Primary Prophylaxis Research Articles

Effectiveness and safety of primary prophylaxis of granulocyte colony-stimulating factor during dose-dense chemotherapy for urothelial cancer: Clinical Practice Guidelines for the Use of G-CSF 2022.

Granulocyte colony-stimulating factor (G-CSF) decreases the incidence, duration, and severity of febrile neutropenia (FN); however, dose reduction or withdrawal is often preferred in the management of adverse events in the treatment of urothelial cancer. It is also important to maintain therapeutic intensity in order to control disease progression and thereby relieve symptoms, such as hematuria, infection, bleeding, and pain, as well as to prolong the survival. In this clinical question, we compared treatment with primary prophylactic administration of G-CSF to maintain therapeutic intensity with conventional standard therapy without G-CSF and examined the benefits and risks as major outcomes. A detailed literature search for relevant studies was performed using PubMed, Ichu-shi Web, and Cochrane Library. Data were extracted and evaluated independently by two reviewers. A qualitative analysis of the pooled data was performed, and the risk ratios with corresponding confidence intervals were calculated and summarized in a meta-analysis. Seven studies were included in the qualitative analysis, two of which were reviewed in the meta-analysis of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) therapy, and one randomized controlled study showed a reduction in the incidence of FN. Primary prophylactic administration of G-CSF may be beneficial, as shown in a randomized controlled study of dose-dense MVAC therapy. However, there are no studies on other regimens, and we made a "weak recommendation to perform" with an annotation of the relevant regimen (dose-dense MVAC).

Primary vs. pre-emptive anti-seizure medication prophylaxis in anti-CD19 CAR T-cell therapy

IntroductionSeizures may occur in up to 30% of non-Hodgkin lymphoma patients who received anti-CD19 CAR T-cell therapy, yet the optimal anti-seizure medication (ASM) prevention strategy has not been thoroughly investigated.MethodsConsecutive patients affected by refractory non-Hodgkin lymphoma who received anti-CD19 CAR T-cells were included. Patients were selected and assessed using similar internal protocols. ASM was started either as a primary prophylaxis (PP-group) before CAR T-cells infusion or as a pre-emptive therapy (PET-group) only upon the onset of neurotoxicity development.ResultsOne hundred fifty-six patients were included (PP-group = 88, PET-group = 66). Overall, neurotoxicity and severe neurotoxicity occurred in 45 (29%) and 20 (13%) patients, respectively, equally distributed between the two groups. Five patients experienced epileptic events (PET-group = 3 [4%]; PP-group = 2 [2%]). For all the PET-group patients, seizure/status epilepticus occurred in the absence of overt CAR-T-related neurotoxicity, whereas patients in the PP-group experienced brief seizures only in the context of critical neurotoxicity with progressive severe encephalopathy. ASMs were well-tolerated by all patients, even without titration. No patients developed epilepsy or required long-term ASMs.ConclusionOur data suggest that both primary and pre-emptive anti-seizure prophylaxis are safe and effective in anti-CD19 CAR T-cell recipients. Clinical rationale suggests a possible more favourable profile of primary prophylaxis, yet no definitive conclusion of superiority between the two ASM strategies can be drawn from our study.

Effectiveness and safety of primary prophylaxis with G-CSF after induction therapy for acute myeloid leukemia: a systematic review and meta-analysis of the clinical practice guidelines for the use of G-CSF 2022 from the Japan society of clinical oncology

Although granulocyte colony-stimulating factor (G-CSF) reduces the incidence, duration, and severity of neutropenia, its prophylactic use for acute myeloid leukemia (AML) remains controversial due to a theoretically increased risk of relapse. The present study investigated the effects of G-CSF as primary prophylaxis for AML with remission induction therapy. A detailed literature search for related studies was performed using PubMed, Ichushi-Web, and the Cochrane Library. Data were independently extracted and assessed by two reviewers. A qualitative analysis of pooled data was conducted, and the risk ratio with corresponding confidence intervals was calculated in the meta-analysis and summarized. Sixteen studies were included in the qualitative analysis, nine of which were examined in the meta-analysis. Although G-CSF significantly shortened the duration of neutropenia, primary prophylaxis with G-CSF did not correlate with infection-related mortality. Moreover, primary prophylaxis with G-CSF did not affect disease progression/recurrence, overall survival, or adverse events, such as musculoskeletal pain. However, evidence to support or discourage the use of G-CSF as primary prophylaxis for adult AML patients with induction therapy remains limited. Therefore, the use of G-CSF as primary prophylaxis can be considered for adult AML patients with remission induction therapy who are at a high risk of infectious complications.

