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Treatment of non-Hodgkin Lymphomas
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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)
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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?
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non-Hodgkin Lymphomas Clinical Staging
History/ Physical examination CT scan thorax CT scan abdomen 18FDG-PET scan: aggressive lymphomas Bone marrow biopsy
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CT scans in lymphoma
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18 FDG-PET scan in lymphoma
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non-Hodgkin Lymphoma Ann Arbor Staging
A = no symptoms B = fever (unexplained) night sweats weight loss >10%
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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
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Survival of NHL patients (till 2004)
100% indolent 50% aggressive very aggressive 10 20 Years since diagnosis
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The results of the treatment of patients with NHL have been improved impressively by the use of antibodies directed against the lymphoma cells
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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
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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
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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
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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
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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.
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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.
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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
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Zevalin™ (Ibritumomab tiuxetan) Mouse anti-CD20 S NH C NH 90
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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
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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.
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New targets lymphoma treatment
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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
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non-Hodgkin Lymphomas Treatment Results
* 15 / 10%
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non-Hodgkin’s Lymphomas Summary
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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)
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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
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CVP ± Rituximab in first line stage III/ IV follicular NHL
Marcus et al Blood 2004
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EORTC 20981 phase III trial: R-CHOP versus CHOP in relapsed follicular NHL
M 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
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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.
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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.
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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
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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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