Experts from the European Leukemia Net (ELN) working group for adult acute lymphoblastic leukemia have identified an unmet need for guidance regarding management of adult acute lymphoblastic leukemia (ALL) from diagnosis to aftercare. The group has previously summarized their recommendations regarding diagnostic approaches, prognostic factors, and assessment of ALL. The current recommendation summarizes clinical management. It covers treatment approaches, including the use of new immunotherapies, application of minimal residual disease for treatment decisions, management of specific subgroups, and challenging treatment situations as well as late effects and supportive care. The recommendation provides guidance for physicians caring for adult patients with ALL which has to be complemented by regional expertise preferably provided by national academic study groups.

• MeSH
• akutní lymfatická leukemie * terapie   diagnóza   MeSH
• dospělí MeSH
• lidé MeSH
• management nemoci MeSH
• prognóza MeSH
• reziduální nádor diagnóza   terapie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• směrnice pro lékařskou praxi MeSH
• Geografické názvy
• Evropa MeSH

Adult B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with t(4;11)(q21;q23);KMT2A/AFF1 is a poor-prognosis entity. This registry-based study was aimed to analyze outcome of patients with t(4;11) BCP-ALL treated with allogeneic hematopoietic stem cell transplantation (alloHSCT) in first complete remission (CR1) between 2000 and 2017, focusing on the impact of measurable residual disease (MRD) at the time of transplant. Among 151 patients (median age, 38) allotransplanted from either HLA-matched siblings or unrelated donors, leukemia-free survival (LFS) and overall survival (OS) at 2 years were 51% and 60%, whereas relapse incidence (RI) and non-relapse mortality (NRM) were 30% and 20%, respectively. These results were comparable to a cohort of contemporary patients with diploid normal karyotype (NK) BCP-ALL with equivalent inclusion criteria (n = 567). Among patients with evaluable MRD pre-alloHSCT, a negative status was the strongest beneficial factor influencing LFS (hazard ratio [HR] = 0.2, p < 0.001), OS (HR = 0.14, p < 0.001), RI (HR = 0.23, p = 0.001), and NRM (HR = 0.16, p = 0.002), with a similar outcome to MRD-negative NK BCP-ALL patients. In contrast, among patients with detectable pretransplant MRD, outcome in t(4;11) BCP-ALL was inferior to NK BCP-ALL (LFS: 27% vs. 50%, p = 0.02). These results support indication of alloHSCT in CR1 for t(4;11) BCP-ALL patients, provided a negative MRD status is achieved. Conversely, pre-alloHSCT additional therapy is warranted in MRD-positive patients.

• MeSH
• DNA vazebné proteiny genetika   metabolismus   MeSH
• dospělí MeSH
• histonlysin-N-methyltransferasa genetika   metabolismus   MeSH
• homologní transplantace MeSH
• indukce remise MeSH
• lidé MeSH
• lidské chromozomy, pár 11 genetika   MeSH
• lidské chromozomy, pár 4 genetika   MeSH
• míra přežití MeSH
• následné studie MeSH
• pre-B-buněčná leukemie genetika   patologie   terapie   MeSH
• příprava pacienta k transplantaci MeSH
• prognóza MeSH
• protoonkogenní protein MLL genetika   metabolismus   MeSH
• retrospektivní studie MeSH
• reziduální nádor genetika   patologie   terapie   MeSH
• transkripční elongační faktory genetika   metabolismus   MeSH
• translokace genetická MeSH
• transplantace hematopoetických kmenových buněk metody   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Názvy látek
• AFF1 protein, human MeSH Prohlížeč
• DNA vazebné proteiny MeSH
• histonlysin-N-methyltransferasa MeSH
• KMT2A protein, human MeSH Prohlížeč
• protoonkogenní protein MLL MeSH
• transkripční elongační faktory MeSH

Local recurrences at the site of tumor resection or after chemotherapy, as well as distant micrometastases represent major problems in oncology. Therapeutic strategies based on insertion of immunostimulatory genes into the genome of tumor cells followed by vaccination with the resulting genetically modified and irradiated cellular vaccines represent a new potential prospect for the treatment of cancer patients. These strategies are based on the presumption that many, if not all tumors, possess cell surface antigens capable of being recognized by defence effectors of the immune system, as well as on the presumption that local treatment of primary tumors can, due to its immunizing potential, result also in the inhibition of distant metastases. Genetically modified cellular vaccines were found to be efficient against cancer both in experimental models and in tumor-bearing patients. It was also shown in various systems that the efficacy of conventional therapeutic modalities can be supported by adjuvant administration of genetically modified vaccines, as well as by depletion of immunosuppressive immunocyte subsets. The purpose of this review was to summarize and evaluate the results obtained with the administration of genetically modified cellular vaccines as well as with depletion of immunosuppressive immunocytes performed as treatment of minimal residual disease after surgery / chemotherapy in the experimental model of murine tumors mimicking human HPV16-associated neoplasms. The prospects and limitations of these adjuvant immunotherapeutic modalities are discussed.

