Need For Dose Reduction Research Articles

Mesna, Doxorubicin, Ifosfamide and Dacarbazine (MAID) Combination Chemotherapy for Retroperitoneal Sarcoma: A Single-center Experience.

There is limited evidence regarding the systemic treatment of retroperitoneal soft-tissue sarcoma, and the current Japanese guidelines fail to make definitive suggestions. Here, we report our experience with combination chemotherapy of mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) in this population. We retrospectively reviewed the records of eight patients (three male and five female) who received MAID for pathologically diagnosed metastatic unresectable retroperitoneal sarcoma (either leiomyosarcoma or pleomorphic sarcoma) between October 2019 and January 2022. Treatment efficacy, tolerability (need for dose reduction), and safety profiles were evaluated and summarized. At initiation, the median age was 56.0 years, and the body mass index was 20.0 kg/cm2 Six patients had Eastern Cooperative Oncology Group performance status scores of 0. The net clinical benefit was a partial response in three (37.5%) patients, stable disease in four (50.0%), and progressive disease in one (12.5%). During the median 90.8 weeks of follow-up, disease in five patients progressed, resulting in a median progression-free survival of 48.4 weeks, and five deaths occurred, resulting in an overall survival of 95.1 weeks. Commonly observed adverse events were neutropenia (eight patients), anemia (eight patients), and decreased platelet count (seven patients), which led to dose reduction (60-80%) in six patients. MAID combination therapy may be an acceptable option for advanced retroperitoneal sarcoma; however, its benefits must be carefully assessed owing to its not insignificant toxicity.

Abstract PO3-16-09: Real-World Experience with Trastuzumab Deruxtecan at a Diverse NCI Comprehensive Cancer Center

Abstract Background: Trastuzumab Deruxtecan (T-DXd) is an antibody-drug conjugate originally approved for use in patients with HER2–positive metastatic breast cancer (MBC). In June 2022, data from the DESTINY-Breast04 trial revealed a near-doubling of progression-free survival (PFS) and significantly improved overall survival (OS) for patients with HER2-low MBC (immunohistochemistry [IHC] grade 1+ or IHC2+ in situ hybridization [ISH]-negative) treated with T-DXd versus standard-of-care chemotherapy. The data from this clinical trial led to the approval of T-DXd for use in patients with HER2-low MBC. However, the DESTINY-Breast studies completed to date have included < 5% black patients. This retrospective study of patients at a racially diverse NCI Comprehensive Cancer Center was designed to study whether T-DXd in a real-world population are comparable to published data. Methods: A retrospective chart review was conducted and identified 72 patients with HER2-low and HER2-positive MBC who received T-DXd between December 2019 and March 2023 at the Winship Cancer Institute at Emory University. Data collected for all patients included demographics, prior breast cancer history, T-DXd -specific and post-T-DXd treatment, and clinical outcomes where applicable. Results: Of the 103 patients who were dosed with T-DXd, 55 (53.4%) had HER2-positive disease, and 48 (46.7%) patients had HER2-low disease. 71 (68.9%) patients had hormone-receptor positive disease and 32 (31.1%) patients had hormone-receptor negative disease. The overall study population was 46% Caucasian; 38% African American; 13% Asian; 4% Unreported. The average number of cycles received was 11 (on treatment an average of 8 months). Pneumonitis occurred in 5 patients (4.9%). HER2-positive patients were typically on T-Dxd for a greater number of cycles than HER2-low patients (Table 1). Additionally, patients with brain metastases were, on average, treated with T-Dxd longer than patients without brain metastases, 14.5 versus 9 cycles. The number of cycles of T-Dxd received, the need for dose reduction, and incidence pneumonitis did not differ significantly between black and white patients. The data for this study is preliminary 48% of the patient population are still actively undergoing T-Dxd treatment. Conclusion: This study reviewed and analyzed T-Dxd treatment in a diverse population of both HER2-positive and HER2-low MBC patients, and in this study, outcomes of treatment did not differ by race. More attention to this topic is needed in future studies of larger populations, along with increased efforts to enroll diverse patient populations in clinical trials. Table 1. Citation Format: Jane Meisel, Maisey Ratcliffe. Real-World Experience with Trastuzumab Deruxtecan at a Diverse NCI Comprehensive Cancer Center [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-16-09.

Towards the establishment of national diagnostic reference levels for abdomen, KUB, and lumbar spine x-ray examinations in Sri Lanka: a multi-centric study

