Mutational profiling of acute lymphoblastic leukemia with testicular relapse

Ding, Ling-Wen; Sun, Qi‐Yun; Mayakonda, Anand; Tan, Kar-Tong; Chien, Wenwen; Lin, De–Chen; Jiang, Yan‐Yi; Xu, Lu; Garg, Manoj; Lao, Zhentang; Lill, Michael; Yang, Henry; Yeoh, Allen Eng Juh; Koeffler, H. Phillip

doi:10.1186/s13045-017-0434-y

Cited by 17 publications

(11 citation statements)

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“…Despite great advances, relapsed and refractory B cell acute lymphoblastic leukemia (B-ALL) shows unfavorable prognosis, especially for adult patients [ 1 , 2 ]. Although newly diagnosed ALL patients co-occurring with extramedullary involvement are rare, ALL with extramedullary tissues (EM-ALL) occurs in about 15 to 20% of all the relapse patients [ 3 ]. The central nervous system (CNS) is a favorable site for ALL relapse, accounting for two thirds of extramedullary relapse [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, incorporation with TLR2 domain improves expansion of CAR-T cells and potentiates the killing capacity of CAR T cells against CD19 + leukemic cells [ 12 ]. Actually, the leukemia cells with potent abilities for cell migration, proliferation, adhesion, and protease activity facilitated themselves extramedullary infiltration [ 3 , 4 ]. In this context, it is highly warranted to find tumor-specific T cells with enhanced activity against the leukemic cells of high affinity for the extramedullary relapse.…”

Section: Introductionmentioning

confidence: 99%

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A novel generation 1928zT2 CAR T cells induce remission in extramedullary relapse of acute lymphoblastic leukemia

et al. 2018

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BackgroundAnti-CD19 chimeric antigen receptor (CAR) T cells have shown promise in the treatment of B cell acute lymphocytic leukemia (B-ALL). However, its efficacy in B-ALL patients with extramedullary involvement is limited due to poor responses and neurotoxicity. Here, we utilized a third generation of CAR T cell vector, which contains the Toll/interleukin-1 receptor (ITR) domain of Toll-like receptor 2 (TLR2), to generate 1928zT2 T cells targeting CD19, and evaluated the efficacy of 1928zT2 T cells in relapse or refractory B-ALL patients with extramedullary involvement.Methods1928zT2 T cells were generated by 19-28z-TLR2 lentiviral vector transfection into primary human T lymphocytes. The anti-leukemia effect of 1928zT2 T cells were determined by killing assays and in xenografts. Three patients diagnosed as relapse or refractory ALL with extramedullary involvement were infused with 1928zT2 T cells, and the clinical responses were evaluated by BM smear, B-ultrasonography, PET/CT, histology, flow cytometry, qPCR, ELISA, and luminex assay.Results1928zT2 T cells exhibited enhanced effector function against CD19+ leukemic cells in vitro and in a xenograft model of human extramedullary leukemia. Notably, the 1928zT2 T cells eradicated extramedullary leukemia and induced complete remission in the three relapse and refractory ALL patients without serious adverse effects. 1928zT2 T cells expanded robustly in the circulation of these three patients and were detected in the cerebrospinal fluid of patient 3. These three patients experienced cytokine release syndrome (CRS) with grade 2 or 3, which remitted spontaneously or after tocilizumab treatment. None of the three patients suffered neurotoxicity or needed further intensive care.ConclusionsOur results demonstrate that 1928zT2 T cells with TLR2 incorporation augment anti-leukemic effects, particularly for eradicating extramedullary leukemia cells, and suggest that the infusion of 1928zT2 T cells is an encouraging treatment for relapsed/refractory ALL patients with extramedullary involvement.Trial registrationClinicalTrials.gov identifier NCT02822326. Date of registration: July 4, 2016.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A novel generation 1928zT2 CAR T cells induce remission in extramedullary relapse of acute lymphoblastic leukemia

et al. 2018

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“…Moreover, BCR-ABL1 compound mutations and other ABL1 tyrosine kinase inhibitors (TKIs) can also confer high-level resistance to imatinib [24]. Several research groups have also screened relapse-related gene mutations, including RAS and CREBBP/NT5C2 mutations in ALL patients [25, 26]. However, the correlation between clonal evolution and FISH signal patterns has not been well established in BCR-ABL1 positive patients.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneous BCR-ABL1 signal patterns identified by fluorescence in situ hybridization are associated with leukemic clonal evolution and poorer prognosis in BCR-ABL1 positive leukemia

