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Rituximab in relapsed indolent lymphoma

Rituximab in relapsed indolent lymphoma. GLSG = German low-grade lymphoma study group EORTC = European Organization for Research and Treatment of Cancer. Rituximab monotherapyPivotal trialMcLaughlin et al JCO 1998Schedule/dose varationPiro et al Ann Oncol 1999 Ghielmini et al Blood 2004

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Rituximab in relapsed indolent lymphoma

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    1. Rituximab in relapsed indolent lymphoma MHJ van Oers Department of Haematology, Academic Medical Centre Amsterdam, The Netherlands

    2. Rituximab in relapsed indolent lymphoma Rituximab monotherapy Pivotal trial McLaughlin et al JCO 1998 Schedule/dose varation Piro et al Ann Oncol 1999 Ghielmini et al Blood 2004 Re-treatment Davis et al JCO 2000 Combination with chemotherapy Phase II Czuczman et al JCO 1999; ASH 2003 abstr 1493 Phase III - GLSG Dreyling et al. ASH 2003 abstr 351 - EORTC 20981 Intergroup study

    3. Rituximab pivotal trial Multicentre, open-label, phase II trial 166 patients with relapsed indolent non-Hodgkins lymphoma (NHL) Rituximab 375mg/m2 weekly x 4 Favourable safety profile (fever, chills) Host antibody responses (HACA) rare B-cell depletion; no increase in infections

    4. Rituximab pivotal trial: overall response The ORR in 166 intent-to-treat patients was 48%, with a CR rate of 6%.79 The ORR in 151 evaluable patients was 50%, with a CR rate of 6%. Median time to onset of response was 50 days. The ORR in 166 intent-to-treat patients was 48%, with a CR rate of 6%.79 The ORR in 151 evaluable patients was 50%, with a CR rate of 6%. Median time to onset of response was 50 days.

    5. Rituximab weekly x 8 in relapsed indolent lymphoma: response Response was defined using the stringent LEXCOR criteria, which were also used in the pivotal trial.79 In the 35 evaluable patients, the ORR and CR rates were 60% and 14%, respectively. These response rates were higher than those seen with weekly x 4 dosing of MabThera in the pivotal trial.89 The average maximum lesion reduction ranged from 79% in partial responders to 100% in complete responders. The mean reduction in lesion size stabilized approximately 5 months after treatment, indicating that MabThera continued to exert a clinical effect even after therapy was completed. Response was defined using the stringent LEXCOR criteria, which were also used in the pivotal trial.79 In the 35 evaluable patients, the ORR and CR rates were 60% and 14%, respectively. These response rates were higher than those seen with weekly x 4 dosing of MabThera in the pivotal trial.89 The average maximum lesion reduction ranged from 79% in partial responders to 100% in complete responders. The mean reduction in lesion size stabilized approximately 5 months after treatment, indicating that MabThera continued to exert a clinical effect even after therapy was completed.

    6. Prolonged rituximab in follicular lymphoma a phase III randomised trial 202 patients, 64 previously untreated Design: rituximab 375 mg/m2 weekly x 4 at week 12 CR/PR : randomised between observation and prolonged rituximab (375 mg/m2 every 2 months, x4) Results in previously treated patients (128 evaluable) ORR 46%, 8% CR Response duration 12.7 vs. 24.7 months (p=0.065)

    7. Rituximab retreatment for relapse after prior response to rituximab: time to progression The Kaplan-Meier estimate for median duration of response is 17.8 months.22 This value is greater than those seen in this population after prior MabThera therapy (12.4 months) and in the pivotal trial (11.6 months). Although response rates in the re-treatment trial are slightly lower than those reported in the pivotal trial, the responses after re-treatment were more durable. The apparent increase in duration of response after MabThera re-treatment (P=0.224) is dramatically different from the reduced response durations seen after re-treatment with chemotherapy. Toxicity was consistent with that seen in the pivotal trial. Unlike chemotherapy, MabThera re-treatment is not associated with cumulative myelosuppression, and its mild toxicity is of particular importance for elderly patients. MabThera re-treatment thus offers both safety and efficacy advantages over re-treatment with chemotherapy. The Kaplan-Meier estimate for median duration of response is 17.8 months.22 This value is greater than those seen in this population after prior MabThera therapy (12.4 months) and in the pivotal trial (11.6 months). Although response rates in the re-treatment trial are slightly lower than those reported in the pivotal trial, the responses after re-treatment were more durable. The apparent increase in duration of response after MabThera re-treatment (P=0.224) is dramatically different from the reduced response durations seen after re-treatment with chemotherapy. Toxicity was consistent with that seen in the pivotal trial. Unlike chemotherapy, MabThera re-treatment is not associated with cumulative myelosuppression, and its mild toxicity is of particular importance for elderly patients. MabThera re-treatment thus offers both safety and efficacy advantages over re-treatment with chemotherapy.

    8. Rituximab combination with chemotherapy Rationale mechanisms of action are not cross resistant each therapy efficacious toxicities do not overlap rituximab increases sensitivity to chemotherapy1 potential to clear minimal residual disease?

    9. Phase II: R-CHOP in indolent lymphoma patient population 40 indolent NHL patients Treatment disposition two patients registered but not treated 38 patients treated and evaluable for efficacy (29 previously untreated) 35 patients received all six infusions of rituximab and six cycles of CHOP

    10. Phase II: R-CHOP in indolent lymphoma 9 years follow-up

    11. Update on patients bcl-2 [t(14;18)] positive at baseline

    12. Phase II: R-CHOP in indolent lymphoma conclusions R-CHOP results in excellent efficacy in indolent NHL 100% ORR prolonged TTP: median of 82.3+ months 16 patients ongoing at 77.3+ to 105.6+ months Combination therapy is safe and does not cause significant added toxicity Conversion of bcl-2 from positive to negative in blood and bone marrow indicates clearance of microscopic disease (i.e. better quality remission) This trial provides a foundation for further studies of chemoimmunotherapy in indolent lymphoma

    13. FCM rituximab in relapsed lymphoma (GLSG) N=126: 65 follicular lymphoma, 48 mantle cell lymphoma 13, other indolent NHL Relapse after CHOP etc. Randomised between 4 x FCM or 4 x R-FCM fludarabine 25mg/m2 days 13, cyclophosphamide 200mg/m2 days 13 mitoxantrone 8mg/m2 day 1)

    14. FCM rituximab in relapsed follicular lymphoma: results

    15. FCM rituximab in relapsed follicular lymphoma: progression-free survival

    16. FCM rituximab in relapsed follicular lymphoma: overall survival

    17. E20981 intergroup study Rituximab in remission induction and maintenance treatment of relapsed follicular NHL: a phase III randomised clinical trial Interim analysis report 10 March, 2004 Cut off date: 27 February, 2004

    18. EORTC 20981 phase III trial: eligibility criteria Follicular NHL (at initial diagnosis) after a maximum of two non-anthracycline-containing systemic regimens either remission (complete remission or partial remission), no change, or progression on first or second regimen prior treatment included at least 2 months of single-agent therapy and/or at least two consecutive cycles of polychemotherapy or purine analogues Age ?18 years Ann Arbor stage IIIV CD20+ Patients with relapsed, follicular NHL (stage III or IV at initial diagnosis) who have received a maximum of 2 nonanthracycline-containing regimens and who are older than 18 and have Ann Arbor stage IIIV, CD20+ disease are eligible for enrollment.Patients with relapsed, follicular NHL (stage III or IV at initial diagnosis) who have received a maximum of 2 nonanthracycline-containing regimens and who are older than 18 and have Ann Arbor stage IIIV, CD20+ disease are eligible for enrollment.

    19. EORTC 20981 phase III trial: R-CHOP versus CHOP: study design 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 15, 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. 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 15, 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.

    20. EORTC 20981 phase III trial: objectives To establish in a prospective, randomised clinical trial in relapsed/resistant follicular lymphoma the effect of addition of rituximab to CHOP chemotherapy on the response rate and quality (partial remission, complete remission and molecular complete remission) the effect of rituximab maintenance treatment on progression-free survival of follicular lymphoma in remission after CHOP with or without rituximab

    21. Accrual by group

    22. EORTC 20981 phase III trial: conclusions from second interim analysis IDMC Both original study questions have been answered Superiority of R-CHOP induction in terms of (complete) response rate and progression-free survival Superiority of rituximab maintenance in terms of progression-free survival Proposal Close the initial randomisation Continue the study with the maintenance randomisation after R-CHOP (200 new patients)

    23. Conclusion Combined immunochemotherapy represents the new standard approach in relapsed follicular lymphoma

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