Léčba chronické myeloidní leukemie se opírá o tyrosinkinázové inhibitory. V současnosti je v našich podmínkách k dispozici pět přípravků působících cestou ATP vazebné domény (imatinib, nilotinib, dasatinib, bosutinib a ponatinib), díky nimž se podařilo 10leté přežití pacientů s chronickou myeloidní leukemií zvýšit na téměř 84 %. K nim přibyl nejnovější přírůstek působící cestou vazby do myristoylové kapsy – asciminib. Na výsledky klinických studií ukazující dobrou účinnost i příznivý profil nežádoucích účinků asciminibu navázaly zkušenosti z reálné klinické praxe, které závěry klinických studií potvrdily. V předkládané práci jsou jednak přiblíženy výsledky klinických studií i znalosti z reálné klinické praxe, a následně prezentovány tři případy mladých pacientů, kteří byli léčeni asciminibem ve třetí linii jak pro selhání, tak pro nesnášenlivost předchozí terapie.

The chronic myeloid leukemia treatment is based on tyrosine kinase inhibitors. Currently, there are five available drugs in our conditions that act through the ATP-binding domain (imatinib, nilotinib, dasatinib, bosutinib, and ponatinib), and as a result, the 10-years survival rate for patients with chronic myeloid leukemia is nearly 84%. There is also the newest drug that works through binding to the myristoyl pocket - asciminib. The results of clinical studies showing good efficacy and a favorable side effects profile of asciminib have been reinforced by experiences from real clinical practice that confirmed the findings of the clinical studies. In the submitted work, the results of clinical studies and knowledge from real clinical practice are presented, followed by three cases of young patients who were treated with asciminib in the third line for both failure and intolerance to previous therapy.

• Klíčová slova
• asciminib,
• MeSH
• bcr-abl fúzní proteiny genetika   účinky léků   MeSH
• chronická myeloidní leukemie * diagnóza   farmakoterapie   MeSH
• inhibitory tyrosinkinasy * farmakologie   klasifikace   terapeutické užití   MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nežádoucí účinky léčiv MeSH
• protein přenášející acyl účinky léků   MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

BACKGROUND: Up to 65% of patients with chronic myeloid leukemia (CML) who are treated with imatinib do not achieve sustained deep molecular response, which is required to attempt treatment-free remission. Asciminib is the only approved BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket. This unique mechanism of action allows asciminib to be combined with adenosine triphosphate-competitive tyrosine kinase inhibitors to prevent resistance and enhance efficacy. The phase II ASC4MORE trial investigated the strategy of adding asciminib to imatinib in patients who have not achieved deep molecular response with imatinib. METHODS: In ASC4MORE, 84 patients with CML in chronic phase not achieving deep molecular response after ≥ 1 year of imatinib therapy were randomized to asciminib 40 or 60 mg once daily (QD) add-on to imatinib 400 mg QD, continued imatinib 400 mg QD, or switch to nilotinib 300 mg twice daily. RESULTS: More patients in the asciminib 40- and 60-mg QD add-on arms (19.0% and 28.6%, respectively) achieved MR4.5 (BCR::ABL1 ≤ 0.0032% on the International Scale) at week 48 (primary endpoint) than patients in the continued imatinib (0.0%) and switch to nilotinib (4.8%) arms. Fewer patients discontinued asciminib 40- and 60-mg QD add-on treatment (14.3% and 23.8%, respectively) than imatinib (76.2%, including crossover patients) and nilotinib (47.6%). Asciminib add-on was tolerable, with rates of AEs and AEs leading to discontinuation less than those with nilotinib, although higher than those with continued imatinib (as expected in these patients who had already been tolerating imatinib for ≥ 1 year). No new or worsening safety signals were observed with asciminib add-on vs the known asciminib monotherapy safety profile. CONCLUSIONS: Overall, these results support asciminib add-on as a treatment strategy to help patients with CML in chronic phase stay on therapy to safely achieve rapid and deep response, although further investigation is needed before this strategy is incorporated into clinical practice. TRIAL REGISTRATION: NCT03578367.

• MeSH
• bcr-abl fúzní proteiny antagonisté a inhibitory   MeSH
• chronická myeloidní leukemie * farmakoterapie   MeSH
• dospělí MeSH
• imatinib mesylát * terapeutické užití   MeSH
• inhibitory proteinkinas terapeutické užití   aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• následné studie MeSH
• niacinamid analogy a deriváty   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   MeSH
• pyrazoly MeSH
• pyrimidiny terapeutické užití   aplikace a dávkování   MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: The BCR::ABL1 is a hallmark of chronic myeloid leukemia (CML) and is also found in acute lymphoblastic leukemia (ALL). Most genomic breaks on the BCR side occur in two regions - Major and minor - leading to p210 and p190 fusion proteins, respectively. METHODS: By multiplex long-distance PCR or next-generation sequencing technology we characterized the BCR::ABL1 genomic fusion in 971 patients (adults and children, with CML and ALL: pediatric ALL: n = 353; pediatric CML: n = 197; adult ALL: n = 166; adult CML: n = 255 patients) and designed "Break-App" web tool to allow visualization and various analyses of the breakpoints. Pearson's Chi-Squared test, Kolmogorov-Smirnov test and logistic regression were used for statistical analyses. RESULTS: Detailed analysis showed a non-random distribution of breaks in both BCR regions, whereas ABL1 breaks were distributed more evenly. However, we found a significant difference in the distribution of breaks between CML and ALL. We found no association of breakpoints with any type of interspersed repeats or DNA motifs. With a few exceptions, the primary structure of the fusions suggests non-homologous end joining being responsible for the BCR and ABL1 gene fusions. Analysis of reciprocal ABL1::BCR fusions in 453 patients showed mostly balanced translocations without major deletions or duplications. CONCLUSIONS: Taken together, our data suggest that physical colocalization and chromatin accessibility, which change with the developmental stage of the cell (hence the difference between ALL and CML), are more critical factors influencing breakpoint localization than presence of specific DNA motifs.

• MeSH
• akutní lymfatická leukemie * genetika   patologie   MeSH
• bcr-abl fúzní proteiny * genetika   MeSH
• body zlomu chromozomu * MeSH
• chronická myeloidní leukemie * genetika   patologie   MeSH
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH

Clinical experience with tyrosine kinase inhibitors (TKIs) over the past two decades has shown that, despite the apparent therapeutic benefit, nearly 30% of patients with chronic myelogenous leukemia (CML) display primary resistance or intolerance to TKIs, and approximately 25% of those treated are forced to switch TKIs at least once during therapy due to acquired resistance. Safe and effective treatment modalities targeting leukemic clones that escape TKI therapy could hence be game changers in the professional management of these patients. Here, we aimed to investigate the efficacy of a novel therapeutic oligonucleotide of unconventional design, called ASP210, to reduce BCR-ABL1 mRNA levels in TKI-resistant CML cells, with the assumption of inducing their apoptosis. Imatinib- and dasatinib-resistant sublines of BCR-ABL1-positive MOLM-7 and CML-T1 cells were established and exposed to 0.25 and 2.5 μM ASP210 for 10 days. RT-qPCR showed a remarkable reduction of the target mRNA level by >99% after a single application. Cell viability was monitored daily by trypan blue staining. In response to the lack of driver oncoprotein BCR-ABL1, TKI-resistant CML cells underwent apoptosis regardless of the presence of the clinically relevant T315I mutation by day 5 after redosing with ASP210. The effect was selective for cancer cells, indicating a favorable safety profile for this therapeutic modality. Furthermore, the spontaneous uptake and high intracellular concentrations of ASP210 suggest its potential to be effective at relatively low doses. The present findings suggest that ASP210 is a promising therapeutic avenue for patients with CML who fail to respond to TKI therapy.NEW & NOTEWORTHY Effective treatment modalities targeting leukemic clones that escape tyrosine kinase inhibitor (TKI) therapy could be game changers in the professional management of patients displaying primary resistance, intolerance, or acquired resistance to TKIs. Although delivering authentic innovations today is more complex than ever, we developed a highly potent and safe oligonucleotide-based modality against BCR-ABL1 mRNA named ASP210 that effectively induces cell death in BCR-ABL1-positive TKI-resistant cells while sparing BCR-ABL1-negative healthy cells.

• MeSH
• apoptóza * účinky léků   MeSH
• bcr-abl fúzní proteiny * genetika   antagonisté a inhibitory   metabolismus   MeSH
• chemorezistence * účinky léků   MeSH
• chronická myeloidní leukemie * farmakoterapie   genetika   patologie   MeSH
• dasatinib farmakologie   MeSH
• imatinib mesylát * farmakologie   terapeutické užití   MeSH
• inhibitory proteinkinas * farmakologie   MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• oligonukleotidy * farmakologie   MeSH
• protinádorové látky farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Patients with newly diagnosed chronic myeloid leukemia (CML) need long-term therapy with high efficacy and safety. Asciminib, a BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket, may offer better efficacy and safety and fewer side effects than currently available frontline ATP-competitive tyrosine kinase inhibitors (TKIs). METHODS: In a phase 3 trial, patients with newly diagnosed CML were randomly assigned in a 1:1 ratio to receive either asciminib (80 mg once daily) or an investigator-selected TKI, with randomization stratified by European Treatment and Outcome Study long-term survival score category (low, intermediate, or high risk) and by TKI selected by investigators before randomization (including imatinib and second-generation TKIs). The primary end points were major molecular response (defined as BCR::ABL1 transcript levels ≤0.1% on the International Scale [IS]) at week 48, for comparisons between asciminib and investigator-selected TKIs and between asciminib and investigator-selected TKIs in the prerandomization-selected imatinib stratum. RESULTS: A total of 201 patients were assigned to receive asciminib and 204 to receive investigator-selected TKIs. The median follow-up was 16.3 months in the asciminib group and 15.7 months in the investigator-selected TKI group. A major molecular response at week 48 occurred in 67.7% of patients in the asciminib group, as compared with 49.0% in the investigator-selected TKI group (difference, 18.9 percentage points; 95% confidence interval [CI], 9.6 to 28.2; adjusted two-sided P<0.001]), and in 69.3% of patients in the asciminib group as compared with 40.2% in the imatinib group within the imatinib stratum (difference, 29.6 percentage points; 95% CI, 16.9 to 42.2; adjusted two-sided P<0.001). The percentage of patients with a major molecular response at week 48 was 66.0% with asciminib and 57.8% with TKIs in the second-generation TKI stratum (difference, 8.2 percentage points; 95% CI, -5.1 to 21.5). Adverse events of grade 3 or higher and events leading to discontinuation of the trial regimen were less frequent with asciminib (38.0% and 4.5%, respectively) than with imatinib (44.4% and 11.1%) and second-generation TKIs (54.9% and 9.8%). CONCLUSIONS: In this trial comparing asciminib with investigator-selected TKIs and imatinib, asciminib showed superior efficacy and a favorable safety profile in patients with newly diagnosed chronic-phase CML. Direct comparison between asciminib and second-generation TKIs was not a primary objective. (Funded by Novartis; ASC4FIRST ClinicalTrials.gov number, NCT04971226).

• MeSH
• bcr-abl fúzní proteiny * antagonisté a inhibitory   genetika   MeSH
• chronická myeloidní leukemie * farmakoterapie   MeSH
• dospělí MeSH
• imatinib mesylát * terapeutické užití   škodlivé účinky   MeSH
• inhibitory tyrosinkinasy * aplikace a dávkování   škodlivé účinky   MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• niacinamid aplikace a dávkování   škodlivé účinky   analogy a deriváty   MeSH
• protinádorové látky * aplikace a dávkování   škodlivé účinky   MeSH
• pyrazoly * aplikace a dávkování   škodlivé účinky   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, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

• MeSH
• bcr-abl fúzní proteiny genetika   MeSH
• blastická krize * genetika   farmakoterapie   patologie   MeSH
• chronická myeloidní leukemie * farmakoterapie   genetika   patologie   MeSH
• imidazoly * terapeutické užití   aplikace a dávkování   MeSH
• inhibitory proteinkinas terapeutické užití   farmakologie   MeSH
• lidé MeSH
• mutace * MeSH
• myši MeSH
• niacinamid analogy a deriváty   MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• pyrazoly MeSH
• pyridaziny * terapeutické užití   aplikace a dávkování   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• dopisy MeSH

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The European Stop Kinase Inhibitors (EURO-SKI) study is the largest clinical trial for investigating the cessation of tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia in stable deep molecular remission (DMR). Among 728 patients, 434 patients (61%; 95% CI, 57 to 64) remained in major molecular response (MMR) at 6 months and 309 patients of 678 (46%; 95% CI, 42 to 49) at 36 months. Duration of TKI treatment and DMR before TKI stop were confirmed as significant factors for the prediction of MMR loss at 6 months. In addition, the type of BCR::ABL1 transcript was identified as a prognostic factor. For late MMR losses after 6 months, TKI treatment duration, percentage of blasts in peripheral blood, and platelet count at diagnosis were significant factors in multivariate analysis. For the entire study period of 36 months, multiple logistic regression models confirmed duration of treatment, blasts, and transcript type as independent factors for MMR maintenance. In addition to the duration of treatment, transcript type as well as blasts in peripheral blood at diagnosis should be considered as important factors to predict treatment-free remission.

• MeSH
• bcr-abl fúzní proteiny genetika   antagonisté a inhibitory   MeSH
• chronická myeloidní leukemie * farmakoterapie   genetika   MeSH
• dospělí MeSH
• imatinib mesylát terapeutické užití   MeSH
• indukce remise * MeSH
• inhibitory proteinkinas * terapeutické užití   MeSH
• inhibitory tyrosinkinasy MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• prognóza MeSH
• pyrimidiny terapeutické užití   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
• multicentrická studie MeSH
• Geografické názvy
• Evropa MeSH

• MeSH
• bcr-abl fúzní proteiny genetika   MeSH
• chemorezistence genetika   MeSH
• chronická myeloidní leukemie * genetika   MeSH
• chronická nemoc MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• mutace MeSH
• myeloidní leukemie * MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH

• Klíčová slova
• asciminib, remise bez nutnosti terapie,
• MeSH
• bcr-abl fúzní proteiny analýza   antagonisté a inhibitory   MeSH
• chronická myeloidní leukemie * diagnóza   farmakoterapie   genetika   MeSH
• cílená molekulární terapie * MeSH
• indukce remise MeSH
• inhibitory tyrosinkinasy farmakologie   terapeutické užití   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

• MeSH
• akutní lymfatická leukemie * farmakoterapie   genetika   MeSH
• bcr-abl fúzní proteiny genetika   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH