maurizio martelli.ppt [sola lettura] - siematologia.itmartelli.pdf · regimens (ice, dhap, mime...

Opzioni terapeutiche di salvataggio neilinfomi aggressivi ricaduti/refrattari dopo

chemio-immunoterapia

Maurizio Martelli Dip. Biotecnologie Cellulari ed Ematologia

Università, “Sapienza” Roma

Management of DLBCL

Primary refractory

RelapseSecond-line

therapySecond-line

therapy

Investigationalprograms HDT/ASCT

Investigationalprograms

CR/PR

CR/PR NR

NR

R-CHOP or R-CHOP-like

CR

Cure

First relapse patients need to receive non cross resistant chemotherapyregimens (ICE, DHAP, MIME etc) with or without rituximab followed ineligible patients, by HDT/SCT. Patients elegible for HDT/SCT include

those aged < 65 years, with chemosensitive disease and goodperformance status and with good avaibility of autologous stem cells.

( Grade A)

Haematologica 2006

PARMA studyPARMA study Improved EFS with transplantation Improved EFS with transplantation

Time from randomisation (months)

Transplantation (n = 55)5-year EFS = 41%

Conventional treatment (n = 54)5-year EFS = 13%

300 60 90 120 150

Even

t-fre

e su

rviv

al (%

) 80

60

40

20

0

100

p = 0.002

Philip T, et al. N Engl J Med 1995; 333:1540–1545.

Median follow-up 8.3 years

CD20+ DLBCL18–60 years

IPI 0,1Stages II–IV,I with bulk(n = 823)

MInT triallow risk

Pfreundschuh M, et al. Lancet Oncol 2006;7:379–91

Relapse rate10-20%

HOW MANY PATIENTS WILL BE ELIGIBLEFOR AUTOTRANSPLANTATION

PFS and Overall Survival of 365 PatientsPFS and Overall Survival of 365 PatientsAccording to Revised IPI (R-IPI)According to Revised IPI (R-IPI)

P<0.0001

Very Good

Poor

Good

Time (years) Time (years)

P<0.0001

Poor

Good

Very Good

PFS Overall Survival

Sehn et al, Blood, 2007

Relapse rate40-45%

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

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

Dose-dense and high-dose chemotherapy plus Rituximab withautologous stem cell transplantation for primary treatment of diffuse

large B-cell lymphoma at poor prognosis: a phase II multicenter study.

Vitolo U et al, Haematologica 2009

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

Relapse rate25-30%

Vitolo U et al, Haematologica 2009

Open questions in DLBCL salvage therapyOpen questions in DLBCL salvage therapywith transplantationwith transplantation

Prognostic factors at relapse

Better salvage regimen and role of Rituximab

Role of PET scan

Role of rituximab pre and post-transplantation

Improving conditioning regimen

Prognostic factors in DLBCL: HDT + ASCT Prognostic factors in DLBCL: HDT + ASCT

100

80

60

40

20

01086420

31%

11%11%

P=0.02

REFRACTORREFRACTORYY

CHEMOSENSITIVE

Event-Free SurvivalEvent-Free Survival

Martelli M et al, EBMT 2001Martelli M et al, EBMT 2001

Progression-free survival CRProgression-free survival CRcompared to PRcompared to PR

Zelenetz et al, Ann Oncol 2003Zelenetz et al, Ann Oncol 2003

CR

PR

0 30 60 90 120 150 180

%

% P

FSPF

S

Months from registrationMonths from registration

P < 0.00001

N

Early relapseLate relapse

0 10 20 30 40 50 60 70 80 90

100

Progression-free survival in theProgression-free survival in the PARMA protocol PARMA protocol

Events RR111 82 177 69 2.08

Guglielmi et al. J.Clin. Oncol. 1998

International Prognostic Index predictsresponse to salvage therapy:

Data from the PARMA study

Partial responseComplete response / CRu

Patie

nts

(%)

80

60

40

20

0

100

0

17

60

ORR = 77%(n = 52)

24

20

ORR = 44%(n = 82)

10

18

ORR = 28%(n = 51)

8

ORR = 8%(n = 19)

1 2 3Blay JY, et al. Blood 1998; 92:3562–3568.

Stage, PS, LDH at relapse

IPI score

Overall Survival of 204 patients according to IPI at relapse

Blay JY, et al. Blood 1998; 92:3562–3568.

IPI=2-3




Role of PET scan



Chemotherapy Salvage Regimens forDLBCL

MitoxantroneIfosfamide

based

Platinumbased

IMVP-16 MINE

VIM MINE-ESHAP

VCMP EMP

DHAP

ESHAP

CEPP-B

ICE

Salvage Rituximab chemotherapyregimens in DLBCL

Regimen N°pts ORR/CR ASCTperformed

ASCT survival

R-ICE 36 78% / 53% 70% 67%R-ESHAP 163 73% / 45% 65% 57%R-ASHAP 20 75% / 45% 40% 62%

R-DHAP/VIM/DHAP +/-R 225 75% / 54% 63%/ vs 46% 50% vs 24%R-ICE vs R-DHAP 396 63% / 38% 52% 49%

R-DHAOX 33 70% / 27% 40% n.rR-DHAP 57 70% / 20% 50% n.r

Long expanding list

R-ICE vs ICE: Does improved responseR-ICE vs ICE: Does improved responsetranslate into improved PFS?translate into improved PFS?Pa

tient

s (%

)

80

60

40

20

0

100

R-ICE

53

25

ORR = 78%

27

44

ORR = 71%

p = 0.01

Kewalramani T, et al. Blood 2004; 103:3684–3688.

ICE*

* Historical controlsMonths from ASCT

Prop

ortio

n pr

ogre

ssio

n-fr

ee

p = 0.25

R-ICE

PFS

0 20 40 60 80 100 1200

0.2

0.4

0.6

0.8

1.0

ICE

Salvage therapy: DHAP vs R-DHAP + ASCTSalvage therapy: DHAP vs R-DHAP + ASCT

Vellenga E et al, Blood 2008; 111: 537-543

HOVON 44 TRIAL239 pts with

relapsed/progressiveaggressive

CD20+ NHL

96% Rituximab naive

Random

DHAP arm: DHAP-VIM-DHAP +

BEAM-ASCT

R-DHAP arm:R + DHAP-VIM-DHAP +

BEAM-ASCT

HOVON trial: ResultsHOVON trial: Results

DHAP vs R-DHAPDHAP vs R-DHAP

ORR 54% vs ORR 54% vs 75%75%ASCT 46% vs ASCT 46% vs 63%63%

Vellenga E et al, Blood 2008; 111: 537-543

R-DHAP/VIM/DHAP

DHAP/VIM/DHAP

96% Rituximab naive

RANDOMISED

ARM 1: Rituximabmaintenance

ARM 2: Monitoring

C1 C2 C3

C1 C2 C3

S0 S3 S6

S0 S3 S6

Evaluation

ARM B: R-DHAP CollectPSC

ARM A: R-ICE CollectPSC

S9

S9

4–6 weeksAfter C3

BEAM+ autograft= (D0)

Evaluation

+M1 +M3 +M5 +M9+M7 +M11 +M12

+M3 +M7 +M12

RANDOMISED

D0 D28

CORAL trial (GELA and others):CORAL trial (GELA and others):R-ICE vs R-DHAPR-ICE vs R-DHAP

First randomization:R-ICE vs R-DHAPReport on 400 patients included between

July 24, 2003 to September 4, 2007

N° pts

N

197

% N

191

%

CR-Cru-PR 125 63.5 120 62.5

PROGRESSIVE/DEATH/ NOTEVALUATED

72 36.5 71 37.2

Response after induction therapy for all patients (Induction ITT)

Orlando ASCO May 2009 / Coral study C. Gisselbrecht

R-ICER-ICE R-DHAPR-DHAP

OVERALL SURVIVALACCORDING TO TREATMENT

ARM (INDUCTION ITT)

PROGRESSION-FREESURVIVAL ACCORDING TO

TREATMENT ARM(INDUCTION ITT)


56%

56%

42%

45%

CORAL STUDY RESPONSE RATE ACCORDING TO PROGNOSTIC FACTORS


Patients ResponseCR/Cru/PR p

All patients 246 63 %CR/CRu 148 38 %

Prior rituximab No 122 83 % < 0.0001Yes 124 51 %

Relapse/Refractory > 12 mo 140 88 %< 0.0001< 12 mo 106 46 %

IPI < 2 160 71 %< 0.0002

> 1 76 52 %

PROGRESSION-FREESURVIVAL ACCORDING TO

PRIOR RITUXIMAB(INDUCTION ITT)

PROGRESSION-FREESURVIVAL

ACCORDING TO FAILUREFROM DIAGNOSIS(INDUCTION ITT)


N=160

N=228

N=147

N=241

31%

64%

30%

62%

MULTIVARIATE ANALYSIS FOR SURVIVAL

PFS EFS OS

Prior Rituximab 0.003 0.0007 0.01 Relapse < 12 months < 0.0001 <0.0001 <0.0001 sIPI > 1 < 0.0001 <0.0004 <0.0001 Treatment Arm 0.1 0.3 0.07

Relapses after rituximab exposure are more severe.

