Understanding clozapine-related blood dyscrasias. Developments, genetics, ethnicity and disparity: it's a CIN.

Clozapine remains the gold standard intervention for treatment-resistant schizophrenia; however, it remains underused, especially for some minority groups. A significant impediment is concern about propensity to neutropenia. The aim of this article is to provide an update on current knowledge relating to: the pattern and incidence of severe blood dyscrasias; the effectiveness of current monitoring regimes in reducing harm; the mechanisms of and the distinctions between clozapine-induced neutropenia and agranulocytosis; benign ethnic neutropenia; and changes to the monitoring thresholds in the USA and other international variations. These all have implications for the practical use of clozapine; specifically, how barriers to initiating, maintaining and restarting clozapine can be understood and in many cases overcome, especially for patients from minority groups, potentially with simpler approaches than the use of lithium or G-CSF.

Safety of BEN guidelines in clozapine treatment: A Canadian perspective.

OBJECTIVE: Unidentified benign ethnic neutropenia (BEN) has been recognized as a factor contributing to clozapine underutilization and discontinuation. Guidelines were implemented to accommodate BEN in Canada, and our main objective was to evaluate clozapine's safety in a sample of Canadian psychiatric patients with BEN. METHOD: A retrospective chart review was conducted at the Centre for Addiction and Mental Health, Toronto, Canada. Through the clozapine clinic registry, participants were identified who (i) received clozapine using the approved BEN guidelines for hematological monitoring, and (ii) had at least one complete blood count pre- and post-clozapine initiation. RESULTS: Our sample population was comprised of 41 BEN patients who were African-Caribbean (49 %), African (34 %), African-North American (12 %), Middle Eastern (2 %), and Indian-Caribbean (2 %). There was a significant reduction in hematological alerts for these patients while monitored under BEN guidelines (p < 0.001). The mean within-patient ANC value was not significantly different one year after clozapine initiation compared to the pre-clozapine baseline (p = 0.069). None of the patients discontinued clozapine for hematological reasons. CONCLUSIONS: Findings demonstrated that patients monitored under the modified hematological guidelines for BEN can be safely treated with clozapine. These findings have important clinical ramifications as increased implementation of BEN guidelines may allow for broader use of clozapine.

Clozapine and neutrophil response in patients of African descent: A six-month, multinational, prospective, open-label clinical trial.

INTRODUCTION: Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, but it is markedly underutilized, particularly in the US Black population, partly because of concern over clozapine-associated low absolute neutrophil count (ANC). People of African descent have a lower normative ANC range than the White population, which is associated with a specific "ACKR1-null" ("Duffy null") CC genotype (SNP rs2814778) on the ACKR1 gene, termed benign ethnic neutropenia (BEN). The range of ANC variability and safety of clozapine have not been established in people with BEN or examined prospectively in people of African descent. METHODS: We completed a multisite, 6-month, prospective, open-label clinical trial of clozapine treatment in people of African descent with schizophrenia spectrum disorders for whom clozapine was clinically indicated, with or without the ACKR1-null genotype. We examined clozapine safety and weekly ANC during clozapine treatment and evaluated ANC variability by ACKR1-null genotype, sex, study site, and clozapine dosing using repeated measures analysis of covariance. Genotype was assayed using TaqMan® technology. RESULTS: We enrolled 274 participants, of whom 227 (82.8 %) completed 6 months of clozapine treatment. There was one case of severe neutropenia (<500 cells/mm3) (0.36 %) over 1467.6 person-months of clozapine exposure. This participant recovered without sequelae after discontinuation of clozapine. Of the 249 participants with known genotypes, 199 (79.9 %) had the ACKR1-null genotype. Neutropenia (<1500 cells/mm3) occurred significantly more often in the ACKR1-null group (33 % [65/199]) than in those with the T allele (6 % (3/50); p < 0.001). Fourteen (5 %) patients discontinued due to adverse events. Rates of infection and fever were low and sialorrhea was the commonest side effect (N = 187, 68 %). CONCLUSION: To our knowledge, this is the largest prospective clozapine trial in people of African descent. Severe neutropenia was rare, despite the high prevalence (80 %) of the ACKR1-null genotype. Our findings suggest that clozapine can be used safely in Black patients including those with BEN.