et al. 2019

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Background Although extensive use of tyrosine kinase inhibitors has resulted in high and durable response rate and prolonged survival time in patients with BCR-ABL1 positive chronic myeloid leukemia (CML) and acute leukemia, relapse and drug resistance still remain big challenges for clinicians. Monitoring the expression of BCR-ABL1 fusion gene and identifying ABL kinase mutations are effective means to predict disease relapse and resistance. However, the prognostic impact of BCR-ABL1 signal patterns detected by fluorescence in situ hybridization (FISH) remains largely unaddressed. Methods BCR-ABL1 signal patterns were analyzed using FISH in 243 CML-chronic phase (CML-CP), 17 CML-blast phase (CML-BP) and 52 BCR-ABL1 positive acute lymphoblastic leukemia (ALL) patients. Results The patterns of BCR-ABL1 signals presented complexity and diversity. A total of 12 BCR-ABL1 signals were observed in this cohort, including 1R1G2F, 1R1G1F, 2R1G1F, 1R2G1F, 2R2G1F, 1R2G2F, 1R1G3F, 1G3F, 2G3F, 1G4F, 1R1G4F and 1R4F. Complex BCR-ABL1 signal patterns (≥ two types of signal patterns) were observed in 52.9% (n = 9) of the CML-BP patients, followed by 30.8% (n = 16) of the ALL patients and only 2.1% (n = 5) of the CML-CP patients. More importantly, five clonal evolution patterns related to disease progression and relapse were observed, and patients with complex BCR-ABL1 signal patterns had a poorer overall survival (OS) time compared with those with single patterns (5.0 vs.15.0 months, p = 0.006). Conclusions Our data showed that complex BCR-ABL1 signal patterns were associated with leukemic clonal evolution and poorer prognosis in BCR-ABL1 positive leukemia. Monitoring BCR-ABL1 signal patterns might be an effective means to provide prognostic guidance and treatment choices for these patients.

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“…35 In another study, mutations in CREBBP and KRAS were also implicated in the mechanism through which the disease returns; aberrations in CREBBP and KRAS were found in a leukemic clone at diagnosis that also persisted at relapse, indicating that a clone harboring such abnormalities were responsible for the disease recurrence. 36 Another piece of evidence of the key role of impaired drug-responsive genes in the therapy failure of pediatric B-ALL came from a study that reported a significant association of deleted genes known to function in glucocorticoid signaling, such as BTG1 (B-cell translocation protein 1), NR3C1 (glucocorticoid receptor) and TBL1XR1 (transducin beta-like 1X-linked receptor 1), with relapsed cases of pediatric B-ALL. 27 Characterization of genome-wide copy number alterations (CANs) in matched diagnosis and relapse samples from 20 patients revealed that the relapse samples were associated with deletions of genes linked to the development and differentiation of B-cells.…”

Section: Omics-based Insights Into Therapy Failure In Patients With Pmentioning

confidence: 99%

Omics-based insights into therapy failure of pediatric B-lineage acute lymphoblastic leukemia

Alsagaby

2019

Oncol Rev

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B-lineage acute lymphoblastic leukemia (B-ALL) is the most common type of cancer seen in children and is characterized by a variable clinical course. Although there have been remarkable improvements in the therapy outcomes of pediatric B-ALL, treatment failure remains the leading-cause of death in 18% of the afflicted patients during the first 5 years after diagnosis. Molecular heterogeneities of pediatric B-ALL play important roles as determinants of the therapy response. Therefore, many of these molecular abnormalities have an established prognostic value in the disease. The present review discusses the omics-based revelations from epigenomics, genomics, transcriptomics and proteomics about treatment failure in pediatric B-ALL. Next it highlights the promise of the molecular aberration-targeted therapy to improve the treatment outcomes.

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Mutational profiling of acute lymphoblastic leukemia with testicular relapse

Cited by 17 publications

References 10 publications

A novel generation 1928zT2 CAR T cells induce remission in extramedullary relapse of acute lymphoblastic leukemia

A novel generation 1928zT2 CAR T cells induce remission in extramedullary relapse of acute lymphoblastic leukemia

Heterogeneous BCR-ABL1 signal patterns identified by fluorescence in situ hybridization are associated with leukemic clonal evolution and poorer prognosis in BCR-ABL1 positive leukemia

Omics-based insights into therapy failure of pediatric B-lineage acute lymphoblastic leukemia

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