Association between albumin-bilirubin grade and plasma trough concentrations of regorafenib and its metabolites M-2 and M-5 at steady-state in Japanese patients.

The aim of the present study was to determine whether the trough plasma concentrations (C0) of regorafenib and its metabolites, the N-oxide metabolite (M-2) and the desmethyl N-oxide metabolite (M-5), in 21 patients receiving regorafenib therapy were affected by albumin-bilirubin (ALBI) grade. Regorafenib was administered at dosages ranging from 40 to 160 mg once daily on a 3-week-on, 1-week-off cycle. C0 values of regorafenib and its major metabolites were measured by high-performance liquid chromatography on day 8 after treatment initiation. The C0 values of regorafenib and metabolites M-2 and M-5 were significantly lower in patients with ALBI grade 2 as compared with grade 1 (P = 0.023, 0.003 and 0.017, respectively). The total C0 of regorafenib and its metabolites was significantly higher in ALBI grade 1 patients relative to grade 2 (3.489 µg/mL vs. 1.48 µg/mL; P = 0.009). The median relative dose intensity (RDI) of patients categorized as ALBI grade 2 was significantly lower than that of grade 1 patients (21.9% vs. 62.9%; P = 0.006). In 15 colorectal cancer patients among the total 21 patients, patients with ALBI grade 2 (n = 9) had a significantly shorter median overall survival time than patients with grade 1 (n = 6; P = 0.013). Administering a low dose of regorafenib to patients with ALBI grade 2 reduces the RDI of regorafenib and lowers treatment efficacy, as an appropriate C0 of regorafenib is not maintained. Monitoring the C0 of regorafenib regularly is necessary to guide dose adjustment.

Influence of genetic polymorphisms in vascular endothelial-related genes on the clinical outcome of axitinib in patients with metastatic renal cell carcinoma.

OBJECTIVE: Axitinib is an oral multi-target tyrosine kinase inhibitor used for the treatment of renal cell carcinoma (RCC). Because of the severe adverse events (AEs) associated with axitinib, patients often need dose reductions or discontinue its use, highlighting the need for effective biomarkers to assess efficacy and/or AEs. The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) in genes involved in the pharmacodynamic action of axitinib and clinical prognosis and AEs in metastatic RCC (mRCC) patients. METHODS: This study included 80 mRCC patients treated with first-, second-, or third-line axitinib (5 mg orally twice daily). Clinical parameters and genetic polymorphisms were examined in 75 cases (53 males and 22 females). We assessed three SNPs in each of three candidate genes namely, angiotensin-converting enzyme (ACE), nitric oxide synthase 3 (NOS3), and angiotensin II receptor type 1 (AT1R), all of which are involved in axitinib effects on vascular endothelial function. RESULTS: Axitinib-treated patients carrying the ACE deletion allele suffered more frequently from hand-foot syndrome and a deterioration in kidney function (p = .045 and p = 0.005, respectively) whereas those carrying the NOS3 G allele suffered more frequently from proteinuria and multiple AEs (p = .025 and p = 0.036, respectively). CONCLUSIONS: Our study found that the ACE deletion allele and the NOS3 G allele are associated with increased AEs.

[Determination of Plasma Concentrations of Imatinib by a Novel Automated Analyzer Based on High-Performance Liquid Chromatography].

LM1010 HPLC is an emerging automated method designed for use in clinical settings. The aim of this study was to compare the analytical performance of LM1010 with the performance of traditional HPLC and LC-MS/MS in the measurement of plasma concentrations of imatinib. Seventy-eight plasma samples from 20 patients (14 men and 6 women) were collected. Plasma concentrations of imatinib in samples from the same patient were analyzed simultaneously using LM1010, HPLC and LC-MS/MS (LSI Medience Corporation). Strong correlations were seen in pairwise comparisons of results from the LM1010 and HPLC methods, the LM1010 and LC-MS/MS methods, and the LC-MS/MS and HPLC methods (Spearman's r=0.936, 0.906, and 0.953, respectively); however, the results from the LC-MS/MS method showed a positive proportional bias in comparison with the results from the LM1010 and HPLC methods, according to Deming analyses (slope=1.064 and 1.105, respectively). In Bland-Altman analyses, the LC-MS/MS method showed a positive mean bias of 98.6 and 112 ng/mL in comparison with the LM1010 and HPLC methods, respectively. Notably, results obtained using the LM1010 method were comparable to those using the HPLC method (positive mean bias=13.6 ng/mL; 95% confidence interval, -7.9-35.1 ng/mL). Biochemical parameters or drugs taken concomitantly with imatinib were not found to affect the bias of the LM1010 method. The LM1010 method can be applied to routine therapeutic drug monitoring of imatinib.

A Prospective Cohort Study Assessing the Relationship between Plasma Levels of Osimertinib and Treatment Efficacy and Safety.

Osimertinib is a standard treatment for patients with EGFR-mutated non-small cell lung carcinoma (NSCLC). We evaluated the relationship between plasma osimertinib concentrations and treatment outcome in patients with NSCLC for this cohort study. The plasma levels of osimertinib and its metabolite AZ5104 were measured a week after the start of treatment (P1). The primary endpoint was to evaluate the correlation between plasma concentration and adverse events (AEs). The correlation with treatment efficacy was one of the secondary endpoints. In patients with CNS metastases, the concentration in the cerebrospinal fluid was also measured. Forty-one patients were enrolled. The frequency of AEs was highest for rash, followed by anorexia and thrombocytopenia. Thirty-eight cases provided measurements for P1. The median plasma concentration of osimertinib was 227 ng/mL, and that of AZ5104 was 16.5 ng/mL. The mean CNS penetration rate of two cases was 3.8%. The P1 in the group with anorexia was significantly higher than that in the group without anorexia (385.0 ng/mL vs. 231.5 ng/mL, p = 0.009). Divided into quartiles by P1 trough level, Q2 + Q3 (164-338 ng/mL) had longer PFS, while Q1 and Q4 had shorter PFS. An appropriate plasma level of osimertinib may avoid some adverse events and induce long PFS. Further large-scale trials are warranted.

Effects of polymorphisms in pregnane X receptor and ABC transporters on afatinib in Japanese patients with non-small cell lung cancer: pharmacogenomic-pharmacokinetic and exposure-response analysis.

PURPOSE: Because of the large interindividual variability of afatinib pharmacokinetics and adverse events, we evaluated the effects of polymorphisms in pregnane X receptor (NR1I2) and ABC transporters (ABCB1, ABCG2, and ABCC2) on the pharmacokinetics of afatinib. METHODS: The steady-state area under the concentration-time curve (AUC)0-24 of afatinib was analyzed using blood sampling just prior to and at 1, 2, 4, 6, 8, 12, and 24 h on day 15 after administration. RESULTS: The median oral clearance (CL/F) of afatinib in patients with the NR1I2 7635A allele was significantly lower than those in patients with the 7635G/G genotype (42.0 and 60.0 L/h, respectively, P = 0.025). There were no significant differences in afatinib CL/F between genotypes for NR1I2 8055C > T, -25385C > T, ABCB1, ABCG2, and ABCC2 polymorphisms. Based on the area under the receiver-operating characteristic curve, the threshold afatinib AUC0-24 value for prediction of dose reduction or withdrawal was 689 ng·h/mL at the best sensitivity (81.0%) and specificity (72.7%). In multivariate logistic regression analysis, an afatinib AUC0-24 above 689 ng·h/mL was independently associated with increased risk of dose reduction or withdrawal (OR: 11.66, P = 0.012). CONCLUSIONS: The NR1I2 7635A allele was related to a lower afatinib CL/F. Based on the AUC of 689 ng h/mL and CL/F, the optimal doses for patients with the NR1I2 7635G/G genotype and 7635A allele were recommended to be set at 40 and 30 mg/day, respectively, and subsequent adjustment of the maintenance dose based on the plasma concentrations of afatinib may be necessary to avoid afatinib-related adverse events.

[Evaluation of Plasma Concentrations of Mycophenolic Acid in Renal Transplant Patients Using LM1010 High-performance Liquid Chromatography].

Plasma concentrations of mycophenolic acid (MPA), an immunosuppressive agent, have been measured in clinical settings using immunoassay methods or HPLC. However, immunoassay methods show cross-reactivity with metabolites of MPA glucuronide. Recently, the LM1010 high-performance liquid chromatography instrument was approved as a new general medical device. In this study, we compared the results of MPA plasma concentrations analyzed using the LM1010 method and the previously described HPLC method. Plasma samples obtained from 100 renal transplant patients (32 women and 68 men) were evaluated using both HPLC instruments. Deming regression analyses showed a very high correlation between the two instruments, with a slope of 0.9892 and an intercept of 0.0235 µg/mL (r2=0.982). Bland-Altman analysis showed an average of -0.0012 µg/mL between the LM1010 method and the previously described HPLC method. For the LM1010 method, the total run time for MPA analysis was 7 min, and the analytical time was short; however, the extraction recovery when using a spin column was extremely low for frozen plasma samples stored at -20°C for 1 month, and the volume required for the assay (150 µL) could not be collected. Thus, for the LM1010 method, analysis using fresh plasma samples was optimal. Overall, our findings showed that the LM1010 method was a rapid, accurate HPLC assay for MPA analysis and could be used in clinical practice for routine monitoring of MPA in fresh plasma samples.

Hypoperfusion intensity ratio and CBV index as predictive parameters to identify underlying intracranial atherosclerotic stenosis in endovascular thrombectomy.

BACKGROUND AND PURPOSE: Intracranial atherosclerotic stenosis (ICAS)-related large vessel occlusion (LVO) is difficult to diagnose before endovascular thrombectomy (EVT) in an emergency. We hypothesized that hypoperfusion intensity ratio (HIR) and cerebral blood volume (CBV) index reflect collateral flow and would be useful parameters to predict underlying ICAS. MATERIALS AND METHODS: Clinical and perfusion imaging parameters of patients receiving EVT for LVO were reviewed retrospectively. Patients were divided into ICAS and embolism groups with angiographical findings. The association between prespecified parameters and underlying ICAS were assessed using multivariable logistic regression analyses. Discriminative ability was assessed using receiver operating characteristic analysis. RESULTS: Among 238 consecutive patients, 47 satisfied the inclusion criteria, including 10 with ICAS-related LVO. In ROC analyses, HIR showed good discrimination with a cutoff value of 0.22 (area under the curve, 0.85; 95%CI, 0.75-0.96; sensitivity, 0.84; specificity, 0.80) for underlying ICAS. CBV index showed excellent discrimination with a cutoff value of 0.90 (area under the curve, 0.92; 95%CI, 0.81-0.98; sensitivity, 0.92; specificity, 0.79). Multivariable logistic regression analysis revealed that HIR ≤ 0.22 (OR, 22.5; 95%CI, 2.9-177.0; P = 0.003) and CBV index ≥ 0.9 (OR, 75.7; 95%CI, 5.8-994.0; P < 0.001) were significantly associated with underlying ICAS. CONCLUSION: HIR ≤ 0.22 and CBV index ≥ 0.9 were associated with underlying ICAS and may predict underlying ICAS before EVT.

Effects of ABCB1 polymorphisms on the transport of ponatinib into the cerebrospinal fluid in Japanese Philadelphia chromosome-positive acute lymphoblastic leukaemia patients.

The effects of polymorphisms of ABCB1 and ABCG2 on the dose-adjusted plasma trough concentrations and cerebrospinal fluid (CSF)-to-plasma ratios of ponatinib were evaluated. Blood (C4 ) and CSF (CSF4 ) concentrations at 4 h after administration were determined. The median (95% confidence interval) CSF4 -to-C4 ratio of ponatinib in subjects homozygous for ABCB1 variants 1236T/T, 2677T/T + T/A or 3435T/T were significantly higher than that in a group of subjects with other genotypes (P = .026, .012 and .015, respectively). The median (95% confidence interval) CSF4 -to-C4 ratio of ponatinib in 4 patients with the combination of ABCB1 variants 1236T/T-2677T/T + T/A-3435T/T was 2.62% (1.42-3.42%); this ratio was significantly higher than that in subjects with other genotypes (1.08% [0.89-1.47%]; P = .006). The brain distribution of ponatinib was affected by ABCB1 polymorphisms and therefore seems to be modulated by P-glycoprotein at the blood-brain and blood-CSF barriers.

