• MeSH
• B-buněčný lymfom komplikace   mortalita   terapie   MeSH
• COVID-19 komplikace   MeSH
• imunoterapie adoptivní MeSH
• leukemie B-buněčná komplikace   mortalita   terapie   MeSH
• lidé MeSH
• prognóza MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH

IMPORTANCE: Blinatumomab is a CD3/CD19-directed bispecific T-cell engager molecule with efficacy in children with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). OBJECTIVE: To evaluate event-free survival in children with high-risk first-relapse B-ALL after a third consolidation course with blinatumomab vs consolidation chemotherapy before allogeneic hematopoietic stem cell transplant. DESIGN, SETTING, AND PARTICIPANTS: In this randomized phase 3 clinical trial, patients were enrolled November 2015 to July 2019 (data cutoff, July 17, 2019). Investigators at 47 centers in 13 countries enrolled children older than 28 days and younger than 18 years with high-risk first-relapse B-ALL in morphologic complete remission (M1 marrow, <5% blasts) or with M2 marrow (blasts ≥5% and <25%) at randomization. INTERVENTION: Patients were randomized to receive 1 cycle of blinatumomab (n = 54; 15 μg/m2/d for 4 weeks, continuous intravenous infusion) or chemotherapy (n = 54) for the third consolidation. MAIN OUTCOMES AND MEASURES: The primary end point was event-free survival (events: relapse, death, second malignancy, or failure to achieve complete remission). The key secondary efficacy end point was overall survival. Other secondary end points included minimal residual disease remission and incidence of adverse events. RESULTS: A total of 108 patients were randomized (median age, 5.0 years [interquartile range {IQR}, 4.0-10.5]; 51.9% girls; 97.2% M1 marrow) and all patients were included in the analysis. Enrollment was terminated early for benefit of blinatumomab in accordance with a prespecified stopping rule. After a median of 22.4 months of follow-up (IQR, 8.1-34.2), the incidence of events in the blinatumomab vs consolidation chemotherapy groups was 31% vs 57% (log-rank P < .001; hazard ratio [HR], 0.33 [95% CI, 0.18-0.61]). Deaths occurred in 8 patients (14.8%) in the blinatumomab group and 16 (29.6%) in the consolidation chemotherapy group. The overall survival HR was 0.43 (95% CI, 0.18-1.01). Minimal residual disease remission was observed in more patients in the blinatumomab vs consolidation chemotherapy group (90% [44/49] vs 54% [26/48]; difference, 35.6% [95% CI, 15.6%-52.5%]). No fatal adverse events were reported. In the blinatumomab vs consolidation chemotherapy group, the incidence of serious adverse events was 24.1% vs 43.1%, respectively, and the incidence of adverse events greater than or equal to grade 3 was 57.4% vs 82.4%. Adverse events leading to treatment discontinuation were reported in 2 patients in the blinatumomab group. CONCLUSIONS AND RELEVANCE: Among children with high-risk first-relapse B-ALL, treatment with 1 cycle of blinatumomab compared with standard intensive multidrug chemotherapy before allogeneic hematopoietic stem cell transplant resulted in an improved event-free survival at a median of 22.4 months of follow-up. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02393859.

• MeSH
• akutní lymfatická leukemie farmakoterapie   mortalita   terapie   MeSH
• antitumorózní látky škodlivé účinky   terapeutické užití   MeSH
• chemoterapie konsolidační škodlivé účinky   MeSH
• dítě MeSH
• imunoterapie * MeSH
• Kaplanův-Meierův odhad MeSH
• kojenec MeSH
• kombinovaná terapie MeSH
• leukemie B-buněčná farmakoterapie   mortalita   MeSH
• lidé MeSH
• míra přežití MeSH
• mladiství MeSH
• následné studie MeSH
• předškolní dítě MeSH
• přežití po terapii bez příznaků nemoci MeSH
• protilátky bispecifické škodlivé účinky   terapeutické užití   MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• recidiva MeSH
• rizikové faktory MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• antitumorózní látky MeSH
• blinatumomab MeSH Prohlížeč
• protilátky bispecifické MeSH

