Late-onset neutropenia after rituximab treatment: case series and comprehensive review of the literature.
Rituximab is a chimeric monoclonal antibody against CD20 that is used mainly for the treatment of CD20-positive lymphoma. Recently, its use has been expanded to include treatment of other nonmalignant diseases such as rheumatologic diseases and autoimmune cytopenia. Correlating with the increased use of rituximab has been an increased number of reports of its late adverse effects. One of these is late-onset neutropenia (LON). Most investigators define LON as grade III-IV neutropenia occurring 3-4 weeks after the last treatment with rituximab, in the absence of an alternative explanation for the neutropenia.We report 6 cases of LON identified in our institution. Four patients were treated for diffuse large B-cell lymphoma, and 2 patients for follicular lymphoma. Median patient age was 68 years (range, 33-83 yr); LON appeared after a median interval of 77 days (range, 42-153 d) and lasted for a median of 5 days (range, 1-45 d). Five of the 6 patients presented with infectious complications, and 4 patients experienced recurrent episodes of neutropenia. One patient presented with LON and concomitant subacute pulmonary disease that was attributed to rituximab therapy.In addition to our own case series we present a systematic review of the literature, which we performed to compile data to describe better the syndrome of LON. Systematic studies, case series, and case reports were extracted. Most studies dealing with LON are retrospective by design and are limited by the heterogeneous populations included in the analysis. The incidence of LON is generally reported to be in the range of 3%-27%. Data regarding populations at risk are not consistent, and in some instances are conflicting.Patients considered at increased risk of LON include patients after autologous stem cell transplantation, patients treated for acquired immunodeficiency syndrome (AIDS)-related lymphoma, and patients treated with purine analogues. Patients who received previous cytotoxic treatment as well as those treated with more intensive chemotherapy or with chemotherapy in combination with radiotherapy are also considered to be at risk of LON. In addition, advanced stages of disease and having received multiple doses of rituximab are risk factors for LON.The mechanism of LON is poorly understood. Direct toxicity is very unlikely. Some speculate that there may be an infectious etiology involved, as well as an antibody-mediated process, but these ideas have not been substantiated. The concept of a lymphocyte subpopulation imbalance leading to LON has been presented based on the demonstration of T-LGL in peripheral blood and bone marrow of patients with LON. Perturbations in stromal-derived factor-1 and in the BAFF cytokine have also been discussed as potential players in the pathogenesis of LON. A recent study correlated specific polymorphism in the immunoglobulin G Fc receptor FCγRIIIa 158 V/F with increased rates of LON.The clinical significance of LON is important because it may affect treatment strategies. Of note, infectious complications are not very frequent and not very severe. Pooling data from the major retrospective studies reveals an infection rate of 16.9%. Most infections were mild and resolved promptly. One death occurred from infection during neutropenia. Repeated episodes of LON are not uncommon, but it is so far impossible to identify those patients at risk of these relapsing episodes of LON. Re-treatment with rituximab after LON may result in recurrent episodes, but the implications and risks are uncertain at the present time. The role of growth factors once LON appears is ill defined, and the decision to use them should be made on a case-by-case basis.
Wolach
Ofir
O
From Internal Medicine A (OW, ML), and Institute of Hematology (OB, ML), Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, Petah Tikva; and Sackler School of Medicine (OW, OB, ML), Tel Aviv University, Tel Aviv, Israel.
Bairey
Osnat
O
Lahav
Meir
M
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000009:adverse effects*; D005260:Female; D006801:Humans; D008171:Lung Diseases / Q000139:chemically induced / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000453:epidemiology; D009503:Neutropenia / Q000139:chemically induced* / Q000453:epidemiology; D012307:Risk Factors; D000069283:Rituximab; D013997:Time Factors
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab
Azoulay E, Attalah H, Harf A, Schlemmer B, Delclaux C. Granulocyte colony-stimulating factor or neutrophil-induced pulmonary toxicity: myth or reality? Systematic review of clinical case reports and experimental data. Chest. 2001;120:1695-1701.
Berentsen S. Rituximab for the treatment of autoimmune cytopenias. Haematologica. 2007;92:1589-1596.
Cairoli R, Grillo G, Tedeschi A, D'Avanzo G, Marenco P, Morra E. High incidence of neutropenia in patients treated with rituximab after autologous stem cell transplantation. Haematologica. 2004;89:361-363.
Cattaneo C, Spedini P, Casari S, Re A, Tucci A, Borlenghi E, Ungari M, Ruggeri G, Rossi G. Delayed-onset peripheral blood cytopenia after rituximab: frequency and risk factor assessment in a consecutive series of 77 treatments. Leuk Lymphoma. 2006;47:1013-1017.
Chaiwatanatorn K, Lee N, Grigg A, Filshie R, Firkin F. Delayed-onset neutropenia associated with rituximab therapy. Br J Haematol. 2003;121:913-918.
Christopeit M, Haak U, Behre G. Late-onset neutropenia following viral bone marrow depression after rituximab therapy. Ann Hematol. 2008;87:761-762.
Coakley G, Iqbal M, Brooks D, Panayi GS, Lanchbury JS. CD8+, CD57+ T cells from healthy elderly subjects suppress neutrophil development in vitro: implications for the neutropenia of Felty's and large granular lymphocyte syndromes. Arthritis Rheum. 2000;43:834-843.
Coiffier B. Rituximab therapy in malignant lymphoma. Oncogene. 2007;26:3603-3613.
Dale DC. Colony-stimulating factors for the management of neutropenia in cancer patients. Drugs. 2002;62(Suppl 1):1-15.
Davis TA, Grillo-Lopez AJ, White CA, McLaughlin P, Czuczman MS, Link BK, Maloney DG, Weaver RL, Rosenberg J, Levy R. Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacy of re-treatment. J Clin Oncol. 2000;18:3135-3143.
Dunleavy K, Hakim F, Kim HK, Janik JE, Grant N, Nakayama T, White T, Wright G, Kwak L, Gress R, Tosato G, Wilson WH. B-cell recovery following rituximab-based therapy is associated with perturbations in stromal derived factor-1 and granulocyte homeostasis. Blood. 2005;106:795-802.
Flinn IW, O'Donnell PV, Goodrich A, Vogelsang G, Abrams R, Noga S, Marcellus D, Borowitz M, Jones R, Ambinder RF. Immunotherapy with rituximab during peripheral blood stem cell transplantation for non-Hodgkin's lymphoma. Biol Blood Marrow Transplant. 2000;6:628-632.
Fukuno K, Tsurumi H, Ando N, Kanemura N, Goto H, Tanabashi S, Okamoto K, Moriwaki H. Late-onset neutropenia in patients treated with rituximab for non-Hodgkin's lymphoma. Int J Hematol. 2006;84:242-247.
Goh MS, McCormack C, Dinh HV, Welsh B, Foley P, Prince HM. Rituximab in the adjuvant treatment of pemphigus vulgaris: a prospective open-label pilot study in five patients. Br J Dermatol. 2007;156:990-996.
Hirayama Y, Kohda K, Konuma Y, Hirata Y, Kuroda H, Fujimi Y, Shirao S, Kobune M, Takimoto R, Matsunaga T, Kato J. Late onset neutropenia and immunoglobulin suppression of the patients with malignant lymphoma following autologous stem cell transplantation with rituximab. Intern Med. 2009;48:57-60.
Horwitz SM, Negrin RS, Blume KG, Breslin S, Stuart MJ, Stockerl-Goldstein KE, Johnston LJ, Wong RM, Shizuru JA, Horning SJ. Rituximab as adjuvant to high-dose therapy and autologous hematopoietic cell transplantation for aggressive non-Hodgkin lymphoma. Blood. 2004;103:777-783.
Jones RB, Ferraro AJ, Chaudhry AN, Brogan P, Salama AD, Smith KG, Savage CO, Jayne DR. A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2009;60:2156-2168.
Kimby E. Tolerability and safety of rituximab (MabThera). Cancer Treat Rev. 2005;31:456-473.
Klepfish A, Rachmilevitch E, Schattner A. Parvovirus B19 reactivation presenting as neutropenia after rituximab treatment. Eur J Intern Med. 2006;17:505-507.
Lai GG, Lim ST, Tao M, Chan A, Li H, Quek R. Late-onset neutropenia following RCHOP chemotherapy in diffuse large B-cell lymphoma. Am J Hematol. 2009;84:414-417.
Lemieux B, Tartas S, Traulle C, Espinouse D, Thieblemont C, Bouafia F, Alhusein Q, Antal D, Salles G, Coiffier B. Rituximab-related late-onset neutropenia after autologous stem cell transplantation for aggressive non-Hodgkin's lymphoma. Bone Marrow Transplant. 2004;33:921-923.
Limper AH. Chemotherapy-induced lung disease. Clin Chest Med. 2004;25:53-64.
Liote H. Organizing pneumonia associated with rituximab: challenges raised by establishing causality. Joint Bone Spine. 2008;75:260-262.
Liu JH, Wei S, Lamy T, Epling-Burnette PK, Starkebaum G, Djeu JY, Loughran TP. Chronic neutropenia mediated by fas ligand. Blood. 2000;95:3219-3222.
Malik SW, Myers JL, DeRemee RA, Specks U. Lung toxicity associated with cyclophosphamide use. Two distinct patterns. Am J Respir Crit Care Med. 1996;154:1851-1856.
Maloney DG, Grillo-Lopez AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, Janakiraman N, Foon KA, Liles TM, Dallaire BK, Wey K, Royston I, Davis T, Levy R. IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood. 1997;90:2188-2195.
McLaughlin P. Late-onset neutropenia following rituximab. Leuk Lymphoma. 2006;47:965-966.
McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998;16:2825-2833.
Nitta E, Izutsu K, Sato T, Ota Y, Takeuchi K, Kamijo A, Takahashi K, Oshima K, Kanda Y, Chiba S, Motokura T, Kurokawa M. 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;18:364-369.
Papadaki T, Stamatopoulos K, Anagnostopoulos A, Fassas A. Rituximab-associated immune myelopathy. Blood. 2003;102:1557-1558.
Papadaki T, Stamatopoulos K, Stavroyianni N, Paterakis G, Phisphis M, Stefanoudaki-Sofianatou K. Evidence for T-large granular lymphocyte-mediated neutropenia in rituximab-treated lymphoma patients: report of two cases. Leuk Res. 2002;26:597-600.
Ram R, Ben-Bassat I, Shpilberg O, Polliack A, Raanani P. The late adverse events of rituximab therapy-rare but there! Leuk Lymphoma. 2009;50:1083-1095.
Rao A, Kelly M, Musselman M, Ramadas J, Wilson D, Grossman W, Shenoy S. Safety, efficacy, and immune reconstitution after rituximab therapy in pediatric patients with chronic or refractory hematologic autoimmune cytopenias. Pediatr Blood Cancer. 2008;50:822-825.
Rios-Fernandez R, Gutierrez-Salmeron MT, Callejas-Rubio JL, Fernandez-Pugnaire M, Ortego-Centeno N. Late-onset neutropenia following rituximab treatment in patients with autoimmune diseases. Br J Dermatol. 2007;157:1271-1273.
Rose AL, Forsythe AM, Maloney DG. Agranulocytosis unresponsive to growth factors following rituximab in vivo purging. Blood. 2003;101:4225-4226.
Saikia TK, Menon H, Advani SH. Prolonged neutropenia following anti CD20 therapy in a patient with relapsed follicular non-Hodgkin's lymphoma and corrected with IVIG. Ann Oncol. 2001;12:1493-1494.
Shimoni A, Hardan I, Avigdor A, Yeshurun M, Raanani P, Ben-Bassat I, Nagler A. Rituximab reduces relapse risk after allogeneic and autologous stem cell transplantation in patients with high-risk aggressive non-Hodgkin's lymphoma. Br J Haematol. 2003;122:457-464.
Shortt J, Spencer A. Adjuvant rituximab causes prolonged hypogammaglobulinaemia following autologous stem cell transplant for non-Hodgkin's lymphoma. Bone Marrow Transplant. 2006;38:433-436.
Stamatopoulos K, Papadaki T, Pontikoglou C, Athanasiadou I, Stavroyianni N, Bux J, Batsis I, Pyrovolaki K, Paterakis G, Anagnostou D, Anagnostopoulos A, Papadaki HA. Lymphocyte subpopulation imbalances, bone marrow hematopoiesis and histopathology in rituximab-treated lymphoma patients with late-onset neutropenia. Leukemia. 2008;22:1446-1449.
Summers KM, Kockler DR. Rituximab treatment of refractory rheumatoid arthritis. Ann Pharmacother. 2005;39:2091-2095.
Terrier B, Ittah M, Tourneur L, Louache F, Soumelis V, Lavie F, Casadevall N, Candon S, Hummel A, Mariette X, Buzyn A. Late-onset neutropenia following rituximab results from a hematopoietic lineage competition due to an excessive BAFF-induced B-cell recovery. Haematologica. 2007;92:e20-e23.
Tesfa D, Gelius T, Sander B, Kimby E, Fadeel B, Palmblad J, Hagglund H. Late-onset neutropenia associated with rituximab therapy: evidence for a maturation arrest at the (pro)myelocyte stage of granulopoiesis. Med Oncol. 2008;25:374-379.
Thatayatikom A, White AJ. Rituximab: a promising therapy in systemic lupus erythematosus. Autoimmun Rev. 2006;5:18-24.
Tsai D, Moore H, Hardy C, Porter D, Loh E, Vaughn D, Luger S, Schuster S, Stadtmauer E. Rituximab (anti-CD20 monoclonal antibody) therapy for progressive intermediate-grade non-Hodgkin's lymphoma after high-dose therapy and autologous peripheral stem cell transplantation. Bone Marrow Transplant. 1999;24:521-526.
van Oers MH, Klasa R, Marcus RE, Wolf M, Kimby E, Gascoyne RD, Jack A, Van't Veer M, Vranovsky A, Holte H, van Glabbeke M, Teodorovic I, Rozewicz C, Hagenbeek A. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood. 2006;108:3295-3301.
Voog E, Morschhauser F, Solal-Celigny P. Neutropenia in patients treated with rituximab. N Engl J Med. 2003;348:2691-2694.
Wagner SA, Mehta AC, Laber DA. Rituximab-induced interstitial lung disease. Am J Hematol. 2007;82:916-919.
Weng WK, Negrin RS, Lavori P, Horning SJ. Immunoglobulin G Fc receptor FcgammaRIIIa 158 V/F polymorphism correlates with rituximab-induced neutropenia after autologous transplantation in patients with non-Hodgkin's lymphoma. J Clin Oncol. 2010;28:279-284.