Terapia dei linfomi follicolari nell’era della immunoterapia e dei farmaci biomolecolari...

Terapia dei linfomi follicolari nell’era della

immunoterapia e dei farmaci biomolecolari

Mediterranean School of Oncology

Rieti, 27-29.10.2006

ALMA UNIVERSITAS TAURINENSIS

UNIVERSITA’ DEGLI STUDI DI

TORINOCorrado Tarella

Divisione Universitaria di Ematologia

B-cell precursor

Naive B-lymphocyte

Mantle-zone Germinal

Centre

Marginal zone

Mature B-lymphocytesplasmacells

Bone marrow and peripheral blood Limph node

PlasmaPlasma CellsCells the antibody producers

“memory” B-lymphocytes

memory of previous

antigens

Acute L. Leukemia

Multiple Myeloma

Marginal-zone L.

MantleCell L.

Lympho-Plasmoc. L.

FollicularFollicular

Diffuse large cells

Burkitt

Follicle-Center Lymphoma

frequently associated to bcl-2bcl-2 rearrangement (60-

80%) bcl-2 rearrangement is

caused by the chr t (14;18) chr t (14;18) (q32;q21)(q32;q21)

the pathogenetic role of bcl-2 through inhibition of cell cell

apoptosisapoptosisthe use of bcl-2 rearrangement

to monitor minimal residual minimal residual diseasedisease

Incidence of various non Hodgkin lymphoma subtypes

Subtype %

Indolent Lymphomas:

Follicle Center

Mantle Cell

non-Malt Marginal Zone + LPL

22

6

4

D L C L 30

WHO Classification of Tumors ofHemopoietic and Lymphoid Tissues

Jaffe, Harris, Stein, Vardiman eds. , 2001

WHO Classification of Tumors ofHemopoietic and Lymphoid Tissues

Jaffe, Harris, Stein, Vardiman eds. , 2001

Histology Follicular

median age 55-60 years

cell proliferation 10-20%

median OS 8-13 years

stage III/IV >80%

chemotherapy palliative ?

radiotherapy (Stage I/II) can be curative

Clinical and biological characteristics

Overall Survival of FL patientsOverall Survival of FL patients

Prognostic factors according to

the Intergruppo Italiano Linfomi

(IIL prognostic model) • Age (< vs. > 60 vs)

• Sex (F vs M)

• Extranodal sites (0-1 vs 2) • Serum LDH (normal vs elevated)

• B symptoms (absent vs present) • ESR (less than 30 vs at least 30)

Survival rates according to: (A) the IIL prognostic model and (B) the IPI score

Federico M et al., Blood 2000, 95: 783-789Prognosis of follicular lymphoma: a predictive model based on a retrospective analysis of 987 cases

Federico M et al., Blood 2000, 95: 783-789Prognosis of follicular lymphoma: a predictive model based on a retrospective analysis of 987 cases

….more on FL

2004 : a new prognostic score specifically

designed for FL has been recently

proposed and termed FLIPI scoreFLIPI score

Variabili Utilizzate per il Calcolo FLIPI

Variabili FLIPIVariabili FLIPI Indice SfavorevoleIndice Sfavorevole

Età

Stadio

Emoglobina

LDH

No. Sedi Nodali

60 anni

III - IV

< 12 gr/dl

> limite superiore

> 4

Survival of the 1795 patients according to risk group as defined by the Follicular Lymphoma International Prognostic

Index (flipi) – Solal-Céligny et al, Blood 2004, 104: 1258

FL: A HIGHLY HETEROGENEOUS DISEASE

HOW SHOULD WE LOOK AT THIS TUMOR?

FL-CLUS: pre-malignant condition

FL NOT REQUIRING TREATMENT

CONVENTIONALLYMANAGEABLE FL

NON-CONVENTIONALLYMANAGEABLE FL

Summers et al JCO, 2001 15: 420-424

THE HIGH INCIDENCE OF NNBR IN THE PB

OF HEALTHY SUBJECTS

CANCER-FREE

12%12%

88%

MULTIPLE MYELOMA

14.5%14.5%

85.5%

SOLID TUMOR 9.7%9.7%

90.3%

CHRONICLYMPHOCYTIC

LEUKEMIA 8.3%8.3%

91.7%WHOLE POPULATION(chemotherapy-naive subjects)

12.2%

87.8%

BCL2/IgH POSITIVE

BCL2/IgH NEGATIVE

INCIDENCE OF NON-NEOPLASTIC BCL-2 REARRANGEMMENTS

Ladetto M, et al. PCR-detectable non-neoplastic Bcl-2 rearrangements are common in normal subjects and cancer

patients at diagnosis, but rare in subjects treated with chemotherapy. J Clin Oncol, 2003, 21(7): 1398-403

Ladetto M, et al. PCR-detectable non-neoplastic Bcl-2 rearrangements are common in normal subjects and cancer

patients at diagnosis, but rare in subjects treated with chemotherapy. J Clin Oncol, 2003, 21(7): 1398-403

14 NLABR-POSITIVE

109 SUBJECTS

SCREENING BY NESTED-PCR

PROSPECTIVE MONITORINGWITH:

Bcl-2/IgH NESTED PCR

Bcl2/IgH REAL-TIME PCR

SEQUENCING ANALYSIS

CHARACTERIZATION OF EACH NLABR BY:

PROSPECTIVE MONITORING OF NLABR

1

1 0

1 0 0

1 0 0 0

1 0 0 0 0

1 0 0 0 0 0

1 0 0 0 0 0 0

0 3 6 9 1 2 1 5 1 8 2 4 3 0 3 3 3 6

H S 1

H S 2

H S 3

H S 4

H S 5

H S 1 0

H S 1 3

0

BST

10

100

1000

10000

100000

MONTHS

PCR-negative

Bcl

-2 r

earr

ang

emen

t / 1

0^6

cells

K M Ardeshna et al. (BNLI group)

Long term effect of a watch and wait policy versus immediate stystemic treatment for asymptomatic advanced-stage non-

Hodgkin’s Lymphoma: a randomised controlled trial

The Lancet 2003, 362: 516-22

KM Ardeshna et al.

W/W vs. immediate chlorambucil

Overall and

cause-specific

survival

KM Ardeshna et al.

W/W vs. immediate chlorambucil

Time to first systemic treatment for patients in the observation group

Therapy in advanced stages (III/IV)

Treatment when necessary !

Ardeshna et al. Lancet 2003

Overall Survival

Indolent non-Hodgkin‘s lymphoma:

overall survival

%

s00 55 1010 1515 2020 2525 3030

100100

8080

6060

4040

2020

00

1987-1996 (n=668)

1976-1987 (n=513)

1960-1976 (n=195)

Horning. Semin Oncol. 1996

years

IT IS REASONABLE TO THINK TO A CURATIVE APPROACH FOR FCL

The lessons learned from the experience with autograft in FCL

• Clinical and

• molecular results

“The estimated risk of death of 14% and relapse of 30% at 10 yrs. in our transplanted follicular lymphoma patients,

the majority of whom had high tumor burdens, compares favorably with our observations

in appropriately matched reference patients”

High-dose therapy and autologous bone marrow transplantation for follicular lymphoma in first complete or partial

remission: results of a phase II clinical trial.

Horning SJ, et al. Blood 97:404-409, 2001

LONG-TERM OUTCOME IN FCL FOLLOWING FRONT-LINE, EX-VIVO PURGED AUTOGRAFT

THE STANFORD EXPERIENCE

86 % at 10 yrs.

THE POSSIBILITY OF ACHIEVING THE MOLECULAR REMISSIONS SUPPORTS THE CONCEPT OF FCL AS A CURABLE DISEASE

The pyoneering experienceThe pyoneering experience

of the Dana Farber groupof the Dana Farber group

Turin-group experience with the i-HDS scheme

a “high-dose” approach aimed to obtain maximal tumor cytoreduction and to exploit the in vivo-purging effect operated bychemotherapy

Corradini P et al, Blood 1997 Jan 15;89:724-31

Tarella C et al, Leukemia 2000 Apr 14:740-7

PBPC/BMharvest

MIT

OX

+ L

-PA

M+

PB

PC

au

togr

aft

I-HDS SCHEME FOR BM+, INDOLENT LYMPHOMAS

APO x 2 DHAP x 2VP-16

2 g/sqmCTX

7 g/sqm

MOLECULAR TIMEPOINTS

Long-term clinical and molecular evaluation

of 70 patients70 patients with low-grade lymphomalow-grade lymphoma

(follicular - mantle-cell - lymphocytic)

all treated with the same intensive approach

Including peripheral blood progenitor cell

(PBPC) autograft

Corradini et al. J Clin Oncol, Apr 15, 2004Corradini et al. J Clin Oncol, Apr 15, 2004

0 40 80 120 1600

25

50

75

100

months

% s

urvi

vors

Non-follicular

Follicular+transf. subtypes

76%

49%

OVERALL SURVIVAL

p< 0.05

Figure 2 A

DISEASE FREE SURVIVAL

0 40 80 120 1600

25

50

75

100

months

% s

urvi

vors

Non-follicular

Follicular+transf. subtypes

66%

26%

p< 0.01

Figure 2 B

0 40 80 120 1600

25

50

75

100

months

% s

urvi

vors

92%

12%

p< 0.001

39%

PCR neg.

PCR mix.

PCR pos.p< 0.01

Disease free survival accordingto PCR status during molecular follow-up

Follicular LymphomaFollicular LymphomaOverall Survival

conventional chemotherapy (mainly

single-agent Chlr)

HDS with PBPC HDS with PBPC autograftautograft

0 40 80 120 1600

25

50

75

100

months

% s

urvi

vors

76%

Corradini et al. J Clin Oncol, Apr 15, 2004Corradini et al. J Clin Oncol, Apr 15, 2004

Indolent non-Hodgkin‘s lymphoma:

overall survival

%

s00 55 1010 1515 2020 2525 3030

100100

8080

6060

4040

2020

00

1987-1996 (n=668)

1976-1987 (n=513)

1960-1976 (n=195)

Horning. Semin Oncol. 1996

years

things are no more like that

since the introduction of the

anti-CD20 Rituximab MoAb

• CVP vs R-CVP randomized trial (Marcus trial)

• FM vs CHOP ± Rituximab (Zinzani’s trial)

• CHOP vs. R-CHOP (German trial)

• CVP ± maintenance Rituximab (ECOG and CALGB trial)

Main randomized trials concluded in the last two years

Follicular NHL (IWF B, C, D) Stage III–IV 18 years No prior treatment Measurable disease WBC <25x109/L No CNS involvement Central histology

review

RANDOMISED

CVP x 4 cycles(every 3 weeks)

Rituximab + CVP x 4 cycles

(every 3 weeks)

RESTAGING

CVP x 4 cycles(every 3 weeks)

Rituximab + CVP x 4 cycles

(every 3 weeks)

SD, PD off treatment

CR, PR

Rituximab 375mg/m2 i.v. day 1Cyclophosphamide 750mg/m2 i.v. day 1Vincristine 1.4mg/m2 i.v. day 1Prednisone 40mg/m2 p.o. days 1–5

CVP ± MabThera:Study design

Marcus, Blood 2005Marcus, Blood 2005

Patient characteristics

CVP (n=159)

R-CVP (n=162)

Median age (years) 53 52

Stage III–IV (%) 99 99

Histology – FL (%)

Grade 1/2

Grade 3

89

8

90

9

Elevated LDH level (%) 26 26

B-symptoms (%) 32 40

Bulky disease (%) 46 39

Extranodal sites >1 (%) 17 17

IPI >1 (%) 54 52

BM involvement (%) 64 64

Grade 3/4 haematologic adverse events and infections

CVP (n=159)

R-CVP (n=162)

Haemoglobin, n (%) 3 (1.9) 1 (0.6)

Neutrophils, n (%) 23 (14.5) 39 (24.1)

Platelets, n (%) 0 2 (1.2)

Leucocytes, n (%) 14 (8.8) 19 (11.7)

Infections, n (%) 7 (4.4) 7 (4.3)

Response rates

Response

CVP (n=159)

R-CVP (n=162)

p value

ORR (%) 57 81 <0.0001

CR (%) 8 30

CRu (%) 3 11

CR/CRu (%) 10 41 <0.0001

PR (%) 47 40

Marcus, Blood 2005Marcus, Blood 2005

Time to disease progression, relapse or death after a median follow-up of 30 months among 321 patients assigned to

chemotherapy with CVP or with R-CVP. Solid line represents CVP; dotted line, R-CVP

Marcus et al, Blood 2005, 105: 1417

Time to treatment failure by baseline FLIPI score — intermediate (2) vs

poor (3–5) prognosis

0.03 6 9 12 15 18 21 24 27 30 33

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0

Study month

Eve

nt-

free

pro

bab

ility

R-CVP

CVP

IntermediatePoor

Poor

Intermediate

Treatment algorithm of

the study

Zinzani et al, JCO 2004Zinzani et al, JCO 2004

FM arm

(FM +/– rituximab)

(n=72)

CHOP arm

(CHOP +/–

rituximab)

(n=68)

Overall

(n=140)

No. Pts % No. Pts % No. Pts %

CR–

CR+

PR–

PR+

51

14

2

2

71

19

3

3

35

20

6

6

51

29

9

9

86

34

8

8

61

24

6

6

P=0.01

Combined clinical/molecular response status

after the complete

sequence of treatment

(FM/CHOP with/without rituximab)

Combined clinical/molecular response status

after the complete

sequence of treatment

(FM/CHOP with/without rituximab)


FM

(n=72)

CHOP

(n=68)

Grade 3-4 toxicity No. Pts % No. Pts % p

Neutropenia

Nausea/vomiting

Alopecia

Peripheral Neurologic Toxicity

Constipation

22

2

10

0

0

30

3

14

/

/

27

15

58

18

22

39

22

85

26

32

n.s.

0.000

0.000

0.000

0.000

TOXICITY OF CHEMOTHERAPYTOXICITY OF CHEMOTHERAPY


Front-line therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) significantly improves the outcome of patients with advanced stage follicular lymphomas as compared to CHOP alone - results of a prospective randomized study of the german low grade lymphoma study group (GLSG)

Hiddemann W, Kneba M, Dreyling M et al

BloodBlood 2005 Dec 1; 106(12): 3725-32

TIME TO TREATMENT FAILURE AFTER START OF THERAPY FOR CHOP OR R-CHOP

Hiddemann et al, Blood 2005Hiddemann et al, Blood 2005

DURATION OF RESPONSE AFTER CHOP OR R-CHOP


OVERALL SURVIVAL (OS) AFTER START OF THERAPY FOR CHOP OR R-CHOP


Not reachedNot reachedMedian event free survival

P< 0.000194% (76%)85% (49%)Response rate (CR/Cru)

184175Patients evaluable

R-CHVP/IFN- CHVP/IFN- Salles et al.27

P< 0.0001Not reached19 monthsMedian event free survival

P<0.00192%75%Response rate


p-valueR-MCPMCP Herold et al. 26

P< 0.000127 months7 monthsMedian time to treatment failure

P< 0.000181%57%Response rate


p-valueR-CVPCVP Marcus et al. 4

P< 0.0001Not reached 31 monthsMedian time to treatment failure

P=0.01196%90%Response rate


p-valueR – CHOPCHOPHiddemann et al. 24

First line treatment: immuno-chemotherapy

CVP ± maintenance rituximab: study treatment

C = cyclophosphamide 1,000mg/m2 i.v. day 1

V = vincristine 1.4mg/m2 (maximum = 2) i.v. day 1

P = prednisone 100mg/m2 p.o. days 1–5

Repeat every 21 days; best response + two cycles (6–8)

MR = rituximab 375mg/m2 weekly x 4

Start 4 weeks after CVP; every 6 months for 2 years

Observation (Obs)

Maintenance rituximab (MR)

CVP

RANDOMISE

RESTAGE

CR, PR, SD

Stratify: histology,residual disease

CVP ± maintenance rituximab: accrual

Induction CVP 401

Randomised for maintenance 322 (81%)