Early relapses and failure are the main adverseprognostic factors.


CONSOLIDATION – PATIENTS WITH BEAM AND ASCT(INDUCTION ITT)

Main Reasons for premature withdrawals:Progressive lymphoma 53%

Toxicity 7%Collection failure 10% (CD 34/kg < 2.106)

Deaths 4%


Arm A : R-ICE n %

Arm B : R-DHAP n %

Consolidationtreatment : BEAM

YES 101 51 105 55

NO 96 49 86 45

Total transplantation 197 100 191 100

Arm of treatment

163 relapsed/refractory DLBCL treated with R-ESHAP.94 (R+ group) received R-chemo in I line treatment, 69 (R-) only chemo.

Martin A et al, Haematologica 2008; 93: 1829-36

Take home messages (1)Take home messages (1) HDT-ASCT is the standard care of patients with

chemosensitive relapsed/refractory DLBCL

Early relapse and high IPI score at relapse are the mainunfavorable prognostic factors

There are no differences between the most wide usedsalvage regimens

The addition of Rituximab to salvage regimens improve theresponse rate

Patients who relapsed after first line Rituximab combinationchemotherapy have a worse outcome.




Role of PET scan



Prognostic significance of PET prior to ASCTAuthor No. Histology IndicationTiming Definition PET- PET+

SCT PET PET resp. Resp. NoResp.

Cremerius 22 NHL First-line Prior > 25% decrease 72% 28%2003 to SCT

Filmont 20 HD/NHL First Prior No residual 88% 8%2003 relapse Disease to SCT

Spaepen 60 HD/NHL First Prior No residual 100% 24%2003 Relapse disease to SCT

Svoboda 50 HL/NHL Relapse Mid No residual 54% 10%2006 Relapse Disease

Schot 53 NHL Relapse Mid CR 72% 38%2007 20 HL Relapse PR residual -- 10%

No response

Jabbour• 68 HL Relapse Prior SCT No residual 69% 23%2007 disease

Filmont 60 NHL/HL Relapse Prior SCT No residual 80% 43%2007 First line Post SCT 81% 25%

Pognostic role of in vivo minimal residual diseasepre-ASCT

60 relapse/refractory DLCLpatients treated with

HDT + ASCT

PET +: 26/30 failurePET -: 3/30 failure

Spaepen K et al, Blood 2003

Predictive role of PET in aggressiveNHL pre ASCTPredictive role of PET in aggressiveNHL pre ASCT

Pre-ASCT PET + and post-ASCT PET -

After ASCT : PET -Initially Before ASCT : PET+

JF Filmont et al Cancer 2007

OS and EFS for pre-ASCT PET in lymphoma

P < 0.001log rank

0.00 0.25 0.750.50 1.00 1.25 1.751.50 2.000.00

0.25

0.50

0.75

1.00

2.250.00 0.25 0.750.50 1.00 1.25 1.751.50 2.000.00

0.25

0.50

0.75

1.00

P < 0.001log rank

OS EFS

92 %80%

43 %53 %

yearsyears

Negative PET Positive PET

p log rank = 0.0003 p log rank = 0.0002

JF Filmont et al Cancer 2007

OS EFS




Role of PET scan



Khoury IF et al. J.Clin.Oncol. 2005; 23: 2240-47

High or standard dose of Rituximab with ASCT?High or standard dose of Rituximab with ASCT?

Day + 7Day + 7RituximabRituximab1000 mg/mq1000 mg/mq

Day Day –– 1 1RituximabRituximab

375 mg/mq375 mg/mq

Edx OREdx ORIfo+VP1Ifo+VP1

66

G-CSF 10 mcg/kgG-CSF 10 mcg/kgGM-CSF 250GM-CSF 250mcg/mqmcg/mq

HARVEST

BEAMBEAM

Day 0Day 0ASCTASCT

Day + 1 and + 8Day + 1 and + 8RituximabRituximab

1000 mg/mq1000 mg/mqDay 0Day 0GM-CSF 250 mcg/mqGM-CSF 250 mcg/mq

OSOS DFSDFS




Role of PET scan



InpatientInpatientOutpatientOutpatient

Day -14 -7 -4 -2-21

Indium-In2B8Indium-In2B8ImagingImaging

9090Y-ibritumomabY-ibritumomabtiuxetantiuxetan therapytherapy

0.4 mCi/Kg0.4 mCi/Kg VP/AraCVP/AraC MelMelTRANSPLANTTRANSPLANT

Close observation,Close observation,discharge upondischarge upon

blood countblood countrecoveryrecovery

Close observationClose observation

BiodistributionBiodistributionstudystudy

BCNUBCNU

-5 -3-6 -1 0

n = 12n = 12 Age: median 61 yrs (20-78 yrs)Age: median 61 yrs (20-78 yrs) Histology: DLCBL, MCLHistology: DLCBL, MCL

9090Y-ibritumomab tiuxetanY-ibritumomab tiuxetan32 mCi/BEAM32 mCi/BEAM

Time to recovery: WBC 11 days,Time to recovery: WBC 11 days,platelets 11 daysplatelets 11 days

Pilot study: Combining conventional dosePilot study: Combining conventional dose Z-BEAM as a conditioning regimen Z-BEAM as a conditioning regimen

Shimoni A, et al. Exp Hematol 2007

Overall survival: Z-BEAM and ASCTOverall survival: Z-BEAM and ASCTin chemo-refractory aggressive NHLin chemo-refractory aggressive NHL

Shimoni A, et al. Exp Hematol 2007

Ove

rall

surv

ival

(%)

100

67% (95% CI, 46–87%)

Months since transplantation

0

25

50

75

0 5 10 15 20 25 30

Z-BEAM in poor risk NHL patients :Z-BEAM in poor risk NHL patients : Overall and progression-free survivalOverall and progression-free survival

89%

70%

Krishnan et al, JCO 26:90-5, 2008

n = 41n = 41 Age: median 60 yrs (19-Age: median 60 yrs (19-

78 yrs)78 yrs) Histology: Histology: DLCBLDLCBL (20), (20),

MCLMCL (13), (13), FLFL (4), (4), Transf.Transf.LNHLNH (4) (4)

90Median time torecovery: WBC: 11 d(range 9-26), PLT: 12 d(range: 3-107)

Inclusion criteria:Inclusion criteria:- age 18-65- age 18-65- CD20+ DLBCL- CD20+ DLBCL- CR or PR to first-line treatment cointaining R-CHOP or R-ACVBP- CR or PR to first-line treatment cointaining R-CHOP or R-ACVBP

Primary objective:Primary objective:- EFS at 2 years >80%- EFS at 2 years >80%

Secondary objective:Secondary objective:- ORR, toxicity, TTP or relapse, DFS, OS, hematological reconstitution,- ORR, toxicity, TTP or relapse, DFS, OS, hematological reconstitution,

Gisselbrecht C et al 2008

Zevalin® - BEAM with autologous stem cell supportZevalin® - BEAM with autologous stem cell supportas DLBCL first-line consolidation (GELA)as DLBCL first-line consolidation (GELA)

Ritu

xim

ab

–21 –14

Zeva

lin®

90Y: 0.4 mCi/Kg

–7 –6 –5 –4 –3 –2 –1 0

B E E E EA A A A M

GR

AFT

B: carmustine

E: etoposide

A: cytarabine

M: melphalan

Day

Zevalin® - BEAM Italian experience:Zevalin® - BEAM Italian experience:Baseline characteristics Baseline characteristics 53 pts53 pts

Median age, y (range) 54 yrs (20-75)

Histology, no. (%) Follicular 16 (30%) Aggressive 37 (70%)

III-IV stage at diagnosis, no. (%) 40 (75%)

Median number of prior chemotherapy 2 (2-5)

IPI, grade 0 8 (15%) > I 45 (85%)

Bone marrow involvement at diagnosis 19 (36%)

Prior rituximab, no. (%) 48 (91%)

high risk high risk patients !!! patients !!!

By courtesy of Enzo Pavone

Early Response post Z-BEAM (90 days)Early Response post Z-BEAM (90 days)

CR 32 (74 %) PR 5 (11 %) PD 6 (14 %)

ORR 85%ORR 85%

RESULTSRESULTS

2 - septic shock (day +6 and +39)

1 - pneumonitis (day +22)

1 – BK viral encephalites (day +61)

1 - MOF (day +14)

Early Death before 90 daysEarly Death before 90 daysTRM all 9.3%TRM all 9.3%

TRM <65 3.4%TRM <65 3.4%(multivariate analysis)(multivariate analysis)


Event-Free-SurvivalEvent-Free-Survival

64%64%


Is there a place for allotransplantation inIs there a place for allotransplantation inrelapsed/refractory DLBCL ?relapsed/refractory DLBCL ?

Refractory disease who have failed a prior ASCT

Precluded from ASCT: - difficulties to stem cell collection - bone marrow infiltration

• Graft failure: n=1 (0.9%)• aGVHD grades II-IV: 33%• cGVHD: 45%

• NRM at 3 years: 32%• Relapse or prog at 3 y: 35%• PFS & OS at 3 y: 33% / 39%

MUD SCT for Patients with DLBCL: A RetrospectiveAnalysis of 118 Patients Registered through the EBMT

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 18 24 30 36

Months

CI

NR

M

Univariate analysis p=0.1Multiv p=0.002; RR:3.5 (1.6-7.8)

Conventional (n=57)

RIC (n=61)

No differences in PFS & OS according to conditioning regimen

Conventional (n=57)

RIC (n=61)

0.00

0.20

0.40

0.60

0.80

1.00

0 12 24 36 48 60

Months

CI

Rel

apse

or p

rog

Univariate analysis p=0.1Multiv p=0.1

LWP EBMT A Sureda 2008

Outcome after RIC allogeneictransplantation in relapsed DLBCL

Study Diagnosis N° pts Regimen SurvivalNagler et al DLBCL 8 Flu,Bu, ATG 13% OS,

63% NRMFulkner et al DLBCL 8 BEAM Alemtuz 17%OS,

68% relapSpitzer et al DLBCL 20 Cycl.ATG 25% EFS

Escalon et al Aggres.NHL 20 Flu,Cyclo,Ritux 31% OS

Dean et al NHL 28 Flu,Cyclo 49% OS25% NRM

Robinson et al Aggres.NHL 62 Various 47% OS 37% NRM

Corradini et al Aggres. NHL 61 Cyclo,Thiotepa,Flu

63% OS15% NRM

Sibling donors

Unrelated donors

chemosensitive

Chemo-refractory

-6 -4 -3 -2 -1 0 +1 +3 +6 +30 +60 +70 +90 +120 +150 +180

Thiotepa 10 mg/kg

Fludarabine 30 mg/mqCyclophosphamide 30 mg/kg

Allo-SCTCyclosporine

MTXMTXMTX

RIC treatment plan

Corradini et al. Blood 2002

Patient CharacteristicsIndolent Aggressive HL

N° patients 69 86 39

Age at Tx (median) 54 51 35

Subtypes 29 FL 36 CLL

4 other

42 B-NHL 28 T-NHL

16 MCL

-

Time diagnosis to Tx(median, months)

47 months 24 months 37 months

N° of previous lines(median)

3 2 3

Previous autograft (%) 31% 54% 82%

Complete Remission atTx (%)

24% 31% 23%

Refractory Disease (%) 31% 29% 31%

Aggressive Lymphomas - survival curves -

0 12 24 36 48 60 72 84 96 108 1200

25

50

75

100 T-NHLB-NHLMCL

Time (months)O

S (%

)0 12 24 36 48 60 72 84 96 108 120

0

25

50

75

100

Time (months)

PFS

(%)

OS at 5 years56% T-NHL versus 68% B-NHL

p=0.43

PFS at 5 years57% T-NHL versus 63% B-NHL

p=0.49

AlloHSCT in aggressive lymphomaConditioning regimens

Pts (173) Myeloablative (60) Reduced intensity (113)

Median age 37 (range 16-61) 47 (range 15-66)

Alive 21 (35%) 54 (48%)

Dead 39 (65%) 59 (52%)

early TRM 10 (17%) 11 (10%)

late TRM 4 (7%) 8 (7%)

aGVH 10 (17%) 27 (24%)

cGVH 8 (13%) 25 (22%)

ORR 31 (52%) 66 (58%)

Median OS 7 months 20 months

TRM according to conditioning regimen

Time after allo-SCT (months)

