Meeting Educazionale:Linfomi non-Hodgkin aggressivi
I linfomi aggressivi a prognosi sfavorevole: possibilità dimiglioramento della prognosi ottimizzando la
chemioimmunoterapia.
Dr. Umberto VitoloSC Ematologia 2 AOU San Giovanni Battista
Torino
• Topics:
– Prognostic factors Clinical Factors Role of PET New histological subtypes
– Treatment Young Elderly
– Novel approaches
Standard and novel chemoimmunotherapyStandard and novel chemoimmunotherapyapproaches as first line treatment to improve theapproaches as first line treatment to improve the
outcome in aggressive lymphoma at high riskoutcome in aggressive lymphoma at high risk
Standard and novel chemoimmunotherapyStandard and novel chemoimmunotherapyapproaches as first line treatment to improve theapproaches as first line treatment to improve the
outcome in aggressive lymphoma at high riskoutcome in aggressive lymphoma at high risk
• Topics:
– Prognostic factors Clinical Factors Role of PET New histological subtypes
– Treatment Young Elderly
– Novel approaches
International Prognostic Index (IPI)International Prognostic Index (IPI)
Risk Factors - Age > 60 years - Stages III or IV - ≥2 extranodal sites - Performance Status ≥2 - LDH> normal
Prognostic Group No. of Factors
Low 0, 1Low/intermediate 2High intermediate 3High 4, 5
Aggressive Non-Hodgkin Lymphomas:Aggressive Non-Hodgkin Lymphomas:Survival of IPI Risk GroupsSurvival of IPI Risk Groups
Group Factors 5y PFS 5y-OS IPI ( Shipp 1993)Low 0-1 70% 73%
Low-int 2 50% 51%
High-int 3 49% 43%
High 4-5 40% 26%
R-IPI (Sehn 2006) Factors 4y-PFS 4y-OS
Very-good 0 94% 94%Good 1-2 80% 79%Poor 3-5 53% 55%
Revised International Prognostic FactorsRevised International Prognostic Factors (R-IPI) vs Standard IPI in patients treated (R-IPI) vs Standard IPI in patients treated
with R-CHOPwith R-CHOP
Sehn LH et al. Blood 2007; 109: 1857-61 Sehn LH et al. Blood 2007; 109: 1857-61
R-IPI: Risk groups remain in DLBCL in theR-IPI: Risk groups remain in DLBCL in therituximab erarituximab era
Sehn et al. Blood. 2007;109:1857
Analisi retrospettiva di unapopolazione non selezionata dipazienti con DLBCL (N= 365)
Tutti i pazienti trattati conR-CHOP: 45% erano alto rischio (IPI
3-5) >50% dei pz ad alto rischio
ha presentato una recidivaentro 4 anni
IPI score rimane unimportante indice
prognostico anche inera del rituximab
Role of PET to monitor response to therapy inRole of PET to monitor response to therapy inaggressive lymphomas?aggressive lymphomas?
• PET at the end of treatment
• Interim PET response
Juweid et al. J Clin Oncol 2005
53 pz con NHL aggressivo53 pz con NHL aggressivoValutazione finale con TAC e FDG-PET dopo CHOPValutazione finale con TAC e FDG-PET dopo CHOP
PFS PFS –– IWC / IWC + PET IWC / IWC + PET
Response Assessment of Aggressive Non-HodgkinResponse Assessment of Aggressive Non-Hodgkin’’ssLymphoma by Integrated International Workshop CriteriaLymphoma by Integrated International Workshop Criteriaand Fluorine-18-Fluorodeoxyglucose Positron Emissionand Fluorine-18-Fluorodeoxyglucose Positron Emission
TomographyTomography
Cheson B et al. J Clin Oncol 2007
Revised Response Criteria for MalignantRevised Response Criteria for MalignantLymphomaLymphoma
Early clinical trials of interim PET in lymphomaEarly clinical trials of interim PET in lymphoma
Kostakoglu et al, Cancer 107: 2678, 2006
Haioun et al, Blood 106: 1376, 2005Mikhaeel et al, Ann Oncol 16: 1514, 2005
Spaepen et al, Ann Oncol 13: 1356, 2002
PET after 4th cycle
PET after 3rd cycle PET after 2nd cyclePPV 50 %NPV 74 %Accuracy 68.5%
PET after 1st cycle
Interim-PET +
DLBCL: PET-adapted TherapyDLBCL: PET-adapted Therapy MSKCC 01-142 MSKCC 01-142
Positive Negative NPV 89%
