News - NPM1-ALK fusion

2ms

ALK-positive large B-cell lymphoma: a clinicopathological and molecular characteristics analysis of seven cases. (PubMed, Pathology)

We present seven cases of ALK+ LBCL, discussing the correlation between fusion genes and ALK protein expression, and enhancing our understanding of the genetic attributes of this tumour. This study also shows the loss of 5hmC in nearly all seven ALK+ LBCL cases, independently of TET2 mutations.

2 months ago

Journal • IO biomarker

ALK (Anaplastic lymphoma kinase) • NPM1 (Nucleophosmin 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • KMT2D (Lysine Methyltransferase 2D) • LRP1B (LDL Receptor Related Protein 1B) • CLTC (Clathrin Heavy Chain) • CHD2 (Chromodomain Helicase DNA Binding Protein 2) • PABPC1 (Poly(A) Binding Protein Cytoplasmic 1) • SEC31A (SEC31 Homolog A COPII Coat Complex Component)

ALK positive • ALK rearrangement • ALK fusion • TET2 mutation • NPM1-ALK fusion

4ms

Racial Differences in ALK Gene Alterations Detected by Tissue and Liquid Biopsy Across Patients with Lung Cancer. (IASLC-WCLC 2024)

Some atypical fusion partners were observed in white and BAA that were not observed in other races. These data emphasize the importance of testing lung cancer patients with assays that allow for unbiased fusion detection and identification of novel fusion partners across racially diverse populations to better understand racial and ethnic differences in ALK-rearranged lung cancers.

4 months ago

Clinical • Liquid biopsy • Biopsy

ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • EML4 (EMAP Like 4) • NPM1 (Nucleophosmin 1) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • PRKAR1A (Protein Kinase CAMP-Dependent Type I Regulatory Subunit Alpha)

TP53 mutation • ALK rearrangement • EML4-ALK fusion • ALK fusion • NPM1-ALK fusion • ALK amplification

Tempus xT Assay

6ms

Spitz melanocytic neoplasms with MLPH::ALK fusions: Report of two cases with previously unreported features and literature review. (PubMed, J Cutan Pathol)

In this report, we present two additional cases, including a previously unreported instance of Spitz melanoma, contributing to the expanding knowledge on ALK-fused Spitz melanocytic neoplasms. In addition, we provide a comprehensive review of the clinical, histopathologic, and molecular features observed in documented cases with this novel fusion.

6 months ago

Clinical • Review • Journal

ALK (Anaplastic lymphoma kinase) • NPM1 (Nucleophosmin 1) • TPM3 (Tropomyosin 3) • DCTN1 (Dynactin Subunit 1) • KANK1 (KN Motif And Ankyrin Repeat Domains 1) • CLIP1 (CAP-Gly Domain Containing Linker Protein 1) • EHBP1 (EH Domain Binding Protein 1) • MLPH (Melanophilin) • RAB27A (RAB27A, Member RAS Oncogene Family)

ALK fusion • NPM1-ALK fusion

10ms

Variant ALK-fusion positive anaplastic large cell lymphoma (ALCL): A population-based paediatric study of the NHL-BFM study group. (PubMed, Br J Haematol)

Five of eight patients with ATIC::ALK-positive ALCL relapsed, none of nine with TPM3::ALK. Variant ALK-partners are rare and potentially associated with different prognoses.

10 months ago

Journal

ALK (Anaplastic lymphoma kinase) • NPM1 (Nucleophosmin 1) • TPM3 (Tropomyosin 3)

ALK positive • ALK fusion • NPM1-ALK fusion

10ms

Molecular Screening in ALK-Positive Anaplastic Large Cell Lymphoma: ALK Analysis, NGS Fusion Gene Detection, and T-cell Receptor Immunoprofiling. (PubMed, Mod Pathol)

NGS reveals new ALK translocation partners. Both the malignant and reactive TCR repertoires in ALK+ ALCL patients are unique and do not consistently occur among different patients.

