Prior Bacillus Calmette-Guérin Research Articles

6684 Multi-Dose BCG Vaccination for Protection Against COVID-19 Disease and Other Respiratory Infections in Subjects with Type 1 Diabetes Late in the US Pandemic

Abstract Disclosure: W. Kühtreiber: None. E. Hostetter: None. G.E. Wolfe: None. M. Vaishnaw: None. R. Goldstein: None. E. Bulczynski: None. N. Hullavarad: None. J.E. Braley: None. H. Zheng: None. D.L. Faustman: None. A Phase II clinical trial previously reported that multiple doses of the bacillus Calmette-Guerin (BCG) vaccine, originally developed for tuberculosis prevention, could protect at-risk individuals with type 1 diabetes (T1D) against COVID-19 disease and infectious diseases early in the pandemic in the United States (US) (Cell Rep Med 2022). As SARS-CoV-2 evolved, COVID-19 disease became more transmissible, but less lethal. In a new, Phase III, randomized, double-blinded, placebo-controlled trial, we tested whether at-risk individuals with T1D given multi-dose, intradermal BCG would be protected against COVID-19 and other infectious diseases (2:1 randomization; BCG: n=93; placebo: n=48). The trial was conducted late in the COVID-19 pandemic during sequential dominance of Beta, Gamma, Delta and Omicron variants. All participants were US citizens and were negative for prior BCG vaccination and negative for tuberculosis. Two co-primary endpoints were protection from COVID-19 disease and platform protection from all infectious diseases. From April 2021 to November 2022, Tokyo-strain BCG vaccination provided significant protection against COVID-19 disease (p=0.023) and strong platform protection against all infectious diseases (p<0.0001). Over the 19-month course of the study, commercial COVID-19 vaccines were rolled out. An observational analysis of the placebo control group (i.e., no BCG vaccination) showed that COVID-19 mRNA vaccination alone provided no protection from COVID-19 disease in the enrolled population (p=0.43). BCG vaccination efficacy against COVID-19 and infectious disease in T1D was unaffected by concurrent COVID-19 vaccinations (observational analysis). These data suggest that BCG has efficacy against a range of SARS-CoV-2 variants, in contrast to current COVID-19 vaccines, which have narrow efficacy against specific viral variants. Further, it shows that individuals with T1D represent a vulnerable population for whom BCG appears to be the only effective vaccine against COVID-19 disease and confirms that, in the US, BCG vaccination protects against infectious disease as well. Presentation: 6/3/2024

Reasons for refusal of or ineligibility for radical cystectomy (RC) in patients (Pts) with bacillus Calmette-Guérin (BCG)–unresponsive high-risk non–muscle-invasive bladder cancer (HR NMIBC) from the SunRISe-1 study.

701 Background: RC is the recommended treatment (tx) option for pts with BCG-unresponsive HR NMIBC. However, RC is associated with significant risk of morbidity, mortality, and impact on quality of life (QoL); some patients may refuse/be ineligible for RC. In a systemic review of 160 real-world studies, <20% of pts with HR NMIBC recurrent after BCG underwent RC (PMID 35046678). For RC-ineligible pts, bladder-sparing tx is recommended. TAR-200, a novel intravesical drug delivery system that provides sustained release of gemcitabine within the bladder, is under investigation in pts with BCG-unresponsive HR NMIBC who are ineligible for/refuse RC in the ongoing ph 2b SunRISe-1 (SR-1) study (NCT04640623). Preliminary results showed a promising complete response (CR) rate of 73% and durable responses in pts with BCG-unresponsive HR NMIBC treated with TAR-200 (Daneshmand et al. AUA 2023). We report reasons for refusal/ineligibility for RC in pts enrolled in the TAR-200 monotherapy cohort of SR-1. Methods: SR-1 is evaluating the efficacy and safety of TAR-200 + cetrelimab (CET; anti–PD-1) (Cohort 1 [C1]), TAR-200 alone (C2), or CET alone (C3). Pts ≥18 y with histologically confirmed carcinoma in situ (CIS) ± papillary disease (T1, high-grade Ta) who completed adequate BCG and recurred ≤12 mo since last BCG dose with ECOG performance status (PS) of 0-2 are randomized to C1, C2, or C3. As of Amendment 4, pts with papillary disease only will be enrolled in C4 with TAR-200 alone. The primary end point is overall CR rate at any time. Refusal/ineligibility for RC was documented in the electronic case report form. Results: As of Aug 24, 2023, 54 pts were treated in C2. Median age was 71 y (range 40-85). Pts had a median of 12 (range 7-42) prior BCG doses with a median of 3.0 mo (range 0.2-22.0) from last BCG dose to recurrence. Most pts (96%) had ECOG PS 0; 33% had CIS with papillary disease. 50%, 48%, and 19% of pts had a medical history of Gr ≥2 metabolic, vascular, and cardiac conditions, respectively, and 9% were current nicotine users. Overall, 51 (94%) pts refused RC; 3 (6%) were ineligible (Table). The most common reason for refusal was a preference for bladder preservation (52%), followed by concern about QoL (37%). Pts were ineligible for RC due to medical/surgical comorbidities (4%) and age (2%). Conclusions: Most pts enrolled in C2 of SR-1 refused RC, with preference for bladder preservation and QoL concerns being the most common reason for refusal. This highlights the need for bladder-sparing tx options for pts with HR NMIBC recurrent after BCG. Clinical trial information: NCT04640623 . [Table: see text]

Salvage therapy for BCG failure with intravesical sequential gemcitabine and docetaxel in patients with recurrent NMIBC.

