Chemotherapy-induced Myelosuppression Research Articles

Trilaciclib dosage in Chinese patients with extensive-stage small cell lung cancer: a pooled pharmacometrics analysis.

This study aimed to analyze potential ethnic disparities in the dose-exposure-response relationships of trilaciclib, a first-in-class intravenous cyclin-dependent kinase 4/6 inhibitor for treating chemotherapy-induced myelosuppression in patients with extensive-stage small cell lung cancer (ES-SCLC). This investigation focused on characterizing these relationships in both Chinese and non-Chinese patients to further refine the dosing regimen for trilaciclib in Chinese patients with ES-SCLC. Population pharmacokinetic (PopPK) and exposure-response (E-R) analyses were conducted using pooled data from four randomized phase 2/3 trials involving Chinese and non-Chinese patients with ES-SCLC. PopPK analysis revealed that trilaciclib clearance in Chinese patients was approximately 17% higher than that in non-Chinese patients with ES-SCLC. Sex and body surface area influenced trilaciclib pharmacokinetics in both populations but did not exert a significant clinical impact. E-R analysis demonstrated that trilaciclib exposure increased with a dosage escalation from 200 to 280 mg/m2, without notable changes in myeloprotective or antitumor efficacy. However, the incidence of infusion site reactions, headaches, and phlebitis/thrombophlebitis rose with increasing trilaciclib exposure in both Chinese and non-Chinese patients with ES-SCLC. These findings suggest no substantial ethnic disparities in the dose-exposure-response relationship between Chinese and non-Chinese patients. They support the adoption of a 240-mg/m2 intravenous 3-day or 5-day dosing regimen for trilaciclib in Chinese patients with ES-SCLC.

Abstract PO5-14-11: Leveraging a pharmacokinetic/pharmacodynamic (PK/PD) model to guide dose optimization of palbociclib (palbo) in combination with vepdegestrant

Abstract Background: Vepdegestrant is a potent, selective, orally bioavailable PROteolysis TArgeting Chimeric (PROTAC) estrogen receptor (ER) degrader. A phase 3 study will evaluate the combination of vepdegestrant and palbo in participants with ER+, human epidermal growth factor receptor negative (HER2[-]) advanced/metastatic breast cancer (NCT05909397). The recommended starting dose of palbo is 125 mg once daily for 3 weeks followed by 1 week off treatment for each 28-day cycle in combination with aromatase inhibitors or fulvestrant.1 Neutropenia is the most frequently reported adverse event for patients receiving palbo in clinical trials.1 When co-administered with vepdegestrant in a phase 1b cohort of the first-in-human phase 1/2 study (NCT04072952), higher rates of medically manageable neutropenia and increased palbo concentrations were observed compared with historical studies of palbo administered with letrozole or fulvestrant.1 Reduced starting doses of palbo (100 mg, 75 mg) are planned to mitigate increased rates of Grade 4 neutropenia while maintaining similar palbo exposure when combined with vepdegestrant. The analysis objective was to leverage a PK/PD model to simulate palbo exposure and neutropenia taking into consideration the dose modification and management for hematologic toxicities provided in the palbo prescribing information.1 Methods: A Monte-Carlo simulation platform2 was utilized to monitor absolute neutrophil count (ANC) in 1000 patients with weekly monitoring over 4 cycles (112 days) of palbo administration. Simulated ANC was determined using a semi-mechanistic model of chemotherapy-induced myelosuppression as previously described.3 Palbo dose modification methods included both dose hold and reduction based on an individual’s ANC and thresholds for Grade 3 (< 1000 mm3) or Grade 4 (< 500 mm3) neutropenia. Simulated neutropenia and exposures from palbo starting doses of 100 mg and 75 mg in the presence of a 25%, 49%, and 67% increase in typical exposure were compared to a palbo starting dose of 125 mg in the absence of increased exposure (historical reference). Average concentration is calculated as the cumulative area under the curve divided by the simulation duration. Results: After a 4-cycle simulation, the 100 mg starting dose of palbo simulated across varying levels of increased exposure resulted in similar Grade 4 neutropenia incidence and average concentration compared to the reference simulation (< 12% difference). The 75 mg starting dose of palbo simulated across varying levels of increased exposure resulted in lower Grade 4 neutropenia incidence as well as lower average concentration compared to the reference simulation (Table 1). Conclusion: The PK/PD model simulation allows for relative comparison of Grade 4 neutropenia incidence and average palbo concentration between the planned reduced starting doses of palbo in the context of increased exposure relative to standard palbo dosing, i.e., without vepdegestrant. This simulation indicates a reduced dose of palbo (100 mg) in combination with vepdegestrant produces similar incidence of Grade 4 neutropenia and comparable average palbo concentration compared to historical reference providing additional support for the study lead-in of NCT05909397. Citations: 1. IBRANCE® (Palbociclib) [Package Insert]. New York, US: Pfizer, Inc. 2. Jermain et al. ACOP13 2023. 3. Friberg et al. J Clin Oncol 2002. Table 1. 4-cycle simulation results comparing reduced starting doses of palbociclib in the presence of increased typical exposure to a reference standard palbociclib dosing in the absence of increased exposure Citation Format: Brian Jermain, Derek Yang, Weiwei Tan, Julia Perkins-Smith, Justin Hoffman, Jason Williams. Leveraging a pharmacokinetic/pharmacodynamic (PK/PD) model to guide dose optimization of palbociclib (palbo) in combination with vepdegestrant [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-14-11.

