Treatment of non-Hodgkin Lymphomas
Over 40 different types of NHL: reflection of the complex growth and
differentatition of normal (B) lymphocytes
Treatment of non-Hodgkin lymphoma
general principles
 It is (still ) not possible to select a specific treatment
for each type of NHL
 Therefore NHL are divided into major subgroups:
– Indolent types (follicular lymphoma)
– Aggressive types (diffuse large B cell lymphoma)
– Very aggressive types (Burkitt)
Treatment of non-Hodgkin lymphoma
considerations as to choice of therapy
• Type of lymphoma (WHO classification)
• Ann Arbor stage (I to IV)
• localizations
• Risk profile/prognostic score of the patient
• Which treatment is possible?
non-Hodgkin Lymphomas
Clinical Staging
• History/ Physical examination
• CT scan thorax
• CT scan abdomen
•
18FDG-PET
scan: aggressive lymphomas
• Bone marrow biopsy
CT scans in lymphoma
18 FDG-PET
scan in lymphoma
non-Hodgkin Lymphoma
Ann Arbor Staging
A=
no symptoms
B=
fever (unexplained)
night sweats
weight loss >10%
Treatment of non-Hodgkin lymphoma
approach till 2004
Indolent (stage II-IV)*
• “Wait and see”
Aggressive (stage II-IV) **
• CHOP chemotherapy
1x / 3 weeks,8x
• (mild) chemotherapy
• (low dose) radiotherapy
* Stage I(II): high dose radiotherpy
** Stage I: 3x CHOP + radiotherapy
Survival of NHL patients (till 2004)
100%
indolent
50%
aggressive
very aggressive
10
Years since diagnosis
20
The results of the treatment of
patients with NHL have been improved
impressively by the use of antibodies
directed against the lymphoma cells
Rituximab (mabthera®) : a mouse/ human
chimeric anti- CD20 monoclonal antibody
Murine variable regions
bind specifically to CD20 on
normal/ malignant B-cells
Human K constant regions
Human IgG1 Fc domain
• interacts with human effector
mechanisms (ADCC, CDC)
• low immunogenicity
CD20 Expression in B-Cell Development
Bone marrow
Pluripotent
stem cell
Lymphoid
stem cell
Blood, lymph
Pre-B cell
B cell
Activated B
cell
Plasma cell
CD 20
Press. Semin Oncol 1999;26(5 suppl 14):58
Anti-CD20 (Rituximab= Mabthera®)
mechanism of action
CD20
Malignant B-cell
Complement
Killer
Leukocyte
CD20
Direct
induction of
apoptosis
Adapted from Male D, et al., Advanced Immunology 1996: 1.1–1.16
Anti-CD20 (Rituximab= Mabthera®)
side effects
•
•
•
•
Mild and transient, mainly during first infusion
Fever, chills ( prevention)
Temporary drop in blood pressure, dyspnea
Rare: antibodies against rituximab
Probability of event-free survival
CHOP ± Rituximab in DLCL in the elderly (60-80 yr)
1.0
0.8
0.6
51% CHOP + rituximab
0.4
0.2
29% CHOP
p=0.00001
0
1
2
3
4
5
Years
Coiffier et al.
Probability of overall survival
DLCL in the elderly :
Rituximab improves overall survival
1.0
0.8
59% Rituximab + CHOP
0.6
47% CHOP
0.4
0.2
0
p=0.01
0
1
2
Years
3
4
5
Coiffier et al.
Rituximab maintenance prolongs progression-free
survival in relapsed Follicular lymphoma
100
PFS (%)
80
60
R-maintenance
median: 44 mo
40
20
Observation
median: 16 mo
p < 0.0001
0
0
1
2
3
4
5
Time (years)
6
7
8
van Oers MHJ, et al. J Clin Oncol 2010; 28:2853-2858.
Zevalin™
(Ibritumomab tiuxetan)
Mouse anti-CD20
S
NH
C
NH
90
Radiolabeled anti-CD20 antibodies in the
treatment of relapsed folicular lymphoma
• Response % higher than with “naked” anti-CD20
• Response duration ~ similar to “naked” anti-CD20
• High dose : response (5-10 years)
cure ?
