Reasons For Treatment Discontinuation Research Articles

Real-world experience of immune checkpoint inhibitors in patients with solid tumours in the Top End of the Northern Territory, Australia from 2016 to 2021: a retrospective observational cohort study.

Use of immune checkpoint inhibitors is growing, but clinical trial data may not apply to Indigenous patients or patients living in remote areas. To provide real-world incidence of immune-related adverse events (irAE) in the Top End of the Northern Territory and compare incidence between demographic subgroups. This retrospective, observational, cohort study collected data from electronic records of patients living in the Top End with solid organ cancer treated with immunotherapy between January 2016 and December 2021. The primary outcome was cumulative incidence of any-grade and severe irAE. Secondary outcomes were overall survival, treatment duration and reason for treatment discontinuation. Two hundred and twenty-six patients received immunotherapy. Forty-eight (21%) lived in a remote or very remote area, and 36 (16%) were Indigenous. Cumulative incidence of any-grade irAE was 54% (122/226 patients); incidence of severe irAE was 26% (59/226 patients). Rates were similar between Indigenous and non-Indigenous patients of any-grade (42% vs 56%, P = 0.11) and severe (11% vs 18%, P = 0.29) irAE. However, Indigenous patients had shorter treatment duration, more frequently discontinued treatment due to patient preference and appeared to have shorter median overall survival than non-Indigenous patients (17.1 vs 30.4 months; hazard ratio (HR) = 1.5, 95% confidence interval (CI) = 0.92-2.66). There was no difference in mortality between remote and urban patients (median overall survival 27.5 vs 30.2 months; HR = 1.1, 95% CI = 0.7-1.7). Rates of irAE in our cohort are comparable to those in the published literature. There was no significant difference in any-grade or severe irAE incidence observed between Indigenous and non-Indigenous patients.

Analysis of Treatment Discontinuation in Orthokeratology: Studying Efficacy, Safety, and Patient Adherence Over Six Months.

This study aimed to evaluate the efficacy, safety, and participant compliance of orthokeratology treatment for the correction of myopic refractive errors over a six-month prospective study and to define the potential reasons for early treatment discontinuation. A total of 32 participants with low-to-moderate myopia were fitted with the spherical model of corneal refractive therapy (CRT) orthokeratology lenses (Paragon Vision Sciences) and followed over six months, with specific attention to alterations in refractive error, corneal topography, and epithelial thickness. Concurrently, participant feedback and reasons for any treatment discontinuation were documented. Significant changes in refractive error and in corneal topography were observed, with approximately 50% of the refractive error being corrected on the first night of use and 100% by the first two weeks (P<0.001). Central epithelial thickness experienced substantial thinning, reducing to 15.65±4.49 μm (67.38%) (P<0.001) after 6 months of lens use. Six participants withdrew from this study for varied reasons, including unmet visual expectations and difficulty adhering to the lens-wearing regimen. Notably, the dropout group exhibited higher baseline low-order aberrations and less prolate corneas than those who persisted with the treatment (P<0.05). Orthokeratology with CRT is efficacious and safe for the correction of low-to-moderate myopia in adults, but a portion of patients discontinue the treatment in the first 6 months of contact lens wear. Special care should be taken when recommending orthokeratology in patients with higher levels of myopia and corneas with less prolate shape, providing more realistic expectations and even changing to dual axis or more sophisticated designs.

The cenobamate KORK study—A prospective monocenter observational study investigating cenobamate as an adjunctive therapy in refractory epilepsy, with comparisons to historical cohorts treated with add‐on lacosamide, perampanel, and brivaracetam

AbstractObjectiveIn Europe, cenobamate has been approved for use as an adjunctive therapy in adult patients with epilepsy (PWE) with focal‐onset seizures (FOS) who have not responded satisfactorily to treatment with at least two antiseizure medications (ASMs). Pivotal trials and real‐world observational studies have demonstrated a high efficacy of cenobamate, even in very difficult‐to‐treat epilepsies. Our aim was to investigate the efficacy of add‐on cenobamate in adult PWE who were prospectively monitored. We compared these results with those previously obtained for add‐on lacosamide, perampanel, and brivaracetam therapy.MethodsPatients were enrolled from the CENKORK study, which is a prospective, non‐interventional, open‐label, monocenter cohort study of adult PWE experiencing FOS. The titration of cenobamate was performed according to the guidelines outlined in the summary of product characteristics. The primary outcome measure was the retention rate at 6 months and 1 year. In addition, we assessed seizure‐free rates, the proportion of patients achieving at least a 50% seizure reduction, adverse events, and the reasons for treatment discontinuation. These outcome measures were compared with historical controls treated with adjunctive lacosamide, perampanel, or brivaracetam at our center.ResultsBetween June 2021 and 2022, 172 PWE with ongoing FOS were included. 22 cases were lost to follow‐up, leaving 150 cases for the 1‐year assessment. The retention rates at 6 months and 1 year were 88.7% and 80%, respectively. Seizure freedom was achieved in 14% of patients at both the 6‐month and 1‐year marks, while the ≥50% responder rates were 50% and 61%, respectively. The 6‐month retention rate was significantly higher in cenobamate than in other ASMs (p &lt; 0.001 for each comparator). Adverse events were significantly more common with perampanel (p &lt; 0.001).SignificanceAdd‐on cenobamate proved to be particularly efficacious compared to our experience with other recently introduced ASMs.Plain Language SummaryThis observational study was carried out in 172 adult patients with difficult‐to‐treat epilepsy who were treated with adjunctive cenobamate. After 1 year, the data of 150 patients could be analyzed. Seizure freedom, in the preceding 3 months, was achieved in 14%. The rate of PWE continuing cenobamate was 80%. In our hands, cenobamate showed promising efficacy and tolerability even when compared to other recently introduced antiseizure medications.

Final analysis of the BIMES trial, a phase II single arm study assessing efficacy and safety of bintrafusp alfa in previously treated advanced malignant pleural mesothelioma (GECP 20/09).

8084 Background: Transforming growth factor β (TGF-β) is involved in tumor immune evasion and epithelial–mesenchymal transition (EMT). As TGF-β upregulation and EMT are associated with resistance to anti-PD1 therapy, we evaluated the efficacy of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in malignant pleural mesothelioma (MPM). Methods: Patients with advanced MPM who were previously treated with platinum-based chemotherapy were enrolled and received bintrafusp alfa 1200mg/m2 every 2 weeks until progression or for a maximum of two years. The primary objective was to determine the progression-free survival (PFS) by modified RECIST v1.1. assessed by the investigators. The expected median PFS was 4.5 months. Secondary objectives were overall response rate, duration of response, overall survival (OS) and safety. Results: Between October 2021 to March 2023, 47 patients were enrolled. Mean age was 70 years (41-84) and 36 (78.3%) were males. Most patients had epithelioid histology (82.9%) and had received only 1 prior line of therapy (84.8%). With a median follow-up of 11.5 months, 43 patients had disease progression and 24 patients died. The median number of doses administered was 4 (1-21) and reasons for treatment discontinuation were disease progression (82.6%), toxicity (6.5%), investigator decision (4.4%) and death (6.5%) by tumor progression. The median PFS was 1.9 months (95% CI 1.7 – 5.4) and the 6 month-PFS rate was 15.9%. Disease control rate was 34.8% (95% CI 22.2-49.9) consisting of 2 patients with partial response and 13 patients with stable disease as best response. The median OS was 11.9 months (95% CI 4.4 – not reached) and 6, 12 and 18-month OS rate was 65.3%, 46.5% and 26.6%, respectively. No significant differences in OS and PFS were observed based on MPM histological subtype. Grade 3-4 treatment-related adverse events occurred in 16 (34%) patients, anemia being the most common (n = 5); skin toxicity (n = 3); colitis (n = 2); adrenal insufficiency, acute kidney injury, allergic reaction, lipase, and amylase increased (n = 1 each). Conclusions: Bintrafusp alfa did not reach the expected efficacy in patients with advanced malignant pleural mesothelioma previously treated with platinum-based chemotherapy. Clinical trial information: NCT05005429 .

Approach to weight management in patients with advanced chronic kidney disease in a real-life clinical setting.

Excess adiposity represents a risk factor for chronic kidney disease (CKD) and progression to end-stage kidney disease. Anti-Obesity Medications (AOMs) are vastly underutilized in patients with advanced CKD because of concerns related to safety and efficacy. This study was conducted to evaluate the real-world approach to weight management and the efficacy and safety of AOMs in people with advanced CKD. This is a retrospective analysis of individuals with Body Mass Index (BMI)≥27kg/m2 and eGFR≤30mL/min/1.73m2 referred to an academic medical weight-management program between 01/2015 and 09/2022. Evaluation of weight-management approaches, body weight change, treatment-related side effects, and reasons for treatment discontinuation were reported. Eighty-nine patients met inclusion criteria, 16 were treated with intensive lifestyle modifications (ILM) alone and 73 with AOMs (all treated with glucagon-like peptide-1 receptor agonist [GLP1-RA] +/- other AOMs) along with ILM. Patients treated with AOMs had a longer duration of on-treatment follow-up (median 924days) compared to (93days) the ILM group. Over 75% of patients treated with AOMs lost ≥5% body weight versus 25% of those treated with ILM. Only 15% of patients treated with AOMs discontinued therapy due to treatment-related side effects. In patients with obesity and advanced CKD, GLP-1RA-based anti-obesity treatment was well-tolerated, effective, and led to durable weight reduction.

Abstract PO3-04-06: A comparison of the efficacy of trastuzumab deruxtecan in advanced HER2-positive breast cancer: active brain metastasis versus progressive extracranial disease alone

Abstract Background Trastuzumab deruxtecan (T-DXd) has demonstrated efficacy in patients with brain metastasis (BM), a group historically with poor outcomes. The prevalence of BMs in patients commencing T-DXd is currently unknown. To date, no direct comparisons have been made of the activity of T-DXd in patients with active BM versus those with extracranial progression alone. This real-world study explored the prevalence of BMs at commencement of T-DXd, the efficacy of T-DXd in active BM versus extracranial progression alone and the safety of T-DXd. Methods Patients with HER2-positive advanced breast cancer treated with T-DXd between June 2021 and February 2023 at our specialist cancer hospital were identified and notes reviewed. Clinico-pathological information, prior treatment, the presence or absence of CNS disease, outcomes and treatment-emergent adverse events (TEAE) were recorded. Data cut-off was 28th February 2023. Results 29 female patients: 16 extracranial disease alone, 12 BM and 1 LMD were identified. Prevalence of BM at commencement of T-DXd was 41% (12 of 29). Median age was 52 (IQR 44-62), with a median 2 (range 2-6) prior lines of HER2 directed and chemotherapy:86% (25 of 29) had received prior trastuzumab and pertuzumab, 100% (29 of 29) T-DM1 and 3% (1 of 29) patient trastuzumab duocarmazine. At a median follow-up of 13.8 months, median progression free survival (PFS) for overall population was 13.9 months (95% CI: 12.4-NE), 16.1 months (95% CI: 15.1-NE) for active BMs, and 12.4 months (95% CI: 8.3-NE) for progressive extracranial disease alone (P=0.106). 12-month OS rate was 74% (95% CI: 59-95) in the overall population, 83% (95% CI: 58-100) and 66% (95% CI: 45-96) for active BMs, and extracranial only disease respectively (P=0.678). Objective response rates: overall population was 69% (95% CI: 52-86), active BMs was 60% (95% CI: 30-90), and progressive extracranial disease alone was 69% (95% CI: 46-91). 6% (1 of 16) with extracranial disease alone developed BM during treatment with T-DXd. Reasons for treatment discontinuation: 67% (10 of 15) disease progression or death; 33% (5 of 15) toxicity. 48% (14 of 29) remain on treatment. Most common TEAEs were fatigue (97%; 28 of 29), alopecia (76%; 22 of 29), and constipation (72%; 21 of 29). Pneumonitis occurred in 9 patients (31%, included 2 deaths). 1 pathologically confirmed case of radionecrosis was documented. An updated analysis with an additional 9 patients who commenced T-DXd since February 2023 will be presented. Conclusion In this real-world study a significant number of patients had BM at the commencement of T-DXd. We demonstrate that in advanced HER2 positive breast cancer that T-DXd is as effective, in terms of PFS and OS, in active BMs as it is in progressive extracranial disease alone. These data provide the first evidence that in contrast to the historical data that active BM may no longer be a detriment to survival as compared to progressive extracranial disease alone when treated with T-Dxd. These observations warrant further investigations in larger series. The high rate of pneumonitis warrants further consideration. Citation Format: James Pearson, Adeel Khan, Talvinder Bhogal, Helen Wong, Andrea Law, Samantha Mills, Nuria Santamaria, Joanne Cliff, Douglas Errington, Allison Hall, Clare Hart, Zafar Malik, Raj Sripadam, Helen Innes, Helen Flint, Gabriella Langton, Eliyaz Ahmed, Jill Bishop, Richard Jackson, Carlo Palmieri. A comparison of the efficacy of trastuzumab deruxtecan in advanced HER2-positive breast cancer: active brain metastasis versus progressive extracranial disease alone [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 PO3-04-06.

Abstract PO2-10-07: Patterns of presentation, treatment and survival for older patients with metastatic breast cancer (MBC): results from a large prospective registry

