CancerCare

Mutations in protein tyrosine phosphatase non-receptor type 11 (PTPN11) have been considered late acquired mutations in acute myeloid leukemia (AML) development. Using single-cell DNA sequencing, we found that PTPN11 mutations can occur as initiating events in some patients with AML when accompanied by strong oncogenic drivers, commonly NPM1 mutations. The resulting AML has a diverse set of variably differentiated myeloid cells with few myeloid cells that lack leukemic mutations. The role of Ptpn11 as a codriver was confirmed in a murine model that exhibits an AML phenotype with a comparable immune diversity that is serially engraftable and reconstituted from early precursor cells. Furthermore, lineage-negative bone marrow cells from these mice reconstitute the full diversity of mature myeloid cells, and these cells exhibit an altered cytokine response after physiologic stimulation. Our work highlights how PTPN11-mutated AML is derived from a multitude of codominant and late acquired aberrations that have a previously unrecognized differentiated myeloid clonal expansion potentially contributing to pathogenesis of the disease.

Background and Aim Bruton tyrosine kinase inhibitors (BTKis) are the standard of care for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Ibrutinib and acalabrutinib are two commonly used BTKis, though hypertension (HTN) and other cardiovascular medical events of interest (CV MEOIs) can impact treatment tolerability and long-term use. This study compared cardiovascular safety and health care resource use (HCRU) of acalabrutinib versus ibrutinib monotherapy for R/R CLL/SLL in real-world community practice. Methods This retrospective comparative study included 270 RR CLL/SLL patients (90 acalabrutinib; 180 ibrutinib) treated from January 2017 through December 2023 across the ONCare Alliance Network, comprising 30 US community hematology practices. Endpoints included new or worsening of existing HTN, development of CV MEOIs, and treatment discontinuation due to adverse events. HCRU metrics consisted of emergency department visits, hospital admissions, length of stay, specialist consultations, and related medical procedures. Propensity score weighted multivariable logistic regression was used for the comparative analysis on the tolerability endpoints. Results At a median follow-up of 33 months, patients treated with acalabrutinib had significantly fewer HTN events (OR = 0.27, 95% CI = 0.074–0.98; p = .046) and adverse events leading to treatment discontinuation (OR = 0.39, 95% CI = 0.20–0.73; p = .002) compared to those on ibrutinib. Hospital admission rates for MEOIs were lower in the acalabrutinib group (0.20 vs. 0.24 per patient), with a shorter median length of stay (3.0 vs. 6.0 days). Additionally, acalabrutinib patients had fewer specialist consultations (0.11 vs. 0.22 per patient) and associated medical procedures (0.11 vs. 0.18 per patient). Conclusions In R/R CLL/SLL, acalabrutinib demonstrated a more favorable cardiovascular safety profile than ibrutinib, with fewer HTN events and CV MEOIs. This translated into reduced hospital admissions and lower HCRU, supporting acalabrutinib as a potentially better tolerated long-term treatment option in community practice.

Abstract Background Childhood obesity can result in adverse health outcomes. Objectives Objectives were to describe the prevalence of obesity and determine the association between obesity at cancer diagnosis and event-free survival (EFS) and overall survival (OS) in children diagnosed with cancer in Canada. Design/Methods We conducted a retrospective cohort study using the Cancer in Young People in Canada database, a population-based surveillance program collecting data from all paediatric cancer patients. This study included all children with newly diagnosed cancer aged 2 to 18 years across Canada from 2001 to 2020. Obesity was defined as age and sex-adjusted body mass index ≥ 95th percentile. EFS was defined as the time from diagnosis to first event (relapse, progression, secondary malignancies, or death). Univariate and multivariable Cox proportional hazards models compared EFS and OS between patients with and without obesity. Results A total of 11,291 patients were included (37.1% leukemias, 14.5% lymphomas, 21.8% central nervous system (CNS) tumors, 26.6% non-CNS solid tumors). At diagnosis, 10.5% were obese and the prevalence of obesity was significantly higher at 1 year (15.7%, p<0.001) and 2 years (20.1%, p<0.001) after diagnosis. The prevalence of obesity was higher in the leukemia and lymphoma cohort compared to other cancer categories (11.4% vs. 9.5%, p=0.001). In multivariable models controlling for age at diagnosis, sex, ethnicity, neighborhood income quintile, treatment era and cancer categories, obesity at diagnosis remained significantly associated with inferior EFS [adjusted HR (aHR) 1.16, 95% CI 1.02–1.32] and OS [aHR 1.29, 95% CI 1.11–1.49]. In children with acute lymphoblastic leukemia (ALL) (n=3458, 82.5% of all leukemias), after adjusting for high-risk features such as age, white blood cell count and CNS status, obesity at diagnosis remained significantly associated with inferior EFS [aHR 1.55, 95% CI 1.17–2.04] and OS [aHR 1.75, 95% CI 1.23–2.49]. In patients with CNS tumors, obesity at diagnosis was also independently associated with inferior EFS [aHR 1.38, 95% CI 1.09–1.76] and OS [aHR 1.47, 95% CI 1.13–1.91]. Conclusion In this population-based study of children with cancer, the prevalence of obesity was 11% at diagnosis and continued to increase in the following 2 years. Obesity at cancer diagnosis was independently associated with inferior survival across the entire cohort, especially in children with ALL and CNS tumors. Prevention of childhood obesity should be emphasized as it can lead to several adverse health outcomes in children with cancer.

