BACKGROUND: Auer rods (AuRs) are prominent intracellular structures found almost exclusively in myeloid cell malignancies, such as acute myeloid leukemia (AML), chronic and juvenile myelomonocytic leukemia and myelodysplastic syndrome. Extremely rare AuRs have been reported in patients with acute lymphoblastic leukemia (ALL) or among ambiguous lineage leukemia patients with a dominantly lymphoblastic immunophenotype. PROCEDURE: We report diagnostic and follow-up data of an international cohort of 11 children suffering from leukemias with AuRs and with significant presence of T and myeloid markers, majority of whom categorized as early T-cell precursor (ETP, n = 7); or T-ALL (ETP status unknown, n = 2), ALAL (acute leukemia of ambiguous lineage, n = 1), and AML reclassified from ALAL (n = 1). We described other diagnostic details and treatment types and responses. Moreover, we summarize previously published data. RESULTS: Among the four patients who started and remained on ALL-type therapy, all were in the first complete remission, whereas both patients who started and remained on AML-type therapy relapsed and died. Of the patients who followed either a combined ALL/AML protocol (Interfant 06) or who switched from one of the two types of therapy to the other, one patient died, and the remaining four were in first complete remission at the most recent follow-up. We also searched for similar cases in the literature and found only three additional children with nonmyeloid leukemia and AuRs and 10 adults with this type of leukemia. CONCLUSIONS: Briefly, ALL- or combined ALL/AML-type therapy may be effective for treating AuR-positive leukemia patients with a lymphoid immunophenotype.

• MeSH
• akutní lymfatická leukemie patologie   terapie   imunologie   MeSH
• akutní myeloidní leukemie patologie   terapie   imunologie   MeSH
• dítě MeSH
• imunofenotypizace * MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• následné studie MeSH
• předškolní dítě 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

OBJECTIVES: Risk-based stratification approaches using measurable residual disease (MRD) successfully help to identify T-acute lymphoblastic leukemia (T-ALL) patients at risk of relapse, whose treatment outcomes are very poor. Because of T-ALL heterogeneity and rarity, a reliable and standardized approach for flow cytometry (FC)-based MRD measurement and analysis is often missing. METHODS: Within the international AIEOP-BFM-ALL-FLOW study group we made a consensus on markers and a standard operating procedure for common 8- and 12-color T-ALL MRD panels. Custom manufactured tubes with dried backbone antibodies were tested in parallel to local FC standards. RESULTS: Altogether, 66 diagnostic and 67 day 15 samples were analyzed. We designed two guided MRD gating strategies to identify blast cells in parallel to expert-based evaluation. We proved that the optimized tubes allowed the correct identification of blast cells in all diagnostic samples. Both, expert and guided analysis of day 15 samples correlated to local standard (Spearman R=0.98 and R=0.94, respectively). Only in 2 (3 %) and 4 (6 %) patients expert gating and guided analysis results were substantially discordant from local standard, respectively. The cases that require an individualized approach may be partially identified at diagnosis through a rare immunophenotype or mixed phenotype acute leukemia status. CONCLUSIONS: Our work shows that standardized operating procedures together with guided analysis are applicable in a great majority of T-ALL cases. Further improvement of MRD detection is needed, as in some cases an individualized analytical approach is still required due to the challenging nature of the T-ALL phenotype.

• MeSH
• dítě MeSH
• kojenec MeSH
• konsensus MeSH
• lidé MeSH
• lymfoblastická leukemie-lymfom z prekurzorových T-buněk * diagnóza   patologie   MeSH
• mladiství MeSH
• předškolní dítě MeSH
• průtoková cytometrie * normy   metody   MeSH
• reziduální nádor * diagnóza   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

The treatment strategy for children and adolescents with chronic myeloid leukemia in the chronic phase (CML-CP) has evolved from allogeneic hematopoietic stem cell transplantation (HSCT) to tyrosine kinase inhibitors (TKIs). With the advent of next-generation TKIs and new targeted therapies in the CML field, an international pediatric CML expert panel provides recommendations based on the medical literature (including previous pediatric guidelines), national standards, and treatment principles used in adults with CML-CP. Recommendations include diagnosis of the disease and details on managing the initial steps of care of children and adolescents with newly diagnosed CML-CP, including complications such as leukostasis. The treatment recommendations are based on the initiation of therapy with a first- or second-generation TKI according to the allocated European Treatment and Outcome Study (EUTOS) long-term survival score risk group of the patient. The subsequent steps are based on the results of recommended monitoring which can justify a switch to another TKI or a drug in development if there is resistance or toxicity. The panel also provides recommendations regarding the discontinuation criteria for TKIs in children and adolescents in sustained deep molecular response. Allogeneic HSCT is not recommended as the first-line of treatment for children with CML-CP but is to be considered in case of progression to the advanced phase or failure of several lines of treatment. The present treatment and management recommendations are intended to provide advice to clinicians in view of optimizing the care and the outcome of children and adolescents with CML-CP.

