Third-line Therapy Research Articles

Advances in the Treatment of Autoimmune Hepatitis.

Autoimmune hepatitis (AIH) is a chronic, progressive inflammatory liver disease caused by autoimmune reactions, with an unknown etiology. If left untreated, it can progress to cirrhosis, liver failure, or even death. While most patients respond well to first-line treatments, a significant number experience poor responses or intolerance, requiring the use of second- or third-line therapies. Ongoing research into the pathogenesis of AIH is leading to the development of novel therapeutic approaches. This review summarized recent advancements in the treatment of AIH both domestically and internationally.

Antibiotic Susceptibility-Guided Concomitant Therapy Regimen with Vonoprazan, High-Dose Amoxicillin, Clarithromycin, and Metronidazole for Helicobacter pylori Eradication as Fourth-Line Regimen: An Interventional Study.

Twenty patients who underwent three rounds of eradication therapies (first- or second-line 7-day triple therapy consisting of amoxicillin and clarithromycin, or metronidazole- and sitafloxacin-based third-line therapy) and had failed eradication based on a urea breath test or fecal antigen test were recruited. All patients underwent endoscopic examination and culture tests before starting eradication therapy. The intervention was concomitant therapy consisting of vonoprazan 20 mg bid, amoxicillin 500 mg qid, clarithromycin 400 mg bid, and metronidazole 250 mg bid for 14 days, which were modified based on the susceptibility test, and the resistant drugs were removed from the regimen. Patients with negative culture results were treated with quadruple therapy. The primary outcome was the eradication rate (UMIN000025765, jRCTs 031180208). The eradication rate of susceptibility-testing-based fourth-line eradication therapy was 63.2% (95%CI: 38.4-83.7%) in intent-to-treat analysis and 70.6% (95%CI: 44.0-89.7%) in per-protocol analysis. Thirteen patients received quadruple therapy, with eradication rates of 61.5% and 75.0%, respectively. No serious adverse events were reported. This vonoprazan-based concomitant therapy modified by the susceptibility test is a potential option as fourth-line eradication after first-line clarithromycin-based 7-day triple, second-line metronidazole-based 7-day triple, and third-line sitafloxacin-based 7-day triple therapy failure.

Real-world treatment patterns, survival outcomes, and health care resource utilization for locally advanced or metastatic urothelial carcinoma in Spain.

Real-world evidence on locally advanced or metastatic urothelial carcinoma (la/mUC) management in Spain is limited. This study describes patient characteristics, treatment patterns, survival, and health care resource utilization (HCRU) in this population. This retrospective observational study included all adults with a first diagnosis/record of la/mUC (index date) from January 2015 to June 2020 at nine university hospitals in Spain. Data were collected up to December 31, 2020 (end of study), death, or loss to follow-up. Patient characteristics, treatment patterns, median overall survival (OS) and progression-free survival (PFS) from index date (Kaplan-Meier estimates), and disease-specific HCRU were described. Among 829 patients, median age at diagnosis was 71years; 70.2% had ≥ 1 comorbidity, and 52.5% were eligible for cisplatin. Median follow-up was 12.7months. Most (84.7%) patients received first-line systemic treatment; of these, 46.9% (n = 329) received second-line and 16.6% (n = 116) received third-line therapy. Chemotherapy was the most common treatment in all lines of therapy, followed by programmed cell death protein 1/ligand 1 inhibitors. Median (95% confidence interval) OS and PFS were 18.8 (17.5-21.5) and 9.9 (8.9-10.5) months, respectively. Most patients required ≥ 1 outpatient visit (71.8%), inpatient admission (56.6%), or emergency department visit (56.5%). Therapeutic patterns were consistent with Spanish guideline recommendations. Chemotherapy had a role in first-line treatment of la/mUC in Spain during the study period. However, the disease burden remains high, and new first-line treatments recommended in the latest European guidelines should be made available to patients in Spain.

Real-world characteristics, treatment patterns, and outcomes of patients with 2 or more LOTs for CLL/SLL in the United States

AbstractThe development of targeted agents for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) has transformed the treatment paradigm for patients with CLL. Because of this evolving treatment landscape, there was a need for contemporaneous evidence related to US treatment patterns and outcomes among patients treated in the real world. Using COTA’s electronic health records–based database, we examined characteristics, treatment patterns, and outcomes of patients receiving ≥2 line of therapy (LOT). A total of 1283 adult patients with CLL/SLL were identified in the data set who initiated second LOT (2L) between 1 January 2014 and 30 June 2022. Of those patients, 542 patients (42.2%) later received third-line (3L) therapy, of whom 228 (42.1%) went on to receive fourth-line (4L) therapy. Overall, >18% of patients died after 2L initiation and before 3L initiation, and more than a quarter died before 4L initiation. The majority of the population was White (77.7%), male (60.6%), aged ≥65 years (68.8%), and treated in a community practice setting (87.8%). Regarding treatment patterns, from 2014 to 2023, use of chemoimmunotherapy in any ≥2L LOT decreased, whereas use of Bruton tyrosine kinase inhibitor and B-cell lymphoma 2 inhibitor therapy increased. Across end points, median time to event(s) were generally shorter with each subsequent LOT received, both in the overall population and among patients receiving a given therapy in different LOTs. With a median follow-up time from 2L initiation of 38.0 months, median real-world time to next treatment, progression-free survival, and overall survival from 2L was 31.9, 33.8, and 80.1 months, respectively. Despite great advancements in CLL/SLL treatments since 2014, unmet need persists for patients receiving late LOT.

Prevalence, rate, and predictors of virologic failure among adult HIV-Infected clients on second-line antiretroviral therapy (ART) in Tanzania (2018–2020): a retrospective cohort study

BackgroundAntiretroviral therapy (ART) has been proven to be highly effective in reducing the impact of human immunodeficiency virus (HIV) infection. However, as more people receive initial ART treatment, the risk of developing resistance and eventual treatment failure increases, leading to the need for second-line treatment regimens. Understanding the factors that contribute to virologic failure to second-line ART is crucial in preventing switching to the more expensive and toxic third-line regimens. This study provides information on the prevalence, rate, and predictors of virologic failure (VF) among clients on second-line ART in Tanzania.ResultsWe followed 4718 clients for 15100 person-years (PY) of observations. Of them, 1402 (29.72%) experienced virologic failure at a rate of 92.85 per 1000 PY of observations (95% CI 88.11, 97.84). Factors that were associated with VF included: having a viral load count of ≥ 1000 copies/mL during first-line ART, with a hazard ratio (HR) 4.65 (95% CI 3.57, 6.07), using lopinavir (LPV/r) as a protease inhibitor during second-line ART (HR 4.20 (95% CI 3.12, 7.10), having a CD4 count < 200 cells/mm3 during second-line ART (HR 1.89 (95% CI 1.46, 2.44), and being on ART for 13–35 months (HR 8.22 (95% CI 2.21, 30.61). Paradoxically, having a CD4 count < 200 cells/mm3 during first-line ART treatment was associated with a reduced risk of virologic failure (HR 0.77 (95% CI 0.60, 0.99).ConclusionsIn Tanzania, approximately 30% of adult clients on second-line ART experience VF at a rate of 92.71 per 1000 person-years. This high virologic failure rate underscores the urgent need for targeted interventions, such as enhancing adherence support, optimizing drug regimens, and regular viral load monitoring. These interventions will reduce the need for switching to the more costly and toxic third-line ART therapy and are also crucial for achieving the UNAIDS goal of 95% viral suppression among treated individuals by 2030.

Abstract C054: Current anticancer drugs differentially impact Black and White prostate cancer cell lines

