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Tremendous strides have been made in the molecular and cytogenetic classification of acute lymphoblastic leukemia based on gene expression profiling data, leading to an expansion of entities in the recent International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias and 2022 WHO Classification of Tumours: Haematolymphoid Tumors, 5th edition. This increased diagnostic and therapeutic complexity can be overwhelming, and this review compares nomenclature differences between the ICC and WHO 5th edition publications, compiles key features of each entity, and provides a diagnostic algorithmic approach. In covering B-lymphoblastic leukemia (B-ALL), we divided the entities into established (those present in the revised 4th edition WHO) and novel (those added to either the ICC or WHO 5th edition) groups. The established B-ALL entities include B-ALL with BCR::ABL1 fusion, BCR::ABL1-like features, KMT2A rearrangement, ETV6::RUNX1 rearrangement, high hyperdiploidy, hypodiploidy (focusing on near haploid and low hypodiploid), IGH::IL3 rearrangement, TCF3::PBX1 rearrangement, and iAMP21. The novel B-ALL entities include B-ALL with MYC rearrangement; DUX4 rearrangement; MEF2D rearrangement; ZNF384 or ZNF362 rearrangement, NUTM1 rearrangement; HLF rearrangement; UBTF::ATXN7L3/PAN3,CDX2; mutated IKZF1 N159Y; mutated PAX5 P80R; ETV6::RUNX1-like features; PAX5 alteration; mutated ZEB2 (p.H1038R)/IGH::CEBPE; ZNF384 rearranged-like; KMT2A-rearranged-like; and CRLF2 rearrangement (non-Ph-like). Classification of T-ALL is complex with some variability in how the subtypes are defined in recent literature. It was classified as early T-precursor lymphoblastic leukemia/lymphoma and T-ALL, NOS in the WHO revised 4th edition and WHO 5th edition. The ICC added an entity into early T-cell precursor ALL, BCL11B-activated, and also added provisional entities subclassified based on transcription factor families that are aberrantly activated., Competing Interests: Declaration of Competing Interest All authors have read and approved the final manuscript. None of the authors have any conflict of interest or investments to be disclosed related to this content., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The updated International Consensus Classification (ICC) of B-acute lymphoblastic leukemia (B-ALL) and T-acute lymphoblastic leukemia (T-ALL) includes both revisions to subtypes previously outlined in the 2016 WHO classification and several newly described entities. The ICC classification incorporates recent clinical, cytogenetic, and molecular data, with a particular emphasis on whole transcriptome analysis and gene expression (GEX) clustering studies. B-ALL classification is modified to further subclassify BCR::ABL1-positive B-ALL and hypodiploid B-ALL. Additionally, nine new categories of B-ALL are defined, including seven that contain distinguishing gene rearrangements, as well as two new categories that are characterized by a specific single gene mutation. Four provisional entities are also included in the updated B-ALL classification, although definitive identification of these subtypes requires GEX studies. T-ALL classification is also updated to incorporate BCL11B-activating rearrangements into early T-precursor (ETP) ALL taxonomy. Additionally, eight new provisional entities are added to the T-ALL subclassification. The clinical implications of the new entities are discussed, as are practical approaches to the use of different technologies in diagnosis. The enhanced specificity of the new classification will allow for improved risk stratification and optimized treatment plans for patients with ALL., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: New B-cell markers are needed for monitoring B lymphoblastic leukemia (B-ALL) in the era of immunotherapies directed against CD19 and CD22. The expression of leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1) on hematogones in bone marrow (BM) and neoplastic B lymphoblasts has not yet been systematically investigated., Methods: We assessed LILRB1 expression pattern on B cells in 19 control BMs and 22 B-ALL cases by flow cytometry., Results: In all cases, mature B cells and hematogones exhibited a consistent pattern of LILRB1 expression with variable intensity over different stages of maturation, including a characteristic V-shaped pattern on hematogones. While neoplastic B lymphoblasts in all cases expressed LILRB1, the pattern of expression was distinctly abnormal relative to hematogones (loss of the dynamic pattern in all cases and abnormal expression levels in 83% of cases)., Conclusions: LILRB1 is a novel diagnostic B-cell marker to aid in distinguishing neoplastic B lymphoblasts from hematogones., (© American Society for Clinical Pathology, 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Infantile leukemia encompasses a heterogeneous group which needs stratifying for treatment selection., Methods: We collected 78 cases of infantile leukemia and retrospectively analyzed their clinicopathological data., Results: Infantile leukemia featured a ratio of acute myeloid leukemia (AML) to B-lymphoblastic leukemia (B-ALL) of 1:2, with a better survival for AML than B-ALL (median survival 36 vs 24 months). When stratified by age, "early" infantile B-ALL (2-6 months) showed a high rate of KMT2A rearrangement (100%), similar to the rate seen in congenital B-ALL (1 month) (100%) and higher than seen in "late" infantile B-ALL (≥7 months) (68%). The three categories of infantile B-ALL exhibited an age-dependent increase in survival (median survival 8.5, 24, and >24 months, respectively). The age-dependent survival benefit remained after excluding the cases negative for KMT2A rearrangement. Conversely, infantile AML lacked an age-dependent pattern of survival., Conclusion: The clinical outcome of infantile leukemia depends on the type of leukemia. Given the age-dependent survival, infantile B-ALL can be divided into three subcategories., (© 2021 John Wiley & Sons Ltd.)

The t(1;11)(p32;q23) translocation is a rare but recurrent cytogenetic aberration in acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (B-ALL). This translocation was initially shown to form a fusion gene between KMT2A exon 8 at 11q23 and EPS15 exon 2 at 1p32 in AML. Activating mutations of FLT3 are frequently found in AML but are very rare in ALL. Here, we describe a 75-year-old woman who was diagnosed with B-ALL since her bone marrow was made up of 98.2% lymphoblasts. These blasts were positive for CD19, CD22, CD79a, CD13, and CD33 but negative for CD10 and myeloperoxidase. The karyotype by G-banding and spectral karyotyping was 46,XX,t(1;11)(p32;q23). Expression of KMT2A/EPS15 and reciprocal EPS15/KMT2A fusion transcripts were shown: KMT2A exon 8 was in-frame fused to EPS15 exon 12, indicating that this fusion transcript was a novel type. Considering three reported B-ALL cases, EPS15 breakpoints were markedly different between AML (exon 2) and B-ALL (exons 10-12). Furthermore, an uncommon type of FLT3 mutation in the juxtamembrane domain was detected: in-frame 4-bp deletion and 10-bp insertion. Accordingly, our results indicate that the novel type of KMT2A/EPS15 fusion transcript and FLT3 mutation may cooperate in the pathogenesis of adult B-ALL as class II and class I mutations, respectively., Competing Interests: Declaration of Competing Interest All authors have no conflict of interest., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: Autologous stem cell transplant with lenalidomide maintenance therapy has greatly improved the relapse-free and overall survival rates of patients with multiple myeloma but also has been associated with an increased risk of secondary B-lymphoblastic leukemia/lymphoma (B-ALL)., Methods: We report a comprehensive review of the clinicopathologic features of 2 patients with multiple myeloma who developed secondary B-ALL during lenalidomide maintenance., Results: Our observations showed that the disease may initially present with subtle clinical, morphologic, and flow-cytometric findings. The flow cytometry findings in such cases may initially mimic an expansion of hematogones with minimal immunophenotypic variation. Both patients achieved complete remission of secondary B-ALL after standard chemotherapy; however, one patient continues to have minimal residual disease, and the other experienced relapse. Next-generation sequencing of the relapse specimen showed numerous, complex abnormalities, suggesting clonal evolution., Conclusions: Our findings suggest the need for increased awareness and further study of this unique form of secondary B-ALL., (© American Society for Clinical Pathology, 2020.)

Background: We analyzed expression profiles of immune checkpoint receptors on T cell subsets and ligands on leukemic blasts in patients with B-lymphoblastic leukemia (B-ALL)., Methods: Total 149 bone marrow (BM) samples obtained from 65 B-ALL patients with four different clinical status (41 at diagnosis, 54 in complete remission [CR], 34 in persistence, and 20 in relapse), and 32 BM control samples were prospectively enrolled. Expression of immune checkpoint receptor (programmed cell death protein-1 [PD-1]) on T cell subsets and ligands (PD-L1, PD-L2) on leukemic blasts was evaluated by flow cytometry, and was compared between patient subgroups., Results: Relapsed patients demonstrated highest PD-1 expression proportion and intensity on CD3 + CD4 + T cells with statistical significance when compared to patients in persistence/CR/BM controls (p = .027/<.001/<.001 and .012/.001/<.001, respectively). Newly diagnosed patients showed significantly lower PD-1 expression proportion on CD3 + CD4 + T cells than relapsed patients (p < .001), but their intensity was not significantly different. Relapsed patients showed significantly higher PD-1 expression proportion and intensity on CD3 + CD8 + T cells than patients in CR/BM controls (p = .022/.045 and .049/.005, respectively), but PD-1 expression status on them were not significantly different between relapsed and newly diagnosed patients. PD-L1/L2 expression on leukemic blasts was not significantly different between patient subgroups., Conclusions: In BM aspirates from B-ALL patients, PD-1 expression on T-cell subsets is increased at diagnosis, and to a greater extent, at relapse. These data suggest the potential usefulness of PD-1 blockade in the treatment of B-ALL, particularly at relapse., (© 2020 International Clinical Cytometry Society.)

Objectives: To improve diagnostic accuracy in differentiating hematogones from leukemic blasts in cases of precursor B-lymphoblastic leukemia/lymphoma (B-ALL), particularly those that are posttreatment or after bone marrow transplant, and to provide an algorithmic approach to this diagnostic challenge., Methods: A seven-color antibody panel including CD10, CD19, CD45, CD38, CD34, CD58, and CD81 was generated to assess the feasibility of a single tube panel and provide an algorithmic approach to distinguish hematogones from B-ALL. Fifty-three cases were analyzed, and results were correlated with histology and ancillary studies., Results: There was a significant difference in mean fluorescent intensity (MFI) for CD81 and CD58 when comparing hematogones and B-ALL populations (P < .001). B-ALL cases had a mean (SD) MFI of 24.6 (27.5; range, 2-125) for CD81 and 135.6 (72.6; range, 48-328) for CD58. Hematogones cases had a mean (SD) MFI of 70.2 (19.2; range, 42-123) for CD81 and 38.8 (9.4; range, 23-58) for CD58., Conclusions: The flow cytometry panel with the above markers and utilization of the proposed algorithmic approach provide differentiation of hematogones from B-ALL. This includes rare cases of hematogones and B-ALL overlap where additional ancillary studies are necessary., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The detection of recurrent genetic abnormalities in B-lymphoblastic leukemia (B-ALL) is critical for risk stratification and therapy-related decisions. Near-haploidy (24-30 chromosomes), a subgroup of hypodiploidy (<46 chromosomes), and BCR/ABL1 gene fusions are both recurrent genetic abnormalities in B-ALL and are considered adverse prognostic findings, although outcomes in BCR/ABL1-positive patients have improved with tyrosine kinase inhibitor therapy. While near-haploid clones are primarily observed in children and rarely harbor structural abnormalities, BCR/ABL1-positive B-ALL is primarily observed in adults. Importantly, recurrent genetic abnormalities are considered mutually exclusive and rarely exist within the same neoplastic clone. We report only the second case to our knowledge of a near-haploid clone that harbors a BCR/ABL1 fusion in an adult with newly diagnosed B-ALL. Conventional chromosome studies revealed a near-haploid clone (27 chromosomes) along with a der(22)t(9;22)(q34.1;q11.2) in 17 of 20 metaphases analyzed. Our B-ALL fluorescence in situ hybridization (FISH) panel confirmed the BCR/ABL1 fusion and monosomies consistent with chromosome studies in approximately 95% of interphase nuclei. Moreover, no evidence of a "doubled" near-haploid clone was observed by chromosome or FISH studies. This highly unusual case illustrates that while rare, recurrent genetic abnormalities in B-ALL can exist within the same neoplastic clone., (© 2019 Wiley Periodicals, Inc.)

Minimal residual disease (MRD) following B-lymphoblastic leukemia (B-ALL) treatment has gained prognostic importance. Clonal immunoglobulin heavy chain (IGH) gene rearrangement is a useful follow-up marker in B-ALL owing to its high positivity rate. We evaluated the performance and clinical applicability of a next-generation sequencing (NGS) assay for IGH rearrangement in B-ALL MRD monitoring. IGH rearrangement was tested by using fluorescence PCR-fragment analysis and the NGS assay in eight B-ALL patients. The NGS assay was run on two platforms: the Ion Torrent PGM (Thermo Fisher Scientific, USA) (18 samples from 1st to 7th patients) and the MiSeq system (Illumina, USA) (four samples from 8th patient). All initial diagnostic samples and four follow-up samples were positive for clonal IGH rearrangement with fluorescence PCR-fragment analysis and the NGS assay, and six follow-up samples were positive only with NGS. In one case with BCR-ABL1 translocation, BCR-ABL1 quantitative PCR was negative but the NGS IGH assay was positive just prior to full-blown relapse, suggesting the high sensitivity and clinical utility of the NGS assay. The NGS assay is proposed for MRD monitoring in B-ALL Additional studies are needed to confirm the clinical implications of cases showing positive results only in NGS., Competing Interests: No potential conflicts of interest relevant to this article were reported., (© The Korean Society for Laboratory Medicine.)

Objective We observed that pediatric patients with B lymphoblastic leukemia which expressed CD36 at diagnosis seemed to have worse outcome than patients whose blasts did not. Here, we describe the patient, disease characteristics, pathological, molecular, and genetic features and outcomes of patients with CD36+ B-LL compared to patients with CD36- B-LL. Methods We retrospectively reviewed all flow cytometry reports from September 2008 to December 2015 to identify patients diagnosed at our institution with CD36 expression on B lymphoblasts. CD36- control patients were chosen from our leukemia database and matched 2:1 to CD36+ patients for National Cancer Institute (NCI) risk group at diagnosis. We reviewed diagnostic marrow slides for cytoplasmic granules and abstracted clinical data from patient charts. To identify underlying genetic abnormalities, clinical FISH testing and RNA sequencing was performed on 5 of our CD36+ patients, and RNA-seq data from the NIH Therapeutically Applicable Research to Generate Effective Treatments (TARGET) ALL Expansion Phase 2 data set were examined. Results Twenty-five of 366 (6.83%) patients diagnosed at our institution in the study period had CD36+ blasts. With a median follow-up of 5.32 years, 5-year event-free survival (EFS) and overall survival (OS) were significantly worse for CD36+ patients compared to CD36- patients who were NCI Standard Risk at diagnosis (EFS: 60% ± 15.49 vs 95% ± 4.87, P = .016; OS: 90% ± 9.5 vs 100%, P = .019). NCI Standard Risk patients whose blasts were both CD36+ and had granules had the worst survival compared to CD36- patients without granules (EFS 25% ± 21.65 vs 95% ± 4.87, P = .0004). From our CD36+ patients and the TARGET database, we found 2 ABL2 mutations, 1 PDGFRB mutation, and 2 NRAS mutations. Conclusions For NCI Standard Risk patients, CD36 expression on B-lymphoblasts identifies patients with B-LL who have especially poor outcome. This may be due to underlying genetic abnormalities that may be amenable to targeted therapy.

Objectives: Study to date suggests that BCL6 protein expression in B-cell neoplasia predominates in germinal center-derived tumors, but less is known regarding its expression in B-lymphoblastic leukemia. Therefore, we designed a comprehensive study of BCL6 expression in B-lymphoblastic leukemia., Methods: BCL6, LMO, and HGAL protein expression in B-lymphoblastic leukemia was investigated using immunohistochemical staining of paraffin-embedded bone marrow specimens. Cryptic TCF3(E2A)-PBX1 rearrangements were investigated using interphase fluorescence in situ hybridization., Results: Six (12%) of 52 B-lymphoblastic leukemias demonstrated BCL6 protein expression, with B-cell lymphoblastic leukemias containing a t(1;19) translocation demonstrating the strongest staining (three of three). Additional t(1;19) cases beyond the screening study showed similar results. Public microarray expression database mining showed that BCL6 messenger RNA expression levels in B-lymphoblastic leukemia correlated with the protein expression findings. Finally, other markers of B-cell development correlated with BCL6 expression in t(1;19) B-lymphoblastic leukemia cases, with LMO2 and HGAL proteins expressed in six (67%) of nine and eight (89%) of nine cases, respectively., Conclusions: BCL6 expression is present in a subset of B-lymphoblastic leukemias, especially in cases containing the 1;19 translocation. Investigation for TCF3(E2A)-PBX1 rearrangements may be useful in BCL6-positive B-lymphoblastic leukemia., (Copyright© by the American Society for Clinical Pathology.)