• MeSH
• chronická fáze myeloidní leukemie * terapie   MeSH
• chronická myeloidní leukemie * terapie   diagnóza   MeSH
• dítě MeSH
• inhibitory proteinkinas * terapeutické užití   MeSH
• lidé MeSH
• management nemoci MeSH
• mladiství MeSH
• transplantace hematopoetických kmenových buněk MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• Publikační typ
• časopisecké články MeSH
• konsensus - konference MeSH
• přehledy MeSH

The superiority of total body irradiation (TBI)-based vs chemotherapy conditioning for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with acute lymphoblastic leukemia (ALL) has been established in the international, prospective phase-3 FORUM study, randomizing 417 patients aged 4-18 years in complete remission (CR), who received allo-HSCT from HLA-matched sibling or unrelated donors. Because of the unavailability of TBI in some regions and to accommodate individual contraindications, this study reports the prespecified comparison of outcomes of patients receiving busulfan (BU)- or treosulfan (TREO)-based regimens from 2013 to 2018. Overall, 180 and 128 patients received BU/thiotepa (THIO)/fludarabine (FLU) or TREO/THIO/FLU, respectively. Data were analyzed as of February 2023, with a median follow-up of 4.2 years (range, 0.3-9.1). 3-year overall survival was 0.71 (BU, 95% confidence interval [0.64-0.77]) and 0.72 (TREO, [0.63-0.79]) and 3-year event-free survival was 0.60 (BU, [0.53-0.67]) and 0.55 (TREO, [0.46-0.63]). The 3-year cumulative incidence of relapse (BU, 0.31 [0.25-0.38]; TREO, 0.36 [0.27-0.44]); and nonrelapse mortality (BU, 0.08 [0.05-0.13]; TREO, 0.09 [0.05-0.15]) were comparable. One case of fatal veno-occlusive disease occurred in each group. No significant differences in acute and chronic graft-versus-host disease (GVHD) or 3-year GVHD-free and relapse-free survival (BU, 0.48 [0.41-0.55]; TREO, 0.45 [0.37-0.54]) were recorded. Outcomes for patients in first and second CR were similar irrespective of the regimen. In conclusion, BU/THIO/FLU or TREO/THIO/FLU regimens can be an alternative to TBI for patients with ALL aged >4 years with contraindications or lack of access to TBI. This trial was registered at www.ClinicalTrials.gov as #NCT01949129.

• MeSH
• akutní lymfatická leukemie * terapie   mortalita   MeSH
• busulfan * analogy a deriváty   terapeutické užití   MeSH
• dítě MeSH
• homologní transplantace MeSH
• lidé MeSH
• mladiství MeSH
• nemoc štěpu proti hostiteli * etiologie   MeSH
• předškolní dítě MeSH
• příprava pacienta k transplantaci * metody   MeSH
• transplantace hematopoetických kmenových buněk * škodlivé účinky   MeSH
• vidarabin analogy a deriváty   terapeutické užití   aplikace a dávkování   MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

Persistent selective T-lymphocytopenia is found both in SCID and congenital athymia. Without molecular diagnosis, it is challenging to determine whether HCT or thymus transplantation ought to be performed. Ex vivo T-lymphopoiesis assays have been proposed to assist clinical decision-making for genetically undefined patients. We investigated 20 T-lymphocytopenic patients, including 13 patients awaiting first-line treatment and 7 patients with failed immune reconstitution after previous HCT or thymus transplantation. Whilst developmental blocks in ex vivo T-lymphopoiesis indicated hematopoietic cell-intrinsic defects, successful T-lymphocyte differentiation required careful interpretation, in conjunction with clinical status, immunophenotyping, and genetic investigations. Of the 20 patients, 13 proceeded to treatment, with successful immune reconstitution observed in 4 of the 6 patients post-HCT and 4 of the 7 patients after thymus transplantation, the latter including two patients who had previously undergone HCT. Whilst further validation and standardization are required, we conclude that assessing ex vivo T-lymphopoiesis during the diagnostic pathway for genetically undefined T-lymphocytopenia improves patient outcomes by facilitating corrective treatment choice.

• MeSH
• buněčná diferenciace MeSH
• dítě MeSH
• imunofenotypizace MeSH
• kojenec MeSH
• lidé MeSH
• lymfopenie * imunologie   MeSH
• lymfopoéza * genetika   MeSH
• mladiství MeSH
• předškolní dítě MeSH
• primární imunodeficience terapie   genetika   imunologie   MeSH
• T-lymfocyty * imunologie   MeSH
• thymus imunologie   MeSH
• transplantace hematopoetických kmenových buněk * metody   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

PURPOSE: Tropomyosin receptor kinase (TRK) fusions are detected in less than 2% of central nervous system tumors. There are limited data on the clinical course of affected patients. EXPERIMENTAL DESIGN: We conducted an international retrospective cohort study of patients with TRK fusion-driven central nervous system tumors. RESULTS: A total of 119 patients were identified. The median age at the time of diagnosis was 4.5 years. The majority were reported to have a histology consistent with a diagnosis of high-grade glioma (HGG; 57.1%) followed by low-grade glioma (LGG; 27.7%). Pediatric patients had a better prognosis, with a median overall survival of 185.5 months compared with 24.8 months in adults (P < 0.0001). Patients with LGG also had a better outcome when compared with HGG (P = 0.0012). The objective response was 68.8% with larotrectinib compared with 38.1% for nontargeted treatment. CONCLUSIONS: Children with LGG had a favorable outcome compared with adult glioma and HGG. TRK inhibitors seem to improve tumor control.

• MeSH
• dítě MeSH
• dospělí MeSH
• fúze genů MeSH
• fúzní onkogenní proteiny * genetika   MeSH
• gliom * genetika   patologie   mortalita   terapie   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové glykoproteiny MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádory centrálního nervového systému * genetika   terapie   mortalita   patologie   MeSH
• předškolní dítě MeSH
• prognóza MeSH
• pyrazoly terapeutické užití   MeSH
• pyrimidiny terapeutické užití   MeSH
• receptor trkA * genetika   antagonisté a inhibitory   MeSH
• receptor trkB genetika   antagonisté a inhibitory   MeSH
• receptor trkC genetika   antagonisté a inhibitory   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• stupeň nádoru MeSH
• výsledek terapie 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

PURPOSE: The AIEOP-BFM ALL 2009 protocol included, at the end of the induction phase, a randomized study of patients with high-risk (HR) ALL to investigate if an intensive exposure to pegylated L-asparaginase (PEG-ASNASE, 2,500 IU/sqm once a week × 4) on top of BFM consolidation phase IB allowed us to decrease minimal residual disease (MRD) and improve outcome. PATIENTS AND METHODS: A total of 1,097 patients presented, from June 2010 to February 2017, with one or more of the following HR criteria: KMT2A::AFF1 rearrangement, hypodiploidy, prednisone poor response, poor bone marrow response at day 15 (Flow MRD ≥10%), or no complete remission (CR) at the end of induction. Of them, 809 (85.1%) were randomly assigned to receive (404) or not receive (405) four weekly doses of PEG-ASNASE. RESULTS: By intention to treat (ITT) analysis, there was no significant difference in the proportion of patients with polimerase chain reaction MRD ≥5 × 10-4 at the end of phase IB in the experimental versus control arm (13.9% v 17.0%, P = .25). The 5-year event-free survival (median follow-up 6.3 years) by ITT in the experimental and control arms was 70.4% (2.3) versus 75.0% (2.2; P = .18), and the 5-year overall survival was 81.5% (2.0) versus 84.0% (1.9; P = .25), respectively. The corresponding 5-year cumulative incidence of death in CR was 9.5% (1.5) versus 5.7% (1.2; P = .08), and that of relapse was 17.7% (1.9) versus 17.2% (1.9), respectively (P = .94). Adverse reactions in phase IB occurred in 22.2% and 8.9% of patients in the experimental and control arm, respectively (P < .001). CONCLUSION: Additional PEG-ASNASE in phase IB did not translate into a benefit for decreasing relapse incidence but was associated with higher toxicity. Further improvements with conventional chemotherapy might be difficult in the context of intensive treatment protocols.

• MeSH
• akutní lymfatická leukemie * MeSH
• asparaginasa * MeSH
• kojenec MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   MeSH
• polyethylenglykoly MeSH
• prednison škodlivé účinky   MeSH
• přežití bez známek nemoci MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   MeSH
• randomizované kontrolované studie jako téma MeSH
• recidiva MeSH
• výsledek terapie MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• protokol klinické studie MeSH

Juvenile myelomonocytic leukaemia (JMML) is characterized by gene variants that deregulate the RAS signalling pathway. Children with neurofibromatosis type 1 (NF-1) carry a defective NF1 allele in the germline and are predisposed to JMML, which presumably requires somatic inactivation of the NF1 wild-type allele. Here we examined the two-hit concept in leukaemic cells of 25 patients with JMML and NF-1. Ten patients with JMML/NF-1 exhibited a NF1 loss-of-function variant in combination with uniparental disomy of the 17q arm. Five had NF1 microdeletions combined with a pathogenic NF1 variant and nine carried two compound-heterozygous NF1 variants. We also examined 16 patients without clinical signs of NF-1 and no variation in the JMML-associated driver genes PTPN11, KRAS, NRAS or CBL (JMML-5neg) and identified eight patients with NF1 variants. Three patients had microdeletions combined with hemizygous NF1 variants, three had compound-heterozygous NF1 variants and two had heterozygous NF1 variants. In addition, we found a high incidence of secondary ASXL1 and/or SETBP1 variants in both groups. We conclude that the clinical diagnosis of JMML/NF-1 reliably indicates a NF1-driven JMML subtype, and that careful NF1 analysis should be included in the genetic workup of JMML even in the absence of clinical evidence of NF-1.

• MeSH
• dítě MeSH
• juvenilní myelomonocytární leukemie * genetika   MeSH
• lidé MeSH
• mutace MeSH
• neurofibromatóza 1 * genetika   MeSH
• signální transdukce MeSH
• tumor supresorové geny MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Acute lymphoblastic leukemia expressing the gamma delta T-cell receptor (γδ T-ALL) is a poorly understood disease. We studied 200 children with γδ T-ALL from 13 clinical study groups to understand the clinical and genetic features of this disease. We found age and genetic drivers were significantly associated with outcome. γδ T-ALL diagnosed in children under 3 years of age was extremely high-risk and enriched for genetic alterations that result in both LMO2 activation and STAG2 inactivation. Mechanistically, using patient samples and isogenic cell lines, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping, resulting in deregulation of gene expression associated with T-cell differentiation. High-throughput drug screening identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which can be targeted by poly(ADP-ribose) polymerase inhibition. These data provide a diagnostic framework for classification and risk stratification of pediatric γδ T-ALL. Significance: Patients with acute lymphoblastic leukemia expressing the gamma delta T-cell receptor under 3 years old or measurable residual disease ≥1% at end of induction showed dismal outcomes and should be classified as having high-risk disease. The STAG2/LMO2 subtype was enriched in this very young age group. STAG2 inactivation may perturb chromatin conformation and cell differentiation and confer vulnerability to poly(ADP-ribose) polymerase inhibition.

• MeSH
• adaptorové proteiny signální transdukční * genetika   metabolismus   MeSH
• dítě MeSH
• genová přestavba MeSH
• kojenec MeSH
• lidé MeSH
• lymfoblastická leukemie-lymfom z prekurzorových T-buněk genetika   patologie   MeSH
• předškolní dítě MeSH
• proteiny buněčného cyklu genetika   metabolismus   MeSH
• proteiny s doménou LIM * genetika   MeSH
• protoonkogenní proteiny MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The prognostic impact of PICALM::MLLT10 status in childhood leukaemia is not well described. Ten International Berlin Frankfurt Münster-affiliated study groups and the Children's Oncology Group collaborated in this multicentre retrospective study. The presence of the PICALM::MLLT10 fusion gene was confirmed by fluorescence in situ hybridization and/or RNA sequencing at participating sites. Ninety-eight children met the study criteria. T-cell acute lymphoblastic leukaemia (T-ALL) and acute myeloid leukaemia (AML) predominated 55 (56%) and 39 (40%) patients, respectively. Most patients received a chemotherapy regimen per their disease phenotype: 58% received an ALL regimen, 40% an AML regimen and 1% a hybrid regimen. Outcomes for children with PICALM::MLLT10 ALL were reasonable: 5-year event-free survival (EFS) 67% and 5-year overall survival (OS) 76%, but children with PICALM::MLLT10 AML had poor outcomes: 5-year EFS 22% and 5-year OS 26%. Haematopoietic stem cell transplant (HSCT) did not result in a significant improvement in outcomes for PICALM::MLLT10 AML: 5-year EFS 20% for those who received HSCT versus 23% for those who did not (p = 0.6) and 5-year OS 37% versus 36% (p = 0.7). In summary, this study confirms that PICALM::MLLT10 AML is associated with a dismal prognosis and patients cannot be salvaged with HSCT; exploration of novel therapeutic options is warranted.

• MeSH
• akutní myeloidní leukemie * genetika   MeSH
• akutní nemoc MeSH
• dítě MeSH
• fúzní onkogenní proteiny genetika   MeSH
• hybridizace in situ fluorescenční MeSH
• lidé MeSH
• monomerní proteiny vytvářející klathrin * genetika   MeSH
• prognóza MeSH
• retrospektivní studie MeSH
• transkripční faktory genetika   MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH