The influence of t(v;22) sole, major route ACAs all (+8, n = 14; +Ph, n = 10; +19, n = 1), and -Y sole on progression-free survival. Survival curves are compared with those of patients with the standard t(9;22) translocation. Other ACAs or complex karyotypes did not influence survival.
- MeSH
- chromozomální aberace * MeSH
- chronická myeloidní leukemie * genetika diagnóza mortalita MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- lidské chromozomy, pár 22 genetika MeSH
- lidské chromozomy, pár 9 genetika MeSH
- přežití bez známek nemoci MeSH
- prognóza MeSH
- senioři MeSH
- translokace genetická * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- dopisy 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
BACKGROUND: Unmet medical needs remain in patients with red blood cell transfusion-dependent (RBC-TD) lower-risk myelodysplastic syndromes (LR-MDS) who are not responding to or are ineligible for erythropoiesis-stimulating agents (ESAs). Imetelstat, a competitive telomerase inhibitor, showed promising results in a phase 2 trial. We aimed to compare the RBC transfusion independence (RBC-TI) rate with imetelstat versus placebo in patients with RBC-TD LR-MDS. METHODS: In phase 3 of IMerge, a double-blind, placebo-controlled trial conducted in 118 sites including university hospitals, cancer centres, and outpatient clinics in 17 countries, patients (aged ≥18 years) with ESA-relapsed, ESA-refractory, or ESA-ineligible LR-MDS (low or intermediate-1 risk disease as per International Prognostic Scoring System [IPSS] criteria) were randomly assigned via a computer-generated schedule (2:1) to receive imetelstat 7·5 mg/kg or placebo, administered as a 2-h intravenous infusion, every 4 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent. Randomisation was stratified by previous RBC transfusion burden and IPSS risk group. Patients, investigators, and those analysing the data were masked to group assignment. The primary endpoint was 8-week RBC-TI, defined as the proportion of patients without RBC transfusions for at least 8 consecutive weeks starting on the day of randomisation until subsequent anti-cancer therapy, if any. Primary efficacy analyses were performed in the intention-to-treat population, and safety analyses were conducted in patients who received at least one dose of trial medication or placebo. This trial is registered with ClinicalTrials.gov (NCT02598661; substudy active and recruiting). FINDINGS: Between Sept 11, 2019, and Oct 13, 2021, 178 patients were enrolled and randomly assigned (118 to imetelstat and 60 to placebo). 111 (62%) were male and 67 (38%) were female. 91 (77%) of 118 patients had discontinued treatment by data cutoff in the imetelstat group versus 45 (75%) in the placebo group; a further one patient in the placebo group did not receive treatment. Median follow-up was 19·5 months (IQR 12·0-23·4) in the imetelstat group and 17·5 months (12·1-22·7) in the placebo group. In the imetelstat group, 47 (40% [95% CI 30·9-49·3]) patients had an RBC-TI of at least 8 weeks versus nine (15% [7·1-26·6]) in the placebo group (rate difference 25% [9·9 to 36·9]; p=0·0008). Overall, 107 (91%) of 118 patients receiving imetelstat and 28 (47%) of 59 patients receiving placebo had grade 3-4 treatment-emergent adverse events. The most common treatment-emergent grade 3-4 adverse events in patients taking imetelstat were neutropenia (80 [68%] patients who received imetelstat vs two [3%] who received placebo) and thrombocytopenia (73 [62%] vs five [8%]). No treatment-related deaths were reported. INTERPRETATION: Imetelstat offers a novel mechanism of action with durable transfusion independence (approximately 1 year) and disease-modifying activity for heavily transfused patients with LR-MDS who are not responding to or are ineligible for ESAs. FUNDING: Janssen Research & Development before April 18, 2019, and Geron Corporation thereafter.
- MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- erytropoéza MeSH
- lidé MeSH
- mladiství MeSH
- myelodysplastické syndromy * farmakoterapie MeSH
- oligonukleotidy * MeSH
- protokoly protinádorové kombinované chemoterapie MeSH
- trombocytopenie * farmakoterapie MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: To evaluate the outcomes of first-line imatinib versus nilotinib treatment for chronic myeloid leukemia in the chronic phase (CML-CP) in real-world clinical practice. METHODS: A propensity score analysis was performed to eliminate imbalances between the treatment groups. In the analysis, 163 patients in the nilotinib group and 163 patients in the matched imatinib group were retrospectively evaluated. RESULTS: Nilotinib-treated patients achieved complete cytogenetic response (CCyR) and major molecular response more rapidly than imatinib-treated patients. However, there was no significant difference in 5-year overall survival (OS) or progression-free survival (PFS) between the two groups (OS: 94.3% vs. 90.5%, p = 0.602; PFS: 92.9% vs. 88.0%, p = 0.614). Nilotinib-treated patients had a higher failure-free survival (FFS) and event-free survival (EFS) than imatinib-treated patients (FFS: 71.7% vs. 54.3%, p = 0.040; EFS: 71.7% vs. 53.5%, p = 0.025). CONCLUSIONS: This retrospective analysis from clinical practice did not confirm any benefit of frontline nilotinib treatment for OS and PFS; however, it did demonstrate higher FFS and EFS in the nilotinib cohort.
- MeSH
- chronická myeloidní leukemie * farmakoterapie mortalita MeSH
- doba přežití bez progrese choroby MeSH
- dospělí MeSH
- imatinib mesylát * terapeutické užití škodlivé účinky MeSH
- inhibitory proteinkinas terapeutické užití škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- protinádorové látky terapeutické užití škodlivé účinky MeSH
- pyrimidiny * terapeutické užití škodlivé účinky MeSH
- retrospektivní studie MeSH
- senioři MeSH
- tendenční skóre MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Luspatercept, an inhibitor of the transforming growth factor beta (TGF-β) pathway, is a novel treatment for anemic patients with lower-risk myelodysplastic syndromes (MDS) with transfusion dependence (TD) who do not respond to erythropoiesis-stimulating agents (ESA) therapy or are not suitable candidates for this treatment. We present real-world experience with luspatercept therapy from two hematology centers in the Czech Republic. METHODS: By January 2024, 54 MDS patients (33 men, 21 women) with a median age of 74 years (range, 55-95) were treated with luspatercept ± ESA at two Charles University hematology centers in Prague and Hradec Králové. According to the WHO 2016 classification, the cohort included 32 MDS-RS-MLD, seven MDS-MLD, two patients with 5q- + ring sideroblasts (RS), 12 RARS-T, and 1 patient with CMML-0 + RS. SF3B1 mutation data were available for 45 patients. All patients were in the IPSS-R and IPSS-M lower-risk groups (except four IPSS-M high). The median follow-up was 17 months (range, 1-54). All patients were transfusion-dependent. Thirty-five (64.8%) patients had a high transfusion burden (HTB) with ≥ 4 transfusion units (TU)/8 weeks, and 19 (35.2%) had a low transfusion burden (LTB) (< 4 TU/8 weeks). The median time between diagnosis and initiation of luspatercept was 27 months (range, 4-156). ESA were used prior to luspatercept in 45 patients, and luspatercept was used as first-line treatment in nine patients. Thirty-one (61%) patients were treated simultaneously with ESA. RESULTS: Only patients who received luspatercept for ≥ 8 weeks (51 patients) were assessed. We evaluated the achievement of transfusion independence (TI) lasting 8, 12, 16, and 24 weeks. Thirty-two (62.7%) patients achieved TI for ≥ 8 weeks, 31 (60.7%) for ≥ 12 weeks, 29 (56.8%) for ≥ 16 weeks, and 25 (49%) for ≥ 24 weeks. Hematologic improvement (HI) without TI was achieved in six patients (11.7%). Overall, HI + TI was achieved in 38 patients (74.5%). Epoetin alfa was used simultaneously in 31 patients (60.7%). In 21 (55.2%) of all responding patients, concomitant therapy with epoetin alfa led to an improved response, with 16 reaching TI. Thirteen (25.5%) patients were nonresponders. Eight (21%) patients experienced therapy failure and became transfusion-dependent again. Optimal response required a gradual increase in the luspatercept dose to 1.75 mg/kg in up to 35 patients, with 23 responders (TI + HI). Response rates varied by transfusion burden: 79% in LTB and 50% in HTB reached TI. Of RS+ patients, 70% reached TI, while only one out of five RS- patients achieved TI. Among 39 SF3B1-positive patients, 61.6% achieved TI. In the low and very low IPSS-M groups, 86% of patients responded (TI + HI), compared to 62% in the moderate-low group. Luspatercept was well-tolerated, with no adverse events higher than grade II toxicity. CONCLUSION: We have demonstrated in real-world clinical practice that luspatercept is a very effective agent, even in an unselected, pretreated, significantly TD MDS population. The effect was particularly high in the IPSS-M low and very low groups. We believe that the relatively high response rate in our patients was influenced by the frequent use of a higher dose (1.75 mg/kg) and especially by adding ESA to luspatercept in poorly responding patients.
- Publikační typ
- časopisecké články MeSH
Chronická myeloidní leukemie (CML) je myeloprolifera- tivní onemocnění charakterizované přítomností Philadelphského chromozomu – translokací BCR::ABL1 – spojenou se vznikem fúzního proteinu Bcr-Abl s vlastní tyrosinkinázovou aktivitou. V terapii CML jsou již mnoho let využívány tyrosinkinázové inhibitory (TKI) Bcr-Abl, které blokují nadměrnou aktivitu tohoto proteinu. Postupně byly do klinického užití zavedeny TKI 1. generace imatinib, TKI 2. generace dasatinib, nilotinib a bosutinib a TKI 3. generace ponatinib. Nejmodernějším lékem, který lze využít u pacien tů s CML, je asciminib, první zástupce skupiny inhibitorů STAMP, který působí jako alosterický inhibitor kinázy Bcr-Abl a je účinný i v přítomnosti mutací BCR::ABL1 spojených s rezistencí vůči TKI. U mladších pa cien tů bez významných komorbidit je při selhání TKI 2. generace a u pokročilejších fází onemocnění vhodnou léčebnou strategií také alognní transplantace krvetvorných buněk.
