Hematological characteristics, cytogenetic features, and post-induction measurable residual disease in thymic stromal lymphopoietin receptor (TSLPR) overexpressed B-cell acute lymphoblastic leukemia in an Indian cohort.

The overexpression of cytokine receptor-like factor-2 (CRLF2) identified by anti-thymic stromal lymphopoietin receptor/TSLPR flow cytometry (FCM) has been reported as a screening tool for the identification of BCR-ABL1-like B-cell acute lymphoblastic leukemia/B-ALL with CRLF2 re-arrangement. TSLPR expression was studied prospectively in consecutive 478 B-ALLs (≤ 12 years (n = 244); 13-25 years (n = 129); > 25 years (n = 105)) and correlated with various hematological parameters and end-of-induction measurable residual disease (day 29; MRD ≥ 0.01% by 10-color FCM). TSLPR positivity in ≥ 10% leukemic cells was detected in 14.6% (n = 70) of B-ALLs. CRLF2 re-arrangement was detected in eight cases (11.4%) including P2RY8-CRLF2 (n = 6), and IgH-CRLF2 (n = 2) with a median TSLPR positivity of 48.8% and 99% leukemic cells, respectively. Recurrent gene fusions/RGF (BCR-ABL1 (17.1%); ETV6-RUNX1 (4.2%), TCF3-PBX1 (1.4%)), other BCR-ABL1-like chimeric gene fusions/CGFs (PDGFRB-rearrangement (2.9%), IgH-EPOR (1.4%)), CRLF2 extra-copies/hyperdiploidy (17.1%), and IgH translocation without a known partner (10%) were also detected in TSLPR-positive patients. CD20 positivity (52.9% vs 38.5%; p = 0.02) as well as iAMP21 (4.3% vs 0.5%; p = 0.004) was significantly more frequent in TSLPR-positive cases. TSLPR-positive patients did not show a significantly higher MRD, compared to TSLPR-negative cases (37% vs 33%). Increasing the threshold cut-off (from ≥ 10 to > 50% or > 74%) increased the specificity to 88% and 100% respectively in identifying CRLF2 translocation. TSLPR expression is not exclusive for CRLF2 translocations and can be seen with various other RGFs, necessitating their testing before its application in diagnostic algorithms. In patients with high TSLPR positivity (> 50%), the testing may be restricted to CRLF2 aberrancies, while patients with 10-50% TSLPR positivity need to be tested for both CRLF2- and non-CRLF2 BCR-ABL1-like CGFs.

Genetics and Diagnostic Approach to Lymphoblastic Leukemia/Lymphoma.

Our understanding of the genetics and biology of lymphoblastic leukemia/lymphoma (acute lymphoblastic leukemia, ALL) has advanced rapidly in the past decade with advances in sequencing and other molecular techniques. Besides recurrent chromosomal abnormalities detected by karyotyping or fluorescence in situ hybridization, these leukemias/lymphomas are characterized by a variety of mutations, gene rearrangements as well as copy number alterations. This is particularly true in the case of Philadelphia-like (Ph-like) ALL, a major subset which has the same gene expression signature as Philadelphia chromosome-positive ALL but lacks BCR-ABL1 translocation. Ph-like ALL is associated with a worse prognosis and hence its detection is critical. However, techniques to detect this entity are complex and are not widely available. This chapter discusses various subsets of ALL and describes our approach to the accurate classification and prognostication of these cases.

[B cell acute lymphoblastic leukemia therapy: an up to date overview].

It is over two decades since the first retrospective analysis indicated the superiority of pediatric-like therapy for adolescent and young adult (AYA) patients in 2000. To date, many prospective studies confirmed the efficacy and safety of pediatric-like therapy for AYA and older adult ALL, while therapy for pediatric ALL also made progress by innovating a new technology such as stratification of therapy by minimal residual disease (MRD). Furthermore, it is expected that further improvements will be achieved by applying newly approved anti-cancer drugs such as inotuzumab ozogamicin and blinatumomab. In this review, I will introduce these front line studies and discuss about the perspective of adult B-ALL treatment.

Philadelphia-Like Acute Lymphoblastic Leukemia in Adults.

