Bridge To Transplantation Research Articles

Effective bridging strategies prior to infusion with tisagenlecleucel results in high response rates and long-term remission in relapsed/refractory large B-cell lymphoma: findings from a German monocentric study

BackgroundIncorporating chimeric antigen receptor (CAR)-T cell therapy into relapsed or refractory large B-cell lymphoma (rr LBCL) treatment algorithms has yielded remarkable response rates and durable remissions, yet a substantial portion of patients experience progression or relapse. Variations in outcomes across treatment centers may be attributed to different bridging strategies and remission statuses preceding CAR-T cell therapy.PatientsTwenty-nine consecutive adult patients receiving tisagenlecleucel (tisa-cel) for rr LBCL from December 2019 to February 2023 at Jena University Hospital were analyzed.ResultsThe median age was 63, with a median of 3 prior treatments. Twenty patients (69%) were refractory to any systemic therapy before CAR-T cell treatment. Following leukapheresis, 25 patients (86%) received bridging therapy with the majority undergoing chemotherapy (52%) or combined modality therapy (32%). Radiotherapy (RT) was part of the bridging strategy in 44%, with moderately hypofractionated involved site RT (30.0 Gy/2.5 Gy) being applied most frequently (64%). Post-CAR-T infusion, the objective response rate at 30 days was 83%, with 55% achieving complete response. Twelve-month progression-free (PFS) and overall survival (OS) were 60% and 74%, respectively, with a median follow up of 11.1 months for PFS and 17.9 months for OS. Factors significantly associated with PFS were chemotherapy sensitivity pre-leukapheresis and response to bridging.ConclusionThe study underscores the importance of minimal tumor burden at CAR-T initiation, emphasizing the need for suitable bridging regimens. The findings advocate for clinical trials and further real-world analyses to optimize CAR-T cell therapy outcomes by identifying the most effective bridging strategies.

Letter to the Editor Regarding “Safety and Efficacy of Direct Thrombectomy Versus Bridging Therapy in Patients with Acute Ischemic Stroke Eligible for Intravenous Thrombolysis: A Meta-Analysis of Randomized Controlled Trials”

Letter to the Editor Regarding “Safety and Efficacy of Direct Thrombectomy Versus Bridging Therapy in Patients with Acute Ischemic Stroke Eligible for Intravenous Thrombolysis: A Meta-Analysis of Randomized Controlled Trials”

Peripheral Nerve Stimulation for Arm Pain in an Adolescent Girl with Ewing Sarcoma as Bridge Therapy to Chemotherapy: A Case Report

BACKGROUND: Cancer commonly presents discomfort from abnormal cell growth in healthy tissue and is often inadequately managed. Peripheral nerve stimulation (PNS), mainly for non-cancer chronic pain, has emerged as a minimally invasive option for neuropathic cancer-related pain when conventional methods fail. Limited research, primarily in adults, has focused on PNS in the non-oncological population. CASE REPORT: A 14-year-old adolescent girl with a history of obesity, diabetes, and Ewing sarcoma in her left proximal humerus experienced severe pain, initially rated at 10/10. After undergoing ultrasound-guided left suprascapular PNS as a 60-day bridge therapy to chemotherapy, her pain improved to 3/10 at lead removal and remained at 4/10 at 3 months postremoval. CONCLUSION: PNS is a promising and less invasive neuromodulation approach for managing tumor-related bone pain. Our case study illustrates the effectiveness of PNS placement for significant pain reduction, although limitations, such as delayed response and the need for further randomized-controlled studies, are acknowledged. KEY WORDS: Neuromodulation, peripheral nerve stimulation, Ewing sarcoma, arm pain, bone pain, chemotherapy, teen, adolescent

Managing Infection Complications in the Setting of Chimeric Antigen Receptor T cell (CAR-T) Therapy.

Chimeric antigen receptor T-cell (CAR T-cell) therapy has changed the paradigm of management of non-Hodgkin's lymphoma (NHL) and Multiple Myeloma. Infection complications have emerged as a concern that can arise in the setting of therapy and lead to morbidity and mortality. In this review, we classified infection complications into three categories, pre-infusion phase from the time pre- lymphodepletion (LD) up to day zero, early phase from day of infusion to day 30 post-infusion, and late phase after day 30 onwards. Infections arising in the pre-infusion phase are closely related to previous chemotherapy and bridging therapy. Infections arising in the early phase are more likely related to LD chemo and the expected brief period of grade 3-4 neutropenia. Infections arising in the late phase are particularly worrisome because they are associated with adverse risk features including prolonged neutropenia, dysregulation of humoral and adaptive immunity with lymphopenia, hypogammaglobinemia, and B cell aplasia. Bacterial, respiratory and other viral infections, protozoal and fungal infections can occur during this time . We recommend enhanced supportive care including prompt recognition and treatment of neutropenia with growth factor support, surveillance testing for specific viruses in the appropriate instance, management of hypogammaglobulinemia with repletion as appropriate and extended antimicrobial prophylaxis in those at higher risk (e.g.high dose steroid use and prolonged cytopenia). Finally, we recommend re-immunizing patients post CAR-T based on CDC and transplant guidelines.

Treatment with Elapegademase Restores Immunity in Infants with Adenosine Deaminase Deficient Severe Combined Immunodeficiency

PurposePatients with adenosine deaminase 1 deficient severe combined immunodeficiency (ADA-SCID) are initially treated with enzyme replacement therapy (ERT) with polyethylene glycol-modified (PEGylated) ADA while awaiting definitive treatment with hematopoietic stem cell transplant (HSCT) or gene therapy. Beginning in 1990, ERT was performed with PEGylated bovine intestinal ADA (ADAGEN®). In 2019, a PEGylated recombinant bovine ADA (Revcovi®) replaced ADAGEN following studies in older patients previously treated with ADAGEN for many years. There are limited longitudinal data on ERT-naïve newborns treated with Revcovi.MethodsWe report our clinical experience with Revcovi as initial bridge therapy in three newly diagnosed infants with ADA-SCID, along with comprehensive biochemical and immunologic data.ResultsRevcovi was initiated at twice weekly dosing (0.2 mg/kg intramuscularly), and monitored by following plasma ADA activity and the concentration of total deoxyadenosine nucleotides (dAXP) in erythrocytes. All patients rapidly achieved a biochemically effective level of plasma ADA activity, and red cell dAXP were eliminated within 2–3 months. Two patients reconstituted B-cells and NK-cells within the first month of ERT, followed by naive T-cells one month later. The third patient reconstituted all lymphocyte subsets within the first month of ERT. One patient experienced declining lymphocyte counts with improvement following Revcovi dose escalation. Two patients developed early, self-resolving thrombocytosis, but no thromboembolic events occurred.ConclusionRevcovi was safe and effective as initial therapy to restore immune function in these newly diagnosed infants with ADA-SCID, however, time course and degree of reconstitution varied. Revcovi dose may need to be optimized based on immune reconstitution, clinical status, and biochemical data.

Step-Up Management in Acute Pancreatitis: A Tertiary Care Center's Experience From Southern India.

Background The clinical spectrum of acute pancreatitis (AP) ranges from mild disease to severe form associated with multiorgan failure, prolonged hospital stay, high morbidity, and mortality. Acute necrotizing pancreatitis (ANP) is a severe form of AP. This study evaluates AP's outcomes after applying principles of the step-upapproach in a tertiary healthcare center in south India. Methodology This prospective observational study was carried out from January 2021 to December 2022. The study population includes patients admitted to our department with AP. Results Ninetypatients were included in the study, most of them were middle-aged males with ethanol ingestion as the common etiology. Thirty-seven (41.1%) patients had mild AP, 25 (27.7%)had moderately severe AP, and 28 (31.1%)had severe AP. Organ failure at admission was noted in 36 (40%) patients. Twenty-three (25.5%) patients developed ANP. Infected necrosis was noted in 3 (3.33%) patients. Eighteen (20%) patients needed image-guided percutaneous drainage. Seven (38.8%) needed necrosectomy following percutaneous drainage. Mortality was observed in 8 (8.8%) patients. Specifically, mortality was noted in 6 (6.6%) patients who presented later in their disease course. Conclusions Percutaneous catheter drainage is a safe and effective therapy to tide over the initial phase of AP. It also serves as a bridging therapy till the patient is clinically fit for a necrosectomy. Severe AP cases presenting late in their course are associated with significant mortality even after step-upmanagement. Standardized protocols for referral and management are essential to obtain a good clinical outcome.

Impact of perioperative low-molecular-weight heparin therapy on clinical events of elderly patients with prior coronary stents implanted > 12 months undergoing non-cardiac surgery: a randomized, placebo-controlled trial

BackgroundLittle is known about the safety and efficacy of discontinuing antiplatelet therapy via LMWH bridging therapy in elderly patients with coronary stents implanted for > 12 months undergoing non-cardiac surgery. This randomized trial was designed to compare the clinical benefits and risks of antiplatelet drug discontinuation via LMWH bridging therapy.MethodsPatients were randomized 1:1 to receive subcutaneous injections of either dalteparin sodium or placebo. The primary efficacy endpoint was cardiac or cerebrovascular events. The primary safety endpoint was major bleeding.ResultsAmong 2476 randomized patients, the variables (sex, age, body mass index, comorbidities, medications, and procedural characteristics) and percutaneous coronary intervention information were not significantly different between the bridging and non-bridging groups. During the follow-up period, the rate of the combined endpoint in the bridging group was significantly lower than in the non-bridging group (5.79% vs. 8.42%, p = 0.012). The incidence of myocardial injury in the bridging group was significantly lower than in the non-bridging group (3.14% vs. 5.19%, p = 0.011). Deep vein thrombosis occurred more frequently in the non-bridging group (1.21% vs. 0.4%, p = 0.024), and there was a trend toward a higher rate of pulmonary embolism (0.32% vs. 0.08%, p = 0.177). There was no significant difference between the groups in the rates of acute myocardial infarction (0.81% vs. 1.38%), cardiac death (0.24% vs. 0.41%), stroke (0.16% vs. 0.24%), or major bleeding (1.22% vs. 1.45%). Multivariable analysis showed that LMWH bridging, creatinine clearance < 30 mL/min, preoperative hemoglobin < 10 g/dL, and diabetes mellitus were independent predictors of ischemic events. LMWH bridging and a preoperative platelet count of < 70 × 109/L were independent predictors of minor bleeding events.ConclusionsThis study showed the safety and efficacy of perioperative LMWH bridging therapy in elderly patients with coronary stents implanted > 12 months undergoing non-cardiac surgery. An alternative approach might be the use of bridging therapy with half-dose LMWH.Trial registrationISRCTN65203415.

Apixaban in bridge to transplant and destination LVAD - rationale and study design: the ApixiVAD trial.

Use of novel anticoagulation in mechanical circulatory support is controversial. We report the rationale and design of the ApixiVad pilot trial, a pilot study testing the safety of apixaban as an anticoagulant in patients bridged to transplant (BTT) or for destination (DT) with Heartmate 3 (HM3) left ventricular assist device (LVAD). Apixaban has been used in small non-randomized cohorts in LVAD patients and shown to be effective in ex vivo studies. The ApixiVAD study examines apixaban use in a multicentre, international, open-label, randomized, controlled trial aiming to include 50 BTT or DT HM3 patients with a 1:1 randomization ratio. This event-driven study has a maximum follow-up period of 24months with interim analysis at 6months. The primary outcome is death, thromboembolic events and major bleeding, including operative bleeding and immediate transplant outcomes. The secondary outcome focuses on patients' quality of life related to anticoagulation. This investigator-driven pilot study is not powered to determine the non-inferiority of apixaban. An increase in primary outcome in the apixaban group of 20% will be considered a signal of harm. A positive outcome in the ApixiVAD study would provide the basis for future, larger, pivotal anticoagulation trials in LVAD patients.

Feasibility and Safety of Bridging Antiplatelet Therapy with Cangrelor in Neuro-Oncology: A Preliminary Experience.

Antiplatelet therapy is mandatory for prevention of thrombotic events in patients with a recent history of acute coronary syndromes and/or percutaneous coronary interventions. However, if an urgent surgery is required during antiplatelet therapy, a compromise between the ischemic/thrombotic and hemorrhagic risk has to be reached. Different bridging schemes are reported in the literature, but there is no clear consensus on the optimal treatment strategy in terms of efficacy and safety. Although some indications about the perioperative management of antiplatelet therapy regarding specific surgical specializations are available, balancing the thrombotic and hemorrhagic risk on an individual basis, no evidence referring to neurosurgical or neuro-oncologic procedures is reported. Herein, we present our preliminary experience in the perioperative management of a patient who underwent a neurosurgical procedure for the resection of a primary malignant brain tumor using an intravenous P2Y12 inhibitor (cangrelor) as bridging therapy after a recent acute myocardial infarction treated with primary percutaneous coronary intervention and stenting. The oral P2Y12 inhibitor (clopidogrel) was withdrawn 5 days prior to the surgical procedure and continuous infusion of cangrelor was started 3 days before the surgery at a dose of 0.75 μg/kg/min. Cangrelor was discontinued 2 hours before surgery and resumed 72 hours after tumor resection for further 60 hours. Neither cangrelor-related bleeding nor cardiac ischemic events were observed in the perioperative period and the following 90 days, supporting data regarding the feasibility and safety of this bridging scheme. Further studies are needed to confirm our promising results.

