Lymphoid Subpopulations and Safety Profile in Untreated-Follicular Lymphoma Receiving Rituximab Monotherapy as Induction and Maintenance Therapy.
Authors: Bassi S. , Mancuso P. , Gigli F. , Antoniotti P. , Bertazzoni P. , Quarna J. , Laszlo D. , Pruneri G. , Orlando L. , Calabrese L. , Cassatella C. , Bertolini F. , Martinelli Giovanni 
Published: April 2020

Abstract
The safety and efficacy of rituximab (R) monotherapy is well established and its excellent tolerability makes it an attractive option for maintenance therapy in incurable indolent lymphomas. The results of maintenance therapy are encouraging because of improved progression-free survival compared to observation. Despite the extensive use of R, it is not yet clearly known the relevant cell subpopulations and effector mechanisms leading to tumor lysis in antibody-dependent cellular cytotoxicity. We monitored the “immune profile” of 18 untreated NHL patients (pts) in a clinical trial, where untreated or relapsed NHL follicular pts received R alone following the schedule described below. Aim of the study was to evaluate if the “immuno profile” could predict response to treatment. 61% of pts were male with a median age at diagnosis of 52 yrs (range 29–79).13 cases showed a G1-2 follicular lymphoma and they belonged mainly to low-intermediate FLIPI group (0–1:11pts;2:6pts). Within 1 month from diagnosis they received R alone at standard dose (375 mg/mq) for 4 weekly administrations and, based on response, they have been randomized to bimonthly maintenance for 8 months or for 5 years. By 4 colours flow-cytometry, we evaluated the absolute count of CD3+CD4+, CD3+CD8+, CD16+CD56+ and CD19+ cells in peripheral blood at diagnosis, at 4th weekly R, at restaging (6–8 weeks after induction) and then each 6 months until progression. After a median time of 8 months from diagnosis 10 pts(55%) obtained a complete remission; the remaining pts showed 5 partial response, 1 stable disease and 2 progression disease. In complete responders we reported a continue increased of the absolute number of CD3+CD4+ (median:672m/L at diagnosis; 699m/L at 4thweekly R; 739m/L at restaging and 805m/L during maintenance) and of CD3+CD8+ (median:376m/L at diagnosis; 464m/L at 4thweekly R; 548m/L at restaging and 559m/L during maintenance), while the absolute number of CD16+CD56+ was stable during therapy (median:203m/L at diagnosis; 290m/L at 4thweekly R; 298m/L at restaging and 173m/L during maintenance). In the other response the pts showed a decrease of CD3+CD8+ (median:815m/L at diagnosis; 518m/L at 4thweekly R; 557m/L at restaging) and CD16+CD56+ (median:325m/L at diagnosis; 265m/L at 4thweekly R; 177m/L at restaging) and the CD3+CD4+ cells demonstrated a temporary increase not confirmed in time (median:691 m/L at diagnosis; 832 m/L at 4thweekly R; 791m/L at restaging). In both response groups, the B-depletion was observed at 4th weekly R. The increased values observed could be correlated to B-depletion, but could be also expression of underlying antitumor activity. After a median time of 12 months (4–60) no grade 3–4 neutropenia were observed. Despite the prolonged B-cell depletion and in 9/18 pts had decrease of IgM, no relevant infections have been observed, except 1 patient that experienced lobar pneumonia responsive to endovenous antibiotics.
R confirmed its safety, even if longer observation is required in pts in maintenance therapy. The monitoring of peripheral blood lymphoid subpopulations could be a feasible and accessible method to predict the response to treatment. It also allows to investigate the complex mechanism of action of monoclonal antibodies, as demonstrated in recent studies. Wider cohort of pts and longer observation are warranted to confirm our preliminary observations.