Efficacy of All- Trans -Retinoic Acid in High-Risk Acute Myeloid Leukemia with Overexpression of EVI1 Abstract Introduction EVI1 (MECOM)-positive acute myeloid leukemia (AML) cells have shown in vitro sensitivity to all-trans-retinoic acid (ATRA) by inducing differentiation, cell death, and decreased leukemic engraftment. Methods In this pilot study, we investigated the response to ATRA in 13 high-risk AML patients with overexpression of EVI1. Results Seven of the 13 patients (53.8%) achieved complete remission (CR), and response can be combined with a decreased of the leukemia stem cell pool. Conclusion These primary results tend to confirm in vitro results and suggest that addition of ATRA might be of benefit in the treatment of patients with EVI1-positive AML.

Excision of a Large Gastrointestinal Stromal Tumour Following 16 Months of Neoadjuvant Therapy with Imatinib (Case Report) Abstract Introduction Although the standard treatment for stromal tumours is surgery, in locally advanced forms, it is often necessary to achieve tumour downstaging to improve surgical outcomes. Neoadjuvant treatment in gastrointestinal stromal tumours (GISTs) with tyrosine kinase inhibitors, including imatinib, has been shown to be effective in several studies, but the duration of this treatment is still a subject of debate. Case report We report a case of a large GIST of the stomach in a 51-year-old patient with atypical presentation that was initially unresectable. Neoadjuvant treatment with imatinib for 16 months resulted in a good response, allowing secondary surgical excision. Conclusion Imatinib in neoadjuvant therapy should be continued as long as there is a good response and tolerance to the medication to obtain tumour downsizing compatible with carcinologic excision.

Validation of Cell-Free DNA Collection Tubes for Determination of EGFR Mutation Status in Liquid Biopsy from NSCLC Patients Abstract Introduction Precision medicine has revolutionized the understanding and treatment of cancer by identifying subsets of patients who are amenable to specific treatments according to their molecular characteristics, as exemplified by epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). Although tissue biopsy is the gold standard for determining molecular alterations in tumors, its limitations have prompted the development of new techniques for studying tumor biomarkers in liquid biopsies, such as mutation analysis in cell-free DNA (cfDNA). cfDNA analysis can accurately determine tumor progression and prognosis and more effectively identify appropriate targeted therapies. However, cfDNA is vulnerable, particularly during plasma sample shipping. Objective We compared the cell- and DNA-stabilizing properties of cell-free DNA blood collection tubes (BCTs) with those of the traditional shipping method (frozen plasma) for EGFR mutation testing using the cobas® EGFR Mutation Test v2 in a prospective cohort of 49 patients from three different Spanish hospitals. Methods In total, 98 NSCLC samples, two from each patient, were studied; five of the 49 cases were considered invalid by cobas® with one of the two shipping methods analyzed. After excluding these samples, we analyzed 88 samples from 44 patients. Considering the current methodology (frozen plasma) for sending samples as the gold standard, we evaluated the sensitivity and specificity of cfDNA BCT shipment. Results The global agreement between the two methods was 95.4%, with 100% sensitivity and 94.6% specificity for the cfDNA BCTs. cfDNA BCTs had a positive predictive value of 81.8% and negative predictive value of 100%. Conclusion cfDNA BCTs have the same sensitivity for EGFR mutation analysis in liquid biopsy as the current methodology and very high specificity. They also have some additional advantages in terms of collection and further shipment. Therefore, cfDNA BCTs can be perfectly incorporated into the routine practice for EGFR mutation determination. Funding Roche Farma S.A., Spain.

A Review of Immune-Mediated Adverse Events in Melanoma Abstract The use of checkpoint inhibitor-based immunotherapy has transformed the treatment landscape for melanoma as well as many other cancer types. With the ability to potentiate tumor-specific immune responses, these agents can result in durable tumor control. However, this activation of the immune system can lead to a unique constellation of side effects, distinct from other cancer therapies, collectively termed immune-mediated adverse events (irAEs). This review will focus on irAEs and guidelines for management related to the most clinically relevant checkpoint inhibitors, those that target programmed death receptor-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4).

Tyrosine Kinase Inhibitor Sequencing in Patients with Chronic Myeloid Leukemia Abstract The management of chronic myeloid leukemia (CML) has been revolutionized by the discovery of tyrosine kinase inhibitors (TKIs) against BCR-ABL1 oncogenic fusion protein. Imatinib, the first BCR-ABL1 TKI, was introduced into clinical practice in the early 2000s. In the following years, the so-called second-generation TKIs (2GTKIs)—dasatinib, nilotinib, and bosutinib were approved, initially for patients resistant to imatinib, and subsequently for front-line treatment. With multiple TKIs available, selection of first-line therapy is challenging. CML risk, patient characteristics and potential toxicities of different TKIs play a fundamental role, in particular when deciding between imatinib and 2GTKIs as frontline treatment. So, when deciding front-line therapy for a patient with CML in the chronic phase (CML-CP), clinicians must consider both the long-term outcomes, such as overall survival and progression-free survival, as well as safety, tolerance and possible treatment discontinuation. This paper offers a practical algorithmic approach for the sequential use of commercially available TKIs in patients with CML-CP along with the data available in the literature.

Methodology of a Novel Risk Stratification Algorithm for Patients with Multiple Myeloma in the Relapsed Setting Abstract Introduction Risk stratification tools provide valuable information to inform treatment decisions. Existing algorithms for patients with multiple myeloma (MM) were based on patients with newly diagnosed disease, and these have not been validated in the relapsed setting or in routine clinical practice. We developed a risk stratification algorithm (RSA) for patients with MM at initiation of second-line (2L) treatment, based on data from the Czech Registry of Monoclonal Gammopathies. Methods Predictors of overall survival (OS) at 2L treatment were identified using Cox proportional hazards models and backward selection. Risk scores were obtained by multiplying the hazard ratios for each predictor. The K-adaptive partitioning for survival (KAPS) algorithm defined four groups of stratification based on individual risk scores. Results Performance of the RSA was assessed using Nagelkerke’s R2 test and Harrell’s concordance index through Kaplan–Meier analysis of OS data. Prognostic groups were successfully defined based on real-world data. Use of a multiplicative score based on Cox modeling and KAPS to define cut-off values was effective. Conclusion Through innovative methods of risk assessment and collaboration between physicians and statisticians, the RSA was capable of stratifying patients at 2L treatment by survival expectations. This approach can be used to develop clinical decision-making tools in other disease areas to improve patient management. Funding Amgen Europe GmbH.

A Phase 1, Open-Label Study in Healthy Subjects to Evaluate the Absolute Bioavailability of AG-221 by a Microtracer Approach Abstract Introduction The purpose of this study was to evaluate the absolute bioavailability (BA) of AG-221 following a single oral dose of 100 mg AG-221 and an intravenous (IV) dose of ~ 100 μg AG-221 containing approximately 300 nCi of [14C]-AG-221. Methods This was a phase 1, open-label study. Six subjects who met all of the inclusion criteria and none of the exclusion criteria were enrolled in the study. After an overnight fast of at least 10 h, the subjects received an oral dose (coated tablet) of 100 mg of AG-221 at 0 h on dosing day. Four hours after the oral dose, the subjects received 100 μg AG-221 containing ~ 300 nCi of [14C]-AG-221 administered as an IV bolus. Blood samples were collected and analyzed for plasma concentrations of AG-221 and [14C]-AG-221 using a validated liquid chromatography with tandem mass spectrometry (LC–MS/MS) system and high-performance liquid chromatography (HPLC) fractionation followed by accelerator mass spectrometry analysis (AMS), respectively. Safety was evaluated throughout the study. Results The absolute BA after a 100-mg oral dose of AG-221 was measured as 57.2%. While the total clearance was 1.37 L/h, ~ 1/60 of the liver blood flow in a typical 70-kg human subject, the first-pass extraction was estimated to be less than 2%, assuming that the total clearance was entirely due to liver metabolism. Thus, the fraction of the AG-221 dose absorbed was at least 50%. AG-221 was safe and well tolerated when given under fasted conditions in a single 100-mg dose as a coated tablet with a microtracer [14C]-AG-221 solution, as few drug-related treatment-emergent adverse events (TEAEs) were reported. No clinically significant changes or findings were noted in the clinical laboratory evaluations, vital sign measurements, and electrocardiograms (ECGs) performed during this study. Conclusions In healthy subjects under fasting conditions, the absolute BA following oral administration of a 100-mg AG-221 tablet was 57.2%. AG-221 was safe and well tolerated in healthy male subjects when administered as a single 100-mg film-coated tablet plus 100 µg [14C]-AG-221 given intravenously. Trial Registration ClinicalTrials.gov identifier, NCT02443168. Funding Celgene Corporation.