Endovascular thrombectomy with versus without intravenous thrombolysis in patients with acute basilar artery occlusion: a systematic review and meta-analysis.

The benefit and safety of intravenous thrombolysis before endovascular thrombectomy in patients with acute ischemic stroke caused by basilar artery occlusion (BAO) remains unclear. This article aims to investigate the clinical outcomes and safety of endovascular thrombectomy with versus without intravenous thrombolysis in acute BAO stroke patients. We conducted a comprehensive search of PubMed, Embase, Cochrane, and Web of Science databases to identify relevant literature pertaining to patients with acute BAO who underwent endovascular thrombectomy alone or intravenous thrombolysis bridging with endovascular thrombectomy (bridging therapy), until January 10, 2024. The primary outcome was functional independence, defined as a score of 0-2 on the modified Rankin Scale at 90days. The safety outcome was mortality at 90days and symptomatic intracranial hemorrhage within 48h. Effect sizes were computed as risk ratio (RR) with random-effect models. This study was registered in PROSPERO (CRD42023462293). A total of 528 articles were obtained through the search and articles that did not meet the inclusion criteria were excluded. Finally, 2 RCTs and 10 cohort studies met the inclusion criteria. The findings revealed that the endovascular thrombectomy alone group had a lower rate of functional independence compared to the bridging therapy group (29% vs 38%; RR 0.78, 95% CI 0.68-0.88, p < 0.001), lower independent ambulation (39% vs 45%; RR 0.89, 95% CI 0.82-0.98, p = 0.01), and higher mortality (36% vs 28%, RR 1.22, 95% CI 1.08-1.37, p = 0.001). However, no differences were detected in symptomatic intracranial hemorrhage between the two groups (6% vs 4%; RR 1.12, 95% CI 0.74-1.71, p = 0.58). Intravenous thrombolysis plus endovascular thrombectomy seemed to led to better functional independence, independent ambulation, and lower risk of mortality without increasing the incidence of intracranial hemorrhage compared to endovascular thrombectomy alone. However, given the non-randomized nature of this study, further studies are needed to confirm these findings.

Outcome and feasibility of radiotherapy bridging in large B-cell lymphoma patients receiving CD19 CAR T in the UK.

Radiotherapy (RT) has potential synergistic effects with chimeric antigen receptor (CAR) T but is not widely used as bridging therapy due to logistical challenges and lack of standardised protocols. We analysed RT bridging in a multicentre national cohort of large B-cell lymphoma patients approved for 3L axicabtagene ciloleucel or tisagenlecleucel across 12 UK centres. Of 763 approved patients, 722 were leukapheresed, 717 had data available on bridging therapy. 169/717 (24%) received RT bridging, 129 as single modality and 40 as combined modality treatment (CMT). Of 169 patients, 65.7% had advanced stage, 36.9% bulky disease, 86.5% elevated LDH, 41.7% international prognostic index (IPI) ≥3 and 15.2% double/triple hit at the time of approval. Use of RT bridging varied from 11% to 32% between centres and increased over time. Vein-to-vein time and infusion rate did not differ between bridging modalities. RT-bridged patients had favourable outcomes with 1-year progression-free survival (PFS) of 56% for single modality and 47% for CMT (1-year PFS 43% for systemic bridging). This is the largest cohort of LBCL patients receiving RT bridging prior to CAR T reported to date. Our results show that RT bridging can be safely and effectively used even in advanced stage and high-risk disease, with low dropout rates and excellent outcomes.

Inhospital outcomes of implantation of a centrifugal left ventricular assist device in patients with endstage heart failure: experience of the Chazov National Medical Research Center of Cardiology

Aim. To study the inhospital outcomes of implantation of a centrifugal left ventricular assist device (LVAD) in patients with end-stage heart failure (HF).Material and methods. There were following inclusion criteria: estimated body surface area &gt;1,2 m2, end-stage HF, LV ejection fraction &lt;30%, cardiac index &lt;2,2 l/min, long-term optimal therapy for HF. Patients were considered for implantation of a centrifugal (LVAD) as part of the final therapy, but subsequent heart transplantation was not ruled out if appropriate.Results. LVAD was implanted in 23 patients. All patients were men (mean age, 59,1±10 years; mean body mass index, 26±4,6 kg/m2). Ten patients had dilated cardiomyopathy, while 13 — ischemic one. Diabetes was revealed on in 3 (13%) patients, while chronic kidney disease and cancer — in 3 (13%) and 4 (17%) patients, respectively. The mean value of the six-minute walk test (6MWT) upon admission to the hospital was 257±71 meters. In one patient with gastric cancer, the device was implanted as a part of bridging therapy strategy. Thirty-day mortality was 9% (n=2). One of the deceased patients had a long history of end-stage heart failure, body weight deficiency, and frailty with severe muscle weakness. The second death was the result of early postoperative right ventricular failure. At discharge, patients had optimal LVAD performance based on anthropometric characteristics and physical activity. According to echocardiography, the criteria for unloading the left heart chambers have been achieved. The distance of 6MWT at discharge was 298±78 meters.Conclusion. Inhospital outcomes of implantation of a centrifugal LVAD in patients with end-stage HF demonstrate high efficiency in supporting systemic hemodynamics with an acceptable safety profile in patients with extremely high perioperative risk.

Prognostic factors in lung transplantation after extracorporeal membrane oxygenation bridging therapy: a systematic review and meta-analysis.

Extracorporeal membrane oxygenation (ECMO) has recently emerged as a critical support system for lung function in patients awaiting lung transplantation. This meta-analysis investigates the prognostic factors of lung transplantation following ECMO bridging therapy. A comprehensive search was conducted in PubMed, Cochrane Library, Embase, CINAHL, Web of Science, Scopus, and ProQuest databases from inception to August 11, 2023. Included were cohort or case-control studies focusing on prognostic factors of lung transplantation with ECMO bridging therapy. Data extraction was performed independently, and study quality was assessed. A meta-analysis was carried out using RevMan 5.4 and Stata17.0 software to aggregate mortality rates and pertinent prognostic factors of ECMO as a bridge to lung transplantation. The search identified eight trials encompassing 1,086 participants. The prognosis of patients undergoing lung transplantation with ECMO bridging was significantly associated with several factors: prolonged ECMO support [odds ratio 1.07, 95% confidence interval (CI): 1.02-1.12, I2=77%], deterioration in liver and kidney function (odds ratio 3.62, 95% CI: 2.37-5.54, I2=0%), and complications during ECMO (odds ratio 2.24, 95% CI: 1.45-3.44, I2=5%). Prolonged ECMO support, declining liver and kidney functions, and complications during ECMO are vital prognostic factors in lung transplantation following ECMO bridging therapy.

Differences Between the 2016 and 2022 Food and Drug Administration Guidance-Implications for Design and Interpretation of Clinical Trials in Ulcerative Colitis.

In 2022, the Food and Drug Administration (FDA) updated its draft guidance for drug development in ulcerative colitis, replacing the version from 2016. Several changes from the 2016 version merit further discussion as they impact clinical trial design and the interpretation of trial results. We compared both documents and critically appraised the changes and implications for future clinical trials. The 2022 guidance recommends full colonoscopy, rather than flexible sigmoidoscopy, to document disease activity in all involved segments of the colon. The concordance between the findings of the 2 procedures is very high and there is little evidence to support colonoscopy over sigmoidoscopy. The use of colonoscopy, rather than sigmoidoscopy, is also associated with a higher burden to trial participants who must undergo full bowel preparation, cost, and a potential for more adverse events. The definition of the Mayo endoscopic score of 0 was changed from the original publication to "normal appearance of mucosa," which suggests that endoscopic signs of prior disease, such as pseudopolyps and scarring, are incompatible with a score 0, even though they are not associated with active disease. The term "mucosal healing" has been abolished and histologic outcomes defined as exploratory. A welcome change is that shorter washout periods than 5 half-lives will be considered to reduce patient exposure to corticosteroids as bridging therapy. The 2022 FDA draft guidance includes changes which for the most part are not informed by empirical evidence, which may ultimately complicate interpretation of future trials and preclude comparisons with past trials.

