Citations

Abstract Optimal treatment of chronic lymphocytic leukemia (CLL) remains unclear. The Connect CLL Registry, a United States–based multicenter prospective observational cohort study, enrolled 1494 patients between 2010 and 2014 from predominantly community-based settings. Patients were grouped by line of therapy (LOT) at enrollment. With a median follow-up of 46.6 months (range, 0-63.0 months), median overall survival (OS) was not reached in LOT1, 63.0 months (95% confidence interval [CI], 46.0-63.0 months) in LOT2, and 38.0 months (95% CI, 33.0-47.0 months) in LOT≥3. Bendamustine and rituximab (BR; 33.5%); fludarabine, cyclophosphamide, and rituximab (FCR; 21.4%); and rituximab monotherapy (18.5%) were the most common regimens across LOTs. Median event-free survival (EFS) was similar in patients treated with BR (59.0 months) and FCR (55.0 months) in LOT1; median OS was not reached. In multivariable analysis, BR or FCR vs other treatments in LOT1 was associated with improved EFS (hazard ratio [HR], 0.60; P < .0001) and OS (0.67; P = .0162). Using the Kaplan-Meier product limit, ibrutinib vs other treatments improved OS in LOT2 (HR, 0.279; P = .009), LOT3 (0.441; P = .011), and LOT≥4 (0.578; P = .043). Prognostic modeling of death at 2 years postenrollment identified 3 risk groups: low (mortality rate, 6.2%), medium (14.5%), and high (27.4%). The most frequent adverse events across LOTs were pneumonia (11.6%) and febrile neutropenia (6.2%). These data suggest that advantages of LOT1 FCR over BR seen in clinical trials may not translate to community practice, whereas receiving novel LOT2 agents improved outcomes. This trial was registered at www.clinicaltrials.gov as NCT01081015.

Abstract Magnetic resonance guided high intensity focused ultrasound is a novel, non-invasive, image-guided procedure that is able to ablate intracranial tissue with submillimetre precision. It is currently FDA approved for essential tremor and tremor dominant Parkinson’s disease. The aim of this update is to review the limitations of current landmark-based targeting techniques of the ventral intermediate nucleus and demonstrate the role of emerging imaging techniques that are relevant for both magnetic resonance guided high intensity focused ultrasound and deep brain stimulation. A significant limitation of standard MRI sequences is that the ventral intermediate nucleus, dentatorubrothalamic tract, and other deep brain nuclei cannot be clearly identified. This paper provides original, annotated images demarcating the ventral intermediate nucleus, dentatorubrothalamic tract, and other deep brain nuclei on advanced MRI sequences such as fast grey matter acquisition T1 inversion recovery, quantitative susceptibility mapping, susceptibility weighted imaging, and diffusion tensor imaging tractography. Additionally, the paper reviews clinical efficacy of targeting with these novel MRI techniques when compared to current established landmark-based targeting techniques. The paper has widespread applicability to both deep brain stimulation and magnetic resonance guided high intensity focused ultrasound.

7519 Background: Acalabrutinib, a highly selective, potent, covalent Bruton tyrosine kinase (BTK) inhibitor, has a 24% overall response rate (ORR) as a single agent in R/R DLBCL. Pem targets PD-1, an immune checkpoint that limits anticancer responses. Pem showed responses in patients (pts) with Richter transformation who failed ibrutinib and can augment acalabrutinib activity in vitro. This study assessed acalabrutinib + Pem in R/R DLBCL. Methods: Pts with DLBCL, ≥1 prior chemoimmunotherapy and no prior allogeneic transplant received acalabrutinib 100 mg PO BID until progressive disease (PD) + Pem 200 mg/kg IV Q3W up to 2 y. Germinal center B-cell (GCB) vs non-GCB subtype was assessed by immunohistochemistry. Primary endpoint was safety. Results: Sixty-one pts (30 GCB; 31 non-GCB) were accrued, with a median age (range) of 67 y (30-85) and a median of 3 (1-8) prior therapies; 1 pt had prior autologous transplant. The most common Gr 3/4 adverse events (AEs) were neutropenia (15%) and anemia (11%). Gr 5 AEs were respiratory failure (n=3), sepsis, septic shock and abdominal abscess (n=1 each). All Gr atrial fibrillation was 5% (n=3), and major hemorrhage (≥ Gr 3) was 11% (4 gastrointestinal, 1 pulmonary, 1 epistaxis, 1 hematuria). Gr 3/4 immune-mediated events were elevated alanine aminotransferase (n=4), pneumonitis (n=2) and colitis (n=1). The ORR was 26% (Table) and was similar in GCB (27%) and non-GCB (26%) tumors. The median time on study was 5.2 mo (0.4-30.4+). Acalabrutinib/Pem discontinuations were due to PD (62%/56%) and AEs (15%/26%). As of June 2018, 10 pts remain on study; 6 on active therapy and 7 without PD. Conclusions: Acalabrutinib + Pem was well tolerated, with meaningful activity and some exceptional responders (>24 mo) in these R/R DLBCL pts. Randomized trials of the combination vs single agent are needed. Clinical trial information: NCT02362035. [Table: see text]