55 pts (59 pts)49 EF
R-CHOP-14 x 4 (87 enrolled)
Interim PET86 pts (97 pts)
31 pts (38 pts)Bx. Pos. Bx. Neg
27 Pts23 EF
4 pts (5 pts)2 EF
A. Zelenetz, personal communication 2008
POD-1
PPV 26%PPV 26%
PET NEG vs. Bx NEG vs. BX POS
Outcome based upon Interim PET ScanOutcome based upon Interim PET Scan
EFSInterim PET(+) vs. PET(-)
60544842363024181260
Cum
ulat
ive
Surv
ival
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
P=0.2
PET NEG (N=55, 49 cen)
PET POS (N=31, 25 cen)
Months
60544842363024181260
Cum
ulat
ive
Surv
ival
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
PET NEG (n=55, 49 cen)
BX NEG (n=27, 23 cen)
BX POS (n=4, 2 cen)
P=NS
EFS
A. Zelenetz, personal communication 2008
Early evaluation of 18-FDG-PET in DLBCLEarly evaluation of 18-FDG-PET in DLBCL
Cashen A et al, ASH 2008Cashen A et al, ASH 2008
FDG-PET/TC after cycle 2FDG-PET/TC after cycle 2 FDG-PET/TC end of therapyFDG-PET/TC end of therapy
These results demonstrate that in DLCBL patients treated with R-CHOP whoThese results demonstrate that in DLCBL patients treated with R-CHOP whoare assessed prospectively, interim FDG-PET/CT does not predict PFS.are assessed prospectively, interim FDG-PET/CT does not predict PFS.
NPVNPV 85%85%PPV 25%PPV 25%
81 DLBCL at diagnosis treated with R-CHOP21/14; median age 56 (22-82)81 DLBCL at diagnosis treated with R-CHOP21/14; median age 56 (22-82)
Pregno P et al.Pregno P et al.Interim 18-FDG-PET Failed to Predict DifferentInterim 18-FDG-PET Failed to Predict DifferentOutcome in DLBCL Patients Treated withOutcome in DLBCL Patients Treated withRituximab-CHOP.Rituximab-CHOP.Oral Presentation ASH 2009.Oral Presentation ASH 2009.
18-months PFS by PET-2 evaluation 18-months PFS by PET-3 evaluation
Final PET pos 61%
Final PET neg 84%
Interim PET pos 74%
Interim-PET neg 84%
Interim PETInterim PET Final PETFinal PET
Early evaluation of 18-FDG-PET in DLBCLEarly evaluation of 18-FDG-PET in DLBCL
Pregno P et al, SIE 2009Pregno P et al, SIE 2009
Early PET evaluation: unsolved issueEarly PET evaluation: unsolved issue
42 year-old gentleman, DLBCL IPI 1 R-CHOP1442 year-old gentleman, DLBCL IPI 1 R-CHOP14
DiagnosisDiagnosis Early PET after 2Early PET after 2coursescourses Final PETFinal PET
Recommended timing of PET (PET/CT) scans inRecommended timing of PET (PET/CT) scans inlymphoma clinical trialslymphoma clinical trials
Cheson B et al, J Clin Oncol 2007Cheson B et al, J Clin Oncol 2007
Ancillary trial 18-FDG-PET in IIL-DLCL04Ancillary trial 18-FDG-PET in IIL-DLCL04
StagingCT scan and 18-FDG-PET
R-CHOP14/R-MegaCHOP14 X 2
R-CHOP14/R-MegaCHOP14 X 2
R-MADx 2
Final restagingCT scan and 18-FDG-PET
Early response evaluation18-FDG-PET
Interim response evaluation by CT scan
R-CHOP14/RMegaCHOP14
18-FDG-PET pre ASCT
BEAM-ASCT
RESPONSEEVALUATION
NO CHANGE OFTREATMENTBASED ONEARLY 18-FDG-PET RESULTS
DLBCL AND EBVDLBCL AND EBV
Park et al, Blood 2007Park et al, Blood 2007
BB--CCell ell LLymphoma, ymphoma, UUnclassifiable, nclassifiable, wwith ith FFeatureseaturesIIntermediate ntermediate BBetween etween DLBCLDLBCL aand nd BLBL
BCLUWFIBDLBCLABLBCLUWFIBDLBCLABL
Standard and novel chemoimmunotherapyStandard and novel chemoimmunotherapyapproaches as first line treatment to improve theapproaches as first line treatment to improve the
outcome in aggressive lymphoma at high riskoutcome in aggressive lymphoma at high risk
• Topics:
– Prognostic factors Clinical Factors Role of PET New histological subtypes
• Treatment Young Elderly
– Novel approaches
Management of DLBCL: first line treatmentManagement of DLBCL: first line treatment
Efficacy of R-CHOP14/21 in DLBCL patients withEfficacy of R-CHOP14/21 in DLBCL patients withpoor prognosis?poor prognosis?
