Citations

Key Points A mixed methods study of surveys, interviews, and focus groups raises concerns about the state of the adult hematology workforce. Hematology/oncology fellowship program directors, fellows, and practicing clinicians offer different strategies to address these problems.

Abstract Introduction: CLL pts who qualify for participation in clinical trials are often thought of as a highly selected population. Therefore whether safety and efficacy data from these trials can be generalized to all CLL pts treated in the community setting is unknown. Prospective, observational studies can provide significant insight into pt and disease characteristics as well as practice patterns in different clinical settings. Here we report on baseline demographics and clinical characteristics for 1495 pts who participated in the Connect CLL observational study and were followed prospectively. Methods: Connect®CLL is a non study-specific intervention treatment registry which collects data on the management and outcomes of CLL pts in clinical, academic and community practices in the US. Clinical information was prospectively collected for pts treated in community (n=1312), academic (n=155), or government (n=28) centers in the US between March 2010 – Jan 2014. Pts eligible for treatment or on treatment not more than 2 months were eligible for enrollment. Here we report on the baseline demographics and clinical characteristics of a large CLL cohort stratified by AG, LOT and type of treatment center. Results: In total,1,495 pts were accrued with a median age at enrollment of 69 (range 22–99). Pts were Caucasian (92.2%), African American (6.9%), and male (63.7%). Median duration from diagnosis until initial therapy was 3.7 years (range 0-32). Age of enrolled pts was as follows; 527 pts age <65 years (AG1; 35%); 511 age 65–75 (AG2; 34%); and 457 age ≥75 (AG3; 31%) at the time of enrollment. Eight hundred and ninety-four pts (60%) were treated with front-line therapy (LOT1); 259 pts (17%) treated with second-line therapy (LOT2); and 342 pts (23%) treated beyond second-line therapy (LOT≥3). Patient age: Pt age was associated with significant variation in several clinical variables: Charlson comorbidity index (CCI) score ≥3 (AG 1-3 35/46/52%; p<0.0001), ECOG PS = 0 (AG1-3 60, 48, 33%, p<0.0001) and mean creatinine clearance (CrCl) decreased (AG 1-3 101/74/53 mL/min; p<0.0001). Line of therapy: Differences in baseline characteristics were observed between pts enrolled at LOT1 (previously untreated) and LOT2/≥3 (relapsed). Median age of pts accrued at LOT1 was 68 vs. 70 years for pts enrolled at LOT2/≥3 (p=0.007). ECOG PS = 0 was more frequent at LOT1 (50%) vs. LOT2/≥3 (42%) (p=0.0057). CCI ≥3 at LOT1 was 41% vs 48% at LOT2/≥3 (p=0.0072). When adjusted for differences in age, logistic regression also demonstrated significant differences in performance status (PS=0; p=0.02) and CCI (p=0.03) stratified by LOT. Treating institution: Baseline characteristics also differed by type of treating institution. Median age was 63 vs 70 at academic vs non-academic (p<0.0001). Pts treated at academic sites also had lower CCI (CCI≤2; 72.9% vs 54.2%, academic vs non-academic) and higher median CrCl (86.4 vs 71.4) (p=0.0017). In this registry, only 16% of patients under age 75 had CCI <= 2, CrCl >= 70 mL/min, ECOG 0-1; 18% of patients on LOT1 and 12% of pts on LOT=2 would satisfy these criteria. They represent 36% of eligible pts from academic treating institutions and 13% from community/government centers. Only 20% of patients on LOT1 would satisfy enrollment criteria for CLL8 (FCR vs. FC; Hallek; Lancet 2010) CLL 10 (BR vs FCR; NCT00769522). which did not have enrollment restrictions for age. Conclusions:Baseline characteristics of pts with CLL vary by age, LOT, and type of treatment center. In this large prospective observational study, our data confirms that older pts typically have a worse ECOG PS, more medical comorbidities, more advanced disease when initiating therapy and a lower probability of being treated at an academic medical center. Based on inclusion criteria used for entry in either CLL10 or CLL8, fewer than 20% of pts satisfy age, renal clearance, and fitness profile to be considered suitable for aggressive chemoimmunotherapy in the front line setting. This observation supports the notion that current clinical trial data might not always be applicable to the general CLL population seen in the community and argues for designing clinical trials that are more generalizable to the broader pt population. Disclosures Sharman: Gilead: Research Funding; Calistoga: Honoraria; Phamacyclics: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; TG therapeutics: Research Funding; Roche: Research Funding. Mato:Millennium: Speakers Bureau; Celgene: Speakers Bureau; Genentech: Speakers Bureau. Kay:Celgene: Research Funding. Kipps:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lamanna:Genentech-Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weiss:Celgene: Consultancy; Phamacyclics: Consultancy; Gilead: Consultancy. Nabhan:Celgene: Honoraria, Research Funding. Flinn:Celgene: Research Funding. Grinblatt:Celgene: Honoraria, Speakers Bureau. Kozloff:Celgene: Consultancy. Farber:Alexion: Equity Ownership, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau; Janssen/Pharmacyclics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees. Sullivan:Celgene: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Swern:Celgene: Employment, Equity Ownership. Flowers:TG Therapeutics: Research Funding; Phamacyclics: Research Funding; Acerta: Research Funding; Abbvie: Research Funding; Infinity: Research Funding; Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Spectrum: Research Funding; Gilead: Research Funding; Genentech: Unpaid consultancy Other; Millennium: Research Funding, Unpaid consultancy, Unpaid consultancy Other; Seattle Genetics: Consultancy; Prescription Solutions: Consultancy; Celgene: Unpaid consultancy Other.

Mentorship Experiences Among Second-Year U.S. Hematology/Oncology Fellows in the 2019 ASH Hematology/Oncology Fellows Survey Introduction: The majority of fellows graduating from U.S. hematology/oncology training programs pursue careers incorporating both fields, albeit with a greater focus on medical oncology than on hematology. Over the past 15 years, the number of physicians in the U.S. identifying as hematologists or seeking certification in hematology has been dwarfed by those identifying as medical oncologists or seeking oncology certification, with only a small percentage of fellows having a primary interest in benign hematology. In response to these concerns, in 2017 the American Society of Hematology (ASH) launched a multiyear study of the U.S. hematology workforce in clinical practice, research, and training in collaboration with the Fitzhugh Mullan Institute for Health Workforce Equity at the George Washington (GW) University. The initial phase of the ASH workforce study was a survey of over 1800 hematology/oncology fellows conducted in 2018, which identified clinical exposure to hematology during training, research experiences, and mentorship to all be positively and strongly associated with career interest in hematology. A follow-up survey of second-year hematology/oncology fellows was competed in 2019, focusing on career interests, mentorship, and job expectations. The present study reports findings of second-year fellows' perceptions regarding mentorship. Methods: The 2019 Hematology/Oncology Fellows Survey was developed by ASH and GW investigators. Survey questions asked about fellows' career and research interests, clinical exposure during training, mentorship, and perceptions of job security and availability after fellowship. Mentorship questions focused on specific mentorship activities (e.g., coauthoring papers, participating in research projects, developing networking, career advice), perceived mentorship needs, and overall satisfaction with mentorship. The survey was pilot-tested in a small group of second-year hematology/oncology fellows. The final survey was sent electronically to second-year fellows in U.S. hematology/oncology fellowship programs (n = 735) in the spring of 2019 using Qualtrics. Descriptive analyses were performed using Stata 15. Results: Among 212 second-year fellows with complete responses (28.8% response rate), 5.2% declared a primary interest in benign hematology, 20.8% malignant hematology, 30.7% solid tumor oncology, and the remainder some combination of hematology and oncology. The vast majority of survey respondents (83.3%) intended to dual board in hematology and oncology. About one-third (31.9%) reported having a new or continuing mentor in benign hematology during their second year of fellowship, compared to 51.2% in malignant hematology and 60.8% in solid tumor oncology. Less than half of all fellows (45.4%) indicated that their training program had a formal mentorship program. When asked to indicate domains where they wanted more support from mentors, second-year fellows prioritized career development strategies (69.9%), job options (43.7%), optimizing fellowship experiences (41.3%), manuscript review prior to submission (19.4%), clinical trial design review (17.5%), and grant review prior to submission (17.5%). The vast majority of fellows expressed a definite (69.7%) or possible (8.7%) interest in interacting with a mentor virtually via Facebook, Skype, email, or other media if in-person mentorship meetings were not an option. Conclusions: Second-year hematology/oncology fellows in the U.S. reported a wide range of mentorship needs and interests. Most second-year fellows believe they could use more advice from mentors about career development strategies. Few fellows have a primary interest in benign hematology, and the percentage of fellows who report having mentors in benign hematology is lower than malignant hematology or solid tumor oncology. The vast majority of fellows are interested in virtual mentorship if local mentorship is not available. Further expansion of existing mentorship systems and the development of new mentorship models including virtual mentorship may improve the mentorship experience for fellows. Disclosures Connell: Michael H. Flanagan Foundation: Membership on an entity's Board of Directors or advisory committees.