Pretransplant use of immune checkpoint inhibitors for hepatocellular carcinoma: A multicenter, retrospective cohort study

Immune checkpoint inhibitors (ICIs) as a downstaging or bridging therapy for liver transplantation (LT) in hepatocellular carcinoma patients are rapidly increasing. However, the evidence about the feasibility and safety of pre-LT ICI therapy is limited and controversial. To this end, a multicenter, retrospective cohort study was conducted in 11 Chinese centers. The results showed that 83 recipients received pre-LT ICI therapy during the study period. The median post-LT follow-up was 8.1 (interquartile range 3.3-14.6) months. During the short follow-up, 23 (27.7%) recipients developed allograft rejection, and 7 of them (30.4%) were diagnosed by liver biopsy. Multivariate logistics regression analysis showed that the time interval between the last administration of ICI therapy and LT (TLAT) ≥ 30 days was an independent protective factor for allograft rejection (odds ratio = 0.096, 95% confidence interval 0.026-0.357; P < .001). Multivariate Cox analysis showed that allograft rejection was an independent risk factor for overall survival (hazard ratio = 9.960, 95% confidence interval 1.006-98.610; P = .043). We conclude that patients who receive a pre-LT ICI therapy with a TLAT shorter than 30 days have a much higher risk of allograft rejection than those with a TLAT longer than 30 days. The presence of rejection episodes might be associated with higher post-LT mortality.

Evaluation of the Validity of Endoscopic Transpapillary Gallbladder Drainage for Acute Cholecystitis Based on the Tokyo Guidelines 2018.

We evaluated the validity of endoscopic transpapillary gallbladder drainage (ETGBD) as a bridging therapy prior to elective Lap-C for the patients with acute cholecystitis (AC). The Tokyo Guidelines 2018 recommend early laparoscopic cholecystectomy (Lap-C) for patients with AC, however, some patients require the preoperative drainage because of inadequate for early Lap-C du to background and comorbidities. We performed a retrospective cohort analysis using data from our hospital records from 2018-2021. In total, 71 cases of 61 patients with AC underwent ETGBD. The technical success rate was 85.9%. Patients in the failure group had more complicated branching of the cystic duct. The length of time until feeding was started and until WBC levels normalized, and the length of hospital stay were significantly shorter in the success group. The median waiting period for surgery was 39 days in the ETGBD success cases. The median operating time, amount of bleeding, and length of postoperative hospital stay were 134 min, 83.2g, and 4 days, respectively. In patients who underwent Lap-C, the waiting period for surgery and the operating time were similar between the ETGBD success and failure groups. However, the temporary discharge period after drainage and the length of postoperative hospital stay were significantly longer in the patients with ETGBD failure. Our study revealed that ETGBD has equivalent efficacy prior to elective Lap-C despite some challenges that lower its success rate. Preoperativ ETGBD can improve patient quality of life by eliminating the need for a drainage tube.

Comparison of the Efficacy and Safety Between Intravenous Thrombolysis, Direct Endovascular Therapy, and Bridging Therapy for Acute Basilar Artery Occlusion in Cerebral Infarction Patients

ObjectiveTo compare the efficacy and safety of intravenous thrombolysis (IVT), direct endovascular therapy (EVT), and bridging therapy (BT=IVT+EVT) for acute basilar artery occlusion cerebral infarction. MethodsOne hundred and fourteen patients with acute basilar artery occlusion cerebral infarctions admitted between January 2020 and August 2023 were selected. Differences in the reperfusion rate, prognosis, incidence of stroke-associated pneumonia, and mortality rate were compared among the three groups. ResultsThere was no statistically significant difference in the percentage of patients who achieved successful reperfusion (86.8% vs. 84.2%) or complete reperfusion (72.1% vs. 68.4%) between the direct EVT and BT groups (both P>0.05). There were no statistically significant differences in the rates of symptomatic intracranial haemorrhage (3.7% vs. 10.3% vs. 10.5%, P=0.763). There were statistically significant differences in the rates of good prognosis (mRS score 0-2) (59.3% vs. 30.9% vs. 26.3%, P=0.021), stroke-related pneumonia (29.6% vs. 66.2% vs. 36.8%, P=0.002), and mortality (14.8% vs. 48.5% vs. 42.1%, P=0.010) among the three treatment groups. According to the binary logistic regression analysis, a good prognosis was independently associated with a baseline National Institutes of Health Stroke Scale (NIHSS) score <=10 (odds ratio [OR], 3.714; 95% confidence interval [CI], 1.207-11.430; P =0.022) and the incidence of stroke-associated pneumonia (OR, 0.640; 95% CI, 0.484-0.845; P=0.002). ConclusionAlthough there were differences in prognosis, mortality, and incidence of complications among the three treatment groups, after adjusting for confounding factors, prognosis was independently correlated only with the baseline NIHSS score and stroke-associated pneumonia but not with treatment methods.

Abstract 3997: PARP inhibitors plus anlotinib as bridging therapy for TGFβ-insensitive CAR-T cell therapy targeting MSLN and CD19 in advanced ovarian cancer

Abstract Background: The efficacy of chimeric antigen receptor (CAR) T cell therapy remains modest for the treatment of solid tumors due to restricted T cell infiltration and immunosuppressive tumor microenvironment (TME). Leveraging the window of opportunity between leukapheresis and infusion using bridging therapy might improve TME and potentiate CAR-T cell therapy. Here, we assessed the potential of poly (ADP-ribose) polymerase (PARP) inhibitors plus anlotinib as bridging therapy for CAR-T cells with resistance to TGFβ and capability of rapid expansion by bait-and-switch strategy of dual-targeting mesothelin (MSLN) and CD19 in preclinical models of advanced ovarian cancer. Methods: Immunocompetent mice bearing ID8 tumors were treated with niraparib (21 days) plus anlotinib (14 days) and euthanized at different timepoints (0, 7, or 14 days since discontinuation) to quantify tumor-infiltrating T cells and profile T cell functions. CAR-T cells transfected with dominant-negative TGFβRII dual-targeting MSLN and CD19 were produced by IASO Biotherapeutics. NSG mice bearing MSLN-positive cell- or patient-derived xenografts (CDX or PDX) of ovarian cancer received CAR-T cells alone or after bridging therapy (niraparib plus anlotinib followed by a wash-out period of 7 days). Tumor volume was balanced before CAR-T cell infusion. Replication-deficient NALM6 cells pre-treated with mitomycin C were injected to provide CD19 antigen. A PET scan that visualized granzyme B release was used to track CAR-T cells and assess immune-mediated tumor killing. Results: Niraparib combined with anlotinib increased tumor-infiltrating T cells without impairing T cell functionality. The effects of promoting T cell infiltration remained significant at 14 days after discontinuation, which might associate with lasting activation of cGAS-STING pathway and secretion of downstream chemokines (CXCL10 and CCL5), and normalized tumor vasculature featured by better perfusion and reduced leakage. The engineered CAR-T cells could resist TGFβ and displayed improved proliferation, cytotoxicity, cytokine release, and in vivo antitumor activities upon CD19 stimulation. Importantly, bridging therapy significantly increased CAR-T cell infiltration, curbed tumor growth, and prolonged survival in mice bearing SKOV3 CDX, HRD-negative PDX, and another multidrug-resistant PDX. PET imaging showed that bridging therapy increased tumor-infiltrating CAR-T cells and boosted tumor-killing capability. Conclusions: PARP inhibitors plus anlotinib as bridging therapy facilitated CAR-T cell infiltration and enhanced antitumor activities in multiple preclinical models of advanced ovarian cancer, and an early phase I trial (NCT05141253) is ongoing to evaluate PARP inhibitors plus anlotinib as bridging therapy for CAR-T cell therapy in patients with refractory MSLN-positive ovarian cancer. Citation Format: Huayi Li, Minghua Xiang, Jiahao Liu, Wei Mu, Li Zhu, Xuejiao Zhao, Gordon B. Mills, Qinglei Gao, Yong Fang. PARP inhibitors plus anlotinib as bridging therapy for TGFβ-insensitive CAR-T cell therapy targeting MSLN and CD19 in advanced ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3997.

Abstract 6327: Impact of G-CSF on safety and efficacy of CAR T-cell therapy in non-Hodgkin lymphoma

Abstract Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy is an established treatment modality for the management of refractory and/or relapsed non-Hodgkin lymphoma (NHL). Despite restrictions on granulocyte colony-stimulating factor (G-CSF) use in registration clinical trials due to potential worsening of cytokine release syndrome (CRS), G-CSF is often prescribed for neutrophil recovery post-CAR-T in clinical practice. We conducted a retrospective study to assess the association between G-CSF use and the safety and efficacy of CAR-T. Methods: Following Institutional Review Board approval, we retrospectively analyzed NHL patients receiving commercial CD19-targeted CAR-T across Mayo Clinic sites (Arizona, Florida, and Minnesota) between October 2017 and May 2023. Demographics, labs, and post CAR-T events were collected. Electronic medical records were reviewed for G-CSF exposure within Day 1 - 100 post-CAR T. Differences by G-CSF status were examined using a Chi-square test and Kruskal Wallis tests. Hazard ratios (HR) and 95% confidence intervals (CI) for overall survival (OS) were calculated using Cox model. Results: Among 270 CAR-T patients; 106 received G-CSF within 30 days and 164 did not. Median age was 56.9 with G-CSF and 58.3 without G-CSF. Most were male (75.2% G-CSF, 62.6% no G-CSF). Diffuse large B cell lymphoma was the predominant NHL subtype (67.0% G-CSF, 65.2% no G-CSF). G-CSF within 30 days was not associated with reduced incidence of neutropenic fever (11.7% G-CSF vs 9.9% no G-CSF, p = 0.6593) or documented infection (22.1% vs 18.3%, p = 0.4439). G-CSF correlated with decreased profound neutropenia duration (ANC &amp;lt; 100 μL, 0 vs 2 days, p &amp;lt; 0.0001) and incidence within 30 days ( 31.7% vs 60.4%, p &amp;lt; 0.0001) as well as incidence of protracted profound neutropenia (&amp;gt; 7 days, 3.8% vs 22.8%, p &amp;lt; 0.0001). G-CSF was associated with a higher incidence of cytopenias between days 30 -100: severe neutropenia (ANC &amp;lt; 500/uL, 28.8% vs 15.2%, p = 0.0075), severe anemia (Hb &amp;lt; 8 g/dL, 21% vs 9.7%, p = 0.0114), and severe thrombocytopenia (Plt &amp;lt; 50 g/L, 35.2% vs 20.9%, p = 0.0099). Logistic regression analysis showed that none of the examined covariates, including prior autologous stem cell transplant, ECOG PS score, and receipt of bridging therapy, were associated with severe neutropenia likelihood. G-CSF was associated with a higher CRS incidence (89.6% vs 79.9%, p = 0.0343), but grade 3 CRS or higher (4.7% vs 3.7%, p = 0.6675) was no different. No difference in complete response rates (66% vs 61.1%, p = 0.4707) or 2-year OS (p = 0.523) was observed between the 2 groups. Conclusion: G-CSF within 30 days was associated with reduced duration and incidence of profound neutropenia without a significant impact on incidence of neutropenic fever or documented infections. There was a signal of association between G-CSF and increased incidence of low-grade CRS and delayed cytopenias (day 30-100) that warrants confirmation in larger studies. Citation Format: Lay She Ng, Claire I. Yee, Radhika Bansal, Mohamed A. Kharfan-Dabaja, Grzegorz S. Nowakowski, Allison C. Rosenthal, Javier Munoz, Januario Castro, Wern Lynn Ng, Hemant S. Murthy, Yi Lin, Matthew R. Buras, Madiha Iqbal, Yucai Wang, Talal Hilal. Impact of G-CSF on safety and efficacy of CAR T-cell therapy in non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6327.

Checkpoint Inhibitors Prior to Autologous Stem Cell Transplantation for Relapsed/ Refractory Hodgkin Lymphoma

Aim: To present the evolution of our patients treated with checkpoint inhibitors before high-dose chemotherapy and autologous stem cell transplantation (ASCT) and to compare the results with data from the literature. Material and methods: We evaluate 3 patients with relapsed/refractory Hodgkin’s Lymphoma, who failed to achieve complete remission after 2 or more lines of salvage chemotherapy and were treated with anti PD1 inhibitors as a bridging therapy to autologous stem cell transplant. To evaluate the treatment response, we used PET CT scan before and 100 days after ASCT. Results: In our study, heavily pre-treated and chemo-refractory patients had increased response rates to conditioning chemotherapy followed by ASCT given after exposure to immune-checkpoint inhibitors. All 3 patients remain in complete response at 14 months, 20 months and respectively 32 months of follow-up. Conclusions: High-dose chemotherapy and ASCT can be curative for many patients with relapsed or refractory Hodgkin’s Lymphoma (HL), but the outcome depends on disease status at ASCT. Patients who have chemorefractory disease, particularly those who fail more than 2 lines of salvage therapy, are considered poor candidates for ASCT. Checkpoint inhibitors are routinely employed in relapsed/refractory classical Hodgkin lymphoma. The results from our center are similar with those from several studies which have suggested that treatment with anti PD1 can sensitize previously chemorefractory HL patients to subsequent high-dose therapy and ASCT.