Roswell Park Comprehensive Cancer Center Research Articles

Abstract PO4-09-06: Area Deprivation Index (ADI) among Patients with Breast Cancer in Buffalo

Abstract Introduction: Socioeconomic and racial disparities can limit access to health care. Prior studies suggest that living in a disadvantaged neighborhood results in poorer outcomes in several malignancies. ADI is an index that categorizes areas based on socioeconomic variables. In this observational study, we aimed to investigate the ADI among patients (pts) with breast cancer (BC) seen at Roswell Park Comprehensive Cancer Center in Buffalo, New York, and study its association with clinical outcomes to identify the areas with the highest unmet need for possible intervention strategies. Methods: We reviewed data of 187 pts diagnosed with stages 1-3 and de-novo stage 4 BC between 2014 to 2018. We obtained information on ADI using pts’ home addresses via Neighborhood Atlas tool www.neighborhoodatlas.medicine.wisc.edu. ADI values were categorized into four quartiles Q1(80-100%), Q2(60-79%), Q3(40- 59%), and Q4(0-39%) from highest deprivation/poor social economic status areas to least disadvantaged areas, respectively. Demographic and clinicopathological characteristics including age, race, comorbidities, stage, type of insurance, duration on treatment were compared by ADI. Kruskal-Wallis and Chi-square was used for comparing continuous and categorical variables, respectively. Recurrence free survival (RFS), time to next treatment (TNT), and overall survival (OS) were estimated using Kaplan Meier method. Multivariate Cox regression model was used to analyze outcomes for pts with stage 4 in the most disadvantaged areas (ADI ≥60%) adjusting for relevant covariates. Analyses were performed using SAS v9.4 at a significance level of < 0.05. Results: 98% pts (183/187) were females, 85% (160/187) Whites, 9% (17/187) African Americans, and 3% (6/187) Asians. 62% (116/187) lived in the most disadvantaged areas: 37% (70/187) in Q1, and 24% (46/187) in Q2, while 27% (51/187) lived in Q3, and 11% (n=20/187) in Q4. 80% (150/187) pts were diagnosed with hormone receptor positive BC, 18% (34/187) HER2 positive, and 15% (28/187) triple negative BC. 45% of pts (83/187) had de novo stage 4, the rest were diagnosed with stages 1-3. There was no difference in the distribution of age, race, employment, insurance, comorbidities, substance use, smoking, access to contraception, screening mammogram, or adherence to anti-estrogen and radiation therapy by ADI. There was a significant difference in adherence to chemotherapy/anti HER2 therapy: 92% (36/39) in Q1,100% (24/24) in Q2 vs. 85% (24/28) in Q3 and 67% (6/9) in Q4, p=0.029. Among pts with stages 1-3, there was no difference in RFS (p= 0.700) or OS (p= 0.400) by ADI. Among stage 4 patients, there was an association between TNT and ADI, where patients living where there was a trend towards worse survival with increasingly disadvantaged neighborhoods, p=0.008 (Table 1). Moreover, there was a significant difference in OS by ADI, p=0.03 (Table 2). There was a significant association between ADI and both TNT and OS, even after adjusting to age, race, BC subtypes p= 0.004 and p= 0.034 respectively (Table 3). Conclusion: Our study in the Western New York region showed that BC pts living in disadvantaged areas had worse survival and shorter TNT despite being more adherent to chemotherapy/anti HER2 therapy. Our study validates prior studies showing that ADI is an important factor impacting BC outcomes. These data will help guide our future efforts to maximize resource allocation towards these disadvantaged areas to improve BC outcomes. Table 1 Table 2 Table 3 Citation Format: Malak Alharbi, Arya Mariam Roy, Archit Patel, Kayla Catalfamo, Kristopher Attwood, Angela Omilian, Elizabeth Bouchard, Ellis Levine, Tracey O'Connor, Amy Early, Shipra Gandhi. Area Deprivation Index (ADI) among Patients with Breast Cancer in Buffalo [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-09-06.

Abstract PO5-06-08: Real-world analysis of efficacy, adverse events and predictive biomarkers for advanced triple negative breast cancer (TNBC) treated with immune check point Inhibitors (ICI): A single center experience

Abstract Introduction KEYNOTE-355 investigated the addition of pembrolizumab to chemotherapy in advanced TNBC patients (pts) with PD-L1 positive tumors showing median overall survival (OS) of 23.0 months (mos) and median progression-free survival (PFS) of 16.1 mos. Given significant OS benefit with pembrolizumab, it is the current standard of care while the indication of atezolizumab has been withdrawn due to lack of OS benefit in IMPASSION-130. Clinical efficacy and adverse events in pts on this treatment regimen in clinical practice is unknown and understanding the real-world outcomes of this regimen is critical. Methods We conducted a retrospective, single-center observational study among TNBC pts treated with ICI (Pembrolizumab or Atezolizumab) at Roswell Park Comprehensive Cancer Center from January 2017 to May 2023. Demographics and clinicopathological variables were collected including comorbidities, laboratory data, sites of metastases (mets), treatment received, immune related adverse events (irAEs), and clinical outcomes. Adverse events were reported using the Common Terminology Criteria for Adverse Events v5.0. Serial CT scans were reviewed and response rate was determined using RECIST v1.1. Patient demographic, clinical and outcome characteristics were summarized by treatment and survival outcomes were obtained using standard Kaplan-Meier methods. Associations between survival outcomes and baseline or treatment characteristics were evaluated using Cox regression models using Firth’s method. All analyses were conducted in SAS v9.4 at a significance level of 0.05. Results A total of 44 pts with advanced TNBC treated with ICI were included (23 received pembrolizumab and 21 received Atezolizumab). The study population consisted of all female pts with stage IV disease, median age 53.7 years (IQR 30.4-85.2), 68.2 % (30/44) White, 25.0% (11/44) Black, 34.1% (15/44) obese (BMI≥30). 27.3% (12/44) pts developed any grade irAEs which included myocarditis (4.5%), rash (9.1%), hyperthyroidism (6.8%), hypothyroidism (4.5%), adrenal insufficiency (2.3%), diabetes mellitus (2.4%), colitis (2.3%), and transaminitis (2.3%). Distribution of reported irAE was 25% grade 1 (3/12), 66.7% grade 2 (8/12) and 8.3% grade 3 (1/12). 75% pts (33/44) received standard treatment (ICI+ chemotherapy) of which 72.7 % (24/33) received it in the first-line setting. Median OS in pts treated in first line was 16.2 mos (95% CI, 10.7-NR) and median PFS was 4.4 mos (95% CI, 2.7-8.4). Overall response rate (ORR) was 29.1% (7/24) of which 8.3% (2/24) had complete response and 20.8% (5/24) had partial response. ORR was 22.2 % (2/9) in pembrolizumab cohort and 33.3 % (5/15) in atezolizumab cohort. Among pts with first line treatment, obese pts were found to have improved PFS compared to non-obese (11.5 vs 3.8 mos, univariate hazard ratio (HR) 0.46, 95% CI 0.23-0.93, p= 0.031), and this difference was maintained in multivariable analysis even after adjusting for age (adjusted HR (aHR) 0.40, 95% CI 0.17-0.98, p= 0.044). Pts with brain mets had poor extracranial PFS compared to those without brain mets (2.8 vs. 5.2 mos, HR 2.25, 95% CI 1.08-4.68, p= 0.036), however this difference was not observed when further adjusted for age (aHR 2.27, 95% CI= 0.91-5.68, p= 0.08). Conclusion Clinical outcomes in our study were inferior to KEYNOTE-355 where median PFS was 16.1 mos and OS was 23.0 mos and ORR was 52.7% for PD-L1 positive population. This may reflect a more heterogeneous population of pts treated in routine clinical practice who are typically less fit than pts on clinical trials. Our study found improved outcomes among obese patients, similar to data reported in other disease settings. These data warrant multi-center validation with larger number of patients. Citation Format: Archit Patel, Arya Mariam Roy, Malak Alharbi, Kristopher Attwood, Chi-Chen Hong, Song Yao, Thaer Khoury, Amy Early, Tracey O'Connor, Ellis Levine, Shipra Gandhi. Real-world analysis of efficacy, adverse events and predictive biomarkers for advanced triple negative breast cancer (TNBC) treated with immune check point Inhibitors (ICI): A single center experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-06-08.