Abstract Background: The median age of breast cancer diagnosis in the U.S. is 62 years; however, older pts with breast cancer are consistently underrepresented in clinical research. In population-based studies, older pts, particularly those aged 70+, do worse than their younger counterparts at every stage of disease, including stage IV. However, our understanding of patterns of recurrence, treatment patterns, and outcomes for older pts with MBC is limited by a lack of available data. Methods: We identified pts age &amp;gt;60 years seen at least once at a single, NCI-designated cancer center for a diagnosis of MBC between 1999-2022 with 1+ years of follow-up from the time of their metastatic diagnosis. We categorized pts into 5-year age groups (60-65; 66-70; 71-75; 76-80; &amp;gt;80) and two groups of 60-70 and &amp;gt;70. Clinicopathologic characteristics, treatment patterns, reason for treatment discontinuation, and the proportion enrolling on clinical trials were compared by tumor subtype and age group using Chi-Square testing. Median overall survival using Kaplan-Meier method was calculated from the date of initial MBC diagnosis to date of death or last follow-up, examined by tumor subtype and age. Results: The final analytic cohort included 1,115 patients diagnosed with MBC with median follow-up of 2.9 years (1.0-18.5). Median age at MBC diagnosis was 66.3 years (60.0-95.4) and 10% were non-White; disease subtype distribution was the following: 70.7% HR+HER2-, 11.9% HER2+, 17.4% TN. Overall, 22.2 presented with de novo MBC. Presentation of MBC did not vary by ages 60-70 vs. 70+, with no differences in disease characteristics such as grade and disease sites at MBC diagnosis (except for bone). However, the proportion of pts with HR+HER2- disease increased with age, from 69% of MBC in ages 60-70 and 76% in ages &amp;gt;70 (p=.02). In pts with this subtype receiving first-line (1L) therapy (n=783), use of endocrine therapy as 1L (with or without a CDK4/6 inhibitor) increased by age (77.8% in ages 60-65 v. 94.7% in ages &amp;gt;80); use of 1L chemotherapy also varied by age (22.2% in ages 60-65 v. 5.3% in &amp;gt;80). Among pts with HER2+ BC, 89% received a trastuzumab-containing regimen in the 1L setting; in pts with TN MBC, 94% received at least 1L line of chemotherapy. Overall, most pts discontinued 1L therapy for progression, not toxicity, and there was no variation in rates of discontinuation due to toxicity by age with 10.4% noted in both age groups, 60-70 and &amp;gt;70. The proportion of patients receiving 3+ lines of chemotherapy across disease subtype decreased with increasing age (e.g., 54% in ages 60-65 v. 25% in ages &amp;gt;80 among HR+HER2-; 69% in ages 60-65 and 33% in ages &amp;gt;80 among TN MBC). Overall, enrollment on a clinical trial in the MBC setting steadily decreased with older age from 40% in ages 60-65 to 13% in ages &amp;gt;80 (p=.0004). Overall median overall survival differed with increasing age from 4.4 yrs in ages 60-65 to 2.7 yrs in ages &amp;gt;80 (p&amp;lt; 0.005). In descriptive analyses, the proportion of pts alive at 2 yrs was variable. For those ages 60-65, 37.8%, 17.1%, and 42.9% of pts with HR+HER2, TN, and HR-HER2+, respectively were alive at 2 yrs. For those ages &amp;gt;80, 23.7%, 0%, and 0% of pts with HR+HER2-, TN, and, HR-HER2+ disease were alive at 2 yrs. Median survival times were &amp;lt; 2 years for pts with TN regardless of age. Conclusions. In a unique, large prospective cohort of older pts with MBC, we examined detailed information on disease presentation, treatments, and outcomes, lending new information on patterns of care and experiences for older pts with MBC in a modern real-world experience. Limitations include a single center experience and small numbers of older pts with HER2+ and TN disease. Although the oldest pts with MBC had similar disease characteristics as younger pts in our dataset, survival outcomes were poor, particularly for those ages 80+. Therapeutic approaches, likely including improved supportive care, are urgently needed to optimize outcomes in the oldest pts with MBC. Table 1. Outcomes for older pts with MBC Citation Format: Melissa Hughes, Alyssa Patterson, Alexandra Newman, Amanda Higgins, Gregory Kirkner, Janet Files, Molly Skeffington, McKenna Moore, Sarah Strauss, Nicole Kuhnly, Lindsey Crowley, Sara Tolaney, Nancy Lin, Rachel Freedman. Patterns of presentation, treatment and survival for older patients with metastatic breast cancer (MBC): results from a large prospective registry [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 PO2-10-07.

P044 Janus Kinase Inhibitors-a retrospective study on side effects and discontinuation reasons

Abstract Background/Aims In light of drug safety warnings for Janus kinase inhibitors (JAKi), we aimed to evaluate the occurrence of adverse events and identify reasons for discontinuation of JAKi in clinical practice. Methods Medical records of all patients prescribed JAKi in NHS Grampian from January 2021 to January 2023 for rheumatic diseases were retrospectively reviewed. Patient demographics, co-morbidities, reasons for treatment discontinuation and occurrence of adverse events (including cardiovascular events) were recorded. Results 160 patients were prescribed JAKi. 131 (81.8%) patients had rheumatoid arthritis, 16 (10%) psoriatic arthritis, five (3%) axial spondyloarthritis, three (2%) juvenile idiopathic arthritis (in adulthood), 3 (2%) undifferentiated inflammatory arthritis, one (0.6%) granulomatous polyangiitis (GPA), one (0.6%) enteropathic arthritis. Mean duration of treatment was 9.9±12 months with 34.4% on treatment for &amp;gt;12 months. 47.5% discontinued JAKi after an average of 7.0 ± 5.1 months. Patients discontinuing treatment were significantly older than patients who continued treatment 60.1yrs ± 11.0 vs 55.9yrs ± 12.5 respectively, p = 0.03. There were no differences between discontinuing and continuing treatment groups with respect to BMI, smoking, diabetes, cardiovascular disease, hypertension or statin use. Discontinuation rates were 66.7 % tofacitinib, 44.4 % filgotinib and 34.4 % upadacitinib. Discontinuation reasons were inefficacy (37.9 %), headache (9.2 %), infections (9.2 %) and gastrointestinal adverse effects (8.0 %). One patient discontinued JAKi due to an arterial embolism (DVT in the context of undiagnosed patent foramen ovale), three developed new onset hypertension. Common infections leading to discontinuation were urinary tract (37.5 %) and chest (25.0 %), with one case of tuberculosis. No herpes zoster infections led to JAKi discontinuation. In patients who continued treatment infections occurred in 27.1% (30% chest, 21.7%, Covid-19, 13% UTIs, 8.7% herpes zoster 8.7% otitis media). Other adverse events such as fatigue and nausea were reported in &amp;lt; 4 % of all patients. No malignancies were recorded. Conclusion Older patients are more likely to discontinue JAKi due to infections. Upadacitinib patients were least likely to discontinue. Treatment inefficacy, urine and chest infections were the commonest reasons for discontinuation. Disclosure J. Klein: None. J. Alexander: None. L. Robertson: Other; LR has received funding for conference attendance from UCB. R. Hollick: None.

Comparison of Safety and Treatment Continuity of Palbociclib and Abemaciclib for Hormone Receptor-Positive, HER2-Negative Metastatic/Recurrent Breast Cancer.

Background: Appropriate adverse event (AE) management and maintenance of therapeutic intensity are necessary to achieve therapeutic benefits of CDK4/6 inhibitors (palbociclib and abemaciclib) in hormone receptor-positive, HER2-negative metastatic/recurrent breast cancer. Objective: This study was aimed at clarifying the effect of AEs associated with palbociclib and abemaciclib on treatment. Methods: A total of 62 and 49 patients were prescribed palbociclib and abemaciclib, respectively, at our hospital from January 1, 2018 to June 30, 2023. The rate and reasons for treatment discontinuation, interruption of administration, and changes in dose and dosing schedule, treatment duration, and relative dose intensity (RDI) were compared between the groups of patients prescribed the 2 treatments. Results: Treatment discontinuation due to AEs occurred more frequently with abemaciclib (12 patients) because of interstitial lung disease and hepatic and renal events than with palbociclib (5 patients; P = .008). Administration was interrupted in 57 (91.9%) and 35 (71.4%) patients treated with palbociclib and abemaciclib, respectively (P = .004). Dose reduction occurred in 37 (67.3%) and 19 (47.5%) patients treated with palbociclib and abemaciclib, respectively (P = .053). The median [range] treatment duration was 301 [21-1643] days for palbociclib and 238 [70-1526] days for abemaciclib (log-rank test, P = .581). The median RDI was 59.7% and 59.6% for palbociclib and abemaciclib, respectively (P = .539). Although the AEs of palbociclib and abemaciclib affected the treatment considerably, the treatment duration and RDI were similar. Conclusion: CDK4/6 inhibitors should be selected based on the tolerability and manageability of each AE.

Abstract CT059: Phase 1b trial Mipasetamab Uzoptirine (ADCT-601-102) dose escalation in patients with advanced bone and soft tissue sarcomas

Abstract Background: AXL is a cell surface receptor tyrosine kinase widely expressed in solid tumors (ST), including sarcomas. ADCT-601 (Mipasetamab uzoptirine; Mipa) is an antibody-drug conjugate comprising a humanized anti-AXL antibody conjugated via a cleavable linker to SG3199 (pyrrolobenzodiazepine dimer cytotoxin). Mipa demonstrated antitumor activity in pre-clinical mice models of sarcoma, adrenocortical carcinoma and pancreatic cancer, and clinical activity in ST patients (pts) in its first-in-human trial. Here, we report initial clinical data in pts with advanced bone and soft tissue sarcomas treated in dose escalation with Mipa. Objective: To characterize the safety and tolerability of Mipa in pts with sarcoma indications who exhausted standard of care therapy. Method: This is a phase 1b, open-label, dose-escalation, dose expansion study of Mipa (NCT05389462; EudraCT: 2021-00566-18). Pts received Mipa every 3 weeks (Q3W) at escalating dose levels, in a 3+3 dose escalation design. Results: As of 04 December 2023, 18 sarcoma patients (15 [83%], soft tissue sarcoma [STS] and 3 [17%] bone sarcoma), unselected for AXL expression, with a median number of 3 prior lines of therapy (1-10), were enrolled in 4 different dose cohorts: 7.5mg, 11mg, 13mg and 15mg. Reasons for treatment discontinuation were disease progression (10 pts [55.6%]), adverse events (3 pts [16.7%]) and consent withdrawal (2 pts [11.1%]). Treatment emergent adverse events (TEAE) were seen in 17 pts (94.4%). Most common TEAE (all grades and relationship [≥20%]) were palmar-plantar erythrodysesthesia syndrome (7 pts [38.9%]); anemia (6 pts [33.3%]); rash maculopapular (5 pts [27.8%]); cheilitis and constipation (4 pts each [22.2%]). TEAE≥grade 3 were seen in 9 pts (50%). Most common TEAE≥grade 3 (≥10%) were GGT increase (2 pts [11.1%]). Two dose limiting toxicities were seen: cheilitis grade 2 and grade 3 at 15mg and 13mg respectively. Cutaneous reactions, all grades, are more prominent in higher doses. Maximum tolerated dose (MTD) has not been established. In 17 sarcoma pts evaluable per RECISTv1.1, best overall response was partial response (PR) (2 pts [11.8%]), including a confirmed PR; stable disease (SD) (8 pts [47.1%]); progressive disease (7 pts [41.2%]). Tumor reductions was observed at 7.5mg, 11mg and 13mg. By week 12, 6/17 pts (35.3%) did not demonstrate PD . Initial IHC staining showed AXL expression in all sarcoma baseline biopsies tested so far. Initial pharmacokinetic (PK) data indicate exposures with moderate to marked interpatient variability; rapid clearance with no accumulation by Cycle 2. Updated biomarkers and PK data will be presented. Conclusion: The MTD was not established. Due to the incidence of TEAE judged related to Mipa and the preliminary activity observed, 15mg was selected as the highest dose to be tested in a fixed dose Q3W regimen. The study continues to enroll to further optimize Mipa dosing regimen and in dose escalation with gemcitabine. Citation Format: Brian Andrew Van Tine, Christopher T. Chen, Victor Moreno, Elizabeth J. Davis, Maria J. de Miguel, Antoine Italiano, Esma Saada-Bouzid, Mohammed Milhem, Claudia Valverde, Sant P. Chawla, Abdul Rafeh Naqash, Louise Carter, Robin Jones, Ilaria Conti, Joe Boni, Karin Havenith, Yvan LeBruchec, Serafino Pantano, Jean-Yves Blay. Phase 1b trial Mipasetamab Uzoptirine (ADCT-601-102) dose escalation in patients with advanced bone and soft tissue sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT059.

Retention of triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine compared to combination methotrexate and leflunomide in rheumatoid arthritis

ObjectiveThere are various combination conventional synthetic disease-modifying-antirheumatic drug (csDMARD) treatment strategies used in rheumatoid arthritis (RA). A commonly used csDMARD combination is triple therapy with methotrexate (MTX), sulfasalazine (SSZ) and hydroxychloroquine (HCQ). Another approach is double therapy with MTX and leflunomide (LEF). We compared the real-world retention of these two treatment combinations. MethodsPatients with RA from the Ontario Best Practices Research Initiative (OBRI) who received triple or double therapy on or after OBRI enrolment were included. Retention rates were compared between these two groups. We also analyzed which medication in the combination was discontinued and the reasons for treatment discontinuation. Disease activity was assessed at baseline, 6 and 12 months after treatment initiation as well as at time of discontinuation. Risk factors for treatment discontinuation were also examined. ResultsSix hundred and ninety-two patients were included (258 triple and 434 double therapy). There were 175 (67.8%) discontinuations in the triple therapy group and 287 (66.1%) discontinuations in patients on double therapy. The median survival for triple therapy was longer (15.1 months; 95% CI: 11.2–21.2) compared to double therapy (9.6 months; 95%CI: 7.03–12.2). However, this was not statistically significant. Disease activity at 6 and 12 months, measured by 28-joint count Disease Activity Score based on erythrocyte sedimentation rate (DAS28-ESR) was lower with triple therapy (mean DAS28 at 6 months 3.4 vs. 3.9, P<0.0001 and at 12 months 3.2 vs. 3.5, P=0.0005). ConclusionPatients on triple therapy remained on treatment longer than patients on double therapy. However, this difference was not statistically significant.

Reasons for Treatment Discontinuation and Their Effect on Outcomes of Immunotherapy in Southwest Finland: A Retrospective, Real-World Cohort Study.

Immune checkpoint inhibitors (ICI) have improved survival in several cancer types. Still, most patients develop disease progression during or after treatment. We evaluated the reasons for treatment discontinuation and their effect on treatment outcomes in adult patients with advanced cancer with ICI in the first or later treatment lines in Southwest Finland between 1 January 2015 and 31 December 2021. Baseline characteristics and treatment outcomes were retrospectively obtained from the electronic medical records. There were 317 patients with 15 different cancer types, most commonly non-small cell lung cancer, melanoma, and kidney cancer, treated with ICI outside clinical trials. During follow-up, 94% of the patients had discontinued treatment. A total of 62% was due to disease progression, 17% due to immune-related adverse events (irAEs), 12% after achieving disease control or radiological response, and 9% due to poor performance status. The median progression-free survival (mPFS) was 5.4 months and the median overall survival (mOS) was 20.3 months in the whole cohort. Longer mPFS and mOS were observed in patients who discontinued ICI due to irAEs (24.3 and 49.2 months) and after disease control (49.7 months and not reached). In total, 46% of the patients who discontinued ICI after irAEs or disease control remained alive and progression-free during follow-up.

First-line FOLFOX therapy for advanced esophageal squamous cell carcinoma: Multicenter prospective study in Japan.

280 Background: Cisplatin (CDDP) plus fluoropyrimidine was the standard first-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC). FOLFOX is promising option especially in patients with ESCC intolerant to CDDP but there were limited data on efficacy and safety of FOLFOX. We conducted a multicenter prospective observational study of FOLFOX for Japanese patients with ESCC intolerant to CDDP. Methods: Eligible participants had clinical stage IVB ESCC, with measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0–2, intolerant to CDDP, but tolerant to FOLFOX. FOLFOX (oxaliplatin 85 mg/m², leucovorin 200 mg/m², bolus fluorouracil 400 mg/m², and infusional fluorouracil 2400 mg/m²) was administered every 14 days. The primary endpoint was the response rate (RR) by RECIST v1.1 and the null hypothesis of RR was 10%. Based on the assumption of performing a one-sided test with an α of 0.10, 29 patients were needed to ensure the statistical power of 90% assuming RR of 30%. Results: In this study, 31 patients were enrolled from 14 hospitals between Apr. 2021, and Jul. 2022 and 30 patients received FOLFOX. The patient characteristics were: median age, 77 (range 66–89); male/female, 30/1; ECOG PS 0/1/2, 16/12/3; median creatinine clearance, 49.9 ml/min (33.4–80.2); median G8 score, 12 (range 7–17); and median CARG score, 8 (range 6–13). As the data cutoff of Jul 2023, all 30 patients discontinued FOLFOX. The reason for treatment discontinuation was disease progression, 86.7%; adverse events, 13.3%. Median follow-up time (interquartile range: IQR) was 20.2 (IQR 13.7–23.1) months. Median number of cycles administered were 5 (range 1–24). The RR was 22.6% (80%CI 0.13–0.35; p = 0.031) and disease control rate was 42.0%. Median progression-free survival was 3.9 months (95% CI 2.3–6.1). Median overall survival was 13.3 months (95% CI 9.5–not reached). The incidence of grade 3 or higher adverse events was 40% (neutropenia 26.7%, anemia 3.3%, nausea 6.7%, anorexia 6.7%, infection 6.7%, peripheral sensory neuropathy 3.3%). There was no treatment related death. Twenty-three patients (76.7%) received subsequent therapies, such as nivolumab (70%). Conclusions: First-line FOLFOX showed an acceptable safety profile and the prespecified statistical efficacy target was achieved. FOLFOX might be a treatment option for advanced ESCC patients who are intolerant to CDDP. Clinical trial information: UMIN000044485 .

A randomized phase III study comparing 2-weekly docetaxel, cisplatin and 5-FU (bDCF) with cisplatin and 5-FU (CF) in patients with metastatic or recurrent esophageal cancer: JCOG1314 (MIRACLE).

322 Background: For metastatic or recurrent esophageal cancer, 2-drug combination of cisplatin and 5-FU (CF) has long been a standard of care before the emergence of immune checkpoint inhibitors (ICIs). Previous phase I/II study of 3-drug combination, 2-weekly docetaxel plus CF (bDCF) showed promising antitumor activity (JCOG0807). We conducted JCOG1314, a randomized phase III study to confirm the survival superiority of bDCF over CF. Methods: Main eligibility criteria were metastatic or recurrent esophageal cancer; histologically proven squamous cell carcinoma or adenocarcinoma; age 20 to 75; no previous systemic therapy for metastatic disease. Patients were randomly assigned to CF arm (cisplatin 80 mg/m2 on day 1, and 5-FU 800 mg/m2 on days 1-5, every 28 days), or bDCF arm (docetaxel 30 mg/m2 on day 1 and day 15 in addition to CF, every 28 days). The primary endpoint was overall survival (OS). To detect a 3-month difference in median OS [hazard ratio (HR) = 0.73] with study-wise, one-sided alpha level of 5% and power of 75%, 240 patients were required. Results: A total of 240 patients were randomly assigned to bDCF (n = 121) and CF (n = 119) between September 2014 to April 2021. Patient background in bDCF/CF arm was median age, 65/64 years; ECOG performance status 0, 69%/75%; metastatic disease, 63%/67%, ≥2 metastatic organs, 59%/56%; squamous cell carcinoma, 94%/97%. As a data cut-off of April 2023, all 240 patients discontinued protocol treatment. The reasons for treatment discontinuation in bDCF/CF arm were disease progression, 58%/71%; adverse events (AEs), 35%/27%; refusal, 1%/1%; others, 7%/5%, respectively. With a median follow-up of 15.3 months (m), bDCF arm was not superior to CF arm in terms of OS with a median of 16.2 m versus 14.8 m [HR, 0.90; 95% confidence interval (CI), 0.68–1.19; p = 0.23], however, progression-free survival (PFS) in bDCF arm was favorable compared to CF arm with a median of 6.0 m versus 5.2 m (HR, 0.68; 95% CI, 0.52–0.88). Response rate in bDCF/CF arm was 52.8%/45.6%. Major grade 3 or 4 AEs observed in bDCF/CF arm were neutropenia (37.8%/27.1%); anorexia (25.2%/16.1%); fatigue (10.1%/15.3%); hyponatremia (13.4%/13.6%). No treatment related death was observed. Subsequent therapy in bDCF/CF arm was provided for 87%/89% of patients. Conclusions: JCOG1314 did not reach its primary objective, although bDCF was associated with significant increases in PFS. CF is still the standard therapy in patients with metastatic or recurrent esophageal cancer if ICIs are not applicable. Clinical trial information: jRCTs031180143 .

Preliminary Results of a Phase 2a Clinical Trial to Evaluate Safety, Tolerability and Antiviral Activity of Intravenous Brincidofovir (BCV IV) in Immunocompromised Patients with Adenovirus Infection

Background: Adenovirus (AdV) may cause life threatening or fatal infections in immunosuppressed patients including recipients of allogeneic hematopoietic cell transplant (allo-HCT). Brincidofovir (BCV) is a lipid conjugate of cidofovir, that crosses target cell membranes by means of facilitated and passive diffusion and has a long intracellular half-life. The safety, tolerability and antiviral activity of intravenous BCV (BCV IV) were evaluated in a dose ascending Phase 2a study (BCV-PA01: ATHENA study, NCT04706923) in sequential cohorts. Methods: Eligible patients aged 2 months or older who were immunocompromised due to allo-HCT, organ transplant, immunosuppressive medications, or congenital immunodeficiency, and had AdV viremia or disseminated AdV disease were included. AdV viremia was defined as 1) AdV viral load in the blood &amp;gt; 10,000 copies/mL OR 2) two samples greater than 48 hours apart with the second result higher than the first and both greater than 1000 copies/mL, within 7 days prior to initiation of BCV IV treatment. BCV IV was administered intravenously twice weekly for 4 weeks or until resolution of AdV viremia up to 14 weeks, whichever occurred later. The dose escalation was as follows: 0.2 mg/kg (Cohort 1), 0.3 mg/kg (Cohort 2), or 0.4 mg/kg (Cohort 3) for patients weighing &amp;lt; 50 kg and 10 mg/dose, 15 mg/dose, or 20 mg/dose, respectively for patients weighing ≥ 50 kg. The patients were subsequently followed up for 30 days after the last BCV IV dosing. AdV viral loads in blood were monitored weekly by quantitative real-time polymerase chain reaction tests (lower limit of detection (LOD) 25 copies/mL, lower limit of quantification 190 copies/mL, upper limit of quantification 1 x 10 9 copies/mL). Viral clearance was defined as two consecutive plasma viral load test results below the LOD. Results: Of 27 patients treated with BCV IV, 8 were in Cohort 1, 9 in Cohort 2 and 10 in Cohort 3. Baseline characteristics of patients are shown in Table 1. Treatment-related adverse events (TRAE) were observed in 7 patients, as shown in Table 2. No serious TRAEs including gastrointestinal and hepatic toxicities were observed. All TRAEs were reversible and resolved after the completion of the treatment. AE-related discontinuations of treatment were observed in 3 of 8 patients in Cohort 1; 2 of 9 patients in Cohort 2; and 1 of 10 patients in Cohort 3 (Table 2). The reason for discontinuation of treatment beyond 4 weeks of treatment in Cohort 3 was successful clearance of AdV viremia. Antiviral activity was dose-dependent, and viral clearance was achieved in 25% (2/8) in Cohort 1; 56 % (5/9) in Cohort 2; and 100% (10/10) in Cohort 3. The duration of treatment with BCV IV and viral responses are summarized in Table 2. In Cohort 3, it is notable that 90 % of patients achieved AdV viremia clearance in ≤ 4 weeks of treatment with BCV IV. In Cohorts 2 and 3, all patients who achieved AdV viremia clearance maintained undetectable AdV in the blood through the follow-up period. Conclusions: BCV IV was found to be safe and well tolerated in immunocompromised patients. Notably, the potentially serious gastrointestinal and hepatic toxicities described with the oral BCV formulation were not observed. BCV IV was highly effective in a dose-dependent manner, led to rapid clearance of AdV viremia within a short treatment period and provided sustained virologic response. In view of promising results and in the absence of any other approved treatments for AdV infection, our results support the need for further exploration and additional clinical trials of BCV IV as a treatment for AdV infection.

High Responses Rates with Single Agent Belantamab Mafodotin in Relapsed Systemic AL Amyloidosis

Introduction: Systemic AL amyloidosis, a rare incurable plasma cell disorder, has no approved treatments at relapse. Belantamab mafodotin is an antibody-drug conjugate which targets BCMA antigen approved for relapsed refractory myeloma. We report our results using belantamab mafodotin monotherapy for the treatment of patients with relapsed refractory AL amyloidosis including those traditionally excluded from clinical trials (eGFR&amp;lt;30 ml/min/1.73m 2 and cardiac Mayo stage IIIb disease). Methods: All patients treated with belantamab mafodotin monotherapy at standard dose (2.5 mg/kg) or dose reduction between April 2021 - July 2023. Standardised assessments including measurement of cardiac biomarkers, clonal parameters and imaging were performed and disease assessment was reported as per International Society of Amyloidosis consensus criteria. Results: Twenty-seven patients were included. The median age at was 65 years (range 41-76) and eight (30%) patients were aged &amp;gt;70 years. Eighteen (67%) had λ AL-type and nine (33%) κ AL-type. A median of two organs were involved at baseline (range 1-4) with renal and cardiac involvement in 20 (74%) and 15 (56%) respectively (3 each for Mayo stage IIIa and stage IIIb). The median time from AL amyloidosis diagnosis to first administration of belantamab mafodotin was 69 (range 5-174) months (~6 years) with a median of 3 prior lines of treatment (range 2-6). Prior drug class exposure included proteasome inhibitors (100%), immunomodulatory drugs (81%) and anti-CD38 antibody (81%) therapy. Ten patients (37%) had undergone prior melphalan-conditioned autologous stem cell transplantation. At the time of first belantamab mafodotin dose, the median involved free light chain concentration was 118mg/l (range 31-1778), eGFR was 40 ml/min (range 7 - 120) and a third (9/27) with an eGFR &amp;lt;30 ml/min/1.73m 2. NT-proBNP was 845 ng/l (range 99-70,000). At data cut-off, a median of 5 (range 1-11) doses of belantamab mafodotin were delivered. Of those with evaluable disease, best haematological overall response rate (partial response or better) was 80% (20/25) at a median time to best haematological response of 2 months (95% CI 1-4, range 1-17). Complete response (CR) or very good partial response (VGPR) was achieved in 64% (16/25). Two patients have only had 1 cycle and too early to perform response assessment. Reasons for treatment discontinuation (n=12) were: inadequate response/progression (n=7), keratopathy (n=1), grade 3 thrombocytopenia (n=1), physician choice (n=3: discontinued due to treatment for unrelated metastatic squamous cell carcinoma but remains in CR; facilitation of renal transplant; prior to BCMA-directed CAR-T in VGPR). At a median follow-up of 13 months follow-up (95% CI 4-18, range 1-27) from belantamab mafodotin initiation, 15 patients (56%) remain on therapy. Two patients died (1 due to progressive disease, 1 unrelated) and seven patients progressed and had subsequent line of therapy at a median time of 6 months (95% CI 2-4) in those that had a next line of therapy. Median treatment-free survival or death was 27 months (10-NR), and 1-year treatment-free survival/death was 69% (95% CI 41-86). Median overall survival (OS) is not reached. 1-year OS is 88% (95% CI 59-97). Bilateral microcystic corneal keratopathy, the most frequent adverse event, was seen in 19 (70%) patients (5%; 1/19 grade 4).Ocular adverse events improved in all patients after treatment delay. Only one patient required treatment cessation due to ocular toxicity (despite achieving PR after one dose). Thrombocytopenia was reported in 3 (11%) (grade 3: 1; grade 2: 1). Only two patients remained on the standard dose of 2.5mg/kg for &amp;gt;3 cycles. Nine patients had eGFR &amp;lt;30ml/min and 6/9 started at a dose of 1.25mg/kg with no unexpected side effects (1 patient had grade 3 keratopathy). One patient post-renal transplantation (on tacrolimus and mycophenolate) had no significant toxicity and achieved a CR after cycle 3. No treatment-related deaths, cardiac or renal toxicities observed in our cohort. Conclusion: Belantamab mafadotin has high efficacy and good tolerability in multiply relapsed AL amyloidosis including efficacy in patients otherwise excluded from clinical trials. Treatment-emergent adverse events (especially keratopathy) do not preclude delivery of drug with appropriate dose reductions.

Elevate-TN: Impact of First-Year Dose Modifications in Patients with Treatment-Naive Chronic Lymphocytic Leukemia Treated with Acalabrutinib

Background: Acalabrutinib (acala), a second-generation Bruton tyrosine kinase inhibitor (BTKi), with or without obinutuzumab (obin), demonstrated superior progression-free survival (PFS) compared with obin plus chlorambucil in patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL) in the phase 3 ELEVATE-TN (NCT02475681) trial. Despite the long-term benefits observed with acala therapy, data from real-world studies in patients with CLL demonstrate that 22% of patients discontinue acala treatment for any reason in the first year of treatment across therapy lines (Roeker et al. Blood. 2022). To assess the impact on survival outcomes of acala discontinuation and dose modifications occurring in the first year of treatment, we conducted a post hoc analysis in patients treated in the acala-containing arms of ELEVATE-TN. Methods: Patients who received acala 100 mg twice daily with or without obin (fixed duration, up to 6 cycles) with at least 1 year of follow-up were included in this analysis. The impact of dose reductions, treatment breaks, or treatment discontinuations in the first year on overall survival (OS) was assessed. Protocol-specified dose-modification guidelines that included dose reductions, breaks, and discontinuations depending on severity and frequency were applied to patients with apparent treatment-related toxicity. To assess the impact of dose reductions, breaks, or discontinuations, patients were divided into 4 dose-modification subgroups: 1) patients with no dose reductions/breaks &amp;gt;14 days during the first year; 2) patients with dose reductions &amp;gt;14 days, but no breaks &amp;gt;14 days during the first year; 3) patients with breaks &amp;gt;14 days, but who continued treatment in the first year; and 4) patients who discontinued treatment during the first year. Results: With a median follow-up of 60 months, 358 patients (n=179, acala monotherapy; n=179, acala-obin) with ≥1 year of follow-up were included in this analysis. In the first year, 269 (75%) patients had no dose reductions/breaks &amp;gt;14 days, 11 (3%) patients had dose reductions &amp;gt;14 days but no breaks &amp;gt;14 days, 32 (9%) patients had breaks &amp;gt;14 days but continued treatment, and 46 (13%) patients discontinued treatment. Reasons for treatment discontinuation during the first year were adverse events (n=26), disease progression (n=7), physician decision (n=5), consent withdrawn (n=3), death (n=2), loss to follow-up (n=1), and other (n=2). Patients who discontinued treatment within the first year had inferior OS compared with patients who did not require dose reductions or breaks (OS hazard ratio [HR]: 8.39, 95% confidence interval [CI]: 3.96-17.8, P&amp;lt;0.0001; Figure 1). In contrast, patients who had dose reductions or breaks &amp;gt;14 days but did not discontinue treatment had statistically similar OS to patients who did not require dose reductions or breaks. Within the group that had no dose reductions or treatment breaks &amp;gt;14 days, there was no difference in the proportion of patients treated with acala monotherapy (n=133) and acala-obin (n=136). However, OS outcomes in this subgroup of patients with no treatment modifications were superior in patients treated with acala-obin compared with those treated with acala monotherapy (HR: 0.37, 95% CI 0.15-0.87, P=0.0183; Figure 2). Conclusions: This post hoc analysis of acala-treated patients with TN CLL in ELEVATE-TN demonstrated superior OS in patients who did not have dose reductions or breaks compared with patients who discontinued treatment within the first year. OS outcomes in patients who required dose reductions or breaks but did not discontinue treatment in the first year were similar to those in patients who did not require dose modification. Accepting the limitations of retrospective analysis, these data suggest that patients who are unable to tolerate standard-dose acala or who require treatment breaks may benefit from continuing or resuming treatment at a reduced dose rather than stopping treatment altogether. For patients who do not require dose modifications, ongoing follow-up of the ELEVATE-TN trial suggests durable and incrementally improved OS benefit from the addition of obin to acala.

LONG-TERM Outcomes after Venetoclax-Hypomethylating Agent Combination Therapy Discontinuation, in Patients with ACUTE Myeloid Leukemia. Experience of a Single Center

CONCLUSION The combination of azacitidine and venetoclax has become the standard of care in patients with acute myeloid leukemia (AML) who are not eligible for intensive chemotherapy ( Di Nardo et al. N Engl J Med 2020; 383:617-629). Despite being considered a low-intensity treatment, long-term administration of venetoclax based combinations treatment can be challenging due to a multitude of factors, ranging from drug-related toxicity to logistical and quality of life obstacles often bringing to dose adjustments or discontinuation. We analyzed long-term outcomes of patients with AML treated with venetoclax in combination with hypomethylanting agents who required discontinuation of treatment, after reaching complete remission (CR), due to toxicity or patient decision treated at the Institut Català d'Oncologia-Hospital Duran i Reynals. Observational and retrospective study that includes patients diagnosed with AML who received treatment with venetoclax in combination with hypomethylating agents as first line or as salvage therapy, between May 2019 and April 2023. Bone marrow was analyzed pre-treatment for somatic mutations via targeted next-generation sequencing (NGS). 68 patients were included in the study. The median age at diagnosis was 75 years (range 33-85 years), with a predominance of males (69%). Twenty-eight (41.2%) patients were classified according to the 2022 ELN classification as an adverse risk, 33 (48.5%) as intermediate risk and 7 (10.3%) as a favourable risk subgroup. Forty-eight (70.6%) patients received the combination as first line treatment and 20 (29.4%) as salvage therapy. No significant differences were found between the two groups regarding sex, age or ELN2022 risk. The median number of cycles received was 7 (range 1-23 cycles). The overall response rate (ORR) was 76.5% (52 of 68 patients), of which 46 (68%) patients achieved a composite CR (CRc) (CR, CR with partial hematologic recovery, and CR with incomplete hematologic recovery). Among the 52 responding patients, 88.5% of the patients obtained the best response in the first 2 treatment cycles. Median overall survival (OS) and event-free survival (EFS) of the series were 12.7 and 10.9 months, respectively. 30 days mortality was 7.7% (3 patients due to infectious event and 1 patient due to progression). Seven of the 52 responding patients (13.5%) discontinued treatment after achieving CRc. The median number of cycles received prior to discontinuation was 2 (range 1-11 cycles). The reasons for treatment discontinuation were: patient decision (4), grade 4 myelotoxicity (2) and recurrent infections (1). Pre-treatment NGS data (n=7) from the patients who discontinued the treatment showed a median of 4 (range 2-9) mutations with a predominance of mutations in genes that encode epigenetic modifiers ( DNMT3A n=4 and TET2 n=3). RUNX1 mutation was also frequently seen at diagnosis in 3 patients. The median follow-up from the end of treatment until last visit or dead was 8.1 (3.5-10.0) months. Two of the 7 patients have died during the treatment-free period, one of them due to non-haematological cause and the other one due to disease relapse. This last patient had a TP53 mutation (VAF 78%), and the observation period without treatment for this patient was 8.5 months. No other patients had a TP53 mutation. Median EFS and OS of patients who discontinued treatment were 7.3 and 8.5 months, respectively. No statistically significant difference was observed in OS of the responding patients according to treatment discontinuation or not (Figure 1). Our findings confirm the high efficacy of venetoclax and azacitidine combination in AML. Discontinuation of treatment in responding patients was associated with similar durable responses and OS compared to patients who continue under treatment. Identifying the subgroup of patients who may benefit from de-escalation strategies is mandatory. Further studies are needed to determine which patients might be appropriate for treatment suspension or discontinuation while in remission.

Acute Myeloid Leukemia Patients Who Stopped Venetoclax or/and Azacytidine for Other Reasons Than Progression Have a Prolonged Treatment Free Remission and Overall Survival. a Filo Study

