Increased Aspartate Aminotransferase Research Articles

Assessment of thiamylal sodium as a euthanasia drug in mice.

Euthanasia agents should rapidly induce death and loss of consciousness without causing pain or distress. Various methods exist for the euthanasia of laboratory animals, and injectable anesthetics, particularly barbiturate derivatives, are widely used due to the rapid onset of unconsciousness induced by these agents. Moreover, pharmaceutical-grade drugs should be used to eliminate undesirable side effects as much as possible. However, in Japan, the sale of pharmaceutical-grade pentobarbital sodium (PB) ended in 2019, and that of secobarbital sodium (SB) ended in 2023, leading to a demand for new pharmaceutical-grade injectable euthanasia drugs. This study evaluates thiamylal sodium (TM), a barbiturate derivative that is available domestically, as a euthanasia agent for mice. The results showed that when administered at dosages of 200 mg/kg or more, TM exhibited effects equivalent to those of PB and SB. In addition, the impact of TM administration on hematological characteristics was examined. In female mice administered TM, decreased blood chloride and calcium levels and increased aspartate aminotransferase and alanine aminotransferase levels, which are markers of liver damage, were observed. These findings suggest that high concentrations of TM may affect renal and liver function. This study revealed that TM is effective as a euthanasia agent at dosages of 200 mg/kg or more. However, considering the potential risks of renal and liver damage due to TM administration, it may be preferable to use alternative euthanasia drugs when these risks could affect the objectives or outcomes of the research.

Efficacy and Safety of Conversion Surgery for Advanced Hepatocellular Carcinoma After Hepatic Arterial Infusion Chemotherapy.

The aim of this study was to investigate the efficacy and safety of conversion surgery for advanced hepatocellular carcinoma (HCC) after hepatic arterial infusion chemotherapy (HAIC). Data from 172 HCC patients treated at Sun Yat-sen University Cancer Center between January 2016 and June 2021 with effective assessment of HAIC treatment response were retrospectively analyzed. Clinical pathological data, treatment process, survival, and occurrence of adverse events were recorded. Patients were grouped according to whether they achieved imaging remission after HAIC, underwent conversion surgery, and met the surgical resection criteria. Efficacy and safety were analyzed. The median progression-free survival (PFS) and overall survival (OS) in the imaging remission group were 8.6 months and 26.3 months, respectively, which were longer than the 4.6 months (P<0.05) and 15.6 months (P<0.05) in the nonremission group. Compared with 6.7 months and 18.9 months in the HAIC maintenance group, the median PFS and median OS in the conversion surgery group were 16.5 months (P<0.05) and 45.0 months (P<0.05), but there was a higher risk of treatment-related hemoglobin decrease, alanine aminotransferase increase, aspartate aminotransferase increase, and total bilirubin increase (P<0.05). The risk of biliary fistula, abdominal hemorrhage and ascites in the HAIC conversion surgery group was higher than that of the single surgery group (P<0.05). Compared with the conversion surgery group, the median PFS and median OS of patients in the HAIC maintenance group who met the resection criteria were shorter: 7.1 months (P<0.05) and 21.7 months (P<0.05), respectively. All adverse events during the study were less than moderate, and no toxicity-related deaths occurred during follow-up. HAIC-based conversion therapy had acceptable toxic effects and could effectively stabilize intrahepatic lesions in advanced HCC, improve the survival benefit of patients, and provide some patients with the opportunity for conversion surgery to further improve prognosis.

Glucosamine attenuates alcohol-induced acute liver injury via inhibiting oxidative stress and inflammation

Alcohol liver disease (ALD) is a liver disease caused by long-term heavy drinking. Glucosamine (GLC) is an amino monosaccharide that plays a very important role in the synthesis of human and animal cartilage. GLC is commonly used in the treatment of mild to moderate osteoarthritis and has good anti-inflammatory and antioxidant properties. In this study, alcoholic injury models were constructed in mice and human normal hepatocyte L02 cells to explore the protective effect and mechanism of GLC on ALD. Mice were given GLC by gavage for 30 days. Liver injury models of both mice and L02 cells were produced by ethanol. Detecting the levels of liver injury biomarkers, lipid metabolism, oxidative stress biomarkers, and inflammatory factors through different reagent kits. Exploring oxidative and inflammatory pathways in mouse liver tissue through Western blot and RT-PCR. The results showed that GLC can significantly inhibit the abnormal increase of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), triglycerides (TG), total cholesterol (TC), very low density lipoprotein (VLDL), low-density lipoprotein cholesterol (LDL-C), and can significantly improve the level of high-density lipoprotein cholesterol (HDL-C). In addition, GLC intervention significantly improved alcohol induced hepatic oxidative stress by reducing the levels of malondialdehyde (MDA) and, increasing the levels of glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD) in the liver. Further mechanisms suggest that GLC can inhibit the expression of ethanol metabolism enzyme cytochrome P4502E1 (CYP2E1), activate the antioxidant pathway Keap1/Nrf2/HO-1, down-regulate the phosphorylation of MAPK and NF-κB signaling pathways, and thus reduce the expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). Therefore, GLC may be a significant candidate functional food for attenuating alcohol induced acute liver injury.

Short-term Outcomes of Adjuvant Nivolumab After Neoadjuvant Chemotherapy in Patients With Resected Esophageal Squamous Cell Carcinoma.

CheckMate 577 evaluated adjuvant nivolumab therapy after neoadjuvant chemoradiotherapy and surgery for esophageal cancers. However, the efficacy of this treatment in patients who received neoadjuvant chemotherapy remains unknown. This study investigated the short-term outcomes of adjuvant nivolumab therapy in patients with advanced esophageal squamous cell carcinoma post-neoadjuvant chemotherapy. Out of 956 patients with thoracic esophageal cancer who underwent radical esophagectomy, 227 who exhibited ypN1-3 after neoadjuvant chemotherapy and surgery were included in this study. Among 227 patients, 30 received adjuvant nivolumab and 197 received non-nivolumab adjuvant therapy. The nivolumab group displayed a higher number of lymph node metastases compared to the control group. Patients with ypN1-2 tended to have longer recurrence-free survival (RFS) in the nivolumab group than in the non-nivolumab group (p=0.095). In the propensity score-matched cohort, no differences in patient characteristics were observed. Adjuvant nivolumab therapy significantly prolonged RFS in patients who received neoadjuvant chemotherapy (p=0.013). Patients with ypN1-2 in the nivolumab group had significantly longer RFS than their counterparts in the non-nivolumab group (p=0.001), but not in ypN3 (p=0.784). The 1-year postoperative recurrence rates were 59% for the non-nivolumab group and 24% for the nivolumab group (p=0.007). Nivolumab-related adverse events in patients receiving neoadjuvant chemotherapy were mostly consistent across all grades, while the frequency of increased aspartate aminotransferase (AST) levels was relatively higher compared to CheckMate577. Adjuvant nivolumab was more likely to prolong 1-year RFS in patients receiving neoadjuvant chemotherapy, especially in those with ypN1-2, and had acceptable adverse events.

The Hepatorenal Protective Potential of Caffeic Acid Consumption on the Arsenic-Exposed Syrian Mice.

