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7 záznamů v Medvik Filtry

Článek

Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network

Dreyling, Martin
Autor Dreyling, Martin Department of Medicine III, LMU University Hospital, Munich, Germany. Electronic address: Martin.Dreyling@med.uni-muenchen.de
Doorduijn, Jeanette
Autor Doorduijn, Jeanette Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
Giné, Eva
Autor Giné, Eva Hematology Department, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain
Jerkeman, Mats
Autor Jerkeman, Mats Cancer Centre, Lund University Faculty of Medicine, Lund, Sweden
Walewski, Jan
Autor Walewski, Jan Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
Hutchings, Martin
Autor Hutchings, Martin Department of Haematology and Phase 1 Unit, Rigshospitalet, Copenhagen, Denmark
Mey, Ulrich
Autor Mey, Ulrich Oncology and Hematology, Kantonsspital Graubuenden, Chur, Switzerland
Riise, Jon
Autor Riise, Jon Department of Oncology, Oslo University Hospital, Oslo, Norway
Trneny, Marek
Autor Trneny, Marek First Faculty of Medicine, Charles University Hospital, Prague, Czech Republic
Vergote, Vibeke
Autor Vergote, Vibeke Department of Hematology, University Hospitals Leuven, Leuven, Belgium

Lancet. 2024 ; 403 (10441) : 2293-2306. [pub] 20240502

ISSN 1474-547X
Medvik
Zdroj

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.

Článek

Elotuzumab, lenalidomide, and dexamethasone in RRMM: final overall survival results from the phase 3 randomized ELOQUENT-2 study

Blood cancer journal. 2020 ; 10 (9) : 91. [pub] 20200904

Blood Cancer J
ISSN 2044-5385
Medvik
Zdroj

Prolonging overall survival (OS) remains an unmet need in relapsed or refractory multiple myeloma (RRMM). In ELOQUENT-2 (NCT01239797), elotuzumab plus lenalidomide/dexamethasone (ERd) significantly improved progression-free survival (PFS) versus lenalidomide/dexamethasone (Rd) in patients with RRMM and 1-3 prior lines of therapy (LoTs). We report results from the pre-planned final OS analysis after a minimum follow-up of 70.6 months, the longest reported for an antibody-based triplet in RRMM. Overall, 646 patients with RRMM and 1-3 prior LoTs were randomized 1:1 to ERd or Rd. PFS and overall response rate were co-primary endpoints. OS was a key secondary endpoint, with the final analysis planned after 427 deaths. ERd demonstrated a statistically significant 8.7-month improvement in OS versus Rd (median, 48.3 vs 39.6 months; hazard ratio, 0.82 [95.4% Cl, 0.68-1.00]; P = 0.0408 [less than allotted α of 0.046]), which was consistently observed across key predefined subgroups. No additional safety signals with ERd at extended follow-up were reported. ERd is the first antibody-based triplet regimen shown to significantly prolong OS in patients with RRMM and 1-3 prior LoTs. The magnitude of OS benefit was greatest among patients with adverse prognostic factors, including older age, ISS stage III, IMWG high-risk disease, and 2-3 prior LoTs.

Článek

Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth

British journal of haematology. 2017 ; 178 (6) : 896-905. [pub] 20170705

Br J Haematol
ISSN 1365-2141
Medvik
Zdroj

The randomized phase III ELOQUENT-2 study (NCT01239797) evaluated the efficacy and safety of elotuzumab + lenalidomide/dexamethasone (ELd) versus lenalidomide/dexamethasone (Ld) in relapsed/refractory multiple myeloma. ELd reduced the risk of disease progression/death by 30% versus Ld (hazard ratio [HR] 0·70). Median time from diagnosis was 3·5 years. We present extended 3-year follow-up data. Endpoints included progression-free survival (PFS), overall response rate (ORR) and interim overall survival (OS). Exploratory post-hoc analyses included impact of time from diagnosis and prior lines of therapy on PFS, and serum M-protein dynamic modelling. ORR was 79% (ELd) and 66% (Ld) (P = 0·0002). ELd reduced the risk of disease progression/death by 27% versus Ld (HR 0·73; P = 0·0014). Interim OS demonstrated a trend in favour of ELd (P = 0·0257); 1-, 2- and 3-year rates with ELd versus Ld were: 91% versus 83%, 73% versus 69% and 60% versus 53%. In patients with ≥ median time from diagnosis and one prior therapy, ELd resulted in a 53% reduction in the risk of progression/death versus Ld (HR 0·47). Serum M-protein dynamic modelling showed slower tumour regrowth with ELd. Adverse events were comparable between arms. ELd provided a durable and clinically relevant improvement in efficacy, with minimal incremental toxicity.

