Efficacy of tyrosine kinase inhibitors in Ph-like acute lymphoblastic leukemia harboring ABL-class rearrangements

Tanasi, Ilaria; Ba, Ibrahima; Sirvent, Nicolas; Braun, Thorsten; Cuccuini, Wendy; Ballerini, Paola; Duployez, Nicolas; Tanguy‐Schmidt, Aline; Tamburini, Jérôme; Maury, Sébastien; Doré, Éric; Himberlin, Chantal; Duclos, Cédric; Chevallier, Patrice; Rousselot, Philippe; Bonifacio, Massimiliano; Cavé, Hélène; Baruchel, André; Dombret, Hervé; Soulier, Jean; Landman‐Parker, Judith; Boissel, Nicolas; Clappier, Emmanuelle

doi:10.1182/blood.2019001244

Cited by 92 publications

(78 citation statements)

References 19 publications

(43 reference statements)

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“…Most JAK2 mutations identified in the present study were pathogenic and involved the tyrosinekinase domains 1 and 2, close to the nucleotide binding site for ATP-ADP exchange (residues 855-863), and structurally distant from the self-regulatory tyrosine 1007 and 1008. Currently, several clinical trials are evaluating the efficacy of JAK and mTOR inhibitors (in addition to TKI inhibitors), alone or in combination with other drugs based on this genetic rationale [24][25][26] .…”

Section: Discussionmentioning

confidence: 99%

A novel targeted RNA-Seq panel identifies a subset of adult patients with acute lymphoblastic leukemia with BCR-ABL1-like characteristics

et al. 2020

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BCR-ABL1-like B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains poorly characterized in adults. We sought to establish the frequency and outcome of adolescent and adult BCR-ABL1-like ALL using a novel RNA-Seq signature in a series of patients with BCP-ALL. To this end, we developed and tested an RNA-Seq custom panel of 42 genes related to a BCR-ABL1-like signature in a cohort of 100 patients with BCP-ALL and treated with risk-adapted ALL trials. Mutations related to BCR-ABL1-like ALL were studied in a panel of 33 genes by next-generation sequencing (NGS). Also, CRLF2 overexpression and IKZF1/CDKN2A/B deletions were analyzed. Twenty out of 79 patients (12-84 years) were classified as BCR-ABL1-like (25%) based on heatmap clustering, with significant overexpression of ENAM, IGJ, and CRLF2 (P ≤ 0.001). The BCR-ABL1-like subgroup accounted for 29% of 15-60-year-old patients, with the following molecular characteristics: CRLF2 overexpression (75% of cases), IKZF1 deletions (64%), CDKN2A/B deletions (57%), and JAK2 mutations (57%). Among patients with postinduction negative minimal residual disease, those with the BCR-ABL1like ALL signature had a higher rate of relapse and lower complete response duration than non-BCR-ABL1-like patients (P = 0.007). Thus, we have identified a new molecular signature of BCR-ABL1-like ALL that correlates with adverse prognosis in adult patients with ALL.

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Section: Discussionmentioning

confidence: 99%

A novel targeted RNA-Seq panel identifies a subset of adult patients with acute lymphoblastic leukemia with BCR-ABL1-like characteristics

et al. 2020

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“…For patients with Ph-like ALL and ABL-class gene fusions (ABL1, ABL2, CSF1R, LYN, PDGFRA, or PDGFRB), ABL1 inhibitors can be combined with chemotherapy. 129,130 For those patients with alterations that activate the JAK-STAT signaling pathway, such as rearrangements or a mutation of CRLF2 (IGH-CRLF2, P2RY8-CRLF2, or CRLF2 F232C), rearrangements of JAK2, EPOR, or TYK2, or mutations/deletions of IL7R, SH2B3, JAK1, JAK3, TYK2, or IL2RB, clinical trials of a JAK inhibitor, ruxolitinib, are ongoing.…”

