Differential responses to taxanes and PARP inhibitors in ATM- versus BRCA2-mutated metastatic castrate-resistant prostate cancer.

BACKGROUND: PARP (poly(ADP-ribose) polymerase) inhibitors (PARPi) are now standard of care in metastatic castrate-resistant prostate cancer (mCRPC) patients with select mutations in DNA damage repair (DDR) pathways, but patients with ATM- and BRCA2 mutations may respond differently to PARPi. We hypothesized that differences may also exist in response to taxanes, which may inform treatment sequencing decisions. METHODS: mCRPC patients (N = 158) with deleterious ATM or BRCA2 mutations who received taxanes, PARPi, or both were retrospectively identified from 11 US academic centers. Demographic, treatment, and survival data were collected. Kaplan-Meier analyses were performed and Cox hazard ratios (HR) were calculated for progression-free survival (PFS) as well as overall survival (OS), from time of first taxane or PARPi therapy. RESULTS: Fifty-eight patients with ATM mutations and 100 with BRCA2 mutations were identified. Fourty-four (76%) patients with ATM mutations received taxane only or taxane before PARPi, while 14 (24%) received PARPi only or PARPi before taxane. Patients with ATM mutations had longer PFS when taxane was given first versus PARPi given first (HR: 0.74 [95% confidence interval [CI]: 0.37-1.50]; p = 0.40). Similarly, OS was longer in patients with ATM mutations who received taxane first (HR: 0.56 [CI: 0.20-1.54]; p = 0.26). Among patients with BRCA2 mutations, 51 (51%) received taxane first and 49 (49%) received PARPi first. In contrast, patients with BRCA2 mutations had longer PFS when PARPi was given first versus taxane given first (HR: 0.85 [CI: 0.54-1.35]; p = 0.49). Similarly, OS was longer in patients with BRCA2 mutations who received PARPi first (HR: 0.75 [CI: 0.41-1.37]; p = 0.35). CONCLUSIONS: Our retrospective data suggest differential response between ATM and BRCA2 mutated prostate cancers in terms of response to PARPi and to taxane chemotherapy. When considering the sequence of PARPi versus taxane chemotherapy for mCRPC with DDR mutations, ATM, and BRCA2 mutation status may be helpful in guiding choice of initial therapy.

Efficacy of enfortumab vedotin in advanced urothelial cancer: Analysis from the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) study.

BACKGROUND: Enfortumab vedotin (EV) is a novel antibody-drug conjugate approved for advanced urothelial cancer (aUC) refractory to prior therapy. In the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) study, the authors looked at the experience with EV in patient subsets of interest for which activity had not been well defined in clinical trials. METHODS: UNITE was a retrospective study of patients with aUC treated with recently approved agents. This initial analysis focused on patients treated with EV. Patient data were abstracted from chart reviews by investigators at each site. The observed response rate (ORR) was investigator-assessed for patients with at least 1 post-baseline scan or clear evidence of clinical progression. ORRs were compared across subsets of interest for patients treated with EV monotherapy. RESULTS: The initial UNITE analysis included 304 patients from 16 institutions; 260 of these patients were treated with EV monotherapy and included in the analyses. In the monotherapy cohort, the ORR was 52%, and it was >40% in all reported subsets of interest, including patients with comorbidities previously excluded from clinical trials (baseline renal impairment, diabetes, and neuropathy) and patients with fibroblast growth factor receptor 3 (FGFR3) alterations. Progression-free survival and overall survival were 6.8 and 14.4 months, respectively. Patients with a pure urothelial histology had a higher ORR than patients with a variant histology component (58% vs 42%; P = .06). CONCLUSIONS: In a large retrospective cohort, responses to EV monotherapy were consistent with data previously reported in clinical trials and were also observed in various patient subsets, including patients with variant histology, patients with FGFR3 alterations, and patients previously excluded from clinical trials with an estimated glomerular filtration rate < 30 mL/min and significant comorbidities. LAY SUMMARY: Enfortumab vedotin, approved by the Food and Drug Administration in 2019, is an important new drug for the treatment of patients with advanced bladder cancer. This study looks at the effectiveness of enfortumab vedotin as it has been used at multiple centers since approval, and focuses on important patient populations previously excluded from clinical trials. These populations include patients with decreased kidney function, diabetes, and important mutations. Enfortumab vedotin is effective for treating these patients. Previously reported clinical trial data have been replicated in this real-world setting, and support the use of this drug in broader patient populations.