Článek

Randomized Phase III Study of Lenalidomide Versus Placebo in RBC Transfusion-Dependent Patients With Lower-Risk Non-del(5q) Myelodysplastic Syndromes and Ineligible for or Refractory to Erythropoiesis-Stimulating Agents

Journal of clinical oncology. 2016 ; 34 (25) : 2988-96. [pub] 20160627

J. clin. Oncol.
ISSN 1527-7755
Medvik
Zdroj

PURPOSE: This international phase III, randomized, placebo-controlled, double-blind study assessed the efficacy and safety of lenalidomide in RBC transfusion-dependent patients with International Prognostic Scoring System lower-risk non-del(5q) myelodysplastic syndromes ineligible for or refractory to erythropoiesis-stimulating agents. PATIENTS AND METHODS: In total, 239 patients were randomly assigned (2:1) to treatment with lenalidomide (n = 160) or placebo (n = 79) once per day (on 28-day cycles). The primary end point was the rate of RBC transfusion independence (TI) ≥ 8 weeks. Secondary end points were RBC-TI ≥ 24 weeks, duration of RBC-TI, erythroid response, health-related quality of life (HRQoL), and safety. RESULTS: RBC-TI ≥ 8 weeks was achieved in 26.9% and 2.5% of patients in the lenalidomide and placebo groups, respectively (P < .001). Ninety percent of patients achieving RBC-TI responded within 16 weeks of treatment. Median duration of RBC-TI with lenalidomide was 30.9 weeks (95% CI, 20.7 to 59.1). Transfusion reduction of ≥ 4 units packed RBCs, on the basis of a 112-day assessment, was 21.8% in the lenalidomide group and 0% in the placebo group. Higher response rates were observed in patients with lower baseline endogenous erythropoietin ≤ 500 mU/mL (34.0% v 15.5% for > 500 mU/mL). At week 12, mean changes in HRQoL scores from baseline did not differ significantly between treatment groups, which suggests that lenalidomide did not adversely affect HRQoL. Achievement of RBC-TI ≥ 8 weeks was associated with significant improvements in HRQoL (P < .01). The most common treatment-emergent adverse events were neutropenia and thrombocytopenia. CONCLUSION: Lenalidomide yields sustained RBC-TI in 26.9% of RBC transfusion-dependent patients with lower-risk non-del(5q) myelodysplastic syndromes ineligible for or refractory to erythropoiesis-stimulating agents. Response to lenalidomide was associated with improved HRQoL. Treatment-emergent adverse event data were consistent with the known safety profile of lenalidomide.

MeSH
dospělí MeSH
dvojitá slepá metoda MeSH
erytropoéza účinky léků MeSH
exprese genu MeSH
kvalita života MeSH
léková rezistence MeSH
lidé středního věku MeSH
lidé MeSH
mutační analýza DNA MeSH
myelodysplastické syndromy krev farmakoterapie genetika terapie MeSH
senioři nad 80 let MeSH
senioři MeSH
thalidomid škodlivé účinky analogy a deriváty terapeutické užití MeSH
transfuze erytrocytů * 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

Článek

Bortezomib, thalidomide and dexamethasone, with or without cyclophosphamide, for patients with previously untreated multiple myeloma: 5-year follow-up

