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.SEQUOIA (ClinicalTrials.gov identifier: NCT03336333) is a phase III, randomized, open-label trial that compared the oral Bruton tyrosine kinase inhibitor zanubrutinib to bendamustine plus rituximab (BR) in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The initial prespecified analysis (median follow-up, 26.2 months) and subsequent analysis (43.7 months) found superior progression-free survival (PFS; the primary end point) in patients who received zanubrutinib compared with BR. At a median follow-up of 61.2 months, median PFS was not reached in zanubrutinib-treated patients; median PFS was 44.1 months in BR-treated patients (hazard ratio [HR], 0.29; one-sided P = .0001). Prolonged PFS was seen with zanubrutinib versus BR in patients with mutated immunoglobulin heavy-chain variable region (IGHV) genes (HR, 0.40; one-sided P = .0003) and unmutated IGHV genes (HR, 0.21 [95% CI, 0.14 to 0.33]; one-sided P < .0001). Median overall survival (OS) was not reached in either treatment arm; estimated 60-month OS rates were 85.8% and 85.0% in zanubrutinib- and BR-treated patients, respectively. No new safety signals were detected. Adverse events were as expected with zanubrutinib; rate of atrial fibrillation was 7.1%. At a median follow-up of 61.2 months, the results supported the initial SEQUOIA findings and suggested that zanubrutinib was a favorable treatment option for untreated patients with CLL/SLL.

• MeSH
• bendamustin hydrochlorid * aplikace a dávkování   terapeutické užití   MeSH
• chronická lymfatická leukemie * farmakoterapie   mortalita   MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• následné studie MeSH
• piperidiny terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   škodlivé účinky   MeSH
• pyrazoly * terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• pyrimidiny * terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• rituximab * aplikace a dávkování   terapeutické užití   škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři 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

OBJECTIVES: The efficacy and safety of macitentan, an endothelin receptor antagonist, were assessed in a 52-week, prospective, multicenter, double-blind, randomized, placebo-controlled, parallel-group study assessing the efficacy and safety of macitentan in Fontan-palliated adult and adolescent patients (RUBATO-DB) and an open-label extension trial (RUBATO-OL). METHODS: Patients aged 12 years and older with New York Heart Association functional class II or III underwent total cavopulmonary connection more than 1 year before screening and showed no signs of Fontan failure/clinical deterioration. In RUBATO-DB, the primary efficacy end point was change in peak oxygen consumption from baseline to week 16; secondary end points were change from baseline over 52 weeks in peak oxygen consumption and change in mean count/minute of daily physical activity via accelerometer from baseline to week 16. Safety was assessed throughout both studies. RESULTS: In RUBATO-DB, 137 patients were randomized to macitentan 10 mg (n = 68) or placebo (n = 69); 92.7% completed 52-week double-blind treatment. At week 16, mean ± SD change in peak oxygen consumption was -0.16 ± 2.86 versus -0.67 ± 2.66 mL/kg/minute with macitentan versus placebo (median unbiased treatment difference estimate, 0.62 mL/kg/minute [99% repeated CI, -0.62 to 1.85]; P = .19). No treatment effect was observed in either of the secondary end points. During RUBATO-DB, most common adverse events with macitentan were headache, nasopharyngitis, and pyrexia. Across RUBATO-DB and RUBATO-OL, most common adverse events were COVID-19, headache, and fatigue. RUBATO-OL was prematurely discontinued because RUBATO-DB did not meet its primary or secondary end point. CONCLUSIONS: The primary end point of RUBATO-DB was not met; macitentan did not improve exercise capacity versus placebo in patients with Fontan palliation. Macitentan was generally well tolerated over long-term treatment.

