Clinical trials evaluating rituximab plus CHOP as first-line therapy in patients with low-grade NHL

One of the earliest studies evaluating six courses of rituximab plus CHOP, conducted by Dr Myron Czuczman from Roswell Park, enrolled about 40 patients with low-grade lymphomas. Thirty of the patients were previously untreated. The initial reports were striking with an overall response rate of 95 to 100 percent, a complete response rate over 45 percent and an impressive duration of response. The latest results from the trial were presented at ASH 2003, and the median time to treatment failure was finally reached at 82.3 months (Czuczman 2003). Many physicians have started using this regimen in patients with low-grade lymphomas.

Because it was a small Phase II trial, it needs to be reconfirmed in a large randomized trial, which has actually been attempted. The Southwest Oncology Group tried to conduct a three-arm trial (SWOG-S0016) comparing CHOP, CHOP plus rituximab, and CHOP plus Bexxar® in patients with newly diagnosed follicular lymphomas. Because it is difficult to persuade physicians to use a regimen without a monoclonal antibody, the CHOP-alone arm had to be closed (2.1). We need randomized trial data to determine if Dr Czuczman’s high response rates with CHOP plus rituximab are reproducible.

Criticisms for using a CHOP plus rituximab regimen up front involve exposing patients to an anthracycline when it’s not proven to improve overall survival. In low-grade lymphomas, especially follicular lymphomas, a large number will transform into a large B-cell lymphoma during the course of the patient’s life span. If the lymphoma transforms, more aggressive treatment will be required, and that’s when CHOP or more aggressive treatment should be considered.

ECOG-E1496: Phase III trial of CVP with or without maintenance rituximab in patients with advanced low-grade NHL

Initially, ECOG-E1496 (1.1) had two chemotherapy arms: (1) CVP and (2) fludarabine/ cyclophosphamide; however, the fludarabine/cyclophosphamide arm was discontinued because of toxicity. Patients treated with CVP who had a complete response, partial response or stable disease were randomly assigned to observation or rituximab maintenance every six months for two years.

Patients receiving maintenance rituximab had a markedly improved time to treatment failure. This was the first trial to demonstrate that maintenance rituximab following up-front chemotherapy kept patients in remission longer than observation. Even though insufficient events occurred to evaluate survival, a nonstatistically significant trend was noted for an improvement in overall survival. Although I don’t believe we’ll see a difference in survival, we can justify maintenance rituximab based on the delay in disease progression.

Transformation in patients with relapsed follicular lymphoma

Transformation of a follicular lymphoma into a DLBCL is not evaluated frequently enough; DLBCL that occurs de novo is curable with CHOP plus rituximab in a certain percentage of patients. When a follicular lymphoma transforms to a DLBCL, cure is not possible and patients often die within six months. Some patients will transform locally, and if local therapy is used, patients may have prolonged survival even after transformation.

Treatment should be approached differently in patients with transformation. We must educate community-based physicians to obtain biopsies more often because transformation can occur in an unusually large mass. If a patient’s disease relapses with a big lymph node in the neck and the rest of the nodes on CT scans are increasing a small amount, then the big mass should be biopsied. If it’s a transformed lymphoma, aggressive therapy may lead to remission, and when the patient’s disease recurs, it can still be a low-grade lymphoma.

When making decisions about the treatment for a patient with transformation, the patient’s age and comorbid conditions should be considered. In a young patient, I use aggressive therapy — CHOP plus rituximab or rituximab plus ifosfamide, carboplatin and etoposide (ICE) — to reduce the tumor burden. Then, if their bone marrow is clear, I harvest their stem cells and do a stem-cell transplant. In an elderly patient with comorbid conditions, I have turned to radioimmunotherapy.

Radioimmunotherapy for patients with low-grade lymphomas

Oncologists who have been using radioimmunotherapy for years find it to be one of the best approaches for patients with low-grade lymphomas because the treatment is completed in one week. Patients do not experience the side effects associated with chemotherapy, such as hair loss. It causes slight nausea and hematologic toxicity six to eight weeks after treatment.

Patients must be appropriately selected for radioimmunotherapy. They must have adequate bone marrow reserves — an absolute neutrophil count of 1,500/µL and platelet count between 100 and 150 X 10³/µL. To avoid hematologic toxicity, a bone marrow biopsy within four to six weeks of starting radioimmunotherapy must show no more than 25 percent involvement with lymphoma. These patients must be evaluated more thoroughly than patients receiving regular treatments for low-grade lymphoma.

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