Prophylaxis of hepatic encephalopathy: current and future drug targets.

Hepatic encephalopathy is described by a broad spectrum of neurological and psychiatric aberrations resulting due to advanced liver dysfunction. It is a neurological disorder due to hepatic insufficiency and/or portosystemic shunts. Its clinical presentation includes neuropsychiatric dysfunction ranging from subclinical changes to comatose state. It is a sign of poor prognosis in cirrhotics with a high 1-year mortality. Each episode of hepatic encephalopathy leads to high hospitalization rate, poor prognosis and raised burden of healthcare. Primary prophylaxis is prevention of initial occurrence and secondary prophylaxis is prevention of reappearance of hepatic encephalopathy in subjects who had prior history. Early detection and management of triggers is very important in the treatment of hepatic encephalopathy. The initial choice of treatment is still lactulose, as it is effective in minimal, overt, and recurrent hepatic encephalopathy. Rifaximin is equally effective as lactulose in managing hepatic encephalopathy and is better tolerated. Branch chain amino acids are beneficial in subjects who are protein intolerant. L-ornithine L-aspartate and probiotics are also useful in the management of hepatic encephalopathy. Rifaximin along with lactulose is effective in managing overt and recurrent hepatic encephalopathy. Large portosystemic shunts embolization and liver transplant is efficacious in certain group of patients. Nutritional therapy and fecal microbiota transplantation are newer therapies for hepatic encephalopathy but the evidences are limited, more research is required to prove their efficacy. Involvement of hospital pharmacists, telemedicine, and providing education are also beneficial in managing hepatic encephalopathy.

Endoscopic Treatment and Prevention of Acute Variceal Hemorrhage

Gastroesophageal varices occur in more than half of patients with cirrhosis and the incidence increases as liver function worsens. Although the mortality rate for acute variceal bleeding has decreased with the development of variceal endoscopic hemostasis and administration of vasoactive drugs and prophylactic antibiotics, it still reaches 20%. Therefore, surveillance of variceal occurrence and the prevention of their bleeding is very important in patients with cirrhosis. In patients with liver cirrhosis accompanied by portal hypertension, esophagogastroduodenoscopy should be performed to diagnose varices and stratify their bleeding risk. The interval of endoscopic surveillance is adjusted according to variceal condition and cirrhosis severity. If varices are diagnosed, primary prophylaxis (e.g., non-selective beta-blockers or endoscopic prophylaxis) is required to prevent variceal bleeding. Appropriate treatment, including timely endoscopic hemostasis, should be performed in patients with acute variceal bleeding, and secondary prophylaxis is required to prevent rebleeding. Endoscopic variceal ligation is the recommended endoscopic treatment for acute esophageal variceal bleeding; endoscopic variceal obstruction is usually recommended in patients with gastric varices. To prevent bleeding, endoscopic surveillance should be performed at regular intervals until the varices have been eradicated, and endoscopic followup should be performed periodically even after their disappearance. In this review, we investigate the role of endoscopy in the treatment and management of gastroesophageal varices.

Mortality in recipients of allogeneic haematopoietic cell transplantation in the era of cytomegalovirus primary prophylaxis: a single-centre retrospective experience

ObjectivesAllogeneic haematopoietic cell transplant (allo-HCT) recipients who are cytomegalovirus (CMV)-seronegative have better post-transplant outcomes than CMV-seropositive recipients. Letermovir (LTV) is approved for CMV primary prophylaxis in adults who are CMV-seropositive after allo-HCT, and its use is associated with improved long-term post-transplant outcomes. We analysed whether LTV has affected the relationship between CMV serostatus and post-transplant outcomes. MethodsWe conducted a retrospective single-centre cohort study of allo-HCT recipients, stratified according to donor (D) and recipient (R). CMV serostatus and the use of LTV: D−/R−, R+/LTV−, and R+/LTV+. Outcomes measured were all-cause and non-relapse mortality, clinically significant CMV infection, graft-versus-host disease, and relapse up to week 48 after allo-HCT. The D−/R− group served as the reference for comparisons in univariate, competing risk regression, and cumulative incidence functions. ResultsThe analysis included 1071 consecutive allo-HCT recipients: 131 D−/R−, 557 R+/LTV−, and 383 R+/LTV+. All-cause mortality by day 100 was 6.1% for the D−/R− group, compared with 14.0% (p 0.024) and 7.8% (p 0.7) for the R+/LTV− and R+/LTV + groups, respectively. Non-relapse mortality by day 100 was 11.0%, 6.8% and 3.8% for R+/LTV−, R+/LTV+, and D−/R− groups, respectively, without significant difference. When including relapse as a competing event, the hazard ratio for non-relapse mortality was 1.83 (95% CI: 1.12–2.99, p 0.017) for R+/LTV− compared with D−/R− and 1.05 (95% CI 0.62–1.77, p 0.85) for R+/LTV + compared with D−/R−. DiscussionCMV primary prophylaxis with LTV abrogated the mortality gap based on CMV serostatus, a protective effect that persisted after discontinuation of primary prophylaxis.