Arsenic can induce lethal hepatorenal insufficiency by inducing progressive cytotoxicity in the two main body's hemostatic regulators, the kidney and liver. In the current study, the hepatorenal protective impact of caffeic acid was investigated in arsenic-exposed Syrian mice. Twenty-four male Syrian mice (30 8g) were provided and randomly divided into 4 groups of 6 receiving nothing, arsenic, arsenic and caffeic, and caffeic acid. The mice passed the 21-day treatment program. The mice's blood was collected and analyzed by measuring the serum ALT/AST enzymes and creatinine/urea levels, respectively. Finally, the histopathological properties in both the kidney and liver organs of the mice were studied. Arsenic administration significantly increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), LDH, urea, and creatinine concentrations (p < 0.05). Simultaneous administration of caffeic acid with arsenic decreased the serum AST and creatinine (p < 0.05). Moreover, the renal glomerulus and liver regeneration in the mice receiving caffeic acid supplements exhibited the caffeic acid hepatorenal protective potential. The histopathological changes caused by arsenic in the mice's liver and kidney tissue including degeneration, necrosis, hyperemia, and tissue hypotrophy were shifted to normal conditions following the caffeic acid administration dose, which was verified by the mice blood biochemical analysis results.

Phase I dose escalation study and pilot efficacy analysis of LXI-15029, a novel mTOR dual inhibitor, in Chinese subjects with advanced malignant solid tumors

BackgroundThe mammalian target of rapamycin (mTOR) kinase, a central component of the PI3K/AKT/mTOR pathway, plays a critical role in tumor biology as an attractive therapeutic target. We conducted this first-in-human study to investigate the safety, pharmacokinetics (PK), and pilot efficacy of LXI-15029, an mTORC1/2 dual inhibitor, in Chinese patients with advanced malignant solid tumors.MethodsEligible patients with advanced, unresectable malignant solid tumors after failure of routine therapy or with no standard treatment were enrolled to receive ascending doses (10, 20, 40, 60, 80, 110, and 150 mg) of oral LXI-15029 twice daily (BID) (3 + 3 dose-escalation pattern) until disease progression or intolerable adverse events (AEs). The primary endpoints were safety and tolerability.ResultsBetween June 2017 and July 2021, a total of 24 patients were enrolled. LXI-15029 was well tolerated at all doses. Only one dose-limiting toxicity (grade 3 increased alanine aminotransferase) occurred in the 150 mg group, and the maximum tolerated dose was 110 mg BID. The most common treatment-related AEs were leukocytopenia (41.7%), increased alanine aminotransferase (20.8%), increased aspartate aminotransferase (20.8%), prolonged electrocardiogram QT interval (20.8%), and hypertriglyceridemia (20.8%). No other serious treatment-related AEs were reported. LXI-15029 was absorbed rapidly after oral administration. The increases in the peak concentration and the area under the curve were greater than dose proportionality over the dose range. Eight patients had stable disease. The disease control rate was 40.0% (8/20; 95% CI 21.7–60.6). In evaluable patients, the median progression-free survival was 29 days (range 29–141).ConclusionsLXI-15029 demonstrated reasonable safety and tolerability profiles and encouraging preliminary antitumor activity in Chinese patients with advanced malignant solid tumors, which warranted further validation in phase II trials.Trial registrationNCT03125746(24/04/2017),http://ClinicalTrials.gov/show/NCT03125746

Abstract A121: Temsirolimus in combination with metformin in patients with advanced or recurrent endometrial cancer

Abstract Background: Molecular alterations in the PI3K/AKT and Ras/Raf/MAPK are frequently seen in endometrial cancers and mTOR is a downstream target activated by both pathways. Blocking mTOR with temsirolimus produced modest response. Studies have shown that metformin, in addition to producing metabolic changes, also causes activation of AMPK, which in turn inhibits the mTOR pathway. Therefore, we enrolled patients with advanced or recurrent endometrial cancer in the expansion cohort of a phase I study of temsirolimus in combination with metformin. Methods: Patients received intravenous (IV) temsirolimus 25 mg weekly and oral metformin 2000 mg daily in 28-day cycles. The objective of this study was to evaluate the efficacy of this combination and assessment of correlatives of target inhibition in tumor biopsies from patients with known mutations. Response was assessed every 2 cycles by clinical evaluation, tumor markers, and imaging per RECIST 1.1. All toxicities were graded using NCI CTCAE, version 4.0. TIL (tumor infiltrating lymphocyte) percentage was assessed in tumor tissue samples collected at baseline and on treatment. Results: A total of 40 patients were included in this study. Among the 33 patients evaluable for response, 2 patients had partial response (PR) and 13 had stable disease (SD), including 11 with SD ≥4 months. The objective response rate was 6% and clinical benefit rate 39%. Molecular alteration in the PI3K and/or RAS pathway was seen in 25 of 33 patients. Eleven of the 25 patients (44%) had either PR or SD ≥4 months. Interestingly, all 3 patients with molecular alteration in both the pathways had SD ≥4 months. The most common treatment-related adverse events included hypertriglyceridemia (n=14), diarrhea (n=13), mucositis (n=13), anorexia (n=12) and anemia (n=10). The grade 3 AEs were anemia and thrombocytopenia (n=2 each) and mucositis, fatigue, weight loss, hypokalemia, hypophosphatemia, and increase in aspartate aminotransferase and alanine transaminase (n=1 each). Although baseline TIL scores did not distinguish responder from non-responder (p=0.25), on-treatment increase in TIL score was significantly higher among responders compared to non-responders (p-value 0.034). Metabolomics portion of the study is ongoing. Conclusions: In conclusion, the combination of temsirolimus with metformin had modest anti-tumor activity in patients with advanced or recurrent endometrial cancer without added safety concerns. Correlative studies may provide further insight about this combination. Citation Format: Jibran Ahmed, Bettzy Stephen, Samir Beyaz, Charlie Chung, Ece Kilic, Muhammad R Khawaja, Yali Yang, Alpa M Nick, Maria G Raso, Elizve B Toro, Daniel D Karp, Sarina A Piha-Paul, Anil Sood, Chaan Ng, Amber M Johnson, Pamela T Soliman, Funda Meric-Bernstam, Karen H Lu, Aung Naing. Temsirolimus in combination with metformin in patients with advanced or recurrent endometrial cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A121.

Abstract B114: A Phase 1/1b study of KAZ954 alone and in combination with spartalizumab (PDR001) and taminadenant (NIR178) in patients with advanced gastrointestinal malignancies

Abstract Background:KAZ954 (KAZ), a humanized immunoglobulin G1 monoclonal antibody, is a potent, selective inhibitor of anti-ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2). Preclinical data show that KAZ blocks the hydrolysis of adenosine triphosphate, enhances immune activation in the tumor microenvironment, and augments the efficacy of PDR001 (PDR, anti-PD-1), and NIR178 (NIR, adenosine A2aR inhibitor). Methods: This is an open-label, multicenter, dose-escalation (ESC)/expansion study (NCT04237649). We present the dose-ESC results of KAZ single-agent (SA) and with PDR or NIR in patients (pts) with advanced gastrointestinal (GI) malignancies. Dose ESC was guided by Bayesian logistic regression models and comprised 3 arms: (1) SA KAZ administered intravenously (IV) at 30, 50, 100, and 150 mg biweekly (Q2W) flat dosing; KAZ 100 mg priming dose followed by 300, 600, and 1200 mg experimental dose; (2) KAZ 100 mg priming dose followed by 300, 600, and 1200 mg experimental dose with PDR 400 mg IV every 4 weeks; and (3) KAZ 100 mg priming dose followed by 300 and 600 mg experimental dose with NIR 160 and 240 mg twice daily orally. Primary objectives were to evaluate safety and tolerability and determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE). Secondary objectives were to assess antitumor activity and pharmacokinetics (PK). Tumor biopsies and blood samples were taken for biomarker analysis. Results: As of March 20, 2023, 77 pts were enrolled in ESC KAZ (n=43), KAZ+PDR (n=18), and KAZ+NIR (n=16) arms. Tumor types enrolled were microsatellite-stable colorectal cancer (37, 48%), pancreatic ductal adenocarcinoma (27, 35%), cholangiocarcinoma (10, 13%), and esophageal cancer (3, 4%). At data cutoff, 43 (100%), 15 (83.3%), and 11 (68.8%) pts discontinued treatment, and treatment-related adverse events (TRAEs) were reported in 37 (86%), 12 (66.7%), and 13 (81.3%) pts in KAZ, KAZ+PDR, and KAZ+NIR arms, respectively. KAZ had an acceptable and manageable safety profile. Given the occurrence of cytokine release syndrome (CRS) observed with cycle 1 day 1 (C1D1), prophylactic premedication with acetaminophen, antihistamine, and corticosteroid, together with a priming dose on C1D1, was established as the recommended regimen to administer KAZ. Grade ≥3 TRAEs were reported in 9 pts(20.9%) in KAZ, most commonly CRS and decreased lymphocyte count (n=2 each); 7 pts(38.9%) in KAZ+PDR, most commonly lymphopenia and increased aspartate aminotransferase (n=2 each); and 2 pts(12.5%) in KAZ+NIR (asthenia and lymphopenia [n=1 each]). No MTDs were reached in any treatment arm explored. Although no objective responses were observed, 12(27.9%), 2(11.1%), and 2(12.5%) pts showed stable disease in the KAZ, KAZ+PDR, and KAZ+NIR arms, respectively. Conclusions: KAZ was considered to be safe and well tolerated at all doses, and PK/PD analysis suggest effective ENTPD2 inhibition from a dose range of 150 to 1200 mg Q2W. Although a biologically active dose range was established, further dose-exploration studies are required to establish an RDE. Citation Format: Devalingam Mahalingam, Chia-Chi Lin, Philippe L. Bedard, Massimo Di Nicola, Zev Wainberg, Patricia LoRusso, Shubham Pant, Brigette B.Y. Ma, Wei-Peng Yong, Mia C. Weiss, Alessio Amatu, Kentaro Yamazaki, Lisa Nardi, Jong Bong Lee, Mike Roy, Anhthu Dang, Shu Yang, Bernard Pereira, Javier A. Otero, Teresa Macarulla. A Phase 1/1b study of KAZ954 alone and in combination with spartalizumab (PDR001) and taminadenant (NIR178) in patients with advanced gastrointestinal malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B114.

Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): a double-blind, randomised, phase 3 trial

Symptoms of anaemia due to clinically significant extravascular haemolysis can affect patients with paroxysmal nocturnal haemoglobinuria (PNH) treated with C5 inhibitors (ravulizumab or eculizumab). The aim of this study was to assess the efficacy and safety of danicopan (ALXN2040), an investigational, first-in-class, oral complement factor D inhibitor, as add-on therapy to ravulizumab or eculizumab in patients with PNH and clinically significant extravascular haemolysis. ALPHA is an ongoing, international, phase 3, randomised, double-blind, placebo-controlled trial evaluating danicopan as add-on therapy to ravulizumab or eculizumab. Eligible patients were adults (age ≥18 years) with PNH and clinically significant extravascular haemolysis (haemoglobin ≤9·5 g/dL; absolute reticulocyte count ≥120 × 109/L) on ravulizumab or eculizumab for at least 6 months. Patients were randomly assigned (2:1) to danicopan or placebo added to ravulizumab or eculizumab for 12 weeks using an interactive response technology system. Randomisation was stratified based on transfusion history, haemoglobin, and patients enrolled from Japan. The initial oral danicopan dose was 150 mg three times a day; escalation to 200 mg three times a day was permitted based on clinical response. The infusion dose level of eculizumab (every 2 weeks) ranged from 900 mg to 1500 mg, and for ravulizumab (monthly or every 8 weeks) ranged from 3000 mg to 3600 mg. The primary endpoint was change in haemoglobin concentration from baseline to week 12. Here we present the protocol-prespecified interim analysis, planned when approximately 75% of participants were randomly assigned to treatment and completed or discontinued at 12 weeks. This trial is registered with ClinicalTrials.gov (NCT04469465). Individuals were randomly assigned between Dec 16, 2020, and Aug 29, 2022. At data cutoff (June 28, 2022), 73 individuals were randomly assigned, received treatment, and were analysed for safety (danicopan, n=49; placebo, n=24). The protocol-prespecified interim efficacy analysis set included the first 63 participants (danicopan, n=42; placebo, n=21). At week 12, danicopan plus ravulizumab or eculizumab increased haemoglobin versus placebo plus ravulizumab or eculizumab (least squares mean [LSM] change from baseline: danicopan, 2·94 g/dL [95% CI 2·52 to 3·36]; placebo, 0·50 g/dL [-0·13 to 1·12]; LSM difference, 2·44 g/dL [1·69 to 3·20]; p<0·0001). Grade 3 adverse events in the danicopan group were increased alanine aminotransferase (two [4%] of 49 patients), leukopenia (one [2%]), neutropenia (two [4%]), cholecystitis (one [2%]), COVID-19 (one [2%]), increased aspartate aminotransferase (one [2%]), and increased blood pressure (one [2%]), and in the placebo group were anaemia (one [4%] of 24 patients), thrombocytopenia (one [4%]), and asthenia (one [4%]). The serious adverse events reported in the danicopan group were cholecystitis (one [2%] patient) and COVID-19 (one [2%]) and in the placebo group were anaemia and abdominal pain, both in one (4%) patient. There were no serious adverse events related to study drug or deaths reported in the study. These primary efficacy and safety results show that danicopan as add-on treatment to ravulizumab or eculizumab significantly improved haemoglobin concentrations at week 12 with no new safety concerns, suggesting an improved benefit-risk profile in patients with PNH and clinically significant extravascular haemolysis. Alexion, AstraZeneca Rare Disease.

Efektivitas Rifapentine Pada Pasien Dewasa Dengan Infeksi TuberkulosisLaten (ITBL): Sebuah Kajian Sistematis

Tuberculosis (TB) is an infectious disease whose successful treatment in Indonesia is affected by malnutrition, smoking, diabetes mellitus, and HIV infection. People with good immunity can prevent developing active disease, but the bacteria persistent in a dormant state. It will be active tuberculosis whenever (in few months) the immune system unable controlling the growth of TB bacteria. This systematic review aims to examine the effectiveness of rifapentine and its use with other regimens in patients with latent tuberculosis infection (LTBI). This study included literature published in the PubMed database from early January 2011 to January 2021, with keywords: "Effectiveness Rifapentine", “Tuberculosis”, and the Boolean operators, "AND". This study reported that there wew seventheen in studies countries, none in Indonesia. This study come to end that a regiment therapy with a combination of Rifapentine (P) and Isoniazid (H) once-weekly dose (called 3HP) for three months shows a good efficacy in LTBI patients, can improve patient adherence because of a shorter regiment administration and reduce the hepatotoxicity risk in patients with a history of chronic liver disease or increased aspartate transaminase (AST) level.

