• MeSH
• Classification MeSH
• Neoplasms diagnosis   MeSH
• Publication type
• Monograph MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• patologie
• onkologie

• Publication type
• Journal Article MeSH

Recently, we defined "CML-like" subtype of BCR::ABL1-positive acute lymphoblastic leukemia (ALL), resembling lymphoid blast crisis of chronic myeloid leukemia (CML). Here we retrospectively analyzed prognostic relevance of minimal residual disease (MRD) and other features in 147 children with BCR::ABL1-positive ALL (diagnosed I/2000-IV/2021, treated according to EsPhALL (n = 133) or other (n = 14) protocols), using DNA-based monitoring of BCR::ABL1 genomic breakpoint and clonal immunoglobulin/T-cell receptor gene rearrangements. Although overall prognosis of CML-like (n = 48) and typical ALL (n = 99) was similar (5-year-EFS 60% and 49%, respectively; 5-year-OS 75% and 73%, respectively), typical ALL presented more relapses while CML-like patients more often died in the first remission. Prognostic role of MRD was significant in the typical ALL (p = 0.0005 in multivariate analysis for EFS). In contrast, in CML-like patients MRD was not significant (p values > 0.2) and inapplicable for therapy adjustment. Moreover, in the typical ALL, risk-prediction could be further improved by considering initial hyperleukocytosis. Early distinguishing typical BCR::ABL1-positive ALL and CML-like patients is essential to enable optimal treatment approach in upcoming protocols. For the typical ALL, tyrosine-kinase inhibitors and concurrent chemotherapy with risk-directed intensity should be recommended; in the CML-like disease, no relevant prognostic feature applicable for therapy tailoring was found so far.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma * genetics   drug therapy   MeSH
• Acute Disease MeSH
• Fusion Proteins, bcr-abl genetics   MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive * drug therapy   genetics   MeSH
• Child MeSH
• Humans MeSH
• Retrospective Studies MeSH
• Neoplasm, Residual genetics   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

INTRODUCTION: BCR-ABL1-like acute lymphoblastic leukemia (ALL) is a high-risk disease with a complex genomic background. Though extensively studied, data on the frequency and mutual associations of present mutations are still incomplete in adult patients. This retrospective study aims to map the genomic landscape of B-other ALL in a cohort of adult patients with a focus on the BCR-ABL1-like ALL subtype. METHODS: We analyzed bone marrow and peripheral blood samples of adult B-other ALL patients treated consecutively at three major Czech teaching hospitals. Samples were analyzed by cytogenetic methods, gene expression profiling, multiplex ligation-dependent probe amplification (MLPA), and next-generation sequencing (NGS). RESULTS: Fifty-eight B-other ALL patients (not BCR-ABL1, KMT2A-rearranged, ETV6-RUNX1, TCF3-PBX1, or iAMP21) were included in the study. Median follow-up was 23.8 months. Samples from 33 patients were available for a gene expression analysis, 48.9% identified as BCR-ABL1-like ALL. Of the BCR-ABL1-like ALL cases, 18.8% harbored IGH-CRLF2 and 12.5% P2RY8-CRLF2 fusion gene. We observed a higher MRD failure rate in BCR-ABL1-like than in non-BCR-ABL1-like ALL patients after the induction treatment (50.0 vs. 13.3%, p=.05). There was a trend to worse progression-free and overall survival in the BCR-ABL1-like group, though not statistically significant. Deletions in IKZF1 gene were found in 31.3% of BCR-ABL1-like cases. Patients with concurrent IKZF1 and CDKN2A/B, PAX5 or PAR1 region deletions (IKZF1plus profile) had significantly worse progression-free survival than those with sole IKZF1 deletion or IKZF1 wild-type (p=.02). NGS analysis was performed in 54 patients and identified 99 short variants in TP53, JAK2, NRAS, PAX5, CREBBP, NF1, FLT3, ATM, KRAS, RUNX1, and other genes. Seventy-five of these gene variants have not yet been described in B-cell precursor ALL to date. CONCLUSION: This study widens existing knowledge of the BCR-ABL1-like and B-other ALL genomic landscape in the adult population, supports previous findings, and identifies a number of novel gene variants.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma * genetics   MeSH
• Adult MeSH
• Genomics MeSH
• Cohort Studies MeSH
• Humans MeSH
• Retrospective Studies MeSH
• Gene Expression Profiling MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH

Novel biological subtypes and clinically important genetic aberrations (druggable lesions, prognostic factors) have been described in B-other acute lymphoblastic leukemia (ALL) during the last decade; however, due to a lack of studies on unselected cohorts, their population frequency and mutual associations still have to be established. We studied 110 consecutively diagnosed and uniformly treated childhood B-other patients using single nucleotide polymorphism arrays and whole exome/transcriptome sequencing. The frequency of DUX4-rearranged, BCR-ABL1-like, ZNF384-rearranged, ETV6-RUNX1-like, iAMP21 and MEF2D-rearranged subtypes was 27%, 15%, 5%, 5%, 4%, and 2%, respectively; 43% of cases were not classified into any of these subtypes (B-rest). We found worse early response to treatment in DUX4-rearranged leukemia and a strong association of ZNF384-rearranged leukemia with B-myeloid immunophenotype. Of the druggable lesions, JAK/STAT-class and RAS/RAF/MAPK-class aberrations were found in 21% and 43% of patients, respectively; an ABL-class aberration was found in one patient. A recently described negative prognostic factor, IKZF1plus , was found in 14% of patients and was enriched in (but not exclusive for) BCR-ABL1-like subtype. PAX5 fusions (including 4 novel), intragenic amplifications and P80R mutations were mutually exclusive and only occurred in the B-rest subset, altogether accounting for 20% of the B-other group. PAX5 P80R was associated with a specific gene expression signature, potentially defining a novel leukemia subtype. Our study shows unbiased European population-based frequencies of novel ALL subtypes, recurrent (cyto)genetic aberrations and their mutual associations. This study also strengthens and widens the current knowledge of B-other ALL and provides an objective basis for optimization of current genetic diagnostics.

• MeSH
• Chromosome Aberrations * MeSH
• Child MeSH
• Oncogene Proteins, Fusion genetics   MeSH
• Genomics methods   MeSH
• Cohort Studies MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Mutation * MeSH
• Biomarkers, Tumor genetics   MeSH
• Follow-Up Studies MeSH
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma epidemiology   genetics   pathology   MeSH
• Child, Preschool MeSH
• Prognosis MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Transcriptome * MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Europe MeSH

BCR/ABL1-like acute lymphoblastic leukaemia (ALL) is a subgroup of B-lineage acute lymphoblastic leukaemia that occurs within cases without recurrent molecular rearrangements. Gene expression profiling (GEP) can identify these cases but it is expensive and not widely available. Using GEP, we identified 10 genes specifically overexpressed by BCR/ABL1-like ALL cases and used their expression values - assessed by quantitative real time-polymerase chain reaction (Q-RT-PCR) in 26 BCR/ABL1-like and 26 non-BCR/ABL1-like cases to build a statistical "BCR/ABL1-like predictor", for the identification of BCR/ABL1-like cases. By screening 142 B-lineage ALL patients with the "BCR/ABL1-like predictor", we identified 28/142 BCR/ABL1-like patients (19·7%). Overall, BCR/ABL1-like cases were enriched in JAK/STAT mutations (P < 0·001), IKZF1 deletions (P < 0·001) and rearrangements involving cytokine receptors and tyrosine kinases (P = 0·001), thus corroborating the validity of the prediction. Clinically, the BCR/ABL1-like cases identified by the BCR/ABL1-like predictor achieved a lower rate of complete remission (P = 0·014) and a worse event-free survival (P = 0·0009) compared to non-BCR/ABL1-like ALL. Consistently, primary cells from BCR/ABL1-like cases responded in vitro to ponatinib. We propose a simple tool based on Q-RT-PCR and a statistical model that is capable of easily, quickly and reliably identifying BCR/ABL1-like ALL cases at diagnosis.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma * diagnosis   genetics   metabolism   mortality   MeSH
• Fusion Proteins, bcr-abl * biosynthesis   genetics   MeSH
• Models, Biological * MeSH
• Child MeSH
• Adult MeSH
• Infant MeSH
• Real-Time Polymerase Chain Reaction * MeSH
• Humans MeSH
• Survival Rate MeSH
• Adolescent MeSH
• Infant, Newborn MeSH
• Predictive Value of Tests MeSH
• Child, Preschool MeSH
• Disease-Free Survival MeSH
• Gene Expression Regulation, Leukemic * MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

We used the genomic breakpoint between BCR and ABL1 genes for the DNA-based monitoring of minimal residual disease (MRD) in 48 patients with childhood acute lymphoblastic leukemia (ALL). Comparing the results with standard MRD monitoring based on immunoglobulin/T-cell receptor (Ig/TCR) gene rearrangements and with quantification of IKZF1 deletion, we observed very good correlation for the methods in a majority of patients; however, >20% of children (25% [8/32] with minor and 12.5% [1/8] with major-BCR-ABL1 variants in the consecutive cohorts) had significantly (>1 log) higher levels of BCR-ABL1 fusion than Ig/TCR rearrangements and/or IKZF1 deletion. We performed cell sorting of the diagnostic material and assessed the frequency of BCR-ABL1-positive cells in various hematopoietic subpopulations; 12% to 83% of non-ALL B lymphocytes, T cells, and/or myeloid cells harbored the BCR-ABL1 fusion in patients with discrepant MRD results. The multilineage involvement of the BCR-ABL1-positive clone demonstrates that in some patients diagnosed with BCR-ABL1-positive ALL, a multipotent hematopoietic progenitor is affected by the BCR-ABL1 fusion. These patients have BCR-ABL1-positive clonal hematopoiesis resembling a chronic myeloid leukemia (CML)-like disease manifesting in "lymphoid blast crisis." The biological heterogeneity of BCR-ABL1-positive ALL may impact the patient outcomes and optimal treatment (early stem cell transplantation vs long-term administration of tyrosine-kinase inhibitors) as well as on MRD testing. Therefore, we recommend further investigations on CML-like BCR-ABL1-positive ALL.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma blood   genetics   MeSH
• Fusion Proteins, bcr-abl genetics   MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive blood   genetics   MeSH
• Gene Deletion MeSH
• Child MeSH
• Genome, Human * MeSH
• Hematopoiesis MeSH
• Humans MeSH
• Adolescent MeSH
• Leukocyte Count MeSH
• Child, Preschool MeSH
• Receptors, Antigen, T-Cell genetics   MeSH
• Neoplasm, Residual genetics   MeSH
• Ikaros Transcription Factor genetics   MeSH
• Treatment Outcome MeSH
• Chromosome Breakage * MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Child, Preschool MeSH
• Publication type
• Journal Article MeSH

• MeSH
• Hematologic Neoplasms * classification   MeSH
• Lymphoma classification   MeSH
• Publication type
• Monograph MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• onkologie
• hematologie a transfuzní lékařství

To characterize the incidence, clinical features and genetics of ETV6-ABL1 leukemias, representing targetable kinase-activating lesions, we analyzed 44 new and published cases of ETV6-ABL1-positive hematologic malignancies [22 cases of acute lymphoblastic leukemia (13 children, 9 adults) and 22 myeloid malignancies (18 myeloproliferative neoplasms, 4 acute myeloid leukemias)]. The presence of the ETV6-ABL1 fusion was ascertained by cytogenetics, fluorescence in-situ hybridization, reverse transcriptase-polymerase chain reaction and RNA sequencing. Genomic and gene expression profiling was performed by single nucleotide polymorphism and expression arrays. Systematic screening of more than 4,500 cases revealed that in acute lymphoblastic leukemia ETV6-ABL1 is rare in childhood (0.17% cases) and slightly more common in adults (0.38%). There is no systematic screening of myeloproliferative neoplasms; however, the number of ETV6-ABL1-positive cases and the relative incidence of acute lymphoblastic leukemia and myeloproliferative neoplasms suggest that in adulthood ETV6-ABL1 is more common in BCR-ABL1-negative chronic myeloid leukemia-like myeloproliferations than in acute lymphoblastic leukemia. The genomic profile of ETV6-ABL1 acute lymphoblastic leukemia resembled that of BCR-ABL1 and BCR-ABL1-like cases with 80% of patients having concurrent CDKN2A/B and IKZF1 deletions. In the gene expression profiling all the ETV6-ABL1-positive samples clustered in close vicinity to BCR-ABL1 cases. All but one of the cases of ETV6-ABL1 acute lymphoblastic leukemia were classified as BCR-ABL1-like by a standardized assay. Over 60% of patients died, irrespectively of the disease or age subgroup examined. In conclusion, ETV6-ABL1 fusion occurs in both lymphoid and myeloid leukemias; the genomic profile and clinical behavior resemble BCR-ABL1-positive malignancies, including the unfavorable prognosis, particularly of acute leukemias. The poor outcome suggests that treatment with tyrosine kinase inhibitors should be considered for patients with this fusion.

• MeSH
• Alternative Splicing MeSH
• Child MeSH
• Adult MeSH
• Phenotype MeSH
• Oncogene Proteins, Fusion genetics   MeSH
• In Situ Hybridization, Fluorescence MeSH
• Polymorphism, Single Nucleotide MeSH
• Infant MeSH
• Leukemia diagnosis   genetics   mortality   therapy   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Child, Preschool MeSH
• Aged MeSH
• Cluster Analysis MeSH
• Gene Expression Profiling MeSH
• Transcriptome MeSH
• Translocation, Genetic MeSH
• Protein-Tyrosine Kinases genetics   MeSH
• DNA Copy Number Variations MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Akutní lymfoblastická leukemie (ALL) je onemocněním převážně dětského věku, u dospělých patří mezi vzácné choroby. Prognóza a léčebné výsledky dospělých pacientů jsou sice zatím velmi neuspokojivé, v posledních letech však dochází k množství nových objevů. Tato práce je souhrnným přehledem aktuálních témat v oblasti diagnostiky a léčby akutní lymfoblastické leukemie dospělých. Zaměřuje se na minimální zbytkovou nemoc a její prognostický význam, nové poznatky v oblasti genetiky onemocnění, především mutace genů IKZF1 (Ikaros), NOTCH1 a nové prognostické kategorie Ph-like (BCR-ABL1-like) ALL a early T-cell precursor (ETP) ALL. Dále je uveden přehled nových testovaných léků, převážně monoklonálních protilátek a jejich konjugátů.

Acute lymphoblastic leukaemia (ALL) is predominantly a childhood disease and its incidence in adults is low. The prognosis and treatment outcome in adults are less satisfactory than in children. However, many new discoveries have been made recently. This review describes diagnostic procedures and treatment options in adult ALL. It focuses on minimal residual disease and its prognostic significance; on several new genetic abnormalities, such as IKZF1 (Ikaros) and NOTCH1 gene mutations and on the new prognostic categories of Ph-like (BCR-ABL1-like) ALL and early T-cell precursor (ETP) ALL. An overview of new drugs currently being tested in clinical trials, especially monoclonal antibodies and antibody-drug conjugates, is also presented.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma * drug therapy   genetics   physiopathology   MeSH
• Antigens, CD19 drug effects   MeSH
• Antigens, CD20 drug effects   MeSH
• Sialic Acid Binding Ig-like Lectin 2 drug effects   MeSH
• Fusion Proteins, bcr-abl MeSH
• Chromosome Aberrations MeSH
• Gene Deletion MeSH
• Child MeSH
• Adult MeSH
• Gene Expression MeSH
• Antibodies, Monoclonal, Humanized therapeutic use   MeSH
• Remission Induction MeSH
• Protein Kinase Inhibitors MeSH
• Janus Kinases MeSH
• Clinical Trials, Phase II as Topic MeSH
• Humans MeSH
• Mutation MeSH
• Antibodies, Monoclonal, Murine-Derived therapeutic use   MeSH
• Biomarkers, Tumor MeSH
• Polymerase Chain Reaction MeSH
• Prognosis MeSH
• Antibodies, Bispecific therapeutic use   MeSH
• Randomized Controlled Trials as Topic MeSH
• Gene Expression Regulation, Leukemic MeSH
• Neoplasm, Residual diagnosis   MeSH
• Signal Transduction genetics   MeSH
• Ikaros Transcription Factor genetics   MeSH
• STAT Transcription Factors MeSH
• Treatment Outcome MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Publication type
• Review MeSH