Study Compares Rituximab Maintenance to Observation After First-Line Treatment in Older Patients With Advanced Follicular Lymphoma


Key Points

  • Brief R-FND induction and rituximab consolidation was associated with high complete remission and progression-free survival rates in older patients with advanced follicular lymphoma.
  • Induction and consolidation therapy were well tolerated.
  • Short rituximab maintenance was associated with nonsignificantly prolonged progression-free survival compared with observation. 

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.


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. 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.