Impact of trough abiraterone level on adverse events in patients with prostate cancer treated with abiraterone acetate.

PURPOSE: We assessed the impact of plasma trough concentrations of abiraterone (ABI) and its metabolite Δ4-abiraterone (D4A) and related polymorphisms on adverse events (AEs) in patients with metastatic prostate cancer who received abiraterone acetate (AA). METHODS: This prospective study enrolled patients with advanced prostate cancer treated with AA between 2016 and 2021. Plasma trough concentrations of ABI and D4A were measured using high-performance liquid chromatography. The impact of HSD3B1 rs1047303, SRD5A2 rs523349, and cytochrome P450 family 3A member 4 rs2242480 polymorphisms on plasma concentrations of ABI and D4A and the incidence of AEs were also assessed. RESULTS: In 68 patients treated with AA, the median ABI and D4A concentrations were 18.1 and 0.94 ng/mL, respectively. The high plasma trough concentration of ABI (≥ 20.6 ng/mL) was significantly associated with the presence of any AE and its independent risk factor based on multivariable analysis (odds ratio, 7.20; 95% confidence interval (CI): 2.20-23.49). Additionally, a high plasma trough concentration of ABI was an independent risk factor of time to withdraw AA (hazard ratio, 4.89; 95% CI: 1.66-14.38). The risk alleles of three polymorphisms were not statistically associated with the ABI and D4A concentrations and the incidence of AEs. CONCLUSIONS: The plasma trough concentration of ABI is associated with the presence of AEs and treatment failure after AA administration. ABI concentration monitoring may be useful in patients with prostate cancer who received AA.

Circulating IL-6 and not its circulating signaling components sIL-6R and sgp130 demonstrate clinical significance in NSCLC patients treated with immune checkpoint inhibitors.

Introduction: Clinical roles of plasma IL-6 levels have been reported in patients with various cancers, including non-small cell lung cancer (NSCLC), treated with immune checkpoint inhibitors (ICIs). However, the roles of other IL-6 signaling components, soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130), in the plasma have not been elucidated. Methods: Blood was collected from 106 patients with NSCLC before initiation of ICI treatment (anti-PD-1 or anti-PD-L1 antibody). Plasma levels of IL-6, sIL-6R, sgp130, and their complexes were assessed by Cox regression hazard model to evaluate their clinical significance. The clinical role of IL-6 or IL-6R genetic polymorphisms was also analyzed. Results: Cox regression analysis showed that higher plasma IL-6 levels significantly predicted unfavorable overall survival (OS; hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.05-1.68, p = 0.012) in NSCLC patients treated with ICIs. However, plasma sIL-6R and sgp130 levels showed no prognostic significance (p = 0.882 and p = 0.934, respectively). In addition, the estimated concentrations of binary IL-6:sIL-6R and ternary IL-6:sIL-6R:sgp130 complexes and their ratios (binary/ternary complex) were not significantly associated with OS (p = 0.647, p = 0.727, and p = 0.273, respectively). Furthermore, the genetic polymorphisms of IL-6 (-634G>C) and IL-6R (48892A>C) showed no clinical role by Kaplan-Meier survival analysis (p = 0.908 and p = 0.639, respectively). Discussion: These findings demonstrated the clinical significance of plasma levels of IL-6, but not of other IL-6 signaling components, sIL-6R and sgp130, suggesting that classical IL-6 signaling, but not trans-signaling, may be related to anti-tumor immune responses in cancer patients treated with ICIs.

A Multi-institutional Study to Diagnose the Risk of Lymph Node Metastasis Using a CRP Genetic Polymorphism Test Kit in pT1, cN0 Thoracic Esophageal Squamous Cell Carcinoma.

BACKGROUND/AIM: For patients with T1a muscularis mucosae (MM) esophageal squamous cell carcinoma (ESCC) with lymphovascular invasion (LVI) or T1b submucosal (SM) ESCC, endoscopic resection is non-curative, and adjuvant treatment entailing esophagectomy or definitive chemoradiotherapy is necessary. This is because about 30% of these cases have lymph node (LN) metastasis. The purpose of this study was to test the utility of a CRP genetic polymorphism test kit for determining the risk of LN metastasis with the aim of eliminating additional invasive adjuvant therapy. PATIENTS AND METHODS: This is a retrospective, multi-institutional, observational study. The CRP 1846C>T genetic polymorphisms were identified using a fully automated genotyping system. The primary end points were an 85% negative predictive value (NPV) for diagnosis of LN metastasis in pT1a (MM) and 80% NPV in pT1b (SM1) patients. RESULTS: A total of 742 ESCC (105 pMM, 166 pSM1 and 471 pSM2-3) patients who had received esophagectomy with 2- or 3-field LN dissection at 65 institutions were enrolled. According to this test, patients with the C/C and C/T genotypes were considered to be low risk. The NPVs using this test were 82.8% in pMM and 71.7% in pSM1 patients. CONCLUSION: CRP 1846C>T genetic polymorphism is not a useful diagnostic indicator for determining the risk of LN metastasis; however, the possibility that CRP gene polymorphisms are involved in the mechanism of lymph node metastasis in solid tumors still remains.

Effects of NR1I2 and ABCB1 Genetic Polymorphisms on Everolimus Pharmacokinetics in Japanese Renal Transplant Patients.

The purpose of this study was to evaluate the effects of NR1I2 (7635G>A and 8055C>T) and ABCB1 (1236C>T, 2677G>T/A, and 3435C>T) genetic polymorphisms on everolimus pharmacokinetics in 98 Japanese renal transplant patients. On day 15 after everolimus administration, blood samples were collected just prior to and 1, 2, 3, 4, 6, 9, and 12 h after administration. The dose-adjusted area under the blood concentration−time curve (AUC0-12) of everolimus was significantly lower in patients with the NR1I2 8055C/C genotype than in those with other genotypes (p = 0.022) and was significantly higher in male patients than female patients (p = 0.045). Significant correlations between the dose-adjusted AUC0-12 of everolimus and age (p = 0.001), aspartate transaminase (p = 0.001), and alanine transaminase (p = 0.005) were found. In multivariate analysis, aging (p = 0.008) and higher alanine transaminase levels (p = 0.032) were independently predictive of a higher dose-adjusted everolimus AUC0-12. Aging and hepatic dysfunction in patients may need to be considered when evaluating dose reductions in everolimus. In renal transplant patients, management using everolimus blood concentrations after administration may be more important than analysis of NR1I2 8055C>T polymorphism before administration.

Quantitation of Venetoclax in Human Plasma by High-Performance Liquid Chromatography with Ultraviolet Detection.

A simple, highly sensitive and specific method based on high-performance liquid chromatography (HPLC) with ultraviolet detection was developed for the measurement of venetoclax concentrations in plasma samples. The chromatographic method employed a mobile phase of acetonitrile: 0.5% KH2PO4 (pH 3.5) (80/20, v/v) on a CAPCELL PAK C18 UG120 column at a flow rate of 0.5 mL/min. The quantitative method was validated based on standards described in "Bioanalytical Method Validation: Guidance for Industry" published by the US Food and Drug Administration. The separation of venetoclax and the internal standard R051012 was satisfactory, and the chromatograms were free of interfering peaks from the biological matrix. The intra- and inter-day coefficients of variation for venetoclax assays were <12.9%, whereas intra- and inter-day accuracies were within 13.6%. Only 100 µL of human plasma was required to detect a lower limit of quantification of 10 ng/mL for venetoclax. The recoveries of venetoclax extracted with an Oasis HLB cartridge were between 81 and 85%. The developed HPLC method was successfully applied to the determination of venetoclax concentrations in plasma of acute myeloid leukemia patients taking venetoclax. The degree of drug interactions between venetoclax and CYP3A4 inhibitors can be determined by this HPLC assay.

Effects of CYP3A4/5 and ABC transporter polymorphisms on osimertinib plasma concentrations in Japanese patients with non-small cell lung cancer.

The effects of polymorphisms in CYP3A4 (20230G > A), CYP3A5 (6986A > G), ABCB1 (1236C > T, 2677G > T/A, 3435C > T), ABCG2 (421C > A), and ABCC2 (-24C > T) on the area under the concentration-time curve (AUC) of osimertinib in 23 patients with non-small cell lung cancer were investigated. Blood sampling was performed just prior to and at 1, 2, 4, 6, 8, 12, and 24 h after osimertinib administration at the steady-state on day 15 after beginning therapy. The osimertinib AUC0-24 was significantly correlated with age (P = 0.038), serum albumin (P = 0.002), and serum creatinine (P = 0.012). Additionally, there were significant differences in the AUC0-24 of osimertinib among the groups administered vonoprazan, histamine 2-receptor antagonists or esomeprazole, and no acid suppressants (P = 0.021). By contrast, there were no significant differences in the AUC0-24 of osimertinib between genotypes of CYP3A4/5 or ABC transporters. Furthermore, there were no significant differences in the AUC0-24 of osimertinib between patients with diarrhea, skin rash, or hepatotoxicity and those without these conditions. In multivariate analysis, only serum albumin value was an independent factor predicting the AUC0-24 of osimertinib. Analysis of CYP3A4/5 and ABC transporter polymorphisms before osimertinib therapy may not predict the efficacy or side effects of osimertinib. The lower serum albumin values were associated with an increase in the AUC0-24 of osimertinib; however, further studies are needed to assess the factors contributing to the interindividual variability of osimertinib pharmacokinetics.

Safe administration and pharmacokinetic monitoring of crushed venetoclax tablets with posaconazole and clarithromycin via percutaneous endoscopic gastrostomy tube in a patient with acute myeloid leukemia.

PURPOSE: Leukemic stem cells in acute myeloid leukemia (AML) express high B cell lymphoma 2 (BCL2) levels, which contribute to leukemic cell survival and resistance to therapy. Venetoclax-a BCL-2 inhibitor-is indicated for the treatment of AML, which may also target leukemic stem cells; however, it is only available as a tablet. There are no reports of venetoclax use in patients who cannot take oral drugs; therefore, the efficacy, safety, and pharmacokinetics (PK) of venetoclax administered through a gastrostomy tube is unknown. CASE PRESENTATION: We report, for the first time, a case of relapsed Japanese AML patient treated with crushed venetoclax tablets through a percutaneous endoscopic gastrostomy (PEG) tube because of esophageal stricture due to complications of stem cell transplantation. The patient was also taking posaconazole and clarithromycin concomitantly. We evaluated the plasma concentrations of venetoclax administered through a PEG tube. Time to maximum concentration, maximum plasma concentration, and the area under the plasma concentration-time curve were similar to the previously reported PK parameters after oral administration of intact venetoclax tablets in Japanese patients with AML. The clinical course passed safely without the occurrence of unexpected adverse events during the administration of crushed venetoclax tablets in combination with azacitidine. CONCLUSIONS: The PK parameters of the crushed administered venetoclax via PEG tube was similar to the previously reported PK parameters of the orally administered venetoclax. Therefore, administration of crushed venetoclax tablets through a PEG tube could be an alternate route for patients who have difficulty with oral administration.

Associations Between Plasma Concentrations of Lenvatinib and Angiopoietin and Clinical Responses to Lenvatinib Therapy in Japanese Patients With Thyroid Cancer.

BACKGROUND/AIM: The purpose of this study was to investigate the relationships between the plasma concentration of Lenvatinib (C0), the levels of angiopoietin (Ang)-1 and Ang-2, and clinical responses to lenvatinib therapy in patients with thyroid cancer. PATIENTS AND METHODS: Lenvatinib C 0 and Ang were measured by high-performance liquid chromatography and enzyme-linked immunosorbent assay, respectively. RESULTS: The median decrease rates of Ang-1 and Ang-2 at 1 month after treatment from baseline were -15.3% and -48.4%, respectively. However, the decrease in the levels of Ang-1 and Ang-2 at 1 month from baseline did not correlate with C0. In patients with partial response (PR) and stable disease, Ang-2 at 1 month was significantly lower than Ang-2 at baseline. The area under the ROC for PR prediction was 0.667, giving the best sensitivity (69.2%) and specificity (73.9%) at a threshold of decrease rate of Ang-2 of -49.83%. CONCLUSION: The decrease in Ang-2 at 1 month of treatment from baseline may be important as a biomarker of the inhibitory effect of lenvatinib on angiogenesis.

Relationship between achievement of major molecular response or deep molecular response and nilotinib plasma concentration in patients with chronic myeloid leukemia receiving first-line nilotinib therapy.

PURPOSE: We evaluated the plasma exposure and response relationships of nilotinib for patients with newly diagnosed chronic myeloid leukemia (CML) in real-world practice. METHODS: For the 26 patients enrolled in this study, at 3, 6, 12, and 24 months after nilotinib administration, the trough plasma concentrations (Ctrough) of nilotinib were analyzed. The relationships between nilotinib Ctrough and the molecular response to nilotinib treatment at each point (each n = 26) were evaluated. RESULTS: Median nilotinib Ctrough values were significantly higher in patients with a major molecular response (MMR) at 3 months than in patients without an MMR (809 and 420 ng/mL, respectively; P = 0.046). Based on the area under the receiver-operating characteristic curve, the threshold value of the nilotinib Ctrough at 3 months for predicting MMR achievement was 619 ng/mL at the best sensitivity (71.4%) and specificity (77.8%). Patients with a nilotinib Ctrough of above 619 ng/mL had a significantly shorter time to achievement of a deep molecular response (DMR; 9.0 and 18.0 months, respectively; P = 0.020) and higher rates of DMR by 2 years in Kaplan-Meier plots (P = 0.025) compared with that in patients with a nilotinib Ctrough of less than 619 ng/mL. CONCLUSION: For patients with newly diagnosed CML, the nilotinib dose may be adjusted using a Ctrough of above 619 ng/mL as the minimum effective concentration, i.e., the lowest concentration required for MMR or DMR achievement within a shorter time, during early stages after beginning therapy to obtain faster and deeper clinical responses.

Association between ABCC2 polymorphism and hematological toxicity in patients with esophageal cancer receiving platinum plus 5-fluorouracil therapy.

BACKGROUND: Platinum agents are taken up into cells by copper transporter (CTR) 1 (gene code: SLC31A1) and are excreted from cells by copper-transporting P-type adenosine triphosphatase (ATP7B) and multidrug resistance-associated protein (MRP) 2 (gene code: ABCC2). In addition, glutathione S transferase (GST) P1 is involved in the metabolism of platinum agents. The present study aimed to determine whether the rate of grade 3-4 hematological toxicity associated with platinum plus 5-fluorouracil (5-FU) therapy in 239 patients with esophageal cancer was affected by the SLC31A1 rs10981694A>C and rs12686377G>T, ATP7B rs9535828A>G, GSTP1 rs1695A>G, and ABCC2 -24C>T polymorphisms. METHODS: Chemotherapy consisted of protracted infusion of 5-FU (800 mg/m2/day) on days 1-5 and cisplatin or nedaplatin (80 mg/m2/day) on day 1. RESULTS: A total of 82 of 239 patients developed grade 3-4 hematological toxicity after chemotherapy. Univariate analysis showed that ABCC2 -24C/T + T/T genotypes (P = 0.038), radiation therapy (P = 0.013), baseline white blood cell count < 6000/µL (P = 0.003), and baseline neutrophil count < 3900/µL (P = 0.021) were statistically significant predictors of grade 3-4 hematological toxicity. Multivariate analysis revealed that ABCC2 -24C/T + T/T genotypes (P = 0.036), radiation therapy (P = 0.005), and baseline white blood cell count < 6000/µL (P < 0.001) were significant risk factors. CONCLUSIONS: We determined that ABCC2 -24C>T is significantly associated with grade 3-4 hematological toxicity after platinum plus 5-FU therapy. These findings might contribute to improved treatment strategies for patients with esophageal cancer.