Optimal pathological response after neoadjuvant chemotherapy for muscle-invasive bladder cancer: results from a global, multicentre collaboration.

OBJECTIVES: To evaluate outcomes of patients achieving a post-treatment pathological stage of

Mitigating time toxicity in lymphoma and multiple myeloma.

The concept of time toxicity in oncology refers to the presence of frequent healthcare-related interactions that can interfere with patient well-being. In this review, we examine several manifestations of time toxicity in non-Hodgkin lymphoma and multiple myeloma and discuss their impact on decision-making with patients. For example, time toxicity may influence the choice of chemoimmunotherapy versus lenalidomide-rituximab in follicular lymphoma. In myeloma, it may inform the optimal dosing schedule for proteasome inhibitors and bisphosphonates. In both malignancies, varying time toxicity profiles are a key distinction between chimeric antigen receptor T-cell therapies and bispecific antibodies. We outline the challenges with measuring time toxicity as a trial endpoint but discuss its importance as a consideration for patient care, both in standard-of-care settings and in clinical trials. Throughout the review, we highlight strategies to lower the time toxicity of therapies in lymphoma and myeloma without compromising their efficacy or patient safety.

Financial Toxicity, Time Toxicity, and Quality of Life in Multiple Myeloma.

BACKGROUND: Patients with multiple myeloma (MM) may be on therapy for years, which can lead to financial toxicity (FinTox) or time toxicity (TimeTox). The prevalence, predictors, and quality of life (QOL) impacts of FinTox and TimeTox during different phases of MM treatment have not been characterized. PATIENTS AND METHODS: We conducted a single-center cross-sectional survey of patients with MM who had undergone transplantation. FinTox+ was defined as a COST-FACIT score <23, TimeTox+ as MM-related interactions (including phone calls) ≥1x weekly or ≥1x monthly in-person among far-residing patients, QOL using PROMIS Global Health, and functional status using patient-reported Karnofsky performance status (KPS). RESULTS: Of 252 patients, 22% and 40% met FinTox+ and TimeTox+ criteria respectively. Respective FinTox+ and TimeTox+ proportions were 22%/37% for patients on maintenance, 22%/82% with active therapy, and 20%/14% with observation. FinTox+ predictors included annual income (P < .01) and out-of-pocket costs (P < .01). TimeTox+ predictors included disease status (P < .001), caregiver status (P = .01), far-residing status (P < .001), and out-of-pocket costs (P = .03). FinTox+ was associated with a clinically meaningful decrease in mental QOL, while TimeTox+ patients were more likely to have KPS ≤ 80. CONCLUSIONS: In our large study, monetary status but not disease status predicted FinTox. Over a third of patients on maintenance reported TimeTox. FinTox+ was associated with decreased mental health, while TimeTox+ was associated with worse performance status. These two toxicities may negatively impact patient wellbeing, and studies of strategies to mitigate their impact are in development.

Defining the Role of the Modern Oncology Provider in Mitigating Financial Toxicity.

Financial toxicity, the cumulative financial hardships resulting from cancer diagnosis and treatment, is a growing problem in the United States. With the proliferation of costly novel therapeutics and improved cancer survival, financial toxicity will remain a major issue in cancer care delivery. Frontline oncology providers serve as gatekeepers in the medical system and, as such, could play essential roles in recognizing and addressing financial toxicity. Providers and health systems could help mitigate financial toxicity through routine financial toxicity screening, financial navigation, and advocacy. Specific strategies include developing and implementing financial screening instruments that can be integrated in electronic medical records and establishing team-based financial navigation programs to help patients with out-of-pocket medical costs, nonmedical spending, and insurance optimization. Finally, providers should continue to advocate for policies and legislation that decrease cost and promote value-based care. In this review, we examine opportunities for provider engagement in these areas and highlight gaps for future research.

