Treatment-limiting Adverse Events Research Articles

Real-world treatment patterns and outcomes of zanubrutinib in chronic lymphocytic leukemia and small lymphocytic leukemia (CLL/SLL).

11158 Background: Zanubrutinib (zanu) is a next-generation selective Bruton’s tyrosine kinase inhibitor (BTKi) with superior efficacy over first generation ibrutinib (ibru) in CLL/SLL patients (pts). Herein we present real-world treatment patterns based on a formulary change from ibrutinib to zanubrutinib in pts with CLL/SLL in an integrated community oncology practice. Methods: We retrospectively analyzed CLL/SLL pts 18 years and older who received at least 3 months of zanubrutinib from October 1, 2018 to September 15, 2023 at Kaiser Permanente Northern California. Treatment patterns, treatment-emergent adverse events (TEAEs: AEs reported during BTKi use), treatment-limiting adverse events (TLAEs: AEs leading to BTKi discontinuation), and mortality were reported. Results: A total of 281 pts received zanu (median age: 71 years; 64% male); 190 pts switched from ibru (ibru-zanu), and 91 pts received zanu only. Most pts were White (75%) followed by Black (10%). Compared with ibru-zanu pts, zanu-only pts were older (median age 74 vs 69 years) and had more comorbidities but were comparable in sex, race, and insurance type. The primary reasons for switching to zanu were formulary change (73%) and progression (15%). Median follow-up time after initiation of first BTKi was longer in the ibru-zanu group (Table). Similar TEAE rates were seen with use of both BTKi therapies, with lower TLAE rates with zanu (Table). Most common TLAE were atrial fibrillation and fatigue for ibru, and cytopenias and rash/bruising for zanu. Cardiac TLAE and non-TLAE rates overall were higher with ibru than zanu, and the rates decreased while on zanu after switching from ibru (Table). Dose modification occurred in 34 pts on ibru and 50 pts on zanu (18 ibru-zanu pts, 32 zanu-only pts), with reductions primarily for grade 1-2 AEs. Of the 281 pts who received zanu, 79% remain on treatment at the end of data collection; 13 pts died (8 from infection, including 5 from COVID), with no reports of treatment-related deaths. Conclusions: In the real-world setting post-formulary change, zanu is effective and safe in pts with or without prior ibru use. Zanu use had lower cardiotoxicity and TLAE rates than ibru though data was limited by a difference in follow-up time. Similar results were seen in zanu-only pts despite being older and having more comorbidities, with discontinuation most often due to grade <3 AEs. [Table: see text]

Application of Electronic Health Record Text Mining: Real-World Tolerability, Safety, and Efficacy of Adjuvant Melanoma Treatments.

Introduction: Nivolumab (N), pembrolizumab (P), and dabrafenib plus trametinib (D + T) have been registered as adjuvant treatments for resected stage III and IV melanoma since 2018. Electronic health records (EHRs) are a real-world data source that can be used to review treatments in clinical practice. In this study, we applied EHR text-mining software to evaluate the real-world tolerability, safety, and efficacy of adjuvant melanoma treatments. Methods: Adult melanoma patients receiving adjuvant treatment between January 2019 and October 2021 at the Leiden University Medical Center, the Netherlands, were included. CTcue text-mining software (v3.1.0, CTcue B.V., Amsterdam, The Netherlands) was used to construct rule-based queries and perform context analysis for patient inclusion and data collection from structured and unstructured EHR data. Results: In total, 122 patients were included: 54 patients treated with nivolumab, 48 with pembrolizumab, and 20 with D + T. Significantly more patients discontinued treatment due to toxicity on D + T (N: 16%, P: 6%, D + T: 40%), and X2 (6, n = 122) = 14.6 and p = 0.024. Immune checkpoint inhibitors (ICIs) mainly showed immune-related treatment-limiting adverse events (AEs), and chronic thyroid-related AE occurred frequently (hyperthyroidism: N: 15%, P: 13%, hypothyroidism: N: 20%, P: 19%). Treatment-limiting toxicity from D + T was primarily a combination of reversible AEs, including pyrexia and fatigue. The 1-year recurrence-free survival was 70.3% after nivolumab, 72.4% after pembrolizumab, and 83.0% after D + T. Conclusions: Text-mining EHR is a valuable method to collect real-world data to evaluate adjuvant melanoma treatments. ICIs were better tolerated than D + T, in line with RCT results. For BRAF+ patients, physicians must weigh the higher risk of reversible treatment-limiting AEs of D + T against the risk of long-term immune-related AEs.

A Comparative Study of the Safety and Efficacy of Intrapleural Fibrinolysis With Streptokinase and Urokinase in the Management of Loculated Pleural Effusions.

BackgroundIntrapleural fibrinolytic therapy (IPFT) with streptokinase (STK), urokinase (UK), and alteplase remains a common practice for managing loculated pleural effusions (LPEs). However, very limited data are available on the comparative efficacy of these agents.MethodologyWe compared the efficacy and safety of intrapleural streptokinase (n = 28) and urokinase (n = 38) in 66 patients with loculated effusions. IPFT was initiated if effusion remained undrained despite the placement of intercostal chest drainage or pigtail catheter. The dose of STK and UK were 250,000 IU twice daily and 100,000 IU once daily, respectively. The volume of fluid drained after IPFT, radiologic response, clinical response, and adverse events were compared between the two groups.ResultsThe mean volume of fluid drained post-IPFT was 1,379 mL in the STK arm and 1,110 mL in the UK arm (p = 0.251). Of the 66 patients, 53 (80.3%) had good clinical response, and 28 (43.7%) had >75% resolution of effusion on chest radiographs. The clinical (79% vs. 82%; p = 0.765) and radiologic response rates (39.3% vs. 44.6%; p = 0.568) were similar in both STK and UK arms. Pain was the most common adverse event in both groups. Significantly more patients in the STK arm developed fever (14% vs. 0%, p = 0.030). Treatment-limiting adverse events occurred in five patients.ConclusionsIPFT is a safe and effective method for managing patients with LPEs. Although the clinical and radiologic response rates were similar with STK and UK, the latter may be the preferred choice because of its better safety profile and ease of administration (once-daily dose).

Abstract 3261: LNG-451, a potent inhibitor of EGFR exon 20 insertion mutations with high CNS exposure

Abstract Exon 20 insertion mutations (Ex20ins) are the 3rd most common type of EGFR oncogenic mutation in lung cancer patients and are often associated with brain metastases. While several small molecules have been approved (mobocertinib) or are in clinical development (e.g. CLN-081, BDTX-189) none have demonstrated meaningful CNS activity and they can be associated with treatment-limiting adverse events, including wild-type (WT) EGFR-mediated toxicities. LNG-451 is a potent covalent inhibitor of EGFR Ex20ins (IC50 7 - 78 nM) and other EGFR oncogenic mutations (e.g L858R IC50 = 3 nM, exon 19 deletion IC50 = 24 nM) while being selective against WT EGFR (IC50 = 1630 nM). LNG-451 causes tumor regression in both cell line-derived and patient-derived EGFR Ex20ins-dependent xenograft tumor models. In a rat CNS PK model, a single oral dose of 30 mg/kg LNG-451 achieved high exposures in plasma (AUC0 - 8h = 9771 ng•h/mL) and brain (AUC0 - 8h = 10,041 ng•h/g). In a rat steady-state CNS PK model, unbound partition coefficient for LNG-451 was determined to be Kpu,u = 0.66. To evaluate the potential for LNG-451 to treat metastatic brain disease driven by EGFR mutations, an intracranial PC9-luc xenograft mouse model harboring an EGFR exon 19 deletion mutation was used (LNG-451 cellular EGFR Del19 IC50 = 10.6 nM). LNG-451 had dose-dependent exposures in the plasma and brain with both high mean brain exposure (e.g 1074 ng/g with 25 mg/kg LNG-451) and high mean brain to plasma ratios (e.g. 0.451 for 25 mg/kg LNG-451). LNG-451 treatments were well-tolerated and produced significant anti-tumor activities with 99.5% (2.5 mg/kg LNG-451) and 99.9% (25 mg/kg LNG-451) reductions in total bioluminescence signal (BLI) and regression of tumor BLI (2.5 mg/kg LNG-451 28.8% regression; 25 mg/kg LNG-451, 80.3% regression). An ex vivo imaging analysis of the brain and spinal cords from all animals at the end of the study showed a dose-dependent decrease in the bioluminescent signal in both brain and spinal cords from mice treated with LNG-451 relative to the vehicle control animals. Taken together, LNG-451 is a CNS-penetrant, wild-type EGFR-sparing, EGFR Ex20ins inhibitor that is expected to provide strong anti-tumor efficacy for patients with advanced/metastatic solid cancers harboring oncogenic EGFR exon 20 insertions with reduced WT EGFR driven toxicities. Citation Format: Paul G. Pearson, Anjali Pandey, Bruce Roth, Tracy Saxton, Daniel J. Estes, Ravi Trivedi, Himanshu Agrawal, Gurulingappa Hallur, Ishtiyaque Ahmad, Helen Jenkins, Brion W. Murray. LNG-451, a potent inhibitor of EGFR exon 20 insertion mutations with high CNS exposure [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 3261.

Abstract 3332: LNG-451 is a potent, CNS-penetrant, wild-type EGFR sparing inhibitor of EGFR exon 20 insertion mutations

Abstract Exon 20 insertion mutations (Ex20ins) are the third most common type of EGFR oncogenic mutation in lung cancer patients. While several small molecules have been approved (mobocertinib) or are in clinical development (e.g. CLN-081, BDTX-189) none have demonstrated meaningful CNS activity and they can be associated with treatment-limiting adverse events, including wild-type (WT) EGFR-mediated toxicities. LNG-451 is a CNS-penetrant, wild-type EGFR-sparing, covalent inhibitor of EGFR Ex20ins. In cell viability assays dependent on five EGFR Ex20ins mutations, LNG-451 was a potent inhibitor (IC50 7 - 78 nM) including the three most prevalent insertions (V769_D770insASV IC50 = 78 nM, D770_N771insSVD IC50 = 53 nM, H773_V774insNPH IC50 = 75 nM). LNG-451 had low potency in WT EGFR dependent cell assays (WT EGFR Ba/F3 IC50=1,960 nM, cell panel IC50 = 1630 nM). LNG-451 was 21-fold selective for its least potent Ex20ins (V769_D770insASV) relative to WT EGFR. LNG-451 potently inhibited cells dependent on EGFR L861Q (IC50 = 6 nM), EGFR G719S (IC50 = 8 nM), and EGFR G719S/T263P (IC50 = 11 nM). LNG-451 is a highly selective kinase inhibitor (1 μM LNG-451, >90% inhibition for 7 of 409 WT kinases) with screening hits having a similarly positioned cysteine as EGFR. In a Ba/F3 cell-derived xenograft model harboring an EGFR V769_D770insASV exon 20 insertion mutation (EGFR V769_D770insASV CDX), 10 and 50 mg/kg LNG-451 QD PO dosing for 15 days was well-tolerated and resulted in tumor growth inhibition (TGI) of 75.7% and 105.4%, respectively. LNG-451 was efficacious and well-tolerated in the EGFR Ex20ins HuPrime® LU0387 H773-V774insNPH patient-derived xenograft tumor model: 10 mg/kg LNG-451 QD, 67% TGI; 50 mg/kg LNG-451 QD, 91% tumor regression. LNG-451 was highly active in the intracranial PC9-luc xenograft mouse model. In a single dose PK/PD study using the EGFR V769_D770insASV CDX, similar LNG-451 concentrations were observed in tumor, large intestine, and skin tissues (e.g. 50 mg/kg LNG-451 3h post dose: tumor, 8387 ng/mL; large intestine tissue, 14483 ng/mL; skin, 4623 ng/mL). LNG-451 potently suppressed EGFR phosphorylation in tumor tissue (e.g. 99%, 3 h post 50 mg/kg dose) but had minimal-to modest suppression of phospho-EGFR in large intestine tissue (e.g. 4.2%, 3h post 50 mg/kg dose) and skin tissue (e.g 1.9%, 3h post 50 mg/kg dose). Taken together, LNG-451 is a wild-type EGFR-sparing, CNS-penetrant EGFR Ex20ins inhibitor that is expected to provide strong anti-tumor efficacy for patients with advanced/metastatic solid cancers harboring oncogenic EGFR exon 20 insertions with reduced WT EGFR-driven toxicities. Citation Format: Brion W. Murray, Anjali Pandey, Bruce Roth, Tracy Saxton, Daniel J. Estes, Himanshu Agrawal, Santosh Vishwakarma, Gurulingappa Hallur, Ishtiyaque Ahmad, Ravi Trivedi, Helen Jenkins, Paul G. Pearson. LNG-451 is a potent, CNS-penetrant, wild-type EGFR sparing inhibitor of EGFR exon 20 insertion mutations [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 3332.

Optimal Thyroid Hormone Replacement Dose in Immune Checkpoint Inhibitor-Associated Hypothyroidism Is Distinct from Hashimoto's Thyroiditis.

Background: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many advanced cancers but are recognized to cause treatment-limiting immune-related adverse events (IrAE). ICI-associated thyroiditis is the most common endocrine IrAE and usually resolves to permanent hypothyroidism. Optimal thyroid hormone replacement in these patients remains unclear. We report the levothyroxine (LT4) dose needed to achieve stable euthyroid state in patients with hypothyroidism from ICI-associated thyroiditis, with comparison to patients with Hashimoto's thyroiditis (HT) and athyreotic state. Methods: We conducted a retrospective study of adults with ICI-associated hypothyroidism treated with LT4 at an academic medical center. Patient data were collected from the electronic medical record. Cases had ICI exposure followed first by hyperthyroidism and then subsequent hypothyroidism. Controls were HT (positive thyroid autoantibodies, requiring LT4) and athyreotic (total thyroidectomy or radioiodine ablation, requiring LT4) patients. Patients with central hypothyroidism, thyroid cancer, pregnancy, gastrointestinal stromal tumors, and use of L-triiodothyronine were excluded. Our primary outcome compared LT4 dose needed to achieve euthyroid state (thyrotropin 0.3-4.7 mIU/L over >6 consecutive weeks) for ICI-associated hypothyroidism, HT, and athyreotic patients, considering the impact of age and possible interfering medications by linear regression modeling. Secondary analysis considered the impact of endocrine specialty care on the time to euthyroid state. Results: One hundred three patients with ICI-associated thyroiditis were identified. Sixty-six of the 103 patients achieved euthyroid state; 2 with intrinsic thyroid gland function recovery and 64 on LT4. The mean LT4 dose achieving stable euthyroid state was 1.45 ± standard deviation (SD) 0.47 mcg/[kg·day] in ICI-associated hypothyroidism, 1.25 ± SD 0.49 mcg/[kg·day] in HT, and 1.54 ± SD 0.38 mcg/[kg·day] in athyreotic patients, using actual body weight. The difference in dose between ICI-associated hypothyroidism and HT was statistically significant (p = 0.0093). Dosing differences were not explained by age or use of interfering medications. Conclusions: ICI-associated thyroiditis represents an increasingly recognized cause of hypothyroidism. Our study demonstrates that patients with ICI-associated hypothyroidism have different thyroid hormone dosing requirements than patients with HT. Based on our findings and prior reports, we recommend that in patients with ICI-associated thyroiditis LT4 therapy be started at an initial weight-based dose of 1.45 mcg/[kg·day] once serum free thyroxine levels fall below the reference range.

Cannabis Use in a Cohort of Healthcare-Seeking United States Military Veterans With Persisting Symptoms After Mild Traumatic Brain Injury: Preliminary Observations.

Cannabis products, including cannabidiol (CBD) and tetrahydrocannabinol (THC), are increasingly easy to procure and use across the United States. The 2018 National Survey on Drug Use and Health (NSDUH) reported a past-month cannabis use rate of 8.6% among adults 26 years of age or older in the U.S. general population. Cannabis use is commonly reported by U.S. Military Veterans with histories of mild traumatic brain injury (mTBI) receiving services at the Marcus Institute for Brain Health (MIBH), a specialty interdisciplinary clinic serving this population. The aims of this study are to describe the frequency and characteristics of cannabis product use among Veterans evaluated at MIBH and to compare the rate of cannabis use in this group to that in the general and Veteran populations reported in the 2018 NSDUH. Study data were collected as part of MIBH clinical assessments between January 2018 and December 2019, which included the evaluation of the current use of cannabis products. Affirmative cannabis use responses were clarified with inquiries about the frequency of use, method of administration, product ingredients (i.e., THC and/or CBD), and reason(s) for use. Among 163 MIBH patients (92.6% male), 72 (44.2%) endorsed cannabis product use during the month preceding the clinical assessment. Cannabis users were significantly younger than nonusers. The frequency of past-month cannabis use was significantly greater than that reported in the comparably aged NSDUH survey general and Veteran populations (44.2% vs. 8.6% and 44.2% vs. 7.7%, respectively, both P < .00001). Among the 72 MIBH patients reporting cannabis use, 62 (86.1%) reported THC or combination product use, and 10 (13.9%) reported CBD product use. Concurrent medication use, including psychotropic medications use, did not differ significantly between cannabis users and nonusers. Self-reported cannabis use is significantly higher in the MIBH population than in similarly aged individuals in the general population and significantly more frequent among younger than older members of this cohort. Self-reported reasons for cannabis use in this cohort included mTBI-associated neuropsychiatric symptoms, sleep disturbances, and pain for which standard treatments (both pharmacologic and nonpharmacologic) provided insufficient relief and/or produced treatment-limiting adverse events. However, cannabis use did not provide sufficient improvement in those symptoms to obviate the need for further evaluation and treatment of those problems at MIBH or to replace, in part or in whole, standard medications and other treatments for those problems. Further study of cannabis use, including standardized individual cannabinoid (i.e., THC and CBD) and whole-plant cannabis preparations, in this and similar cohorts is needed to more fully understand the drivers, benefits, risks, and safety of cannabis use in this and in similar Veteran populations, as well as the potential pharmacological and/or nonpharmacological therapeutic alternatives to cannabis use.

Efficacy of Lycium barbarum polysaccharide in adolescents with subthreshold depression: interim analysis of a randomized controlled study

Subthreshold depression is a highly prevalent condition in adolescents who are at high risk for developing major depressive disorder. In preclinical models of neurological and psychiatric diseases, Lycium barbarum polysaccharide (LBP) extracted from Goji berries had anti-depressant effects including but not limited to anti-oxidative and anti-inflammatory properties. However, the effect of LBP on subthreshold depression is unclear. To investigate the clinical efficacy and safety of LBP for treating subthreshold depression in adolescents, we conducted a randomized, double-blind, placebo-controlled trial (RCT) with 29 adolescents with subthreshold depression recruited at The Fifth Affiliated Hospital of Guangzhou Medical University. The participants were randomly assigned to groups where they received either 300 mg LBP (LBP group, n = 15, 3 boys and 12 girls aged 15.13 ± 2.17 years) or a placebo (placebo group, n = 14, 2 boys and 12 girls aged 15 ± 1.71 years) for 6 successive weeks. Interim analyses revealed that the LBP group exhibited a greater change in Hamilton Depression Scale (HAMD-24) scores relative to the baseline and a higher remission rate (HAMD-24 total score ≤ 7) at 6 weeks compared with the placebo group. Scores on the Beck Depression Inventory-II (BDI-II), Pittsburgh Sleep Quality Index (PSQI), Kessler Psychological Distress Scale (Kessler), and Screen for Child Anxiety-Related Emotional Disorders (SCARED) were similar between the LBP and placebo groups. No side effects related to the intervention were reported in either group. These results indicate that LBP administration reduced depressive symptoms in adolescents with subthreshold depression. Furthermore, LBP was well tolerated with no treatment-limiting adverse events. Clinical trials involving a larger sample size are needed to further confirm the anti-depressive effects of LBP in adolescents with subthreshold depression. This study was approved by the Medical Ethics Committee of the Fifth Affiliated Hospital of Guangzhou Medical University (Guangzhou, China; approval No. L2019-08) on April 4, 2019 and was registered on ClinicalTrials.gov (identifier: NCT04032795) on July 25, 2019.

5.5 TRANSCRANIAL PHOTOBIOMODULATION IN THE TREATMENT OF SOCIAL AND EXECUTIVE FUNCTION DEFICITS IN AUTISM SPECTRUM DISORDER

No established treatments exist for the core features of autism spectrum disorder (ASD). Transcranial photobiomodulation (tPBM) is thought to enhance neuronal activity and promote cellular plasticity. Recent clinical research interest has focused on its role as a potential treatment in mental illness and neurological conditions including depression and traumatic brain injury. The efficacy of tPBM treatment in ASD remains unexplored. Adult participants meeting the diagnostic criteria for ASD were enrolled to receive twice-weekly tPBM treatments for 8 weeks in an open-label single-group design. ASD symptom severity and executive function deficits were assessed at baseline and endpoint by clinician-, self-, and informant-rated measures. Paired samples t test analyses were performed. Findings were placed in the context of the existing sparse research consisting of clinical trials identified by a detailed MEDLINE literature search with resulting articles assessed for strength of evidence. Finally, interim results from the ongoing 8-week open-label study of daily tPBM treatment in youth with ASD diagnosis are presented. Ten participants (9 males; 30.0 ± 11.9 years old) completed the study. Five participants (50%) met the responder criteria at endpoint. Eight-week transcranial laser therapy (TLT) was associated with significant improvement in ASD severity (Total SRS-2 reduction: –30.6 ± 23, p < 0.001), particularly in Social Awareness (–3.0 ± 1.9, p < 0.001), Social Communication (–10.3 ± 6, p < 0.001), Social Motivation (–5.0 ± 2.4, p < 0.001), and Restricted/Repetitive Behaviors (–7.4 ± 4.1, p < 0.001). Statistically significant improvement at endpoint was shown in Global Assessment of Functioning (GAF) scores (+12.8 ± 4.2, p < 0.001) and Quality of Life Enjoyment and Satisfaction Questionnaire scores (+6.0 ± 7.9, p = 0.02). There were no treatment-limiting adverse events. The adherence rate was 98%. tPBM treatment was associated with improvements in the core features of ASD as well as executive dysfunction, and a significant improvement in overall function. The 98% rate of adherence to scheduled study visits and procedures suggests a high potential of acceptance of this noninvasive intervention. tPBM is a safe, feasible treatment approach and further research into its efficacy in the treatment of the core features of ASD is warranted.

Intra-Anal Imiquimod Cream against Human Papillomavirus Infection in Men Who Have Sex with Men Living with HIV: A Single-Arm, Open-Label Pilot Study.

Men who have sex with men (MSM) living with HIV have a high prevalence and incidence of anal high-risk human papillomavirus (hrHPV) and anal cancer. We conducted an open-label, single-arm pilot study to examine the tolerability of imiquimod cream among MSM aged ≥18 years, living with HIV, who tested positive for anal hrHPV at Melbourne Sexual Health Centre between April 2018 and June 2020. We instructed men to apply 6.25 mg imiquimod intra-anally and peri-anally 3 doses per week for 16 weeks (period 1) and then one dose per week for a further 48 weeks (period 2). Twenty-seven MSM enrolled in period 1 and 24 (86%) applied at least 50% of doses. All men reported adverse events (AEs), including 39.5% grade 1, 39.5% grade 2, and 21% grade 3 AEs on at least one occasion. Eighteen MSM (67%) temporarily stopped using imiquimod during period 1, most commonly due to local AEs (n = 11) such as irritation and itching. Eighteen MSM continued in period 2 and all applied at least 50% of doses with no treatment-limiting AEs reported. Imiquimod 3 doses per week caused local AEs in most men and was not well tolerated. In contrast, once-a-week application was well tolerated over 48-weeks with no treatment-limiting AEs.

Racial and ethnic disparities in treatment response and tolerability in multiple sclerosis: A comparative study

BackgroundInter-individual response and tolerability profiles associated with available disease-modifying treatments (DMTs) are an important aspect of the therapeutic decision-making process in multiple sclerosis (MS). In the absence of racially diverse clinical studies, the possible effect of race and ethnicity on treatment outcome remains uncertain. This study aims to compare disease outcome among Hispanic, Black, and White patients with MS, and assess the impact of race/ethnicity on long-term outcome. MethodsA retrospective review of electronic medical records was performed on a multiethnic cohort of MS patients treated in a large academic center. Sociodemographic characteristics, treatment regimens, and disability outcomes were compared between the three groups. ResultsA total of 300 age- and gender-matched MS patients (100 Hispanic, 100 Black, and 100 White) were included in the study. When assessing the overall survival of MS patients without ambulatory disability 5 years from diagnosis, Hispanics and Blacks attained lower survival times compared to Whites (survival time ratio [STR] 0.17, p = 0.004; and 0.14, p = 0.002, respectively). Black patients had the highest rate of disease progression and treatment-limiting adverse events despite similar sociodemographic profiles and DMT exposure relative to Hispanics and Whites. ConclusionRacial/ethnic disparities in treatment outcome create an unmet need to identify tailored, multifaceted approaches to therapy selection in MS.

Safety and Efficacy of Veverimer in Acidotic Patients With CKD and Heart Failure

Safety and Efficacy of Veverimer in Acidotic Patients With CKD and Heart Failure

Enfortumab Vedotin: Nursing Perspectives on the Management of Adverse Events in Patients With Locally Advanced or Metastatic Urothelial Carcinoma.

Many patients with locally advanced or metastatic urothelial carcinoma (mUC) need additional treatment options beyond PD-1 or PD-L1 inhibitors and platinum-based chemotherapies. Enfortumab vedotin-ejfv (EV) is an antibody-drug conjugate directed at Nectin-4 that received accelerated approval for treatment of adults with locally advanced or mUC previously treated with PD-1/PD-L1 inhibitors and platinum- containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic settings. This article provides practical considerations and recommendations regarding common and potentially treatment-limiting adverse events that may arise with EV therapy. The clinical data that supported the approval of EV are reviewed, and supporting safety and management considerations are provided based on the authors' experience. EV therapy can be optimized through patient and caregiver education, proactive patient monitoring, early identification of adverse events, and timely intervention to alleviate symptoms.

Safety and efficacy of reduced-dose pentamidine as second-line treatment for HIV-related pneumocystis pneumonia

ObjectivesParenteral pentamidine isethionate (PM) 4 mg/kg/day is recommended as an alternative therapeutic regimen after failure of first-line treatment for pneumocystis pneumonia (PCP). However, the dose is often reduced to 3 mg/kg/day in clinical settings because of high rates of adverse events and drug toxicity. Although considered equally efficacious, this lower dose has not been well evaluated. MethodsThis was a single-center, retrospective cohort study that analyzed 75 patients with HIV-PCP who were treated with trimethoprim-sulfamethoxazole, but discontinued treatment because of treatment failure or adverse events; they were then administered 3 mg/kg/day of intravenous PM as a salvage therapy. The primary outcomes were the regimen completion rate with the reduced PM dose. Results and conclusionsIn total, 40 (53.3%) of the eligible patients completed PCP therapy with reduced-dose PM salvage treatment. The overall survival rate of PCP was 73 (97.3%). The median duration of second-line PM treatment was 8.0 days (interquartile range: 6.0–10.0). Although, the adverse events with reduced-dose PM were observed in 41 (54.7%), including 35 treatment-limiting adverse events, grade 3 or 4 adverse events occurred in only three patients (thrombocytopenia, one patient; neutropenia, two patients). Life-threating adverse events, such as hypoglycemia and arrhythmia, were not observed with reduced-dose PM. Salvage therapy with reduced-dose PM for patients with HIV-PCP is relatively safe and effective; moreover, life-threating adverse events did not occur. This therapy could be recommended for patients with HIV-PCP who fail to respond to first-line treatment with trimethoprim-sulfamethoxazole.

Safety and tolerability of IV ketamine in adults with major depressive or bipolar disorder: results from the Canadian rapid treatment center of excellence

ABSTRACT Objectives Rigorous clinical trials suggest ketamine is safe and well-tolerated in patients with treatment-resistant depression (TRD). There is a paucity of data on the safety and tolerability of ketamine in community-based clinics treating patients with TRD. Methods Retrospective data was analyzed from 203 patients with TRD who received repeat-dose IV ketamine. Safety was operationalized as hemodynamic changes. Tolerability was evaluated through the reporting of adverse events and dissociation symptom severity, as measured by the Clinician-Administered Dissociative States Scale. Results Ketamine was well-tolerated, with less than 5% of patients withdrawing due to tolerability concerns. Blood pressure significantly increased during infusion, with 44.3% meeting criteria for treatment-emergent hypertension (i.e., blood pressure ≥ 165/100 mmHg). 12% of patients exhibiting hypertension required pharmacological intervention. The most frequently reported adverse events included drowsiness (56.4%), dizziness (45.2%), dissociation (35.6%), and nausea (13.3%). Dissociation severity significantly attenuated after the first infusion, but plateaued for subsequent infusions. Conclusion Intravenous ketamine was safe and well-tolerated. Hypertension was commonly observed and was often transient. Dissociation was most frequently reported after the first infusion but remained a consistent but not treatment-limiting adverse event thereafter. No patients exhibited psychosis, mania, or new onset suicidality with IV ketamine.

Rechallenging with immune checkpoint inhibition after a treatment-limiting immune-related adverse event.

