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Treatment of non-Hodgkin Lymphomas

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

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Treatment of non-Hodgkin Lymphomas

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  1. Treatment of non-Hodgkin Lymphomas

  2. Over 40 different types of NHL: reflection of the complex growth and differentatition of normal (B) lymphocytes

  3. 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)

  4. 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?

  5. non-Hodgkin LymphomasClinical Staging • History/ Physical examination • CT scan thorax • CT scan abdomen • 18FDG-PET scan: aggressive lymphomas • Bone marrow biopsy

  6. CT scans in lymphoma

  7. 18 FDG-PET scan in lymphoma

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

  9. 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

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

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

  12. 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

  13. Bone marrow Blood, lymph Pluripotent stem cell Lymphoid stem cell Pre-B cell B cell Activated B cell CD 20 Press. Semin Oncol 1999;26(5 suppl 14):58 CD20 Expression in B-Cell Development Plasma cell

  14. Complement Anti-CD20 (Rituximab= Mabthera®) mechanism of action Malignant B-cell CD20 Killer Leukocyte CD20 Direct induction of apoptosis Adapted from Male D, et al., Advanced Immunology 1996: 1.1–1.16

  15. 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

  16. 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 29% CHOP 0.2 p=0.00001 0 1 2 3 4 5 Years Coiffier et al.

  17. DLCL in the elderly :Rituximab improves overall survival 1.0 0.8 0.6 0.4 0.2 0 59% Rituximab + CHOP Probability of overall survival 47% CHOP p=0.01 0 1 2 3 4 5 Years Coiffier et al.

  18. Rituximab maintenance prolongs progression-free survival in relapsed Follicular lymphoma 100 80 60 R-maintenance median: 44 mo PFS (%) 40 Observation median: 16 mo 20 p < 0.0001 0 0 1 2 3 4 5 6 7 8 Time (years) van Oers MHJ, et al. J Clin Oncol 2010; 28:2853-2858.

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

  20. Radiolabeled anti-CD20 antibodies in the treatment of relapsed folicular lymphoma • Response % higher than with “naked” anti-CD20 • Responseduration ~ similar to “naked” anti-CD20 • High dose : response (5-10 years) cure ? • Also effective in patients resistant to “naked” anti-CD20

  21. Zevalin as consolidation in FL:PFS in All Patients* Log rankP < 0.0001HR 0.463 Zevalin: median 37 mon = 208 Control: median 13.5 mon = 206 Hagenbeek et al. ASH 2007, abstr 643 *Median observation 3.5 years.

  22. New targets lymphoma treatment

  23. 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

  24. non-Hodgkin LymphomasTreatment Results * 15 / 10%

  25. non-Hodgkin’s LymphomasSummary

  26. 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)

  27. 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

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

  29. EORTC 20981 phase III trial:R-CHOP versus CHOP in relapsed follicular NHL R A N D O M I S E D R A N D O M I S E D CHOP every21 daysmaximum six cycles Observation Rituximab + CHOP every21 daysmaximum six cycles Rituximab maintenance* *375mg/m2 every 3 months for 2 years or until relapse Van Oers et al ASH 2005

  30. Rituximab maintenance significantly improves overall survival from 2nd rand. 100 Rituximab maintenance: 3 years 85.1% 90 80 70 60 Patients (%) 50 40 Observation: 3 years 77.1% 30 20 p = 0.011 HR: 0.52 10 0 0 1 2 3 4 6 5 Years van Oers M, et al. Blood 2006; 108:3296–3301.

  31. 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 Therapy of aggressiveNHL • polychemotherapy • golden standard till 2004 :CHOP

  32. 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

  33. 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

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