Brusamolino E et al, Haematologica 2006Sehn LH et al, Blood 2007
164 pts poor-RIPI R-CHOP21:4-yr OS 55%
31 pts poor IPI R-CHOP14:4-yr OS 45%
How to improve survival in DLBCLHow to improve survival in DLBCLwith poor-prognosis?with poor-prognosis?
Add more drugs and/or intensify the administration ofAdd more drugs and/or intensify the administration ofchemotherapy and/or Rituximabchemotherapy and/or RituximabRituximab-Dose dense therapyRituximab-Dose dense therapy
Rituximab-HDC+ASCT as first-line therapyRituximab-HDC+ASCT as first-line therapy
Add more and new drugs with different mechanismAdd more and new drugs with different mechanismof action beyond Rituximabof action beyond Rituximab
HDC and ASCT as first line treatment in aggressiveHDC and ASCT as first line treatment in aggressivelymphomas in pre-Rituximab era: contradictory resultslymphomas in pre-Rituximab era: contradictory results
Event-free survivalEvent-free survivalDLCL IPI 1-2DLCL IPI 1-2
Event-free survivalEvent-free survivalDLCL IPI 2-3DLCL IPI 2-3
GOELAMS GOELAMSstudystudy
Milpied et alMilpied et alNEJM 2004NEJM 2004
Intergruppo IntergruppoItaliano LinfomiItaliano Linfomi
studystudyVitolo et alVitolo et al
HaematologicaHaematologica20052005
Martelli etal. J Clin
Oncol 2003
Event-free survivalEvent-free survivalDLCL IPI 2-3DLCL IPI 2-3
P = 0.2P = 0.2
EFS LNH93-3 study. 370EFS LNH93-3 study. 370pts; age < 60yrs; AAIPI 2-3pts; age < 60yrs; AAIPI 2-3
Gisselbrechtet al: JCO
2002
Induction chemotherapy
Months 1 and 2
Intensified chemotherapy MAD(HD-ARAC + Mitoxantrone x 3
days)Months 3 and 4
High dosechemotherapyBEAM + ASCT
Month 5
R
MegaCEOP14 x 4
R R
MAD MAD BEAM
R RPBSC
ASCT
months
RR--HHDDCC
R = Rituximab
R
0 1 2 3 4 5
R-MEGACEOP14
R 375 mg/m2 d 1Epi 110 mg/m2 d 3Ctx 1200 mg/m2 d 3Vcr 1.4 mg/m2 d 3Pdn 40 mg/m2 dd 1 5G-CSF 5 mcg/kg dd 5 12
R-MAD
Mito 8 mg/m2 dd 1 3ARA-C 2 g/m2/12h dd 1 3Dex 4 mg/m2/12h dd 1 3R 375 mg/m2 d 4 and d -1PBSCG-CSF 5 µg/Kg d 4
+/- RT-IF to bulkydisease or residual
mass
R-Dose Dense + HDC supplemented with Rituximab + ASCTR-Dose Dense + HDC supplemented with Rituximab + ASCT
Vitolo U, et al. Haematologica 2009; 94: 1250-58Vitolo U, et al. Haematologica 2009; 94: 1250-58
R-HDC: June 2002 – December 2005 94 patients
4-yr OS 80%(95%CI: 71.6%-88.4%)
4-yr FFS 73%(95%CI: 63.5%-82.5%)
73% R-HDC73% R-HDC
44% HDC44% HDC