Bacillus Calmette-Guérin (BCG) failure occurs in approximately 40% of patients with non-muscle-invasive bladder cancer (NMIBC) within two years. We describe our institutional experience with sequential intravesical gemcitabine and docetaxel (gem/doce) as salvage therapy post-BCG failure in patients who were not candidates for or declined radical cystectomy (RC). We retrospectively reviewed NMIBC patients with BCG failure who received gem/doce from April 2019 through October 2022 at the CHU de Québec-Université Laval. Patients received at least five weekly intravesical instillations according to published protocols. Patients who responded to gem/doce had maintenance instillations monthly for up to two years. Primary outcome was progression-free survival (PFS). Secondary outcomes included recurrence-free survival (RFS), cystectomy-free survival (CFS), cancer-specific survival (CSS), overall survival (OS), and treatment adverse events. Survival probabilities were estimated using the Kaplan-Meier method from the first gem/doce instillation. Thirty-five patients with a median age of 78 years old were included in the study. The median followup time was 21 months (interquartile range 10-29). More than 25% of patients received two or more prior BCG induction treatments. Overall and MIBC PFS estimates at one year were 85% and 88%, and at two years, 60% and 70%, respectively. Adverse events occurred in 37% of the patients, but only two patients didn't complete the treatment due to intolerance. Three patients underwent RC due to cancer progression. OS was 94% at two years. With 60% of PFS at two years, gem/doce appears to be a safe and well-tolerated option for BCG failure patients. Further studies are needed to justify widespread use.

A-285 Performance Evaluation of LIAISON® QuantiFERON®-TB Gold Plus Assay and Its Use in Long-Term Care Facilities

Abstract Background Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis with 7860 cases reported in 2021 in the United State and estimated 13 million people are living with Latent TB infection (LTBI); Early detection of TB infection is crucial to prevent the spread of the disease; there are two types of tests for TB and LTBI: Tuberculin Skin Test (TST) and Interferon-Gamma Release Assay (IGRA). Although TST has good sensitivity but false-negative reactions occur in certain population and the specificity of is decreased among persons with prior Bacillus Calmette-Guérin (BCG) vaccination, especially those vaccinated post-infancy and those with repeat vaccination. Similarly, persons living in areas where nontuberculous mycobacteria are common are at increased risk of having false-positive TST reactions. IGRA is blood-based laboratory test that measures responses to TB-specific peptide antigens in whole blood. Like the tuberculin skin test (TST), it is an indirect test for M. tuberculosis infection, but is more specific than TST and is unaffected by prior BCG vaccination and most environmental mycobacterial infections. Methods The LIAISON® QuantiFERON®-TB Gold Plus assay is an in vitro diagnostic test for the detection of interferon-γ (IFN-γ) in human lithium heparin plasma by chemiluminescence immunoassay (CLIA) using the LIAISON ® XL Analyzer. The clinical specificity and sensitivity were 96.9% and 84.4% respectively. Clinical studies have shown Positive Percent Agreement (PPA) of 97.4% and Negative Percent Agreement (NPA) of 98.6%. We evaluated the precision, reproducibility, and correlated patient results to our reference lab results. 452 samples collected from Long-Term Care facilities resident were run over 9 months. Statistical analyses were done using Analyse-it. Results The percentage agreement for precision, reproducibility, and accuracy were 100%. The correlation with the reference laboratory was 100% agreement. We found 14.8% of samples tested were positive, 83.2% were negative and 2.0% were indeterminate. Conclusion The LIAISON® QuantiFERON®-TB Gold Plus assay offers the benefit of a fully automated with high sensitivity and specificity. The faster turnaround will aid the physician in the diagnosing M. tuberculosis, eliminates the need for two-step testing, and is preferred in patients who received BCG vaccination. In addition, with the growing geriatric population, the availability of this test will give the physician the opportunity to follow the 2016 American Thoracic Society (ATS)/Infectious Disease Society of America (IDSA)/CDC clinical practice guidelines for using IGRAs in older patients.

Phase 1b/2 dose expansion, open-label study to evaluate safety and anti-tumor activity of intravesical instillation of TARA-002 in adults with high-grade non-muscle invasive bladder cancer.

TPS4618 Background: Bladder cancer is the most common malignancy involving the urinary system, with over 700,000 individuals living with bladder cancer in the US in 2019. In the US, approximately 80,000 new cases and 18,000 deaths occur each year due to bladder cancer. Approximately 70% of new urothelial bladder cancer cases are classified as non-muscle invasive bladder cancer (NMIBC). With the current Bacillus Calmette-Guerin (BCG) shortage and limited effective alternate therapies, there continues to be a significant unmet need for treatment options for patients with NMIBC. TARA-002 is being developed for intravesical instillation for the treatment of high-grade (HG) NMIBC. TARA-002 is a lyophilized biological preparation for instillation containing cells of Streptococcus pyogenes (Group A, type 3) Su strain treated with benzylpenicillin. The chemical characteristics of TARA-002 are intended to be comparable to OK-432. Therefore, nonclinical and clinical evidence with OK-432 and TARA-002 support the ADVANCED-1 study (dose escalation Phase 1a [NCT05085977] and dose expansion Phase 1b/2 [NCT05085990]). The dose for the planned Phase 1b/2 study (ADVANCED-1-Ph1b/2) will be based on the recommended Phase 2 dose (RP2D) established in the Phase 1a study. Methods: ADVANCED-1-Ph1b/2 is a Phase 1b/2, dose expansion, open-label study of intravesical instillation of TARA-002 in adults with HG carcinoma in situ (CIS) NMIBC. The purpose of this study is to evaluate the safety and anti-tumor activity of TARA-002 administered intravesically for the treatment of subjects with CIS NMIBC (± Ta/T1) with active disease. The study includes approximately 102 eligible male and female subjects ≥ 18 years of age enrolled in 2 cohorts based on their prior BCG experience. Cohort A includes subjects unable to obtain BCG or subjects who have not received BCG in the last 24 months prior to CIS diagnosis, and Cohort B includes subjects with CIS who are BCG unresponsive after completion of adequate BCG therapy (at least 5 of 6 doses of an initial induction course plus either at least 2 of 3 doses of maintenance therapy or at least 2 of 6 doses of a second induction course). Those with current or a history of penicillin allergy or current evidence of any condition, therapy, or laboratory abnormality that might confound the results are excluded. The overall study duration is 6 months/24 weeks per subject for Ph1b/2-Cohort A (includes induction, reinduction [if applicable]), and 24 months/96 weeks per subject for Ph1b/2-Cohort B (includes induction, reinduction [if applicable], maintenance until 18 months). The ADVANCED-1 study started in March 2022. Phase 1a is open for enrollment. Phase 1b/2 is expected to begin enrollment in May 2023. Clinical trial information: NCT05085977 ; NCT05085990 .

MP08-18 ASYMPTOMATIC BACTERIURIA DOES NOT INCREASE THE RISK OF INFECTIVE COMPLICATIONS IN PATIENTS WITH NON-MUSCLE-INVASIVE BLADDER CANCER UNDERGOING INTRAVESICAL BACILLUS CALMETTE-GUERIN IMMUNOTHERAPY

You have accessJournal of UrologyCME1 Apr 2023MP08-18 ASYMPTOMATIC BACTERIURIA DOES NOT INCREASE THE RISK OF INFECTIVE COMPLICATIONS IN PATIENTS WITH NON-MUSCLE-INVASIVE BLADDER CANCER UNDERGOING INTRAVESICAL BACILLUS CALMETTE-GUERIN IMMUNOTHERAPY Antti Nummi, Pertti Nurminen, Olli Kesti, Mikael Högerman, Otto Ettala, Peter Boström, Antti Kaipia, Jukka Sairanen, and Riikka Järvinen Antti NummiAntti Nummi More articles by this author , Pertti NurminenPertti Nurminen More articles by this author , Olli KestiOlli Kesti More articles by this author , Mikael HögermanMikael Högerman More articles by this author , Otto EttalaOtto Ettala More articles by this author , Peter BoströmPeter Boström More articles by this author , Antti KaipiaAntti Kaipia More articles by this author , Jukka SairanenJukka Sairanen More articles by this author , and Riikka JärvinenRiikka Järvinen More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003223.18AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Asymptomatic bacteriuria (ABU) is common in patients with non-muscle-invasive bladder cancer (NMIBC). Even though ABU is not considered as an absolute contraindication for bacillus Calmette-Guérin (BCG) administration, many urologists prefer sterile urine or use prophylactic antibiotics prior BCG instillation, aiming to prevent acute urinary tract infection (UTI), bacterial sepsis and BCG infection. However, the use of antibiotics may potentially lead to multidrug-resistant bacterial strains, while the clinical benefit is not clear. The aim of this study was to determine whether ABU increases the risk of infective complications and whether it is justified to screen asymptomatic patients for bacteriuria before BCG instillations. METHODS: We analyzed retrospectively patients who received ≥1 BCG instillations as treatment of NMIBC in our institutions during 2009-2018. Patients had submitted urine specimen 1-7 days prior every BCG instillation. Urine cultures were recorded as no growth or the presence of bacteriuria. ABU was classified as having any positive urine culture but no dysuria or fever. Antibiotic prophylaxis prior BCG administration was recorded. Our primary endpoints were admission to hospital because of UTI, BCG toxicity and BCG infections within 2 weeks of BCG instillation. RESULTS: We analyzed 802 patients and 12 882 BCG instillations. ABU was recorded with 2 200 (17%) instillations. Antibiotics were used in 519 (21%) instillations in bacteriuria group. Hospital admission was recorded after 8 (0.3%) and 37 (0.4%) instillations in the bacteriuria and in the no growth group, respectively (p=0.9). There was no significant difference in hospital admissions between the groups with or without antibiotic prophylaxis (p=0.4). CONCLUSIONS: BCG instillation with ABU is safe and does not increase the risk of developing a symptomatic UTI or severe BCG complications. By consequence, our results do not support routine screening of asymptomatic patients for bacteriuria prior intravesical BCG treatment. Antibiotic prophylaxis should only be used with consideration. Symptomatic UTI remains contraindication for BCG instillation. Source of Funding: Finnish Association of Urology © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e101 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Antti Nummi More articles by this author Pertti Nurminen More articles by this author Olli Kesti More articles by this author Mikael Högerman More articles by this author Otto Ettala More articles by this author Peter Boström More articles by this author Antti Kaipia More articles by this author Jukka Sairanen More articles by this author Riikka Järvinen More articles by this author Expand All Advertisement PDF downloadLoading ...

LBA03-08 PEMBROLIZUMAB (PEMBRO) FOR PATIENTS (PTS) WITH HIGH-RISK NON-MUSCLE-INVASIVE BLADDER CANCER (HR NMIBC) UNRESPONSIVE TO BACILLUS CALMETTE-GUERIN (BCG): EFFICACY AND EVALUATION OF SUBSEQUENT CYSTECTOMY FROM COHORT B OF THE PHASE 2 KEYNOTE-057 STUDY

LBA03-08 PEMBROLIZUMAB (PEMBRO) FOR PATIENTS (PTS) WITH HIGH-RISK NON-MUSCLE-INVASIVE BLADDER CANCER (HR NMIBC) UNRESPONSIVE TO BACILLUS CALMETTE-GUERIN (BCG): EFFICACY AND EVALUATION OF SUBSEQUENT CYSTECTOMY FROM COHORT B OF THE PHASE 2 KEYNOTE-057 STUDY

Pembrolizumab (pembro) monotherapy for patients (pts) with high-risk non–muscle-invasive bladder cancer (HR NMIBC) unresponsive to bacillus Calmette–Guérin (BCG): Results from cohort B of the phase 2 KEYNOTE-057 trial.

LBA442 Background: Although most pts with HR NMIBC respond to BCG, pts whose cancer does not respond or who relapse within 12 mo have poor prognosis and require radical cystectomy (RC). The single-arm, multicohort phase 2 KEYNOTE-057 trial (NCT02625961) was designed to investigate the safety and efficacy of pembro monotherapy for pts with BCG-unresponsive HR NMIBC (per FDA) who were ineligible or declined to undergo RC. Results from cohort A (carcinoma in situ [CIS] ± papillary tumors) showed a clinical complete response rate of 41% at 3 mo and led to approval of pembro monotherapy for such pts in the United States. We describe the results from cohort B (papillary tumors without CIS). Methods: Pts were aged ≥18 y with BCG-unresponsive HR NMIBC with papillary tumors only (high-grade Ta or any-grade T1) at baseline and ECOG PS 0-2. Pts received pembro 200 mg every 3 wk (Q3W) for ≤35 cycles (~2 y). Cancer was assessed at 12 wk and Q12W thereafter if no recurrent HR NMIBC or progression was observed; CT urography was done Q24W. Primary end points for cohort B were 12-mo disease-free survival (DFS) rate of HR NMIBC as assessed by central pathology/radiology review and safety, assuming a 12-mo DFS of >20% for HR NMIBC. Secondary efficacy end points were 12-mo DFS rate of any disease; progression-free survival (PFS) to worsening of grade, stage, or death; PFS to muscle invasion, metastasis, or death; and overall survival (OS). Results: Overall, 132 pts received pembro for a median of 9.5 cycles (range, 1.0-35.0). Median age was 72 y (range, 37-87); 57 pts (43.2%) had T1 stage; all pts (100%) had urothelial histology; 104 pts (78.8%) were male; pts received a median of 10 (range, 6-33) prior BCG instillations. Median follow-up was 45.4 mo (range, 14.9-77.1). Efficacy data are shown in Table. Thirty-one pts (23.5%) had RC after stopping pembro. Treatment-related AEs occurred in 97 pts (73.5%); 19 (14.4%) had a grade 3/4 treatment-related AE and 14 pts (10.6%) discontinued due to a treatment-related AE. No deaths from treatment-related AEs occurred. Conclusions: Pembro showed notable antitumor activity in pts with BCG-unresponsive non-CIS papillary HR NMIBC after ~45 mo of follow-up. Toxicity was manageable and consistent with that in cohort A, with no new safety signals. Results suggest pts with non-CIS papillary HR NMIBC unresponsive to BCG who declined or were ineligible to undergo RC may also benefit from pembro monotherapy. Clinical trial information: NCT02625961 . [Table: see text]

Hyperthermic intravesical chemotherapy with mitomycin-C for the treatment of high-risk non-muscle-invasive bladder cancer patients.

The objectives of the study are to explore tolerability, acceptability and oncological outcomes for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) treated with hyperthermic intravesical chemotherapy (HIVEC) and mitomycin-C (MMC) at our institution. Our single-institution, observational study consists of consecutive high-risk NMIBC patients treated with HIVEC and MMC. Our HIVEC protocol included six weekly instillations (induction), followed by two further cycles of three instillations (maintenance) (6 + 3 + 3) if there was cystoscopic response. Patient demographics, instillation dates and adverse events (AEs) were collected prospectively in our dedicated HIVEC clinic. Retrospective case-note review was performed to evaluate oncological outcomes. Primary outcomes were tolerability and acceptability of HIVEC protocol; secondary outcomes were 12-month recurrence-free, progression-free and overall survival. In total, 57 patients (median age 80.3 years) received HIVEC and MMC, with a median follow-up of 18 months. Of these, 40 (70.2%) had recurrent tumours, and 29 (50.9%) had received prior Bacillus Calmette-Guérin (BCG). HIVEC induction was completed by 47 (82.5%) patients, but only 19 (33.3%) completed the full protocol. Disease recurrence (28.9%) and AEs (28.9%) were the most common reasons for incompletion of protocol; five (13.2%) patients stopped treatment due to logistical challenges. AEs occurred in 20 (35.1%) patients; the most frequently documented were rash (10.5%), urinary tract infection (8.8%) and bladder spasm (8.8%). Progression during treatment occurred in 11 (19.3%) patients, 4 (7.0%) of whom had muscle invasion and 5 (8.8%) subsequently required radical treatment. Patients who had received prior BCG were significantly more likely to progress (p = 0.04). 12-month recurrence-free, progression-free and overall survival rates were 67.5%, 82.2%, and 94.7%, respectively. Our single-institution experience suggests that HIVEC and MMC are tolerable and acceptable. Oncological outcomes in this predominantly elderly, pretreated cohort are promising; however, disease progression was higher in patients pretreated with BCG. Further randomised noninferiority trials comparing HIVEC versus BCG in high-risk NMIBC are required.

Multi-Institution Evaluation of Sequential Intravesical Gemcitabine and Docetaxel in the Treatment of Bacillus Calmette-Guerin Naïve Patients with Non-Muscle Invasive Bladder Cancer

<h2>Abstract</h2><h3>Introduction</h3> <b>:</b> Single agent intravesical chemotherapy regimens have historically compared unfavorably to Bacillus Calmette-Guerin (BCG) as initial treatment following resection for patients with high-risk non-muscle invasive bladder cancer (NMIBC). However, there have been few reports of multi-agent intravesical chemotherapy regimens in this setting. Our objective is to determine the efficacy of sequential intravesical gemcitabine and docetaxel (Gem/Doce) in BCG naïve patients with NMIBC. <h3>Patients and Methods</h3> <b>:</b> Collaborating institutions retrospectively identified patients with NMIBC who were treated with Gem/Doce between 6/2009 and 5/2018. An sub-cohort of patients without prior BCG and treated with Gem/Doce was identified. Treatment consisted of 6 weekly instillations of gemcitabine (1 gram/50mL) followed immediately by docetaxel (37.5 mg/50mL). Maintenance was utilized at the discretion of the treating physician. Recurrence-free survival (RFS), progression (PFS), and overall survival (OS) were assessed. Treatment tolerance and discontinuation were also evaluated. Statistical analysis was descriptive in nature. <h3>Results</h3> <b>:</b> Sixty-five patients were treated, with median age 75 years and median follow-up of 15.2 months. 77% had high-grade disease and 40% had carcinoma in-situ (CIS). RFS was 82%, 76%, and 66% at 6, 12 and 24 months respectively. Amongst patients with high-grade disease, high-grade RFS was 85%, 78%, and 66% at 6, 12, and 24 months respectively. One patient progressed to muscle-invasive bladder cancer. Limitations include the retrospective study design, small cohort size, and lack of a comparator arm. <h3>Conclusion</h3> : Intravesical Gem/Doce may be an effective treatment for BCG naïve NIMBC and warrants further investigation. <h3>MicroAbstract</h3> <b>:</b> BCG is the gold-standard adjuvant treatment following TURBT for high-risk NMIBC. Unfortunately, ongoing production shortages have diminished BCG availability. In a multi-institutional retrospective cohort of 65 patients, we f 56098[mound sequential intravesical gemcitabine and docetaxel (Gem/Doce) provided significant relief of recurrence (66% RFS at 2-years) and was well-tolerated (97% finished a full induction). Prospective evaluation of Gem/Doce is underway.

MP54-04 A PHASE II STUDY OF CHECK POINT INHIBITOR, DURVALUMAB (MEDI4736) FOR BACILLUS CALMETTE-GUERIN UNRESPONSIVE CARCINOMA IN SITU OF THE BLADDER

You have accessJournal of UrologyCME1 May 2022MP54-04 A PHASE II STUDY OF CHECK POINT INHIBITOR, DURVALUMAB (MEDI4736) FOR BACILLUS CALMETTE-GUERIN UNRESPONSIVE CARCINOMA IN SITU OF THE BLADDER Roger Li, Kyle Rose, Michael Poch, Philippe Spiess, Scott Gilbert, Wade Sexton, and Jingsong Zhang Roger LiRoger Li More articles by this author , Kyle RoseKyle Rose More articles by this author , Michael PochMichael Poch More articles by this author , Philippe SpiessPhilippe Spiess More articles by this author , Scott GilbertScott Gilbert More articles by this author , Wade SextonWade Sexton More articles by this author , and Jingsong ZhangJingsong Zhang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002633.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Bacillus Calmette-Guerin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC) represents a difficult clinical scenario, for which radical cystectomy (RC) is standard of care. Many patients are either unfit or unwilling to undergo RC, and bladder preserving treatment options are limited. We aimed to investigate the efficacy of durvalumab, a PD-L1 inhibitor, in the treatment of BCG-unresponsive carcinoma in situ (CIS) containing NMIBC. METHODS: This was a single center, open-label, phase II study of patients with BCG-unresponsive CIS of the bladder. After enrollment, patients received IV Durvalumab 1500mg IV, every 4 weeks for a total of 12 months. Cystoscopy with for-cause biopsy was performed every 3 months during the 12-month administration period, then every 4 months for a second 12 month surveillance period. Patients were taken off study if disease persistence or progression to invasive disease occurred. The primary endpoint was complete response (CR) by mapping biopsy at 6 months. Secondary outcomes were the duration of complete response and recurrence free survival (RFS). Pre- and post-treatment PD-L1 status was determined by the SP263 assay. Adverse events were captured using CTCAE v4.03. RESULTS: Seventeen patients were enrolled and began durvalumab for BCG-unresponsive CIS-containing NMIBC. Median age was 77 years (IQR 69-79), 13 (76.5%) patients had CIS alone, and the median number of prior BCG instillations was 12 (IQR 12-12). Four patients came off of study after 3 month bladder biopsy demonstrating persistent high grade NMIBC. Among the 13 patients who underwent 6-month mapping biopsy, 3 (18%) patients had a 6-month CR with a median duration of response of 14 months. Three (18%) patients progressed to muscle invasive or metastatic disease and 9 (53%) underwent RC. No correlation was observed between PD-L1 expression and clinical response to durvalumab. Grade 1-2 treatment-related adverse events occurred in 11 patients; most frequently fatigue (35%), diarrhea (18%), pancreatic enzyme elevation (12%), rash (6%), and hypothyroidism (6%). CONCLUSIONS: Immune checkpoint inhibition with durvalumab in BCG-unresponsive CIS-containing NMIBC demonstrated a favorable safety profile, but a modest CR rate. Additional research is needed in a larger cohort to determine generalizable efficacy with immune checkpoint inhibitors, and to better understand the safety profile in NMIBC. Source of Funding: AstraZeneca © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e927 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Roger Li More articles by this author Kyle Rose More articles by this author Michael Poch More articles by this author Philippe Spiess More articles by this author Scott Gilbert More articles by this author Wade Sexton More articles by this author Jingsong Zhang More articles by this author Expand All Advertisement PDF DownloadLoading ...

Can Bacillus Calmette-Guérin (BCG) treat localized prostate cancer?

The Bacillus Calmette-Guérin (BCG) vaccine has been used for a century to prevent tuberculosis and non-specific effects of BCG vaccination have provided a degree of protection from other non-mycobacterial pathogens and even some cancers. As such, intravesical BCG instillation is an accepted and well tolerated immunotherapy for non-muscle-invasive bladder cancer. Notably, during BCG instillations there is commonly reflux of urine from the prostatic urethra into the prostatic ducts and most men develop an asymptomatic granulomatous prostatitis in the peripheral zone of the prostate, typically where prostate cancer occurs. In the United States, prostate cancer is the most common diagnosed cancer in men; and most men are diagnosed over age sixty. There are several treatment options for localized intermediate-risk prostate cancer; they include active surveillance, radical prostatectomy, radiotherapy, and androgen deprivation therapy. However, these treatments can cause urinary, sexual, and rectal toxicities; as such, some older men defer treatment and instead choose watchful waiting, which is associated with a worse survival outcome compared to treatment options. We posit that intravesical BCG can target prostate cancer directly by refluxing from the prostatic urethra via ducts into the peripheral zone of the prostate and at that location initiate a robust immunologic anti-tumor response. Moreover, there is evidence that a prior BCG vaccination will augment the immune response from intravesical BCG therapy. Hence, we hypothesize that BCG vaccination followed by intravesical BCG instillation might be a treatment option for localized intermediate-risk prostate cancer, will have limited side effects, and be particularly suited for older men who have chosen watchful waiting. We have suggested how this hypothesis can be safely tested.

Response and Outcomes to Immune Checkpoint Inhibitors in Advanced Urothelial Cancer Based on Prior Intravesical Bacillus Calmette-Guerin.

Immune checkpoint inhibitors (ICI) improve overall survival (OS) in patients with locally advanced, unresectable, or metastatic urothelial carcinoma (aUC), but response rates can be modest. We compared outcomes between patients with and without prior intravesical Bacillus Calmette-Guerin (BCG), who received ICI for aUC, hypothesizing that prior intravesical BCG would be associated with worse outcomes. We performed a retrospective cohort study across 25 institutions in US and Europe. We compared observed response rate (ORR) using logistic regression; progression-free survival (PFS) and OS using Kaplan-Meier and Cox proportional hazards. Analyses were stratified by treatment line (first line/salvage) and included multivariable models adjusting for known prognostic factors. A total of 1026 patients with aUC were identified; 614, 617, and 638 were included in ORR, OS, PFS analyses, respectively. Overall, 150 pts had history of prior intravesical BCG treatment. ORR to ICI was similar between those with and without prior intravesical BCG exposure in both first line and salvage settings (adjusted odds radios 0.55 [P= .08] and 1.65 [P= .12]). OS (adjusted hazard ratios 1.05 [P= .79] and 1.13 [P= .49]) and PFS (adjusted hazard ratios 1.12 [P= .55] and 0.87 [P= .39]) were similar between those with and without intravesical BCG exposure in first line and salvage settings. Prior intravesical BCG was not associated with differences in response and survival in patients with aUC treated with ICI. Limitations include retrospective nature, lack of randomization, presence of selection and confounding biases. This study provides important preliminary data that prior intravesical BCG exposure may not impact ICI efficacy in aUC.

No Added Benefit of Systematic Bladder Biopsies after BCG Induction in High-Risk Non-Muscle-Invasive Bladder Cancer Optimally Managed

Objectives: To evaluate the added detection benefit of routine transurethral biopsies after an induction course of intravesical Bacillus Calmette-Guérin (BCG) for high-grade NMIBC. Methods: We retrospectively included all patients who underwent white and blue light TURB, subsequent adjuvant induction scheme of BCG, followed by post-instillation biopsies. We excluded patients in whom a prior BCG induction course failed those with synchronous upper tract urothelial carcinoma, and those who did not receive the full 6-week course. A total of 62 patients met inclusion criteria and their records were analyzed. Cystoscopy findings, urine cytology and pathological results of transurethral biopsy were evaluated. Sensitivity, specificity, positive predictive value, negative predictive value, positive and negative likelihood ratios and diagnostic accuracy were calculated for cystoscopy and cytology separately and in combination. Results: After BCG, a total of 342 bladder biopsy were taken with a median of 5 (IQR 2) per case. The biopsy was positive in 13 patients (21%). The median number of positive biopsies was 2 (IQR 1) and the total number of positive biopsies was 27 (8%). The biopsy was positive at the initial tumor site in 8 patients (61.5%). No complications of Clavien III to V were reported. Out of 62 patients who underwent systematic transurethral biopsy, only 3 (5%) presented complications from grade I to II. We found a significant association of positive biopsy with positive urinary cytology (p &lt;0.001) and the presence of erythematous lesions (p &lt;0.02) or visible tumors (p &lt;0.001) at cystoscopy. The pre-BCG stage T (p = 0.32), the presence of CIS (p = 0.71), the multifocal tumor (p = 0.41) and the size (p = 0.52) were not associated with a positive biopsy occurrence. For normal bladder mucosa the predictive value of negative biopsy in cases with negative vs positive cytology was 98% vs 79% (p 0.001). Conclusion: Routine transurethral bladder biopsies after a BCG induction course are not mandatory in the modern era of NMIBC management.

Poor Prognosis With Intravesical Bacillus Calmette-Guérin History After Photodynamic Diagnosis-assisted Transurethral Resection Using 5-Aminolevulinic Acid.

