Pattern of infections and impact on immunocompetence of next generation B-cell depleting immunotherapies in non-Hodgkin's lymphomas: Results from a multicentre retrospective real- life cohort.

Abstract Introduction: Novel immunotherapies (including antiCD19 CAR-T cells, bispecific antiCD20/antiCD3 Monoclonal Antibodies (MoAbs), AntiCD19 Antibodies Drug-Conjugated (ADC)) completely changed the outcome of relapsed/refractory lymphomas. Patients undergoing these therapies showed increased risk of infection due to prior immunosuppression, deep B-cell depletion, treatment of unique toxicities with anti-interleukins and steroids, on-target effects of hypogammaglobulinemia and prolonged cytopenia. On these bases, we conducted this observational retrospective multicenter study to evaluate pattern of infections and impact on outcome in a cohort of non-Hodgkin's lymphomas (NHL) patients. Methods: This is an observational retrospective multicenter study, aimed to evaluate infections incidence, type and timing, and the outcome of NHL patients, treated with novel immunotherapies in the first two years from treatment start. All patients diagnosed with NHL in three Italian centers, who started the treatment from Dec 1st, 2019 to Apr 30th, 2025 were consecutively included in the analysis. Results: 110 NHL patients were treated with 131 lines of immunotherapies, including 91 with antiCD19 CAR-T cells (46 Axi-cel, 29 Tisa-cel, 16 Brexu-cel), 30 with antiCD20/antiCD3 bispecific MoAbs (10 glofitamab, 14 epcoritamab and 6 mosunetuzumab), and 10 with AntiCD19 ADC (loncastuximab). Among 110 patients, 13 cases received 2 and 4 patients 3 consecutive lines of immunotherapies, respectively. Median age was 63 years (range 18- 84), with significantly older age in patients receiving bispecific MoAbs (72 years, range 40- 84), if compared with those receiving CAR-T and ADC (p < 0.001). Seventy-one (65%) were male, while NHL histology was: Diffuse Large B-cell (DLBCL) in 67 (61%), High grade B-cell (HGBCL) in 9 (8%), Primary mediastinal (PMBCL) in 5 (5%), Mantle (MCL) in 16 (14%) and Follicular lymphoma (FL) in 13 (12%) cases, respectively. Median number of previous lines of treatment was 2 (range 1- 7), with 1 previous therapy in 13 (10%), 2 in 76 (58%), 3 in 26 (20%), > 3 in 16 (12%) cases, respectively. Response to the last prior line of treatment was refractory in 70 (53%), early relapse (3- 12 months) in 30 (23%), late relapse (>12 months) in 31 (24%) cases. Thirty-two patients had previously received autologous stem cell transplantation, in one case both auto and allogeneic transplantation. Total infective events recorded in the first two years from treatment were 112 (72 (64%) bacterial, 30 (28%) viral, 4 cases of concomitant viral + bacterial, 4 cases of fever with unknown origin (FUO) and 2 fungal infections). COVID19 still represented 16% of whole infections, while the most frequent site was pneumonia, followed by colitis. Infection grade was: 1-2 in 62%, 3-4 in 33%, 5 in 5% of cases. Hospitalization was required in 42% of cases. Median time from starting of immunotherapy to first infection was 15 days (range 1- 420), with 82% of infections occurring in the first 100 days and 71% in the first 30 days. Among 131 lines of immunotherapies administered: 70 (53%) had no infective complications, while 61 (47%) showed at least 1 (range per treatment 1- 6). We observed one infective event in 40 cases (31%), two infective events in 12 cases (9%), three infective events in 3 cases (2%) and more than 3 episodes in 6 (5%) cases. Very Early infections (< 30 days) were more frequently of bacterial origin (69%), while late infections (> 100 days) were more often viral (60%). Only 2 mycoses were recorded: one early (21 days) fungal and bacterial pneumonia, one late onset (more than one year after starting therapy) aspergillosis, both in DLBCL patients treated with bispecific MoAbs. Mantle cell and follicular lymphomas histology were associated to relative higher risk of infections (HR 1.45, 95% CI 1.25- 1.78, p 0.045), along with higher number of previous lines of treatment (p 0.032), while no differences were seen according to IgG level, Hb, plts, GN level, or support with IGIV or G-CSF. Fifty-five deaths occurred, caused by: lymphoma progression in 43 (78%), grade 5 infections in 3 (5%), other causes in 9 (16%) patients. Conclusions: Infections are common complications during novel immunotherapy treatments in NHL: nonetheless, in our real-life cohort most of cases occurred early (< 100 days) and showed manageable mild-moderate severity. Overall, in this setting of relapsed/refractory NHL patients the main cause of death remains lymphoma progression.