Non

rela

pse

mor

talit

y

100806040200

1,0

,9

,8

,7

,6

,5

,4

,3

,2

,1

0,0

Myeloablative

RIT

p 0.01

Allotransplant as salvage therapy after ASCT in relapsed DLBCL: a retrospective GITMO study

AlloHSCT in aggressive lymphoma

Progression Free Survival after allo-HSCT

Months

120100806040200

Pro

gres

sion

free

sur

viva

l

1,0

,8

,6

,4

,2

0,0

50%


PFS: response after allo-HSCT

Months

120100806040200

Pro

gres

sion

free

sur

viva

l

1,0

,8

,6

,4

,2

0,0

p=0.0000

CR

PR

NR-progression


Months

120100806040200

Pro

gres

sion

free

sur

viva

l

1,0

,8

,6

,4

,2

0,0

p=0.05

c-GVHD

no-GVHD


Months

120100806040200

Pro

gres

sion

free

sur

viva

l

1,0

,8

,6

,4

,2

0,0

p= 0.01

PFS: conditioning regimen

RIC

Myeloablative

Allotransplant as salvage therapy after ASCT in relapsed DLBCL: a retrospective GITMO study

RIC- SCT should be considered an effectivesalvage strategy for poor prognosis DLBCL

Tandem Autograft and RIC Allograftfor poor prognosis relapse refractory DLBCL

High DoseTherapy

AUTO

RICALLO

Immunesupression

Carella et al BEAM Flu/Cyclo Cyclosporin+MTX 2000

Gutman et al2005

Bu/CyBEAM

TBI 2Gy+/-Flu

DLBCL salvage therapy not elegible for DLBCL salvage therapy not elegible fortransplantation: older patientstransplantation: older patients

Low-risk patients High-risk patients

Coiffier at al ASCO 2007

Low-risk patients High-risk patients

Relapse rate40%

R-CHOP study: PFS according to aaIPI

Relapse rate60%



New salvage chemotherapy regimensintroducing new drugs

Increase response with adjuvant biologicalagents during first line to prevent relapse.

Palliative care

Rituximab, Gemcitabine and Oxaliplatin(R-GEMOX)

Rituximab: 375 mg/m² d1 Gemcitabine: 1000 mg/m² d2 Oxaliplatin: 100 mg/m² d2

Pts = 46ORR 83% CR 50%Median TTP 20 m

El Gnaoui et al Ann Oncol 2007 18:1363-8

El Gnaoui, T et al. Ann Oncol 2007 18:1363-1368

Overall survival and event-free survival in patients treatedwith R-GEMOX

PLANNEDPLANNEDENROLLEMENTENROLLEMENT45 PATIENTS45 PATIENTS

DLBCL de novo or transformed, age 18-70 yrs, stage II/III/IV,BM involvement <25%, chemoresistant/relapsed diseaseafter first line treatment not-eligible for HDC+ASCT

Debulking chemotherapy:R-DHAP 2 courses every 21 days

Blood stem cell harvestafter 2nd DHAP

Radioimmunotherapy: Day +1 Rituximab 250 mg/mqDay +8 Rituximab 250 mg/mq + Zevalin 0.4 mCi/kgDay+16 PBPC reinfusion >2x 106/kg

Radioimmunotherapy: Day + 30-45Rituximab 250 mg/mq + Zevalin 0.2 mCi/kg

CR,PR,SD

CR,PR,SD

PD

PD

Off study

Off study

111In Dosimetria(5 paz)‏

111In Dosimetria(5 paz)‏

STUDIO ZETAL-07STUDIO ZETAL-07Zevalin twice in Aggressive LymphomaZevalin twice in Aggressive Lymphoma

Efficacy and Safety of Lenalidomide Oral Monotherapy inEfficacy and Safety of Lenalidomide Oral Monotherapy inPatients with Relapsed or Refractory Aggressive NHL.Patients with Relapsed or Refractory Aggressive NHL.

International Study (NHL-003).International Study (NHL-003).

•• Patient eligibility criteria:Patient eligibility criteria:–– Relapsed/refractory aggressive NHLRelapsed/refractory aggressive NHL–– Measurable disease (Measurable disease (≥≥ 2 cm) after at least 1 prior treatment 2 cm) after at least 1 prior treatment–– Patients with MCL were included in this subset analysisPatients with MCL were included in this subset analysis–– ECOG performance status score ECOG performance status score ≤≤ 2 2

Day17142128

Lenalidomide25mgorally

Therapy continued as tolerated oruntil disease progression

1 Cycle

International Study (NHL-003)International Study (NHL-003)

Entered 203

DLBCL107

MCL53

TSF24

FL gr. 319

Response: 73 DLBCL N (%)Complete response 3 (4)

Partial response 18 (25)Stable disease 11 (15)Progressive disease 41 (56)

ORRORR 29%29%

Czuczman MS, Blood 2008: 112 abstr 268

PFS 73 DLBCL

Enzastaurin – Distinct Mechanism of Action

Adapted from Graff J, et al. Cancer Res. 2005;65:7462-7469 andEnzastaurin HCl Investigator’s Brochure. 10/2007. Eli Lilly and Company.Indianapolis, IN.

Enzastaurin targetsPKCβ and PI3K/AKTcascades to suppresscancer signaling

Apoptosis ProliferationAngiogenesis Protein Synthesis

ENZASTAURIN

ENZASTAURIN

Phase II Trial: Results of Enzastaurin in DLBCL

Pt. Age(yrs) Sex PS Prior therapy No.

cycles

ResponseAfter 6cycles

At lastanalysis

1 67 F 0 1 x chemo, 1 xRT

50+ SD CR

2 59 F 0 2 x chemo 33+ SD SD

3 71 F 0 2 x chemo 29+ CR CR4 70 M 0 3 x chemo, 2 x

RT20+ PR CR

Singleagentenzastaurinwastakendailyun2ldiseaseprogression(1cycle:28days)

8/55ptshadprolongedfreedomfromprogression(FFPfor≥4cycles)

4/55ptsexperiencedFFPfor≥20cycles

Robertsonetal.,JCO.2007;25:1741.

AbdominalCTScans

PelvicCTScans

Baseline 12months

Todate,3ptsremaininCR.llfourptsremainonstudytherapyandhavenotshownsignsofprogression.

PRELUDE Trial:A Phase III study to determine thePrevention of Relapse Using Daily Enzastaurin

DLBCLptswithCRorCRu*orPETscannega2vefollowing6‐8cyclesofinduc2onR‐CHOP‐14orR‐CHOP‐21

PRELUDE

Arm A (306 pts): Oral enzastaurin, 500 mg/day (Loading dose on Day 1 only)

Arm B (153 pts): Oral placebo, daily(Loading dose on Day 1 only)

2:1 Randomization(N = 709)

PrimaryEndpoint:

OverallDiseaseFreeSurvival(DFS)(HR=0.68)

SecondaryEndpoints:

DiseaseFreeSurvival(DFS)at2yrs

– 15%improvement

Overallsurvival(OS)

Event‐FreeSurvival(EFS)

RateofEFSat2yrs

AdverseEvents

Biomarker,correla2vestudies

Inclusioncriteria:•IPI≥3atdiagnosis•Stage3or4disease,orbulkystage2(≥10cm),atdiagnosis

Mul2‐centerstudy:•200sitesworldwide•10sitesinItaly

*AsdeterminedbytheInterna2onalWorkshopCriteria(Chesonetal.,1999)

:473pts :236pts

Interimanalysis#1:51DFSevents(1aFu2lity)Interimanalysis#2:163DFSevents(Efficacy&Fu2lity)Finalanalysis(primaryendpoint):250DFSeventsStudyclosure:366deaths

Take home messages (2)Take home messages (2) PET scan before and after ASCT is high predective for

outcome in relapsed/refractory DLBCL

Patients with early relapse and residual disease on functionalimaging pre ASCT should be consider at poor prognosis

Poor prognosis patients should be enrolled in prospectivetrials evaluating intensified conditioning regimens (Z-BEAM)or allogeneic RIC-SCT.

Patients inelegible for transplant should incorporate newdrugs in salvage regimens or biological targeted agents inthe current first-line treatment strategies.

AcknowledgmentsAcknowledgments

G. Meloni C. Minotti ,E. Finolezzi , A. Di Rocco,G. Meloni C. Minotti ,E. Finolezzi , A. Di Rocco,E. Russo, S. Capria , A.P. IoriE. Russo, S. Capria , A.P. Iori

maurizio martelli.ppt [sola lettura] - siematologia.itmartelli.pdf · regimens (ice, dhap, mime...

Documents