Teclistamab in relapsed refractory multiple myeloma: multi-institutional real-world study

The objective of our study was to report real-world data on the safety and efficacy of standard-of-care teclistamab in patients with relapsed/refractory multiple myeloma (MM). This is a multi-institutional retrospective cohort study and included all consecutive patients that received at least one dose of teclistamab up until August 2023. One hundred and ten patients were included, of whom, 86% had triple-class refractory disease, 76% penta-refractory disease, and 35% had prior exposure to B-cell maturation antigen (BCMA)-targeting therapies. The overall response rate (ORR) in our cohort was 62%, with a ≥ very good partial remission (VGPR) rate of 51%. The ORR in patients with and without prior BCMA-targeted therapies was 54% vs 67%, respectively (p = 0.23). At a median follow-up of 3.5 months (range, 0.39–10.92), the estimated 3 month and 6 month progression free survival (PFS) was 57% (95% CI, 48%, 68%) and 52% (95% CI, 42%, 64%) respectively. The incidence of cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) was 56% and 11% respectively, with grade ≥3 CRS and ICANS noted in 3.5% and 4.6% of patients respectively. 78 unique infections were diagnosed in 44 patients, with the incidence of all-grade and grade ≥3 infections being 40% vs 26% respectively. Primary prophylaxis with intravenous immunoglobulin (IVIG) was associated with a significantly lower infection risk on multivariate analysis (Hazard ratio [HR] 0.33; 95% CI 0.17, 0.64; p = 0.001).

Real-Life Data on the Efficacy and Safety of Letermovir for Primary Prophylaxis of Cytomegalovirus in Allogeneic Hematopoietic Stem Cell Recipients: A Single-Center Analysis

Cytomegalovirus (CMV) reactivation is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). Introduction of letermovir (LMV) seems to improve post-transplant outcomes, but delayed-onset CMV reactivation still remains a challenge. In this study, we report on our first experience with LMV prophylaxis in 93 CMV-seropositive adult patients receiving HSCT in our center. We retrospectively analyzed the data of 93 adult CMV-seropositive recipients receiving LMV as CMV prophylaxis after HSCT for hematological malignancies between 2019 and 2023. The starting LMV dose was 480 mg daily, reduced to 240 mg daily for those receiving cyclosporin A co-administration. CMV DNA in the blood was measured by real-time polymerase chain reaction weekly for the first 2 months after transplantation, then every other week until the end of immunosuppressive treatment. LMV was continued to day +100 or to CMV reactivation. The median recipient age at the time of transplant was 51 (range: 20-71) years. All patients received grafts from peripheral blood, mostly for acute myeloid leukemia (60%). The median time from transplantation to LMV initiation was 3 (range: 0-24) days. While 55% of patients were transplanted from matched related donors, 32% had unrelated donors and 13% underwent haploidentical HSCT. Four patients (4%) had CMV “blips” while on LMV, but the drug was continued and repeated assays were negative. Only 2 patients (2%) experienced CMV reactivation while on LMV, on days 48 and 34 after HSCT, respectively. Seven patients (7%) developed late-onset CMV reactivation after a median of 124 days after HSCT (range: 118-152 days) and they were successfully treated with ganciclovir. CMV disease was not observed. Grade III-IV acute graft-versus-host disease occurred in 6 patients (6%) during LMV treatment. LMV treatment was free of side effects. LMV prophylaxis was effective in preventing CMV reactivation with a favorable safety profile. CMV reactivation occurred mostly after LMV discontinuation; thus, extending the duration of prophylaxis beyond 100 days could be beneficial.

Arthroscopic ankle surgery in people with haemophilia.

People with haemophilia (PWH) not administered primary haematological prophylaxis since childhood, that is, those treated haematologically on demand or not treated at all, often experience the degeneration of the ankles, leading to pain and functional impairment. To analyse the outcomes and complications of arthroscopic ankle surgery performed on PWH. For this narrative review of the literature, a search was conducted in PubMed on 2, December 2023, using the keywords "haemophilia", "ankle" and "arthroscopy". Of the 29 articles identified, 15 specifically related to ankle arthroscopy in PWH were selected (inclusion criterion). The remaining articles did not meet this requirement (exclusion criterion) and were therefore eliminated. Arthroscopic procedures (arthroscopic synovectomy, debridement and arthrodesis of the ankle) are increasingly used in the surgical treatment of haemophilic ankle arthropathy. Although arthroscopic ankle surgery offers good outcomes in patients with haemophilia, the procedure is not free of complications, which range from 7.9% for arthroscopic ankle debridement to 13.1% in arthroscopic ankle synovectomy and 17.8% in arthroscopic ankle arthrodesis, respectively. The non-union rate of arthroscopic ankle arthrodesis is 7.1% (2/28). Although arthroscopic interventions in the haemophilic ankle (synovectomy, debridement, arthrodesis) offer good functional outcomes, they are associated with a non-negligible rate of complications. Arthroscopic ankle surgery in PWH is major surgery and should be treated as such.

The Use of Granulocyte Colony-Stimulating Factor as Primary Prophylaxis in Patients Undergoing Chemotherapy: An Experience of Moroccan Oncologists.

Febrile neutropenia (FN) is a frequent and serious emergency for oncologic patients undergoing chemotherapy. Using granulocyte colony-stimulating factor (G-CSF) as primary prophylaxis of febrile neutropenia is an integral part of the management of cancer patients. Our study aims to identify the challenges that prevent Moroccan oncologists from prescribing G-CSF for primary prevention. Seventy doctors participated in our study, with a participation rate of 35.35%. Twenty-two participants had at least five years of experience in oncology. Most participants were medical oncologists (82.9%), and two-thirds of them practiced in teaching hospitals. Regarding the use of G-CSF in primary prevention, all participants complied with the recommendations for FN risk assessment and the prescription of G-CSF for prophylaxis in patients at high risk of FN (>20%). However, their use in intermediate-risk patients remains limited mainly by the cost of these drugs (45.7% of participants). FN remains a dreadful complication in oncology. Since the introduction of G-CSF into standard oncology practice, particularly in primary prevention, the management of certain patients has improved considerably. Nevertheless, the indications for G-CSF in our context, essentially in intermediate-risk patients, are uncertain.

Effectiveness and safety of primary prophylaxis with G-CSF for lung cancer: a systematic review and meta-analysis to develop clinical practice guidelines for the use of G-CSF 2022.

Granulocyte colony-stimulating factor (G-CSF) is commonly administered to cancer patients undergoing myelosuppressive chemotherapy, especially when incidence rate of febrile neutropenia (FN) surpasses 20%. While primary prophylaxis with G-CSF has been proven effective in preventing FN in patients with cancer, there is limited evidence regarding its efficacy in specifically, lung cancer. Our systematic review focused on the efficacy of G-CSF primary prophylaxis in lung cancer. We extracted studies on non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) using the PubMed, Ichushi Web, and Cochrane Library databases. Two reviewers assessed the extracted studies for each type of lung cancer and conducted quantitative and meta-analyses of preplanned outcomes, including overall survival, FN incidence, infection-related mortality, quality of life, and musculoskeletal pain. A limited number of studies were extracted: two on NSCLC and six on SCLC. A meta-analysis was not conducted owing to insufficient data on NSCLC. Two case-control studies explored the efficacy of primary prophylaxis with G-CSF in patients with NSCLC (on docetaxel and ramucirumab therapy) and indicated a lower FN frequency with G-CSF. For SCLC, meta-analysis of five studies showed no significant reduction in FN incidence, with an odds ratio of 0.38 (95% confidence interval 0.03-5.56, P = 0.48). Outcomes other than FN incidence could not be evaluated due to low data availability. Limited data are available on G-CSF prophylaxis in lung cancer. Primary prophylaxis with G-CSF may be weakly recommended in Japanese patients with NSCLC undergoing docetaxel and ramucirumab combination therapy.

