prof F. Merletti
44 G. CicconeG. Ciccone44 M. CeccarelliM. Ceccarelli44 F. SacconaF. Saccona
All Physicians of IILAll Physicians of IILCentersCenters
NUCLEAR MEDICINENUCLEAR MEDICINEProf G. BisiProf G. Bisi
44 M. LadettoM. Ladetto44 B. MantoanB. Mantoan
NUCLEAR MEDICINENUCLEAR MEDICINEUniversity of Torino Prof G.BisiUniversity of Torino Prof G.Bisi
44 M. BellòM. Bellò44 P. ScapoliP. Scapoli
HEMATOLOGY 1HEMATOLOGY 1Prof M. BoccadoroProf M. Boccadoro
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