Presence of minimal residual disease (MRD), detected by flow cytometry, is an important prognostic biomarker in the management of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, data-analysis remains mainly expert-dependent. In this study, we designed and validated an Automated Gating & Identification (AGI) tool for MRD analysis in BCP-ALL patients using the two tubes of the EuroFlow 8-color MRD panel. The accuracy, repeatability, and reproducibility of the AGI tool was validated in a multicenter study using bone marrow follow-up samples from 174 BCP-ALL patients, stained with the EuroFlow BCP-ALL MRD panel. In these patients, MRD was assessed both by manual analysis and by AGI tool supported analysis. Comparison of MRD levels obtained between both approaches showed a concordance rate of 83%, with comparable concordances between MRD tubes (tube 1, 2 or both), treatment received (chemotherapy versus targeted therapy) and flow cytometers (FACSCanto versus FACSLyric). After review of discordant cases by additional experts, the concordance increased to 97%. Furthermore, the AGI tool showed excellent intra-expert concordance (100%) and good inter-expert concordance (90%). In addition to MRD levels, also percentages of normal cell populations showed excellent concordance between manual and AGI tool analysis. We conclude that the AGI tool may facilitate MRD analysis using the EuroFlow BCP-ALL MRD protocol and will contribute to a more standardized and objective MRD assessment. However, appropriate training is required for the correct analysis of MRD data.

• MeSH
• dítě MeSH
• dospělí MeSH
• imunofenotypizace metody   MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• pre-B-buněčná leukemie * patologie   diagnóza   MeSH
• předškolní dítě MeSH
• průtoková cytometrie * metody   MeSH
• reprodukovatelnost výsledků MeSH
• reziduální nádor * patologie   diagnóza   MeSH
• senioři MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

Resistance to glucocorticoids (GC), the common agents for remission induction in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), poses a significant therapeutic hurdle. Therefore, dissecting the mechanisms shaping GC resistance could lead to new treatment modalities. Here, we showed that CD9- BCP-ALL cells were preferentially resistant to prednisone and dexamethasone over other standard cytotoxic agents. Concordantly, we identified significantly more poor responders to the prednisone prephase among BCP-ALL patients with a CD9- phenotype, especially for those with adverse presenting features including older age, higher white cell count and BCR-ABL1. Furthermore, gain- and loss-offunction experiments dictated a definitive functional linkage between CD9 expression and GC susceptibility, as demonstrated by the reversal and acquisition of relative GC resistance in CD9low and CD9high BCP-ALL cells, respectively. Despite physical binding to the GC receptor NR3C1, CD9 did not alter its expression, phosphorylation or nuclear translocation but potentiated the induction of GC-responsive genes in GC-resistant cells. Importantly, the MEK inhibitor trametinib exhibited higher synergy with GC against CD9- than CD9+ lymphoblasts to reverse drug resistance in vitro and in vivo. Collectively, our results elucidate a previously unrecognized regulatory function of CD9 in GC sensitivity, and inform new strategies for management of children with resistant BCP-ALL.

• MeSH
• antigeny CD9 * metabolismus   genetika   MeSH
• chemorezistence * genetika   MeSH
• dexamethason farmakologie   MeSH
• dítě MeSH
• glukokortikoidy * farmakologie   terapeutické užití   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• pre-B-buněčná leukemie * farmakoterapie   metabolismus   genetika   patologie   MeSH
• předškolní dítě MeSH
• receptory glukokortikoidů metabolismus   genetika   MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

In the effort to improve immunophenotyping and minimal residual disease (MRD) assessment in acute lymphoblastic leukemia (ALL), the international Berlin-Frankfurt-Münster (iBFM) Flow Network introduced the myelomonocytic marker CD371 for a large prospective characterization with a long follow-up. In the present study, we aimed to investigate the clinical and biological features of CD371-positive (CD371pos) pediatric B-cell precursor ALL (BCP-ALL). From June 2014 to February 2017, 1812 pediatric patients with newly diagnosed BCP-ALLs enrolled in trial AIEOP-BFM ALL 2009 were evaluated as part of either a screening (n = 843, Italian centers) or validation cohort (n = 969, other iBFM centers). Laboratory assessment at diagnosis consisted of morphological, immunophenotypic, and genetic analysis. Response assessment relied on morphology, multiparametric flow cytometry (MFC), and polymerase chain reaction (PCR)-MRD. At diagnosis, 160 of 1812 (8.8%) BCP-ALLs were CD371pos. This correlated with older age, lower ETV6::RUNX1 frequency, immunophenotypic immaturity (all P < .001), and strong expression of CD34 and of CD45 (P < .05). During induction therapy, CD371pos BCP-ALLs showed a transient myelomonocytic switch (mm-SW: up to 65.4% of samples at day 15) and an inferior response to chemotherapy (slow early response, P < .001). However, the 5-year event-free survival was 88.3%. Among 420 patients from the validation cohort, 27 of 28 (96.4%) cases positive for DUX4-fusions were CD371pos. In conclusion, in the largest pediatric cohort, CD371 is the most sensitive marker of transient mm-SW, whose recognition is essential for proper MFC MRD assessment. CD371pos is associated to poor early treatment response, although a good outcome can be reached after MRD-based ALL-related therapies.

• MeSH
• buněčný rodokmen MeSH
• dítě MeSH
• imunofenotypizace MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• pre-B-buněčná leukemie * genetika   mortalita   farmakoterapie   patologie   diagnóza   terapie   metabolismus   MeSH
• předškolní dítě MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• reziduální nádor * diagnóza   MeSH
• tetraspaniny genetika   metabolismus   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
• multicentrická studie MeSH
• práce podpořená grantem MeSH

• MeSH
• dítě MeSH
• genová přestavba * MeSH
• jaderné proteiny genetika   MeSH
• kojenec MeSH
• lidé MeSH
• míra přežití MeSH
• nádorové proteiny genetika   MeSH
• pre-B-buněčná leukemie genetika   mortalita   patologie   terapie   MeSH
• prognóza MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

AIM: To evaluate serum levels of selected cytokine receptors in B-cell precursor acute lymphoblastic leukemia (B-ALL) and their association with acknowledged prognostic factors, relapse-free survival (RFS) and overall survival (OS). MATERIALS AND METHODS: A total of 42 de novo adult B-ALL patients, 19 BCR/ABL positive, were included in this study. Soluble receptor α for IL-2 (sIL-2Rα), soluble receptor for IL-6 (sIL-6R), soluble receptor for TNF-α type I and II (sTNFR-1, sTNFR-2) and matrix metalloproteinase-9 (MMP-9) were measured by biochip array technology at diagnosis and in complete remission (CR). RESULTS: At diagnosis of B-ALL, we found significantly higher levels of sIL-2Rα, sIL-6R, sTNFR-1, sTNFR-2 and significantly lower levels MMP-9 in comparison with CR (p < 0.001 in all cases). BCR/ABL positive patients had higher levels of sIL-2Rα at diagnosis (r = 0.484; p = 0.014). Serum levels of evaluated cytokines were not associated with achievement of CR after one cycle of induction therapy, RFS or OS. CONCLUSION: Serum levels of all evaluated cytokines are significantly altered in newly diagnosed B-ALL reflecting activity of the disease. No significant correlations with response to first induction therapy, RFS or OS were found. Further studies with a longer follow-up will be needed.

• MeSH
• dospělí MeSH
• indukční chemoterapie mortalita   MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• mladý dospělý MeSH
• nádorové biomarkery krev   MeSH
• následné studie MeSH
• pre-B-buněčná leukemie krev   farmakoterapie   mortalita   patologie   MeSH
• prognóza MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• receptory cytokinové krev   MeSH
• senioři 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

• MeSH
• fúzní onkogenní proteiny genetika   MeSH
• genová přestavba MeSH
• histonlysin-N-methyltransferasa genetika   MeSH
• kojenec MeSH
• lidé MeSH
• onkogenní fúze * MeSH
• pre-B-buněčná leukemie genetika   patologie   terapie   MeSH
• protoonkogenní protein MLL genetika   MeSH
• retrospektivní studie MeSH
• zárodečné buňky patologie   MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH

• MeSH
• dítě MeSH
• dospělí MeSH
• genová přestavba * MeSH
• kojenec MeSH
• lidé MeSH
• míra přežití MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádorové biomarkery genetika   MeSH
• následné studie MeSH
• pre-B-buněčná leukemie genetika   patologie   MeSH
• předškolní dítě MeSH
• prognóza MeSH
• retrospektivní studie MeSH
• trans-aktivátory genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural 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

