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Tyrosine kinase inhibitors (TKIs) have revolutionized Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) treatment. The combination of blinatumomab and a TKI in the frontline setting has shown the safety and efficacy of the chemotherapy-free treatment approach in patients with Ph + ALL. This retrospective analysis included 19 patients with Ph + ALL and Ph-like ALL treated with the combination of blinatumomab and a TKI. Of the 14 newly diagnosed patients, the overall response, complete remission (CR), and molecular response (CMR) rates after one cycle of blinatumomab were 100% (10/10), 90% (9/10), and 57% (8/14), respectively. Of the five relapsed patients, the CR and CMR rates were 50% (2/4) and 40% (2/5). Blinatumomab in combination with TKIs is safe and effective and hence this combination therapy could be a viable therapeutic option in front-line treatment of patients with Ph + ALL.

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OBJECTIVE: To explore the clinical characteristics, molecular characteristics, treatment and prognosis of pediatric Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) with a therapeutic target. METHODS: A total of 27 patients of Ph-like ALL with targeted drug target were initially diagnosed in Children's Hospital of Soochow University from December 2017 to June 2021. The data of age, gender, white blood cell (WBC) count at initial diagnosis, genetic characteristics, molecular biological changes, chemotherapy regimen, different targeted drugs were given, and minimal residual disease (MRD) on day 19, MRD on day 46, whether hematopoietic stem cell transplantation (HSCT) were retrospective analyed, and the clinical characteristics and treatment effect were summarized. Survival analysis was performed by Kaplan-Meier method. RESULTS: The intensity of chemotherapy was adjusted according to the MRD level during induced remission therapy in 27 patients, 10 patients were treated with targeted drugs during treatment, and 3 patients were bridged with HSCT, 1 patient died and 2 patients survived. Among the 24 patients who did not receive HSCT, 1 patient developed relapse, and achieved complete remission (CR) after treatment with chimeric antigen receptors T cells (CAR-T). The 3-year overall survival, 3-year relapse-free survival and 3-year event-free survival rate of 27 patients were (95.5±4.4)%, (95.0±4.9)% and (90.7±6.3)% respectively. CONCLUSION: Risk stratification chemotherapy based on MRD monitoring can improve the prognosis of Ph-like ALL in children, combined with targeted drugs can achieve complete remission as soon as possible in children whose chemotherapy response is poor, and sequential CAR-T and HSCT can significantly improve the therapeutic effect of Ph-like ALL in children whose MRD is continuously positive during induced remission therapy.

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SSBP2-CSF1R is an important biomarker for clinical diagnosis and prognosis of Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL). This case report presents a pediatric Ph-like ALL patient carrying the SSBP2-CSF1R fusion gene. The patient was resistant to most conventional chemotherapy regimens and to dasatinib, an inhibitor that has been reported to have a therapeutic effect on SSBP2-CSF1R fusion Ph-like ALL, as she remained minimal residual disease (MRD) positive (detection by flow cytometry) and SSBP2-CSF1R fusion gene (detection by RT-PCR) positive after five rounds of such regimens. We thus conducted a large-scale in vitro screening to assess the sensitivity of the patient's leukemic cells to anti-cancer drugs. Based on the susceptibility results, we chose to combine cytarabine, homoharringtonine, dexamethasone, fludarabine, vindesine, and epirubicin for treatment. Clinical results showed that after a course of treatment, both MRD and SSBP2-CSF1R fusion gene turned negative, and there was no recurrence during an 18-month follow-up. In conclusion, our study suggests that the SSBP2-CSF1R fusion gene may be an important biomarker of primary drug resistance in Ph-like ALL, and indicate that the combination of cytarabine, homoharringtonine, dexamethasone, fludarabine, vindesine, and epirubicin can achieve optimal therapeutic results in this category of patients.

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Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a refractory and recurrent subtype of B-cell ALL enriched with kinase-activating rearrangements. Incomplete understanding of the heterogeneity within the tumor cells presents a major challenge for the diagnosis and therapy of Ph-like ALL. Here, we exhibited a comprehensive cell atlas of one Ph-like ALL patient with a novel TPR-PDGFRB fusion gene at diagnosis and relapse by using single-cell RNA sequencing (scRNA-seq). Twelve heterogeneous B-cell clusters, four with strong MKI67 expression indicating highly proliferating B cells, were identified. A relapse-enriched B-cell subset associated with poor prognosis was discovered, implicating the transcriptomic evolution during disease progression. Integrative single-cell analysis was performed on Ph-like ALL and Ph+ ALL patients, and revealed Ph-like specific B-cell subpopulations and shared malignant B cells characterized by the ectopic expression of the inhibitory receptor CLEC2D. Collectively, scRNA-seq of Ph-like ALL with a novel TPR-PDGFRB fusion gene provides valuable insights into the underlying heterogeneity associated with disease progression and offers useful information for the development of immunotherapeutic techniques in the future.

