Risk of Thromboembolism in Patients Receiving Immunotherapy-Based Combinations as Front-Line Therapy for Metastatic Renal Cell Carcinoma.

BACKGROUND: Most patients with treatment-naïve metastatic renal cell carcinoma (mRCC) receive combination-based immunotherapy with either 2 immune-oncology checkpoint inhibitors (IO/IO) or an IO agent in combination with a vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitor (IO/TKI). The rates of thromboembolism (TE) in these cohorts are not clearly described and can potentially impact decision-making between IO/IO and IO/TKI. METHODS: We conducted a retrospective investigation of patients with treatment-naïve mRCC treated with IO-based combinations between January 2015 and April 2021 at the Cleveland Clinic. TE events, including venous and arterial, were identified in each group. Competing risk regression was done to identify factors associated with the development of TE following therapy, with all-cause mortality treated as a competing event. RESULTS: Of 180 patients identified, 77 (43%) received IO/TKI and 103 (57%) received IO/IO. Median age was 65 years, 75% were male, and 80% had clear cell histology. Baseline characteristics were similar between the 2 groups. At a median follow-up of 22.0 months, 10.0% of all patients had a TE. The one-year incidence of TE was 8.1% (95% CI: 3.3%-15.8%) with IO/TKI and 9.8% (95% CI: 5.0%-16.5%) with IO/IO and was not significantly different between the 2 groups (HR 0.89, 95% CI: 0.35%-2.28%). Occurrence of TE was associated with decreased overall survival regardless of IO/IO or IO/TKI therapy (HR 2.80, 95% CI: 1.57-5.02). There was no difference in incidence of TE based on patient age, gender, prior history of TE, International Metastatic Renal Cell Carcinoma (IMDC) risk group, or Khorana score. CONCLUSIONS: Incidence of TE is similar between IO/IO and IO/TKI regimens in treatment-naïve mRCC and is also associated with decreased overall survival. While risk of TE may not guide decision-making in choice of front-line mRCC therapy, careful attention should be given to the high risk of TE in this population.

Thromboembolism in Patients with Metastatic Urothelial Cancer Treated with Immune Checkpoint Inhibitors.

BACKGROUND: Immunotherapy has become one of the mainstays for metastatic urothelial carcinoma treatment. Whether immune checkpoint inhibitor therapy increases thromboembolism (TE) risk is unknown. OBJECTIVE: We investigated the incidence of arterial thromboembolism (ATE) and venous thromboembolism (VTE) events and its associated outcomes in patients with metastatic urothelial cancer treated with immune checkpoint inhibitors. METHODS: Patients with urothelial cancer treated with immune checkpoint inhibitors at the Cleveland Clinic from 1/1/2015 to 12/31/2019 were identified. The Kaplan-Meier method estimated overall survival and Cox proportional hazards regression evaluated the impact of TE on overall survival. RESULTS: Of 279 patients, 72% were men with pure urothelial cancer (62%) who started atezolizumab (40%), nivolumab (3%), or pembrolizumab (57%). At a median follow-up of 5.6 months (range 0.3-51.6), 42 patients developed a TE (VTE n = 37, 13%, ATE n = 5, 2%). The cumulative incidence of TE after immune checkpoint inhibitor therapy was 9.1% (95% confidence interval 6.0-13.0) at 6 months and 13.6% (95% confidence interval 9.6-18.4) at 12 months. Most TE (VTE 62%, ATE 100%) occurred within 6 months of immune checkpoint inhibitor initiation (median doses 5, range 1-59), and the majority (VTE 81%, ATE 100%) resulted in hospitalization (median: 5 days, 4 days, respectively). Thromboembolism (hazard ratio 2.296, p = 0.0004), Bajorin score 1 or 2 (hazard ratio 1.490, p = 0.0315), and Bajorin score 2 (hazard ratio 3.50, p < 0.0001) were associated with worse overall survival. CONCLUSIONS: Immune checkpoint inhibitors are associated with a high TE risk. Thromboembolism is associated with worsened survival, among other poor outcomes. Further investigation into the mechanism behind immune checkpoint inhibitor-associated TE is needed.

Thromboembolism in Patients with Metastatic Renal Cell Carcinoma Treated with Immunotherapy.

