Citations

Abstract Purpose: We sought to improve upon frontline bendamustine/rituximab (BR) induction therapy followed by rituximab maintenance in untreated high-risk follicular lymphoma (FL). Patients and Methods: Patients were randomized to BR induction followed by 2-year rituximab maintenance (BR-R), BR with bortezomib and rituximab maintenance (BVR-R), or BR followed by lenalidomide (1 year) with rituximab maintenance (BR-LR). Dual primary objectives were complete remission (CR) rate and 1-year disease-free survival (DFS); 289 patients enrolled (NCT01216683). Results: For induction, 92%, 87%, and 86% of patients randomized to BR-R, BVR-R, or BR-LR received six cycles, respectively. CR rate with BR versus BVR induction was 62% versus 75%, respectively (P = 0.04). One-year DFS rates with BR-R versus BR-LR were 85% versus 67%, respectively (P = 0.0009). This was due to an imbalance in CR rates post-BR induction and discontinuation due to adverse events (AEs). The most common grade 3–4 AEs for BVR versus BR were neutropenia and sensory neuropathy (12% vs <1%); 83% of the latter occurred with intravenous bortezomib. The most common grade 3–4 AEs related to LR versus rituximab maintenance were neutropenia 66% versus 21%, respectively (P < 0.0001), and febrile neutropenia 10% versus 2%, respectively (P = 0.05). The overall treatment-related mortality was 1.4%. With 5-year median follow-up, 3-year PFS rates for BR-R, BVR-R, and BR-LR were 77%, 82%, and 76%, respectively (P = 0.36) with OS rates of 87%, 90%, and 84%, respectively (P = 0.79). For prognostication, CR rate and POD-24 were associated with survival. Conclusions: Altogether, neither bortezomib added to BR induction nor lenalidomide added to rituximab maintenance immediately post-BR induction is recommended in untreated FL.

Abstract Colon polyps are the most common neoplastic finding at colonoscopy and have the potential to transform to cancer. Understanding the mechanisms involved in the transformation from normal colon to polyp is central to the identification of interventions to prevent or stop a polyp from forming or, in the worst case, from transforming. Therefore, the clinical conundrum is to predict which polyps will progress. It is crucial to understand if there are molecular features that define premalignant lesions and that may contribute to the final steps of transformation, which could potentially be targets for early detection or more individualized clinical management. Cellular transformation is driven by the interplay of genetic and epigenetic changes, and a large body of research has identified modifications of chromatin and the role of those modifications in regulating genes. Telomeres, telomere maintenance mechanisms, and chromatin remodelers maintain genetic stability, and their disruption is associated with the development of many diseases, including cancer. Organoids are multicellular structures grown from the stem cells of an organ to recapitulate the diverse cell types of the parent organ. This renewable resource of an individual’s tissue provides the opportunity to study colon carcinogenesis in combination with advanced genomic tools such as gene editing. The overall objective of this study is to determine the role of telomere and chromatin remodeler alterations in neoplastic transformation. The functional interaction between hTERT and specific chromatin remodelers will be resolved in two steps: 1) activating telomerase in normal colon and polyp organoids from patients and measuring chromatin remodeler expression, and 2) incorporating mutations in the chromatin remodelers using genome editing and then measuring the expression of hTERT in the normal colon and polyp organoids from patients with cancer-adjacent and cancer-free polyps. Gene editing experiments were performed utilizing transposon-based vectors (PiggyBac), short homology arm-based knockin (GeneWeld), or CRISPR/Cas9, coupled with electroporation for cargo delivery. To assess neoplastic transformation as a result of the gene edits, we used histology and cellular morphology of the organoid specimen by hematoxylin and eosin staining and pathologist review, and the markers by immunofluorescence. These models of neoplastic transformation in organoids from patient tissues provide an accessible tool to visualize the functional changes that correspond to alterations in telomerase and chromatin remodelers and how alterations in these targets affect growth, proliferation, differentiation, and cell turnover. Identification of epigenomic molecular alterations linked with progression of polyps to cancer could lead to modifiable targets for preventive interventions and provide candidate molecular markers in order to better tailor polyp patient screening recommendations. Note: This abstract was not presented at the conference. Citation Format: Brooke R. Druliner, Brandon Simone, Miguel Munoz-Gomez, Kim Kossick, Daniel O'Brien, Alexej Abyzov, Stephen Ekker, Lisa A. Boardman. Characterizing telomere and chromatin dynamics in colorectal cell transformation [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A33.