Correlation of Bronchoscopy and CT in Characterizing Malignant Central Airway Obstruction.

Malignant Central Airway Obstruction (MCAO) presents a significant challenge in lung cancer management, with notable morbidity and mortality implications. While bronchoscopy is the established diagnostic standard for confirming MCAO and assessing obstruction subtype (intrinsic, extrinsic, mixed) and severity, Computed Tomography (CT) serves as an initial screening tool. However, the extent of agreement between CT and bronchoscopy findings for MCAO remains unclear. To assess the correlation between bronchoscopy and CT, we conducted a retrospective review of 108 patients at Roswell Park Comprehensive Cancer Center, analyzing CT and bronchoscopy results to document MCAO presence, severity, and subtype. CT correctly identified MCAO in 99% of cases (107/108). Agreement regarding obstruction subtype (80.8%, Cohen's κ = 0.683, p < 0.001), and severity (65%, Quadratic κ = 0.657, p < 0.001) was moderate. CT tended to equally overestimate (7/19) and underestimate (7/19) the degree of obstruction. CT was also poor in identifying mucosal involvement in mixed MCAO. CT demonstrates reasonable agreement with bronchoscopy in detecting obstruction. Nevertheless, when CT indicates a positive finding for MCAO, it is advisable to conduct bronchoscopy. This is because CT lacks reliability in determining the severity of obstruction and identifying the mucosal component of mixed disease.

Abstract 2246: The impact of a waitlist control group on physical activity level in the activity after cancer treatment exercise oncology randomized pilot study

Abstract Background: In randomized clinical trials, control conditions such as blinding are essential for mitigating threats to validity. In exercise oncology trials, researchers are unable to blind participants to randomization, which may confer unintended consequences (i.e., crossover or dropout) that may threaten validity. Despite prior suggestions that a waitlist control is optimal for lessening these consequences, to date there is little agreement concerning control conditions in exercise oncology. Further, the use of a waitlist control is complicated by concerns regarding the ethical implications of instructing participants to delay healthy behavior change. Herein, we leveraged data from the Activity after Cancer Treatment (ACT) study to evaluate the impact of randomization to a waitlist control group on objectively assessed physical activity (PA) levels in breast cancer (BC) survivors. Methods: The ACT Study (PI: Ambrosone) was a 12-week, four-arm pilot study at Roswell Park Comprehensive Cancer Center. Participants included 37 BC survivors who were randomized to either a waitlist control group (n=10), or one of three exercise interventions of varying intensities including home-based walking (n=9), home-based Zumba (n=9), or a supervised high-intensity interval training treadmill protocol (n=9) delivered by study personnel at Roswell Park Comprehensive Cancer Center. The waitlist group was asked to maintain their usual PA during the 12-week intervention. All participants received weekly phone calls to optimize engagement and ensure Fitbit data were properly synced. For the current analysis, the primary analytic exposure was randomization assignment (control or active intervention); the analytic outcomes included steps/day, moderate-to-vigorous PA (MVPA) minutes/week and total active minutes/week as measured by the Fitbit Charge 2. ANOVA was used to assess mean group differences in steps and active minutes. Results: At study conclusion, the control group accumulated significantly fewer steps/day [6,087 (±1,353)] than the active intervention groups [8,729 (±2,585), p=0.0003]. The control group also accumulated significantly fewer MVPA minutes/week [146.2 (±114.9) vs. 264.1 (±192.3), p=0.045] and total active minutes/week [1,478 (±291.0) vs. 1,976.8 (±658.6), p=0.003] in comparison to the active intervention groups, respectively. Conclusions: BC survivors randomized to active intervention accumulated significantly more steps, MVPA and total active minutes than the waitlist group. Although the waitlist was effective for minimizing PA relative to the active arms, waitlisted participants exceeded the national step average of 4800 steps/day by 1200 steps and nearly met the minimum PA recommendation of 150 minutes of MVPA/week, potentially assuaging ethical or public health concerns regarding the delay of health-seeking behavior. Citation Format: Rikki Cannioto, Evan Davis, Karen Hulme, Chi-Chen Hong, Carol DeNysschen, Tracey O'Connor, Christine Ambrosone. The impact of a waitlist control group on physical activity level in the activity after cancer treatment exercise oncology randomized pilot study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2246.

Abstract 1058: Immune biomarkers for recurrence in stage II and III melanoma to guide patient stratification

Abstract Stage II-III melanoma patients lack needed biomarkers to avoid over-treatment and determine need for combination immunotherapy. A “hot” tumor immune micro-environment (TIME) is predictive of survival and immunotherapy benefit in multiple tumor types. We have previously identified the ratio of CD8+/CD68+ cells as well as a 53-gene melanoma immune panel (MIP) as indicative of a favorable “hot” TIME. CD8/CD68 ratio and MIP were evaluated in specimens from 213 previously untreated patients including 164 from Roswell Park Comprehensive Cancer Center (RPCCC) and 49 from Geisinger Health Systems (GHS, n=36). Tumors were stained with Sox10, CD8, CD68, MPO, PDL1 and HLA-DR using the MOTiF workflow (Akoya Biosciences, AB). Image analysis was completed using inForm software (AB). RNA was extracted and NanoString analysis performed using published methods. Receiving Operator Curves (ROC) were generated and KM curves using cutoffs selected using maximally selected log-rank statistics to quantify survival benefit. We tested whether the CD8/CD68 ratio correlated with disease specific survival (DSS) and distant metastatic recurrence (DMR). In the RPCCC cohort (n=164), 138 specimens were evaluated by a pathologist and stained of which 15 were excluded based on tissue quality, and inForm analysis was completed on 80. Of these 80, 16 had DMR of whom 8 had died. ROC showed CD8/CD68 ratio to correlate with DMR (p=0.0397). KM analysis showed high CD8/CD68 ratio correlated with DMR free survival (p=0.00079). Within the GHS samples, 36 of 49 patients had sufficient quality tissue, of whom 13 had died. DMR data was not available. A high CD8/CD68 ratio correlated with DSS by ROC curve (p=0.027) and KM analysis (p=0.0009). MIP was run on 166 patients of whom 147 passed quality control for analysis. MIP correlated with DSS in the RPCCC cohort by ROC analysis (p=0.025) and cutoff defined based on prior cohort showed correlation with DSS (p=0.01) and trend towards correlation with DMRFS (p=0.065). To include diverse samples in the training set, MIP was retrained with the addition of 81 patients from Columbia University (CUMC). KM analysis performed using the retrained signature showed a favorable signature correlated with DSS (p=0.032) and DMRFS (p=0.00077). Immune based biomarkers including CD8/CD68 ratio and immune gene signature have potential to assist clinicians in selecting early-stage melanoma patients for more intensive immunotherapy regimens. Full analysis of the data from the RPCCC and GHS cohorts will be presented at the conference. Citation Format: Gerardo A. Espinoza, Chenxin Zhang, Jee-Young Moon, Divya B. Kenchappa, Matteo Abbruzzese, Lydia Bioh, Yadriel M. Bracero, Sharmin Sultana, Ajay Singh, Thazin Aung, John J. Krolewski, Robyn D. Gartrell, Larisa J. Geskin, Lawrence W. Leung, Tammie Ferringer, Rui Chang, Basil Horst, Kent Nastiuk, Yvonne M. Saenger. Immune biomarkers for recurrence in stage II and III melanoma to guide patient stratification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1058.

