Trial of CVP plus rituximab in follicular lymphoma

At the last American Society of Hematology meeting, an international group presented data on the combination of CVP chemotherapy and rituximab in patients with advanced-stage follicular lymphoma (1.1).

The trial demonstrated a higher complete and overall response rate and a highly significant difference in time to progression, but no difference in survival, to date, with the rituximabchemotherapy combination.

These results demonstrate a clinically meaningful benefit of a year or longer in a population with a relatively unfavorable prognosis. Using the new Follicular Lymphoma International Prognostic Index (FLIPI), 90 percent of the study’s participants had intermediate or high-risk disease. However, a survival benefit was not seen and will be difficult to see in this disease.

We have gone decades without demonstrating a clear improvement in a time-to-progression endpoint for most agents that have been evaluated, including different chemotherapy combinations and the use of interferon. The rituximab-chemotherapy combination offers a clear, highly significant benefit in time to progression with almost no additional toxicity.

This is a unique observation. We now have many acceptable treatment options for follicular lymphoma. I believe that a treatment with little toxicity offered as part of induction therapy — which increases the time in remission — would sound pretty good to patients presented with these data.

Trials of maintenance rituximab after chemotherapy

ECOG-1496 was presented at the ASCO meeting. In this trial, patients with advanced-stage disease received induction CVP chemotherapy and were then randomly assigned to no further treatment or to maintenance rituximab, four weekly doses every six months for four courses. Our Data Monitoring Committee chose to release the data after only about half of the expected events had occurred because we had passed a prespecified boundary of benefit from maintenance rituximab, with a high level of significance — a p-value with many zeros.

A key question will be: Should rituximab be given as part of induction therapy, maintenance therapy or both? ECOG has also conducted a study in diffuse large-cell lymphoma of rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) versus CHOP alone, with a secondary randomization to maintenance rituximab or observation. The results have been difficult to interpret. We saw that rituximab benefited patients as induction or maintenance therapy; however, for patients who received R-CHOP as induction therapy, maintenance rituximab offered no additional benefit.

I don’t believe this data answers that question for indolent or follicular lymphoma. Fortunately, the European Organisation for Research and Treatment of Cancer (EORTC) is conducting a similar study for patients with recurrent indolent lymphoma who have never received rituximab. It is anticipated that we’ll have the results in about two years. The European PRIMA study will also address these issues.

Watchful waiting or delayed treatment in indolent disease

Several randomized trials with more than 10 years of follow-up demonstrate no detriment in overall survival in patients with indolent disease who were randomly assigned to watchful waiting. However, oncologists are continually challenged to identify appropriate patients up front and select an appropriate management strategy.

Two trials are opening for asymptomatic patients with indolent disease and limited tumor burden in terms of number of sites or bulky disease. In the United Kingdom, the study will compare rituximab alone to no therapy. In the United States, ECOG recently opened a study evaluating two different ways of administering rituximab: the conventional schedule versus induction rituximab with maintenance doses administered every 12 weeks until disease progression.

Our recent retrospective review in the Journal of Clinical Oncology evaluated patients with limited-stage indolent lymphoma with no initial therapy. This was a select older population, but the bottom line is that the median survival of 19 years is as good as or better than that of any reports in the literature with radiation therapy or with the combination of chemotherapy and radiation therapy.

It is often initially difficult for patients to accept the strategy of watchful waiting; however, once they have accepted it, it is difficult to convince them to accept treatment when we recommend it. Patients prefer the idea of going about their lives without the side effects of treatment.

Rationale for the schedule of maintenance rituximab

The original schedules for maintenance rituximab were derived based on the three- to six-month delay in repopulation of normal B cells after rituximab. Concern about a potential infectious disease risk from administering rituximab for a long period of time was also a factor.

However, although B cells are suppressed for long periods of time, the incidence of infectious diseases is not increased. In general, the safety profile of rituximab has been excellent with any schedule of administration tested in clinical trials. The every three-month administration schedule being used by the EORTC, and every 12 weeks in our current trial, were derived based on pharmacokinetic data and maintaining serum levels of 25 µg/mL or higher after a course of rituximab.

Correlating prognosis with gene expression in aggressive lymphoma

The molecular modeling data we have is based on combination chemotherapy in a small group of patients with diffuse large B-cell lymphoma who received doxorubicin as part of their treatment. The initial analysis from a collaborative project involving Stanford, the National Cancer Institute and the University of Nebraska demonstrated that large cell lymphoma that looked identical under the microscope had different patterns of gene expression and different prognoses.

Another group evaluated the differences between patients with large cell lymphomas who do well versus those who don’t. They came up with a somewhat different group of genes.

Others have taken the raw data from the two groups to further evaluate these different sets of genes. In a recent issue of the New England Journal of Medicine, we described a six-gene model that utilizes data from both groups to predict survival in large cell lymphoma, independent of the clinical parameters (1.2). A similar 14-gene model has also utilized data from the two groups.

Our plan is to compare these two models prospectively. We believe this is important because CHOP chemotherapy is no longer the standard — now it’s R-CHOP — and preliminary data suggest that some of the biomarkers that were predictive for outcome in the pre-rituximab era (BCL-2 in particular) are less predictive now.

The molecular models have certainly taught us a great deal about the underlying biology of large cell lymphoma. The prognostic significance of these molecular models is still in question with R-CHOP, and this will require further prospective assessment.

Radioimmunotherapy in non-Hodgkin’s lymphoma

Interesting data from Europe will soon be reported evaluating ibritumomab tiuxetan (Zevalin®) in patients with recurrent diffuse large cell lymphoma. This could potentially open up another group of patients for study with radioimmunotherapy earlier in the disease and in patients for whom the risks and benefits are different than in indolent disease.

ECOG is conducting two trials of Zevalin® with chemotherapy. ECOG-1499 is a Phase II trial in mantle cell lymphoma, evaluating R-CHOP followed by Zevalin® (1.3). The other is a Phase II trial in patients with limited-stage diffuse large B-cell lymphoma, incorporating functional imaging with PET scans. These patients will undergo a course of rituximab, chemotherapy and a PET scan, followed by Zevalin® thereafter. We will determine what percentage of patients has residual disease that can be detected by PET after a brief course of chemotherapy and then conversion, and we will follow the long-term outcome of these patients.

Role of combined modality therapy in diffuse large cell lymphoma

ECOG trial 1484 is a very old study evaluating eight cycles of CHOP chemotherapy and randomization to radiotherapy or not for patients who achieved complete remission. Mature data demonstrate a persistent benefit for patients who received combined modality therapy in the range of 14 percent — just at the cusp of statistical significance, because the study is underpowered with fewer than 100 patients per arm. Patients who had a partial remission had very good survival but the use of radiation therapy demonstrated no survival benefit.

The SWOG trial compared three cycles to eight cycles of chemotherapy and involved-field radiation for patients with early-stage diffuse large B-cell lymphoma and demonstrated a benefit from the combined modality therapy for time to progression and a strong trend toward a survival advantage.

This study was later updated and, in the last two years, SWOG has reported that relapses have occurred between five and 10 years in the combined modality arm, and that the benefit in favor of CHOP plus radiation at 10 years is no longer observed. This has led to further confusion about how to interpret the overall data from this country and elsewhere. Dr Miller, the principal investigator of the SWOG study, still favors combined modality therapy because it demonstrated a benefit at five years that hasn’t gone away.

In practice, the use of radiotherapy in combination with chemotherapy is and probably must be individualized for that setting. I evaluate these patients individually based on their presenting features: location and size of the disease and other parameters we routinely evaluate such as age, LDH, hemoglobin, etcetera, and then, if the patients are not in a clinical trial, the decision for radiotherapy can be further individualized based on their response to chemotherapy.

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