Highlights from the American society of hematology conference 2020

American Society of Hematology conducts an annual meeting, where investigators from around the globe presented ground-breaking research in the fields of malignant and non-malignant hematology. We provide a summary of non-malignant hematology abstracts from the 2020 meeting. Topics included range from those related to thrombosis, including thrombotic complications of COVID-19, bleeding and novel therapies such as gene therapies. Readers are encouraged to access meeting materials for a more detailed coverage of the event

A cytomorphological study of secretions in breast cancer

Background: Secretions are seen in a range of breast cancer that includes invasive ductal carcinoma, mucinous carcinoma and secretory carcinoma. Evaluation of the quantity and location of secretions and the contours of the cell clusters complement cell morphology could improve diagnostic cytopathological criteria. Aim: To identify the range of breast carcinomas with secretions on fine-needle aspiration. Materials and Methods: A retrospective study of 160 patients with breast carcinoma was carried out. The tumors were typed by evaluating the quantity and location of secretions, cellularity and nuclear grade. Results: Secretions were seen in 16 of 160 breast carcinomas. Eleven were invasive ductal carcinoma (IDC), three were mucinous and two were secretory carcinomas. In IDC, minimal intracytoplasmic secretions were seen in 10, nuclear grades of 2 and 3 in 9, cell clusters with irregular margins in 6, and necrosis in 4. All mucinous and secretory carcinomas were nuclear grade 1. Extensive extracellular secretions and cell clusters with rounded contours were seen in mucinous carcinomas. In secretory carcinomas, the secretions were predominantly intracellular; stringy vasculature was a unique feature. Conclusion: Secretions in breast cancer are seen in a range of lesions that include IDC, mucinous, and secretory carcinomas. The quantity and location of secretions in breast cancer offer clues to differentiating these

COVID‐19 pandemic and impact on cancer clinical trials: An academic medical center perspective

The COVID-19 pandemic changed health-care operations around the world and has interrupted standard clinical practices as well as created clinical research challenges for cancer patients. Cancer patients are uniquely susceptible to COVID-19 infection and have some of the worst outcomes. Importantly, cancer therapeutics could potentially render cancer patients more susceptible to demise from COVID-19 yet the poor survival outcome of many cancer diagnoses outweighs this risk. In addition, the pandemic has resulted in risks to health-care workers and research staff driving important change in clinical research operations and procedures. Remote telephone and video visits, remote monitoring, electronic capture of signatures and data, and limiting sample collections have allowed the leadership in our institution to ensure the safety of our staff and patients while continuing critical clinical research operations. Here we discuss some of these unique challenges and our response to change that was necessary to continue cancer clinical research; and, the impacts the pandemic has caused including increases in efficiency for our cancer research office

Genomic characterization of p16+ compared to p16- HNSCC patients treated with immune checkpoint inhibitors and overall survival

e18024 Background: Multiple studies investigating immune checkpoint inhibitors (ICI) in head and neck squamous cell cancer (HNSCC) patients have demonstrated prolonged survival of p16+ versus p16- tumors. However, the data has been conflicting. Methods: We queried the Caris Life Sciences CODEai database to assess survival outcomes of HNSCC patients who received ICIs comparing p16+ and p16- subgroups. A standard cut-off of 2+, >70% p16 staining was used. Presence of HPV16/18 genomes was tested using whole exome sequencing. Patients were considered smokers if they had >15 pack-years of tobacco use. PD-L1 expression was assessed by the 22c3 antibody, ≥1 being positive. Gene mutations were evaluated using Next-Generation Sequencing (NGS) (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was assessed by somatic nonsynonymous missense mutations. Real world overall survival (rwOS) was obtained from insurance claims data and Kaplan-Meier estimates were calculated from the date of treatment start to the date of last contact. Time on treatment (TOT) was calculated from date of start to completion of ICIs. Results: 2905 patients with HNSCC were identified in the Caris database. 41% (215/525) were smokers. Among patients who were tested for p16 and/or HPV, 32% (251/791) expressed p16 and 28% (91/236) were HPV+. The majority of p16+ tumors were oropharynx (OP) in origin (68%, 171/251). 87% (970/1111) of tumors expressed PD-L1 and 16% (216/1362) had TMB ≥10/Mb. TP53 (54%, n=1115/2076) and CDKN2A (17%, n=281/1649) were the most common mutations. When compared to p16-, the p16+ group had a higher prevalence of TMB ≥10/Mb (26% vs 17%) and RB1 mutations (21% vs 4%) but lower number of smokers (15% vs 34%) and TP53 mutations (32% vs 58%). Similar to previous reports, p16+ oropharynx squamous cell carcinoma (OPSCC) patients survived longer than p16- patients, rwOS, 47 vs. 20 months (HR=0.55, p = 0.014) respectively. Among patients who were treated with ICIs, p16+ and p16- non-OP HNSCC, rwOS was not reached (NR) for both groups at follow up of 22 months while TOT for p16+ and p16- respectively, was 3.5 vs. 2.7 months, HR 0.507, p=0.039. No statistically significant difference was found in rwOS (19.3 vs. 24 months, HR 1.8, p=0.27) or TOT (3.7 vs. 4.1 months, HR 0.78, p=0.38) between p16+ and p16- OPSCC groups treated with ICIs, respectively. Conclusions: P16+ non-OP HNSCC patients receiving ICIs were found to remain on treatment longer compared to p16- patients which was not reproduced in the OPSCC subgroup. Randomized controlled trials are needed to verify p16 as a prognostic marker for ICI therapy.[Table: see text

Molecular profiling and survival outcomes of p16+ compared to p16- oropharynx squamous cell cancer patients

e18026 Background: Previous studies have consistently shown that p16+ oropharynx squamous cell cancer (OPSCC) patients have better outcomes. The significance of molecular and transcriptional signatures and its correlation with p16 expression remains unclear. Methods: We queried the Caris Life Sciences database to assess the molecular and transcriptional signatures related to p16+ and p16- head and neck squamous cell cancer (HNSCC) patients. Comprehensive molecular profiling including whole exome sequencing (WES), targeted Next-Generation Sequencing (NGS), and immunohistochemistry (IHC) 22c3 for PD-L1 was performed (CPS ≥1 considered positive) (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations. A standard cut-off of 2+, > 70% p16 staining was used. HPV16/18 was tested using WES. Patients were considered smokers if they had > 15 pack-years. Real world overall survival (rwOS) was obtained from insurance claims data and Kaplan-Meier estimates were calculated from the date of start of treatment to the date of last contact. Results: 948 cases of OPSCC were identified in the Caris database. 41% (82/199) were smokers. Where p16 and HPV data was available, 41% were p16+ (171/420) while HPV positivity rate was 52% (71/148). We noted a small number of patients with discordant p16 and HPV status (7 p16+/HPV-, 8 p16-/HPV+) in 327 patients who had HPV status available. Most common mutations were TP53 (33%), PIK3CA (17%) and KMT2D (10.6%). 87% were PD-L1 positive (342/394), with high expression in both p16+ and p16- subgroups, 90% and 85% respectively. 10% had TMB≥10/Mb (48/463). TP53 mutations were more common in p16- (49%) tumors in contrast to p16+ (10%) (p < 0.0005), while no statistical difference was detected in TMB≥10/Mb between the groups. CDKN2A, TERT and NOTCH1 mutations were more prevalent in tumors that were p16- or HPV- in contrast to tumors that were p16+ or HPV+ (p < 0.05). FGF3, CCND1, FGF4, FGF19 copy number alterations (CNA) were less common in p16+ OPSCC compared to p16- or HPV16- OPSCC (p < 0.0005). P16+ patients had longer rwOS when compared to p16-, 47 months versus 20 months (HR = 0.55, p = 0.014) respectively. Conclusions: Higher frequency of CDKN2A, TERT and NOTCH1 mutations among p16- (versus p16+) raise the possibility of potential targets for treatment in this group with poor prognosis. However, it remains unclear if these can serve as independent predictors of survival.[Table: see text

Treatment outcomes of recurrent and metastatic adenoid cystic carcinoma: A retrospective analysis

e18056 Background: Adenoid cystic carcinoma (ACC) is a rare malignancy of glandular tissue with a high rate of local recurrence and metastatic disease. Despite being regarded as an indolent disease, the clinical course of recurrent and metastatic ACC (R/M ACC) is highly variable. Responses to chemotherapy (chemo) are uniformly poor. Several multi-targeted tyrosine-kinase inhibitors (mTKIs), EGFR inhibitors (EGFRi) and other targeted agents have been studied in single-arm early phase trials with response rates ranging from 0-16% and progression free survival ranging from 2.5-17 months. However, there have been no comparative clinical trials and it is not known if one treatment strategy is superior. We undertook this retrospective study to assess the real-world clinical outcomes in patients with adenoid cystic carcinoma using the Caris Life Sciences database. Methods: Real world overall survival (rwOS) for cases of ACC was obtained from insurance claims data and Kaplan-Meier estimates were calculated from the date of collection to the date of last contact. Cases were divided into subgroups based on treatment received – chemo (including platinum agents, taxanes, 5FU, topoisomerase inhibitors, anthracyclines), EGFRi (cetuximab, erlotinib, lapatinib), mTKIs (pazopanib, axitinib, sunitinib, cabozantinib, lenvatinib, sorafenib) and immune checkpoint inhibitors (ICIs) (atezolizumab, ipilimumab, pembrolizumab, nivolumab). Results: 368 patients (pts) were identified with ACC, 16 were locally recurrent and 216 tumors were taken from metastatic sites. 50 pts received chemo, 6 were treated with EGFRi and 15 with mTKIs. Pts who received combination EGFRi and chemo or mTKI and chemo were excluded. The median overall survival (mOS) all patients with metastatic ACC was 2.8 years (yrs). The mOS of pts with R/M ACC was 3 yrs for chemo, 2.9 yrs for EGFRi and 1.5 yrs for mTKIs. There was no significance in mOS between chemo vs mTKIs (HR 0.85, 95% CI 0.3 - 2, p = 0.72) and chemo vs EGFRi (HR = 0.88, 95% CI 0.3 - 2.5, p = 0.78). We further compared the outcomes of those treated with EGFRi (n = 8) with mTKIs (n = 19) in the entire cohort. For most pts, these agents were given as front line therapy. 25% (2/8) of patients had received treatment prior to EGFRi and 20% (4/9) prior to mTKIs (p = 1). There was no significant difference in mOS with HR 0.6 (95% CI 0.16 - 2.6), p = 0.6. We also compared the mOS of patients who received ICIs (n = 22) with those who did not (n = 346) but there was no significant difference (mOS 3.19 vs 3.17 yrs respectively, HR 0.87, 95% CI 0.47- 1.61, p = 0.65). Conclusions: There was no significant difference in the mOS between pts with R/M ACC who were treated with chemo, EGFRi or TKIs and in those who received ICIs compared to those who did not in our limited patient population. This highlights the need for predictive biomarkers for better patient selection with the goal of personalizing treatment strategies for this disease