Abstract Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Abstract Patients with glioblastoma (GBM) have a median survival of 15 months despite aggressive treatment. Immunotherapies such as dendritic cell (DC) vaccines have modest clinical efficacy in small clinical trials. Treatment-related pseudo-progression confounds outcome assessment by MRI, particularly in patients receiving immunotherapy. Thus, there is a need for additional non-invasive methods to monitor treatment response. Extracellular vesicles (EVs), especially plasma exosomes, contain tumor-specific microRNA (miRNA) cargo that could serve as a liquid biopsy to distinguish true progression from treatment-related pseudo-progression. Plasma exosomes were isolated by serial density gradient ultracentrifugation from 20 newly diagnosed GBM patients enrolled in a clinical trial of allogeneic tumor lysate-pulsed autologous DC vaccination. Short non-coding RNA sequencing and bioinformatics analysis was performed for each patient at three time points (TP): pre-vaccine (TP1), post-initial vaccine (TP2), and at end of treatment (TP3). miRNA expression analysis revealed a total of 14 upregulated and 12 downregulated miRNAs across time points (p-value < 0.05, |logFC| >1), few of which have been previously reported to be differentially expressed in GBM. Interestingly, patients’ miRNA profile expression differed more at the beginning of treatment (e.g. TP1-vs-TP2) and at subsequent time points (e.g. TP2-vs-TP3). Ingenuity Pathway Analysis is in progress to identify pathways associated with immunotherapy treatment response in malignant gliomas. In conclusion, miRNA sequencing from GBM patients’ plasma exosomes enrolled in our DC clinical trial shows marked differential miRNA expression between time points. These results suggest that as patients progress through treatment, consistent differences in plasma exosomal miRNA expression profile can be identified that could be utilized as predictors of treatment response. Thus, plasma EVs may serve as a robust platform to monitor treatment outcome.

Abstract Central nervous system hemangioblastoma (CNS HGB) is a rare neoplasm. Sporadic and von-Hippel Lindau (VHL)-associated forms exist. Predicting tumor growth is difficult, making the indication for intervention challenging. A retrospective analysis of consecutive, neurosurgically managed CNS HGB at Mayo Clinic spanning 1988–2018 was performed to clarify their characteristics. 117 sporadic and 67 VHL HGBs were reviewed. 9 sporadic lesions (8 cases) and 80 VHL lesions (35 cases) had tumor size data at ≥4 follow-up time-points beyond 1 year. The median follow-up was 8.0 years. No statistical difference existed between sporadic and VHL lesions regarding growth speed or growth latency (period of time without growth). Symptomatic lesions showed faster growth than asymptomatic lesions (2.79 vs 0.59 cm3/month, p=0.005). Solid and cystic portions often showed different growth patterns in cases harboring both (66.7%). Cyst growth was faster than solid portions (1.22 vs 1.05cm3/month, p=0.009) and growth latency was longer in the latter (15.2 vs 18.5%, p=0.25). Lesions’ growth were classified as linear (7), exponential (49), cubic (regressed to cubic function curve, 7), saltatory (19) and no-growth (7) patterns. Growth latency often existed in growing lesions (27-out-of-64 linear/exponential/cubic lesions, 57.8%), being average 8.3% of follow-up time. Contrarily, although saltatory lesions grew slower than exponential lesions (p=0.03), their overall growth speed was comparable to linear/cubic lesions (0.67cm3/month), and 9-out-of-19 showed growth surges at their ends. Growth speed at each follow-up roughly depended on the tumor size in cubic regression (R2=0.52). However, whereas total 18/821 time-point lesions showed rapid growth (≥1cm3/m, 2.2%), relatively small lesions (≤2cm3) also occasionally showed rapid growth (5/687, 0.73%). Not all large (>5cm3) lesions grew rapidly (8/62, 12.9%). These results revealed while symptomatic/large/cystic lesions tend to grow more rapidly, HGB behavior is difficult to predict, which stresses the importance of careful follow-up.

Abstract BACKGROUND Treatment of temporal lobe glioma (TLG) frequently includes partial or complete temporal lobectomy (TL) followed by radiotherapy (RT). However, there are two approaches for temporal resection cavity RT, 1) standard target volumes (STV) targeting the entire TL resection cavity, dura, and peri-tumoral brain parenchyma or 2) modified target volumes (MTV) targeting only the adjacent peri-tumoral brain parenchyma. We report patterns of failure and a dosimetric comparison of these approaches. MATERIALS AND METHODS This was a retrospective review of 49 patients with WHO grade II-IV TLG who underwent partial or complete TL and post-operative RT between 1998 and 2018. Progression-free survival (PFS) was estimated using the Kaplan-Meier method. RESULTS The median patient age was 56 years (range,21–76). Patients were diagnosed with glioblastoma (n=32,65%), anaplastic glioma (n=10,20%) and low-grade glioma (n=7,14%). Treatment included partial TL with STV (n=33,67%), partial TL with MTV (n=5,10%), complete TL with STV (n=8,16%) and complete TL with MTV (n=3,6%). Mean RT dose was 60 Gy (range,40–76) in 30 fractions (range,15–39). At median follow-up time of 18 months (range, 3–161), 44 patients (90%) experienced recurrence: 34 (77%) in-field, 5 (11%) out-of-field, and 5 (11%) both in- and out-of-field. Among the 39 in-field failures, the location of recurrence included brain parenchyma (n=38,97%), ventricle (n=6,15%), and dura (n=5,13%). No patient experienced isolated dural recurrence regardless of tumor grade, extent of TL, or radiation volume. Median PFS was 20 months (95% confidence interval [CI]: 15–24). RT volume (STV vs. MTV) was not associated with worsened PFS (hazard ratio: 1.1, 95% CI: 0.5–2.6). MTV was associated with significant reductions in mean or max doses to brain stem, optic chiasm, optic nerves, hippocampus, and pituitary compared to STV. CONCLUSION Omitting RT to the entire TL cavity may reduce dose to multiple normal tissues with no detriments in dural recurrence or PFS.

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Median survival is 15 months despite surgery, radiation, and chemotherapy. Immunotherapy is promising but GBM-mediated immunosuppression remains a barrier. Recently, extracellular vesicles (EVs) have been implicated in GBM-mediated immunosuppression through expression of the immune checkpoint molecule PD-L1. Data from our group has suggested this is predominantly through induction of immunosuppressive monocytes including myeloid-derived suppressor cells (MDSCs) and non-classical monocytes (NCMs). PD-L1 expression is increased in most nucleated cells following IFN-γ exposure. We, therefore, sought to determine if IFN-γ exposure would result in super-induction of immunosuppressive GBM EVs. EVs were harvested in vitro from matched differentiated and stem-like human GBM cell lines +/- IFN-γ. IFN-γ exposure did not alter EV production or expression of common EV markers but increased PD-L1 expression in EVs from differentiated but not stem-like GBM cells. In keeping with our earlier findings, no direct inhibition of T cell proliferation by stem-like or differentiated GBM EVs was observed regardless of IFN-γ exposure or PD-L1 expression. In contrast, differentiated but not stem-like GBM cell EVs induced MDSC and NCM differentiation from normal monocytes. This was increased following IFN-γ exposure and was dependent upon PD-L1 expression. Monocytes exposed to differentiated but not stem-like GBM cell EVs inhibited T cell proliferation in a similar manner (increased with IFN-γ exposure, decreased with PD-L1 knockdown). Thus, IFN-γ exposure results in super-induction of immunosuppressive EVs from differentiated but not stem-like GBM cells that increase MDSC and NCM differentiation in normal monocytes and increase their ability to inhibit T cell proliferation. These effects are dependent upon PD-L1 up-regulation induced by IFN-γ. This may be an important mechanism GBMs utilize to suppress anti-tumor T cell responses that are typically accompanied by increased IFN-γ expression.