Abstract B044: Results of a phase 1 dose escalation clinical trial of NXP800, a novel GCN2 activator, in patients with advanced or metastatic solid tumors

Abstract Background: NXP800 is an antineoplastic, oral, small molecule discovered in a phenotypic screen for inhibitors of the heat shock factor 1 stress response. In a panel of human carcinoma cell lines NXP800 induced the expression of genes associated with activation of the integrated stress response (ISR). Orthogonal experimental approaches revealed that activation of the kinase GCN2 was required for ISR activation by NXP800. In tumor samples from ARID1a-mutated ovarian carcinoma xenografts, treatment with NXP800 resulted in substantial tumor growth inhibition and tumor regressions. Induction of the ISR effector ATF4 was observed. Here we present data on the safety, pharmacokinetics and pharmacodynamics of NXP800 from the dose escalation phase 1 trial in patients with advanced or metastatic solid tumors. Methods: This is a first-in-human, open label, dose escalation and expansion Phase 1 study in patients with advanced solid tumors (Part A, all comers) and ovarian cancer (Part B).Dose escalation was guided by a Bayesian modified continual reassessment method that targeted a dose-limiting toxicity DLT probability (DLTp) closest to 30% but &amp;lt;33%.The primary objective of the dose escalation was to identify a dose and dosing schedule for Part B, in which the clinical activity of NXP800 is being evaluated in patients with platinum resistant,ARID1a-mutated ovarian carcinoma. Results: Eighteen patients were treated in Part A: at baseline, the median age was 65 years (range 42-77), 9 (50%) were female and 14/18 (78%) had an ECOG score of 1. Two schedules (once per day [QD] and twice per day [BID] and a dose range of 50 to 150 mg/day were evaluated. The most common (incidence &amp;gt;20%) non-laboratory, treatment emergent adverse events (TEAEs) were vomiting, nausea, diarrhea, fatigue, and decreased appetite, all reported as Grade 1-2 except for nausea and diarrhea that were reported as Grade 3 in one patient each. The most common laboratory TEAEs were thrombocytopenia and aspartate aminotransferase increase, all reported as Grade 1-2 except in two patients in whom thrombocytopenia was reported as Grade 3. Two Grade 4 TEAEs that were considered unrelated to study drug and no Grade 5 TEAEs were reported. The DLT for the QD schedule was 150 mg/day, with an estimated Dose Limiting Toxicity Probability (DLTp) of 34% (no doses in the BID schedule had estimated DLTp of &amp;lt;33%). The maximum tolerated dose was 100 mg/day (DLTp=26%). Model-based simulations demonstrated that NXP800 exposures obtained following 50, 75 and 100 mg QD were comparable to the drug exposure achieved in xenograft model of ARID1a-mutated ovarian carcinoma. ATF4 protein and ISR genes were induced in peripheral blood mononuclear cell samples obtained from patients treated with NXP800. Conclusion: The NXP800 doses and dosing schedules selected for Part B are 50 and 75 mg/day in a QD schedule. At these dose levels, NXP800 was tolerable, achieved relevant systemic exposure levels and induced ISR PD biomarkers. Part B is open for enrollment of patients with platinum resistant, ARID1a-mutated ovarian carcinoma. Citation Format: Udai Banerji, Simon Pacey, Karen Finkelstein, Simon Rodney, Ana Filipa Palma DosReis, Giovanni Codaccipisanelli, Mark Sloan, Florence I Raynaud, Ruth Ruddle, Karen Swales, Matthew Tall, Shay Shemesh, Diane Marsolini, Megan Sardone, Justin Hay, Robin Bliss, Enrique Poradosu, Paul Workman. Results of a phase 1 dose escalation clinical trial of NXP800, a novel GCN2 activator, in patients with advanced or metastatic solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B044.

A Phase II Study of Intermittent Duvelisib Dosing in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Background. Targeting phosphatidylinositol 3-kinase (PI3K) has emerged as an efficacious approach for treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). However, toxicities of the PI3K inhibitors are an important concern limiting their use. Duvelisib is a potent oral inhibitor of both the PI3K-δ and PI3K-γ isoforms with proven efficacy in CLL/SLL. Here we report the results of a phase 2 study evaluating efficacy and safety of duvelisib with intermittent dosing in patients with relapsed/refractory CLL/SLL Methods. This open-label, single arm, phase 2 study enrolled patients with CLL/SLL treated with at least 1 prior line of therapy with active disease as defined by the iWCLL 2008 criteria. Duvelisib was given at a dose of 25 mg PO BID for 28-day cycles for a total of 12 weeks during the induction phase, followed by 75 mg PO BID 2 days on and 5 days off for repeated 28-day cycles during the maintenance phase until death, intolerance or disease progression. The primary endpoint was progression free survival (PFS) at 12 months; secondary endpoints were safety and clinical benefit. The trial was originally planned to enroll 27 patients but was stopped early due to difficulties with enrollment following changing FDA guidance for the use of PI3K inhibitors. Results. Fifteen patients were enrolled. Median age was 74 (59-82) years, 8/15 (53%) were female; patients were primarily Caucasian (13/15; 87%); performance status was 0-1, with 27% (4/15) ECOG 0 and 73% (11/15) ECOG 1. This was a heavily pre-treated patient population with a median of 3 prior lines of therapy (1-6). Among patients where results were available, 79% (11/14) had abnormal FISH results including 36% with TP53 gene loss, 27% del(13q), and 18% del(11q). Sixty-seven percent (8/12) had unmutated IGHV. Of the 15 patients treated, 4 were not evaluable for efficacy due to coming off study early for toxicity (2), development of MDS unrelated to study drug (1) or death due to complications from COVID-19 infection (1). Among the 11 efficacy-evaluable patients, 82% achieved PR, and 18% had stable disease. The 12-month PFS was 43% (95%CI: 18%-66%) and the median PFS was 9.9 months (95% CI: 5.5-NA). Among the 9 responders, the median duration of response (DOR) was 5.3 months (95%CI: 1.9-NA) and 12-month DOR was 22% (95%CI:3%-51%). Five patients (33%) discontinued therapy due to adverse events, which occurred during the induction phase in 4/5 of the patients. Five patients (33%) discontinued due to progressive disease - all during the maintenance phase of treatment. Additionally, 2 patients discontinued due to MD decision; one patient developed MDS which was unrelated to duvelisib; one patient died during treatment due to complications from COVID-19. Treatment was generally well tolerated with the most common grade 3 or higher adverse events being leukocytosis (20%), alanine aminotransferase (ALT) increase (13%), aspartate aminotransferase (AST) increase (13%), oral mucositis (13%) and colitis (13%). The adverse events leading to treatment discontinuation occurred primarily during induction. The most common adverse events of any grade included fatigue in 5 patients (33%), leukocytosis, vomiting, ALT increase, AST increase, diarrhea, and elevation of alkaline phosphatase, which occurred in 4 patients each (27%). Conclusions. We report the results of an open-label, phase 2 study utilizing a continuous dosing induction phase followed by an intermittent dosing maintenance phase of the PI3K inhibitor duvelisib in patients with relapsed/refractory CLL/SLL. Patients who received duvelisib on an intermittent schedule achieved some clinical benefit, however, the desired 12-month PFS goal of 50% was not reached. Adverse events in general were manageable and mainly related to gastrointestinal and liver toxicity, and patient died during treatment from complications from COVID-19 pneumonia. After an initial 12 weeks of continuous duvelisib treatment, the incorporation of intermittent dosing appears to be a viable option for patients with previously treated CLL/SLL.

Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): a randomised, double-blind, phase 3 trial

Systemic therapies have improved the management of hepatocellular carcinoma, but there is still a need to further enhance overall survival in first-line advanced stages. This study aimed to evaluate the addition of pembrolizumab to lenvatinib versus lenvatinib plus placebo in the first-line setting for unresectable hepatocellular carcinoma. In this global, randomised, double-blind, phase 3 study (LEAP-002), patients aged 18 years or older with unresectable hepatocellular carcinoma, Child Pugh class A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no previous systemic treatment were enrolled at 172 global sites. Patients were randomly assigned (1:1) with a central interactive voice-response system (block size of 4) to receive lenvatinib (bodyweight <60 kg, 8 mg/day; bodyweight ≥60 kg, 12 mg/day) plus pembrolizumab (200 mg every 3 weeks) or lenvatinib plus placebo. Randomisation was stratified by geographical region, macrovascular portal vein invasion or extrahepatic spread or both, α-fetoprotein concentration, and Eastern Cooperative Oncology Group performance status. Dual primary endpoints were overall survival (superiority threshold at final overall survival analysis, one-sided p=0·019; final analysis to occur after 532 events) and progression-free survival (superiority threshold one-sided p=0·002; final analysis to occur after 571 events) in the intention-to-treat population. Results from the final analysis are reported. This study is registered with ClinicalTrials.gov, NCT03713593, and is active but not recruiting. Between Jan 17, 2019, and April 28, 2020, of 1309 patients assessed, 794 were randomly assigned to lenvatinib plus pembrolizumab (n=395) or lenvatinib plus placebo (n=399). Median age was 66·0 years (IQR 57·0-72·0), 644 (81%) of 794 were male, 150 (19%) were female, 345 (43%) were Asian, 345 (43%) were White, 22 (3%) were multiple races, 21 (3%) were American Indian or Alaska Native, 21 (3%) were Native Hawaiian or other Pacific Islander, 13 (2%) were Black or African American, and 46 (6%) did not have available race data. Median follow up as of data cutoff for the final analysis (June 21, 2022) was 32·1 months (IQR 29·4-35·3). Median overall survival was 21·2 months (95% CI 19·0-23·6; 252 [64%] of 395 died) with lenvatinib plus pembrolizumab versus 19·0 months (17·2-21·7; 282 [71%] of 399 died) with lenvatinib plus placebo (hazard ratio [HR] 0·84; 95% CI 0·71-1·00; stratified log-rank p=0·023). As of data cutoff for the progression-free survival final analysis (April 5, 2021), median progression-free survival was 8·2 months (95% CI 6·4-8·4; 270 events occurred [42 deaths; 228 progressions]) with lenvatinib plus pembrolizumab versus 8·0 months (6·3-8·2; 301 events occurred [36 deaths; 265 progressions]) with lenvatinib plus placebo (HR 0·87; 95% CI 0·73-1·02; stratified log-rank p=0·047). The most common treatment-related grade 3-4 adverse events were hypertension (69 [17%] of 395 patients in the lenvatinib plus pembrolizumab group vs 68 [17%] of 395 patients) in the lenvatinib plus placebo group), increased aspartate aminotransferase (27 [7%] vs 17 [4%]), and diarrhoea (25 [6%] vs 15 [4%]). Treatment-related deaths occurred in four (1%) patients in the lenvatinib plus pembrolizumab group (due to gastrointestinal haemorrhage and hepatorenal syndrome [n=1 each] and hepatic encephalopathy [n=2]) and in three (1%) patients in the lenvatinib plus placebo group (due to gastrointestinal haemorrhage, hepatorenal syndrome, and cerebrovascular accident [n=1 each]). In earlier studies, the addition of pembrolizumab to lenvatinib as first-line therapy for advanced hepatocellular carcinoma has shown promising clinical activity; however, lenvatinib plus pembrolizumab did not meet prespecified significance for improved overall survival and progression-free survival versus lenvatinib plus placebo. Our findings do not support a change in clinical practice. Eisai US, and Merck Sharp & Dohme, a subsidiary of Merck.

Four-Year Follow-up of the Alta Study, a Phase 1/2 Study of Giroctocogene Fitelparvovec (PF-07055480/SB-525) Gene Therapy in Adults with Severe Hemophilia Α

Introduction: Hemophilia A is an X-linked ( F8 gene) recessive disorder of hemostasis that results in insufficient factor VIII (FVIII) activity. Adeno-associated virus (AAV)-based gene therapy enables delivery of a modified F8 cDNA, allowing synthesis of functional endogenous FVIII, which prevents bleeding events. We present updated results with nearly 4 years of follow-up on an ongoing gene therapy study in participants with severe hemophilia A (FVIII activity &amp;lt;1%). Methods:The phase 1/2 Alta study (NCT03061201) is a dose-ranging study of giroctocogene fitelparvovec (PF-07055480, previously called SB-525), a recombinant AAV serotype 6 vector encoding a modified B-domain-deleted F8 coding sequence. Four ascending doses of giroctocogene fitelparvovec (9e11, 2e12, 1e13, and 3e13 vg/kg) were infused into adults aged ≥18 years with severe hemophilia A across 4 cohorts (n=2 each). The high-dose (3e13 vg/kg) cohort was expanded to 5 participants. Key endpoints included safety, circulating FVIII activity, use of FVIII replacement therapy, and frequency of bleeding events. Results: Eleven male participants were enrolled in the study (mean [SD] age, 30.3 [7.8] years; White, 81.8%). As of the cutoff date (May 19, 2023), participants had been followed for 153 to 290 weeks. Two participants left the study after Week 156. Of the remaining, 1 participant had not yet completed 4 years (208 weeks). The most common treatment-related adverse events (AEs) reported in the high-dose cohort (n=5) were elevated liver enzymes and infusion-related reactions: increased alanine aminotransferase (ALT; n=3 [60.0%]), increased aspartate aminotransferase (AST; n=2 [40.0%]), pyrexia (n=3 [60.0%]), and tachycardia (n=2 [40.0%]). Treatment-related serious AEs were reported in 1 participant in the high-dose cohort who experienced hypotension and fever, with onset ≈6 h after infusion; the events fully resolved with treatment. AEs (all causality) of ALT increases requiring ≥7 days of corticosteroids were observed in 4 of 5 participants in the high-dose cohort. ALT elevations were managed with tapering courses of corticosteroids (median duration: 56 days; range: 7-135 days), with maintenance of efficacious levels of FVIII activity. Participants in the high-dose cohort have not required steroids since Week 65, have had ALT values in the normal range (follow-up: 156-208 weeks) and normal findings via liver MRI (follow-up: 104-208 weeks). No participant developed a confirmed inhibitor to FVIII. No thrombotic events or liver masses have been detected. Of the 5 participants in the high-dose cohort, 2 had data available through Week 208 and FVIII activity was maintained in the mild to normal range ( Table), consistent with Week 156 results. Of those without Week 208 data, 2 had data through Week 182. One participant maintained FVIII activity in the mild range (14.1% and 24.1% of normal, measured with a chromogenic and 1-stage assay, respectively); the other had FVIII activity of 3.1% and 7.2%. The remaining participant left the study after Week 156, with FVIII activity maintained in the mild range (11.8% and 22.9%). In the high-dose cohort, the mean annualized total bleeding rate [(number of all bleeding episodes starting 3 weeks after study drug infusion) / (observation period in years)] was 0 for the first year post infusion and 1.2 (SD 2.58) throughout the total duration of follow-up. In this cohort, the participant with the lowest FVIII activity level experienced a total of 22 bleeds, with 21 necessitating treatment (8 traumatic; 7 spontaneous; 6 unknown). The other 4 participants had no or very minimal bleeds, including 1 who experienced a bleed in a target joint. No participants in the high-dose cohort have resumed prophylaxis. Conclusion:A single infusion of giroctocogene fitelparvovec gene therapy in participants with severe hemophilia A remains generally well tolerated over a period of nearly 4 years post infusion, with associated increases in FVIII levels in the moderate to normal range, without sustained AEs and with no AEs associated with increased liver function tests since Week 59. The ongoing phase 3 study (NCT04370054) in a larger cohort will provide more long-term data on the safety and durability of giroctocogene fitelparvovec in participants with moderately severe to severe hemophilia A.