Diagnostic reference levels (DRLs) and achievable doses (ADs) provide guidance to optimise radiation doses for patients undergoing medical imaging procedures. This multi-centre study aimed to compare institutional DRLs (IDRLs) across hospitals, propose ADs and multi-centric DRLs (MCDRLs) for four common x-ray examinations in Sri Lanka, and assess the potential for dose reduction. A prospective cross-sectional study of 894 adult patients referred for abdomen anteroposterior (AP), kidney-ureter-bladder (KUB) AP, lumbar spine AP, and lumbar spine lateral (LAT) x-ray examinations was conducted. Patient demographic information (age, sex, weight, BMI) and exposure parameters (tube voltage, tube current-exposure time product) were collected. Patient dose indicators were measured in terms of kerma-area product (PKA) using a PKA meter. IDRLs, ADs, and MCDRLs were calculated following the International Commission on Radiological Protection guidelines, with ADs and MCDRLs defined as the 50th and 75th percentiles of the median PKA distributions, respectively. IDRL ranges varied considerably across hospitals: 1.42–2.42 Gy cm2 for abdomen AP, 1.51–2.86 Gy cm2 for KUB AP, 0.83–1.65 Gy cm2 for lumbar spine AP, and 1.76–4.10 Gy cm2 for lumbar spine LAT. The proposed ADs were 1.82 Gy cm2 (abdomen AP), 2.03 Gy cm2 (KUB AP), 1.27 Gy cm2 (lumbar spine AP), and 2.21 Gy cm2 (lumbar spine LAT). MCDRLs were 2.24 Gy cm2 (abdomen AP), 2.40 Gy cm2 (KUB AP), 1.43 Gy cm2 (lumbar spine AP), and 2.38 Gy cm2 (lumbar spine LAT). Substantial intra- and inter-hospital variations in PKA were observed for all four examinations. Although ADs and MCDRLs in Sri Lanka were comparable to those in the existing literature, the identified intra- and inter-hospital variations underscore the need for dose reduction without compromising diagnostic information. Hospitals with high IDRLs are recommended to review and optimise their practices. These MCDRLs serve as preliminary national DRLs, guiding dose optimisation efforts by medical professionals and policymakers.

Study protocol: fish oil supplement in prevention of oxaliplatin-induced peripheral neuropathy in adjuvant colorectal cancer patients – a randomized controlled trial. (OxaNeuro)

BackgroundOxaliplatin-induced peripheral neuropathy (OIPN) in general and painful OIPN in particular is a debilitating late effect that severely affects cancer survivors’ quality of life and causes premature cessation of potentially lifesaving treatment. No preventive treatments and no effective treatment for chronic OIPN exist despite many attempts. One of several suggested mechanisms includes neuroinflammation as a contributing factor to OIPN. Fish oil containing long-chain n-3 polyunsaturated fatty acids (n-3 LCPUFAs) are precursors to specialized proresolving mediators that mediate the resolution of inflammation. Our primary hypothesis is that a high supplementation of n-3 LCPUFAs will lower the prevalence and severity of OIPN.MethodsThe OxaNeuro project is an investigator-initiated, multicenter, double-blinded, randomized, placebo-controlled clinical study. We will include 120 patients eligible to receive adjuvant oxaliplatin after colorectal cancer surgery. Patients will receive fish oil capsules containing n-3 LCPUFAs or corn oil daily for 8 months.The primary endpoint is the prevalence of OIPN at 8 months defined as relevant symptoms, including one of the following: abnormal nerve conduction screening, abnormal vibration threshold test, abnormal skin biopsy, or abnormal pinprick test. Additional endpoints include the intensity and severity of OIPN-related neuropathic pain, patient-reported OIPN symptoms, quality of life, mental health symptoms, body composition, and cognitive evaluation. Furthermore, we will evaluate inflammatory biomarkers in blood samples and skin biopsies, including the potential OIPN biomarker neurofilament light protein (NfL) which will be measured before each cycle of chemotherapy.DiscussionIf readily available fish oil supplementation alleviates OIPN prevalence and severity, it will significantly improve the lives of both cancer survivors and palliative cancer patients receiving oxaliplatin; it will improve their quality of life, optimize chemotherapeutic treatment plans by lowering the need for dose reduction or premature cessation, and potentially increase survival.Trial registrationClinicalTrial.gov identifier: NCT05404230Protocol version: 1.2, April 25th. 2023

Effectiveness of senna in treating chronic constipation in geriatric patients presenting to the emergency department: A randomized, double-blind, multicenter study

Introduction: Chronic constipation is prevalent in the geriatric population. Undiagnosed and untreated constipation can lead to complications and decreased health-related quality of life. The aim of this study was to compare the therapeutic effectiveness of senna alone with a combination of bisacodyl and senna in patients diagnosed with chronic constipation. Materials and Method: This prospective, multicenter, double-blind, randomized controlled trial included patients aged 65 years and older who presented to the emergency department with chronic constipation, diagnosed according to the Rome IV criteria, between July and October 2023. Patients were randomly assigned to either the senna group (20 mg sennoside B) or the senna + bisacodyl group (3 mg sennoside B + 5 mg bisacodyl). Participants took the drugs twice daily for 28 days. The Constipation Scoring System and Patient Assessment of Constipation Quality of Life scores were calculated before and after treatment for each patient. Results: The study included 105 patients, with 54 in the senna group and 51 in the senna + bisacodyl group. There was a statistically higher need for dose reduction because of drug side effects in the senna + bisacodyl group compared with the senna group (p=0.026). Following treatment, the senna group had a higher score on the Constipation Scoring System and Patient Assessment of Constipation Quality of Life compared with the senna + bisacodyl group, and the difference was statistically significant (p<0.001, p=0.012). Conclusion: In geriatric patients, short-term treatment of chronic constipation with senna is more effective than senna+bisacodyl regarding constipation severity and quality of life. Keywords: Aged; Bisacodyl; Constipation; Quality of Life; Sennosides.

Simple and safe digitoxin dosing in heart failure based on data from the DIGIT-HF trial

BackgroundThe present study aimed to develop a simple dosing score when starting the cardiac glycoside digitoxin in heart failure with reduced ejection fraction (HFrEF) employing first data from the randomized, double-blinded DIGIT-HF trial.Methods and resultsIn DIGIT-HF, digitoxin was started with a dose of 0.07 mg once daily (o.d.) in all patients. For score derivation, 317 patients were analyzed who had been randomized to digitoxin. In these patients, after scheduled determination of serum levels at study week 6, the digitoxin dose had remained unchanged or had been reduced to 0.05 mg o.d. (97% of patients) to achieve serum concentrations within a predefined range (10.5–23.6 nmol/l). In logistic regression analyses, sex, age, body mass index (BMI), and estimated glomerular filtration rate (eGFR) were associated with need for dose reduction and, therefore, selected for further developing the dosing score. Optimal cut-points were derived from ROC curve analyses. Finally, female sex, age ≥ 75 years, eGFR < 50 ml/min/1.73 m2, and BMI < 27 kg/m2 each were assigned one point for the digitoxin dosing score. A score of ≥ 1 indicated the need for dose reduction with sensitivity/specificity of 81.6%/49.7%, respectively. Accuracy was confirmed in a validation data set including 64 patients randomized to digitoxin yielding sensitivity/specificity of 87.5%/37.5%, respectively.ConclusionIn patients with HFrEF, treatment with digitoxin should be started at 0.05 mg o.d. in subjects with either female sex, eGFR < 50 ml/min/1.73m2, BMI < 27 kg/m2, or age ≥ 75 years. In any other patient, digitoxin may be safely started at 0.07 mg o.d.Graphical

In vitro-in vivo extrapolation of bexarotene metabolism in the presence of chronic kidney disease and acute kidney injury in rat using physiologically based pharmacokinetic modeling and extrapolation to human.

Renal impairment can affect the elimination of hepatically metabolized drugs. Bexarotene (BXT) used for cutaneous T-cell lymphoma is highly bound in plasma and metabolized by CYP3A4. The BXT European Medicine Agency and Food and Drug Administration packages recommended the evaluation of renal impairment on BXT metabolism. The plasma protein binding of BXT can be changed in patients with renal dysfunction due to hypoalbuminemia and accumulation of uremic toxins. In vitro, microsomal stability and plasma protein binding studies were pursued. A preclinical pharmacokinetic study was pursued in control, chronic kidney disease (CKD), and acute kidney injury (AKI) rats. A BXT physiologically based pharmacokinetic (PBPK) model that utilized in vitro-in vivo extrapolation of metabolism was established and verified in healthy rats, customized to CKD and AKI rats, and extrapolated to healthy human subjects and those with CKD stages 3, 4, and 5. In vitro studies showed that AKI and CKD significantly increased the BXT fraction unbound in plasma (from 0.011 to 0.018 and 0.022, respectively) and decreased intrinsic clearance (from 4.1 to 2.5, and 2.2mL/min/g liver, respectively). This could explain the reduced in vivo clearance observed in CKD rats (from 0.4 to 0.28L/h/kg) and the 1.3-fold increase in BXT exposure. Changes in BXT disposition in AKI rats were not straightforward due to simultaneous changes in BXT distribution. The human PBPK model predicted an increased BXT exposure by 2-fold in CKD patients, suggesting the need for dose reduction and drug monitoring. The reduced BXT metabolism due to renal impairment is especially relevant in cancer patients with CKD.

Abstract 12861: Demographics and Clinical Characteristics of Patients Presenting With Sinus Bradycardia After Bariatric Surgery

Introduction: Sinus bradycardia following bariatric surgery has been described in current literature. Whether certain demographics and clinical characteristics affect this occurrence remains a topic of discussion. Hypothesis: We assessed the hypothesis that certain patient characteristics may affect the prevalence of sinus bradycardia after bariatric surgery. Methods: This cross-sectional analysis nested in a community cohort assessed 321 bariatric surgeries from 2012 to 2020. Due to incomplete data, 179 patients were excluded. A descriptive analysis was made using means and standard deviation (SD) for continuous variables and count and percentages for categorical variables. Odds ratios (OR) were calculated for associations with 95% confidence intervals (CI), and Student’s t-test was used to compare means. Results: For the categorical variables evaluated, only beta blocker usage was significantly different ( p = 0.014) with nearly a tripling of the estimated odds for bradycardia [OR: 2.702 (95%, CI: 1.291 - 5.658)]. For the quantitative measures, only the heart rates showed significant differences between the groups (with and without bradycardia) and they were significant at all follow-up times. Conclusions: Our study showed that sinus bradycardia is a common occurrence among patients undergoing bariatric surgery. The use of beta blockers was significantly predictive of bradycardia. Further studies are needed to evaluate the need for dose reduction or discontinuation of beta blockers in the perioperative period in select cases. Additionally, medical centers should be aware of this development to avoid over-treatment.

