Citations

Abstract Background: In metastatic cancer, Circulating Tumor cells (CTCs) are established prognostic indictors of patients (pts) less likely to respond to new lines of systemic therapy, with poor clinical outcomes, such as shorter progression free survival (PFS) and overall survival (OS). However, CTCs are typically found in specific malignancies (breast, prostate & colon), often in <20% of pts with metastatic disease, and pts without CTCs may also rapidly progress. Recently, an inflammatory pro-tumorigenic macrophage emanating from tumor stroma (i.e. Cancer associated macrophage-like cell [CAML]) was found in >90% of metastatic cancer pts, and whose phagocytic engorgement appears to correlate with poor outcomes, independent of CTCs. As CTCs and CAMLs are isolated in conjunction from a single blood sample, and both are prognostic for outcomes, we evaluated their utilization prior to induction of new systemic therapy in 6 types of metastatic cancer to model pt risk stratification based on 2 year outcomes. Methods: A prospective 2 year blind multi-institutional study was undertaken to model CTCs and CAMLs in prognosticating outcomes prior to induction of a new line of systemic therapy (n=233) in metastatic: Breast (n=60), Prostate (n=40), Pancreas (n=25), Colon (n=28), Renal Cell Carcinoma (RCC) (n=39), and Lung (n=40). Blood was filtered by CellSieveTM filters with subtypes of CTCs & hyper-enlarged CAMLs (≥100µm) enumerated. A machine learning algorithm was trained on this initial data set to develop predictive models which could stratify pt populations by risk for likelihood of PFS & OS over 2 years, including known clinical variables. Results: CTCs were absent in 80% (n=185/233) of pts, and their absence was prognostic for better PFS (HR=1.6, p=0.046), but not OS (HR=1.3, p=0.2045). In parallel, enlarged CAMLs (≥100µm) were found in 28% (n=51/185) of pts without CTCs, and were also prognostic for worse PFS (HR=2.0, p=0.0082) and OS (HR=1.9, p=0.0412). Specifically, CTCs were found in 55% (n=33) breast, 20% (n=8) prostate, 12% (n=3) pancreas, 11% (n=3) colon, 0% (n=0) RCC, and 0% (n=0) lung pts. Enlarged CAMLs were found in 45% (n=27) breast, 20% (n=8) prostate, 44% (n=11) pancreas, 44% (n=17) colon, 18% (n=7) RCC and 20% (n=8) lung pts. Overall, models indicated that ≥1 CTC (n=47) had mPFS=3.9 & mOS=14.9, while pts with 0 CTCs and ≥100µm CAMLs (n=51) had a mPFS=6.9 & mOS=13.8, and pts with 0 CTCs and <100µm CAMLs (n=134) had a mPFS=10.7 & mOS>24 months. Conclusions: These initial models confirm that both CTCs and enlarged CAMLs are prognostic indicators of worse PFS & OS. The simultaneous quantification both CTCs and CAMLs allows for more accurate pan-cancer risk stratification in an array of cancer pt populations. Additional clinical variables incorporated into the models may allow better risk subtyping and possibly forecast optimal treatment regimens. Citation Format: Daniel L. Adams, Steven H. Lin, Massimo Cristofanilli, Carolina Reduzzi, Saranya Chumsri, Martin J. Edelman, Susan Tsai, Raymond C. Bergan, Mohammed Aldakkak, Thai H. Ho, Cha-Mei Tang. Combining circulating tumor cells and cancer associated macrophage-like cells enhances risk stratification models in pan-cancer metastatic disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1068.

Background: Pancreatitis significantly alters the microbial composition of the oral and intestinal compartments, causing dysbiosis that may contribute to disease mechanisms and potentially serve as a basis for diagnosis or treatment. Objective: To determine whether the oral or gut microbial signature can classify chronic pancreatitis (CP). Methods: Stool samples (n=707) were collected from participants in the Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED). Samples were distributed among 200 healthy (HC), 310 CP, 49 acute pancreatitis (AP), and 148 recurrent acute pancreatitis (RAP). In addition, saliva samples were collected for a subset of participants (n=156). Whole genome sequencing was performed to assess microbiome composition. Machine learning algorithms were utilized to identify a signature with microbial features predictive of CP. Results: Gut alpha diversity was significantly decreased in AP, RAP, and CP compared with HC, with CP exhibiting the lowest diversity. In contrast, oral microbial diversity showed no significant variation across groups. Beta diversity analysis revealed distinct gut microbiome compositions between HC and pancreatitis subtypes, with CP showing the most pronounced differences. Random forest models using gut microbial species demonstrated robust predictive performance for CP using a minimum of 10 species (Area under the curve—AUC: 0.834; accuracy: 0.774). Despite similarities in gut microbiome composition across pancreatitis subtypes, a unique gut microbial signature for CP was identified highlighting the microbiome’s potential in CP diagnosis. Conclusion: Our study reveals a gut microbial signature predictive of CP using machine learning models in a large US multi-institutional cohort.