Section: Molecularly Targeted Agentsmentioning

confidence: 99%

Pediatric acute lymphoblastic leukemia

Inaba¹,

Mullighan²

2020

haematol

364

267

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The last decade has witnessed great advances in our understanding of the genetic and biological basis of childhood acute lymphoblastic leukemia (ALL), the development of experimental models to probe mechanisms and evaluate new therapies, and the development of more efficacious treatment stratification. Genomic analyses have revolutionized our understanding of the molecular taxonomy of ALL, and these advances have led the push to implement genome and transcriptome characterization in the clinical management of ALL to facilitate more accurate risk-stratification and, in some cases, targeted therapy. Although mutation- or pathway-directed targeted therapy (e.g., using tyrosine kinase inhibitors to treat Philadelphia chromosome [Ph]-positive and Phlike B-cell-ALL) is currently available for only a minority of children with ALL, many of the newly identified molecular alterations have led to the exploration of approaches targeting deregulated cell pathways. The efficacy of cellular or humoral immunotherapy has been demonstrated with the success of chimeric antigen receptor T-cell therapy and the bispecific engager blinatumomab in treating advanced disease. This review describes key advances in our understanding of the biology of ALL and optimal approaches to risk-stratification and therapy, and it suggests key areas for basic and clinical research.

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“…Interestingly, RNA-seq allowed the identification of 12 fusion transcripts which were not suspected with usual analysis recommended in the diagnosis of haematological malignancies 25 . As more and more case reports describe successful opportunistic use of targeted therapies in patients with fusion transcripts [26][27][28] , the identification of unexpected fusion transcripts might offer interesting targets in relapsed/refractory patients. In the series reported here, the patient with an hypereosinophilic syndrome associated with the novel EEA1-PDGFRB fusion was treated with imatinib and achieved a durable haematological remission.…”

Section: Discussionmentioning

confidence: 99%

Performances of targeted RNA-sequencing for the analysis of fusion transcripts, gene mutation and expression in haematological malignancies

Hayette

Grange

Vallée

et al. 2020

Preprint

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RNA sequencing holds great promise to improve the diagnostic of haematological malignancies, because this technique enables to detect fusion transcripts, to look for somatic mutations in oncogenes, and to capture transcriptomic signatures nosological entities. However, the analytical performances of targeted RNA sequencing have not been extensively described in diagnostic samples. Using a targeted panel of 1385 cancer-related genes in a series of 100 diagnosis samples and 8 controls, we detected all the already known fusion transcripts, and also discovered unknown and/or unsuspected fusion transcripts in 12 samples. Regarding the analysis of transcriptomic profiles, we show that targeted RNA sequencing is performant to discriminate acute lymphoblastic leukemia entities driven by different oncogenic translocations. Additionally, we show that 86% of the mutations identified at the DNA level are also detectable at the mRNA level, except for nonsense mutations which are subjected to mRNA decay. We conclude that targeted RNA sequencing might improve the diagnosis of haematological malignancies. Standardization of the preanalytical steps and further refinements of the panel design and of the bioinformatical pipelines will be an important step towards its use in standard diagnostic procedures.

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Efficacy of tyrosine kinase inhibitors in Ph-like acute lymphoblastic leukemia harboring ABL-class rearrangements

Abstract: Tanasi et al present a prospective strategy for identifying patients with Philadelphia-like acute lymphoblastic leukemia, demonstrating the efficacy of early introduction of tyrosine kinase inhibitors in improving outcomes.

Cited by 92 publications

References 19 publications

A novel targeted RNA-Seq panel identifies a subset of adult patients with acute lymphoblastic leukemia with BCR-ABL1-like characteristics

A novel targeted RNA-Seq panel identifies a subset of adult patients with acute lymphoblastic leukemia with BCR-ABL1-like characteristics

Pediatric acute lymphoblastic leukemia

Performances of targeted RNA-sequencing for the analysis of fusion transcripts, gene mutation and expression in haematological malignancies

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