• MeSH
• antagonisté endotelinového receptoru terapeutické užití   škodlivé účinky   MeSH
• časové faktory MeSH
• dítě MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• Fontanova operace * škodlivé účinky   MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• paliativní péče MeSH
• prospektivní studie MeSH
• pyrimidiny * terapeutické užití   škodlivé účinky   MeSH
• spotřeba kyslíku účinky léků   MeSH
• sulfonamidy * terapeutické užití   škodlivé účinky   MeSH
• tolerance zátěže účinky léků   MeSH
• vrozené srdeční vady chirurgie   patofyziologie   MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

OBJECTIVE: Ischemic complications account for significant patient morbidity following aneurysmal subarachnoid hemorrhage (aSAH). The Prevention and Treatment of Vasospasm with Clazosentan (REACT) study was designed to assess the safety and efficacy of clazosentan, an endothelin receptor antagonist, in preventing clinical deterioration due to delayed cerebral ischemia (DCI) in patients with aSAH. METHODS: REACT was a prospective, multicenter, randomized, double-blind, phase 3 study. Eligible patients had aSAH secured by surgical clipping or endovascular coiling, and had presented with thick and diffuse clot on admission CT scan. Patients were randomized (1:1 ratio) to 15 mg/hour intravenous clazosentan or placebo within 96 hours of the aSAH for up to 14 days, in addition to standard of care treatment including oral or intravenous nimodipine. The primary efficacy endpoint was the occurrence of clinical deterioration due to DCI up to 14 days after initiation of the study drug. The main secondary endpoint was the occurrence of clinically relevant cerebral infarction at day 16 after study drug initiation. Other secondary endpoints included clinical outcome assessed on the modified Rankin Scale (mRS) and the Glasgow Outcome Scale-Extended (GOSE) at week 12 post-aSAH. Imaging and clinical endpoints were centrally adjudicated. RESULTS: A total of 409 patients were randomized between February 2019 and May 2022 across 74 international sites. Three patients did not start study treatment and were not included in the analysis set. The occurrence of clinical deterioration due to DCI was 15.8% (32/202 patients) in the clazosentan group and 17.2% (35/204 patients) in the placebo group, and the difference was not statistically significant (relative risk reduction [RRR] 7.2%, 95% CI -42.6% to 39.6%, p = 0.734). A nonsignificant RRR of 34.1% (95% CI -21.3% to 64.2%, p = 0.177) was observed in clinically relevant cerebral infarcts treated with clazosentan (7.4%, 15/202) versus placebo (11.3%, 23/204). Rescue therapy was less frequently needed for patients treated with clazosentan compared to placebo (10.4%, 21/202 vs 18.1%, 37/204; RRR 42.6%, 95% CI 5.4%-65.2%). A nonsignificant relative risk increase of 25.4% (95% CI -10.7% to 76.0%, p = 0.198) was reported in the risk of poor GOSE and mRS scores with clazosentan (24.8%, 50/202) versus placebo (20.1%, 41/204) at week 12 post-aSAH. Treatment-emergent adverse events were similar to those reported previously. CONCLUSIONS: Clazosentan administered for up to 14 days at 15 mg/hour had no significant effect on the occurrence of clinical deterioration due to DCI. Clinical trial registration no.: NCT03585270 (ClinicalTrials.gov) EU clinical trial registration no.: 2018-000241-39 (clinicaltrialsregister.eu).

• MeSH
• dioxany * terapeutické užití   škodlivé účinky   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• intrakraniální vazospazmus etiologie   prevence a kontrola   farmakoterapie   diagnostické zobrazování   MeSH
• ischemie mozku * prevence a kontrola   etiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• prospektivní studie MeSH
• pyridiny * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• pyrimidiny * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• senioři MeSH
• subarachnoidální krvácení * komplikace   diagnostické zobrazování   MeSH
• sulfonamidy * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• tetrazoly * terapeutické užití   škodlivé účinky   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 III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

PURPOSE: Tropomyosin receptor kinase (TRK) fusions are detected in less than 2% of central nervous system tumors. There are limited data on the clinical course of affected patients. EXPERIMENTAL DESIGN: We conducted an international retrospective cohort study of patients with TRK fusion-driven central nervous system tumors. RESULTS: A total of 119 patients were identified. The median age at the time of diagnosis was 4.5 years. The majority were reported to have a histology consistent with a diagnosis of high-grade glioma (HGG; 57.1%) followed by low-grade glioma (LGG; 27.7%). Pediatric patients had a better prognosis, with a median overall survival of 185.5 months compared with 24.8 months in adults (P < 0.0001). Patients with LGG also had a better outcome when compared with HGG (P = 0.0012). The objective response was 68.8% with larotrectinib compared with 38.1% for nontargeted treatment. CONCLUSIONS: Children with LGG had a favorable outcome compared with adult glioma and HGG. TRK inhibitors seem to improve tumor control.

