The prevalence of agranulocytosis and related death in clozapine-treated patients: a comprehensive meta-analysis of observational studies.

BACKGROUND: Clozapine treatment increases the risk of agranulocytosis, but findings on the epidemiology of agranulocytosis have been inconsistent. This meta-analysis examined the prevalence of agranulocytosis and related death in clozapine-treated patients. METHODS: A literature search in the international (PubMed, PsycINFO, and EMBASE) and Chinese (WanFang, Chinese National Knowledge Infrastructure, and Sinomed) databases was conducted. Prevalence estimates of agranulocytosis and related death in clozapine-treated patients were synthesized with the Comprehensive Meta-Analysis program using the random-effects model. RESULTS: Thirty-six studies with 260 948 clozapine-treated patients published between 1984 and 2018 were included in the meta-analysis. The overall prevalence of agranulocytosis and death caused by agranulocytosis were 0.4% (95% CI 0.3-0.6%) and 0.05% (95% CI 0.03-0.09%), respectively. The prevalence of agranulocytosis was moderated by sample size, study quality, year of publication, and that of data collection. CONCLUSIONS: The prevalence of clozapine-associated agranulocytosis is low. Agranulocytosis-related death appears rare.

PROGNOSIS OF THE COURSE OF CHORNOBYL-ORIGINATED ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDREN IN UKRAINE DEPENDING ON THE REASON OF STANDARD CHEMOTHERAPY INTERRUPTION. / PROGNOZ PEREBIGU GOSTRYKh LIMFOBLASTNYKh LEY̆KEMIY̆ ChORNOBYL'S'KOGO POKhODZhENNIa U DITEY̆ UKRAÏNY ZALEZhNO VID PRYChYN PERERV PRY PROVEDENNI STANDARTNOÏ KhIMIOTERAPIÏ.

OBJECTIVE: Estimation of the bone marrow haemopoietic status depending on the reasons and duration of breaks in a standard chemotherapy (BFM-ALL protocol) to predict the course of acute lymphoblastic leukemia (ALL) in chil- dren exposed to low doses of ionizing radiation after the Chornobyl accident. MATERIALS AND METHODS: The ALL patients (n = 34) were examined within 5 stages of a program chemotherapy. The clinical symptoms, hemogram and myelogram data were analyzed. The radiation dose on bone marrow, initial leuko- cyte count, variants and prognosis of ALL course were accounted. Days of the stopped chemotherapy, type and fre- quency of complications (septic processes, febrile neutropenia, toxic hepatitis, granulocytopenia degree), and the prognosis of disease course (child living status, i.e. alive or died) were estimated. RESULTS: There were abnormal differentiation processes and high percentage of lymphoblasts (86.2 ± 3.3) % in bone marrow in the 1st acute period. Hematological remission was established in all patients on the 33rd day of chemothe- rapy. In a half of cases the haematopoietic recovery occurred by a granulocyte-monocyte type. One third of patients presenting an erythroid type of haemopoiesis died later. The inverse correlation was found between the number of myelocaryocytes and disease prognosis (rs = -0.49). Breaks in chemotherapy for various reasons were recorded. The number of patients with granulocytopenia was greater at the phase 1 and 2 of protocol I and protocol M application, coinciding with a higher incidence of complications. An inverse correlations between the prediction of ALL course and sum of days of breaks between the protocol M and phase 1 of protocol II (rs = -0.56), as well as the duration of the phase 2 of protocol II (rs = -0.62) were found. The radiation dose on bone marrow was (5.37 ± 1.23) mSv. No relationship was found between the radiation doses, ALL variants and disease course. CONCLUSIONS: Prognosis of ALL course in children depends on the type of haemopoietic recovery and reasons of breaks in a standard chemotherapy. Interaction between the haemopoiesis functioning and microenvironment and that of their regulation are the key mechanisms of above-mentioned abnormalities, which is the basis for further research.

Adverse events with fatal outcome associated with alemtuzumab treatment in multiple sclerosis.

OBJECTIVE: Sporadic fatal adverse events have been reported during treatment of multiple sclerosis with alemtuzumab. To provide a systematic overview, we searched the centralized European Medicines Agency database of suspected adverse reactions related to medicinal products (EudraVigilance) for fatal adverse events associated with treatment with alemtuzumab (Lemtrada®) for multiple sclerosis. Four independent reviewers with expertise on MS, clinical immunology, infectious diseases and clinical pharmacology reviewed the reports, and scored the likelihood for causality. RESULTS: We identified nine cases with a probable and one case with a possible causal relationship between alemtuzumab treatment and a fatal adverse event. Six of these patients died within one month after treatment; one from intracerebral hemorrhage, two from acute multiple organ failure and septic shock, one from listeriosis, one from pneumonia and one from agranulocytosis. Four patients died several months after administration of alemtuzumab from either autoimmune hepatitis, immune-mediated thrombocytopenia, autoimmune hemolytic anemia or agranulocytosis. Four of the 10 cases had been published previously in case reports or congress abstracts. Fatal adverse events related to treatment with alemtuzumab occur more frequently than previously published in the literature. A significant proportion occurs in the first month after treatment.

Non-chemotherapy drug-induced neutropenia - an update.

INTRODUCTION: To date, non-chemotherapy drug-induced severe neutropenia (neutrophil count of ≤0.5 x 109/L) also called idiosyncratic drug-induced agranulocytosis is little discussed in the literature. In the present paper, we report and discuss the clinical data and management of this rare disorder. Areas covered: To do this, we carried out a review of the literature using PubMed database of the US National Library of Medicine. We also used data from the American Society of Hematology educational books, textbooks of Hematology and Internal medicine, and information gleaned from international meetings. Expert opinion: Idiosyncratic agranulocytosis remains a potentially serious adverse event due to the frequency of severe sepsis with severe deep tissue infections (e.g., pneumonia), septicemia, and septic shock in approximately two-thirds of all hospitalized patients. In this context, several prognostic factors have been identified that may be helpful when identifying 'susceptible' patients. Old age (>65 years), septicemia or shock, renal failure, and a neutrophil count ≤0.1 × 109/L have been consensually accepted as poor prognostic factors. In our experience, modern management with pre-established procedures, intravenous broad-spectrum antibiotics and hematopoietic growth factors (particularly G-CSF) is likely to improve the prognosis. Thus with appropriate management, the mortality rate is currently between 5 to 10%.

The Effect of Eosinopenia on Mortality in Patients with Intracerebral Hemorrhage.

INTRODUCTION: Inflammation may determine the prognosis of intracerebral hemorrhage (ICH), which has high mortality and morbidity rates. Recent studies have increasingly demonstrated eosinopenia as a prognostic factor, particularly in bacteremia, chronic obstructive pulmonary disease, and myocardial and cerebral infarction. Nonetheless, its significance regarding the determination of prognosis in patients with ICH has not yet been clarified. MATERIALS AND METHODS: Our study included 296 patients who presented to our clinic within 24 hours of the onset of symptoms and who were diagnosed with ICH between January 2008 and June 2016, along with 180 age- and sex-matched controls. During their hospitalization, 120 of these 296 patients died. Patients and controls were compared in terms of neutrophil count/percentage and eosinophil count/percentage; these were also compared between nonsurviving and surviving patients. The significance of eosinopenia in predicting mortality was also evaluated. RESULTS: Patients had a significantly higher neutrophil count/percentage and a significantly lower eosinophil count/percentage than controls; these results were similar between nonsurviving and surviving patients (P < .001). Consequently, the patient group was divided into 4 subgroups depending on the presence of eosinopenia and/or neutrophilia. The mortality rate was highest (62%) in the group that had both eosinopenia and neutrophilia. Univariate and multivariate logistic regression analyses indicated that neutrophilia and eosinopenia were independent predictors of mortality in ICH (P = .002; P = .004) DISCUSSION: These results indicate that eosinopenia can occur in patients with ICH and that although the mechanism is unclear, eosinopenia is closely associated with mortality in these patients, particularly when accompanied by neutrophilia.

Antithyroid Drug-Induced Agranulocytosis: State of the Art on Diagnosis and Management.

Agranulocytosis is a rare but serious complication of antithyroid drug therapy, and an up-to-date understanding of this topic is important. Both direct toxicity and immune-mediated responses have been described as possible mechanisms. Some major susceptibility loci have recently been identified, which may lead the diagnosis of agranulocytosis into a genomic era. Onset is acute and patients present with symptoms and signs of infection together with high fever. Clinical suspicion is pivotal and should prompt blood sampling. An absolute neutrophil count of <500/µl in the presence of antithyroid drugs establishes the diagnosis. The causative drug should immediately be stopped to prevent further damage. Treatment includes broad-spectrum antibiotics and granulocyte-colony stimulation factor in selected patients. Later, patients will need definitive treatment for hyperthyroidism, usually with radioactive iodine or surgery. The best way to avoid the mortality associated with antithyroid drug-induced agranulocytosis is patient education.

Clozapine-associated neutropenia and agranulocytosis in Argentina (2007-2012).

The risks of severe leukopenia and agranulocytosis have varied over time and among geographical regions and cultures, with little information available on South American populations. Accordingly, we reviewed and analyzed data from a 6-year experience monitored by an Argentine national registry to which reporting of adverse events reports is required. We analyzed data for 2007-2012 from the pharmacovigilance program of the Argentine drug-regulatory agency (ANMAT) using standard bivariate and multivariate statistical methods and survival analysis. We identified 378 cases of adverse hematological events over 6 years among an average of 12 305 individuals/year treated with clozapine (308±133 mg/day) to estimate the mean annualized rates of leukopenia [0.19 (95% confidence interval [CI] 0.11-0.27)], neutropenia [0.38 (95% CI 0.34-0.43)], and agranulocytosis [0.05 (95% CI 0.02-0.08)] % per year [median latency 2 (95% CI 1.3-2.1) months]; fatalities related to agranulocytosis averaged 4.2 (95% CI 0.0-9.2) per 100 000 treated individuals/year. Factors associated significantly and independently with agranulocytosis were female sex, older age, and use of other drugs in addition to clozapine. With monitoring by international standards, recent risks of clozapine-associated agranulocytosis in Argentina were lower, but fatality rates were higher than that in other regions of the world. Risk factors include the use of multiple psychotropic drugs, female sex, and older age.

Characteristics of agranulocytosis as an adverse effect of antithyroid drugs in the second or later course of treatment.

BACKGROUND: Agranulocytosis is a serious adverse effect of antithyroid drugs (ATDs) and mainly develops within three months after the start of uninterrupted ATD treatment. Agranulocytosis can also develop for the first time after interruption and subsequent resumption of the same ATD treatment. However, little is known with regard to agranulocytosis that develops after resumption of the same ATD treatment. OBJECTIVES: We investigated the characteristics of patients who developed agranulocytosis during their second or later course of ATD treatment. METHODS: A total of 81 patients at our hospital were diagnosed with ATD-induced agranulocytosis. In 14 of the cases (methimazole (MMI), n=10; propylthiouracil (PTU), n=4), the agranulocytosis developed for the first time in the context of the second or later course of treatment with the same ATD; those patients were designated the "resumed group." The 35 patients (MMI, n=28; PTU, n=7) who developed agranulocytosis during their first uninterrupted course of ATD therapy were designated the "first group." RESULTS: The median total duration of ATD treatment before the diagnosis of agranulocytosis was 559 days (range 86-1775 days), and the median interval between the final day of the previous course and the first day of the course in which agranulocytosis was diagnosed was 916.5 days (range 153-8110 days). There were no cases in which agranulocytosis developed when treatment with the same ATD was resumed after discontinuation for less than five months. The difference between the start of ATD treatment in the course in which agranulocytosis was diagnosed and the time interval at which agranulocytosis was diagnosed was similar when comparing the first group and the resumed group (39 (20-98) days in the first group vs. 32.5 (21-95) days in the resumed group; n.s.). There were no significant differences between the groups in terms of granulocyte count at the time agranulocytosis was diagnosed, mortality rate, or the interval between the diagnosis of agranulocytosis and recovery. CONCLUSIONS: When ATD treatment is resumed, patient follow-up is essential in order to monitor for the development of agranulocytosis.

Clozapine and agranulocytosis: re-assessing the risks.

OBJECTIVE: The aim of the study was to estimate the maximum incidence of agranulocytosis which clozapine would have caused between 2006 and 2010 had there been no blood monitoring system; and to determine the number of clozapine-associated cases of agranulocytosis and related deaths recorded between 1993 and 2011. METHOD: Records associating clozapine use with white blood cell deficiency (WBCD), in the Therapeutic Goods Administration's Case Line Listing of adverse drug reactions, were examined. The figure of 11,000 was used as the population on clozapine each year from 2006-2010. RESULTS: Between 2006 and 2010 there were 209 cases of clozapine-associated WBCD recorded, probably caused by clozapine in 141 cases. WBCD caused by clozapine could have progressed to agranulocytosis if clozapine had not been withdrawn. The risk of WBCD/agranulocytosis decreased with increasing duration of clozapine use. Between 1993 and 2011 there were 141 recorded cases of agranulocytosis, and four deaths, from clozapine-associated WBDC. CONCLUSIONS: During 2006-2010, without any monitoring system, the maximum annual incidence of agranulocytosis caused by clozapine would have been 0.26%. The risks of agranulocytosis, and related deaths, decreased with length of time on clozapine. During 1993-2011 141 cases of agranulocytosis, with four deaths, were recorded in association with clozapine use. The monitoring system could have successfully prevented relatively few deaths.

Beyond white blood cell monitoring: screening in the initial phase of clozapine therapy.

OBJECTIVE: Clozapine is the preferred option for treatment-resistant schizophrenia. However, since 1975, clozapine has been known to cause agranulocytosis. In the clozapine screening guidelines, white blood cell count is mandatory. In the past 20 years, after its reintroduction, 3 other serious side effects, namely, diabetic ketoacidosis, gastrointestinal hypomotility, and myocarditis have been documented but have so far failed to be incorporated in the screening guidelines. The objective of this review is to determine whether an update of the screening guidelines for serious side effects with clozapine is evidence based. DATA SOURCES: The English-language literature, available via MEDLINE or PubMed, on the incidence of 4 clozapine-related side effects, using clozapine, agranulocytosis, diabetic ketoacidosis, and gastrointestinal hypomotility as keywords, that have been published over the period 1976-2010, was collected. STUDY SELECTION: 16 studies that provided incidence rates or data from which these rates could be calculated were included. DATA EXTRACTION: We compared 1-year incidence rates, mortality rates in the whole study population and in the affected cases. When rates reflected longer periods of observation, the given rate was recalculated to obtain a 1-year incidence rate. RESULTS: The incidence of clozapine-induced agranulocytosis varies between 3.8‰-8.0‰. The mortality rate is 0.1‰-0.3‰, and the case-fatality rate is 2.2‰-4.2‰. In diabetic ketoacidosis, the incidence was calculated at 1.2‰-3.1‰, and the case-fatality rate was 20%-31%. In gastrointestinal hypomotility, the incidence was 4‰-8‰, and the case-fatality rate was 15%-27.5%. The discrepancy in incidence rates between Australia (7‰-34‰) and the rest of the world (0.07‰-0.6‰) impairs a general approach of this side effect. CONCLUSIONS: In 2 of the 3 studied side effects, diabetic ketoacidosis and gastrointestinal hypomotility, reduction of mortality to the level of agranulocytosis is both necessary and feasible. In order to obtain this outcome, the screening guidelines need to be modified; early detection of treatment-emergent hyperglycemia, that might-via diabetes mellitus-develop into diabetic ketoacidosis, requires obligatory monthly measurement of fasting plasma glucose. To prevent gastrohypomotility, and complications therefrom, the clinician should be required to choose between either weekly monitoring or standard coprescription of laxatives for prevention. The reported incidence of myocarditis (high in Australia, low in the rest of the world) is too divergent to allow for an overall recommendation outside Australia.

Clozapina como tratamiento de primera elección en primeros episodios psicóticos ¿qué sabemos? / Clozapine as treatment of first choice in first psychotic episodes. What do we know?

La esquizofrenia se conceptualiza, en la actualidad, como una enfermedad del neurodesarrollo con un deterioro clínico, neurofisiológico y neuroestructural, especialmente notorio en las etapas iniciales de la enfermedad. En los últimos años, los programas de intervención precoz buscan tratar de modificar el curso natural de la enfermedad. La elección de un tratamiento antipsicótico ajustado a las necesidades específicas del paciente permitiría optimizar los resultados de los programas de intervención en primeros episodios psicóticos. La clozapina ha sido un fármaco clave en la historia del tratamiento de la psicosis y sus aportaciones en el tratamiento de la esquizofrenia han sido múltiples. Ha demostrado su superioridad sobre otros antipsicóticos en términos de eficacia y efectividad con un costo efectividad comparable al aceptado para numerosas intervenciones médicas. Por otro lado, estudios recientes indican que la incidencia y mortalidad asociadas a la agranulocitosis por clozapina serían inferiores a las estimadas en estudios previos y la mortalidad global por clozapina inferior a la asociada a otros antipsicóticos. A pesar de las recomendaciones de las guías clínicas, la clozapina se emplea con mucha menor frecuencia y más tardíamente de lo recomendado y los ensayos clínicos comparando la eficacia y efectividad de la clozapina frente a otros antipsicóticos en primeros episodios psicóticos son prácticamente inexistentes. En el presente artículo de revisión selectiva pretendemos revisar la evidencia clínica existente acerca del empleo de clozapina en primeros episodios psicóticos que nunca han recibido tratamiento farmacológico (AU)

Schizophrenia is currently conceptualized as a neurodevelopmental disorder with progressive clinical, neurophysiological and neurostructural deterioration mostly occurring at early stages of the disease. During the last years, several early intervention programs have tried to modify the natural history of the disease. The choice of antipsychotic treatment adapted to the specific needs of the patient would make it possible to optimize the results of the intervention programs in first psychotic episodes. Clozapine has become a keystone in the treatment of psychosis, with multiple contributions to the treatment of schizophrenia. Clozapine has been proven superior to other antipsychotics in efficacy and effectiveness with comparable cost-effectiveness to that accepted for many medical interventions. On the other hand, recent studies indicate that the incidence and mortality of clozapine-induced agranulocytosis could be lower than previously estimated and that all-cause mortality due toclozapine is less than that associated to other antipsychotic drugs. However, in spite of clinical guideline recommendations, clozapine is used less and later than recommended. There is a lack of studies comparing clozapine with other antipsychotics in first episode psychosis patients. The aim of our paper is to review the current medical evidence about the use of clozapine as a first-line treatment for naive first episode psychosis patients (AU)

[Fibrinolysis system in patients with sepsis in state of myelotoxic agranulocytosis].

PURPOSE: Hemostasis disorders are the part of multiple organ failure (mOF) in sepsis. This work objective is to evaluate the system parameters in septic patients. PATIENTS AND METHODS: 55 oncohaematological patients were included in study: 45 with sepsis and 10 patients in control group (no signs of infection). Septic patients were subdivided into septic patients without multiple organ failure, patient with multiple organ failure and patients with septic shock. The C-reactive protein (CRP), procalcitonine (pCT), interleukine-6 (IL-6) serum concentration and fibrinolysis parameters were measured Patients were examined daily during first 5 days, later once a week during 28 days, control group was examined one time. RESULTS: Levels of CRP IL-6 and PCT were raised since 1st day. PCT and IL-6 concentrations were higher in sepsis and MOF group and septic shock group, than in sepsis without MOF group. CRP was raised in all patients. PCT went to normal at 7th day, CRP and IL-6 have started to decrease after 7th day, but both were higher than in control group. T-PA and plasmin inhibitors were comparable to control group and haven't changed significantly. Septic shock patients and patients with MOF have shown a decrease of plasminogen activity. Patients without MOF have shown an initially decreased plasminogen activity, but after 2 days it was similar to control group. PAI-I activity was increased only in septic shock and MOF groups in first days, and was similar to control group in cases of no MOF. Exended XIIa-dependent fibrinolysis time in average was present in all septic patients since 1st day, and extended twice in MOF and septic shock groups. Clot lysis time tended to decrease starting from 8th day, but it was longer than in control group till 28th day. A raised D-dimer concentration compared to control group was present in 75% of patients, but no difference was found among subgroups. A raised D-dimer serum concentration was relevant for prognosis. CONCLUSION: The most sensitive diagnostic test in sepsis is XIIa-dependent fibrinolysis. Plasminogen and PAI-I activity changes are mostly present inpatient with MOF and septic shock. The 28-day survival rate was 60% in MOF and septic shock groups and 95% in no MOF groups. A raised D-dimer concentration was found in 75% of septic patients.

A multivariate meta-analysis approach for reducing the impact of outcome reporting bias in systematic reviews.

Multivariate meta-analysis allows the joint synthesis of multiple correlated outcomes from randomised trials, and is an alternative to a separate univariate meta-analysis of each outcome independently. Usually not all trials report all outcomes; furthermore, outcome reporting bias (ORB) within trials, where an outcome is measured and analysed but not reported on the basis of the results, may cause a biased set of the evidence to be available for some outcomes, potentially affecting the significance and direction of meta-analysis results. The multivariate approach, however, allows one to 'borrow strength' across correlated outcomes, to potentially reduce the impact of ORB. Assuming ORB missing data mechanisms, we aim to investigate the magnitude of bias in the pooled treatment effect estimates for multiple outcomes using univariate meta-analysis, and to determine whether the 'borrowing of strength' from multivariate meta-analysis can reduce the impact of ORB. A simulation study was conducted for a bivariate fixed effect meta-analysis of two correlated outcomes. The approach is illustrated by application to a Cochrane systematic review. Results show that the 'borrowing of strength' from a multivariate meta-analysis can reduce the impact of ORB on the pooled treatment effect estimates. We also examine the use of the Pearson correlation as a novel approach for dealing with missing within-study correlations, and provide an extension to bivariate random-effects models that reduce ORB in the presence of heterogeneity.

Where to position clozapine: re-examining the evidence.

OBJECTIVE: To review clozapine's position in treatment algorithms for schizophrenia. METHOD: Clozapine's status is reviewed in the context of its initial discovery and unique clinical and (or) pharmacological profile, withdrawal and link with hematologic concerns, reintroduction with monitoring guidelines, prototype for atypicality, positioning in treatment algorithms, and current evidence regarding efficacy, effectiveness, and side effects. RESULTS: The hematologic monitoring implemented with clozapine's reintroduction here in North America has proven successful in preventing clozapine-related deaths secondary to agranulocytosis. While its other side effects are not without concern, present evidence does not link clozapine to increased mortality rates; indeed, it appears better than other antipsychotics in this regard. Moreover, its clinical superiority compared with all other antipsychotics has been confirmed both in efficacy and in effectiveness trials. CONCLUSIONS: Schizophrenia continues to represent a treatment challenge, with many people demonstrating suboptimal response and poor functional outcome. Clozapine is routinely positioned as a third-line treatment in schizophrenia, but in light of existing evidence this warrants re-examination.

[Clozapine-induced agranulocytosis and Sweet's syndrome in a 74-year-old female patient. A case study]. / Clozapinegeïnduceerde agranulocytose en het syndroom van Sweet bij een 74-jarige patiënte.

A 74-year-old psychotic female patient who was treated with clozapine developed Sweet's syndrome followed by agranulocytosis from which she later died. A link between these two conditions seems unlikely. Sweet's syndrome is characterised by an acute onset of fever, leukocytosis and erythematous plaques with dense neutrophilic infiltrates. Frequent counting of the numbers of neutrophiles is advisable when skin disorders appear during treatment with clozapine.

Use of granulocyte colony-stimulating factor (G-CSF) and outcome in patients with non-chemotherapy agranulocytosis.

PURPOSE: The use of granulocyte colony-stimulating factor (G-CSF) in the treatment of non-chemotherapy drug- induced agranulocytosis is controversial. We aimed at assessing the effect of G-CSF on the duration of agranulocytosis. METHODS: To assess the effect of G-CSF on the duration of agranulocytosis, a Cox proportional hazard model with an estimated propensity score covariate adjusting for several prognostic factors was used. RESULTS: One hundred and forty-five episodes of agranulocytosis were prospectively collected from January 1994 to December 2000 in Barcelona (Spain). No differences were found in the case-fatality rate between treated (9 of 101, 8.9%) and not treated (5 of 44, 11.4%) patients. The median time to reach a neutrophil count > or =1.0 x 10(9)/L was 5 days (95%CI 5-6) in patients treated with G-CSF compared to 7 days (95%CI 6-8) in those not treated, with a hazard ratio of 1.58 (95% CI 1.1-2.3). CONCLUSIONS: G-CSF shortens time to recovery in patients with agranulocytosis. However, as an effect on case-fatality has not been recorded, and data on cost-effectiveness are lacking, it would be wise to restrict its use to high-risk patients.

Diagnosis and management of autoimmune complications of chronic lymphocytic leukemia/ small lymphocytic lymphoma.

Autoimmune cytopenia is an important but poorly understood clinical complication of chronic lymphocytic leukemia/ small lymphocytic lymphoma. We review the pathogenesis, clinical presentation, and management of autoimmune hemolytic anemia, immune thrombocytopenia, and pure red blood cell aplasia in patients with chronic lymphocytic leukemia/ small lymphocytic lymphoma.

Risk of clozapine-associated agranulocytosis and mandatory white blood cell monitoring.

OBJECTIVE: To provide information for physicians and patients on which to base a decision as to whether to stop mandatory blood testing. DATA SOURCES: Articles on drug-induced blood dyscrasias were identified by searches of MEDLINE (1966-September 2005) and review of their bibliographies. Novartis was asked to provide additional data on clozapine, leukopenia, agranulocytosis, and suicidality. STUDY SELECTION AND DATA EXTRACTION: Data on the chance of clozapine-induced leukopenia and agranulocytosis were combined with data about possible fatality and compared with the risks associated with other medications and with life in general. DATA SYNTHESIS: The chance of clozapine-induced leukopenia or agranulocytosis decreases exponentially over time. In the US, the chance in the second 6 months of treatment is 0.70/1000 patient-years and, after the first year, 0.39/1000 patient-years. The case fatality rate of clozapine-induced agranulocytosis is estimated as 4.2-16%, depending on whether a granulocyte colony-stimulating factor is used. Nevertheless, treatment with clozapine reduces overall mortality, probably because it reduces suicidality. CONCLUSIONS: After at least 6 months' treatment with clozapine, the mortality involved in stopping white blood cell monitoring is about the same as the mortality associated with other medications, such as mianserin or phenylbutazone, and with life in general (traffic or occupational accident). If the patient has been well informed and wishes to stop the monitoring, it is a medically justifiable option to do so and is preferable to stopping treatment with clozapine since this drug reduces overall mortality.