Only 50% of patients with relapsed Hodgkin lymphoma (HL) can be cured with intensive induction chemotherapy, followed by high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT). Based on the results of the HDR2 trial two courses of DHAP and subsequent HDCT/ASCT are the current standard of care in relapsed HL. In order to assess the prognostic relevance of DHAP dose density, we performed a retrospective multivariate analysis of the HDR2 trial (N=266). In addition to four risk factors (early or multiple relapse, stage IV disease or anemia at relapse, and grade IV hematotoxicity during the first cycle of DHAP) a delayed start of the second cycle of DHAP>day 22 predicted a significantly poorer progression-free survival (PFS, p=0.0356) and overall survival (OS, p=0.0025). In conclusion, our analysis strongly suggests that dose density of DHAP has a relevant impact on the outcome of relapsed HL patients.

• Klíčová slova
• DHAP, dose density, hematotoxicity, outcome, relapsed Hodgkin lymphoma,
• MeSH
• adjuvantní radioterapie MeSH
• cisplatina škodlivé účinky   terapeutické užití   MeSH
• cytarabin škodlivé účinky   terapeutické užití   MeSH
• dexamethason škodlivé účinky   terapeutické užití   MeSH
• dospělí MeSH
• Hodgkinova nemoc farmakoterapie   mortalita   patologie   MeSH
• kombinovaná terapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• opakovaná terapie MeSH
• prognóza MeSH
• proporcionální rizikové modely MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• recidiva MeSH
• staging nádorů MeSH
• transplantace hematopoetických kmenových buněk MeSH
• výsledek terapie MeSH
• záchranná terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví 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
• Geografické názvy
• Německo MeSH
• Názvy látek
• cisplatina MeSH
• cytarabin MeSH
• dexamethason MeSH

High-dose chemotherapy followed by autologous stem cell transplantation can improve the outcome of relapsed and refractory Hodgkin's disease (HD) patients. The objective of the trial was to determine the mobilizing potential of the DHAP salvage regimen (dexamethasone, cytarabine, cisplatin) for the collection of peripheral blood stem cells (PBSC) in patients with relapsed HD. The target yield of harvesting CD34 + cells was > or =2 x 10(6)/kg in order to support the subsequent myeloablative chemotherapy. Most of the 105 patients included were intensively pre-treated with different combination chemotherapy regimens prior to mobilization. The use of DHAP followed by granulocyte colony-stimulating factor (G-CSF; 10 microg/kg) resulted in the successful collection of adequate numbers of PBSC in 97.1% of patients (102 of 105) with a median harvest of CD34+ cells of 13 x 10(6)/kg (range 2.6 - 85.1). More than 2.0 x 10(6) CD34+ cells/kg were achieved in 65 of 103 (63%) patients after 1 apheresis, the maximum number of aphereses for all patients was 3. It was found that the optimal time of PBSC harvest was at days 13 - 16 after initiating the mobilization regimen. These results demonstrate that the salvage chemotherapy regimen, such as DHAP combined with G-CSF, can be successfully used to mobilize PBSC in HD patients.

• MeSH
• cisplatina terapeutické užití   MeSH
• cytarabin terapeutické užití   MeSH
• dexamethason terapeutické užití   MeSH
• dospělí MeSH
• faktor stimulující kolonie granulocytů terapeutické užití   MeSH
• hematopoetické kmenové buňky metabolismus   MeSH
• Hodgkinova nemoc krev   patologie   terapie   MeSH
• kombinovaná farmakoterapie MeSH
• kostní dřeň účinky léků   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru krev   patologie   terapie   MeSH
• mladiství MeSH
• mobilizace hematopoetických kmenových buněk metody   MeSH
• prognóza MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• záchranná terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cisplatina MeSH
• cytarabin MeSH
• dexamethason MeSH
• faktor stimulující kolonie granulocytů MeSH