Evaluable 305*

Rituximab 157

Observation 148

*16 wrong histology, one prior radiotherapy

CVP ± maintenance rituximab: PFS

Years from maintenance randomisation

Pro

bab

ilit

y1.0

0.8

0.6

0.4

0.2

00 1.0 2.0 3.0 4.0 5.0

0–1 1–2 2–3 3–4 4–5MR 22/157 8/78 3/42 3/26 1/10Obs 46/148 14/61 1/19 1/13 3/6

(number of events/number at risk)

p=0.00003 HR=0.5 (0.3–0.7)

MR (n=157)

Obs (n=148)

74%

42%

Median:4.2 vs. 1.5 years

CVP ± maintenance rituximab: PFS – follicular histology


MR (n=121)

Obs (n=117)

1.0

0.8

0.6

0.4

0.2

0

p=0.0002 HR=0.4

71%

41%

Pro

bab

ilit

y

0 1 2 3 4 5

Median: Not reached vs. 1.5 years

CVP ± maintenance rituximab: overall survival


Pro

bab

ilit

y

1.0

0.8

0.6

0.4

0.2

00 1 2 3 4 5

MR (n=157)

Obs (n=148)

p=0.06 HR=0.6 (0.3–1.2)

(number of events/number at risk)

0–1 1–2 2–3 3–4 4–5 5–6

MR 2/157 2/104 1/59 3/44 2/20 0/2

Obs 4/148 6/103 3/56 3/35 1/17 0/1

96%

89%

Copyright © American Society of Clinical Oncology

Hainsworth, J. D. et al. J Clin Oncol; 23:1088-1095 2005

Fig 1. Study design



Fig 2. Actuarial progression-free survival (PFS)



Fig 3. Actuarial duration of rituximab benefit



Fig 4. Actuarial survival curves: 3-year actuarial survival for the maintenance versus re-treatment groups are 72% and 68%, respectively

Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide and mitoxantrone (R-FCM) in patients with relapsed and refractory follicular and mantle cell lymphomas - results of a prospective randomized study of the German low grade lymphoma study group (GLSG).

Forstpointner R, Unterhalt M, Dreyling M, et al

BloodBlood 2006 Aug 31; [Epub ahead of print]

Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin's lymphoma, both in patients with and without rituximab during induction: results of a prospective randomized phase III intergroup trial.

van Oers MH, Klasa R, Marcus RE, et al

BloodBlood 2006 Jul 27; [Epub ahead of print]

* * * * * * * * *

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Forstpointner+R%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Forstpointner+R%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Unterhalt+M%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Unterhalt+M%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Dreyling+M%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Dreyling+M%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22van+Oers+MH%22%5BAuthor%5D




http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Klasa+R%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Klasa+R%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Marcus+RE%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_AbstractPlus&term=%22Marcus+RE%22%5BAuthor%5D

reports published in 2005 have demonstrated

both feasibility and efficacy of radio-radio-

immunotherapyimmunotherapy (radiolabelled anti-CD20) in the

treatment strategy for FL

….more on FL

Leonard JP et al. Abbreviated chemotherapy with fludarabine

followed by tositumomab and iodine I 131 tositumomab for

untreated follicular lymphoma.

J Clin Oncol. 2005 Aug 20;23(24):5696-704

Portlock CS Should radioimmunotherapy be an initial treatment

option in advanced-stage follicular lymphoma?

Nat Clin Pract Oncol. 2005 Jul;2(7):346-7

Kaminski MS et al. 131I-tositumomab therapy as initial treatment

for follicular lymphoma.

N Engl J Med. 2005 Feb 3;352(5):441-9

Kaminski MS et al. 131I-

tositumomab therapy as

initial treatment for

follicular lymphoma.

N Engl J Med. 2005 Feb

3;352(5):441-9

Figure 2. Progression-free and Overall Survival for All Patients.

Kaminski MS et al. N Engl J Med. 2005; 352(5): 441-9Kaminski MS et al. N Engl J Med. 2005; 352(5): 441-9

Figure 3. Progression-free Survival for Patients with a Partial

Response and Those with a Complete Response.

(57 pts.)

(15 pts.)

Kaminski MS et al. N Engl J Med. 2005; 352(5): 441-9Kaminski MS et al. N Engl J Med. 2005; 352(5): 441-9

Kaminski MS et al.