ObjectiveThis study aims to describe presenting characteristics of patients diagnosed with non‐invasive chronic rhinosinusitis (CRS) following liver or kidney transplant and determine factors associated with disease‐related complications, selection of endoscopic sinus surgery (ESS), and disease resolution in this population.Study designRetrospective chart review.SettingAn academic tertiary care center (Mayo Clinic, Rochester, Minnesota).Subjects and methodsLiver and kidney transplant recipients evaluated by Mayo Clinic otolaryngologists for CRS between 1998 and 2018 were identified. Univariate and multivariate logistic regression analyses were used to determine patient factors and treatment modalities associated with developing complications, selection of ESS, and disease resolution.ResultsFifty‐seven patients met inclusion criteria. No patients developed intraorbital or intracranial complications of their CRS. Multivariate modeling demonstrated that the presence of polyps (P = 0.036) was associated with undergoing ESS within one year of presentation. A higher Lund–Mackay (LM) computed tomography score (P = 0.023) and older age (P = 0.018) were significantly associated with decreased disease resolution. No other factors were significantly associated with the use of endoscopic sinus surgery within one year of otolaryngology presentation or resolution of CRS in this cohort.ConclusionThe risk of developing CRS‐related intraorbital or intracranial complications in this immunecompromised patient cohort may be lower than originally thought. For liver‐ and kidney‐recipients stable on immunosuppressive medication for many years, prognostic factors for CRS may mirror those for immunocompetent patients.

Abstract Aims To determine the extent of shared decision-making (SDM), during selection of oral anticoagulant (OAC) and rhythm control treatments, in patients with newly diagnosed atrial fibrillation (AF). Methods and results We evaluated survey data from 1006 patients with new-onset AF enrolled at 56 US sites participating in the SATELLITE substudy of the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT II). Patients completed surveys at enrolment and at 6-month follow-up. Patients were asked about who made their AF treatment decisions. Shared decision-making was classified as one that the patient felt was an autonomous decision or a shared decision with their healthcare provider (HCP). Approximately half of patients reported that their OAC treatment decisions were made entirely by their HCP. Compared with those reporting no SDM, patients reporting SDM for OAC were more often female (47.2% vs. 38.4%), while patients reporting SDM for rhythm control were more often male (62.2% vs. 57.6%). The most important factors cited by patients during decision-making for OAC were reducing stroke and bleeding risk, and their HCP’s recommendations. After adjustment, patients with self-reported understanding of OAC, and rhythm control options, had higher odds of having participated in SDM [odds ratio (OR) 2.54, confidence interval (CI): 1.75–3.68 and OR 2.36, CI: 1.50–3.71, both P ≤ 0.001, respectively]. Conclusion Shared decision-making is not widely implemented in contemporary AF practice. Patient understanding about available therapeutic options is associated with a more than a two-fold higher likelihood of SDM, and may be a potential target for future interventions.

Background Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. Methods We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). Findings In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Interpretation Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.

Abstract We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.

Abstract Dasatinib is approved as a second line therapy (Rx) for Philadelphia chromosome (Ph)-positive chronic myeloid leukemia, as it targets Bcr/Abl tyrosine kinase. Due to its activity against other kinases, like KIT and PDGFR, we conducted a Phase II study of dasatinib in patients with Ph-negative acute and chronic myeloid diseases. Sixty-eight patients were treated at the starting dose of 70mg PO BID (9 patients with SM received 140mg as a single dose daily); 4 weeks=1 cycle. All patients were assessed for response and toxicity (no Grade 4 toxicity was observed). The results by disease type are detailed. Systemic mastocytosis: 33 patients were treated (18 indolent, 9 aggressive, 6 with associated hematologic malignancy); median age 57 years (29–74); 14 were males, all PDGFRA−; # prior Rx 1 (0–4), 16 not previously treated; median # cycles 4 (1–20). Two achieved CR: one SM-MF (JAK2 V617F+, complex cytogenetics) and one SM-HES; both c-KIT mutation negative, low tryptase, anemic, failed erythropoietin, and had abnormal WBC differential. SM-MF patient progressed to AML after 8 months on Rx and died, and SM-HES is still in CR after 18+ months. Nine patients had improvement in symptoms related to SM, lasting from 3–18+ months. Nineteen Grade 3 toxicities were observed; dose was reduced to −1 level in 15, and to −2 level in 5 patients. Acute myeloid leukemia: 9 patients were treated; median age 70 years (51–91); 7 were males, 4 had abnormal cytogenetics; # prior Rx 2 (0–3); median # cycles 1 (1–18). CR was observed in an 80y old male with trisomy 8, previously treated with 3+7 chemotherapy with short CR. He relapsed on dasatinib Rx after 60 weeks. Eight patients had no response (4 stopped Rx within first month). Six Grade 3 toxicities were observed. Myelodysplastic syndrome/chronic myelomonocytic leukemia: 6 patients were treated (3+3); median age 68 years (51–75); 4 were males, 1 with abnormal cytogenetics; # prior Rx 1.5 (0–5); median # cycles 1 (1–2). No responses were observed (2 stopped Rx within first month); one Grade 3 toxicity was observed. Hypereosinophilic syndrome/chronic eosinophilic leukemia: 8 patients were treated (5+3); median age 58 years (23–75); 5 were males, 3 had abnormal cytogenetics, all PDGFRA-; # prior Rx 1.5 (0–3); median # cycles 3 (1–17). One female patient with HES achieved CR (previously Rx with gleevec without response). She relapsed after 58 weeks while off Rx due to toxicity. Other patients did not respond (1 stopped Rx within first month); 5 Grade 3 toxicities were observed. Polycythemia vera: one patient was treated; 50yr old female, with no prior Rx, had no response after 3 months of dasatinib Rx. Chronic idiopathic myelofibrosis: 11 patients were treated; median age 63 years (47–77); 10 were males, 2 had abnormal cytogenetics; # prior Rx 2 (0–7); median # cycles 6 (1–9). No responses were observed (1 stopped Rx within first month); 4 Grade 3 toxicities were observed. Conclusion: Dasatinib is active in systemic mastocytosis (overall response rate 33%). Updated clinical and molecular results will be presented.

Abstract To describe the demographic and tumor related characteristics and outcomes for patients with primary T-cell central nervous system lymphoma (TPCNSL). A retrospective series of patients with TPCNSL was compiled from twelve cancer centers and seven countries. This study involved 35 male and 10 female patients with a median age of 60 years (range 3–84). Twenty (44%) had Eastern Cooperative Oncology Group performance status (PS) of 0 or 1. Twenty six (58%) had involvement of a cerebral hemisphere and sixteen (36%) had lesions of deeper sites in the brain. Two patients had primary spinal cord lesions and one had meningeal disease only. Serum lactate dehydrogenase (LDH) was elevated in 7 of the 22 cases (32%) and cerebrospinal fluid (CSF) protein was elevated above normal in 19 of the 24 cases (79%) with available data. The median disease specific survival (DSS) for all patients was 25 months (95% confidence interval (CI) 11–38 months). The two and five-year DSS were 51 % (CI 35–66 %) and 17 % (CI 6–34 %) respectively. Univariate and multivariate analyses were conducted for the following factors: age (≤ 60 vs. > 60 years), PS (0 or 1 vs. 2, 3 or 4), involvement of deep structures of the central nervous system (no vs. yes), and methotrexate (MTX) use in the primary treatment (yes vs. no). Only PS and MTX use were significantly associated with better outcome with hazard ratios (HR) of 0.2 (CI 0.1–0.4) and 0.4 (CI 0.2–0.8) respectively. This is the largest series ever assembled of TPCNSL. The presentation and outcome appear similar to that of PCNSL of B cell origin. PS 0 or 1 and administration of MTX are associated with better survival. TPCNSL does not appear to require a different therapeutic management approach than B-cell PCNSL.

Abstract Next‐generation sequencing identified about 60 genes recurrently mutated in chronic lymphocytic leukemia (CLL). We examined the additive prognostic value of the total number of recurrently mutated CLL genes (i.e., tumor mutational load [TML]) or the individually mutated genes beyond the CLL international prognostic index (CLL‐IPI) in newly diagnosed CLL and high‐count monoclonal B‐cell lymphocytosis (HC MBL). We sequenced 59 genes among 557 individuals (112 HC MBL/445 CLL) in a multi‐stage design, to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time‐to‐first treatment (TTT), adjusted for CLL‐IPI and sex. TML was associated with shorter TTT in the discovery and validation cohorts, with a combined estimate of continuous HR = 1.27 (CI:1.17‐1.39, P = 2.6 × 10 −8 ; c ‐statistic = 0.76). When stratified by CLL‐IPI, the association of TML with TTT was stronger and validated within low/intermediate risk (combined HR = 1.54, CI:1.37‐1.72, P = 7.0 × 10 −14 ). Overall, 80% of low/intermediate CLL‐IPI cases with two or more mutated genes progressed to require therapy within 5 years, compared to 24% among those without mutations. TML was also associated with shorter TTT in the HC MBL cohort (HR = 1.53, CI:1.12‐2.07, P = .007; c ‐statistic = 0.71). TML is a strong prognostic factor for TTT independent of CLL‐IPI, especially among low/intermediate CLL‐IPI risk, and a better predictor than any single gene. Mutational screening at early stages may improve risk stratification and better predict TTT.