Abstract Introduction/Background: In pre-clinical models of prostate cancer (PCa) such as the utilization of cell lines, it is important to address the limited diversity present. This acknowledgment is vital to facilitate equitable assessment of the efficacy and safety of drug development across various races and ethnicities. Of all commercially available PCa cell lines, 98% of them are of European origin. The genetic and biological disparities between PCa cell lines derived from men of European ancestry (MEA) and men of African ancestry (MAA) may underlie the observed enhanced responsiveness of tumours to existing anticancer agents in MEA compared to MAA. This difference is notable given that MAA are 2.5 times more likely to succumb to PCa. This study compared the cytotoxic effects of five anticancer drugs (Docetaxel, Cabazitaxel, Abiraterone, Olaparib, Enzalutamide) and the natural product betaine on MAA (ACRJ-PC28, MDA-PCA-2b) and MEA (DU-145, PC-3) PCa cell lines. Method: After a 72-hour treatment with the anti-cancer drugs and the natural product, the inhibitory effects of these anti-cancer agents on the four cell lines were investigated using three different assays. CellTiter Aqueous, Neutral Red, and Crystal Violet assays were utilized due to distinct growth patterns observed in the various cell lines. By comparing the optical density (OD) readings and examining the cellular morphology through microscopic visualization, we aimed to determine which assay(s) yielded the most reliable results in determining accurate IC50 values. Results: Drug selectivity was observed for Abiraterone and Olaparib that were most effective in ACRJ-PC28 (IC50 = 1.10 μM) and PC-3 (IC50 = 0.28 μM) cells compared to the other PCa cell lines. Enzalutamide differentially impacted MAA, (IC50= 206 μM for ACRJ-PC28 and 104 μM for MDA-PCA-2b) and MEA (IC50 = 37 μM for PC-3 and 48 μM for DU-145) PCa cell lines. However, no distinct impact was observed for Docetaxel (IC50s = 0.05 nM for ACRJ-PC28; 0.08 nM for MDA-PCA-2b, 0.07 nM for PC-3 and 0.08 nM for DU-145) and Cabazitaxel ((IC50s = 0.56 nM for ACRJ-PC28; 0.45 nM for MDA-PCA-2b, 0.43 nM for PC-3 and 0.38 nM for DU-145) as both drugs impacted the cell lines very potently in the nM range. Conclusion: Due to the heterogenous nature of cancers, especially in PCa, a single drug or drug class may not be the best course of treatment. Instead, a combination of drugs with different mechanisms may be more suitable for addressing the diversity in cancer types. This points to the evolving understanding of personalized cancer treatment, where a strategic integration of first, second, and third-line therapies can effectively address the genetic and epigenetic factors that are unique to individuals in cancer management. Citation Format: Simone Badal, Bor-Jang Hwang, Ashlianne Nelson, Kristoff Frank, Rory Thompson, Belinda Morison, Valerie Marah, Camille Ragin. Current anticancer drugs differentially impact Black and White prostate cancer cell lines [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C054.

Stage IV gastric cancer with microsatellite instability–high achieving long-term survival by gastrectomy after nivolumab as third-line therapy: a case report and literature review

BackgroundThe prognosis for stage IV gastric cancer remains poor; however, the advent of immune checkpoint inhibitors (ICIs) such as nivolumab has increased the number of patients with long-term survival. Patients with microsatellite instability (MSI)–high gastric cancer have been recognized as a highly effective population for ICIs. Herein, we report a patient with MSI–high advanced gastric cancer treated with gastrectomy after the administration of nivolumab as third-line therapy.Case presentationA 73-year-old woman presented with a type 3 tumor in the lower part of the gastric body, which was diagnosed as gastric cancer through biopsy. Staging laparoscopy revealed that the tumor had invaded the pancreas and the posterior lobe of the transverse mesocolon, and disseminated nodules were found near the ligament of Treitz. After 4 courses of S-1 plus cisplatin therapy, laparoscopic gastrojejunal bypass was performed because of difficulty in oral intake. She received S-1 plus oxaliplatin therapy after a gastrojejunal bypass; however, her regional lymph nodes were enlarged. After six courses of paclitaxel plus ramucirumab as second-line chemotherapy, computed tomography (CT) showed exacerbation of peritoneal dissemination; thus, nivolumab was selected as the third-line therapy. The tumor was characterized by MSI–high. At 24 courses, CT and gastroscopy revealed a complete clinical response of the tumor; however, re-growth of the primary tumor was observed at 36 courses. The patient underwent distal gastrectomy with D1 + lymph node dissection, and received S-1 monotherapy as adjuvant therapy for 1 year. No recurrence was noted at 39 months after the surgery.ConclusionsWe report a patient with highly advanced gastric cancer with peritoneal dissemination, which worsened during second-line therapy and was successfully treated with gastrectomy after nivolumab administration as a third-line therapy. MSI–high gastric cancer is a target that should be actively considered for the administration of ICIs, such as nivolumab, and multidisciplinary treatment combined with chemotherapy and gastrectomy, including conversion surgery, can lead to patients’ long-term survival.