Chronic myeloid leukaemia (CML) is a myeloproliferative disorder characterized by the presence of the Philadelphia chromosome, i.e. BCR::ABL1 translocation, associated with the formation of the Bcr-Abl fusion protein with intrinsic tyrosine kinase activity. Tyrosine kinase inhibitors (TKIs) of Bcr-Abl have been used in CML therapy for many years to block the excessive activity of this protein. The first- generation TKI imatinib, the second-generation TKIs dasatinib, nilotinib and bosutinib, and the third-generation TKI ponatinib have gradually been introduced into clinical use. The most recent drug that can be used in CML patients is asciminib, the first representative of the STAMP inhibitor group, which acts as an allosteric inhibitor of the Bcr-Abl kinase and is effective even in the presence of BCR::ABL1 mutations associated with TKI resistance. In younger patients without significant comorbidities, allogeneic hematopoietic cell transplantation is also an appropriate treatment strategy in the case of failure of the 2nd generation TKIs and in more advanced stages of the disease.
Pro první linii léčby chronické myeloidní leukemie chronické fáze (CML-CP) jsou schváleny čtyři tyrozinkinázové inhibitory (TKIs), imatinib, dasatinib, bosutinib a nilotinib. Klinické studie s druhou generací TKIs prokázaly významně hlubší a rychlejší dosažení léčebných odpovědí, ale neměly žádný dopad na prodloužení přežití, pravděpodobně kvůli dostupnosti účinných terapií pro rezistentní pacienty. Ve druhé, třetí linii léčby CML-CP je volba TKIs závislá na příčině selhání léčby (rezistence, intolerance preparátu), komorbiditách pacienta a individuálních léčebných cílech. Asciminib je alosterický inhibitor, který se váže na myristoylové místo proteinu BCR::ABL1 a jeho mechanismus účinku je tedy odlišný od ostatních TKIs. Asciminib je schválen pro léčbu dospělých pacientů s CML-CP, kteří byli již léčeni minimálně dvěma TKIs. Jeho výhodou kromě dobré účinnosti je i relativně nízká toxicita.
Four tyrosine kinase inhibitors (TKIs), imatinib, dasatinib, bosutinib, and nilotinib, have been approved for the first-line treatment of chronic myeloid leukaemia in chronic phase (CML-CP). Clinical trials with second-generation TKIs demonstrated significantly deeper and faster therapeutic responses, but there was no impact on prolonging survival, probably due to the availability of effective treatments for resistant patients. In the second or third line of treatment of CML-CP, the choice of TKIs depends on the cause of treatment failure (resistance or intolerance to the drug), patient comorbidities, and individual therapeutic goals. Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein and its mechanism of action is thus different from that of other TKIs. Asciminib is approved for the treatment of adult patients with CML-CP who were previously treated with at least two TKIs. In addition to its good efficacy, it has the advantage of relatively low toxicity.
Polycythemia vera (PV) představuje časté Ph-negativní myeloproliferativní onemocnění, kdy základním léčebným cílem je snížení a udržení hematokritu pod 0,45 a snížení rizika vzniku trombotických či krvácivých komplikací. Pacienty podle věku a prodělané trombotické události dělíme na riziko nízké a vysoké. U nemocných nízkého rizika se mohou provádět pouze venepunkce, ale při jejich nemožnosti nebo výrazném nárůstu leukocytů, trombocytů či progresi splenomegalie je indikováno zahájení cytoredukční léčby. Cytoredukční léčba je vždy indikována pro léčbu PV vysokého rizika a zahrnuje léčbu interferonem (mladší nemocní) nebo hydroxyureou (starší nemocní). U všech pacientů je vždy zahájena léčba kyselinou acetylosalicylovou. Ruxolitinib je inhibitor Janus kinázy 1/2 a představuje léčebnou možnost při rozvoji rezistence či intolerance preparátů první linie (1-3).
Polycythemia vera (PV) is a frequent Ph-negative myeloproliferative disease where the primary therapeutic goals are to reduce and maintain haematocrit below 0.45 and to reduce the risk of developing thrombotic or haemorrhagic complications. Patients are classified into low-risk and high-risk categories according to age and a past thrombotic event. In low-risk patients, only venepuncture can be performed, but in the case of its infeasibility or a significant increase in leukocytes and thrombocytes or progression of splenomegaly, initiation of cytoreductive therapy is indicated. Cytoreductive therapy is always indicated for the treatment of high-risk PV patients and involves treatment with interferon (younger patients) or hydroxyurea (elderly patients). Treatment with acetylsalicylic acid is always commenced in all patients. Ruxolitinib is a Janus kinase 1/2 inhibitor and is a treatment option when resistance or intolerance to first-line drugs develop (1-3).
- Klíčová slova
- ruxolitinib,
- MeSH
- inhibitory Janus kinas terapeutické užití MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- polycythaemia vera * farmakoterapie MeSH
- protinádorové látky terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy 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
- Geografické názvy
- Česká republika MeSH