Trilaciclib: A Novel Approach to Mitigate Chemotherapy-Induced Myelosuppression in Cancer Treatment

AbstractTrilaciclib, a novel cyclin-dependent kinase 4/6 inhibitor, has demonstrated the ability to protect bone marrow from chemotherapy toxicity, improving patients' quality of life (QoL). This review describes the mechanism of action, efficacy, and toxicity profile of trilaciclib. Trilaciclib halts retinoblastoma protein phosphorylation during the early G1 phase, preventing the transition from the G1/S phase and inducing the cell cycle arrest in the G1 phase, which protects the hematopoietic cell lineages. Trilaciclib is indicated by the United States Food and Drug Administration and National Comprehensive Cancer Network to decrease the incidence of chemotherapy-induced myelosuppression in adult patients before a platinum/etoposide or topotecan containing regimen for extensive stage small cell lung cancer. Its ease of administration as an intravenous infusion, given before starting chemotherapy, and the favorable side effect profile make it a better-tolerated drug, improving patient QoL.

Laryngeal Small Cell Neuroendocrine Carcinoma: Case Report and Literature Review

Neuroendocrine malignancy of the larynx are rare but represents the first nonsquamous tumor in this localization. The World Health Organization (WHO) classifies these tumors into 3 groups: typical carcinoid, atypical carcinoid tumor, and small cell neuroendocrine carcinoma (SmCC). SmCC have an aggressive natural history characterized by widespread metastasis. Treatment is based on concomitant or sequential chemoradiation. We report herein the case of a 69 years old men, who presented with laryngeal small cell neuroendocrine carcinoma revealed by progressive dysphonia and cervical lymphadenopathy. The diagnosis was confirmed by biopsy and histopathological study. Pre-treatment workup was negative for metastatic disease. He has received chemotherapy based on etoposide and cisplatin followed by chemoradiation. The evolution was marked by the development of metachronous lung metastasis. Unfortunately, the patient passed away during a chemotherapy-induced myelosuppression after the first palliative chemotherapy cure.

Effect of Hepatic Impairment on Trilaciclib Pharmacokinetics.

Trilaciclib is a first-in-class, intravenous cyclin-dependent kinase 4 and 6 inhibitor approved for reducing the incidence of chemotherapy-induced myelosuppression in adult patients with extensive-stage small cell lung cancer receiving a platinum/etoposide-containing or topotecan-containing regimen. No dose adjustment is recommended for participants with mild hepatic impairment (HI) based on previous population pharmacokinetic (PK) analysis. This open-label, parallel-group study examined the impact of moderate and severe HI on the PK of trilaciclib. The study employed a reduced study design. Participants with moderate (Child-Pugh B, n = 8) and severe (Child-Pugh C, n = 5) HI and matched healthy controls (n = 11) received a single intravenous dose of trilaciclib 100 mg/m2. The unbound fraction of trilaciclib was comparable between the HI groups and the matched healthy control group. The unbound trilaciclib extent of exposure (i.e., area under the concentration-time curve) in participants with moderate and severe HI was ∼40% and ∼60% higher, respectively, compared with healthy matched controls based on Child-Pugh classification. Ad hoc analysis using National Cancer Institute classification showed similar results. The US Food and Drug Administration-approved trilaciclib dose of 240 mg/m2 should be reduced by ∼30%, to 170 mg/m2, for patients with moderate or severe HI.