Heterogeneous Expression of PD-L1, B7x, B7-H3, and HHLA2 in Pulmonary Sarcomatoid Carcinoma and the Related Regulatory Signaling Pathways.

Immunotherapy has transformed lung cancer management, but PSC remains an aggressive subtype with a poor prognosis. This study investigates the differential expression of PD-L1 and alternative immune checkpoints (ICs; B7x, B7-H3, and HHLA2), and genetic alterations in PSCs. Tumor specimens of 41 PSC patients were evaluated. PD-L1, B7x, B7-H3, and HHLA2 were positive in 75.0%, 67.6%, 73.0%, and 91.9% of tumors, respectively. PD-L1 expression was significantly higher in the epithelial compared to the sarcomatoid component (median TPS: 50% vs. 0%, p = 0.010). Expression of PD-L1 in both components was only seen in 32.1% of patients. However, at least one IC was expressed in 92.9% of epithelial and 100% of sarcomatoid components. Furthermore, METex14 was detected in 19.5% of patients and was associated with a higher sarcomatoid percentage. Our preclinical studies revealed that METex14 induced PD-L1 expression via MAPK or PI3K/Akt pathways, and MET inhibitors decreased PD-L1 expression. Our findings demonstrate distinct expressions of ICs in PSC subcomponents. Thus, combination IC inhibition as a therapeutic strategy in PSC warrants further exploration. A high percentage of METex14 in PSC and its role in regulating PD-L1 expression reveal different therapeutic targets in this aggressive NSCLC subtype.

Divergent Patterns in Care Utilization and Financial Distress between Patients with Blood Cancers and Solid Tumors: A National Health Interview Survey Study, 2014-2020.

Introduction: Important differences exist between the presentation, treatment, and survivorship of patients and survivors with blood cancers. Furthermore, existing research in financial toxicity has not fully addressed the relationship between medical care utilization and patient-reported outcomes of financial barriers and distress. We answered these questions by using a nationally representative survey. Methods: Respondents with blood cancers and solid tumors from the National Health Interview Survey were identified (2014−2020). We identified 23 survey questions as study outcomes and grouped them into three domains of medical care utilization, financial barriers to care, and financial distress. Associations between the three domains and associations of study outcomes between cancer types were examined using weighted univariate analyses and multivariable linear and logistic regressions. Results: The final study group consisted of 6248 respondents with solid tumors and 398 with blood cancers (diagnosed ≤ 5 years). Across all respondents with cancer, higher medical care utilization is generally associated with increased financial barriers to care. Compared to respondents with solid tumors, respondents with blood cancers had a higher level of medical care utilization (ß = 0.36, p = 0.02), a lower level of financial barriers to care (ß = −0.19, p < 0.0001), and a higher level of financial distress in affording care (ß = 0.64, p = 0.03). Conclusions: Patients and survivors with blood cancers and solid tumors demonstrate divergent patterns in care utilization, financial barriers, and financial distress. Future research and interventions on financial toxicity should be tailored for individual cancer groups, recognizing the differences in medical care utilization, which affect the experienced financial barriers.

Case report: Immune-mediated meibomian gland dysfunction following pembrolizumab therapy for advanced urothelial carcinoma.

Ocular immune-related adverse events are a relatively rare complication of immune checkpoint inhibitors. Common ocular toxicities range from dry eyes to inflammatory uveitis and ocular myasthenia gravis. Here, we present the case of a 55-year-old woman with recurrent urothelial carcinoma of the ureter after initially being managed with neoadjuvant cisplatin-based chemotherapy and surgical resection. She was treated with pembrolizumab which was complicated by immune-mediated pneumonitis after the eighth cycle, which was managed with a prolonged steroid course. The patient also developed red eyes along with recurrent styes. Eye examination revealed decreased tear breakup time, expression of thick and turbid meibum, and meibomian gland atrophy on infrared meibography. The patient was diagnosed with suspected immune-mediated meibomian gland dysfunction (MGD) as a result of pembrolizumab, a previously unreported complication of immunotherapy. The goal of MGD therapy is to stabilize the tear film and minimize evaporation with lipid-based lubricants and other conservative treatments.

Outcomes of metastatic urothelial carcinoma following discontinuation of enfortumab-vedotin.

BACKGROUND: Enfortumab vedotin (EV) is approved to treat metastatic urothelial carcinoma (mUC) following platinum and PD1/L1 inhibitors. Since the outcomes and patterns of therapy of patients following discontinuation of EV are unknown, we conducted a retrospective study to assess this issue. METHODS: Data were retrospectively obtained from patients with mUC following discontinuation of EV after prior platinum-based chemotherapy and PD1/L1 inhibitors. Objective response rate (ORR) was evaluated in those who received therapy post-EV. Statistical analyses were performed to describe the overall survival (OS) and compare patient characteristics and outcomes of those who did or did not receive treatment post-EV. RESULTS: Data were available for 63 patients from 6 institutions: 46 (73%) were male and median age was 68 years (range 43-83). The median OS was 32 weeks. Thirty-two patients (51%) received therapy after EV. The OS of those who did vs. did not receive post-EV therapy was significantly different (median 43.1 vs. 16.9 weeks, P = .015). Longer duration of prior EV therapy was associated with receipt of post-EV therapy (P = .0437) as well as OS in both the treated (P = .045) and untreated groups (P = .012). Objective response was observed in 3 of 32 patients (9.4%) who received therapy post-EV. CONCLUSION: Outcomes of patients with mUC following discontinuation of EV are dismal and only 51% received therapy after discontinuation of EV. This study identifies benchmarks for the interpretation of activity of new agents following EV and raises the hypothesis for duration of EV as a potential prognostic factor following discontinuation of EV.

Geriatric risk factors for serious COVID-19 outcomes among older adults with cancer: a cohort study from the COVID-19 and Cancer Consortium.

BACKGROUND: Older age is associated with poorer outcomes of SARS-CoV-2 infection, although the heterogeneity of ageing results in some older adults being at greater risk than others. The objective of this study was to quantify the association of a novel geriatric risk index, comprising age, modified Charlson comorbidity index, and Eastern Cooperative Oncology Group performance status, with COVID-19 severity and 30-day mortality among older adults with cancer. METHODS: In this cohort study, we enrolled patients aged 60 years and older with a current or previous cancer diagnosis (excluding those with non-invasive cancers and premalignant or non-malignant conditions) and a current or previous laboratory-confirmed COVID-19 diagnosis who reported to the COVID-19 and Cancer Consortium (CCC19) multinational, multicentre, registry between March 17, 2020, and June 6, 2021. Patients were also excluded for unknown age, missing data resulting in unknown geriatric risk measure, inadequate data quality, or incomplete follow-up resulting in unknown COVID-19 severity. The exposure of interest was the CCC19 geriatric risk index. The primary outcome was COVID-19 severity and the secondary outcome was 30-day all-cause mortality; both were assessed in the full dataset. Adjusted odds ratios (ORs) and 95% CIs were estimated from ordinal and binary logistic regression models. FINDINGS: 5671 patients with cancer and COVID-19 were included in the analysis. Median follow-up time was 56 days (IQR 22-120), and median age was 72 years (IQR 66-79). The CCC19 geriatric risk index identified 2365 (41·7%) patients as standard risk, 2217 (39·1%) patients as intermediate risk, and 1089 (19·2%) as high risk. 36 (0·6%) patients were excluded due to non-calculable geriatric risk index. Compared with standard-risk patients, high-risk patients had significantly higher COVID-19 severity (adjusted OR 7·24; 95% CI 6·20-8·45). 920 (16·2%) of 5671 patients died within 30 days of a COVID-19 diagnosis, including 161 (6·8%) of 2365 standard-risk patients, 409 (18·5%) of 2217 intermediate-risk patients, and 350 (32·1%) of 1089 high-risk patients. High-risk patients had higher adjusted odds of 30-day mortality (adjusted OR 10·7; 95% CI 8·54-13·5) than standard-risk patients. INTERPRETATION: The CCC19 geriatric risk index was strongly associated with COVID-19 severity and 30-day mortality. Our CCC19 geriatric risk index, based on readily available clinical factors, might provide clinicians with an easy-to-use risk stratification method to identify older adults most at risk for severe COVID-19 as well as mortality. FUNDING: US National Institutes of Health National Cancer Institute Cancer Center.

Emerging therapies for relapsed/refractory multiple myeloma: CAR-T and beyond.

The pace of innovation of multiple myeloma therapy in recent years is remarkable with the advent of monoclonal antibodies and the approval of novel agents with new mechanisms of action. Emerging therapies are on the horizon for clinical approval with significant implications in extending patient survival and advancing closer to the goal of a cure, especially in areas of immunotherapy such as chimeric antigen receptor T cells, bispecific T cell engager antibodies, antibody drug conjugates, newer generations of monoclonal antibodies, and small molecule inhibitor and modulators. This review provides an update of current myeloma therapeutics in active preclinical and early clinical development and discusses the mechanism of action of several classes of novel therapeutics.

Affordable Care Act and Cancer Survivors' Financial Barriers to Care: Analysis of the National Health Interview Survey, 2009-2018.

PURPOSE: Since Affordable Care Act (ACA) implementation in 2014, studies have demonstrated gains in insurance coverage for cancer survivors < 65 years. We assessed the impact of ACA implementation on financial barriers to care by stratifying survivors at age 65 years, when individuals typically become Medicare-eligible. METHODS: We used data from respondents with cancer in the 2009-2018 National Health Interview Survey. We identified 21,954 respondents representing approximately 7.4 million survivors, who were then age-stratified at age 65 years. Survey responses regarding financial barriers to medical care and medications were analyzed, and age-stratified multivariable logistic regression modeling was performed, which evaluated the impact of ACA implementation on these measures, adjusted for demographic and socioeconomic variables. RESULTS: After multivariable logistic regression, ACA implementation was associated with higher adjusted odds of Medicaid insurance (odds ratio [95% CI] 2.02 [1.72 to 2.36]; P < .0001) and lower adjusted odds of no insurance (0.57 [0.48 to 0.68]; P < .0001). Regarding financial barriers, ACA implementation was associated with lower adjusted odds of inability to afford medications (0.68 [0.59 to 0.79]; P < .0001), inability to afford dental care (0.83 [0.73 to 0.94]; P = .004), and delaying care (0.78 [0.69 to 0.89]; P = .002) in the 18-64 years group. Similarly, ACA implementation was associated with lower adjusted odds of secondary outcomes such as delaying refills, skipping doses, and anxiety over medical bills. Similar associations were not seen in the > 65 years group. CONCLUSION: Survivor-reported measures of financial barriers in cancer survivors age 18-64 years significantly improved following ACA implementation. Similar changes were not seen in the Medicare-eligible cohort, likely because of high Medicare enrollment and few uninsured.

A Scoping Review of Behavioral Interventions Addressing Medical Financial Hardship.

Little information has been compiled across studies about existing interventions to mitigate issues of medical financial hardship, despite growing interest in health care delivery. The purpose of this qualitative systematic scoping review was to examine content and outcomes of interventions to address medical financial hardship. PRISMA guidelines were applied to present results using PubMed, Scopus, and CINAHL, published between January 1980 and August 2020. Additional studies were identified through reference lists of selected papers. Included studies focused on mitigating medical financial hardship from out-of-pocket (OOP) health care expenses as an intervention strategy with at least 1 evaluation component. Screening 2412 articles identified 339 articles for full-text review, 12 of which met inclusion criteria. Variation was found regarding targets and outcome measurement of intervention. Primary outcomes were in the following categories: financial outcomes (eg, OOP expenses), behavioral outcomes, psychosocial, health care utilization, and health status. No included studies reported significant reduction in OOP expenses, perceptions of financial burden/toxicity, or health status. However, changes were observed for behavioral outcomes (adherence to treatment, patient needs addressed), some psychosocial outcomes (mental health symptoms, perceived support, patient satisfaction), and care utilization such as routine health care. No patterns were observed in the achievement of outcomes across studies based on intensity of intervention. Few rigorous studies exist in this emerging field, and studies have not shown consistent positive effects. Future research should focus on conceptual clarity of the intervention, align outcome measurement and achieve consensus around outcomes, and employ rigorous study designs, measurement, and outcome follow-up.

Characterization of outcomes in patients with advanced genitourinary malignancies treated with immune checkpoint inhibitors.

PURPOSE: Several immune checkpoint inhibitors (ICIs) are FDA approved for treatment of genitourinary (GU) malignancies. We aim to determine demographic and clinicopathologic characteristics that significantly affect clinical outcomes in patients with advanced stage GU malignancies treated with ICIs. MATERIALS AND METHODS: We performed a single-center, consecutive, retrospective cohort analysis on patients with metastatic or unresectable GU malignancies who were treated with ICIs at the University of Michigan. Immune-related adverse events (irAEs), putative immune-mediated allergies, and overall response rates (ORR) were assessed. Comorbidity index scores were calculated. Survival analysis was performed to evaluate progression-free survival (PFS) and overall survival (OS), stratifying and controlling for a variety of clinicopathologic baseline factors including site of metastases. RESULTS: A total of 160 patients were identified with advanced renal cell carcinoma (RCC) or urothelial carcinoma. Median PFS and OS were 5.0 and 23.6 months for RCC, and 2.8 and 9.6 months for urothelial carcinoma, respectively. Patients who experienced increased frequency and higher grade irAEs had better ICI treatment response (P < 0.0001). Presence of liver metastases was associated with poor response to ICI therapy (P = 0.001). Multivariable modeling demonstrates that patients with urothelial carcinoma and liver metastases had statistically worse PFS and OS compared to patients with RCC or other sites of metastases, respectively. CONCLUSION: Greater frequency and higher grades of irAEs are associated with better treatment response in patients with RCC and urothelial malignancy receiving ICI therapy. The presence of liver metastases denotes a negative predictive marker for immunotherapy efficacy. SUMMARY: Immune checkpoint inhibitors (ICI) are increasingly used to treat genitourinary (GU) malignancies. However, clinical data regarding patients with advanced-stage GU malignancies treated with ICI is lacking. Thus, we performed a single-center, retrospective cohort study on patients with metastatic and unresectable renal cell carcinoma (RCC) and urothelial carcinoma who were treated with ICIs at the University of Michigan to provide demographic and clinicopathologic data regarding this population. We specifically focused on immune-related adverse events (irAEs), immune-mediated allergies, and the associated overall response rates (ORR). To better assess performance status, we calculated comorbidity scores for all patients. Finally, survival analyses for progression-free survival (PFS) and overall survival (OS) were performed using Kaplan-Meier analysis and Cox proportional hazards modeling, stratifying and controlling for clinicopathologic baseline factors, including sites of metastases, in our multivariable analysis. A total of 160 patients were identified with advanced RCC or urothelial carcinoma. We found decreased PFS (2.8 vs. 5.0 months) and decreased OS (9.8 vs. 23.6 months) for urothelial carcinoma compared to RCC patients. We noted that patients who experienced increased frequency and higher grades of irAEs had better treatment ORR with ICI therapy (P ≤ 0.0001). The presence of liver metastases was associated with worse ORR (P = 0.001), PFS (P = 0.0014), and OS (P = 0.0028) compared to other sites of metastases including lymph node, lung, and CNS/bone. The poor PFS and OS associated with urothelial carcinoma and liver metastases were preserved in our multivariable modeling after controlling for pertinent clinical factors. We conclude that greater frequency and higher grades of irAEs are associated with better treatment response in GU malignancy patients receiving ICI, a finding that is consistent with published studies in other cancers. The presence of liver metastases represents a significantly poor predictive marker in GU malignancy treated with ICI. Our findings contribute to the growing body of literature that seeks to understand the clinicopathologic variables and outcomes associated with ICI therapy.

Association of Convalescent Plasma Therapy With Survival in Patients With Hematologic Cancers and COVID-19.

Importance: COVID-19 is a life-threatening illness for many patients. Prior studies have established hematologic cancers as a risk factor associated with particularly poor outcomes from COVID-19. To our knowledge, no studies have established a beneficial role for anti-COVID-19 interventions in this at-risk population. Convalescent plasma therapy may benefit immunocompromised individuals with COVID-19, including those with hematologic cancers. Objective: To evaluate the association of convalescent plasma treatment with 30-day mortality in hospitalized adults with hematologic cancers and COVID-19 from a multi-institutional cohort. Design, Setting, and Participants: This retrospective cohort study using data from the COVID-19 and Cancer Consortium registry with propensity score matching evaluated patients with hematologic cancers who were hospitalized for COVID-19. Data were collected between March 17, 2020, and January 21, 2021. Exposures: Convalescent plasma treatment at any time during hospitalization. Main Outcomes and Measures: The main outcome was 30-day all-cause mortality. Cox proportional hazards regression analysis with adjustment for potential confounders was performed. Hazard ratios (HRs) are reported with 95% CIs. Secondary subgroup analyses were conducted on patients with severe COVID-19 who required mechanical ventilatory support and/or intensive care unit admission. Results: A total of 966 individuals (mean [SD] age, 65 [15] years; 539 [55.8%] male) were evaluated in this study; 143 convalescent plasma recipients were compared with 823 untreated control patients. After adjustment for potential confounding factors, convalescent plasma treatment was associated with improved 30-day mortality (HR, 0.60; 95% CI, 0.37-0.97). This association remained significant after propensity score matching (HR, 0.52; 95% CI, 0.29-0.92). Among the 338 patients admitted to the intensive care unit, mortality was significantly lower in convalescent plasma recipients compared with nonrecipients (HR for propensity score-matched comparison, 0.40; 95% CI, 0.20-0.80). Among the 227 patients who required mechanical ventilatory support, mortality was significantly lower in convalescent plasma recipients compared with nonrecipients (HR for propensity score-matched comparison, 0.32; 95% CI, 0.14-0.72). Conclusions and Relevance: The findings of this cohort study suggest a potential survival benefit in the administration of convalescent plasma to patients with hematologic cancers and COVID-19.

Differential Activity of PARP Inhibitors in BRCA1- Versus BRCA2-Altered Metastatic Castration-Resistant Prostate Cancer.

Two poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and rucaparib) are US Food and Drug Administration-approved for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA1/2 mutations, but the relative efficacy of PARP inhibition in BRCA1- versus BRCA2-altered mCRPC is understudied. METHODS: We conducted a multicenter retrospective analysis involving 12 sites. We collected genomic and clinical data from 123 patients with BRCA1/2-altered mCRPC who were treated with PARP inhibitors. The primary efficacy end point was the prostate-specific antigen (PSA) response (≥ 50% PSA decline) rate. Secondary end points were PSA progression-free survival (PSA-PFS), clinical or radiographic PFS, and overall survival. We compared clinical outcomes, and other genomic characteristics, among BRCA1- versus BRCA2-altered mCRPC. RESULTS: A total of 123 patients (13 BRCA1 and 110 BRCA2) were included. PARP inhibitors used were olaparib (n = 116), rucaparib (n = 3), talazoparib (n = 2), and veliparib (n = 2). At diagnosis, 72% of patients had Gleason 8-10 disease. BRCA1 patients were more likely to have metastatic disease at presentation (69% v 37%; P = .04). Age, baseline PSA, metastatic distribution, and types of previous systemic therapies were similar between groups. There were equal proportions of germline mutations (51% v 46%; P = .78) in both groups. BRCA1 patients had more monoallelic (56% v 41%; P = .49) and concurrent TP53 (55% v 36%; P = .32) mutations. PSA50 responses in BRCA1- versus BRCA2-altered patients were 23% versus 63%, respectively (P = .01). BRCA2 patients achieved longer PSA-PFS (HR, 1.94; 95% CI, 0.92 to 4.09; P = .08), PFS (HR, 2.08; 95% CI, 0.99 to 4.40; P = .05), and overall survival (HR, 3.01; 95% CI, 1.32 to 6.83; P = .008). Biallelic (compared with monoallelic) mutations, truncating (compared with missense) mutations, and absence of a concurrent TP53 mutation were associated with PARP inhibitor sensitivity. CONCLUSION: PARP inhibitor efficacy is diminished in BRCA1- versus BRCA2-altered mCRPC. This is not due to an imbalance in germline mutations but might be related to more monoallelic mutations and/or concurrent TP53 alterations in the BRCA1 group.

Derivation of a Model to Guide Empiric Therapy for Carbapenem-Resistant Klebsiella pneumoniae Bloodstream Infection in an Endemic Area.

BACKGROUND: Appropriate therapy for carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream infection (BSI) is often given late in the course of infection, and strategies for identifying CRKP BSI earlier are needed. METHODS: A retrospective case-control study was performed at a tertiary care hospital, university hospital, and community hospital in Bronx, New York. All participants had a blood culture sent and received an antibiotic within 48 hours of the culture. The case group (n = 163) had a blood culture with CRKP. The control group (n = 178) had a blood culture with carbapenem-susceptible Klebsiella. Data were obtained by electronic or conventional medical record abstraction. A multiple logistic regression model was built to identify associated factors and develop a clinical model for CRKP BSI. Model performance characteristics were estimated using a 10-fold cross-validation analysis. RESULTS: A prior nonblood culture with carbapenem-resistant Enterobacteriaceae, skilled nursing facility (SNF) residence, mechanical ventilation, and admission >3 days were strongly associated risk factors. A significant interaction led to development of separate clinical models for subjects admitted <3 days at the time of positive blood culture from those admitted at least 3 days. The derived models had a good ability to discriminate between subjects with and without CRKP BSI. A clinical classification rule to guide therapy can prioritize sensitivity or specificity. CONCLUSIONS: Prior nonblood cultures showing resistance and exposure to SNF and health care settings are factors associated with carbapenem resistance. The clinical classification rules derived in this work should be validated for ability to guide therapy.

Survival Disparities in Black Patients With EGFR-mutated Non-small-cell Lung Cancer.

BACKGROUND: Little is known about the difference between black and non-black patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), particularly regarding survival. We thus characterized the EGFR expression profile, clinical characteristics, and survival outcome in these patients. PATIENT AND METHODS: We reviewed the cancer registry and patient charts at a New York-Bronx network (n = 2773) treating a large population of minority patients, for non-squamous NSCLC (n = 1986) diagnosed between 2009 and 2015. Survival was adjusted for smoking, gender, age, weight, and stage. RESULTS: The EGFR mutation rate was 15% (98/652) in tested patients (black, 14%; non-black, 16%). There was no significant difference between the 2 cohorts with respect to age at diagnosis, gender, presenting stages, and socioeconomic status. On the other hand, weight was noted to be heavier in black patients with EGFR-mutated NSCLC than their non-black counterparts (P = .012). After adjusting for gender, age, smoking status, weight, and stage, the multivariate analysis revealed no racial disparity in survival among patients with wild-type EGFR (P = .774); However, among patients with EGFR-mutated NSCLC, black patients had shorter survival in comparison with non-black patients (P = .001), with 2-year survival rates being 33% versus 61%, respectively. Such shorter survival was also observed among EGFR-inhibitor treated patients with common EGFR mutations (P = .040). CONCLUSIONS: To our knowledge, this is the first report of inferior survival among black patients with NSCLC with EGFR mutations, relative to non-black patients. The survival disparities suggest the need of more tailored management for this patient population.