British journal of haematology. 2015 ; 171 (3) : 344-54. [pub] 20150707

Br J Haematol
ISSN 1365-2141
Medvik
Zdroj

This follow-up extension of a randomised phase II study assessed differences in long-term outcomes between bortezomib-thalidomide-dexamethasone (VTD) and VTD-cyclophosphamide (VTDC) induction therapy in multiple myeloma. Newly diagnosed patients (n = 98) were randomised 1:1 to intravenous bortezomib (1·3 mg/m(2); days 1, 4, 8, 11), thalidomide (100 mg; days 1-21), and dexamethasone (40 mg; days 1-4, 9-12), with/without cyclophosphamide (400 mg/m(2); days 1, 8), for four 21-day cycles before stem-cell mobilisation/transplantation. After a median follow-up of 64·8 months, median time-to-next therapy was 51·8 and 47·9 months with VTD and VTDC, respectively. Type of subsequent therapy was similar in both arms. After adjusting for asymmetric censoring, median time to progression was not significantly different between VTD and VTDC [35·7 vs. 34·5 months; Hazard ratio (HR) 1·26, 95% confidence interval: 0·76-2·09; P = 0·370]. Five-year survival was 69·1% and 65·3% with VTD and VTDC, respectively. When analysed by minimal residual disease (MRD) status, overall survival was longer in MRD-negative versus MRD-positive patients with bone marrow-confirmed complete response (HR 3·66, P = 0·0318). VTD induction followed by transplantation provides long-term disease control and, consistent with the primary analysis, there is no additional benefit from adding cyclophosphamide. This study was registered at ClinicalTrials.gov (NCT00531453).

Článek

Comparison of subcutaneous versus intravenous administration of rituximab as maintenance treatment for follicular lymphoma: results from a two-stage, phase IB study

Journal of clinical oncology. 2014 ; 32 (17) : 1782-91.

J. clin. Oncol.
ISSN 1527-7755
Medvik
Zdroj

PURPOSE: This two-stage phase IB study investigated the pharmacokinetics and safety of subcutaneous (SC) versus intravenous (IV) administration of rituximab as maintenance therapy in follicular lymphoma. PATIENTS AND METHODS: In stage 1 (dose finding), 124 patients who responded to rituximab induction were randomly assigned to SC rituximab (375 mg/m2, 625 mg/m2, or an additional group at 800 mg/m2) or IV rituximab (375 mg/m2). The objective was to determine an SC dose that would yield a rituximab serum trough concentration (Ctrough) in the same range as that of IV rituximab. In stage 2, 154 additional patients were randomly assigned (1:1) to SC rituximab (1,400 mg) or IV rituximab (375 mg/m2) given at 2- or 3-month intervals. The objective was to demonstrate noninferior rituximab Ctrough of SC rituximab relative to IV rituximab 375 mg/m2. RESULTS: Stage 1 data predicted that a fixed dose of 1,400 mg SC rituximab would result in a serum Ctrough in the range of that of IV rituximab. Noninferiority (ie, meeting the prespecified 90% CI lower limit of 0.8) was then confirmed in stage 2, with geometric mean Ctrough SC:Ctrough IV ratios for the 2- and 3-month regimens of 1.24 (90% CI, 1.02 to 1.51) and 1.12 (90% CI, 0.86 to 1.45), respectively. Overall safety profiles were similar between formulations (in stage 2, 79% of patients experienced one or more adverse events in each group). Local administration-related reactions (mainly mild to moderate) occurred more frequently after SC administration. CONCLUSION: The fixed dose of 1,400 mg SC rituximab predicted by using stage 1 results was confirmed to have noninferior Ctrough levels relative to IV rituximab 375 mg/m2 dosing during maintenance, with a comparable safety profile. Additional investigation will be required to determine whether the SC route of administration for rituximab provides equivalent efficacy compared with that of IV administration.

Článek

Hybridní pozitronová emisní a výpočetní tomografie (PET-CT) spolehlivě předpovídá výsledek léčby pacientů s folikulárním lymfomem po indukční terapii: analýza PET-CT u podskupiny účastníků studie PRIMA

Journal of Clinical Oncology (České vyd.). 2011 ; 3 (8) : 349-355.

J. clin. Oncol. (Čes. vyd.)
ISSN 1803-8506
Medvik
Zdroj

Cíl Přínos pozitronové emisní tomografi e s použitím [18F]fl uorodeoxyglukózy (FDG) spojené s výpočetní tomografi í ([18F]fl uorodeoxyglucose positron emission tomography–computed tomography, PET-CT) je při hodnocení odpovědi po indukční terapii dobře doložen u Hodgkinových a difuzních B-velkobuněčných lymfomů, nebyl však dosud stanoven přínos tohoto postupu u folikulárního lymfomu (follicular lymphoma, FL). Zkoumali jsme prognostický význam PET-CT provedené po terapii první linie u pacientů s FL léčených v prospektivní studii PRIMA (Primary Rituximab and Maintenance). Pacienti a metody Výsledky PET-CT scanů provedených po indukční imunochemoterapii byly zaznamenány retrospektivně. Pacienti pokračovali buď v léčbě observací, nebo v udržovací léčbě rituximabem podle protokolu, nezávisle na výsledku PET-CT. Následně byly zhodnoceny charakteristiky pacientů a dosažené výsledky. Výsledky Ze 122 PET-CT scanů provedených na konci indukční imunochemoterapie bylo 32 (26 %) posouzeno zkoušejícím v místě studie jako pozitivní. Počáteční demografi cké charakteristiky a charakteristiky onemocnění nebyly u pacientů s pozitivní PET-CT (pozitivní PET) odlišné od těchto charakteristik u pacientů s negativním výsledkem PET-CT (negativní PET). Status PET koreloval s odpovědí podle konvenčních kritérií (p < 0,001). Pacienti s trvajícím pozitivním PET scanem měli významně kratší (p < 0,001) přežití bez progrese (progression-free survival, PFS), a to 42měsíční ve 32,9 % (95% interval spolehlivosti [confi dence interval, CI] 17,2–49,5 %), než pacienti, u nichž se PET změnila na negativní, a to 70,7 % (95% CI 59,3–79,4 %). Status výsledku PET byl nezávislým předpovědním faktorem progrese lymfomu, což však neplatilo o konvenčně hodnocené odpovědi podle kritérií IWC z r. 1999 (kompletní odpověď nebo nepotvrzená kompletní odpověď vs. částečná odpověď). Pacienti s pozitivní PET měli také vyšší riziko úmrtí (poměr rizik [hazard ratio, HR] 7,0; p < 0,0011). Závěr Status [18F]FDG PET-CT na konci indukční imunochemoterapie pacientů s FL účinně předpovídá výsledek a měl by být považován za smysluplný klinický výsledný ukazatel pro budoucí studie.

PURPOSE: The utility of [(18)F]fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) in assessing response at the end of induction therapy is well documented in Hodgkin's and diffuse large B-cell lymphomas, but its role in follicular lymphoma (FL) remains undetermined. We investigated the prognostic significance of PET-CT performed after first-line therapy in patients with FL treated in the prospective Primary Rituximab and Maintenance (PRIMA) study. PATIENTS AND METHODS: Results of PET-CT scans performed after induction immunochemotherapy were recorded retrospectively. Patients went on to either observation or rituximab maintenance per protocol independent of the PET-CT result. Patient characteristics and outcomes were then evaluated. RESULTS: Of 122 PET-CT scans performed at the end of the induction immunochemotherapy, 32 (26%) were reported as positive by the local investigator. Initial demographic or disease characteristics did not differ between PET-CT-positive (PET-positive) and PET-CT-negative (PET-negative) patients. PET status correlated with conventional response criteria (P < .001). Patients remaining PET positive had a significantly (P < .001) inferior progression-free survival at 42 months of 32.9% (95% CI, 17.2% to 49.5%) compared with 70.7% (95% CI, 59.3% to 79.4%) in those who became PET negative. PET status, but not conventional response (complete response or complete response unconfirmed v partial response) according to IWC 1999, was an independent predictive factor for lymphoma progression. The risk of death was also increased in PET-positive patients (hazard ratio 7.0; P = .0011). CONCLUSION: [(18)F]FDG PET-CT status at the end of immunochemotherapy induction in patients with FL is strongly predictive of outcome and should be considered a meaningful clinical end point in future studies.

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