• MeSH
• infekce papilomavirem farmakoterapie   imunologie   chirurgie   MeSH
• lidé MeSH
• lidský papilomavirus 16 genetika   imunologie   MeSH
• melanom experimentální genetika   imunologie   terapie   MeSH
• myši MeSH
• protinádorové vakcíny terapeutické užití   MeSH
• regulační T-lymfocyty imunologie   MeSH
• reziduální nádor genetika   imunologie   terapie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• protinádorové vakcíny MeSH

OBJECTIVE: Our objective was to determine the value of frequent minimal residual disease (MRD) monitoring in acute myeloid leukemia (AML) as a robust marker of impending relapse, and whether treatment benefits patients during the MRD-positive phase of their disease. MATERIALS AND METHODS: Frequent MRD monitoring was performed in all AML treatment phases using real-time quantitative polymerase chain reaction for fusion transcripts (CBFB/MYH11; RUNX1/RUNX1T1 fusion transcripts of MLL gene) and for the Wilms' tumor (WT1) gene. A total of 2,664 samples, taken from 79 AML patients and 6 healthy volunteers, were examined. Presence of fusion gene was detected in 25 of 79 examined patients. RESULTS: Vast correlation was discovered for fusion transcripts as well as for the WT1 gene between levels in bone marrow (BM), peripheral blood, CD34(+) BM cells, and CD34(-) BM cells. WT1 expression, however, was usually positive for cases showing fusion transcripts negativity and in healthy volunteers. Moreover, no universal value of the WT1 expression could unequivocally discriminate between remission and relapse. Therefore, detection of molecular relapses relied on fusion transcripts only and was characterized by strong expression in CD34(+) cells. Considering relapsed patients, duration from molecular to hematological relapse was 8 to 79 days (median: 25.5 days). Twelve patients were treated (chemotherapy, gemtuzumab ozogamicin, or immunomodulation after allogeneic transplantation) for 21 molecular relapses and 14 responses to treatment were observed. CONCLUSIONS: Frequent quantitative monitoring of fusion transcripts is useful for reliably predicting hematological relapse in AML patients. Treatment for molecular relapse of AML can be successful.

• MeSH
• akutní myeloidní leukemie diagnóza   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• nádorové biomarkery analýza   MeSH
• nádorové proteiny analýza   MeSH
• protein CBFB analýza   MeSH
• protein PEBP2A2 analýza   MeSH
• proteiny WT1 analýza   MeSH
• protoonkogenní protein MLL analýza   MeSH
• recidiva MeSH
• reziduální nádor diagnóza   terapie   MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• translokace genetická * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CBFB protein, human MeSH Prohlížeč
• nádorové biomarkery MeSH
• nádorové proteiny MeSH
• protein CBFB MeSH
• protein PEBP2A2 MeSH
• proteiny WT1 MeSH
• protoonkogenní protein MLL MeSH
• RUNX1 protein, human MeSH Prohlížeč

Downregulation of MHC class I molecules is believed to be often the cause of tumor immune escape and at the same time it is the major obstacle to T-cell based immunotherapy of tumors. In our experimental model, the C57BL/6 mice bearing tumors induced by TC-1/A9 cells characterized by expression of HPV16 oncogenes and downregulation of H-2b molecules were immunized with highly immunogenic E7GGG.GUS DNA vaccine expressing the fused gene of modified HPV16 E7 (E7GGG) with E.coli beta-glucuronidase (GUS). The DNA vaccine was administered by gene gun on days 7 and 14 after s.c. injection of tumor cells. The tumors in situ were injected with recombinant vaccinia virus MVA expressing the gene for murine granulocyte-macrophage colony-stimulating factor (MVA-GM-CSF). Two doses of the DNA vaccine combined with at least two consecutive local treatments with MVA-GM-CSF were able to inhibit significantly the growth of tumors. We have shown by ELISPOT-IFNgamma that in situ expression of the GM-CSF gene did not enhance the E7 specific systemic Tcell response. We found that local injections of MVA-GM-CSF induced an increase of intratumoral CD3+ T cell counts and that the DNA vaccination resulted in up-regulation of MHC type I molecules on tumor cells in vivo. We suppose that i.t. delivery of MVA-GM-CSF changed the local tumor microenvironment and rendered tumors more attractive and better accessible to effector T cells.

