Required Dose Reduction Research Articles

Antiretroviral therapy in people with HIV and end-stage kidney disease.

To summarize antiretroviral therapy (ART) use in the setting of end-stage kidney disease (ESKD). Cross-sectional analysis. Descriptive analysis of ART regimens and dose of nucleoside/nucleotide reverse-transcriptase inhibitors (NRTI) in people with HIV and ESKD (dialysis, kidney transplantation, or estimated glomerular filtration rate (eGFR) <15 mL/min/1.73m2) receiving HIV and renal care at five London centres. Exposures of interest were use of dual/unboosted ART regimens and higher than recommended doses of renally-cleared NRTI. A total of 157 participants were included (median age 55 years, 66% male, 84% black ethnicity, median CD4 cell count 382 cells/mm3, 99% HIV RNA <200 copies/mL). Fifty-eight (37%) were on dual/unboosted ART regimens, mainly dolutegravir/lamivudine. Participants on dual/unboosted ART had similar rates of HIV suppression as those on triple-ART. Two participants currently virologically controlled on triple-ART had previously failed to suppress on dual/unboosted ART (dolutegravir/rilpivirine and dolutegravir/lamivudine [50 mg]). Lamivudine doses were higher than recommended in 75 (77%) and lower than recommended in 8 (8%) participants. Full dose lamivudine (300 mg daily) was used by 24 (32%) participants with eGFR <30 mL/min/1.73m2. None of those currently on reduced-dose lamivudine had required dose reductions for previous toxicity concerns. Dual/unboosted ART regimens such as dolutegravir/lamivudine provide robust viral efficacy in the setting of ESKD, and higher than recommended, including full-dose, lamivudine was well tolerated. The dolutegravir/lamivudine (300 mg) fixed-dose combination provides a single-tablet regimen for use across the eGFR spectrum, avoids under-exposure to lamivudine, and merits further evaluation in this population.

Sex differences in toxicities and survival outcomes among Japanese patients with Stage III colorectal cancer receiving adjuvant fluoropyrimidine monotherapy: A pooled analysis of 4 randomized controlled trials (JCOG2310A).

Fluoropyrimidine remains the key agent of adjuvant chemotherapy for stage III colorectal cancer (CRC). Western studies have shown that female sex is a favorable prognostic factor after surgery, but it is also a risk factor for adverse events (AEs) during adjuvant chemotherapy with fluoropyrimidine. However, little is known about whether sex differences in treatment outcomes exist in this setting in the Asian population. Patients with stage III CRC who received adjuvant fluoropyrimidine monotherapy in 4 randomized controlled trials were analyzed. Incidences of AEs and survival outcomes were compared between female and male patients. A total of 3170 patients (female, 1516; male, 1654) were included in this analysis. Compared with males, females were less likely to have a relative dose intensity (≥90%: female 59.1% vs. male 67.6%), with a higher proportion of requiring dose reduction (28.8% vs. 20.4%) and a lower proportion of completing adjuvant chemotherapy (77.0% vs. 81.7%). Multivariable analyses demonstrated that female sex was associated with a higher incidence of grade 3-4 AEs (odds ratio 1.80 [95% CI 1.51-2.14]). Female sex was identified as a favorable prognostic factor for overall survival (hazard ratio [HR]: 0.80 [0.65-0.97]) and relapse-free survival (HR: 0.73 [0.63-0.85]) in multivariable analyses. Female patients had fewer time-to recurrence (TTR) events than male patients (5-year TTR: 17.7% vs. 22.3%). Sex had implications for the development of AEs and survival outcomes of Japanese patients with stage III CRC who received adjuvant fluoropyrimidine monotherapy.

Outcome of osimertinib-treated patients with epidermal growth factor receptor mutation-positive nonsmall cell lung cancer requiring dose reduction: a secondary analysis of the Reiwa study.

Osimertinib is effective in patients with epidermal growth factor receptor (EGFR) mutation-positive nonsmall cell lung cancer (NSCLC). However, some patients require osimertinib dose reduction because of adverse events. This study assessed the characteristics of osimertinib dose reduction and compared the efficacies of reduced-dose and regular-dose osimertinib. This multicenter, prospective, observational study enrolled patients with EGFR mutation-positive NSCLC who started first-line osimertinib treatment between September 2018 and August 2020. We categorized the patients into two groups: those who required dose reduction during osimertinib treatment (reduction group) and those who continued osimertinib treatment at a dose of 80mg/day without dose reduction (nonreduction group). The primary endpoints were progression-free survival (PFS) and pattern of progression, whereas the secondary endpoints included overall survival (OS) and reasons for osimertinib dose reduction. Of the included 575 patients, 175 (30.4%) and 400 (69.6%) were classified into the reduction and nonreduction groups, respectively. PFS was significantly better in the reduction group than in the nonreduction group [hazard ratio (HR)=0.67, 95% confidence interval (CI)=0.54-0.84; P<0.001]. Meanwhile, the pattern of progression and OS (HR=0.82, 95% CI=0.62-1.08; P= 0.15) did not differ significantly between the two groups. Osimertinib was reduced due to physician's decision or adverse events and the main reasons were rash and gastrointestinal symptoms such as nausea and diarrhea. Many patients require osimertinib dose reduction due to adverse events, but this process does not adversely affect the drug efficacy.

Ceftriaxone encephalopathy in a very elderly dialysis patient.

Ceftriaxone is widely used clinically but it can potentially cause ceftriaxone encephalopathy in individuals who are on dialysis. We describe ceftriaxone encephalopathy in a dialysis patient. The 87-year-old Japanese woman had a 9-year dialysis history. She was admitted to our department with right subcostal pain and lower back pain and was diagnosed with renal cyst hemorrhage and infection. Post-admission, we treated her with ceftriaxone (CTRX) 2g/day and bed rest, which improved her symptoms. On the 7th hospitalization day, she began to exhibit incoherent speech and unresponsiveness; by day 10, her consciousness level had decreased to grade III and myoclonus appeared. Brain MRI and a cerebrospinal fluid examination ruled out cerebrovascular disease and encephalitis. EEG showed triphasic waves predominantly in the frontal lobe. Suspecting ceftriaxone encephalopathy, we switched the antibiotic to cefazolin 1g/day. By day 12, the myoclonus decreased and the patient was able to communicate. By day 14, her consciousness level had improved to her admission level. We treated ceftriaxone encephalopathy in a dialysis patient. Although CTRX is generally thought to not require dose reduction in patients with renal failure (due to its hepatic excretion), caution is necessary as overdosage in dialysis patients can lead to myoclonus and encephalopathy.

Prolonged clinical response is possible with regorafenib in refractory osteosarcoma: A case report

&lt;b&gt;Background:&lt;/b&gt; Treatment options for metastatic unresectable osteosarcoma are limited, and there is no standard approach after the failure of first-line chemotherapy. Conventional chemotherapy in the second and subsequent lines typically yield a median progression-free survival (PFS) of less than 4 months, with objective response rates ranging from 3 to 29%. The activity of anti-vascular endothelial growth factor receptor multi-tyrosine kinase inhibitors (TKIs) in bone sarcomas has been demonstrated. We present a case of metastatic osteosarcoma exhibiting a durable response to regorafenib treatment.&lt;br /&gt; &lt;b&gt;Case: &lt;/b&gt;We discuss a 30-year-old male with metastatic osteosarcoma who had extensive bone and lung metastases and was ineligible for metastasectomy. The patient had received all active chemotherapy regimens in the early and metastatic stages except ifosfamide. Next generation sequencing analysis of resected tumor tissue revealed a possibly pathogenic missense mutation (P.G472E) in NOTCH1 gene. Due to the presence of heart failure with a reduced ejection fraction, chemotherapy was not considered, and regorafenib was initiated. After four cycles of regorafenib, a partial metabolic response was achieved. The patient was followed up without progression under regorafenib for 15 months, without requiring dose reduction. Unfortunately, the treatment had to be interrupted for an extended period due to challenges with recurrent tumor infection and the necessity for repeated surgeries. Following successful wound site control, we restarted full-dose regorafenib and achieved a metabolic partial response again.&lt;br /&gt; &lt;b&gt;Conclusion: &lt;/b&gt;To our knowledge, this case represents the longest achieved PFS with regorafenib in metastatic osteosarcoma. TKIs can provide a durable clinical response in metastatic osteosarcoma patients. Clinical and molecular biomarkers are required to determine which patients are most likely to benefit from these treatments.

Low-dose trimethoprim-sulfamethoxazole treatment for Pneumocystis pneumonia: a systematic review and meta-analysis.

The recommended standard treatment for Pneumocystis jirovecii pneumonia (PJP) is high-dose trimethoprim-sulfamethoxazole (TMP-SMX) (15-20mg/kg/d TMP). However, the standard regimen may cause a high incidence of dose-related adverse events (AEs). Therefore, we aimed to conduct a systematic review and meta-analysis to evaluate the efficacy and safety of low-dose TMP-SMX regimens (<15mg/kg/d of TMP) compared with the standard regimen in patients with PJP. We searched PubMed, Embase, and the Cochrane database for relevant articles from inception to 10 March 2024. Studies were included if they focused on PJP patients receiving a low-dose TMP-SMX regimen compared with a standard regimen. The primary outcome was mortality. We assessed study quality and performed subgroup analysis and sensitivity analysis to explore potential heterogeneity among the included studies. Seven studies were included. Overall, the low-dose regimen significantly reduced the risk of mortality (odds ratio [OR] = 0.49; 95% CI, 0.30-0.80; I 2 = 16%; P = 004). This finding was confirmed in further sensitivity and subgroup analyses. The low-dose regimen also significantly reduced total AEs (OR = 0.43; 95% CI, 0.29-0.62; I 2 = 0%; P < 0.0001), and improved the incidence of most specific AEs (ORs ranged from 0.13 to 0.89). In addition, the low-dose regimen had significantly more patients completing the initial regimen (P = 0.002), fewer patients requiring dose reductions (P = 0.04), and almost significantly fewer patients requiring a switch to a second-line regimen (P = 0.06). The limited available evidence suggests that a low-dose TMP-SMX regimen significantly reduced mortality and total AEs in PJP patients. Thus, it is one of the potentially promising therapies to PJP and more high-quality and multi-center randomized trials should be conducted in the future.

QOL-29. PREVALENCE, MANAGEMENT, AND OUTCOMES OF PROCARBAZINE-ASSOCIATED HYPERSENSITIVITY REACTIONS IN PATIENTS RECEIVING PCV FOR LOW-GRADE GLIOMA

Abstract Procarbazine is an alkylating agent commonly used to treat low-grade gliomas as part of the PCV regimen. The use of procarbazine is frequently limited by the development of hypersensitivity reactions (HSRs), which often require dose reduction or cessation of procarbazine therapy prior to the completion of a planned treatment course. The prevalence, clinical characteristics, and potential predictors of these reactions are not well defined. We conducted a retrospective cohort study of patients with low-grade glioma who received PCV between January 2016 and January 2024 at a tertiary academic hospital. Data on patient demographics, tumor type, clinical characteristics, treatment course, and hypersensitivity reactions were collected and analyzed. 61 total patients were included. The overall prevalence of HSRs was 60.7% (95% CI: 48.4% - 72.9%). The median cycle during which HSRs occurred was cycle 3 (IQR: 2-4, Range: 1-5). All HSRs involved the development of rash, with 86.5% being pruritic and 21.6% involving the face. Treatments for HSRs included antihistamines (62.2%), topical corticosteroids (35.1%), and systemic corticosteroids (27.0%). Three patients with HSRs presented to the emergency department with concern for anaphylaxis, and one required treatment with epinephrine. Out of six patients rechallenged with procarbazine after experiencing HSRs, one patient redeveloped a diffuse, pruritic rash that resolved with systemic corticosteroids. A multiple logistic regression analysis was performed to assess the association between HSRs and gender, age at PCV C1D1, elevated liver enzymes, and concomitant anticonvulsant use, but no significant correlation was observed. In summary, our study provides a contemporary and comprehensive analysis of the prevalence and severity of HSRs to procarbazine in patients with low-grade glioma. The high rate of HSRs in this population, including a relatively high rate of suspected anaphylaxis, should be considered carefully by clinicians in choosing chemotherapy for low-grade glioma and warrants routine counseling and close monitoring.

CSIG-29. BRAF INHIBITOR THERAPY IN BRAF-MUTATED PRIMARY BRAIN TUMORS: A SINGLE-CENTER EXPERIENCE

Abstract BACKGROUND BRAF pathway alterations are frequent in glial/neuroepithelial tumors. BRAF-targeted therapy with BRAF inhibitors (BRAFi) and/or MEK inhibitors (MEKi) has proven efficacy in clinical trials, though mainly enrolling pediatric patients. We sought to investigate real-world data for adult patients with BRAF-pathway mutant glial/neuroepithelial neoplasms treated with BRAFi/MEKi. METHODS Adults with BRAF-pathway mutated glial/neuroepithelial neoplasms treated with BRAFi/MEKi were retrospectively reviewed. RESULTS Five patients (n=4 female, median age at diagnosis 36) were identified (tumor types: glioblastoma n=1, high-grade astrocytoma with epithelioid features n=1, low-grade neuroepithelial tumor n=1, pilocytic astrocytoma n=1, pleomorphic xanthoastrocytoma n=1). Four had BRAF V600E and one had NF1 p.S2687Cfs*5 mutant tumors. Prior to targeted therapy initiation, patients underwent a median 2.4 treatments including surgery (n=4), radiation therapy (n=4), chemotherapy (temozolomide n=4; carboplatin/vincristine n=1). BRAF-targeted therapies included dabrafenib/trametinib (n=4), binimetinib/encorafenib (n=2), binimetinib (n=2). One NF1-mutant glioblastoma received binimetinib followed by binimetinib/bevacizumab. Median BRAFi/MEKi treatment was 15.2 months (range: 6-36 months). Toxicities included leukopenia (n=3), peripheral edema (n=1), reduced ejection fraction (n=1), skin rash (n=5), transaminitis (n=1) with all patients requiring dose reductions and 3 cases requiring discontinuation. Among patients where BRAFi/MEKi was discontinued due to toxicity, 2 received other treatments at progression, then switched to a different BRAFi/MEKi combination, which they tolerated (duration 6-10months). Best radiographic response was partial response, noted in 3 patients treated with dabrafenib/trametinib. Four patients remain alive and continue BRAFi/MEKi. CONCLUSIONS In this cohort of heavily-pretreated patients with glial/neuroepithelial neoplasms, BRAF-targeted therapy was associated with durable responses. Interestingly, two patients who were unable to tolerate one combination of BRAFi/MEKi were able to tolerate a different combination with sustained response. Our findings support ongoing use of BRAF targeted therapy for CNS tumors. Optimal timing and duration of treatment requires further prospective evaluation in adult patients.

Genomic variations associated with risk and protection against vincristine-induced peripheral neuropathy in pediatric cancer patients

Vincristine-induced peripheral neuropathy is a common and highly debilitating toxicity from vincristine treatment that affects quality of life and often requires dose reduction, potentially affecting survival. Although previous studies demonstrated genetic factors are associated with vincristine neuropathy risk, the clinical relevance of most identified variants is limited by small sample sizes and unclear clinical phenotypes. A genome-wide association study was conducted in 1100 cases and controls matched by vincristine dose and genetic ancestry, uncovering a statistically significant (p < 5.0 × 10−8) variant in MCM3AP gene that substantially increases the risk of neuropathy and 12 variants protective against neuropathy within/near SPDYA, METTL8, PDE4D, FBN2, ZFAND3, NFIB, PAPPA, LRRTM3, NRG3, VTI1A, ARHGAP5, and ACTN1. A follow-up pathway analysis reveals the involvement of four key pathways, including nerve structure and development, myelination, neuronal transmission, and cytoskeleton/microfibril function pathways. These findings present potential actionable genomic markers of vincristine neuropathy and offer opportunities for tailored interventions to improve vincristine safety in children with cancer. This study is registered with ClinicalTrials.gov under the title National Active Surveillance Network and Pharmacogenomics of Adverse Drug Reactions in Children (ID NCT00414115, registered on December 21, 2006).

Angiotensin receptor-neprilysin inhibitor (Sacubitril/Valsartan) in cancer therapy-related cardiac dysfunction: real-world experience from a nurse-led cardio-oncology clinic

Abstract Introduction Cancer therapy-related cardiac dysfunction (CTRCD) is a common toxicity amongst patients receiving anti-cancer treatment1. Angiotensin receptor-neprilysin inhibitor (ARNI) Sacubitril/Valsartan is recommended to reduce Heart Failure (HF) admissions and cardiovascular mortality2. However, patients with active cancer were excluded from the key trials of ARNI. This study aims to provide a real-world experience of ARNI prescription and management from the perspective of a nurse-led Cardio-Oncology clinic. Methods This is a single centre, retrospective, observational cohort study performed at a Cardio-Oncology specialist centre between the period of 2021 to 2024. Adult cancer patients receiving anti-cancer therapy were included if they had symptomatic HF or asymptomatic CTRCD, were initiated on ARNI and followed up in the nurse-led Cardio-Oncology clinic. Results Twenty-nine patients were started on ARNI (see Figure 1). The mean age of the patients was 66+11 years and 17 (59%) were male. Cardiovascular risk factors were common: hypertension (45%), hyperlipidaemia (35%), diabetes mellitus (21%), and smoking (17%). Haematological and breast malignancies were most common (31% and 21% respectively), followed by gynaecological malignancies (14%). Twenty-one (72%) were treated with cytotoxic chemotherapy including 10 (35%) received anthracyclines. Five (17%) patients received human epidermal growth factor receptor 2 (HER2) targeted therapies, 3 (10%) were on tyrosine kinase inhibitors, and 2 (7%) received immunotherapy. Twenty-five (86%) patients presented with symptomatic HF while 4 (14%) had asymptomatic CTRCD. The median N-terminal-pro B-type natriuretic peptide (NTproBNP) level was elevated at 1325(806-4330)ng/L. Thirteen (45%) patients tolerated the maximum dose of 200mg twice daily, while 16 (56%) could only tolerate middle and lowest dosages. ARNI dose up titration to the maximum tolerated dose took 26 (15-79) days. Twenty-eight (97%) patients were on beta blockers, 26 (90%) received SGLT2 inhibitors, 25 (86%) on mineralocorticoid receptor antagonists, and 10 (35%) patients required diuretics. The most common side effect was symptomatic hypotension in 11 (38%) patients. Two (7%) had hyperkalemia, 1 (3%) acute kidney injury following initiation, and 1 (3%) had dizziness without significant hypotension. Nine (31%) required dose reduction allowing ARNI to be continued, while 3 (10%) patients had to permanently discontinue ARNI. There were no cardiovascular deaths, cancer deaths or HF admissions. Conclusion The Cardio-Oncology nurse-led clinic permits rapid up-titration of ARNI to target dosages in patients with CTRCD, resulting in significant improvements in cardiac function. The nurse lead clinic education, support and side effect management allowed uninterrupted continuation of cancer treatment. Whether this approach translates into be better cardiac and cancer outcomes requires further study.

Burosumab in adults with X-linked hypophosphatemia: real-world experience from a retrospective study in Sydney

Abstract X-linked hypophosphatemia (XLH) is a chronic disabling hereditary musculoskeletal disorder associated with inactivating PHEX mutations and elevated circulating FGF-23 concentrations. In a placebo-controlled trial of adults with XLH, burosumab (anti-FGF-23 antibody) demonstrated durable improvements in phosphate concentrations, and self-reported stiffness and physical limitation. However, real-world data regarding burosumab efficacy and tolerability in adults with XLH is lacking. A retrospective audit was performed of patients (age ≥ 18-years) who commenced four-weekly subcutaneous burosumab for XLH at Royal North Shore and Westmead Hospitals, Sydney, between January 2021 and June 2024. Patients were managed per standard clinical care and burosumab dose adjusted as necessary according to manufacturer instructions. Electronic medical records were reviewed to collate data regarding patient demographics, XLH-related complications and prior treatment, burosumab dosage and side effects, and pre- and post-burosumab biochemistry and Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores. Of thirteen adults with XLH, all had hypophosphatemia before commencing burosumab (mean 0.64 ± 0.08 mmol/L). Mean WOMAC scores demonstrated baseline impairments in stiffness, pain and physical limitation. Burosumab was administered for median 15 months during follow-up (median dose 70 mg). Hypophosphatemia resolved in all patients within three months of burosumab (mean 1.03 ± 0.38 mmol/L). Two patients developed hyperphosphatemia two weeks after commencing burosumab requiring dose reduction. One patient ceased burosumab in the setting of hypercalcaemia and constipation secondary to pre-existing tertiary hyperparathyroidism. Adverse events were mild, including transient musculoskeletal discomfort (n = 4), restless legs (n = 2), injection site reaction (n = 2) and headache (n = 1). Repeat WOMAC within 12 months of commencing burosumab (n = 9) demonstrated clinically meaningful improvements in stiffness (-33.3 ± 12.5, P&amp;lt;.001) and physical function (-14.3 ± 16.2, P=.029). This study reports real-world outcomes of adults with XLH treated with burosumab. Clinical experience from two centres in Sydney support trial findings that burosumab is well-tolerated and associated with improved serum phosphate concentrations and self-reported stiffness and physical function.

Doxorubicin, Paclitaxel, and Cisplatin (ATP) for Relapsed/Refractory Germ Cell Tumors

Patients with relapsed/refractory germ cell tumors (GCT) have limited treatment options and poor survival outcomes. We describe our institutional experience with doxorubicin, paclitaxel, and cisplatin (ATP) as an outpatient regimen for 35 patients with relapsed/refractory GCT between 2017 and 2022. Twenty-four patients received nonpalliative intent ATP, with a median of 2 lines of prior therapy, 23 (96%) having received at least 1 cisplatin-based regimen and 1 (4%) with a prior stem cell transplant. The objective response rate for the nonpalliative intent cohort was 37.5% (1 complete response and 8 partial responses). Post-ATP, 12 patients underwent stem cell transplant, 7 patients had surgical resections, and 4 patients received radiation. The median PFS was 4.3 months (95% CI: 3.8, 32.7) and median OS of 13.1 months (95% CI: 10.7, NA) for the nonpalliative intent cohort. Eleven patients received palliative intent ATP, with a median of 4 lines of prior therapy, all having received at least 1 cisplatin-based regimen, and 7 (64%) having received prior stem cell transplants. Within the palliative intent cohort, the objective response rate was 9% (1 partial response). Patients who received palliative intent ATP had a median PFS of 0.92 months (95% CI 0.46, NA) and median OS of 5.2 months (95% CI 3.3, NA). Treatment toxicities occurred in 5 (14%) patients who required dose reductions and 5 (14%) patients who were admitted for treatment related toxicities, most commonly for myelosuppression. Our results support the use of ATP in a primarily anthracycline naïve patient population and show the safety of continued cisplatin use in patients who have previously received cisplatin-based regimens. Therefore, ATP is a feasible and well tolerated chemotherapy regimen in the salvage setting and can serve as a bridge to other treatments for patients with relapsed/refractory GCT.

Phase II Trial of Gemcitabine and Nab-Paclitaxel for Recurrent Osteosarcoma with Serial Monitoring Using Liquid Biopsy: A Report from the National Pediatric Cancer Foundation.

The combination of gemcitabine and docetaxel is often used to treat patients with recurrent osteosarcoma. Nab-paclitaxel has preclinical activity against osteosarcoma and is potentially less myelosuppressive than docetaxel. We conducted a prospective multi-institutional phase II trial combining gemcitabine and nab-paclitaxel for patients aged 12 to 30 years with recurrent osteosarcoma and measurable disease. A Simon's two-stage design was used to test a 4-month progression-free survival (PFS-4) of 10% vs. 35%. Patients received nab-paclitaxel 125 mg/m2 and gemcitabine 1,000 mg/m2 weekly × 3 in 4-week cycles. Immunohistochemical analysis of archival tissue and serial assessment of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) using ultralow passage whole-genome sequencing were performed to identify potential biomarkers of response. Eighteen patients received 56 total cycles (median 2, range 1-12). Two patients (11%) experienced confirmed partial response and six (33%) received >2 cycles. The PFS-4 was 28% (95% confidence interval, 13%-59%). Six patients required dose reductions and three patients were removed due to toxicities. All 18 patients had detectable CTCs and 10 had ctDNA identified. All eight patients with MYC amplification at study entry experienced disease progression. Gemcitabine and nab-paclitaxel demonstrated similar clinical activity and toxicity compared to previous retrospective reports utilizing gemcitabine and docetaxel in patients with recurrent osteosarcoma. Serial analysis of CTC and ctDNA was feasible in this prospective multi-institution study and provides preliminary data on the use of these assays in patients with relapsed disease.

Evaluation of bleeding risk in patients who received pirtobrutinib in the presence or absence of antithrombotic therapy.

Clinical bleeding events are reported here from 773 patients with B-cell malignancies receiving pirtobrutinib monotherapy from the phase 1/2 BRUIN study (ClinicalTrials.gov identifier: NCT03740529), either in the presence or absence of antithrombotic therapy (antithrombotic exposed [AT-E], n=216; antithrombotic nonexposed [AT-NE], n=557). Among the AT-E cohort, 51.9% received platelet aggregation inhibitors, 36.6% received direct factor Xa inhibitors, 18.5% received heparins, 5.6% received salicylic acid for indications other than platelet aggregation inhibition, and 2.3% received thrombolytics. Warfarin was not permitted. Any-grade bleeding/bruising events occurred in 97 patients (44.9%; 95% confidence interval [CI], 38.3-51.5) in the AT-E cohort and 181 patients (32.5%; 95% CI, 28.6-36.4) in the AT-NE cohort. Most bleeding/bruising events in both cohorts began within the first 6 months of treatment (AT-E: 65.4%; AT-NE: 72.5%). Contusion was the most common bleeding/bruising event in both cohorts (AT-E: 22.7%; AT-NE: 18.1%). Grade ≥3 bleeding/bruising events were reported in six patients (2.8%) in the AT-E cohort and 11 patients (2.0%) in the AT-NE cohort. Bleeding/bruising events requiring or prolonging hospitalization were reported in 2.3% and 1.6% of patients in the AT-E and AT-NE cohorts, respectively. No bleeding/bruising events led to pirtobrutinib dose reduction or permanent discontinuation in the AT-E cohort, and one patient (0.2%) in the AT-NE cohort experienced an event requiring dose reduction. These data support the safety of pirtobrutinib in patients requiring antithrombotic therapies.

Pattern of care and treatment outcomes of metastatic non-clear cell kidney cancer: a single centre experience from India.

Non-clear-cell renal cell carcinoma (nccRCC) refers to a rare diverse heterogeneous group of tumours; usually treated with immune check point inhibitors and or tyrosine kinase inhibitors (TKIs). Prospective large-scale data from Asian countries is limited. This is a retrospective study of patients with metastatic nccRCC treated at Tata Medical Centre, Kolkata, India, from 2012 to 2022. Demographic profiles, histologic subtypes, treatment details, response to therapy (by response evaluation criteria in solid tumours (RECIST v1.1)) and survival status were captured from electronic medical records (EMRs) of hospitals up till May 2023. Kaplan Meier methods were estimated to assess progression-free survival (PFS) and overall survival (OS). A total of 89 consecutive patients were screened for this study, 24 were excluded due to inadequate data in EMR. 65 patients were included in the final analysis, with a median age at diagnosis of 59 years (range 20-84) of which 81% were male. Histologic subtypes comprised of 43% papillary, 31% clear cell with mixed histology, 3% sarcomatoid and 23% others including chromophobe, mucinous-tubular, spindle cell, oncocytic, medullary, poorly differentiated and rhabdoid). The most common site of metastasis was the lung 62% (n = 40) followed by non-regional nodes 32%, bone 26% and liver 14%. 15% patients presented with haematuria and 62% underwent nephrectomy prior to systemic therapy. The majority received pazopanib 46% (n = 30), chemotherapy 20% (n = 13) including bevacizumab plus erlotinib, sunitinib 15% (n = 10) or cabozantinib 14% (n = 9). Only 3(5%) patients received nivolumab plus cabozantinib combination. Response to treatment showed complete response in 1.5%, partial response in 20%, stable disease in 51% and progressive disease in 23% as per RECIST v1.1. 17 patients required dose reduction and interruption due to adverse effects and 33% (n = 22) received second-line therapy with nivolumab 18% (n = 4), axitinib and everolimus among others. After a median follow up of 44 months, the median PFS was 13 months (95%CI 7.2-18.9) and the median OS was 17 months (95%CI 12.1-22.1) for the entire cohort. The overall response and survival for metastatic nccRCC was relatively better in comparison with published data, despite the limited number of patients treated with ICIs due to cost and access barriers.

Tolerability and Safety of Miltefosine for the Treatment of Cutaneous Leishmaniasis.

Miltefosine, an orally administered drug, is an important component of the therapeutic arsenal against visceral and mucosal forms of leishmaniasis. However, data regarding the safety and tolerability of miltefosine treatment for cutaneous leishmaniasis (CL) are relatively limited. The aim of this study was to evaluate the tolerability, safety, and adverse events (AEs) of miltefosine treatment in patients with CL. In this cohort study, we reviewed the medical records of all miltefosine-treated patients between 1 January 2016 and 31 December 2022, at Israel Defense Forces military dermatology clinics and the dermatology and Tropical Medicine Clinics at Chaim Sheba Medical Center, Ramat-Gan, Israel. A total of 68 patients (54 males, 79%) with a median age of 30.3 ± 15.6 years (range: 18-88) were included in this study. Leishmania species were identified as L. major (n = 37, 54.4%), L. tropica (n = 12, 17.6%), L. braziliensis (n = 18, 26.5%), and L. infantum (n = 1, 1.5%) using polymerase chain reaction (PCR). Miltefosine tablets were administered orally at a dose of 50 mg, three times daily, for 28 days. Overall, 44 patients (65%) completed the 28-day treatment, and the remaining patients required dose reduction or early discontinuation of treatment. AEs (of any degree) were common, reported in 91% of patients. Both previously reported and previously unreported AEs were documented. Gastrointestinal symptoms (66.1%) and malaise (23.5%) typically occurred during the first two weeks of treatment and tended to subside. Other AEs, including acute renal failure (20.6%), sudden and severe pleuritic chest pain (7.6%), acne exacerbation (11.8%), suppuration of CL lesions (17.8%), and AEs related to the male genitourinary system (39.6% of males), typically occurred towards the end of treatment. The latter included testicular pain, epididymitis, diminution or complete absence of ejaculate, inability to orgasm, and impotence. Severe AEs necessitated treatment discontinuation (29.4%) or hospitalization (10.3%). URTI-like symptoms, arthritis, cutaneous eruption, pruritus, and laboratory abnormalities were also observed. Overall, the cure rate (for all patients combined) evaluated 3 months after the completion of treatment was 60%. The tolerability of miltefosine treatment for CL is low. Close clinical and laboratory monitoring is required during treatment, as severe AEs are not uncommon. As new insights regarding its toxicities emerge, further studies are required to define the role of miltefosine in the treatment of CL.

A phase II study of FOLFOX combined with nab-paclitaxel in the treatment of metastatic or advanced unresectable gastric, gastroesophageal junction adenocarcinoma: a Big Ten Cancer Research Consortium trial.

Doublet platinum or taxane-based therapies are the current standard backbone of treatment for advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma. Previously used anthracycline-based triplet regimens are no longer used routinely due to toxicity and lack of superior efficacy. We hypothesized that the addition of nab-paclitaxel to FOLFOX (FOLFOX-A) would induce higher efficacy and better tolerability. Eligible patients with chemotherapy-naïve advanced unresectable HER2-negative gastric or GEJ adenocarcinoma were enrolled in this phase II single-arm trial of FOLFOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU 2400 mg/m2 over 46-48 hours) + nab-paclitaxel (150 mg/m2) every 14 days of a 28-day cycle. Evaluable disease according to RECIST v1.1 for solid tumors was required. The primary endpoint was the objective response rate. Simon's optimal 2-stage design was used to test 5% versus 20% response rate with 90% power and 10% one-sided type I error rate. The study enrolled 39 patients. Median age was 63 (range 20-80) years, 30 (77%) were male, 34 (94%) were White, and 21 (57%) had gastric tumors. The median number of cycles completed was 4.5 (range: 0-36), and 25 patients required dose reductions or discontinuation of at least one component due to toxicity. Of the 38 patients evaluable for response, 15 (42.9%) had complete/partial response (CR/PR) as the best response, and 13 (37.1%) had stable disease. progression-free survival (PFS) and OS data were available for 38 patients, with a median follow-up duration of 27 months (range: 18.2-51.9 months for censored patients). Median PFS was 6.6 months (95% CI: 5.6-12.9), with 31.0% (95% CI: 18.4%-52.4%) 12-month PFS rate. The median OS was 10.5 months (95% CI: 8.8-20.7), 12-month OS rate was 44.7% (95% CI: 31.4%-63.7%). Treatment-related grade 3-4 toxicities included peripheral sensory neuropathy and anemia (18.4% each), neutropenia (15.8%), and diarrhea and lymphopenia (7.9% each). FOLFOX-A has a significant response rate, expected toxicities, and should be considered for future investigation in combination with immunotherapy given the recent approvals.

Analysis of budget planning specifics in providing targeted therapy to patients with breast cancer

The article is devoted to the analysis of the specifics of budget planning when using CDK4/6 inhibitors (ribociclib, palbociclib, and abemaciclib) for the treatment of HER2-negative metastatic breast cancer in postmenopausal patients. Based on clinical trial data and cost analysis, ribociclib was found to be advantageous in terms of efficacy and cost-effectiveness. According to randomized clinical trial data, not all the CDK4/6 inhibitors demonstrated a statistically significant increase in overall survival in combination with aromatase inhibitors. Ribociclib in combination with aromatase inhibitors has a statistically significant difference in overall survival compared to aromatase inhibitor monotherapy and reduces the risk of death by 24%. More than 30% of patients receiving CDK 4/6 inhibitors therapy require dose reduction, which is accomplished in a variety of ways depending on the dosage forms. Dose reduction has an impact on the cost per CDK4/6 inhibitors treatment cycle: before dose reduction, the cost per cycle of therapy with palbociclib and abemaciclib is lower compared to ribociclib. At the first dose reduction, the cost per cycle of therapy for all CDK 4/6 inhibitors is comparable. At the second dose reduction, the cost of a cycle of therapy on ribociclib is half that of palbociclib and abemaciclib. When planning the budget for providing CDK4/6 inhibitors to patients with metastatic cancer, it is necessary to consider a number of key characteristics of drugs that affect the costs and organization of the treatment process. An important aspect of budget planning is forecasting the need for drugs, considering the need for dose reduction. For ribociclib, the calculation of annual need is simplified by the possibility of reducing the number of tablets taken, which allows the use of a single dosage form, whereas for palbociclib and abemaciclib it is necessary to purchase several dosage forms with different dosages, which complicates planning, reduces the predictability of consumption, and requires additional administrative measures.