Abstract Idecabtagene vicleucel (ide-cel) is a chimeric antigen receptor (CAR) T-cell therapy approved for relapsed and refractory multiple myeloma (RRMM). Out-of-specification (OOS) CAR T cells not meeting criteria for commercial release are considered an investigational product; the expanded access protocol (EAP) allows release of OOS product for administration. The manufacturing analysis of capability, reliability, and timely delivery of ide-cel in the United States over >3 years since its approval included patients with RRMM who underwent leukapheresis for ide-cel treatment after ≥2 prior lines of therapy between 23 February 2021 and 1 November 2024. Additionally, the BB2121-EAP-001 study evaluated safety and efficacy of OOS ide-cel and included patients who had undergone leukapheresis for commercial ide-cel treatment not meeting commercial release specifications, most commonly due to high CD137 activation or low-infused dose. Primary end point was safety. Secondary end points were overall response rate (ORR) and complete response rate (CRR). At data cutoff (1 November 2024), the manufacturing success rate of ide-cel improved from 95.3% in 2021 to 96.8% in 2024. Turnaround time also improved from 31 days in 2021 to 24 days in 2024. In BB2121-EAP-001, 68 (72.3%) patients experienced ≥1 cytokine release syndrome event (mostly grade 1/2) and 15 (16.0%) had neurological toxicities (2 grade 3, 13 grade 1/2). ORR was 75.4% (95% confidence interval [CI], 63.1-85.2), and CRR was 35.4% (95% CI, 23.9-48.2). The manufacturing success of ide-cel is reliable and consistently high, and when OOS ide-cel products emerged, they demonstrated consistent clinical efficacy and safety. The BB2121-EAP-001 study was registered at www.clinicaltrials.gov as NCT04771078.

PURPOSE Chronic myelomonocytic leukemia (CMML) is a rare myeloid neoplasm characterized by clinical heterogeneity and is associated with poor outcomes. To date, limited molecular information has been incorporated into disease classification and risk stratification. We aimed to integrate genomic features into the clinical decision-making process for CMML. PATIENTS AND METHODS We analyzed a retrospective cohort of 3013 patients with CMML (training set) and a prospective population of 516 patients (validation set). Using an innovative framework for multimodal data analysis, we developed molecular-based disease taxonomy and prognostication. RESULTS Unsupervised clustering identified nine entities with distinct genomic features and outcomes ( P < .001), including splicing machinery, transcription factors, signal transduction and tyrosine kinase pathways aberrations, and high-risk molecular signatures. Notably, 15% of patients showed molecular/clinical overlap with other myeloid neoplasms. We integrated molecular and clinical information to build the international CMML Prognostic Scoring System (iCPSS), incorporating mutations in nine genes together with hematologic parameters and cytogenetic abnormalities. The iCPSS identified five groups with distinct probability of overall and leukemia-free survival in both training and validation cohorts ( P < .001), outperforming existing prognostic models. Importantly, 55% of patients were reassigned to higher or lower risk groups by the iCPSS. Decision analysis demonstrated that iCPSS could refine the optimal timing of allogeneic transplantation at the individual level; compared with conventional prognostic tools, iCPSS-based decision modeling changed transplantation strategy in 31% of cases, resulting in a significant gain-in-life expectancy for eligible patient population ( P < .001). A federated learning platform was implemented to enable continuous, privacy-preserving model update across multiple centers. CONCLUSION Molecular information improves CMML classification and prognostication, supports more effective clinical decision making, and potentially refines the design of clinical trials.

Objective Identifying eligible patients for precision oncology clinical trials is challenging, particularly for rare molecular subpopulations. To address this challenge, A2 Biotherapeutics developed BASECAMP-1 ( NCT04981119 ), a non-interventional master screening study to identify patients eligible for interventional studies of logic-gated Tmod chimeric antigen receptor T-cell therapies. Eligible patients for these interventional trials have an advanced solid malignancy and are germline human leucocyte antigen (HLA)-A*02 heterozygous, with tumour-associated HLA-A loss of heterozygosity (LOH). HLA-A LOH occurs in ~16% of advanced solid malignancies; therefore, an efficient screening strategy is required. This report describes BASECAMP-1; compares the efficiency of two screening methods; and discusses the broader advantages of BASECAMP-1 beyond efficient enrolment. Methods and analysis Patients are identified for BASECAMP-1 using two approaches. In the traditional approach, common for clinical trials, investigators consent and screen all patients who might be good candidates for cell therapy trials, with no prior knowledge of patient HLA-A type or LOH status. To further optimise our approach, we co-developed with Tempus AI (Tempus) the bioinformatic programme Aware, which identifies potentially eligible patients with tumour-associated HLA-A*02 LOH within a clinico-genomic database that includes linked genomic and transcriptomic sequencing and clinical data collected during routine care. Results Over 42 months of using a traditional approach to identify eligible patients, 1918 patients at 13 study sites were consented and screened for BASECAMP-1; of these, 30 patients with tumour-associated HLA-A*02 LOH were enrolled (~0.7 participants per month). Over the last 30 months of that same period, Tempus Aware screening was implemented and 55 patients with tumour-associated HLA-A*02 LOH were enrolled (~1.8 participants per month). The bioinformatic approach identified more patients than the traditional approach and used sequencing results produced as part of the standard clinical tumour sequencing workflow, reducing resource use and study staff burden. Additional advantages of using a screening study, such as BASECAMP-1, include manufacturing efficiencies and collection of a large dataset of molecular and clinical parameters that can be used to supplement trial analyses. Conclusions The BASECAMP-1 study demonstrates a clinico-genomic screening approach can more efficiently identify patients for precision oncology trials. Furthermore, precision oncology can be enhanced through collaborative data-sharing. Trial registration number NCT04981119 .

ABSTRACT Introduction and Methods Cancer therapy–related cardiac dysfunction (CTRCD) is a well established and potentially life‐threatening complication of contemporary oncologic treatment. Although comprehensive cardio‐oncology guidelines have been developed, their integration into routine hematology and oncology practice remains inconsistent. This consensus statement, developed by a multidisciplinary panel of cardio‐oncology experts, aims to provide practical, case‐based guidance to help oncology providers recognize, assess, and manage CTRCD across a spectrum of malignancies and cardiovascular presentations. Clinical Scenarios and Discussion We present representative clinical scenarios that illustrate real‐world challenges in cardio‐oncology and apply evidence‐based recommendations from current guidelines, including those from the European Society of Cardiology (ESC) and the International Cardio‐Oncology Society (ICOS)—to support informed decision‐making. Key areas of focus include baseline cardiovascular risk stratification prior to initiating potentially cardiotoxic therapies, with an emphasis on biomarker and imaging surveillance strategies tailored to individual risk profiles. Also, this document outlines the application of guideline‐directed medical therapy (GDMT) for cancer patients with heart failure. Conclusion By offering a structured, user‐friendly framework, this document seeks to bridge the implementation gap between oncology and cardiology disciplines. Our goal is to equip oncology providers with accessible tools that facilitate early recognition, consistent surveillance, and timely referral, thereby preserving cancer treatment intensity while minimizing cardiovascular morbidity.

