Response-Adapted Treatment with Rituximab/Bendamustine/Mitoxantrone/Dexamethasone and Maintenance Therapy with Rituximab in Patients with Follicular Lymphoma in Relapse or Refractory to First-Line Treatment with Immunochemotherapy. RBMDGELTAMO08 Trial

Objectives: To evaluate the efficacy and toxicity of a response-adapted therapy with rituximab/bendamustine/mitoxantrone/dexamethasone (RBMD), followed by rituximab (R) maintenance therapy in patients with relapsed or refractory follicular lymphoma (R/R FL) to first-line treatment with R-chemotherapy (R-ChemoT).

Material and methods: Multicenter phase II trial including 60 patients with R/R FL, after a first R-ChemoT line. Induction therapy: R 375 mg/m² IV, day 1; bendamustine 90 mg/m² IV, days 1 and 2; mitoxantrone 6 mg/m² IV, day 1; dexamethasone 20 mg/day, PO, days 1 to 5. Cycles of 28 days. Evaluation of response after third cycle. If stable (SD) or progression disease (PD): patient withdrawn from the study. If complete response (CR) or unconfirmed complete response (CRu): administration of fourth cycle. If partial response (PR): administration up to 6 cycles. If CR, CRu, or PR after induction: patient received maintenance therapy with R (375 mg/m²/day every 12 weeks for 2 years).

Results: N=60 patients: 50% female, age 63 (32-76) years. Ann Arbor stage III-IV 70% (42/60). FLIPI intermediate-high risk: 50% (30/60). Refractory to R-ChemoT: 18% (11/60). Received RCHOP as first line therapy: 77% (43/60). R maintenance after first line therapy: 43% (26/60). Number of administered RBMD cycles: 4 (1-6).

Efectiveness: CR/CRu after 3 cycles (CR-3), 27 patients. Response after induction therapy (4-6 cycles): Overall response (OR), 88.5% (53/60); CR, 58.5% (35/60); CRu, 12% (7/60); PR, 18% (11/60); SD, 1.5% (1/60); PD, 10% (6/60). Median follow-up: 24.41 mo. (15.58-30.15). Progression free survival, median not reached (NR) (28.28-NR). Overall survival, median NR (NR-NR). OR after RBMD in patients who received R maintenance after first line therapy, 96% (25/26; CR + CRu, 65%). OR in patients who did not receive R maintenance after first line therapy, 94% (32/34; CR + CRu, 82%).

Safety: Grade 3/4 hematologic toxicity: neutropenia, 60% (n=36; 34 patients received G-CSF); anemia, 2% (n=1); thrombopenia, 4% (n=2). Grade 3/4 infections: 8% (n=4); febrile neutropenia 8%, (n=4). Exitus, 2/60 (PD, cycle 1; influenza A, cycle 5). Grade 3/4 non-hematologic toxicity: infusion reaction, 4% (n=2). No skin reactions.

Patient withdrawals before R maintenance therapy: no inclusion criteria (NIC), 2/60; protocol delay of over 4 weeks, 7/60. Forty-four patients began R maintenance therapy (CR-3, 24/44). During R maintenance therapy: PD, 8/44 (18%; 5/8 in CR-3 patients); SD, 1/44 (2.5%); NIC, 3/44 (7%, all CR); protocol delay, 1/44 (2.5%); toxicity, 1/44 (2.5%, myelodysplastic syndrome). Response to R maintenance therapy: OR, 68% (30/44); CR, 61% (27/44; in CR-3 patients, 65%, 17/26); CRu, 4.5% (2/44); PR, 2.5% (1/44).

Conclusions: RBMD is an effective and safe alternative for patients with R/R FL who have received first line treatment with R-ChemoT and R maintenance therapy. This response-adapted treatment strategy achieved results similar to the scheme with 6 cycles and may allow reduction of the intensity and duration of induction therapy and minimize toxicity. No skin reactions were reported, possibly due to the inclusion of dexamethasone in the treatment scheme.