First-line Treatment Option For Patients Research Articles

Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma.

Bortezomib, lenalidomide, and dexamethasone (VRd) is a preferred first-line treatment option for patients with newly diagnosed multiple myeloma. Whether the addition of the anti-CD38 monoclonal antibody isatuximab to the VRd regimen would reduce the risk of disease progression or death among patients ineligible to undergo transplantation is unclear. In an international, open-label, phase 3 trial, we randomly assigned, in a 3:2 ratio, patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation to receive either isatuximab plus VRd or VRd alone. The primary efficacy end point was progression-free survival. Key secondary end points included a complete response or better and minimal residual disease (MRD)-negative status in patients with a complete response. A total of 446 patients underwent randomization. At a median follow-up of 59.7 months, the estimated progression-free survival at 60 months was 63.2% in the isatuximab-VRd group, as compared with 45.2% in the VRd group (hazard ratio for disease progression or death, 0.60; 98.5% confidence interval, 0.41 to 0.88; P<0.001). The percentage of patients with a complete response or better was significantly higher in the isatuximab-VRd group than in the VRd group (74.7% vs. 64.1%, P = 0.01), as was the percentage of patients with MRD-negative status and a complete response (55.5% vs. 40.9%, P = 0.003). No new safety signals were observed with the isatuximab-VRd regimen. The incidence of serious adverse events during treatment and the incidence of adverse events leading to discontinuation were similar in the two groups. Isatuximab-VRd was more effective than VRd as initial therapy in patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation. (Funded by Sanofi and a Cancer Center Support Grant; IMROZ ClinicalTrials.gov number, NCT03319667.).

Review of the In Vitro Microbiological Activity of Mecillinam Against Common Uropathogens in Uncomplicated Urinary Tract Infection: Focus on Resistant Pathogens.

Antimicrobial resistance in uropathogens commonly causing urinary tract infections (UTIs) is a growing problem internationally. Pivmecillinam, the oral prodrug of mecillinam, has been used for over 40 years, primarily in Northern Europe and Canada. It is recommended in several countries as a first-line agent for the treatment of uncomplicated UTIs (uUTIs) and is now approved in the United States. We performed a structured literature search to review the available evidence on susceptibility of common uUTI-causing uropathogens to mecillinam. Among 38 studies included in this literature review, susceptibility rates for Escherichia coli to mecillinam-including resistant phenotypes such as extended-spectrum β-lactamase-producing E. coli-exceed 90% in most studies. High rates of susceptibility were also reported among many other uropathogens including Klebsiella spp., Enterobacter spp., and Citrobacter spp. In the current prescribing climate within the United States, pivmecillinam represents a viable first-line treatment option for patients with uUTI.

Iatrogenic injuries to reservoirs of inflatable penile prosthesis during urologic surgery: a scoping review and case report.

First-line treatment options for patients with erectile dysfunction whose medical management has failed include the inflatable penile prosthesis (IPP). Many patients with an IPP require subsequent urologic surgery, during which the reservoir of the IPP can be injured. This review aims to present a summary of current literature related to iatrogenic injuries to the IPP sustained during urologic surgery. Two reviewers independently performed a systematic search on PubMed using standardized search terms to identify pertinent articles. After preliminary review, relevant studies were analyzed to identify the presence of perioperative complications resulting in IPP reservoir injury. Results were categorized by surgical procedures. Among 13 articles included, all were based on urologic surgery. Four studies identified IPP reservoir injury as a result of surgical injury. Of these, injuries occurred during radical prostatectomy (n = 3) and prostatic urethral lift surgery (UroLift, n = 1). Most radical prostatectomy studies without IPP reservoir injuries also described intentional surgical techniques that were employed to prevent reservoir damage, including modulation of reservoir inflation-deflation (n = 3), temporary reservoir repositioning (n = 1), or reservoir capsule dissection to improve visualization (n = 1). Findings from an additional novel case report on IPP injury during a UroLift procedure are presented in this review. Approximately one-third of studies identified intraoperative IPP reservoir injury as a significant complication of urologic surgery, particularly during radical prostatectomy. Novel case report findings also contribute the only other case of IPP reservoir damage sustained from delivery of UroLift implants. Findings are used to create a standardized surgical checklist that guides perioperative planning measures prior to pursuing surgery in adjacent spaces.

Overview of Rheumatoid Arthritis-Associated Interstitial Lung Disease and Its Treatment.

Interstitial lung disease (ILD) is a common pulmonary complication of rheumatoid arthritis (RA), causing significant morbidity and mortality. Optimal treatment for RA-ILD is not yet well defined. Reliable prognostic indicators are largely byproducts of prior ILD progression, including low or decreasing forced vital capacity and extensive or worsening fibrosis on imaging. In the absence of validated tools to predict treatment response, decisions about whether to initiate or augment treatment are instead based on clinical judgment. In general, treatment should be initiated in patients who are symptomatic, progressing, or at high risk of poor outcomes. Retrospective data suggest that mycophenolate mofetil, azathioprine, and rituximab are likely effective therapies for RA-ILD. Abatacept is also emerging as a potential first-line treatment option for patients with RA-ILD. Further, recent data demonstrate that immunosuppression may be beneficial even in patients with a usual interstitial pneumonia (UIP) pattern on imaging, suggesting that immunosuppression should be considered irrespective of imaging pattern. Recent randomized controlled trials have shown that antifibrotic medications, such as nintedanib and likely pirfenidone, slow forced vital capacity decline in RA-ILD. Consideration can be given to antifibrotic initiation in patients progressing despite immunosuppression, particularly in patients with a UIP pattern. Future research directions include developing tools to predict which patients will remain stable from patients who will progress, discriminating patients who will respond to treatment from nonresponders, and developing algorithms for starting immunosuppression, antifibrotics, or both as first-line therapies.