Brentuximab Vedotin, Nivolumab, Doxorubicin, and Dacarbazine (AN+AD) for Early-Stage Classical Hodgkin Lymphoma (SGN35-027 Part C)

Introduction Brentuximab vedotin (BV) with AVD is approved in classical Hodgkin lymphoma (cHL) and has demonstrated statistically significant improvement in 6-year overall survival (OS) as compared with ABVD; associated neuropathy and neutropenia may be related to overlapping mechanisms of BV and vinblastine (Ansell 2022). A study in nonbulky early-stage cHL showed preserved efficacy with improved safety when omitting vinblastine in the BV-AD regimen (Abramson 2023). Here, we present results of a phase 2 trial adding nivolumab to the BV-AD regimen without radiation in patients (pts) with nonbulky early-stage cHL (SGN35-027 Part C). Methods SGN35-027 (NCT03646123) Part C enrolled pts with Ann Arbor stage I or II cHL without bulky disease, defined as those with a single node or nodal mass with a &amp;lt;10-cm diameter on computed tomography imaging. Pts received 4 cycles of AN+AD (BV 1.2 mg/kg [A], nivolumab 240 mg [N], doxorubicin 25 mg/m 2 [A], and dacarbazine 375 mg/m 2 [D] intravenously on days 1 and 15 of each 28-day cycle). Per protocol, G-CSF prophylaxis was not required for subjects receiving the treatment regimen. The primary endpoint is complete response (CR) rate at end of treatment (EOT). Secondary endpoints include progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and duration of complete response (DOCR), as well as safety and tolerability. The Lugano Classification Revised Staging System for malignant lymphoma (Cheson 2014) incorporating Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) for nodal non-Hodgkin and Hodgkin Lymphomas (Cheson 2016) per investigator was used to assess disease response and progression. Exploratory endpoints include baseline and longitudinal circulating tumor DNA analysis on a subset of pts. Results Part C has completed enrollment with 154 pts having received at least 1 dose of study treatment. The majority of treated pts were white (84%), aged &amp;lt;65 years (92%), and female (55%), and presented with nonbulky stage I (11%) or II (89%) cHL. Median age was 31.0 years (range, 18-77). All findings were based on a data cutoff of 22 May 2023. Among 150 efficacy evaluable pts, the ORR was 98% (95% CI, 94.3-99.6) and the CR rate was 93% (95% CI, 87.3-96.3) at EOT (Table 1). Among all pts treated (N = 154), the ORR was 95% (95% CI, 90.9-98.2) and the CR rate was 90% (95% CI, 84.4-94.4) at EOT. With a median follow-up of 15.2 months, 3 of 154 pts (2%) had progressive disease (at 12.5, 16.4, and 24.0 months) and no deaths occurred. The PFS rate at 12 months was 100% (95% CI, 100-100) (Figure 1). A total of 99.2% of pts (95% CI, 94.3-99.9) had a DOR of least 12 months, and 97.2% (95% CI, 91.5-99.1) had a DOCR of at least 12 months. The planned treatment course of 4 cycles was completed by 94% of pts. Forty-four percent received G-CSF, primarily for primary prophylaxis, for 1 or more cycles. Three percent of pts discontinued treatment (all drugs) due to treatment-emergent adverse events (TEAEs). No events of febrile neutropenia were reported. Thirty four percent of pts experienced grade ≥3 treatment-related TEAEs, and 3% experienced grade ≥3 treatment-related peripheral sensory neuropathy. The most common grade ≥3 treatment-related TEAEs were neutropenia (9%), increased alanine aminotransferase (ALT) (7%), and increased aspartate aminotransferase (5%). Treatment-emergent immune-mediated adverse events (IMAEs) occurred in 22% of pts, and grade ≥3 treatment-emergent IMAEs occurred in 7% of pts. The most common treatment-emergent IMAE of any grade was hypothyroidism (6%). Twelve percent of pts experienced treatment-related serious TEAEs. The most common treatment-related serious TEAEs were pyrexia (3%), increased ALT (1%), and peripheral sensory neuropathy (1%). Conclusions Results from SGN35-027 Part C show promising efficacy and an acceptable safety profile for BV and nivolumab in combination with chemotherapy (AN+AD) for pts with nonbulky early-stage cHL. Pts had high ORR (98%) and CR rates (93%) at EOT, and a 12-month PFS of 100% with a median follow-up of 15.2 months. There was a low incidence of grade 3 or higher neuropathy and there were no cases of febrile neutropenia. AN+AD demonstrates encouraging efficacy in nonbulky early-stage cHL and may avoid toxicities associated with radiation, bleomycin, and vinblastine. Follow-up of Part C is ongoing with 92% of pts in long-term follow-up.

Ibrutinib in Combination with Revlimid/Dexamethasone (Rd) in Relapsed/Refractory Multiple Myeloma (AFT-15)

Introduction: Preclinical studies have suggested synergism between lenalidomide (LEN) and ibrutinib (IBR) in multiple myeloma (MM). Both downregulate IRF4, a master transcriptional factor that regulates myeloma cell survival. Single agent oral IBR combined with dexamethasone proved well tolerated and active in advanced, steroid refractory relapsed MM as part of a large Phase1/2 study in 60 patients, with durable stabilization and minimal response seen in most evaluable patients (Richardson PG et al, BJH 2018). LEN is considered a standard of care in newly diagnosed MM, as maintenance and in relapsed disease, and a backbone of oral therapy in the MM treatment paradigm (Laubach JP et al, Leukemia 2016). Methods: We therefore conducted a 3+3 phase I trial to determine the maximum tolerated dose (MTD) of IBR in combination with LEN + dexamethasone (DEX) in patients with relapsed/refractory (RR) MM who had at least 2 prior lines of therapy. Three dose levels (DL) were planned. Cycle length was 28 days. IBR was administered orally daily at 560mg on DL1-2 and 840mg on DL3, LEN orally days 1-21 at 15mg on DL1 and 25mg on DL2-3, and DEX orally days 1, 8, 15, and 22 at 40 mg if age &amp;lt; 75 or 20 mg if ≥75 for DL1-3. Patients with GFR ≥ 30 and &amp;lt; 60 were treated according to manufacturer's instructions with lenalidomide dosed at 10mg/d. Dose limiting toxicities (DLT) included grade 4 thrombocytopenia; grade 4 neutropenia lasting more than 5 days or febrile neutropenia; grade 4 nausea, vomiting or diarrhea; grade 3 thrombocytopenia with bleeding or platelet transfusion; grade 3-4 hyperglycemia or thrombotic/embolic event, treatment delays ≥ 21 days for toxicity; and treatment related death. Due to changes in standard of care during the study, eligibility was modified to allow the enrollment of patients with RRMM who had at least 1 prior line of therapy. Response was assessed using IMWG/Uniform Criteria. Results: Fourteen patients (DL1-6 pts; DL2-3 pts; DL3-5 pts) registered to the study from March 2019 to May 2023, prior to its closure due to slow accrual. One patient on DL3 cancelled participation prior to start of treatment due to disease progression (PD). The remaining 13 patients are included in summary of toxicities and response but 2 patients on DL3 are excluded from determination of MTD due to discontinuing cycle 1 treatment due to COVID and receiving 280 mg/day of IBR instead of assigned 840 mg/day dose during cycle 1, respectfully. Twelve patients were evaluable for response. The median number of prior lines of therapy was 3 (range: 2-9), reflecting a heavily pretreated relapsed and refractory population. One of the 6 patient on DL1 developed a DLT, grade 3 non-viral hepatitis. None of the 3 patients on DL2 or the 2 patients on DL3 had a DLT. One patient on DL1 remains on treatment with stable disease for 42+ cycles. The median number of cycles administered was 3 (range: 1-42+). Severe toxicities reported included grade 3 lymphocytopenia (3), anemia (2), alanine aminotransferase increase (1), aspartate aminotransferase increase (1), blood bilirubin increase (1), hypocalcemia (1), hypokalemia (1) hypophosphatemia (1), febrile neutropenia (1), chronic kidney disease (1), non-viral hepatitis (1), soft tissue infection (1), and fatigue (1); grade 4 lymphocytopenia (1), and grade 5 sepsis (1). End of treatment reasons included: PD (7), toxicity (2), death [soft tissue infection that turned into sepsis considered to be likely related to DEX] (1), and concomitant conditions (2). Stable disease (SD) or better was achieved in 10 of 12 evaluable patients (83%), including one patient who achieved disease control for over 3.5 years. One patient (8%) on DL3 had a complete response (CR) but stopped treatment after 2 cycles due to reversible toxicity and comorbid conditions, based upon physician advice and patient choice. Conclusions: The combination of lenalidomide with Ibrutinib as an all-oral approach in RR MM proved feasible and generally tolerable, with the majority of discontinuation seen in this Phase I study due to disease progression. No COVID related - mortality was seen. SD or better was achieved in 83% of patients, including one CR. Potential future directions include combination approaches with next generation IMids such as pomalidomide, as well as other orally bioavailable novel agents with potent immune activating properties, such as CelMoDs. Support: AFT; Pharmacyclics; Clinicaltrials.gov Identifier: NCT03702725

Polatuzumab Vedotin, Zanubrutinib and Rituximab Achieved Rapid and Deep Response in Previously Untreated Frail and Elderly Diffuse Large B-Cell Lymphoma Patients

Introduction: The incidence of diffuse large B-cell lymphoma (DLBCL) increases with age, while first-line treatment for frail and elderly DLBCL is a debating topic. R-miniCHOP, a reduced intensity regimen of R-CHOP, is currently the standard of care for this population, yet with limitation due to toxicities (Frédéric Peyrade et al., Lancet Oncol, 2011). Chemo-free regimens combining Bruton kinase inhibitors, rituximab and lenalidomide showed fewer toxicities, but compromised on efficacy in elderly DLBCL in multiple previous reports (Pengpeng Xu et al., Lancet Healthy Longev, 2022; Haiyan Yang et al., ASH 2022). First-line treatment balancing efficacy with safety is urgently needed for frail and elderly DLBCL patients. Since polatuzumab vedotin was approved in China for first-line DLBCL this year and reportedly had synergistic effect with rituximab in cell line research (Natsumi Kawasaki et al., Br J Haematol, 2022), we conducted a study of polatuzumab vedotin plus zanubrutinib and rituximab (ZPR) in previously untreated frail and elderly DLBCL to assess the efficacy and safety. Here we present the characteristics of 12 enrolled patients and preliminary results. Methods: Previously untreated DLBCL patients aged over 70 years old, or aged between 60 to 69 with ECOG score 2 to 4 were enrolled in this study. All patients received a triplet regimen of ZPR. Twenty-one days was a cycle. Zanubrutinib was given 160mg twice a day orally from day 1 to day 21. Rituximab was given 375mg/m 2 intravenously on day 1. Polatuzumab vedotin was administered at a dosage of 1.8mg per kilogram intravenously on day 1. Patients would receive 6 cycles of ZPR regimen if assessed partial response (PR) or complete response (CR) after 3 cycles. If assessed CR after 6 cycles of ZPR, patients would receive zanubrutinib 160mg twice a day alone for another 6 cycles. Whole body 18F-FDG PET/CT scan or contrast-enhanced CT scan of cervical, thoracic, abdominal and pelvic parts was scheduled every 3 cycles. Treatment response was assessed by 2014 Lugano response criteria. Adverse events were graded by CTCAE 5.0. The primary endpoint is overall response rate (ORR) after 6 cycles of ZPR. The secondary endpoints are CR rate after 6 cycles of ZPR, and 2-year progression-free survival (PFS). Other endpoint is safety (Figure 1). Results: Twelve patients were enrolled in our study until Jul 24, 2023. Median age was 75 (range: 67-87). Six patients were female and six patients were male. Nine (75%) patients were classified non-GCB type according to cell of origin by Hans algorithm. Nine (75%) patients were assessed stage Ⅲ to Ⅳ by Ann Arbor staging system. Nine (75%) patients had an international prognostic index (IPI) score of 2 or more. One (11%) patient had double-hit risk factor in 9 patients with gene rearrangement results. Six (75%) patients had MYD88 L265P mutation in 8 patients with sequencing results. After a median follow up of 2.1 months, four patients had PET/CT assessment results after 3 cycles of ZPR, and four (100%) of them achieved CR. The ORR after 3 cycles of ZPR regimen was 100% (Figure 2).Grade 3 to 4 adverse events occurred in two patients, that one patient had grade 3 aspartate aminotransferase increase and alanine aminotransferase increase, and the other patient had grade 3 pneumonitis. Grade 1 to 2 adverse events included neutrophil count decrease (16%), dizziness (8%), and epistaxis (8%). All patients recovered from adverse events under best supportive care. There was no discontinuation of ZPR regimen due to severe adverse events. Conclusion: Based on these results in our study, ZPR regimen showed rapid and deep response in previously untreated frail and elderly DLBCL patients with manageable safety profiles. We registered and initiated a phase 2b trial (NCT05940064) to further evaluate the efficacy and safety of ZPR regimen as first-line treatment for this population. Ongoing treatment and follow up of these twelve patients will also be further updated.

No Place like Home: Home-Based Intravenous Arsenic Trioxide for the Treatment of Acute Promyelocytic Leukemia (APL)

Introduction: APL has transitioned from a highly fatal malignancy to a disease that is curable with a combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Intravenous (IV) administration of ATO remains the standard of care for consolidation, however, its use is associated with long infusion times, electrolyte disturbances, and QTc prolongation that has historically required frequent outpatient infusion center administration and monitoring. Following induction, patients receive a cumbersome schedule of ATO through daily infusions 5 days each week (typically Monday-Friday) 4 weeks on 4 weeks off for 4 cycles. Oral formulations of ATO are poorly water soluble, have not demonstrated adequate absorption in the gastrointestinal (GI) tract leading to significant GI upset and are not approved for use in the United States. Beginning in 2020, patients treated at our institution were given the option of receiving ATO at home through a partnership via Qualitas Specialty Pharmacy of RWJBarnabas Health. This retrospective review evaluates the feasibility, safety, and efficacy of administration of ATO in the home infusion setting for patients with APL receiving ATO consolidation. Methods: Through retrospective chart review, we evaluated patients who received consolidation therapy of ATO through home infusion from 2020-2023. Eligible patients included those with an ECOG of &amp;lt;2, absence of baseline QTc prolongation (defined as &amp;gt;500ms), and patients without significant kidney dysfunction or hepatotoxicity at baseline. We evaluated each patient for adverse effects such as QTc prolongation, electrolyte disturbances, liver function test (LFT) abnormalities, neutropenic fever, bacteremia, unplanned Emergency Room (ER) or urgent care visits, and unexpected hospitalizations (via Common Terminology Criteria for Adverse Events version 5). Results: Fifteen patients aged 19-79 (median = 43) were reviewed with 60% being male and 40% female. Sixty percent had a baseline ECOG 1 and 40% had an ECOG 0. Twenty percent of patients had a prior malignancy (n=3). Eighty percent of the patients experienced grade (gd) 1-3 electrolyte abnormalities (47% gd 1 hyperphosphatemia, 13% gd 1 hyperkalemia, 7% gd 2 hyperkalemia, 7% gd 3 hyperkalemia, 13% gd 1 hypokalemia, 13% gd 1 hypermagnesemia, 7% gd 3 hypermagnesemia, 7% gd 1 hypomagnesemia, 33% gd 1 hypernatremia, 33% gd 1 hyponatremia, &amp; 7% gd 2 hyponatremia). Of the 15 patients receiving treatment, 27% experienced gd 1 alanine aminotransferase (ALT) increase, 13% of patients experienced gd 1 aspartate aminotransferase (AST) increase, and 7% of patients experienced gd 2 hyperbilirubinemia. For QTc prolongation, 53% of patients experienced gd 1 prolongation, 7% of patients experienced gd 2 prolongation, and 13% of patients experienced gd 3 prolongation. One out of the 15 patients experienced treatment delays due to QTc prolongation. While forty percent of patients visited either the ER and/or urgent care during consolidation therapy, no visits were deemed therapy related. Reasons for urgent evaluation included infections (n=3), vertigo (n=1), low back pain (n=1), facial numbness (n=1), fall (n=1), abdominal pain (n=1), and hemorrhoidal bleeding (n=1). Two patients were hospitalized, due to a renal infarct (n=1) and a subdural hematoma after a fall (n=1). None of the 15 patients experienced febrile neutropenia/bacteremia while receiving consolidation therapy. Of the 11 patients who completed consolidation at the time of this abstraction, all (100%) had complete remission demonstrated on post-consolidation bone marrow. One of the 11 patients relapsed within 6 months of consolidation; however, is now in remission following two additional consolidation courses and a bone marrow transplant. Four patients have not yet completed four cycles of ATO consolidation. One patient was transitioned from home infusion to clinic treatment due to out-of-pocket cost. Conclusions: Our study demonstrates that home infusion of ATO is both safe and highly effective for patients. Therapy was well tolerated with predictable and manageable toxicity. Prospective studies are needed to evaluate the efficacy and safety in comparison to patients receiving ATO in the infusion center as well as to assess patient-reported and cost outcomes. Given the safety profile of home-based ATO, we have implemented at home ATO consolidation as standard therapy for all eligible patients.

Influence of pneumatic tube delivery system on laboratory results.

The pneumatic tube system (PTS) is an automated and fast modality of transportation of biological samples, but it has been reported to induce preanalytical errors. To study the influence of transportation by PTS on biochemistry tests which are particularly sensitive to haemolysis and atmospheric pressure variation. We compared laboratory results of arterial blood gas, sodium, potassium, chloride, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, glucose and haemolysis index of samples conveyed simultaneously by PTS and by courier. We recruited 30 patients from the sampling room and 40 patients from the intensive care unit. Transport through PTS resulted in a significant increase in aspartate aminotransferase and potassium without exceeding the limits of acceptability. Potassium was significantly more increased for samples transported in a higher speed line (p = .048) but without exceeding the limits of acceptability. No significant impact was noted on haemolysis indices. The pO2 variations due to PTS transportation exceeded the limit of acceptability with significant intra-individual variations. Our PTS is validated for biochemistry tests results. It reduces turnaround times without affecting sample quality. However, the interpretation of arterial blood gas results should be careful for samples transported by PTS.

Penetrance and expressivity of mitochondrial variants in a large clinically unselected population.

Whole genome sequencing (WGS) from large clinically unselected cohorts provides a unique opportunity to assess the penetrance and expressivity of rare and/or known pathogenic mitochondrial variants in population. Using WGS from 179 862 clinically unselected individuals from the UK Biobank, we performed extensive single and rare variant aggregation association analyses of 15 881 mtDNA variants and 73 known pathogenic variants with 15 mitochondrial disease-relevant phenotypes. We identified 12 homoplasmic and one heteroplasmic variant (m.3243A>G) with genome-wide significant associations in our clinically unselected cohort. Heteroplasmic m.3243A>G (MAF = 0.0002, a known pathogenic variant) was associated with diabetes, deafness and heart failure and 12 homoplasmic variants increased aspartate aminotransferase levels including three low-frequency variants (MAF ~0.002 and beta~0.3 SD). Most pathogenic mitochondrial disease variants (n = 66/74) were rare in the population (<1:9000). Aggregated or single variant analysis of pathogenic variants showed low penetrance in unselected settings for the relevant phenotypes, except m.3243A>G. Multi-system disease risk and penetrance of diabetes, deafness and heart failure greatly increased with m.3243A>G level ≥ 10%. The odds ratio of these traits increased from 5.61, 12.3 and 10.1 to 25.1, 55.0 and 39.5, respectively. Diabetes risk with m.3243A>G was further influenced by type 2 diabetes genetic risk. Our study of mitochondrial variation in a large-unselected population identified novel associations and demonstrated that pathogenic mitochondrial variants have lower penetrance in clinically unselected settings. m.3243A>G was an exception at higher heteroplasmy showing a significant impact on health making it a good candidate for incidental reporting.