Correspondence
Neutropenia in Patients Treated with Rituximab
N Engl J Med 2003; 348:2691-2694June 26, 2003
- Article
To the Editor:
Rituximab is effective in B-cell lymphomas either as a single agent or combined with chemotherapy. Its toxic effects are generally mild and transient.1,2 We report eight cases of acute and severe neutropenia that occurred 8 to 23 weeks after the administration of rituximab for non-Hodgkin's lymphoma or chronic lymphocytic leukemia. All patients had a normal polymorphonuclear-cell count before rituximab treatment (Table 1Table 1
Characteristics of the Patients before and after Rituximab Treatment.). None of the known causes of neutropenia were found. Previous treatment with rituximab two to four months before the development of neutropenia was a common factor in these eight patients, which suggests that rituximab treatment was a potential cause of the neutropenia.In all eight patients, the features were suggestive of immune-mediated neutropenia. Tests for anti-neutrophil antibodies were performed in Patients 1 and 2 — before the administration of granulocyte colony-stimulating factor (G-CSF) in Patient 2 and eight days after G-CSF treatment ended in Patient 1. IgG-type antibodies, bound to the surface of neutrophils, were revealed by direct immunofluorescence testing. No antibody was found in the serum of either patient by flow cytometric analysis or granulocyte agglutination testing. Thus, the specificity of these antibodies cannot be established.
A direct toxic effect of rituximab is unlikely, since granulocytes and uncommitted hematopoietic precursor stem cells do not express CD20. Autoimmune neutropenia, mostly of the IgM type, has been reported rarely in non-Hodgkin's lymphoma.3 In these reported cases, neutropenia preceded or was concomitant with non-Hodgkin's lymphoma, whereas non-Hodgkin's lymphoma was in prolonged, complete remission in all our patients.
Rituximab treatment depletes the normal B-lymphocyte population, which recovers within three to nine months. During recovery, the acquisition of a new immune repertoire occurs under nonphysiologic conditions. These conditions may favor the transient production of autoantibodies, some of which may be directed against neutrophils or hematopoietic precursors.
3 ReferencesEric Voog, M.D.
Centre Jean Bernard, 72 000 Le Mans, France
voog.eric@wanadoo. fr Franck Morschhauser, M.D.
Centre Hospitalier Universitaire, 59 000 Lille, FrancePhilippe Solal-Céligny, M.D., Ph.D.
Centre Jean Bernard, 72 000 Le Mans, France1
Czuczman MS ,Grillo-Lopez AJ ,White CA , et al. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 1999;17:268-276
Web of Science | Medline2
Coiffier B ,Lepage E ,Briere J , et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235-242
Full Text | Web of Science | Medline3
Cartron J ,Fior R ,Boue F ,Tertian G ,Gane P ,Cartron JP . Non Hodgkin's lymphoma presenting as neutropenia related to an IgM monoclonal anti-i antibody. Hematol Cell Ther 1996;38:225-230
CrossRef | Medline
Author/Editor Response
We concur with Voog and colleagues that rituximab as monotherapy or in combination with myelosuppressive chemotherapy for treatment of B-cell cancers may be associated with the development of late-onset, reversible neutropenia. Seven of the eight patients they treated had received previous myelosuppressive therapy, including fludarabine in three, and four had undergone stem-cell transplantation before neutropenia developed; only one patient received only rituximab monotherapy for non-Hodgkin's lymphoma. Four patients had bone marrow biopsies, which showed hypocellularity in three and decreased numbers of neutrophils and neutrophil precursors in one. The complex nature of these cases suggests that the etiology of the reversible neutropenia is multifactorial.
We have received and reviewed other rare reports of late-onset neutropenia (>4 weeks after the last dose of rituximab). Most of these reports came from experimental studies of rituximab in the setting of autologous hematopoietic stem-cell transplantation. Rare occurrences of late-onset neutropenia in patients with non-Hodgkin's lymphoma treated with rituximab as monotherapy or in combination with other chemotherapy have also been reported. Our calculated post-marketing reporting rate (not incidence) of late-onset neutropenia is currently less than 0.02 percent, with more than 300,000 patients worldwide exposed to rituximab.
Mark C. Benyunes, M.D.
Genentech, South San Francisco, CA 94080Pratik S. Multani, M.D.
IDEC Pharmaceuticals, San Diego, CA 92121Andrew Saunders, M.D.
F. Hoffmann–La Roche, CH-4070 Basel, Switzerland- Citing Articles (53)
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