There have been no large comparisons of the clinical and laboratory features of familial neonatal hemophagocytosis (f-nHLH) and infectious neonatal hemophagocytosis (i-nHLH). The objectives of this study were the following: (1) Describe the demographic, diagnostic, and clinical features of patients with familial nHLH (F-nHLH) and infectious HLH (i-nHLH). (2) Compare key variables between f-nHLH and i-nHLH. (3) Compare the clinical outcomes of f-nHLH and i-nHLH. (4) Summarize literature on cytokine levels in patients with nHLH. Data from a previously published nHLH meta-analysis report were used to describe and compare features of infants with f-nHLH versus i-nHLH. Variables were tested with the χ 2 test or Fisher exact test, Cochran-Armitage test, independent 2-sample t test, or Wilcoxon rank-sum test as appropriate. Odds ratios were calculated for any comparison with a P -value of <0.05. Data extracted from 99 cases of f-nHLH and 54 cases of i-nHLH were included in this analysis. Infants with f-HLH met HLH criteria at the following rates: fever (84%); organomegaly (100%); pancytopenia (75%); hypofibrinogenemia (84%); hypertriglyceridemia (48%); hypofibrinogenemia or hypertriglyceridemia (82%); hemophagocytosis (81%); hyperferritinemia (99%); low or absent NK cell activity (91%); and elevated soluble CCD25 (91%). Infants with i-nHLH had higher median ferritin levels (22,537 ng/mL) than infants with f-nHLH (7587 ng/mL) ( P =0.072). Infants with f-nHLH had higher rates of symptoms in utero, preterm birth, family history of HLH, and family history of infant death. The overall survival among infants with familial nHLH was lower than infectious nHLH ( P =0.037). Management of nHLH requires rapid diagnosis and prompt treatment, as current literature suggests nHLH has high mortality rates. Distinguishing between familial and infectious causes of nHLH can aid in determining the correct treatment of choice.

ABSTRACT Purpose Malignant rhabdoid tumor of the kidney (MRTK) is a rare, aggressive tumor seen in young children. The optimal timing of resection for locally advanced tumors is not well‐defined. The purpose of this study is to evaluate modern oncologic outcomes and the impact of surgical timing. Methods A multicenter retrospective review was performed by institutions participating in the Pediatric Surgical Oncology Research Collaborative. Children younger than 21 years old with MRTK diagnosed between 2000 and 2022 were included. Results Sixty‐nine patients were identified with MRTK and met the inclusion criteria. Median age of diagnosis was 10.1 months. Overall survival (OS) at 1, 5, and 10 years was 49%, 32%, and 19%, respectively. Patients with local Stage III disease who underwent upfront resection ( n = 18) compared to those who had delayed resection after NAT ( n = 15) had a similar OS, median OS greater than 60 months versus 14.6 months, respectively; p = 0.396. The surgical timing groups were balanced in terms of the presence of metastasis, length of follow‐up, and tumor characteristics. There was one occurrence of primary intraoperative tumor spill and two occurrences of organ injury in the upfront resection group compared to none in the delayed resection group. Conclusion MRTK carries a poor prognosis despite multimodal treatment. Histologic diagnosis may not be confirmed at presentation, and MRTK cannot be reliably distinguished from Wilms tumor on imaging alone. As overall survival is similar, the decision regarding surgical timing in locally advanced tumors should be individualized based on perceived resectability, balancing the risk of intraoperative complications against the possibility of tumor progression during neoadjuvant therapy.

RET fusions appear in 1%-2% of non–small cell lung cancers (NSCLCs). The results from the ARROW study (ClinicalTrials.gov identifier: NCT03037385 ) supported US Food and Drug Administration approval of pralsetinib, an oral selective RET inhibitor, for metastatic RET -altered NSCLC and RET fusion–positive thyroid cancers. ARROW was a phase I/II open-label study of pralsetinib 400 mg once daily in RET fusion–positive NSCLCs. Coprimary end points were overall response rate (ORR) and safety. Key secondary end points included duration of response, progression-free survival, and overall survival (OS). At data lock (May 20, 2024), 281 patients initiated pralsetinib (median treatment duration, 15.0 months). ORR (measurable disease patients; n = 259) was 78% (95% CI, 69 to 86) for treatment-naïve patients and 63% (95% CI, 54 to 71) for prior platinum-based chemotherapy patients. Median OS was 44.3 months (95% CI, 30.9 to 53.1), 50.1 months (95% CI, 28.3 to not reached) in treatment-naïve patients, and 39.7 months (95% CI, 27.8 to 53.2) in prior platinum patients. Common grade ≥3 treatment-related adverse events were anemia (21%), hypertension (15%), and decreased neutrophils (13%). Three treatment-related deaths occurred (pneumonia, n = 2; interstitial lung disease and rhabdomyolysis, n = 1 each). Safety was consistent with previous ARROW reports; no hypersensitivity was reported in patients receiving prior immunotherapies. Pralsetinib produced robust, durable responses with manageable safety in treatment-naïve and previously treated patients with RET fusion–positive NSCLCs, confirming previous findings with longer follow-up.