LINFOMI

LINFOMI
Dr. 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
Eterogeneità in:
prognosi e sviluppo
• Outcome clinico Diverse
di target theraoy
• Alterazioni genetiche
• Espressione di marker
Identificazione di nuove
identità e forme
intermedie (es. linfoma
della grey zone)
Genomic stratification for the treatment of lymphomas – S. S. Dave
GENOMICA E TERAPIA MIRATA
Genomic stratification for the treatment of lymphomas – S. S. Dave
LINFOMI
NON
HODGKIN
TERAPIE MIRATE CONTRO IL BCR
GS1101
IPI-145
Fostamatinib
GS-9973
Ibutinib
CC292
ONO-WG307
Targeting B-cell receptor signaling:changing the paradigm N.Fowler and E.Davis
TERAPIE MIRATE CONTRO IL BCR
Inibisce l’isoforma delta
Inibisce l’isoforma
gamma
Somministrazione orale
Si lega al residuo Cys-481
del BTK
Ben tollerato
Inibisce il segnale del BCR
Riduce l’effetto protettivo delle cellule stromali
Targeting B-cell receptor signaling:changing the paradigm N.Fowler and E.Davis
TERAPIE MIRATE CONTRO IL BCR
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
Targeting B-cell receptor signaling:changing the paradigm N.Fowler and E.Davis
MYC E LINFOMI B AGGRESSIVI
Understanding MYC-driven aggressive B-cell lymphomas: pathogenesis
and classification - G.Ott, A.Rosendwald and E. Campo
MYC E LINFOMI B AGGRESSIVI
MYC-rearranged DLBCL
BCLU
PBLMYC rearranged
Understanding MYC-driven aggressive B-cell lymphomas: pathogenesis
and classification - G.Ott, A.Rosendwald and E. Campo
MYC E LINFOMI B AGGRESSIVI
Understanding MYC-driven aggressive B-cell lymphomas: pathogenesis
and classification - G.Ott, A.Rosendwald and E. Campo
TERAPIA PER I LINFOMI B AGGRESSIVI
Treatment strategies for aggressive Lymphomas: what works? W.H.Wilson
TERAPIA PER I LINFOMI B AGGRESSIVI
ABC, GCP e PMBL
PER GLI ABC: bortezomub, lenalidomide, ibrutinib, temsirolimus, everolimus
PER GLI GCB DA-EPOCH-R:
1) contiene degli inibitori della topoisomerasi II, etoposide e
doxorubicina
2) si ottimizza l’effetto tramite l’infusione continua
PER I PMBL: R-CHOP + RT oppure DA-EPOCH-R (per minimizzare gli effetti della RT)
Treatment strategies for aggressive Lymphomas: what works? W.H.Wilson
NUOVE STRATEGIE PER I DLBCL
Farmaci ipometilanti
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
DNMT1 in 48% DLBCL
DNA
METILTRANSFERASI
DNMT3A in 13% DLBCL
DNMT3B in 45% DLBCL
Targeting the epigenome and other new strategies in diffuse B-cell
lymphoma - L.Cerchietti and J.P.Leonard
NUOVE STRATEGIE PER I DLBCL
Inibitori dell’istone deacetilasi
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
Targeting the epigenome and other new strategies in diffuse B-cell
lymphoma - L.Cerchietti and J.P.Leonard
LINFOMI FOLLICOLARI: VALUTAZIONE
DEL RISCHIO
Eterogeneità biologica
IMMUNOFENOTIPO: CD10+, CD20+, CD19+, CD22+, Ig di superficie, Bcl2+,
Bcl6+, CD5-
GRADI
N° CENTROBLASTI
1
<5 centroblasti/campo
2
6-15 centroblasti/campo
3a
Qualche centrocita evidente
3b
Tutti centroblasti
CD10Espressione maggiore di TP53 e di MUM 1/IRF4
Comportamento clinico simile a DLBCL
Dissecting follicular lymphoma: high versus low risk - S.M.Smith
LINFOMI FOLLICOLARI: VALUTAZIONE
DEL RISCHIO
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
Dissecting follicular lymphoma: high versus low risk - S.M.Smith
LINFOMI FOLLICOLARI: VALUTAZIONE
DEL RISCHIO
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
Dissecting follicular lymphoma: high versus low risk - S.M.Smith
LINFOMI FOLLICOLARI: VALUTAZIONE
DEL RISCHIO
…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
LINFOMI FOLLICOLARI: VALUTAZIONE
DEL RISCHIO
Dissecting follicular lymphoma: high versus low risk - S.M.Smith
LINFOMA MANTELLARE
Prima linea
ARA-C HD
R-HyperCVAD
alternato a
R+ MTX e ARA-c
HD
R-CHOP
alternato a
R-DHAP
R-DHAP
ASCT
MRD t(11;14)
Transplantation for mantle cell lymphoma: is it the right thing to
do?- M.E.Williams
LINFOMA MANTELLARE
Trapianto 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
BORTEZOMIB
LENALIDOMIDE
TEMSIROLIMUS
R-CHOP
R- BENDAMUSTINA
R-FC
Transplantation for mantle cell lymphoma: is it the right thing to
do?- M.E.Williams
LINFOMA MANTELLARE
Terapia di mantenimento
Ogni due mesi
RTX
Settimanalmente per 4 dosi ogni 6 mesi per 2 anni
LENALIDOMIDE
Nuove strategie terapeutiche
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
Transplantation for mantle cell lymphoma: is it the right thing to
do?- M.E.Williams
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
…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
EBV and posttransplantation lymphoproliferative disease: what to do?
Zimmermann H. and Trappe R.U.
HHV8
geni latenti (espressi nelle cellule B, nelle cellule dendritiche KS, nelle cellule endoteliali atipiche KS)
geni della fase litica (più frequenti nel MCD)
Human herpesvirus-8: Kaposi sarcoma, multicentric Castelman disease,
and primary effusion lymphoma – L.D.Kaplan
HHV8
KS
Patogenesi
Clinica
Terapia
Espressione di v-GPCR,
VEGF e bFGF, cKIT,
espressione di mRNA di
multiple
metalloproteasi della
matrice
MCD
Espressione geni della
fase litica.
PEL
Espessione dei geni
della fase latente.
Coinfezione con EBV
talvolta
Immunoistochimica:
CD20-, CD38+, CD138+
Lesioni mucocutanee,
linfoedema,
coinvolgimento GI e
respiratorio
Linfoadenomegalie
diffuse, febbre, perdita
di peso,
epatosplenomegalia,
polineuropatia, polmonite
intestiziale linfocitaria
Effusione sierose:
dispnea, dolore
toracico, distensione
addominale
LOCALIZZATI: azoto
liquido, VCR, RT
SISTEMICI: cART,
doxorubicina e
paclitaxel, IFN α,
COL3, imatinib,
lenalidomide, sirolimus
Chemioterapia (VBL,
CHOP, ABV, etoposide
orale, ciclofosfamide),
IFN α, tp
antiherpesvirus, RTX (4
dosi settimanali), HuAnti-IL6
CHOP like, IFN α, ifn α
+ cidofovir, CHT al alte
dosi + autologo,
Bortezomib, Sirolimus,
IFN α + ATO,
Brentuximab Vedotin,
inibitore dell’istone
deacetilasi
Human herpesvirus-8: Kaposi sarcoma, multicentric Castelman disease,
and primary effusion lymphoma – L.D.Kaplan
HELICOBACTER PYLORI E MALT
Infezione da HP MALT gastrico DLBCL (MALT) gastrico DLBCL gastrico
Helicobacter Pylori and mucosa-associated lymphoid tissue: what’s
new? – S. Kuo and A. Cheng
HELICOBACTER PYLORI E MALT
Helicobacter Pylori and mucosa-associated lymphoid tissue: what’s
new? – S. Kuo and A. Cheng
HELICOBACTER PYLORI E MALT
MALT
pCR: 56-100%
Malt refrattario: 7,2%
pCR: 58,9% (se limitato alla
sottomucosa 80% - se limitato
alla muscolaris propria 29,4%)
Gastric DLBCL (MALT)
Tempo per raggiungere la pCR
al termine della tp è di 4 mesi
Associazione con Hp: 85-89%
dei casi
Early stage:
Pure DLBCL gastric
- tempo per raggiungere la
pCR al termine della tp è di 2,1
mesi
- DFS mediana: 3,9 anni
Alto grado:
-Tasso di efficacia 50%
- pCR: 26,7%
- tempo per raggiungere la
pCR al termine della tp è di 3
mesi
LINFOMI
DI
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
Novel therapy for Hodgkn lymphoma – C. L. Batlevi and A. Younes
NUOVE TERAPIE
Novel therapy for Hodgkn lymphoma – C. L. Batlevi and A. Younes
RT E EARLY STAGE
TOSSICITA’ TARDIVA DA RT
CARDIOVASCOLARE
-Aterosclerosi accelerata
-Fibrosi valvolare
-Scompenso cardiaco congestizio
-Pericardite
-Anomalie valvolari
-Ischemia miocardica
SECONDE
NEOPLASIE
DEFICIT DI
ACCRESCIMENTO
OSSEO
- K epiteliali
-SMD e LAM
-K mammella
-K polmoni
-Mesotelioma
-Ipotiroidismo subclinico
-K tiroide
Il rischio varia a seconda delle zone irradiate e della
potenza dell’irradiazione
!!
Riducendo il campo da irradiare, si riducono i rischi
!!
Management of early-stage Hodgkin lymphoma: is there still a role
for radiation?– P.W.M.Johnson
RT E EARLY STAGE
Management of early-stage Hodgkin lymphoma: is there still a role
for radiation?– P.W.M.Johnson
RT E EARLY STAGE
85%
1yrPFS:
94,9%
1yrPFS: 100%
74%
1yrPFS:
94,7%
1yrPFS: 97,3%
75%
3yrPFS:
94,5%
90,8%
Management of early-stage Hodgkin lymphoma: is there still a role
for radiation?– P.W.M.Johnson
LINFOMA DI HODGKIN A PREVALENZA
LINFOCITARIA: NLPHL
• 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+
CD30CD15IgV gene
Bcl 6
CD10CD19CD4+/CD8+
Lymphocyte-predominant Hodgkin lymphoma: what is the optimal
treatment? - M.Fanale
NLPHL
Stadi precoci
Stadio IA o
IIA
Stadi IB o
IIB
Stadio IA
recidivati
Stadio IA
pediatrici
Lymphocyte-predominant Hodgkin lymphoma: what is the optimal
treatment? - M.Fanale
NLPHL
Stadi avanzati
Regimi
LH - like
Regimi
DLBCL - like
Lymphocyte-predominant Hodgkin lymphoma: what is the optimal
treatment? - M.Fanale
NLPHL
Lymphocyte-predominant Hodgkin lymphoma: what is the optimal
treatment? - M.Fanale
ABSTRACT
BIOLOGIA DEI
LINFOMI
DLBCL ABC and GCP
ABSTRACT 84
Accurate 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
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
• 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
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, EZH2 e bcl6
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
Significance and mechanism of action of EZH2 in normal GC
development and lymphomagenesis
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 chromatin
domains.
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.
DLBCL, MYC gene
ABSTRACT 363
MYC Mutation Profiling In 708 De Novo Diffuse Large B-Cell Lymphoma Demonstrates That
Genetic Abnormalities In The Coding Sequence and Untranslated Regions Have Different
Prognostic and Clinical Significance: A Report From The International DLBCL Rituximab-CHOP
Consortium Program
Zijun Y. Xu-Monette et al.
Objective: To determine the spectrum of MYC mutations in a large group of DLBCL
patients 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.
BCL, PD-L1 protein
ABSTRACT 361
Blood Soluble PD-L1 Protein In Aggressive Diffuse Large B-Cell Lymphoma Impacts
patient’s Overall Survival
Thierry 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 autologous
stem 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
DLBCL, TP53/MIR34A
ABSTRACT 83
Diffuse Large B-Cell Lymphoma With Combined TP53 mutation and MIR34A
methylation: Another “double hit” Lymphoma With Very Poor Outcome?
Fazila Asmar, MD
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.
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 methylated
MIR34A promoter in cells with and without TP53 mutations.
A novel rare, aggressive, but treatable “double-hit” DLBCL
DLBCL, genetic signature
ABSTRACT 499
Whole-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 Cdoxorubicin uptake and are more sensitive to doxorubicin-induced cell death
FL, STAT6 mutation
ABSTRACT 503
Recurrent 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 FACSsorted 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)
GZL
ABSTRACT 847
Gray 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.
mediastinal involvement GZL: 44% non mediastinal involvement GZL: 56%
UNIVARIATE ANAYSIS
Characteristics (at diagnosis)
PFS
OS
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 01)
3.44
1.65-7.17
.001
2.07
0.44-9.77
.35
elevated LDH was the only
Hemoglobin <10.5 g/dl
2.13
1.15-3.94
.02
1.83
0.53-6.23
.33
predictor of poor outcome for
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
significant for inferior OS
Stage (IV vs I-III)
2.76
1.57-4.83
.000
4
7.05
1.85-26.85
.004
including B symptoms;
HR
95% CI
P
HR
95% CI
P
2.50
1.91
1.31-4.76
0.98-3.72
.006
.06
3.89
4.77
1.12-13.46
0.92-24-82
.03
.06
Prognostic Scores
IPI (3-5 vs 0-2)
IPS (3-7 vs 0-2)
On multivariate regression
PFS; several factors were
hypoalbuminemia;stage 4 vs 1-3
MGZL had lower risk features but similar PFS and OS than NMGZL at univariate analysis
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.
