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I LINFOMI NON HODGKIN A BASSO GRADO DIMALIGNITA’
PESCARA 2008
MARIO PETRINI Ematologia PISA
linfomi mantellari
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Mantle Cell Lymphoma
Cytology
Typical(Classic)
Blastoid(Blastic)
small to medium-sized Lywith scanty cytoplasm,irregular nuclei, condensedchromatin. Rarely roundnuclei (mimicking CLL), orabundant pale cytoplasm(mimicking Marginal ZoneLymphoma)
Classic Blastoid Variant: medium-sized Ly withscanty cytoplasm and
round nuclei with finelydispersed chromatin and
high mitotic index
Pleomorphic BlastoidVariant:
heterogeneous large cellswith irregular cleaved
nuclei, finely dispersedchromatin, small distinct
nucleoli
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Mantle Cell Lymphoma - Morphology
Architectural Patterns in nodes
3-26%
13-39%
28-78%
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Mantle Cell Lymphoma - Immunophenotype
• Monoclonal B cell expressing– CD19+– CD20+– CD22+– CD79a+– intense surface immunoglobulin IgM (± IgD)
• more λ light chain than κ light chain
– CD5+ (11% -)– CD43+
-CD 10 –
-CD 23 –
-BCL 6 –
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Mantle Cell Lymphoma / CD5 negative
Positive t(11;14) by fluorescence in situ hybridization from a CD5- mantlecell lymphoma. Note 1 green, 1 red, and 2 orange fusion signals. Thefusion signals indicate the presence of the t(11;14) translocation.
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Mantle Cell Lymphoma – Molecular Biology
• CDK (Cyclin Dependent Kinase)– Cell cycle POSITIVE regulators
Cyclin/CDK complex
Cyclin D1 CDK4
RetinoblastomaProtein
PhosphorilationRelease of Transcription factor
E2F
Cell-cycleprogression in S
phase
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Rosenwald et al. Cancer Cell. 2003;3:185-97.
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Rosenwald et al. Cancer Cell. 2003;3:185-97. KI-67 results are parallel Other prognostics:Stage, IPI, blastoid morphol.
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MCL - PFS according to RAF1 expression
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MCL - PFS according to MYC expression
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MCL - PFS according to RAF1 expression
19 pz con MCL
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MCL - PFS according to RAF1 expression
Leuk Res. 2007;31:1595-7.
A New Prognostic Index (MIPI) for Patients withAdvancedStage Mantle Cell Lymphoma
Based on data of 455 patients with advanced stage MCL from three randomized trialsHoster E, GLSG & European MCL Network.Blood First Edition Paper, prepublished online October 25, 2007
IPI FLIPI
MIPI (età, EGOG, LDH, GB) MIPI b ( + Ki 67%)
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INITIAL OBSERVATION WITHOUT THERAPY IN PATIENTS WITH ASYMPTOMATIC, NEWLYDIAGNOSED MANTLE CELL LYMPHOMA (MCL)P. Martin1 Lugano 2008
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G. Lenz, M. Dreyling, W. Hiddemann Ann Hematol 2004
Mantle Cell Lymphoma – Treatment: Conventional Chemotherapy
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Mantle Cell Lymphoma – Treatment: Rituximab
• Romaguera et al, Blood, 2001: R-Hyper-CVAD in 75 MCL pts
77%96%96%87%2-year OS
41%60%75%84%2-year FFS
70%90%100%89%CR
Hyper-CVAD +ABMTR-Hyper-CVADHyper-CVAD +ABMTR-Hyper-CVAD
> 66 years< 66 years
UO Ematologia - PisaCopyright © American Society of Clinical Oncology
Lenz, G. et al. J Clin Oncol; 23:1984-1992 2005
German Low Grade Lymphoma Study Group: R-CHOP significantly improvesresponse and time to treatment failure but not long-term outcome in untreated
MCL
Time to treatment failure Overall survival
P=.0131
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Mantle Cell Lymphoma – Treatment: SCT
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Mantle Cell Lymphoma – Treatment: SCT
89%79%
18% 42%
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Mantle Cell Lymphoma – Treatment: SCT
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MCL - PFS according to FCGR3A genotype
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MCL - PFS according to FCGR2A genotype
