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 lymphomageneral 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 lymphomaconsiderations 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 LymphomasClinical Staging
• History/ Physical examination• CT scan thorax• CT scan abdomen• 18FDG-PET scan: aggressive lymphomas• Bone marrow biopsy
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”
• (mild) chemotherapy
• (low dose) radiotherapy
Aggressive (stage II-IV) **
• CHOP chemotherapy 1x / 3 weeks,8x
* Stage I(II): high dose radiotherpy ** Stage I: 3x CHOP + radiotherapy
Survival of NHL patients (till 2004)
Years since diagnosis
indolent
aggressive
very aggressive
100%
50%
10 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
Plasma cellPluripotent
stem cellLymphoid stem cell
Pre-B cell B cell Activated B cell
Bone marrow Blood, lymph
CD 20
Press. Semin Oncol 1999;26(5 suppl 14):58
Anti-CD20 (Rituximab= Mabthera®)mechanism of action
Adapted from Male D, et al., Advanced Immunology 1996: 1.1–1.16
Malignant B-cell
Complement
CD20
CD20
Direct induction of apoptosis
Killer Leukocyte
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
CHOP ± Rituximab in DLCL in the elderly (60-80 yr)Pr
obab
ility
of e
vent
-free
sur
viva
l
Years0 1 2 3 4 5
p=0.00001
51% CHOP + rituximab
29% CHOP
1.0
0.8
0.4
0.6
0.2
Coiffier et al.
DLCL in the elderly :Rituximab improves overall survival
Years
1.0
0.8
0.6
0.4
0.2
00 1 2 3 4 5
p=0.01
59% Rituximab + CHOP
47% CHOP
Prob
abili
ty o
f ove
rall
surv
ival
Coiffier et al.
Rituximab maintenance prolongs progression-free survival in relapsed Follicular lymphoma
R-maintenancemedian: 44 mo
Observationmedian: 16 mo
0 1 2 3 4 5 6 7 8
p < 0.0001
Time (years)
0
20
40
60
80
100
PFS
(%)
van Oers MHJ, et al. J Clin Oncol 2010; 28:2853-2858.
S
NH C
NH90
Zevalin™(Ibritumomab tiuxetan)
Mouse anti-CD20
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” anti-
CD20
Zevalin as consolidation in FL:PFS in All Patients*
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48 54 60 66
PFS time from randomization (months)
Prop
ortio
n re
mai
ning
pr
ogre
ssio
n fr
ee (%
) Log rankP < 0.0001HR 0.463
Zevalin: median 37 mon = 208
Control: median 13.5 mon = 206
*Median observation 3.5 years. Hagenbeek et al. ASH 2007, abstr 643
New targets lymphoma treatment
non-Hodgkin’s LymphomasTreatment
• Surgery: NEVER !!• Wait and see (indolente lymfomen)• Radiotherapy: stage I indolent
stage I aggressive (+CT!)• (poly) chemotherapy• Immunotherapy: monoclonal antibodies• Immuno-chemotherapy
non-Hodgkin LymphomasTreatment 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 LymphomasSummary
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 NHLMarcus et al Blood 2004
RANDOMISED
CHOP every21 days
maximum six cycles
Rituximab + CHOP every
21 daysmaximum six cycles
EORTC 20981 phase III trial:R-CHOP versus CHOP in relapsed follicular NHL
RANDOMISED
Observation
Rituximab maintenance*
*375mg/m2 every 3 months for 2 years or until relapse
Van Oers et al ASH 2005
Rituximab maintenance significantly improves overall survival from 2nd rand.
Years0 1 2 3 4 6
0102030405060708090
100
Patie
nts
(%)
p = 0.011HR: 0.52
5
Rituximab maintenance: 3 years 85.1%
Observation: 3 years 77.1%
van Oers M, et al. Blood 2006; 108:3296–3301.
Therapy of aggressive NHLTherapy 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