10 months ago

Journal • Next-generation sequencing • IO biomarker

ALK (Anaplastic lymphoma kinase) • NPM1 (Nucleophosmin 1) • TPM3 (Tropomyosin 3) • SQSTM1 (Sequestosome 1) • CLTC (Clathrin Heavy Chain) • CAPRIN1 (Cell Cycle Associated Protein 1) • SATB1 (SATB Homeobox 1) • TPM4 (Tropomyosin 4) • TRB (T Cell Receptor Beta Locus)

ALK positive • ALK rearrangement • ALK fusion • ALK translocation • NPM1-ALK fusion

1year

Circulating Tumor DNA (ctDNA) for Plasma Genotyping and Disease Monitoring in ALK-Positive Anaplastic Lymphoma (ALK+ALCL): A Proof of Concept Study (ASH 2023)

Interestingly, CGP allowed the identification of the ALK:c.3520T>C; p.(Phe1174Leu) mutation in a plasma sample collected during disease progression while the patient was on long lasting crizotinib therapy...Additionally, our unique patient-specific ddPCR approach was proven to be a cost-effective method for MRD monitoring. Altogether, these findings serve as a proof-of-concept for the development of ctDNA techniques in the clinical management of ALK+ALCL.

1 year ago

Tumor mutational burden • Circulating tumor DNA

ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • LRP1B (LDL Receptor Related Protein 1B) • MDM4 (The mouse double minute 4) • EP300 (E1A binding protein p300) • TRAF1 (TNF Receptor Associated Factor 1) • ANKRD26 (Ankyrin Repeat Domain Containing 26) • EEF1G (Eukaryotic Translation Elongation Factor 1 Gamma)

TP53 mutation • ALK positive • ALK rearrangement • ALK fusion • NPM1-ALK fusion

Xalkori (crizotinib)

1year

Comprehensive Mutational Profiling of Pediatric Acute Myeloid Leukemias Diagnosed at a Single Center (2022 WHO-HAEM5 Classification) (AMP 2023)

Though <40% are cured after relapse in pAML, chemotherapy intensification is often not feasible, as toxicity causes ~10% mortality rate. Besides evaluating measurable residual disease, detecting unique driving events and concurrent molecular alterations impacts pAML management. Integration of genomic findings into clinical care for highrisk/refractory pAML patients, shows that ~14% can get targeted therapies.

1 year ago

Clinical

KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • WT1 (WT1 Transcription Factor) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1) • NUP98 (Nucleoporin 98 And 96 Precursor 2) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • MECOM (MDS1 And EVI1 Complex Locus) • NSD1 (Nuclear Receptor Binding SET Domain Protein 1) • NUP214 (Nucleoporin 214) • GATA2 (GATA Binding Protein 2) • GATA1 (GATA Binding Protein 1) • MLLT3 (MLLT3 Super Elongation Complex Subunit) • MSI2 (Musashi RNA Binding Protein 2) • HNRNPH1 (Heterogeneous Nuclear Ribonucleoprotein H1) • MLLT10 (MLLT10 Histone Lysine Methyltransferase DOT1L Cofactor) • PRDM16 (PR/SET Domain 16) • MRTFA (Myocardin Related Transcription Factor A) • RBM15 (RNA Binding Motif Protein 15)

NPM1 mutation • ALK fusion • ALK mutation • KMT2A rearrangement • MLL rearrangement • CEBPA mutation • NPM1-ALK fusion

over1year

ALK-POSITIVE ANAPLASTIC LARGE CELL LYMPHOMA WITH VARIANT ALK-FUSION PARTNER: A POPULATION-BASED ANALYSES OF THE NHL-BFM STUDY GROUP (ICML 2023)

In our population-based cohort of ALK-positive ALCL-patients, less than 10% carried variant ALK-fusion partners, 60% of which were TPM3 or ATIC. In patients with exclusive cytoplasmic ALK staining patterns, NPM1::ALK positivity should be excluded by molecular analysis. The tendency of a different relapse risk between ATIC::ALK and TPM3::ALK -positive ALCL-patients suggests that the fusion partner might confer tumor aggressiveness or drug resistance.