Carboplatin and Paclitaxel Chemoradiation for Localized Anal Cancer in Patients Not Eligible for Mitomycin and 5-Fluorouracil.

Although squamous cell carcinoma of the anus (SCCA) is a relatively uncommon malignancy in the United States, it continues to increase in incidence. Treatment for locoregional disease includes mitomycin and 5-fluorouracil with radiation. This combination is associated with significant toxicity, limiting its use in patients who are older or have certain comorbidities. Carboplatin and paclitaxel (C/P) is an accepted treatment regimen for metastatic SCCA. We aim to evaluate the efficacy and toxicity of weekly C/P given with radiation for patients unable to receive standard chemoradiation for SCCA. From our cancer registry, adult patients who received weekly intravenous C/P concurrent with standard-dose radiation for localized SCCA were included in this study. Clinical response was determined based on the evidence of disease on imaging and/or anoscopy. Toxicities were graded according to the CTCAE v5. Ten patients were included; eight were female, and the median age was 75.5 years (54-87). Six had T2 disease, and four had T3 tumors. Four had node-positive disease. The majority (70%) of patients were dosed at standard C (AUC 2) and P (50 mg/m2), with a limited subset requiring dose reduction for baseline performance status. Patients completed a mean of 78.3% (40-100%) of the intended treatments. A total of 89% of the patients achieved a complete clinical response. With a median follow-up of 25.8 months (3.4-50.4 months), 67% of the patients are alive and without recurrence. Two patients have had local recurrence, and one patient had metastatic progression. The most common toxicities of any grade included leukopenia (100%), anemia (100%), radiation dermatitis (100%), diarrhea (100%), and fatigue (100%). Grade 3 or higher toxicities included neutropenic fever (20%), neutropenia (30%), and anemia (30%). This study demonstrates promising tolerability and efficacy for weekly C/P chemoradiation for patients with anal cancer unable to receive mitomycin and 5-fluorouracil. This regimen merits further investigation in prospective clinical trials.

523. FIVE YEARS OF FLOT THERAPY. RANDOMIZED CONTROLLED TRIAL EVIDENCE IN PRACTICE

Abstract Introduction The combination of 5-flurouracil, oxaliplatin, leucovorin and docetaxel (FLOT) is an effective chemotherapy regime in locally advanced, resectable gastro-oesophageal adenocarcinoma. Since the FLOT4-AIO randomised controlled trial demonstrated superiority over ECF/ECX it has been standard of care at many centres and European Society of Medical Oncology’s recommended perioperative regimen. After over five years of offering this treatment to patients we assessed how this evidence had translated into practice; identifying factors that predict dose reduction or incomplete therapy and overall survival. Method Patients who had the combination of neoadjuvant FLOT chemotherapy and oesophagectomy for adenocarcinoma of the oesophagus or gastro-oesophageal junction between February 2018 and September 2023 were identified from a prospectively collected database. Data on completion of chemotherapy, perioperative outcomes and long-term survival were collected. Pathological regression was assessed using Mandard tumour regression grade (TRG). The peri-operative, pathological, and long-term outcomes of patients who completed four cycles of neoadjuvant FLOT was compared with those who had reduced dose or early cessation. Statistical analysis used IBM SPSS, with Mann-Whitney U and Chi squared for variable analysis and univariate cox regression for survival. Results Eighty patients were included with a median age of 66 (47-79), 84% were male. Full dose completion was achieved by 57 (71%) patients, 20 (25%) had dose reduction and 7(8%) did not complete four cycles. Age, anaerobic threshold and VO2 max were not significantly different between those completing or not completing neoadjuvant chemotherapy (p=0.460, p=0.624, p=0.104 respectively); or requiring dose reductions (p=0.317, p=0.587, p=0.82). Median TRG across all three groups was 3. Median follow up was 55.4 months and mean overall survival was 53.4 months. No difference in survival was observed between those who completed or did not complete neoadjuvant FLOT (p=0.45). Conclusion Completion of neoadjuvant chemotherapy was lower in this cohort of patients than FLOT4-AIO. Rates of pathological complete response were similar. This translated into similar mean overall survival. Median survival was unable to be calculated as survival exceeds 50% at the time of our study. The use of FLOT has translated well into the routine neoadjuvant clinical setting with acceptable short- and long-term outcomes.