Regulatory T Cell as a Biomarker of Treatment-Free Remission in Patients with Chronic Myeloid Leukemia.

Treatment-free remission (TFR) has become a therapeutic goal in chronic myeloid leukemia (CML), and approximately half of the patients with chronic phase-CML (CML-CP) with deep molecular remission (DMR) by tyrosine-kinase inhibitors (TKIs) have achieved TFR. However, the mechanism of continuous TFR is still unclear, as there are "fluctuate" patients who have BCR-ABL-positive leukemia cells but do not observe obvious relapse. We focused on the immune response and conducted an immune analysis using clinical samples from the imatinib discontinuation study, JALSG-STIM213. The results showed that, in the group that maintained TFR for 3 years, changes in regulatory T (Treg) cells were observed early after stopping imatinib treatment. The effector Treg (eTreg) cells increased transiently at 1 month after stopping imatinib and then returned to baseline at 3 months after stopping imatinib treatment. There was no difference in the Treg phenotype, and CD8+ T cells in the TFR group were relatively activated. High concentrations of imatinib before stopping were negatively correlated with eTreg cells after stopping imatinib. These data suggest immunological involvement in the maintenance of the TFR, and that Treg cells after stopping imatinib might be a biomarker for TFR. Furthermore, high imatinib exposure may have a negative immunological impact on the continuous TFR.

Low-dose dasatinib in older patients with chronic myeloid leukaemia in chronic phase (DAVLEC): a single-arm, multicentre, phase 2 trial.

BACKGROUND: BCR-ABL1 tyrosine kinase inhibitors (TKIs) are commonly initiated in older patients with chronic myeloid leukaemia in the chronic phase at standard doses. However, because of their safety profile in this population, appropriate therapy has not been established. We aimed to investigate whether a lower than standard dose of dasatinib was an appropriate therapy for older patients with chronic myeloid leukaemia in the chronic phase. METHODS: DAsatinib, Very Low-dose, for Elderly CML-CP patients (DAVLEC) was a multicentre, single-arm, phase 2 trial done in 25 Japanese hospitals. We enrolled patients older than 70 years with newly diagnosed chronic myeloid leukaemia in the chronic phase, ECOG performance status 0-2, and no previous treatment for CML other than hydroxyurea within 4 weeks. Second-generation TKI dasatinib was given orally at a starting dose of 20% of the standard dose (20 mg/day). If the treatment was assessed as optimal response at 3 months, 6 months, and 9 months and adverse events were grade 2 or better (according to the NCI Common Toxicity Criteria v 4.0), the same dose was continued. If response was suboptimal and adverse events were grade 2 or better, the dose was increased by 20 mg/day. Once a dose reduction had been made because of a grade 3 or worse adverse event, there were no further dose increases. Treatment was discontinued if assessed as failure (disease progression to the accelerated phase or acute phase). The primary endpoint was the achievement of major molecular response at 12 months, assessed using a per-protocol analysis. This trial is registered at with the UMIN clinical trial registry, UMIN000024548, and has completed its planned observation period. FINDINGS: Between Nov 1, 2016, and Oct 30, 2019, 52 patients received first-line dasatinib therapy at 20 mg/day. The median age at diagnosis was 77·5 years (73·5-83·0). 35 (67%) patients were male and 17 (33%) were female. 31 (60%) of 52 patients reached major molecular response at 12 months (one-sided 95% CI 48-71), with a median follow-up of 366 days (IQR 353-372). Grade 3-4 adverse events were reported in 12 (23%) patients. Neutropenia was the most frequent grade 3-4 adverse event, occurring in three (6%) patients. No treatment-related deaths were observed. INTERPRETATION: Low-dose dasatinib at 20mg/day is worthy of consideration as a starting dose for older patients with newly diagnosed chronic myeloid leukaemia in the chronic phase. However, this dose needs to be further studied in a larger cohort and with a more ethnically diverse population. FUNDING: Bristol-Myers Squibb.