3053 Background: Immune checkpoint inhibition (ICI) with cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), or programmed death ligand-1 (PD-L1) blockade can be associated with the development of immune related adverse events (irAE), many of which can be treatment-limiting. Due to an absence of randomized controlled trials, the current approach in regards to ICI discontinuation versus rechallenging remains controversial. Methods: We assessed all patients who had received ICI at a single academic institution from 5/2015 to 1/2019, identifying those who had delays in their treatment. Retrospective chart review was performed to determine type of ICI, type and grade of irAE, treatment of irAE, and recurrence and grades of irAE if ICI was resumed, as well as to assess overall survival (OS). Results: 562 patients received ICI (lung cancer [232, 41%], melanoma [66, 12%], kidney cancer [43, 8%], bladder cancer [27, 5%], and other cancers [194, 34.5%]) from 5/2015 – 1/2019. Of these, 121 (22%) had a treatment-limiting irAE (most commonly dermatitis [24%], colitis [17%], pneumonitis [14%], and hepatitis [12%]). Of the patients who had ICI held, 80/121 (66%) were eventually rechallenged, while 41/121 (34%) discontinued permanently. When rechallenged with ICI, 47/80 (59%) had no further treatment-limiting irAEs, 16/80 (20%) had a recurrence of the same irAE, and 17/80 (21%) developed a different irAE. Of those who were rechallenged, only 17/80 (21%) ultimately had to discontinue because of a second irAE. At a median follow up time of 12.1 months, median OS was not reached in those patients who experienced a treatment limiting irAE and was 8.1 months in those who did not (hazard ratio [HR] for death, 0.33; 95% CI 0.23 – 0.48; p &lt; 0.001). At 12 months from initiation of ICI, 77.0% of patients who had a treatment-limiting irAE were alive, compared to 39.6% of those who did not have an event. Restarting ICI after a treatment-limiting irAE was not associated with a change in OS (HR 0.66 [95% CI 0.27 – 1.66], p = 0.38). Conclusions: Patients who discontinued ICI secondary to irAEs had relatively low rates of recurrent toxicity when rechallenged with treatment. These patients were just as likely to develop a new toxicity as a recurrence of the original irAE, and relatively few had to discontinue permanently. Development of a treatment-limiting irAE was associated with improved OS compared to those who did not. This study suggests that rechallenging with ICI may be safe in selected patients, though this did not have an impact on OS.

Toxicities with combination BRAF and MEK inhibition in resected stage III melanoma.

e22086 Background: Patients with stage III melanoma are at high risk for recurrence after resection of the primary lesion. The Combi-AD study showed adjuvant therapy with BRAF inhibitor, dabrafenib (D), and MEK inhibitor, trametinib (T), in patients with resected stage III BRAF mutant melanoma offers recurrence free survival benefit at 3 and 4 years compared to placebo. In this study, adverse events led to dose interruption in 66% of patients, dose reduction in 38% of patients, and permanent discontinuation in 26% of patients. This is a retrospective case series of patients with resected stage III melanoma treated with adjuvant BRAF and MEK inhibition reporting toxicities in a real-world population. Methods: Medical records of all patients with resected Stage III melanoma treated with adjuvant D+T by multiple, independent oncologists at our institution between November 2017 and December 2019 were reviewed. Planned treatment was dabrafenib 150 mg bid and trametinib 2 mg daily for 1 year. Primary outcome of interest was development of toxicities. Secondary outcomes included number of treatment interruptions, dose reductions, and total time on combination therapy. Results: Twenty patients were treated with adjuvant D+T during the study period. Eighteen patients (90%) required at least 1 treatment interruption due to adverse events. Eleven patients (55%) required a dose reduction and 14 (70%) permanently discontinued therapy due to an adverse event. The 9 patients who did not require dose reduction had been initiated on a lower dose of dabrafenib (75 mg BID) due to physician experience with toxicities in prior patients. The most common treatment-limiting adverse events were recurrent pyrexia (85%) and liver laboratory abnormalities (50%). Permanent discontinuation was secondary to recurrent pyrexia in 9 patients (45%) and liver laboratory abnormalities in 5 patients (25%). For the 16 patients who completed or discontinued therapy, the median total time on therapy was 76 days, 20.8% of the intended duration. The majority of these patients never reached the FDA labeled combination dose. Conclusions: We report our findings of the side effects of adjuvant D+T to demonstrate the frequency and severity of treatment limiting toxicities in a real-world population, which exceeds what has been reported in clinical trials. Adjuvant D+T is an approved treatment for resected stage III melanoma but requires diligent toxicity assessment and management.

PCN285 USE OF REAL-WORLD DATA AND MACHINE LEARNING TO REDUCE TREATMENT-LIMITING ADVERSE EVENTS IN AN ACUTE MYELOID LEUKEMIA CLINICAL TRIAL POPULATION

Acute Myeloid Leukemia is an aggressive malignancy with poor prognosis despite significant efforts to identify new therapies. Adverse events can account for 24-47% of clinical trial discontinuation1. In this study we leverage real-world data and machine learning approaches to identify patient-level predictors of common adverse events in AML patients. We then validate the model’s accuracy in a clinical trial population to evaluate its potential utility for improving clinical trial conduct and helping patients avoid adverse events. De-identified Oncology Electronic Medical Record (EMR) data was used from the Guardian Research Network™ (GRN) of integrated delivery systems from Jan 1990 – July 2018. Pooled trial patients with relapsed/refractory AML were from Medidata Enterprise Data Store from March 2008 - Nov 20173. All data sets were converted into the OMOP Common Data Model, v5. Analyses were conducted in SHYFT Quantum v7.1.1 and Python 3.6. All subjects had at least 180 days pre- and post-index activity, indexed at initiation of most recent chemotherapy regimen. Rates were calculated for adverse events commonly associated with treatment discontinuation – neutropenia, thrombocytopenia, anemia and pneumonia2. Features included, but were not limited to, age, gender, current and prior chemotherapy, prior stem cell transplant, and support medications. Predictors were assessed using multiple machine learning algorithms (Logistic Regression, Gradient Boosted Classification, Random Forest, and XGBoost Classification). A 3:1 training/test split and cross validation scoring with a K-fold of 6 was employed. Model performance was measured by AUC ROC scores, PPV and NPV. For EMR-derived models, AUC scores were 0.60-0.75 for top performing models. Testing in clinical trial data had somewhat lower performance, with AUC’s .56-.61. Best performance was seen in models for neutropenia. Real-world data and machine learning can assess risk of potentially treatment-limiting adverse events, with potential applications for reducing clinical trial discontinuation and managing patient treatment burden.

Rechallenge of denosumab in jaw osteonecrosis of patients with unresectable giant cell tumour of bone: a case series analysis and literature review

ObjectivesGiant cell tumour of bone (GCTB) is a rare tumour, generally managed with surgery. Treatment of the very rare unresectable advanced/metastatic GCTB is challenging and denosumab is the only current available medical option, an anti-RANKL monoclonal antibody inhibiting osteolysis. An uncommon but severe and treatment-limiting adverse event of denosumab is the osteonecrosis of the jaw (ONJ). The clinical management of GCTB patients stopping denosumab for medication-related (MR)-ONJ and the possible reintroduction of denosumab after MR-ONJ resolution is matter of debate. We performed a retrospective study to describe the incidence, clinical features and outcome of MR-ONJ in unresectable GCTB patients treated with denosumab at our Institution.Design and settingRetrospective, single-institutional study.ParticipantsAdult patients receiving denosumab as antineoplastic therapy for GCTB and experiencing MR-ONJ at Fondazione IRCCS Istituto Nazionale Tumori of Milan between January 2008 and July 2019.Main outcome measuresIncidence, time of onset and clinical features of MR-ONJ.Results29 patients with locally advanced and/or metastatic GCTB treated with denosumab were identified. At a median follow-up of 70 months (range 1–125), 4 (13.8%) patients experienced MR-ONJ while on treatment, after 125, 119, 85 and 41 months of denosumab, respectively. All patients showed an ongoing tumour stabilisation with denosumab at the MR-ONJ onset and in all cases denosumab was stopped. All four patients were treated with ozone therapy. Two are waiting for surgery, two were already operated on. Both of them experienced disease progression and were thus rechallenged with denosumab. One is still on therapy after 25 months. The other had an MR-ONJ relapse after 39 months and was treated again with ozone therapy and surgery. She is under surveillance, GCTB being currently stable.ConclusionA clinical algorithm of denosumab rechallenge after complete resolution of MR-ONJ in progressing GCTB patients should be prospectively validated.

A prospective open-label trial of long-acting liquid methylphenidate for the treatment of attention deficit/hyperactivity disorder in intellectually capable adults with autism spectrum disorder

Objectives: This treatment trial is aimed at assessing the short-term tolerability and efficacy of liquid-formulation extended-release methylphenidate (MPH-ER) for the treatment of attention deficit/hyperactivity disorder (ADHD) in adults with high-functioning autism spectrum disorder (HF-ASD).Methods: A 6-week open-label trial (ClinicalTrials.gov: NCT02096952) was conducted in 15 HF-ASD adults (mean age 24.9 ± 4.6; male, 12 (80%)) suffering from moderate-severe ADHD. MPH-ER was administered based on a flexible titration schedule. Efficacy was assessed on clinician- and self-rated measures. Tolerability was assessed by documenting treatment-emergent adverse events (AEs) and other safety measures.Results: Short-term MPH-ER treatment was associated with significant improvement in ADHD severity (Adult ADHD Investigator Symptom Report Scale (AISRS) mean change (MC), −22.8 ± 8.8, P < 0.001; Adult ADHD Self-Report Scale (ASRS) MC, −8.2 ± 15.3, P < 0.001). Twelve (80%) participants were deemed responders, based on ≥30% reduction in AISRS score and an ADHD Clinical Global Impression-Improvement score ≤2. MPH-ER was well-tolerated (treatment-limiting AEs, 1/15; severe AEs, 1/15) at mean dose of 48.7 ± 15 mg/day. AEs were transient and experienced by 13/15 (87%) participants at mild to moderate severity. Frequently reported AEs were as typically expected (headache (53%), insomnia (33%), anxiety (33%), decreased appetite (27%)).Conclusions: Our findings suggest that MPH-ER is effective and well-tolerated in the treatment of ADHD in HF-ASD adults.