Therapy for patients with follicular lymphoma

I divide the patients with follicular lymphoma into two groups. Generally, one group consists of younger patients and patients with a high International Prognostic Index (IPI) score.

These are patients who cannot be followed for five to 10 years without treatment. If the patients are only in their forties, they won’t be happy with a median survival of 10 years. In those patients, based on the recent data, I’m using R-CHOP chemotherapy for six courses as first-line therapy.

The rituximab plus fludarabine-based regimens are equally efficacious. The goal in these patients is to obtain a complete remission. In view of the data with these rituximab combinations demonstrating higher clinical complete remissions, higher molecular complete remissions and longer progression-free survival, I’d be surprised if we don’t see some survival advantage.

I tend to use a different treatment approach in older patients and middle-aged patients with very low-risk disease. Those patients usually have a very prolonged course and may live for 10 to 20 years with sequential or minimal treatment. When I treat those patients, I use single-agent rituximab. I observe some patients without treatment, but I use that approach less frequently now because we have a treatment option that is minimally toxic. The choice is no longer limited to chemotherapy or observation. Now, we have the option to treat them with single-agent rituximab.

Trials evaluating rituximab plus chemotherapy as first-line therapy in patients with follicular lymphoma

In younger patients and patients with a high IPI score, key findings from a number of Phase II trials have led me to use more aggressive first-line therapy with rituximab plus chemotherapy. All of those trials consistently demonstrated a higher clinical complete response rate and a much higher molecular complete response rate than reported with chemotherapy alone.

The molecular complete response rates in many of those Phase II trials were approximately 40 to 50 percent. With any combination chemotherapy regimen, the molecular complete response rate in patients with low-grade lymphoma is less than 20 percent. The molecular complete response rate is thought to be a surrogate marker for a better quality response.

Recent data from two large randomized Phase III trials comparing CVP or CHOP alone or with rituximab demonstrate that the addition of rituximab to chemotherapy more than doubled the median progression-free survival (2.1).

Neither of those two trials has sufficient follow-up to draw any final conclusions about overall survival, but it is difficult to ignore a therapy that will probably make a difference. Therefore, I now treat that group of patients with a combination of rituximab and chemotherapy instead of chemotherapy or rituximab alone.

Rituximab monotherapy and maintenance therapy in patients with follicular lymphoma

In patients who are elderly, are not good candidates for chemotherapy or have low-risk disease, I’ve been using single-agent rituximab, which, as first-line therapy, has about a 75 percent response rate. In those patients, I follow initial single-agent rituximab with maintenance rituximab. Maintenance rituximab trials have demonstrated about a 35-month median progression-free survival.

My maintenance schedule consists of four more four-week courses of rituximab administered every six months. Another maintenance schedule involves one dose of rituximab administered every two months. A major cooperative group trial (ECOG-4402) will evaluate maintenance rituximab administered once every three months (2.2).

Trial combining rituximab with a vaccine in patients with follicular lymphoma

In our trial evaluating first-line and maintenance rituximab followed by a vaccine, we are studying two biologic agents without chemotherapy. This is a follow-up study to our previous trials utilizing single-agent rituximab followed by maintenance rituximab.

This trial will assess various T-cell parameters supposedly stimulated by the vaccine to determine if the vaccine works when administered with rituximab. Since the vaccine is made specifically for a particular patient’s tumor, patients will receive their first course of rituximab during weeks one through four while the vaccine is being manufactured. On week 10, the vaccine will be available, and one dose per month will be administered.

Phase II trial of rituximab, chemotherapy and Zevalin® as first-line therapy in patients with follicular lymphoma

In other reported trials, Zevalin® has been used as monotherapy. Our study, like many others, attempted to intensify first-line therapy by adding drugs other than chemotherapy. The intent was to obtain higher clinical complete response rates and molecular complete response rates with the hope that those would translate into a survival advantage. We used rituximab plus chemotherapy followed five weeks later by the investigational part of the trial, which was the addition of a dose of Zevalin®. The toxicity wasn’t much different from what has been seen with Zevalin® monotherapy. The patients experienced myelosuppression, and a couple of times patients required platelet transfusions.