• MeSH
• dítě MeSH
• dospělí MeSH
• fúze genů MeSH
• fúzní onkogenní proteiny * genetika   MeSH
• gliom * genetika   patologie   mortalita   terapie   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové glykoproteiny MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádory centrálního nervového systému * genetika   terapie   mortalita   patologie   MeSH
• předškolní dítě MeSH
• prognóza MeSH
• pyrazoly terapeutické užití   MeSH
• pyrimidiny terapeutické užití   MeSH
• receptor trkA * genetika   antagonisté a inhibitory   MeSH
• receptor trkB genetika   antagonisté a inhibitory   MeSH
• receptor trkC genetika   antagonisté a inhibitory   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• stupeň nádoru MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

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

Current treatments for persistent or chronic immune thrombocytopenia (ITP) are limited by inadequate response, toxicity, and impaired quality of life. The Bruton tyrosine kinase inhibitor rilzabrutinib was evaluated to further characterize safety and durability of platelet response. LUNA2 Part B is a multicenter, phase 1/2 study in adults with ITP (≥ 3 months duration, platelet count < 30 × 109/L) who failed ≥ 1 ITP therapy (NCT03395210, EudraCT 2017-004012-19). Oral rilzabrutinib 400 mg bid was given over 24 weeks, with optional long-term extension (LTE). Primary endpoints were safety and platelet counts ≥ 50 × 109/L on ≥ 8 of the last 12 weeks of main treatment without rescue medication. From 22 March2018 to 31 January2023, 26 patients were enrolled. Patients had baseline median platelet count 13 × 109/L, ITP duration 10.3 years, and six prior ITP therapies (46% splenectomized). Nine (35%) patients achieved the primary endpoint. Platelet counts ≥ 50 × 109/L or ≥ 30 × 109/L and doubling from baseline without rescue therapy were sustained for a mean 9.3 weeks. 11 (42%) LTE-eligible patients were ongoing with median LTE platelet > 80 × 109/L. Three (12%) patients received rescue medication during main treatment, none in LTE. Clinically meaningful improvements were observed in fatigue and women's health. With a median treatment duration of 167 days (main treatment), 16 (62%) patients had ≥ 1 treatment-related adverse event (AE), mainly grade 1, including diarrhea (35%), headache (23%), and nausea (15%). There was no treatment-related grade ≥ 2 bleeding/thrombotic events/infections, serious AE, or death. Rilzabrutinib continues to demonstrate durable platelet responses with favorable safety profile in previously treated ITP patients. Trial Registration: NCT03395210, EudraCT 2017-004012-19.

• MeSH
• aplikace orální MeSH
• dospělí MeSH
• idiopatická trombocytopenická purpura * farmakoterapie   MeSH
• inhibitory proteinkinas * škodlivé účinky   terapeutické užití   aplikace a dávkování   MeSH
• inhibitory tyrosinkinasy MeSH
• lidé středního věku MeSH
• lidé MeSH
• počet trombocytů MeSH
• proteinkinasa BTK * antagonisté a inhibitory   MeSH
• pyrazoly terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• pyrimidiny aplikace a dávkování   škodlivé účinky   terapeutické užití   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 I MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie 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

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

• MeSH
• adenin * analogy a deriváty   terapeutické užití   MeSH
• chemorezistence * MeSH
• chronická lymfatická leukemie * farmakoterapie   MeSH
• inhibitory proteinkinas * terapeutické užití   škodlivé účinky   MeSH
• lidé MeSH
• piperidiny * terapeutické užití   MeSH
• protinádorové látky 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

• Klíčová slova
• milvexian, žaludeční polypy,
• MeSH
• cévní mozková příhoda * farmakoterapie   prevence a kontrola   MeSH
• gabapentin farmakologie   terapeutické užití   MeSH
• genetické markery MeSH
• inhibitory protonové pumpy * škodlivé účinky   MeSH
• lidé MeSH
• nežádoucí účinky léčiv MeSH
• pánevní bolest * farmakoterapie   MeSH
• polypy etiologie   MeSH
• pyrimidiny farmakologie   terapeutické užití   MeSH
• randomizované kontrolované studie jako téma MeSH
• triazoly farmakologie   terapeutické užití   MeSH
• žaludek patologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH