BackgroundOsimertinib is efficacious in lung cancer patients with epidermal growth factor receptor (EGFR) mutations and acquired resistance (AR) to EGFR tyrosine kinase inhibitors due to EGFR-T790M mutation (T790M). We sought to describe T790M changes in serum/plasma during osimertinib therapy and correlate these changes with treatment outcomes.Material and methodsSerum/plasma from EGFR-mutant lung cancer patients with T790M-AR was collected before and during osimertinib treatment. Changes in T790M were evaluated using a peptide-nucleic acid-PCR assay, and correlated with clinical and radiographic response.ResultsThirteen patients were included. Median time on osimertinib treatment was 10.6 months with a median progression-free survival of 13.6 months. Best response to osimertinib was partial response (PR), stable disease (SD) or progression (PD) in 46.1%, 30.8% and 23.1% of patients, respectively.Most of the patients were paucisymptomatic at baseline. Symptom improvement was reported in 66.6% of responder patients; while symptoms remained stable in 75% of patients with SD, and 66% of patients with PD had clinical deterioration.Three patterns of T790M changes during osimertinib treatment were identified. T790 remained detectable with PD or a short-lasting SD in 15.4% of the patients. T790M disappeared in 69.2% of patients with PR or SD. T790M disappeared, despite clinical and/or radiographic progression in 15.4% of the patients.ConclusionChanges of T790M in serum/plasma in EGFR-mutant lung cancer patients with T790M-AR might be a useful marker of symptomatic and radiographic outcome to osimertinib. Longer follow-up is needed to establish if subsequent emergence of T790M could be a marker of resistance.

The nuclear SET domain (NSD) protein lysine methyltransferases (KMT) family is composed of three members, NSD1/KMT3B, NSD2/WHSC1/MMSET, and NSD3/WHSC1L1, which regulate gene expression through methylation of lysine 36 of histone H3 (H3K36). NSD2 overexpression was reported in multiple myeloma with t(4;14)/IgH-MMSET. NSDs gene expression profile is unknown in acute leukemias; however, NSD1 and NSD3 were described to be fused with the nucleoporin 98 gene (NUP98) in rare AML and myelodysplastic syndrome cases and both fusion proteins were associated with poor prognosis. The aims of the present study were to characterize the expression of NSD-KMTs in patients with AML and healthy controls, to determine if this expression is associated with specific genetic abnormalities and/or with treatment outcome. Bone marrow aspirates from four healthy donors and 94 AML patients (50♀, 44♂) at diagnosis were included in the study. Our cohort included 10 patients with acute promyelocytic leukemia (APL), 8 with core binding factor (CBF) leukemias [6 with t(8;21) and 4 with inv(16)], and 74 patients with non-APL non-CBF AML. NSD family gene expression was evaluated by qPCR using the comparative Ct method for analysis. A higher expression of the NSD1 gene was observed in AML cells compared to normal bone marrow (BM) samples (median [range] = 3.8835 [0.6804-11.5598] vs. 1.003 [0.7956-1.265], p=0.0243). Similarly, the expression of NSD3 was higher in AML only for the comparison between healthy BM and CBF-AML groups (median [range] = 1.070 [0.6360-1.410] vs. 2.719 [1.238-8.830], p=0.0265). No significant differences were detected in the analysis of NSD2 expression. The association between expression levels of NSD-KMT with age, gender, prognosis (favorable vs. unfavorable), presence or absence of FLT3-ITD and NPM1 mutations, and presence or absence of karyotype abnormalities was evaluated. With the exception of NSD3 and presence/absence of karyotype abnormalities, NSD-KMT gene expression levels were higher in AML subgroups when compared to healthy donors, in all above parameters. NSD2 was more expressed in AML when compared to NSD1/NSD2 groups. NPM1 mutations and FLT3 internal tandem duplications (FLT3-ITD) were detected in 19.1% (18/94) of the patients with AML. NSD1/NSD3 were more expressed in FLT3-ITD mutant vs. FLT3 wild-type group. In addition, NSD2 was frequently more observed in patients aged 65 or older. Next, patients were stratified into two groups according to the median value of each NSD-KMT evaluated. We assessed the correlation between age, white blood cells count, hemoglobin, platelets, and blasts percentage at bone marrow and NSD-KMT expression levels. A positive correlation was observec between NSD1/NSD3 and the percentage of bone marrow blasts at diagnosis (r2 = 0.08080/p-value = 0.0084, and r2 = 0.04937/p-value = 0.0410, respectively). NSD3 was also correlated to the higher number of bone marrow blasts (r2 = 0.1219/p-value = 0.0217), followed by a decrease into the platelet count (r2 = 0.09795/p-value = 0.0436). Regarding the analysis of treatment outcome, patients with non-APL AML were stratified into high and low NSD1 or NSD2 expression subgroups using the criteria above. The median overall survival of patients in the low NSD2 expression subgroup was 333.023 days (95% CI:158.541-507.505 days) whereas that of patients in the high NSD2 expression subgroup was 817.629 days (95% CI:238.702-1396.555 days) (p=0,633). No significant difference was observed between the overall survival of patients in the high and low NSD1 expression subgroups. Our data suggest a correlation between the overexpression levels of NSD-KMT with histone modifications, suggesting that this modification and not only DNA methylation can contribute to epigenomic changes associated with AML pathogenesis. Citation Format: Virginia Mara de Deus Wagatsuma, Luisa C. A. Koury, Silvia Helena Sánchez, Lorena Lobo Figueiredo-Pontes, Fernanda Borges da Silva, Fernanda Borges da Silva, Adriana Ines Dore, Ana Silvia Gouvea de Lima, Antonio Roberto Lucena-Araujo, Fabiola Traina, Felipe Saldanha-Araujo, Fabio Pittella, Eduardo Magalhães Rego. Nuclear SET domain (NSD) protein lysine methyltransferases (KMT) are higher expressed in acute myeloid leukemia [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A39.

Alternative dosage regimens for some anticancer therapies have been proposed in the midst of the SARS-COV-2 pandemic in order to protect the patients from attending to health care facilities. Flatdosing of several immune-checkpoint inhibitors (ICIs), including nivolumab, have been established. Although generally well tolerated with no new safety signals, new dosages can associate novel individual toxicities. As the use of ICIs is increasing in cancer patients, the present case report is a reminder for clinicians of potential novel toxicities, as well as the need for an interdisciplinary approach for their recognition and treatment. We report the occurrence of a severe neurologic toxicity in a patient with non-small cell lung cancer (NSCLC) who developed should be changed to which occurred after two doses of extended higher interval flat-dose nivolumab despite two years of clinical stability on prior nivolumab regimen. Patient developed fever, language impairment and altered mental status. The work-up tests excluded other potential causes and the most likely diagnosis was meningoencephalitis. Fortunately, with medical treatment, which consisted of high dose steroids, the patient recovered to his baseline situation and symptoms did not recurred, even though nivolumab was resumed. Alternate ICI regimens may have unique immune-related adverse event profiles.

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