Efficacy and safety of infliximab in patients with autoimmune hepatitis.

A limited number of drugs are used as standard or alternative therapies in autoimmune hepatitis (AIH). No specific recommendations are available for patients failing to respond to these therapies. We analyzed the efficacy and safety of infliximab in patients with AIH. We performed a retrospective study of 42 patients with AIH who received infliximab at 21 liver centers in 12 countries. Patients were categorized according to the reason for infliximab therapy. Patients in group 1 (n=20) had failed standard, second-line (mycophenolate mofetil and 6-mercaptopurine) or third-line (tacrolimus or cyclosporine) therapy. In group 2 (n=22), infliximab was given for treatment of concomitant extrahepatic autoimmune diseases. Patients received a median of 17 (range: 3-104) infliximab infusions. Complete biochemical response (CR) was achieved or maintained in 33 (78%) patients during infliximab therapy. In group 1, infliximab induced CR in 11 of 20 (55%) patients. In group 2, 16 patients with CR prior to infliximab maintained remission, and the remaining 6 patients with active AIH (5 on standard and 1 on both second-line and third-line therapy) showed CR following infliximab therapy. Infliximab led to CR in 75% (6/8) of nonresponders to second-line and in 46% (6/13) of failing third-line therapy. Overall, 65% (17/26) of the patients with active AIH achieved CR on infliximab. Infliximab was discontinued in 3 patients of group 1. One patient had a severe allergic reaction and 2 developed anti-infliximab autoantibodies. Our study suggests that infliximab may be an effective and safe rescue therapy in AIH.

Efficacy and safety of RS plus bevacizumab versus RS plus fruquintinib as the third-line therapy in patients with refractory metastatic colorectal cancer: A real-world propensity score matching study.

This study aims to compare the effectiveness and safety of the combination of raltitrexed, S-1 (RS), and fruquintinib with the combination of RS and bevacizumab in patients with refractory metastatic colorectal cancer (mCRC). This retrospective cohort included mCRC patients who received the RS plus fruquintinib or regorafenib as the third-line therapy from May 2019 to April 2023. A propensity score matching (PSM) analysis was used to balance the baseline characteristics of all patients. Overall survival (OS), progression-free survival (PFS), tumor response, and safety of the two regimens were evaluated. Of the 153 patients enrolled, 123 patients received the RS plus bevacizumab and 30 patients received the RS plus fruquintinib. After PSM, 30 pairs were analyzed. Patients treated with RS plus fruquintinib had a longer PFS than those treated with RS plus bevacizumab before PSM (5.0 months vs. 4.3 months, p=0.008) and after PSM (5.0 months vs. 4.4 months, p=0.012). A longer OS was also observed in RS plus fruquintinib group before PSM and after PSM, but there was no statistic difference between two groups after PSM. Both objective response rate and disease control rate were higher in the RS plus fruquintinib cohort than those in the RS plus bevacizumab cohort before PSM, and the difference in values between the two groups reduced after PSM. The adverse effects (AEs) of both groups were well tolerated. In patients with refractory mCRC, RS plus fruquintinib demonstrated a superior OS, PFS than RS plus bevacizumab and had manageable AEs.

Glucagon-Like Peptide-1 Receptor Agonist (GLP-1R): An Important Therapy to Treat Type 2 Diabetes

The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone, and it has the ability to decrease blood sugar levels in a glucose-dependent nature to increase the secretion of insulin, and consequently, it reduces hyperglycaemia in T2D. GLP-1 has a half-life of about 1.5 minutes and is rapidly proteolytic degraded by dipeptidyl peptidase-4 (DPP-4). But GLP-1 receptor agonist (GLP-1R) works like GLP-1 but last much longer. GLP-1R control glycemia via glucose-dependent mechanisms of action and promote weight loss in obese and diabetic individuals. It also suppresses inappropriately elevated glucagon levels, both in fasting and postprandial states, slows gastric emptying, and decreases appetite. It reduces glycosylated hemoglobin (HbA1c) and fasting plasma glucose levels. It is associated with weight loss, and reductions in blood pressure with a low risk of hypoglycaemia. It is generally recommended as second- and third-line therapy for T2D. In this study an attempt has been taken to discuss aspects of GLP-1R in briefly.