Correction to: Uveal Melanoma: A Review of the Literature The category of this article was incorrectly published as an Original Research Article, when it should have been published as a Review.

Immune Checkpoint Inhibitors and Radiotherapy in NSCLC Patients: Not Just a Fluke Abstract The discovery of immune checkpoint inhibitors (ICIs) such as programmed cell death protein 1 (PD-1) inhibitors, nivolumab and pembrolizumab, and programmed cell death ligand 1 (PD-L1) inhibitors, atezolizumab and durvalumab, has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). Concurrent radiotherapy (RT) is of particular interest with regard to the potential role for this combination in many settings. The purpose of this commentary is to evaluate the potential for the combination of immune checkpoint inhibitors and radiotherapy, including analysis of studies that have considered this combination in various settings.

Real-World Impact of Physician and Patient Discordance on Health-Related Quality of Life in US Patients with Acute Myeloid Leukemia Abstract Introduction There is limited understanding concerning the health-related quality of life (HRQoL) in acute myeloid leukemia (AML) patients. Due to an overlap of symptoms, it can be difficult to separate disease versus treatment-related effects. Study objectives were to understand the impact of factors that might influence patients’ HRQoL, assess the degree of concordance in symptom reporting by patients and physicians, and assess the impact of any discordance on HRQoL in AML patients. Methods Physicians in the USA captured demographics, current AML treatment and symptoms for 82 AML patients who completed the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu), 5-Dimension EuroQol Questionnaire (EQ-5D-3L) and Cancer Treatment Satisfaction Questionnaire (CTSQ). Effect size (ES) and clinically meaningful differences between AML subgroups were assessed, as was the impact of disagreement between patients and physicians regarding symptom recognition. Results Clinically meaningful lower overall FACT-Leu scores were observed for: relapsed/refractory versus non-relapsed/refractory AML patients (92.5 vs. 103.7; P = 0.09; ES = 0.439), hypomethylating agent (HMA) monotherapy versus other therapies in patients with low treatment intensity (89.9 vs. 112.9; P = 0.0021; ES = 0.971) and presence/absence of FLT3-ITD mutation (85.5 vs. 100; P = 0.148; ES = 0.816). Differences in health state were also clinically meaningful between patients with/without FLT3-ITD; EQ-5D-Visual Analog Scale (VAS) (47.6 vs. 63.7; P = 0.0428; ES = 0.816). Patients were more likely than physicians to report bruising (κ = 0.1292), fatigue (κ = 0.0836), bleeding (κ = 0.0177), weight loss (κ = 0.0821) and appetite loss (κ = − 0.0246). FACT-Leu was associated with patient-physician discordance on bleeding (difference − 14.12; P = 0.046), weight loss (− 21.22; P = 0.001) and appetite loss (− 12.58; P = 0.027). Conclusions HRQoL is generally low for AML patients, especially for particular subgroups. Discordance in symptom reporting between patients and physicians was common and associated with further negative impacts on HRQoL. There may be many reasons for this but better communication between physicians and patients may lead to shared objectives and improvement in patients’ HRQoL. Funding Astellas Pharma, Inc.