The impact of antiphospholipid antibodies/antiphospholipid syndrome on systemic lupus erythematosus.

aPLs are a major determinant of the increased cardiovascular risk in patients with SLE. They adversely affect clinical manifestations, damage accrual and prognosis. Apart from the antibodies included in the 2006 revised classification criteria for APS, other non-classical aPLs might help in identifying SLE patients at increased risk of thrombotic events. The best studied are IgA anti-β2-glycoprotein I, anti-domain I β2-glycoprotein I and aPS-PT. Major organ involvement includes kidney and neuropsychiatric systems. aPL/APS severely impacts pregnancy outcomes. Due to increased thrombotic risk, these patients require aggressive cardiovascular risk factor control. Primary prophylaxis is based on low-dose aspirin in high-risk patients. Warfarin is the gold-standard drug for secondary prophylaxis.

Modeling Invasive Aspergillosis Risk for the Application of Prophylaxis Strategies.

The epidemiology of invasive aspergillosis (IA) is evolving. To define the patient groups who will most likely benefit from primary or secondary Aspergillus prophylaxis, particularly those whose medical conditions and IA risk change over time, it is helpful to depict patient populations and their risk periods in a temporal visual model. The Sankey approach provides a dynamic figure to understand the risk of IA for various patient populations. While the figure depicted within this article is static, an internet-based version could provide pop-up highlights of any given flow's origin and destination nodes. A future version could highlight links to publications that support the color-coded incidence rates or other actionable items, such as bundles of applicable pharmacologic or non-pharmacologic interventions. The figure, as part of the upcoming Infectious Diseases Society of America's aspergillosis clinical practice guidelines, can guide decision-making in clinical settings.

A retrospective cohort study to monitor real-world safety in patients with locally advanced or metastatic urothelial carcinoma (LA/mUC) treated with sacituzumab govitecan (SG) in the United States.

608 Background: Patients with LA/mUC experience poor outcomes, with few treatment options historically available. In April 2021, SG (a TROP-2-directed antibody drug conjugate) received accelerated approval for patients with LA/mUC who progressed after platinum-based chemotherapy and immune checkpoint inhibitor therapy, based on the pivotal TROPHY U-01 trial (NCT03547973). We sought to evaluate SG safety in patients with LA/mUC treated in routine clinical practice in this study. Methods: A retrospective cohort of patients aged ≥ 18 years with LA/mUC treated with SG in the United States was evaluated using data from the nationwide Flatiron Health electronic health record–derived de-identified database (from Jan 2011 to Oct 2022). Outcomes included patient characteristics, treatment patterns, adverse events (AEs) of interest incidence, and granulocyte-colony stimulating factor (G-CSF) use. Descriptive statistics were used for data analysis. Results: This study included 86SG-treated patients (male, 70%; median age, 71 [range: 25-85] years; 27% with ECOG ≥ 2; 84% treated in community settings). Most patients (71%) received enfortumab vedotin (EV) in the direct prior line. The majority of patients received SG as monotherapy (94%), with most patients overall (99%) receiving SG as second-line (2L) or later. The most common AEs of interest (any grade, overall) were diarrhea (35%), neutropenia (40%) and nausea/vomiting (21%) (Table). Of the 86 patients, 14 (16%) patients were hospitalized, 8 (9%) discontinued SG treatment likely due to AEs/toxicity, and 3 (3%) died during or within 7 days after the line of treatment. During SG treatment, 52% of patients used G-CSF (primary prophylaxis 24%; secondary prophylaxis 19%; therapeutic use 28%). Only 1 (4.5%) patient who had primary G-CSF prophylaxis developed grade ≥ 3 neutropenia. Conclusions: This study is the largest analysis of SG use in a real-world population with LA/mUC to date; it provides insights into the safety of SG in this setting. Compared with prior data, this real-world population was older, with poorer functionality, and the majority received EV in the direct prior line. Observed AEs were consistent with the known safety profile of SG and indicate that this sequencing is feasible. [Table: see text]

Letermovir for Cytomegalovirus infection in pediatric patients undergoing allogenic hematopoietic stem cell transplantation: a real-life study by the Infectious Diseases Working Group of Italian Association of Pediatric Hematology-Oncology (AIEOP).

