HATTORIY,KAKIMOTOT,OKAMOTOS,et al.Thalido-mide-induced severe neutropenia during treatment of multiple myeloma[J].,2004,79(3):283-288.
<a name="Abs1"></a>Recent reports have shown that thalidomide has antiangiogenic activity and is effective for the treatment of refractory multiple myeloma. Unlike other antineoplastic drugs, thalidomide is reported to rarely cause severe hematologic toxicity. In Keio University Hospital, 44 patients with refractory multiple myeloma, including 18 who had relapsed after hematopoietic stem cell transplantation, were treated with this drug as a single agent. Severe grade 3 or 4 neutropenia during thalidomide treatment was observed in 10 patients.This phenomenon was not noted in previous reports. Neutropenia usually occurred in the first or second week of treatment. Concomitant progression of thrombocytopenia occurred in 5 cases, and bone marrow hypoplasia without a significant increase in myeloma cell numbers was also observed in 5 cases. Neutropenia was not correlated with antitumor response or the plasma concentration of thalidomide but was more frequently observed in patients with a low neutrophil and platelet count, anemia, or a high plasma cell percentage in the bone marrow before thalidomide treatment.Thus, this drug should be used carefully for patients with pretreatment cytopenia or a high tumor burden in the bone marrow.
MAZZOTTAS,GOZZETTIA,PIRROTTA MT,et al.Low-dose thalidomide-induced agranulocytosis in a multiple myeloma patient treated at diagnosis[J].,2005,46(12):1837-1838.
Thalidomide represents a recent and innovative therapeutic approach in multiple myeloma. Main toxicity usually consists in somnolence, constipation, peripheral neuropathy and deep vein thrombosis, but, unlike alkylating agents, thalidomide is reported to rarely induce severe hematologic toxicity. The majority of patients developing neutropenia are heavily pretreated with three or more lines of chemotherapy. Here, we report, for the first time, clinical and laboratory data of a 66-year-old female patient with multiple myeloma at diagnosis who, after 4 weeks of thalidomide treatment, developed a grade 4 WHO neutropenia with septicemia. A brief review of the literature and suggestions for possible predictive factors of this toxicity are made.
KIEROND,FRANCESH,HYUN HK,et al.B-cell reco-very following rituximab-based therapy is associated with perturbations in stromal derived factor-1 and granulocyte homeostasis[J].,2005,106(3):795-802.
The occurrence of delayed neutropenia following rituximab is poorly defined and of unknown cause. We hypothesized it may be related to perturbations of stromal derived factor-1 (SDF-1) and granulocyte homeostasis. Late-onset neutropenia (LON) was investigated in 130 patients with untreated aggressive B-cell lymphoma receiving DA-EPOCH (dose-adjusted etoposide, prednisone, Oncovin [vincristine], cyclophosphamide, and hydroxydaunorubicin) chemotherapy with or without rituximab. All patients were in remission and had no known causes for neutropenia. LON occurred in 6 (8%) of 76 patients receiving rituximab and 0 of 54 patients not receiving rituximab (P = .04). The median onset was 175 days (range, 77-204 days) after treatment with a median duration of 14 days (range, 11-16 days). In a subset of 24 patients, a significant correlation was found between rapid B-cell recovery and granulocyte decline over the 6-month recovery period (R = -0.53; P = .04). Rapid B-cell recovery directly correlated with prerecovery SDF-1 levels (R = 0.65; P = .015) and SDF-1 decline (R = -0.67; P = .013) after recovery. Our results suggest that early B-cell lymphopoiesis is important for B-cell recovery following rituximab, and that perturbation of SDF-1 during B-cell recovery retards neutrophil egress from the bone marrow. These findings illustrate the dual role of SDF-1 in human B-cell and granulocyte homeostasis.
BESADAE,KOLDINGSNESW,NOSSENTJ.Characteris-tics of late onset neutropenia in rheumatologic patients treated with rituximab:a case review analysis from a single center[J].,2012,105(6):545-550.
BACKGROUND: Late onset neutropenia (LON) secondary to rituximab has been reported as an adverse event in the treatment of hematological malignancies but reports on autoimmune diseases are scarce. AIM: To review the characteristics of LON in rheumatologic patients from a single center. DESIGN: Retrospective case record study. METHODS: Clinical and laboratory data since the introduction of rituximab in our clinic in 2006 were collected and analyzed retrospectively. LON was defined as an absolute neutrophil count <1.0鈥壝椻10(9)/l occurring 4 weeks after the last rituximab infusion. RESULTS: LON was identified in eight patients (6% of all patients receiving rituximab). All patients had complicated and refractory disease and had been treated with a median of 4.5 different immunosuppressive drugs prior to rituximab. LON appeared after a median interval of 23 weeks with recovery of LON after a median of 6.5 days. Four patients had concomitant infection at the onset of neutropenia, when six patients had both low immunoglobulin M and immunoglobulin G. Six patients were rechallenged with rituximab without recurrence of LON. CONCLUSION: The characteristics of LON after rituximab treatment in patients with autoimmune disease are comparable with experiences from hematological malignancies. LON seems to precede B-cell recovery implying a perturbation of the granulocyte homeostasis. LON with its rapid recovery does not seem to increase the risk for serious infection in contrast to the sustained hypogammaglobulinemia that may follow rituximab. The risk of LON recurrence after rechallenge is low.
NITTAE,IZUTSUK,SATOT,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[J].,2007,18(2):364-369.
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KIMM,LEE JK,HONG YJ,et al.Late-onset neutropenia following rituximab therapy as a treatment of diffuse large B-cell lymphoma:a single institution study[J].,2010,309(6):575-579.
Background: Late-onset neutropenia (LON) following rituximab therapy has been reported in recent years. However, its incidence has not been reported in Korea. The aim of this study is to investigate the incidence of LON after rituximab therapy in Korean patients with diffuse large B-cell lymphoma (DLBCL). Methods: Ninety-eight cases of DLBCL treated with rituximab between 2004 and 2008 were eva...
ROZMANS,SONCM,NOVAKOVIC BJ.Late-onset neutro-penia following primary treatment of diffuse large B-cell lymphoma with rituximab-containing therapy[J].,2012,53(10):1945-1948.
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ARAIY,YAMASHITAK,MIZUGISHIK,et al.Risk factors for late-onset neutropenia after rituximab treatment of B-cell lymphoma[J].,2015,20(4):196-202.
Objectives Late-onset after rituximab (RTX) therapy (R-) has been widely reported, but clinical studies on a large number of cases are limited. In this study, we aimed to investigate the incidence and risk factors of R-. Patients and methods In this study, we retrospectively analyzed data of 213 enrolled patients (male 114; female 99) treated with RTX at a single institution. R-was defined as otherwise unexplained grade III-IV after RTX. The median age of the patients was 62 years, and 129 of them were initially diagnosed at advanced stages (stage III-IV). Results R-occurred in 19 patients within a median of 121 (range, 49-474) days after the last RTX administration. The 1-year cumulative incidence was 9.0%. On univariate analysis, older age (>60 years), advanced stage, and analog or administration were significant or borderline significant risk factors for R-, whereas sex, disease type, bone marrow invasion, combination with cytotoxic chemotherapeutic drugs, intensified therapy (compared with R-), prior autologous transplantation, and repeated RTX administration were not. On multivariate analysis, older age (hazard ratio (HR), 2.95) and advanced stage (HR, 3.56) were significant risk factors. Treatment with was feasible in grade IV R-patients with high risk of . Discussion and conclusion Careful follow-up is therefore necessary after treatment, especially in high-risk patients with advanced disease or of older age.
GRANTC,WILSON WH,DUNLEAVYK.Neutropenia ass-ociated with rituximab therapy[J].,2011,18(1):49-54.
Purpose of review;Several recent studies have reported the occurrence of late-onset neutropenia (LON) following the use of rituximab or rituximab-based therapies. While this phenomenon is typically self-limiting and of no clinical significance, recognizing its existence is important given the expanding use of rituximab in both hematologic and nonhematologic disorders. This review discusses the incidence of LON and explores several hypotheses that have been proposed to explain its occurrence.<br/>Recent findings;While the etiology of LON is uncertain and poorly understood, mechanisms that have been suggested include the production of antineutrophil antibodies following rituximab, the expansion of large granular lymphocyte (LGL) populations that may induce neutrophil apoptosis through Fas and Fas-ligand interactions, and aberrant B-cell reconstitution following rituximab leading to immune dyscrasias and the development of neutropenia. We explored an alternative hypothesis that LON following rituximab is caused by perturbations of granulocyte homeostasis, mediated by a complex interaction between B-cell recovery and the chemokine stromal-derived factor-1 (SDF-1).<br/>Summary;While rituximab has been associated with both early and late neutropenia, LON occurring several weeks to several months after the administration of rituximab is a distinct biologic phenomenon that appears to be related to B-cell recovery. Though it occurs frequently, it is a self-limiting process and is rarely associated with significant clinical sequelae.
KEANEC,NOURSE JP,CROOKSP,et al.Homozygous FCGR3a-158V alleles predispose to late onset neutropenia after CHOP-R for diffuse large B-cell lymphoma[J].,2012,42(10):1113-1119.
Background Recent reports suggest genetic polymorphisms influence susceptibility to rituximab-induced late-onset neutropenia (LON), which in turn may be a predictor of good outcome in B-cell lymphoma. Aims We report the largest study to date assessing FCGR3A-V158F polymorphisms in diffuse large B-cell lymphoma (DLBCL) treated with cyclophosphamide/hydroxydaunorubicin/Oncovin (vincristine)/prednisone/rituximab (CHOP-R). The influence of C1qA-A276G polymorphisms in DLBCL, and the impact of both polymorphisms on susceptibility to LON and outcome were also examined. Methods 115 DLBCL patients treated with CHOP-R were compared with 105 healthy White people controls with regards to FCGR3A-V158F and C1qA-A276G polymorphisms. LON incidence and event-free and overall survival (EFS and OS) were analysed for linkage to either polymorphism. Results The FCGR3A-V158F but not the C1qA-A276G polymorphism influenced the risk of developing LON. 50% of FCGR3A-158V/V patients experienced LON. In contrast, only 7% V/F and 2% F/F experienced LON. The FCGR3A-158V/V genotype was associated with LON compared with V/F (P = 0.028) and F/F genotypes (P = 0.005). Although no patients with either LON or FCGR3A-158V homozygosity relapsed compared with 33% FCGR3A-158F/F and 21% non-LON, this did not translate into improved EFS or OS. Conclusions Polymorphic analysis may be a predictive tool to identify those at high risk of LON. Prospective studies are required to establish definitively if LON or FCGR3A-158V/V genotype influences outcome.
BREUER GS,EHRENFELDM,ROSNERI.Late-onset ne-utropenia following rituximab treatment for rheumatologic conditions[J].,2014,33(9):1337-1340.
Rituximab is a monoclonal antibody directed against the CD20 antigen on the surface of normal and malignant B lymphocytes. Its use in autoimmune conditions is rapidly expanding. Late-onset neutropenia (LON) is a well-recognized side effect of rituximab therapy in lymphoma patients. Only a small number of cases of LON have been reported in patients with autoimmune disorders. The aim of this work is to review cases in Israel and to compare them to published cases in the literature thus adding to the body of knowledge regarding this unusual phenomenon. Members of the Israeli Rheumatology Association were encountered by e-mail, requesting reports of cases of LON after therapy with rituximab. Submitted cases were reviewed, with demographics and clinical data collated and tabled. Current cases were compared to previously published rheumatology cases. Twelve episodes of LON following rituximab therapy were reported. All patients were female with an average age of 50 years (range 22-78). LON occurred at an average of 155 days after therapy (range 71-330). The average leukocyte count was1,456 white cells, with an average of 413 neutrophils (range 0-1,170 neutrophils). Three of the patients underwent bone marrow biopsies which showed white cell line maturation arrest with an increased number of lymphocytes. No blasts were seen. Our results add support to the growing evidence that this adverse event usually follows a benign course and is not an absolute contraindication for repeat treatment if required in the future. However, vigilance is recommended with routine periodic blood counts, especially 5 months following rituximab administration when the risk is expected to be the highest.
LI SC,CHEN YC,EVENS AM,et al.Rituximab-induced late-onset neutropenia in newly diagnosed B-cell lymphoma correlates with Fc receptor FcγRIIIa 158(V/F) polymorphism[J].,2010,85(10):810-812.
Rituximab is a commonly utilized treatment agent for B-cell lymphoma. Late onset neutropenia (LON) has been identified as a complication associated with rituximab, primarily in conjunction with hematopoietic stem cell transplantation (HSCT). Scant data exists regarding rituximab-related LON outside the spectrum of HSCT, including newly-diagnosed lymphoma. We examined a large cohort of newly-diagnosed B-cell lymphoma patients treated with rituximab-based therapy. We identified patients with LON and analyzed the characteristics and outcomes. Furthermore, we utilized multiplex PCR for the detection of the FcgRIIIa 158 V/F polymorphism and correlated this with LON. Eighty consecutive B-cell lymphoma patients were examined. Nine of 80 (11.3%) patients developed LON. The clinical course of LON was generally self-limiting without adverse events. The onset of LON occurred at a mean of 66 days after the last course of treatment, while the mean duration of LON was 97 days. Moreover, the V/V and V/F polymorphisms were significantly associated with the occurrence of LON (P 5 0.046) yielding an odds ratio for the development of LON of1.47 (95% CI 1.21-1.78). We identified an incidence of LON following frontline rituximab-based treatment of 11.3%. The FcgRIIIa polymorphism was highly associated with development of LON.
WOLACHO,BAIREYO,LAHAVM.Late-onset neutrop-enia after rituximab treatment:case series and comprehensive review of the literature[J].,2010,89(5):308-318.
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 FC纬RIIIa 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.
Characteris-tics of late onset neutropenia in rheumatologic patients treated with rituximab:a case review analysis from a single center
2012
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
2007
Late-onset neutropenia following rituximab therapy as a treatment of diffuse large B-cell lymphoma:a single institution study
2010
Late-onset neutro-penia following primary treatment of diffuse large B-cell lymphoma with rituximab-containing therapy
2012
Risk factors for late-onset neutropenia after rituximab treatment of B-cell lymphoma