N Engl J Med. 2005;

352(5): 441-9

Kaminski MS et al.

N Engl J Med. 2005;

352(5): 441-9


Leonard, J. P. et al. J Clin Oncol; 23:5696-5704 2005

Fig 1. Duration of response for all patients



Fig 3. Progression-free survival by Follicular Lymphoma International Prognostic Index (FLIPI) risk group

since the use of more effective schedules (i.e. CHOP, FND) as well as the introduction

of RITUXIMAB, FL patients might have some chances of prolonged survival with

no need for intensified treatments

indeed, you no longer need to be a transplanter to achieve molecular

remission in FCL patients

Long-Term Follow-Up of Autologous Bone Marrow Transplantation in Patients With Relapsed Follicular Lymphoma

By Freedman A et al.: Blood, 94: 3325-3333, 1999

FFR after ABMT for 113 informative patients who were either PCR- or PCR+ after ex vivo purging

no more an exclusive job of

the transplanter

Molecular monitoring after sequential CHOP (6 cycles)

and Rituximab administration asfront line treatment in 128 FCL patients

after CHOP 36% BM PCR neg

after Rituximab 74% BM PCR neg

A Rambaldi et al, Blood 2002, 99: 856-62

a number of large prospectively randomized phase III

studies

demonstrating superiority of rituximab plus standard

chemotherapy compared to chemotherapy alone

immuno-chemotherapy new standard in the first line

treatment of advanced stage follicular lymphoma

in the era of initial immuno-chemotherapy new

evaluation of ASCT in 1st remission necessary






• CHOP-R vs. R-HDS in high-risk FL (GITMO trial)

29 active Centers 136 patients enrolled and evaluable

RITUXIMAB-supplemented HDS

versus

RITUXIMAB-supplemented CHOP

RECENTLY CONCLUDED THE 2nd GITMO TRIAL

IN POOR-RISK FCL AT DISEASE ONSET

R-HDS vs CHOP-R GITMO RANDOMIZED TRIAL

OS failuresOS failures

9

24

33

16

3

15

18

51

EFS failuresEFS failures

6

3

5

2

7

9

TOTALTOTAL 136136136136

CHOP I-II

CHOP III

HDS I-II

HDS III

CHOP total

HDS total

52

17

18

49

69

67

PD/SD *

CR/CRu ***

TOTAL

R-CHOPR-CHOP

7(11%)18(31%)

34(58%) 52(87%)

59(100%) 60(100%)

OR(PR+CR) ** 39(66%) 52(87%)

PR 0(0%) 5(8%)

NON EVALUABLE FOR TOXICITY

1(2%) 2(3%)

R-HDSR-HDS

RESPONSE AT THE END OF TREATMENT

p

p<0.01

p<0.001

p=NS

p<0.05

p=NS

1

R-HDS vs R-CHOP RANDOMIZED TRIAL EVALUABLE PATIENTS: 108

Overall Survival

0,2

0,4

0,6

0 10 20 30 40 50 60 70

0,8

1

0

0,10,2

0,3

0,40,5

0,6

0,7

0,80,9

1

0 12 24 36 48 60 72

EFS: CHOP-R vs R-HDS

R-HDS

CHOP-RP<0.001

R-HDS vs CHOP-R RANDOMIZED TRIAL EVALUABLE PATIENTS: 119

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 12 24 36 48 60 72

PFS: R-CHOP vs R-HDS

R-HDS

CHOP-RP<0.001


EFS: CHOP-R vs R-HDSEFS: CHOP-R vs R-HDS


0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 12 24 36 48 60 72 84

p<0,001R-HDS

CHOP-R

66 %66 %

36 %36 %

PRELIMINARY PCR RESULTS

A stable molecular remission (MR) was achieved in 26% of CHOP-R26% of CHOP-R patients and 78% of R-HDS78% of R-HDS patients (p<0.001)

A persistent MR was associated to an improved PFS (p<0.001) regardless of the regardless of the treatment received treatment received

the superior outcome of R-HDS the superior outcome of R-HDS compared to CHOP-R is largely explained compared to CHOP-R is largely explained by its higher rate of MRs achievementby its higher rate of MRs achievement

