Transcript Document

Low grade B cell
Lymphoid Malignancies (LGBLM)
This term is used to describe mainly 2 major disease
entities of adults and elderly (median age >50) that
originate from mature (predominantly small)
B lymphocyte
Indolent
B cell NHL
B cell
CLL
REAL/WHO Classification
 Precursor B-Cell
 Precursor T-Cell
 B lymphoblastic
 T lymphoblastic
 Mature (Peripheral) B-Cell
 Mature (Peripheral) T-Cell
 B-cell CLL/small lymphocytic lymphoma
 Mycosis fungoides/Sezary syndrome
 Follicular lymphoma [Grades I, II , III]
 Adult T-cell lymphoma/leukemia
 Marginal zone B-cell lymphoma
 Peripheral T-cell lymphoma, not
 MALT type
otherwise specified
 Nodal marginal zone B-cell lymphoma
 Angioimmunoblastic T-cell lymphoma
 Splenic marginal zone B-cell lymphoma
 Anaplastic large T/null-cell lymphoma
 Lymphoplasmocytic lymphoma (immunocytoma)  Entranodal nasal NK/T-cell lymphoma
 Mantle-cell lymphoma
 Enteropathy type T-cell lymphoma
 Diffuse large B-cell lymphoma
 Hepatosplenic gd T-cell lymphoma
 Burkitt lymphoma
 Subcutaneous panniculitic-like T-cell
Adapted from Harris et al. Blood, 84: 1361, 1994
& Harris et al. JCO 17: 3835, 1999
lymphoma
Low Grade B Cell Lymphoma
Frequency and Diagnostic Accuracy
Type
Frequency
Accuracy
Follicular center cell
22%
94%
Marginal zone B-cell, MALT
8%
86%
Marginal zone B-cell, nodal
2%
63%
Small lymphocytic/CLL
7%
87%
Lymphoplasmocytoid
1%
56%
40%
Adapted from Harris et al. Blood; 84: 1361, 1994
Low Grade B cell Lymphoma according
to the last WHO classification 2008.
• Chronic lymphocytic leukemia/small
lymphocytic lymphoma
• B-cell prolymphocytic leukemia
• Splenic marginal zone lymphoma
• Hairy cell leukemia
• .Hairy cell leukaemia-variant
• Splenic lymphoma/leukemia,
unclassifiable
• Splenic diffuse red pulp small B-cell
lymphoma
• Lymphoplasmacytic lymphoma
• Waldenstrom’s macroglobinemia
•Heavy chain diseases
• Alpha heavy chain disease
• Gamma heavy chain disease
• Mu heavy chain disease
• Plasma cell myeloma
• Solitary plasmacytoma of bone
• Extraosseous plasmacytoma
• Extranodal marginal zone
lymphoma of mucosa-associated
• ymphoid tissue (MALT type)
• Nodal marginal zone lymphoma
• Pediatric nodal marginal zone
lymphoma
• Follicular lymphoma
• Pediatric follicular lymphoma
• Primary cutaneous follicle center
lymphoma
Adapted from Harris et al 2008
Low Grade B cell Lymphoma
Is it equally common throughout the world
An EGYPTIAN large study (1009 cases)
Frequency of Low Grade B cell Lymphoma : 8%
Follicular subtypes : 5%
Azim et al. Proc ASCO; abs#72, 1998
Low grade B cell Lymphoid
Malignancies
(LGBLM)
Similarities
o Natural History / Biological behavior
o Treatment response and outcome
LGBLM
Natural History & Biology
1.
Histological transformation to high grade
lymphoma observed in 30-40% of follicular
Tendency
for
lymphoma and 5-10% of SLL/CLL
Acker et al. JCO ;1:11, 1983
2.
Spontaneous remission (20%) especially
in low grade follicular lymphoma
Horning and Rosenberg N Engl J Med ;311: 1471, 1984
LGBLM
Natural History and Biology
3. BM and peripheral blood involvement
is common because the mature B
lymphocytes retain their normal ability
to traffic throughout the lymphatic
system and hence the majority of
patients have an advanced stage at the
time of diagnosis
Grogan Ann Oncol7; (suppl 6): 3, 1996
LGBLM
Natural History & Biology
4. The vast majority of neoplastic B cells are non
proliferating i.e In the Go phase (Quiescent
phase) of the cell cycle
e.g.