Bevacizumab and gamma knife radiosurgery for first-recurrence glioblastoma

IntroductionGlioblastoma (GBM) is the most common central nervous system malignancy in adults. Despite decades of developments in surgical management, radiation treatment, chemotherapy, and tumor treating field therapy, GBM remains an ultimately fatal disease. There is currently no definitive standard of care for patients with recurrent glioblastoma (rGBM) following failure of initial management.ObjectiveIn this retrospective cohort study, we set out to examine the relative effects of bevacizumab and Gamma Knife radiosurgery on progression-free survival (PFS) and overall survival (OS) in patients with GBM at first-recurrence.MethodsWe conducted a retrospective review of all patients with rGBM who underwent treatment with bevacizumab and/or Gamma Knife radiosurgery at Roswell Park Comprehensive Cancer Center between 2012 and 2022. Mean PFS and OS were determined for each of our three treatment groups: Bevacizumab Only, Bevacizumab Plus Gamma Knife, and Gamma Knife Only.ResultsPatients in the combined treatment group demonstrated longer post-recurrence median PFS (7.7 months) and median OS (11.5 months) compared to glioblastoma patients previously reported in the literature, and showed improvements in total PFS (p=0.015), total OS (p=0.0050), post-recurrence PFS (p=0.018), and post-recurrence OS (p=0.0082) compared to patients who received either bevacizumab or Gamma Knife as monotherapy.ConclusionThis study demonstrates that the combined use of bevacizumab with concurrent stereotactic radiosurgery can have improve survival in patients with rGBM.

Machine Learning-Facilitated Cross-Panel Automatic Classification at Both Sample and Cell Level in Acute Myeloid Leukemia

Introduction Flow cytometry (FC) immunophenotyping is essential for accurate and prompt diagnosis of acute myeloid leukemia (AML), with up to 95% of AML patients showing detectable aberrant immunophenotype (IP) by FC. Current manual and subjective analysis of clinical FC data, however, lacks reproducibility and leads to interpretation variation. In previous studies, we showed that supervised machine learning (ML) approaches can detect IP abnormalities and identify the acute leukemia subclassification accurately at the specimen level. We also found that comparable classification performance can be achieved using only a subset of markers of the reagent panel (Ko et al., 2018; Monaghan et al., 2022). To interpret the ML classification results, we have developed data clustering and discriminative learning methods to identify and visualize the diagnostic cell populations in a 2D space for hematopathology review (Ji et al., 2020; Lee et al., 2018). Built upon these approaches, this study reports our findings on developing an interpretable cross-panel ML classification model to support timely and accurate diagnosis and subclassification of AML. Materials and Method The AML diagnosis model at the sample level utilized FC data obtained from 53 bone marrow (BM) aspirate samples from Roswell Park Comprehensive Cancer Center (RPCCC) and 50 BM aspirate samples from UPMC. Data from RPCCC were acquired using a Beckman Coulter Navios EX and measured with the ClearLLab10C panel; while data from UPMC were acquired using a BD FACSCantoII and measured with a UPMC-developed diagnostic panel. We used only the common parameters collected within these 103 FC data sets and applied a previously published Gaussian Mixture Model-Support Vector Machine (GMM-SVM) based approach to train a cross panel sample-level classification model for AML diagnosis (Ko et al., 2018; Monaghan et al., 2022). Three-fold cross-validation was conducted to assess the model performance, using sensitivity, specificity, classification accuracy, and area under the receiver operating characteristic curve (AUC). For the cell-level visualization and analysis, all samples in the training set were pooled together, before a uniform manifold approximation and projection (UMAP) process was applied to transform and visualize the cell populations within the samples. Specifically, 26 non-neoplastic and 27 AML samples from the M2 panel of the ClearLLab10C from the RPCCC cohort were combined for the UMAP visualization. Then the FlowSOM unsupervised clustering method and the DAFI semi-supervised clustering method (Lee et al., 2018) were applied to identify all of the cell populations that have significant differences between the AML samples and the non-neoplastic controls. Results The cross-panel AML versus non-neoplastic classifier, combining FC data from UPMC and RPCCC achieved exceptional performance. The AML detection model using all parameters on the ClearLLab10C panel achieved an AUC of 100%. When using only the overlapping parameters between the ClearLLab10C and the UPMC panels, the classification model achieved an AUC of 99.5%, while the cross-panel classifier achieved an AUC of 99.1% (Table 1). Specimen-level visualization confirmed the separation of AML versus non-neoplastic controls. The UMAP plots, created by pooling non-neoplastic and AML samples, exhibited distinct patterns for different AML subtypes (M1 to M5) and a genetic mutation (e.g., AML IDH1), which were distinct from control samples. Using the automated gating analysis, cell populations identified as different between AML and control samples were characterized and visualized in 2D-by-2D scatter plots for straightforward interpretation and assessment based on their immunophenotype. Conclusion Our study demonstrated the feasibility to develop and assess a ML classification model for AML detection and diagnosis using overlapping markers in FC data across reagent panels and sites. Advanced visualization and automated gating analysis enabled the interpretation of the ML classification by identifying and characterizing the diagnostic cell populations and their phenotypic heterogeneity, providing insights into AML heterogeneity at both the specimen and the single cell level. These findings highlight the potential of ML capability for improving patient care by timely and accurate diagnosis and subclassification of AML.

Increased Monocytic Myeloid-Derived Suppressor Cells Are Associated with Inferior Overall Survival in Patients with Newly Diagnosed Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) is an aggressive malignancy associated with poor long-term outcomes. This malignancy arises in the context of an immunosuppressive milieu, which fosters immune escape and tumor growth. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous group of immature myeloid cells with immunosuppressive activity, the most potent of which are the monocytic MDSCs (mMDSCs). The impact of mMDSCs on AML relapse and overall survival has yet to be fully characterized. Therefore, we sought to address this unanswered question through a retrospective analysis of a cohort of AML patients (pts) at Roswell Park Comprehensive Cancer Center. Methods: Medical records were retrospectively reviewed under an IRB approved protocol to identify pts aged ≥ 18 years old with newly diagnosed AML treated with standard cytarabine and anthracycline based chemotherapy from 2004-2017 at Roswell Park Comprehensive Cancer Center. Demographics, disease-specific variables, baseline clinical characteristics, and treatment response were analyzed using descriptive statistics. Detailed analysis of previously collected clinical multiparameter flow cytometric data was performed utilizing WinList software to identify mMDSCs at serial clinical time points (diagnosis, after induction chemotherapy, and relapse). A mononuclear gate was created utilizing CD45 vs. SSC (blasts excluded), followed by FSC vs. SSC to eliminate dead cells and aggregates. mMDSCs were defined as the subset of marrow cells co-expressing CD14+ and HLA-DR dim and was reported as the percentage of total monocytes in the marrow aspirate sample. mMDSC populations were dichotomized into “Low” and “High” groups based on the median value of the entire cohort. Overall survival (OS) and relapse-free survival (RFS) were estimated utilizing Kaplan-Meier (KM) analysis. Results: 81 pts with newly diagnosed AML who received induction with a cytarabine and anthracycline based regimen were identified. Median age was 55 years (range 20 - 85), with 52 men (64.2%) (Table 1). Cytogenetics per ELN 2022 were high risk in 38 pts (46.9%), intermediate risk in 28 pts (34.6%), and favorable risk in 15 pts (18.5%). 6/69 (8.7%) pts had FLT3-ITD mutations. Following induction therapy, 15 pts (18.5%) had primary refractory disease with 66 (81.5%) achieving complete remission (CR). 28 pts (34.6%) underwent allo HSCT. Pts with intermediate risk disease and “High” mMDSCs at time of diagnosis and post induction chemotherapy had inferior OS compared to those with “Low” mMDSCs (16 vs. 34 months, P=0.008; 16 vs. 27 months, P=0.03) (Figure 1). There were no significant differences in RFS in intermediate or poor risk pts, and no difference in OS in poor risk pts when comparing “Low” vs. “High” mMDSCs at any time point. Mean duration of follow up was 23.7 months (range 1 - 148 months). Analysis of favorable risk cohort is ongoing. Conclusions: This retrospective analysis suggests that high numbers of marrow mMDSCs are associated with poor overall survival in pts with intermediate risk AML receiving intensive induction therapy. Of note, other risk factors for poor risk disease such as complete molecular profiling were not available. However, our findings support a potential role of mMDSCs in promoting disease recurrence. Additional studies to further quantify and delineate the biological role of mMDSCs in a larger pt cohort are needed to corroborate these findings and determine the potential role of these immune cells in therapy resistance in AML.