Aspirin has been fundamental in secondary prevention of cardiovascular disease (CVD) due to its antithrombotic effect. Its use in primary prevention, that is, preventing first-time cardiovascular events in persons without known CVD, has been controversial. Early trials, which were done in the late 20th century, showed moderate myocardial infarction reductions with aspirin, but they also showed an increased risk of bleeding. Over the past 10 years, several large randomized controlled trials (including Aspirin to Reduce Risk of Initial Vascular Events, A Study of Cardiovascular Events in Diabetes, and Aspirin in Reducing Events in the Elderly) have revisited this problem in diverse populations, which yielded mixed results that generally question the net benefit of routine aspirin use in low- to moderate-risk individuals. These findings brought some major guideline updates. Recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines restrict aspirin to a few groups who are at a higher risk and advise against the routine use of aspirin in the rest of the population, while European Society of Cardiology guidelines generally discourage aspirin usage in primary prevention; its use is limited to specific, very high-risk settings. This article provides us with an overall summary of the evidence for aspirin primary prevention of CVD, taking into account prominent trials, the balance between benefits (eg, reduction in myocardial infarction) and harms (eg, bleeding), evolving clinical guidelines, and practical considerations of risk stratification and patient selection. Our work tried to highlight the manner in which aspirin's use in primary prevention in current practice is narrowly focused and should be individualized by careful consideration of risk-benefit and shared decision-making.

Background/Objectives: Pancreatic cancer (PC) is a diagnosis with a poor prognosis which can be associated with significant distress and may hinder a patient's ability to understand treatment details. Educating patients based on their learning preferences (LPs) and emotions may allow for personalized, enhanced care. Methods: This prospective project enrolled patients with non-metastatic PC. Phase 1 utilized the Learning Preference Barometer (LPB) and Emotional Journey Barometer (EJB), which are digital instruments co-designed by CANCER101 (C101) and the Health Collaboratory, to assess patient LPs and emotional states. Phase 2 provided information prescriptions aligned with LPs through C101's Prescription to Learn® (P2L) platform. Collected data included demographics, treatment, LPs (auditory, kinesthetic, linguistic, visual), patient engagement with P2L, and patient emotional states with qualitative verbal validation. Descriptive variables were used to report outcomes. Results: Primary LPs in the 47 participating patients were as follows: linguistic 45%, visual 34%, auditory 11%, and kinesthetic 9%, with secondary preferences in the majority (53%). Those patients (66%) who accessed P2L had linguistic and visual preferences; the majority accessed 1- 2 resources out of the 25 provided. Resources accessed aligned to 88% of patient LPs. The majority of patients (60%) initiated treatment prior to initial EJB, and 40% were treatment naive. Common baseline emotions were optimistic (47% vs. 36%, respectively), satisfied (11% vs. 25%), acceptance (11% vs. 11%), and overwhelmed (5% vs. 11%). Conclusions: Assessing LPs and emotional state allows for personalized patient education and clinical encounters for PC patients. Future work includes examining the effects of personalized approaches on patient satisfaction, decision-making, health outcomes, and the overall patient-clinician relationship.

2542 Background: Lymphopenia and high CA19-9 levels are associated with poor prognosis in pancreatic cancer patients. N-803 (ANKTIVA), an IL-15 superagonist is the first FDA approved molecule with a mechanism of action of rescuing lymphopenia by proliferating lymphocytes (NK and T cells). In QUILT-88, a Phase 2 multi-center study (NCT04390399), participants with 2nd line or greater locally advanced or metastatic pancreatic cancer (mPC) received N-803 and PD-L1-targeted high-affinity natural killer (PD-L1 t-haNK) cell therapy in combination with low-dose chemotherapy as ≥ 3 rd line therapy. The absolute lymphocyte count (ALC), CA19-9 level, and correlation with overall survival (OS) was assessed. Methods: Patients (n = 84) received low-dose SBRT and low-dose chemotherapy in combination with N-803 and PD-L1 t-haNK cells to orchestrate responses of the innate and adaptive immune system, a paradigm change in the treatment of mPC. The association between OS and ALC < or ≥ median 1.045 x 10 9 cells/L and CA19-9 < or ≥ median 4079.6 U/mL at baseline was assessed. Results: Median OS for 3 rd line patients (n = 43) was 6.2 months (95% CI 5.0 - 7.1;) and for all patients ≥ 3 rd to 6 th line patients (n = 84) was 5.7 months (95% confidence interval [CI] 4.3 – 6.4). OS was positively associated with both higher ALC and lower baseline CA19-9 levels. OS was significantly higher for participants (median OS: 7.1 months) with ALC ≥ 1.045 x 10 9 cells/L and CA19-9 < 4079.6 U/mL than for those participants (median OS: 3.1 months) with ALC < 1.045 x 10 9 cells/L and CA19-9 ≥ 4079.6 U/mL (HR 3.6, p < 0.001). Higher ALC count was associated with prolonged OS over the course of the study. Grade 3 or higher TEAEs occurred in 95% of patients and were largely chemotherapy-associated. Conclusions: The multimodal chemo-immunotherapy protocol to induce immunogenic cell death resulted in OS that exceeded 6 months for both 3 rd and ≥ 5 th line patients, exceeding OS achieved by other therapies in this setting by ~2 months. It is notable that both favorable baseline ALC/CA19-9 and on-study higher ALC was associated with prolonged survival, given N-803’s ability to increase both NK and CD8+/CD4+ T cells, the first FDA approved agent that proliferates lymphocytes in the face of lymphopenia. These findings support further investigation of this novel therapeutic regimen that includes PD-L1 t-haNK, and N-803 that, as an IL-15 superagonist, may be able to overcome lymphopenia and improve prognosis. Clinical trial information: NCT04390399 .

Abstract Background The internet is a primary source of health information for breast cancer patients, but online content quality varies widely. This study aimed to evaluate the capability of Large Language Models (LLMs), including ChatGPT and Claude, to assess the quality of online Japanese breast cancer treatment information by calculating and comparing their DISCERN scores with those of expert raters. Methods We analyzed 60 Japanese web pages on breast cancer treatments (surgery, chemotherapy, immunotherapy) using the DISCERN instrument. Each page was evaluated by the LLMs ChatGPT and Claude, along with two expert raters. We assessed LLMs evaluation consistency, correlations between LLMs and expert assessments, and relationships between DISCERN scores, Google search rankings, and content length. Results Evaluations by LLMs showed high consistency and moderate to strong correlations with expert assessments (ChatGPT vs Expert: r = 0.65; Claude vs Expert: r = 0.68). LLMs assigned slightly higher scores than expert raters. Chemotherapy pages received the highest quality scores, followed by surgery and immunotherapy. We found a weak negative correlation between Google search ranking and DISCERN scores, and a moderate positive correlation (r = 0.45) between content length and quality ratings. Conclusions This study demonstrates the potential of LLM-assisted evaluation in assessing online health information quality, while highlighting the importance of human expertise. LLMs could efficiently process large volumes of health information but should complement human insight for comprehensive assessments. These findings have implications for improving the accessibility and reliability of breast cancer treatment information.