Rationale: Despite growing evidence for mitochondria's involvement in cancer, the roles of specific metabolic components outside the respiratory complex have been little explored. We conducted metabolomic studies on mitochondrial DNA (mtDNA)-deficient (ρ0) cancer cells with lower proliferation rates to clarify the undefined roles of mitochondria in cancer growth. Methods and results: Despite extensive metabolic downregulation, ρ0 cells exhibited high glycerol-3-phosphate (G3P) level, due to low activity of mitochondrial glycerol-3-phosphate dehydrogenase (GPD2). Knockout (KO) of GPD2 resulted in cell growth suppression as well as inhibition of tumor progression in vivo. Surprisingly, this was unrelated to the conventional bioenergetic function of GPD2. Instead, multi-omics results suggested major changes in ether lipid metabolism, for which GPD2 provides dihydroxyacetone phosphate (DHAP) in ether lipid biosynthesis. GPD2 KO cells exhibited significantly lower ether lipid level, and their slower growth was rescued by supplementation of a DHAP precursor or ether lipids. Mechanistically, ether lipid metabolism was associated with Akt pathway, and the downregulation of Akt/mTORC1 pathway due to GPD2 KO was rescued by DHAP supplementation. Conclusion: Overall, the GPD2-ether lipid-Akt axis is newly described for the control of cancer growth. DHAP supply, a non-bioenergetic process, may constitute an important role of mitochondria in cancer.

• Klíčová slova
• DHAP, GPD2, cancer, ether lipids, mitochondria,
• MeSH
• energetický metabolismus MeSH
• ethery metabolismus   MeSH
• glycerolfosfátdehydrogenasa * genetika   metabolismus   MeSH
• lidé MeSH
• mitochondrie * enzymologie   MeSH
• myši MeSH
• nádory * enzymologie   patologie   MeSH
• protoonkogenní proteiny c-akt * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ethery MeSH
• glycerolfosfátdehydrogenasa * MeSH
• protoonkogenní proteiny c-akt * MeSH

BACKGROUND: Treatment of Hodgkin's disease (HD) and non-Hodgkin lymphomas (NHL) is still unsatisfactory in patients resistant to primary therapy or those with early relapses. The objective of the trial was to test whether salvage regimens based on a combination of iphosphamide and etopozide have a sufficient anti-lymphoma effect, while the toxicity is still acceptable, and in conjunction with growth factors as satisfactory mobilizing potential for the collection of peripheral stem cells (PBSC). METHODS AND RESULTS: A group of 40 patients with relapsing and/or primary therapy resisting lymphomas (14 NHL, 26 HD) were treated by life saving or stimulating chemotherapy VIM (etopozide, iphosphamide, methotrexate) and MINE (iphosphamide mitoxanthrone, etopozide; mostly NHL). If the response to these regimes was inadequate, to some patients in addition mini (dexa) regimes were administered, BEAM and DHAP resp., with the objective to achieve maximum reduction of the tumourous mass before high-dosage treatment with the support of autologous PBSC. The authors administered 119 cycles of salvage chemotherapy (51 VIM, 46 MINE, 22 mini-dexa-BEAM and DHAP). The toxicity of chemotherapy and the therapeutic response were evaluated according to WHO criteria. The toxicity of VIM and MINE, with the exception for mobilization of desirable transient leukopenia, was not serious. During stimulation of PBSC on average three leukophereses were made and on average 9.9. 10(6) CD34+ cells/kg body weight of the patient were obtained and 53.2. 10(4) CFU-GM/kg (VIM), and 13.5. 10(6) CD34+ cells/kg 53.4. 10(4) CFU-GM/kg (MINE) resp. A total of 64% (MINE) and 61% (VIM) therapeutic responses were obtained, 14% (MINE) and 26% (VIM) complete remissions and 50% (MINE) and 35% (VIM) partial remissions. CONCLUSIONS: Life saving regimes, VIM and MINE, have a good antilymphoma activity, low toxicity and in combination with growth factors (filgrastim) they ensure a good collection of PBSC. As compared with other regimens, in particular for stimulation, VIM and MINE appear to be better.