Duffy-Null Phenotype-Associated Neutropenia is the Most Common Etiology for Leukopenia/Neutropenia Referrals to a Tertiary Children's Hospital.

Duffy-null phenotype-associated neutropenia was present in 77.7% of leukopenia/neutropenia referrals to our center in Detroit with a high prevalence in Yemeni (96.6%), African American (91%), and non-Yemeni Middle Eastern (52.9%) patients. Greater availability of Duffy typing in patients with neutropenia but without recurrent/frequent/serious infections may lessen the need for additional consultations and investigations.

A Protected Class, An Unprotected Condition, and A Biomarker - A Method/Formula for Increased Diversity in Clinical Trials for the African American Subject with Benign Ethnic Neutropenia (BEN).

Expanding on previous industry guidance relative to increased clinical trial diversity, while honing more exacting treatments and better ways to fight diseases that have often disproportionately impacted people of color, is a topic being discussed by multidisciplinary public health experts across the nation.This writing draws attention to the African American demographic, which is continually subject to health care disparities. Any glimpses of knowledge or medical discovery that could potentially help to redress harm or reinforce a weakened familial-cultural infrastructure should be emphasized for sanative restoration of the impacted communities. The focus of this writing is the African American cohort and its nexus to Benign Ethnic Neutropenia as the diverse target population of discussion, hoping to convey a harmonized approach in the examination of (1) the African American Benign Ethnic Neutropenia cohort within the context of basic scientific understanding, (2) the interplay of applicable governing regulatory protections, and (3) increased clinical trial participation to enlarge the pathway for increased diversity in clinical trials.

Diagnosis and management of isolated neutropenia: A survey of pediatric hematologist oncologists.

BACKGROUND: Isolated neutropenia is a common referral to pediatric hematology oncology (PHO) physicians. There are no established consensus guidelines in the diagnosis and management of patients with isolated, asymptomatic, and incidentally discovered neutropenia. METHODS: A survey was distributed to PHO physicians on the American Society of Pediatric Hematology Oncology member discussion page to determine the common diagnostic and management decisions regarding patients with isolated neutropenia and to explore beliefs regarding the term "benign ethnic neutropenia." RESULTS: One hundred twenty-six PHO attending physicians completed the survey. The most common tests reportedly ordered for this patient population included complete blood cell count (CBC) (98%), peripheral smear (75%), antineutrophil antibody testing (29%), and immunoglobulins (24%). Providers were more likely to order an antineutrophil antibody in toddlers (p = .0085), and antinuclear antibody (ANA) panels in adolescents (p < .001). Half of providers do not request additional CBCs prior to their initial consultation, and most suggest referring patients with mild neutropenia after confirming a declining absolute neutrophil count (ANC) (51%). The three most important factors influencing ongoing follow-up included: history of recurrent/severe infections (98%), family history of blood disorders (98%), and more severe/progressively worsening neutropenia (97%). Seventy percent of respondents have diagnosed patients with "benign ethnic neutropenia," and 75% support replacement of the term to "typical neutrophil count with Fy(a-/b-) status," if confirmed with red cell phenotyping. CONCLUSION: We identified practice patterns of PHO physicians for the diagnosis and management of patients referred for asymptomatic and isolated neutropenia. These data provide the framework to conduct cost-effectiveness studies.

Racial disparities in neutrophil counts among patients with metastatic breast cancer during treatment with CDK4/6 inhibitors.

