Association of sarcopenia with severe chemotherapy toxicities and survival in patients with advanced gastric cancer.

BACKGROUND: Sarcopenia or skeletal muscle depletion is a poor prognostic factor for gastric cancer (GC). However, existing cutoff values of skeletal muscle index (SMI) for defining sarcopenia have been found to have limitations when clinically applied. This study aimed to determine the optimal cutoff for SMI to predict severe toxicities of chemotherapy and overall survival (OS) in patients with advanced GC. METHODS: Patients with metastatic gastric adenocarcinoma who received first-line palliative chemotherapy between January 2014 and December 2021 at Queen Mary Hospital, Hong Kong, were included in this study. The SMI was determined via a pre-chemotherapy computed tomography scan. Optimal cutoff points of SMI were identified by recursive partitioning analysis. Univariate and multivariate analyses evaluating risk factors of severe chemotherapy toxicities and OS were also performed. RESULTS: A total of 158 patients (male: 108 (68.4%), median age: 65.3) were included. The SMI cutoff to define low SMI was ≤33 cm2/m2 for males and ≤28 cm2/m2 for females; 30 patients (19.0%) had low SMI. Patients with low SMI had a higher incidence of hematological toxicities (63.3% vs 32.0%, P = .001) and non-hematological toxicities (66.7% vs 36.7%, P = .003). Multivariable analysis indicated that low SMI and low serum albumin (≤28 g/L) were independent predictive factors of hematological toxicity, while low SMI and neutrophil-lymphocyte ratio ≥5 were predictive factors of non-hematological toxicity. Moreover, patients with low SMI had a significantly shorter OS (P = .011), lower response rate to chemotherapy (P = .045), and lower utilization of subsequent lines of treatment (P < .001). CONCLUSIONS: Using pre-chemotherapy SMI cutoff (≤33 cm2/m2 for males and 28 cm2/m2 for females) one can identify individuals with a higher risk of severe chemotherapy toxicities and worse prognosis.

Chronic Lymphocytic Leukemia: Management of Adverse Events in the Era of Targeted Agents.

The treatment landscape for CLL has undergone a profound transformation with the advent of targeted agents (TAs) like Bruton's Tyrosine Kinase inhibitors (BTKis) and BCL-2 inhibitors (BCL-2is). These agents target crucial cellular pathways in CLL, offering superior efficacy over traditional chemo-immunotherapy, which has led to improved progression-free and overall survival rates. This advancement promises enhanced disease control and potentially normal life expectancy for many patients. However, the journey is not without challenges, as these TAs are associated with a range of adverse events (AEs) that can impact treatment efficacy and patient quality of life. This review focuses on detailing the various AEs related to TA management in CLL, evaluating their frequency and clinical impact. The aim is to present a comprehensive guide to the effective management of these AEs, ensuring optimal tolerability and efficacy of TAs. By reviewing the existing literature and consolidating findings, we provide insights into AE management, which is crucial for maximizing patient outcomes in CLL therapy.

Therapeutic Drug Monitoring of Linezolid in Drug-Resistant Tuberculosis Patients: Clinical Factors and Hematological Toxicities.

Purpose: Previous studies have indicated that the development of severe adverse events is associated with linezolid peak concentration (Cmax), but the factors affecting linezolid Cmax and evidences on therapeutic drug monitoring to anticipate toxicity in drug-resistant tuberculosis (DR-TB) patients have not been clarified clearly. This study aimed to explore the factors influencing linezolid Cmax and investigate the association between linezolid concentration and hematological toxicity. Patients and Methods: This study included patients with drug-resistant tuberculosis treated with linezolid from January 2022 to September 2023. We analyzed the factors affecting linezolid Cmax using chi-squared and binary logistic regression. The diagnostic utility of linezolid Cmax in predicting hematological toxicity was evaluated using receiver operating characteristic (ROC) analysis. Results: A total of 76 patients were enrolled in the study. 63.20% met the standard rates for linezolid Cmax. Age (P=0.036), weight (P=0.0016), and creatinine clearance (P=0.0223) significantly correlated with the Cmax. Hematological toxicity was observed in 46.05% (35/76) of patients, characterized by thrombocytopenia (31.58%, 24/76), anemia (6.58%, 5/76), and leukopenia (21.05%, 16/76). ROC curve analysis confirmed the predictive value of linezolid Cmax for thrombocytopenia with an area under curve of 0.728. Conclusion: Suboptimal linezolid Cmax was prevalent among patients with DR-TB, with age, weight, and renal function emerging as influential factors. Elevated linezolid Cmax increases the risk of thrombocytopenia. Meticulous monitoring of linezolid Cmax is imperative during anti-DR-TB therapy to tailor treatment and mitigate hematological toxicity.

Hematological toxicity of cyclin-dependent kinase 4/6 inhibitors in patients with breast cancer: a network meta-analysis and pharmacovigilance study.

