Therapy-related Adverse Events Research Articles

Study on the role of iron chelators in the management of iron overload among transfusion-dependent thalassemia (TDT) pediatric patients

This study aims to investigate the efficacy and safety of Deferasirox, an oral iron chelator, in reducing iron burden in pediatric patients with transfusion-dependent beta-thalassemia. Thalassemia syndromes, particularly beta-thalassemia, are inherited hemoglobin disorders requiring regular blood transfusions, leading to iron overload and subsequent complications. Effective management of iron overload is crucial to prevent morbidity and mortality. It was a descriptive observational study on Children between the ages of 2 years and 12 years who present with transfusion-dependent thalassemia and areon blood transfusion and develop iron overload, which is evaluated by serum ferritin levels of more than 2000mcg/l are administered iron chelator Deferasirox (14 mg/kg/d)and patients are evaluated for myocardial, hepatic, pancreatic iron burden and conditions of iron toxicity with the help of Cardiac MRI T2, LIC (Liver Iron Concentration), MRI T2 Pancreas, LVEF (Left Ventricular Ejection Fraction). A total of 22 patients enrolled in the study; significant reductions were observed in mean serum ferritin levels (2,388 mcg/dl to 2,054 mcg/dl, p=0.0009), transferrin saturation (70.45% to 64.32%, p=0.00005), and serum transaminases (44.55 U/L to 40.27 U/L, p=0.003) at 6 months. Cardiac MRI T2* increased from 19.55 ms to 22.95 ms (p=0.045) at the end of 6 months and at the end of 12 months from 19.55 to 28.23 (p=0.0016), and LIC reduced from 20.73 mg Fe/g dw to 11.59 mg Fe/g dw (p=0.00005). Pancreatic T2 improved from 15.96 ms to 20.23 ms at 12 months (p=0.007). A transient increase in serum creatinine was observed at 6 months from 0.64+/-0.14 mg/dL to 0.7+/-0.13mg/dL(p=0.009), which returned to normal at the end of 12 months to 0.63 mg/dL, no additional therapy-related adverse events were reported. Deferasirox has demonstrated significant efficacy in reducing iron overload in pediatric patients with transfusion-dependent beta thalassemia over a 12-month period. The substantial improvements in serum ferritin, cardiac MRI T2*, LIC, transferrin saturation, and pancreatic T2, coupled with its excellent safety profile, support the use of DFX as a cornerstone in the management of iron overload in this vulnerable population.

INDIVIDUAL ARTICLE: NECOM 4: Algorithm Integrating Skincare for the Management of Immunotherapy-Related Cutaneous Adverse Events for Cancer Patients and Survivors.

In the Nordic European Countries, cancer is the leading cause of death. The last decade has brought revolutionizing cancer treatments including immune checkpoint inhibitors (ICIs). Patients on ICIs have a high risk of developing cutaneous immune-related adverse events. Treating these side effects is of high importance to improve patient's quality of life (QoL) and continue the anti-cancer treatment. The Nordic European Cutaneous Oncodermatology Management (NECOM) project develops tools to prevent and treat cancer therapy-related cutaneous adverse events (cAEs). The first 2 NECOM papers presented various cAEs and skincare regimens involving hygiene, moisturization, sun protection, and camouflage products for preventing and managing cAEs. The NECOM 3 practical algorithm was on the prevention and treatment of acute radiation dermatitis. This NECOM 4 practical algorithm is intended to prevent and manage cutaneous immunotherapy-related adverse events (cirAEs), improving cancer patients' QoL and outcomes. The NECOM advisors discussed the results of a systematic literature review and obtained consensus on the evidence and expert opinion-based practical algorithm for cirAEs to support all healthcare providers treating cancer patients in the Nordic European Countries. The algorithm starts with a simple skincare regimen of cleansing, moisturizing, and protection, followed by the exclusion of severe cutaneous adverse reactions, and then specific interventions to treat the most common cirAEs (pruritus, maculopapular eruption, eczematous eruption, psoriasis, lichenoid eruption, and bullous eruption). CirAEs are the most common side effects induced by ICIs and may lead to cancer treatment interruption or even discontinuation. Patient education on the prevention of cirAEs using a skincare regimen and treatment recommendations given in the NECOM 4 algorithm may help prevent and manage cirAEs and improve the QoL and outcome of patients receiving ICIs. J Drugs Dermatol. 2024;23:8(Suppl 2):s4-10.