• MeSH
• chemorezistence MeSH
• dospělí MeSH
• etoposid aplikace a dávkování   škodlivé účinky   MeSH
• Hodgkinova nemoc farmakoterapie   MeSH
• ifosfamid aplikace a dávkování   škodlivé účinky   MeSH
• leukaferéza MeSH
• lidé středního věku MeSH
• lidé MeSH
• mesna aplikace a dávkování   škodlivé účinky   MeSH
• methotrexát aplikace a dávkování   škodlivé účinky   MeSH
• mitoxantron aplikace a dávkování   škodlivé účinky   MeSH
• mladiství MeSH
• nehodgkinský lymfom farmakoterapie   MeSH
• příprava pacienta k transplantaci MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• recidiva MeSH
• transplantace hematopoetických kmenových buněk MeSH
• záchranná terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• klinické zkoušky MeSH
• Názvy látek
• etoposid MeSH
• ifosfamid MeSH
• mesna MeSH
• methotrexát MeSH
• mitoxantron 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
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Geografické názvy
• Evropa MeSH
• Izrael MeSH
• Názvy látek
• adenin * MeSH
• cyklofosfamid * MeSH
• dexamethason MeSH
• doxorubicin MeSH
• ibrutinib MeSH Prohlížeč
• piperidiny * MeSH
• prednison MeSH
• R-CHOP protocol MeSH Prohlížeč
• rituximab * MeSH
• vinkristin * MeSH

The authors evaluated a group of 48 patients with relapsing or resistant Hodgkin's disease. The patients were treated by life-saving chemotherapy followed by large doses of chemotherapy and autologous transplantation of haematopoietic cells. For life-saving chemotherapy they used most frequently a combination of VIM in 40 patients and combinations of DHAP, MINE, MiniDexaBEAM. In 11 patients they changed the regime of life-saving chemotherapy because of a poor response. After completed life-saving chemotherapy 18 (37.5%) patients were in CR, 27 (56.2%) in PR and in 3 (6.3%) the disease progressed. For large dose chemotherapy the authors used BEAM in 32 patients, CBV in 2, Busulfan with Cyclophosphamide in 13 patients and Busulfan with Melfalan in one patient. After completion of large dose chemotherapy and subsequent autologous transplantation of bone marrow 31 (64.6%) patients were in CR, 8 (16.7%) in PR and the disease progressed in 9 (18.7%). In August 1999 a total of 44.9% patients in CR survive, the median period of follow up after autologous transplantation was 23 months. Life-saving chemotherapy with subsequent large dose chemotherapy led in the investigated group to induction of CR in 64.6% patients which is the basic prerequisite of long-term survival.

• MeSH
• chemorezistence MeSH
• dospělí MeSH
• Hodgkinova nemoc farmakoterapie   mortalita   MeSH
• kombinovaná terapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• protokoly protinádorové kombinované chemoterapie aplikace a dávkování   MeSH
• recidiva MeSH
• transplantace kostní dřeně MeSH
• záchranná terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH

High-dose chemotherapy with autologous stem cell transplantation remains the current standard of treatment for young patients with Hodgkin lymphoma in first relapse or in those who are refractory to first-line treatment. The most important prognostic factors in relapses are clinical stage IV, poor performance status, bulky mass, and less than partial remission after salvage chemotherapy. Standard salvage chemotherapy in relapse before autologous transplantation has not been defined; however, DHAP and ICE are most frequently used in this setting. A standard conditioning regimen before autologous transplantation is BEAM. Tandem autologous transplantation has been investigated in high-risk patients. Brentuximab vedotin is recommended as a consolidation treatment in patients with a high risk of relapse after autologous transplantation. Brentuximab vedotin is the standard of treatment for relapse after autologous transplantation, and subsequent allogeneic stem cell transplantation should be considered in young patients. Bretuximab vedotin in combination with bendamustine, nivolumab, and pembrolizumab, and combinations thereof with other drugs, were investigated in clinical trials in relapsed or refractory patients with Hodgkin lymphoma.Key words: Hodgkin lymphoma - autologous stem cell transplantation - brentuximab vedotin - nivolumabThis work was supported by grant awarded by AZV 16-29857, Ministry of Health in Czech Republic, Research project P 27/2012 awarded by Charles University in Prague, 3rd Faculty of Medicine, Prague.The authors declare they have no potential confl icts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 7. 6. 2016Accepted: 24. 8. 2016.

• MeSH
• autologní transplantace MeSH
• chemorezistence * MeSH
• Hodgkinova nemoc patologie   terapie   MeSH
• lidé MeSH
• lokální recidiva nádoru patologie   terapie   MeSH
• míra přežití MeSH
• prognóza MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• záchranná terapie * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH