Paludo, Jonas

Abstract The treatment of patients with Bing-Neel syndrome (BNS) is not standardized. We included patients with Waldenström macroglobulinemia (WM) and a radiologic and/or cytologic diagnosis of BNS treated with ibrutinib monotherapy. Response assessment was based on criteria for BNS from the 8th International Workshop for WM. Survival from BNS diagnosis (BNS survival), survival from ibrutinib initiation to last follow-up or death (ibrutinib survival), and time from ibrutinib initiation to ibrutinib discontinuation for toxicity, progression, or death (event-free survival [EFS]) were estimated. Twenty-eight patients were included in our study. The median age at BNS diagnosis was 65 years. Ibrutinib was the first line of treatment for BNS in 39% of patients. Ibrutinib was administered orally at a dose of 560 and 420 mg once daily in 46% and 54% of patients, respectively; symptomatic and radiologic improvements were seen in 85% and 60% of patients within 3 months of therapy. At best response, 85% of patients had improvement or resolution of BNS symptoms, 83% had improvement or resolution of radiologic abnormalities, and 47% had cleared the disease in the cerebrospinal fluid. The 2-year EFS rate with ibrutinib was 80% (95% confidence interval [CI], 58%-91%), the 2-year ibrutinib survival rate was 81% (95% CI, 49%-94%), and the 5-year BNS survival rate was 86% (95% CI, 63%-95%). Ibrutinib therapy is effective in patients with BNS and should be considered as a treatment option in these patients.

Abstract Background Early phase clinical trials evaluate the safety and efficacy of new treatments. The exclusion/inclusion criteria in these trials are usually rigorous and may exclude many patients seen in clinical practice. Our objective was to study the comorbidities limiting the participation of patients with breast, colorectal, or lung cancer in clinical trials. Materials and Methods We queried ClinicalTrials.gov on December 31, 2016. We reviewed the eligibility criteria of 1,103 trials. Logistic regression analyses were completed, and exclusion was studied as a binary variable. Results Out of 1,103 trials, 70 trials (6%) excluded patients >75 years of age, and 45% made no reference to age. Eighty-six percent of trials placed restrictions on patients with history of prior malignancies. Regarding central nervous system (CNS) metastasis, 416 trials (38%) excluded all patients with CNS metastasis, and 373 (34%) only allowed asymptomatic CNS metastasis. Regarding chronic viral infections, 347 trials (31%) excluded all patients with human immunodeficiency virus, and 228 trials (21%) excluded all patients with hepatitis B or C infection. On univariate analysis, chemotherapy trials were more likely to exclude patients with CNS metastasis and history of other malignancies than targeted therapy trials. Multivariate analysis demonstrated that industry-sponsored trials had higher odds of excluding patients with compromised liver function. Conclusion Many clinical trials excluded large segments of the population of patients with cancer. Frequent exclusion criteria included patients with CNS metastasis, history of prior malignancies, and chronic viral infections. The criteria for participation in some clinical trials may be overly restrictive and limit enrollment. Implications for Practice The results of this study revealed that most early phase clinic trials contain strict exclusion criteria, potentially excluding the patients who may be more likely to represent the population treated in clinical settings, leaving patients susceptible to unintended harm from inappropriate generalization of trial results. Careful liberalization of the inclusion/exclusion criteria in clinical trials will allow investigators to understand the benefits and drawbacks of the experimental drug for a broader population, and possibly improve recruitment of patients with cancer into clinical trials.

Key Points Cytokines in the BM microenvironment regulate PD-1 ligand expression and secretion in WM. Secreted PD-1 ligands modulate T-cell function in WM.

8034 Background: Multiple myeloma (MM), a monoclonal plasma cell disorder, is one of the most common hematologic malignancies in the US. In preclinical studies, metformin demonstrated plasma cells cytotoxicity. However, there is lack of studies translating the effect of metformin into the clinical setting. Therefore, we assessed the clinical effect of metformin in patients (pts) with MM. Methods: All MM pts who underwent stem cell transplant (SCT) at the Mayo Clinic Rochester from 2007 to 2012 were reviewed. Patients were grouped based on metformin use. Initial diagnosis at our institution and ≥12 months of follow up were required. Kaplan-Meier method and Cox regression were used for time-to-event and multivariate analysis. Results: Out of 687 pts, 78 (11.4%) were using metformin at the time of MM diagnosis. Baseline characteristics in the metformin (Mt) and no-metformin (NMt) groups were similar (Table). Median (M) metformin dose was 2000 mg daily and m duration of metformin use from MM diagnosis was 22 months. Pts on the Mt group achieved higher rates of CR after SCT (41% vs. 29%, p<0.02). Median PFS after SCT was longer in the Mt group, 31.3 months (95% CI: 10.4-52.2) vs. 16.6 months in the NMt group (95%CI: 14.5-18.7) p<0.04. There was a trend towards longer OS in the Mt group, but it was not statistically significant (170 vs. 106 months, p<0.10). In a multivariate analysis of metformin use, age, ISS, LDH, and cytogenetics/FISH, the former was an independent predictor of PFS after SCT (OR: 0.38, 95%CI: 0.20-0.68, p<0.001). Conclusions: Metformin use was associated with a better PFS and higher CR after SCT in our MM cohort. A trend towards better OS was also noted in the Mt group. Larger studies are needed to enhance our understanding of the clinic effect of metformin on MM. [Table: see text]

3558 Background: Anti-programmed death-1 (PD-1) antibodies have been shown to be effective in the treatment of dMMR CRC. We describe an updated analysis from a cohort of 19 patients (pts) with dMMR CRC treated with pembrolizumab. Methods: Pts were identified through review of the Mayo Clinic electronic medical record (EMR) and chemotherapy administration records from May 2015 through January 2017. All pts with dMMR CRC who received treatment with pembrolizumab were included. The EMR was reviewed to identify demographic, clinical, pathologic and treatment details. Overall survival (OS), progression free survival (PFS) and disease control rate (DCR = CR+PR+SD) are reported. Time to event analysis was calculated using the Kaplan-Meier method. Results: Nineteen pts were included in this analysis; median age at diagnosis was 48.6 years (range 25-93); 53% were female. Most primary tumors were right sided (n = 12; 63%), 6 (32%) were left sided and 1 (5%) was a tumor of unknown primary within the bowel. Twelve (63%) pts received ≥2 lines of therapy prior to pembrolizumab (range 1-4). Five pts received 2 mg/kg every 3 weeks, 11 received 200 mg/day every 3 weeks and 2 pts received 10 mg/kg (1 every 2 weeks, the other every 3 weeks). The most common alterations identified were loss of MLH1 (11/15) and PMS2 (12/15); 4 pts had germline mutations (mut) identified. KRAS mut was identified in 6/16 pts and 2 pts had BRAF mut. Three pts had MLH1 hypermethylation. Median number of cycles of pembrolizumab was 8 (range 1-35+), with 13 (68%) pts receiving ≥6 cycles. DCR at first assessment was 68%, with 5% CR, 47% PR and 16% SD. Median follow-up from diagnosis was 29 months (95% CI 18-42). Median OS was 103 months (95% CI 85-103); 12-month OS was 89%. Median OS from PD-1 therapy was 16.1 months (95% CI 16-NR); 12-month OS from PD-1 therapy was 79%. Median PFS was NR (95% CI 5-NR); 12-month PFS was 54%. At time of analysis, 9 pts remain on PD-1 therapy; 5 pts have died; 3 have received subsequent therapy. Conclusions: Anti-PD1 blockade with pembrolizumab can provide long lasting benefit in dMMR mCRC, even in heavily pretreated pts.

2533 Background: Many cancer clinical trials (CT) lack appropriate representation of specific patients populations, limiting the generalizability of the evidence obtained. Therefore, we determined the representation of ethnic minorities in oncology CT. Methods: Enrollment data from all therapeutic trials reported as completed in clinicaltrial.gov from 2003 to 2016 were analyzed. CT in rare cancers (< 1% incidence) or with recruitment outside of the US were excluded. Enrollment fraction (EF) was defined as the number of enrollees divided by the 2013 SEER database cancer prevalence. Chi-square test was used to estimate differences in categorical data. Results: Out of 1,012 CT, 310 (31%) reported ethnicity with a total of 55689 enrollees. Distribution by race and comparison with data from 1996-2002, US cancer prevalence and US census are described in the Table. Participation in CT varied significantly across ethnic groups, non-Hispanic Whites (NHW) were more likely to be enrolled in CT (EF of 1.2%) than African Americans (EF of 0.7%, p < 0.001) and Hispanics (EF of 0.4%, p<0.001). A decrease in African Americans (AA) and Hispanics (H) enrollment was observed when compared with historical data from 1996 to 2002. Hispanics were less represented in breast and prostate cancer CT contributing only to 3% and 1.5% of the study population; African Americans were less represented in lung (5.4%) and renal cell carcinoma (3%) trials. Asians were well represented and their recruitment doubled over the past 14 years (2% vs 5.3%). Conclusions: African Americans and Hispanics were less likely to be enrolled in CT. Comparing with historical data; we observed a decrease in minorities’ recruitment in the past 14 years. This change could be attributed to the increased complexity of CT and mandatory molecular testing as many minorities lack access to institutions with genetic testing capacity. Future trials should take extra measures to recruit participants that adequately represent the U.S. cancer population. [Table: see text]