PURPOSE: The three CDK4/6 inhibitors (CDK4/6i) approved for use in HR-positive/HER2-negative metastatic breast cancer (MBC), palbociclib, ribociclib, and abemaciclib, are generally well tolerated; however, neutropenia is a common toxicity. Within the general population, neutropenia has been shown to be more common in individuals of African descent. The landmark CDK4/6i trials in MBC lacked racial diversity in their patient populations. We aimed to assess the toxicity profiles of CDK4/6is in a racially diverse population. METHODS: We conducted a retrospective study at Montefiore Medical Center in patients with HR-positive/HER2-negative MBC prescribed CDK4/6i as first or subsequent line therapy between January 2015 and April 2020. Baseline characteristics and laboratory data at various treatment timepoints were collected. RESULTS: The final analysis included 182 patients, of whom 46% were Black. Baseline absolute neutrophil count (ANC) was lower in the Black vs. Non-Black cohort (p = 0.001) but the change in ANC from baseline (delta-ANC) was smaller in the Black cohort, and the ANC at different treatment timepoints was similar between groups. There was no difference in the rate of infection or number of dose delays/reductions between racial groups. We did not find any difference in PFS between Black and Non-Black groups, regardless of the presence of CDK4/6i-induced neutropenia. CONCLUSION: We analyzed toxicity profiles of 182 patients with HR-positive/HER2-negative MBC treated with CDK4/6i. Despite the lower baseline ANC seen in our Black cohort, treatment toxicities were similar between racial groups. Long-term outcomes with CDK4/6i therapy, measured by PFS, were similar between Black vs. Non-Black patients.

Ethnic inequalities in clozapine use among people with treatment-resistant schizophrenia: a retrospective cohort study using data from electronic clinical records.

PURPOSE: Clozapine is the most effective intervention for treatment-resistant schizophrenia (TRS). Several studies report ethnic disparities in clozapine treatment. However, few studies restrict analyses to TRS cohorts alone or address confounding by benign ethnic neutropenia. This study investigates ethnic equity in access to clozapine treatment for people with treatment-resistant schizophrenia spectrum disorder. METHODS: A retrospective cohort study, using information from 11 years of clinical records (2007-2017) from the South London and Maudsley NHS Trust. We identified a cohort of service-users with TRS using a validated algorithm. We investigated associations between ethnicity and clozapine treatment, adjusting for sociodemographic factors, psychiatric multi-morbidity, substance misuse, neutropenia, and service-use. RESULTS: Among 2239 cases of TRS, Black service-users were less likely to be receive clozapine compared with White British service-users after adjusting for confounders (Black African aOR = 0.49, 95% CI [0.33, 0.74], p = 0.001; Black Caribbean aOR = 0.64, 95% CI [0.43, 0.93], p = 0.019; Black British aOR = 0.61, 95% CI [0.41, 0.91], p = 0.016). It was additionally observed that neutropenia was not related to treatment with clozapine. Also, a detention under the Mental Health Act was negatively associated clozapine receipt, suggesting people with TRS who were detained are less likely to be treated with clozapine. CONCLUSION: Black service-users with TRS were less likely to receive clozapine than White British service-users. Considering the protective effect of treatment with clozapine, these inequities may place Black service-users at higher risk for hospital admissions and mortality.

Benign ethnic neutropenia: an analysis of prevalence, timing and identification accuracy in two large inner-city NHS hospitals.

BACKGROUND: Benign ethnic neutropenia (BEN) is the most common cause of chronic neutropenia seen in individuals of African, Middle Eastern and West Indian descent. This phenotype is broadly defined by an absolute neutrophil counts (ANC) below 1.8 × 109 cells/L in the absence of other causes, without an increased risk of infection. BEN has been implicated as a potential source of disparity in patients treated with clozapine, the antipsychotic of choice in treatment-resistant schizophrenia. Our main objective was to examine the current level of BEN recognition in a cohort of patients treated with clozapine and the potential impact of unidentified BEN on the initiation and maintenance of clozapine treatment. METHODS: This was an observational, retrospective analysis of patients registered with clozapine haematological monitoring systems in two large mental health trusts, chosen because they serve an ethnically diverse population. The first objective was to establish certified BEN prevalence in current users of clozapine. The second objective was to explore the stage of treatment at which BEN was identified. The third objective was to evaluate the extent of unrecognised BEN in patients registered on the Central Non-Rechallenge Database (CNRD), a database for patients whose haematological parameters fall below set thresholds when receiving clozapine treatment, meaning they cannot ordinarily be prescribed clozapine again. RESULTS: The study population comprised of 2020 patients on the clozapine register. 111 patients were monitored under BEN criteria. BEN was mostly identified after a below threshold haematological result or clozapine rechallenge (68%) compared to at clozapine initiation (32%). Eight of the 18 (42%) black patients registered on the CNRD were classified as BEN after assessment by a haematologist. Of these 8 patients, none would have met CNRD criteria again if monitored with BEN criteria at clozapine initiation. CONCLUSIONS: Current evidence suggests that BEN remains an uncommonly recognised haematological phenotype. Improved timely identification of BEN will reduce unnecessary interruption or discontinuation of clozapine treatment. Our results suggest consideration should also be given to determining BEN status prior to initiating clozapine. Moreover, adoption of current FDA BEN monitoring criteria in the UK may further reduce clozapine discontinuation due to perceived neutropenia as drug toxicity, particularly in treatment-refractory schizophrenia patients.

Hematologic safety of palbociclib in combination with endocrine therapy in patients with benign ethnic neutropenia and advanced breast cancer.

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including palbociclib, are approved to treat hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) and are associated with hematologic toxicity. African American women, who are underrepresented in CDK4/6 inhibitor clinical trials, may experience worse neutropenia because of benign ethnic neutropenia. The authors specifically investigated the hematologic safety of palbociclib in African American women with HR-positive/HER2-negative ABC. METHODS: PALINA was a single-arm, open-label, investigator-initiated study of palbociclib (125 mg daily; 21 days on and 7 days off) plus endocrine therapy (ET) in African American women who had HR-positive/HER2-negative ABC and a baseline absolute neutrophil count ≥1000/mm3 (ClinicalTrials.gov identifier NCT02692755). The primary outcome was the proportion of patients who completed 12 months of therapy without experiencing febrile neutropenia or treatment discontinuation because of neutropenia. Single nucleotide polymorphism analysis was used to assess Duffy polymorphism status. RESULTS: Thirty-five patients received ≥1 dose of palbociclib plus ET; 19 had a Duffy null polymorphism (cytosine/cytosine). There were no reports of febrile neutropenia or permanent study discontinuation because of neutropenia. Significantly more patients with the Duffy null versus the wild-type variant had grade 3 and 4 neutropenia (72.2% vs 23.1%; P = .029) and required a palbociclib dose reduction (55.6% vs 7.7%; P = .008). Patients with the Duffy null versus the wild-type variant had lower overall relative dose intensity (mean ± SD, 81.89% ± 15.87 and 95.67% ± 5.89, respectively; P = .0026) and a lower clinical benefit rate (66.7% and 84.6%, respectively). CONCLUSIONS: These findings suggest that palbociclib is well tolerated in African American women with HR-positive/HER2-negative ABC. Duffy null status may affect the incidence of grade 3 neutropenia, dose intensity, and possibly clinical benefit.

Isolated Neutropenia/Benign Ethnic Neutropenia: A Common Clinical and Laboratory Finding in Southern and Western Saudi Arabia.

OBJECTIVE: Isolated mild neutropenia is a common clinical problem in some ethnicities including Arabs and Middle Eastern population. The current study aims to authenticate the prevalence of isolated neutropenia in Southern and Southwestern Saudi Arabia, explore the effect of altitude or regional differences and to suggest a new reference range for neutrophil count. METHODS: In this retrospective cross-sectional study, laboratory results of a commercial laboratory were screened over a period of 5 years (2016-2020) in seven different cities of different altitudes in South and southwestern Saudi Arabia. Participants' laboratory investigations were reviewed and excluded for any abnormal complete blood count, renal profile, liver profile, lipid profile, thyroid function test, fasting blood glucose, or HbA1c findings. Descriptive analysis and 95th percentile range were calculated using standard statistical methods. RESULTS: A total of 91,880 complete blood count results were included in the final analysis. Isolated neutropenia was common laboratory finding, with a prevalence ranging from 11% to 23%. The 2.5th percentile of the neutrophil count was lower than currently utilized 1.5×109/L in all studied seven cities. CONCLUSION: Mild to moderate neutropenia is common in Southern and Southwestern Saudi Arabia. Benign ethnic neutropenia (BEN) likely explains this high prevalence. Since BEN has no clinical significance, the reference range for normal neutrophil counts needs to be adjusted to reflect the effect of BEN.

Benign ethnic neutropenia.

Benign ethnic neutropenia (BEN) is one of the most common causes of chronic neutropenia seen in individuals of African, Middle Eastern and West Indian descent, affecting many individuals worldwide. Despite its prevalence, many physicians are not familiar with this benign condition, resulting in unnecessary evaluation and testing for neutropenia in otherwise healthy individuals. Clinically, patients with BEN are at no increased risk of infection despite their neutropenia. Implications of this condition are highlighted in those patients receiving therapies that have a known side effect of neutropenia, most commonly chemotherapy agents. Studies have suggested that disparities in survival among those patients receiving chemotherapy between patients of European decent and African decent may be attributed to measured neutropenia in these populations, questioning whether BEN could be an influential factor. This review encompasses all aspects of benign ethnic neutropenia, providing information about this condition and helping to guide clinical decision-making as to when an aggressive work up and referral are indicated and when it is appropriate to monitor. Additionally, we review the role of genetic studies in identifying the genes related to BEN, summarize the theories that offer the most accepted mechanisms behind the condition, and address the importance of pursuing larger studies to assess the implication of BEN in oncology patients as well as patients taking neutropenia-causing medications.

Prognostic value of neutrophil-to-lymphocyte ratio in castration resistant prostate cancer: Single-centre study of Nigerian men.

BACKGROUND: Elevated neutrophil-to-lymphocyte ratio (NLR) has been suggested to be a useful prognosticator of overall survival (OS) in several cancers including castration resistant prostate cancer. However, its utility in black populations known to have benign ethnic neutropenia is unknown. We evaluated the prognostic value of NLR in Nigerian men with CRPC in terms of OS. MATERIALS AND METHODS: We retrospectively analysed 58 patients with castration resistant prostate cancer who received androgen deprivation therapy (ADT) and docetaxel chemotherapy at our institution. Baseline NLR was calculated from available complete blood counts. NLR cut-off point value was determined based on receiver operator characteristic (ROC) curves for mortality. A multivariate analysis was performed to investigate the association between NLR and OS. RESULTS: Based on the ROC curves, the NLR (AUC 0.85, 95% CI 0.74-0.97, P = 0.0001) cut-off point was determined to be 1.8. This cut-off point has a sensitivity of 92% and specificity of 70%. Median OS was 20 months (95% CI 14-27 months); the median OS in patients with NLR <1.8 and those with NLR of ≥1.8 was 40 months and 12 months respectively. Kaplan-Meier plots showed that a higher NLR of ≥1.8 correlated significantly with an increased risk of mortality, Log rank P = 0.001. Multivariate Cox regression analyses confirmed NLR as an independent prognostic biomarker for OS (HR = 1.49, 95% CI: 1.18-1.87). CONCLUSIONS: This study demonstrated that NLR is a useful prognostic biomarker in Nigerian men with CRPC and that elevated baseline NLR ≥1.8 is associated with poorer OS.

Natural history of benign ethnic neutropenia in individuals of African ancestry.

BACKGROUND: Benign ethnic neutropenia (BEN), defined by neutrophil count <1.5 k/µL in the absence of other causes, is an asymptomatic condition more commonly observed in individuals of African ancestry. However, the natural history of this condition has been less well described. METHODS: Individuals with BEN were retrospectively identified by chart review or referral to hematology clinics. They were then invited to enroll in a prospective natural history study. Retrospective and prospective clinical and laboratory data were combined for descriptive analyses. FINDINGS: 46 participants, younger and older adults from 2 institutions, had BEN. Hypertension was reported in 30%, musculoskeletal disorders in 15%, and upper respiratory infection in 33% of these adults. Their leukopenia resulted from isolated neutropenia, ranging from 1000 and 1500 cells/µL. The severity of infections was mild and the frequency was similar to other healthy individuals in the ambulatory clinic. INTERPRETATION: In this group of BEN participants, their leukopenia was stable over time, and they had low rates of infections or common medical disorders, confirming the benign nature of this condition. The presence of BEN in children, younger adults, and older adults suggest a hereditary pattern for BEN.

FDA changes clozapine monitoring guidelines: Implications for worldwide practice.

US FDA decision to change their clozapine monitoring guidelines in 2015 for the first time. The changes proposed are as follows: lowering the neutrophil count before ceasing clozapine from 1.5 to 1.0×10(9)/l, allowing the potential for re-challenge following severe neutropenia (<1.0×10(9)/l) and allowing those with benign ethnic neutropenia the opportunity to be commenced on clozapine. These changes will allow a greater number of patients with schizophrenia in USA to be continued on clozapine. In our correspondence we summarize the evidence that support these changes. The FDA changes will likely have impact on clozapine monitoring protocols in other countries.

Human polymorphonuclear neutrophils specifically recognize and kill cancerous cells.

Polymorphonuclear neutrophils (PMNs), the main effectors of the innate immune system, have rarely been considered as an anticancer therapeutic tool. However, recent investigations using animal models and preliminary clinical studies have highlighted the potential antitumor efficacy of PMNs. In the current study, we find that PMNs from some healthy donors naturally have potent cancer-killing activity against 4 different human cancer cell lines. The killing activity appears to be cancer cell-specific since PMNs did not kill primary normal epithelial cells or an immortalized breast epithelial cell line. Transfecting the immortalized mammary cells with plasmids expressing activated forms of the rat sarcoma viral oncogene homolog (Ras) and teratocarcinoma oncogene 21 (TC21) oncogenes was sufficient to provoke aggressive attack by PMNs. However, transfection with activated Ras-related C3 botulinum toxin substrate (Rac1) was ineffective, suggesting specificity in PMN-targeting of neoplastic cells. Furthermore, PMNs from lung cancer patients were also found to exhibit relatively poor cancer-killing activity compared to the cytolytic activity of the average healthy donor. Taken together, our results suggest that PMN-based treatment regimens may represent a paradigm shift in cancer immunotherapy that may be easily introduced into the clinic to benefit a subset of patients with PMN-vulnerable tumors.

Prevalência de neutropenia étnica benigna entre os trabalhadores de um hospital público no município de São Paulo / Benign ethnic neutropenia among public hospital employees in São Paulo

JUSTIFICATIVA E OBJETIVOS: Neutropenia étnica benigna é uma condição caracterizada por uma redução da contagem dos neutrófilos abaixo de 1.500 mm³ na circulação sanguínea, estando ausentes as causas secundárias, adquiridas ou congênitas. Ocorre,principalmente, em populações negras e seus descendentes, não apresentando problemas recorrentes de infecção. Diversos estudos realizados em outros Países, em que a etnia negra é importante na composição populacional, como no Brasil, mostram a importância do conhecimento da neutropenia étnica. O objetivo deste estudofoi investigar a prevalência de neutropenia étnica benigna, no meio de uma população trabalhadora, aparentemente saudável, realizado em um hospital de grande porte.MÉTODO: Trata-se de um estudo transversal, envolvendo 347 voluntários,que estavam dentro dos critérios de inclusão do estudo.RESULTADOS: Os dados deste estudo demonstraram entre os trabalhadores estudados, nove (2,59%) entraram nos critérios diagnósticos para neutropenia étnica benigna. Relativamente em relação aos brancos participantes, os negros, pardos e amarelos apresentaram menor contagem de neutrófilos.CONCLUSÃO: Levando-se em consideração o aspecto racial, este estudo mostrou que pessoas negras e seus descendentes podem apresentar diminuição na contagem de neutrófilos, sem predisposição a infecções.(AU)

BACKGROUND AND OBJECTIVES: Benign ethnic neutropeniais a condition characterized by a neutrophil count reduction under 1.500 mm³ in blood circulation, with absence of acquired or congenital secondary causes. It occurs mainly among afro populations or their descendants not presenting problems with recurrent infections. Different papers performed in other countries, in which the Black ethnicity is important in the population composition, such as in Brazil, discuss the importance of knowing about ethnic neutropenia. The aim of this paper was to investigate the prevalence of benign ethnic neutropeniain an apparently healthy working population of a large hospital.METHOD: This transversal study comprised 347 volunteers whomet the study inclusion criteria.RESULTS: According to this paper, nine (2.59%) among the studied employees met the diagnostic criteria for benign ethnic neutropenia.Relatively in relation to Caucasian participants, Black, Brownand Yellow people presented a lower neutrophil count.CONCLUSION: Considering the racial aspect, this study showedthat afro people and their descendants may present a neutrophilcount reduction, without predisposition to infections.(AU)