Diagnostic efficacy and treatment outcome of orally administered 5 aminolevulinic acid (ALA) assessment for photodynamic diagnosis (PDD) in transurethral resection for non-muscle-invasive bladder cancer (NMIBC) in clinical practice. A retrospective analysis was performed of 105 patients who underwent PDD transurethral resection using orally administered ALA and were pathologically diagnosed with Ta, T1, or Tis at the Ishikawa Prefectural Central Hospital from December 2018 to May 2022. Fluorescent light had a significantly higher sensitivity but a lower specificity in detecting carcinoma compared to white light (91.7% vs. 77.1%; p<0.05 and 43.0% vs. 85.2%; p<0.05, respectively), as well as in detecting carcinoma in situ lesions (80.4% vs. 28.6%; p<0.05 and 23.3% vs. 84.5%; p<0.05, respectively). The cumulative frequency of recurrence and progression 1 year after treatment were 26.3% and 12.3%, respectively. Multivariate analyses indicated that a Bacillus Calmette-Guérin (BCG) history instillation was an independent predictive factor for intravesical recurrence (hazard ratio=4.439; p=0.002) and disease progression (hazard ratio=8.534; p=0.005). The 1-year cumulative recurrence rates were 66.2% and 16.5%, respectively (p<0.001), and progression rates for patients with and without prior BCG intravesical instillation were 50.4% and 3.5%, respectively (p<0.001). Sufficient diagnostic accuracy and relatively good treatment outcome was shown in PDD-transurethral resection using ALA. However, prior BCG intravesical instillation for NMIBC patients was a poor prognostic factor of cancer recurrence and progression, and may be useful for clinicians in their postoperative follow-up.

Impact of Bacillus Calmette-Guérin (BCG) vaccination on postoperative mortality in patients with perioperative SARS-CoV-2 infection.

There is little evidence around the potentially protective role of previous Bacillus Calmette-Guerin (BCG) vaccination on postoperative mortality in patients with perioperative SARS-CoV-2 vaccination. Prior BCG vaccination did not protect SARS-CoV-2 infected patients against postoperative pulmonary complications and 30-day mortality.

EFFECTIVENESS OF BCG VACCINATION AGAINST SARS-COV-2

Background: Bacillus Calmette-Guerin (BCG) vaccine is weakened Mycobacterium bovis based preparation that provides protective effects and immunotherapy against many ailments and may be tested against SARS-COV-2. Herein, we compare the prevalence of COVID-19 in countries with and without mandatory BCG vaccination program along with a study to examine its incidence in doctors working at quarantine facility with and without history of prior BCG vaccination. Methods: For cross-sectional examination, the data was collated from worldometer.info, BCG World Atlas and COVID-19 stats at National Command and Operation Centre (NCOC), Government of Pakistan accessed on Apr 30, 2021. For a real-time analysis, total of one hundred random male and female doctors working at a COVID-19 healthcare facility in Pakistan were voluntarily selected. Chi-square test was used to perform the statistical analysis with the help of SPSS-22. Results: The prevalence of COVID-19 in countries with and without a mandatory BCG vaccination policy was found to be 5,512 and 75,592 cases per million, respectively, and mortality rates were 98 and 1,435 per million, respectively. Amongst our randomly selected doctors, only 28% of the BCG vaccinated doctors were affected by COVID-19 contrary to 94% of those who were unvaccinated. Conclusions: The incidence of COVID-19 was considerably lower in the doctors with a history of BCG vaccination supported by the evidence that the countries with a universal BCG vaccine policy had a significantly low incidence and lower mortality rate due to COVID-19.