Lenvatinib for the treatment of hepatocellular carcinoma—a real-world multicenter Australian cohort study

IntroductionHepatocellular carcinoma (HCC) is a serious complication of chronic liver disease. Lenvatinib is an oral multikinase inhibitor registered to treat advanced HCC. This study evaluates the real-world experience with lenvatinib in Australia.MethodsWe conducted a retrospective cohort study of patients treated with lenvatinib for advanced HCC between July 2018 and November 2020 at 11 Australian tertiary care hospitals. Baseline demographic data, tumor characteristics, lenvatinib dosing, adverse events (AEs) and clinical outcomes were collected. Overall survival (OS) was the primary outcome. Progression free survival (PFS) and AEs were secondary outcomes.ResultsA total of 155 patients were included and were predominantly male (90.7%) with a median age of 65 years (interquartile range [IQR]: 59–75). The main causes of chronic liver disease were hepatitis C infection (40.0%) and alcohol-related liver disease (34.2). Median OS and PFS were 7.7 (95% confidence interval [CI]: 5.8–14.0) and 5.3 months (95% CI: 2.8–9.2) respectively. Multivariate predictors of mortality were the need for dose reduction due to AEs (Hazard ratio [HR] 0.41, p < 0.01), new or worsening hypertension (HR 0.42, p < 0.01), diarrhoea (HR 0.47, p = 0.04) and more advanced BCLC stage (HR 2.50, p = 0.04). Multivariable predictors of disease progression were higher Child–Pugh score (HR 1.25, p = 0.04), the need for a dose reduction (HR 0.45, p < 0.01) and age (HR 0.96, p < 0.001). AEs occurred in 83.9% of patients with most being mild (71.6%).ConclusionsLenvatinib remains safe and effective in real-world use. Treatment emergent diarrhoea and hypertension, and the need for dose reduction appear to predict better OS.

Abstract 5237: B-Raf V600E harboring non-melanoma cancers treated with Vemurafenib monotherapy and in combination with Everolimus/Sorafenib/Crizotinib/Paclitaxel+ Carboplatin: A pooled analysis of five phase 1/2 studies

Abstract BACKGROUND: BRAF V600 mutations are driver oncogenes in multiple human cancers. Given complex resistance mechanisms beyond combined MEK inhibition, limited data exists to evaluate combinations with CRAF/ARAF/MET/mTOR inhibitors and cytotoxic chemotherapy in sustaining response and overcoming resistance. We explore patient outcomes comparing vemurafenib monotherapy with the above combination therapies in this analysis. METHODS: A pooled analysis of 5 phase 1/2 clinical trials containing vemurafenib was conducted between January 2012 and October 2020 in BRAF V600E mutant advanced or metastatic tumors. Overall survival (OS) and Progression free survival (PFS) in vemurafenib monotherapy (V) arm compared with vemurafenib + crizotinib (VC), vemurafenib + sorafenib (VS), vemurafenib + everolimus (VE) and vemurafenib + paclitaxel + carboplatin (VPC) arms were assessed. Objective Response Rate (ORR) and Clinical Benefit Rate (CBR=CR+PR+SD≥6 months) and safety profile of combination arms were also explored. RESULTS: 99 patients were enrolled across 5 studies. Median age was 57 years with 78% of ECOG 1 and M:F ratio at 1:1. Tumor types included NSCLC (13%), Thyroid cancer (12%), Low and High-grade Gliomas (7%), Colorectal cancer (6%), Cholangiocarcinoma (5%) and ECD (3%). V arm derived greatest clinical benefit with median OS at 21 months while addition of PC arm dropped median OS to 2 months. Inferior OS was seen in VPC arm when compared to V arm (p=0.00616). Median PFS peaked at 11 months in VC arm versus 3 months for the VPC arm. Of 85 evaluable patients, 2 complete responses were noted in the V (n=25) and VPC (n=14) arms and 8 Partial Responses (PR) were noted with 5 (18%) patients with NSCLC in V arm followed by 4 PRs in the VC (n=12) arm. PR rates were equally seen in the other arms. ORR (36%) and CBR (40%) rates were the highest for the V arm. G3/G4 treatment related adverse events with neutropenia (63%), thrombocytopenia (50%) and fatigue (63%) were highest in VPC. 1 patient died from G4 thrombocytopenia with intracranial hemorrhage in the VPC arm. CONCLUSIONS: No significant added clinical benefit was noted when vemurafenib was combined with other targeted agents or cytotoxic therapy. Combinations resulted in poor tolerance and need for dose reductions compromising clinical efficacy. Prospective studies to analyze resistance mechanisms to BRAF inhibitor therapy in BRAF+ tumors and in real time tailoring therapy based on co-occuring alterations is warranted. Citation Format: Blessie Elizabeth Nelson, Jason Roszik, Filip Janku, David Hong, Shumei Kato, Aung Naing, Sarina Piha-Paul, Siqing Fu, Apostolia Tsimberidou, Maria Cabanillas, Naifa Busaidy, Milind Javle, Lauren Byers, John Heymach, Funda Meric-Bernstam, Vivek Subbiah. B-Raf V600E harboring non-melanoma cancers treated with Vemurafenib monotherapy and in combination with Everolimus/Sorafenib/Crizotinib/Paclitaxel+ Carboplatin: A pooled analysis of five phase 1/2 studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5237.

Exposure\u2013response analyses of cabozantinib in patients with metastatic renal cell cancer

AimIn the registration trial, cabozantinib exposure ≥ 750 ng/mL correlated to improved tumor size reduction, response rate and progression free survival (PFS) in patients with metastatic renal cell cancer (mRCC). Because patients in routine care often differ from patients in clinical trials, we explored the cabozantinib exposure–response relationship in patients with mRCC treated in routine care.MethodsCabozantinib trough concentrations (Cmin) were collected and average exposure was calculated per individual. Exposure–response analyses were performed using the earlier identified target of Cmin > 750 ng/mL and median Cmin. In addition, the effect of dose reductions on response was explored. PFS was used as measure of response.ResultsIn total, 59 patients were included:10% were classified as favourable, 61% as intermediate and 29% as poor IMDC risk group, respectively. Median number of prior treatment lines was 2 (0–5). Starting dose was 60 mg in 46%, 40 mg in 42% and 20 mg in 12% of patients. Dose reductions were needed in 58% of patients. Median Cmin was 572 ng/mL (IQR: 496–701). Only 17% of patients had an average Cmin ≥ 750 ng/mL. Median PFS was 52 weeks (95% CI: 40–64). No improved PFS was observed for patients with Cmin ≥ 750 ng/mL or ≥ 572 ng/ml. A longer PFS was observed for patients with a dose reduction vs. those without (65 vs. 31 weeks, p = .001). After incorporating known covariates (IMDC risk group and prior treatment lines (< 2 vs. ≥ 2)) in the multivariable analysis, the need for dose reduction remained significantly associated with improved PFS (HR 0.32, 95% CI:0.14–0.70, p = .004).ConclusionIn these explorative analyses, no clear relationship between increased cabozantinib exposure and improved PFS was observed. Average cabozantinib exposure was below the previously proposed target in 83% of patients. Future studies should focus on validating the cabozantinib exposure required for long term efficacy.

Management of Psychiatric Disorders in Patients with Chronic Kidney Diseases.

Management of Psychiatric Disorders in Patients with Chronic Kidney Diseases.

Efficacy and Safety of Ruxolitinib in the Treatment of Elderly Patients with Policythemia Vera Resistant/Intolerant to Hydroxyurea

▪Introduction: Ruxolitinib (Rux) has been recently approved as second-line therapy in patients (pts) with Polycythemia Vera (PV) resistant/intolerant to hydroxyurea (HU). Median age of PV pts enrolled in the pivotal Response trials was around 60 yrs; at present, no data is reported on the use of Rux in elderly pts.Aims: In a real-world cohort of PV pts treated with Rux, we investigated whether the efficacy and safety of Rux were comparable in pts who initiated therapy when aged ≥75 years compared with younger pts.Methods: After IRB approval, clinical/laboratory data of 934 WHO2016-defined PV pts followed in 29 Hematology Centers were retrospectively collected. Of them, 168 (17.9%) were considered resistant/intolerant to HU at any time during follow-up by responsible physician and shifted to Rux as second-line therapy.Results: Among the 168 pts treated with Rux, 42 (25%, median age 78.2 years) were aged ≥75 yrs at Rux start, 74 (44%, median age 67.7) were aged 60-74 and 52 (31%, median age 53) were <60 at Rux start.No significant differences were observed between the 3 groups, apart from a lower need for phlebotomies in pts aged ≥75 yrs and lower presence of palpable spleen in older pts (age ≥60), that more frequently switched to Rux due to HU intolerance (Table 1).Median duration of HU treatment was 41.0 months (IQR 14.6 - 85.8), with a trend for a longer median treatment duration in pts aged ≥75 [61.0 months (IQR 21.5 - 89.6) vs 35.9 months (IQR 13.4 - 79.6), p=0.04]. Rux starting dose was similar across age groups; however, more elderly pts underwent Rux dose reductions during follow-up (45.2% in pts aged ≥75 vs 28.6% in younger pts, p=0.04).Responses during Rux therapy are reported in Table 2, with no significant differences between the 3 groups at any time. In the overall cohort, response on PV-related symptoms at 6 and 12 months was significantly higher in pts who switched to Rux because of HU intolerance; however, this difference was not observed in pts aged ≥75 yrs.As to the most common hematologic Rux-related toxicities, grade 3-4 anemia and thrombocytopenia were observed in only 2 (1.2%) and 5 (3%) pts, with no difference across age groups (p=0.45 and p=0.18). However, any grade anemia and thrombocytopenia during Rux were more frequently observed in pts aged ≥75 (68.3% vs 51.7% of anemia, p=0.06 and 12.2% vs 3.5% of thrombocytopenia in younger pts, p=0.04). Nineteen and 4 pts experienced infectious and thrombotic complications during Rux with incidence rates of 0.59 and 0.12 per 100 patient-months, respectively, comparably in younger and older (≥75) pts (p=0.75 and p=0.29, respectively). Notably, 6 infections were herpes simplex/zoster virus, comparably distributed between the 3 groups (p=0.60).Permanent Rux discontinuation was needed in 14 pts (8.3%) after a median Rux exposure of 7.8 months (IQR 4.6 - 17.6) (incidence: 0.41 per 100 pts/months). Discontinuation was comparable between age groups, with Rux stop in 4 pts aged ≥75 yrs and 10 younger pts (2.4% vs 5.2% at 8 months, log-rank p=0.75). At last follow-up, 2 pts had died (1 from 2 nd neoplasia after 19.1 months from Rux start and 1 from acute leukemia after 3.3 years), both pts aged 60-74 yrs.Conclusions. In this real-world analysis, use of Rux in HU resistant/intolerant elderly PV pts was effective and safe despite the more frequent need for dose reductions. Older age should not discourage Rux therapy, but stricter hematological monitoring may be suggested. [Display omitted] DisclosuresLatagliata: BMS Cellgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Breccia: Pfizer: Honoraria; Incyte: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Abbvie: Honoraria; Novartis: Honoraria. Bonifacio: Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Cavo: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Palandri: AOP: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Ixazomib Plus Lenalidomide/Dexamethasone (IRd) Versus Lenalidomide /Dexamethasone (Rd) Maintenance after Autologous Stem Cell Transplant in Patients with Newly Diagnosed Multiple Myeloma: Results of the Spanish GEM2014MAIN Trial