BACKGROUND: Metastatic renal cell carcinoma (mRCC) is associated with a high risk of thromboembolism (TE). OBJECTIVE: We investigated whether immunotherapy (IO) increases the hypercoagulable state in this high-risk population. PATIENTS AND METHODS: Patients with mRCC treated with IO between 1 January 2015 and 31 December 2019 at the Cleveland Clinic were identified. Cumulative incidence analysis calculated TE rates over time and Gray's test determined differences in TE rates among groups. The Kaplan-Meier method estimated survival, while Cox proportional hazard regression evaluated the impact of TE on OS. RESULTS: Of 351 patients, 75% were men with clear cell mRCC (81%) and International Metastatic Renal Cell Carcinoma (IMDC) intermediate- to poor-risk disease (77%). Patients received single-agent IO (52%), doublet IO (31%), or IO with non-IO therapy (17%). The median number of IO doses was 8 (range 1-81). At a median follow-up of 12.8 months, 12% of patients (n = 43) had a TE event (venous n = 37 [11%], arterial n = 6 [2%]). The cumulative TE incidence at 6 months was 4.4% (95% confidence interval [CI] 2.6-6.9) and 9.8% (95% CI 6.8-13.4) at 12 months. No factors, including IMDC or Khorana score, were identified to predict TE development. Seventy-two percent of TE resulted in hospitalization (9% TE-related mortality and 21% TE-related dose delay). TE (p < 0.0001), poor IMDC score (p < 0.0001), and Khorana score ≥ 2 (p < 0.0001) were associated with worse OS. CONCLUSIONS: Patients with mRCC treated with IO had a high incidence of TE. TE was associated with risk of treatment delay, hospitalization, and mortality, while TE, IMDC poor risk, and Khorana score ≥ 2 were associated with worse survival. Further investigations into IO-associated TE are needed to identify benefit from primary thromboprophylaxis.

Patients with advanced renal cell carcinoma carry an increased risk of clotting, both in their arteries and veins. Historically, risk scores such as the Khorana score were used to assess which patients with solid tumors would benefit from preventative blood thinning medications as they undergo chemotherapy. Whether the Khorana score can be applied to use with immunotherapy is not known. Currently, limited knowledge exists of the impact of immunotherapy on additional clotting in patients with renal cell carcinoma. This study shows an increased incidence of clotting under immunotherapy treatment in patients with advanced renal cancer compared with rates seen in the literature. This study highlights an associated risk of hospitalization, need to stop cancer therapy, as well as risk of death from clotting. Additionally, we determine that clotting, poor disease pathology (as assessed by the International Metastatic Renal Cell Carcinoma Database Consortium), and a Khorana score of ≥2 are predictors of a worse overall survival. This information will be useful in future studies that will address the usefulness of preventative blood thinner medications in this high-risk population.

Volume matters and intensification is needed: emerging trends in the management of advanced prostate cancer.

Significant changes in the management of patients with de novo metastatic prostate cancer have led to the use of novel oral agents and docetaxel-based chemotherapy earlier in the natural history of their disease. Our main challenge is the lack of prospective randomized data comparing these regimens. It is clear that treatment intensification is needed. Yet, the heterogeneity of this patient population coupled with the lack of understanding of the specific biology for a given individual makes treatment selection challenging. The aim of this narrative review is to discuss the importance of defining advanced disease by volume, the necessity for treatment intensification, and the current and future landscape of metastatic hormone-sensitive prostate cancer management.

Implications of the United States Preventive Services Task Force Recommendations on Prostate Cancer Stage Migration.

BACKGROUND: Prostate-specific antigen screening is controversial. In 2008, the United States Preventive Services Task Force recommended against screening men aged ≥ 75 years, and in 2012, expanded this to include all men. The impact of these changes continues to unfold. We hypothesized that these screening changes could delay the diagnosis of advanced prostate cancer. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results database was used to identify men (age, 55-69 years) diagnosed with prostate cancer in 2004 to 2008 (group 1), 2009 to 2012 (group 2), and 2013 to 2015 (group 3). Groups reflect United States Preventive Services Task Force guideline changes. Descriptive statistics were used to present baseline statistics and the number of patients diagnosed in aforementioned groups. Data was adjusted for population growth. RESULTS: A total of 328,586 men were identified (group 1, 135,625; group 2, 117,979; group 3, 74,982). The average number of men diagnosed annually with N1M0 (group 1, 381; group 2, 477; group 3, 660) and M1 (group 1, 523; group 2, 761; group 3, 1037) disease increased. With group 1 as control, there was a decrease in the incidence of localized disease (group 2, 9.2%; group 3, 33.2%). However, the incidence of N1M0 (group 2, 5.3%; group 3, 30.1%) and M1 disease (group 2, 22.6%; group 3, 49.2%) increased. Separate analyses of patients (age 50-75 years) and African Americans showed similar trends. CONCLUSION: With each recommendation, there was increased incidence of de novo metastatic prostate cancer. The sequelae of advanced disease include financial, emotional, and physical burden. Future studies are needed to identify screening strategies that reduce the risk of developing metastatic disease without over-diagnosing indolent cancers.