Maintenance therapy with rituximab leads to a significant prolongation ofresponse duration after salvage therapy with a combination of rituximab,
fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients withrecurring and refractory follicular and mantle cell lymphomas: results of a
prospective randomized study of the German Low Grade Lymphoma StudyGroup (GLSG)
Forstpointner et Al BLOOD, 2006; 108: 4003
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Zevalin in MCL: PFS
RIT induction RIT consolidation
Weigert O, Jurczak W et al. Proc Am Soc Clin Oncol 2006; 24: #7533
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RIT induction RIT consolidation
Zevalin in MCL: OS
Weigert O, Jurczak W et al. Proc Am Soc Clin Oncol 2006; 24: #7533
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•Phase II Study•56 Pts. eligible for treatment
•50 Pts. evaluable post R-CHOP– ORR 72% (CR/CRu 14%, PR 58%); SD
26%
•44 Pts. evaluable post Zevalin– ORR 84% (CR 45%)– Responses improved in 15/ 37 Pts. with
< CR/CRu•Conclusion
– Zevalin consolidation improves thenumber and quality of responses
Smith MR et al. Proc Am Soc Clin Oncol 2006; 24: # 7503
E1499 Trial: R-CHOP followed by Zevalin Consolidation in 1st line MCL
7284
14
45
0
20
40
60
80
100
After R-CHOPinduction
(n=50)
After Zevalinconsolidation
(n=44)
Res
pond
ers
(%)
ORR CR/Cru
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Comparison of 3 Trials assessing RIT consolidation in MCL1st and 2nd line
Jurczak W. et al., Blood 2006;108:#2747
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Z-BEAM Consolidating Remission
OS by disease histology (N=41) PFS by disease histology
Krishnan et al J Clin Oncol 2008;28:90–5
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Radioimmunotherapy as an Alternative Consolidation for Mantle Cell Lymphoma (MCL) patients not Eligiblefor Transplant Protocols Final Analysis of Multicentre PLRG Trial with 90Y-Zevalin (90Y-ibritumomabtiuxetan) W Jurczak1, et AL Lugano 2008
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PHASE I TRIAL OF BORTEZOMIB IN COMBINATION WITH RITUXIMABHYPERCVAD/ METHOTREXATE ANDCYTARABINE FOR UNTREATEDMANTLE CELL LYMPHOMA. J. E. Romaguera et Al Lugano 2008
• Bortezomib can be safely combined with R-M/Aat 0.7 mg/m2, toxicity similar to prior experiencewith R-HyperCVAD. Accrual is ongoing. (7 Pt)
• BORTEZOMIB IN ASSOCIATION WITH FCM-R AS SALVAGE TREATMEN FOR PATIENTS WITH NONHODGKIN LYMPHOMA F. Zaja Lugano 2008
• The results of this pilot study indicate that FCM-BR can be administered without major toxicityand with good activity in the majority of cases.
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R-CHOP + THALIDOMIDE FOR PREVIOUSLY UNTREATED MANTLE CELL LYMPHOMAJ. Drach et Al. Lugano 2008
• All 10 pts experienced a response to R-CHOP-Thal (with8 patients in CR; 4 pts were also negative by FDG-PET).
• DURABLE RESPONSES WITH THE ANTI-ANGIOGENIC METRONOMIC REGIMEN RT-PEPC INRECURRENT MANTLE CELL LYMPHOMA (MCL) J. Ruan et Al. Lugano 2008
• RT-PEPC has significant and durable clinical activity inMCL by targeting both tumor cells and tumorangiogenesis.
• LENALIDOMIDE IN COMBINATION WITH RITUXIMAB IS EFFECTIVE WITHMANAGEABLE TOXICITYIN A PHASE I/II STUDY IN RELAPSED/REFRACTORY MANTLE CELL LYMPHOMA M. Wang
• The MTD for Len+R in relapsed/refractory MCL was 20mg (days 1–21 of a 28-day cycle). Early evidence ofresponse is promising with a favorable toxicity profile at20 mg.
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EUROPEAN MANTLE CELL LYMPHOMA NETWORK: AN UPDATE ON CURRENT FIRST LINETRIALS M. Dreyling et Al Lugano 2008
• In MCL elderly, 302 patients are initially randomizedbetween 8 cycles of R-CHOP or 6 cycles of R-FC (experimental arm).Patients who achieve either a PR or CR, receive subsequently eitherinterferon maintenance (standard arm) or a single rituximab doseevery 2 months.
• In MCL younger, 314 patients the standard arm (R-CHOPinduction followed by myeloablative consolidation: 12 Gray TBI, 2x 60mg/kgcyclophosphamide) is compared to the implementation of high dosecytarabine into induction (R-CHOP/R-DHAP) and consolidation (10 Gray TBI,4x1,5 g/m2 Ara-C, 140mg/m2 melphalan).
