terapia dei linfomi follicolari nell’era della immunoterapia e dei farmaci biomolecolari...
TRANSCRIPT
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
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
FL-CLUS: pre-malignant condition
FL NOT REQUIRING TREATMENT
CONVENTIONALLYMANAGEABLE FL
NON-CONVENTIONALLYMANAGEABLE FL
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
FL-CLUS: pre-malignant condition
FL NOT REQUIRING TREATMENT
CONVENTIONALLYMANAGEABLE FL
NON-CONVENTIONALLYMANAGEABLE FL
PROSPECTIVE MONITORING OF NLABR
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
• 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
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)
Zinzani et al, JCO 2004Zinzani et al, JCO 2004
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
Zinzani et al, JCO 2004Zinzani et al, JCO 2004
• 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
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
Hiddemann et al, Blood 2005Hiddemann et al, Blood 2005
OVERALL SURVIVAL (OS) AFTER START OF THERAPY FOR CHOP OR R-CHOP
Hiddemann et al, Blood 2005Hiddemann et al, Blood 2005
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
10596Patients evaluable
p-valueR-MCPMCP Herold et al. 26
P< 0.000127 months7 monthsMedian time to treatment failure
P< 0.000181%57%Response rate
162159Patients evaluable
p-valueR-CVPCVP Marcus et al. 4
P< 0.0001Not reached 31 monthsMedian time to treatment failure
P=0.01196%90%Response rate
223205Patients evaluable
p-valueR – CHOPCHOPHiddemann et al. 24
First line treatment: immuno-chemotherapy
• 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
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
Years from maintenance randomisation
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
Years from maintenance randomisation
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
Copyright © American Society of Clinical Oncology
Hainsworth, J. D. et al. J Clin Oncol; 23:1088-1095 2005
Fig 2. Actuarial progression-free survival (PFS)
Copyright © American Society of Clinical Oncology
Hainsworth, J. D. et al. J Clin Oncol; 23:1088-1095 2005
Fig 3. Actuarial duration of rituximab benefit
Copyright © American Society of Clinical Oncology
Hainsworth, J. D. et al. J Clin Oncol; 23:1088-1095 2005
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]
* * * * * * * * *
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
Copyright © American Society of Clinical Oncology
Leonard, J. P. et al. J Clin Oncol; 23:5696-5704 2005
Fig 1. Duration of response for all patients
Copyright © American Society of Clinical Oncology
Leonard, J. P. et al. J Clin Oncol; 23:5696-5704 2005
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
FL-CLUS: pre-malignant condition
FL NOT REQUIRING TREATMENT
CONVENTIONALLYMANAGEABLE FL
NON-CONVENTIONALLYMANAGEABLE FL
PROSPECTIVE MONITORING OF NLABR
• 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
• 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
R-HDS vs CHOP-R RANDOMIZED TRIAL EVALUABLE PATIENTS: 119
EFS: CHOP-R vs R-HDSEFS: CHOP-R vs R-HDS
R-HDS vs CHOP-R RANDOMIZED TRIAL EVALUABLE PATIENTS: 136
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
R-HDS vs CHOP-R RANDOMIZED TRIAL EVALUABLE PATIENTS: 136
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
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
FL-CLUS: pre-malignant condition
FL NOT REQUIRING TREATMENT
CONVENTIONALLYMANAGEABLE FL
NON-CONVENTIONALLYMANAGEABLE FL
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
Years from maintenance randomisation
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
Years from maintenance randomisation
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
Copyright © American Society of Clinical Oncology
Leonard, J. P. et al. J Clin Oncol; 23:5696-5704 2005
Fig 2. Progression-free survival for all patients