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Histological transformation (HT) in Waldenström's macroglobulinemia (WM) is a rare complication and despite growing literature in the last years, no consensus recommendations exist. Consensus Panel 6 (CP6) of the 12th International Workshop on Waldenström's Macroglobulinemia (IWWM-12) was convened to review the current data on transformed WM and make recommendations on its diagnosis and management. The key recommendations from IWWM-12 CP6 included: (1) in case of suspected HT, tissue biopsy is the gold standard for diagnosis; (2) the initial work-up should comprise 18FDG-PET/CT for the evaluation of disease extent and, for patients with clinical suspicion or for high-risk patients (CNS-IPI, multiple and/or specific extranodal involvements), cerebrospinal fluid examination and brain MRI; (3) standard dose chemoimmunotherapy (CIT) such as R-CHOP (rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone) or R-CHP + polatuzumab vedotin are the preferred front-line regimen; (4) CNS prophylaxis and consolidation with autologous stem cell transplantation (SCT) can be considered according to de novo diffuse large B-cell lymphoma (DLBCL) guidelines; (5) T-cell-engaging therapies (CAR T-cells, bispecific antibodies) should be used in the relapse/refractory setting according to international guidelines for DLBCL and local access to these therapies. Key unanswered questions include the role of TP53 abnormalities and CXCR4 mutations on the risk of HT, the prognostic role of clonal relationship between WM and HT, the optimal front-line therapy (addition of novel agents to CIT, dose-intensive CIT, consolidation with autologous SCT), and the sequence of T-cell-engaging therapies. International collaboration and consideration of and inclusion in clinical trials is critical to address these issues in a rare patient population.
In previous research, we revealed that murine leukemia cells L1210 with induced expression of P-glycoprotein (P-gp, a membrane drug transporter, product of the Abcb1 gene) are better able to withstand endoplasmic reticulum (ER) stress (ERS) than their P-gp negative counterparts. This was associated with increased GRP78/BiP expression and modulation of the expression of several other proteins active in the cellular response to ERS (like CHOP, spliced XBP1, 50-kDa ATF6 protein fragment and others) in P-gp positive cells. Wolframin is an ER transmembrane protein, product of the WFS1 gene whose mutations are associated with Wolfram syndrome. However, this protein is frequently overexpressed in cells undergoing ERS and its expression may accompany changes in the above ERS markers. Therefore, our aim in this work was to investigate wolframin expression in P-gp-negative and P-gp-positive murine leukemia L1210 cells in relation to ERS related proteins in normal or ERS condition. We induced ERS in cells either by blocking N-glycosylation in the ER with tunicamycin or by blocking ER Ca2+-ATPase activity with thapsigargin, as known ER stressors. The results of this paper demonstrated increased wolframin expression in P-gp positive cells compared to P-gp negative cells. Immunoprecipitation experiments revealed the formation of complexes between wolframin and ERS related proteins (PERK, ATF6 and GRP78/BiP), the amount of which varied depending on the presence of the above ER stressors.
- Publikační typ
- časopisecké články MeSH
Difuzní velkobuněčný B lymfom (diffuse large B-ceU lymphoma, DLBCL) patří mezi dobře léčitelné malignity s šancí na dosažení dlouhodobé remise u 60-70 % pacientů při terapii režimem R-CHOP. Konjugáty monoklonální protilátky a léčiva (antibody-drug conjugates, ADC) polatuzumab vedotin, lonkastuximab tesirin, brentuximab vedotin a zilovertamab vedotin představují moderní terapeutický přístup pro nemocné s lymfomy. Tyto molekuly kombinují specificitu monoklonálních protilátek s cytotoxickým účinkem chemoterapeutik, což umožňuje přesnější doručení cytostatik přímo do lymfomových buněk. Polatuzumab vedotin, první schválený ADC pro léčbu DLBCL, se používá jak v kombinaci s bendamustinem a rituximabem (Pola-BR) pro relabující/refrakterní (R/R) DLBCL u pacientů nevhodných pro intenzivní terapii, tak v první linii s režimem R-CHP (Pola-R-CHP) pro nemocné se středně vysokým nebo vysokým rizikem podle mezinárodního prognostického indexu. Lonkastuximab tesirin je schválen pro pacienty s R/R DLBCL po dvou nebo více liniích předchozí léčby, přičemž léčba je podávána do progrese nemoci nebo nepřijatelné toxicity. Brentuximab vedotin a zilovertamab vedotin jsou aktuálně ve fázi klinického výzkumu. Léčba DLBCL se díky novým terapeutickým možnostem neustále vyvíjí. Konjugáty monoklonální protilátky a léčiva představují významný pokrok v terapii tohoto onemocnění, nicméně jejich dlouhodobá účinnost a bezpečnost musí být nadále testována jak v monoterapii, tak v kombinaci s jinými léčebnými modalitami, a podpořena analýzami pacientů z reálného světa. S rozvojem dalších terapeutických modalit, jako je imunoterapie, vyvstává otázka optimálního načasování jednotlivých léčebných postupů, účinnosti sekvenčního podávání různých ADC a opakování terapie zaměřené na antigen CD19 (CAR-T lymfocyty, lonkastuximab tesirin, tafasitamab).
Diffuse large B-cell lymphoma (DLBCL) is a highly treatable malignancy, with a 60-70% chance of achieving long-term remission when treated with the first-line R-CHOP regimen. Antibody-drug conjugates (ADC) such as polatuzumab vedotin, loncastuximab tesirine, brentuximab vedotin, and zilovertamab vedotin represent a modern approach to lymphoma therapy. These molecules combine the specificity of monoclonal antibodies with the cytotoxic effect of chemotherapeutics, enabling more precise drug delivery directly to lymphoma cells. Polatuzumab vedotin, the first approved ADC for DLBCL treatment, is used in combination with bendamustine and rituximab (Poia-BR) for reiapsed/refractory (R/R) DLBCL in patients ineligible for intensive therapy, as weii as in the frontline setting with the R-CHP regimen (Poia-R-CHP) for intermediateto high-risk patients according to the International Prognostic Index. Loncastuximab tesirine is currently approved for patients with R/R DLBCL after two or more prior lines of treatment as continuous therapy until disease progression or unacceptable toxicity. Brentuximab vedotin and ziiovertamab vedotin are currently being tested in clinical research. Diffuse large B-ceii lymphoma treatment is continuousiy evoiving with the advent of new therapeutic options. Antibody-drug conjugates represent a significant advancement in the treatment of this disease, though their iong-term efficacy and safety have to be studied further, both as monotherapy and in combination with other treatment modaiities, supported by reai-worid patient data. As additionai therapeutic modaiities, such as immunotherapy, emerge, questions remain regarding the optimai timing of individuai treatments, the effectivity of sequentiai administration of different ADC, and the retreatment with therapies targeting the CD19 antigen (CAR T-ceii, ioncastuximab tesirin, tafasitamab).
- Klíčová slova
- polatuzumab vedotin, zilovertamab vedotin, lonkastuximab tesirin,
- MeSH
- brentuximab vedotin farmakologie terapeutické užití MeSH
- cytostatické látky aplikace a dávkování farmakologie terapeutické užití MeSH
- difúzní velkobuněčný B-lymfom * diagnóza farmakoterapie MeSH
- humanizované monoklonální protilátky farmakologie klasifikace terapeutické užití MeSH
- imunokonjugáty * farmakologie imunologie klasifikace terapeutické užití MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
PURPOSE: We report an analysis of minimal residual/detectable disease (MRD) as a predictor of outcome in previously untreated patients with follicular lymphoma (FL) from the randomized, multicenter GALLIUM (ClinicalTrials.gov identifier: NCT01332968) trial. PATIENTS AND METHODS: Patients received induction with obinutuzumab (G) or rituximab (R) plus bendamustine, or cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or cyclophosphamide, vincristine, prednisone (CVP) chemotherapy, followed by maintenance with the same antibody in responders. MRD status was assessed at predefined time points (mid-induction [MI], end of induction [EOI], and at 4-6 monthly intervals during maintenance and follow-up). Patients with evaluable biomarker data at diagnosis were included in the survival analysis. RESULTS: MRD positivity was associated with inferior progression-free survival (PFS) at MI (hazard ratio [HR], 3.03 [95% CI, 2.07 to 4.45]; P < .0001) and EOI (HR, 2.25 [95% CI, 1.53 to 3.32]; P < .0001). MRD response was higher after G- versus R-chemotherapy at MI (94.2% v 88.9%; P = .013) and at EOI (93.1% v 86.7%; P = .0077). Late responders (MI-positive/EOI-negative) had a significantly poorer PFS than early responders (MI-negative/EOI-negative; HR, 3.11 [95% CI, 1.75 to 5.52]; P = .00011). The smallest proportion of MRD positivity was observed in patients receiving bendamustine at MI (4.8% v 16.0% in those receiving CHOP; P < .0001). G appeared to compensate for less effective chemotherapy regimens, with similar MRD response rates observed across the G-chemo groups. During the maintenance period, more patients treated with R than with G were MRD-positive (R-CHOP, 20.7% v G-CHOP, 7.0%; R-CVP, 21.7% v G-CVP, 9.4%). Throughout maintenance, MRD positivity was associated with clinical relapse. CONCLUSION: MRD status can determine outcome after induction and during maintenance, and MRD negativity is a prerequisite for long-term disease control in FL. The higher MRD responses after G- versus R-based treatment confirm more effective tumor cell clearance.
- MeSH
- bendamustin hydrochlorid MeSH
- cyklofosfamid MeSH
- doxorubicin MeSH
- folikulární lymfom * MeSH
- galium * terapeutické užití MeSH
- lidé MeSH
- prednison MeSH
- protokoly protinádorové kombinované chemoterapie škodlivé účinky MeSH
- reziduální nádor farmakoterapie MeSH
- rituximab MeSH
- vinkristin MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
Viral infection may represent a stress condition to the host cell. Cells react to it by triggering the defence programme to restore homeostasis and these events may in turn impact the viral replication. The knowledge about tick-borne encephalitis virus (TBEV) infection-associated stress is limited. Here we investigated the interplay between TBEV infection and stress pathways in PMJ2-R mouse macrophage cell line, as macrophages are the target cells in early phases of TBEV infection. First, to determine how stress influences TBEV replication, the effect of stress inducers H2O2 and tunicamycin (TM) was tested. Viral multiplication was decreased in the presence of both stress inducers suggesting that the stress and cellular stress responses restrict the virus replication. Second, we investigated the induction of oxidative stress and endoplasmic reticulum (ER) stress upon TBEV infection. The level of oxidative stress was interrogated by measuring the reactive oxygen species (ROS). ROS were intermittently increased in infected cells at 12 hpi and at 72 hpi. As mitochondrial dysfunction may result in increased ROS level, we evaluated the mitochondrial homeostasis by measuring the mitochondrial membrane potential (MMP) and found that TBEV infection induced the hyperpolarization of MMP. Moreover, a transient increase of gene expression of stress-induced antioxidative enzymes, like p62, Gclm and Hmox1, was detected. Next, we evaluated the ER stress upon TBEV infection by analysing unfolded protein responses (UPR). We found that infection induced gene expression of two general sensors BiP and CHOP and activated the IRE1 pathway of UPR. Finally, since the natural transmission route of TBEV from its tick vector to the host is mediated via tick saliva, the impact of tick saliva from Ixodes ricinus on stress pathways in TBEV-infected cells was tested. We observed only marginal potentiation of UPR pathway. In conclusion, we found that TBEV infection of PMJ2-R cells elicits the changes in redox balance and triggers cellular stress defences, including antioxidant responses and the IRE1 pathway of UPR. Importantly, our results revealed the negative effect of stress-evoked events on TBEV replication and only marginal impact of tick saliva on stress cellular pathways.
- MeSH
- buněčné linie MeSH
- klíšťová encefalitida * MeSH
- myši MeSH
- peroxid vodíku metabolismus MeSH
- protein-serin-threoninkinasy metabolismus MeSH
- reaktivní formy kyslíku metabolismus MeSH
- replikace viru MeSH
- viry klíšťové encefalitidy * genetika MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Rituximab (RTX) plus chemotherapy (R-CHOP) applied as a first-line therapy for lymphoma leads to a relapse in approximately 40% of the patients. Therefore, novel approaches to treat aggressive lymphomas are being intensively investigated. Several RTX-resistant (RR) cell lines have been established as surrogate models to study resistance to R-CHOP. Our study reveals that RR cells are characterized by a major downregulation of CD37, a molecule currently explored as a target for immunotherapy. Using CD20 knockout (KO) cell lines, we demonstrate that CD20 and CD37 form a complex, and hypothesize that the presence of CD20 stabilizes CD37 in the cell membrane. Consequently, we observe a diminished cytotoxicity of anti-CD37 monoclonal antibody (mAb) in complement-dependent cytotoxicity in both RR and CD20 KO cells that can be partially restored upon lysosome inhibition. On the other hand, the internalization rate of anti-CD37 mAb in CD20 KO cells is increased when compared to controls, suggesting unhampered efficacy of antibody drug conjugates (ADCs). Importantly, even a major downregulation in CD37 levels does not hamper the efficacy of CD37-directed chimeric antigen receptor (CAR) T cells. In summary, we present here a novel mechanism of CD37 regulation with further implications for the use of anti-CD37 immunotherapies.
- MeSH
- antigeny CD20 * imunologie metabolismus genetika MeSH
- antigeny nádorové imunologie genetika MeSH
- B-buněčný lymfom * imunologie terapie genetika farmakoterapie MeSH
- chemorezistence účinky léků MeSH
- chimerické antigenní receptory imunologie genetika metabolismus MeSH
- cyklofosfamid farmakologie terapeutické užití MeSH
- doxorubicin farmakologie aplikace a dávkování MeSH
- imunoterapie * metody MeSH
- lidé MeSH
- monoklonální protilátky farmakologie terapeutické užití MeSH
- nádorové buněčné linie MeSH
- protokoly protinádorové kombinované chemoterapie farmakologie terapeutické užití MeSH
- regulace genové exprese u nádorů MeSH
- rituximab * farmakologie terapeutické užití MeSH
- tetraspaniny * genetika metabolismus MeSH
- vinkristin farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Difúzní velkobuněčný B-lymfom (DLBCL) tvoří 40 % všech nehodgkinských lymfomů, a je prototypem agresivního lymfomu. Léčebným postupem v první linii byl dosud chemoimunoterapeutický režim R-CHOP (rituximab, cyklofosfamid, doxorubicin, vinkristin, prednison) s 60-70% šancí na dosažení dlouhodobé remise. Nově je v klinické praxi nahrazován režimem Pola-R-CHP (výměna vinkristinu za konjugát monoklonální protilátky a léčiva polatuzumab vedotin), který snižuje riziko relapsu a prodlužuje dobu do progrese u pacientů s nově diagnostikovaným DLBCL se středně vysokým a vysokým rizikem dle prognostického indexu IPI. Ve druhé linii je pro pacienty s časným relapsem do 12 měsíců od ukončení předchozí linie nejúčinnější metodou léčba buněčnou terapií pomocí CAR (chimérický antigenní receptor) T lymfocytů. U pozdních relapsů mladších pacientů do 65-75 let bez významných komorbidit nadále zůstává standardem léčby záchranný platinový chemoterapeutický režim s následnou konsolidací pomocí vysokodávkované chemoterapie a autologní transplantace kostní dřeně. Spektrum terapeutických možností třetí a další linie se neustále rozšiřuje, a kromě CAR T-cell terapie máme nyní k dispozici bispecifické protilátky a další cílenou léčbu. Díky tomuto pokroku se z původně paliativní léčby opakovaných relapsů DLBCL stává léčba s kurativním záměrem.
