BACKGROUND: Gastrointestinal stromal tumour (GIST) is commonly treated with tyrosine kinase inhibitors (TKIs), but most patients ultimately develop secondary resistance. Cabozantinib, a multi-targeted TKI inhibitor, has activity in patient-derived GIST mouse xenograft models and can overcome compensatory MET signalling occurring on TKI treatment. European Organisation for Treatment of Cancer (EORTC) 1317 'CaboGIST' assessed the safety and activity of cabozantinib in patients with GIST who had progressed on imatinib and sunitinib. METHODS: In this multi-center, open label, single arm phase II study, eligible GIST patients received oral cabozantinib (60 mg) once daily. Primary end-point was the progression-free survival rate at 12 weeks assessed by the local investigator per Response Evaluation Criteria in Solid Tumours 1·1. If at least 21 of the first 41 eligible and evaluable patients were progression-free at week 12, the activity of cabozantinib was sufficient to warrant further exploration according to the A'Hern one-stage study design. FINDINGS: A total of 50 eligible patients started treatment between 02/2017 and 08/2018, including four (8%) still continuing cabozantinib at clinical cut-off (09/2019). The number of 3-weekly treatment cycles ranged from 1 to 30. Among the first 41 eligible and evaluable patients, 24 were progression-free at week 12 (58·5%, 95% confidence interval [CI] 42·0-74·0%). Among all 50 patients, 30 were progression-free at week 12 (60%, 95% CI 45-74%). Seven patients achieved a partial response (14%, 95% CI 6-27%), and 34 had stable disease (68%, 95% CI 53-80%) as best response. Progression was seen in eight patients (16%, 95% CI 7-29%), and one was not evaluable. Disease control was achieved in 41 patients (82%, 95% CI 69-91%). Median progression-free survival was 5·5 months (95% CI 3·6-6·9). The most common adverse events were diarrhoea (76%), palmar-plantar erythrodysesthesia syndrome (60%), fatigue (50%), hypertension (42%), weight loss (40%) and oral mucositis (30%), with 32 (64%) patients requiring dose reductions, 27 (54%) having treatment interruptions and no cabozantinib-related deaths observed. INTERPRETATION: EORTC 1317 met its primary end-point, with 24/41 patients being progression-free at week 12 of treatment. The objective response was 14% with an encouraging disease control rate of 82%. Results of this trial confirm preclinical findings and warrant further exploration of cabozantinib in GIST. CLINICAL TRIAL NUMBERS: EORTC 1317, NCT02216578, EudraCT 2014-000501-13.

• Klíčová slova
• AXL, Cabozantinib, GIST, Gastrointestinal stromal tumour, Imatinib, KIT, MET, Resistance, Sunitinib, VEGFR,
• MeSH
• anilidy aplikace a dávkování   MeSH
• chemorezistence účinky léků   MeSH
• dospělí MeSH
• gastrointestinální nádory farmakoterapie   patologie   MeSH
• gastrointestinální stromální tumory farmakoterapie   sekundární   MeSH
• imatinib mesylát aplikace a dávkování   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• následné studie MeSH
• prognóza MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• pyridiny aplikace a dávkování   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• sunitinib aplikace a dávkování   MeSH
• záchranná terapie * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• anilidy MeSH
• cabozantinib MeSH Prohlížeč
• imatinib mesylát MeSH
• inhibitory proteinkinas MeSH
• pyridiny MeSH
• sunitinib MeSH

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors most often caused by activating mutations of the KIT gene. KIT tyrosine kinase inhibitors provide targeted therapy for the underlying genetic mutation, and adjuvant therapy is indicated for patients who are at significant risk of relapse following GIST resection. This is a report of the safety of imatinib in patients with GIST in the adjuvant setting in an expanded access program. METHODS: In this multicenter, open-label, single-arm trial, safety was assessed based on the frequency of adverse events (AEs). RESULTS: Three hundred patients were treated and analyzed; 40 patients discontinued treatment. Median overall exposure during the program was 181 days (range 9-420); most patients (260/300 treated) completed the study. Six patients had disease recurrence, 4 of whom discontinued. In line with previously published reports, the most frequent AEs were nausea, diarrhea, and periorbital edema. The AEs were mild to moderate in most cases (76%). CONCLUSIONS: These findings are in agreement with the known safety profile of imatinib and confirm the safety of imatinib at 400 mg/day in the adjuvant setting. The incidence of severe AEs was low.

• Klíčová slova
• Adjuvant treatment, Gastrointestinal stromal tumor, Imatinib mesylate, Safety, Tolerability, Tyrosine kinase inhibitors,
• MeSH
• adjuvantní chemoterapie MeSH
• analýza přežití MeSH
• dospělí MeSH
• gastrointestinální nádory farmakoterapie   chirurgie   MeSH
• gastrointestinální stromální tumory farmakoterapie   chirurgie   MeSH
• imatinib mesylát aplikace a dávkování   škodlivé účinky   MeSH
• inhibitory proteinkinas aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• multicentrická studie MeSH
• Názvy látek
• imatinib mesylát MeSH
• inhibitory proteinkinas MeSH

BACKGROUND: Sunitinib is approved for treatment of adults with imatinib-resistant gastrointestinal stromal tumor (GIST) or imatinib intolerance. METHODS: This single-arm, multicenter, multinational phase I/II clinical trial (NCT01396148) enrolled eligible patients aged 6 to < 18 years with advanced, unresectable GIST with non-mutant KIT, or who demonstrated disease progression or intolerance to imatinib. Patients received sunitinib 15 mg/m2 per day, 4-weeks-on/2-weeks-off (schedule 4/2), for ≤ 18 cycles over 24 months. Intra-patient dose escalation to 22.5 and subsequently 30 mg/m2 were permitted based on individual patient tolerability and supported by real-time pharmacokinetics (PK). Primary objective was PK characterization. Secondary objectives included safety, antitumor activity and PK/pharmacodynamic relationships. RESULTS: Six patients were enrolled with median (range) age of 14 (13-16) years. All six patients completed at least three treatment cycles, with one completing all 18 cycles. Five patients had a dose increase to 22.5 mg/m2; two of them had a further dose increase to 30 mg/m2. The average daily dose at cycle 3 was 21.1 mg/m2 (n = 6). Steady-state plasma concentrations were reached by day 15, cycle 1. No tumor responses were observed, but three patients had stabilization of the disease (50%). Median progression-free survival was 5.8 months (95% CI 2.3-not reached). There were no serious adverse events. CONCLUSIONS: The tolerable dose of sunitinib in chemotherapy-naïve pediatric patients is at least 20 mg/m2 on schedule 4/2. The safety profile and PK of sunitinib in pediatric patients with GIST are comparable to those in adults.

• Klíčová slova
• Gastrointestinal stromal tumor, Pediatric, Pharmacokinetics, Safety, Sunitinib,
• MeSH
• chemorezistence MeSH
• doba přežití bez progrese choroby MeSH
• gastrointestinální nádory farmakoterapie   patologie   MeSH
• gastrointestinální stromální tumory farmakoterapie   patologie   MeSH
• imatinib mesylát aplikace a dávkování   MeSH
• lidé MeSH
• mladiství MeSH
• protinádorové látky aplikace a dávkování   škodlivé účinky   farmakokinetika   MeSH
• sunitinib aplikace a dávkování   škodlivé účinky   farmakokinetika   MeSH
• výsledek terapie MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• imatinib mesylát MeSH
• protinádorové látky MeSH
• sunitinib MeSH

• Klíčová slova
• Philadelphia chromosome, acute lymphoblastic leukemia (ALL), pre-tyrosine kinase inhibitors (TKIs),
• MeSH
• akutní lymfatická leukemie diagnóza   farmakoterapie   mortalita   MeSH
• dítě MeSH
• filadelfský chromozom * MeSH
• imatinib mesylát aplikace a dávkování   MeSH
• kojenec MeSH
• lidé MeSH
• míra přežití MeSH
• mladiství MeSH
• následné studie MeSH
• počet leukocytů MeSH
• předškolní dítě MeSH
• přežití bez známek nemoci MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• imatinib mesylát MeSH

A total of 156 patients (age range 1.3-18.0 years, median 13.2 years; 91 (58.3%) male) with newly diagnosed CML (N = 146 chronic phase (CML-CP), N = 3 accelerated phase (CML-AP), N = 7 blastic phase (CML-BP)) received imatinib up-front (300, 400, 500 mg/m2, respectively) within a prospective phase III trial. Therapy response, progression-free survival, causes of treatment failure, and side effects were analyzed in 148 children and adolescents with complete data. Event-free survival rate by 18 months for patients in CML-CP (median follow-up time 25 months, range: 1-120) was 97% (95% CI, 94.2-99.9%). According to the 2006 ELN-criteria complete hematologic response by month 3, complete cytogenetic response (CCyR) by month 12, and major molecular response (MMR) by month 18 were achieved in 98, 63, and 59% of the patients, respectively. By month 36, 86% of the patients achieved CCyR and 74% achieved MMR. Thirty-eight patients (27%) experienced imatinib failure because of unsatisfactory response or intolerance (N = 9). In all, 28/148 patients (19%) underwent stem cell transplantation (SCT). In the SCT sub-cohort 2/23 patients diagnosed in CML-CP, 0/1 in CML-AP, and 2/4 in CML-BP, respectively, died of relapse (N = 3) or SCT-related complications (N = 2). This large pediatric trial extends and confirms data from smaller series that first-line imatinib in children is highly effective.

• MeSH
• biologické markery MeSH
• chronická myeloidní leukemie farmakoterapie   mortalita   patologie   MeSH
• dítě MeSH
• imatinib mesylát aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• inhibitory proteinkinas aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• kojenec MeSH
• kombinovaná terapie MeSH
• kostní dřeň patologie   MeSH
• lidé MeSH
• mladiství MeSH
• neúspěšná terapie MeSH
• předškolní dítě MeSH
• prognóza MeSH
• progrese nemoci MeSH
• protinádorové látky aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• staging nádorů MeSH
• stupeň nádoru MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biologické markery MeSH
• imatinib mesylát MeSH
• inhibitory proteinkinas MeSH
• protinádorové látky MeSH

Leukemias harboring the ETV6-ABL1 fusion represent a rare subset of hematological malignancies with unfavorable outcomes. The constitutively active chimeric Etv6-Abl1 tyrosine kinase can be specifically inhibited by tyrosine kinase inhibitors (TKIs). Although TKIs represent an important therapeutic tool, so far, the mechanism underlying the potential TKI resistance in ETV6-ABL1-positive malignancies has not been studied in detail. To address this issue, we established a TKI-resistant ETV6-ABL1-positive leukemic cell line through long-term exposure to imatinib. ETV6-ABL1-dependent mechanisms (including fusion gene/protein mutation, amplification, enhanced expression or phosphorylation) and increased TKI efflux were excluded as potential causes of resistance. We showed that TKI effectively inhibited the Etv6-Abl1 kinase activity in resistant cells, and using short hairpin RNA (shRNA)-mediated silencing, we confirmed that the resistant cells became independent from the ETV6-ABL1 oncogene. Through analysis of the genomic and proteomic profiles of resistant cells, we identified an acquired mutation in the GNB1 gene, K89M, as the most likely cause of the resistance. We showed that cells harboring mutated GNB1 were capable of restoring signaling through the phosphoinositide-3-kinase (PI3K)/Akt/mTOR and mitogen-activated protein kinase (MAPK) pathways, whose activation is inhibited by TKI. This alternative GNB1K89M-mediated pro-survival signaling rendered ETV6-ABL1-positive leukemic cells resistant to TKI therapy. The mechanism of TKI resistance is independent of the targeted chimeric kinase and thus is potentially relevant not only to ETV6-ABL1-positive leukemias but also to a wider spectrum of malignancies treated by kinase inhibitors.

