ORLANDO, Fla.—Historically, patients with asymptomatic, advanced-stage follicular lymphoma (FL) have shown no benefit from immediate chemotherapy when compared with a watchful-waiting approach; therefore, chemotherapy—with its attendant adverse events—has been deferred until disease progression.
Recent findings, however, may change the management of this patient population: initial treatment with rituximab was found to delay significantly the need for new therapy, reported Kirit M. Ardeshna, MD, of the University College London Hospitals, London, UK.
Adult patients with asymptomatic stage 2, 3, or 4 FL (grades 1-2 and 3a) and adequate bone marrow reserve were randomized to watchful waiting (Arm A), rituximab 375 mg/m2 weekly for 4 weeks (Arm B), or rituximab 375 mg/m2 weekly for 4 weeks followed by rituximab maintenance every 2 months for 2 years (starting at month 3 until month 25)(Arm C), Dr. Ardeshna outlined in an oral presentation to those attending the 52nd American Society of Hematology Annual Meeting and Exposition.
Between September 2004 and May 2009, 462 patients were randomized (186 Arm A, 84 Arm B, and 192 Arm C); 95% of patients had low tumor burden (Groupe d’Etude des Lymphomes Folliculaires [GELF] criteria); the other 5% had raised LDH but fulfilled remaining GELF criteria. Of the 462 patients, 98% were entered into the study within 4 months of diagnostic biopsy. Median age was 60 years (range, 27-87 years); 54% were female. ECOG performance status was 0/1 in 91% and 9% of patients, respectively. Eighty-nine percent of patients had grade 1-2; 21% were stage 2; 40%, stage 3; and 39%, stage 4; 42% had bone marrow involvement. The Follicular Lymphoma International Prognostic Index (FLIPI) score was 0 in 9%, 1 in 26%, 2 in 41%, 3 in 22%, and 4 in 2% of patients.
The two primary end points were time to initiation of new therapy (chemotherapy or radiotherapy) and quality of life. The study was designed to detect an improvement in median time to initiation of therapy in each of the rituximab arms of 18 months (from 30-48 months) with 2.5% significance level and 90% power. A total of 230 events were required and 600 patients were planned. In September 2007, a decision was made to discontinue Arm B, as evidence of the efficacy of maintenance rituximab became clear. With the 2-arm comparison, using a significance level of 5%, a total of 360 patients in Arm A and Arm C were enrolled. It was estimated that 192 patients would be required to show the 18-month improvement in the 2-arm study.
In March 2010, the Data Monitoring committee concluded that the data regarding time to initiation of new therapy was mature and recommended full analysis of data to be performed and presented, with the knowledge that rituximab maintenance was still ongoing in 20 patients. To date, 45 serious adverse events (AEs) have been reported, 14 in Arm A, 6 in Arm B, and 25 in Arm C. Fourteen serious AEs were considered possibly, probably, or definitely related to the study drug—4 in Arm B and 10 in Arm C; these were 5 allergic reactions (2, grade 3), 6 infections, and 3 episodes of grade 4 neutropenia.
Responses were assessed at months 7, 13, and 25. CT was compulsory at months 7 and 25. Bone marrow was required only if CR on clinical and CT criteria. An interim analysis was performed on February 9, 2010. At month 7, in Arm A, spontaneous remission was seen in 3% of patients, PR in 6%, no change in 74%, and disease progression in 17%. In Arm B, CR+CRu were observed in 45% of patients, PR in 33%, no change in 19%, and disease progression in 3%. In Arm C, CR+CRu were observed in 49%, PR in 36%, no change in 11%, and disease progression in 3% of patients.
At interim analysis, 93 (20%) patients had initiated new treatment; 84 of the 93 (90%) had clinically reported disease progression. New treatment was chemotherapy in 78 (84%), radiotherapy in 10 (11%), rituximab monotherapy in 2 (2%), surgery in 1 (1%), and currently not known in 2 (2%). Estimated median time to initiation of new therapy in Arm A was 33 months, similar to a previous trial of watchful waiting published by the investigators (Ardeshna et al. Lancet. 2003). Time to initiation of new therapy was significantly longer in the rituximab arms (Figure 1; P-value of log-rank test <0.001 for each of rituximab arms vs arm A) and median time was not reached at 4 years. Not all patients who were reported to have clinically progressed (n=142) warranted initiation of therapy (n=84). Please click here for more study data.
Significant differences in PFS were noted between the observation and rituximab arms (Figure 2; P-value of log-rank test <0.001 for each of rituximab arms vs arm A). No difference was observed in overall survival among the 3 arms; 96% of patients remain alive (P>0.5). Please click here for more study data.
The discussion following the presentation involved members of the audience challenging change to the standard practice of watchful waiting outside of demonstrable survival benefit. Dr. Ardeshna concluded that, while upfront rituximab may not replace watchful waiting, favorable quality-of-life data would support its use as an alternative option. “It is too early to make definitive treatment recommendations as we need to analyze the quality-of-life data. However, if these do not demonstrate a detriment to quality of like in the rituximab arm, this option is likely to be a popular one for patients and their doctors,” stated Dr. Ardeshna.
Off Label Use: Rituximab is currently not licensed for use as a single agent in previously untreated patients with asymptomatic advanced stage follicular lymphoma.