COMPARISON OF EFFICACY OF PDE5 INHIBITORS (SILDENAFIL) VERSUS ALPHA-BLOCKERS (TAMSULOSIN) IN TREATMENT OF LOWER URINARY TRACT SYMPTOMS (LUTS) SECONDARY TO BENIGN PROSTATIC HYPERPLASIA

Benign prostatic hyperplasia (BPH) is a prevalent condition leading to lower urinary tract symptoms (LUTS) in men, affecting their quality of life. Various medications, including phosphodiesterase five inhibitors (PDE5-Is) and alpha-blockers (ABs), are used for treatment, but direct comparison studies between these drugs are limited. This study aimed to compare the efficacy of sildenafil (PDE5 inhibitor) versus tamsulosin (alpha-blocker) in patients with LUTS secondary to BPH. A randomized controlled trial was conducted at the Department of Urology, KEMU/Affiliated Hospital, Lahore. A sample size of 100 patients (50 in each group) was calculated using the WHO calculator based on expected efficacy rates. Patients aged 40-70 years with BPH and LUTS were included. Exclusion criteria included high PSA levels, history of prostatic surgery, acute urinary retention, or active urinary tract infection. Patients were randomly assigned to receive sildenafil 25mg OD or tamsulosin 0.4mg HS for three months. Efficacy was assessed by changes in the International Prostate Symptom Score (IPSS) after treatment. The demographic characteristics of the study population showed a mean age of 60 years with a similar distribution of comorbidities between the groups. After three months of treatment, 80.9% of patients in the sildenafil group showed a significant improvement in IPSS compared to 55.5% in the tamsulosin group. The chi-square test indicated a significant difference in efficacy between the two groups (p &lt; 0.05). Sildenafil demonstrated superior efficacy compared to tamsulosin in reducing LUTS secondary to BPH. These findings suggest that sildenafil may be considered as a first-line treatment option for patients with BPH and LUTS.

Differential liver function at cessation of atezolizumab-bevacizumab versus lenvatinib in HCC: a multicenter, propensity-score matched comparative study.

Atezolizumab+bevacizumab (AB) and lenvatinib have been proposed as first-line treatment options for patients with advanced hepatocellular carcinoma (HCC), but comparative efficacy and associated factors are controversial. This real-world multicenter study analysed patients with HCC who received AB (n=169) or lenvatinib (n=177). First, 1:1 propensity score matching (PSM) was performed, resulting in 141 patients in both the AB and lenvatinib groups. After PSM, overall survival (OS) was better in the AB group than in the lenvatinib group [hazard ratio (HR)=0.642, P=0.009], but progression-free survival (PFS) did not vary between the two groups (HR=0.817, P=0.132). Objective response rate (ORR) was also similar between AB and lenvatinib (34.8% vs. 30.8%, P=0.581). In a subgroup of patients with objective responses (OR, n=78), OS (HR=0.364, P=0.012) and PFS (HR=0.536, P=0.019) were better in the AB group (n=41) than in the lenvatinib group (n=37). Time-to-progression from time of OR was also better in the AB group (HR=0.465, P=0.012). Importantly, residual liver function was a significant factor related to OS in both treatments. Child-Pugh score following cessation of the respective treatments was better in the AB group (n=105) than in the lenvatinib group (n=126) (median 6 versus 7, P=0.008), and proportion of salvage treatment was also higher in the AB group (52.4% versus 38.9%, P=0.047). When we adjusted for residual liver function or salvage treatment, there was no difference in OS between the two treatments. Our study suggests that residual liver function and subsequent salvage treatments are major determinants of clinical outcomes in patients treated with AB and lenvatinib; these factors should be considered in future comparative studies.

Impact of baseline liver function on survival outcomes in patients with unresectable hepatocellular carcinoma (uHCC) treated with camrelizumab + rivoceranib vs sorafenib: A post hoc analysis of study CARES-310.

509 Background: CARES-310 study (NCT03764293) evaluated the combination of camrelizumab, an anti-PD-1 inhibitor, and rivoceranib, a highly selective VEGFR-2 tyrosine kinase inhibitor, (cam + rivo) vs sorafenib (sora) for the treatment of uHCC. Cam + rivo significantly improved median overall survival ([mOS] 22.1 months [mo] vs 15.1 mo) and median progression-free survival ([mPFS] 5.6 mo vs 3.7 mo) compared to sora. This post-hoc analysis evaluated the impact of baseline albumin-bilirubin (ALBI) grade and Child-Pugh (CP) class on survival outcomes. Methods: In this randomized, open-label, international, multicenter, phase 3 study, patients were randomized 1:1 to receive cam 200 mg IV Q2W + rivo 250 mg PO QD (n=272) or sora 400 mg PO BID (n=271). Median overall survival (mOS), median progression free survival (mPFS), objective response rate (ORR), disease control rate (DCR), and safety were assessed by baseline ALBI grade and CP class. Results: mOS, mPFS, DCR, and ORR improved with cam + rivo vs sora regardless of baseline liver function (Table). Although treatment-related grade 3/4 AEs occurred at a greater rate in the cam + rivo arm vs the sora arm, the rate of these events was similar for patients with baseline ALBI grade 1 and grade 2 (cam + rivo, 82.1% and 81.7% vs sora, 53.9% and 54.0%, respectively). Median time-to-deterioration (mTTD) to CP class B was similar between treatment arms for ALBI grade 1 (not evaluable [NE], NE) and grade 2 (cam + rivo, 10.1 mo; sora, 10.6 mo; HR, 0.99). Conclusions: In this post-hoc analysis of Study CARES-310, the efficacy of cam + rivo was superior to sora regardless of baseline liver function as measured by both ALBI grade and CP class. Despite a higher rate of grade 3/4 AEs, there was no detrimental effect of cam +rivo on liver function in patients with both well- and moderately- preserved liver function compared to sora. These results support cam + rivo as a potential new first-line treatment option for patients with uHCC regardless of baseline liver function. Clinical trial information: NCT03764293 . [Table: see text]

The long-term efficacy and safety of apatinib are inferior to sorafenib in the first-line treatment of advanced hepatocellular carcinoma: A systematic review and meta-analysis.

Apatinib, a novel tyrosine kinase inhibitor independently developed by China, has been widely used in the treatment of advanced hepatocellular carcinoma (HCC) in recent years. For more than a decade, sorafenib has been the classic first-line treatment option for patients with advanced HCC. However, the results of clinical studies comparing the efficacy and safety of these 2 drugs are still controversial. Therefore, the aim of this meta-analysis is to evaluate the efficacy and safety of apatinib versus sorafenib as first-line treatment for advanced HCC. Up to August 14, 2023, the databases of PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, China National Knowledge Infrastructure, and Wanfang were searched, and clinical studies of experimental group (apatinib or apatinib plus transarterial chemoembolization [TACE]) versus control group (sorafenib or sorafenib plus TACE) in the first-line treatment of advanced HCC were included. Two researchers evaluated the quality of the included studies and extracted the data. Revman 5.4 software was used for meta-analysis. A total of 12 studies involving 1150 patients were included. Five studies are apatinib alone versus sorafenib alone, and the other 7 studies are apatinib plus TACE versus sorafenib plus TACE. The results of the meta-analysis showed that compared with sorafenib alone, apatinib could improve (OR = 3.06, 95%CI: 1.76-5.31), had no advantage in improving DCR (OR = 1.52, 95%CI: 0.86-2.68) and prolonging PFS (HR = 1.35, 95%CI: 0.94-1.96), and was significantly worse in prolonging OS (HR = 1.43, 95%CI: 1.08-1.88). Similarly, apatinib plus TACE was inferior to sorafenib plus TACE in prolonging OS (HR = 1.15, 95%CI: 1.03-1.28), although it improved ORR (OR = 1.49, 95%CI: 1.03-2.16). In terms of adverse drug events, the overall incidence of adverse events, and the incidence of drug reduction and discontinuation in the experimental group were significantly higher than those in the control group (P < .05). The incidence of hypertension, proteinuria, and oral mucositis in the experimental group was significantly higher than that in the control group (P < .05). In the setting of first-line treatment of advanced HCC, apatinib has improved short-term efficacy (ORR) compared with sorafenib, but the safety and long-term efficacy of apatinib are inferior to sorafenib.

Huzursuz Bacaklar Sendromu: Tanıdan Tedaviye

Restless legs syndrome (RLS) can be described by an urge to move limbs that typically coincides with an uncomfortable sensation. When at rest or inactivity, signs may start or develop worse; they usually go away when one moves or gets up for a walk. RLS can be both idiopathic or secondary to many kinds of health conditions, such as deficiency of iron, diabetes, obesity, hypothyroidism, and chronic renal failure. At the admission, secondary causes and iron tests, such as transferrin saturation and ferritin, must be evaluated. Assessments should be repeated when symptoms worsen, or when augmentation develops. Augmentation is a significant adverse effect of therapy by levodopa and dopamine agonists. More severe signs, early appearance of symptoms, and spreading of symptoms from the legs to other body parts are indicative of augmentation. Non-pharmacological treatments help some RLS patients control their symptoms. Iron-replacement therapy is a first-line treatment option for patients with indications of low body iron stores. The use of α2δ ligands as initial treatments instead of dopamine agonists has been recommended recently.

First report of furmonertinib as a first-line treatment in advanced lung adenocarcinoma patients harboring EGFR exon 20 insertion mutations after the kinase domain αC-helix: Two case reports and a literature review

Rationale: Many studies have shown that first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors are less effective in patients with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations. The efficacy of third-generation epidermal growth factor receptor tyrosine kinase inhibitors is still under investigation. Although new targeted tyrosine kinase inhibitors and monoclonal antibody-based agents have made significant advances in the treatment of epidermal growth factor receptor exon 20 insertion (EGFR ex20ins) mutation, the efficacy of these novel agents is not quite satisfactory. Platinum- and pemetrexed-based chemotherapy remains the standard first-line treatment for patients harboring EGFR ex20ins mutation. Patient concerns: We report for the first time 2 Chinese patients diagnosed with advanced lung adenocarcinoma with EGFR ex20ins mutations after analysis of the αC-helix sequence by next-generation sequencing. Both patients were treated with furmonertinib as the first-line therapy. Interventions: The first case included a 38-year-old female who had an EGFR ex20ins mutation (p.S768_D770dupSVD). After 1 month of treatment with furmonertinib, her symptoms of pain and cough were significantly alleviated. She achieved a partial response according to response evaluation criteria in solid tumors.[1] The final progression-free survival was 8.13 months. The second case included a 40-year-old male who had an EGFR ex20ins mutation (p.N771_P772insVal). He had a good response to furmonertinib and exhibited stable disease according to response evaluation criteria in solid tumors with a progression-free survival of 10.90 months. Outcomes: Both patients experienced significant improvement in symptoms and prolonged survival after furmonertinib was used as first-line treatment. Side effects were limited but manageable. Conclusion: The present study indicates that furmonertinib may be a first-line treatment option for patients with non-small cell lung cancer harboring EGFR ex20ins mutation.

Mechanisms of tyrosine kinase inhibitor resistance in renal cell carcinoma.

Renal cell carcinoma (RCC), the most prevalent type of kidney cancer, is a significant cause of cancer morbidity and mortality worldwide. Antiangiogenic tyrosine kinase inhibitors (TKIs), in combination with immune checkpoint inhibitors (ICIs), are among the first-line treatment options for patients with advanced RCC. These therapies target the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase pathway and other kinases crucial to cancer proliferation, survival, and metastasis. TKIs have yielded substantial improvements in progression-free survival (PFS) and overall survival (OS) for patients with advanced RCC. However, nearly all patients eventually progress on these drugs as resistance develops. This review provides an overview of TKI resistance in RCC and explores different mechanisms of resistance, including upregulation of alternative proangiogenic pathways, epithelial-mesenchymal transition (EMT), decreased intracellular drug concentrations due to efflux pumps and lysosomal sequestration, alterations in the tumor microenvironment including bone marrow-derived cells (BMDCs) and tumor-associated fibroblasts (TAFs), and genetic factors such as single nucleotide polymorphisms (SNPs). A comprehensive understanding of these mechanisms opens the door to the development of innovative therapeutic approaches that can effectively overcome TKI resistance, thereby improving outcomes for patients with advanced RCC.

Pyrotinib plus docetaxel as first-line treatment for HER2-positive metastatic breast cancer: the PANDORA phase II trial

The role of pyrotinib in the treatment of HER2-positive metastatic breast cancer (MBC) has been well-established. This multicenter, single-arm phase II trial (NCT03876587) aimed to assess the benefit of pyrotinib plus docetaxel as a first-line treatment for HER2-positive MBC. Women with HER2-positive MBC who had not undergone HER2 blockade or chemotherapy for metastatic disease were enrolled in the study and received daily oral pyrotinib 400 mg plus intravenous docetaxel 75 mg/m2 every 3 weeks. The primary endpoint was the objective response rate (ORR), secondary endpoints included progression-free survival (PFS), duration of response (DoR), clinical benefit rate (CBR), overall survival (OS) and safety. From June 2019 to June 2021, 79 patients were enrolled. The confirmed ORR was 79.7% (95% confidence interval [CI], 70.8-88.6), and the CBR was 87.3% (95%CI, 80.0-94.6) in the intention-to-treat population. The pre-specified primary endpoint was met. The median DoR was 15.9 months (interquartile range, 8.3-19.5); the median PFS was 16.0 months (95% CI, 11.2-20.8), and the median OS was not reached. The most common grade ≥3 treatment-related adverse events observed were leukopenia (29.1%), neutropenia (27.8%), and diarrhea (21.5%). This study demonstrates that pyrotinib plus docetaxel show an acceptable safety profile and promising antitumor activity as a first-line treatment option for patients with HER2-positive MBC.

The short-term cost-effectiveness of once-weekly semaglutide versus once-weekly dulaglutide for the treatment of type 2 diabetes mellitus in Colombian adults.

Type 2 Diabetes Mellitus (T2DM) is a highly prevalent disease worldwide and in Colombia, representing one of the main causes of death and placing a considerable burden on healthcare systems. 13 classes of drugs are approved for the treatment of T2DM, with Glucagon-like Peptide-1 (GLP-1) receptor agonists being a first-line treatment option for patients with or at high risk of certain cardiovascular diseases and chronic kidney disease. The objective of this study is to conduct a short-term cost-effectiveness analysis of once-weekly semaglutide versus once-weekly dulaglutide in Colombian adults with T2DM, from a third-party payer perspective. Numbers needed to treat were calculated for different single and composite endpoints of the SUSTAIN 7 trial, annual costs for once weekly semaglutide 1.0 mg and dulaglutide 1.5 mg were extracted from the public SISMED database. With these inputs a cost of control model was developed, to obtain the annual cost of bringing one T2DM patient to relevant clinical outcomes by using semaglutide or dulaglutide. Semaglutide was considered cost-effective compared to dulaglutide across all pre-specified endpoints, even in the different scenarios evaluated in the sensitivity analyses, and in a particularly pronounced manner for weight loss outcomes. Semaglutide at a dose of 1.0 mg once-weekly was cost-effective compared to dulaglutide 1.5 mg across all outcomes in the short-term, making it an appropriate first-line choice in the treatment of T2DM when deciding between these two GLP-1 receptor agonists. This is the first short-term cost-effectiveness study of semaglutide and dulaglutide in T2DM Colombian patients. Our modeled results suggest that once-weekly semaglutide represents a cost-effective option for treating individuals with T2DM in Colombia who are not achieving glycaemia control with metformin, and it would be expected to improve HbA1C, promote greater weight loss and reduce costs from a third-payer perspective compared with treatment with dulaglutide.

Efficacy and Safety of CD19-Specific CAR-T Cell Therapy Following Immunochemotherapy in Newly Diagnosed B-Cell Lymphoma Associated Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) represents a grave and potentially fatal systemic inflammatory condition. Lymphoma associated hemophagocytic lymphohistiocytosis (LAHS), as a common type in secondary HLH, suffers the worst outcome among sHLH. B cell Lymphoma associated hemophagocytic lymphohistiocytosis (B-LAHS) typically presents as high-risk lymphoma and is associated with a poorer prognosis compared to B cell lymphoma without HLH with standard first-line chemoimmunotherapy. As a result, there is an urgent need for more effective therapeutic strategies. Recent advancements in chimeric antigen receptor (CAR) T-cell therapy have demonstrated remarkable responses in relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL), as well as in some high-risk newly diagnosed B-cell lymphoma. However, There have been no clinical reports regarding the application of CAR-T cell treatment as part of first-line therapy in B-LAHS. We assessed the effectiveness and safety of autologous anti-CD19 CAR-T cell therapy following an immunochemotherapeutic regimen based on R-DEP (Rituximab-doxorubicin-etoposide-methylprednisolone) as a first-line treatment option for patients with B-LAHS. As of 1 July 2023, a cohort of 13 patients diagnosed with B-LAHS（with 3 cases enrolled before registration for clinical trials）was recruited for evaluation and met the criteria for assessing treatment efficacy at our institution. The overall response rate (ORR) for HLH was 100% (with 7 cases achieving complete response and 6 cases achieving partial response) prior to infuse CAR-T cells and the ORR for lymphoma also was 100% (with 10 cases achieving complete response and 3 cases achieving partial response) on the time of a month after CAR-T cell infusion. As of the follow-up date on 1 July 2023 (with a median follow-up time of 14 months), all 13 patients were still alive, 12 cases maintained sustained remission, while 1 case experienced relapse at 16 months after CAR-T cell infusion. The median overall survival (OS) has not been reached, and the median progression-free survival (PFS) was 31.5 months. To provide comparison, we included a group of 26 patients diagnosed with B-LAHS who did not receive CAR-T cell therapy during the same period. The non-CAR-T group demonstrated a significantly lower median OS of 5.93 months and a median PFS of 4.43 months, highlighting the superior prognosis of the CAR-T group (p &amp;lt; 0.001). Regarding adverse events, the CAR-T group exhibited a cytokine release syndrome (CRS) incidence of 53.8% (7/13) and an immune effector cell-associated neurotoxicity syndrome (ICANS) incidence of 30.7% (4 /13), all of which were classified as grade 1. None of the patients experienced non-hematologic toxicity of grade ≥3. While all 13 patients developed cytopenias, hematologic toxicity reactions ≥ grade 3 were observed in 76.9% (10 /13) of patients, but blood cell counts recovered within 3 weeks. Robust expansion of CAR T-cells occurred in all patients, with a median time to peak expansion of 8 days. Importantly, no exacerbation of hemophagocytic syndrome occurred following CAR-T cell infusion, and no patients succumbed to adverse events. In conclusion, our findings suggest that CD19 CAR-T cell treatment exhibits high efficacy as part of first-line therapy for B-LAHS, with a manageable safety profile.

Effectiveness and Safety of Hetrombopag-Containing Therapy in Patients with Severe Aplastic Anemia: A Multicenter Real-World Study

Background: In recent years, immunosuppressive therapy (IST) in combination with thrombopoietin receptor agonist (TPO-RA) with or without other hematopoietic interventions has emerged as the first-line treatment option for patients with severe aplastic anemia (SAA) who are not eligible for hematopoietic stem cell transplantation. Hetrombopag, an innovative orally administered, non-peptide, small-molecule TPO-RA, has shown impressive efficacy and safety as a monotherapy for managing patients with relapsed or refractory SAA. Despite these promising findings, there is a lack of comprehensive real-world evidence on the benefit of hetrombopag in combination with IST-based therapy for patients with SAA. This study aims to fill this knowledge gap by evaluating the effectiveness and safety of hetrombopag-containing therapy for patients with SAA in a real-world setting. Methods: In this multicenter, real-world study, the clinical records of SAA patients who underwent hetrombopag-containing therapy were retrospectively reviewed in six hematological medical centers across China from August 2021 to November 2022. The therapeutic regimen encompassed cyclosporine (CsA) and hetrombopag, with the optional addition of anti-thymocyte globulin (ATG) and/or stanozolol according to the patients' condition. Hetrombopag was initially administered at a daily dose of either 5 or 7.5 mg, which could be escalated to a maximum of 15 mg daily. CsA was introduced at a preliminary dosage of 3-5 mg/kg/day, later tailored to sustain a trough concentration between 150 and 250 μg/L. ATG was given at doses of 2.5-3.5 mg/kg/day for rabbit ATG, or 20-30 mg/kg/day for pig ATG, over five days. Stanozolol was administered at 2-6 mg/day. Hematologic response (HR) was characterized based on evaluations of platelet (PLT), hemoglobin (HGB), and neutrophil (ANC) counts. PLT response was defined as an elevation to 20×10 9/L above the baseline or maintenance ≥20×10 9/L without transfusion for ≥8 weeks. HGB response was defined as an increase by 1.5 g/dL above the baseline, or for those receiving transfusions, an absolute decrease of ≥ 4 units of transfusions over an unbroken 8-week period, relative to that in the 8 weeks preceding treatment. ANC response was classified as a doubling from the baseline, or an increment in ≥ 0.5×10 9/L. Fulfillment of all three response criteria was classified as a complete response (CR), whereas meeting at least one of the three was considered an HR. Results: Our study comprised thirty-two patients diagnosed with SAA, of which 18 were treatment-naive, and 14 were refractory to previous IST. These patients were administered a median dose of hetrombopag of 7.5 mg (range: 5-15 mg) daily for a median duration of 8 months (range: 3-13 months). In treatment-naive SAA patients, the HR and CR rates after three months of hetrombopag-containing therapy were 44.4% and 16.7%, respectively. These rates increased to 87.5% for HR and 25.0% for CR after six months. Meanwhile, refractory SAA patients exhibited HR and CR rates of 50.0% and 14.3% respectively, after three months of therapy, and these rates improved to 60.0% and 40.0% at the six-month mark. Significantly, no patients developed hepatic or renal toxicity of grade 3 or higher. Additionally, no cases of clonal evolution or serious adverse events were documented throughout the treatment period. Conclusions: The hetrombopag-containing therapy demonstrated remarkable effectiveness in both treatment-naïve and refractory SAA patients in the real-world setting, with manageable safety profile. Most notably, the response rates and depth of remission in SAA patients significantly improved over time, signifying the ongoing therapeutic advantage of extended hetrombopag-containing therapy.

First-line treatment option for patients with ALK-positive metastatic NSCLC

Non-small cell lung cancer (NSCLC) that occupies a leading place in the pattern of cancer incidence and mortality is a highly heterogeneous group of diseases. The presence of a wide spectrum of NSCLC driver mutations has led to a fundamentally different understanding of the treatment strategy for this cohort of patients and a significant improvement in long-term oncological outcomes, even in the metastatic process. Chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene loci on chromosome 2 are found in approximately 3–5% of patients with metastatic NSCLC (mNSCLC) and in most cases are associated not only with a number of specific clinical features, but also with high sensitivity to targeted therapy with tyrosine kinase inhibitors (TKI). Crizotinib was the first approved ALK inhibitor, but although most patients achieved response within the first two years after start of the treatment, disease progression occurred often due to intracranial injury. The development of second-(ceritinib, alectinib), brigatinib and third-generation (lorlatinib) drugs has led to a statistically significant improvement in progression-free survival (PFS) rates, as well as control over intracranial manifestations of the disease and a change in the initial treatment strategy for these patients. In addition, new-generations of TKIs were developed to solve the problem of acquired resistance, as well as to achieve the best outcomes in the presence of such unfavourable factors as the presence of a TP53 mutation and/or ALK inhibitor low-sensitive translocation variants of the intracellular kinase domain of EML4 (echinoderm microtubule‐associated protein‐like 4)‐ALK (anaplastic lymphoma kinase) protein. Thus, advances in the therapeutic options for ALK-positive mNSCLC has completely changed the course of the disease, resulting in a significant increase in overall survival (OS) rates not only with the sequential use of different generation TKIs, but also with the choice of the most effective first-line option. In this article, we present an analysis of data on the efficacy and toxicity of lorlatinib, a third-generation TKI, in the first-line treatment for ALK+ mNSCLC.

Comparative analysis of using atezolizumab vs. durvalumab in combination with platinum-containing chemotherapy in adult patients with advanced small cell lung cancer

Background. In recent decades, a course of chemotherapy with etoposide (EP) and platinum preparations (сarboplatinum, CP) has been recommended as a standard first-line treatment option in patients with advanced small cell lung cancer (SCLC), but with the advent of new immunological drugs, immune checkpoint inhibitors, approaches to therapy have changed. Based on randomized clinical trials, courses combining traditional platinum-containing chemotherapy with inhibitors of programmed death-ligand 1 (PD-L1) atezolizumab (ATZ) or durvalumab (Durv) have been included in many clinical recommendations for oncologists.Objective: to evaluate the clinical and cost-effectiveness of using ATZ and Durv as first-line therapy in advanced SCLC adult patients within the Russian healthcare system.Material and methods. The model of treatment of advanced SCLC adult patients in conditions of the healthcare system of the Russian Federation included the most popular options for first-line immunochemotherapy: CP/EP + ATZ and CP/EP + Durv courses. Pharmacoeconomic cost-effectiveness analysis, sensitivity analysis of the selected model to changes in its initial parameters, budget impact analysis were carried out.Results. The total medical costs for CP/EP + ATZ course (2,310,546.07 rubles) were significantly lower than for the CP/EP + Durv course (4,081,833.98 rubles). With comparable costs for the treatment of complications (426,175.17 and 407,704.50 rubles, respectively), the cost of Durv exceeded ATZ by 94.8%. When conducting a cost-effectiveness analysis, the advantage was retained by the CP/EP + ATZ course, the cost-effectiveness ratios for which amounted to 187,849.27 rubles per month of patient's life and 444,335.78 rubles per month of patient's life without progression (for CP/EP + Durv, 316,421.24 and 800,359.60 rubles, respectively). When choosing the CP/ET + ATZ strategy, the savings will be 128,571.96 rubles per month of life and 356,023.82 rubles per month of life without progression. Sensitivity analysis demonstrated the stability of the developed model: to increase in the price of the CP/EP + ATZ course up to +68%; to decrease in overall survival with the course of CP/EP + ATZ up to –40%; to decrease in progression-free survival with the course of CP/EP + ATZ to –44%. Budget impact analysis showed that with a possible cohort size of 4,448 people an increase in the proportion of patients receiving CP/EP + ATZ course from 70% to 90% will reduce budget costs by 1,575,737,725.38 rubles per year, which will allow additional treatment of 681.9 advanced SCLC patients per year (+15.3%).Conclusion. The use of ATZ combined with standard platinum-containing chemotherapy in advanced SCLC adult patients as the first-line therapy is clinically and cost-effective strategy within the Russian healthcare system, as it allows to reduce therapy costs compared to Durv and treat more SCLC patients, which fully corresponds to the target indicators of the federal program “Oncology”.

Brentuximab Vedotin, Nivolumab, Doxorubicin, and Dacarbazine for Advanced Stage Classical Hodgkin Lymphoma: Efficacy and Safety Results from the Single Arm Phase 2 Study

Introduction: Brentuximab vedotin (BV) is an antibody-drug conjugate approved for multiple cancer types, including previously untreated stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine (AVD) in adults. The combination of BV and nivolumab are both individually active and well tolerated in patients with cHL and have distinct and complementary mechanisms of action. BV and nivolumab have been previously studied in combination and with multiagent chemotherapy as BV+AD (omitting vinblastine) and N+AVD. It was hypothesized that the combination of BV and nivolumab with doxorubicin and dacarbazine (AN+AD) would result in high response rates and a well-tolerated safety profile with potentially less toxicity than vinblastine-containing regimens. SGN35-027 (NCT03646123; EudraCT Number 2020-004027-17; Part B) is an open-label, multiple-part, multicenter, phase 2 clinical trial. Preliminary results of this study showed promising efficacy (objective response rate [ORR] 93%; complete response [CR] rate 88% at end of therapy [EOT]) with no cases of febrile neutropenia or grade 5 adverse events (AEs) (Lee ASCO 2022). Of the patients with stage III or IV cHL who relapse, most will relapse within 18 to 24 months of treatment initiation. Methods: Part B enrolled patients with stage II bulky mediastinal disease (≥10 cm), stage III, or stage IV cHL. Patients received up to 6 cycles of AN+AD (BV 1.2 mg/kg [A], nivolumab 240 mg [N], doxorubicin 25 mg/m 2 [A], and dacarbazine 375 mg/m 2 [D]). The primary efficacy endpoint was CR rate at EOT. Key secondary endpoints included safety and tolerability, ORR, duration of response (DOR), duration of complete response (DOCR), and progression-free survival (PFS). Disease response and progression were assessed by investigator using Lugano Classification Revised Staging System for malignant lymphoma, incorporating Lymphoma Response to Immunomodulatory Therapy Criteria for nodal non-Hodgkin and Hodgkin lymphomas. Results: Fifty-eight patients were enrolled; all but 1 patient received ≥1 dose of study drug (data cutoff 22 May 2023). Median age was 35 years (range, 19-78 years). Among efficacy evaluable patients (n = 56), ORR (CR+ PR) at EOT was 95% (95% CI: 85.1, 98.9); CR rate was 89% (95% CI: 78.1, 96.0) (Table 1). A total of 88.3% (95% CI: 75.7, 94.6) of responders had a DOR of at least 24 months, and 88.4% (95% CI: 76.0, 95.0) of responders had a DOCR of at least 24 months. Seven patients (12%) had a PFS event: 6 with disease progression and 1 who died (sepsis, outside safety reporting period). The estimated PFS rate at 24 months was 88.3% (95% CI: 75.7, 94.6) (Figure 1). Median follow-up was 24.2 months (95% CI: 23.4, 26.9). The most common treatment-related AEs of any grade were nausea (37 patients [65%]), fatigue (28 patients [49%]), and peripheral sensory neuropathy (25 patients [44%]). Of the patients with treatment-related peripheral sensory neuropathy, most (23 of 25 patients [92%]) were grade 1 or 2; the remaining 2 patients had grade 3 peripheral sensory neuropathy. Dose modifications due to peripheral sensory neuropathy occurred in 9 patients (16%). Grade ≥3 treatment-related AEs occurred in 19 patients (33%) (most common: alanine aminotransferase increased in 6 [11%] and neutropenia in 5 [9%]). No febrile neutropenia or Grade 5 AEs occurred. Treatment-related serious AEs (SAEs) occurred in 8 patients (14%). Seven patients (12%) had a treatment-emergent AE that led to discontinuation of BV. Treatment-emergent immune-mediated AEs (IMAEs) occurred in 19 patients (33%); treatment-emergent IMAEs that occurred in ≥5% of patients were hypothyroidism (5 patients [9%]) and pneumonitis and rash maculopapular (3 patients [5%] each). All cases of pneumonitis resolved. Conclusions: The use of 2 active, targeted agents with distinct and complementary mechanisms of action for the frontline treatment of advanced stage cHL resulted in promising efficacy, safety, and tolerability. These results demonstrate continued tolerability of AN+AD with no new safety signals observed. AN+AD may provide a future first-line treatment option for patients with advanced stage cHL; long-term follow-up is ongoing.

Community-Based Practice Patterns and Perceptions of Challenges Integrating New Therapies for High-Risk Myelodysplastic Syndrome

BACKGROUND : With a limited number of approved therapies for myelodysplastic syndrome (MDS), first-line treatment options for patients with high-risk MDS remain an unmet need. As many patients can become refractory to treatment or relapse, it is imperative that they receive the most suitable and effective therapy upfront based on their risk stratification. Several treatment strategies, including immunotherapy, are being investigated and have shown encouraging results with the potential to transform care for this patient population. To create effective education on new therapies for MDS, a two-phase educational initiative was designed. METHODS : The first phase consisted of a deep-dive survey evaluating current practice patterns, barriers, attitudes, and challenges in management of newly-diagnosed high-risk MDS which was launched in February 2023 and closed in March 2023. The survey was disseminated via a partnership with IQVIA with criteria for inclusion set as: treating physicians confirmed by ICD-10 code matching and at least one prescription for any pharmaceutical product for MDS during the prior 3 months from survey launch. The second phase of the initiative was a live and endured CME-certified activity led by two experts in MDS. This was hosted on OMedLive.com and remains on-demand through June 2024. Microlearning clips were disseminated via LinkedIn. The expert panel addressed the identified challenges from the survey results and discussed practice-changing clinical data. Knowledge and competence questions were administered pre-, immediate post-activity, and during the program as interactive polling. Attitude, perceptions, and practice patterns associated with management of MDS were also assessed. RESULTS : The phase one survey was completed by 23 hematologists/oncologists currently treating patients with MDS. The insights from the survey showed a preference for use of the IPSS-R classification system (96%); however, only 52% ‘always’ utilize a risk stratification scoring system. The top three factors influencing treatment decisions for newly-diagnosed MDS were: molecular and genetic prognostic factors (78%), comorbidities (70%), and long-term evidence/real-world data (48%). Across the continuum of care, the most challenging treatment setting was identified as intermediate/high-risk relapsed/refractory MDS. The top three challenges were requirements to follow specific treatment algorithms, access to investigational agents in clinical trial, and managing patients relapsed or are refractory to approved therapies. Clinical perceptions of emerging therapies revealed that 17% of survey respondents would not consider an investigational therapy for a newly diagnosed high-risk patient. To date, 1,371 clinicians have participated in the educational initiative, 91% of whom were physicians and 89% identified their specialty as hematology/oncology. Low baseline knowledge and competence (&amp;lt;40%) was observed across assessment questions. Insights gathered throughout the activity indicated intermediate/low and intermediate/high as the MDS risk categories that are most difficult to manage. Mixed reports of classifications systems was observed with IPSS-R as the highest at 35%, IPSS reported by 28%, and IPSS-M used by 20%. Participants reported equivalent difficulty in treatment of lower vs higher-risk MDS and newly diagnosed vs relapsed/refractory MDS. Following the educational activity, intended practice changes were reported as applying the latest guidelines, improve referral of patients, and refine treatment/management approaches. CONCLUSIONS: This initiative provided insights into provider current practices and perceptions on management of newly diagnosed high-risk MDS. These adequately informed the educational initiative with some differences in perceptions seen post activity compared with the survey analysis from phase one. There are gaps remaining for clinicians to align on use of risk stratification scoring systems and improve algorithmic approaches based on treatment setting and risk status. Educational interventions are needed to address these practice gaps, employ strategies to effectively integrate new therapies, and stay abreast of the rapidly changing MDS landscape.

Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial

PD-1 inhibitors combined with chemotherapy have shown efficacy in gastric or gastro-esophageal junction cancer. We compared the efficacy and safety of pembrolizumab plus chemotherapy with placebo plus chemotherapy in participants with locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma. KEYNOTE-859 is a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial, done at 207 medical centres across 33 countries. Eligible participants were aged 18 years and older with previously untreated histologically or cytologically confirmed locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) to receive pembrolizumab or placebo 200 mg, administered intravenously every 3 weeks for up to 35 cycles. All participants received investigator's choice of fluorouracil (intravenous, 800 mg/m2 per day) administered continuously on days 1-5 of each 3-week cycle plus cisplatin (intravenous, 80 mg/m2) administered on day 1 of each 3-week cycle or capecitabine (oral, 1000 mg/m2) administered twice daily on days 1-14 of each 3-week cycle plus oxaliplatin (intravenous, 130 mg/m2) administered on day 1 of each 3-week cycle. Randomisation was done using a central interactive voice-response system and stratified by geographical region, PD-L1 status, and chemotherapy in permuted block sizes of four. The primary endpoint was overall survival, assessed in the intention-to-treat (ITT) population, and the populations with a PD-L1 combined positive score (CPS) of 1 or higher, and PD-L1 CPS of 10 or higher. Safety was assessed in the as-treated population, which included all randomly assigned participants who received at least one dose of study intervention. Here, we report the results of the interim analysis. This study is registered with ClinicalTrials.gov, NCT03675737, and recruitment is complete. Between Nov 8, 2018, and June 11, 2021, 1579 (66%) of 2409 screened participants were randomly assigned to receive pembrolizumab plus chemotherapy (pembrolizumab group; n=790) or placebo plus chemotherapy (placebo group; n=789). Most participants were male (527 [67%] of 790 participants in the pembrolizumab plus chemotherapy group; 544 [69%] of 789 participants in the placebo plus chemotherapy group) and White (426 [54%]; 435 [55%]). Median follow-up at the data cutoff was 31·0 months (IQR 23·0-38·3). Median overall survival was longer in the pembrolizumab group than in the placebo group in the ITT population (12·9 months [95% CI 11·9-14·0] vs 11·5 months [10·6-12·1]; hazard ratio [HR] 0·78 [95% CI 0·70-0·87]; p<0·0001), in participants with a PD-L1 CPS of 1 or higher (13·0 months [11·6-14·2] vs 11·4 months [10·5-12·0]; 0·74 [0·65-0·84]; p<0·0001), and in participants with a PD-L1 CPS of 10 or higher (15·7 months [13·8-19·3] vs 11·8 months [10·3-12·7]; 0·65 [0·53-0·79]; p<0·0001). The most common grade 3-5 adverse events of any cause were anaemia (95 [12%] of 785 participants in the pembrolizumab group vs 76 [10%] of 787 participants in the placebo group) and decreased neutrophil count (77 [10%] vs 64 [8%]). Serious treatment-related adverse events occurred in 184 (23%) participants in the pembrolizumab group and 146 (19%) participants in the placebo group. Treatment-related deaths occurred in eight (1%) participants in the pembrolizumab group and 16 (2%) participants in the placebo group. No new safety signals were identified. Participants in the pembrolizumab plus chemotherapy group had a significant and clinically meaningful improvement in overall survival with manageable toxicity compared with participants in the placebo plus chemotherapy group. Therefore, pembrolizumab with chemotherapy might be a first-line treatment option for patients with locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma. Merck Sharp and Dohme.