Letermovir prophylaxis revolutionized the approach to Cytomegalovirus infection in adult hematopoietic stem cell transplant (HCT), while data in pediatric setting are still lacking. We retrospectively analyzed 87 HCT children transplanted in 11 AIEOP centers receiving letermovir as off-label indication between January 2020 and November 2022. Letermovir was used as primary, secondary prophylaxis or CMV treatment in 39, 26 and 22 cases, respectively; no discontinuation due to toxicity was reported. Median duration was 100 days (14-256) for primary and 96 days (8-271) for secondary prophylaxis, respectively. None of the patients experienced CMV-clinically significant reactivation during Letermovir primary prophylaxis; one patient developed breakthrough infection during secondary prophylaxis, and 10 and 1 patient experienced asymptomatic CMV-reactivation and CMV-primary infection after drug discontinuation, respectively. Median duration of letermovir in CMV treatment was 40 days (7-134), with 4/22 patients suffering CMV-pneumonia, with an overall response rate of 86.4%. With a median follow-up of 10.7 months (8.2-11.8), estimated 1-year overall survival was 86%; no CMV-related deaths were reported in prophylaxis groups. This is the largest report on Letermovir use in pediatric HCT; real-life data confirm an excellent toxicity profile, with high efficacy as CMV prophylaxis; results in CMV-infection treatment should be investigated in larger, prospective trials.

Cost-effectiveness analysis of mecapegfilgrastim and recombinant human granulocyte stimulating factor for primary prophylaxis of chemotherapy-induced neutropenia innon-small cell lung cancer.

To evaluate the efficacy, safety, and economics of mecapegfilgrastim and recombinant human granulocyte colony-stimulating factor (rhG-CSF) in the primary prevention of chemotherapy-related neutropenia in non-small cell lung cancer (NSCLC). Data from 181 patients with NSCLC who received intermediate risk chemotherapy were collected from the information system of a tertiary hospital in China. Patients were categorized into two groups: those treated with mecapegfilgrastim (n=91) and those treated with rhG-CSF (n=90). The clinical efficacy rates of neutropenia prevention were used as effect indicators, and a cost-effectiveness analysis was conducted from the perspective of the Chinese healthcare system. Logistic regression, generalized linear regression, and bootstrap methods were used for sensitivity analyses. There was no statistical difference between the mecapegfilgrastim and rhG-CSF groups in clinical efficacy rates (98.9 vs. 97.8%). However, the total cost in the mecapegfilgrastim group was significantly higher than that in the rhG-CSF group (16,341.6 CNY vs. 14,371.1 CNY, p=0.03). The cost-minimization analysis shows that mecapegfilgrastim is not cost-effective. The sensitivity analyses confirm that these results are robust. Compared with rhG-CSF, mecapegfilgrastim is not a cost-effective strategy for NSCLC patients in neutropenia prevention in China.

Impact of primary prophylaxis (PP) with granulocyte colony-stimulating factor on the outcomes of patients with locally advanced gastric cancer treated with FLOT: A single-center retrospective analysis.

414 Background: The role of primary prophylaxis (PP) with granulocyte colony-stimulating factor (G-CSF) for patients with locally advanced gastric cancer (LAGC) treated with FLOT is currently unknown. Although original FLOT4 study did not recommend PP, the use of G-CSF is common in clinical practice to avoid serious complications. However, its use is associated with increased financial costs. Methods: This is a retrospective, single-institution study. We included patients with pathologically confirmed LAGC who received perioperative FLOT4. Patients were categorized in two groups: PP versus no- PP. Our objectives were to compare frequency of grades 3 or 4 neutropenia (G3/4N) and febrile neutropenia (FN) between PP and non-PP patients. We also evaluate the association between pathological complete response (pCR) and disease-free survival (DFS) and overall survival (OS) according to the use of PP. Binomial variables were compared using Fisher's exact test. Kaplan-Meier method was used to calculate median DFS and OS and respective 95% confidence intervals [95%CI] and any difference assessed by the log-rank test. Results: From January 2019 until December 2022, 122 LAGC patients were treated with perioperative FLOT. Median age was 56 years, 53.2% were female and 84.4% were ECOG 0. Primary prophylaxis (PP) was used by 58 patients (47.5%); there was no difference between clinical and tumor features between both groups regarding age, sex, ECOG, T and N staging and Lauren’s subtype. PP costs raised treatment costs up to 15%. Grade 3 or 4 neutropenia occurred more frequently among patients without PP (65.6 vs. 1.7%; p < 0.001). There was no difference in the frequency of FN between groups (7.8 vs. 0%; p = 0.06). Overall patients, pCR occurred in 11.8% os patients. Regarding the influence of PP in pathological response after FLOT chemotherapy, there was no difference between PP vs non-PP patients with pCR (14.3% vs 9.5%, p = 0.57). Median follow-up was 27.4 (range 2.8 – 70.6 months). Twenty-six patients (21.3%) died during follow-up. Median OS was 52.5 months (95% CI: 47.1-57.8). Median OS for patients in PP and no PP groups were 44.5 and 56.2 months (log-rank P =0.06), respectively. Median DFS was 43.1 months (95% CI: 37.2-48.9). Median DFS for patients in PP and no PP groups were 39.6 and 43.5 months (log-rank P =0.80), respectively. Conclusions: Despite the reduction in the frequency of G3/4N, rates of FN among patients treated with FLOT with G-CSF are too low to justify its use in a routine basis. Furthermore, PP is not associated with relevant clinical endpoints such as pCR neither OS or DFS. Based on this, PP in such situations should not be routinely used due to its financial costs.

Phase II study of the safety and efficacy of discontinuing pegfilgrastim for pancreatic adenocarcinoma treated with FOLFIRINOX.

663 Background: The original FOLFIRINOX regimen (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) for pancreatic ductal adenocarcinoma (PDAC) is associated with a high risk of febrile neutropenia (FN), and pegfilgrastim has been used to reduce the risk. However, it remains unclear how long pegfilgrastim needs to continue. This study evaluated the safety and efficacy of FOLFIRINOX after discontinuing pegfilgrastim in PDAC patients. Methods: This prospective phase II trial included patients with PDAC who received the first three courses of FOLFIRINOX, with primary pegfilgrastim prophylaxis for FN, and did not experience FN. The patients continued on FOLFIRINOX without pegfilgrastim from the fourth course. The primary endpoint was development of FN. The secondary endpoints included relative dose intensity (RDI), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The threshold and expected development of FN were 20% and 7%, respectively, at a one-sided significance level of 0.10 and statistical power of 80%. Based on this hypothesis, we calculated the number of patients needed to be 33. Results: In total, 34 patients (20 male, median age 66 years) were enrolled from August 2017 to September 2021. Twenty-three patients were unresectable, and 11 were borderline resectable. FN developed in one patient. Grade 4 neutropenia was observed in six patients, grade 3 neutropenia in 10 (29.4%), anemia in four (11.8%), diarrhea in two (5.9%), and malaise, lung infection, peripheral sensory neuropathy, colitis, and biliary tract infection in one (2.9%) each. Twenty-two patients required dose reduction, mainly because of neutropenia. Mean RDIs at the sixth course of oxaliplatin, irinotecan, leucovorin, acute infusion of fluorouracil, and continuous infusion of fluorouracil were 77.0%, 88.2%, 81.8%, 84.4%, and 87.6%, respectively. ORR, median PFS, and median OS were 44.1%, 15.8 months, and 25.8 months, respectively. Conclusions: FOLFIRINOX can be continued safely with a low incidence of FN after discontinuing pegfilgrastim in PDAC patients who did not experience FN during the first three courses of FOLFIRINOX, if the drug dose is reduced appropriately for neutropenia from the fourth course. Clinical trial information: UMIN000028055 .

Efficacy and safety of dendrimer-enhanced (DEP) cabazitaxel (CTX-SPL9111) in advanced esophagogastric cancers in a phase 1/2 trial.