p = .0008p = .0008
R-HDC 94 patients CR 82%R-HDC 94 patients CR 82% HDC 41 patients CR 68%HDC 41 patients CR 68%
Retrospective Comparison:Retrospective Comparison:Rituximab-HDC+ASCT vs HDC+ASCTRituximab-HDC+ASCT vs HDC+ASCT
54% HDC54% HDC
80% R-HDC80% R-HDC
p = .0017p = .0017
4-yrs Failure-Free Survival4-yrs Failure-Free Survival 4-yrs Overall Survival4-yrs Overall Survival
FFS R-HDC R-HDC vs HDCHDC = 0.44 (95% CI=0.24-0.81, p=.01)= 0.44 (95% CI=0.24-0.81, p=.01)
OS R-HDC R-HDC vs HDCHDC = 0.45 (95% CI=0.22-0.90, p=.03)= 0.45 (95% CI=0.22-0.90, p=.03)
CoxCox’’s model:s model:adjusted Hazardadjusted Hazard
RatioRatio
ASCT upfront with Rituximab pretransplantASCT upfront with Rituximab pretransplant LNH 03 B. DLBCL: 18-60 yr, IPI 2-3 factors LNH 03 B. DLBCL: 18-60 yr, IPI 2-3 factors
Rituximab
R R R R
ACVBP
ACVBP
ACVBP
ACVBP
Wk 0 2 4 6 PBPCcollection
10 12 14 16 18 21 23
MTX3g/sqm BEAM+ASCT
Gisselbrecht C et al, ASH 2008Gisselbrecht C et al, ASH 2008
Median Follow-up 27 m %3-year PFS 763-year OS 813-year OS 60
GITIL trial: R-HDS maps in first line DLBCLGITIL trial: R-HDS maps in first line DLBCL112 patients age < 65, aa-IPI 2-3112 patients age < 65, aa-IPI 2-3
Tarella C et al, Leukemia 2007Tarella C et al, Leukemia 2007
OS by IPIOS by IPI EFS by IPIEFS by IPI
Most recent studies in poor-prognosis DLBCL treated with (Rituximab)dose-dense chemotherapy with R-HDC and ASCT
AUTHOR TREATMENT INCLUSION FFS/OS CR% TD%
CosoBMT 2006
RISC<61yr, aa-IPI 2-3,
stage II-IV5yr FFS 63% OS 65% 72 3
IntragumtornchaiLeuk Lymphoma
2006
CHOP<66yr, aaIPI2-3,
stage III-IV
5yr FFS 16% OS 24% 36 8CHOP-ESHAP-HDT 5yr FFS 34% OS 43% 44 17
RCHOP-ESHAP 5yr FFS 61% OS 61% 67 11Stewart
Blood 2006CHOP+DICEP+BEAM <65yr, aa-IPI 2-3 4yr EFS 72% OS 79% n.a. 1.8
TarellaLeukemia 2007
RHDS-maps<66yr, aa-IPI 2-3,
stage II-IV4yr FFS 73% OS 76% 80 5
ArranzEur J Haematol
2008
MegaCHOP (+/- IFE) +BEAM
18-65yr, low IPIwith
beta2microglobulinor
Intermediate/highrisk
5yr PFS 56% OS 64% n.a. 3.5
HaiounAnn Oncol 2009
ACE + HDT+ASCT +/- R18-60yr, aa-IPI 2-3 4yr EFS 71-80% OS 48-53% 72 4ACVBP + HDT+ASCT +/-
RVitolo
Haematologica 2009RMegaCEOP-RMAD-
BEAM<61yr, aa-IPI 2-3,
stage III-IV4yr FFS 73% OS 80% 82 5
Who are the patients at poor-risk for whom isWho are the patients at poor-risk for whom isworthwhile to intensify treatment?worthwhile to intensify treatment?
We need randomized controlled trials in youngWe need randomized controlled trials in youngpoor-prognosis DLBCLpoor-prognosis DLBCL
DLBCL age <60/65, aaIPI 2-3DLBCL age <60/65, aaIPI 2-3Ongoing Randomized TrialsOngoing Randomized Trials
Groups Risk categories OutlineDSHNHLDSHNHL Age < 60, aaIPI 2-3 R-megaCHOEP x 4 vs R-CHOEP14 x 8
IIL (DLCL04)IIL (DLCL04) Age < 60, aaIPI 2-3
R-CHOP14 x 8vs R-megaCHOP14 x 6
vs R-CHOP14 x 4 + R-HDCT + ASCTvs R-megaCHOP14 x 4 + R-HDCT + ASCT
(early FDG-PET evaluation)
HOVON (63 NHL)HOVON (63 NHL) Age < 65 aa IPI 2-3R-iCHOP x 6
vs R-iCHOP x 3 + R-HDCT x 2 +ASCT
US IntergroupUS IntergroupS9704S9704 Age < 60, aaIPI 2-3
R-CHOP21 x 8 vs R-CHOP21 x 5 + ASCT(early FDG-PET evaluation)
GOELAMGOELAM Age < 60, aaIPI 2-3R-CHOP14 x 8
vs R-CEEP x 2 + HDMTX/Ara-C + ASCT
NORDICNORDIC Age < 60, aaIPI 2-3R-CHOEP14 x 6 + HDMTX + HDAra-C x 6
(early FDG-PET evaluation)
GITILGITIL Age < 60, aaIPI 2-3 R-CHOP14 x 8 vs R-HDS
CALGBCALGB All patient groups R-CHOP21 x 8 vs DA-EPOCH x 6-8
NCRINCRIAll patient groups
Stratification according toIPI and age: < 60 vs ≥ 60
R-CHOP21 x 8 vs R-CHOP14 x 6 (R x 8)
mCHOEP IV
CYC 6000ADR 70VCR 2ETO 1480PRD 500
PBSC
R64
PBSCPBSC
mCHOEP III
CYC 4500ADR 70VCR 2ETO 960PRD 500
43
mCHOEP II
CYC 4500ADR 70VCR 2ETO 960PRD 500
mCHOEP I
CYC 1500ADR 70VCR 2ETO 600PRD 500
221 77 98 days
CH
OEP
-14
CH
OE
P-14
CH
OEP
-14
CH
OEP
-14
CH
OEP
-14
CH
OEP
-14
CH
OEP
-14
CH
OEP
-14
CHOEP-14: CYC 750 VCR 2ADR 50 PRED 500ETO 300 G-CSF
DSHNHL 2002-1 (DSHNHL 2002-1 („„Mega-CHOEPMega-CHOEP““):):TRIAL DESIGN (TRIAL DESIGN (≤≤60 YRS60 YRS, AGE-ADJUSTED IPI , AGE-ADJUSTED IPI ≥≥2)2)
n=230
n=230rituximab
CR/PRCR/PR
CR/PRCR/PR
Off studyOff study
R-MegaCHOP14 x 4R-MegaCHOP14 x 4
R-CHOP14 x 4R-CHOP14 x 4R-MAD x 2 +R-MAD x 2 +BEAM + ASCTBEAM + ASCT
NRNR
RRAANNDDOOMMIIZZAATTIIOONN
R-MegaCHOP14 x 4R-MegaCHOP14 x 4
R-CHOP14 x 4R-CHOP14 x 4
RR
EE
SS
TT
AA
GG
II
NN
GG
188188PtsPts
188188PtsPts
R-MegaCHOP14 x 2R-MegaCHOP14 x 2
R-CHOP14 x 4R-CHOP14 x 4
Off studyOff studyNRNR
Phase III randomized, multicenter study in poor-prognosisPhase III randomized, multicenter study in poor-prognosis(aaIPI2-3) DLBCL young patients. Dose-dense(aaIPI2-3) DLBCL young patients. Dose-dense
chemotherapy + Rituximab +/- intensified and HDC withchemotherapy + Rituximab +/- intensified and HDC withASCT. ASCT. Study ID: IIL-DLCL04.Study ID: IIL-DLCL04.
*Patients at risk of CNS recurrence*Patients at risk of CNS recurrence(SIE guidelines 2006): IT Mtx 4 or 6 doses(SIE guidelines 2006): IT Mtx 4 or 6 doses
Accrual Target 376 patientsAccrual October 2009:
310 patients
Haematologica 2006
Prophylaxis of CNS relapse should be performed in patientswith involvement of specific extranodal sites such as the:testis, paranasal sinuses, hard palate, orbit, paravertebralmasses and bone marrow. (Grade B)
Prophylaxis of CNS relapse should be considered inpatients with involvement of more than one extranodal siteand increased LDH. (Grade B)
DLCL04 Enrollement: october 2009DLCL04 Enrollement: october 2009
Aggiornato al 6 ottobre 2009
TARGET TOTALEARRUOLATI
RandomSCHEMA
1SCHEMA
1 BIS SCHEMA 2 SCHEMA 2BIS IPI 2 IPI 3
376 310 75 78 80 77 224 86
0
50
100
150
200
250
300
mar
-06
apr-
06m
ag-0
6
giu-
06
lug-
06ag
o-06
set-0
6
ott-0
6no
v-06
dec-
06
gen-
07fe
b-07
mar
-07
apr-
07m
ag-0
7
giu-
07
lug-
07ag
o-07
set-0
7
ott-0
7
nov-
07di
c-07
gen-
08
feb-
08m
ar-0
8
apr-
08
mag
-08
giu-
08
lug-
08
ago-
08se
t-08
ott-0
8
nov-
08di
c-08
gen-
09
feb-
09m
ar-0
9
apr-
09
mag
-09
giu-
09
lug-
09
ago-
09
set-0
9ot
t-09
Arruolamento Pazienti
Arruolamento ideale
Response and safetyResponse and safety
Patients enrolled 317Evaluable for response andtoxicity
226
CR + CRu 167 (73.8%)2-year FFS 63%Toxic deaths 9/241 (3.7%)SAE + SUSAR 114 + 23
DLCL04: 2-year FFSDLCL04: 2-year FFS
At risk:
226 177 122 63 43 17 0
0.00
0.25
0.50
0.75
1.00
0 6 12 18 24 30 36Months
FAILURE-FREE SURVIVAL
63%
Standard and novel chemoimmunotherapyStandard and novel chemoimmunotherapyapproaches as first line treatment to improve theapproaches as first line treatment to improve the
outcome in aggressive lymphoma at high riskoutcome in aggressive lymphoma at high risk
• Topics:
– Prognostic factors Clinical Factors Role of PET New histological subtypes
• Treatment Young Elderly
– Novel approaches
GELA-LNH 98.5:GELA-LNH 98.5:5-year OS5-year OS
Feugier P, et al. J Clin Oncol 2005 Pfreundschuh et al. Lancet Oncology 2008
RICOVER-60: 1222 Elderly.RICOVER-60: 1222 Elderly.OS by TrOS by Treatment Armeatment Arm
p<0.007
R-CHOP 58%
CHOP 45%
6x R-CHOP 14
8x R-CHOP 14
8x CHOP 14
6x CHOP 14
PFS - According to mid-therapy restagingPFS - According to mid-therapy restagingResponse adapted addition of chemotherapy is notResponse adapted addition of chemotherapy is not
justifiedjustified
0 10 20 30 40 50 60 70 80
CRu
Months
PR
0 10 20 30 40 50 60 70 80
Months6 x CHOP-14 (n=59)8 x CHOP-14(n=76)6 x R-CHOP-14(n=65)8 x R-CHOP-14(n=76)
6 x CHOP-14(n=112)8 x CHOP-14(n=118)6 x R-CHOP-14(n=122)8 x R-CHOP-14(n=107)
6 x CHOP-14 (n=59)8 x CHOP-14 (n=63)6 x R-CHOP-14(n=74)8 x R-CHOP-14(n=65)
100 90 80 70 60 50 40 30 20 10 0
%
CR
Months0 10 20 30 40 50 60 70 80
6xR- CHOP 14
8x R-CHOP 14
6x R-CHOP 14
8x R-CHOP 14
6x R-CHOP 14
8x R-CHOP 14
Pfreundschuh et al. Lancet Oncol. 2008
4 IT MTXR
R-CHOP 21x 8
0 3 6 9 Wks12 15 18 21
0 2 4 6 10 14 Wks8 12
R-CHOP 14 x 8
Primary endpoint: EFSExpected improvement: 10% at 3 years with R-CHOP 14 (55 to 65%)600 patients required (over 4 years)
GELA study LNH 03-6BGELA study LNH 03-6B61-80 years, aaIPI = 1,2,361-80 years, aaIPI = 1,2,3
Chair: R. Delarue, A. BoslyChair: R. Delarue, A. Bosly
0
10
20
30
40
50
60
70
Neutopenia
Thrombocytopenia
InfectionCardiac
% p
atie
nts
51%
37%
5%9%
22%17%
1% 2%
NCRI: R-CHOP-21 vs. R-CHOP-14: Grade 3&4NCRI: R-CHOP-21 vs. R-CHOP-14: Grade 3&4ToxicityToxicity
R-CHOP-14
R-CHOP-21
Cunningham et al. ASCO 2009; Abstract # 8506
RICOVER-60: Poor outcome for elderly DLBCLRICOVER-60: Poor outcome for elderly DLBCLpts with higher risk disease (IPI 3-5)pts with higher risk disease (IPI 3-5)
Pfreundschuh et al., Lancet Oncol. 2008; 9: 105. Personal communication: N. Schmitz.
DENSE-R-CHOP-14
CD20+ DLBCLStages I-IV
61 to 80 years
CHOP
CHOP
CHOP
CHOP
CHOP
CHOP
12 1410 8 6 4 2 0
W e e k s
Dose-dense Rituximab Improves Outcome of Elderly Patients withDose-dense Rituximab Improves Outcome of Elderly Patients withPoor-Prognosis Diffuse Large B-Cell Lymphoma (DLBCL):Poor-Prognosis Diffuse Large B-Cell Lymphoma (DLBCL):
Results of the DENSE-R-CHOP-14 Trial of the German High-Grade Non-Results of the DENSE-R-CHOP-14 Trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)Hodgkin Lymphoma Study Group (DSHNHL)
By Courtesy of Pfreundschuh M et al; Blood 2007; 110, abs 789.By Courtesy of Pfreundschuh M et al; Blood 2007; 110, abs 789.
Rituximab 4 + 8
020406080100120140160180200
1 9 17 25 33 41 49 57 65 73 81 89 97 105 113day of treatment
n g
/ m
l • ••R-CHOP-14
RITUXIMAB PHARMACOKINETICS:RITUXIMAB PHARMACOKINETICS:Trough Serum LevelsTrough Serum Levels
Reiser et al., ASH 2006, Abs # 778
020406080100120140160180200
1 9 17 25 33 41 49 57 65 73 81 89 97 105 113day of treatment
n g
/ m
l
••• • • • • • • • •
• ••
•
•R-CHOP-14
DENSE-R-CHOP-14
RITUXIMAB PHARMACOKINETICS:RITUXIMAB PHARMACOKINETICS:Trough Serum LevelsTrough Serum Levels
Reiser et al., ASH 2006, Abs # 778
* with censoring at 12 months
RICOVER-60(n=183)CHOP-R-ESC(n=44)
0 2 4 6 8 10 120
0.10.20.30.40.50.60.70.80.91
Months
%
IPI 1, 2 IPI 3 - 5
0 2 4 6 8 10 120
0.10.20.30.40.50.60.70.80.9
1
Months
%
RICOVER-60(n=123)CHOP-R-ESC(n=53)
Event-free Event-freeSurvivalSurvivalDENSE-R-CHOP-14
RICOVER: 65%
DENSER: 74%
0%
10%
20%
# <=20 # >200%
20%
40%
# <=20 # >20
p=0.023 p=0.136
12.7%
6.4%
36%
19%
P a t i e n t s P a t i e n t s
Grade 3&4 Infectionsper Cycle
Grade 3&4 Infectionsper Patient
Effect of Prophylaxis on Effect of Prophylaxis on Grade 3&4 Infections Grade 3&4 InfectionsDENSE-R-CHOP-14
R-CHOP 14 + pegfilgrastim in DBLCLR-CHOP 14 + pegfilgrastim in DBLCLSevere adverse events*Severe adverse events*
Type Number
Total cycles 269Interstital pneumonitis (3 PC)Interstital pneumonitis (3 PC) 88Septic shock 2Pneumonia 2GI hemorrhage 1SAE/Cycles 13/269 (5%)Dead from SAE 1 (septic shock)1 (septic shock)
*By Courtesy of Brusamolino E et al;*By Courtesy of Brusamolino E et al;Haematologica 2006.Haematologica 2006.
**R-dose dense chemotherapy **R-dose dense chemotherapy carefull carefullprophylaxis and surveillance in elderly patientsprophylaxis and surveillance in elderly patients
**Habermann TM; educational session**Habermann TM; educational sessionASH 2007ASH 2007
Standard and novel chemoimmunotherapyStandard and novel chemoimmunotherapyapproaches as first line treatment to improve theapproaches as first line treatment to improve the
outcome in aggressive lymphoma at high riskoutcome in aggressive lymphoma at high risk
• Topics:
– Prognostic factors Clinical Factors Role of PET New histological subtypes
• Treatment Young Elderly
– Novel approaches
Elderly R-CHOP14
EFS according to IPI
Months
0 10 20 30 40 50 60 70
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
IPI IH risk elderly R-CHOP14
IPI H risk elderly R-CHOP14
aa-IPI H risk young R-HDC+ASCT
aa-IPI IH risk young R-HDC+ASCT
Pfreundschuh et al. Lancet Oncology 2008Vitolo U et al. Haematologica 2009
Historical perspective: high-risk patientsR-HDC+ASCT and RICOVER-60
New drugs to improvethe induction
treatment?
Young R-HDC+ASCT25-40% of patients failed
to achieve CompleteRemission
LR-CHOP21 IIL-REAL07: study designLR-CHOP21 IIL-REAL07: study design
Course I
Course II
Course III
Course IV
Course V
Course VI
Day –28 to 0Pretreatment screening
Day +14 cohorts5, 10, 15, 20 mgLenalidomide
days 1-14 plus R-CHOP
Patients accrued:3 per cohort
Continual reassessment
CR, Cru, PRPD, SD, toxicity
Off study
Day +21
Day +42
Day +63
Day +84
Day +105
R-CHOP TherapyRituximab 375 mg/m2 D0 or D1
Cyclophosphamide 750 mg/m2 D1Doxorubicin 50 mg/m2 D1 Vincristine 1.4 mg/m2 D1
Prednisone 40 mg/m2 D1-D5PEG-filgrastim or G-CSF
Bortezomib + CHOP-Rituximab in DLBCLBortezomib + CHOP-Rituximab in DLBCL
Design Phase I/II trial Eligibility DLBCL ( 40 patients treatment naïve IPI= 2,3-5) Therapy Arm : Bortezomib (0.7, 1.0, 1.3 mg/m2) days 1 and 4 of a
21-day cycle with R-CHOP 21, G-CSF
Leonard et al. ASCO Proceedings vol. 25:8031,2007
Safety- Most common AE:3 pts did not complete therapy (1=withdrawal by patient,1= pulmonarytoxicity,1=concurrent meningitis
Grade 4 hematologic toxicity thrombocytopenia (15%) and leukopenia(15%)
Peripheral neuropathy: 22(55%), grade 4 hematologic toxicity: 7 (35%)
Response to TherapyEvaluable forResponse (n) CR/CRu PR OR
DLBCL 40 75% 25% 100%
2-yrs PFS= 72%
UntreatedN=13100 %
DLBCL
Ganjoo et al. Leuk Lymphoma 2006
Bevacizumab Efficacy in aggressive lymphoma:Bevacizumab Efficacy in aggressive lymphoma:Phase II experience plus R-CHOP (RA-CHOP)Phase II experience plus R-CHOP (RA-CHOP)
Day 1
Bevacizumab15 mg/kg
Cycle 1
Day 2
CHOP +Rituximab
3 weeks (RA-CHOP-21)
Day 1
Bevacizumab +CHOP + Rituximab
Cycles 2 - 8
EfficacyOverall response rate Complete remission Partial remission
85 % (n=11)38 % (n=5)46 % (n=6)
Responders in remission (median follow-up)
9/11 (16.9 months)
1-year PFS 77 %[51 %; 93 %]
Main Study: R-CHOP14/21 ± Bevacizumab in untreatedMain Study: R-CHOP14/21 ± Bevacizumab in untreatedDLBCL age 18-80, IPI DLBCL age 18-80, IPI ≥≥ 1 1
R-CHOP21 and/or R-CHOP14 are the standard of careR-CHOP21 and/or R-CHOP14 are the standard of carein DLBCLin DLBCL
The identification of poor-prognosis patients is aThe identification of poor-prognosis patients is apriority because they have no more than 50% chancespriority because they have no more than 50% chancesof cureof cure
Outside clinical trial a modification of treatment basedOutside clinical trial a modification of treatment basedon early-PET results is not supported by clinicalon early-PET results is not supported by clinicalevidenceevidence
Take-Home messages (1)Take-Home messages (1)
HDC supplemented with Rituximab + ASCT is anHDC supplemented with Rituximab + ASCT is aneffective treatment in high risk young patients thateffective treatment in high risk young patients thatshould be compared to Rituximab-dose-denseshould be compared to Rituximab-dose-densechemotherapy in large randomized trialschemotherapy in large randomized trials
Early PET scan and molecular biomarkers need to beEarly PET scan and molecular biomarkers need to beincorporated and tested into the ongoing trials toincorporated and tested into the ongoing trials tovalidate their predictive valuevalidate their predictive value
Novel drugs should be associated to R-CHOP regimenNovel drugs should be associated to R-CHOP regimeninto clinical trials to evaluate their efficacy and safetyinto clinical trials to evaluate their efficacy and safety
Take-Home messages (2)Take-Home messages (2)
4 G. Benevolo4 C. Boccomini4 B. Botto4 A. Chiappella4 C. Frairia4 L. Orsucci4 P. Pregno
Hematology 2 AOU S.Giovanni BattistaHematology 2 AOU S.Giovanni BattistaTorinoTorino
4 M. Ceccarelli4 A. Evangelista4 F. Saccona4 G. Ciccone
STATISTICAL ANALYSISSTATISTICAL ANALYSISCancer EpidemiologyCancer Epidemiology
University TorinoUniversity Torino
ACKNOWLEDGMENTSACKNOWLEDGMENTS
IIL CENTERSIIL CENTERS