CHAPTER 26 LATE BREAKING DEVELOPMENTS: IMPACT OF ANTI-CD20 MONOCLONAL ANTIBODIES ON LYMPHOMA THERAPY

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1 CHAPTER 26 LATE BREAKING DEVELOPMENTS: IMPACT OF ANTI-CD20 MONOCLONAL ANTIBODIES ON LYMPHOMA THERAPY 26.1 Introduction rituximab Subsequent to the completion of drafts for the guidelines earlier in 2004, several important studies in both low-grade and aggressive lymphomas have been published, either in full or at the American Society of Haematology (ASH) meeting in December These revolve in particular around the use of the chimeric human-mouse anti-cd20 monoclonal antibody (rituximab, MabThera). This is a human immunoglobulin antibody with variable regions isolated from a murine anti-cd20 monoclonal antibody. Its use is described in Chapters 12 and 13. It has been studied extensively in vitro and is able to lyse CD-20 positive cells by complement activation or antibody-dependent cell-mediated cytotoxicity. It has other mechanisms of action, which include induction of apoptosis, block of the G1S transition, and an impairment of differentiation. CD-20 is expressed on normal B-cell lymphocytes and in most malignant B-cell lymphomas. It appears essential for the regulation of cell cycle and differentiation. 1 Currently in Australia it is available under the PBS Authority system, where the approved indication is relapsed or refractory low-grade B-cell lymphomas, relapsed or refractory follicular B-cell lymphomas, or untreated CD-positive diffuse large B-cell non-hodgkin s lymphoma in combination with chemotherapy in patients over 60 years of age. The new information that has emerged through the course of 2004 and into 2005 will widen the indications for the use of rituximab in the treatment of lymphomas Low-grade lymphomas new indications for rituximab The German Low-grade Lymphoma Study Group (GLSG) has shown that the addition of rituximab to a combination of fludarabine, cyclophosphamide, and mitozantrone (FCM) significantly increases the response rate and prolongs survival when compared with chemotherapy alone in patients with relapsed and refractory follicular and mantle cell lymphomas. 1 This was a randomised study of some 147 patients. The response rate for R-FCM overall was 79%, including 33% complete remissions as compared with 58% for chemotherapy alone, with 13% complete remissions. The R-FCM arm was significantly superior in terms of progression-free survival and overall survival. There were no differences in clinical relevant side effects in both study arms. However, in a separate study carried out by the same group, the addition of rituximab to CHOP chemotherapy had a long lasting impact on subsequent treatment in remission in follicular lymphoma, but not in mantle cell lymphoma. 2 The GLSG embarked on two parallel studies in follicular lymphoma and mantle cell lymphoma. One was a prospective randomised comparison of R-CHOP versus CHOP alone. This was followed by a second randomisation in remission for interferon maintenance versus myeloablative radio-chemotherapy with subsequent stem cell transplantation in patients under the age 60. All older patients received interferon maintenance. The disease-stage status of these patients is defined in the presentation abstract. In the follicular lymphoma group,the treatment with R-CHOP appeared to have a long-lasting beneficial effect on progression-free survival, which appears to be in the range previously achieved only by chemotherapy followed by peripheral stem cell transplantation. Similarly, a significantly higher response rate and a longer time to disease failure was observed in patients with mantle cell lymphoma. However, no difference was revealed for the progression-free survival after R-CHOP versus CHOP and subsequent therapy with interferon or peripheral blood stem cell transplantation. Therefore, in follicular lymphoma, the addition of rituximab to CHOP has a long-lasting beneficial effect, with a substantial impact on subsequent treatment in remission. In mantle cell lymphoma, the benefit of rituximab appears to be restricted to the remission induction period only. 2 Of greatest Impact of anti-cd20 monoclonal antibodies on lymphoma therapy 417

2 interest, however, are the data suggesting that the addition of rituximab to chemotherapy in previously untreated patients increases event-free survival and response duration. The Roswell Park Cancer Institute has reported a nine-year follow up of patients with low-grade or follicular non-hodgkin s lymphoma (including patients with no prior treatment), treated with rituximab plus CHOP chemotherapy. The overall response rate was 100%, with 87% of patients achieving a complete response. The median times to progression and disease relapse were 82.3 months and 83.5 months respectively. The authors concluded that the rituximab/chop combination provided a lengthy response duration in patients with relapsed or newly diagnosed indolent non- Hodgkin s lymphoma. 3 Similarly, the first analysis of the GELA GOELAMS FL-2000 study of untreated patients with follicular lymphoma was presented at the 2004 ASH meeting. Patients were randomised to a CHOPlike regime containing etoposide in association with interferon, versus a similar arm in which six infusions of rituximab had been added. The first analysis of all patients in this trial demonstrated a significant improvement of response to therapy in the rituximab arm. In the control arm, the eventfree survival at 2.5 years was 62%, versus 78% in the rituximab arm. 4 At ASH 2004, the East German Study Group (Haematology and Oncology) also presented results of a prospective randomised phase III study comparing rituximab plus mitozantrone, chlorambucil and prednisolone chemotherapy (RMCP) versus MCP alone in untreated advanced indolent non- Hodgkin s lymphoma and mantle cell lymphoma. Some 358 patients were randomised. The overall response rate in the RMCP arm was 85.5%, versus 65.5% in the MCP group. Event-free survival (EFS) was significantly prolonged for patients receiving RMCP versus MCP alone. The median EFS for MCP was 19 months, and at this stage the EFS for RMCP was 73%. 5 Similarly, a United States/Canadian group study presented results of a randomised trial of CVP chemotherapy with or without maintenance rituximab in patients with advanced indolent lymphoma. Some 332 stable, responding patients were randomised after chemotherapy to either four cycles of rituximab or observation. Progression-free survival estimates at two and four years from maintenance randomisation were 74% versus 42% and 59% versus 34% for the rituximab and observation arm respectively. The estimated two-year survival from maintenance randomisation was 95% for rituximab and 91% for observation. 6 The Swiss Group for Clinical Cancer Research (SAKK) carried out a randomised trial comparing standard schedule rituximab with a more prolonged treatment in some 200 patients with newly diagnosed or refractory relapsed follicular lymphoma. 7 All patients received standard treatment rituximab 375 mg/m 2 weekly x 4 or were randomised to, in addition, a single 375 mg/m 2 rituximab infusion every two months x 4. Patients with stage I IV disease were included. In 185 evaluable patients, the overall response rate was 67% in chemotherapy naïve patients and 46% in pretreated cases. Patients responding or with stable disease at week 12 were randomised to no further treatment or the prolonged rituximab administration. At a median follow up of 35 months, the medium event-free survival was 12 months in the no-treatment group versus 23 months in the prolonged treatment group. The difference was particularly notable in the chemotherapy naïve patients (19 versus 36 months) and as well in patients responding to induction treatment (16 versus 36 months). It was concluded that in patients with follicular lymphoma, the administration of four additional doses of rituximab at eight-week intervals significantly improved the event-free survival. Richard Fisher presented a review entitled New treatment options have changed the natural history of follicular lymphoma at the 2004 ASH meeting. He showed that trials with chemotherapy followed by monoclonal antibodies have had a significant effect on both progression-free survival and overall survival, thereby changing the natural history of follicular lymphoma Clinical practice guidelines for the diagnosis and management of lymphoma

3 Guideline Low-grade lymphoma aggressive combination chemotherapy Where it is considered appropriate to treat patients with combination chemotherapy, the addition of rituximab increases both complete response rate and duration of response. Level of evidence Refs II Large-cell lymphoma new indications for rituximab At ASH 2004 the GELA Group presented longer-term results of their study of R-CHOP versus CHOP in elderly patients with diffuse large-cell lymphoma. The five-year event-free survival in R-CHOP was 47% versus 29% with CHOP. The five-year overall survival was 58% versus 45%. They concluded that these long-term results continue to show a major benefit for the addition of rituximab to CHOP in the treatment of patients with large B-cell lymphoma (over the age of 60) and that this improvement increases with time. 9 By contrast, Michael Pfreundschuh presented the results of the MinT trial, which was the first analysis of the completed MabThera international trial in young or patients (i.e. less than 60 years) with lowrisk diffuse large B-cell lymphoma. They found that the addition of rituximab to a CHOP-like regime significantly improves outcome of all patients, with the identification of a very favourable subgroup with IPI = 0 and no bulky disease. 10 Guideline Diffuse large-cell lymphoma The outcome of patients, both over and under the age of 60, who are treated with CHOP chemotherapy, is improved by the addition of rituximab. Level of evidence Refs II 9, References 1. Forstpointner R, Dreyling M, Repp R, et al. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2004; 104: Hiddemann W, Forstpointner R, Kneba M, et al. The addition of rituximab to combination chemotherapy with CHOP has a long lasting impact on subsequent treatment in remission in follicular lymphoma but not in mantle cell lymphoma: results of two prospective randomized studies of the German Low Grade Lymphoma Study Group American Society of 3. Czuczman MS, Weaver R, Alkuzweny B, Berlfein J, Grillo-Lopez AJ. Prolonged clinical and molecular remission in patients with low-grade or follicular non-hodgkin s lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol 2004; 22: Salles G, Foussard C, Mounier N, et al. Rituximab added to aifn+chvp improves the outcome of follicular lymphoma in patients with a high tumor burden: first analysis of the GELA-GOELAMS FL-2000 randomized trial in 359 patients American Society of Impact of anti-cd20 monoclonal antibodies on lymphoma therapy 419

4 5. Herold M, Pasold R, Srock S, et al. Results of a prospective randomised open label phase III study comparing rituximab plus mitoxantrone, chlorambucile, prednisolone chemotherapy (R- MCP versus MCP alone in untreated advanced indolent non-hodgkin s lymphoma (NHL) and mantle-cell-lymphoma (MCL) American Society of 6. Hochster H, Weller E, and Ryan T. Results of E1496: A phase III trial of CVP with or without maintenance rituximab in advanced indolent lymphoma (NHL) ASCO. 7. Ghielmini M, Schmitz SF, Cogliatti SB, et al. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood 2004; 103: Fisher RI, LeBland M, Press OW, et al. New treatment options have changed the natural history of follicular lymphoma American Society of 9. Coiffier B, Geugler P, Sebban C, et al. Long term results of the GELA study, R-CHOP vs CHOP in elderly patients with diffuse large C-cell lymphoma American Society of 10. Pfreundschuh M, Truemper L, Gill D, et al. First analysis of the completed Mabthera international (MinT) trial in young patients with low-risk diffuse large B-cell lymphoma (DLBCL): addition of rituximab to a CHOP-like regimen significantly improves outcome of all patients with the identification of a very favourable subgroup with IPI=O and no bulky disease American Society of 420 Clinical practice guidelines for the diagnosis and management of lymphoma

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