Treatment Selection and Clinical Outcomes in Lymphoplasmacytic Lymphoma/Waldenstrom Macroglobulinemia (LPL/WM) - a Single Center Analysis

Introduction: Lymphoplasmacytic lymphoma (LPL) is as an indolent neoplasm of B-lymphocytes with plasmacytic differentiation causing bone marrow infiltration along with variable involvement of lymph nodes/or spleen. Most common subtype of LPL, Waldenstrom Macroglobulinemia (WM) involves IgM monoclonal gammopathy of any concentration. Due to widespread availability of targeted therapy drugs (BTKi), the treatment landscape of LPL is changing. The aim of this study is to analyze disease characteristics, patterns of real-world treatment selection and its impact on clinical outcomes (Objective response rate (ORR), Progression free survival (PFS) and Overall survival (OS). Methods: A retrospective analysis of patients (age ≥18 years) with diagnosis of LPL/WM between January 1, 2003, to March 31, 2023, seen in consultation at Roswell Park Comprehensive Cancer Center was performed. ORR (CR, VGPR, PR and MR) was calculated according to response criteria at 6 th International Workshop for WM. Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC). OS and PFS were reported using standard Kaplan-Meier methods. Multivariate cox regression modeling was used to assess associations between first line regimen and survival outcomes (OS / PFS). Predictor variables, namely age at diagnosis, gender, Charlson Comorbidity Index (CCI) score, and rIPSS (revised International Prognostic Score System) were included in multivariable models. Results: A total of 127 patients were included in this study. The median age at diagnosis was 68 years (range 41 to 88), of which 75 (59.1%) were men. Majority of the population was White (n=112, 88.2%) and had ECOG of 0 (n=70, 67.3%). Monoclonal gammopathy of IgM subtype was present in 114 (94.2%), IgG in 3 (2.5%) and IgA in 1 (0.8%) patient. MYD88 mutation testing was positive in 69.8%, negative in 14% and unknown in 16.3% patients. Two out of 10 patients tested for CXCR4 mutation were positive. Sixteen (28.1%) patients had hyperviscosity symptoms and underwent plasmapheresis with first line treatment. These patients had a mean IgM level of 6249.5 mg/dL and mean M-spike of 4.53 g/dL. Of 121 patients with data on treatment strategy, 20 (16.5%) were monitored with observation alone. The most common treatment modality used in first line was chemo-immunotherapy (C-I) in 61 (50.4%) patients followed by Rituximab immunotherapy (R-I) in 20 (16.5%) patients and BTK inhibitors in 12 (9.9%) patients. ORR was highest 90.7% (39/43) in chemoimmunotherapy group, 87.5% (7/8) in BTKi group and 71.4% (10/14) in Immunotherapy group. Bendamustine-Rituximab was the most common used treatment regimen (n=42), with resultant CR in 20% and VGPR in 23.3% patients. At median follow-up duration of 36.9 months, median OS was 113.9 months in R-I, 159.8 months in C-I and not reached (NR) in BTKi group. The median PFS was 50.2 months in R-I, 61.2 in C-I and 23 months in BTKi group. Although Multivariate Cox Regression analysis failed to show statistically significant difference in PFS, there is tendency towards improved OS in C-I group (p=0.08) among all the groups when adjusted for age, sex, CCI. Conclusion: In our single center experience, chemoimmunotherapy combination with Bendamustine-Rituximab is the most used treatment choice in first line settings followed by single agent anti-CD20 therapy and BTKi. Although Multivariate Cox Regression analysis failed to show statistically significant difference in PFS, there is a tendency towards improved OS in the chemoimmunotherapy subgroup (p=0.08). The shorter PFS in BTKi group is likely due to toxicity of targeted therapy leading to treatment interruption and change of therapy.

Mitochondrial Reprogramming By Bcl-2 Inhibitor Venetoclax Enhances αCD19 CAR-T Cell Fitness and Anti-Tumor Efficacy

Introduction Patients undergoing anti-CD19 chimeric antigen receptor T cell (CAR T) therapy for the treatment of aggressive B-cell non-Hodgkin lymphomas (B-NHL) can expect a complete response rate of merely 43-68%. Insubstantial clinical responses to CAR T therapy and a small window of survival for patients facing relapsed/refractory (R/R) disease highlights the critical need for improvement of CAR T therapy in aggressive B-NHL cases. Recent findings suggest that enriching for a CD8 + T Stem Cell Memory (T SCM) population within adoptive cell therapies translates to enhanced antitumor function and persistence in vivo, and thus produces favorable clinical outcomes. T SCM cells display heightened self-renewal, low mitochondrial membrane potential (∆Ψm), and are metabolically dependent upon oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). Selection of CD8 + T SCM subsets is therefore necessary to ensure a robust antitumor response. Previously, we revealed synergy between the Bcl-2 inhibitor, Venetoclax, and CAR T cells in the context of B-NHL. Venetoclax exposure increased CD8 + T SCM cell frequency, decreased ∆Ψm, reduced T Regulatory (T REG) cell frequency, and bolstered effector cytokine production. Though the role of Bcl-2 inhibition within B-NHLs is well characterized (FDA-approved for frontline and relapsed/refractory chronic lymphocytic leukemia [CLL] treatment), further investigation regarding the impact of Venetoclax on the patient T cell compartment is needed. In this study, we demonstrate a role for Venetoclax as a qualitative enhancer of bulk CAR T cell product using both healthy-donor and B-NHL patient-derived T cells, and implicate modulation of mitochondrial pathways as a likely mechanism of action. Methods Whole peripheral blood mononuclear cells were collected from consenting healthy human donors or CLL patients undergoing ramp-up with Venetoclax (BDR 164122) at Roswell Park Comprehensive Cancer Center, and activated with αCD3/αCD28. CLL samples were collected at baseline, 1 day, 7 days, and 1-month timepoints. Transduction was performed with lentiviral vectors encoding CD28 or 4-1BB-based α-CD19 CAR constructs 24 hours post-activation. Transduced cells were cultured in RPMI with hIL-2 and hIL-7. In vivo studies were performed on 7-week-old SCID mice using Raji-Luc, Rec-1, and U2932. Venetoclax was given daily [100mg/kg] via oral gavage. CAR T cells were delivered by single infusion via tail-vein injection at a dose of either 1x10 6 or 3x10 6 cells total.Mice were imaged via IVIS spectrum. Western blot was performed on stimulated untransduced T cells or CAR T cells exposed to Venetoclax. Total protein was quantified, and membranes were probed for apoptotic and mitochondrial protein expression. Patient sample immunophenotyping was performed on CLL patient samples using panels interrogating memory differentiation, exhaustion, and T REG populations. Results Consistent with our hypothesis, a significant increase in mitochondrial proteins associated with FAO and OXPHOS - ACC, PDH, and AMPKα - was observed in exposed CAR T cells, as well increased expression of transcription factor FOXO1 - an essential driver of CD8 + memory differentiation. Voltage-dependent anion channel (VDAC) expression increased, suggesting heightened efflux of respiratory substrates into the tricarboxylic acid cycle. Hexokinase-I, a critical glycolytic enzyme, was significantly downregulated. We next investigated our combination therapy in vivo and observed extended survival outcome by 15 days. Further in vivo studies investigating preclinical models of mantle cell lymphoma and activated B-cell diffuse large B-cell lymphoma are currently ongoing. Within our CLL patient samples, 24-hour and 7-day timepoints reflected a favorable population increase in CD8 + T SCM cells as compared to baseline samples, and marginally restored CD8 + T cell frequencies. Conclusion Metabolic properties guide T cell memory differentiation and fitness. There exists potential to manipulate this mechanism and select the most metabolically fit T cell population for adoptive cell therapies. In addition to answering fundamental questions of CAR T cell biology, the combination of Venetoclax and CAR T cell therapy may provide a solution to the observed clinical gap, in which CAR T therapy as a single agent does not afford favorable response rates in the context of aggressive and R/R B-NHLs.

Optimal Therapeutic Strategies in Relapsed/Refractory AML with Prior Exposure to Venetoclax Based Therapy

Background: Acute myeloid leukemia (AML) is an aggressive hematological malignancy arising from immature myeloid progenitors with notoriously poor outcomes, particularly in the elderly. Venetoclax (Ven) plays an essential role in acute myeloid leukemia (AML) directed therapy as it is approved for frontline therapy in combination with azacitidine (Aza), decitabine (Dec), or low-dose cytarabine (LDAC) for patients aged 75 years and older, or those with significant comorbidities. However, venetoclax-based therapy is not curative, and the ideal salvage regimen is unclear in these patients. We performed a retrospective review that analyzed a single center's venetoclax-based regimens to identify rational subsequent lines of therapy after failing venetoclax. Methods: We conducted a retrospective review of adult patients at Roswell Park Comprehensive Cancer Center who had a confirmed AML diagnosis and received a venetoclax-based regimen as upfront therapy between January 2015-February 2023. Demographics, prior hematological disorders, ELN risk stratification, Eastern Cooperative Oncology Group (ECOG) performance status, treatment received in upfront vs relapsed/refractory settings, date of remission/relapse, disease-specific variables [molecular data, cytogenetics], and outcomes [duration of response, time to progression, MRD status, and overall survival] were collected. Of note, in patients who received upfront venetoclax regimen, the subsequent salvage therapy was grouped by targeted (Gliterinib, Enasidenib, Ivosidenib), low-intensity (single agent hypomethylating therapy, gemtuzumab, ozogamicin), or intensive groups (CLAG-M) and analysis was performed for progression-free survival (PFS). The patient demographics and clinical characteristics were summarized by group (i.e. response, regimens) using the Mann-Whitney U and Fisher's exact test. Survival functions were described by the Kaplan-Meier method and compared with the Log-rank test. Analyses were performed in SAS v9.4 (Cary, NC) at a significance level of 0.05. Results: The retrospective study analyzed 97 patients. In the upfront analysis, the median age was 73.4 years (range: 51.4-89.8) and 64 (66.0%) of the patients were male. 65 patients (67.0%) received Aza/Ven, 26 (26.8%) Dec/Ven, and 6 (6.2%) LDAC/Ven. Per ELN 2022 criteria, 13.3% of patients were stratified as favorable,12.2% as intermediate, and 74.4% as adverse risk. Of the adverse risk patients, 67/97 (69.1%) patients received Aza/Ven. Median survival time for all upfront induction regimens was 15.8 months (95% CI: 8.1-22.6), greatest median survival with Aza/Ven of 19.1 months (95% CI:10.4-23.6). Median PFS by all induction regimens was 8.9 months (95% CI: 5.0-13.9) with the greatest median PFS being Aza/Ven at 10.9 months (95% CI: 6.6-20.2); p=0.045). Overall, 29 out of 97 (29.9%) patients received salvage therapy. These included 19 (65.5%) males with 93.1% of patients being Caucasian. The majority of patients (81.5%) had adverse ELN risk stratification (Table 1). Total 1-year survival rate is 0.050 (0.31-0.67), with intensive 0.050 (0.16-0.67), low intensity 0.67 (0.35-0.86), targeted 0.39 (0.18-0.60). Total 3-year survival rate is 0.19 (0.06-0.38) with intensive 0.17 (0.02-0.46), low intensity 0.30 (0.08-0.56), and targeted 0.20 (0.05-0.41). Patients receiving subsequent salvage therapy after upfront venetoclax regimen showed the greatest PFS after receiving low-intensity therapy compared to targeted or intensive regimens with a median survival of 13.9 months (95% CI: 0.0-35.9); p&amp;lt;0.001) (Figure 1). Median survival after intensive therapy was 1.3 months (95% CI:0.5-3.9) and targeted therapy 5.8 months (95% CI: 2.8-10.0). Total OS 14.9 (95% CI: 6.1-22.7) with a low-intensity median survival of 22.7 months (95% CI:1.4-Not Reached (NR)). Conclusion: In this single-center retrospective review, it was found that a low-intensity salvage regimen after the upfront venetoclax regimen showed the greatest PFS compared to targeted or intensive regimens, however, there is no statistically significant difference in OS. Our study results were limited by a small sample size. Further studies are needed to clearly define the ideal salvage regimen for AML patients failing upfront venetoclax-based therapy.

Germinal Center B-Cell-like (GCB) Phenotype Predicts Improved Outcomes in Central Nervous System Diffuse Large B-Cell Lymphoma Patients Receiving Stereotactic Radiosurgery (SRS)

Background: Diffuse large B cell lymphoma (DLBCL) constitutes most cases of both primary and secondary central nervous system lymphoma (CNSL). They represent a highly aggressive subset of non-Hodgkin lymphoma and prognosis varies depending on the cell of origin. Immunohistochemistry using antibodies for CD10, BCL-6, and MUM-1, also known as the Hans algorithm, is the most common method for determining the cell of origin and predicting outcomes in DLBCL. The study by Hans et al. found that the germinal center B-cell-like (GCB) group had a much better prognosis compared to the non-GCB group, with 5-year overall survival (OS) of 76% and 34% respectively. Despite chemotherapy, recurrence is common in these patients, and up to 40-50% do not achieve durable remission. It is important to identify who may benefit from more aggressive or experimental therapy at diagnosis. Stereotactic radiosurgery (SRS) is the administration of a localized, high dose of ionizing radiation and limited studies exist exploring SRS as a treatment modality in relapsed/refractory (r/r) CNSL or prognostic implications of the Hans algorithm in these patients. Aim/Objective: To perform a retrospective analysis of outcomes of patients with CNSL, phenotypes determined by the Hans algorithm, treated with SRS at a single comprehensive cancer center. Methods: We studied the demographic, clinical, pathological, and treatment characteristics of r/r CNSL patients (N=27), age ≥ 18 years, who received SRS at Roswell Park Comprehensive Cancer Center between 01/2000 and 01/2023. The Hans algorithm was used to group the patients into non-GCB (N=17) and GCB (N=10) cohorts. Overall survival (OS) and progression-free survival (PFS) were calculated and reported using Kaplan-Meier analyses and log-rank tests. Cox regression models were used to describe cross-cohort comparisons of survival. Results: The median Karnofsky performance status at diagnosis was 70 for both groups. The overall response rate (ORR) to SRS in GCB-type was 80% (7 complete response and 1 partial response; CR, PR). The ORR in non-GCB type was 58% (6 CR and 4 PR). Post-SRS, stem cell transplant (SCT) was avoided in 100% of the patients in the GCB group, while 17% of the patients in the non-GCB group received SCT. The 6-month overall survival (OS) rate was 100% and 46% for the GCB-type and non-GCB type respectively (p=0.096, Figure 1A). The 6-month progression-free survival (PFS) rate was 80% for the GCB-type and 33% for the non-GCB type (p=0.024, Figure 1B). In the GCB group, the median OS was 18.0 months while the median PFS was 13.8 months. In the non-GCB group, the median OS was 4.9 months while the median PFS was 3.6 months. The median time from chemotherapy completion to SRS administration was 8.0 months in the GCB-type and 2.0 months in the non-GCB type. Conclusion: Our data support that the GCB-type predicts a more favorable outcome in CNSL, with improved OS and PFS rates compared to the non-GCB type. In addition, the non-GCB type patients required earlier SRS administration and had a lower ORR to SRS. Classifying CNSL into GCB and non-GCB phenotypes using the Hans algorithm might help characterize patients into groups with different prognoses.

Inotuzumab Ozogamicin + Blinatumumab +/- Rituximab + Mini-Hcvd Shows Improved Tolerability with Similar Efficacy Compared to E1910 in Treatment of Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia in Older Adults

CONCLUSION Philadelphia chromosome negative acute lymphoblastic leukemia (Ph- ALL) boasts contradicting survival rates given its binodal age distribution. While children and adolescents post 5-year overall survival (OS) rates of 89%, the stark contrast of 5-year OS of 20.4% in older adults greater than 65 years, makes this a challenging population to treat. Currently, there is no standard of care for the treatment of ALL with various regimens utilized dependent on age, co-morbidities, performance status, as well as physician/institute preference. One regimen that is commonly used is a combination of targeted therapies along with reduced intensity chemotherapy (inotuzumab ozogamicin, rituximab (if CD20+), blinatumomab and mini hyper fractionated cyclophosphamide, vincristine, and dexamethasone [Mini-HCVD]), which has demonstrated both improvements in survival while reducing treatment related toxicity. Another commonly accepted approach is a modified Berlin-Frankfurt-Munster (BFM) backbone (i.e., E1910). Despite the available options, there is a lack of comparison of these regimens. To answer this unanswered question, we compared the characteristics, outcomes, and toxicities of older adults with ALL treated with either Mini-HCVD or E1910 at our academic medical center. Medical records were retrospectively reviewed at Roswell Park Comprehensive Cancer Center to identify patients diagnosed with Ph- ALL treated with Mini-HCVD or E1910 between January 1 2016 - May 31 2022. Those with relapsed/refractory ALL or received E1910 in the setting of a clinical trial were excluded from the study. Demographics, disease-specific variables, and overall outcomes were collected in accordance with the institutional review board approved protocol. Primary outcome was 3-year overall survival rate, while secondary outcomes included best response in first 3 months, minimal residual disease (MRD) status at 3 months, 30-day mortality, as well as the frequency and incidence of toxicities per cycle. Best response was defined as less than 5% blasts on bone marrow biopsy with complete (CR) or incomplete (CRi) absolute neutrophil or platelet count recovery. MRD status was assessed via flow cytometry and next generation sequencing using ClonoSEQ®. Adverse events and their severity were characterized according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Differences in OS between two groups were examined by log-rank test. Propensity scores were obtained based on the baseline variables that with potentially imbalanced distributions (p&amp;lt;0.1). MRD status and response to treatment were compared using Fisher's exact test. Toxicities were summarized as frequencies for each treatment cycle. The incidence of grade 3-4 toxicities was defined as the number occurrence per treatment cycle and were compared using Poisson regression. 27 patients were included, with 15 (55.5%) receiving Mini-HCVD and 12 (44.5%) receiving E1910. Median age was 70 years (49-83), in Mini-HCVD arm and 63 years (47-74), in E1910 arm. Three-year OS was 61.9% for those who received Mini-HCVD (95% CI 40.2-95.3) and 28.1% for those who received E1910 (95% CI 10.9-72.9; p=0.23). In Mini-HCVD 77% and 69% of patients achieved CR/CRi and MRD negative status in the first three months, compared to 60% and 70% in E1910. Only 13% of patients in Mini-HCVD proceeded to transplant or CAR-T, compared to 58% in E1910 (p=0.0198). The most common treatment-related adverse events in both arms were cytopenias. Febrile neutropenia occurred in 47% of Mini-HCVD patients compared to 83% in E1910. There was no difference in rates of infections between arms. Mean incidence of grade 3/4 toxicity per cycle was 0.85/0.96 with Mini-HCVD and 1.03/1.65 with E1910 (p=0.0098). This retrospective single institute study demonstrates that the clinical outcomes of Mini-HCVD plus immunotherapeutic agents in older adults with Ph- ALL are similar to modified BFM backbone with reduced incidence of toxicity. While limited by small numbers, these results suggest that reduced intensity chemotherapy in combination with novel targeted agents could represent a new standard of care regimen in this historically difficult to treat patient population.

Cryopreservation Changes the Immune Effector Cell Composition of Peripheral Blood Stem Cell Grafts: An Analysis from the DKMS and NMDP Graft Composition Study

The impact of the cellular composition of PBSC grafts on the immune reconstitution as well as graft-versus-host and graft-versus-leukemia effects after allogeneic hematopoietic cell transplantation (alloHCT) is only poorly understood. DKMS and NMDP joined forces to comprehensively characterize the cellular composition of 2,000 PBSC products using a 34-color flow cytometry panel to define immune effector cell subsets of interest and hematopoietic stem cells. In parallel, we have created a biobank of unstimulated donor PBMC and PBSC graft samples for future analyses. As part of this larger effort, we investigated the effect of cryopreservation on the cellular composition of PBSC products. Cryopreservation of PBSC grafts was used frequently during the COVID19-pandemic and facilitated more flexible timelines for transplantation. Still, one third of the US patients and 15% of the German patients continue to receive cryopreserved PBSC grafts. Ongoing studies are investigating the impact of cryopreservation on immune-effector cell function and the outcome of hematopoietic stem cell transplantation. Several observational studies have reported delayed neutrophil and platelet engraftment with cryopreserved products. More recently, less chronic GVHD was reported for patients who had received cryopreserved PBSC products. Cryopreservation affects the cellular composition and hence has the potential to change immune effector cell functions of the graft, but available data on the alterations of cell population frequencies are scarce. We analyzed the cellular composition of 20 fresh grafts and compared them to their frozen and thawed counterparts. Cryopreservation of product samples followed routine clinical procedures using a 10% DMSO containing cryo-medium and a controlled rate freezing. After thawing at 37°C, cells were washed, stained with a 34-parameter phenotyping panel, fixed and analyzed immediately on a full spectrum flow cytometer. Following spectral unmixing and manual spillover correction, proportions of immune cells were assessed using manual gating. First, we investigated the relative frequencies of 10 non-overlapping individual cell populations relative to viable CD45+ cells, including several lymphocyte populations, monocytes, granulocytes, hematopoietic stem cells (HSC) and dendritic cells. Granulocytes showed the largest decrease after cryopreservation and thawing (18.2 % vs 3.5 %; p&amp;lt;0.001). The loss of granulocytes results in an increase of relative frequencies of many other immune cell populations including monocytes (35.4 % vs 44.7 %; p=0.018), B cells (5.8 % vs 9.6 %; p=0.006), and HSC (1.0 % vs 1.5 %; p&amp;lt;0.001). We therefore also calculated changes relative to the viable non-granulocyte cells. By doing so, a significant relative increase of cells was observed for HSC (1.2 % vs 1.6 %; p&amp;lt;0.001), whereas monocyte and B cell frequencies changed only marginally. This suggests that HSC are more resilient to freezing than other cell types. When comparing the proportions of 40 other immune cell (sub-) populations relative to their parent population in the gating hierarchy, we found a profound and significant decrease of the relative frequencies for CD16+ myeloid dendritic cells (mDCs, 68 % vs 30 % of all mDCs; p&amp;lt;0.001) and granulocytic myeloid derived suppressor cells (gMDSCs, 2 % vs 1 % of all MDSCs; p&amp;lt;0.001). In an independent set of analyses performed at Roswell Park Comprehensive Cancer Center, Buffalo, comparable results were obtained with a significant increase of HSC, a significant decrease of CD16+ mDCs, and a trend of a decrease of gMDSCs. As CD16+ mDCs may have a role in the development of chronic GVHD after alloHCT, this decrease may be meaningful. In summary, we found that cryopreservation of PBSC allografts resulted in a decreased relative frequency of granulocytes, and CD16+ mDCs, as well as an increased relative frequency of HSCs. The results provide some insight into the impact of cryopreservation on PBSC graft composition and warrant further efforts to explore the potential mechanisms for the differential outcomes observed using fresh vs cryopreserved PBSCs.

Palliative Management of Inoperable Malignant Bowel Obstruction: Prospective, Open Label, Phase 2 Study at an NCI Comprehensive Cancer Center

ContextMalignant bowel obstruction (MBO) is a common complication of intra-abdominal cancer, frequently seen in advanced gastrointestinal and gynecologic cancer. Management of MBO can be challenging, particularly if the patient is not a surgical candidate. No consensus exists on how best to manage these patients medically. Retrospective studies suggest that the combination of dexamethasone, octreotide and metoclopramide may lead to relief of obstruction and improvement in symptoms associated with the obstruction. ObjectivesThis study seeks to prospectively evaluate the combination of drug “triple therapy” dexamethasone 4 mg BID, metoclopramide 10 mg Q6 and octreotide 300 mcg TID to assess tolerability, safety, and effect on symptoms and deobstruction. MethodsAdults admitted at Roswell Park Comprehensive Cancer Center with malignant bowel obstruction were eligible. Eligible patients who constented to the study were started on the triple therapy with close monitoring of symptoms and for adverse effects. ResultsA total of 15 patients enrolled in the study. Two patients experienced bradycardia as adverse effect and there was no incidence of bowel perforation. All patients who completed the study had complete resolution of their nausea, and improvement in other symptoms including pain, constipation, tolerance of oral intake and resumption of bowel movements. Only two of the 15 patients were alive to complete the six-month post study follow up. Conclusion“Triple therapy” with dexamethasone, metoclopramide, and octreotide for management of nonsurgical MBO in this small sample size appears safe and well tolerated however a diagnosis of inoperable MBO remains associated with poor prognosis and death within months.

Nano therapy Spotlight: Arestin™ Minocycline Microspheres

Within the last ten years, recent advancements in nanotechnology and repurposed pharmaceutical development has led several successful therapeutics through clinical trials and subsequently onto the market. On the nanotechnology side, size, shape, charge, and formulation are all considered in improving the overall efficacy or delivery of the therapeutic. Nanoparticle therapies hit the market in the late 90’s when the FDA approved CosmoFer®, an iron sugar colloid that also saw use in the European market. While these early nano pharmaceuticals were primitive compared to today’s standards, these medications proved that a nanoparticulate therapeutic can and would be accepted by the FDA, albeit under much scrutiny. On the pharmaceutical side, older legend drugs that have been proved efficacious for many years are beginning to be repurposed for other uses. For example, Pfizer’s 2015 approval of Rapamune® (Rapamycin) is indicated for the treatment of Lymphangioleiomyomatosis (LAM) a rare lung disease infecting mostly women in early adulthood. The drug, however, was first approved in 1999 and was used in the prophylaxis of organ rejection as an immunosuppressant. Another indication for Rapamycin is in age related diseases; a 2006 paper published by Dr. Blagosklonny at the Roswell Park Comprehensive Cancer center showed that Rapamycin could inhibit certain pathways that are related to aging. Many other medications on the market such as monoclonal antibody therapies have also seen a rise in new implication discovery and there is much evidence to suggest other drugs will be researched in the future for other alternative treatments. Because of such developments, pharmaceutical companies have tapped into the nanoparticle development world to find novel therapies for diseases we once thought were unavoidable. This is shown by the sheer expected market growth of about two billion dollars from 2021-2026, and the fifteen different nanoparticle-based therapeutics that have already been FDA approved since in just the last three years. Although the nanoparticle technology scope may seem to hover over novel cancer therapies, autoimmune disorders, blood borne diseases and neurological disorders, many therapies have come about in some interesting fields of study. One such therapeutic is called Arestin®, a new dentistry medication for the treatment of severe periodontitis, better known as gum disease. Gum disease is caused by poor oral hygiene and is attributed to various bacterial infections within the gum-line and if left untreated it can cause soft tissue damage or jawbone degradation. Typically, an antibiotic mouthwash or ultrasonic dental cleaner can be used to treat minor periodontitis but, in severe cases where there is significant gum-line recession, a more direct therapeutic is needed to treat the infection directly at the source. Arestin® is a nanoparticle formulation containing minocycline HCl impregnated within a bio-reabsorable polymer that is delivered directly into the gum-line via a blunt tip syringe. Minocycline is a tried-and-true antibiotic with a rich history of over thirty years on the market as a second-generation tetracycline derivative. It is both a gram positive and gram negative [broad spectrum] antibiotic and is very well tolerated in patients making it an excellent candidate in late-stage gum disease intervention. Here, this review, discuss Arestin® and subsequently Minocycline Hydrochloride’s: history, mechanism of action, formulation/production, side effects and the future of reformulated nano pharmaceuticals that are continuing to move the market share up.

Association of pre-treatment lymphocyte-monocyte ratio with survival outcome in patients with head and neck cancer treated with chemoradiation

BackgroundGiven the role of systematic inflammation in cancer progression, lymphocyte-monocyte ratio (LMR) from peripheral blood has been suggested as a biomarker to assess the extent of inflammation in several solid malignancies. However, the role of LMR as a prognostic factor in head and neck cancer was unclear in several meta-analyses, and there is a paucity of literature including patients in North America. We performed an observational cohort study to evaluate the association of LMR with survival outcomes in North American patients with head and neck cancer.MethodsA single-institution, retrospective database was queried for patients with non-metastatic head and neck cancer who underwent definitive chemoradiation from June 2007 to April 2021 at the Roswell Park Comprehensive Cancer Center. Primary endpoints were overall survival (OS) and cancer-specific survival (CSS). The association of LMR with OS and CSS was examined using nonlinear Cox proportional hazard model using restricted cubic splines (RCS). Cox multivariable analysis (MVA) and Kaplan–Meier method were used to analyze OS and CSS. Pre-radiation LMR was then stratified into high and low based on its median value. Propensity scored matching was used to reduce the selection bias.ResultsA total of 476 patients met our criteria. Median follow up was 45.3 months (interquartile range 22.8–74.0). The nonlinear Cox regression model showed that low LMR was associated with worse OS and CSS in a continuous fashion without plateau for both OS and CSS. On Cox MVA, higher LMR as a continuous variable was associated with improved OS (adjusted hazard ratio [aHR] 0,90, 95% confidence interval [CI] 0.82–0.99, p = 0.03) and CSS (aHR 0.83, 95% CI 0.72–0.95, p = 0.009). The median value of LMR was 3.8. After propensity score matching, a total of 186 pairs were matched. Lower LMR than 3.8 remained to be associated with worse OS (HR 1.59, 95% CI 1.12–2.26, p = 0.009) and CSS (HR 1.68, 95% CI 1.08–2.63, p = 0.02).ConclusionLow LMR, both as a continuous variable and dichotomized variable, was associated with worse OS and CSS. Further studies would be warranted to evaluate the role of such prognostic marker to tailor interventions.

