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Results of E1496: A phase III trial of CVP with or without maintenance rituximab in advanced indolent lymphoma (NHL)

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

This presentation discusses the off-label use of rituximab for the treatment of indolent NHL.

Background

Indolent lymphomas (IL), as the name implies, have a "waxing and waning" pattern featuring multiple disease relapses over a large time period. It is not typically aggressive or fatal, and thus patients often have a long survival, but one that is characterized by periods of disease relapse and remission. The management of disease relapse typically consists of chemotherapy. The introduction of molecular targetted anticancer therapy has revolutionized the treatment of various tumors. In the case of lymphomas, the anti-CD20 agent rituximab plays a major role. The main study question here is whether induction chemotherapy and rituximab can improve the progression-free survival (PFS) compared to chemotherapy alone in patients with advanced indolent lymphoma (AIL).  Of note, the authors initially intended to also compare the effects of CF (cyclophosphamide, fludarabine) vs. CVP (cyclophosphamide, vincristine, prednisone) chemotherapy on outcome. However, the CF arm was terminated secondary to unaccpetable toxicity (32 deaths vs. 8 in the CVP arm). The results reported here are for only those patients studied after discontinutaion of the CF arm.

Materials and Methods

• Eligible patients had stage III-IV follicular grade 1 and 2 (small cleaved cell, mixed) and small lymphocytic NHL, never previously treated, age >/= 18 years old, with ECOG status of 0 or 1. 
• Eligible patients were accrued from 3/1998 to 2/2000.
• 401 patients received CVP induction chemotherapy.
• 322 patients achieved complete or partial remission or had stable disease on restaging after completion of chemotherapy.
• These 322 patients were randomized to receive maintenance rituximab 375 mg/m2 weekly x 4 q 6 months for 2 years (MR, n=157) or undergo observation (OBS, n=148).
• The randomized patients were stratified by histology, tumor burden, and degree of residual disease after chemotherapy.
• Both arms were well-balanced for the prognostic factors listed above.
• 305 were evaluable at the time of analysis.
• Primary endpoint was the progression free survival (PFS) as measured from the time of the randomization to maintenenace rituximab vs. observation (avg ~6 mos from the time of study entry). 
• The study was designed to have planned analyses at timepoints corresponding to 25%, 50% and 75% of projected events. 

Results

• Results are reported for the MR arm vs. the OBS arm:. Median folllow-up for survivors is 1.7 years.
• The median PFS was 4.2 vs. 1.5 years (p=0.00003, HR = 0.5)
• The estimated 2-year PFS rate was 73% vs. 43%.
• The estimated 2-year overall survival (OS) was 96% vs. 89%, although this was not statistically significant.
• On subset analysis, the MR arm was associated with significantly higher PFS and OS regardless of histology, residual disease, or the presence of a high tumor burden (as measured using the GELF criteria).

Author's Conclusions

• Maintenance rituximab in IL patients is well-tolerated and not associated with any increase in grade 3/4 toxicity.
• CVP chemotherapy achieves high response rates with acceptable toxicity compared to CF, which had to be discontinued.
• The addition of maintenance rituximab after CVP chemotherapy increases the median PFS by 2.7 years.
• The benefit of maintenance rituximab is seen in subgroups of patients with follicular histology, high tumor burden, or minimal residual disease.
• The overall survival is not statistically significant yet, but may prove to be with longer follow-up.

Clinical/Scientific Implications

The results of this trial establish the efficacy of CVP chemotherapy in achieving complete or partial remissions or disease stabilization in patients with advanced relapsed IL. The randomization analyzed here also supports the post-chemotherapy administration of at least 2 years of maintenance rituximab therapy in those patients achieving good response to induction chemotherapy. Furthermore, this benefit of additional maintenance treatment compared to observation appears to hold even in patients with follicular histology, high tumor burdens, and minimal residual disease post-chemotherapy.

While the results presented here are very promising, it is important to remember that this trial has relatively short follow-up, and for a disease with a long natural history, does not suffice to make far reaching conclusions. The long-term effect of the maintenance therapy on relapse rates "down the road" remains to be seen with longer follow-up of these patients. A second point to bear in mind is whether it would be preferable and reasonable to reserve rituximab for time of relapse, rather than providing it as maintenance, particularly in those with a complete response to chemotherapy. The authors feel, however, that the benefit of rituximab seen even in patients with minimal residual disease supports its use as maintenance. 

Future studies might evaluate the use of induction chemotherapy and rituximab rather than induction chemotherapy alone, thus providing the benefits of rituximab to the whole group. Those patients could then later be randomized to additonal, maintenance rituximab versus no further treatment, in order to truly determine if rituximab provides beneift as a preventive agent, above and beyond its use as initial therapy.

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