Janus kinase (JAK) inhibitors are effective anti-inflammatory agents for treatment of ulcerative colitis (UC).1 According to drug regulatory agencies and international guidelines, JAK inhibitors should be avoided during pregnancy and lactation.2-4 The existing evidence on safety of JAK inhibitors during pregnancy is scarce and almost exclusively limited to tofacitinib.4-7.
- MeSH
- dospělí MeSH
- fetální krev * chemie MeSH
- inhibitory Janus kinas terapeutické užití MeSH
- komplikace těhotenství farmakoterapie MeSH
- lidé MeSH
- mateřské mléko * chemie MeSH
- novorozenec MeSH
- piperidiny * terapeutické užití MeSH
- pyrimidiny * terapeutické užití MeSH
- těhotenství MeSH
- ulcerózní kolitida farmakoterapie krev MeSH
- výsledek těhotenství * MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- novorozenec MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
The ALPINE trial established the superiority of zanubrutinib over ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma; here, we present data from the final comparative analysis with extended follow-up. Overall, 652 patients received zanubrutinib (n = 327) or ibrutinib (n = 325). At an overall median follow-up of 42.5 months, progression-free survival benefit with zanubrutinib vs ibrutinib was sustained (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.54-0.84), including in patients with del(17p)/TP53 mutation (HR, 0.51; 95% CI, 0.33-0.78) and across multiple sensitivity analyses. Overall response rate remained higher with zanubrutinib compared with ibrutinib (85.6% vs 75.4%); responses deepened over time with complete response/complete response with incomplete bone marrow recovery rates of 11.6% (zanubrutinib) and 7.7% (ibrutinib). Although median overall survival has not been reached in either treatment group, fewer zanubrutinib patients have died than ibrutinib patients (HR, 0.77 [95% CI, 0.55-1.06]). With median exposure time of 41.2 and 37.8 months in zanubrutinib and ibrutinib arms, respectively, the most common nonhematologic adverse events included COVID-19-related infection (46.0% vs 33.3%), diarrhea (18.8% vs 25.6%), upper respiratory tract infection (29.3% vs 19.8%), and hypertension (27.2% vs 25.3%). Cardiac events were lower with zanubrutinib (25.9% vs 35.5%) despite similar rates of hypertension. Incidence of atrial fibrillation/flutter was lower with zanubrutinib vs ibrutinib (7.1% vs 17.0%); no cardiac deaths were reported with zanubrutinib vs 6 cardiac deaths with ibrutinib. This analysis, at 42.5 months median follow-up, demonstrates that zanubrutinib remains more efficacious than ibrutinib with an improved overall safety/tolerability profile. This trial was registered at www.ClinicalTrials.gov as #NCT03734016.
- MeSH
- adenin * analogy a deriváty terapeutické užití MeSH
- chronická lymfatická leukemie * farmakoterapie mortalita MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- piperidiny * terapeutické užití škodlivé účinky aplikace a dávkování MeSH
- pyrazoly * terapeutické užití aplikace a dávkování škodlivé účinky MeSH
- pyrimidiny * terapeutické užití 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
- 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
- adenin * analogy a deriváty terapeutické užití MeSH
- antitumorózní látky terapeutické užití MeSH
- chemorezistence * MeSH
- chronická lymfatická leukemie * farmakoterapie MeSH
- inhibitory proteinkinas * terapeutické užití škodlivé účinky MeSH
- lidé MeSH
- piperidiny * terapeutické užití MeSH
- pyraziny terapeutické užití MeSH
- pyrazoly * terapeutické užití MeSH
- pyrimidiny * terapeutické užití MeSH
- thiazoly terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of B-cell malignancies. They target BTK, a key effector in the B-cell receptor (BCR) signaling pathway, crucial for B-cell survival and proliferation. The first-in-class irreversible BTK inhibitor, ibrutinib, was approved for various B-cell malignancies but has limitations due to off-target effects. Second-generation inhibitors, such as acalabrutinib and zanubrutinib, offer improved selectivity and reduced side effects. However, resistance to BTK inhibitors, driven by BTK mutations, remains a challenge. Combinatorial therapies with PI3K inhibitors, immune checkpoint inhibitors, BH3 mimetics, and anti-CD20 antibodies show promise in overcoming resistance. Noncovalent BTK inhibitors and proteolysis-targeting chimeras (PROTACs) are emerging strategies with potential to combat resistance. Overall, advancements in BTK-targeted therapies provide hope for improved outcomes in patients with B-cell malignancies and a promising avenue to address drug resistance. Further research is needed to optimize combination therapies and identify optimal treatment regimens.
- MeSH
- B-buněčný lymfom farmakoterapie metabolismus patologie MeSH
- chemorezistence * MeSH
- inhibitory proteinkinas * terapeutické užití farmakologie MeSH
- inhibitory tyrosinkinasy MeSH
- lidé MeSH
- piperidiny * terapeutické užití farmakologie MeSH
- proteinkinasa BTK * antagonisté a inhibitory MeSH
- pyrazoly * terapeutické užití farmakologie MeSH
- pyrimidiny * terapeutické užití farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
OBJECTIVE: To evaluate the overall survival (OS) of patients with chronic lymphocytic leukemia (CLL) receiving either ibrutinib monotherapy as a first-line (1L) treatment or chemotherapy/chemoimmunotherapy-based (CT/CIT) regimens in 1L followed by ibrutinib in the second line (1L CT/CIT-2L ibrutinib) after disease progression by emulating a randomized trial comparing both treatment sequences. METHODS: Patient-level data from the RESONATE-2 trial (NCT01722487) and real-world PHEDRA databases were analyzed. Three scenarios were considered using the following data sources: (1) RESONATE-2, (2) combined RESONATE-2/PHEDRA, (3) combined RESONATE-2/PHEDRA for 1L ibrutinib and PHEDRA for 1L CT/CIT-2L ibrutinib. Propensity score-based weights and inverse probability of censoring weighting were used to adjust for baseline (Scenarios 2 and 3) and time-dependent confounding (all scenarios), and to address potential biases. A weighted Cox proportional hazards model was used to estimate the OS hazard ratio (HR) and 95% confidence interval (CI) for 1L ibrutinib versus 1L CT/CIT-2L ibrutinib. RESULTS: Results from Scenario 1 showed a significantly lower risk of death with 1L ibrutinib compared with 1L chlorambucil followed by 2L ibrutinib (HR 0.35 [95% CI 0.20-0.62]). Results from Scenarios 2 and 3 demonstrated a reduced risk of death with 1L ibrutinib compared with 1L CT/CIT-2L ibrutinib (HR 0.35 [0.21-0.61] and 0.64 [0.39-1.04], respectively). CONCLUSION: The analyses consistently showed a reduced risk of death when ibrutinib was used as a 1L treatment in CLL compared with delaying its use until 2L after CT/CIT regimens, which suggests that initiating ibrutinib in 1L is advantageous for improving survival outcomes.
- MeSH
- adenin * analogy a deriváty terapeutické užití MeSH
- chronická lymfatická leukemie * farmakoterapie mortalita MeSH
- imunoterapie metody MeSH
- lidé středního věku MeSH
- lidé MeSH
- míra přežití MeSH
- piperidiny * terapeutické užití aplikace a dávkování MeSH
- protokoly antitumorózní kombinované chemoterapie terapeutické užití aplikace a dávkování MeSH
- pyrazoly * terapeutické užití aplikace a dávkování MeSH
- pyrimidiny * terapeutické užití aplikace a dávkování MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
Pokročilý karcinom prostaty (KP) má relativně často změny v genech, které se účastní opravy DNA. V tom případě můžeme opravu zlomů DNA zablokovat pomocí inhibitorů poly(adenosindifosfát-ribóza)polymerázy (PARP). Nejvíce dat máme o účinnosti inhibitoru PARP olaparibu, který je možné podat pacientům s metastatickým kastračně rezistentním KP (mCRPC) a pozitivitou mutace BRCA1/2 po předchozí léčbě abirateronem nebo enzalutamidem. Druhou indikaci představuje kombinace olaparibu s abirateronem v 1. linii léčby mCRPC (bez nutnosti genetického testování), pokud není klinicky indikována chemoterapie. Talazoparib můžeme podat v kombinaci s enzalutamidem pacientům s mCRPC, u kterých také není indikována chemoterapie. Testování nádorových mutací není vyžadováno. Obdobně také niraparib v kombinaci s abirateronem můžeme použít u pacientů s mCRPC a mutacemi genu BRCA1/2, u kterých nezvažujeme chemoterapii. Výsledky v léčbě mCRPC má ještě rukaparib, který v České republice zatím není možné mužům s KP podávat.
Advanced prostate cancer (PC) relatively often has alterations in genes involved in DNA repair. In that case, we can block the repair of DNA breaks using poly-adenosine diphosphate-ribose-polymerase (PARP) inhibitors. The most studied PARP inhibitor is olaparib, which can be given to patients with metastatic castration-resistant PC (mCRPC) and a positive BRCA1/2 mutation after previous treatment with abiraterone or enzalutamide. The next indication is the combination of olaparib with abiraterone in the firstline treatment of mCRPC (without the need for genetic testing), if chemotherapy is not clinically indicated. Talazoparib can be given in combination with enzalutamide to patients with mCRPC who are also not indicated for chemotherapy. Tumor mutation testing is not required. Similarly, we can also use niraparib in combination with abiraterone in patients with mCRPC and BRCA1/2 gene mutations, if chemotherapy is not considered. Also rucaparib has results in the treatment of mCRPC, but is not yet available for men with PC in the Czech Republic.
BACKGROUND: Adding ibrutinib to standard immunochemotherapy might improve outcomes and challenge autologous stem-cell transplantation (ASCT) in younger (aged 65 years or younger) mantle cell lymphoma patients. This trial aimed to investigate whether the addition of ibrutinib results in a superior clinical outcome compared with the pre-trial immunochemotherapy standard with ASCT or an ibrutinib-containing treatment without ASCT. We also investigated whether standard treatment with ASCT is superior to a treatment adding ibrutinib but without ASCT. METHODS: The open-label, randomised, three-arm, parallel-group, superiority TRIANGLE trial was performed in 165 secondary or tertiary clinical centres in 13 European countries and Israel. Patients with previously untreated, stage II-IV mantle cell lymphoma, aged 18-65 years and suitable for ASCT were randomly assigned 1:1:1 to control group A or experimental groups A+I or I, stratified by study group and mantle cell lymphoma international prognostic index risk groups. Treatment in group A consisted of six alternating cycles of R-CHOP (intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous cyclophosphamide 750 mg/m2 on day 1, intravenous doxorubicin 50 mg/m2 on day 1, intravenous vincristine 1·4 mg/m2 on day 1, and oral prednisone 100 mg on days 1-5) and R-DHAP (or R-DHAOx, intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1-4, intravenous cytarabine 2 × 2 g/m2 for 3 h every 12 h on day 2, and intravenous cisplatin 100 mg/m2 over 24 h on day 1 or alternatively intravenous oxaliplatin 130 mg/m2 on day 1) followed by ASCT. In group A+I, ibrutinib (560 mg orally each day) was added on days 1-19 of R-CHOP cycles and as fixed-duration maintenance (560 mg orally each day for 2 years) after ASCT. In group I, ibrutinib was given the same way as in group A+I, but ASCT was omitted. Three pairwise one-sided log-rank tests for the primary outcome of failure-free survival were statistically monitored. The primary analysis was done by intention-to-treat. Adverse events were evaluated by treatment period among patients who started the respective treatment. This ongoing trial is registered with ClinicalTrials.gov, NCT02858258. FINDINGS: Between July 29, 2016 and Dec 28, 2020, 870 patients (662 men, 208 women) were randomly assigned to group A (n=288), group A+I (n=292), and group I (n=290). After 31 months median follow-up, group A+I was superior to group A with 3-year failure-free survival of 88% (95% CI 84-92) versus 72% (67-79; hazard ratio 0·52 [one-sided 98·3% CI 0-0·86]; one-sided p=0·0008). Superiority of group A over group I was not shown with 3-year failure-free survival 72% (67-79) versus 86% (82-91; hazard ratio 1·77 [one-sided 98·3% CI 0-3·76]; one-sided p=0·9979). The comparison of group A+I versus group I is ongoing. There were no relevant differences in grade 3-5 adverse events during induction or ASCT between patients treated with R-CHOP/R-DHAP or ibrutinib combined with R-CHOP/R-DHAP. During maintenance or follow-up, substantially more grade 3-5 haematological adverse events and infections were reported after ASCT plus ibrutinib (group A+I; haematological: 114 [50%] of 231 patients; infections: 58 [25%] of 231; fatal infections: two [1%] of 231) compared with ibrutinib only (group I; haematological: 74 [28%] of 269; infections: 52 [19%] of 269; fatal infections: two [1%] of 269) or after ASCT (group A; haematological: 51 [21%] of 238; infections: 32 [13%] of 238; fatal infections: three [1%] of 238). INTERPRETATION: Adding ibrutinib to first-line treatment resulted in superior efficacy in younger mantle cell lymphoma patients with increased toxicity when given after ASCT. Adding ibrutinib during induction and as maintenance should be part of first-line treatment of younger mantle cell lymphoma patients. Whether ASCT adds to an ibrutinib-containing regimen is not yet determined. FUNDING: Janssen and Leukemia & Lymphoma Society.
- MeSH
- adenin * analogy a deriváty aplikace a dávkování terapeutické užití MeSH
- autologní transplantace * MeSH
- cyklofosfamid * aplikace a dávkování terapeutické užití MeSH
- dexamethason aplikace a dávkování terapeutické užití MeSH
- dospělí MeSH
- doxorubicin aplikace a dávkování MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfom z plášťových buněk * terapie farmakoterapie MeSH
- mladiství MeSH
- mladý dospělý MeSH
- piperidiny * aplikace a dávkování terapeutické užití MeSH
- prednison aplikace a dávkování terapeutické užití MeSH
- protokoly antitumorózní kombinované chemoterapie * terapeutické užití MeSH
- rituximab * aplikace a dávkování terapeutické užití MeSH
- senioři MeSH
- transplantace hematopoetických kmenových buněk metody MeSH
- vinkristin * aplikace a dávkování terapeutické užití MeSH
- výsledek terapie 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
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
- Geografické názvy
- Evropa MeSH
- Izrael MeSH
BACKGROUND AND AIMS: Tofacitinib (TFB) appears to be effective in the treatment of ulcerative colitis (UC); however, available real-world studies are limited by cohort size. TFB could be an option in the treatment of acute severe ulcerative colitis (ASUC). We aimed to investigate efficacy and safety of TFB in moderate-to-severe colitis and ASUC. METHODS: This retrospective, international cohort study enrolling UC patients with ≥6-week follow-up period was conducted from February 1 to July 31, 2022. Indications were categorized as ASUC and chronic activity (CA). Baseline demographic and clinical data were obtained. Steroid-free remission (SFR), colectomy, and safety data were analyzed. RESULTS: A total of 391 UC patients (median age 38 [interquartile range, 28-47] years; follow-up period 26 [interquartile range, 14-52] weeks) were included. A total of 27.1% received TFB in ASUC. SFR rates were 23.7% (ASUC: 26.0%, CA: 22.8%) at week 12 and 41.1% (ASUC: 34.2%, CA: 43.5%) at week 52. The baseline partial Mayo score (odds ratio [OR], 0.850; P = .006) was negatively associated with week 12 SFR, while biologic-naïve patients (OR, 2.078; P = .04) more likely achieved week 52 SFR. The colectomy rate at week 52 was higher in ASUC group (17.6% vs 5.7%; P < .001) and decreased with age (OR, 0.94; P = .013). A total of 67 adverse events were reported, and 17.9% resulted in cessation of TFB. One case of thromboembolic event was reported. CONCLUSIONS: TFB is effective in both studied indications. TFB treatment resulted in high rates of SFR in the short and long terms. Higher baseline disease activity and previous biological therapies decreased efficacy. No new adverse event signals were found.
- MeSH
- dospělí MeSH
- indukce remise MeSH
- inhibitory proteinkinas terapeutické užití MeSH
- kolektomie MeSH
- lidé středního věku MeSH
- lidé MeSH
- následné studie MeSH
- piperidiny * terapeutické užití MeSH
- pyrimidiny * terapeutické užití MeSH
- retrospektivní studie MeSH
- stupeň závažnosti nemoci MeSH
- ulcerózní kolitida * farmakoterapie MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
Targeting Anaplastic lymphoma kinase (ALK) is a promising therapeutic strategy for aberrant ALK-expressing malignancies including neuroblastoma, but resistance to ALK tyrosine kinase inhibitors (ALK TKI) is a distinct possibility necessitating drug combination therapeutic approaches. Using high-throughput, genome-wide CRISPR-Cas9 knockout screens, we identify miR-1304-5p loss as a desensitizer to ALK TKIs in aberrant ALK-expressing neuroblastoma; inhibition of miR-1304-5p decreases, while mimics of this miRNA increase the sensitivity of neuroblastoma cells to ALK TKIs. We show that miR-1304-5p targets NRAS, decreasing cell viability via induction of apoptosis. It follows that the farnesyltransferase inhibitor (FTI) lonafarnib in addition to ALK TKIs act synergistically in neuroblastoma, inducing apoptosis in vitro. In particular, on combined treatment of neuroblastoma patient derived xenografts with an FTI and an ALK TKI complete regression of tumour growth is observed although tumours rapidly regrow on cessation of therapy. Overall, our data suggests that combined use of ALK TKIs and FTIs, constitutes a therapeutic approach to treat high risk neuroblastoma although prolonged therapy is likely required to prevent relapse.
- MeSH
- anaplastická lymfomová kináza * genetika metabolismus antagonisté a inhibitory MeSH
- apoptóza účinky léků genetika MeSH
- chemorezistence genetika účinky léků MeSH
- dibenzocyklohepteny * MeSH
- farnesyltranstransferasa * antagonisté a inhibitory metabolismus MeSH
- GTP-fosfohydrolasy * genetika metabolismus MeSH
- inhibitory proteinkinas * farmakologie terapeutické užití MeSH
- lidé MeSH
- membránové proteiny metabolismus genetika MeSH
- mikro RNA * genetika metabolismus MeSH
- mutace MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- neuroblastom * farmakoterapie genetika patologie metabolismus MeSH
- piperidiny * farmakologie terapeutické užití MeSH
- pyridiny * farmakologie terapeutické užití MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- synergismus léků MeSH
- xenogenní modely - testy antitumorózní aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Klíčová slova
- zanubrutinib,
- MeSH
- chronická lymfatická leukemie * MeSH
- inhibitory tyrosinkinasy farmakologie terapeutické užití MeSH
- lidé MeSH
- piperidiny farmakologie terapeutické užití MeSH
- protokoly antitumorózní kombinované chemoterapie MeSH
- pyrazoly farmakologie terapeutické užití MeSH
- pyrimidiny farmakologie terapeutické užití MeSH
- randomizované kontrolované studie jako téma MeSH
- Check Tag
- lidé MeSH
