Late-Onset Neutropenia in Patients Treated with Rituximab for Non-Hodgkin's Lymphoma

Fukuno, Kenji; Tsurumi, Hisashi; Ando, Nobuhiro; Kanemura, Nobuhiro; Goto, Hideko; Tanabashi, Shinobu; Okamoto, Kiyonao; Moriwaki, Hisataka

doi:10.1532/ijh97.05105

Cited by 40 publications

(25 citation statements)

References 21 publications

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“…In further support of this notion, Voog et al [14] identified eight patients with LON and detected antineutrophil antibodies in two of these patients. However, the absence of anti-neutrophil antibodies in other studies [8,10,11,21,22] suggests that additional factors are also involved in LON.…”

Section: Discussionmentioning

confidence: 86%

“…The erythropoiesis is left-shifted and shows megaloblastoid features. There is impaired maturation in the granulocytopoeisis with abundant promyelocytes (arrows), although some rods and mature neutrophils are seen duration from 1 week to 1 month in the literature [7][8][9][10][11][12][13][14]. This is much higher than post-marketing reporting rates of LON 0.02% [20].…”

Section: Discussionmentioning

confidence: 99%

“…Although rituximab is well tolerated and has a favorable hematological toxicity profile [6], late-onset neutropenia (LON) occurring at least 4 weeks after rituximab therapy has recently been reported and the incidence has been calculated to be 5.6-27.3% [7][8][9][10][11][12][13][14]. However, predisposing features and pathogenic mechanisms are still poorly defined.…”

Section: Introductionmentioning

confidence: 99%

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Late-onset neutropenia associated with rituximab therapy: evidence for a maturation arrest at the (pro)myelocyte stage of granulopoiesis

et al. 2008

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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.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Late-onset neutropenia associated with rituximab therapy: evidence for a maturation arrest at the (pro)myelocyte stage of granulopoiesis

et al. 2008

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“…One theory is that neutropenia arises from impaired myelopoiesis due to altered growth factors and/or competition between cell lineages in the marrow niche during homeostatic restoration of B cells (Dunleavy et al 2005;Terrier et al 2007). Alternatively, Fas-mediated apoptosis of neutrophils by increased Fas associated with expansion of reactive granular T lymphocytes has been demonstrated by one group (Stamatopoulos et al 2008) but has not been confirmed by other investigators (Fukuno et al 2006;Terrier et al 2007;Tesfa et al 2008).…”

Section: Rituximabmentioning

confidence: 92%

Unexpected Hematologic Effects of Biotherapeutics in Nonclinical Species and in Humans

Everds

Tarrant²

2013

Toxicol Pathol

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Biotherapeutics are expanding the arsenal of therapeutics available for treating and preventing disease. Although initially thought to have limited side effects due to the specificity of their binding, these drugs have now been shown to have potential for adverse drug reactions including effects on peripheral blood cell counts or function. Hematotoxicity caused by a biotherapeutic can be directly related to the activity of the biotherapeutic or can be indirect and due to autoimmunity, biological cascades, antidrug antibodies, or other immune system responses. Biotherapeutics can cause hematotoxicity primarily as a result of cellular activation, cytotoxicity, drug-dependent and independent immune responses, and sequelae from initiating cytokine and complement cascades. The underlying pathogenesis of biotherapeutic-induced hematotoxicity often is poorly understood. Nonclinical studies have generally predicted clinical hematotoxicity for recombinant cytokines and growth factors. However, most hematologic liabilities of biotherapeutics are not based on drug class but are species specific, immune-mediated, and of low incidence. Despite the potential for unexpected hematologic toxicity, the risk-benefit profile of most biotherapeutics is favorable; hematologic effects are readily monitorable and managed by dose modification, drug withdrawal, and/or therapeutic intervention. This article reviews examples of biotherapeutics that have unexpected hematotoxicity in nonclinical or clinical studies.

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“…One mysterious toxicity of RTX is late-onset neutropenia (LON). LON, defined as an absolute neutrophil count (ANC) <1.5 × 10 9 /L occurring greater than 4 weeks after the last dose of RTX without another identifiable cause, has been reported after administration for hematologic malignancies [9][10][11] and recently in case series when given for rheumatologic disorders [12][13][14][15][16]. Patients usually present without symptoms and recover spontaneously, although patients may initially present with infections [17] of varying ranges of severity.…”

Section: Introductionmentioning

confidence: 99%

Rituximab associated late-onset neutropenia—a rheumatology case series and review of the literature

2016

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Recently in the rheumatology literature, Rituximab (RTX) has been associated with late-onset neutropenia (LON), defined as an absolute neutrophil count (ANC) <1.5 × 10(9)/L at least 4 weeks after the last infusion. We determined the incidence of LON in patients with rheumatic disease at a single tertiary medical center, ascertained patient characteristics including results of bone marrow biopsies performed on four neutropenic patients, and performed a literature review. The incidence at our institution was 6.5 %, similar to that reported in the literature. Bone marrow biopsies from four neutropenic patients had the predominant cell line as lymphocytes, comprising an average of 41 % (range 24-50 %) of the cellular aspirate suggesting that there is a selective reduction in granulopoiesis and maturation arrest at the promyelocyte stage. Sixty percent of patients presented without serious infections, and all survived without adverse sequelae. Treatment with granulocyte colony-stimulating factor shortened time to recover of ANC but did not change overall outcomes. Among 25 patients re-challenged with RTX after resolution of LON, only two developed recurrence of LON. Among patients at our institution and identified from a review of the literature, LON is not usually associated with serious infections that lead to significant adverse outcomes, G-CSF therapy does not appear to be necessary as it does not change outcomes, and RTX re-treatment after recovery from LON appears safe.

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Late-Onset Neutropenia in Patients Treated with Rituximab for Non-Hodgkin's Lymphoma

Cited by 40 publications

References 21 publications

Late-onset neutropenia associated with rituximab therapy: evidence for a maturation arrest at the (pro)myelocyte stage of granulopoiesis

Late-onset neutropenia associated with rituximab therapy: evidence for a maturation arrest at the (pro)myelocyte stage of granulopoiesis

Unexpected Hematologic Effects of Biotherapeutics in Nonclinical Species and in Humans

Rituximab associated late-onset neutropenia—a rheumatology case series and review of the literature

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