OBJECTIVES: We aimed to evaluate and compare the risk of hematological adverse events (AEs) associated with CDK4/6 inhibitors using data from randomized controlled trials (RCTs) and Food and Drug Adverse Event Reporting System (FAERS) database. METHODS: The PubMed, Embase, and Cochrane Library databases were searched for RCTs related to abemaciclib, palbociclib, and ribociclib. A network meta-analysis (NMA) was conducted to compare the risks of hematological AEs, and a disproportionality analysis was performed to detect signals of hematological AEs. RESULTS: 16 RCTs comprising 16,350 breast cancer patients were included. Palbociclib and ribociclib had similar risks for hematological AEs, except a higher risk of grade 3-4 leukopenia observed with palbociclib (risk ratio [RR]: 7.84, 95% confidence interval [95%CI]: 1.33-41.28). Abemaciclib had a higher risk of anemia than both ribociclib (grade 1-4: RR: 2.23, 95% CI: 1.25 - 3.96; grade 3-4: RR: 3.52, 95% CI: 1.59 - 8.11) and palbociclib (grade 1-4: RR: 1.65, 95%CI: 1.03 - 2.59), but a lower risk of grade 3-4 of both leukopenia (RR: 0.12, 95%CI: 0.02 - 0.49) and neutropenia (RR: 0.15, 95%CI: 0.04 - 0.52) compared with palbociclib. Signals indicating occurrence of leukopenia, neutropenia, anemia, and thrombocytopenia were identified for three CDK4/6 inhibitors. CONCLUSION: Abemaciclib, palbociclib, and ribociclib showed significant but inconsistent hematological toxicity risks.

Dose-Volume Parameters of Spared Magnetic Resonance Imaging-Defined Active Bone Marrow Predict Hematologic Toxicity in Pelvic Malignancies Patients Undergoing Radiotherapy: A Cohort Study.

Background: The objective of this investigation is to evaluate the superiority of dose-volume parameters relying on magnetic resonance imaging (MRI)-defined active bone marrow (ABM) over those based on total bone marrow (TBM) contoured via CT in the prediction of hematologic toxicity (HT) occurrence among patients with pelvic malignancies undergoing radiotherapy. Methods: The clinical data of 116 patients with pelvic malignancies treated with pelvic radiotherapy were analyzed retrospectively. The ABM areas on T1-weighted MRI were contoured. The statistical significance between TBM and ABM dose-volume measures was assessed through the utilization of either Student's t-test or Wilcoxon signed rank test. Logistic and linear regression models were employed to analyze the correlation between dose-volume parameters (V5-V50) and HT occurrence in pelvic ABM and TBM. Receiver operating characteristic (ROC) curves were used to compare predictors of HT2+. Results: There were significant differences in dosimetric parameters between ABM and TBM. Logistic regression analysis showed that ABM V5, ABM V10, ABM V15, ABM V20, and TBM V5 were significantly associated with the occurrence of HT2+ in pelvic malignancies. Linear regression analysis showed that ABM V5, ABM V10, and ABM V15 were significantly associated with white blood cell (WBC), absolute neutrophil count (ANC), hemoglobin (Hb), and lymphocyte (Lym) nadir. ABM V5, ABM V10, ABM V15, and ABM V30 were predictive of HT2+. Conclusions: More accurate prediction of HT in patients receiving pelvic radiotherapy may be achieved by relying on dose-volume parameters of MRI-based ABM. Further prospective studies are needed to confirm this.

Impact of Skeletal Muscle Depletion on Patients with Myelodysplastic Syndrome Treated with Azacitidine.

BACKGROUND: Azacitidine (AZA) is the standard treatment for patients with high-risk myelodysplastic syndromes (MDS). The impact of skeletal muscle depletion (SMD), which is associated with outcomes of hematological malignancies, on the clinical course of MDS patients treated with AZA was investigated. METHODS: This retrospective, observational study included 50 MDS patients treated with AZA. Muscle mass was evaluated using the skeletal muscle index (SMI), which is the area of muscle mass at the third lumbar vertebra on CT images divided by the square of the height. RESULTS: Of the enrolled patients, 39 were males, and their median age was 69.5 years. Twenty-seven (20 male and 7 female) patients showed SMD. The median survival was 13.4 months in the SMD group and 15.2 months in the non-SMD group, with no significant difference and no significant association between the response rate or severe non-hematological toxicities and the presence of SMD. By contrast, grade 3-4 anemia and thrombocytopenia were significantly more frequent in the SMD group than in the non-SMD group. SMD was associated with severe anemia and thrombocytopenia in MDS patients treated with AZA. CONCLUSION: Reduced skeletal muscle mass may predict severe hematological toxicity in MDS patients treated with AZA.

Visceral obesity and sarcopenia as predictors of efficacy and hematological toxicity in patients with metastatic breast cancer treated with CDK 4/6 inhibitors.

PURPOSE: We aimed to investigate whether visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and skeletal muscle area (SMA) index are predictive for efficacy and hematological toxicity in ER + HER2-metastatic breast cancer (BC) patients who received CDK 4/6 inhibitors. METHODS: This retrospective cohort study analyzed 52 patients who were treated with CDK 4/6 inhibitors between January 2018 and February 2021. The values of VAT, SAT, SMA indices and hematological parameters were noted before the start, at the third and sixth months of this treatment. The skeletal muscle area (SMA) and adipose tissue measurements were calculated at the level of the third lumbar vertebra. A SMA-index value of <40 cm2/m2 was accepted as the threshold value for sarcopenia. RESULTS: Patients with sarcopenia had a worse progression-free survival (PFS) compared to patients without sarcopenia (19.6 vs. 9.0 months, p = 0.005). Patients with a high-VAT-index had a better PFS (20.4 vs. 9.3 months, p = 0.033). Only the baseline low-SMA- index (HR: 3.89; 95% CI: 1.35-11.25, p = 0.012) and baseline low-VAT-index (HR: 2.15; 95% CI: 1.02-4.53, p = 0.042) had significantly related to poor PFS in univariate analyses. The low-SMA-index was the only independent factor associated with poor PFS (HR: 3.99; 95% CI: 1.38-11.54, p = 0.011). No relationship was observed between body composition parameters and grade 3-4 hematological toxicity. CONCLUSION: The present study supported the significance of sarcopenia and low visceral adipose tissue as potential early indicators of poor PFS in patients treated with CDK 4/6 inhibitors.

Pelvic bone marrow dose-volume predictors of late lymphopenia following pelvic lymph node radiation therapy for prostate cancer.

BACKGROUND AND PURPOSE: Given the substantial lack of knowledge, we aimed to assess clinical/dosimetry predictors of late hematological toxicity on patients undergoing pelvic-nodes irradiation (PNI) for prostate cancer (PCa) within a prospective multi-institute study. MATERIALS AND METHODS: Clinical/dosimetry/blood test data were prospectively collected including lymphocytes count (ALC) at baseline, mid/end-PNI, 3/6 months and every 6 months up to 5-year after PNI. DVHs of the Body, ileum (BMILEUM), lumbosacral spine (BMLS), lower pelvis (BMPELVIS), and whole pelvis (BMTOT) were extracted. Current analysis focused on 2-year CTCAEv4.03 Grade ≥ 2 (G2+) lymphopenia (ALC < 800/µL). DVH parameters that better discriminate patients with/without toxicity were first identified. After data pre-processing to limit overfitting, a multi-variable logistic regression model combining DVH and clinical information was identified and internally validated by bootstrap. RESULTS: Complete data of 499 patients were available: 46 patients (9.2 %) experienced late G2+ lymphopenia. DVH parameters of BMLS/BMPELVIS/BMTOT and Body were associated to increased G2+ lymphopenia. The variables retained in the resulting model were ALC at baseline [HR = 0.997, 95 %CI 0.996-0.998, p < 0.0001], smoke (yes/no) [HR = 2.9, 95 %CI 1.25-6.76, p = 0.013] and BMLS-V ≥ 24 Gy (cc) [HR = 1.006, 95 %CI 1.002-1.011, p = 0.003]. When acute G3+ lymphopenia (yes/no) was considered, it was retained in the model [HR = 4.517, 95 %CI 1.954-10.441, p = 0.0004]. Performances of the models were relatively high (AUC = 0.87/0.88) and confirmed by validation. CONCLUSIONS: Two-year lymphopenia after PNI for PCa is largely modulated by baseline ALC, with an independent role of acute G3+ lymphopenia. BMLS-V24 was the best dosimetry predictor: constraints for BMTOT (V10Gy < 1520 cc, V20Gy < 1250 cc, V30Gy < 850 cc), and BMLS (V24y < 307 cc) were suggested to potentially reduce the risk.

Comparative Analysis of VMAT and IMRT Techniques: Evaluation of Dose Constraints and Bone Marrow Sparing in Cervical Cancer Patients Undergoing Chemoradiotherapy.