MP16-06 A NOVEL NOMOGRAM TO PREDICT BCG RESPONSE IN PATIENTS WITH HIGH-GRADE NON-MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyBladder Cancer: Non-invasive II (MP16)1 Sep 2021MP16-06 A NOVEL NOMOGRAM TO PREDICT BCG RESPONSE IN PATIENTS WITH HIGH-GRADE NON-MUSCLE INVASIVE BLADDER CANCER Kelly Bree, Patrick Hensley, Nathan Brooks, Lianchun Xiao, Yu Shen, Neema Navai, H. Barton Grossman, Colin Dinney, and Ashish Kamat Kelly BreeKelly Bree More articles by this author , Patrick HensleyPatrick Hensley More articles by this author , Nathan BrooksNathan Brooks More articles by this author , Lianchun XiaoLianchun Xiao More articles by this author , Yu ShenYu Shen More articles by this author , Neema NavaiNeema Navai More articles by this author , H. Barton GrossmanH. Barton Grossman More articles by this author , Colin DinneyColin Dinney More articles by this author , and Ashish KamatAshish Kamat More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002001.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Current risk tables for outcome prediction in patients with non-muscle invasive bladder cancer (NMIBC) are based upon studies comprised primarily of low-grade tumors. We developed nomograms that predict disease recurrence and progression in patients with high-grade NMIBC using a large institutional dataset. METHODS: The log rank test, univariate and multivariate Cox proportional hazards regression models were used to identify risk factors of histologically confirmed disease recurrence and progression using data on 519 patients treated with adequate induction bacillus Calmette-Guerin (BCG) at our institution from 2000 to 2018. The first set of models predicted bladder cancer recurrence free survival (RFS), and the second set predicted tumor progression (any upstaging) free survival (PFS). RESULTS: At an estimated median follow-up time was 60.4 months (95% CI: 54-66.2), recurrence or death, whichever occurred first was recorded in 248 patients (47.8%) with a median RFS time of 73 months (95% CI, 52.6-91.2). Recurrent tumors (HR 1.78, 95% CI 1.33-2.33, p<0.0001), larger tumor size (HR 1.07, 95% CI 1.00-1.15, p=0.0487), and diabetes mellitus (HR 1.57, 95% CI 1.14-2.15, p=0.0055) were significantly associated with a higher risk of recurrence or death. Conversely, the receipt of maintenance BCG (mBCG) (HR 0.46, 95% CI 0.29-0.73, p=0.0008) and number of doses of mBCG (HR 0.92, 95% CI 0.89-0.94, p<0.0001) were associated with lower risk of events. Progression or death occurred in 128 patients (24.7%) with a median PFS time of 151 months (95% CI, 121.32-NA). Prior BCG (HR 2.19, 95% CI 1.23-3.88, p=0.0075) and older age (HR 1.041, 95% CI 1.02-1.06, p<0.001) were associated with higher risk of progression or death, while BMI≥25 (HR 0.519, 95% CI 0.35-0.78, p=0.0015) and number of doses of mBCG (HR 0.88, 95% CI 0.86-0.91, p<0.0001) were associated with lower risk of progression or death. These prognostic factors were integrated to construct nomograms for prediction of PFS and RFS. CONCLUSIONS: These nomograms provide personalized prediction of recurrence and progression in patients with high-grade NMIBC treated with BCG, and may help identify patients who may benefit most from early radical cystectomy. Source of Funding: This research was supported by the Wayne B. Duddlesten Professorship in Cancer Research, the Raymond and Maria Floyd Bladder Cancer Research Foundation Grant to AMK, and NIH/NCI UTMD Anderson SPORE in Genitourinary Cancer (Bladder) (P50CA091846) to CPND © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e298-e298 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kelly Bree More articles by this author Patrick Hensley More articles by this author Nathan Brooks More articles by this author Lianchun Xiao More articles by this author Yu Shen More articles by this author Neema Navai More articles by this author H. Barton Grossman More articles by this author Colin Dinney More articles by this author Ashish Kamat More articles by this author Expand All Advertisement Loading ...

Effect of Bacillus Calmette-Guerin (BCG) exposure on severity of COVID-19 infection: A COVID-19 and Cancer Consortium (CCC19) study.

4529 Background: Oncology patients experience more severe disease outcomes from COVID-19 infection than the general population. BCG is a live bovine tuberculosis bacillus with immunotherapeutic effects in urothelial cancers; it is also used as vaccination against Mycobacterium tuberculosis in parts of the world. As BCG vaccination has been associated with broad protection against viral pathogens, BCG exposure through vaccination or intravesical therapy may modulate host immunity and reduce the severity of COVID-19 infection. We report the effect of BCG exposure on COVID-19 severity in oncology patients from the CCC19 registry. Methods: The CCC19 registry (NCT04354701) was used to identify patients with prior BCG exposure. Cohort A received intravesical treatment for bladder carcinoma, and cohort B received prior BCG vaccination. Each cohort was matched 3:1 to non-BCG-exposed controls by age, sex, race, primary cancer type, cancer status, ECOG performance status (PS) and calendar time of COVID-19 infection. The primary endpoint was COVID-19 severity reported on an ordinal scale (uncomplicated, hospitalized, admitted to ICU +/- ventilated, died within 30 days) of patients exposed to prior BCG compared to matched non-exposed controls. 2-sided Wilcoxon rank-sum tests were used. Results: As of 6-Feb-2021 we included 124 patients with BCG exposure, 68 patients with bladder carcinoma who had received intravesical BCG (Cohort A), and 64 cancer patients with prior BCG vaccination (Cohort B). Median age was 76 years, IQR 69-83 (Cohort A) and 67 years, IQR 62-74 (Cohort B). Bladder cancer pts were predominately male (78%) vs 55% for Cohort B. Patients with PS 2+ were uncommon, 18% in Cohort A and 16% in Cohort B. COVID-19 illness severity was no different in patients exposed to prior intravesicular BCG (p=0.87). COVID-19 illness severity was no different in patients exposed to prior intradermal BCG vaccination (p=0.60). Conclusions: Despite this being the largest such cohort reported to date, we failed to demonstrate an association of prior BCG exposure with modulation of severity of COVID-19 illness. Prospective trials evaluating the protective effect of BCG vaccination are ongoing and will add further insight into the effect of BCG on COVID-19 illness.[Table: see text]

Bacillus Calmette-Guerin vaccine and bladder cancer incidence: Scoping literature review and preliminary analysis

Background: The Bacillus Calmette-Guerin (BCG) vaccine has long been used for the prevention of tuberculosis (TB) around the world. BCG is also used as an immunotherapy agent for the treatment of non-muscle invasive urinary bladder cancer. This scoping literature review and preliminary data analysis aims to summarize the literature correlating infantile BCG vaccination with the incidence of future bladder cancer. Methods: Studies were identified by a formal literature search of MEDLINE and Cochrane Central Registrar of Controlled Trials following PRISMA guidelines. Preliminary data analysis was conducted on publicly accessible data summarizing the impact of gender, BCG vaccination, and socio-economic effects on crude and age-standardized rates of bladder cancer. Results: As part of our analysis, preliminary regression models demonstrated BCG vaccination status, gender, and socio-economic status to have statistically significant effects on crude and age-standardized rates of bladder cancer incidence. BCG vaccination was associated with a 35-37% lower age-standardized rate of bladder cancer incidence. Conclusions: There is very little literature examining the relationship between prior BCG vaccination and rates of bladder cancer incidence. Our limited data analysis indicates that a relationship does exist between infantile BCG vaccination and later bladder cancer development, although extensive future investigation is needed in this area.