PURPOSE OF REVIEW: This study aims to provide an overview of the classification, incidence, genomic alterations, and clinical implications of Philadelphia-like Acute Lymphoblastic Leukemia (Ph-like ALL) in adults. RECENT FINDINGS: Ph-like ALL is a high-risk subtype of B cell precursor ALL with characteristic genomic alterations in children and adults. A standard approach for diagnosis is missing and currently mainly based on gene expression analysis. The incidence is age depended and highest in adolescents and younger adults (age 16-39) where 19-28% of patients belong to this subtype. Ph-like ALL is associated with persistence of minimal residual disease (MRD) and inferior prognosis. Some genomic alterations respond to specific treatment approaches and provide hope for tailored therapies. Ph-like ALL in adults is an aggressive and high-risk subtype of B cell precursor ALL. Without consensus definition, diagnosis is difficult and current publications highlight the importance of stringent MRD monitoring to guide risk-adapted treatment strategies.

Genetic Alterations and Therapeutic Targeting of Philadelphia-Like Acute Lymphoblastic Leukemia.

Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a subgroup of B-cell precursor ALL which by gene expression analysis clusters with Philadelphia-positive ALL although lacking the pathognomonic BCR-ABL1 oncoprotein. Its prevalence increases with age and similar to BCR-ABL1-positive ALL, Ph-like ALL is characterized by IKZF1 or other B-lymphoid transcription factor gene deletions and by poor outcome to conventional therapeutic approaches. Genetic alterations are highly heterogenous across patients and include gene fusions, sequence mutations, DNA copy number changes and cryptic rearrangements. These lesions drive constitutively active cytokine receptor and kinase signaling pathways which deregulate ABL1 or JAK signaling and more rarely other kinase-driven pathways. The presence of activated kinase alterations and cytokine receptors has led to the incorporation of targeted therapy to the chemotherapy backbone which has improved treatment outcome for this high-risk subtype. More recently, retrospective studies have shown the efficacy of immunotherapies including both antibody drug-conjugates and chimeric antigen receptor T cell therapy and as they are not dependent on a specific genetic alteration, it is likely their use will increase in prospective clinical trials. This review summarizes the genomic landscape, clinical features, diagnostic assays, and novel therapeutic approaches for patients with Ph-like ALL.

Philadelphia chromosome-like acute lymphoblastic leukemia: A review of the genetic basis, clinical features, and therapeutic options.

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a recently identified high-risk subtype of B-lineage ALL (B-ALL), characterized by a gene expression profile similar to that of Philadelphia-positive (Ph+) ALL, but without the hallmark BCR-ABL1 oncoprotein. Ph-like ALL represents approximately 15% of childhood ALL and its frequency rises with age, peaking among adolescents, and young adults with B-ALL. This subtype is associated with adverse clinical features, persistence of minimal residual disease, and a poor prognosis despite modern chemotherapy regimens. While Ph-like ALL lacks the BCR-ABL1 fusion, it is characterized by a diverse spectrum of kinase fusions and cytokine receptor gene rearrangements that may be similarly amenable to molecularly targeted therapies. While survival rates for childhood ALL have drastically improved with intensive conventional chemotherapy, Ph-like ALL represents a novel paradigm of precision medicine in ALL. This review aims to provide a comprehensive review of the clinical picture and genetic basis of Ph-like ALL and to illustrate how these findings can translate into tailored targeted therapies with the hopes of improving the outcomes of Ph-like ALL patients.

Why and how to treat Ph-like ALL?

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL), or BCR-ABL1-like ALL, is a high-risk subtype of B-cell precursor ALL characterized by a gene expression profile similar to Ph-positive ALL, a high frequency of IKZF1 alterations, and poor outcome. The prevalence of Ph-like ALL is common among all ages, ranging from 10% to 15% in children to over 25% in young adults. Patients with Ph-like ALL harbor a diverse range of genetic alterations that activate cytokine receptor and kinase signaling and can be targeted with tyrosine kinase inhibitors. The majority of Ph-like ALL alterations are divided into two main groups based on activation of ABL-class or JAK-STAT alterations. Accordingly, preclinical studies and anecdotal reports suggest patients harboring ABL-class fusions are candidates for ABL1-inhibitors, whilst alterations activating the JAK-STAT pathway may be amenable to treatment with JAK inhibitors. Diagnostic screening approaches and precision medicine trials are now being developed and implemented to test the efficacy of targeted therapy with a backbone of chemotherapy, similar to the treatment of Ph-positive ALL.

Advances in Philadelphia chromosome-like acute lymphoblastic leukemia / 上海交通大学学报（医学版）

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.