BACKGROUND: Carcinoma of the cervix is a globally significant cause of morbidity and mortality among women. Concurrent chemoradiotherapy, a standard approach for locally advanced cervical cancer, invariably involves pelvic irradiation. Although this strategy is effective, it inevitably affects the pelvic bone marrow, a crucial hematopoietic site, and leads to hematological toxicity The potential of IMRT to spare bone marrow in pelvic irradiation settings has been an area of significant interest, with the aim to mitigate the hematological toxicity associated with pelvic radiotherapy. Radiotherapy techniques have evolved in terms of conformity and normal tissue sparing. Our study intends to explore the use of BM sparing techniques among patients of carcinoma cervix. PATIENTS AND METHODS: Twenty patients of carcinoma cervix FIGO Stage IIIB treated with concurrent chemoradiotherapy were selected for this study. The external contour of bones was delineated on planning CT as a surrogate for BM. We generated three plans on a single patient:1. without BM as the dose constraint, namely N-IMRT plan; 2. with BM constraint, namely BMS-IMRT plan; 3. VMAT plan in which BM constraint was given. The dose volume histogram (DVH) for planning target volume (PTV) and organs at risk (OAR) were analyzed. BM parameters: V10, V20, V30, V40, mean, maximum and minimum dose were compared.  Results: PTV coverage was comparable in all techniques. VMAT plans resulted in superior BM sparing compared with N-IMRT plan (P-<0.001) and BMS-IMRT plan (P-<0.001, 0.021 and 0.001 respectively for V20, V30 and V40). VMAT plans had better CI compared with BMS-IMRT (P-0.002) and N-IMRT (P-0.001) plans. CONCLUSION: Our study adds to the growing evidence that VMAT might be the preferred technique for patients with carcinoma of the cervix undergoing concurrent chemoradiotherapy, as it provides comparable target coverage and better sparing of bone marrow compared to IMRT.

A novel model to predict the risk of hematological toxicity in lung adenocarcinoma patients with pemetrexed plus platinum chemotherapy based on real-world data.

BACKGROUND: Pemetrexed plus platinum chemotherapy is the first-line treatment option for lung adenocarcinoma. However, hematological toxicity is major dose-limiting and even life-threatening. The ability to anticipate hematological toxicity is of great value for identifying potential chemotherapy beneficiaries with minimal toxicity and optimizing treatment. The study aimed to develop and validate a prediction model for hematologic toxicity based on real-world data. METHODS: Data from 1754 lung adenocarcinoma patients with pemetrexed plus platinum chemotherapy regimen as first-line therapy were used to establish and calibrate a risk model for hematological toxicity using multivariate and stepwise logistic regression analysis based on real-world data. The predictive performance of the model was tested in a validation cohort of 753 patients. An area under the curve (AUC) of the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis were used to assess the prediction model. RESULTS: 5 independent factors (platinum, pre-use vitamin B12, cycle of chemotherapy before hematological toxicity, Hb before first chemotherapy, and PLT before first chemotherapy) identified from multivariate and stepwise logistic regression analysis were included in the prediction model. The hematological toxicity prediction model achieved a sensitivity of 0.840 and a specificity of 0.822. The model showed good discrimination in both cohorts (an AUC of 0.904 and 0.902 for the derivation and validation cohort ROC) at the cut-off value of 0.591. The calibration curve showed good agreement between the actual observations and the predicted results. CONCLUSION: We developed a prediction model for hematologic toxicity with good discrimination and calibration capability in lung adenocarcinoma patients receiving a pemetrexed plus platinum chemotherapy regimen based on real-world data.

The Protective Potential of Petroselinum crispum (Mill.) Fuss. on Paracetamol-Induced Hepatio-Renal Toxicity and Antiproteinuric Effect: A Biochemical, Hematological, and Histopathological Study.

Background and Objectives: Paracetamol overdose is a significant global issue due to its widespread use, which can lead to a lack of awareness regarding its potential side effects. Paracetamol can harm the liver, possibly resulting in liver failure. Conversely, this study employed extracts from Petroselinum crispum (PC), known for its rich content of bioactive compounds, with demonstrated antioxidant properties shown in previous research as well as protective effects against various diseases. The primary objective of this study was to investigate the potential protective effects of Petroselinum crispum on altered hematological and biochemical parameters in the blood of rats exposed to paracetamol. Materials and Methods: The study involved twenty Wistar rats divided into four groups. Different groups of male rats were administered PC extract at 200 mg/kg body weight daily for 15 days, along with a standard reference dose of paracetamol at 200 mg/kg. The study assessed hepatoprotection capacity by analyzing liver enzymes such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, albumin, and lipid profiles. Renal safety was evaluated through creatinine, urea, uric acid, lactate dehydrogenase (LDH), and total protein. Additionally, histopathological examinations of the liver and kidneys were conducted. Results: Following Paracetamol overdose, there were reductions in hemoglobin levels, serum total protein, albumin, and uric acid. Paracetamol overdose also elevated levels of several blood biomarkers, including creatinine, urea, nitrogen, ALT, AST, triglycerides, LDH activity, white blood cell count, and platelet count compared to the control group. However, using an ethanolic extract of Petroselinum crispum significantly mitigated the severity of these alterations and the extent of the effect correlated with the dose administered. Parsley extract helped prevent proteinuria and low hemoglobin, which are common side effects of Paracetamol. Conclusions: Therefore, parsley may hold promise in managing liver and kidney conditions-particularly in addressing proteinuria. Ultimately, these results may have implications for human health by potentially mitigating paracetamol-induced renal, hepatic, and hematological toxicity.

[Hematological immune-related adverse events of immune checkpoint inhibitors and their management].

Immune checkpoints suppress inappropriate immune responses to self-molecules or cells. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) expressed in T cells are representative molecules involved in the immune checkpoint system. The recent advent of immune checkpoint inhibitors (ICIs) has drastically changed cancer immunotherapy because a substantial proportion of patients with advanced cancers have responded to ICIs and some of them have been cured. This benefit is due to T-cell rescue from immune suppression in their tumor microenvironment by blocking cluster of differentiation 80/CTLA-4 and PD-L1/PD-1 interactions. However, blocking these interactions also liberates T cells that are reactive to self-antigens from tolerance, resulting in the occurrence of autoimmune diseases, that is, immune-related adverse events. Although the primary target organs are the lungs, gastrointestinal tract, and endocrine glands, hematopoietic cells are also affected in 0.5-3% of patients, potentially resulting in anemia or thrombocytopenia. Because hematopoietic system homeostasis is critical to maintaining life support, the occurrence of grade 3-4 irAEs in the hematopoietic system is directly life-threatening. Herein, we review the relationship between ICIs and toxicities in patients with cancer and describe the characteristics and management strategies for hematological immune-related adverse events.

First-line maintenance therapy with niraparib in advanced platinum-sensitive ovarian cancer: two 'long responder' case reports and review of the current literature.

The standard of care for newly diagnosed advanced ovarian cancer is surgical cytoreduction plus platinum-based chemotherapy; however, recurrent disease frequently occurs after treatment. Poly(ADP-ribose) polymerase (PARP) inhibitors as first-line maintenance therapy have been demonstrated to significantly reduce the risk of disease progression or death in patients with advanced ovarian cancer who have a complete or partial response to first-line platinum-based chemotherapy. Niraparib is the only PARP inhibitor that offers a significant progression-free survival benefit compared with placebo in this patient population regardless of the homologous recombination status. However, predictive factors for treatment responses and approaches to dose optimization remain to be investigated. In this study, two Chinese patients with newly diagnosed advanced ovarian cancer exhibited long-term responses to niraparib treatment, and hematological toxicity was successfully managed by dose adjustment. The literature on clinical trials and real-world experience on the efficacy, tolerability, and dose individualization of niraparib treatment in Western and Chinese patients was also reviewed. Future research is warranted to identify the characteristics of 'long responders' to niraparib treatment.

The Incidence of Hematological Toxicities in Colorectal Cancer Patients Treated With Fluoropyrimidine-Based Regimens at Princess Noorah Oncology Center.

Background Fluoropyrimidine-based regimens are used for the management of colorectal cancer, which is the second most common cancer in Saudi Arabia. We aimed to study the incidence of hematological toxicities in colorectal cancer patients treated with fluoropyrimidine and fluoropyrimidine-based regimens at Princess Noorah Oncology Center, King Abdulaziz Medical City- Jeddah, Saudi Arabia.  Methods A retrospective cohort study that included adult colorectal cancer patients who were treated with fluoropyrimidine-based regimens from January 1, 2018 to December 31, 2018 at Princess Noorah Oncology Center, Jeddah, Saudi Arabia was performed. Our primary objective was to determine the incidence of anemia, neutropenia, and thrombocytopenia in colorectal cancer patients treated with fluoropyrimidines and fluoropyrimidine-based regimens. Secondary objectives were to assess the grade of hematological toxicities associated with 5-fluorouracil (5-FU) use and to determine the frequency of unplanned hospital admissions or emergency department (ED) visits after receiving fluoropyrimidine-based regimens. The collected data contained patients' characteristics (weight, height, age, gender, and diagnosis), chemotherapy agents, and hematological toxicity-related findings such as absolute neutrophil count, hemoglobin, platelet count, and number of ED visits or hospital admissions during fluoropyrimidine-based chemotherapy regimens. Results Of the 570 cycles of the fluoropyrimidine-based regimen received by 68 patients, hematological toxicities were observed in 508 (89.1%) cycles, and grade ≥ 3 grade toxicities were found in 46 (8.1%) cycles. The results demonstrated a statistically significant difference in the incidence of grade 3-4 neutropenia between patients who received bolus administration of 5-FU and those who did not (8.5% vs. 2.3% respectively, p=0.025). The incidence of grade 3-4 anemia was higher in the bolus group (11.3%) compared to the group where bolus was omitted (4.6%); however, the difference was not statistically significant (p=0.059). Furthermore, there was no significant difference among the two groups for grade 3 and grade 4 thrombocytopenia (0.0% with bolus given and 0.7% with bolus omission p=1.00). Conclusion Our retrospective study showed that there have been significantly higher grade 3-4 hematological toxicities observed with bolus administration of 5-FU, which confirms the previous reports.

Influencia de la hiperfiltración glomerular en la menor toxicidad hematológica inducida por linezolid / Influence of augmented renal clearance on the lower incidence of linezolid-related hematological toxicity

Objetivos linezolid es una oxazolidina frecuentemente implicada en el desarrollo de toxicidad hematológica, siendo el aclaramiento renal el mecanismo mayoritario en su eliminación. Se evaluó la influencia de la hiperfiltración glomerular en la toxicidad hematológica inducida por linezolid en pacientes con aclaramiento incrementado frente a pacientes con función renal normal. Material y métodos se diseñó un estudio observacional y retrospectivo en pacientes hospitalizados, tratados al menos 5 días con linezolid entre 2014 y 2019. Se compararon pacientes con aclaramiento de creatinina incrementado (≥130 mL/min) y normal (60–90 mL/min). Se definió la toxicidad hematológica como el descenso en plaquetas y hemoglobina del 25% y en neutrófilos del 50% frente a los valores basales. Se clasificó el grado de toxicidad según Common Terminology Criteria for Adverse Events v5 y se comparó la incidencia entre ambos grupos mediante Chi-cuadrado y Fisher. Así mismo, se calculó el porcentaje de disminución de los 3 parámetros y su asociación mediante el test de Mann–Whitney y se registraron las interrupciones y transfusiones asociadas.Resultados se evaluaron 30 pacientes hiperfiltradores y 38 normofiltradores. El 16,66% de hiperfiltradores presentó toxicidad hematológica frente al 44,74% (p = 0,014). La trombocitopenia fue del 13,33 vs. 36,84% (p = 0,051), la anemia del 3,3 vs. 10,52% (p = 0,374) y la neutropenia del 10 vs. 23,68% (p = 0,204). La mediana del porcentaje de descenso plaquetario en hiperfiltradores frente a normofiltradores fue del −10,36 (−193,33–62,03) vs. 2,68 (−163,16–82,71) (p = 0,333), de hemoglobina 2,50 (−12,12–25,93) vs. 9,09 (−17,72–30,63) (p = 0,047) y de neutrófilos 9,14 (−73,91–76,47) vs. 27,33 (−86,66–90,90) (p = 0,093). El 10,5% con filtrado normal presentó toxicidad grado 3 o superior, el 2,6% interrumpió el tratamiento y el 5,2% requirieron transfusiones... (AU)

Objectives Linezolid is an oxazolidin commonly related to the development of hematological toxicity, being renal clearance the major factor involved in the drug clearance. The aim of this study is to evaluate the influence of increased filtration rates in the incidence of linezolid-induced hematological toxicity by comparing augmented renal clearance (ARC) patients versus normal renal function patients. Material and methods A retrospective, observational study was conducted on hospitalized patients treated with linezolid for 5 days or more during 2014–2019 period. Patients with a filtration rate of ≥130 mL/min versus reference patients (60–90 mL/min) were compared. Hematological toxicity was defined as a decrease of 25% in platelets, of 25% in hemoglobin and/or 50% in neutrophils from baseline. Toxicity relevance was classified according to Common Terminology Criteria for Adverse Events v5. Incidence of hematological toxicity between groups was studied by chi-square and Fisher test. Furthermore, percentaje disminution of all three parameters was calculated and compared by Mann–Whitney test and treatment interruption and tranfusion requirements were registered. Results 30 ARC patients and 38 reference patients were included. Hematological toxicity was observed in 16.66% of ARC patients vs 44.74% of reference patients (p = 0.014); thrombocytopenia in 13.33% vs 36.84% (p = 0.051), anemia in 3.3% vs 10.52% (p = 0.374) and neutropenia in 10% vs 23.68% (p = 0.204). Median percentaje of platelets decrease in ARC patients was −10.36 (−193.33–62.03) vs 2.68 (−163.16–82.71) in reference patients (p = 0.333), while hemoglobin decrease was 2.50 (−12.12–25.93) vs 9.09 (−17.72–30.63) (p = 0.047) and neutrophils decrease was 9.14 (−73.91–76.47) vs 27.33 (−86.66–90.90) (p = 0.093). 10.5% of normal renal function patients reported at least one adverse event grade 3 or superior while 2.6% of them interrupted treatment and 5.2% had tranfusion requirements... (AU)

A prediction model for severe hematological toxicity of BTK inhibitors.

Bruton's tyrosine kinase inhibitor (BTKi) has revolutionized the treatment of B-cell lymphomas. However, BTKi-related hematological toxicity hinders treatment continuity and may further affect clinical efficacy. To identify risk factors and predict the likelihood of BTKi-related hematological toxicities, we constructed and validated a prediction model for severe hematological toxicity of BTKi. Approved by the hospital medical science research ethics committee (No. M2022427), we collected real-world data in patients treated with BTKi from a Lymphoma Research Center in China. The outcome of interest was severe hematological toxicity caused by BTKi. 36 candidate variables were categorized into demographics, diagnostic and treatment information, laboratory data, and medical history. The study sample was randomly divided into training (70%) and validation (30%) sets. We developed and compared the performance of various modelling methods, including decision tree (DT), random forest (RF), gradient boosting decision tree (GBDT), extreme gradient boosting (XGBoost), light gradient boosting machine (LightGBM), and logistic regression (LR). Finally, we constructed a Web-calculator of the optimal model to estimate the risk of hematological toxicity. This study was designed, conducted and reported strictly in compliance with the TRIPOD checklist. Data from a total 121 patients were included [median age, 65 years (range, 56-73 years); 74 (61.15%) men; 47 (38.84%) severe hematological toxicity]. The XGBoost model demonstrated better overall properties than other models, achieving high discrimination (AUC: 0.671; accuracy: 0.730; specificity: 0.913) and clinical benefit. The following 10 variables were used to develop the XGBoost model: white blood cell count (WBC), neutrophil count (Neut), red blood cell count (RBC), platelet count (PLT), fibrinogen (Fib), total protein (TP), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), gender and type of BTKi. SHAP values demonstrated insightful associations between these variables and hematological toxicity. Finally, to facilitate clinical and research use, we also deploy the XGBoost model on a web-calculator for free access. The XGBoost model with promising accuracy was developed to predict the severe hematological toxicity of BTKi. It helps to strengthen the proactive monitoring and management of patients with hematological toxicity, and thus achieve long-term continuous BTKi treatment.

The CAR-HEMATOTOX score as a prognostic model of toxicity and response in patients receiving BCMA-directed CAR-T for relapsed/refractory multiple myeloma.

BACKGROUND: BCMA-directed CAR T-cell therapy (CAR-T) has altered the treatment landscape of relapsed/refractory (r/r) multiple myeloma, but is hampered by unique side effects that can lengthen hospital stays and increase morbidity. Hematological toxicity (e.g. profound and prolonged cytopenias) represents the most common grade ≥ 3 toxicity and can predispose for severe infectious complications. Here, we examined the utility of the CAR-HEMATOTOX (HT) score to predict toxicity and survival outcomes in patients receiving standard-of-care idecabtagene vicleucel and ciltacabtagene autoleucel. METHODS: Data were retrospectively collected from 113 r/r multiple myeloma patients treated between April 2021 and July 2022 across six international CAR-T centers. The HT score-composed of factors related to hematopoietic reserve and baseline inflammatory state-was determined prior to lymphodepleting chemotherapy. RESULTS: At lymphodepletion, 63 patients were HTlow (score 0-1) and 50 patients were HThigh (score ≥ 2). Compared to their HTlow counterparts, HThigh patients displayed prolonged severe neutropenia (median 9 vs. 3 days, p < 0.001), an increased severe infection rate (40% vs. 5%, p < 0.001), and more severe ICANS (grade ≥ 3: 16% vs. 0%, p < 0.001). One-year non-relapse mortality was higher in the HThigh group (13% vs. 2%, p = 0.019) and was predominantly attributable to fatal infections. Response rates according to IMWG criteria were higher in HTlow patients (≥ VGPR: 70% vs. 44%, p = 0.01). Conversely, HThigh patients exhibited inferior progression-free (median 5 vs. 15 months, p < 0.001) and overall survival (median 10.5 months vs. not reached, p < 0.001). CONCLUSIONS: These data highlight the prognostic utility of the CAR-HEMATOTOX score for both toxicity and treatment response in multiple myeloma patients receiving BCMA-directed CAR-T. The score may guide toxicity management (e.g. anti-infective prophylaxis, early G-CSF, stem cell boost) and help to identify suitable CAR-T candidates.

Influence of augmented renal clearance on the lower incidence of linezolid-related hematological toxicity. / Influencia de la hiperfiltración glomerular en la menor toxicidad hematológica inducida por linezolid.

OBJECTIVES: Linezolid is an oxazolidin commonly related to the development of hematological toxicity, being renal clearance the major factor involved in the drug clearance. The aim of this study is to evaluate the influence of increased filtration rates in the incidence of linezolid-induced hematological toxicity by comparing augmented renal clearance (ARC) patients versus normal renal function patients. MATERIAL AND METHODS: A retrospective, observational study was conducted on hospitalized patients treated with linezolid for 5 days or more during 2014-2019 period. Patients with a filtration rate of ≥130 mL/min versus reference patients (60-90 mL/min) were compared. Hematological toxicity was defined as a decrease of 25% in platelets, of 25% in hemoglobin and/or 50% in neutrophils from baseline. Toxicity relevance was classified according to Common Terminology Criteria for Adverse Events v5. Incidence of hematological toxicity between groups was studied by chi-square and Fisher test. Furthermore, percentaje disminution of all three parameters was calculated and compared by Mann-Whitney test and treatment interruption and tranfusion requirements were registered. RESULTS: 30 ARC patients and 38 reference patients were included. Hematological toxicity was observed in 16.66% of ARC patients vs 44.74% of reference patients (p = 0.014); thrombocytopenia in 13.33% vs 36.84% (p = 0.051), anemia in 3.3% vs 10.52% (p = 0.374) and neutropenia in 10% vs 23.68% (p = 0.204). Median percentaje of platelets decrease in ARC patients was -10.36 (-193.33-62.03) vs 2.68 (-163.16-82.71) in reference patients (p = 0.333), while hemoglobin decrease was 2.50 (-12.12-25.93) vs 9.09 (-17.72-30.63) (p = 0.047) and neutrophils decrease was 9.14 (-73.91-76.47) vs 27.33 (-86.66-90.90) (p = 0.093). 10.5% of normal renal function patients reported at least one adverse event grade 3 or superior while 2.6% of them interrupted treatment and 5.2% had tranfusion requirements. No major events or interruptions were reported in ARC patients. CONCLUSION: Our findings suggest a lower incidence and clinical relevance of hematological toxicity in augmented renal clearance patients. Thrombocytopenia was the major event in both populations. This might be related to a lower exposure to the drug due to the higher clearance and likely lower therapeutic efficiency. These results suggest a potential benefit of therapeutic drug monitoring on high risk patients.

The effect of radiotherapy time and dose on acute hematologic toxicity during concurrent postoperative chemoradiotherapy for early high-risk cervical cancer.

Objective: This study aims to analyze the characteristics and factors that influence acute hematological toxicity (HT) during concurrent chemoradiotherapy (CCRT) for cervical cancer, as well as to provide reference data for clinical practice. Methods: Patients with FIGO IB1-IIA2 cervical cancer who underwent CCRT from May 2018 to August 2020 were included in this study retrospectively. All patients had received external beam radiation therapy and platinum-based concurrent chemotherapy. HT was assessed according to CTCAE 5.0. The pelvic bone marrow was redrawn on the original CT images and divided into four parts: the whole pelvic bone marrow (WP-BM), iliac bone marrow (IL-BM), lower pelvic bone marrow (LP-BM), and lumbosacral bone marrow (LS-BM). The radiation dose and volume of each part of the pelvic bone marrow were recalculated in a new plan created using the original planning parameters. The corresponding dose-volume histogram (DVH) was generated to obtain the bone marrow volumes receiving 10Gy, 20Gy, 30Gy, 40Gy, 45Gy, and 50Gy. Results: In 112 patients, the incidences of grade 2 or higher leukopenia, anemia, thrombocytopenia, and neutropenia were 49.1%, 2.7%, 1.8%, and 20.5%, respectively. Leukopenia was linked to LS-V20 (r = -0.310; P = 0.006) and radiotherapy treatment lengths (days) (r = -0.416; P = 0.013). Anemia was associated with WP-V30, WP-V40, WP-V45, WP-V50, IL-V20, IL-V40, ILV45, IL-V50, LP-V30, LP-V40, LP-V45, and LP-V50 (P <0.05). Thrombocytopenia (r = -0.304, P = 0.007) and neutropenia (r = -0.368, P = 0.009) was associated only with the length of radiotherapy treatment (day). Multiple regression analysis showed that only anemia was negatively correlated with WP-V30, IL-V40, and LP-V40 (P <0.05). Conclusions: Acute HT during CCRT in early-stage high-risk cervical cancer may be related to the duration of radiotherapy and the volume of different radiotherapy doses received at different parts in the pelvic bone marrow.

Dosimetric correlation of bone marrow irradiation with acute hematological toxicity in concurrent chemoradiation of cervical carcinoma patients.

Background: Many acute toxicities are associated with concurrent chemoradiation in cervical carcinoma, which includes burning micturition, burning defecation, pain lower abdomen, increased frequency of stools along with Acute Hematological Toxicity (AHT). AHT is often an expected adverse effect, which can lead to treatment interruptions and decreased response rates. The purpose of this study is to analyze if there are any dosimetric constraints on the volume of bone marrow irradiated with AHT in cervical carcinoma patients treated with concurrent chemoradiation. Material and Methods: In this retrospective study of 215 patients, a total of 180 patients were eligible for analysis. Multiple parameters of bone marrow volumes (whole pelvis bone marrow and its sub-volumes--ilium, lower pelvis, and lumbosacral spine) which were contoured individually for all patients were assessed to have any statistically significant association with AHT. Results: The median age of the cohort was 57 years and majority of cases were locally advanced (stage IIB-IVA: 88.3%). Grade I, II, III leukopenia was seen in 44, 25, and 6 patients, respectively. A statistically significant correlation between grade 2+ and 3+ leukopenia was seen if bone marrow V10, V20, V30, and V40 were more than 95%, 82%, 62%, and 38%, respectively. In subvolume analysis, volumes of lumbosacral spine V20, V30, and V40 more than 95%, 90%, and 65%, respectively, were statistically significant for AHT. Conclusion: Bone marrow volumes should also be given a constraint and should be tried to be achieved so that it leads to minimal treatment breaks due to AHT.