i linfomi non hodgkin a basso grado di malignita’ pescara 2008 · i linfomi non hodgkin a basso...

UO Ematologia - Pisa

I LINFOMI NON HODGKIN A BASSO GRADO DIMALIGNITA’

PESCARA 2008

MARIO PETRINI Ematologia PISA

linfomi mantellari


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


Mantle Cell Lymphoma - Morphology

Architectural Patterns in nodes

3-26%

13-39%

28-78%


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 –


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.


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


Rosenwald et al. Cancer Cell. 2003;3:185-97.


Rosenwald et al. Cancer Cell. 2003;3:185-97. KI-67 results are parallel Other prognostics:Stage, IPI, blastoid morphol.


MCL - PFS according to RAF1 expression


MCL - PFS according to MYC expression



19 pz con MCL



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%)


INITIAL OBSERVATION WITHOUT THERAPY IN PATIENTS WITH ASYMPTOMATIC, NEWLYDIAGNOSED MANTLE CELL LYMPHOMA (MCL)P. Martin1 Lugano 2008


G. Lenz, M. Dreyling, W. Hiddemann Ann Hematol 2004

Mantle Cell Lymphoma – Treatment: Conventional Chemotherapy


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


Mantle Cell Lymphoma – Treatment: SCT



89%79%

18% 42%


MCL - PFS according to FCGR3A genotype


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


Zevalin in MCL: PFS

RIT induction RIT consolidation

Weigert O, Jurczak W et al. Proc Am Soc Clin Oncol 2006; 24: #7533


RIT induction RIT consolidation

Zevalin in MCL: OS

Weigert O, Jurczak W et al. Proc Am Soc Clin Oncol 2006; 24: #7533


•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


Comparison of 3 Trials assessing RIT consolidation in MCL1st and 2nd line

Jurczak W. et al., Blood 2006;108:#2747


Z-BEAM Consolidating Remission

OS by disease histology (N=41) PFS by disease histology

Krishnan et al J Clin Oncol 2008;28:90–5


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


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.


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.


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).


• 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


Phase II Trial of Single-Agent Temsirolimus (CCI-779) for Relapsed Mantle CellLymphoma Thomas E. Witzig Et Al JCO 2005


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


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.


Fludarabine

Bortezomib

Myocet

Mabthera(cycle 2 only)

Day 1 214 118

25 mg/m2

1.3 mg/m2

50 mg/m2

375 mg/m2


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


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


19. 54 F IV 3 1 no resistant


21. 57 M IV 3 4 yes relapse


051015202530354045

CR/uCR PR SD PD Mortality

ORR 57%

14.3% 14.3%

42.7%

9.5% 9.5%


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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


Pazienti

Follow-up

6 mesiAncora in RCJH- BCL1-6 mesi#6




12 mesiAncora in RCJH+ BCL1-12 mesi#2

12 mesirelapseJH+ BCL1+7 mesi#1

OS post RITEventoBiol molEFSPz

i linfomi non hodgkin a basso grado di malignita’ pescara 2008 · i linfomi non hodgkin a basso...

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