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer carrier containing the anticancer drug doxorubicin and targeted with B1 monoclonal antibody (mAb) to BCL1 leukemia cells was synthesised and tested in vitro and in vivo. BCL1 leukemia growing in syngenic Balb/c mice was selected as a tumor model system. B1 mAb recognising the idiotype of surface IgM on BCL1 cells was used as a targeting moiety. Both B1 mAb and doxorubicin were conjugated to HPMA copolymer carrier by aminolysis through a tetrapeptidic Gly-Phe(D,L)-Leu-Gly spacer to ensure the intracellular delivery and controlled release of the drug. B1 mAb-targeted conjugate was shown to possess strictly tumor-specific binding capacity to target BCL1 cells in vitro. A similar conjugate, but containing human nonspecific Ig (HuIg) instead of B1 mAb, failed to bind to BCL1 cells. In vitro, B1 mAb-targeted conjugate demonstrated 40-fold higher cytotoxic effect than nontargeted or human nonspecific Ig-containing HPMA copolymer-bound doxorubicin. Conjugate targeted with B1 mAb was also shown to bind to target BCL1 cells in vivo. B1 mAb-targeted conjugate was shown to be more efficient in the treatment of established BCL1 leukemia than free doxorubicin, nontargeted and human nonspecific Ig-containing conjugate. Antibody-targeted polymeric drugs are thus promising conjugates for cancer treatment.

• MeSH
• akrylamidy chemie   terapeutické užití   MeSH
• antigeny nádorové imunologie   MeSH
• buněčné dělení účinky léků   MeSH
• doxorubicin chemie   terapeutické užití   MeSH
• hydrogely chemie   MeSH
• imunokonjugáty krev   farmakologie   terapeutické užití   MeSH
• inhibiční koncentrace 50 MeSH
• injekce intraperitoneální MeSH
• injekce intravenózní MeSH
• leukemie B-buněčná farmakoterapie   imunologie   mortalita   MeSH
• leukocyty mononukleární chemie   MeSH
• míra přežití MeSH
• monoklonální protilátky analýza   chemie   farmakologie   MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• počet retikulocytů MeSH
• protilátky anti-idiotypické analýza   chemie   farmakologie   MeSH
• průtoková cytometrie MeSH
• slezina chemie   MeSH
• systémy cílené aplikace léků metody   MeSH
• tělesná hmotnost účinky léků   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• akrylamidy MeSH
• antigeny nádorové MeSH
• doxorubicin MeSH
• hydrogely MeSH
• imunokonjugáty MeSH
• monoklonální protilátky MeSH
• N-(2-hydroxypropyl)methacrylamide co-polymer-doxorubicin conjugate MeSH Prohlížeč
• protilátky anti-idiotypické MeSH

Treatment of an established BCL1 leukaemia in mice showed that the use of hydrogels is advantageous in comparison with free doxorubicin (DOX), partially due to the different pharmacokinetic profile of the drug release. Pharmacologically active concentrations ranging from 100 to 800 ng/ml were detectable in the bloodstream for more than 4 days when DOX-loaded hydrogels were implanted into mice. Animals treated with free DOX survived for 35 days, survival of hydrogel-DOX treated animals increased up to 60 days and long-term survivors were achieved, when the second hydrogel was implanted 2 weeks after the first one. Hydrogels containing vinblastine (VLB) were ineffective. N-(2-hydroxypropyl)methacrylamide (HPMA) hydrogels were also used in combined therapy against multidrug resistant leukaemia P388-MDR to achieve a synergistic effect of both the cytostatic drug and chemosensitising agent. It was shown that when 4 times the maximal tolerated dose (MTD) of free DOX was incorporated into HPMA-hydrogels, tumour volume was reduced by approximately 50% after implantation of the hydrogel containing DOX and cyclosporine A (CsA) and survival was slightly prolonged.

• MeSH
• antitumorózní látky aplikace a dávkování   MeSH
• chemorezistence MeSH
• cyklosporin aplikace a dávkování   MeSH
• doxorubicin aplikace a dávkování   MeSH
• hydrogely aplikace a dávkování   MeSH
• leukemie B-buněčná farmakoterapie   mortalita   MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• systémy cílené aplikace léků MeSH
• transplantace heterologní MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• cyklosporin MeSH
• doxorubicin MeSH
• hydrogely MeSH