Making sense of the dollars: Evaluation of financial toxicity in patients of breast medicine receiving oral chemotherapy at Roswell Park.

e18519 Background: Increasing costs of oral chemotherapy have become a significant barrier to cancer care with the potential to cause treatment abandonment and noncompliance. The primary objective of this study is to evaluate the financial toxicity of oral chemotherapy in the Breast Medicine Service at Roswell Park Comprehensive Cancer Center (RPCCC). Methods: This was a retrospective chart review of patients at RPCCC who were diagnosed with breast cancer and prescribed oral chemotherapy between 8/1/21 - 7/31/22. The primary outcome evaluated was average out-of-pocket (OOP) cost of an oral chemotherapy prescription. Secondary outcomes studied included 1) the number of patients enrolled in manufacturer patient assistance programs (PAPs), copay cards, foundation grants, and/or New York State Elderly Pharmaceutical Insurance Coverage (EPIC) program, and 2) median days to treatment start date, approval of prior authorization (PA) and/or PAPs. For patients who filled at outside pharmacies, days to first insurance claim were collected and compared to days to first fill for patients who filled at Roswell Park Pharmacy. Results: A total of 116 patients with a median age of 64 and 122 oral chemotherapy prescriptions were included. Majority of the patients were white (n = 93; 80%) and enrolled in Medicare managed plans (n = 58; 50%). Palbociclib (n = 47; 39%) and capecitabine (n = 29; 24%) were most commonly prescribed. 49 patients filled at Roswell Park Pharmacy; average OOP cost was $48.00 (range: 0-2239.50) per prescription claim. Average OOP cost was $85.18 for patients with Medicare managed plans, $23.35 for patients with commercial insurance, and $3.66 for patients with government-funded insurance. Twenty patients (17%) enrolled in PAPs, foundation grants, copay cards, and/or EPIC program. OOP costs prior to any financial assistance was available for thirteen patients; median OOP cost was $2491.51 (403.62-18165.94). Median days to approval of PAPs and approval of PA was 10 (1-50) and 0 (0-14), respectively. When filling internally at Roswell Park Pharmacy, median days to treatment start date was 6 (0-61) compared to 9 (0-67) for those who filled at outside pharmacies. There was a significant difference (p = 0.0111) between the median days to first fill for patients who filled at Roswell Park Pharmacy (0 days [0-25]) and the median time to first insurance claim (2 days [0-20]) for patients filling at outside pharmacies. Conclusions: Despite utilization of financial assistance program, OOP costs remain high for cancer patients. Having a defined workflow to screen and identify patients at risk for financial toxicity and the ability to refer to appropriate resources to mitigate OOP costs promptly is vital to prevent delays in treatment. Utilizing an integrated health-system specialty pharmacy can be helpful to streamline patient access and avoid further treatment delays.

Treatment patterns and outcomes of diffuse alveolar hemorrhage: Findings from a single-center retrospective study.

e19063 Background: Diffuse alveolar hemorrhage (DAH) is a life-threatening complication seen in patients with malignancy most commonly after a hematopoietic stem cell transplant (HSCT). Systemic therapy with corticosteroids to reduce inflammation and control bleeding is the mainstay of treatment for DAH, however ideal dosing strategies are not known. Methods: This single-center, retrospective study reviewed patients presenting to Roswell Park Comprehensive Cancer Center (RPCCC) from January 2010 through November 2022. Patients were included in this review if they were &gt;18 years and were actively treated at RPCCC for presumed or definite DAH. The bone marrow transplant database, ICD-9, and ICD-10 codes were used to screen patients for inclusion. Upon meeting inclusion criteria, patients were stratified based on daily methylprednisolone dosing equivalents [low-dose: &lt; 250 mg, intermediate-dose: &gt;250 mg or &lt; 1000 mg, high-dose: &gt;1000 mg, or no steroid]. The primary endpoint was 30-day mortality. Secondary endpoints included ICU mortality, ICU length of stay (LOS), overall LOS, hemorrhage recurrence, steroid complications, and utilization of other DAH treatments. Steroid complications, including hyperglycemia, infection, and uremia were evaluated as safety endpoints. Results: Thirty-seven patients met inclusion criteria; 23 HSCT and 14 non-transplant patients. Analysis included 20 patients in the low-dose, 2 patients in the intermediate-dose, 12 patients in the high-dose, and 3 patients in the no steroid group. The median duration of steroids was 15, 4, and 14 days in the low, intermediate, and high groups, respectively. There was no statistically significant difference in 30-day mortality across treatment groups (p = 0.76). The overall 30-day mortality rate was 24.3%, with 25%, 50%, and 17% in the low, intermediate, and high-dose groups, respectively. A 30-day mortality rate of 33% was seen in patients who did not receive steroids. Hemorrhage recurrence occurred in 9 patients (24.3%), most commonly in the high-dose treatment group. Utilization of additional agents including aminocaproic acid, etanercept, and inhaled factor VIIa was most common in the intermediate-dose group. Conclusions: Despite variable steroid dosing, 30-day mortality was not found to be statistically significant among patients treated for DAH. Based on our findings of similar efficacy between dosing strategies, yet increased rates of steroid complications and hemorrhage recurrence in the high-dose group, lower steroid doses for the treatment of DAH can be considered. [Table: see text]

Association of pretreatment lymphocyte-monocyte ratio with survival outcome in patients with head and neck cancer treated with chemoradiation.

6052 Background: Lymphocyte-monocyte ratio (LMR) from peripheral blood has been suggested as a biomarker to assess the extent of inflammation in several solid malignancies. However, the role of LMR as a prognostic factor in head and neck cancer (HNC) was unclear in several meta-analyses, and there is a paucity of literature including patients in North America. We performed an observational cohort study to evaluate the association of pre-radiation LMR with survival outcomes in North American patients with HNC. Methods: A single-institution database was queried for patients with non-metastatic HNC who underwent curative-intent definitive chemoradiation from 6/2007 to 4/2021 at the Roswell Park Comprehensive Cancer Center. Patients were excluded if they underwent induction chemotherapy or postoperative radiation. Primary endpoints were overall survival (OS) and cancer-specific survival (CSS). The association of LMR with OS and CSS was examined using nonlinear Cox proportional hazard model using restricted cubic splines (RCS), Cox multivariable analysis (MVA), and Kaplan-Meier method. LMR was stratified into high and low based on its median. Logistic MVA was performed to identify variables associated with low LMR. Propensity scored matching was used to reduce selection bias. Subgroup analyses were performed among those with available human papillomavirus (HPV) status. Results: A total of 476 patients (391 male [82.1%], median [interquartile range] age, 61 [55-67] years) met our criteria. Median follow up was 45.3 months (interquartile range 22.8-74.0). The nonlinear Cox regression model using RCS showed that low LMR was associated with worse OS and CSS in a continuous fashion without plateau and crossed the hazard ratio of 1 at LMR 3.4 for both OS and CSS. On Cox MVA, higher LMR as a continuous variable was associated with improved OS (adjusted hazard ratio [aHR] 0.90, 95% confidence interval [CI] 0.82-1.00, p = 0.04) and CSS (aHR 0.81, 95% CI 0.70-0.94, p = 0.005). The median value of LMR was 3.8. On logistic MVA, patients with other racial background (adjusted odds ratio [aOR] 0.85, 95% CI 0.74-0.97, p = 0.02) and positive HPV status (aOR 0.82, 95% CI 0.72-0.94, p = 0.005) were less likely to have low LMR. Higher T staging was associated with low LMR (aOR 1.15, 95% CI 1.04-1.27, p = 0.005). A total of 186 pairs were matched with well balanced baseline characteristics. LMR lower than 3.8 remained associated with worse OS (HR 1.60, 95% CI 1.13-2.28, p = 0.009) and CSS (HR 1.69, 95% CI 1.07-2.67, p = 0.03). In the subgroup of 319 patients (67.0%) with available HPV data, LMR status was not associated with both OS and CSS regardless of HPV status. Conclusions: Low LMR was associated with worse OS and CSS. Low LMR was also associated with higher T staging, negative HPV status, and White race. Further studies are warranted to evaluate the role of such prognostic marker to tailor interventions.