Fludarabine Compared with CVP Chemotherapy in Newly diagnosed Patients with Stages III and IV Low Grade Malignant Non-Hodgkin?s Lymphoma. Final Analysis of a Prospective Randomized Phase III Intergroup Study in 381 Patients

Reviewer: Mary Kara Bucci, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: December 13, 2001

Presenter: A. Hagenbeek
Presenter's Affiliation:
Type of Session: Scientific

Background
In 1993, the EORTC lymphoma group initiated a prospective randomized trial in newly diagnosed, low grade non-Hodgkin?s lymphoma (NHL) patients to investigate the efficacy and toxicity of Fludarabine compared to the conventional regimen of cyclophosphamide, vincristine and prednisone (CVP). This report is the final analysis of that trial.

Materials and Methods

381 patients from 60 centers in 9 countries with Grade III or IV low-grade NHL were enrolled on this trial.

Eligible histologies were NHL Working Formulation class A (CLL excluded), B or C.

Patients were either started on treatment immediately after diagnosis (n=248), or observed until either the development of B symptoms, progression over a 3 month period, or the involvement of a critical organ (n=133).

At the start of treatment, patients were randomized to either 8 cycles of Fludarabine or 8 cycles of CVP.

Staging with CT scans and bone marrow biopsy was performed at the time of study entry and after completion of the last cycle of chemotherapy.

Primary endpoints of this study were rate of response to treatment, duration of response, and toxicities.

Results

Central pathology review declared 78 patients (20%) ineligible for review.

In the Fludarabine group, overall response rate (ORR) was 75%, complete response (CR) rate was 39%, partial response (PR) 36%, stable disease (SD) 2%. Seventeen percent of patients in the CV group achieved a CR and 41% achieved a PR.

There was no difference in overall response rate between patients who were treated immediately and those who were observed until progression. In the immediate treatment group, ORR in was 76% in the Fludarabine group and 58% in the CVP group. In the observed group ORR was 74% for Fludarabine and 58% for CVP.

There was no significant difference in time to progression (TTP) or overall survival (OS) between the Fludarabine and CVP treatment groups; median TTP 21 months vs 15 months, 5 year OS 68% vs 60%. Median OS has not yet been reached in either group.

Granulocytopenia and thrompbocytopenia (Grade 2 or above) were significantly more common in the Fludarabine group; 28% vs 12 %, p<.001 and 8% vs 1%, p=.002 respectively. The frequency of severe infections was not significantly different between the two groups.

Only multivariate analysis, only elevated serum LDH was a significant adverse prognostic factor (p<.001) for TTP. For OS; age, elevated LDH, and evidence of liver involvement were significant as adverse prognostic factors.

Author's Conclusions

There was a significant increase in overall response and more CRs in the Fludarabine group with no difference in life-threatening toxicities between the two groups. There was no difference in TTP or OS.

The authors conclude that Fludarabine is a safe and effective therapy for low grade NHL that can contribute to new treatment modalities such as immunotherapy and stem cell transplant.

Clinical/Scientific Implications
This randomized Phase III study demonstrates the safety and efficacy of Fludarabine as first-line treatment for low-grade NHL. Fludarabine will likely be part of many first-line strategies, and should be studied further in combination with other modalities.

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