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Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a high-risk subtype of B cell ALL. It accounts for 20% of all B cell ALL cases and is similar to BCR-ABL1 in gene expression profile but lacks BCR-ABL fusion. It is highly heterogeneous and is characterized by genetic alterations that activate kinase and cytokine receptor signaling. Most of these alterations are amenable to tyrosine kinase inhibitors. Ph-like ALL is prevalent in pediatric and young adults, more common in males, and frequently seen in patients with Hispanic ancestry. It is associated with inadequate response to induction therapy, high minimal residual disease (MRD) levels, and increased risk of relapse. Overall survival and event-free survival are also inferior in these patients as compared to non-Ph-like ALL. In the clinical practice, low-density array, real-time quantitative polymerase chain reaction (RQ-PCR), flow cytometry, fluorescence in situ hybridization are used to identify genetic alteration in these patients. With the advent of next-generation sequencing (NGS), our understanding of disease pathogenesis and precision medicine has been improved. In this review, we analyzed data from several studies that used NGS as one of the diagnostic methods to identify genomic lesions in this high-risk subtype of B cell ALL. Studies have shown that NGS is a vital technique to identify various genomic lesions at diagnosis and throughout the treatment that can be missed by the widely used current methods. NGS has improved our understanding of various genomic lesions associated with Ph-like ALL and has helped define disease pathogenesis, MRD evaluation, and stratify therapy to prevent over or under treatment. We are in the era of precision medicine. Therefore unbiased, comprehensive genomic characterization of Ph-like ALL is important to implicate treatment directed against these genomic lesions and improve outcomes in these patients. We also analyzed data from studies that compared NGS with multi-flow cytometry and RQ-PCR for the evaluation of MRD. In the future, more extensive prospective studies are required to confirm the prognostic usefulness of NGS.

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PAX5-KIDINS220 (PAX5-K220) is a novel chimeric fusion gene identified in a pediatric Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) patient, but the function of the encoded fusion protein has not yet been analyzed. Here, we report the functional analysis of PAX5-K220 in vitro. We successfully generated PAX5-K220 expressing cells and demonstrate that PAX5-K220 is a nuclear protein. Luciferase reporter assay reveals that PAX5-K220 inhibits wild-type PAX5 transcriptional activity in a dominant-negative fashion like other PAX5-related fusion proteins, and may contribute to lymphocyte differentiation block. However, although identified in Ph-like ALL, PAX5-K220 does not induce IL-3-independent proliferation when transduced in the IL-3-dependent Ba/F3 murine leukemia cells, but rather attenuates growth. These results reveal that PAX5-K220 certainly shares the character with other PAX5-related fusion proteins rather than other fusion proteins with tyrosine kinase activity identified in Ph-like ALL, and did not contribute to proliferation activity. Precise functional analysis of each differently partnered PAX5 fusion protein is warranted in the future for better understanding of PAX5-related translocations and their effects.

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Philadelphia chromosome-like acute lymphoblastic leukemia (BCR-ABL1-like ALL) is a newly defined ALL subtype in 2009. It is Philadelphia chromosome (Ph)/BCR-ABL1-negative and characterized by a set of gene expression profile which is highly similar to that of Ph/BCR-ABL1-positive ALL. However, there is no definitive unified diagnostic criteria yet. BCR-ABL1-like ALL is generally resistant to chemotherapy, with a high relapsed rate and poor prognosis. It harbors a diverse range of genetic alterations that affect cytokine receptor and/or signal transduction pathway of tyrosine kinase. Overexpression of CRLF2, JAK-STAT pathway abnormalities and ABL-class gene rearrangements are the most common. These genetic aberrations could be therapeutic targets. Both in vitro and in vivo experiments and clinical data support the efficacy of targeted therapy. Beside conventional multi-drug chemotherapy, the combination of targeted therapy, cellular immunotherapy and allogeneic hematopoietic stem cell transplantation is promising to improve the prognosis of BCR-ABL1-like ALL. In this paper, the research status of BCR-ABL1-like ALL is described from five aspects: definition, diagnosis, clinical characteristics, molecular biological characteristics and treatment.

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Philadelphia chromosome_like acute lymphoblastic leukemia (Ph_like ALL) characterized by a high rate of relapse and poor outcome of chemotherapy and prognosis, also known as BCR_ABL1_like ALL, is a kind of B_ALL subtypes, a pattern of gene expression profiling similar to that of BCR_ABL1 ALL positive but lacking BCR_ABL1 fusion gene. With the better understanding of gene expression profiling, the World Health Organization (WHO) (2016) has regarded Ph_like ALL as an independent subtype of B_ALL. The diagnosis highly depends on the laboratory techniques, and a wide range of diagnostic methods can be applied in clinic, which may bring a big challenge for the clinicians. This paper reviews the various laboratory techniques of Ph_like ALL and subtype group analysis, to provide a basis for target therapy and to improve the prognosis.