• Also effective in patients resistant to “naked” antiCD20
Zevalin as consolidation in FL:
PFS in All Patients*
Log rank
P < 0.0001
HR 0.463
Proportion remaining
progression free (%)
100
80
Zevalin: median 37 mo
n = 208
60
40
20
Control: median 13.5 mo
n = 206
0
0
6
12
18
24
30
36
42
48
54
60
66
PFS time from randomization (months)
*Median observation 3.5 years.
Hagenbeek et al. ASH 2007, abstr 643
New targets lymphoma treatment
non-Hodgkin’s Lymphomas
Treatment
• Surgery: NEVER !!
• Wait and see (indolente lymfomen)
• Radiotherapy: stage I indolent
stage I aggressive (+CT!)
• (poly) chemotherapy
• Immunotherapy: monoclonal antibodies
• Immuno-chemotherapy
non-Hodgkin Lymphomas
Treatment Results
Malignancy
Grade
Stage
Cure Rate
(%)
Indolent
I / II *
III / IV
50-60
0 !!
Aggressive
I/ II
III / IV
70-80
40-45
* 15 / 10%
non-Hodgkin’s Lymphomas
Summary
Indolent
Aggressive
Stage I
< 15%
~ 30%
Survival
untreated
years
months
Response
to mono-CT
++
---
Response
to poly-CT
Response
to anti-CD20
Cure
++
++
++
++
rare
frequent
New developments in the treatment of
lymphoma
•
New monoclonal antibodies (HumaxCD20, CD22)
•
Radio-immunotherapy
•
New agents (bortezomib, lenalidomide, bendamustine,
apoptosis-inducers, small molecules)
•
New combinations
•
Allogeneic SCT (RIST)
Unconjugated anti-CD20-mAbs in lymphoma
(Rituximab )
• Monotherapy in relapsed indolent lymphoma
– ORR ~ 50 % (6% CR)
– Response duration ~1 year
• Combination with chemotherapy (induction)
– Indolent lymphoma
– Aggressive lymphoma
• Maintenance treatment : Indolent lymphoma
CVP ± Rituximab in first line stage III/ IV follicular NHL
Marcus et al Blood 2004
EORTC 20981 phase III trial:
R-CHOP versus CHOP in relapsed follicular NHL
R
A
N
D
O
M
I
S
E
D
CHOP every
21 days
maximum six cycles
Rituximab + CHOP
every
21 days
maximum six cycles
R
A
N
D
O
M
I
S
E
D
Observation
Rituximab
maintenance*
2
*375mg/m every 3 months for 2 years or until relapse
Van Oers et al ASH 2005
Rituximab maintenance significantly
improves overall survival from 2nd rand.
100
Rituximab maintenance: 3 years 85.1%
90
Patients (%)
80
70
60
50
40
Observation: 3 years 77.1%
30
20
p = 0.011
HR: 0.52
10
0
0
1
2
3
4
5
6
Years
van Oers M, et al. Blood 2006; 108:3296–3301.
Therapy of aggressive NHL
• polychemotherapy
• golden standard till 2004 : CHOP
Drug
Dose
Route
Day
Cyclophosphamide
750 mg/m2
i.v.
1
Doxorubicin
(hydroxydaunorubicine)
50 mg/ m2
i.v.
1
Vincristine (oncovin)
1.4 mg/ m2 *
i.v.
1
Predniso(lo)ne
100 mg
p.o.
1-5
* max. dose per cycle: 2 mg
non-Hodgkin’s lymphoma
Why treatment with antibodies?
•
With present chemotherapy no or insufficient
cure
• Treatment of minimal residual disease after
chemotherapy might improve prognosis
• Antibodies are more specific than cytostatic
drugs
• Antibodies are less toxic
• Antibodies have a different mechanism of action
Conclusions
• Monoclonal antibodies have become an important
component of treatment of malignant lymphomas
• Combination of Rituximab and chemotherapy : new
standard for untreated and relapsed indolent and
aggressive lymphoma
• After induction (in relapsed FL): Rituximab maintenance
• Radio-immunotherapy has yielded promising results