• MeSH
• DNA vakcíny aplikace a dávkování   MeSH
• down regulace MeSH
• Escherichia coli enzymologie   MeSH
• faktor stimulující granulocyto-makrofágové kolonie genetika   MeSH
• genetická terapie MeSH
• glukuronidasa MeSH
• H-2 antigeny metabolismus   MeSH
• infekce papilomavirem mortalita   MeSH
• lidé MeSH
• lidský papilomavirus 16 genetika   MeSH
• míra přežití MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• onkogenní proteiny virové genetika   MeSH
• Papillomavirus E7 - proteiny MeSH
• protinádorové vakcíny aplikace a dávkování   MeSH
• reziduální nádor etiologie   patologie   terapie   MeSH
• vakcinace MeSH
• virus vakcinie genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA vakcíny MeSH
• faktor stimulující granulocyto-makrofágové kolonie MeSH
• glukuronidasa MeSH
• H-2 antigeny MeSH
• oncogene protein E7, Human papillomavirus type 16 MeSH Prohlížeč
• onkogenní proteiny virové MeSH
• Papillomavirus E7 - proteiny MeSH
• protinádorové vakcíny MeSH

Moderately immunogenic HPV16-associated tumours TC-1 (MHC class I+, HPV16 E6/E7+, G12V Ha-ras+) and MK16/1/IIIABC (MK16, MHC class I-, HPV16 E6/E7+, G12V Ha-ras+), both of the H-2b haplotype and transplanted in syngeneic mice, were used to examine the effects of local IL-2 and GM-CSF cytokine or gene therapy in the treatment of minimal residual tumour disease. The mice carrying MHC class I+ TC-1 tumour residua after surgery were injected into the site of the surgery either with irradiated, IL-2 gene-modified MK16 tumour cells, or with recombinant IL-2. It has been found that both, the recombinant IL-2 and the IL-2 gene-modified tumour vaccine substantially reduced the percentage of tumour recurrences in the operated mice. Similarly, when the mice carrying TC-1 tumour residua after surgery were injected with recombinant GM-CSF, the recombinant GM-CSF inhibited growth of the tumour residua in the operated mice. Gene therapy with irradiated, GM-CSF secreting MK16 cells did not produce any tumour-inhibitory effect. In further experiments, mice bearing s.c. TC-1 tumours were injected i.p. with ifosfamide derivative CBM-4A and 8 days later, peritumourally, either with IL-2 gene-modified and IL-2-producing MK16 cells, or with recombinant IL-2. It has been found that both, the recombinant IL-2 and the IL-2 gene therapy substantially reduced the percentage of tumour-bearing mice. When the mice bearing s.c. TC-1 tumours were injected i.p. with ifosfamide derivative CBM-4A and then, peritumourally, either with irradiated, GM-CSF gene-modified and GM-CSF-producing MK16 cells, or with recombinant GM-CSF, it was found that both, the recombinant GM-CSF and GM-CSF gene therapy inhibited growth of tumour residua. Comparative experiments were performed with the MHC class I-, metastasizing tumour MK16. It has been found that both, recombinant IL-2 and GM-CSF, can inhibit growth of the tumour residua after surgery or chemotherapy. The lung metastases in mice with surgical minimal residual tumour disease or in mice with tumour residua after chemotherapy were inhibited by IL-2 but not by GM-CSF. The MK16 tumour vaccine producing IL-2 inhibited growth of tumour residua after chemotherapy, but not the tumour residua after surgery. The GM-CSF-producing vaccine was without significant effect in both, surgically- and chemotherapeutically-induced minimal residual MK16 tumour disease. In conclusion, the MHC class I+ and MHC class I-, HPV16-associated tumours were found to be sensitive to IL-2 and GM-CSF therapy after surgery or after cytoreductive chemotherapy. It is yet to be addressed if this is more general case with HPV16-associated experimental tumours. If so, it would be of interest to further investigate whether such adjuvant therapy can also help to eradicate the residua after surgery and chemotherapy in patients carrying HPV16-associated neoplasms.

• MeSH
• časové faktory MeSH
• cytokiny aplikace a dávkování   genetika   MeSH
• faktor stimulující granulocyto-makrofágové kolonie aplikace a dávkování   genetika   MeSH
• genetická terapie metody   MeSH
• inbrední kmeny myší MeSH
• interleukin-2 aplikace a dávkování   genetika   MeSH
• lokální recidiva nádoru prevence a kontrola   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   chirurgie   virologie   MeSH
• náhodné rozdělení MeSH
• onkogenní proteiny virové metabolismus   MeSH
• Papillomaviridae metabolismus   MeSH
• Papillomavirus E7 - proteiny MeSH
• protinádorové vakcíny aplikace a dávkování   MeSH
• rekombinantní proteiny aplikace a dávkování   genetika   MeSH
• represorové proteiny * MeSH
• reziduální nádor genetika   patologie   terapie   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokiny MeSH
• E6 protein, Human papillomavirus type 16 MeSH Prohlížeč
• faktor stimulující granulocyto-makrofágové kolonie MeSH
• interleukin-2 MeSH
• oncogene protein E7, Human papillomavirus type 16 MeSH Prohlížeč
• onkogenní proteiny virové MeSH
• Papillomavirus E7 - proteiny MeSH
• protinádorové vakcíny MeSH
• rekombinantní proteiny MeSH
• represorové proteiny * MeSH

Experiments were designed to examine the efficacy of IL-2 gene therapy in a surgical minimal residual tumour disease, using moderately immunogenic MK16/1/IIIABC murine cells transformed by activated ras and HPV 16 E6/E7 oncogenes (MK16 cells). Previously we demonstrated that surgical minimal residual tumour disease (SMRTD) could be effectively cured when murine Mc12 sarcoma had been resected and the operated mice were treated with irradiated Mc12 sarcoma cells engineered to secrete IL-2. In this study we performed IL-2 gene therapy of MK16 carcinoma with two types of irradiated MK16-unrelated tumour cell vaccines. One type of vaccine was derived from MHC class I-matched Mc12 sarcoma cells engineered to secrete IL-2 and the other from MHC class I-discordant IL-2 producing plasmacytoma X63-m-IL-2. The vaccines did not share any tumour rejection antigen with the MK16 cells and served exclusively as a local source of IL-2 production. Both vaccines were capable of inhibiting MK16 tumours when administered peritumorally up to 15 days after MK16 tumour challenge. The irradiated MHC class I-matched and IL-2-producing Mc12 sarcoma vaccine was then selected for therapy of MK16 SMRTD. Whereas the recurrence rate in the operated MK16 carcinoma bearers was 80%, so that only 20% of mice were cured by surgery, approximately 65% of the MK16 carcinoma bearers were permanently protected when the surgery was followed by local administration of the IL-2-producing Mc12 sarcoma vaccine.

• MeSH
• genetická terapie * MeSH
• interleukin-2 aplikace a dávkování   genetika   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• Papillomaviridae * patogenita   MeSH
• reziduální nádor imunologie   terapie   virologie   MeSH
• transplantace nádorů MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• interleukin-2 MeSH

Our study was designed to examine the effects of IL-2 gene therapy in a surgical minimal residual tumour disease (SMRTD). Mice were inoculated s.c. with methylcholanthrene (MC)-induced MC12 sarcoma cells. When the tumours reached 8 to 12 mm in diameter, they were excised, either completely ("microscopic SMRTD") or incompletely ("macroscopic SMRTD"). On day 90 after surgery, the tumour recurrence rate in untreated mice with microscopic SMRTD was approximately 30%, whereas in those with macroscopic SMRTD it was 75%. After surgery, experimental mice were treated with 2 types of irradiated, IL-2 gene-modified, IL-2-producing tumour cell vaccine. One type of vaccine was derived from the MC12 sarcoma cells (MC12-1L2/IV-3); the other type was derived from an unrelated X63-Ag8.653 plasmacytoma (X63-m-IL-2). Both types of vaccine failed to cure the macroscopic SMRTD. Whereas the X63-m-IL-2 vaccine was also ineffective in the microscopic SMRTD, the MC12-IL2/IV-3 vaccine was capable of preventing growth in all but one mouse (1164) with microscopic SMRTD when administered 2 to 5 days after surgery. If the vaccination took place 2 days before surgery or later than 5 days after surgery, the therapeutic activity was lost. Vaccination with irradiated parental MC12 cells did not produce any significant benefit compared to the operated-only mice. The protective effect of the MC12-L2/IV-3 vaccine was specific and comparatively long-lasting. Vaccinated mice, which had rejected the MC12 tumour residuum, were capable of rejecting a second inoculum of the MC12 sarcoma cells injected on days 35 to 110 after surgery but succumbed to the growth of 2 other unrelated murine sarcomas carrying different tumour-rejection antigens.

• MeSH
• experimentální sarkom chemicky indukované   terapie   MeSH
• genetická terapie * MeSH
• imunologická paměť MeSH
• interleukin-2 genetika   MeSH
• methylcholanthren MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• počet lymfocytů MeSH
• podskupiny lymfocytů MeSH
• reziduální nádor chirurgie   terapie   MeSH
• transfekce MeSH
• vakcinace MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• interleukin-2 MeSH
• methylcholanthren MeSH