Dr. Guido Gini Clinica di Ematologia Ospedali Riuniti ... · polineuropatia, polmonite...

LINFOMIDr. Guido Gini

Clinica di Ematologia

Ospedali Riuniti

Università Politecnica delle Marche

I LINFOMI ALL’ ASH 2013• 4 Educational• 5367/31822 Abstract e poster il 16,8% del totale• 291 Comunicazioni orali• 35 Abstract sulla biologia dei linfomi di Hodgkin• 205 Abstract sulla biologia dei Linfomi Non Hodgkin• 97 Abstract su risultati di schemi di chemioterapia in protocolli di ricerca

• 90 Abstract sulla terapia con agenti biologici in protocolli clinici

• 74 Abstract sulla terapia con chemioterapici e agenti biologici in fase pre-clinica

•EDUCATIONAL

GENOMICA

GENOMICA E TERAPIA MIRATA

Genomic stratification for the treatment of lymphomas – S. S. Dave

Eterogeneità in:

• Outcome clinico �

• Alterazioni genetiche

• Espressione di marker

Identificazione di nuove identità e forme intermedie (es. linfoma della grey zone)

Diverse prognosi e sviluppo di target theraoy

GENOMICA E TERAPIA MIRATA

Genomic stratification for the treatment of lymphomas – S. S. Dave

LINFOMINON

HODGKIN

TERAPIE MIRATE CONTRO IL BCR

Targeting B-cell receptor signaling:changing the paradigm -N.Fowler and E.Davis

IbutinibCC292

ONO-WG-307

GS1101IPI-145

FostamatinibGS-9973



Somministrazione oraleSi lega al residuo Cys-481 del BTKBen tollerato

Inibisce l’isoforma delta

Inibisce l’isoforma gamma

Inibisce il segnale del BCRRiduce l’effetto protettivo delle cellule stromali



Al momento non è possibile identificare i pazienti che si possono giovare di questa terapia

È necessario trovare delle strategie terapeutiche multiple per possibilità di sviluppare resistenza se usati come agenti singoli

MYC E LINFOMI B AGGRESSIVI

Understanding MYC-driven aggressive B-cell lymphomas: pathogenesisand classification - G.Ott, A.Rosendwald and E. Campo



MYC-rearranged DLBCL BCLU PBLMYC rearranged

TERAPIA PER I LINFOMI B AGGRESSIVI

Treatment strategies for aggressive Lymphomas: what works? -W.H.Wilson

TERAPIA PER I LINFOMI B AGGRESSIVIABC, GCP e PMBL

Treatment strategies for aggressive Lymphomas: what works? -W.H.Wilson

PER GLI ABC: bortezomub, lenalidomide, ibrutinib, temsirolimus, everolimus

PER GLI GCB � DA-EPOCH-R:1) contiene degli inibitori della topoisomerasi II, etoposide e

doxorubicina2) si ottimizza l’effetto tramite l’infusione continua

PER I PMBL: R-CHOP + RT oppure DA-EPOCH-R (per minimizzare gli effetti della RT)

NUOVE STRATEGIE PER I DLBCLFarmaci ipometilanti

Targeting the epigenome and other new strategies in diffuse B-celllymphoma - L.Cerchietti and J.P.Leonard

L’ipermetilazione del DNA si associa a:-Inappropriato silenzio trascrizionale � perdita di alcuni check point del ciclo cellulare- Resistenza ad altri farmaci per inattivazione epigenetica di alcuni trasportatori e per l’alterazione di alcuni meccanismi di riparazione del DNA

DNA METILTRANSFERASI

DNMT1 � in 48% DLBCL

DNMT3A � in 13% DLBCL

DNMT3B � in 45% DLBCL

NUOVE STRATEGIE PER I DLBCLInibitori dell’istone deacetilasi

Targeting the epigenome and other new strategies in diffuse B-celllymphoma - L.Cerchietti and J.P.Leonard

L’istone deacetilasi agisce:- Deregolando la trascrizione del DNA- Permettendo di adattare le cellule linfomatose al microambiente e alle condizioni cellulari intrinseche

Non è chiaro il ruolo sulla linfomagenesi

LINFOMI FOLLICOLARI: VALUTAZIONE DEL RISCHIO

Eterogeneità biologica

Dissecting follicular lymphoma: high versus low risk - S.M.Smith

IMMUNOFENOTIPO: CD10+, CD20+, CD19+, CD22+, Ig di superficie, Bcl2+, Bcl6+, CD5-

GRADI N° CENTROBLASTI

1 <5 centroblasti/campo2 6-15 centroblasti/campo3a Qualche centrocita evidente3b Tutti centroblasti

CD10-

Espressione maggiore di TP53 e di MUM 1/IRF4

Comportamento clinico simile a DLBCL


Eterogeneità biologica


Ancora non hanno un ruolo sulla prognosi:

• CARATTERISTICHE GENETICHE E EPIGENETICHE:-t(14,18)-Riarrangiamento BCL6- MYC +- del1p36- mutazione TP53- mutazione MLL2- mutazione EZH2- delezione CDKN2A

• MICROAMBIENTE:-Subset delle cellule T (per esempio: FOXP3+, PD-1)- macrofagi associati ai linfociti


Eterogeneità clinica


..ma anche…la RISPOSTA:

• TIPO DI RISPOSTA: una RC dopo la I linea aumenta la curva della OS alla I ricaduta• PROFONDITA’ DELLA RISPOSTA:

-MRD: Bcl2- IMAGING: pet intermedia e finale


…nei pazienti ricaduti…

• numero di precedenti trattamenti• caratteristiche cliniche alla ricaduta• declino progressivo della riserva midollare• durata della risposta • resistenza al RTX

…alla ricaduta di trasformazione…

• diagnosi clinica:- progressione rapida di malattia- aumentato LDH- insorgenza di sintomi B

• eventi genetici e epigenetici:- riarrangiamento Bcl6- perdita TP53- del1p36- altre alterazioni del DNA Dissecting follicular lymphoma: high versus low risk - S.M.Smith

LINFOMA MANTELLAREPrima linea

Transplantation for mantle cell lymphoma: is it the right thing todo?- M.E.Williams

ARA-C HD

R-HyperCVADalternato a

R+ MTX e ARA-c HD

R-DHAPR-CHOP

alternato a R-DHAP

ASCT

MRD �� t(11;14)

LINFOMA MANTELLARETrapianto allogenico


Indicazioni:- Paziente giovane e senza comorbidità- Dopo la prima recidiva o progressione di malattia

OS 25-30%PFS 20-25%

Terapia dei pazienti non eleggibili a trapianto

BORTEZOMIBLENALIDOMIDE

TEMSIROLIMUS

R-CHOPR- BENDAMUSTINA

R-FC

LINFOMA MANTELLARETerapia di mantenimento

Nuove strategie terapeutiche


�RTX

� LENALIDOMIDE

Ogni due mesi

Settimanalmente per 4 dosi ogni 6 mesi per 2 anni

�Agenti immunomodulanti: Lenalidomide

� Inibitori di mTOR: Temsirolimus, Everolimus

� Inibitori del segnale mediato dal BCR: Ibrutinib, Idelalisb, IPI-145,

Fosfamatinib, Enzastaurin

� Inibitore dell’istone deacetilasi: Vorinostat, Abexinostat

� Inibitori del ciclo cellulare: Flavopiridolo, PD0332991

� Inibitori del Bcl2/BH3 mimetici: ABT-199, obatoclax, navitoclax

INFEZIONI CORRELATE AI LINFOMI

PTLD dopo SOT

EARLY PTLD correlato con:-EBV negatività prima del trapianto- ATG

LATE PTLD correlato con:- Età-Uso degli inibitori della calcineurina

Utile impedire la riattivazione dell’EBV: • Ig vena anti CMV• Monitoraggio stretto di EBV DNA sierico• Trattamento preventivo con RTX

Utile una completa stadiazione della PTLD!!!(10% dei casi coinvolgimento midollare)

EBV and posttransplantation lymphoproliferative disease: what to do? Zimmermann H. and Trappe R.U.

PTLD dopo SOT

EBV and posttransplantation lymphoproliferative disease: what to do? Zimmermann H. and Trappe R.U.

…e inoltre:CTLs che hanno un ruolo nei PTLD SNC e nelle malattie refrattarie

Recidivi/refrattari: • CE +/- RTX• CTLs• come la I linea se è una recidiva tardiva• non indicazione per auto e allotrapianto

HHV8

Human herpesvirus-8: Kaposi sarcoma, multicentric Castelman disease, and primary effusion lymphoma – L.D.Kaplan

geni latenti (espressi nelle cellule B, nelle cellule dendritiche KS, nelle cellule endoteliali atipiche KS)geni della fase litica (più frequenti nel MCD)

HHV8

Human herpesvirus-8: Kaposi sarcoma, multicentric Castelman disease, and primary effusion lymphoma – L.D.Kaplan

KS MCD PEL

Patogenesi

Espressione di v-GPCR, VEGF e bFGF, cKIT, espressione di mRNA di multiple metalloproteasi della matrice

Espressione geni della fase litica.

Espessione dei geni della fase latente.Coinfezione con EBV talvoltaImmunoistochimica: CD20-, CD38+, CD138+

Clinica

Lesioni mucocutanee, linfoedema, coinvolgimento GI e respiratorio

Linfoadenomegaliediffuse, febbre, perdita di peso, epatosplenomegalia, polineuropatia, polmonite intestiziale linfocitaria

Effusione sierose: dispnea, dolore toracico, distensione addominale

Terapia

LOCALIZZATI: azoto liquido, VCR, RTSISTEMICI: cART, doxorubicina e paclitaxel, IFN α, COL3, imatinib, lenalidomide, sirolimus

Chemioterapia (VBL, CHOP, ABV, etoposideorale, ciclofosfamide), IFN α, tpantiherpesvirus, RTX (4 dosi settimanali), Hu-Anti-IL6

CHOP like, IFN α, ifn α+ cidofovir, CHT al alte dosi + autologo, Bortezomib, Sirolimus, IFN α + ATO, Brentuximab Vedotin, inibitore dell’istone deacetilasi

HELICOBACTER PYLORI E MALT

Helicobacter Pylori and mucosa-associated lymphoid tissue: what’snew? – S. Kuo and A. Cheng

Infezione da HP � MALT gastrico � DLBCL (MALT) gastrico� DLBCL gastrico


Helicobacter Pylori and mucosa-associated lymphoid tissue: what’snew? – S. Kuo and A. Cheng


MALTpCR: 56-100%Malt refrattario: 7,2%

Gastric DLBCL (MALT)

pCR: 58,9% (se limitato alla sottomucosa 80% - se limitato alla muscolaris propria 29,4%)Tempo per raggiungere la pCRal termine della tp è di 4 mesi

Pure DLBCL gastric

Associazione con Hp: 85-89% dei casiEarly stage: - tempo per raggiungere la pCR al termine della tp è di 2,1 mesi- DFS mediana: 3,9 anniAlto grado: -Tasso di efficacia 50%- pCR: 26,7%- tempo per raggiungere la pCR al termine della tp è di 3 mesi

LINFOMIDI

HODGKIN

NUOVE TERAPIE

Novel therapy for Hodgkn lymphoma – C. L. Batlevi and A. Younes

NUOVE TERAPIE


• ANTICORPI MONOCLONALI:- CD30: Brentuximab Vedotin- CD20: Rituximab- CD40: Lucatumumab- CD80: Galiximab- PDL!/PD1: CT011 e Nivolumab

• FARMACI CONTRO I SEGNALI ONCOGENICI:- PI3K/AKT/mTOR: Idelalisib, IPI-145, Everolimus- JAK/STAT: SB1518, AZD1480- NF-KB: Bortezomib

• TERAPIE EPIGENETICHE:-Vorinostat, Mocetinostat, Panobinostat, Entinostat

• IMMUNOMODULATORI:- Lenalidomide

NUOVE TERAPIE


RT E EARLY STAGE

TOSSICITA’ TARDIVA DA RT

Management of early-stage Hodgkin lymphoma: is there still a rolefor radiation?– P.W.M.Johnson

CARDIO-VASCOLARE

- K epiteliali-SMD e LAM-K mammella-K polmoni-Mesotelioma-Ipotiroidismo subclinico-K tiroide

SECONDENEOPLASIE

-Aterosclerosi accelerata-Fibrosi valvolare-Scompenso cardiaco congestizio-Pericardite-Anomalie valvolari-Ischemia miocardica

DEFICIT DIACCRESCIMENTO

OSSEO

Il rischio varia a seconda delle zone irradiate e della potenza dell’irradiazione

Riducendo il campo da irradiare, si riducono i rischi!! !!

RT E EARLY STAGE


RT E EARLY STAGE


85%

1yrPFS: 94,9%

1yrPFS: 100%

74%

1yrPFS: 94,7%

1yrPFS: 97,3%

75%

3yrPFS:94,5% 90,8%

LINFOMA DI HODGKIN A PREVALENZA LINFOCITARIA: NLPHL

Lymphocyte-predominant Hodgkin lymphoma: what is the optimaltreatment? - M.Fanale

• 5% dei casi di linfoma di Hodgkin• Overlap tra Linfoma di Hodgkin e Linfoma non Hodgkin indolente o linfoma B T-cell-rich• Le cellule L&H sono < 1% della cellula tumorale

Espressione di: CD20+CD30-CD15-IgV geneBcl 6CD10-CD19-CD4+/CD8+

NLPHLStadi precoci


Stadio IA o IIA

Stadi IB o IIB

Stadio IA recidivati

Stadio IA pediatrici

NLPHLStadi avanzati


Regimi LH - like

Regimi DLBCL - like

NLPHL


ABSTRACT

BIOLOGIA DEI LINFOMI

ABSTRACT 84Accurate Classification Of GCB/ABC and MYC/BCL2 Diffuse Large B-Cell Lymphoma With a 14 Genes Expression Signature and a Simple and Robust RT-MLPA Assay

Philippe Ruminy, et al

• ABC cases � worst EFS and lower OS• Expression of several individual genes within this signature � poor prognosis (LMO2 low: OS; BCL6 low: OS). • Double MYC+/BCL2+ � worst outcome and poor prognosis within the ABC subtype

10 genes expression signature discriminates ABC from GCB cases (ABC: IRF4, FOXP1, IGHM, TNFRSF13B, CCND2; GCB: LMO2, MYBL1, BCL6, NEK6, TNFRSF9), incorporated into a Reverse Transcriptase Multiplex Ligation-dependant Probe Amplification assay (RT-MLPA)

together with cMYC and BCL2 and the CCND1 and MS4A1 (encoding CD20).

141 DLBCLs treated between 2001 and 2011

This RT-MLPA assay is a RAPID (less than one day, tested up to 40 patients in parallel), CHEAP (less than 5 dollars), and EFFICIENT to discriminate ABC from GCB DLBCLs ; not require specific equipments and could easily be transferred in

many routine diagnosis laboratories.

DLBCL ABC and GCP

ABSTRACT EZH2 and BCL6 Cooperate To Create The Germinal Center B-Cell Phenotype and

Induce Lymphomas Through Formation and Repression Of Bivalent Chromatin Domains Wendy Béguelin, et al

� DLBCL patients with mutant EZH2 display a unique signature consisting of silencing of GC bivalent genes, suggesting that mutant EZH2 contributes to human lymphomagenesis through paralysis of bivalent chromatindomains.

� HP: 1) EZH2 and BCL6 cooperate to mediate the GC B-cell phenotype and when aberrantly active may cooperate to form GC-derived B-cell lymphomas 2) rational combinatorial therapy with BCL6 and EZH2 inhibitors might synergistically kill DLBCLs.

� Results: Treatment of DLBCL cells with EZH2 or BCL6 inhibitors or siRNA partially derepressed these genes indicating that both factors cooperate and are required to mediate full repression of these crucial loci. By combining the EZH2 inhibitor GSK343 and the RI-BPI, a drug that inhibits BCL6 by abrogating its interaction with BCoR, a potent synergistic effect on the inhibition of DLBCL cell lines proliferation were observed.

The first epigenetic mechanism of lymphomagenesis involving aberrant repression of GC-specific bivalent domains by EZH2 (PRC2) in cooperation with BCL6-BCoR (PRC1) complexes, as well as a rational epigenetic-based and molecular targeted therapeutic approach with the potential to

eradicate lymphomas without harming normal tissues.

Significance and mechanism of action of EZH2 in normal GC development and lymphomagenesis

DLBCL, EZH2 e bcl6

ABSTRACT 363MYC Mutation Profiling In 708 De Novo Diffuse Large B-Cell Lymphoma Demonstrates ThatGenetic Abnormalities In The Coding Sequence and Untranslated Regions Have Different

Prognostic and Clinical Significance: A Report From The International DLBCL Rituximab-CHOPConsortium Program

Zijun Y. Xu-Monette et al.

Objective: To determine the spectrum of MYC mutations in a large group of DLBCLpatients treated with R-CHOP immunochemotherapy, and to evaluate the clinical significance of MYC mutations in this study group.

Patients and Methods: The MYC gene assessed by Sanger sequencing methods in 708 de novo DLBCL patients. The results of MYC sequencing compared with the MYC reference sequence in the Genebank database. The variants subdivided as either single nucleotide polymorphisms (SNP) or novel single nucleotide variations (SNV). The MYC genetic status correlated with clinical outcome, including treatment response, overall survival (OS) and progression-free survival (PFS).

Results :351 (49.6%) patients harbored variations in MYC gene sequence. Most variations occurred in the CDS and 5’UTR, whereas infrequently (9.4%) in the 3’UTR. Variations in the

CDS, 5’UTR and 3’UTR had different prognostic implications. Variations in the CDS region were associated with better survival (P=0.0005 for OS and P=0.0002 for PFS), whereas variations in

the 3’UTR and 5’UTR variations had no prognostic significance. Deregulation or MYC expression by microRNAs is important in pathogenesis and progression of DLBCL.

DLBCL, MYC gene

ABSTRACT 361Blood Soluble PD-L1 Protein In Aggressive Diffuse Large B-Cell Lymphoma Impacts

patient’s Overall SurvivalThierry Fest, et al

Programmed death 1 (PD-1) protein = key immune-checkpoint receptor expressed by activated T cells which mediates immunosuppression. The blockade of PD-1 or its ligand, PD-L1, by monoclonal antibodies may lead to significant antitumor effects.

288 pts receiving 8 courses of R-CHOP or high-dose cht associated to rtx followed by autologousstem cell support. Available plasma collected at the time of diagnosis before any treatment. Soluble PD-L1 was measured using an ELISA assay.

• sPD-L1 levels increased at diagnosis;• High-level sPD-L1 significantly associated with: BM-involvement, more than one extranodal localization, 2-4 performance ECOG status;• No association between sPD-L1 and tumor PD-L1 expressions;• Patients with elevated PD-L1�� poor prognosis

�� Soluble PD-L1 protein expression in peripheral blood at the time of diagnosis is a potent predicting biomarker in diffuse large B-cell lymphoma and may indicate usefulness of alternative therapeutic strategies using PD1 axis inhibitors

BCL, PD-L1 protein

ABSTRACT 83Diffuse Large B-Cell Lymphoma With Combined TP53 mutation and MIR34A methylation: Another “double hit” Lymphoma With Very Poor Outcome?

Fazila Asmar, MD

MIR34B/C methylation, Mutation of TP53

Methylation of MIR34A (+/- MIR34B/C methylation)

NOT INFLUENCE SURVIVAL

TP53/MIR34A “double-hit”:

9.4 months median survival (P<0.0001)

independent negative prognostic factor for survival (P=0.0002)

� miR34s are downregulated by promoter hypermethylation� miR34a-5p can be upregulated by a hypomethylating agent in DLBCL cells with a methylatedMIR34A promoter in cells with and without TP53 mutations.

A novel rare, aggressive, but treatable “double-hit” DLBCL

To investigate a large panel (150 pts) of newly diagnosed cases of DLBCLs for MIR34A and MIR34B/C promoter methylation, TP53 mutational status clinical presentation patterns, and outcome.

DLBCL, TP53/MIR34A

ABSTRACT 499Whole-Exome Analysis Of DLBCL Tumors Reveals a Unique Genetic Signature

Associated With Aggressive Disease Anne J Novak, et al.

• to evaluate the association of somatic coding single nucleotide (cSNV) and copy number (CNV) variants with aggressive DLBCL• All patients (54) treated with R-CHOP or immunochemotherapy, and disease aggressiveness based on relapse, with patients classified as having aggressive disease (AD) versus non-aggressive disease • cSNV: CIITA (mutational target in DLBCL) was associated with AD (p=0.01) analysis. CIITA could be placed in the same regulatory network around CREB1.• CNV:245 gene amplifications and 209 gene deletions associated with AD (p ≤ 0.05). SLC22A16 in the 6p21 locus significantly associate with AD (p=0.002). Successful drug response has been correlated with the level of activity and expression of this transporter: cells expressing SLC22A16 have increased C-doxorubicin uptake and are more sensitive to doxorubicin-induced cell death

DLBCL, genetic signature

ABSTRACT 503Recurrent STAT6 Mutations In Follicular Lymphoma

Sami Malek, et al.

To further understanding of the genetic basis of follicular lymphoma (FL)� used solution exon capture of sheared and processed genomic DNA isolated from FACS-sorted lymphomatous B-cells and paired CD3+ T-cells isolated from 23cases of FL and one case of DLBCL (which was transformed from prior FL), followed by paired-end massively parallel sequencing.

Results: In addition to frequent mutations in MLL2, CREBBP, BCL2, TNFRSF14, EZH2, OCT2, ARID1A, IRF8 and MEF2B, novel mutations��STAT6, identified in 11% (12/114) of FL and predominantly affected the DNA binding domain. Of interest, the majority of FL-associated STAT6 mutations affected a single amino acid codon

(codon 419), resulting in the STAT6 mutants p.419D>D/G or p.419D>D/H.

Conclusion: Identification of somatic mutations in STAT6 in 11% of FL. These mutations predominantly affected the STAT6 DNA binding domain.

Identified a novel STAT6 mutation hotspot in STAT6 codon 419 (p.419D>D/G or p.419D>D/H), distinct from mutations previously described

in primary mediastinal B-cell lymphoma (PMBCL)

FL, STAT6 mutation

ABSTRACT 847Gray Zone Lymphoma (GZL) With Features Intermediate Between Classical Hodgkin Lymphoma (cHL) and Diffuse Large B-Cell Lymphoma (DLBCL): A Large Retrospective

Multicenter Analysis Of Clinical Characteristics, Treatment, Outcomes, and Prognosis In The Current Era

Andrew M Evens, et al.

UNIVARIATE ANAYSIS PFS OS

Characteristics (at diagnosis) HR 95% CI P HR 95% CI P

B symptoms (yes vs no) 1.56 0.85-2.86 .15 7.80 0.99-61.60 .05

Performance Status (2-4 vs 0-1)

3.44 1.65-7.17 .001 2.07 0.44-9.77 .35

Hemoglobin <10.5 g/dl 2.13 1.15-3.94 .02 1.83 0.53-6.23 .33

Increased ESR 5.81 0.75-44.97 .09 - - .99

Hypoalbuminemia (3.5 g/dl) 1.57 0.80-3.11 .19 3.14 0.84-11.72 .09

Stage (III/IV vs I/II) 1.91 1.08-3.39 .03 11.85 1.51-92.74 .02

Stage (IV vs I-III) 2.76 1.57-4.83 .0004 7.05 1.85-26.85 .004

Prognostic Scores HR 95% CI P HR 95% CI P

IPI (3-5 vs 0-2)IPS (3-7 vs 0-2)

2.501.91

1.31-4.760.98-3.72

.006.06

3.894.77

1.12-13.460.92-24-82

.03

.06

mediastinal involvement GZL: 44% non mediastinal involvement GZL: 56%

On multivariate regression

elevated LDH was the only

predictor of poor outcome for

PFS; several factors were

significant for inferior OS

including B symptoms;

hypoalbuminemia;stage 4 vs 1-3

The largest series of GZL reported to date (100 pts). NMGZL has distinct characteristics but similar outcomes than MGZL. Overall PFS appeared inferior to that observed in cHL and DLBCL. OS was excellent, suggesting the success of salvage therapy.

MGZL had lower risk features but similar PFS and OS than NMGZL at univariate analysis

GZL

LINFOMIDI

HODGKINTerapia

� No significant PFS or OS difference in patients with ≤4 or >4 cycles of bleomycin . No significant PFS or OS difference in patients with ≤3 or >3 cycles of vincristine.

� Bleomycin and vincristinediscontinuation due to drug-specific side effects seemed to be safe in this setting; Bleomycin and vincristine may have a limited role in the BEACOPP regimen.

Bleomycin and Vincristine acute and long-term toxicity �� dose reduction �� Impacton outcome and tolerability of BEACOPP

Retrospective analysis of patients treated within the GHSG trials HD12 (8xBEACOPPescalated versus 4xBEACOPPescalated plus 4xBEACOPPbaseline) and HD15 (8xBEACOPPescalated versus 6xBEACOPPescalated versus

8xBEACOPP14) trials for advanced stages.

ABSTRACT 637Impact Of Dose Reduction Of Bleomycin and Vincristine In Patients With Advanced

Hodgkin Lymphoma Treated With Beacopp: A Comprehensive Analysis Of The German Hodgkin Study Group (GHSG) HD12 and HD15 Trials

Bastian von Tresckow et al

HD, Bleomycin and Vincristine reduction

LINFOMINON

HODGKINTerapia

ABSTRACT 764Diffuse Large B-Cell Lymphoma (DLBCL) Patients Failing Second-Line R-DHAP Or R-

ICE Chemotherapy Included In The Coral StudyEric Van Den Neste et al

• 145 pts included in the CORAL study who failed R-DHAP or R-ICE and could not proceed to scheduled ASCT• Overall response rate to third-line chemotherapy 43%• 64 pts (44%) could eventually be transplanted (ASCT 56, allogeneic SCT 8)

OS (months) according to transplantation status in DLBCL pts after third-line regimen (No, no transplantation performed; Yes, transplantation performed).

DLBCL

ABSTRACT 372Epirubicin Does Not Lower The Risk Of Cardiac Toxicity Than Doxorubicin In

Diffuse Large B-Cell Lymphoma (DLBCL) and Follicular Lymphoma Grade 3 (FLG3): Results From a 398-Case Prospective Randomized Phase III Clinical Trial

(NCT00854568) Kai Xue et al

DLBCL (Stage I-IV, N = 359) FLG3 patients (Stage I-IV, N=38)

Randomisation 1:1

CHOP/R+CHOP CEOP/R+CEOP

� CEOP/R+CEOP not superior to CHOP/ R+CHOP in terms of cardiac toxicity� Similar ORR and Complete Remission Rate (CR) :

ORR CHOP/R+CHOP vs. CEOP/R+CEOP= 95.8% vs. 96.1% (P=0.895) CR CHOP/R+CHOP vs. CEOP/R+CEOP = 70.0% vs. 72.6% (P=0.695)

CHOP regimen is more economic, especially in developing countries. However, CEOP/R+CEOP appear to induce less myeloid suppression than

CHOP/R+CHOP

DLBCL

ABSTRACT 640Impact Of Induction Regimen and Consolidative Stem Cell Transplantation In Patients

With Double Hit Lymphoma (DHL): A Large Multicenter Retrospective Analysis Mitul Gandhi et al

� 106 Pts treated with either R-CHOP, or intensified regimens: R-HyperCVAD, R-EPOCH, R-CODOX-M/IVAC, R-ICE.

� R-EPOCH superior in achieving complete response (CR) compared with R-CHOP

� Primary predictor of OS�� primary refractory disease � Poor outcomes of DHL

DHL, induction and SCT

ABSTRACT 849Dose-Dense Chemoimmunotherapy and Early Central Nervous System Prophylaxis For High-Risk Diffuse Large B-Cell Lymphoma. Preliminary Results From a Nordic Phase II

Study Sirpa Leppa et al

�Treatment: two courses of high dose (HD)-Mtx in combination with R-CHOP14, four courses of R-CHOEP14 and a course of HD-AraC with R. In addition, liposomal AraC is administered intrathecally in courses 1, 3 and 5.

�Toxicity: Grade 4 hematological toxicity and infections in 78% and 11% of the patients, grade 3-4 mucositis and gastrointestinal toxicity in 27% and 42%, and grade 3 arachnoiditis in 2.2% of the patients

�� CR, CRu, PR and PD rates at the end of chemoimmunotherapy: 69.0%, 14.3%, 14.3% and 2.4 %, respectively. After a median follow up time of 19 months, four patients have relapsed, two of whom with fatal CNS manifestations.

Highly satisfactory response rates and reasonable toxicity despite intensive therapy. HD-Mtx in combination with R-CHOP in the beginning of therapy and further intensification of treatment with CNS targeted liposomal AraC seem

feasible and safe.

DLBCL

ABSTRACT 641Radiation Therapy Significantly Improves Survival Of Patients With Diffuse Large B-Cell Lymphoma Associated With MYC Translocation: A Report From The International

DLBCL Rituximab-CHOP Consortium ProgramZijun Y. Xu-Monette et al

Purpose� to evaluate the efficacy of radiotherapy as a part of the therapeutic regimen for patients with MYC-translocation+ DLBCL.

Patients and methods� 581 patients with de novo DLBCL treated with standard R-CHOP immunochemotherapy

Results• MYC translocations in 59 DLBCL patients. These patients more often had bulky tumors, involvement of multiple extranodal sites, and poorer OS and PFS• Poor survival primarily attributable to patients with MYC+/BCL2+ double-hit• Radiotherapy abolished the adverse impact of MYC translocations.• Radiotherapy associated with better survival in the subset of patients with MYC+/BCL2+ double-hit lymphoma• Multivariate analysis after adjustment for stage and IPI score validated that radiotherapy significantly improved OS (HR: .28, 95% CI: .10 - .81, P= .018) and PFS (HR: .32, 95% CI: .13 -.80, P= .015) of MYC-translocation+ DLBCL patients

DLBCL

ABSTRACT 248Lenalidomide In Combination With R-CHOP (R2-CHOP) In Patients With High Burden

Follicular Lymphoma: Phase 2 StudyHerve Tilly et al

Combination of lenalidomide and rituximab yields high response rates in patients with FL

Methods: • 80 Pts with previously untreated FL grade 1, 2 or 3a and a high tumor

burden. • Induction therapy with 6 cycles of R2-CHOP given every 3 weeks (25 mg

oral lenalidomide on days 1-14) followed by two additional rituximab infusions

primary endpoint: complete remission

(CR/CRu) rate74% and ORR 94%

secondary endpoint: safety (Hematologic toxicity was in the range of that observed with R-CHOP regimen ),

PFS, OS

DLBCL, Lenalidomide

ABSTRACT 250High Response Rate To Combination Lenalidomide-Rituximab In FcγRIIIa-F Carriers

With Indolent Or Mantle Cell Lymphomas Previously Refractory To RituximabElise A. Chong et al

Part I: Lenalidomide + DesamatasonePart II: Lenalidomide + Desamatasone + Rituximab (cycle 3)

Lenalidomide + dexamethasone were continued during and subsequent to rituximab; stable and responding pts continued lenalidomide + dexamethasone until disease progression or development of

clinically unacceptable toxicity

Fc-gamma receptorRIIIA (FCGR3A) polymorphisms at aa158 (V/V vs. V/F and F/F) �� impact on ORR, CR, timeto progression

DLBCL, Lenalidomide

ABSTRACT 850Final Results Of Phase II Study Of Lenalidomide Plus Rituximab-CHOP21 In Elderly Untreated Diffuse Large B-Cell Lymphoma Focusing On The Analysis Of Cell Of

Origin: REAL07 Trial Of The Fondazione Italiana LinfomiAnnalisa Chiappella et al

Lenalidomide showed activity in heavily pretreated DLBCL and in vivo and in vitro data demonstrated a synergism with rituximab. In the phase I trial REAL07 FIL demonstrated that the association of LRCHOP21 was feasible in elderly untreated DLBCL

Inclusion criteria: �Age: 60-80 FIT � untreated CD20+ DLBCL� Ann Arbor stage: II/III/IV� IPI: low-intermediate/intermediate-high/high (LI/IH/H) risk

49 pts treated with RCHOP21 +

15 mg lenalidomidefrom day 1 to 14 for 6 courses

Results: � ORR= 92%. CR= 42 (86%) PR= 3 (6%). � 2-year OS (median follow-up of 28 months)= 92%; PFS= 80%; EFS= 70%� Hematological and extra-hematological toxicities were mild, with no grade IV

extra-hematological events and no toxic deaths during treatment� ORR for GCB and non-GCB= 88%; 2-year PFS (median follow-up of 28

months)= 71% in GCB-group and 81% in non-GCB-group

LRCHOP21 is effective, also in poor risk patients, namely in non-GCB subgroup

DLBCL, Lenalidomide

ABSTRACT 247Combination Biologic Therapy Without Chemotherapy As Initial Treatment For Mantle

Cell Lymphoma: Multi-Center Phase II Study Of Lenalidomide Plus RituximabJia Ruan et al

INDUCTION PHASE - Lenalidomide: 20 mg daily on days 1-21 (28-day cycle for 12 cycles), with dose escalation to 25 mg daily if tolerated. - Rituximab (standard dose): weekly x 4 during cycle 1, then once every other cycle, for a total of 9 doses

MANTEINECE PHASE From cycle 13.- Lenalidomide: 15 mg daily on days 1-21 of a 28-day cycle.- Rituximab maintenance once every other cycle until progression of disease.

The preliminary ORR for evaluable patients (27) is 77% with 40% CR/CRu.Median time to objective response was 2.8 months, with CR typically confirmed

between 6-12 months

Neither MIPI score nor Ki67 index correlated with response

This study provides the first demonstration that a chemotherapy-free, combination biologic approach is feasible as initial therapy for mantle cell

lymphoma

Preliminary efficacy data on response rates are encouraging

MCL, Lenalidomide

ABSTRACT 509Updated 6 Year Follow-Up Of The PRIMA Study Confirms The Benefit Of 2-Year RituximabMaintenance In Follicular Lymphoma Patients Responding To Frontline Immunochemotherapy

Gilles Andre Salles, et al

With 3 additional years of follow-up, these data demonstrate a sustained and persistent benefit of 2 years of rituximab maintenance therapy after immunochemotherapy, resulting in improved progression free survival. No additional or

unexpected long term toxicities were observed and second line therapy efficacy results did not

significantly differ between the 2 study arms. Overall survival appears very favourable for these

randomized patients.

ABSTRACT 851Rituximab Maintenance Significantly Prolongs Event Free (EFS) and Progression Free Survival

(PFS) In Male Patients With Aggressive B-Cell Lymphoma In The NHL13 StudyUlrich Jaeger et al

Rituximab manteinance

NUOVI FARMACIABSTRACT 85

Mature Response Data From a Phase 2 Study Of PI3K-Delta Inhibitor Idelalisib In Patients With Double (Rituximab and Alkylating Agent)-Refractory Indolent B-Cell

Non-Hodgkin Lymphoma (iNHL) Ajay Gopal, Brad S. Kahl, Sven De Vos

double-refractory

iNHL

IDELALISIB, oral

inhibitor of PI3Kδ

• 125 patients iNHL “double-refractory” to rituximab + alkylating agents (BR, R-CHOP)• 150 mg PO BID was administered continuously until disease progression or intolerance.

� Idelalisib was well tolerated, had an acceptable safety profile, and was highly effective in this double-refractory iNHL population with an ORR of 57%.

Kahl B S et al. Blood 2013;122:85

Idelalisib

ABSTRACT 367Phase II Trial Of Brentuximab Vedotin For CD30+ Cutaneous T-Cell Lymphomas and

Lymphoproliferative DisordersMadeleine Duvic, et al.