The impact of myelosuppression on quality of life of patients treated with chemotherapy.

Side effects from chemotherapy-induced myelosuppression can negatively affect patients' quality of life (QoL). Neutropenia increases infection risk, and anemia frequently results in debilitating fatigue. Additionally, the bleeding risk associated with thrombocytopenia can lead to fear and anxiety. However, traditional interventions for myelosuppression fall short of the ideal. Granulocyte colony-stimulating factors reduce the risk of severe neutropenia but commonly lead to bone pain. Erythropoiesis-stimulating agents are not always effective and may cause thromboembolic events, while transfusions to correct anemia/thrombocytopenia are associated with transfusion reactions and volume overload. Trilaciclib, which is approved for reducing myelosuppression in patients with extensive-stage small cell lung cancer, together with several investigational agents in development for managing myelosuppression have the potential to improve QoL for patients on chemotherapy.

Enhancer mutations modulate the severity of chemotherapy-induced myelosuppression.

Non-small cell lung cancer is often diagnosed at advanced stages, and many patients are still treated with classical chemotherapy. The unselective nature of chemotherapy often results in severe myelosuppression. Previous studies showed that protein-coding mutations could not fully explain the predisposition to myelosuppression. Here, we investigate the possible role of enhancer mutations in myelosuppression susceptibility. We produced transcriptome and promoter-interaction maps (using HiCap) of three blood stem-like cell lines treated with carboplatin or gemcitabine. Taking advantage of publicly available enhancer datasets, we validated HiCap results in silico and in living cells using epigenetic CRISPR technology. We also developed a network approach for interactome analysis and detection of differentially interacting genes. Differential interaction analysis provided additional information on relevant genes and pathways for myelosuppression compared with differential gene expression analysis at the bulk level. Moreover, we showed that enhancers of differentially interacting genes are highly enriched for variants associated with differing levels of myelosuppression. Altogether, our work represents a prominent example of integrative transcriptome and gene regulatory datasets analysis for the functional annotation of noncoding mutations.

Oral manifestations associated with neutropenia in Syrian patients diagnosed with hematological malignancies and undergoing chemotherapy: A cross-sectional study.

Neutropenia can be caused by a variety of congenital and acquired factors, with Chemotherapy-induced myelosuppression being the most common cause. Neutropenia significantly affects oral health, leading to the manifestation of oral lesions such as ulcers, fungal and viral infections, and mucositis. This study aims to investigate oral lesions in patients with hematological malignancies who developed neutropenia after chemotherapy. This cross-sectional study included 50 patients with hematological malignancies. The participants were divided into 2 groups: the first group consisted of 25 patients with hematological malignancies who developed chemotherapy-induced neutropenia and the second group consisted of 25 patients with hematological malignancies who did not develop chemotherapy-induced neutropenia. Patients were assigned to one of the groups based on the absolute neutrophil count (ANC). Full oral clinical examination was performed to determine the presence of oral lesions. In the Chemotherapy-Induced Neutropenia group, the most common lesion was ulceration, observed in 12 patients (48%). Fungal infections were the second most common, present in 5 patients (20%), followed by viral infections in 4 patients (15%), and mucositis, which occurred in a single patient (4%). A statistically significant association was found between neutropenia and the presence of oral ulcers (P value = .015). In contrast, in the Chemotherapy group, oral changes were less frequent. Fungal infections were the most common, occurring in 4 patients (15%), followed by oral mucositis in 3 patients (12%). Ulceration and viral infections were the least common, each observed in 1 patient (4%). The frequency of various forms of oral ulcers increases with the severity of neutropenia. However, there was no significant increase in other oral lesions in patients with neutropenia.

Myeloprotection with trilaciclib in Chinese patients with extensive-stage small cell lung cancer receiving chemotherapy: Results from a randomized, double-blind, placebo-controlled phase III study (TRACES)

IntroductionTrilaciclib is a transient cyclin-dependent kinase 4/6 inhibitor that decreases the incidence of chemotherapy-induced myelosuppression in extensive-stage small cell lung cancer (ES-SCLC). TRACES study was designed to assess the safety, efficacy and pharmacokinetics (PK) of trilaciclib before chemotherapy in Chinese patients with ES-SCLC. MethodsThe study included an open-label safety run-in part (Part 1) and double-blinded, placebo-controlled part (Part 2) where patients received trilaciclib or placebo before chemotherapy. Treatment-naïve or previously treated ES-SCLC patients received intravenous trilaciclib (240 mg/m2) or placebo before etoposide/carboplatin or topotecan, respectively. Primary endpoints were PK, safety and duration of severe neutropenia (DSN) in Cycle 1 in Part 1 and Part 2. Exploratory endpoints included the effect of trilaciclib on other myeloprotection endpoints, safety and antitumor efficacy. ResultsOverall, 95 Chinese patients were enrolled, of which 12 and 83 patients were in Part 1 and Part 2, respectively. In Part 1, trilaciclib was well tolerated. Non-compartmental analysis results revealed no substantial differences in the main exposure parameters. In Part 2, 41 patients received trilaciclib, and 42 received placebo. Patients in trilaciclib arm vs placebo arm had a clinically and statistically significant decrease in DSN (mean [SD]) in Cycle 1 (0 [1.7] vs 2 [3.0] days; P = 0.0003), with improvements in additional neutrophil, red blood cell, and platelet measures. After a median follow-up of 14.1 months, the median overall survival was 12.0 months in trilaciclib arm and 8.8 months in placebo arm (HR, 0.69; 95 % CI: 0.40–1.22). Median progression-free survival was 4.8 months and 4.3 months, respectively (HR, 0.86; 95 % CI: 0.53–1.39). Trilaciclib had a well-tolerated safety profile. ConclusionsTrilaciclib in the Chinese population demonstrated a similar PK and safety profile as seen in other global trials. There was significant reduction of DSN in Cycle 1, thereby substantiating the myeloprotective effects of trilaciclib in Chinese ES-SCLC patients.

Association between chemotherapy-induced myelosuppression and curative efficacy of 2-cycle chemotherapy in small cell lung cancer.

The association of chemotherapy-induced myelosuppression with tumor response and overall survival remained controversial. The study was conducted to investigate the association between them in small cell lung cancer (SCLC). 204 eligible patients with SCLC were respectively included and categorized into three groups (no, mild, and severe myelosuppression) based on myelosuppression degree after the first chemotherapy. Curative efficacy of 2-cycle chemotherapy was evaluated by the objective response rate (ORR) and disease control rate (DCR). Univariate and multivariate logistic regression analyses were conducted to investigate their association. Receiver operator characteristic (ROC) curves, net reclassification index (NRI), and integrated discrimination improvement (IDI) were used to assess the predictive ability of myelosuppression. In the fully-adjusted model, mild (OR, 4.61; 95% CI, 1.35 to 18.27; P = 0.020) and severe (OR, 7.22; 95% CI, 1.30 to 72.44; P = 0.046) myelosuppression were positively associated with DCR. However, only mild myelosuppression was significantly associated with ORR (OR, 2.78; 95% CI, 1.30 to 6.14; P = 0.010). Although we observed evidence of increased ORR in severe myelosuppression, the difference was not statistically significant. Furthermore, based on the results of the ROC curve, NRI and IDI, chemotherapy-induced myelosuppression cannot be used as a accurate and independent predictor for curative efficacy, but it can improve overall prediction accuracy. Chemotherapy-induced myelosuppression was significantly associated with curative efficacy of 2-cycle chemotherapy in SCLC, which could help predict treatment efficacy and guide chemotherapy dosage.

Effect and Mechanism of Specnuezhenide on Chemotherapy-induced Myelosuppression.

This study aimed to investigate the therapeutic effect of Specnuezhenide on myelosuppression induced by chemotherapy and clarify its mechanism. In this study, we measured peripheral blood cells, thymus index, spleen index, bone marrow nucleated cells (BMNCs), and the number of cell colonies counted in vitro by hematopoietic progenitor cells (HPCs) to determine the effect of SPN on cyclophosphamide (CTX)-induced myelosuppression. The alterations in the expression of relevant proteins, the cell cycle, and cytokines associated with hematopoietic cells were examined to better understand how it works. In the cyclophosphamide-induced mouse model, our study discovered that SPN can increase the number of peripheral blood cells and BMNCs after treatment, increase the thymus index and decrease the spleen index, and promote the proliferation and differentiation of HPCs. SPN can improve the production of cultured colonies in vitro, reduce the level of hematopoietic factors in vivo, regulate the proportion of G0/G1 phase cells, and promote the normal growth and development of cells. SPN can increase the expression levels of key proteins MEK and p-ERK in the MAPK signaling pathway, which may be one of the important mechanisms for improving myelosuppression. SPN can enhance the hematological and immunological functions of myelosuppressionmice, and it is hypothesized that SPN is extremely helpful to the hematopoietic and immune functions of tumor patients following chemotherapy. SPN might be used to treat myelosuppression. Additionally, high doses of SPN have a stronger therapeutic effect than low levels of SPN.

Myelosuppression and healthcare utilization among patients with chemotherapy-treated extensive-stage small cell lung cancer (ES-SCLC) with and without trilaciclib from community oncology practices.

527 Background: Trilaciclib has been recently approved for decreasing chemotherapy-induced myelosuppression among adults with ES-SCLC when administered prior to chemotherapy in US. The objective of this study was to estimate the reduction in myelosuppression with trilaciclib use using real-world data. Methods: This study compared ES-SCLC patients receiving trilaciclib and chemotherapy (T) during Feb 2021- Jan 2023 to a comparison cohort not receiving trilaciclib (C) during Apr 2020 – Jan 2023 using EMOL Health’s database, which includes >7 million patients from > 500 community oncology practices. The C cohort was matched to the T cohort based on age, chemotherapy, and line of therapy. Index date was the date of trilaciclib initiation for the T cohort and the date of chemotherapy initiation for the C cohort. Primary outcome measures were the number of events in grade ≥3 myelosuppression (in ≥1, ≥2, 3 lineages). Poisson regression models used to estimate the reduction in risk between the groups. Descriptive statistics of grade ≥3 myelosuppression, cytopenia-related healthcare utilization, and all-cause healthcare resource utilization are presented. Results: 77 T patients and 77 C patients were identified. Demographics and baseline clinical characteristics were similar (age 69.6 vs. 70.8, female 48.1% vs. 55.8% for T and C, respectively, ECOG 0/1 63.6% and 83.1% received 1st line treatment at index for both). Median duration of index treatment was 4 cycles for both cohorts. Rates of grade ≥3 myelosuppression in ≥1, ≥2, 3 lineages were estimated to be reduced in the T by 63.4% (95% CI: 44.1% - 76.7%, p < 0.001), 90.9% (95% CI: 74.7% - 97.8%, p < 0.001), and 91.9% (95% CI: 59.1% - 99.6%, p =0.016), respectively. T patients had lower prevalence of grade ≥3 myelosuppression in ≥1, ≥2, 3 lineages (11.5% vs. 27.1%; 1.2% vs. 11.7%; 0.4% vs. 4.4% per cycle) than C patients during index treatment (Table). Cytopenia-related healthcare utilization was also lower for T patients (G-CSF use 25.9% vs. 59.0%, ESA use 3.7% vs. 5.1%, blood transfusion 1.7% vs. 8.4%, platelet transfusion 1.2% vs. 2.6% per cycle during index treatment). Number of all-cause hospitalizations per patient was 0.35 for T vs. 0.51 for C during index treatment. Among those with ≥1 hospitalizations, median number of hospitalizations was 1.0 for T and 2.0 for C during index treatment. Conclusions: Results from this study suggest that trilaciclib reduces myelosuppression and cytopenia-related healthcare utilization among patients with ES-SCLC in the real world.[Table: see text]

Moxibustion for chemotherapy-induced myelosuppression: A systematic review and meta-analysis

Moxibustion for chemotherapy-induced myelosuppression: A systematic review and meta-analysis

Real-World Outcomes of Trilaciclib Among Patients with Extensive-Stage Small Cell Lung Cancer Receiving Chemotherapy.

Trilaciclib was recently approved in the USA for reducing chemotherapy-induced myelosuppression (CIM) among adults with extensive-stage small cell lung cancer (ES-SCLC) when administered prior to chemotherapy. There is limited understanding of real-world outcomes of trilaciclib. A comprehensive literature review was conducted using a keyword search in the MEDLINE, Embase, and conference abstracts. Additional studies were identified through communications with the authors of relevant studies. Published and unpublished real-world studies of trilaciclib- and comparable non-trilaciclib-treated patients with ES-SCLC were included. Evidence on myelosuppressive hematologic adverse events (HAEs), cytopenia-related healthcare utilization, and other reported outcomes(e.g., hospitalizations, dose reduction, and treatment delay) were synthesized. If feasible, outcomes were compared qualitatively between the trilaciclib and historical reference groups, and between first-line trilaciclib initiators and the overall trilaciclib population. Weighted averages were estimated for selected outcomes using sample size as the weight. The literature search identified five unique studies based on eight records-two included trilaciclib only, two non-trilaciclib only, and one both. In trilaciclib cohorts, the weighted average prevalence of grade ≥ 3 myelosuppressive HAEs in ≥ 1 lineage, ≥ 2 lineages, and all three lineages was 40.5%, 14.5%, and 7.5%, respectively. All rates were numerically lower compared to the historical non-trilaciclib cohorts (58.8%, 28.0%, 13.0% respectively). Cytopenia-related healthcare utilization was also lower in the trilaciclib cohorts. In general, first-line trilaciclib initiators had numerically lower myelosuppressive HAEs and cytopenia-related healthcare utilization than the overall trilaciclib patients. The existing evidence suggests that trilaciclib may reduce single and multilineage grade ≥ 3 myelosuppressive HAEs and cytopenia-related healthcare utilization among patients with ES-SCLC in the real world. It is a promising new treatment for CIM prevention in ES-SCLC and may bring greater benefits to first-line trilaciclib initiators. Future studies are recommended to further evaluate the real-world effectiveness of trilaciclib.

Prospective Observational Study on the Risk Factors of Chemotherapy-Induced Myelosuppression and Its Management in a Tertiary Care Hospital

Abstract Introduction Myelosuppression is a commonly observed dose-limiting side effect of majority of chemotherapeutic drugs, characterized by a decrease in blood cell production. They cause neutropenia, thrombocytopenia, and anemia and can be life threatening in few susceptible individuals. Attempts to lessen chemotherapy-induced myelosuppression have been minimally effective. Managing myelosuppression has been a challenge to medical practitioners and pharmacist. Identifying their risk factors and the management strategies can help prevent the debilitating effects on chemotherapy patients. Objectives The aim of this study was to determine the risk factors for chemotherapy-induced myelosuppression and identify its management in a tertiary care hospital. We also observed the cycle it predominantly occurs and its prevalence rate in the region. Materials and Methods The study is a prospective observational cohort study conducted in a tertiary care hospital in Coimbatore, Tamil Nadu. The sample size was calculated using RAO software for a study duration of 4 months from 73 patients who were prescribed the inclusion criteria drugs paclitaxel, carboplatin, 5-fluorouracil, doxorubicin, and cyclophosphamide. The complete blood count was obtained and followed up to find myelosuppression occurrence on day 8 of first three cycles. The National Cancer Institute grading system was used to assess the severity of myelosuppression. It was done from May 2022 to August 2022. Chi-squared tests and percentages were adopted by using the SPSS software. Result The result for primary objective is that among the total 73 patients employed, 30 patients were found to be myelosuppressive (41%) and the prevalence rate was 41%. Risk factors such as age, gender, and diagnosis showed statistically significant association (confidence interval: 95% and p-value <0.005). The drugs paclitaxel, carboplatin, 5-fluorouracil, cyclophosphamide, and adriamycin proved to be highly myelosuppressive with a p-value of 0.049.The results for secondary objectives were that cycle 1 was reported to be highly myelosuppressive with 27%. The treatment options that was highly used was granulocyte-colony stimulating factor (90%), followed by packed red blood cell transfusion (7%). Conclusion The incidence of chemotherapy-induced myelosuppression from this study showed that it was important to monitor the complete blood count levels in patients undergoing chemotherapy. Early assessment of risk for developing myelosuppression may prevent or reduce its severity.

Myeloprotection with activated carbon in doxorubicin-treated rats

Chemotherapy can often cause a variety of side effects including bone marrow (BM) suppression, termed as myelosuppression. Accordingly, facile and effective management of chemotherapy-induced myelosuppression is currently a pivotal task for experimental pathologists and oncologists. Here, we chose to use activated carbon (AC) with an extensive surface area for studying its possible protective effectiveness with respect to BM in doxorubicin (DOX)-treated rats. Spherical AC with an extended surface area up to 4490 m2/g was prepared for per os (p/o) delivery, whereas for intraperitoneal (i/p) delivery we used the powdered form of AC that was derived from the aforementioned spherical AC. During the monthly treatment of animals with AC and DOX these two components were delivered alternately (not in the same day). After treatment, BM cells were isolated from femurs of sacrificed animals, stained with acridine orange (AO) and analyzed by flow cytometry. Regardless of the route of AC delivery (p/o or i/p), apparent myeloprotection with a possible regenerative effect was observed in animals that received DOX, as evidenced by recovery of the populations of total nucleated cells (TNC) and polychromatic (immature) erythrocytes accompanied by a considerable reduction of the number of apoptotic/dead cells among TNC (≤2.0%). Moreover, as a result of AC administrations, there was a significant increase of AO green and far-red fluorescence intensities in the population of TNC, which is suggestive of the ongoing quantitative and conformational changes in DNA and RNA associated with cell recovery and proliferation. Thus, AC preparations under the present experimental conditions can effectively tackle DOX-induced myelosuppression via mechanisms not necessarily associated with adsorptive detoxification.

EPH181 An Analysis of Patient Characteristics Associated with Myelosuppression Among Small Cell Lung Cancer (SCLC) Patients Treated in US Community Cancer Care Practices

Chemotherapy induced myelosuppression (CIM), usually manifested as neutropenia, anemia and/or thrombocytopenia, is a common complication of chemotherapy. Although published literature exists on predicting neutropenia risk based on patients' characteristics among patients with breast, colorectal, lung, lymphoid, or ovarian cancer,1,2 or predicting myelosuppression (neutropenia, anemia and/or thrombocytopenia) among NSCLC patients3-4, there is a paucity of studies examining the risk of myelosuppression among patients with SCLC. The association between patient characteristics and myelosuppression in SCLC is examined in this study.

Real world outcomes of trilaciclib in ES-SCLC.

e20637 Background: Carboplatin, etoposide, and atezolizumab (PEA) is the most widely used combination for first-line treatment of extensive-stage small cell lung cancer (ES-SCLC). Chemotherapy-induced myelosuppression is a common sequalae that is traditionally managed with lineage-specific supportive care modalities. Studies that evaluated trilaciclib versus placebo in combination with chemotherapy demonstrated statistically significant improvements in the duration of severe neutropenia (SN), defined as ANC < 500 cells/µL, in cycle 1 and incidence of SN as a result of its transient myeloprotective effects. There remains considerable controversy in the adoption of trilaciclib as a supportive medication in clinical practice. The objective of this quality assessment study was to assess utility of trilaciclib in real-world ES-SCLC patients. Methods: This was a single center study with quasi-experimental design comparing patients with confirmed ES-SCLC who received trilaciclib + PEA (PEAT) from April 2021 to July 2022 versus those who received PEA without trilaciclib (PEA) from February 2020 to February 2021. Patients with limited-stage SCLC, prior treatment with immunotherapies, carboplatin dose AUC < 3.5 with cycle 1, and active clinical trial enrollment were excluded. The primary endpoint evaluated was incidence of SN after cycle 1 and during treatment period. Additional measures related to myelopreservation and patient outcomes were assessed as secondary endpoints. Demographic data was analyzed using descriptive statistics. Dichotomous and continuous variables were compared by Mann-Whitney U or one-sided Fisher’s exact test. Progression-free survival (PFS) and overall survival (OS) were evaluated by Kaplan-Meier (KM) estimate. Results: 34 patients received PEAT and 44 patients received PEA. Demographic and baseline clinical characteristics were similar between both cohorts except for older median age of patients (69 years old vs 64 years old) and higher proportion of male patients (65% vs 39%) in the trilaciclib cohort. Even though there was a numerically lower rate of SN (3%) and hospitalization due to febrile neutropenia (FN) or infection (6%) in the PEAT versus the PEA (18%;11%) cohort, statistical significance was not met (p = 0.07;p = 0.065). Likewise, incidence of FN, platelet transfusion requirements, all-cause chemotherapy reductions, and treatment delays were not statistically different. However, the PEAT cohort as compared to PEA experienced a statistically significant reduction in red blood cell transfusion requirements (3% vs 23%; p = 0.02) and grade 3-4 anemia (6% vs 25%; p = 0.03). PFS and OS between the two cohorts were not statistically different. Conclusions: Based on this single center retrospective study, use of trilaciclib appears to confer improvement in the safety profile of PEA without negatively impacting survival outcomes. Therefore, results of this study support the integration of trilaciclib with PEA for ES-SCLC.

EE279 Real-World Evidence Relating Cytopenia Diagnosis to Hospitalization and Cost of Care in the Treatment of Non-Small Cell Lung Cancer Patients

Neutropenia is a driver of infection-related mortality in Non-Small Cell Lung Cancer (NSCLC) patients with chemotherapy-induced myelosuppression. Prior research found incident neutropenia in 24% of advanced NSCLC Medicare patients during first-line chemotherapy. Neutropenia-related care comprised up to one-third of total patient cost. We first confirmed the real-world incidence of cytopenia in an NSCLC population. Then we estimated the subsequent hospitalizations and total cost of care using OncoHealth Real-World Data (RWD). Our objective was to temporally sequence cytopenia diagnosis, hospitalization and accrual of costs to identify a window for targeting symptom management and patient engagement.

Development of a Machine Learning-Based Prediction Model for Chemotherapy-Induced Myelosuppression in Children with Wilms' Tumor.

Purpose: Develop and validate an accessible prediction model using machine learning (ML) to predict the risk of chemotherapy-induced myelosuppression (CIM) in children with Wilms' tumor (WT) before chemotherapy is administered, enabling early preventive management. Methods: A total of 1433 chemotherapy cycles in 437 children with WT who received chemotherapy in our hospital from January 2009 to March 2022 were retrospectively analyzed. Demographic data, clinicopathological characteristics, hematology and blood biochemistry baseline results, and medication information were collected. Six ML algorithms were used to construct prediction models, and the predictive efficacy of these models was evaluated to select the best model to predict the risk of grade ≥ 2 CIM in children with WT. A series of methods, such as the area under the receiver operating characteristic curve (AUROC), the calibration curve, and the decision curve analysis (DCA) were used to test the model's accuracy, discrimination, and clinical practicability. Results: Grade ≥ 2 CIM occurred in 58.5% (839/1433) of chemotherapy cycles. Based on the results of the training and validation cohorts, we finally identified that the extreme gradient boosting (XGB) model has the best predictive efficiency and stability, with an AUROC of up to 0.981 in the training set and up to 0.896 in the test set. In addition, the calibration curve and the DCA showed that the XGB model had the best discrimination and clinical practicability. The variables were ranked according to the feature importance, and the five variables contributing the most to the model were hemoglobin (Hgb), white blood cell count (WBC), alkaline phosphatase, coadministration of highly toxic chemotherapy drugs, and albumin. Conclusions: The incidence of grade ≥ 2 CIM was not low in children with WT, which needs attention. The XGB model was developed to predict the risk of grade ≥ 2 CIM in children with WT for the first time. The model has good predictive performance and stability and has the potential to be translated into clinical applications. Based on this modeling and application approach, the extension of CIM prediction models to other pediatric malignancies could be expected.