over 1 year ago

Clinical

ALK (Anaplastic lymphoma kinase) • NPM1 (Nucleophosmin 1) • TPM3 (Tropomyosin 3)

ALK positive • ALK rearrangement • ALK fusion • ALK translocation • NPM1-ALK fusion

over1year

IMPORTANCE OF ALK GENE SEQUENCING IN PEDIATRIC ANAPLASTIC LARGE CELL LYMPHOMA (ASPHO 2023)

He achieved complete remission after 2 cycles with multi-agent chemotherapy (dexamethasone, ifosfamide, methotrexate, cytarabine, etoposide, cyclophosphamide, doxorubicin and brentuximab)...He had progressive disease after 3 weeks and was changed to combination chemotherapy with brentuximab and nivolumab with the addition of alectinib, a second generation ALK inhibitor. He again had progressive disease within 3 weeks and received therapy with ifosfamide, carboplatin and etoposide with a mixed response...Based on preclinical studies and limited clinical studies demonstrating that ALKI1171T mutations are resistant to crizotinib and alectinib but may maintain sensitivity to ceritinib, the patient started ceritinib in combination with brentuximab... Testing for the presence of ALK rearrangements via IHC is standard in pediatric ALCL but cannot solely predict sensitivity to specific inhibitors. Consideration should be made for upfront ALK gene sequencing as this may drive therapeutic decisions regarding which inhibitor is most likely to result in a clinical response.

over 1 year ago

Clinical • PD(L)-1 Biomarker

ALK (Anaplastic lymphoma kinase) • NPM1 (Nucleophosmin 1)

ALK positive • ALK rearrangement • ALK fusion • ALK I1171T • ALK negative • NPM1-ALK fusion • ALK I1171 • NPM1-ALK I1171T

Opdivo (nivolumab) • Xalkori (crizotinib) • carboplatin • Alecensa (alectinib) • cytarabine • doxorubicin hydrochloride • Zykadia (ceritinib) • cyclophosphamide • ifosfamide • etoposide IV • methotrexate • Adcetris (brentuximab vedotin) • dexamethasone

over1year

Treatment-free remission after discontinuation of ALK tyrosine kinase inhibitors (TKIs) in patients with ALK-positive anaplastic large cell lymphoma (ALCL) (AACR 2023)

Out data demonstrated that treatment-free remission was durable for more than two years in ALK-positive ALCL patients following the cessation of ALK TKIs. MRD-guideddiscontinuation decision may be considered for ALK-positive ALCL patients treated with ALK inhibitors who had undetectable MRD.Table 1. Summary of patient characteristics and outcomes of ALK TKI discontinuationNo.SexAge at diagnosisAnn Arbor stageALK TKILines of prior therapyTreatment duration of ALK TKI (months)Reason for cessationDuration of ALK TKI cessation (months)Best response to ALK TKITime of MRD assessment after TKI cessationMRD after TKI cessation1M22IIBCrizotinib393.9Fertility27.8CR5.6Negative2F20IVBCrizotinib190.9Fertility25.9CR0.0Negative3M23IVCeritinib142.7Adverse event61.9CR61.9Negative4F58IVCrizotinib31.7Cost86.6CR72.1Negative5F64IVBCrizotinib113.6Cost31.0CR14.4Negative6M75IVCrizotinib211.7Cost80.2CR62.0Negative

over 1 year ago

Clinical

ALK (Anaplastic lymphoma kinase) • NPM1 (Nucleophosmin 1) • E2F2 (E2F Transcription Factor 2)

ALK positive • ALK fusion • NPM1-ALK fusion • NPM-ALK fusion

Xalkori (crizotinib) • Zykadia (ceritinib)

over1year

Long-read sequencing of pediatric cancer genomes identifies multiple clinically relevant variants (AACR 2023)

The difference in 5mC modification probability between the two alleles of the known imprinted genes was 81.5. Our results demonstrate that lrSeq can detect multiple CRGAs across several different types of genetic variants and pediatric cancers, bringing us closer to the promise of an all-in-one genetic test for cancer characterization.