PFS: PCR NEG vs POS


0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 12 24 36 48 60 72 84

PCR POS

PCR NEG

p<0.001

67-76 %67-76 %

25-32 %25-32 %

Survival of the 1795 patients according to risk group as defined by the Follicular Lymphoma International Prognostic

Index (flipi) – Solal-Céligny et al, Blood 2004, 104: 1258

2004 : the new prognostic FLIPI scoreFLIPI score

patients in the high-risk group (≥ 3 factors) of the FLIPI score account for approximately 27% of all FL patients

According to FLIPI, patients in the high-risk group (≥ 3 factors) have a median life expectancy around 5-6 years (pre-Rituximab era)

The Follicular Lymphoma International Prognostic Index (FLIPI) separates high-risk from intermediate- or low-risk patients with advanced-stage follicular lymphoma treated front-line with rituximab and the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with respect to treatment outcome

Buske C, Hoster E, Dreyling M, Hasford J, Unterhalt M, Hiddemann W.

BloodBlood 2006 Sep 1; 108(5): 1504-1508

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16690968&query_hl=14&itool=pubmed_docsum













Copyright ©2006 American Society of Hematology. Copyright restrictions may apply.

Buske, C. et al. Blood 2006;108:1504-1508

Figure 2. Time to treatment failure of patients with advanced-stage FL treated with front-line CHOP

Copyright ©2006 American Society of Hematology. Copyright restrictions may apply.

Buske, C. et al. Blood 2006;108:1504-1508

Figure 1. Time to treatment failure of patients with advanced-stage FL treated with front-line R-CHOP

3 Courses q 21 days hd-CY / hd-Ara-C+ PBPC harvests

responsive disease responsive disease

Follicular Lymphoma - Grade I-II-IIIaAge 18-65 y.o. - FLIPI Score ≥ 3

C R P R C RP R

Clinical and Molecular Assessment and Follow - Up

Random

Arm 1R-CHOP

Arm 2R-HDS

Second Clinical Assessment

3 Courses q 21 days 1 APO + 2 DHAP Courses

First Clinical Assessment

B E A M +PBPC

autograft

Rituximab maintainance





PROSPECTIVE MONITORING OF NLABRTREATMENT ECOLOGY TREATMENT AGGRESSIVENES

Given the prolonged disease-free survival of patients achieving Molecular Remission (MR), including those in MR following CHOP-R, is it still acceptable the watchful-waiting option in younger Follicular Lymphoma patients ?

AKNOWLEDGEMENTS

Cattedra di Ematologia - Università di TorinoDir. Prof. M. BoccadoroLymphoma Team:Daniele CaraccioloMarco LadettoAlessandra CutticaIrene RiccaManuela ZanniLuciana BerguiPaolo Gavarotti

Istituto Tumori di MilanoPaolo CorradiniAlessandro Massimo Gianni

Prof. Alessandro Pileri

ALL THE ENROLLING

CENTERS

PFS: R-CHOP I-II vs R-HDS I-II

R-HDS vs R-CHOP RANDOMIZED TRIAL GRADE I-II FL EVALUABLE PATIENTS: 85

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 12 24 36 48 60 72

R-HDS

R-CHOPP<0.001

0

PFS R-CHOP III vs R-HDS III

0,10,20,30,40,50,60,70,80,9

1

0 12 24 36 48 60 72

R-HDS

R-CHOP

P<0.01

R-HDS vs R-CHOP RANDOMIZED TRIAL GRADE III FL EVALUABLE PATIENTS: 34

CVP ± maintenance rituximab: PFS – high tumour burden


1.0

0.8

0.6

0.4

0.2

00 1 2 3 4 5

Obs (n=100)MR (n=98)

71%

33%Pro

bab

ilit

y

p=0.0001 HR=0.4

Median: 4.2 vs. 1.4 years

CVP ± maintenance rituximab: PFS – minimal residual disease


MR (n=89)

Obs (n=82)p=0.0001HR=0.3

1.0

0.8

0.6

0.4

0.2

0

85%

47%

0 1 2 3 4 5

Pro

bab

ilit

y

Median: Not reached vs. 1.9 years



Fig 2. Progression-free survival for all patients

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