99% of B CLL cells are in the Go phase at the time
of diagnosis
Caligaris Cappio et al. JCO 17: 399, 1999
LGBLM
Natural History & Biology
5. Disease progression is mediate (at least initially) via
gradual accumulation of malignant mature B
lymphocytes rather than rapid proliferation. These
cells enjoy a selective survival advantage relative to
their normal counterparts
e.g.
CD5 +ve B cells has an average ½ life of
5-7 days versus several weeks-months in case of
CLL/SLL
Maclenna & Gray Immunol; Rev91: 61, 1986
LGBLM
Natural History and Biology
6.
Cells Refusing to Die
Majority of follicular NHL have genetic abnormality
involving translocation between chromosomes 14
and 18 [t (14 ; 18) ( q 32 ; q 21)]
Overexpression of BCL-2 gene
(originally on chromosome 18)
BCL-2 is an anti-apoptotic protein
Korsmyer Blood; 80: 879, 1992
Translocation between chromosomes 14 and
18 [t (14 ; 18) ( q 32 ; q 21)] which results in
BcL2 overexpression
This brings the
BCL2 gene under
the control of
immunoglobulin
heavy chain gene
(IgH) enhancers
and leads to
overexpression of
BCL2 protein
LGBLM
Cells refusing to die
Cells Refusing to Die
The t(14 ; 18) translocation (seen in the majority of
follicular lymphoma) is exceedingly rare in
SLL/CLL. However BCL-2 protein is consistently
over expressed in these cells. Furthermore
SLL/CLL do not respond to extra cellular
apoptotic signals
Caligamis Cappio et al. JCO 17: 399, 1999
Treatment of LGBLM
General Rules
LGBLM
Treatment Response/Outcome
1.
The majority of LGBLM are quite sensitive to
radiotherapy and wide range of chemotherapeutic drugs
including: Alkylating agent, Corticosteroids,
Anthracyclines & Purine analogs
2.
Induction of remission is high especially in chemo-naive
patients. However CRs are not as highly seen in
aggressive lymphoma. More frequent CRs are
encountered in follicular lymphoma compared to other
subtypes of LGBLM
LGBLM
Treatment Response/Outcome
3.
The major therapeutic challenges in these disease is the
maintenance of remission (not the induction of remission)
as almost all the patients in remission would subsequently
relapse ( + histologic transformation )
4.
Because of eventual relapse no curative treatment has
been established before the era of Rituximab.
Low grade B cell lymphoma
Management of advanced stage
Treatment strategy
No prospective study has shown that treatment of
asymptomatic patients (low tumor burden) at the time
of diagnosis would prolong survival.
Treatment of indolent lymphoma
NCI study
45 patients initial aggressive therapy
(ProMace/Mopp) followed by total lymphoid irradiation
VS
44 patients were observed,
No initial therapy (Watch &Wait)
Conclusion
No survival advantage over Watch & Wait
Young et al Semin. Hematol 25: 11, 1988 .
Indications to initiate treatment in LGBLM
GELF criteria (High tumor Burden)
Leukemia or blood cytopenia
Mass > 7cm
Nodal sites > 3 (3cm)
Constitutional symptoms
Substantial spleenomegaly
Ureteric/mediastinal/epidural compression
Serous effusion
Solal Celigny P et al. N Engl Med;329: 1608, 1993
Follicular Lymphoma
International Prognostic Index
(FLIPI)
The best predictive five parameters
Age > 60
Stage III/IV
Increased LDH
HB < 12 gm
Number of nodal sites
5 or more
The records of 1795 patients with full clinical and 10 years survival data from
Europe , North America and some far east countries were used to construct this
prognostic model.
The Follicular Lymphoma International
Prognostic Index (FLIPI): Overall survival
Probability of survival
1.0
Good (01)
0.8
Intermediate (2)
0.6
Poor (35)
0.4
0.2
Months
N = 1,795
P < 0.0001
0
0
Risk group
Good
Intermediate
Poor
12
24
No. of
factors
36
48
60
72
84
Patients
(%)
5-year
(%)
10-year
(%)
Relative
risk
01
36
91
71
1.0
2
37
78
51
2.3
3
27
53
36
4.3
Solal-Céligny P, et al. Blood 2004; 104:12581265.