• MeSH
• chemorezistence účinky léků   MeSH
• fúzní onkogenní proteiny genetika   MeSH
• imatinib mesylát aplikace a dávkování   MeSH
• inhibitory proteinkinas aplikace a dávkování   MeSH
• leukemie farmakoterapie   genetika   patologie   MeSH
• lidé MeSH
• malá interferující RNA genetika   MeSH
• mutace MeSH
• nádorové buněčné linie MeSH
• proteiny vázající GTP - beta-podjednotky genetika   MeSH
• signální transdukce účinky léků   MeSH
• tyrosinkinasy genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fúzní onkogenní proteiny MeSH
• GNB1 protein, human MeSH Prohlížeč
• imatinib mesylát MeSH
• inhibitory proteinkinas MeSH
• malá interferující RNA MeSH
• proteiny vázající GTP - beta-podjednotky MeSH
• TEL-ABL fusion protein, human MeSH Prohlížeč
• tyrosinkinasy MeSH

BACKGROUND: Through high-throughput next-generation sequencing of promoters of solute carrier and ATP-binding cassette genes, which encode drug transporters, we aimed to identify SNPs associated with the response to imatinib administered for first-line treatment of patients with chronic myeloid leukemia. METHODS: In silico analysis using publicly available databases was done to select the SLC and ABC genes and their promoters for the next-generation sequencing. SNPs associated with the imatinib response were identified using Fisher's exact probability tests and subjected to the linkage disequilibrium analyses with regulatory loci of concerned genes. We analyzed cumulative achievement of major molecular response and probability of event free survival in relation to identified SNP genotypes in 129 CML patients and performed multivariate analysis for determination of genotypes as independent predictors of outcome. Gene expression analysis of eight cell lines naturally carrying different genotypes was performed to outline an impact of genotypes on the gene expression. RESULTS: We observed significant differences in the frequencies of the rs460089-GC and rs460089-GG (SLC22A4) genotypes among rs2631365-TC (SLC22A5) genotype carriers that were associated with optimal and non-optimal responses, respectively. Loci rs460089 and rs2631365 were in highly significant linkage disequilibrium with 12 regulatory loci in introns of SLC22A4 and SLC22A5 encoding imatinib transporters. Genotype association analysis with the response to imatinib indicated that rs460089-GC carriers had a significantly higher probability of achieving a stable major molecular response (BCR-ABL1 transcript level below or equal to 0.1% in the international scale). In contrast, the rs460089-GG represented a risk factor for imatinib failure, which was significantly higher in rs460089-GG_rs2631365-TC carriers. CONCLUSIONS: This exploratory study depicted potentially important genetic markers predicting outcome of imatinib treatment, which may be helpful for tailoring therapy in clinical practice.

• Klíčová slova
• CML, Imatinib, Response, SLC,
• MeSH
• buňky K562 MeSH
• chronická myeloidní leukemie farmakoterapie   genetika   MeSH
• genotyp MeSH
• imatinib mesylát aplikace a dávkování   terapeutické užití   MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé MeSH
• mutační rychlost MeSH
• nádorové buněčné linie MeSH
• promotorové oblasti (genetika) MeSH
• proteiny přenášející organické kationty genetika   MeSH
• protinádorové látky aplikace a dávkování   terapeutické užití   MeSH
• rodina nosičů rozpuštěných látek 22, člen 5 genetika   MeSH
• sekvenční analýza DNA metody   MeSH
• symportéry MeSH
• vazebná nerovnováha MeSH
• výsledek terapie MeSH
• vysoce účinné nukleotidové sekvenování metody   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• imatinib mesylát MeSH
• proteiny přenášející organické kationty MeSH
• protinádorové látky MeSH
• rodina nosičů rozpuštěných látek 22, člen 5 MeSH
• SLC22A4 protein, human MeSH Prohlížeč
• SLC22A5 protein, human MeSH Prohlížeč
• symportéry MeSH