Background Recent update of the VIALE-A study showed a long-term survival for approximately 30% of acute myeloid leukemia (AML) patients treated with venetoclax and azacitidine (VEN-AZA) for a newly-diagnosed AML (ND-AML) (Pratz K.W et al., ASH 2022). A recent report of a small cohort of responding patients who interrupted VEN-AZA displayed a sustained treatment-free remission (TFR) period suggesting that treatment interruptions might be considered (Chua CC. et al., Blood Adv. 2022). To evaluate the impact of VEN-AZA discontinuation on survival and time without treatment, we retrospectively analyzed the characteristics and outcomes of patients who stopped VEN and/or AZA for reasons other than progression (e.g. hematological or other toxicities). We presented the first 51 patients from our cohort last year at ASH meeting (Garciaz S. et al, ASH 2022). In this abstract, we analyzed separately ND-AML and relapsed/refractory (R/R) AML. Methods Eligible patients 1) have been treated with VEN-AZA for a ND or R/R AML, 2) have stopped AZA and/or VEN for more than 3 months, 3) are in remission (CR, CRi or Morphologic leukemia-free state, [MLFS]) at the time of treatment interruption, 4) are ≥ 18-year-old. Main endpoints were overall survival (OS) and treatment-free remission (TFR) calculated from the time between the last day of VEN to relapse, retreatment, or death. We measured the impact of prognostic factors on OS by a Cox regression taking disease status (ND vs R/R), the discontinued treatment (VEN vs VEN-AZA), the cytogenetics and NPM1 or IDH mutations. Results We included 83 patients from French Innovative Leukemia Organization (FILO) centers and Moffit Cancer Center (US) treated with VEN-AZA for a ND-AML or a R/R AML between 11/18 and 07/23. Regarding the ND-AML patients (n=60; 32 males and 28 females), the median age was 76 (range, 26-86.5), median platelet count, WBC, ANC and bone marrow blast involvement was 52 G/L (range, 9-296), 2.8 G/L (range, 0.6-200), 0.6 G/L (range, 0.02-31.6) and 40% (range, 10-99), respectively. Cytogenetics was intermediate (int.) in 48 cases (80%) and unfavorable (unfav.) in 12 patients (20%). Eleven AML (18.3%) had NPM1 mutations, and 19 (31.6%), IDH alterations including 7 IDH1, 8 IDH2R140 and 4 IDH2R172. Six (10%) and 5 (8.3%) patients had FLT3 or TP53 mutations, respectively. The median number of VEN-AZA cycle was 4 (1-17). The best response was CR (n=44, 73.3%), CRi (n=13, 18.3%) and MLFS (n=3, 5%). Twenty-one patients out of 25 (78%) reached MRD negativity assessed by molecular (n=11) or flow cytometry (n=10) techniques. Twenty-six patients (43.3%) stopped VEN-AZA and 34 (56.7%) stopped VEN and continued AZA monotherapy for a median number of 7 AZA cycles (1-41). Reasons for treatment discontinuation were prolonged cytopenia, non-hematological toxicities, patient choice or unknown in 35 (58%), 6 (10%), 8 (13.3%), and 11 (18.3%) patients, respectively. We registered 27 relapses and 24 deaths. Fourteen patients were retreated including 11 patients who were rechallenged with VEN-AZA. Second CR/CRi rate with VEN-AZA was 3/11 (27.7%). With a median follow of 23 months, median TFR was 15 months (ranges, 3-47) and median OS was 44 months (ranges, 7-50). We also analyzed a smaller cohort of 23 R/R responding patients who stopped AZA and/or VEN. The median age was 73, median number of previous lines was 1 (1-3). Twenty-one patients (91.3%) received prior intensive chemotherapy and 4 (17.4%) prior allogeneic hematopoietic transplantation. Cytogenetic risk was int. in 17 (73.9%) and unfav. in 5 patients (21.7%) and missing in one patient. NPM1 and IDH genes were mutated in 6 (26%) and 10 (43.4%) cases, respectively. Sixteen patients (69.6%) stopped VEN-AZA and 7 (30.4%) interrupted VEN only. Nine patients resumed a treatment including 6 patients rechallenged with VEN-AZA. Among them, 3/6 (50%) obtained a second CR/CRi. Median TFR and OS were 10 (ranges, 3-23) and 19 (ranges, 7-32), respectively. Factor impacting OS in multivariate analysis were R/R AML disease status (Hazard Ratio [HR] =0.47, ranges, 0.23-0.87), and IDH mutations (HR= 2.1, ranges, 1.05-4.34), but not unfav. cytogenetics, NPM1 mutations, or the discontinued treatment (VEN vs VEN-AZA). Conclusion: Discontinuation of VEN and/or AZA in responding patients was associated with sustained responses and long-term survival rates. Resuming treatment may induce a second remission in some patients.

The Efficacy and Safety of Selinexor in Combination with Ruxolitinib in Ruxolitinib-Treated Myelofibrosis Patients： the Interim Analysis of a Prospective, Open-Label, Multicenter, Parallel-Cohort, Phase 2 Study

Background: Myelofibrosis is a chronic hematologic malignancy characterized by constitutional symptoms, bone marrow fibrosis, extramedullary hematopoiesis resulting in splenomegaly and a propensity toward leukemic progression. Although JAK inhibitors have improved patients' splenomegaly and symptom burden, the clinical management of MF is still challenging for its limited treatment options, especially when patients become less responsive or intolerable to Ruxolitinib (RUX) treatment. Selinexor (SEL) is a novel, first-in-class, oral selective inhibitor of nuclear export agent that binds the karyopherin protein exportin 1 (XPO1). Preclinical studies showed SEL decreased viable cells and colony formation both in newly diagnosed and RUX-exposed MF cells. ESSENTIAL trial showed SEL's sustained spleen responses as a single agent in JAKi refractory MF. Besides, a phase I study reported, with SEL plus RUX in treatment-Naïve MF, 92% patients(pts) achieved SVR35, 69% had symptom response and 65% had stable or improved Hgb levels. We have presented promising efficacy and safety data in real-world setting of SEL plus RUX regimen in MF patients in 2023 EHA. Here we are to report the efficacy and safety of the regimen in RUX-treated patients in a prospective clinical trial. Methods: This is a prospective, open-label, multi-center, parallel-cohort phase 2 study, examining SEL plus RUX regimen in RUX-treated MF pts. The study includes MF pts with suboptimal RUX responses or intolerable to RUX treatment. Pts are given SEL 40mg or 60mg QW plus RUX (dosage per investigator judgement, RUX intolerable pts will receive reduced dose of RUX). A total of 40 pts will be included into the study. The primary endpoint is spleen response assessed by palpation or CT/MRI scan per IWG-MRT and ELN response criteria. Key secondary endpoints include anemia response, symptom response defined as symptom resolution or alleviation according to TSS or physician's judgement, and safety. Results: Characteristics As of July 2023, 28 pts had received at least one dose of oral weekly SEL, including 12 suboptimal RUX responses pts and 16 RUX intolerable pts. The median age was 65 years old. Mean duration of prior RUX treatment was 24.5 months (range: 4-77). 18 pts had primary MF, 4 had post-PV MF, and 6 had post-ET MF. Median time from MF diagnosis to study enrollment was 5 years (0.25-29). JAK2, CALR and MPL mutations were present in 18 (64.28%), 5 (17.85%) and 1 (3.57%) pts respectively. All pts presented constitutional symptoms, 25 (89.29%) had splenomegaly, and 7 (25.00%) had packed red blood cell (PRBC) transfusion-dependent anemia. DIPSS risk category was intermediate 23 (82.14%), high risk 3 (10.71%) and unknown 2 (7.14%). Median treatment duration was 134 days (14-525) (Table 1). 15 pts (53.57%) discontinued SEL. Reasons for treatment discontinuation were death in 4 pts (3 from covid-19, 1 sepsis), participation in clinical trial in 2 pts, unsatisfactory response in 2, transplantation in 1, toxicity in 2, economic burden in 1 patient and lost to follow-up in 3. Efficacy Analysis The analysis of spleen response included 21 pts with spleen length assessment data by either palpation or CT/MRI. Spleen response is defined as length reduction more than 50% per IWG-MRT and ELN response criteria. 15 (71.42%) pts had a reduction in spleen volume and 8 (38.09%) achieved spleen response ( Figure 1). For symptom response, 27 pts are with available data. 23 (85.18%) pts had symptom alleviation, 9 (33.33%) achieved ≥50% reduction in TSS or symptom response assessed by physician, of which 1 achieved symptom resolution. There are 12 pts with PRBC transfusion-independent anemia (Hgb≤100g/L) at baseline and had received study treatment for at least 28 days. 10 (83.33%) pts had maintained stable or improved Hgb levels at the last follow up. 5/7 (71.42%) PRBC transfusion-dependent pts became transfusion independent (1 pt) or had reduced transfusion frequency (4 pts), and 2 pts remained stable. Safety The most common TEAEs were nausea 14 (50.00%), vomiting 9 (32.14%), decreased appetite 8 (28.57%), and anemia 7 (25.00%). The most frequent TEAEs ≥ Grade 3 were anemia 3(10.71%) and thrombocytopenia 2(7.14%). Conclusion: In this preliminary analysis, the combination of SEL and RUX showed encouraging efficacy and manageable safety in RUX-treated pts with myelofibrosis.