Identifying Prostate Surface Antigen Patterns of Change in Patients with Metastatic Hormone Sensitive Prostate Cancer Treated with Abiraterone and Prednisone.

BACKGROUND: Despite treatment with abiraterone acetate and prednisone (AA/P), most patients with metastatic hormone sensitive prostate cancer (mHSPC) will develop castration-resistant disease (metastatic castration-resistant prostate cancer [mCRPC]). The early identification of who will progress on AA/P is limited. OBJECTIVE: This study investigates the role of prostate surface antigen (PSA) kinetics as a predictor of progression in mHSPC patients treated with AA/P. PATIENTS AND METHODS: All patients with mHSPC who initiated androgen deprivation therapy (ADT) and AA/P from June 2017 to February 2019 at the Cleveland Clinic were eligible. PSA-mCRPC was defined as a PSA rise at two consecutive time points. Patients were followed until first mCRPC or last contact after AA/P. Patterns of PSA change were evaluated using a longitudinal mixed model at time 0, 3, 6, 9, and 12 months from AA/P initiation. The association between PSA profile at 3 months and PSA-mCRPC was examined using survival analysis. Radiographic progression (Rad-mCRPC) was also analyzed. RESULTS: A total of 130 men with follow-up were included. The median (interquartile range [IQR]) follow-up time was 15.3 (10.5, 22.5) months. Eighty-two percent were Caucasian (median age 68.5 years); participants had a median (IQR) PSA of 16.8 (5.3, 48.0) ng/mL. Half of the patients had de novo disease, and 46.2% had high-risk disease (61% had a Gleason score ≥ 8, 16% had visceral disease, and 54% had three or more bony lesions). The greatest PSA percentage reduction from baseline after AA/P initiation occurred at the first 3 months (median 98.3%). The reduction at 6-12 months from baseline was small (99.7-100%). Patients without PSA-mCRPC had a significantly greater 3-month reduction of PSA values compared to patients who developed PSA-mCRPC (p interaction = 0.0002). 50.8% of patients were able to achieve a non-detectable PSA (median 13.1 months). PSA-mCRPC (n = 20) was observed from 4 to 24 months after AA/P, with the majority of events occurring within the first 12 months. Patients with PSA < 0.3 ng/mL (12-month PSA-mCRPC-free 94.5% vs. 69.4%, p = 0.0004) or a ≥ 98% reduction (94.9% vs. 68.0%, p = 0.0002) at 3 months had better PSA-mCRPC-free survival compared to their counterparts. Absolute reduction at 3 months was not associated with PSA-mCRPC. Similar PSA patterns were seen in those who had Rad-mCRPC compared to no Rad-mCRPC (p interaction < 0.05). CONCLUSION: The degree of PSA decline at 3 months predicted serologic progression to mCRPC. Those who developed castration-resistant disease had higher PSA and a lower percentage reduction by 3 months. Tracking early PSA pattern changes may alert clinicians to poor treatment effect and potential progression; they should consider frequent PSA measurement and imaging, as well as the initiation of sequential therapy.

Ipilimumab and Nivolumab as First-Line Treatment of Patients with Renal Cell Carcinoma: The Evidence to Date.

Immunotherapy has revolutionized the management of metastatic renal cell carcinoma with four checkpoint inhibitors (nivolumab, ipilimumab, avelumab, and pembrolizumab) approved either as monotherapy or as combination therapy. The use of ipilimumab and nivolumab for treatment-naïve, intermediate to poor risk, metastatic renal cell carcinoma was the first checkpoint inhibitor-based combination therapy and remains the only dual checkpoint inhibitor combination approved in mRCC. In this article, we review the trials that led to the approval of ipilimumab and nivolumab in this setting. We also highlight the ongoing trials using this combination, its use in special populations, and clinically relevant unanswered questions.

Non-metastatic castration-resistant prostate cancer: current status and future directions.

