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Randomized intergroup trial of first line treatment for patients </= 60 years with diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) with a CHOP-like regimen with or without the anti-CD20 antibody rituximab- early stopping after the first interim analysis

Reviewer: Neha Vapiwala, MD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 5 de junio del 2004

This study discusses an off-label use of rituximab for the treatment of NHL.

Background

Non-Hodgkin's lymphoma (NHL) is the fifth most common malignancy in the United States, with over 50,000 cases diagnosed yearly. The majority of these cases occur in adults, with an average age at diagnosis of 60 years. The era of molecular anti-cancer therapy has ushered in a variety of targetted agents employed in conjunction with more standard NHL treatment such as chemotherapy. Rituximab was the first monoclonal antibody approved by the US FDA for anti-cancer therapy. It is specifically approved for the treatment of relapsed or refractory low-grade or follicular, CD20+, B-cell non-Hodgkin's lymphoma. It has been or is being extensively studied in over 200 clinical trials, and is well established in the treatment of older NHL patients. The data are not as robust in its use for younger, low-risk NHL patients, and thus the authors designed this trial to specifically evaluate its possible benefit in this specific group.

Materials and Methods

• Intergroup study with 18 countries participating
• Untreated patients with confirmed CD20-positive low-risk DLBCL, defined as stages II, III, IV or bulky stage I
• Patient ages 18-60 years
• Total of 824 patients recruited between 5/2000 and 10/2003
• Randomized to one of two arms:
1. CHEMO 6 cycles of a CHOP-like regimen (CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone)
2. R-CHEMO same chemotherapy + Rituximab 375 mg/m² x 6 cycles
• Planned interim analysis was performed on 326 evaluable patients 
• Evaluable was defined as having CD20+-confirmed NHL with data available from the first follow-up visit  
• Median age of this subgroup was 48 years
• Stage III/IV disease in 24%, elevated LDH in 32%, bulky disease in 50%
• Majority of patients received CHOP (40%) or CHOEP (50%, CHOP + Etoposide) regimens
• Primary endpoint of study was time to treatment failure (TTF)
• A failure event was defined as one of the following: lack of complete remission after treatment, progressive disease, relapse or death.
• Study was designed to detect a 10% difference in the 3-year TTF rate
• Secondary endpoints included complete remission rate, progressive disease under therapy, and overall survival

Results

• CHEMO arm (n= 165) vs. the R-CHEMO arm (n= 161). 
• The two arms were well-balanced for prognostic factors such as age, histology, and ECOG perfomance status.
• No significant differences in adverse effects were found between the two arms (overall toxicity rates = 57% CHEMO vs. 53% R-CHEMO).
• At a median follow-up time of 24 months, the R-CHEMO arm had a significantly longer TTF rate (81.0% vs. 58%,  p< 0.000005) than the CHEMO arm.
• At a median follow-up time of 24 months, the R-CHEMO arm had a significantly longer overall survival (95% vs. 85%, p= 0.0026) than the CHEMO arm.
• The complete remission rate was 85% in the R_CHEMO arm vs. 65% in the CHEMO arm.
• The R-CHEMO group had a significantly lower rate of progressive disease (5% vs. 16%).
• The trial was stopped in 12/2003 because the p-value for TTF (calculated from the log-rank test) exceeded the official alpha value criterion designated for trial termination.

Author's Conclusions

• The use of rituximab together with CHOP-like chemotherapy increased the remission rate and decreased the disease progression rate in young, low-risk DLBCL patients.
• Rituximab significantly increased the TTF and overall survival.
• The addition of rituximab to chemotherapy did not appear to significantly increase the toxicity rate.
• Along with the use of rituximab, the presence of bulky disease and the international prognostic index score (IPI) were also statistically significantly associated with failure events.

Clinical/Scientific Implications

The results of this study are very promising in the management of young, low-risk DLBCL patients. The addition of rituximab to standard chemotherapy regimens appears to improve the outcome in terms of time to treatment failure, disease progression, and overall survival. Furthermore, these improvements are achieved without an undesirable increase in adverse effects. This supports the already well-established role of rituximab by demonstrating its benefit in a relatively low-risk group compared to the elderly patient cohorts in whom it has traditionally been applied.

However, while these data are very encouraging, it is important to remember that this is an interim analysis of a smaller subset of the overall patient group. In order to make a truly comprehensive and meaningful analysis, a final intention-to-treat analysis for the entire group will be needed . Also, it is important to note that this study did exclude the MOST low-risk patients of all, those with stage I, non-bulky disease. It remains to be seen if this subgroup would also benefit from the addition of rituximab, and future studies are likely to address this.

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