Limited data is available on the health-related quality of life (HRQoL) and symptoms of patients with chronic myeloid leukemia (CML) who are in treatment-free remission (TFR). We herein report HRQoL results from the EURO-SKI trial. Patients who had been on tyrosine kinase inhibitors (TKIs) therapy for at least 3 years and achieved MR4 for at least 1 year were enrolled from 11 European countries, and the EORTC QLQ-C30 and the FACIT-Fatigue questionnaires were used to assess HRQoL and fatigue respectively. Patients were categorized into the following age groups: 18-39, 40-59, 60-69 and ≥70 years. Of 728 patients evaluated at baseline, 686 (94%) completed HRQoL assessments. The median age at TKI discontinuation was 60 years. Our findings indicate that HRQoL and symptom trajectories may vary depending on specific age groups, with younger patients benefiting the most. Improvements in patients aged 60 years or older were marginal across several HRQoL and symptom domains. At the time of considering TKI discontinuation, physicians could inform younger patients that they may expect valuable HRQoL benefits. Considering the marginal improvements observed in patients aged 60 years or above, it may be important to further investigate the value of TFR compared to a lowest effective dose approach in this older group of patients.

• MeSH
• chronická myeloidní leukemie * farmakoterapie   MeSH
• dospělí MeSH
• inhibitory tyrosinkinasy * terapeutické užití   MeSH
• kvalita života * MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• přerušení léčby MeSH
• průzkumy a dotazníky MeSH
• senioři MeSH
• únava chemicky indukované   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• inhibitory tyrosinkinasy * MeSH

Blast phase (BP) of chronic myeloid leukemia (CML) still represents an unmet clinical need with a dismal prognosis. Due to the rarity of the condition and the heterogeneity of the biology and clinical presentation, prospective trials and concise treatment recommendations are lacking. Here we present the analysis of the European LeukemiaNet Blast Phase Registry, an international collection of the clinical presentation, treatment and outcome of blast phases which had been diagnosed in CML patients after 2015. Data reveal the expected heterogeneity of the entity, lacking a clear treatment standard. Outcomes remain dismal, with a median overall survival of 23.8 months (median follow up 27.8 months). Allogeneic stem cell transplantation (alloSCT) increases the rate of deep molecular responses. De novo BP and BP evolving from a previous CML do show slightly different features, suggesting a different biology between the two entities. Data show that outside clinical trials and in a real-world setting treatment of blast phase is individualized according to disease- and patient-related characteristics, with the aim of blast clearance prior to allogeneic stem cell transplantation. AlloSCT should be offered to all patients eligible for this procedure.

• MeSH
• blastická krize * patologie   MeSH
• chronická myeloidní leukemie * farmakoterapie   patologie   terapie   mortalita   MeSH
• dospělí MeSH
• homologní transplantace MeSH
• inhibitory tyrosinkinasy * terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• management nemoci MeSH
• míra přežití MeSH
• mladiství MeSH
• mladý dospělý MeSH
• následné studie MeSH
• prognóza MeSH
• registrace * MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• transplantace hematopoetických kmenových buněk metody   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• inhibitory tyrosinkinasy * MeSH

• MeSH
• chronická myeloidní leukemie * farmakoterapie   MeSH
• chronická nemoc MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• inhibitory tyrosinkinasy MeSH
• lidé MeSH
• myeloidní leukemie * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• inhibitory proteinkinas MeSH
• inhibitory tyrosinkinasy MeSH

Membrane transporters are important determinants of drug bioavailability. Their expression and activity affect the intracellular drug concentration in leukemic cells impacting response to therapy. Pharmacogenomics represents genetic markers that reflect allele arrangement of genes encoding drug transporters associated with treatment response. In previous work, we identified SNP rs460089 located in the promotor of SLC22A4 gene encoding imatinib transporter OCTN1 as influential on response of patients with chronic myeloid leukemia treated with imatinib. Patients with rs460089-GC pharmacogenotype had significantly superior response to first-line imatinib treatment compared to patients with rs460089-GG. This study investigated whether pharmacogenotypes of rs460089 are associated with sustainability of treatment-free remission (TFR) in patients from the EUROpean Stop Kinase Inhibitor (EURO-SKI) trial. In the learning sample, 176 patients showed a significantly higher 6-month probability of molecular relapse free survival (MRFS) in patients with GC genotype (73%, 95% CI: 60-82%) compared to patients with GG (51%, 95% CI: 41-61%). Also over time, patients with GC genotype had significantly higher MRFS probabilities compared with patients with GG (HR: 0.474, 95% CI: 0.280-0.802, p = 0.0054). Both results were validated with data on 93 patients from the Polish STOP imatinib study. In multiple regression models, in addition to the investigated genotype, duration of TKI therapy (EURO-SKI trial) and duration of deep molecular response (Polish study) were identified as independent prognostic factors. The SNP rs460089 was found as an independent predictor of TFR.

• MeSH
• chronická myeloidní leukemie * farmakoterapie   genetika   MeSH
• imatinib mesylát terapeutické užití   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• membránové transportní proteiny terapeutické užití   MeSH
• prognóza MeSH
• protinádorové látky * škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• imatinib mesylát MeSH
• inhibitory proteinkinas MeSH
• membránové transportní proteiny MeSH
• protinádorové látky * MeSH

Recent studies have underscored the importance of gamma-delta (γδ) T cells in mediating potent MHC-unrestricted cytotoxicity in numerous malignancies. Here, we analyzed Vδ1 and Vδ2 γδ T cell subsets in newly diagnosed chronic myeloid leukemia (CML) patients (n = 40) who had initiated tyrosine kinase inhibitor (TKI) therapy including imatinib (n = 22), nilotinib (n = 14) and dasatinib (n = 4). Patient peripheral blood samples were analyzed at diagnosis and monitored prospectively at 3, 6, 12 and 18 months post-TKI. γδ T cells isolated from healthy donors and CML patients were used against K562, LAMA-84 and KYO-1 cell lines and against primary CML cells in cytotoxicity assays. We found large expansions of Vδ1 and Vδ2 T cells in patients at diagnosis compared to age-matched healthy donors (n = 40) (p < 0.0001). The γδ T cell reconstitution in patients on imatinib and also on nilotinib showed significant reductions of Vδ1 T cell and Vδ2 T cell absolute counts at 3 months compared to diagnosis. Importantly, Vδ1 and Vδ2 T absolute cell counts remained at normal levels from 3 months throughout the follow-up. Next, we observed susceptibility to specific lysis of primary CML tumor cells by Vδ1 T cells from healthy donors. Furthermore, we determined inherent cytotoxic reactivity by autologous patients' Vδ1 T lymphocytes against primary CML tumor cells. Finally, the TCR clonality profiles showed in CML patients mostly polyclonal repertoires regardless of the TKI. Our results provide further evidence into γδ T cell antileukemia immunity in CML that might be beneficial for long-term disease control and treatment outcome.

• Klíčová slova
• Chronic myeloid leukemia, Clonality, Gamma-delta T cells, Tumor immunotherapy,
• MeSH
• buněčné linie MeSH
• chronická myeloidní leukemie * farmakoterapie   metabolismus   MeSH
• imatinib mesylát farmakologie   terapeutické užití   MeSH
• lidé MeSH
• myeloidní leukemie * metabolismus   MeSH
• receptory antigenů T-buněk gama-delta metabolismus   MeSH
• T-lymfocyty - podskupiny MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• imatinib mesylát MeSH
• receptory antigenů T-buněk gama-delta MeSH

The treatment outcome in patients with chronic myeloid leukaemia (CML) in blast crisis (BC) is unsatisfactory despite the use of allogeneic stem cell transplantation (ASCT). Moreover, in some patients ASCT is contraindicated, with limited treatment options. We report the case series of two patients with lymphoid BC CML in whom ASCT was not approachable. The first patient developed BC two months after diagnosis in association with dic(7;9)(p11.2;p11.2) and T315I mutation. Blast crisis with central nervous system leukemic involvement and K611N mutation of the SETD2 gene developed abruptly in the second patient five years after ceasing treatment with nilotinib in major molecular response (MMR) at the patient's request. Both underwent one course of chemotherapy in combination with rituximab and imatinib, followed by dasatinib and interferon α (INFα) treatment in the first and dasatinib alone in the second case. Deep molecular response (DMR; MR 4.0) was achieved within a short time in both cases. It is probable that DMR was caused by a specific immune response to CML cells, described in both agents. The challenging medical condition that prompted these case series, and the subsequent results, suggest a re-visit to the use of a combination of well-known drugs as an area for further investigation.

• Klíčová slova
• blast crisis, chronic myeloid leukaemia, interferon alpha, tyrosine kinase inhibitor,
• MeSH
• blastická krize * farmakoterapie   genetika   MeSH
• chronická myeloidní leukemie * farmakoterapie   genetika   MeSH
• dasatinib terapeutické užití   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• interferon alfa terapeutické užití   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• dasatinib MeSH
• inhibitory proteinkinas MeSH
• interferon alfa MeSH

• MeSH
• bcr-abl fúzní proteiny genetika   MeSH
• časové faktory MeSH
• chronická myeloidní leukemie farmakoterapie   genetika   patologie   MeSH
• indukce remise MeSH
• inhibitory proteinkinas škodlivé účinky   MeSH
• klinické zkoušky jako téma metody   MeSH
• lidé MeSH
• lokální recidiva nádoru chemicky indukované   diagnóza   epidemiologie   MeSH
• nenasazení léčby statistika a číselné údaje   MeSH
• prognóza MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH
• Názvy látek
• bcr-abl fúzní proteiny MeSH
• inhibitory proteinkinas MeSH

This work investigated patient-specific genomic BCR-ABL1 fusions as markers of measurable residual disease (MRD) in chronic myeloid leukaemia, with a focus on relevance to treatment-free remission (TFR) after achievement of deep molecular response (DMR) on tyrosine kinase inhibitor (TKI) therapy. DNA and mRNA BCR-ABL1 measurements by qPCR were compared in 2189 samples (129 patients) and by digital PCR in 1279 sample (62 patients). A high correlation was found at levels of disease above MR4, but there was a poor correlation for samples during DMR. A combination of DNA and RNA MRD measurements resulted in a better prediction of molecular relapse-free survival (MRFS) after TKI stop (n = 17) or scheduled interruption (n = 25). At 18 months after treatment cessation, patients with stopped or interrupted TKI therapy who were DNA negative/RNA negative during DMR maintenance (green group) had an MRFS of 80% and 100%, respectively, compared with those who were DNA positive/RNA negative (MRFS = 57% and 67%, respectively; yellow group) or DNA positive/RNA positive (MRFS = 20% for both cohorts; red group). Thus, we propose a "traffic light" stratification as a TFR predictor based on DNA and mRNA BCR-ABL1 measurements during DMR maintenance before TKI cessation.

• MeSH
• bcr-abl fúzní proteiny genetika   MeSH
• chronická myeloidní leukemie farmakoterapie   genetika   mortalita   MeSH
• dospělí MeSH
• indukce remise MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• messenger RNA analýza   MeSH
• nenasazení léčby MeSH
• polymerázová řetězová reakce metody   MeSH
• reziduální nádor MeSH
• senioři MeSH
• tyrosinkinasy antagonisté a inhibitory   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• bcr-abl fúzní proteiny MeSH
• BCR-ABL1 fusion protein, human MeSH Prohlížeč
• inhibitory proteinkinas MeSH
• messenger RNA MeSH
• tyrosinkinasy MeSH

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.

• MeSH
• analýza přežití MeSH
• aniliny terapeutické užití   MeSH
• bcr-abl fúzní proteiny antagonisté a inhibitory   genetika   metabolismus   MeSH
• chinoliny terapeutické užití   MeSH
• chronická myeloidní leukemie diagnóza   farmakoterapie   genetika   mortalita   MeSH
• dasatinib terapeutické užití   MeSH
• exprese genu MeSH
• imatinib mesylát terapeutické užití   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• klinické rozhodování MeSH
• konsensuální konference jako téma MeSH
• kvalita života MeSH
• lidé MeSH
• management nemoci MeSH
• monitorování fyziologických funkcí MeSH
• naděje dožití trendy   MeSH
• nitrily terapeutické užití   MeSH
• protinádorové látky terapeutické užití   MeSH
• pyrimidiny terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• aniliny MeSH
• bcr-abl fúzní proteiny MeSH
• BCR-ABL1 fusion protein, human MeSH Prohlížeč
• bosutinib MeSH Prohlížeč
• chinoliny MeSH
• dasatinib MeSH
• imatinib mesylát MeSH
• inhibitory proteinkinas MeSH
• nilotinib MeSH Prohlížeč
• nitrily MeSH
• protinádorové látky MeSH
• pyrimidiny MeSH

PURPOSE: The advent of tyrosine kinase inhibitor (TKI) therapies has revolutionized the treatment of chronic myeloid leukemia (CML). The European LeukemiaNet (ELN) recommends quantification of BCR-ABL1 transcripts by real-time quantitative PCR every 3 months during TKI treatment. Since a proportion of patients in deep molecular response (DMR: MR4, MR4.5, MR5) maintain remission after treatment stop, assessment of DMR is crucial. However, systematically collected molecular data, monitored with sensitive standardized assays, are not available outside clinical trials. METHODS: Data were collected on the standardized assessment of molecular response in the context of real-life practice. BCR-ABL1 transcript levels after > 2 years of TKI therapy were evaluated for DMR by local laboratories as well as standardized EUTOS laboratories. Since standardized molecular monitoring is a prerequisite for treatment discontinuation, central surveillance of the performance of the participating laboratories was carried out. RESULTS: Between 2014 and 2017, 3377 peripheral blood samples from 1117 CML patients were shipped to 11 standardized reference laboratories in six European countries. BCR-ABL1 transcript types were b3a2 (41.63%), b2a2 (29.99%), b2a2/b3a2 (3.58%) and atypical (0.54%). For 23.72% of the patients, the initial transcript type had not been reported. Response levels (EUTOS laboratory) were: no MMR, n = 197 (6.51%); MMR, n = 496 (16.40%); MR4, n = 685 (22.64%); MR4.5, n = 937 (30.98%); MR5, n = 710 (23.47%). With a Cohen's kappa coefficient of 0.708, a substantial agreement between EUTOS-certified and local laboratories was shown. CONCLUSIONS: Multicenter DMR assessment is feasible in the context of real-life clinical practice in Europe. Information on the BCR-ABL1 transcript type at diagnosis is crucial to accurately monitor patients' molecular response during or after TKI therapy.

• Klíčová slova
• BCR–ABL, CML, Chronic myeloid leukemia, Deep molecular remission, Eureka, Molecular monitoring, Standardization, TFR, Treatment-free remission,
• MeSH
• chronická fáze myeloidní leukemie krev   farmakoterapie   genetika   MeSH
• chronická myeloidní leukemie krev   farmakoterapie   genetika   MeSH
• dospělí MeSH
• inhibitory proteinkinas aplikace a dávkování   MeSH
• kohortové studie MeSH
• laboratoře normy   statistika a číselné údaje   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• registrace MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• inhibitory proteinkinas MeSH