title: Late-onset neutropenia associated with rituximab therapy: evidence for a maturation arrest at the (pro)myelocyte stage of granulopoiesis.
abstract: Late-onset neutropenia, i.e. an absolute neutrophil count of <1.5 x 10(9)/l, may follow 4 weeks or more after therapy with rituximab for lymphoma. However, incidence, predisposing factors, and pathogenic mechanisms are still poorly defined. In a retrospective study of 113 consecutive lymphoma patients treated with rituximab, with or without chemotherapy, we found eight patients (7%) with late-onset neutropenia (LON). Median time to onset was 88 days (range, 1-9 months) after last rituximab dose. Median duration of LON was 54 days (range, 1-17 weeks). Four of the eight patients underwent stem cell transplantation. Three patients developed febrile neutropenia and two required treatment with granulocyte colony-stimulating factor. In four subsequently identified patients with severe LON, a maturation arrest at the (pro)myelocyte stage was observed in the bone marrow, similar to that found in severe congenital neutropenia or Kostmann disease. However, none carried mutations in HAX1, thus ruling out such mutations in the development of the maturation arrest in these patients. Nevertheless, our data suggest that rituximab-related LON and congenital neutropenia might share similar neutropenia-causing mechanisms resulting in maturation arrest.
authors.affiliation: Department of Medicine and Hematology Center, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, 14186, Sweden. daniel.tesfa@karolinska.se
authors.forename: Daniel
authors.initials: D
authors.lastname: Tesfa
authors.forename: Tobias
authors.initials: T
authors.lastname: Gelius
authors.forename: Birgitta
authors.initials: B
authors.lastname: Sander
authors.forename: Eva
authors.initials: E
authors.lastname: Kimby
authors.forename: Bengt
authors.initials: B
authors.lastname: Fadeel
authors.forename: Jan
authors.initials: J
authors.lastname: Palmblad
authors.forename: Hans
authors.initials: H
authors.lastname: Hägglund
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002454:Cell Differentiation / Q000187:drug effects; D004252:DNA Mutational Analysis; D005260:Female; D042381:Granulocyte Precursor Cells / Q000187:drug effects*; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced* / Q000235:genetics; D009504:Neutrophils / Q000187:drug effects*; D011506:Proteins / Q000235:genetics; D000069283:Rituximab; D013995:Time
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; C104759:HAX1 protein, human; D011506:Proteins; D000069283:Rituximab