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• BENDAMUSTINE PLUS RITUXIMABVERSUS CHOP PLUS RITUXIMAB IN THEFIRST-LINE TREATMENT OF PATIENTSWITH INDOLENT AND MANTLE CELLLYMPHOMAS –INTERIM RESULTS OF ARANDOMIZED PHASE IIISTUDY OF THESTIL (STUDY GROUP INDOLENTLYMPHOMAS, GERMANY) M. J. Rummel
• In this interim analysis the combination ofBendamustine plus Rituximab appears to benon-inferior to CHOP-R while showing a bettertolerability profile
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Phase II Trial of Single-Agent Temsirolimus (CCI-779) for Relapsed Mantle CellLymphoma Thomas E. Witzig Et Al JCO 2005
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Phase 3 study of patients with relapsed. Refractory MCL: comparison oftreatment with Temsirolimus vs investigator’s choice therapy. Verhoef
E.G, et Al. EHA 2008
• 162 pt• 2-7 previous lines• Pt treated with 175/75 mg showed longher PFS• Pt treated with 175/25 mg did not significantly
differ from controls.• No significant improving of OS• Adverese events: Thrombocytemia, anemia,
neutropenia, asthenia
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Distinct functional significance of Akt and mTOR constitutive activation inmantle cell lymphoma J Dal Col et Al. Blood 2008
To assess whether the PI3-K/Akt and/or mTORsignalings regulate MCL cell survival, weinvestigated the effects of wortmannin,SH-5 (Akt inhibitor), and rapamycin in Granta519 and SP-53 cells.
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Fludarabine
Bortezomib
Myocet
Mabthera(cycle 2 only)
Day 1 214 118
25 mg/m2
1.3 mg/m2
50 mg/m2
375 mg/m2
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Age, years median 66 range 54-75Sex Male 14 Female 7Stage IV 15 IV ext 4 IV int 2IPI median 3 range 2-4No. previous CT median 3 range 0-4ABMT yes 2 no 19Disease status front line 5 resistant 5 relapsed 11
Pazienti 21 Pretrattati 18 Fragili 5
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Patient No. Age at diagnoses Sex Stage IPI No. previous CT ABMT Resistant/relapsed
1. 55 M IV int 3 1 no relapse
2. 60 F IV 2 1 no relapse
3. 66 F IV 2 3 no resistant
4. 70 M IV 3 4 no resistant
5. 59 F IV int 3 3 no resistant
6. 67 F IV 2
7. 66 M IV 3 2 no resistant
8. 75 M IV 4
9. 73 M IV ext 3 1 no relapse
10. 61 F IV 2 3 no relapse
11. 69 M IV ext 3 3 no relapse
12. 63 M IV ext 3
13. 69 M IV 3 3 no relapse
14. 67 M IV 3
15. 62 M IV 3
16. 60 M IV 3 4 yes relapse
17. 73 F IV ext 3 4 no relapse
18. 70 M IV 3 3 no relapse
19. 54 F IV 3 1 no resistant
20. 66 M IV 2 2 no relapse
21. 57 M IV 3 4 yes relapse
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051015202530354045
CR/uCR PR SD PD Mortality
ORR 57%
14.3% 14.3%
42.7%
9.5% 9.5%
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0
5
10
15
20
25
neut
rope
nia
pias
trino
peni
aan
emia
card
ioto
xicity
naus
eadi
arrh
eavo
mitin
gco
utan
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ras
hFU
Opn
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onia
deat
h
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Zevalin
Zevalin
Zevalin
Zevalin
Zevalin
Zevalin
Zevalin
Zevalin
RIT
RC
RC
RP
RC
RC
RC
RP
RC
Risposta
RC
RC
RP
RC
RC
RC
RP
RC
Risposta
JH- BCL1-
JH- BCL1-
JH- BCL1-
JH- BCL1-
JH- BCL1-
JH- BCL1-
JH+ BCL1-
JH+ BCL1-
Biol mol
#8
#7
#6
#5
#4
#3
#2
#1
Pz
In corso
In corso
JH- BCL1-
JH- BCL1-
JH- BCL1-
JH- BCL1-
JH+ BCL1-
JH- BCL1-
Biol mol
Pazienti
Radioimmunoterapia
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Pazienti
Follow-up
6 mesiAncora in RCJH- BCL1-6 mesi#6
6 mesiAncora in RCJH- BCL1-6 mesi#5
8 mesiAncora in RCJH- BCL1-8 mesi#4
11 mesiAncora in RCJH- BCL1-11 mesi#3
12 mesiAncora in RCJH+ BCL1-12 mesi#2
12 mesirelapseJH+ BCL1+7 mesi#1
OS post RITEventoBiol molEFSPz
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