LINFOMI
DI
HODGKIN
Terapia
HD, Bleomycin and Vincristine reduction
ABSTRACT 637
Impact 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
Bleomycin and Vincristine acute and long-term toxicity dose reduction Impact
on 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.
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 vincristine
discontinuation 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.
LINFOMI
NON
HODGKIN
Terapia
DLBCL
ABSTRACT 764
Diffuse Large B-Cell Lymphoma (DLBCL) Patients Failing Second-Line R-DHAP Or RICE Chemotherapy Included In The Coral Study
Eric 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 372
Epirubicin 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
DHL, induction and SCT
ABSTRACT 640
Impact 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: RHyperCVAD, R-EPOCH, R-CODOX-M/IVAC, R-ICE.
R-EPOCH superior in achieving complete response (CR) compared with RCHOP
Primary predictor of OS
primary refractory disease
Poor outcomes of DHL
DLBCL
ABSTRACT 849
Dose-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 641
Radiation Therapy Significantly Improves Survival Of Patients With Diffuse Large BCell Lymphoma Associated With MYC Translocation: A Report From The International
DLBCL Rituximab-CHOP Consortium Program
Zijun 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, Lenalidomide
ABSTRACT 248
Lenalidomide In Combination With R-CHOP (R2-CHOP) In Patients With High Burden
Follicular Lymphoma: Phase 2 Study
Herve 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 250
High Response Rate To Combination Lenalidomide-Rituximab In FcγRIIIa-F Carriers
With Indolent Or Mantle Cell Lymphomas Previously Refractory To Rituximab
Elise A. Chong et al
Fc-gamma receptor
RIIIA (FCGR3A)
polymorphisms at aa
158 (V/V vs. V/F
and F/F) impact
on ORR, CR, time
to progression
Part I: Lenalidomide + Desamatasone
Part 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
DLBCL, Lenalidomide
ABSTRACT 850
Final 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 Linfomi
Annalisa 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
lenalidomide
from 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
MCL, Lenalidomide
ABSTRACT 247
Combination Biologic Therapy Without Chemotherapy As Initial Treatment For Mantle
Cell Lymphoma: Multi-Center Phase II Study Of Lenalidomide Plus Rituximab
Jia 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
Rituximab manteinance
ABSTRACT 509
Updated 6 Year Follow-Up Of The PRIMA Study Confirms The Benefit Of 2-Year Rituximab
Maintenance 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 851
Rituximab Maintenance Significantly Prolongs Event Free (EFS) and Progression Free Survival
(PFS) In Male Patients With Aggressive B-Cell Lymphoma In The NHL13 Study
Ulrich Jaeger et al
Idelalisib
NUOVI FARMACI
ABSTRACT 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
IDELALISIB, oral
inhibitor of PI3Kδ
double-refractory
iNHL
• 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 doublerefractory iNHL population with an ORR of 57%.
Kahl B S et al. Blood 2013;122:85
Brentuximab
ABSTRACT 367
Phase II Trial Of Brentuximab Vedotin For CD30+ Cutaneous T-Cell Lymphomas and
Lymphoproliferative Disorders
Madeleine 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 848
A 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.
Ibrutinib
ABSTRACT 251
A Prospective Multicenter Study Of The Bruton’s Tyrosine Kinase Inhibitor Ibrutinib
In Patients With Relapsed Or Refractory Waldenstrom’s Macroglobulinemia
Steven 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
Ibrutinib
ABSTRACT 852
Combining 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 1
Ibrutinib at 280, 420, or 560 mg/d + standard doses of R-CHOP
PART 2
Ibrutinib 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.
Zevalin
ABSTRACT 369
A 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 RCHOP. Preliminary Results At 36 Months From Randomization
Armando Lopez-Guillermo et al.
Crizotinib
ABSTRACT 368
High Response Rates To Crizotinib In Advanced, Chemoresistant ALK+ Lymphoma
Patients
Sara 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 505
A 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
Nella speranza che le mie indicazioni vi
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