Diffuse large B-cell lymphoma is a prototype of aggressive lymphomas. Until recently, the standard of care in the first-line setting has been the chemoimmunotherapeutic regimen R-CHOP (consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) with a 60-70% chance of achieving long-term remission. The newly introduced Pola-R-CHP regimen (replacing vincristine by the antibody-drug conjugate polatuzumab vedotin) decreases the risk of DLBCL relapse and prolongs the progression-free survival of the patients. This regimen is being gradually implemented into a daily practice and is currently approved for patients with high-intermediate and high-risk disease according to IPI prognostic index. CAR (chimeric antigen receptor) T-cell therapy is approved for primary progressive disease and early relapses up to 12 months after the first-line treatment. The salvage platinum-based regimen with consolidation treatment using the high-dose chemotherapy and autologous stem cell transplantation for younger and fit patients remains the standard of care for late DLBCL relapses. The spectrum of therapeutic strategies in the third and subsequent lines of treatment is expanding with innovative treatment options, including bispecific antibodies, and other targeted therapy. Thanks to these advances, the strategy for third-line treatment is now shifting from palliative to curative intent.
- MeSH
- chimerické antigenní receptory terapeutické užití MeSH
- cílená molekulární terapie metody MeSH
- difúzní velkobuněčný B-lymfom * terapie MeSH
- imunokonjugáty terapeutické užití MeSH
- kombinovaná terapie metody MeSH
- lidé MeSH
- monoklonální protilátky terapeutické užití MeSH
- protilátky bispecifické terapeutické užití MeSH
- protokoly protinádorové kombinované chemoterapie terapeutické užití MeSH
- recidiva MeSH
- Check Tag
- lidé MeSH
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 protinádorové 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
Resveratrol (RSV) is a polyphenol antioxidant that has been shown to have neuroprotective effects. We sought molecular mechanisms that emphasize the anti-inflammatory activity of RSV in traumatic brain injury (TBI) in mice associated with endoplasmic reticulum stress (ERS). After establishing three experimental groups (sham, TBI, and TBI+RSV), we explored the results of RSV after TBI on ERS and caspase-12 apoptotic pathways. The expression levels of C/EBP homologous protein (CHOP), glucose regulated protein 78kD (GRP78), caspase-3, and caspase-12 in cortical brain tissues were assessed by western blotting. The qPCR analysis was also performed on mRNA expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1β in cortical brain tissue. In addition, the expression of GRP78 in microglia (ionized calcium binding adaptor molecule 1; Iba-1) and neurons (neuronal nuclei; NeuN) was identified by immunofluorescence staining. The neurological function of mice was assessed by modified neurological severity scores (mNSS). After drug treatment, the expression of CHOP, GRP78, caspase-3 and caspase-12 decreased, and qPCR results showed that TNF-α and IL-1β were down-regulated. Immunofluorescence staining showed down-regulation of Iba-1+/GRP78+ and NeuN+/GRP78+ cells after RSV treatment. The mNSS analysis confirmed improvement after RSV treatment. RSV improved apoptosis by downregulating the ERS signaling pathway and improved neurological prognosis in mice with TBI.
- MeSH
- apoptóza účinky léků MeSH
- buněčná smrt účinky léků MeSH
- chaperon endoplazmatického retikula BiP * MeSH
- interleukin-1beta metabolismus genetika MeSH
- kaspasa 12 metabolismus genetika MeSH
- mikroglie účinky léků metabolismus patologie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- neurony účinky léků patologie metabolismus MeSH
- neuroprotektivní látky farmakologie terapeutické užití MeSH
- prognóza MeSH
- proteiny tepelného šoku metabolismus genetika MeSH
- resveratrol * farmakologie terapeutické užití MeSH
- stres endoplazmatického retikula * účinky léků MeSH
- TNF-alfa metabolismus MeSH
- transkripční faktor CHOP metabolismus genetika MeSH
- traumatické poranění mozku * farmakoterapie patologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Difuzní velkobuněčný B lymfom je nejčastějším maligním lymfomem v našich podmínkách. Standardní léčbou založenou na imunochemoterapii R-CHOP (rituximab, cyklofosfamid, doxorubicin, vincristin, prednison) a záchranné terapii na bázi platinového režimu a vysokodávkované chemoterapie s autologní transplantací je možno vyléčit asi 60-70 % pacientů. Zlepšení prognózy v první linii ve srovnání s režimem R-CHOP u pacientů s rizikovým onemocněním přinesla kombinace polatuzumab vedotinu s R-CHP (rituximab, cyklofosfamid, doxorubicin, prednison) s 27% redukcí rizika progrese, relapsu nebo úmrtí ve dvou letech s 2letým přežitím bez progrese 76,7 % vs. 70,2 % při standardní léčbě (poměr rizik [hazard ratio, HR] 0,73; p = 0,02). Jako perspektivní se dále v první linii jeví kombinace režimu R-CHOP s tafasitamabem a lenalidomidem, resp. bispecifickými protilátkami glofitamabem, epcoritamabem a odronextamabem zapojujícími mechanismy T buněčné imunity. V situaci relabované nemoci u pacientů s progresí nemoci do 1 roku je nyní standardním postupem buněčná terapie přípravky CAR-T terapie (T lymfocyty s chimérickým antigenním receptorem) axicabtagen ciíoíeuceíem (axi-cel) a lisocabtagen maraleucelem (liso-cel), které ve srovnání s platinovými režimy a vysokodávkovanou chemoterapií s autologní transplantací přinesly 60-65% redukci rizika selhání léčby: 2leté přežití bez události (event free survival, EFS) 41 % u axi-celu vs. 16 % (HR 0,40; p < 0,001); 2leté EFS 45 % u liso-celu vs. 24 % (HR 0,35; p < 0,0001). Ve třetí a vyšší linii se velmi účinná jeví terapie bispecifickými protilátkami glofitamabem a epcoritamabem, u kterých v monoterapii je možno dosáhnout až 39 % kompletních remisí s následným trváním odpovědi delší než 12 měsíců až u 80 % pacientů. Dalšími nadějnými léky jsou imunokonjugát loncastuximab tesirin a kombinace monoklonální protilátky tafasitamabu s lenalidomidem.
Diffuse large B-cell lymphoma is the most common subtype of aggressive malignant lymphoma. First line therapy based on R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and platinum-based salvage therapy with high dose chemotherapy and autologous stem cell support leads to cure in approximately 60-70% of patients. In first line setting in patients with high risk profile disease, polatuzumab vedotin in combination with R-CHP (rituximab, cyclophosphamide, doxorubicin, prednisone) improved prognosis with 27% risk reduction of progression, relapse or death at 2 years with 2years progression free survival of 76.7% vs. 70.2% with standard therapy. (HR 0.73; p = 0.02). Further, the combination of R-CHOP regimen with tafasitamab and lenalidomide or T-cell immunity activating bispecific antibodies glofitamab, epcoritamab and odronextamab seems promising. In relapsed setting, in patients with disease progression within 1 year CAR-T (chimeric antigen receptor T-lymphocytes) therapy with axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) represents now a standard of care, that in comparison to platinum based therapy and high-dose chemotherapy with autologous stem cell support leads to 60-65% reduction of risk of treatment failure: 2year event free survival (EFS) 41% with axi-cel vs. 16% (HR 0.40; p < 0.001); 2year EFS 45% with liso-cel vs. 24% (HR 0.35; p < 0.0001). In a third or later line of therapy, bispecific antibodies glofitamab and epcoritamab seems to be effective modality with complete remission rate of 39% and duration of complete response more than 12 months in up to 80% of patients. Another promising option include immunoconjugate loncastuximab tesirin and combination of monoclonal antibody tafasitamab with lenalidomide.
- Klíčová slova
- tafasitamab, loncastuximab vedotin, polatuzumab vedotin,
- MeSH
- chimerické antigenní receptory terapeutické užití MeSH
- cílená molekulární terapie MeSH
- difúzní velkobuněčný B-lymfom * farmakoterapie MeSH
- imunokonjugáty klasifikace terapeutické užití MeSH
- klinická studie jako téma MeSH
- lenalidomid terapeutické užití MeSH
- lidé MeSH
- monoklonální protilátky klasifikace terapeutické užití MeSH
- protilátky bispecifické terapeutické užití MeSH
- protinádorové látky imunologicky aktivní klasifikace terapeutické užití MeSH
- protokoly protinádorové kombinované chemoterapie MeSH
- Check Tag
- lidé MeSH