7545 Background: Interpretation of lung cancer clinical trials is complicated by the heterogeneity of the patient population due to disease burden and comorbidities making pre-trial assessment of OS probability challenging. Methods: To create and validate a scoring system to estimate OS and improve the quality of future trials, this study evaluated the pretreatment prognostic factors of 2,442 pts with NSCLC. Univariate (UV) and multivariate (MV) Cox models were used to evaluate the prognostic importance of each baseline factor on OS. Those prognostic factors significant on both UV and MV analyses that were used to develop the scoring system included overall quality of life, age, sex, stage, ECOG performance status, the presence of other cancers, and smoking cessation. The score for each factor was determined by dividing the 5-year OS rate (in %) by 10 and summing these scores to form a total score. Multivariate models and the score for each factor were validated using bootstrapping with 1000 iterations from the original samples. Results: The score for each factor ranged from 1 to 7 points and the total scores ranged between 23 and 39 points. Higher scores reflected better OS. Categorization of the score was delineated first by clinician expert opinion (see Table) and then by multiple statistically defined empirical cut points. All categorization schemes demonstrated successful prognostic power. The bootstrap method confirmed the reliability of multivariate Cox model and score (Spearman correlation coefficient= 0.45). Conclusions: Prognostic factors significantly associated with OS on both UV and MV analysis were used to construct a valid scoring system which can be used to predict survival of NSCLC pts. This scoring system can be used by clinicians in counseling pts and for stratification in future trial design. [Table: see text]

7501 Background: The first objective of RTOG 0617 was to compare the overall survival(OS) of patients(pts) treated with standard-dose(SD)(60Gy) versus high-dose(HD)(74Gy) radiotherapy with concurrent chemotherapy(CT). Methods: This Phase III Intergroup trial randomized 464 pts with Stage III NSCLC to the SD(60Gy) vs. HD(74Gy) arms prior to closure of the HD arm. Concurrent CT included weekly paclitaxel(45 mg/m2) and carboplatin(AUC=2). Pts randomized to cetuximab received a 400 mg/m2 loading dose on Day 1 followed by weekly doses of 250 mg/m2. All pts were to receive consolidation CT. We are reporting the final results on radiation dose. Results: 464 pts were accrued prior to closure of the HD arm in 6/11, of which 419 were eligible for analysis. Median follow up was 17.2 months. There were 2 and 10 grade 5 treatment-related adverse events(AEs) on the SD and HD arms, respectively. Grade 3+AEs were 74.2% and 78.2% on SD and HD arms, respectively (p=0.34). The median survival times and 18-month OS rates for the SD and HD arms were 28.7 vs 19.5 months, and 66.9% vs 53.9% respectively (p=0.0007). The primary cause of death was lung cancer (72.2% vs 73.5%)(p=0.84). Local failure rates at 18 months were 25.1% vs 34.3% for SD and HD patients, respectively(p=0.03). Local-regional and distant failures at 18 months were 35.3% vs 44%(p=0.04) and 42.4% vs 47.8%(p=0.16) for SD and HD arms, respectively. Factors predictive of less favorable OS on multivariate analysis were higher radiation dose, higher esophagitis/dysphagia grade, greater gross tumor volume, and heart volume >5 Gy. Conclusions: In this setting of chemoradiation for locally-advanced Stage III NSCLC, 60 Gy is superior to 74 Gy in terms of OS and local-regional control. The effect of the anti-EGFR antibody (cetuximab) awaits further follow up. This project was supported by RTOG grant U10 CA21661, CCOP grant U10 CA37422, and ATC U24 CA 81647 from the National Cancer Institute (NCI) and Eli Lilly and Company. Clinical trial information: NCT00533949.

