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THE ROLE OF MINIMAL THE ROLE OF MINIMAL RESIDUAL DISEASE (MRD) RESIDUAL DISEASE (MRD)
EVALUATION IN THE EVALUATION IN THE MANAGEMENT OF LYMPHOMASMANAGEMENT OF LYMPHOMAS
Sara Galimberti - Ematologia Pisa
DOCTORATE IN GENETICS,
ONCOLOGY AND CLINICAL MEDICINE
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SUMMARY
NHL: what are they?MRD: what is it?
Which techniques? Which techniques? The FIL MRD NET experienceClinical aspects and role of MRD
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I.
NHL: what are they?MRD: what is?
Which techniques? Which techniques? The FIL MRD NET experienceClinical aspects and role of MRD
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NHLLymphomas represent 2,9% of all cancers in men
and 3,2% in women, with an incidence of about 20/100000/year. Every year in Italy more than 10000 new cases are diagnosed.
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HL & NHL
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NHL – CLINICAL FEATURES
Skin involvement
Mediastinum enlargement
Lymph nodes
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NHL – CLINICAL FEATURES
Skin involvementMediastinum enlargement
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Lymph nodes enlargement
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Lymph nodes enlargement
Diagnosis is made by lymph node biopsylymph node biopsy. .
Often the node is superficial and easily accessible.
If it is deep in the abdomen, nodes can be biopsied If it is deep in the abdomen, nodes can be biopsied
under CT guidance or via the laparascope.
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WHO CLASSIFICATION
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WHO CLASSIFICATION
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LIMPH NODE
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MOLECULAR PATHWAYS in B -CELL LYMPHOMAGENESIS
GERMINAL CENTER
MARGINAL ZONE
PLASMA CELL
VIRGIN B-CELLS
Mantle cell lymphoma
BCL-1/JH
Primary effusion lymphoma
HHV-8
Lymphoplasmacytoid lymphoma
PAX-5
MALT lymphoma
API2/MLT
MANTLEMEMORY
B-CELS
BCL-2/JH
DLBCLp53
c-MYCp53
BCL-6 mutations Burkitt lymphoma
Follicular lymphoma
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NHLMantle cell marginalBurkitt
lymphoplasmocyticfollicularDLBCL
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ANN ARBOR STAGING SYSTEM
Stage I - disease in single lymph node or lymph node region.
Stage II - disease in two or more lymph node regions on sameside of diaphragm.
Stage III - disease in lymph node regions on both sides of thediaphragm are affected.
Stage IV - disease is wide spread, including multiple involvement at one or more extranodal (beyond the lymph node) sites, such as the bone marrow
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ANN ARBOR STAGING SYSTEM
A: if there is no constitutional symptoms
B: if there is fever, weight loss, night sweats
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II.
NHL: what are they?MRD: what is?
Which techniques? Which techniques? The FIL MRD NET experienceClinical aspects and role of MRD
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MRD
IMAGINGIMAGING
CITOFLUORIMETRIACITOFLUORIMETRIA
t(14;18), t(11;14), t(8;14)t(14;18), t(11;14), t(8;14)
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FLOW CYTOMETRYsIg intensity
dim bright
CD5 +/± CD5 + CD5 +/±
CD23 + / ±
CD23 +
CD23 –
CD10 –
CD10 ++ / ±
CLL
CD49c +
+ – – CD23 + / –
+
v-CLL PLL
MCL PLL
SMZL, SLVL,
IC, CyIg +/–
HCL, CD25 ++ CD11c ++ , CD103 +
FoLy
CD49 + / –
bcl-1, PRAD-1
CD43 – bcl-2 +
MCSS: 3.5–5
MCSS: 2.5–3
MCSS: 2
extra- MCSS
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CLL MATUTES' SCORECLL = 3-5
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TECHNIQUES
Max SENSITIVITYMax SENSITIVITYNO NEG FALSES
Max SPECIFICITYMax SPECIFICITYNO POS FALSES
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TECHNIQUES
FLOW CYTOMETRY:FLOW CYTOMETRY:BM, PB, lymph nodesFew hoursFew hours10-3/10-4
Useful at diagnosis and follow-up
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FLOW CYTOMETRY - CLL
CD5+/19+
FMC7-
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TECHNIQUES
MOL BIOL:MOL BIOL:BM, PB, lymph nodes2 days2 days10-4/10-5
Useful at diagnosis and follow-up
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PB vs BM
Pott, Blood 2006
BM vs PB
Pott, Blood 2010
BM vs PB in MCL at diagnosis: + 19%
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TECHNIQUES
MOL BIOL:MOL BIOL:BM, PB, lymph nodes2 days2 days10-4/10-5
Useful at diagnosis and follow-up
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BCL2/IGH
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IGH REARRANGEMENT
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ASO-PCR
Consensus primer 5’ Consensus primer 3’
FIRST PCR NOT TUMOR-SPECIFIC
FR1 FR2 FR4FR3CDR1 CDR2L CDR3
NOT TUMOR-SPECIFIC
FR1 FR2 FR4FR3CDR1 CDR2L CDR3
primer 3’ specific patientprimer 5’ specific patient
SECOND PCRTUMOR-SPECIFIC
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TECHNIQUES
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FLOW vs PCRFLOW vs PCR
92 samples analyzedby FC and ASO PCR
85% concordant
Sensitivity:
Bottcher, Leukemia 2004
Sensitivity:5 x 10-3 FC5 x 10-3-2 x 10-4 PCR
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FIL-MRD NETWORK
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ORBAL
CAND
TO
NO
GE
FI
PE
MO
REPR BO
RA
ANPG
TR
UD
VR
VI PD
ROZZANO HUMANITAS
BSMI
MONZA
TN
BZ
PV
PC
IVREA
BR
BA
TA
TRANI
NU
CA
ROMA
LT
NANOCERA INF
PA
CT
MERC
CZ
CS
RIONERO PT
TRICASE
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NHL-Task 2 RESULTSMRD measurement of 8 Follow-up
LAB CODE
MRD-FU1 MRD-FU2 MRD-FU3 MRD-FU4 MRD-FU5 MRD-FU6 MRD-FU7 MRD-FU8
TO NEG POS POS NEG POS POS NEG POS
NHL-Task 2 RESULTSMRD measurement of 8 Follow-up
RO NEG POS POS
debole
NEG POS POS NEG POS
PI NEG POS POS NEG POS POS NEG POS
BO NEG POS POS NEG POS POS NEG POS
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Task 3 RESULTS
LAB S QR SLOPE CORR.C. FU1 FU2 FU3 FU4 FU5 FU6 FU7 FU8
TO 1E-05 5E-05 3,64 1,00 1E-08 2E-01 6E-05 1E-08 2E-01 4E-04 1E-08 3E-04
borderline samples
QUANTITATIVE PCR
RO 1E-05 1E-04 3,7 0,98 1E-08 2E-01 1E-06 1E-08 4E-01
4E-04
1E-08 2E-04
PI 1E-05 5E-05 3,5 0,99 1E-08 3E-01 1E-06 1E-08 5E-01 4,6E-04 1E-08 1,5E-04
BO 1E-05 1E-04 3,7 1,00 1E-08 1E-01 1E-06 1E-08 9E-02 4E-04 1E-08 3E-04
linea
altre patologie
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II.
NHL: what are they?MRD: what is?
Which techniques? Which techniques? The FIL MRD NET experienceClinical aspects and role of MRD
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HOT TOPIC
Adapted from Ferrero, Hematol Oncol 2011
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MRD & LETTERATURAyearyear markermarker methodmethod ptspts statusstatus txtx PFSPFS
1991 Bcl2 Q-PCR 114 Rel ASCT <0.05
1995 Bcl2, IgH Q-PCR 24 Rel ASCT <0.05
1999 Bcl2 Q-PCR 113 Rel ASCT <0.05
2000 Bcl2 Q-PCR 53 Rel ASCT Ns
2002 Bcl2, IgH Q-PCR 42 Dx ASCT <0.05
2004 bcl2., IgH Q-PCR 35 Dx ASCT <0.05
2006 Bcl2, IgH Q-PCR 42 Rel ASCT <0.05
2008 Bcl2, IgH QT-PCR 60 Dx HD/R-CHOP <0.05
2009 Bcl2 QT-PCR 127 Dx zevalin <0.05
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CHOPCHOP--RR
PB
PCR+ predicts the FFS also in multivariate analysis
Rambaldi, Blood 2002
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RR--CHOP / RCHOP / R--BB
179 pts receiving R -CHOP vs R-Bendamustine
@ dx: PCR + 63% - QUANTITATIVE PCR
2y-EFS= 82% pts low PCR vs 47% high PCR
Post -tx: PCR - = 86%Post -tx: PCR - = 86%median 2y- PFS= 9 m pts PCR + vs n.r. PCR -
Outcome is significantly conditioned Outcome is significantly conditioned
by the PCR status @ diagnosis and postby the PCR status @ diagnosis and post--therapytherapyZohren, ASH 2009
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RR--CHOP CHOP EORTC 20981
238 pts with relpased follicular lymphoma randomized to CHOP vs R-CHOP
Pts in PR/CR randomized to Rituximab maintenance vs observation
Van Oers, JCO 2010
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RR--CHOP CHOP EORTC 20981
PFS is conditioned by the PCR status @ diagnosis...
Van Oers, JCO 2010
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RR--CHOP CHOP EORTC 20981
...but not conditioned by the PCR status at the end of therapy...
Van Oers, JCO 2010
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CR/CRuoppure
ZEVALIN® (n=208)
Rituximab 250 mg/m2 I.V.
Random
izzazione
Inizio dello studio
Terapia di prima linea con CVP,
CHOP/CHOP-like,
ConsolidamentoInduzione
RADIORADIO--IMMUNO TXIMMUNO TX
STUDIO FIT (409 pts) )
oppure PR
NRPD
Esclusione
Rituximab 250 mg/m2 I.V.nei giorni –7 e 0
+ ZEVALIN® (max 1184 MBq) nel giorno 0
Nessun ulteriore trattamento
(n=20)6)
Random
izzazione
CHOP/CHOP-like, combinazioni
con fludarabina, clorambucile o rituximab
Controllo
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ZEVALIN®, n/N* (%)Controllo, n/N* (%)
PCR qualitativa
RADIORADIO--IMMUNO TXIMMUNO TX
61/68 (90%)21/59 (36%)PB
90% converted from PCR+ to PCR –after ZEVALIN ®
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RADIORADIO--IMMUNO TX RQIMMUNO TX RQ--PCRPCR
Goff, JCO 2009
@randomization 54% PCR + zevalin 46% PCR+ obs2% HIGH10% INTERMEDIATE88% LOW
+ 3m: red >1 log76% zevalin vs 25%+6m: PCR –84% vs 30%
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ZEVALINZEVALIN
Only in PCR+ pts zevalin prolongs PFS
Goff, JCO 2009
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AutoSCT & MRD postAutoSCT & MRD post
70 pts affected by indolent NHL
receiving autologours transplantation
Post-autoTMO PCR - : 70% foll
25% SLL
Corradini, JCO 2004
25% SLL
25% MCL
EFS is significantly conditioned
by the PCR status after transplantation
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AutoSCT & AFERESIAutoSCT & AFERESI
The contamination molecularly assessed
of aphereses does condition EFS
Corradini, JCO 2004
APHERESES PCR - : 54% foll
25% SLL
12% MCL
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OS PFS
aph high
AutoSCT & AFERESIAutoSCT & AFERESI
aph high
aph low
aph intermediate
deathhigh
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MCL & ASCTMCL & ASCT160 pts
Pott, Blood 2010
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MCL & ASCTMCL & ASCT
PCR status after transplantation does impact
on durability of response
MRD-
Pott, Blood 2010
MRD+
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MCL & FCRMCL & FCR
99 pts
Pott, Blood 2010
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MCL & FCRMCL & FCR
MRD-
PCR status during rituximab maintenance
does impact on durability of response
Pott, Blood 2010
MRD+
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CLL & FCRCLL & FCR
493 pts randomized to FC vs FCR
MRD assessed by 4 -color FC
MRD - = 0.01%
FCR > FCFCR > FC
Bottcher, Blood 2012
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CLL & FCRCLL & FCR
2. MRD does impact on OS
Bottcher, Blood 2012
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CLL & FCRCLL & FCR
...and PFS for both arms...
Bottcher, Blood 2012
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CLL & ASCTCLL & ASCT
40 pts receiving ASCT
FC (100% +) ASO-PCR (97% +)
MRD after 3 and 6 m impacts on PFS and OS
Moreno, Blood 2006
MRD+
MRD+
MRD- MRD-
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CLL & ALLOSCTCLL & ALLOSCTThe relapse rate after allogeneic transplantation is conditioned by MRD status
Bottcher, Blood Revies 2011
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CLL & TMOCLL & TMO
CLLX3 trial – 90 pts
an MRD-driven approach reduces relapse rate
Dreger, Blood 2010
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CONCLUSIONSCONCLUSIONS
• In 2013 the MRD still represents a real “hot topic”
• Perhaps more conclusive data will be produced by the new trials adopting produced by the new trials adopting quantitative PCR
• THE NEW FIL TRIALS ARE MOLECULARLY ORIENTED!!!
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THE NEW FOLL12
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THANK YOU THANK YOU VERY MUCH TO VERY MUCH TO
MY LABMY LABMY LABMY LABMY COLLEAGUESMY COLLEAGUES
...AND ALL OF YOU......AND ALL OF YOU...