Adjustment of Chemotherapy Duration in Follicular Lymphoma According to Minimal Residual Disease Status

Follicular lymphoma (FL) is the second most common type of non-Hodgkin's lymphoma, with an estimated incidence of 3.18 cases per 100000 people a year in the United States The disease is characterized by an indolent behavior, where often treatment is unnecessary at diagnosis, and a "watch \& wait" approach is the standard of care for asymptomatic patients. FL is also a highly responsive disease for immuno-chemotherapeutic combinations, although most patients will eventually relapse. Since the disease is incurable \& indolent in nature, the therapeutic strategy should aim for disease control, while using treatments with high safety profile in order to minimize the chance for life threatening adverse events. Therapy with rituximab cyclophosphamide, doxorubicin, vincristine \& prednisone (R-CHOP) combination \& subsequent rituximab maintenance therapy for 24 months shows excellent results with a median progression free survival (PFS) of above a decade. The more recent GALLIUM trial has shown that combining the monoclonal antibody obinutuzumab with chemotherapy is even more efficacious compared to rituximab combinations. When different combinations were examined in this trial the best results were achieved with the bendamustine-obinutuzumab (BO) combination with 3 year PFS of 84%. Unfortunately the trial also revealed a downside for this effective combination with higher rate of fatal adverse events among patients receiving 6 cycles of bendamustine combinations. In patients with acute leukemia evaluation for minimal residual disease (MRD) is a routine procedure, and the nature \& length of treatment are guided by MRD status at different time points during therapy. Among FL patients treated with obinutuzumab-chemotherapy combinations, it has been shown that after 3 cycles of treatment about 90% of patients were MRD negative. In addition MRD negativity at the end of induction in either peripheral blood or bone marrow was found to be associated with improved outcomes in patients with 1st line treatment for FL as well as in the relapsed setting. These findings raise the possibility for an MRD based treatment approach, where the duration of chemotherapy could be guided by MRD status at mid-induction. Eliminating chemotherapy while continuing immunotherapy after achievement of MRD negativity \& complete metabolic remission on PET-CT at mid-induction could reduce treatment toxicity, while potentially preserving efficacy.