Use Of Ketamine In Refractory Status Epilepticus With Hemodynamic Instability

The use of benzodiazepines, such as midazolam, as a last-resort treatment for refractory status epilepticus is widely practiced, particularly in patients who are hemodynamically stable. However, as the dosage of this antiepileptic agent is increased, it potentiates γ-aminobutyric acid (GABA) activity, which can lead to hypotension and subsequently necessitate the administration of vasopressor agents, especially in cases involving hemodynamic instability, as illustrated by this case where a young man who arrived at the emergency department with complaints of epileptic seizures and was already on regular anti-epileptic medications. During a seizure episode in the department, he was administered intravenous Lorazepam according to standard protocol to stop the seizure, and then placed on an IV infusion of Midazolam. However, his hemodynamics became unstable due to the side effects of the benzodiazepines administered. To address this instability, the decision was made to initiate an infusion of Ketamine along with a low dose of Midazolam. This combination successfully terminated the epileptic activity and stabilized his hemodynamics. In these instances, either concurrent or standalone administration of N-methyl-D-aspartate (NMDA) receptor antagonists might prove beneficial for managing refractory status epilepticus. For example, ketamine infusion can inhibit the reuptake of catecholamines into the systemic circulation, thereby aiding in the maintenance of blood pressure in hemodynamically unstable patients. The initial application of a combined third-line therapy, which involves blocking NMDA receptors while simultaneously enhancing GABAergic activity, appears promising for the management of refractory status epilepticus

A case of pagetoid spread of urothelial carcinoma with notable reduction achieved through enfortumab vedotin, resulting in complete surgical resection.

Secondary extramammary Paget's disease is a rare condition associated with the contiguous extension of tumor cells from the underlying adnexal structures, genitourinary, or gastrointestinal tracts. We report the case of an 80-year-old female with a 7-year history of urothelial carcinoma who presented with erythema of the labia majora. The diagnosis was pagetoid spread of urothelial carcinoma. The patient declined surgical resection of the lesion. She underwent nine cycles of first-line platinum-based chemotherapy and received one course of pembrolizumab for metastatic urothelial carcinoma. As the lesion progressively enlarged, third-line therapy with enfortumab vedotin was initiated, which resulted in significant tumor reduction. This allowed for a successful surgical complete resection of the tumor. Enfortumab vedotin was highly effective and demonstrated dramatic efficacy for controlling extramammary Paget's disease secondary to urothelial carcinoma.

Real-world use of pemigatinib for the treatment of cholangiocarcinoma in the US.

Pemigatinib demonstrated efficacy in fibroblast growth factor receptor (FGFR)-altered cholangiocarcinoma (CCA) in the FIGHT-202 trial. However, limited real-world evidence exists on treatment patterns and outcomes in this setting. Patient characteristics, treatment patterns, and outcomes of US adults who received pemigatinib for unresectable, locally advanced or metastatic CCA were collected via retrospective physician-abstracted chart review. Results were summarized using descriptive statistics. Data from 120 patients (49.2% male; 55.0% White; 19.2% Hispanic; median age at initial pemigatinib prescription, 64.5 years) were collected from 18 physicians/practices. At the time of prescribing, 90.0% of patients had metastatic disease. FGFR2 testing was completed for 92.5% of patients; of those, all but one (result unknown) tested positive, and 95.5% were tested using next-generation sequencing. Pemigatinib was prescribed as second- and third-line therapy among 94.2% and 5.8% of patients, respectively. The most common starting dosage was 13.5mg daily for 14 days of 21-day cycles (87.5% of patients). Among 60 patients (50.0% of the full cohort) who discontinued pemigatinib during the 6.5-month median study follow-up period, 68.3% discontinued due to disease progression. The median real-world progression-free survival (rwPFS) from the date of pemigatinib initiation was 7.4 months (95% CI: 6.4-8.6), and the real-world overall response rate (rwORR) was 59.2% (95% CI: 50.0%-68.4%). This study complements the FIGHT-202 clinical trial by assessing the use of pemigatinib among a diverse population of patients with CCA under real-world conditions. Findings support the clinical benefit of pemigatinib demonstrated in FIGHT-202.

Prognostic factors of second-line nivolumab monotherapy for unresectable or metastatic esophageal cancer: a multi-institutional cohort study for 184 cases.

The real-world efficacy, prognostic factors, and adverse events of second-line nivolumab monotherapy and subsequent third-line therapy for unresectable or metastatic esophageal cancer have not been fully evaluated. This multi-institutional retrospective cohort study evaluated 184 consecutive patients treated with second-line nivolumab monotherapy for esophageal cancer between March 2021 and December 2022. We assessed tumor response, adverse events, long-term survival, and prognostic factors. Among 128 patients with measurable lesions, the response rate was 23% and the disease control rate for all enrolled patients was 45%. The incidence of grade 3 or higher adverse events was 14%, but no treatment-related deaths presented. Median progression-free survival was 5.1months and overall survival was 14months, respectively. C-reactive protein level and performance status were identified as significant prognostic factors of overall survival through Cox proportional hazards analysis. The group with two favorable prognostic factors showed better overall survival than the groups with either one or zero prognostic factors (median overall survival: 22, 15, and 4.4months, respectively). Among 69 patients who received third-line taxane anticancer agents, the progression-free survival was 6.7months. Our study demonstrated that the real-world outcomes of second-line nivolumab monotherapy were comparable to those of previous randomized clinical trials in terms of tumor response, safety, and long-term survival. Furthermore, a good performance status and low C-reactive protein levels may identify patients who are likely to benefit from therapy. Third-line chemotherapy after nivolumab treatment may have an enhanced effect; however, further prospective studies are required to confirm this finding.

Peptide Receptor Radionuclide Therapy in Advanced Refractory Meningiomas: Efficacy and Toxicity in a Long Follow-up.

Recurrence of meningiomas after surgery and radiotherapy deserves specific attention because of the lack of active third-line therapies. Somatostatin receptors are usually overexpressed on the cell membrane of meningiomas, and this has led the way to a radionuclide theranostic approach. Diagnoses with 68Ga-DOTA-octreotide and peptide receptor radionuclide therapy (PRRT) with 90Y/177Lu-DOTA-octreotide are currently possible options within experimental protocols or as compassionate use in small patient groups. Methods: From October 2009 to October 2021, 42 meningioma patients with radiologic recurrence after standard therapies were treated with 90Y-DOTATOC (dosage of 1.1 or 5.5 GBq) or with 177Lu-DOTATATE (dosage of 3.7 or 5.5 GBq) in a mean of 4 cycles. All patients showed intense uptake at diagnostic 68Ga-DOTATOC PET/CT or in an 111In-octreotide scan. Results: Of 42 patients treated, 5 patients received 90Y-DOTATOC with a cumulative activity of 11.1 GBq and 37 patients received 177Lu-DOTATATE with a cumulative activity of 22 GBq. The disease control rate was 57%. With a median follow-up of 63 mo, median progression-free survival was 16 mo, and median overall survival was 36 mo. Retreatment 177Lu-PRRT was performed in 6 patients with an administered median activity of 13 GBq in a mean of 5 cycles. With a 75.8-mo follow-up, median progression-free survival and overall survival were 6.5 and 17 mo, respectively. Only 1 patient discontinued the treatment because of grade 3 platelet toxicity. A rapidly transient grade 2 neutropenia was recorded in 1 retreated patient. Conclusion: PRRT in patients with advanced meningiomas overexpressing somatostatin receptor 2 was active and well tolerated, showing a 57% disease control rate. Furthermore, PRRT could represent a potential retreatment option. Further studies, also in combination with other treatments, are warranted.

Mycophenolate Mofetil for the Treatment of Warm Autoimmune Haemolytic Anaemia Post-Rituximab Therapy: A Case Series.