Radioimmunoconjugate therapy

Zevalin® and tositumomab (Bexxar®) are very good drugs for some patients with follicular lymphoma. The majority of patients I’ve treated with those agents, outside of a trial, have been patients with disease that has failed multiple previous regimens.

The time course for myelosuppression after the administration of radioimmunoconjugates is prolonged — the nadir occurs at about six weeks instead of 10 or 14 days, and usually by 12 weeks the counts are back to normal.

Future strategies for management of patients with low-grade lymphoma

I suspect the combination rituximab and chemotherapy regimens will be the first treatments to prolong survival. I also expect we will probably use combinations of targeted treatments within the next few years. Those combinations may be better than a single targeted agent, or they may, in some instances, allow a reduction in the amount or duration of chemotherapy. In 10 years, treatments may involve combined targeted treatments and less chemotherapy.

I expect an improvement in survival with the addition of rituximab to chemotherapy because evidence indicates that the quality of remission is better. Combination chemotherapy regimens like CHOP provide a higher complete response rate than single-agent chlorambucil. However, those complete remissions are clinical complete remissions, and the molecular remissions with CHOP alone are very low — 15 percent or less. I don’t believe those patients have truly complete remissions; therefore, it isn’t surprising that continuous relapses occur and survival is not prolonged.

With the addition of rituximab to chemotherapy, an appreciably higher molecular complete response rate can be obtained, but it is unknown whether that will translate into a survival advantage in patients with low-grade lymphoma. We do, however, know that a molecular complete response rate in other hematologic malignancies (eg, acute leukemia and chronic myelogenous leukemia) has translated directly into prolonged survival.

Even if the addition of rituximab to chemotherapy doesn’t prolong survival, the improvement in median progression-free survival from 15 to 50 months for rituximab plus chemotherapy compared to chemotherapy alone is enough of a difference for me to consider the addition of rituximab.

If the difference in progression-free survival were short, deciding whether to use rituximab would be more difficult. The toxicity of the treatment also affects my decision. If chemotherapy can be reduced or less toxic agents can be used, I’m more likely to consider adding rituximab.

Management of patients with diffuse large B-cell lymphoma

I think the standard of care for patients with diffuse large B-cell lymphoma is R-CHOP. I would use R-CHOP across the board, regardless of the patient’s age. It is still debated whether six or eight courses should be used.

In European trials and many of the Southwest Oncology Group trials, the standard is eight courses, but six courses are frequently used in practice. This may be based on a complete remission being documented after four courses and then an extra two courses of treatment being administered. I’d use at least six courses of R-CHOP, and I’d probably use eight courses in patients who are tolerating it well or have been slow to respond.

Future expectations for the management of patients with highgrade lymphoma

I believe we will have incremental advances for patients with aggressive lymphomas. Because the treatment is effective in some groups of patients, those advances will have to come through large randomized trials. The next trials will have to compare R-CHOP with or without some new drug. Those trials take a longer time to complete and are riskier to undertake.

Bortezomib trials in patients with lymphoma

Phase II trials of single-agent bortezomib have demonstrated responses in patients with follicular, mantle cell and small lymphocytic lymphoma who were heavily pretreated. Follow-up single-agent trials are ongoing in patients with mantle cell and follicular lymphoma. Two trials are evaluating R-CHOP combined with bortezomib in patients with mantle cell and diffuse large B-cell lymphoma. If some of the Phase II trials with single-agent bortezomib have high response rates and the combination trial results are reasonable, enthusiasm will exist for a randomized trial to compare R-CHOP with or without bortezomib.

The R-CHOP and bortezomib regimen has been tolerable. However, based on the toxicity profile for single-agent bortezomib, I believe it will have excess toxicity in a combination regimen — a mild increase in myelosuppression and probably neuropathy. Neuropathy may be a problem for the combination of bortezomib and vincristine.

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