INTRODUCTION: The emergence of novel hormonal therapies and the increase availability of sensitive next-generation imaging techniques has significantly changed the management of recurrent prostate cancer. AREAS COVERED: In this review, we summarize the definition, diagnosis, treatment, and ongoing clinical trials in non-metastatic castration resistant prostate cancer (M0CRPC). We have also discussed the role of newer imaging modalities in the detection of advanced prostate cancer. EXPERT OPINION: M0CRPC is a disease state in prostate cancer when serologic progression (PSA only disease) occurs despite castrated levels of testosterone and imaging shows no evidence of metastasis. With the availability of next-generation imaging, more patients are migrating from M0CRPC to mCRPC space. This stage migration impacts the treatment options currently available in clinical practice and requires the integration of novel imaging in prospective studies moving forward. Until that data become available men with M0CRPC should be considered for therapy with any of these three novel oral AR inhibitors, with a positive impact in metastasis-free and overall survival. Treatment selection should be based on Quality of Life, side effects, and drug-drug interactions.

Blood Myeloid-Derived Suppressor Cells Correlate with Neutrophil-to-Lymphocyte Ratio and Overall Survival in Metastatic Urothelial Carcinoma.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) were linked to pathologic stage in bladder urothelial carcinoma (UC). Neutrophil lymphocyte ratio (NLR) is an inflammatory biomarker with a prognostic role in metastatic (m)UC. OBJECTIVE: We hypothesized that MDSC levels correlate with NLR and overall survival (OS) in mUC. PATIENTS AND METHODS: MDSCs were measured in blood samples from patients with mUC in fresh unfractionated whole blood (WB) and peripheral blood mononuclear cells (PBMC) by flow cytometry and defined as LinloCD33+/HLADR- (Total MDSC). MDSC subsets were defined as polymorphonuclear (PMN-MDSC: CD15+/CD14-), monocytic (M-MDSC: CD15-/CD14+), and uncommitted (UNC-MDSC: CD15-/CD14-). MDSC populations were presented as a percentage of live nucleated blood cells. Spearman's rank correlation assessed correlations between MDSC and NLR. Kaplan-Meier curves and log-rank test estimated OS from the time of MDSC collection to last follow-up or date of death. RESULTS: Of the 76 patients, 78% were men and 43% were never smokers with a median age of 69 years (range 31-83); 72% had pure UC and 76% had lower tract UC. Prior therapies included intravesical therapy (22%), neoadjuvant chemotherapy (30%), cystectomy or nephroureterectomy (55%). Median follow-up for all patients was 12 months (0.6-36.5). PMN-MDSC was the predominant subset in WB and PBMC. There was significant correlation between individual MDSC subsets in WB and PBMC (p ≤ 0.001). Both WB UNC-MDSC/PMN-MDSC ratios (rho = - 0.27, p = 0.03) and PBMC UNC-MDSC/PMN-MDSC (rho = - 0.28, p = 0.02) were negatively correlated with NLR. Median OS was 17.7 months (95% CI: 11.0-NE). Overall 1-year and 3-year survival rates were 0.60 (95% CI 0.49-0.73) and 0.15 (95% CI 0.03-0.67), respectively. Higher WB UNC-MDSC levels (HR 3.78, p = 0.0022) and higher NLR (HR 2.6, p = 0.0179) were associated with shorter OS. CONCLUSIONS: Specific MDSC subsets correlate with NLR. Higher WB UNC-MDSC levels and higher NLR were negative prognostic factors. Given the feasibility of serial blood draws, dynamic assessment of MDSC over time and further validation with longer follow-up are warranted.

Tailoring Immunotherapy Treatment of Synchronous Renal Cell Carcinoma (RCC) and Triple-Negative Breast Cancer (TNBC).

Synchronous tumors are defined as two tumors arising concurrently or within six months of each other. Reports of synchronous RCC and breast cancer are limited to nonmetastatic renal cell carcinoma (RCC) and hormone receptor-positive infiltrative ductal carcinoma. We present the first case of synchronous metastatic renal cell carcinoma and metastatic triple-negative breast cancer, managed with a novel combination of immunotherapy and chemotherapy.

Immunotherapy for renal cell carcinoma.

Introduction: Advanced renal cell cancers (aRCC) has historically been responsive to immune system manipulation. A better understanding of the anti-tumor immune response has fueled the emergence of immunotherapy-based regimens, including combinations with vascular endothelial growth factor (VEGF) inhibitors. Areas covered: In this review, we will describe the historic use of immunotherapies and their integration with newer agents, specifically in clear cell aRCC. Expert opinion: Novel immunotherapeutic agents, as well as combinations with VEGF/TKI therapy, will become the standard of care initial therapy in the management of aRCC. Further studies in the sequencing of drug administration, managing treatment-related adverse events (TRAE), and exploring innovative approaches are warranted.

Tolerability of ADXS11-001 Lm-LLO Listeria-Based Immunotherapy With Mitomycin, Fluorouracil, and Radiation for Anal Cancer.

PURPOSE: To obtain safety and preliminary efficacy data of the combination of ADXS11-001, live attenuated Listeria monocytogenes bacterium, with mitomycin, 5-fluorouracil (5-FU), and intensity modulated radiation therapy in locally advanced anal cancer. PATIENTS AND METHODS: Eligibility included patients with previously untreated, nonmetastatic anal cancer with a primary tumor >4 cm or node-positive disease. Patients received 2 cycles of mitomycin and 5-FU concurrent with 54.0 Gy intensity modulated radiation therapy. One intravenous dose of ADXS11-001 (1 × 109 colony-forming units) was administered before chemoradiation; 3 additional monthly doses were given after chemoradiation. RESULTS: Ten patients were treated, including 1 with N2 and 4 with N3 disease. Two patients had grade 3 acute toxicities after the initial dose of ADXS11-001, including chills/rigors (n = 2), back pain (n = 1), and hyponatremia (n = 1). All ADXS11-001 toxicities occurred within 24 hours of administration. There was no apparent increase in chemoradiation toxicities or myelosuppression. One patient had a grade 5 cardiopulmonary event shortly after beginning 5-FU treatment. All 9 assessable patients had complete clinical responses by sigmoidoscopy. Eight of 9 patients (89%) are progression-free at a median follow-up of 42 months. CONCLUSIONS: Preliminary data show that ADXS11-001 can be safely administered with standard chemoradiation for anal cancer. Further studies of listeria-based immunotherapy with radiation are warranted.

Infiltrative Rash Secondary to Leukemic-Phase Diffuse Large B-Cell Lymphoma With t(14;18), CDKN2A and MLL Deletion.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous and highly aggressive subtype of non-Hodgkin's lymphoma. It commonly presents as rapidly-growing, painless lymphadenopathy (LAD). DLBCL presenting in leukemic-phase is rare, with fewer than 40 cases published. Chemotherapy remains the standard approach, although selecting the correct regimen has become more perplexing in patients with CDKN2A mutations. Patients with MLL- and CDKN2A-positive DLBCL may benefit from therapy with a dose-adjusted regimen of rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-R-EPOCH) compared to traditional rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP). Herein, we report a case of leukemic-phase DLBCL presenting as a cutaneous eruption of the bilateral lower extremities, which has not been previously reported in the literature.

Feasibility of retinal screening in a pediatric population with type 1 diabetes mellitus.

PURPOSE: To study the feasibility of using a nonmydriatic camera to screen children with type 1 diabetes mellitus (DM1) as young as 2 years for diabetic retinopathy. METHODS: Prospective pilot imaging study involving children with DM1 aged 2 to 17 years. The screening consisted of: (1) intake form; (2) measurement of blood pressure, pulse, and oximetry; (3) assessment of visual acuity (SIMAV, Padova, Italy); and (4) nonmydriatic color imaging (Canon CX-1 45° 15.1 megapixel camera; Canon Corp., Tokyo, Japan). Images were assessed for signs of diabetic retinopathy and graded for quality on a scale of 1 to 5 by two clinicians. Kappa coefficient was calculated to determine inter-observer agreement. RESULTS: One hundred four of 106 (98%) children underwent imaging (mean age: 11.1 years, 51% male, 88% white). One (1%) child had nonproliferative diabetic retinopathy and 2 (1.9%) had incidental findings. Only 62% of children had an eye examination within the past year, with children with DM1 for more than 5 years significantly more likely to have done so (P = .03). Children who had an eye examination within the past year were significantly older than their counterparts (P = .01). Images of high quality (grades 4 and 5) were acquired in 178 (86%) eyes, and images of some clinical value (grades ≥ 2) were obtained in 207 (99.5%) eyes. Inter-observer agreement for image quality was 0.896. CONCLUSIONS: The feasibility of using a nonmydriatic camera to screen children as young as 2 years for changes related to diabetic eye disease was demonstrated. Nonmydriatic imaging may supplement standard dilated clinical ophthalmology examinations for select patient populations.