over 1 year ago

Clinical

ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • NPM1 (Nucleophosmin 1) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • NOTCH1 (Notch 1) • KMT2A (Lysine Methyltransferase 2A) • CEBPA (CCAAT Enhancer Binding Protein Alpha)

TP53 mutation • NTRK2 fusion • ALK fusion • CDKN2A deletion • KMT2A rearrangement • MLL rearrangement • NPM1-ALK fusion

2years

The ALK-OBS Trial: Results of a Multicenter Prospective Study Assessing the Prognostic Value of New Markers in Adults with ALK-Positive ALCL Treated By CHOEP: A Lysa Study (ASH 2022)

In all, 36 pts (92%) received the planned 6 cycles of treatment, and 34 pts (87%) received all cycles of etoposide...MRD1 identified a high-risk group, for which specific approaches may be needed. CHOEP was overall well tolerated and induced high rates of PFS and OS.

2 years ago

Clinical

ALK (Anaplastic lymphoma kinase) • NPM1 (Nucleophosmin 1) • TNFRSF8 (TNF Receptor Superfamily Member 8)

ALK positive • ALK fusion • TNFRSF8 expression • ALK translocation • NPM1-ALK fusion

etoposide IV

over2years

Primary Central Nervous System Anaplastic Large Cell Lymphoma, ALK Positive. (PubMed, Am J Clin Pathol)

We present the largest case series to date of a rare primary CNS lymphoma with additional diagnostic and clinical information.

over 2 years ago

Journal

ALK (Anaplastic lymphoma kinase) • NPM1 (Nucleophosmin 1)

ALK positive • ALK rearrangement • ALK fusion • NPM1-ALK fusion

over2years

Preclinical activity of NVL-655 in ALK-driven cancer models beyond non-small cell lung cancer (AACR 2022)

TRKB inhibition in the central nervous system has been implicated in adverse events observed with FDA-approved ALK inhibitor lorlatinib. In cell-based assays, NVL-655 was observed to inhibit proliferation of a human anaplastic large cell lymphoma cell line harboring NPM1-ALK fusion and human neuroblastoma cell lines harboring ALK activating mutations or amplification. In conclusion, the preclinical profile of NVL-655 supports its potential to address a medical need for patients with ALK-driven disease in both NSCLC and other cancers such as anaplastic large cell lymphoma and neuroblastoma.

over 2 years ago

Preclinical

ALK (Anaplastic lymphoma kinase) • NPM1 (Nucleophosmin 1)

ALK fusion • ALK mutation • NPM1-ALK fusion • ALK I1171

Lorbrena (lorlatinib) • NVL-655

over3years

Precision therapy with anaplastic lymphoma kinase inhibitor ceritinib in ALK-rearranged anaplastic large cell lymphoma. (PubMed, ESMO Open)

This ceritinib translational study in NPM1-ALK+ ALCL provides a strong rationale for a prospective study of ceritinib in ALK+ T-cell lymphomas and other ALK+ hematologic malignancies.

over 3 years ago

Journal

ALK (Anaplastic lymphoma kinase) • NPM1 (Nucleophosmin 1) • STAT3 (Signal Transducer And Activator Of Transcription 3)

ALK positive • ALK rearrangement • ALK fusion • ALK translocation • NPM1-ALK fusion

Zykadia (ceritinib)

almost4years

Preclinical evaluation of gilteritinib on NPM1-ALK driven Anaplastic Large Cell Lymphoma Cells. (PubMed, Mol Cancer Res)

In summary, our preclinical studies explored the novel therapeutic potential of gilteritinib in the treatment of ALCL cells expressing NPM1-ALK and potentially in other ALK or ALK-fusion driven hematologic or solid malignancies. Implications: Our preclinical results explore the use of gilteritinib for the treatment of NPM1-ALK driven anaplastic large cell lymphoma cells and pave a path for developing future clinical trials.