Evaluation of anticancer therapy-related dermatologic adverse events: Insights from Food and Drug Administration's Adverse Event Reporting System dataset

New anticancer therapies have improved patient outcomes but associated dermatologic adverse events (AEs) may cause morbidity and treatment discontinuation. A comprehensive estimation of associations between cancer drugs and skin AEs is lacking. This study utilized the Food and Drug Administartion (FDA)'s Adverse Event Reporting System database (January 2013-September 2022), with 3,399,830 reports involving 3084 drugs and 16,348 AEs. A nearest neighbor matching model was employed to select 10 controls for each case report, utilizing the cosine similarity of demographic and AE severity factors to minimize false positives/negatives. There were 10,698 unique anticancer drugs (n=212) to skin AE (n=873) pairs, of which 676 had significant reporting odds ratios (ROR)>1, comprising 113 drugs and 144 AEs. The minimum ROR was 1.25, and 50% of associations displayed a ROR >10. The most common were rash (51 agents) and dry skin (28 drugs). Methotrexate induced the most distinct AEs (34), then mechlorethamine (33), and vemurafenib (24). Targeted therapies accounted for 49% of pairs, cytotoxic chemotherapies for 35.9%, and immunotherapies for 11%. A total of 113 anticancer drugs were identified as significantly associated with skin AEs, most frequently rash and dry skin. Data are likely under-reported but enable quick postmarketing identification of skin toxicity signals.

Global post‑marketing safety surveillance of Tumor Treating Fields (TTFields) therapy in over 25,000 patients with CNS malignancies treated between 2011–2022

BackgroundTumor Treating Fields (TTFields) are alternating electric fields that disrupt cancer cell processes. TTFields therapy is approved for recurrent glioblastoma (rGBM), and newly-diagnosed (nd) GBM (with concomitant temozolomide for ndGBM; US), and for grade IV glioma (EU). We present an updated global, post-marketing surveillance safety analysis of patients with CNS malignancies treated with TTFields therapy.MethodsSafety data were collected from routine post-marketing activities for patients in North America, Europe, Israel, and Japan (October 2011–October 2022). Adverse events (AEs) were stratified by age, sex, and diagnosis.ResultsOverall, 25,898 patients were included (diagnoses: ndGBM [68%], rGBM [26%], anaplastic astrocytoma/oligodendroglioma [4%], other CNS malignancies [2%]). Median (range) age was 59 (3–103) years; 66% patients were male. Most (69%) patients were 18–65 years; 0.4% were < 18 years; 30% were > 65 years. All-cause and TTFields-related AEs occurred in 18,798 (73%) and 14,599 (56%) patients, respectively. Most common treatment-related AEs were beneath-array skin reactions (43%), electric sensation (tingling; 14%), and heat sensation (warmth; 12%). Treatment-related skin reactions were comparable in pediatric (39%), adult (42%), and elderly (45%) groups, and in males (41%) and females (46%); and similar across diagnostic subgroups (ndGBM, 46%; rGBM, 34%; anaplastic astrocytoma/oligodendroglioma, 42%; other, 40%). No TTFields-related systemic AEs were reported.ConclusionsThis long-term, real-world analysis of > 25,000 patients demonstrated good tolerability of TTFields in patients with CNS malignancies. Most therapy-related AEs were manageable localized, non-serious skin events. The TTFields therapy safety profile remained consistent across subgroups (age, sex, and diagnosis), indicative of its broad applicability.

Implications and hidden toxicity of cardiometabolic syndrome and early-stage heart failure in carfilzomib-induced cardiotoxicity.

Cancer therapy-related cardiovascular adverse events (CAEs) in presence of comorbidities, are in the spotlight of the cardio-oncology guidelines. Carfilzomib (Cfz), indicated for relapsed/refractory multiple myeloma (MM), presents with serious CAEs. MM is often accompanied with co-existing comorbidities. However, Cfz use in MM patients with cardiometabolic syndrome (CMS) or in heart failure with reduced ejection fraction (HFrEF), is questionable. ApoE-/- and C57BL6/J male mice received 14 weeks Western Diet (WD) (CMS models). C57BL6/J male mice underwent permanent LAD ligation for 14 days (early-stage HFrEF model). CMS- and HFrEF-burdened mice received Cfz for two consecutive or six alternate days. Daily metformin and atorvastatin administrations were performed additionally to Cfz, as prophylactic interventions. Mice underwent echocardiography, while proteasome activity, biochemical and molecular analyses were conducted. CMS did not exacerbate Cfz left ventricular (LV) dysfunction, whereas Cfz led to metabolic complications in both CMS models. Cfz induced autophagy and Ca2+ homeostasis dysregulation, whereas metformin and atorvastatin prevented Cfz-mediated LV dysfunction and molecular deficits in the CMS-burdened myocardium. Early-stage HFrEF led to depressed LV function and increased protein phosphatase 2A (PP2A) activity. Cfz further increased myocardial PP2A activity, inflammation and Ca2+-cycling dysregulation. Metformin co-administration exerted an anti-inflammatory potential on the myocardium without improving LV function. CMS and HFrEF seem to exacerbate Cfz-induced CAEs, by presenting metabolism-related hidden toxicity and PP2A-related cardiac inflammation, respectively. Metformin retains its prophylactic potential in the presence of CMS, while mitigating inflammation and Ca2+ signalling dysregulation in the HFrEF myocardium.

Abstract 5841: A genome wide CRISPR-Cas9 screen identifies mediators of resistance to dual PI3K/mTOR inhibition in glioblastoma multiforme

Abstract Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor with a devastating 5-year survival rate of 6.8%. The current standard of care, consisting of surgery, radiation, and temozolomide (TMZ), has remained unchanged for over the past 15 years despite its limited efficacy and the serious therapy-related adverse events associated to this regimen. Although some frequent genetic alterations have been identified in GBM, no targeted therapies have shown efficacy in these patients to date. Among these, the phosphoinositide 3-kinase (PI3K) pathway is a signaling network that regulates cell growth, proliferation, migration, and invasion. Extensive molecular characterization of GBM has identified alterations in the components of the PI3K pathway in 80% of primary GBMs, including amplification of receptor tyrosine kinases (RTKs), activating mutations in the PI3K catalytic subunit (PIK3CA), loss-of-function mutations in the PI3K regulatory subunit (PIK3R1), and loss of the major tumor suppressor of the pathway, phosphatase and tensin homologue (PTEN). Despite the universal upregulation of PI3K pathway signaling associated with these genetic alterations, clinical trials investigating PI3K inhibitors in GBM have failed due to insufficient antitumor activity and dose-limiting toxicities. To elucidate mechanisms of resistance to PI3K inhibition in GBM, we used a genome-wide functional CRISPR-Cas9 knockout screen to identify genes that mediate resistance to the dual PI3K/mTOR inhibitor XL765 in PTEN-null SF295 GBM cells. We identified reactivation of the PI3K pathway and inhibition of autophagy as potential resistance mechanisms to dual PI3K/mTOR inhibition. Using orthogonal approaches, we will functionally validate our candidate hits through mechanistic studies, with patient-derived models, and with in vivo orthotopic xenografts. Our findings will elucidate novel mechanisms of resistance to PI3K/mTOR inhibition in GBM and will streamline rational drug combinations aimed to overcome resistance, thus eventually maximizing therapeutic responses to PI3K inhibitors in GBM. Citation Format: Annalisa V. Ferrotta, Arianna Izawa-Ishiguro, Meaghan Grogan, Ingo K. Mellinghoff. A genome wide CRISPR-Cas9 screen identifies mediators of resistance to dual PI3K/mTOR inhibition in glioblastoma multiforme [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5841.

Treatment Strategies Guided by [18F]FDG-PET/CT in Patients with Locally Advanced Cervical Cancer and [18F]FDG-Positive Lymph Nodes.

Modern treatment guidelines for women with advanced cervical cancer recommend staging using 2-deoxy-2-[18F]fluoro-D-glucose positron emission computed tomography ([18F]FDG-PET/CT). However, the risk of false-positive nodes and therapy-related adverse events requires caution in treatment planning. Using data from the Netherlands Cancer Registry (NCR), we estimated the impact of [18F]FDG-PET/CT on treatment management in women with locally advanced cervical cancer, i.e., on nodal boosting, field extension, and/or debulking in cases of suspected lymph nodes. Women diagnosed between 2009 and 2017, who received chemoradiotherapy for International Federation of Gynaecology and Obstetrics (2009) stage IB2, IIA2-IVB cervical cancer with an [18F]FDG-positive node, were retrospectively selected from the NCR database. Patients with pathological nodal examination before treatment were excluded. The frequency of nodal boosting, extended-field radiotherapy, and debulking procedures applied to patients with [18F]FDG-positive lymph nodes was evaluated. Among the 434 eligible patients with [18F]FDG-positive nodes, 380 (88%) received interventions targeting these lymph nodes: 84% of these 380 patients received nodal boosting, 78% extended-field radiotherapy, and 12% debulking surgery. [18F]FDG-positive nodes in patients receiving these treatments were more likely to be classified as suspicious than inconclusive (p = 0.009), located in the para-aortic region (p < 0.001), and larger (p < 0.001) than in patients who did not receive these treatments. While existing guidelines advocate [18F]FDG-PET/CT-guided treatment planning for the management of advanced cervical cancer, this study highlights that not all cases of [18F]FDG-positive nodes received an intervention, possibly due to the risk of false-positive results. Improvement of nodal staging may reduce suboptimal treatment planning.

Quality of treatment with targeted agents for advanced prostate cancer by treating specialist.

88 Background: Urologists are increasingly prescribing oral targeted agents to men with advanced prostate cancer, who traditionally have been cared for by medical oncologists. These agents require close monitoring, since they mechanistically affect androgen biosynthesis and can lead to cardiovascular and metabolic adverse events. It is unclear whether patients treated by urologists—whose practice scope typically does not involve systemic therapies—experience more frequent therapy-related adverse events. Further, these medications are expensive, often subjecting patients to high out-of-pocket costs, which can lead to coping strategies like treatment non-adherence. Urologists may have less experience discussing these costs and exploring cheaper alternatives. Methods: A 20% sample of National Medicare claims was used to perform a retrospective cohort study of Medicare beneficiaries with advanced prostate cancer between 2012-2020 who were treated with a targeted agent (abiraterone or androgen receptor blocker). The primary outcome was the composite of any hospital or emergency department visit for a cardiometabolic event within 1 year of starting a targeted agent. Secondary outcomes included monthly out-of-pocket costs in those without low-income subsidies and adherence to treatment in first 6 months after initiating treatment. Multivariable regression models were fitted to assess the association between prescribing specialist (urologist or medical oncologist) and each outcome. Results: There were 1,462 (25%) and 4,501 (75%) patients who were prescribed a targeted agent by a urologist and medical oncologist. Men who were managed by urologists were more often started on an androgen receptor blocker, compared to those managed by medical oncologists (67% vs 36%, p&lt;0.001).There were no differences in the adjusted frequencies of composite adverse events of patients managed by urologists and medical oncologists in those who were started on abiraterone (7.7 % vs 8.1%, P=0.79) or an androgen receptor blocker (6.4% vs 6.2%, p=0.91). Out-of-pocket costs did not vary between patients who were managed by urologists vs medical oncologists in those who were started on abiraterone ($748 % vs $778%, P=0.48) or an androgen receptor blocker ($795 vs $834, p=0.33). Adherence to treatment was similar between the specialties in those prescribed abiraterone (67% vs 64%, P=0.15), but the likelihood of adherence was higher in men prescribed an androgen receptor blocker by a urologist (65% vs 61%, p=0.04). Conclusions: Although urologists may be less accustomed to primarily managing advanced prostate cancer than medical oncologists, patients fared no worse when assessing adverse events, out-of-pocket costs, or adherence to treatment. This study provides further support for urologists’ increased role in managing advanced prostate cancer.

Protocol for Evaluating the Efficacy and Safety of Radiotherapy for Prostate and Oligometastatic Lesions in Patients With Low-Burden Sensitive Oligometastatic Prostate Cancer: An Open, Exploratory Pilot Clinical Trial.

The existing large prospective study demonstrates the benefits of primary radiotherapy in patients with low-volume oligometastatic prostate cancer (OMPC), and there is additional evidence of the benefits of local metastasis-directed therapy (MDT) for metastatic lesions. However, there are no results from a prospective study to demonstrate the efficacy of radiotherapy for prostate and oligometastases. Therefore, the aim of the protocol is to illustrate the efficacy of radiotherapy for prostate and oligometastatic lesions in patients with low-volume de novo hormone-sensitive OMPC. This study involves a prospective, single-center, limited-sample, single-arm exploration of radiotherapy for prostate and oligometastatic lesions in patients diagnosed with low-volume hormone-sensitive OMPC. Eligible participants undergo thorough assessments and treatment involving endocrine therapy alongside radiation targeting metastatic lesions and the pelvic region. The primary site is treated with volumetric modulated arc therapy (VMAT), while metastatic sites are treated with either VMAT or stereotactic body radiation therapy (SBRT) depending on their location. All patients received radiation therapy for both the primary and metastatic lesions combined with endocrine therapy. Endocrine therapy with an antiandrogen (bicalutamide, for 4 weeks) androgen deprivation therapy combined with novel hormonal agents (acetate abiraterone) will be continued for 2 years. The primary objective is to evaluate progression-free survival-2 (PFS-2), while secondary endpoints include androgen deprivation therapy (ADT)-free survival, quality of life (QoL), overall survival, time to castration-resistant prostate cancer (CRPC), radiation-related complications, and endocrine therapy-related adverse events. Approval was obtained from the ethics committee of the First Affiliated Hospital of Naval Medical University (CHEC2023-220). This is a single-arm exploration pilot trial evaluating radiotherapy for prostate and oligometastatic lesions in patients with OMPC. It aims to disseminate its findings through peer-reviewed journals and relevant medical conferences, with the intention of publication and presentation at these events. Clinicaltrials.gov identifier NCT06198387.

Machine-Learning Based Risk Assessment for Cancer Therapy-Related Cardiac Adverse Events Among Breast Cancer Patients.

The study aims to develop machine-learning models to predict cardiac adverse events in female breast cancer patients who receive adjuvant therapy. We selected breast cancer patients from a retrospective dataset of the Taipei Medical University Clinical Research Database and Taiwan Cancer Registry between January 2004 and December 2020. Patients were monitored at the date of prescribed chemo- and/or -target therapies until cardiac adverse events occurred during a year. Variables were used, including demographics, comorbidities, medications, and lab values. Logistics regression (LR) and artificial neural network (ANN) were used. The performance of the algorithms was measured by the area under the receiver operating characteristic curve (AUC). In total, 1321 patients (an equal 15039 visits) were included. The best performance of the artificial neural network (ANN) model was achieved with the AUC, precision, recall, and F1-score of 0.89, 0.14, 0.82, and 0.2, respectively. The most important features were a pre-existing cardiac disease, tumor size, estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), cancer stage, and age at index date. Further research is necessary to determine the feasibility of applying the algorithm in the clinical setting and explore whether this tool could improve care and outcomes.

P694 Age is a strong of predictive risk factor for anti-TNF therapy related adverse events in IBD patients

Abstract Background Anti-TNFα is the first class of biologics approved for treatment of moderate-to-severely active Inflammatory Bowel Disease (IBD). More than two decades on, anti-TNFs remain one of the most commonly used biologics for both Ulcerative Colitis (UC) and Crohn’s Disease (CD), and often as first-line therapy. Although effective, they cause several adverse events (AEs), sometimes requiring withdrawal of therapy. We aimed to record AEs and understand factors that could predict risk of AEs. Methods All IBD patients exposed to anti-TNF therapy were identified from EMR at two centres of a large tertiary hospital between January 2009 and June 2022. All relevant demographic and clinical data were collected for those patients with well recorded AEs and follow-up. Data on cumulative AEs directly attributed to anti-TNFs that ranged from mild reactions to serious AEs (defined as those requiring review/withdrawal of anti-TNF), were collected. Adverse events (AEs) were recorded as per relevant systems involved e.g.- haematological, cardiac etc., including infections and malignancies as separate categories. All analysis (normalization, hypothesis testing, and visual reports were performed using R software package Version: R 4.2.1. Results A total of 844 IBD patients (Male =408) were included with an age range of 18-75yrs. Majority were Caucasian in ethnicity (514) and more patients with CD [605(71%)] were exposed to anti-TNF than UC. The age profiling analysis was performed across ethnic groups (Asian, Caucasian and Others). Age associated AE was reported across all the groups (data not shown). It must be mentioned that though not significant, Caucasian patients were more susceptible towards AE as compared to Asian. Conclusion · Patient age above 50yrs has a strong predictive risk factor for AEs related to anti-TNF therapy for IBD. · In our cohort, more than half of patients &amp;gt;50yrs reported at least one AE in UC, and the age was lower in CD. · Although Caucasians were more vulnerable to AEs, this was not statistically significant. · Clinicians should consider and discuss this risk before selecting patients for anti-TNF therapy. · With multiple biologic choices currently available, another class could be considered where possible, for the &amp;gt;50yr patient cohort.

Evaluation of Adverse Drug Events in Patients on Anti-Retroviral Therapy Regimen at Omdurman Voluntary Counselling and Testing and Anti-Retroviral Therapy Center in Sudan - A Cross-Sectional Study.

Anti-retroviral therapy-related adverse drug events are accounted as a main cause of anti-retroviral therapy non-adherence. In Sudan, pharmacovigilance studies are relatively rare and obstructed by the problem of under-reporting. It is a well-defined issue worldwide and is highly reported in developing countries. This study aimed to evaluate the prevalence of adverse events associated with anti-retroviral therapy among adult patients with immunodeficiency virus at Omdurman Voluntary Counselling and Testing and Anti-retroviral Therapy Center. The study was a descriptive cross-sectional study conducted through direct interviews with 429 patients at the selected center using the Adverse Drug Events (ADEs) reporting form. The collected data were analyzed by The Statistical Package for Social Sciences. More than half (55.5%) of the participants experienced adverse events, with 48.7% having experienced them at the beginning of treatment. Central nervous system manifestations were the most common adverse events. By using the Naranjo scale, most adverse events showed a "probable" relationship to anti-retroviral medicines. Based on the chi-square test, medication regimen was significantly associated with the presence of ADEs (namely abdominal pain and jaundice) (p values = 0.03 and 0.001), respectively. This study clearly stated that ART-related ADEs are common among Sudanese PLHIV and with central nervous system being the main adverse events. More pharmacovigilance studies and efforts by healthcare providers should be applied targeting ART-related ADEs under-reporting in Sudanese healthcare facilities.

High- vs regular-dose recombinant human thrombopoietin plus cyclosporine A in patients with newly diagnosed non-severe aplastic anemia: a retrospective cohort study

ABSTRACT Background: Cyclosporine A (CsA) and regular doses of recombinant human thrombopoietin (rhTPO) can accelerate platelet recovery in patients with non-severe aplastic anemia (NSAA). However, it is unclear whether CsA plus rhTPO at a higher dose can further increase the efficacy. Methods: Data from patients with newly diagnosed NSAA, who had been treated with CsA in combination with different doses of rhTPO between February 2021 and August 2021 at Peking Union Medical College Hospital, were reviewed. All the enrolled patients had been treated with CsA at 3–5 mg/(kg/d), and patients were further classified into high-dose (with rhTPO 30000U qd × 14 days for 2 months) group or regular-dose (with rhTPO 15000U qd × 7days for 3 months) group. The treatment response and therapy-related adverse events were compared. Results: 36 patients including 16 (44.4%) in the high-dose and 20 (55.6%) in the regular-dose group were enrolled. The baseline characteristics were compatible between the two groups. The platelet counts were significantly higher at 1/3/6 months in the high-dose group (p = 0.028, 0.0063 and p = 0.040, respectively). The high-dose group had a significantly shorter time to platelet transfusion independence ([1 (0.5–6) months vs 2.5 (1–12) months, p = 0.040]). There was no significant difference in overall response and complete response rate between the two groups at 1/3/6/12 months (p > 0.05). Treatment-related morbidities were similar between the two groups (p > 0.05). Conclusions: Adding a higher dose of rhTPO can further accelerate platelet recovery and platelet transfusion independence in patients with newly diagnosed NSAA.

Long-term survival and portal vein patency with novel PVTT surgery approach in advanced HCC patients with Vp3/4 PVTT following combination therapy of TKIs and PD-1 inhibitors

BackgroundIt is controversial whether patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) should undergo salvage surgery following the combination therapy of tyrosine kinase inhibitors (TKIs) and programmed cell death protein 1 (PD-1) inhibitors. This study aimed to elucidate the efficiency and safety of salvage surgery following combination therapy, while also summarizing a novel surgical approach for Vp3/4 PVTT.MethodsBetween April 2019 and December 2022, a consecutive series of unresectable HCC patients with PVTT who received salvage surgery following combination therapy were enrolled. Evaluation included perioperative and long-term follow-up outcomes. The complete removal of Vp3/4 PVTT was achieved using a novel surgical approach characterized by “longitudinal incision and transverse suturing” and “angle-to-straight conversion”.ResultsForty patients including 22 patients with Vp3 and 18 patients with Vp4 were included. Long-term follow-up showed similar rates of portal vein patency (Vp3: 95.5%, Vp4:94.4%, p = 0.900), and 3-year portal vein patency rates were 95.0%. There were no significant differences observed in combination therapy-related adverse events (p = 0.253) and perioperative complications (p = 0.613) between the Vp3 and Vp4 groups. The recurrence patterns were similar between the two groups (p = 0.131). There were no significant differences in overall survival (OS) and recurrence-free (RFS) survival between the Vp3 and Vp4 groups (OS p = 0.457, RFS p = 0.985). Patients who achieved a pathological complete response had significantly better RFS (p = 0.011).ConclusionSalvage surgery after combination therapy demonstrated favorable efficacy and safety. The novel surgical approach for PVTT can effectively achieve complete removal of PVTT and ensured long-term portal vein patency.

Serious Adverse Events and Laboratory Monitoring Regimens for Outpatient Parenteral Antimicrobial Therapy With Cefazolin and Ceftriaxone.

The optimal laboratory monitoring frequency for outpatient parenteral antimicrobial therapy-related adverse events (OPAT-AEs) during cefazolin and ceftriaxone therapy is not well defined. We identified 2.7 OPAT-AEs per 1000 sets of weekly laboratory tests in this population, suggesting that less intensive laboratory monitoring may be safe and reasonable.

A Phase Ib Study to Evaluate the Safety and Efficacy of Nivolumab in Combination with R-CHOP in High-Risk DLBCL

Introduction Chemoimmunotherapy with R-CHOP is an established standard of care for diffuse large B-cell lymphoma (DLBCL) but is not curative in all patients (pts). Approximately 20% of DLBCL have aberrations involving the PD-L1/PD-L2 locus. This justifies the investigation of PD-1 checkpoint inhibitors in pts with DLBCL. This Phase 1b study was conducted to determine the maximum tolerated dose (MTD) for nivolumab in combination with R-CHOP in pts with DLBCL and to evaluate the preliminary efficacy of the regimen. Methods Patients with newly diagnosed de novo DLBCL or transformed low-grade lymphoma (tLL) were enrolled from 2019-2022. Treatment comprised a lead-in phase (LIP) with nivolumab 240 mg x 1 followed 2 weeks later by combination nivolumab-R-CHOP given every 3 weeks for 6 cycles. For combination therapy, nivolumab was administered on Day 1 followed by R-CHOP on Days 1-5 (Days 2-6 for Cycle 1). To establish MTD with Phase 1, nivolumab dosing followed a modified 3+3 dose escalation, starting with 1 mg/kg (dose level 1), escalating to 240 mg (dose level 2). MTD was administered for the Phase Ib portion of the study. Primary endpoints were determination of MTD and rate of complete metabolic response (CMR) by PET/CT using Lugano 2014 as best response by completion of 6 cycles of combination therapy (EOT). Correlations of immune subsets with durability of response and toxicity were exploratory. Results Thirty-three patients were enrolled, of which 25 and 22 pts were evaluable for toxicity and efficacy, respectively. The majority were men (n=21, 64%), White (n=26, 79%) with ECOG performance status of 0-1 (n=30, 91%). Twenty-seven (82%) had advanced stage and/or intermediate/high risk IPI score and 20 (65%) had germinal center subtype. Fifteen (45%) and 16 (48.5%) had tLL (2 with prior therapy for LL prior to transformation) and MYC aberrancy (13 with gains; 2 with single-hit and 1 with double-hit rearrangements), respectively. A dose of 240 mg of nivolumab was established as MTD. Twenty of 22 (91%) achieved CMR and 2 partial metabolic response (PMR) by EOT with overall response in 100%. One pt died from COVID-19 after 4 cycles but was in CMR on interim imaging. With median follow-up of 12 months (mo), 4 pts had progression. Both pts with PMR by EOT have not relapsed. Estimated 18-mo OS &amp; PFS were 95.4% &amp; 71.6%, respectively. Correlation of PFS with PD-L1 expression is underway. Most common therapy-related adverse events (TRAEs) attributed to nivolumab-R-CHOP were fatigue in 22 (88%), HTN in 21 (84%), lymphopenia in 21 (84%), and neutropenia in 18 (72%). High-grade (grade 3/4) neutropenia occurred in 15 (60%) with growth factor use per discretion of treating physician. Fifteen (60%) pts had infections, 47% high-grade. Immunotoxicities (IT) were the most common TRAEs attributed to nivolumab in 18 pts (72%), including thyroiditis (n=5, 20%), dermatitis (n=4, 16%), hepatitis (n=3, 12%), and infusion reactions (n=3, 12%). Most common high-grade IT: 1 case each of colitis, hepatitis, myocarditis (discontinued nivolumab), and dermatitis (discontinued nivolumab). For biologic correlates (Figures 1 &amp; 2): non-progressors (NP) were enriched for T regulatory cell (e.g., IFN-γ producing CD4+Foxp3+ phenotype) fragility while progressors (PD) were enriched for exhausted T cell immunophenotype (CD4+PD-1+CD39+) prior to both LIP and initiation of combination therapy (C1D1). Furthermore, exhausted-like T cell levels were significantly reduced at C1D1 in comparison to LIP in NP but not PD. Toxicities correlated to less exhausted-like effector T cell phenotype, decreased CD4+ naïve and central memory T cells, and increased circulating B cells and myeloid-derived suppressor cells. Conclusions This study demonstrates promising efficacy of frontline combination nivolumab-R-CHOP for high-risk DLBCL including pts with intermediate/high risk IPI, tLL, and MYC aberrancy. While limited by small sample size, this regimen resulted in response, PFS, and OS rates above historical rates reported in high-risk pts and provides basis for further evaluation of nivolumab-based therapies in such pts. We found correlations between progression, toxicity and specific immune subset populations. Attention to these biologic correlates as predictors of durable response and toxicity may allow for better patient selection to optimize benefits of therapeutic effect and risks of increased toxicity with nivolumab-based therapies in DLBCL.

Assessment of Motor Unit Potentials Duration as the Biomarker of DT-DEC01 Cell Therapy Efficacy in Duchenne Muscular Dystrophy Patients up to 12 Months After Systemic–Intraosseous Administration

Duchenne muscular dystrophy (DMD) is a lethal X-linked disease caused by mutations in the dystrophin gene, leading to muscle degeneration and wasting. Electromyography (EMG) is an objective electrophysiological biomarker of muscle fiber function in muscular dystrophies. A novel, DT-DEC01 therapy, consisting of Dystrophin Expressing Chimeric (DEC) cells created by fusing allogeneic myoblasts from normal donors with autologous myoblasts from DMD-affected patients, was assessed for safety and preliminary efficacy in boys of age 6–15 years old (n = 3). Assessments included EMG testing of selected muscles of upper (deltoideus, biceps brachii) and lower (rectus femoris and gastrocnemius) extremities at the screening visit and at 3, 6, and 12 months following systemic–intraosseous administration of a single low dose of DT-DEC01 therapy (Bioethics Committee approval no. 46/2019). No immunosuppression was administered. Safety of DT-DEC01 was confirmed by the lack of therapy-related Adverse Events or Serious Adverse Events up to 22 months following DT-DEC01 administration. EMG of selected muscles of both, ambulatory and non-ambulatory patients confirmed preliminary efficacy of DT-DEC01 therapy by an increase in motor unit potentials (MUP) duration, amplitudes, and polyphasic MUPs at 12 months. This study confirmed EMG as a reliable and objective biomarker of functional assessment in DMD patients after intraosseous administration of the novel DT-DEC01 therapy.

Effective and Safe Molecular-Pharmacodynamic Once Weekly Dosing of Decitabine and Venetoclax Is a Highly Effective and Well-Tolerated Induction Therapy for AML: Interim Results of a Phase 2 Trial

Background: Hypomethylating agents (HMAs) (5-azacytidine or decitabine) combined with venetoclax (Ven) have become the new standard of care for patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy. However, myelosuppression and infectious complications are common adverse events of currently approved HMA/Ven regimens, requiring dose interruptions/delays that often undermine treatment goals. Previous studies have identified the minimum dose of decitabine needed to deplete DNA methyltransferase-1 (DNMT1) without causing cytotoxicity. Administration of a single venetoclax dose synergizes with low dose weekly decitabine by inhibiting de-novo pyrimidine synthesis - a major mechanism of resistance to HMAs. A recently reported retrospective experience has shown proof of concept for a regimen of once weekly low dose decitabine combined with a single weekly dose of venetoclax in MDS and AML. Here, we report the feasibility portion of an ongoing Phase II clinical trial evaluating tolerability and efficacy of a metronomic dosing of decitabine and venetoclax for treatment of older patients with AML. Aims: The primary endpoint of this study is percentage of patients who are able to continue on treatment during the 12-week induction period without dose interruptions or delays. The key secondary endpoints include best overall response, rate of Grade &amp;gt;3 adverse events, infections, and hospitalizations. Correlative studies evaluate DNMT1 depletion in bone marrow at the time of diagnosis and at week 12. Methods: This is a single arm open-label Phase II clinical trial (NCT05184842). Patients &amp;gt;18 years old with a diagnosis of AML, MDS, CMML, MDS/MPN, and MDS/AML not fit for intensive chemotherapy are eligible. Subcutaneous decitabine and oral venetoclax are administered on the same day, once a week at 0.2mg/kg and 400mg, respectively. A bone marrow exam and measurable residual disease (MRD) assessment by multiparametric flow cytometry (MFC) are performed following 12-week induction period. Results: Between June 2022 and April 2023, twenty patients on this study have completed the 12-week induction period, these included AML (n=14), MDS (n=2), MF (n=1), MDS/MPN (n=1), CMML (n=2). Median age was 75 and 50% of patients were minorities (Table 1). Seventeen patients (85%) were able to complete all 12 weeks of induction treatment without dosing interruptions or delays and only one patient (5%) had a dose interruption post-induction. There were no Grade &amp;gt; 3 non-heme therapy-related adverse events. Eight patients (40%) required hospitalization during the induction period and no patient required hospitalization post-induction. Of the 14 AML patients who have completed the 12-week induction period, the median age was 75 years old (63-87). At the end of induction, the ORR was 71% with 8 patients (57%) achieving a CR, 1 CRI and 1 PR; 5/8 CRs were MRD negative by MFC. At a median followup of 10.9 months, 7/14 (50%) responses are ongoing and 11/14 patients (79%) remain alive. Of the six patients with TP53 mutations, four achieved MRD-negative CR with transfusion independence and two with no response (one post-MPN AML and other with erythroid leukemia). During the induction period, four patients (29%) had progression of disease (POD). The primary refractory cases included one patient with post-MPN AML, one patient with FLT3-ITD and two patients with monocytic-M5 AML with RAS mutations. One of two patients with MDS, had an MRD negative CR and achieved transfusion independence while the other transformed to erythroid leukemia. Of the two patients with CMML, one had a CR with transfusion independence, and one with stable disease. The 30 and 60-day mortality was zero. Studies evaluating DNMT1 staining on bone marrow samples from patients treated on this study are ongoing. Summary/Conclusion: In this preliminary analysis we demonstrate safety and efficacy of weekly, low-dose, metronomic dosing of decitabine and venetoclax, by allowing frequent sustained drug exposure often not possible with standard HMA/Ven regimens. The minimal cytotoxic nature of this regimen allowed for blood count recovery without drug interruptions with a high rate of clinical responses. (Figure 1). Additional cohorts are being enrolled in an expansion phase of the study in order to more fully assess the efficacy of this regimen in subsets of AML and MDS patients, including patients with p53 mutations.

T-Cell Engaging Antibodies in Diffuse Large B Cell Lymphoma—An Update

Novel cellular immunotherapies such as T-cell engaging antibodies (TCEAbs) are changing the landscape of treatment for diffuse large B cell lymphoma (DLBCL), especially in the relapsed/refractory (R/R) setting. TCEAbs harness the power of the host immune system to induce killing of tumor cells by binding to both the tumor antigen and the T-cell receptor. Since the approval of blinatumomab for R/R acute lymphoblastic leukemia, there has been significant development in novel TCEAbs. Many of these novel TCEAbs have shown promising effectiveness in R/R DLBCL, with favorable response rates including complete remissions, even in heavily pretreated patients. There are unique therapy-related toxicities with TCEAbs, namely cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS), and it is important to both recognize and manage these side effects appropriately. This review examines the development and mechanism of action of these TCEAbs, and the available published data from clinical trials. Their role in the treatment of DLBCL, the management of therapy-related adverse events, and the mechanisms of resistance will also be discussed.

The evolution of antiseizure medication therapy selection in adults: Is artificial intelligence -assisted antiseizure medication selection ready for prime time?

Antiseizure medications (ASMs) are the mainstay of symptomatic epilepsy treatment. The primary goal of pharmacotherapy with ASMs in epilepsy is to achieve complete seizure remission while minimizing therapy-related adverse events. Over the years, more ASMs have been introduced, with approximately 30 now in everyday use. With such a wide variety, much guidance is needed in choosing ASMs for initial therapy, subsequent replacement monotherapy, or adjunctive therapy. The specific ASMs are typically tailored by the patient's related factors, including epilepsy syndrome, age, sex, comorbidities, and ASM characteristics, including the spectrum of efficacy, pharmacokinetic properties, safety, and tolerability. Weighing these key clinical variables requires experience and expertise that may be limited. Furthermore, with this approach, patients may endure multiple trials of ineffective treatments before the most appropriate ASM is found. A more reliable way to predict response to different ASMs is needed so that the most effective and tolerated ASM can be selected. Soon, alternative approaches, such as deep machine learning (ML), could aid the individualized selection of the first and subsequent ASMs. The recognition of epilepsy as a network disorder and the integration of personalized epilepsy networks in future ML platforms can also facilitate the prediction of ASM response. Augmenting the conventional approach with artificial intelligence (AI) opens the door to personalized pharmacotherapy in epilepsy. However, more work is needed before these models are ready for primetime clinical practice.