• MeSH
• akutní lymfatická leukemie genetika   MeSH
• B-lymfocyty imunologie   MeSH
• bcr-abl fúzní proteiny genetika   MeSH
• chronická myeloidní leukemie genetika   MeSH
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• protoonkogenní proteiny c-abl imunologie   MeSH
• senioři MeSH
• věkové faktory MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABL1 protein, human MeSH Prohlížeč
• bcr-abl fúzní proteiny MeSH
• BCR-ABL1 fusion protein, human MeSH Prohlížeč
• protoonkogenní proteiny c-abl MeSH

Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) comprises ∼10% to 15% of childhood ALL cases, many of which respond exquisitely to tyrosine kinase inhibitors (TKIs), for example, imatinib in PDGFRB-rearranged ALL. However, some cases developed drug resistance to TKIs and the mechanisms are poorly understood. In this study, we identified a novel PDGFRB fusion gene, namely AGGF1-PDGFRB, and functionally characterized its oncogenic potential in vitro. Further genomic profiling of longitudinally collected samples during treatment revealed the emergence of a mutation, PDGFRBC843G , which directly conferred resistance to all generations of ABL TKIs, including imatinib, dasatinib, nilotinib, and ponatinib. PDGFRB-mutant leukemia cells are highly sensitive to multitarget kinase inhibitor CHZ868, suggesting potential therapeutic options for some patients resistant to ABL TKIs. In summary, we describe a complex clonal evolution pattern in Ph-like ALL and identified a novel PDGFRB point mutation that drives leukemia relapse after ABL TKI treatment.

• MeSH
• akutní lymfatická leukemie farmakoterapie   genetika   metabolismus   patologie   MeSH
• angiogenní proteiny genetika   MeSH
• chemorezistence genetika   MeSH
• fúzní onkogenní proteiny MeSH
• inhibitory proteinkinas farmakologie   terapeutické užití   MeSH
• lidé MeSH
• mutace * MeSH
• nádorové buněčné linie MeSH
• předškolní dítě MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• recidiva MeSH
• růstový faktor odvozený z trombocytů - receptor beta genetika   MeSH
• sekvenování celého genomu MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• AGGF1 protein, human MeSH Prohlížeč
• angiogenní proteiny MeSH
• fúzní onkogenní proteiny MeSH
• inhibitory proteinkinas MeSH
• PDGFRB protein, human MeSH Prohlížeč
• protinádorové látky MeSH
• růstový faktor odvozený z trombocytů - receptor beta MeSH

We present two patients with Ph-negative chronic myeloid leukemia (CML) and fusion signal BCR/ABL on both chromosomes 9, located in region 9q34. The first case was a 27 years old man with CML. Molecular studies (RT-PCR) revealed the rearrangement in the major-BCR region and expression of chimeric BCR/ABL mRNA of b3a2 configuration. By classical cytogenetic studies (G-banding) karyotype 46,XY was found in short-term cultivated bone marrow cells and phytohemagglutinin (PHA) stimulated peripheral lymphocytes. FISH studies revealed the BCR/ABL fusion signals on both chromosomes 9 and green BCR signals on both chromosomes 22 in all mitoses studied. Detection of the alleles of ABL1 intragenic STR locus by fluorescence PCR followed by fragmentation analysis in the patient and his parents provided no information about transmission of the ABL gene. Quantitative assessment of BCR/ABL transcript level by RT-PCR showed 60 and 70% BCR/ABL positivity in two peripheral blood samples at 6,5 and 10,5 months after diagnosis, respectively, which does not correspond to the expression from two identical BCR/ABL hybrid genes. Therefore, the possible mechanism of the origin of two BCR/ABL fusion signals present on both chromosomes 9 could not be resolved and remains speculative. The second case was a 53 years old male with diagnosis of chronic phase of CML, with first sign of acceleration one month after diagnosis and death because of sepsis in blastic phase within four months. The cytogenetic findings were identical to those in case No. 1., i.e. karyotype 46, XY by G-banding, two BCR/ABL fusion signals on both chromosomes 9 and RT-PCR molecular studies proved b3a2 breakpoints. It is generally accepted that prognosis of the patients with fused BCR/ABL gene located on chromosome 9 is poor. The presence of two fused genes could be anticipated as two Ph chromosomes in accelerated and blastic phases of the disease. However, in our study, quantitative findings of BCR/ABL transcripts did not corresponded to the expression of two BCR/ABL genes originating from duplication. If this assumption is correct then the expression of both fused genes BCR/ABL was in case No. 1 equally suppressed and total expression reached about the level of one BCR/ABL gene.

• MeSH
• bcr-abl fúzní proteiny genetika   MeSH
• chronická myeloidní leukemie genetika   MeSH
• dospělí MeSH
• hybridizace in situ fluorescenční MeSH
• leukemie myeloidní chronická atypická BCR-ABL-negativní genetika   MeSH
• lidé MeSH
• lidské chromozomy, pár 9 * MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• bcr-abl fúzní proteiny MeSH

In 193 patients with Ph-positive chronic myeloid leukaemia (CML) Sokal's calculation formulae prognosticating initial risk status were applied, using the computer program PHCML. The aim of this study was to the prognostic reproducibility of these prognostic staging systems in our patient population. Our results confirm the previous conclusions that prognostic discrimination is possible at the time of diagnosis of CML but in our patients with poorer prognosis the stratification seems to be more accurate. No significant advantage was achieved when we prognosticated our patients younger than 46 years using the formula recommended by Sokal et al. specifically for younger patients. We analyzed different criteria when segregating patients in groups with better or poorer prognosis. We found that the coefficient of the patient's relative risk as the boundary, was 1.9 our patient's group contrary to 1.2 in Sokal's studies.

• MeSH
• chronická myeloidní leukemie klasifikace   mortalita   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• prognóza MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• software * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH

OBJECTIVES: Detectable minimal residual disease (MRD) after therapy for acute lymphoblastic leukemia (ALL) is the strongest predictor of hematologic relapse. This study evaluated outcomes of patients with B-cell precursor ALL with MRD of ≥10-4 Methods: Study population was from ALL study groups in Europe managed in national study protocols 2000-2014. MRD was measured by polymerase chain reaction or flow cytometry. Patients were age ≥15 years at initial ALL diagnosis. Patients were excluded if exposed to blinatumomab within 18 months of baseline or prior alloHSCT. RESULTS: Of 272 patients in CR1, baseline MRD was ≥10-1, 10-2 to <10-1, 10-3 to <10-2, and 10-4 to <10-3 in 15 (6%), 71 (26%), 109 (40%), and 77 (28%) patients, respectively. Median duration of complete remission (DoR) was 18.5 months (95% confidence interval [CI], 11.9-27.2), median relapse-free survival (RFS) was 12.4 months (95% CI, 10.0-19.0) and median overall survival (OS) was 32.5 months (95% CI, 23.6-48.0). Lower baseline MRD level (P ≤ .0003) and white blood cell count <30,000/µL at diagnosis (P ≤ .0053) were strong predictors for better RFS and DoR. Allogeneic hematopoietic stem cell transplantation (alloHSCT) was associated with longer RFS (hazard ratio [HR], 0.59; 95% CI, 0.41-0.84) and DoR (HR, 0.43; 95% CI, 0.29-0.64); the association with OS was not significant (HR, 0.72; 95% CI, 0.50-1.05). DISCUSSION: In conclusion, RFS, DoR, and OS are relatively short in patients with MRD-positive ALL, particularly at higher MRD levels. AlloHSCT may improve survival but has limitations. Alternative approaches are needed to improve outcomes in MRD-positive ALL.

• Klíčová slova
• Acute lymphoblastic leukemia, MRD, allogeneic stem cell transplant, minimal residual disease,
• MeSH
• alografty MeSH
• dospělí MeSH
• filadelfský chromozom MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• mladiství MeSH
• následné studie MeSH
• pre-B-buněčná leukemie * krev   mortalita   terapie   MeSH
• přežití bez známek nemoci MeSH
• senioři MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• multicentrická studie MeSH
• Geografické názvy
• Evropa MeSH

Minimal residual disease (MRD) is a powerful prognostic factor in acute lymphoblastic leukemia (ALL) and is used for patient stratification and treatment decisions, but its precise role in Philadelphia chromosome positive ALL is less clear. This uncertainty results largely from methodological differences relating to the use of real-time quantitative PCR (qRT-PCR) to measure BCR-ABL1 transcript levels for MRD analysis. We here describe the first results by the EURO-MRD consortium on standardization of qRT-PCR for the e1a2 BCR-ABL1 transcript in Ph + ALL, designed to overcome the lack of standardisation of laboratory procedures and data interpretation. Standardised use of EAC primer/probe sets and of centrally prepared plasmid standards had the greatest impact on reducing interlaboratory variability. In QC1 the proportion of analyses with BCR-ABL1/ABL1 ratios within half a log difference were 40/67 (60%) and 52/67 (78%) at 10-3 and 36/67 (53%) and 53/67 (79%) at 10-4BCR-ABL1/ABL1. Standardized RNA extraction, cDNA synthesis and cycler platforms did not improve results further, whereas stringent application of technical criteria for assay quality and uniform criteria for data interpretation and reporting were essential. We provide detailed laboratory recommendations for the standardized MRD analysis in routine diagnostic settings and in multicenter clinical trials for Ph + ALL.

• MeSH
• akutní lymfatická leukemie genetika   MeSH
• bcr-abl fúzní proteiny genetika   MeSH
• filadelfský chromozom * MeSH
• konsensus MeSH
• kvantitativní polymerázová řetězová reakce metody   MeSH
• lidé MeSH
• messenger RNA analýza   MeSH
• reziduální nádor MeSH
• směrnice pro lékařskou praxi jako téma * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• bcr-abl fúzní proteiny MeSH
• BCR-ABL1 fusion protein, human MeSH Prohlížeč
• messenger RNA MeSH

Adults with relapsed/refractory acute lymphoblastic leukemia have an unfavourable prognosis, which is influenced by disease and patient characteristics. To further evaluate these characteristics, a retrospective analysis of 1,706 adult patients with Ph-negative relapsed/refractory B-precursor acute lymphoblastic leukemia diagnosed between 1990-2013 was conducted using data reflecting the standard of care from 11 study groups and large centers in Europe and the United States. Outcomes included complete remission, overall survival, and realization of stem cell transplantation after salvage treatment. The overall complete remission rate after first salvage was 40%, ranging from 35%-41% across disease status categories (primary refractory, relapsed with or without prior transplant), and was lower after second (21%) and third or greater (11%) salvage. The overall complete remission rate was higher for patients diagnosed from 2005 onward (45%, 95% CI: 39%-50%). One- and three-year survival rates after first, second, and third or greater salvage were 26% and 11%, 18% and 6%, and 15% and 4%, respectively, and rates were 2%-5% higher among patients diagnosed from 2005. Prognostic factors included younger age, longer duration of first remission, and lower white blood cell counts at primary diagnosis. This large dataset can provide detailed reference outcomes for patients with relapsed/refractory Ph-negative B-precursor acute lymphoblastic leukemia. clinicaltrials.gov identifier: 02003612.

• MeSH
• analýza přežití MeSH
• chemorezistence MeSH
• dospělí MeSH
• filadelfský chromozom * MeSH
• indukce remise MeSH
• kombinovaná terapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• opakovaná terapie MeSH
• pre-B-buněčná leukemie diagnóza   genetika   mortalita   terapie   MeSH
• prognóza MeSH
• průzkumy zdravotní péče MeSH
• recidiva MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

Since the patent for imatinib has expired, the role of generic imatinib (GI) in the management of Philadelphia chromosome-positive (Ph+) leukemia in pediatric patients has had ongoing discussion. Some studies in adults demonstrated that equivalent doses of GI and branded imatinib (BI) result in comparable plasma concentrations and clinical efficacy. However, other studies found that GI users are more likely to stop imatinib, with intolerance and decreased persistence as the main causes. Economic factors also heavily influence GI selection. This article aims to review the present knowledge to support further discussion on the role of GI in the management of pediatric Ph+ leukemia.

• Klíčová slova
• Ph+ leukemia, generic medication, imatinib inhibitor, pediatric, tyrosine kinase,
• MeSH
• chronická myeloidní leukemie farmakoterapie   MeSH
• dítě MeSH
• generika terapeutické užití   MeSH
• imatinib mesylát terapeutické užití   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• protinádorové látky terapeutické užití   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• generika MeSH
• imatinib mesylát MeSH
• inhibitory proteinkinas MeSH
• protinádorové látky MeSH

Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by clonal proliferation of primitive hematopoietic stem cell. The median age at diagnosis is 55 to 60 years with less than 10% of patients younger 20 years. Incidence of CML in children in the Czech Republic is 0.106 cases/100 thousands per year. Here we report outcome of 38 pediatric patients (median age 12.5 years; range 1.8 - 17.3) with Ph-positive CML diagnosed between years 1989 to 2006. Primarily chronic phase of the disease was diagnosed in 32 (84%) patients. 32 (84.2%) patients underwent hematopoietic stem cell transplantation (HSCT) with the median age at transplantation of 14.9 years (range 6.9 - 20.5 years). Out of transplanted patients 16 (50%) obtained graft from unrelated donor, 13 (41%) from matched sibling donor, 2 from haploidentical family donor and autologous transplantation has been performed in one case. 6 patients were not transplanted, 4 of them died (median 1.2 years from diagnosis), 2 are alive 0.6 and 17.8 years from the diagnosis. Overall survival (OS) in 25 patients after HSCT at our department during the whole period is 66.7% with 15/16 being in stable continuous molecular-genetic remission (94%). During the period of time results of transplantations have been significantly improved (p=0.0071). OS after HSCT until year 1997 is 25% while from year 1998 until now is 87.5%. All centers OS of patients after HSCT is 71%. Results of HSCT in children with CML obtained from the year 1998 at our center are fully comparable with results achieved in large and experienced centers. HSCT remains the only proven and effective method for the treatment of CML. Clinical studies assessing the role of tyrosine kinase inhibitors in children instead of early HSCT should be planned carefully in order to avoid sub-optimal outcomes.

• MeSH
• benzamidy MeSH
• časové faktory MeSH
• chronická myeloidní leukemie mortalita   terapie   MeSH
• dítě MeSH
• imatinib mesylát MeSH
• lidé MeSH
• mladiství MeSH
• nemoc štěpu proti hostiteli mortalita   MeSH
• piperaziny terapeutické užití   MeSH
• prognóza MeSH
• pyrimidiny terapeutické užití   MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• benzamidy MeSH
• imatinib mesylát MeSH
• piperaziny MeSH
• pyrimidiny MeSH

The influence of t(v;22) sole, major route ACAs all (+8, n = 14; +Ph, n = 10; +19, n = 1), and -Y sole on progression-free survival. Survival curves are compared with those of patients with the standard t(9;22) translocation. Other ACAs or complex karyotypes did not influence survival.

• Klíčová slova
• additional chromosomal abnormalities, chronic myeloid leukemia, cytogenetics, prognosis,
• MeSH
• chromozomální aberace * MeSH
• chronická myeloidní leukemie * genetika   diagnóza   mortalita   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidské chromozomy, pár 22 genetika   MeSH
• lidské chromozomy, pár 9 genetika   MeSH
• přežití bez známek nemoci MeSH
• prognóza MeSH
• senioři MeSH
• translokace genetická * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• dopisy MeSH