Warm autoimmune haemolytic anaemia (wAIHA) is an acquired haemolytic disorder most commonly treated with a combination of corticosteroids, rituximab and/or splenectomy. Third-line therapies for refractory cases include immunosuppressive agents. Mycophenolate mofetil is frequently used in these scenarios, although its use is supported by small studies and anecdotal evidence rather than large-scale data. We describe three cases of refractory warm autoimmune haemolytic anaemia successfully treated with mycophenolate mofetil. Case 1: A persistent case of autoimmune haemolytic anaemia in a 56-year-old was ultimately managed with mycophenolate mofetil, leading to successful steroid tapering and stable haemoglobin levels without relapse. Case 2: A woman with a complex oncological history, including lymphoma and breast cancer, achieved remission with mycophenolate therapy, maintaining stability post-steroid treatment. Case 3: Mycophenolate proved effective for a 63-year-old with cirrhosis after recurrent autoimmune anaemia and deep vein thrombosis, enabling cessation of steroids and maintaining remission. Management of this condition can be challenging and balancing the available treatments is crucial to reduce potential complications from long-term therapies that appear to be ineffective. Our case series demonstrates anecdotal experience on successful use of mycophenolate mofetil for complex refractory cases of wAIHA. Warm autoimmune haemolytic anaemia can be a challenging condition to manage. Refractory cases that are steroid-dependent can benefit from trialling steroid-sparing agents such as mycophenolate.Anti-CD20 agents such as rituximab can be very effective in refractory cases, however there is a small percentage of patients that might not be responsive to this monoclonal antibody.Autoimmune haemolytic anaemias can be frequently complicated by thrombotic events, and part of the backbone treatment is establishing good thromboprophylaxis.

SUCCESSFUL TREATMENT OF METASTATIC LUNG ADENOCARCINOMA WITH LAZERTINIB: A CASE REPORT

Lung cancer is one of the most common social diseases affecting the quality and length of life. A feature of lung cancer is the high frequency of genetic mutations. EGFR mutation is the most common among them. The prognosis for patients, especially with advanced stages, remains unfavorable since this type of tumor is resistant to chemotherapy. Tyrosine kinase inhibitors (TKIs) are considered the promising direction of targeted therapy. Gefitinib, afatinib, and erlotinib are TKIs widely used to treat patients. However, the significant problem remains the acquired resistance, which is most often associated with the additional mutation T790M. Lazertinib is a new and most promising third-generation EGFR-TKI.The study aimed to investigate the indications for lazertinib and to report the results of the successful treatment of a patient with metastatic lung adenocarcinoma with a follow-up period of 35 months.Case report and discussion. Lazertinib is used to treat patients with single (L858R, Ex19del, or T790M) or combined mutations (L858R and T790M, Ex19del and T790). This drug is effective for the first, second, and third lines of therapy, as it can block the T790M mutation, penetrate the blood-brain barrier, and counteract the emergence of acquired resistance. Lazertinib is used as monotherapy, but treatment effectiveness increases if combined with chemotherapy and/or amivantamab (a bispecific antibody against EGFR and MET). Our case report demonstrates that progression-free survival in patients receiving lazertinib can be very high. In patients taking tyrosine kinase inhibitors of the first generation, disease progression occurs after about 12 months. In our case, the patient has no progression within 35 months of treatment. Skin dryness and grade 1 thrombocytopenia have been reported as side effects. The high efficiency of lazertinib in the presented case report can be explained by the presence of the most sensitive to EGFR-TKI mutation - Ex19del, and the absence of uncommon mutations such as Ex20ins, G719X, L861Q, S768I, and T790M.Conclusions. Lazertinib is a highly effective EGFR-TKI with a low toxicity profile that may significantly improve the treatment outcomes of EGFR-mutated patients.

Predicting Survival of Metastatic Clear Cell Renal Cell Cancer Treated with VEGFR-TKI-Based Sequential Therapy.

(1) Objective: To develop a clinically useful nomogram that may provide a more individualized and accurate estimation of cancer-specific survival (CSS) for patients with clear-cell (CC) metastatic renal cell carcinoma (mRCC) treated with nephrectomy and vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI)-based sequential therapy. (2) Methods: A prospectively maintained database of 145 patients with mRCC treated between 2008 and 2018 was analyzed to predict the CSS of patients receiving sunitinib and second- and third-line therapies according to current standards of practice. A nomogram based on four independent clinical predictors (Eastern Cooperative Oncology Group status, International Metastatic RCC Database Consortium score, the Morphology, Attenuation, Size and Structure criteria and Response Evaluation Criteria in Solid Tumors response criteria) was calculated. The corresponding 1- to 10-year CSS probabilities were then determined from the nomogram. (3) Results: The median age was 60 years (95% CI 57.9-61.4). The disease was metastatic at diagnosis in 59 (40.7%), and 86 (59.3%) developed metastasis during follow-up. Patients were followed for a median 48 (IQR 72; 95% CI 56-75.7) months after first-line VEGFR-TKI initiation. The concordance probability estimator value for the nomogram is 0.778 ± 0.02 (mean ± SE). (4) Conclusions: A nomogram to predict CSS in patients with CC mRCC that incorporates patient status, clinical risk classification and response criteria to first-line VEGFR-TKI at 3 months is presented. This new tool may be useful to clinicians assessing the risk and prognosis of patients with mRCC.

Design of 225Ac-PSMA for targeted alpha therapy in prostate cancer.

The first alpha emitting radiopharmaceutical, 223RaCl2, radium dichloride, was approved 10 years ago into the clinical armament of treating bone metastases in metastatic castration-resistant prostate cancer (mCRPC). In addition to this, the first beta-emitting radionuclide Lu-177 chelated with a prostate-specific membrane antigen (PSMA) compound, got last year its marketing approval for the third line treatment of mCRPC. Therefore, there is great excitement about combining alpha-emitters and prostate cancer targeting PSMA compounds. This review describes the clinical history of alpha-emitting PSMA in treating mCRPC. Here, we present the potential, current status, and opportunities for 225Ac-PSMA therapy. The work reviews the basic concepts, current treatment outcome, and toxicity, and areas requiring further investigations such as dosimetric aspects in clinical studies covering more than 400 patients. In general, approximately two-thirds of the patients benefit from this third-line therapy. There is also successful evidence of using 225Ac-PSMA in the second-line of prostate cancer management. The future potential of 225Ac-PSMA therapy and targeted alpha therapy (TAT) of cancer in general is enormous. According to our overview the clinical experience with 225Ac-PSMA therapy to date has shown great benefit and physicians dedicated to theragnostics are anxiously waiting for new applications. Hopefully, this review helps in deeper understanding of the strengths and limitations of TAT and may help in creating effective therapy protocols.

Real-world anti-seizure treatment and adverse events among individuals living with drug-resistant focal epilepsy in the United States.

This study aimed to understand how people living with drug-resistant focal epilepsy (DRE) navigate through lines of antiseizure medications (ASM) and experience adverse events (AEs) in the real-world setting in the United States. A retrospective study was conducted with medical chart data from clinical practices in the United States. Eligible adults had a confirmed diagnosis of DRE and initiated a third-line ASM therapy between January 2013 and January 2020 (i.e., the index date). Subjects must have medical history data available for ≥1 year prior to (the baseline) and ≥2 years after the index date (the follow-up). Treatment patterns were captured from first to fourth lines. After the emergence of drug resistance, time to ASM discontinuation, reasons for discontinuation, AE experience and AE management were reported separately during third and fourth lines of treatment and beyond. The study included a total of 345 individuals, with an average (standard deviation) age of 23.9 (11.9) years at first diagnosis. All individuals had at least three lines of ASMs with first and second lines during baseline, and third line during follow-up. The first line for most individuals was monotherapy. As individuals progressed through additional lines of ASM therapy, they were more likely to receive polytherapy. The regimens were more individualized after meeting drug resistance criteria. The top reasons for discontinuing were uncontrolled seizure and/or intolerance/AEs for both third and subsequent lines. More than a third of individuals experienced at least one AE. Among those with at least one AE, many individuals had to manage these AEs with dose adjustment (39.4%), discontinuation of offending ASM (37.9%), de novo pharmacotherapy (25.8%), emergency room visit (13.6%), and hospitalization (12.1%). This study demonstrated that individuals living with DRE experience significant AEs, and many of these AEs lead to treatment disruption and significant healthcare resource utilization. This study examined how individuals with focal epilepsy are treated across various clinics in United States and reported the adverse events these individuals experienced during treatment, along with the consequence associated with these adverse events. We found that as individuals progressed through additional treatments, they were more and more likely to receive more than one antiseizure medication, and a significant portion of individuals experienced at least one adverse event, often manifested as headache, somnolence, dizziness, and fatigue.