Population: 48 patients with primary cutaneous CD30+ lymphoproliferative disorders including lymphomatoid papulosis (LyP) and primary cutaneous pc-ALCL (pc-ALCL) or CD30+ mycosis fungoides (MF)

Results:� ORR= 71% (34/48) with CR of 35% (17/48)� ORR= 50% in 28 MF patients regardless of whether their lesions had low, medium, or high CD30 at baseline. LyP and pc-ALCL patients had a 100% ORR and two pc-ALCL patients had CRs� PFS = 9.7 years from diagnosis and 1.68 years from first dose. � Soluble CD30 levels from baseline to end of study differed significantly among those patients achieving a CR compared to those with PR or SD (p= 0.036). �The most common related adverse event (AE) of any grade was peripheral neuropathy(PN) in 29/48 (60%)

Conclusion:This phase II clinical trial demonstrates that brentuximab vedotin is active for mycosis fungoides (ORR 50%) irrespective of level of CD30+ expression. The ORR was 100% for CD30+ pc-ALCL, and LyP patients and was 71% with a CR of 36% for all evaluable patients.

Brentuximab

ABSTRACT 848A Phase 2 Study Of Brentuximab Vedotin In Patients With Relapsed Or Refractory CD30-Positive Non-Hodgkin Lymphomas: Interim Results In Patients With DLBCL

and Other B-Cell Lymphomas Nancy L. Bartlett,Jeff P. Sharman, Yasuhiro Oki

• 43 DLBCL patients, 40% objective response (7 CR, 10 partial remission PR);• 18 patients with other Bcell neoplasms, 22% achieved an objective response: PMBL (1 CR), PTLD (1 CR), and grey zone lymphoma (2 PRs);• No correlation between CD30 expression and response rate has been observed.

ABSTRACT 251A Prospective Multicenter Study Of The Bruton’s Tyrosine Kinase Inhibitor Ibrutinib

In Patients With Relapsed Or Refractory Waldenstrom’s MacroglobulinemiaSteven Peter Treon, Christina K Tripsas, Maria Lia Palomba

MYD88 L265P is present in >90% of patients with Waldenstrom’s Macroglobulinemia and supports malignant growth via signaling involving Bruton’s Tyrosine Kinase. Ibrutinib inhibits BTK, and in vitro induces apoptosis of WM cells bearing MYD88 L265P. WHIM-like mutations in CXCR4 are present in 1/3 of patients with WM, and their expression induces BTK activity and confers decreased sensitivity to ibrutinib mediated growth suppression in WM cells.

�� 63 patients trated with 420 mg of oral ibrutinib daily for 2 years or until progression, or unacceptable toxicity

Brentuximab

Ibrutinib

ABSTRACT 852Combining Ibrutinib With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP): Updated Results From a Phase 1b Study In Treatment-Naïve

Patients With CD20-Positive B-Cell Non-Hodgkin’s Lymphoma (NHL)Anas Younes et al,

Eligibility criteria:� Stage 1AX to stage IV disease� ≥ 1 measurable disease site� Eastern Cooperative Oncology Group score: 0-2� Adequate bone marrow, liver, and renal function

PART 1Ibrutinib at 280, 420, or 560 mg/d + standard doses of R-CHOP

PART 2Ibrutinib at the RP2D (560 mg) with standard doses of R-CHOP

(eligible patients with newly diagnosed DLBCL)

�The current ORR for all evaluable patients across Parts 1 and 2 is 100%: Part 1 (n = 15; final data), complete response (CR) 73%, partial response (PR) 27%; Part 2 (n = 15; interim data), CR 60%, PR 40%; DLBCL patients (n = 22; interim data), CR 64%, PR 36%.

The combination of ibrutinib and R-CHOP has an acceptable safety profile in treatment-naïve patients with NHL, with no new toxicities noted.

Ibrutinib

ABSTRACT 369A Randomized Phase II Study Comparing Consolidation With a Single Dose Of 90y Ibritumomab Tiuxetan (Zevalin®) (Z) Vs. Maintenance With Rituximab (R) For Two Years In Patients With Newly Diagnosed Follicular Lymphoma (FL) Responding To R-

CHOP. Preliminary Results At 36 Months From Randomization Armando Lopez-Guillermo et al.

Zevalin

ABSTRACT 368High Response Rates To Crizotinib In Advanced, Chemoresistant ALK+ Lymphoma

PatientsSara Redaelli et al.

Crizotinib , ALK inhibitor

Crizotinib exerted a potent antitumor activity in advanced ALK+ lymphoma and produced durable responses in this population of heavily pre-treated patients, with a

benign safety profile.

ABSTRACT 505A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Of The

Efficacy and Safety Of Siltuximab, An Anti-Interleukin-6 Monoclonal Antibody, In Patients With Multicentric Castleman’s Disease

Raymaond S Wong et al

79 patients were randomized and treated with siltuximab (n=53) or placebo (n=26) from Feb 2010 to Feb 2013

Crizotinib

Nella speranza che le mie indicazioni vi siano state utili………

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Dr. Guido Gini Clinica di Ematologia Ospedali Riuniti ... · polineuropatia, polmonite...

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