almost 4 years ago

Preclinical • Journal • PARP Biomarker

ALK (Anaplastic lymphoma kinase) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • NPM1 (Nucleophosmin 1) • TNFRSF8 (TNF Receptor Superfamily Member 8) • MCL1 (Myeloid cell leukemia 1) • BIRC5 (Baculoviral IAP repeat containing 5) • CASP3 (Caspase 3) • CASP9 (Caspase 9)

ALK positive • ALK fusion • TNFRSF8 expression • ALK translocation • MCL1 expression • NPM1-ALK fusion • BIRC5 expression

Xospata (gilteritinib)

almost4years

Minimal residual disease monitoring using a 3'ALK universal probe assay in ALK-positive anaplastic large cell lymphoma: ddPCR, an attractive alternative method to real-time quantitative PCR. (PubMed, J Mol Diagn)

A major benefit of digital droplet PCR is a reduced experimental set-up compared with quantitative PCR, without generation of standard curves, leading to a reliable protocol for multilaboratory validation, in multicenter clinical trials essential for this rare pathology. Our ALK universal method could be used for the screening of ALK fusion transcripts in liquid biopsy of other ALK positive tumors, including non-small cell lung carcinomas.

almost 4 years ago

Journal

ALK (Anaplastic lymphoma kinase) • EML4 (EMAP Like 4) • NPM1 (Nucleophosmin 1) • TPM3 (Tropomyosin 3)

ALK positive • ALK fusion • ALK translocation • NPM1-ALK fusion

4years

Clinical, Histologic, and Molecular Characteristics of Anaplastic Lymphoma Kinase-positive Primary Cutaneous Anaplastic Large Cell Lymphoma. (PubMed, Am J Surg Pathol)

Immunohistochemically, 3 cases (50%) showed combined nuclear and cytoplasmic ALK expression with underlying NPM1-ALK fusions, while 3 cases (50%) showed solely cytoplasmic ALK expression with variant ALK fusion partners (TRAF1, ATIC, TPM3). ALK-positive C-ALCL is extremely uncommon, has a comparable favorable prognosis to ALK-negative C-ALCL, and should be treated in the same way with radiotherapy as first-line treatment.

4 years ago

Clinical • Journal

ALK (Anaplastic lymphoma kinase) • NPM1 (Nucleophosmin 1) • TPM3 (Tropomyosin 3)

ALK positive • ALK fusion • ALK translocation • ALK negative • NPM1-ALK fusion

over4years

[VIRTUAL] Pathology and Pathogenesis of T-Cell Lymphoma (SOHO 2020)

Recognizing this unique process is important as mimics NK/T cell lymphoma and can result in erroneous diagnosis, leading to aggressive chemotherapy. The etiology of this process is unknown.

over 4 years ago

PD(L)-1 Biomarker • IO biomarker

PD-L1 (Programmed death ligand 1) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • CD20 (Membrane Spanning 4-Domains A1) • DNMT3A (DNA methyltransferase 1) • CD8 (cluster of differentiation 8) • TNFRSF8 (TNF Receptor Superfamily Member 8) • TET2 (Tet Methylcytosine Dioxygenase 2) • JAK3 (Janus Kinase 3) • NCAM1 (Neural cell adhesion molecule 1) • ALK1 (Activin A Receptor Like Type 1) • STAT5B (Signal Transducer And Activator Of Transcription 5B) • SYK (Spleen tyrosine kinase) • IRF4 (Interferon regulatory factor 4) • TBX21 (T-Box Transcription Factor 21) • TYK2 (Tyrosine Kinase 2) • SH2B3 (SH2B Adaptor Protein 3) • TP63 (Tumor protein 63) • GATA3 (GATA binding protein 3) • TCL1A (TCL1 Family AKT Coactivator A)

PD-L1 expression • TP53 mutation • ALK positive • IDH2 mutation • DNMT3A mutation • ALK fusion • TET2 mutation • TNFRSF8 positive • TNFRSF8 expression • ALK translocation • ALK negative • NPM1-ALK fusion • STAT3 mutation • TP53 mutation + ALK positive • JAK3 mutation • IDH2 R172