1. Treatment of non-Hodgkin Lymphomas

2. 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)

3. 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?

4. non-Hodgkin Lymphomas Clinical Staging
History/ Physical examination
CT scan thorax
CT scan abdomen
18FDG-PET scan: aggressive lymphomas
Bone marrow biopsy

5. CT scans in lymphoma

6. 18 FDG-PET scan in lymphoma

7. non-Hodgkin Lymphoma Ann Arbor Staging
A = no symptoms
B = fever (unexplained)
night sweats
weight loss >10%

8. 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

9. Survival of NHL patients (till 2004)
100%
indolent
50%
aggressive
very aggressive 10 20
Years since diagnosis

10. The results of the treatment of patients with NHL have been improved impressively by the use of antibodies directed against the lymphoma cells

11. 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

12. CD20 Expression in B-Cell Development
Pluripotent stem cell
Lymphoid 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
Key Point: Targeting of CD20 antigen with radioimmunotherapy targets B-cell, but not stem cells or plasma cells.
CD20 is expressed on the surface of normal mature B cells and >90% of all B-cell NHL cells.1,2
Cell-line continuity is maintained after RIT as CD20 is not expressed on pluripotent haematopoietic stem cells and progenitor B cells1
Immunological memory is not compromised by RIT as CD20 is not expressed on antibody-producing plasma cells. This means that the patient is able to fight infection during and after RIT.
Normal B cells are found near malignant cells, such as in lymph nodes or the spleen. These normal B cells may also deliver the crossfire action produced by RIT, providing additional cytotoxicity.3
Anderson KC, Bates MP, Slaughenhoupt BL, Pinkus GS, Schlossman SF, Madler LM. Expression of human B cell-associated antigens on leukemias and lymphomas: a model of human B cell differentiation. Blood. 1984;63:
Tedder T, Boyd A, Freedman A, et al. The B cell surface molecule B1 is functionally linked with B cell activation and differentiation. J Immunol 1985;135:973-9.
Press OW. Radiolabeled antibody therapy of B-cell lymphomas. Semin Oncol. 1999; 26:5(suppl 14):58-65.
Plasma cell

13. Anti-CD20 (Rituximab= Mabthera®) Direct induction of apoptosis
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

14. 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

15. CHOP ± Rituximab in DLCL in the elderly (60-80 yr)
1.0
0.8
0.6
51% CHOP + rituximab
Probability of event-free survival
0.4
0.2
29% CHOP p=
Years
Coiffier et al.

16. DLCL in the elderly : Rituximab improves overall survival
1.0
0.8
0.6
0.4
0.2
59% Rituximab + CHOP
Probability of overall survival
47% CHOP
p=0.01
Years
Coiffier et al.

17. Rituximab maintenance prolongs progression-free survival in relapsed Follicular lymphoma
100 80 60
R-maintenance
median: 44 mo
PFS (%) 40 20
Observation
median: 16 mo
p < 1 2 3 4 5 6 7 8
Time (years)
van Oers MHJ, et al. J Clin Oncol 2010; 28: 17 17

18. Zevalin™
(Ibritumomab tiuxetan)
Mouse anti-CD20 S NH C NH 90

19. 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

20. Zevalin as consolidation in FL: PFS in All Patients*
Log rank P < HR 0.463
Zevalin: median 37 mo n = 208
Control: median 13.5 mo n = 206
Hagenbeek et al. ASH 2007, abstr 643
*Median observation 3.5 years.

21. New targets lymphoma treatment21

22. 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

23. non-Hodgkin Lymphomas Treatment Results
* 15 / 10%

24. non-Hodgkin’s Lymphomas Summary24

25. 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)

26. 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

27. CVP ± Rituximab in first line stage III/ IV follicular NHL
Marcus et al Blood 2004

28. EORTC 20981 phase III trial: R-CHOP versus CHOP in relapsed follicular NHLM I S E R A N D O M I S E
CHOP every 21 days maximum six cycles
Observation
Rituximab + CHOP every 21 days maximum six cycles
Rituximab maintenance*
A phase III intergroup collaborative study (EORTC 20981) is being conducted to evaluate the efficacy of both combination therapy with MabThera® + CHOP and maintenance therapy with MabThera® in patients with relapsed CD20+ follicular NHL.
Patients are being randomized to receive either CHOP (750 mg/m2 cyclophosphamide on day 1, 50 mg/m2 doxorubicin on day 1, 1.4 mg/m2 vincristine on day 1, and 100 mg oral prednisolone on days 1–5, administered every 3 weeks for a maximum of 6 cycles) or MabThera® + CHOP (375 mg/m2 as a slow infusion on day 1). Patients are assessed after 3 cycles, and patients with no change or progressive disease are taken off the study.
Patients who achieve a PR or CR are then randomized to receive MabThera® (375 mg/m2) administered as a slow IV infusion once every 3 months until relapse or for a maximum of 2 years.
*375mg/m2 every 3 months for 2 years or until relapse
Van Oers et al ASH 2005

29. Rituximab maintenance significantly improves overall survival from 2nd rand.
100 90
Rituximab maintenance: 3 years 85.1% 80 70 60
Patients (%) 50 40
Observation: 3 years 77.1% 30 20
p = 0.011
HR: 0.52 10 1 2 3 4 5 6
Years
van Oers M, et al. Blood 2006; 108:3296–3301.

30. 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
Vincristine (oncovin)
1.4 mg/ m2 *
Predniso(lo)ne
100 mg
p.o.
1-5
* max. dose per cycle: 2 mg
Voor behandeling van stadium III-IV agressieve lymfomen is het inmiddels klassieke CHOP schema (cyclofosfamide, doxorubicine = hydroxydaunorubicine, vincristine = oncovine, prednison) (nog steeds) de gouden standaard. Dit schema resulteert in 60 tot 70% complete remissies en een ziektevrije overleving van 30 tot 40%. Uiteraard zijn deze resultaten sterk voor verbetering vatbaar.
De zeer agressieve lymfoblastaire lymfomen en het Burkitt-lymfoom worden veelal behandeld als acute lymfatische leukemie, inclusief profylactische behandeling van het centrale zenuwstelsel. Vooral voor het Burkitt-lymfoom lijkt een hoge dosis methotrexaat van grote betekenis.

31. 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

32. 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