Treatment of LGBLM
Symptomatic patients/high tumor burden
 For many decades, the standard therapy for symptomatic
low grade B cell lymphoid malignancies (low grade
lymphoma and CLL) was based on alkylating agents
(usually chlorambucil) with or without prednisone
 The triple combination of cyclophosphamide, vincristine
and prednisone (CVP) and /or external beam
radiotherapy have been recommended if rapid response
is required for relief of sever symptoms
Portlock CS Semin Oncol; 17(1):51, 1990
Treatment of LGBLM
Anthracycline
based
regimens
can
produce higher response rates (and CRs)
compared
to
CVP
or
Chlorambucil.
However no improvement in long-term
disease free or overall survival has been
demonstrated.
Vose Ann Oncol 7; (suppl 6):13, 1996
Conventional Chemotherapies
Overall survival of patients treated with
cyclophosphamide vs. CHOP-Bléo
(from Peterson et al.,JCO 2003)
The positive impact of adding
alfa-Interferon to ADR based regimen in
follicular lymphoma with high tumor burden
(GELF-86 Trial)
N=123
N=119
Solal-Celignc et al. JCO 16(7): 2332, 1998
Meta analysis of 10 randomized studies
evaluating the role of  interferon in
follicular lymphoma
2005 cases at a median follow up period of 7 years
Conclusions
Addition of Interferon alpha did significantly improve
survival incase of:
1. Use of relatively intensified chemotherapy (ADR or
Mitoxantrone based regimens)
2. Adequate dose of interferon alpha ( ≥ 5 million unit per
injection and ≥ 36 million unit / month)
Rohatiner et al. Proc. ASCO; abs#1053, 2002
Purine Analogs
Rational for use in LGBLM
 They have unique Cytotoxicity against both dividing and
non dividing lymphocytes (Go phase)
Seto et al J Clin Inves. 75; 377, 1985
 They can initiate programmed cell death
Carson& Ribeiro Lancet 341; 1251, 1993
 Potential synergy with other useful drugs:
cyclophosphamide & mitoxantrone
Koel et al. Proc AACR38 : 2; abs#10,1997
Fludarabine monotherapy in low
grade lymphoma
Previously
Treated
Response rate
40-50%
CR
12-15%
Redman et al. JCO 10:790, 1992
Hiddman e al. Semin Oncol 20; (suppl7): 28, 1993
Previously
untreated
Response rate
CR
65-70%
35%
Solal-Celigny et al. JCO14: 514, 1996
Pigaditou et al. Semin Oncol 20;(suppl 7): 24, 1993
Fludarabine is particularly
effective in LGLwhile it has
a much lower activity in
high grade NHL (RR 10-15%)
Redman et al. JCO 10:790, 1992
Fludarabine combination in LGBC
lymphomas
FMD regimen
Previously Treated Recurrent/refractory (N=51)
oResponse rate
oCR
oResponse duration
of CR
94%
47%
21 mons
FMD protocol
Fludarabine 25mg/m2 D1,2,3
Mitoxantrone 10mg/m2 D1
Dexamethasone 20mg D1-5
Recycle every 4 weeks x 8
Mclaughlin et al. JCO 14: 1262, 2996
Number : 381 cases
Immediately treated : 248
Treatment after W/W : 133
Phase III study
Marcus et al. Ann Oncol 13; (suppl2): abs#181, 2002
CVP x 8
Fludarabine x 8
68%
ORR
51%
P = 0.001
38%
CR
15%
21mon
TTP
15mon
68%
5 years
survival
60% (NS)
Adverse Events
Number : 381
Immediately treated : 248
Treatment after W/W : 133
Fludarabine
28%
8%
2%
CVP
Neutropenia (Gr III/IV)
Thrombo (Gr III/IV)
Infection
Alopecia
12% (p<0.005)
1% (p<0.01)
3%
more significant
Marcus et al. Ann Oncol 13; (suppl2): abs#181, 2002
FM compared to CHOP in follicular
lymphoma (BCL2 +ve BM/PB)
FM X 6
CHOP x 6
72
Number
68
68%
CR
42% P=0.003
39%
Molec CR
19% P=0.001
Zinzani et al. JCO 2004 (july)
Toxicity of chemotherapy
Grade 3-4 toxicity
Zinzani et al, JCO 2004
FM
CHOP
(n=72)
(n=68)
No. Pts
%
No. Pts
%
p
22
30
27
39
n.s.
2
3
15
22
0.000
10
14
58
85
0.000
Peripheral Neurologic Toxicity
0
/
18
26
0.000
Constipation
0
/
22
32
0.000
Neutropenia
Nausea/vomiting
Alopecia
What is the optimal first-line
chemotherapy?
Up-front Anthracycline: why
and why not?
• PROS
– More quickly active
– Active on a minor
large cell population ?
• CONS
– Cardiac toxicity
– Alopecia
– Hampers salvage
treatments
– No beneficial effect of
CHOP vs regimens
without adriamycin in
Terms of OS
CHOP is not a standard first-line regimen for low grade lymphoma.
Adriamycin is an important drug for :
- relapses
- histological transformations
Should we use
Fludarabine as
first line in
LGB Lymphoma
…??
Fludarabine may induce unique toxicities
Fludarabine is both myelotoxic and lymphotoxic
leading to marked immuno suppression

susceptibility to opportunistic infections
(reduction of CD4 T helper cells is seen up to 1
year of discontinuation of the drug)
Wijermans et al. Eur J hematology; 50: 292, 1993
Fludarabine may induce
unique toxicities including:
1. Stem cell depletion
2. Hemolytic anemia
3. Neurotoxicity
4. Pulmonary toxicity
5. Hearing loss
6. Renal impairment
Effect of up-front Anthracycline and Purine
analogue on risk of transformation
• Retrospective review of 260 patients
Anthracyclinebased
Alkylator plus purine
analogue
Transformation
18%
27%
5-year risk of
transformation
9%
24% (p < 0.0095)
Annual risk of
transformation
(10 year follow-up)
1.5%
3.0%
J Clin Oncol 2006; 24:Abstract 7510.
Low Grade B Cell Lymphoma
Fludarabine
Currently available data
do not recommend the use
of this agent as first line
outside controlled clinical
studies except in CLL and
SLL
Low Grade B Cell Lymphoma
Fludarabine
• In cases with small lymphocytic lymphoma (as in CLL)
there is a good reason to use first line Fludarabine in
combination with Cyclophosphamide with or without
Mitoxantrone.
• Also in patients with Lymphoplasmacytic Lymphoma and
macroglobuliaemia ,Fludarabine usually in combination
with Cyclophosphamide may be considered in front line
management.
• In Hairy cell leukemia treatment with another purine
analog (2CDA) is considered as the standard of care in
this disease. Of notice , 85% of the treated patients
achieve very durable remissions with only 2 courses of
2CDA
FLUDARABINE IN W M
FLUDARABINE
CAP
N=46
N=46
OR
30%
11% p=0.019
MRD
19Ms
3Ms p<0.01
Leblond el al Blood,2001
Bendamustine
Bendamustine
• Bendamustine is a novel nitrogen mustard and
antimetabolite hybrid which is noncross-resistant
with other alkylating agents.
• This drug has been extensively used in East Germany
for over 40 years with activity in NHL, chronic
lymphocytic leukemia, and multiple myeloma, with
an acceptable safety profile. During the last few
years, the drug was made available in other countries
Bendamustine
• Bendamustine was found to be one of the most
promising agents in the treatment of B cell NHL.
• Around 70% of patients with relapsed/refractory
low grade B cell NHL and mantle cell lymphoma
respond to Bendamustine as single agent,
( including 15-30% CRs), thus setting the new
standard for drug activity in such patients
Friedberg JW, Cohen P, Chen L et al. Bendamustine in patients with rituximab-refractory indolent and transformed nonHodgkin's lymphoma: Results from a phase II multicenter, single-agent study. J Clin Oncol 2008;26:204–210
Target therapy in NHL
Target Antigens in
Lymphoid Malignancies
Idiotype
CD19
CD20
B cell
CD22
HLA-DR
CD52
CD23
• Many cell-surface antigens are
expressed on lymphoma cells
TCR
which are virtually always
expressedCD4/8
on their nonmalignant
counterparts as well.
• Therefore, the
malignant B cells
CD3
can be targeted and
eradicated by
CD25
antibodies directed
Tspecific
cell
against their surface antigens.
• However surface
antigens
CD52
suitable for targeting should have
certain features to allow effective
and safe therapeutic use in the
clinic.
CD 20 as an Ideal Target for
Immunotherapy of B cell Lymphomas
1. CD20 is a transmembrane surface antigen
involved in B cell growth and maturation
2. It is expressed only on B cells (precursor and mature)
BUT NOT on stem cells, normal mature plasma cells
or other normal tissues
Tedder & Engel. Immunol Today;15 : 450, 1994
3. It is expressed on more than 85% of B cell Lymphoma
Anderson et al. Blood;63 : 1424, 1984
CD20 expression in B-cell malignancies
Hairy cell
Large cell
Burkitt’s lymphoma
Marginal zone
Follicular small cell
Small cleaved
LP/Waldenström’s
Mantle cell
CLL/PLL
CLL
0
100
200
300
400
Mean channel fluorescence
LP = lymphocyte predominant
PLL = prolymphocytic leukaemia
500
600
Adapted from Maloney GD.
Semin Hematol 2000;37(4 Suppl. 7):17–26
CD20 as an Ideal Target
4. It can be safely eradicated from the body
without causing excessive toxicity, since normal
B-cells will re-emerge following differentiation
from stem cells, while serum immunoglobulin
levels can be maintained by persisting plasma
cells.
CD20 as an Ideal Target Antigen
5. It is not normally shed from the cell surface and serum
levels of the antigen are undetectable.
o If a cellular target was also found in soluble form in
significant levels in the blood, this could attenuate
the function of the therapeutic antibody.
•Although not tumor specific, it is B-cell restricted
Press et al. Blood ;69:584, 1987
Rituximab binding
to CD 20 binging to CD20
Rituximab versus Ofatumumab
Rituximab
Ofatumumab
Extra-cellular domain
Transmembrane
Intra-cellular
CD20
Rituximab : A mouse/human
chimaeric monoclonal antibody
Rituximab is a chimeric human IgG1 kappa antibody,
with a variable region isolated from a Murine anti-CD20 antibody
The rest of the antibody is of human origin allowing invivo ADCC, CDC
Adapted from Reff et al. Blood; 83: 435, 1994
Rituximab : Proposed Mechanisms
of Action
Fcg receptors
affinity with
IgG1
ADCC
Complement
fixation
CR3
FcgR
Active signaling
(apoptosis induction)
CD20
on malignant
cell surface
Antibody-dependent cellular cytotoxicity
major mechanism of action of rituximab
• in vitro have shown that depletion of malignant
B cells by rituximab requires the presence of
functional mononuclear cells.
• binding of the antibody’s Fc portion to Fcγ receptors
expressed in immune cells with cytotoxic capabilities such
as
– monocytes,
– natural killer cells
– granulocytes,
– which would then lead to destruction of rituximab-bound B cells
either by phagocytosis or by the release of cytotoxic granules
contained in immune effector cells.
Rituximab: Induction of apoptosis
• In vitro studies have shown that engagement of
CD20 by rituximab triggers a cascade of
intracellular signaling events and selectively
down-regulates the antiapoptotic molecule bcl-2
and subsequently enhance drug-induced
apoptosis.
– This is mediated via inhibition of the MAPK
signaling pathway, as well as NF-κB pathways, two
major survival pathways in B cells .
Alas S, Bonavida B. Rituximab inactivates signal transducer and activator of transcription 3 (STAT3) activity in B-non-Hodgkin’s
lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of bcl-2 and sensitization
to cytotoxic drugs.Cancer Res 2001;61:5137-44
Rituximab
Unique therapeutic features
•
As monotherapy Rituximab produces high response rate
with extremely favorable toxicity profile
•
Classic dosing 375mg/m2/week x 4
Previously treated
50%
(166 patients)
McLaughlin et al. JCO; 16:2825, 1998
Median TTP = 12.5 m
Previously untreated
70%
Colombat et al Blood;97:101, 2001
Rituximab as an ideal partner to
use with convential chemotherapy
•Rituximab may act synergistically on induction of
apoptosis with the following chemotherapeutic drugs:
 Fludarabine
 Doxorubicin
 Cisplatinum
 Ara-c
Rational for use in
combination
(concomitantly)
Alas et al Clin. Cancer Res; 7: 709, 2001
Rituximab and Fludarabine reciprocal
synergy in LGBLM
Fludarabine Downregulates
Complement Inhibitors
Expression of CD55
(complement inhibitor)
100
80
Fludarabine
downregulates
membrane expression of 55
60
CD55, a complement inhibitor
Cell Lysis
CD55+ Cells (%)
Cell Lysis (%)
100
80
69
60
40
20
96
14
40
20
2
0
0
Golay et al. Blood; 96(suppl 1)339a, abs#1463, 2000
R-chemotherapy
Rituximab + chemotherapy in first-line
FL: Effect on overall survival
Overall survival (%)
Study name and author
Follow-up
Control
Rituximab
P
M3902; Marcus et al.1
4 years
77
83

GLSG; Hiddemann et al.2
5 years
84
90

M39023; Herold et al.3
4 years
75
89
FL2000; Salles et al.4
5 years
79
84


(high risk pts)
Cochrane analysis:
HR = 0.63 [0.51–0.79]
Schulz H et al. Cochrane Database Syst Rev. 2007 Oct
17;(4):CD003805.
1. Marcus R, et al. J Clin Oncol 2008; 26:4579–4586.
2. Buske C, et al. Blood 2008; 112:abstract 2599.
3. Herold M, J Clin Oncol 2007; 25:1986–1992.
4. Salles G, et al. Blood 2008; 112:4824–4831.
Conclusions
• Several large prospectively randomised phase III
studies
– demonstrating superiority of R plus standard
chemotherapy compared to chemotherapy alone
Immunochemotherapy new standard in the first-line
and salvage treatment of advanced stage follicular
lymphoma
B-R vs CHOP-R as Initial Therapy for
FL and MCL
first interim analysis Median observation period 18 months
315 patients
Rummel et al, Proc ASH, 2007
Toxicity
IF YOU TREAT BY CLASSIC
CVP AND THERE IS NO
PROGRESSION
CVP ± rituximab maintenance in
untreated FL (ECOG 1496): trial design
• Phase III trial of CVP ± rituximab maintenance
• 401 patients with previously untreated follicular NHL, 322
randomised
CVP
6–8
cycles
PR, CR or
stable
R
A
N
D
O
M
I
S
E
Rituximab maintenance
• 375 mg/m2 q1wk  4
• q6mo  4
Observation
Hochster HS, et al. Proc Am Soc Clin Oncol 2004; 22:Abstract 6502.
Hochster HS, et al. Blood 2005; 106:Abstract 349.
ECOG 1496 observation vs rituximab
maintenance after CVP: PFS
100-
PFS (%)
8060-
Rituximab maintenance
402000
Observation
HR = 0.4
One-sided log rank p < 0.0000001
2
4
Time (years)
6
8
HR = hazard ratio
Hochster H, et al. J Clin Oncol 2009; 27:1540–1542.
ECOG 1496 observation vs rituximab
maintenance after CVP: OS
Overall surival(%)
100-
Rituximab maintenance
80Observation
604020-
00
HR = 0.6
One-sided log rank p < 0.08
2
4
Time (years)
6
8
HR = hazard ratio
Hochster H, et al. J Clin Oncol 2009; 27:1540–1542.
E1496: follicular lymphoma survival
1.0
MR (120)
Probability
0.8
OBS (117)
0.6
0.4
0.2
Log-rank one-sided p=0.03
HR 0.5 (0.3–1.1)
0
0
1
2
3
4
5
6
Years from maintenance randomisation
HR = hazard ratio; MR = maintenance rituximab; OBS = observation
Hochster HS, et al. Blood 2005; 106:Abstract 349.
E1496: OS at 3 years from
randomisation
Characteristic (n)
MR
Obs
p value
HR
(95% CI)
All patients
92%
83%
0.03
0.5 (0.3–1.1)
0–2 (118)
91%
88%
0.08
0.5 (0.1–1.4)
3–5 (68)
91%
70%
0.16
0.6 (0.2–1.7)
Low (85)
93%
99%
0.38
1.3 (0.2–7.9)
High (152)
92%
74%
0.01
0.4 (0.2–0.6)
Minimal (170)
95%
90%
0.11
0.5 (0.2–1.5)
Gross (134)
89%
75%
0.08
0.5 (0.3–1.5)
12
21
–
–
FLIPI score
Tumour burden
Residual disease
Total events
Hochster HS, et al. Blood 2005; 106:Abstract 349.
IF YOU TREATED BY CLASSIC
SINGLE AGENT OR CVP AND THEN
YOUR PATIENT PROGRESSED
EORTC 20981
• Phase III trial of CHOP ± R, with or without rituximab
maintenance
• 474 patients with relapsed/refractory follicular NHL, 316
randomised for maintenance/observation
R
A
N
D
O
M
I
S
E
R-CHOP x 6
CHOP x 6
R
A
N
D
O
M
I
S
E
Rituximab maintenance
• 375 mg/m2
• q3mo to relapse or 2 yrs maintenance
Observation
Van Oers MHJ, et al. Blood 2005; 106:Abstract 353
EORTC 20981:
response to induction therapy
CHOP (%)
R-CHOP (%)
ORR
167 (73)
199 (85)*
CR
36 (16)
69 (29)*
PR
NC
PD
Death
Not ass.
Total
131 (57)
24 (10)
22 (10)
2 (1)
16 (7)
231
130 (56)
13 (6)
6 (3)
1 (<1)
15 (6)
234
*p<0.0001 (Mantzel Haenszel test for trend)
Van Oers MHJ, et al. Blood 2005; 106:Abstract 353
EORTC 20981 phase III trial
Progression free-survival from second randomisation
Subgroups according to induction treatment
PFS after CHOP (n=145)
100
MabThera maintenance therapy
Median 42.2 months
80
80
70
70
60
50
40
Observation
Median 11.6 months
30
MabThera maintenance therapy
Median 51.9 months
90
PFS (%)
PFS (%)
90
PFS after R-CHOP (n=189)
100
60
50
40
Observation
Median 23.1 months
30
20
20
10
Overall log-rank test: p<0.0001; HR: 0.30
0
10
Overall log-rank test: p=0.004; HR: 0.54
0
0
O N
55 69
32 76
1
2
3
4
Years
Number of patients at risk
31
11
4
1
61
38
20
4
5
0
O N
55 98
34 91
1
2
3
4
5
Years
Number of patients at risk
59
31
13
4
65
48
27
8
van Oers MHJ, et al. Blood 2006;108:3295–301
Overall survival from 2nd randomisation:
subgroup analysis
OS after R-CHOP
MabThera maintenance
therapy
100
90
80
70
60
50
40
30
20
10
0
Observation
MabThera maintenance therapy
100
90
80
70
60
50
40
30
20
10
0
Observation
OS (%)
OS (%)
OS after CHOP
Overall log-rank test: p=0.073
HR: 0.52
0
1
2
3
Years
4
O N Number of patients at risk
19 69
42
23
7
2
12 76
49
30
8
2
5
6
Overall log-rank test: p=0.059
HR: 0.49
0
O N
20 98
11 91
1
2
3
Years
4
5
6
Number of patients at risk
87
57
27
7
0
80
63
39
11
2
van Oers MHJ, et al. Blood 2005;106:107a (Abstract 353) Updated in oral presentation
Meta-analysis: Rituximab maintenance
improves overall survival
HR (95% CI)
Study
Weight (%)
Forstpointner 2006
Ghielmini 2004
Hainsworth 2005
Hochster 2005
Hochster 2007
van Oers 2006
8.1
20.7
25.3
15.2
1.5
29.1
100
Subtotal (95% CI)
HR (95% CI)
0.49 (0.18–1.30)
0.50 (0.27–0.92)
0.86 (0.49–1.49)
0.51 (0.25–1.04)
4.51 (0.47–43.4)
0.51 (0.31–0.86)
0.60 (0.45–0.79)
p < 0.0003
0.001
0.1
1
Favours rituximab
10
1000
Favours observation
Vidal L, et al. J Natl Cancer Inst 2009; 101:248–255.
Meta-analysis: Rituximab maintenance
Infectious adverse events
• As expected, there were more infections with prolonged
rituximab
• However, the absolute numbers were low and
discontinuation rates were low
• No deaths were associated with infections
p = 0.007
0.1 0.2 0.5 1 2
5 10
Favours
Favours
rituximab
observation
Vidal L, et al. J Natl Cancer Inst 2009; 101:248–255.
Rituximab maintenance
• the GELA (the PRIMA study) is currently
evaluating the benefit of a 2-year rituximab
maintenance after rituximab plus
chemotherapy.
• More than 1200 patients have been currently
registered, and the first interim analysis may
be presented in ASH 2009.
Rituximab Resistance
• Approximately 50% of patients with relapsed/refractory
CD20+ follicular lymphomas do not respond to initial
therapy with rituximab (innate resistance)
• close to 60% of prior rituximab responding patients
will not longer benefit with retreatment with this
monoclonal antibody (acquired resistance).
• Whether these forms of rituximab-resistance are due to an
adaptive property of the malignant B cell or to an impaired
host’s immune effector mechanisms remains unclear.
Antibody-dependent cellular cytotoxicity
major mechanism of action of rituximab
• The properties of the host’s FcγR to which the antibody
binds on leukocyte effector cells influences the efficacy of
rituximab therapy.
• Three classes of FcγR (FcγRI, FcγRII and FcγRIII) have
been described in immune effector cells.
•
the FCGR3A gene encodes FcγRIIIa(CD16) with either the
amino acid phenylalanine (F) or valine (V) at amino acid
position 158.
Cartron G, Dacheux L, Salles G, et al. Therapeutic activity of humanized anti-CD20 monoclonal
antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood.2002;99:754-758.
Host-related mechanisms
• Change in a single amino acid significantly affects
the affinity of the FcγRIIIa for human
immunoglobulin G1 and the subsequent efficacy of
ADCC.
• it is now well established that human IgG1 binds
more strongly to homozygous FcγRIIIa-158
valine/valine (V/V) expressed in natural killer (NK)
cells than homozygous FcγRIIIa-158
phenylalanine/phenylalanine (F/F) or heterozygous
FcγRIIIa-158F carriers.
SAKK 35/98
• Phase III trial of rituximab maintenance therapy
• 202 patients with previously untreated (n=64) or
relapsed/refractory FL; 151 (51 previously untreated)
patients randomised
Rituximab
• 375 mg/m2
• q1wk  4
PR, CR or
stable
R
A
N
D
O
M
I
S
E
Rituximab maintenance
• 375 mg/m2
• q2mo (3, 5, 7, 9)
Observation
Ghielmini M, et al. Blood 2004; 103:4416–4423.
SAKK 35/98 results: Event-free survival
polymorphism 0f FcγRIIIa(CD16)
Rituximab maint : median 23.2 Ms
Observation: median 11.8 months
maintenance
Observation
M. Ghielmini1*, et alAnnals of Oncology 16: 1675–1682, 2005
Second generation anti CD20
Anti-Bodies
• several groups engineer the Fc portion of
MAbs as a strategy to increase their binding to
the low- affinity receptors FcγRIIIa-158F/F or
V/F (which accounts for the large majority of
the population) that augments ADCC and
ultimately try to improve the response to
antibody therapy.
Second generation antibody therapies may offer
improved efficacy
• New anti-CD20 antibodies are under development and
show promising early clinical efficacy, including:
• GA101 (humanised antibody with increased ADCC
and cell death)
• Ofatumumab (fully human)
• Ocrelizumab (humanised)
• Veltuzumab (humanised)
Radio Immunotherapy
MAb
+
Radio
Isotope
Cytotoxicity attributed to
MAB for (Antigen +ve) in addition to
target irradiation for antigen +ve
and adjacent antigen –ve tumor cells
(cross firing)
Leading to potential advantage
of increasing tumor cell killing (& increased toxicity)
Radio Immunotherapy (RIT)
VS
Conventional External Beam Radiotherapy
• RIT delivers radiation at a continuous but variable
dose rate (starting low then building up as the
MAB accumulates in the tumor and finally
decreasing according to the biological half life of
the isotope)
• Unlike the external beam radiation (daily
fractions) RIT provides continuous delivery of
radiation and hence offering less opportunity of
repair of DNA sublethal damage
Press Semin Hematology 37 (7): 2 , 2000
Radio Immunotherapy in LGBLM
• B cell Lymphoma are particular candidates for
RIT because of their inherent radiation sensitivity
• The relative immune paresis specially seen in
previously treated patients would reduce the likely
hood of developing HAMA
• Systemic nature of the disease would render
systemic RIT a more logic approach compared to
localized / extended field irradiation
Radio Immunotherapy for Low
Grade Lymphoma
Bexxar
Zevalin
Murine MAb
Ibrituxomab (parent of Rituximab)
+ linker chelator (Tiuxetan)
+ radioisotope Yttrium-90
FDA approved (Feb 2002)
Tusimomab
+ radioisotope I-131
FDA approved
Are we improving survival in
LGBCL
• The MD Anderson Cancer Center reported 580
patients with stage IV disease treated from
1972 until 2002 with different
immunochemotherapy regimens.
• These investigators reported a marked
improvement in 5-year failure-free survival
(from 29% to 60%) and overall survival (OS;
from 64% to 95%) in this period.
Liu Q, Fayad L, Cabanillas F, et al. J Clin Oncol. 2006;
Are we close to a cure in
first-line treatment of patients with follicular
lymphoma?
Treatment of LGBLM
Few Steps Forwards
Better histo-pathological classification
(clinically distinct entities)
Better understanding of the
disease biology on molecular basis
Better target therapy
More effective salvage therapy
Improvement of OAS
Y
E
S