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Journal of Neuroimmunology Aug 2023A contribution of neutrophil granulocytes to the pathogenesis of multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) is recognized. Anti-CD20...
INTRODUCTION
A contribution of neutrophil granulocytes to the pathogenesis of multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) is recognized. Anti-CD20 treatments applied in these diseases are associated with infectious complications and neutropenia. No data is available about functional characteristics of neutrophils obtained from patients with anti-CD20 treatments.
METHODS
In neutrophils isolated from 13 patients with anti-CD20 treatment (9 MS, 4 NMOSD), 11 patients without anti-CD20 treatment (9 MS, 2 NMOSD) and 5 healthy controls, we analyzed chemotaxis, production of reactive oxygen species (ROS), phagocytosis, and formation of neutrophil extracellular traps (NET) in vitro.
RESULTS
Chemotaxis and ROS production were found unchanged between patients with and without anti-CD20 treatment or between patients and healthy controls. We found a higher proportion of non-phagocytosing cells in patients without anti-CD20 treatment compared to patients with anti-CD20 treatment and healthy controls. As compared to healthy controls, a higher proportion of neutrophils from patients without anti-CD20 treatments underwent NET formation, either unstimulated or stimulated with phorbol 12-myristate 3-acetate for 3 h. In about half of patients with anti-CD20 treatment (n = 7), NET formation of unstimulated neutrophils occurred already within 20 min of incubation. This was not observed in patients without anti-CD20 treatment and healthy controls.
CONCLUSION
Anti-CD20 treatment in MS and NMOSD patients does not alter chemotaxis and ROS production of neutrophils in vitro but might restore their impaired phagocytosis in these diseases. Our study reveals a predisposition to early NET formation in vitro of neutrophils obtained from patients with anti-CD20 treatment. This may contribute to associated risks of neutropenia and infections.
Topics: Humans; Neutrophils; Reactive Oxygen Species; Neutropenia; Central Nervous System Diseases; Multiple Sclerosis; Central Nervous System
PubMed: 37364519
DOI: 10.1016/j.jneuroim.2023.578136 -
British Journal of Haematology Oct 2023Since its first description by Evans in 1951, this syndrome has been linked to chronic immune thrombocytopenia with the concurrent or delayed onset of autoimmune... (Review)
Review
Since its first description by Evans in 1951, this syndrome has been linked to chronic immune thrombocytopenia with the concurrent or delayed onset of autoimmune haemolytic anaemia or neutropenia. For decades, the evolution of Evans syndrome (ES) has carried a poor prognosis and often resulted in chronic steroid exposure, multiple immune suppressing medications directed against T or B lymphocytes, and splenectomy. This paper presents a new view of ES based on recent advances in genomics which begin to classify patients based on their underlying molecular variants in previously described primary immune disorders. This has opened up new avenues of targeted therapy or bone marrow transplant at rather than broad long-term immune suppression or splenectomy. Importantly, recent studies of the full lifespan of ES suggest that at least 80% of those paediatric patients will progress to various clinical or biological immunopathological manifestations with age despite the resolution of their cytopenias. Those patients merit long-term follow-up and monitoring in dedicated transition programs to improve outcome at the adult age.
Topics: Adult; Humans; Child; Anemia, Hemolytic, Autoimmune; Purpura, Thrombocytopenic, Idiopathic; Thrombocytopenia; Neutropenia
PubMed: 37735545
DOI: 10.1111/bjh.19073 -
Frontiers in Pharmacology 2023Given that the fight against coronavirus disease 2019 (COVID-19) is not over, we aimed to explore the occurrence of agranulocytosis and infectious complications in...
Agranulocytosis and secondary infection related to JAK inhibitors and IL-6 receptor blockers: a disproportionality analysis using the US Food and drug administration adverse event reporting system.
Given that the fight against coronavirus disease 2019 (COVID-19) is not over, we aimed to explore the occurrence of agranulocytosis and infectious complications in patients with and without COVID-19 following immunoregulatory therapy based on real-world data. This was a retrospective disproportionality analysis based on the US Food and Drug Administration Adverse Event Reporting System (FAERS). All cases reported between the first quarter of 2004 and the fourth quarter of 2022 about Janus kinase inhibitors (baricitinib, tofacitinib, ruxolitinib) and interleukin-6 receptor blockers (tocilizumab, sarilumab) were collected. Disproportionality analyses were conducted by reporting odds ratio (ROR) and information component (IC). A total of 211,363 cases were recognized from the FDA Adverse Event Reporting System database. Data analysis showed that tocilizumab (reporting odds ratio: 3.18, 95% CI: 3.18-3.29; information component: 1.37, 95% CI: 1.31-1.42), sarilumab (ROR: 1.64, 95% CI: 1.55-1.73; IC: 0.61, 95% CI: 0.43-0.79), baricitinib (ROR: 3.42, 95% CI: 3.19-3.67; IC: 1.43, 95% CI: 1.21-1.65), tofacitinib (ROR: 2.53, 95% CI: 2.49-2.57; IC: 1.11, 95% CI: 1.05-1.16), and ruxolitinib (ROR: 1.87, 95% CI: 1.83-1.91; IC: 0.77, 95% CI: 0.70-0.84) were all associated with secondary infection. The association in the combination group was higher than that in the monotherapy group (ROR: 4.69, 95% CI: 4.53-4.86; IC: 1.73, 95% CI: 1.62-1.84). As for agranulocytosis, tocilizumab (ROR: 1.61, 95% CI: 1.53-1.69; IC: 0.67, 95% CI: 0.50-0.84) and ruxolitinib (ROR: 2.32, 95% CI: 2.21-2.43; IC: 1.18, 95% CI: 1.02-1.33) showed the significant signals. The association was higher in the combination group than in the monotherapy group (ROR: 2.36, 95% CI: 2.15-2.58; IC: 1.20, 95% CI: 0.90-1.51). Secondary infection after treatment with tofacitinib (ROR: 1.37, 95% CI: 1.02-1.84), tocilizumab (ROR: 1.46, 95% CI: 1.01-2.09), and sarilumab (ROR: 2.46, 95% CI: 1.10-5.50) was reported more frequently in COVID-19 than in non-COVID-19 patients. Both Janus kinase inhibitors and interleukin-6 receptor blockers are significantly associated with secondary infection and agranulocytosis, and the combined treatment further increases the association. The correlation with secondary infection in patients treated with tofacitinib, tocilizumab, and sarilumab is higher in COVID-19 than in non-COVID-19 patients.
PubMed: 38264533
DOI: 10.3389/fphar.2023.1323240 -
Fetal and Pediatric Pathology Oct 2023Maternal hypertension is considered a risk factor for early neonatal neutropenia. We sought to explore this relationship. This retrospective cohort study compared...
Maternal hypertension is considered a risk factor for early neonatal neutropenia. We sought to explore this relationship. This retrospective cohort study compared initial neutrophil counts in infants born to mothers with preeclampsia with severe features (PSF) and infants born to normotensive mothers using Negative Binomial Regression (NBR) and logistic regression models. Maternal hypertension negatively affected the early neonatal neutrophil count (adjusted NRB coefficient 0.4 [0.2, 0.6], < 0.0001) but did not increase the risk of neutropenia (OR 2.07 [0.97, 4.41], = 0.06). The initial neutrophil count and neutropenia risk were not different between PSF subgroups. Gestational age had the greatest impact on neutropenia risk (OR 0.72 [0.64, 0.81], < 0.0001). Almost all neutropenia resolved within 48 h. Maternal hypertension negatively affects the early neonatal neutrophil count while not increasing the risk of neonatal neutropenia.
Topics: Infant, Newborn; Infant; Pregnancy; Female; Humans; Pre-Eclampsia; Retrospective Studies; Leukocyte Count; Neutropenia; Hypertension
PubMed: 37272337
DOI: 10.1080/15513815.2023.2220406 -
Targeted Oncology Sep 2023Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, is approved in patients with relapsed/refractory multiple myeloma (RRMM) who have previously...
BACKGROUND
Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, is approved in patients with relapsed/refractory multiple myeloma (RRMM) who have previously received an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.
OBJECTIVE
We report the population pharmacokinetics of teclistamab administered intravenously and subcutaneously (SC) and exposure-response relationships from the phase I/II, first-in-human, open-label, multicenter MajesTEC-1 study.
METHODS
Phase I of MajesTEC-1 consisted of dose escalation and expansion at the recommended phase II dose (RP2D; 1.5 mg/kg SC weekly, preceded by step-up doses of 0.06 and 0.3 mg/kg); phase II investigated the efficacy of teclistamab RP2D in patients with RRMM. Population pharmacokinetics and the impact of covariates on teclistamab systemic exposure were assessed using a 2-compartment model with first-order absorption for SC and parallel time-independent and time-dependent elimination pathways. Exposure-response analyses were conducted, including overall response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and the incidence of grade ≥ 3 anemia, neutropenia, lymphopenia, leukopenia, thrombocytopenia, and infection.
RESULTS
In total, 4840 measurable serum concentration samples from 338 pharmacokinetics-evaluable patients who received teclistamab were analyzed. The typical population value of time-independent and time-dependent clearance were 0.449 L/day and 0.547 L/day, respectively. The time-dependent clearance decreased rapidly to < 10% after 8 weeks of teclistamab treatment. Patients who discontinue teclistamab after the 13th dose are expected to have a 50% reduction from C in teclistamab concentration at a median (5th to 95th percentile) time of 15 days (7-33 days) after T and a 97% reduction from C in teclistamab concentration at a median time of 69 days (32-163 days) after T. Body weight, multiple myeloma type (immunoglobulin G vs non-immunoglobulin G), and International Staging System (ISS) stage (II vs I and III vs I) were statistically significant covariates on teclistamab pharmacokinetics; however, these covariates had no clinically relevant effect on the efficacy of teclistamab at the RP2D. Across all doses, ORR approached a plateau at the concentration range associated with RP2D, and in patients who received the RP2D, a flat exposure-response curve was observed. No apparent relationship was observed between DoR, PFS, OS, and the incidence of grade ≥3 adverse events across the predicted exposure quartiles.
CONCLUSION
Body weight, myeloma type, and ISS stage impacted systemic teclistamab exposure without any clinically relevant effect on efficacy. The exposure-response analyses for ORR showed a positive trend with increasing teclistamab systemic exposure, with a plateau at the RP2D, and there was no apparent exposure-response trend for safety or other efficacy endpoints. These analyses support the RP2D of teclistamab in patients with RRMM.
CLINICAL TRIAL REGISTRATION
NCT03145181 (phase I, 09 May 2017); NCT04557098 (phase II, 21 September 2020).
Topics: Humans; Multiple Myeloma; Antineoplastic Agents; Proteasome Inhibitors; Neutropenia; Body Weight
PubMed: 37713090
DOI: 10.1007/s11523-023-00989-z -
American Journal of Hematology Nov 2023CD19-directed CAR T-cell therapy with brexucabtagene autoleucel (brexu-cel) has substantially improved treatment outcomes for patients with relapsed/refractory mantle... (Observational Study)
Observational Study
The CAR-HEMATOTOX score identifies patients at high risk for hematological toxicity, infectious complications, and poor treatment outcomes following brexucabtagene autoleucel for relapsed or refractory MCL.
CD19-directed CAR T-cell therapy with brexucabtagene autoleucel (brexu-cel) has substantially improved treatment outcomes for patients with relapsed/refractory mantle cell lymphoma (r/r MCL). Prolonged cytopenias and infections represent common and clinically relevant side effects. In this multicenter observational study, we describe cytopenias and infections in 103 r/r MCL patients receiving brexu-cel. Furthermore, we report associations between the baseline CAR-HEMATOTOX (HT) score and toxicity events, non-relapse mortality (NRM), and progression-free/overall survival (PFS/OS). At lymphodepletion, 56 patients were HT (score 0-1) while 47 patients were HT (score ≥2). The HT cohort exhibited prolonged neutropenia (median 14 vs. 6 days, p < .001) and an increased rate of severe infections (30% vs. 5%, p = .001). Overall, 1-year NRM was 10.4%, primarily attributed to infections, and differed by baseline HT score (high vs. low: 17% vs. 4.6%, p = .04). HT patients experienced inferior 90-day complete response rate (68% vs. 93%, p = .002), PFS (median 9 months vs. not-reached, p < .0001), and OS (median 26 months vs. not-reached, p < .0001). Multivariable analyses showed that high HT scores were independently associated with severe hematotoxicity, infections, and poor PFS/OS. In conclusion, infections and hematotoxicity are common after brexu-cel and contribute to NRM. The baseline HT score identified patients at increased risk of poor treatment outcomes.
Topics: Humans; Adult; Treatment Outcome; Immunotherapy, Adoptive; Progression-Free Survival; Lymphoma, Mantle-Cell; Neutropenia
PubMed: 37584447
DOI: 10.1002/ajh.27056 -
BMC Infectious Diseases Oct 2023The intravenous form of fosfomycin, a bactericide antibiotic used to treat multiresistant bacterial infections is little prescribed. The most common reported adverse... (Review)
Review
BACKGROUND
The intravenous form of fosfomycin, a bactericide antibiotic used to treat multiresistant bacterial infections is little prescribed. The most common reported adverse effects are hypokaliemia and hypernatremia. We describe a case of agranulocytosis, a rarely described side effect that may be fatal.
CASE PRESENTATION
A 45 year-old woman was admitted to the intensive care unit for post-surgical meningitis following meningioma resection. Meropenem and vancomycin were first introduced. A DRESS-syndrom with meropenem was suspected. Neutropenia was diagnosed three days after the introduction of parenteral fosfomycin and agranulocytosis four days later. Eosinophilia was also observed. A bone marrow aspiration was performed showing a disappearance of the neutrophil granulocyte line and a significant eosinophilia. Meropenem was discontinued. Fosfomycin was maintained and filgrastim was added. As filgrastim had no effect, the relationship with fosfomycin was suspected, so it was then withheld. An increase of the neutrophil count was observed. Because of the complexity of the case, the unfavorable course of the illness and the urgent need for revision surgery, a rechallenge with fosfomycin was done followed by a decrease of the neutrophil count.
CONCLUSION
This is the third paper reporting agranulocytosis induced by fosfomycin, and the first detailed description of a case. Based on chronological and semiological criteria and bibliographic data, the event was qualified as probable with the Naranjo adverse drug probability scale. Literature data is scarce. The summary of product characteristics mentions that only a few cases of transient neutropenia and agranulocytosis have been reported. An analysis of the FDA Adverse Event Reporting System Database highlighted a higher than expected frequency of agranulocytosis in patients treated with fosfomycin. Parenteral fosfomycin is often used in patients receiving other medications, so that it is rarely the only suspect. In our case, the results of the bone marrow aspiration, the sudden drop of the neutrophil count with concomitant eosinophilia and the absence of improvement despite the dose decrease, point towards an immuno-allergic mechanism. However, the overlap between the suspected DRESS induced by meropenem and the agranulocytosis do not allow to conclude with certainty on the causality. Awareness should be raised about this side effect.
Topics: Female; Humans; Middle Aged; Fosfomycin; Filgrastim; Meropenem; Neutropenia; Anti-Bacterial Agents; Drug-Related Side Effects and Adverse Reactions; Eosinophilia
PubMed: 37833638
DOI: 10.1186/s12879-023-08652-8 -
BMC Cancer Oct 2023Aponermin, a circularly permuted tumor necrosis factor-related apoptosis-inducing ligand, is a potential death receptor 4/5-targeted antitumour candidate. Previous phase... (Randomized Controlled Trial)
Randomized Controlled Trial
Aponermin or placebo in combination with thalidomide and dexamethasone in the treatment of relapsed or refractory multiple myeloma (CPT-MM301): a randomised, double-blinded, placebo-controlled, phase 3 trial.
BACKGROUND
Aponermin, a circularly permuted tumor necrosis factor-related apoptosis-inducing ligand, is a potential death receptor 4/5-targeted antitumour candidate. Previous phase 1/2 studies have demonstrated the efficacy of aponermin in patients with relapsed or refractory multiple myeloma (RRMM). To confirm the superiority of aponermin plus thalidomide and dexamethasone (aponermin group) over placebo plus thalidomide and dexamethasone (placebo group) in RRMM, a randomized, double-blinded, placebo controlled phase 3 trial was performed.
METHODS
Four hundred seventeen patients with RRMM who had previously received at least two regimens were randomly assigned (2:1) to receive aponermin, thalidomide, and dexamethasone or placebo, thalidomide, and dexamethasone. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and overall response rate (ORR).
RESULTS
A total of 415 patients received at least one dose of trial treatment (276 vs. 139). The median PFS was 5.5 months in the aponermin group and 3.1 months in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.49-0.78; P < 0.001). The median OS was 22.4 months for the aponermin group and 16.4 months for the placebo group (hazard ratio, 0.70; 95% CI, 0.55-0.89; P = 0.003). Significantly higher rates of ORR (30.4% vs. 13.7%, P < 0.001) and very good partial response or better (14.1% vs. 2.2%, P < 0.0001) were achieved in the aponermin group than in the placebo group. Treatment with aponermin caused hepatotoxicity in some patients, as indicated by the elevated alanine transaminase, aspartate transaminase, or lactate dehydrogenase levels (52.2% vs. 24.5%, 51.1% vs. 19.4% and 44.9% vs. 21.6%, respectively), mostly grade 1/2, transient and reversible. The main grade 3/4 adverse events included neutropenia, pneumonia and hyperglycemia. The incidence of serious adverse events was similar between the two groups (40.6% vs. 37.4%). There was no evidence that aponermin leads to hematological toxicity, nephrotoxicity, cardiotoxicity, or secondary tumors.
CONCLUSIONS
Aponermin plus thalidomide and dexamethasone significantly improved PFS, OS and ORR with manageable side effects in RRMM patients who had received at least two prior therapies. These results support the use of aponermin, thalidomide, and dexamethasone as a treatment option for RRMM patients.
TRIAL REGISTRATION
The trial was registered at http://www.chictr.org.cn as ChiCTR-IPR-15006024, 17/11/2014.
Topics: Humans; Multiple Myeloma; Thalidomide; Dexamethasone; Neoplasm Recurrence, Local; Neutropenia; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37838670
DOI: 10.1186/s12885-023-11489-8 -
Leukemia Jan 2024Multiple myeloma (MM) bears heterogeneous cells that poses a challenge for single-target immunotherapies. Here we constructed bispecific CS1-BCMA CAR-T cells aiming to...
Multiple myeloma (MM) bears heterogeneous cells that poses a challenge for single-target immunotherapies. Here we constructed bispecific CS1-BCMA CAR-T cells aiming to augment BCMA targeting with CS1. Sixteen patients with relapsed or refractory (RR) MM received CS1-BCMA CAR-T infusion. Six patients (38%) had cytokine release syndrome, which was of grade 1-2 in 31%. No neurological toxicities were observed. The most common severe adverse events were hematological, including leukopenia (100%), neutropenia (94%), lymphopenia (100%) and thrombocytopenia (31%). Three patients with solitary extramedullary disease (sEMD) did not respond. At a median follow-up of 246 days, 13 patients (81%) had an overall response and attained minimal residual disease-negativity, and six (38%) reached a stringent complete response (sCR). Among the 13 responders, 1-year overall survival and progression-free survival were 72.73% and 56.26%, respectively. Four patients maintained sCR with a median duration of 17 months. Four patients experienced BCMA+ and CS1+ relapse or progression. One patient responded after anti-BCMA CAR-T treatment failure. Lenalidomide maintenance after CAR-T infusion and the resistance mechanism of sEMD were preliminarily explored in three patients. CAR-T cells persisted at a median of 406 days. Soluble BCMA could serve as an ideal biomarker for efficacy monitoring. CS1-BCMA CAR-T cells were clinically active with good safety profiles in patients with RRMM. Clinical trial registration: This study was registered on ClinicalTrials.gov, number NCT04662099.
Topics: Humans; Multiple Myeloma; Receptors, Chimeric Antigen; B-Cell Maturation Antigen; Neoplasm Recurrence, Local; Immunotherapy, Adoptive; Anemia; Neutropenia; T-Lymphocytes
PubMed: 37848634
DOI: 10.1038/s41375-023-02065-x -
Annals of Hematology Aug 2023The GALLIUM study showed a progression-free survival advantage of 7% in favor of obinutuzumab vs. rituximab-based immunochemotherapies as first-line therapy in...
The GALLIUM study showed a progression-free survival advantage of 7% in favor of obinutuzumab vs. rituximab-based immunochemotherapies as first-line therapy in follicular lymphoma (FL) patients. Yet, the toxicity appears to be increased with obinutuzumab-based therapy. This is a multicenter retrospective-cohort study including adult FL patients comparing the toxicity of first-line rituximab vs. obinutuzumab-based chemo-immunotherapies (R and O groups, respectively). We compared the best standard-of-care therapy used per time period, before and after obinutuzumab approval. The primary outcome was any infection during induction and 6 months post-induction. Secondary outcomes included rates of febrile neutropenia, severe and fatal infections, other adverse events, and all-cause mortality. Outcomes were compared between groups. A total of 156 patients were included in the analysis, 78 patients per group. Most patients received bendamustine (59%) or CHOP (31.4%) as adjacent chemotherapy. Half of the patients received growth-factor prophylaxis. Overall, 69 patients (44.2%) experienced infections, and a total of 106 infectious episodes were recorded. Patients in the R and O groups had similar rates of any infection (44.8% and 43.5%, p = 1), severe infections (43.3% vs. 47.8%, p = 0.844), febrile neutropenia (15% vs. 19.6%, p = 0.606), and treatment discontinuation, as well as similar types of infections. No covariate was associated with infection in multivariable analysis. No statistically significant difference was evident in adverse events of grades 3-5 (76.9% vs. 82%, p = 0.427). To conclude, in this largest real-life study of first-line treated FL patients comparing R- to O-based therapy, we did not observe any difference in toxicity during the induction and 6 months post-induction period.
Topics: Adult; Humans; Rituximab; Lymphoma, Follicular; Retrospective Studies; Cohort Studies; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Immunotherapy; Febrile Neutropenia
PubMed: 37335322
DOI: 10.1007/s00277-023-05306-2