374 Background: There is a significant unmet need in esophagogastric cancers (EGC) due to limited effective treatments (Tx) and poor prognosis. Dendrimers are highly branched nanoparticles that enable sustained delivery of cytotoxic drugs and achieve selective tumor targeting via an enhanced permeability and retention effect. DEP cabazitaxel is a highly optimised dendrimer formulation of cabazitaxel. Unlike standard cabazitaxel, DEP cabazitaxel is highly water soluble, does not contain toxic excipients such as polysorbate-80 associated with anaphylaxis, and avoids the need for steroid/antihistamine pre-medication. The objective of this Phase 1/2 trial was to assess preliminary efficacy and safety of DEP cabazitaxel in patients (pts) with advanced solid tumors including EGC, for which standard cabazitaxel is not approved. Methods: In the P2 part of the trial, advanced EGC pts with measurable disease were treated with DEP cabazitaxel 20 mg/m2 cabazitaxel, the recommended Phase 2 dose, IV 3-weekly. Anti-tumour activity was assessed by RECIST v1.1, safety by CTCAE v4.03. (EudraCT 2017-003424-76). Results: Fifteen pts with advanced EGC were enrolled; 9 adenocarcinoma (ADENOCA) (3 gastric, 2 esophageal and 4 EG junction) and 6 esophageal squamous cell carcinoma (ESCC); median age 62 yrs (26–73 yrs), with all pts having ≤3 prior anticancer Tx, and the majority (9) having progressed on or immediately after 1st line Tx (1L). All had ≥1 prior platinum-based regimen and 4 pts had received prior taxanes. Pts received a median of 4.5 DEP cabazitaxel cycles without the need for routine steroid/antihistamine or primary G-CSF prophylaxis. In all evaluable pts, disease control rate (DCR) was 80%. Disease control was observed in both histological subtypes and was durable, including stable disease (SD) for up to 27 weeks and partial responses (PR) for up to 17 weeks, with objective response rate (ORR) of 30%. In EG ADENOCA pts, DCR was 100%, ORR was 33%, and median progression free survival (mPFS) was 4.0 months. In ESCC pts, DCR was 50% and ORR was 25%, with mPFS of 1.9 months. DEP cabazitaxel was well-tolerated with mostly mild (62.9%, Grade (G) 1)/moderate (20.2%, G2) treatment-related adverse events (TRAEs), including nausea, vomiting, fatigue, neuropathy, neutropenia (only 1 pt had G-CSF Tx, 1 pt had secondary G-CSF prophylaxis) and anemia, that were like those observed with standard cabazitaxel Tx. Of severe TRAEs (G3/4; 16.9%) most (80%) were observed in 2 pts, including neutropenia, anemia, thrombocytopenia, fistula, elevated liver enzymes. Conclusions: DEP cabazitaxel exhibited highly encouraging anti-tumor activity in >1L, advanced EGC in multiple anatomic locations and of different histological sub-types. The preliminary efficacy and safety results compare favorably to available treatment options and highlight the promising clinical potential of DEP cabazitaxel in advanced EGC. Clinical trial information: EudraCT 2017-003424-76 .

Utility of P²MS Index in Predicting Esophageal Varices in Patients with Hepatitis C Associated Chronic Liver Disease in Pakistani Population

Background: Screening for esophageal varices (EVs) in patients with chronic liver disease is critical for identifying those needing primary prophylaxis against variceal bleeding. The gold standard for EV screening is endoscopy, an invasive and costly procedure often avoided by patients. This necessitates the need for non-invasive predictive tools for the presence of EVs and high-risk varices (HRVs). The P²MS index, a relatively new model, has shown promise in this regard. Objective: This study aimed to evaluate the effectiveness of the P²MS index, alongside APRI and FIB-4 scores, in predicting the presence of EVs and HRVs in patients with hepatitis C-related chronic liver disease. Methods: Conducted at the Sindh Institute of Urology and Transplantation's Hepato-Gastroenterology department, this cross-sectional study involved 375 participants aged 18-50 years, recently diagnosed with liver cirrhosis due to hepatitis C. Excluding those with varied medical backgrounds, the study used non-probability consecutive sampling. Diagnostic procedures included esophagogastroduodenoscopy (EGD) and complete blood count. P²MS index, APRI, and FIB-4 scores were calculated for each participant. Data analysis was performed using SPSS version 25.0, focusing on the Area Under the Receiver Operating Curve (AUROC) to assess diagnostic accuracy. Results: In our population, the P²MS index at a cutoff of <10.7 showed a specificity of 93.22% and sensitivity of 87.88% for predicting the presence of EVs, with a PPV and diagnostic accuracy exceeding 90%. For HRVs, a cutoff of <5.4 demonstrated an excellent NPV, alongside good sensitivity, specificity, and diagnostic accuracy. Compared to APRI and FIB-4, the P²MS index had the highest AUROC for predicting the presence of EVs (0.92, 95% CI 0.89-0.95, p<0.001). For HRVs, it was comparable to APRI (AUROC=0.88, 95% CI 0.85-0.92, p<0.01) and superior to FIB-4. Conclusion: The P²MS index is an effective non-invasive tool for screening EVs in patients with hepatitis C-related chronic liver disease, demonstrating high accuracy for predicting the presence of EVs. However, its efficacy in predicting HRVs is comparable to other non-invasive indices and warrants further validation.