Myeloma and Lymphoma: Management of Relapsed, Refractory Follicular Lymphoma

Posted by James

Speaker: Stephanie A. Gregory, Rush University Medical Center, Chicago, Illinois

Clinical trials in patients with relapsed follicular lymphoma have shown that rituximab plus CHOP therapy (R-CHOP) is better than CHOP therapy alone. Rituximab maintenance therapy following initial FCM (fludarabine, cyclophosphamide, mitoxantrone) chemotherapy, with or without rituximab, resulted in a 94% overall response rate (P = .011). There was a trend toward improved overall survival following rituximab maintenance therapy after three years.

Radioimmunotherapy using ibritumomab tiuxetan (linked to the indium 111 radioisotope) in these patients demonstrated long-term positive responses (overall response, 85%). I-Tosi-tumomab in patients with refractory disease produced a durable (event-free) responder rate of 30% up to eight years.
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In another study, which compared I-tositumomab with chemotherapy, the overall response rate was greater with I-tositumomab than with chemotherapy after seven encounters. Clinical responses after treatment resulted in 40% responders with I-tositumomab after many remissions and after several lines of therapy.

Thus, radioimmunotherapy yields higher overall response and clinical remission rates when integrated earlier in the treatment sequence for relapsed follicular lymphoma. There is a high incidence of durable responses, especially in patients who achieved clinical responses. Radioimmunotherapy with I-tositumomab or ibritumomab tiuxetan should be given early consideration for patients with relapsed, low-grade fol-licular or transformed NHL.

The potential for long-term, disease-free survival for patients with recurrent follicular lymphoma who receive high-dose chemotherapy and an autologous HSCT is unknown. A retrospective study was conducted in 248 patients with recurrent follicular lymphoma who received high-dose chemotherapy and autologous HSCT. The median follow-up of surviving patients was six years (range, 1-16 years). Disease progressed in 117 patients (47%); 80 patients subsequently died, and as of this writing, 37 have survived after disease progression.

The study showed that long-term event-free survival is possible following high-dose chemotherapy and autologous HSCT for follicular lymphoma.
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Myeloablative single-agent I-tositumomab and autolo-gous HSCT phase 1 and 2 trials are ongoing. Allogeneic HSCT in relapsed follicular lymphoma, as seen in the Seattle study, utilized a nonmyeloablative regimen in matched related donors and unrelated donors. After three years, in the matched-related donor group of patients, rates were 80% for overall survival and 60% for event-free survival; in the unrelated donor patients, the rate of overall survival and event-free survival was about 60%.

In the MD Anderson Cancer Center transplant study, non-myeloablative transplantation—rituximab, initially followed by fludarabine/cyclophosphamide, followed by rituximab 1,000 mg/m² once daily—showed an overall survival rate of approximately 90% at 50 months after transplantation.

The following therapeutic agents are being studied in clinical trials of follicular lymphoma:

• galiximab + rituximab
• bortezomib + rituximab
• denileukin diftitox (Ontak™, Seragen) + rituximab
• favid vaccine (made from a patient’s biopsy tumor specimen)
• oblimersen sodium (Genasense®, Genta) + rituximab
• bendamustine (Treanda™, Salmedix) + rituximab
• bendamustine + mitoxantrone (Novantrone®, Serono) + rituximab
• epothilones

Treatment of Early-Stage and Late-Stage Diffuse, Large B-Cell Lymphoma

Speaker: Richard I. Fisher, University of Rochester Medical Center, Rochester, New York

Rituximab plus CHOP (R-CHOP) is the standard initial therapy for all patients with advanced-stage, diffuse, large B-cell lymphoma. This standard was obtained following a randomized clinical study that compared CHOP chemotherapy plus rituximab with CHOP alone in elderly patients with diffuse, large B-cell lymphoma.
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The rate of complete responses was higher in the patients who received R-CHOP (76%) than in those receiving CHOP alone (63%) (P = .005). With a median follow-up of two years, event-free and overall survival times were significantly higher in the R-CHOP group (P < .001 and P = .007, respectively). Adding rituximab to standard CHOP chemotherapy markedly reduced the risk of treatment failure and death. Clinically relevant toxicity was not significantly greater with R-CHOP.

Thus, the addition of rituximab to the CHOP regimen increases the complete response rate and prolongs event-free and overall survival in elderly patients with diffuse, large B-cell lymphoma, without a clinically significant increase in toxicity. A four-year update of this study shows that these survival rates were better with R-CHOP than with standard CHOP.

Treatment of aggressive lymphomas includes new therapeutic approaches, including monoclonal antibodies plus chemotherapy, dose intensification using cytokines, modifiers of drug resistance, ablative chemotherapy with bone marrow or peripheral blood stem-cell support, and new chemo-therapeutic agents. One new approach is CHOP therapy every two weeks instead of the standard 21 weeks. CHOP every two weeks improved overall survival in patients older than 60 years of age. A study of rituximab plus dose-accelerated CHOP is ongoing. suhagra

A number of studies of new and older agents for the treatment of aggressive lymphomas are under way. A few Southwest Oncology Group (SWOG) trials are in progress:

• SWOG 0349 is utilizing CHOP, rituximab, and G3139 phosphorothioate oligonucleotide (bcl-2 antisense) therapy for patients younger than 60 years of age with advanced-stage diffuse, large B-cell lymphoma and NHL of low and low-intermediate risk.
• SWOG 0515, phase 2, is evaluating CHOP and rituximab plus bevacizumab for patients older than 60 years of age with advanced-stage diffuse, large B-cell lymphoma and NHL. The objective is to determine the complete response rate and the two-year failure-free survival. R-CHOP plus bevacizumab is used for eight cycles.
• SWOG-0433, phase 2, is under way to assess I-tositu-momab in combination with CHOP and rituximab for patients older than 60 years of age with advanced-stage diffuse, large B-cell lymphoma and for NHL patients.

Chemoradiotherapy is standard treatment for localized aggressive lymphoma. To determine the optimal therapy for non-elderly persons with low-risk localized lymphoma, a randomized trial comparing chemoradiotherapy with chemotherapy alone was conducted. After five years, chemotherapy with three cycles of ACVBP (doxorubicin [Adriamycin^®], cyclo-phosphamide, vindesine, bleomycin, prednisone), followed by sequential consolidation, was superior to three cycles of CHOP plus radiotherapy for the treatment of low-risk localized lym-phoma in patients under 61 years of age. Radiotherapy should have an impact on early-stage disease.