Comprehensive genomic profiling and immune characterization of adenoid cystic carcinoma

e18050 Background: Adenoid cystic carcinoma (ACC) is a rare malignancy of glandular tissue with a high rate of local recurrence and metastatic disease for which clinical behavior varies widely. Currently, no standard therapy exists, and available therapies have low response rates. Therefore, prognostic biomarkers to determine optimal treatment strategies are urgently needed. Here we investigate the molecular landscape and therapeutic targets of ACC. Methods: ACC samples were analyzed using next generation sequencing (NGS) (NextSeq, 592 gene panel) or whole exome sequencing (NovaSeq) (Caris Life Sciences, Phoenix, AZ). Pathogenic fusion events were detected using whole transcriptome sequencing (NovaSeq). Statistical significance was determined using the Chi-square test and adjusted for multiple comparisons. Tumor infiltrating Immune cell fractions were determined using the QuanTIseq deconvolution algorithm and WTS data. Results: 327 ACC patients were identified, median age of 58 years, 62% female and 62% metastatic disease. The most frequent mutations (excluding indeterminate results) involved genes in the NOTCH pathway ( NOTCH1 16% [41 of 298 cases]), chromatin remodeling ( ARID1A 24.3% [27 of 138 cases], KDM6A 12.5% [28 of 224 cases], KMT2C 10.7% [21 of 197 cases]) and TP53 10.2% (25 of 246 cases). Chromatin remodeling genes were co-mutated with NOTCH1. NOTCH1 mutations were found in 41 cases, 18 primary and 23 metastatic were associated with reduced median overall survival (mOS 1.8 years vs 3.8 years, p = 0.01). Mutations were most frequent in the PEST (n = 35), NRR (n = 18), PEST+NRR (n = 16) and EGF-like domains (n = 11). PEST domain mutations were found exclusively in ACC originating from the head and neck (H&N). GSEA showed that MYC, E2F and G2M target pathways were enriched in NOTCH1 mutated ACC regardless of the presence of MYB fusions. All three pathways were enriched in PEST domain mutations whereas only MYC targets were enriched in NRR and NRR+PEST domain mutations indicating that PEST domain mutations drive transcriptomic changes in NOTCH1 mutated ACC. MYC gene expression was significantly upregulated in NOTCH1 mutated ACC. Fusion events were detected in 45% (104/231). MYB:NFIB was the most common fusion (40%) and was more frequent in H&N origin than other sites. There was no difference in the mOS between MYB fusion positive and negative ACC (4.4 years vs 5.5 years, p = 0.14). M2-polarized macrophages, myeloid dendritic cells and neutrophils were significantly higher in metastatic compared to primary ACC while NK cells were more abundant in primary tumor. Conclusions: ACC is a genetically heterogenous disease with an immune-excluded microenvironment. NOTCH1 mutations were associated with worse, while MYB:NFIB fusion was not associated with prognosis. Our study shows that M2 macrophages and MYC are potential novel therapeutic targets in ACC

Interplay of immunosuppression and immunotherapy among patients with cancer and COVID-19

Importance: Cytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation. Objective: To determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer. Design, setting, and participants: This registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings. Exposures: Immunosuppression due to therapy; systemic anticancer therapy (IO or non-IO). Main outcomes and measures: The primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm. Results: The median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79). Conclusions and relevance: This cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm. Trial registration: ClinicalTrials.gov Identifier: NCT04354701