Incidence of Neutropenia and Hypogammaglobulinemia and Correlation with the Infections Rate in Indolent Non-Hodgkin Lymphoma (NHL) Receiving Rituximab Maintenance.
Authors: Marin-Niebla Ana , Rios-Herranz Eduardo , Falantes Jose F. , Martino Mariluz , Espigado Ildefonso , Urbano-Ispizua Alvaro 
Published: October 2019

Abstract
Rituximab (R) maintenance has demonstrated a significant increase in both median PFS and OS in follicular lymphoma. However, such an effective strategy carries a concern about the long-term effects of rituximab on the immune system and the risk of infectious complications. In fact, neutropenia, and less frequently, hypogammaglobulinemia, occur with rituximab treatment, but this is still a scarcely explored issue. We analyzed our experience with R-maintenance in patients with indolent non-Hodgkin lymphoma (NHL) to evaluate the incidence of neutropenia and hypogammaglobulinemia, the type and incidence of infections and the factors associated with infection.
Patients and Methods: Patients (pts) with indolent NHL in CR or PR after induction or salvage treatment (either with or without R), receiving R maintenance (R= 375 mg/m2; 2 schedules: 4 weekly doses every 6 months (4/6) in high-risk patients and 1 dose every 3 months (1/3) in low-risk. Total duration= 2 years) from June 2003 to June 2007. We examined the following variables for correlation with the incidence of infection: number and type of previous treatments (with/without R, with/without fludarabine), previous splenectomy and/or radiotherapy, response to previous treatments before R-maintenance, and R-maintenance schedule used.
Results: Forty-seven pts (age (Mean[R]): 57[34–76]; gender F26:M21) with indolent NHL [FL 27 (57.4%), MCL 2 (4.3%), MZL 7 (14.9%), LPL/Waldestrom 5 (10.6%), MALT 6 (12.8%)] were retrospectively evaluated. At diagnosis: ECOG 0–1: 29 (61.7%), 2–3: 6 (12.8%); stage III–IV 43 (91.5%); B-symptoms 23 (48.9%); FLIPI 0–2: 56.4%, 3–5: 43.6%. Marrow involvement 34 (72.3%), splenomegaly 14 (29.8%) and hepatomegaly 5 (10.5%). LDH (Mean[R]): 346 [115–854], b2–microglobulin: 3.17 [1.3–7.9], Neutrophil count (x 109/L): 8.89 [0.14–31.6], IgG: 1044.8 [214–2080], IgA: 186.8 [35–570], IgM: 532.3 [17–6670]. Number of treatments before R-maintenance (M[R]): 1 [1–3]. Thirty-eight (80.9%) pts had received R-containing therapy and 43 (91.5%) fludarabine-containing regimens. Forty (85.1%) had achieved CR and 7 (15.2%) PR. Follow-up from diagnosis (Mean[R]): 35.4 months [8–116]; follow-up from start of R-maintenance: 16.8 months [1–53]. After R-maintenance, 9 pts (19.1%) presented neutropenia grade 3–4. The presence of splenomegaly (p=0.03) and hepatomegaly (p=0.03) at diagnosis significantly correlated with neutropenia 3–4. No relationship was found with the maintenance schedule used (4/6 vs 1/3), previous R or fludarabine, or with the number of previous treatments. Incidence of hypogammaglobulinemia was (*data available from 33 pts): IgG<500: 8 (24.2%), IgA<60: 10 (30.3%), IgM<50: 13 (39.4%). Infections recorded in the 47 pts: recurring gastroenteritis 1 patient, HZV 2 pts, ORL infections 1 patient, and 2 cases of severe pulmonary infections requiring hospitalization. A significant correlation was found between infection and IgG<500 (p=0.04) and with neutropenia 3–4 (p=0.03).
Conclusions: Rituximab maintenance is a safe strategy with a low incidence of infectious complications. Although severe neutropenia and hypogammaglobulinemia are not rare side effects of prolongued R treatment, only 2 patients presented severe infectious complications in our cohort. The only factors significantly influencing the incidence of infection were neutropenia 3–4 and low levels of IgG. No differences were observed between both schedules of R-maintenance regarding the infections rate.