Abstract
Late-onset neutropenia, i.e. an absolute neutrophil count of <1.5 × 109/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.
Access this article
We’re sorry, something doesn't seem to be working properly.
Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.
Similar content being viewed by others
References
Marcus R, Hagenbeek A. The therapeutic use of rituximab in non-Hodgkin’s lymphoma. Eur J Haematol 2007;67:5–14.
Flinn IW, et al. Immunotherapy with rituximab during peripheral blood stem cell transplantation for non-Hodgkin’s lymphoma. Biol Blood Marrow Transplant 2000;6:628–32.
Dalle S, Dumontet C. Rituximab: mechanism of action and resistance. Bull Cancer 2007;94:198–202.
Thatayatikom A, White AJ. Rituximab: a promising therapy in systemic lupus erythematosus. Autoimmunity Rev 2006;5:18–24.
Summers KM, Kockler DR. Rituximab treatment of refractory rheumatoid arthritis. The Ann Pharmacother 2005;39:2091–5.
Kimby E. Tolerability and safety of rituximab (MabThera). Cancer Treat Rev 2005;31:456–73.
Chaiwatanatorn K, Lee N, Grigg A, Filshie R, Firkin F. Delayed-onset neutropenia associated with rituximab therapy. Br J Haematol 2003;121:913–8.
Cairoli R, et al. High incidence of neutropenia in patients treated with rituximab after autologous stem cell transplantation. Haematologica 2004;89:361–3.
Lemieux B, et al. Rituximab-related late-onset neutropenia after autologous stem cell transplantation for aggressive non-Hodgkin’s lymphoma. Bone Marrow Transplant 2004;33:921–3.
Dunleavy K, et al. B-cell recovery following rituximab-based therapy is associated with perturbations in stromal derived factor-1 and granulocyte homeostasis. Blood 2005;106:795–802.
Fukuno K, et al. Late-onset neutropenia in patients treated with rituximab for non-Hodgkin’s lymphoma. Int J Hematol 2006;84:242–7.
Cattaneo C, et al. Delayed-onset peripheral blood cytopenia after rituximab: frequency and risk factor assessment in a consecutive series of 77 treatments. Leuk Lymphoma 2006;47:1013–7.
Nitta E, et al. A high incidence of late-onset neutropenia following rituximab-containing chemotherapy as a primary treatment of CD20-positive B-cell lymphoma: a single-institution study. Ann Oncol 2007;18:364–9.
Voog E, Morschhauser F, Solal-Celigny P. Neutropenia in patients treated with rituximab. N Engl J Med 2003;348:2691–4.
Welte K, Zeidler C, Dale DC. Severe congenital neutropenia. Semin Hematol 2006;43:189–95.
Carlsson G, et al. Kostmann syndrome: severe congenital neutropenia associated with defective expression of Bcl-2, constitutive mitochondrial release of cytochrome c, and excessive apoptosis of myeloid progenitor cells. Blood 2004;103:3355–61.
Cario G, et al. Heterogeneous expression pattern of pro- and anti-apoptotic factors in myeloid progenitor cells of patients with severe congenital neutropenia treated with granulocyte colony-stimulating factor. Br J Haematol 2005;129:275–8.
Palmblad JE, von dem Borne AE. Idiopathic, immune, infectious, and idiosyncratic neutropenias. Semin Hematol 2002;39:113–20.
Klein C, et al. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat Genet 2007;39:86–92.
Benyunes MMP, Saunders A. Neutropenia in patients treated with rituximab (response letter). N Engl J Med 2002;348:2694.
Papadaki T, et al. Evidence for T-large granular lymphocyte-mediated neutropenia in rituximab-treated lymphoma patients: report of two cases. Leuk Res 2002;26:597–600.
Terrier B, et al. Late-onset neutropenia following rituximab results from a hematopoietic lineage competition due to an excessive BAFF-induced B-cell recovery. Haematologica 2007;92:ECR10.
Carlsson G, et al. Kostmann syndrome or infantile genetic agranulocytosis, part one: celebrating 50 years of clinical and basic research on severe congenital neutropenia. Acta Paediatr 2006;95:1526–32.
Carlsson G, et al. Kostmann syndrome or infantile genetic agranulocytosis, part two: understanding the underlying genetic defects in severe congenital neutropenia. Acta Paediatr 2007;96:813–19.
Spielberg SP. Pharmacogenetics and blood dyscrasias. Eur J Haematol 1996;60:93–7.
Amacher DE. Reactive intermediates and the pathogenesis of adverse drug reactions: the toxicology perspective. Curr Drug Metab 2006;7:219–29.
Nagasawa T, et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 1996;382:635–8.
Lum JJ, Bren G, McClure R, Badley AD. Elimination of senescent neutrophils by TNF-related apoptosis-inducing ligand. J Immunol 2005;175:1232–8.
Acknowledgements
The study was supported by grants from the Swedish Society for Medical Research, the Swedish Cancer Foundation, Roche Pharmaceutical, and the Stockholm County Council (ALF project).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Tesfa, D., Gelius, T., Sander, B. et al. Late-onset neutropenia associated with rituximab therapy: evidence for a maturation arrest at the (pro)myelocyte stage of granulopoiesis. Med Oncol 25, 374–379 (2008). https://doi.org/10.1007/s12032-008-9049-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12032-008-9049-z