Study Compares Rituximab Maintenance to Observation After First-Line Treatment in Older Patients With Advanced Follicular Lymphoma
In an Italian study reported in the Journal of Clinical Oncology by Umberto Vitolo, MD, and colleagues in the Fondazione Italiana Linfomi, treatment-naive patients aged > 60 years with advanced follicular lymphoma were randomized to rituximab [Rituxan] maintenance or observation after brief first-line therapy with R-FND (rituximab, fludarabine, mitoxantrone, and dexamethasone) and rituximab consolidation. R-FND and rituximab consolidation produced high response and progression-free survival rates. Rituximab maintenance was associated with nonsignificant prolongation of progression-free survival.
Study Details
In this phase III study, 234 treatment-naive 60- to 75-year-old patients received chemoimmunotherapy with four monthly courses of R-FND followed by four weekly cycles of rituximab consolidation. R-FND consisted of rituximab at 375 mg/m2 on day 1, fludarabine at 25 mg/m2 on days 2 to 4, mitoxantrone at 10 mg/m2 on day 2, and dexamethasone at 10 mg on days 2 to 4. One month after the fourth course of R-FND, patients underwent tumor response evaluation, and those with response or stable disease received four weekly infusions of rituximab consolidation at 375 mg/m2.
Responders were stratified into two groups: stratum 1 consisted of those with clinical complete response who achieved polymerase chain reaction (PCR) negativity in bone marrow for BCL2/IgH rearrangement; stratum 2 consisted of clinical complete responders who were bone marrow PCR–positive, partial responders independent of PCR status, or complete responders who had no PCR-amplifiable BCL2/IgH rearrangement at baseline. Stratified responders were randomized to observation or rituximab maintenance at 375 mg/m2 once every 2 months for a total of four doses.
Among the 234 patients receiving induction therapy, median age was 66 years, 58% were women, 55% had Follicular Lymphoma International Prognostic (FLIPI) scores > 2, 86% had Ann Arbor stage III/IV disease, 13% had hemoglobin < 120 g/L, 18% had lactate dehydrogenase (LDH) > upper limit of normal, 48% had more than four involved nodal sites, 55% had abnormal bone marrow, 76% had Eastern Cooperative Oncology Group (ECOG) performance status of 0, 18% had B symptoms, 60% had 1 or more comorbidities (> 1 in 24%), and 50% had BCL2/IgH rearrangement.
Induction/Consolidation Outcomes
After induction and consolidation therapy, the overall response rate was 86%, with 69% of patients having complete remission or unconfirmed complete remission. After median follow-up of 42 months, estimated 3-year progression-free survival was 66% (95% confidence interval [CI] = 59%–72%) and 3-year overall survival was 89% (95% CI = 85%–93%). Three-year progression-free survival was 80% among patients with FLIPI scores of 1 or 2 and 54% among those with scores ≥ 3.
Age did not appear to have a significant effect on 3-year progression-free survival (hazard ratio [HR] per 5-year increase = 1.04, P = .776). Three-year progression-free survival was 67% among patients younger than 70 years and 63% among those ≥ 70 years. There were no differences in 3-year progression-free survival among patients with no, 1, or ≥ 2 comorbidities.
Randomized Groups
Overall, 210 patients completed the planned induction and consolidation treatment, and 202 responders were randomly assigned to rituximab maintenance (n = 101) or observation (n = 101).
For the rituximab and observation groups, median age was 66 and 65 years, 63% and 55% were women, 56% and 51% had FLIPI scores > 2, 88% and 84% had Ann Arbor stage III/IV disease, 14% and 6% had hemoglobin < 120 g/L, 18% and 13% had LDH > upper limit of normal, 49% and 47% had > 4 involved nodes, 50% and 59% had abnormal bone marrow, 80% and 78% had ECOG performance status of 0, 16% and 15% had B symptoms, 60% and 61% had ≥ 1 comorbidity (> 1 in 25% and 20%), 12% and 16% had BCL2/IgH rearrangement, and 79% of both groups had complete remission as response to induction/consolidation treatment.
Maintenance Outcomes
After a median follow-up of 34 months from randomization, 2-year progression-free survival was 81% in the rituximab group and 69% in the observation group (stratified HR = 0.74, 95% CI = 0.45–1.21, P = .226; adjusted HR = 0.71, 95% CI = 0.43–1.17, P = .174). Subgroup analyses showed no significant difference from the overall effect according to FLIPI score, symptoms, age, comorbidities, sex, bone marrow involvement, or ECOG performance status.
At 3 months after the end of the maintenance phase, 87% of the rituximab group vs 71% of the observation group were in complete remission or unconfirmed complete remission (P = .006) and more patients with partial response at the time of randomization had converted to complete remission/unconfirmed complete remission (60% vs 15%, P = .008). No differences in overall survival were found between study groups.
Significant predictors of progression in the randomized groups were male sex (HR = 1.95, P = .009), FLIPI score ≥ 3 vs ≤ 2 (HR = 0.86, P < .001), and stratum 2 vs stratum 1 (HR = 2.11, P = .015). Age (per 5-year increase) was not a significant predictor.
Toxicities
Induction and consolidation treatment were well tolerated. The most common grade 3 to 4 toxicity during induction and consolidation was neutropenia, which occurred in 25% of courses, including 23% in patients aged < 70 years and 31% in older patients. Only 13 serious infections (1% of patients) were observed.
Granulocyte colony-stimulating factor support (Neupogen in the United States) was required in 15% of patients. Grade 3 or 4 anemia, rituximab infusion reactions, and cardiac and pulmonary adverse reactions occurred in < 1% of courses. There were no differences in the frequency of adverse events according to age or presence of comorbidities.
Two patients (0.8%) died during treatment, one due to hepatitis B virus reactivation in an occult carrier not receiving viral prophylaxis and the other due to Stevens-Johnson syndrome. Treatment was also well-tolerated in the maintenance phase, with comparable adverse event rates in both groups.
Grade 3 or 4 neutropenia occurred in 14 patients in the rituximab arm and 1 in the observation arm; all but 1 of the patients recovered, and no grade 3 or 4 infections occurred during neutropenic periods. Overall, grade 3 or 4 infection occurred in 1 rituximab patient and 3 observation patients.
The investigators concluded, “A brief R-FND induction plus rituximab consolidation achieved excellent results with high [complete remission] and [progression-free survival] rates, supporting the feasibility of this regimen in patients older than 60 years. A short rituximab maintenance did not achieve a statistically significant [progression-free survival] improvement over observation.”
The study was supported by Roche SpA.
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