Late Onset, Acute Severe Neutropenia in Patients Treated with Rituximab for B-Cell Lymphoproliferation.
Authors: Solal-Celigny Philippe , Morschhauser F. , Tournilhac O. , Foussard C. , Fitoussi O. , Louet A. Lillo-Le , Brice P. , Lamy T. , Tilly H. , Gyan E. , Agape Ph. , Suc E. , Saad A. , Devidas A. , Blanc M. , Le Rol A. , Galanaud P. , Muller J. Y. , Voog E. 
Published: April 2020

Abstract
We report 28 patients (pts) who experienced late onset severe neutropenia (NCI/CTC grade III/IV) after rituximab. Rituximab had been given for the treatment of DLCL(N=15), follicular lymphoma (N=9), mantle cell lymphoma (N=2), CLL (N=2). Rituximab was administered as a front line treatment (N=11), for recurrent disease (N=17), before ASCT (N=1) or after ASCT (N=5). Rituximab was given as a single agent (N=14), with CHOP (N=9) or with other regimen (N=5). Rituximab was given at a dose of 375mg/m2 at weekly intervals over a period of 4 weeks when used as a single agent, or as a single dose of 375mg/m2 with chemotherapy.
Characteriscs of neutropenia are summarized in Table. At the time of the neutropenia, all the pts were in CR or VGPR. In 3 pts, the neutropenia had relapsed. All 3 pts were still in CR, and had not been retreated with rituximab. 3 patients were retreated with rituximab for a recurrence of their NHL after the outbreak of neutropenia and 1 pt experienced a further episode of neutropenia after the reintroduction of rituximab.
Tests for anti PMN antibodies were performed in 6 pts. In 4 pts, antibodies bound to the surface of neutrophils were detected by the direct neutrophil immunofluorescence test. No antibody could be detected in the serum. A direct toxic effect of rituximab can be ruled out as granulocytes and uncommitted hematopoietic precursor stem cells do not express CD 20. We propose the following hypothesis. The rituximab-induced depletion of the normal B-lymphocyte population was followed by the acquisition of a new immune repertoire under non physiological condition which could promote the transient production of autoantibodies. Some of these antibodies might target either neutrophils or hematopoietic precursors. Some of these antibodies might also be directed against other cells since other delayed-onset cytopenia have been reported after the administration of rituximab, pure red aplasia in particular. An other possible mechanism can be proposed. Rituximab administration could lead to the production of antibodies directed against the complex formed when rituximab is bound to the FcγRIIIb receptor on the PMN. This hypothesis does not account for the delay between the administration of rituximab and the onset of the neutropenia.
Characteristics of neutropenic episodes.
Characteristics N *: interval between the last infusion of rituximab and the nadir of neutropenia. **: 1 pt was lost to follow-up for 4.5 months but had a normal blood count subsequently. Median time to neutropenia (range) (weeks)* 15 (4–33) Nadir PMN 10x9/L median (range) 0.135 (0–0.760) Bone marrow aspiration 14 Hypocellular marrow 7 Normocellular marrow with severe reduction in mature neutrophils 6 Normal 1 Fever/sepsis 6/1 Patients treated with G-CSF/duration (range) (days) 12/6 (3–21) Duration of neutropenia (range) (days) Patients treated with G-CSF N=12 4 (2-53) Patients not treated with G-CSF N=16 12 (4–105)** Follow-up from the nadir of neutropenia (range) (month) 6 (0.5–36) NHL/CLL status at follow-up CR or CRu 22 VGPR 1 Progression 5 Status of PMN count at follow-up Normal 26 Neutropenia 2