Early Real-World First-Line Treatment With Venetoclax Plus HMAs Versus HMA Monotherapy Among Patients With AML in a Predominately US Community Setting.

BACKGROUND: Venetoclax in combination with hypomethylating agents (HMAs) is standard-of-care in patients with newly diagnosed acute myeloid leukemia (AML) who are ≥ 75 years old or unfit for intensive chemotherapy. We examined early real-world treatment experience among patients with AML receiving venetoclax+HMAs or HMA monotherapy. PATIENTS AND METHODS: This retrospective cohort study used an electronic health record-derived, deidentified, United States nationwide database comprised of patient-level structured and unstructured data, curated via technology-enabled abstraction. Patients with an AML diagnosis on or after January 1, 2014, who had ≥ 2 clinic visits, and initiated treatment with venetoclax+HMAs from June 1, 2018 to March 31, 2021, or HMA monotherapy from January 1, 2016 to May 31, 2018, were included. Kaplan-Meier analysis was used to estimate time to last administration (TTLA) and overall survival (OS). RESULTS: Overall, 619 patients treated with venetoclax+HMAs and 480 treated with HMA monotherapy were selected from the database. Median age at diagnosis was 76 and 78 years, respectively, most patients were treated in community practice (83.4% and 89.4%, respectively), and almost half had secondary AML (47.2% and 47.3%, respectively). Adjusted analyses showed both significantly longer TTLA (3.6 months vs. 2.3 months; hazard ratio [HR] = 0.69 [95% confidence interval (CI), 0.60-0.80], P< .0001) and OS (9.3 months vs. 5.9 months; HR = 0.71 [95% CI, 0.61-0.82], P < .0001) in patients treated with venetoclax+HMAs versus HMA monotherapy, respectively. CONCLUSION: This study shows benefit in real-world outcomes of venetoclax+HMAs relative to HMA monotherapy in patients with newly diagnosed AML, using a predominantly community-based database.

Venetoclax and Hypomethylating Agents as First-line Treatment in Newly Diagnosed Patients with AML in a Predominately Community Setting in the US.

BACKGROUND: Treatment with venetoclax + hypomethylating agents (HMAs) is standard-of-care for newly diagnosed (ND) patients with acute myeloid leukemia (AML) aged ≥75 years, or with comorbidities precluding intensive chemotherapy. We describe real-world venetoclax + HMA treatment practices and outcomes in patients with ND AML in the US. PATIENTS AND METHODS: This retrospective cohort study used an electronic health record-derived, US nationwide, de-identified database, and included adults with ND AML, initiating venetoclax + HMA treatment ≤30 days from diagnosis (June 1, 2018-January 31, 2020). Venetoclax treatment variables included dosing information, schedule modifications, and drug-drug interactions. The median venetoclax + HMA treatment duration and overall survival (OS) from venetoclax initiation to discontinuation, death, or end of follow-up (August 31, 2020) were examined by Kaplan-Meier analyses. RESULTS: Overall, 169 patients were included. The median age at diagnosis was 77 years; 85.2% of patients were treated in community practice. Ninety-five of 169 patients (56.2%) had evaluable bone marrow response data following the start of treatment; 53.7% were assessed approximately at the end of cycle 1. Following the first treatment cycle, treatment schedule modifications were recorded in 101 patients and dose changes in 56, primarily due to toxicity. The median treatment duration was 5.2 months; the median OS was 8.6 months (median follow-up was 7.2 months). Venetoclax dose changes did not modify efficacy outcomes, but longer median OS was associated with venetoclax treatment schedule modifications (P = .02). CONCLUSIONS: This study reflects early real-world experience with venetoclax + HMAs in a predominantly community setting and emphasizes the importance of appropriate venetoclax management in optimizing patient outcomes.

T-DM1 after Pertuzumab plus Trastuzumab: Treatment Sequence-Induced Selection Bias in HER2-Positive Metastatic Breast Cancer.

Real-world studies have suggested decreased trastuzumab emtansine (T-DM1) effectiveness in patients with metastatic breast cancer (mBC) who received prior trastuzumab plus pertuzumab (H + P). However, these studies may have been biased toward pertuzumab-experienced patients with more aggressive disease. Using an electronic health record-derived database, patients diagnosed with mBC on/after 1 January 2011 who initiated T-DM1 in any treatment line (primary cohort) or who initiated second-line T-DM1 following first-line H ± P (secondary cohort) from 22 February 2013 to 31 December 2019 were included. The primary outcome was time from index date to next treatment or death (TTNT). In the primary cohort (n = 757), the percentage of patients with prior P increased from 37% to 73% across the study period, while population characteristics and treatment effectiveness measures were generally stable. Among P-experienced patients from the secondary cohort (n = 246), median time from mBC diagnosis to T-DM1 initiation increased from 10 to 14 months (2013-2019), and median TTNT increased from 4.4 to 10.2 months (2013-2018). Over time, prior H + P prevalence significantly increased with no observable impact on T-DM1 effectiveness. Drug approval timing should be considered when assessing treatment effectiveness within a sequence.

Treatment patterns and outcomes according to cytogenetic risk stratification in patients with multiple myeloma: a real-world analysis.

A clearer understanding of the prognostic implications of t(11;14) in multiple myeloma (MM) is needed to inform current and future therapeutic options. We utilized real-world data from a US database to examine treatment patterns and outcomes in patients by t(11;14) status compared with high- and standard-risk subgroups across different lines of therapy (LoT). This retrospective, observational cohort study used de-identified patient-level information from adults with MM and first-line treatment initiation between January 2011 and January 2020, followed until February 2020. The high-risk cohort comprised patients with high-risk genetic abnormalities per mSMART criteria (including those with co-occurring t(11;14)). Among 6138 eligible patients, 6137, 3160, and 1654 received first-, second-, and third-line treatments, respectively. Of 645 patients who had t(11;14), 69.1% had t(11;14) alone, while 30.9% had co-occurring high-risk abnormalities. Altogether, 1624 and 2544 patients were classified as high- and standard-risk, respectively. In the absence of biomarker-driven therapy, treatment patterns remain similar across LoT in high-risk, t(11;14)+, and standard-risk subgroups. Across all LoT, patient outcomes in the high-risk subgroup were less favorable than those in the t(11;14)+ and standard-risk subgroups. Thus, there is an opportunity for novel therapeutics targeted to t(11;14) and other defined subgroups to personalize MM therapy and optimize patient outcomes.

Prospective Case-crossover Study Investigating the Possible Association Between Nonarteritic Anterior Ischemic Optic Neuropathy and Phosphodiesterase Type 5 Inhibitor Exposure.

OBJECTIVE: To evaluate the association between intermittent phosphodiesterase type 5 inhibitor (PDE5i) exposure and risk of acute nonarteritic anterior ischemic optic neuropathy (NAION) using a case-crossover design. METHODS: Male adults with suspected NAION were enrolled at 41 US ophthalmology sites from 2010 to 2015 and were interviewed regarding risk factors for NAION, medical history, and PDE5i use before NAION onset (index date of onset [IDO]). An adjudication committee confirmed the NAION cases. The primary analysis, using the person-time method, examined the rate of PDE5i exposure within 5 half-lives of NAION onset relative to PDE5i exposure over a 30-day study period preceding the IDO in men exposed to PDE5i intermittently as a measure of NAION risk associated with PDE5i exposure. Rate ratios were estimated using the Mantel-Haenszel estimator. Secondary analyses included person-time analyses over the 12-months preceding the IDO and matched-interval analyses over 42 days preceding the IDO. RESULTS: Of 279 men with confirmed NAION, 22 were exposed to PDE5i intermittently within 30 days of IDO. The Mantel-Haenszel rate ratio for risk of NAION associated with PDE5i exposure within 5 half-lives of IDO was 2.27 (95% confidence interval [CI]: 0.99-5.20) over the 30-day period (n = 22) and 3.52 (95% CI: 1.59-7.79) over the 12-month period (n = 26). Sensitivity analyses showed similar results and were statistically significant. The matched-interval method found no association (hazard ratio = 1.64 [95% CI: 0.60-4.51]). CONCLUSION: Overall, the study suggests an increased risk of NAION associated with PDE5i use. Patients and health-care providers should continue to weigh the risks and benefits of PDE5i use, including the potential for NAION.

Recent prediagnostic aspirin use, lymph node involvement, and 5-year mortality in women with stage I-III breast cancer: a nationwide population-based cohort study.

Lymph node-positive breast tumors are more likely to express COX2 than node-negative tumors. In preclinical studies, COX2 inhibition prevents breast tumor spread to lymph nodes. Therefore, we examined the association between recent (1 year) prediagnostic use of aspirin (COX1/COX2 inhibitor), lymph node involvement at breast cancer diagnosis, and breast cancer-specific mortality. Women with stage I-III breast cancer diagnosed from 2001 to 2006 (N = 2,796) were identified from Ireland's National Cancer Registry. These data were linked to prescription refill and mammographic screening databases. Relative risks (RR) were estimated for associations between prediagnostic aspirin use and lymph node-positive status at diagnosis. HRs were estimated for associations between pre- and postdiagnostic aspirin use and 5-year mortality, stratified by lymph node status. Women with prediagnostic aspirin use were statistically significantly less likely to present with a lymph node-positive tumor than nonusers [RR = 0.89; 95% confidence interval (CI), 0.81-0.97], particularly those with larger (Pinteraction = 0.036), progesterone receptor (PR)-negative (Pinteraction < 0.001) or estrogen receptor (ER)-negative (Pinteraction = 0.056) tumors. The magnitude of this association increased with dose (Ptrend < 0.01) and dosing intensity (Ptrend < 0.001) and was similar in women with or without screen-detected tumors (Pinteraction = 0.70). Prediagnostic aspirin use was associated with lower 5-year breast cancer-specific mortality among women with lymph node-negative tumors (HR, 0.55; 95% CI, 0.33-0.92) but not node-positive tumors (HR, 0.91; 95% CI, 0.37-1.22). Tests for effect-modification were, however, not statistically significant (Pinteraction = 0.087). Postdiagnostic aspirin use was not associated with breast cancer-specific mortality (HR, 0.99; 95% CI, 0.68-1.45). Our findings indicate that recent prediagnostic aspirin use is protective against lymph node-positive breast cancer. This is a plausible explanation for reductions in breast cancer mortality reported in observational studies of aspirin use.

Prostate specific antigen testing is associated with men's psychological and physical health and their healthcare utilisation in a nationally representative sample: a cross-sectional study.

BACKGROUND: Prostate cancer incidence has risen considerably in recent years, primarily due to Prostate Specific Antigen (PSA) testing in primary care. The objective of this study was to investigate associations between PSA testing and the psychological and physical health, and healthcare utilisation of men in a population where PSA testing is widespread. METHODS: A cross-sectional study was carried out in a population-representative sample of men ≥ 50 years enrolled in The Irish Longitudinal Study on Ageing (TILDA). TILDA participants underwent structured interviews, health assessments and completed standardised questionnaires. Men were classified as ever/never having received a PSA test. Multivariate logistic regression (Odds Ratios (OR) and 95% Confidence Intervals (CI) was used to determine associations between PSA testing, and men's psychological and physical health and healthcare utilisation. RESULTS: This analysis included 3,628 men, 68.2% of whom ever had a PSA test. In adjusted analysis, men with sub-threshold depression were significantly less likely to have had a PSA test, (OR=0.79, 95% CI 0.64-0.97). Likelihood of having a PSA test was inversely associated with anxiety, but this was not significant (OR=0.79, 95% CI 0.57-1.09). Frailty (OR=0.61, 95% CI 0.31-1.05) and eligibility for free primary care (OR=0.63, 95% CI 0.52-0.77) were also inversely associated with PSA testing. Positive associations were observed between PSA testing and more chronic illnesses (OR=1.11, 95% CI 1.05-1.19), more primary care visits (OR=1.03, 95% CI 1.01-1.05) and preventative health practices, including cholesterol testing and influenza vaccination (OR=1.35, 95% CI 1.13-1.60). CONCLUSIONS: Men's psychological and physical health and their healthcare utilisation are associated with PSA testing in primary care. The association between poorer psychological health, in particular sub-threshold depression, and reduced likelihood of PSA testing in primary care requires further investigation. These findings may have wider implications for other cancer screening.

Low-dose aspirin and survival in men with prostate cancer: a study using the UK Clinical Practice Research Datalink.

PURPOSE: Aspirin use is associated with reduced risk of, and death from, prostate cancer. Our aim was to determine whether low-dose aspirin use after a prostate cancer diagnosis was associated with reduced prostate cancer-specific mortality. METHODS: A cohort of newly diagnosed prostate cancer patients (1998-2006) was identified in the UK Clinical Practice Research Datalink (confirmed by cancer registry linkage). A nested case-control analysis was conducted using conditional logistic regression to compare aspirin usage in cases (prostate cancer deaths) with up to three controls (matched by age and year of diagnosis). RESULTS: Post-diagnostic low-dose aspirin use was identified in 52 % of 1,184 prostate cancer-specific deaths and 39 % of 3,531 matched controls (unadjusted OR 1.51, 95 % CI 1.19, 1.90; p < 0.001). After adjustment for confounders including treatment and comorbidities, this association was attenuated (adjusted OR  1.02 95 % CI 0.78, 1.34; p = 0.86). Adjustment for estrogen therapy accounted for the majority of this attenuation. There was also no evidence of dose-response association after adjustments. Compared with no use, patients with 1-11 prescriptions and 12 or more prescriptions had adjusted ORs of 1.07 (95 % CI 0.78, 1.47; p = 0.66) and 0.97 (95 % CI 0.69, 1.37; p = 0.88), respectively. There was no evidence of a protective association between low-dose aspirin use in the year prior to diagnosis and prostate cancer-specific mortality (adjusted OR 1.04 95 % CI 0.89, 1.22; p = 0.60). CONCLUSION: We found no evidence of an association between low-dose aspirin use before or after diagnosis and risk of prostate cancer-specific mortality, after potential confounders were accounted for, in UK prostate cancer patients.

A cohort study of digoxin exposure and mortality in men with prostate cancer.

OBJECTIVE: To examine the association between digoxin exposure and mortality in men with prostate cancer using linked Irish National Cancer Registry and pharmacy claims data. PATIENTS AND METHODS: Prostate cancer cases were identified from the database and digoxin exposure at prostate cancer diagnosis was identified from prescription claims. Digoxin users were matched to non-users using a propensity score to identify men with similar cardiovascular comorbidity. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for the association between digoxin exposure and all-cause and prostate cancer-specific mortality (PCSM). Analyses were repeated in the propensity score-matched cohort. Effect modification of treatment with radiation or androgen-deprivation therapy by digoxin exposure was also assessed. RESULTS: In all, 5732 men with a prostate cancer diagnosis (2001-2006) were identified (digoxin exposed, 391). The median follow-up was 4.3 years. Digoxin exposure was associated with a small non-significant increase in PCSM in the full cohort (HR 1.13, 95% CI 0.91, 1.42) and the propensity. score-matched cohort (HR 1.17, 95% CI 0.88, 1.57). Adjusted HRs for all-cause mortality were increased for digoxin exposed men (HR 1.24, 95% CI 1.07, 1.43). Interactions with treatments received were not significant. CONCLUSIONS: These results suggest digoxin exposure is not associated with reduced PCSM. Further investigation of other cardiac glycosides that have shown anti-cancer potential may be warranted.