OBJECTIVES: Survival outcomes from a single-arm phase 2 blinatumomab study in patients with minimal residual disease (MRD)-positive B-cell precursor (BCP)-acute lymphoblastic leukaemia (ALL) were compared with those receiving standard of care (SOC) in a historic data set. METHODS: The primary analysis comprised adult Philadelphia chromosome (Ph)-negative patients in first complete haematologic remission (MRD ≥ 10-3 ). Relapse-free survival (RFS) and overall survival (OS) were compared between blinatumomab- and SOC-treatment groups. Baseline differences between groups were adjusted by propensity scores. RESULTS: The primary analysis included 73 and 182 patients from the blinatumomab and historic data sets, respectively. When weighted by age to the blinatumomab-treatment group, median RFS was 7.8 months and median OS was 25.9 months in the SOC-treated group. In the blinatumomab study, median RFS was 35.2 months; median OS was not evaluable. Propensity score weighting achieved balance with seven baseline prognostic factors. With adjustment for haematopoietic stem cell transplantation (HSCT) status, a 50% reduction in risk of relapse or death was observed with blinatumomab vs SOC. Median RFS, unadjusted for HSCT status, was 35.2 months with blinatumomab and 8.3 months with SOC. CONCLUSIONS: These analyses suggest that blinatumomab improves RFS, and possibly OS, in adults with MRD-positive Ph-negative BCP-ALL vs SOC.

• MeSH
• analýza přežití MeSH
• antitumorózní látky terapeutické užití   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• pre-B-buněčná leukemie farmakoterapie   patologie   MeSH
• protilátky bispecifické terapeutické užití   MeSH
• recidiva MeSH
• reziduální nádor MeSH
• senioři MeSH
• standardní péče * 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

PURPOSE: Minimal residual disease (MRD) helps to accurately assess when children with late bone marrow relapses of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) will benefit from allogeneic hematopoietic stem-cell transplantation (allo-HSCT). More detailed dissection of MRD response heterogeneity and the specific genetic aberrations could improve current practice. PATIENTS AND METHODS: MRD was assessed after induction treatment and at different times during relapse treatment until allo-HSCT (indicated in poor responders to induction; MRD ≥ 10-3) for patients being treated for late BCP-ALL bone marrow relapses (n = 413; median follow-up, 9.4 years) in the ALL-REZ BFM 2002 trial/registry (ClinicalTrials.gov identifier: NCT00114348). RESULTS: Patients with both good (MRD < 10-3) and poor responses to induction treatment reached excellent event-free survival (EFS; 72% v 65%) and overall survival (OS; 82% v 74%). Patients with MRD of 10-2 or greater after induction had reduced EFS (56%), and their MRD persisted until allo-HSCT more frequently than it did in patients with MRD of 10-3 or greater to less than 10-2 (P = .037). Patients with 25% or more leukemic blasts after induction (early nonresponders) had the poorest prognosis (EFS, 22%). Interestingly, patients with MRD of 10-3 or greater before allo-HSCT (late nonresponders) still had an EFS of 50% and OS of 63%, which in principle justifies allo-HSCT in these patients. From a panel of selected candidate genes, TP53 alterations (frequency, 8%) were the only genetic alteration with independent prognostic value in any MRD-based response subgroup. CONCLUSION: After induction treatment, MRD-based treatment stratification resulted in excellent survival in patients with late relapsed BCP-ALL. Prognosis could be further improved in very poor responders by intensifying treatment directly after induction. TP53 alterations can be defined as a novel genetic high-risk marker in all MRD response groups in late relapsed BCP-ALL. Here we identified early and late nonresponders to be considered as events in future trials.

• MeSH
• antitumorózní látky terapeutické užití   MeSH
• dítě MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   MeSH
• mladiství MeSH
• pre-B-buněčná leukemie klasifikace   patologie   terapie   MeSH
• přežití po terapii bez příznaků nemoci MeSH
• reziduální nádor genetika   patologie   MeSH
• transplantace hematopoetických kmenových buněk MeSH
• výběr pacientů MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH