Treatment of non-Hodgkin Lymphomas

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” (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) 100% indolent 50% aggressive very aggressive 10 20 Years since diagnosis

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 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;63:1424-1433. 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

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

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) 1.0 0.8 0.6 51% CHOP + rituximab Probability of event-free survival 0.4 0.2 29% CHOP p=0.00001 0 1 2 3 4 5 Years Coiffier et al.

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 0 1 2 3 4 5 Years Coiffier et al.

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 < 0.0001 1 2 3 4 5 6 7 8 Time (years) van Oers MHJ, et al. J Clin Oncol 2010; 28:2853-2858. 17 17

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” anti-CD20

Zevalin as consolidation in FL: PFS in All Patients* Log rank P < 0.0001 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.

New targets lymphoma treatment 21

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 * 15 / 10%

non-Hodgkin’s Lymphomas Summary 24

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 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

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.

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.

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