Ixazomib Plus Lenalidomide/Dexamethasone (IRd) Versus Lenalidomide /Dexamethasone (Rd) Maintenance after Autologous Stem Cell Transplant in Patients with Newly Diagnosed Multiple Myeloma: Results of the Spanish GEM2014MAIN Trial

Preoperative pembrolizumab for MSI high, EBV positive or PD-L1 positive locally advanced gastric cancer followed by surgery and adjuvant chemoradiation with pembrolizumab: Interim results of a phase 2 multi-center trial (NCT03257163).

e16111 Background: Despite advances in therapy, outcomes of patients with gastric cancer in the US remain poor. Recent data demonstrated that certain subtypes of gastric cancer are less responsive to perioperative chemotherapy. Preliminary data suggest that patients with microsatellite unstable tumors (MSI-H), EBV expressing tumors, and tumors with high PD-L1 expression may benefit from immunotherapy. We initiated a clinical trial to evaluate the benefit of PD-1 checkpoint immunotherapy in this subset of patients with resectable gastric cancer. Methods: Interim analysis performed on this phase 2 multi-institutional clinical trial (NCT03257163) is presented. Patients with clinically staged T2-T4, N0-N3, M0 gastric adenocarcinoma are evaluated for loss of mismatch repair proteins, expression of EBV or PDL1 expression with CPS &gt; 1%. Consented patients receive 2 cycles of neoadjuvant pembolizumab followed by surgical resection. Following surgery, patients receive adjuvant chemoradiation (45 Gy) with 5 cycles of capecitabine and concurrent pembrolizumab, followed by up to 1 year of pembrolizumab. The primary endpoint is disease-free survival. Results: Of the 15 patients currently enrolled (planned enrollment = 40), 6 patients were MSI-H, 2 EBV (+), and 7 had PDL1 expression with CPS &gt; 1%. Two patients did not undergo surgical resection as 1 patient was found to have peritoneal disease at time of exploration and second was deemed too frail to proceed with surgery. In the 13 patients who underwent surgical resection, all are alive without evidence of recurrent disease (follow up 1 month – 22 months). After 2 cycles of pembrolizumab, 2 patients with MSI-H tumors had pathologic complete response. Clinical T stage was downstaged in 5 patients and clinical N stage was downstaged in 2 patients. PD-1 checkpoint immunotherapy was well tolerated with minimal need for dose reduction and limited toxicity. Conclusions: Early results from our phase 2 clinical trial show immunotherapy to be well tolerated with limited toxicity. Following 2 cycles of pembrolizumab, 2 patients with MSI-H had complete pathologic response and above a third of our patients were downstaged. No recurrences have been observed in the short-term follow-up of surgically resected patients. Clinical trial information: NCT03257163.

A phase Ib/II study of selinexor in combination with imatinib in patients with advanced gastrointestinal stromal tumor (GIST): SeliGIST/GEIS-41 trial.

11534 Background: KIT or PDGFRA oncogenic activation drives GIST progression throughout the disease course. Accordingly, currently approved agents in metastatic GIST focus on the therapeutic suppression of these receptors. However, the clinical benefit after imatinib (IM) progression is still modest, suggesting the co-operation of KIT/PDGFRA-independent mechanisms in GIST cell survival. Selinexor is an oral, selective inhibitor of XPO1-mediated nuclear export, and preclinical studies evidenced antitumoral activity in GIST as single agent and in combination with IM in both IM-sensitive and IM-resistant models. Methods: The phase Ib portion studied IM 400 mg daily plus weekly selinexor in patients (pts) with IM-resistant, advanced GIST. Prior intolerance to IM was not allowed. A standard 3+3 dosing schema was utilized to determine the recommended phase II dose (RP2D) of this combination. Investigator-assessed response was evaluated every 8 weeks using RECIST 1.1. Results: At data cutoff of Sep 25, 2020, 12 pts were enrolled and received treatment with IM 400 mg and selinexor once weekly at dose levels (DL) 1 (60 mg), DL2 (80 mg) and DL3 (100 mg). Median age 57 (range 46-77), 42% female, median prior therapies 4 (range 2-7). Although only 1/6 pts developed a dose limiting toxicity (DLT) at DL3, the RP2D was defined at DL2 (IM 400 mg daily and selinexor 80 mg once weekly) based on activity data in the DL2 and the need for dose reductions in 5/6 pts at DL3 after the DLT window. All pts were evaluable for toxicity and response. One DLT occurred at DL3 (G3 nausea). Non-DLT G3/4 toxicities were anemia (1/12 pts), neutropenia (1/12 pts), vomiting (1/12 pts) and fatigue (2/12 pts). Common G1/2 toxicities were nausea (11/12 pts), vomiting (10/12 pts), neutropenia (5/12 pts) and anemia, fatigue, diarrhea, and periorbital edema (4/12 pts each). No unexpected toxicities were observed. Overall response rate in the 12 pts evaluable for response was 67% (95% CI 0.349-0.901), with 2 pts achieving PR (17%) and 6 pts SD (50%) as the best response. Clinical benefit rate (CBR = CR, PR, SD) ≥ 16 weeks was 42% (95% CI 0.157-0.723). Median progression free survival was 3.5 months (95% CI 1.7-7.3). Four pts remain on trial at data cutoff. Conclusions: IM and selinexor combination is well-tolerated and has clinical activity in heavily pretreated GIST pts. The trial is currently exploring selinexor as single agent in the IM-resistant GIST population. Clinical trial information: NCT04138381.

A generic deep learning model for reduced gadolinium dose in contrast-enhanced brain MRI.

With rising safety concerns over the use of gadolinium-based contrast agents (GBCAs) in contrast-enhanced MRI, there is a need for dose reduction while maintaining diagnostic capability. This work proposes comprehensive technical solutions for a deep learning (DL) model that predicts contrast-enhanced images of the brain with approximately 10% of the standard dose, across different sites and scanners. The proposed DL model consists of a set of methods that improve the model robustness and generalizability. The steps include multi-planar reconstruction, 2.5D model, enhancement-weighted L1, perceptual, and adversarial losses. The proposed model predicts contrast-enhanced images from corresponding pre-contrast and low-dose images. With IRB approval and informed consent, 640 heterogeneous patient scans (56 train, 13 validation, and 571 test) from 3 institutions consisting of 3D T1-weighted brain images were used. Quantitative metrics were computed and 50 randomly sampled test cases were evaluated by 2 board-certified radiologists. Quantitative tumor segmentation was performed on cases with abnormal enhancements. Ablation study was performed for systematic evaluation of proposed technical solutions. The average peak signal-to-noise ratio (PSNR) and structural similarity index measure (SSIM) between full-dose and model prediction were dB and , respectively. Radiologists found the same enhancing pattern in 45/50 (90%) cases; discrepancies were minor differences in contrast intensity and artifacts, with no effect on diagnosis. The average segmentation Dice score between full-dose and synthesized images was (median = 0.91). We have proposed a DL model with technical solutions for low-dose contrast-enhanced brain MRI with potential generalizability under diverse clinical settings.

Retrospective-prospective study of safety and efficacy of sofosbuvir-based direct-acting antivirals in HIV/HCV-coinfected participants with decompensated liver disease pre- or post-liver transplant.

Direct-acting antiviral (DAA) therapy has transformed the management of human immunodeficiency virus (HIV) and hepatitis C (HCV) coinfected patients with advanced liver disease. STOP-Coinfection was a multicenter prospective and retrospective, open-label study using sofosbuvir-based DAA therapy to treat HIV/HCV-coinfected participants pre- or post-liver transplant (LT). Sixty-eight participants with end-stage liver disease (Child-Turcotte-Pugh score ≥7 and Model for End-Stage Liver Disease score 6-29) were enrolled, 26 had hepatocellular carcinoma. Forty-two participants were treated pre-LT and 26 post-LT. All participants completed therapy without need for dose reduction or transfusion; eight required two or more courses of therapy. Ninety-three percent achieved a sustained virologic response and DAA therapy was well tolerated. Despite HCV cure, 12 end-stage liver disease participants required subsequent LT, 7 for decompensated liver disease. Thirteen participants died, 10 with decompensated liver disease pre-LT and three post-LT. Overall, transplant free survival was 42.8% at 4years and post-LT survival was 87.9% at 5years. We conclude that sofosbuvir-based DAA therapy is safe and highly effective in HCV-HIV patients with decompensated liver disease and post-LT, with post-LT survival rates comparable to other indications. This removes one of the last barriers to liver transplantation in this challenging cohort of recipients.

A Multicenter Prospective Study on Efficacy and Safety of Ponatinib in Patients with Chronic Myeloid Leukemia Resistant or Intolerant to Previous Therapy: A 3-Year Report

Introduction Tyrosine kinase inhibitors (TKIs) have transformed outcomes in chronic myeloid leukemia (CML). Patients who respond to imatinib, have a life expectancy comparable with that of the global population, however, up to 40% of patients discontinue imatinib due to resistance or intolerance. Ponatinib is a third-generation highly-potent-pan-inhibitor of tyrosine kinases, active in all single resistance ABL kinase mutations, including the T315l mutation. This report presents the results of a prospective analysis of 3-year ponatinib therapy available in Poland by Angelini's donation program for patients in all phases of CML resistant or intolerant to previous TKI therapy. Methods 43 CML patients (20 women, 24 men, aged 19 to 76 years, mean age 49 ± 15 years) were treated in 20 Polish Hematology Centers with ponatinib initiated between March 2016 and December 2019. 23 pts (53%) were in the chronic phase (CP), 3 pts (7%) in accelerated phase (AP), and 17 pts (40%) in blastic phase (BP) (9 myeloblastic and 8 lymphoblastic). The majority of patients received three lines of TKI therapy. The T315I mutation was detected in 30% of patients (the initial characteristics of the 43 analyzed patients are shown in Table 1). The indication for ponatinib and its dose schedule was made according to the discretion of the attending physician. The initial dose of ponatinib was 45 mg/d in 60% of all patients (without statistically significant differences in the initial dose between patients starting treatment in CP, AP, and BP). Molecular biology tests were performed according to ELN guidelines and BCR-ABL/ABL ratios were expressed as % [IS] in all patients. Treatment responses were calculated at each specific time points recommended by ELN. Statistica 12 software (StatSoft, Tulsa, OK, USA) was used for calculations. Results The follow-up ranged from one week to 35.4 months (median 11.4 months) (one male patient died on infection one week after ponatinib introduction and was excluded from further analysis, he did not achieve CHR and he transformed to blast phase-BP). The responses to ponatinib are shown in Table 2. Among 23 CP patients, 18 achieved CHR (78%), 6 (26%) MCyR, 5 (22%) CCyR, and 1 (4%) MMR at 1 month of treatment. There were only 2 patients in this group (9%) who did not achieve CHR. Eleven CP patients (48%) achieved stable MMR. In all 3 AP patients, the best responses (CHR, CCyR, and MMR) were maintained until the end of observation (Table 2). Among 17 BP patients, 8 (47%) achieved CHR. The overall survival was significantly better in those patients who achieved CHR at 1 month of therapy (Figure 1). 19 patients (44%) experienced toxicity of ponatinib including: increase in blood pressure overall 9 patients (21%), hematological toxicity grade 3-4- 12 patients (28%).A total of 19 patients (44%) remained on ponatinib at the end of the observation. Ponatinib dose was reduced during the study in 18 patients (42%): in 11 (61% of those requiring dose reduction) because of toxicity, in 6 (33%) because of good response to treatment, and in 1 patient (6%) because of both reasons. The need for dose reduction was not significantly associated with comorbidities (p=0.4). Eight patients (19%) underwent allo-SCT during the observation. Ponatinib was discontinued in eight patients (19%), in six CP and two BP-patients. In five patients (12%), ponatinib was discontinued because of toxicity (hematological in one, non-hematological in two, and both in one patient); all were CP patients. In two patients (one CP, one BP patient), ponatinib was discontinued as they underwent allo-SCT. Overall, 16 patients (37%) died during the study: 12 of them (28%) due to CML progression. In all 43 patients, median survival was not reached. The estimated 2-year survival was 60% (95% confidence interval 44-76%) (Figure 2A) 84% in CP patients, 100% in AP patients (Figure 2B), and 20% in BP patients. None of the CP patients progressed to AP or BP during the study, i.e. progression-free survival was 100% at the end of observation (35.4 months). The presence of T315I mutation (p=0.2) or the initial dose of ponatinib (p=0.4) was not significantly associated with the overall survival. Conclusion Our study confirmes that ponatinib could induce durable responses with acceptable toxicity profiles in highly pretreated patients with CML resistant or intolerant to previous TKIs treated in standard clinical practice. Disclosures Sacha: Adamed:Consultancy, Honoraria;Bristol-Myers Squibb Company:Consultancy, Honoraria, Speakers Bureau;Pfizer:Consultancy, Honoraria, Speakers Bureau;Novartis:Consultancy, Honoraria, Speakers Bureau;Incyte:Consultancy, Honoraria, Speakers Bureau.Niesiobedzka-Krezel:Angelini Pharma:Other: lecture fee and meeting partcipation.Ciepluch:Copernicus Wojewodzkie centrum Onkologii:Current Employment.

New therapy for chemotherapy-induced hepatic failure in leukemia; a randomized double-blind clinical trial study

Introduction: Hepatotoxicity is usual toxicity after chemotherapy in acute lymphoblastic leukemia (ALL) patients. Conventional treatment methods such as supportive care did not have an effective role in the improvement of hepatotoxicity. Objectives: In this study clinical efficacy of milk thistle in contrast with placebo was compared in leukemia patients with chemotherapy-induced hepatotoxicity. Patients and Methods: In this double-blind study, 93 ALL patients with chemotherapy-induced hepatotoxicity were randomized to a clinical trial with milk thistle or placebo. Liver enzymes level evaluated during 70 days. We divided patients randomly into two groups. Milk thistle at dosage of 7 mg/kg daily was prescribed in the intervention group while in the control group, placebo pills similar to milk thistle in shape and color were prescribed daily. Results: At day 35 and day 70 of the study, in the milk thistle arm ALT and AST mean serum levels were lower than the placebo group (P&lt;0.001). In the milk thistle group there was a significant reduction in mean of AST and ALT during the first 35 days in patients who were taking livergol in comparison to next 35 days that patients stopped taking it. Children’s age was between 3-15 years. Conclusion: Based on our results, milk thistle improves liver function in chemotherapy-induced hepatotoxicity and there was no need for dose reduction or discontinuation of chemotherapy. Future clinical trials should be conducted to explore longtime effect of livergol in leukemia patients and to determine if there is any need for prophylactic administration of antioxidants. Trial Registration: This clinical trial has been approved by the Iranian Registry of Clinical Trials at 2018-02-14 (identifier: IRCT20170821035831N2; http://en.irct.ir/trial/26957).