7086 Background: The HRQOL of patients (pts) with chronic lymphocytic leukemia (CLL) has not been adequately delineated across patient, disease and treatment characteristics. We evaluated HRQOL of CLL pts undergoing treatment in the United States (US) by age, gender and line of therapy. Methods: Data were collected in Connect CLL, a prospective observational US registry. Physicians provided data on demographics, clinical characteristics and line of therapy at enrollment. HRQOL was self-reported by pts at enrollment using the Functional Assessment of Cancer Therapy-Leukemia, an instrument that yields a leukemia-specific total HRQOL score (FACT-Leu) and a cancer-specific total HRQOL score (FACT-G). Mean total scores were analyzed by line of therapy, age and gender. Statistical significance was ascertained by ANOVA using SAS 9.2. Multivariate analyses were conducted to assess the relative association of line of therapy, age and gender with HRQOL. Results: Among 1,252 pts enrolled from 161 geographically diverse centers (90% community, 8% academic, 2% veterans/military), pts were predominantly male (63%), white (89%) with mean age 69 yrs. Pts were categorized by line of therapy at enrollment: First 61%, Second 18%, Third 11%, Higher 9%; and by age group: <65 33%, 65-74 35%, 75+ 32%. Univariate analyses suggested that the total FACT-Leu score was significantly better in men than women (P=0.004); in pts aged 65-74 vs younger or older pts (P=0.033); and in pts initiating first-line treatment vs pts receiving subsequent treatments (P=0.0002). Similar results were found with the FACT-G score except that gender differences were not statistically significant. Multivariate analysis confirmed that line of therapy (P=0.007), gender (P<0.0001), and age group (P=0.039) were each associated with significant differences in the FACT-Leu total score. Conclusions: Results from the Connect CLL Registry indicate that HRQOL is better among pts initiating first-line therapy compared to pts initiating subsequent treatments, and that this remains true when age and gender are considered. Future analyses should determine how HRQOL may change over time relative to treatment and treatment response.

6587 Background: Recently the Patient-Reported Outcomes version of the CTCAE was developed to augment clinically graded adverse events with information reported directly by patients on clinical trials (Basch, 2009). The validation and potential application of PRO-CTCAE in phase I clinical trials are of great interest as toxicity is the primary endpoint. Methods: Selected PRO-CTCAE items (21 items measuring 12 symptomatic adverse events) corresponding to the major adverse events required to be graded clinically were collected in an ongoing phase I clinical trial of weekly cilengitide and paclitaxel in patients with advanced solid malignancies (NCT01276496). PRO-CTCAE was administered in a paper booklet by a clinical research associate prior to treatment on days 1, 8 and 15 of their regular visits. These PRO-CTCAE items were summarized descriptively in comparison to clinician-assessed CTCAE ver 4.0 (NCI, 2009) during the first cycle. As a pilot study to assess feasibility of PRO-CTCAE in phase I trials, PRO-CTCAE was not intended for determination of dose-limiting toxicity. Results: Twelve patients were accrued to two separate doses of cilengitide and paclitaxel. The median age was 56 (range 36—67) and half of patients were female. All patients had an ECOG performance score <= 1. Over 90% of patients had received prior surgery and chemotherapy. All but one patient completed weekly PRO-CTCAE during the first cycle, the only patient refused to complete weeks 2 and 3 did not give a reason. PRO-CTCAE captured most of the symptomatic adverse events reflected in clinician-assessed CTCAE. Some symptomatic adverse events were not reported clinically by CTCAE but were reported by patients by PRO-CTCAE. Overall, PRO-CTCAE items indicated slightly more severe degree of symptoms experienced by patients than those reported in CTCAE. Conclusions: This is the first study that PRO-CTCAE items were integrated within regular study visits in a phase I trial. The administration of PRO-CTCAE has been proved feasible and fruitful, providing consistent and enhanced symptomatic toxicity from the patient point of view. The addition of PRO-CTCAE did not significantly increase patient burden. Clinical trial information: NCT01276496.