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Ref Type Journal Article
PMID (31905241)
Authors Nardi V, Ku N, Frigault MJ, Dubuc AM, Tsai HK, Amrein PC, Hobbs GS, Brunner AM, Narayan R, Burke ME, Foster J, Dal Cin P, Maus MV, Fathi AT, Hock H
Title Clinical response to larotrectinib in adult Philadelphia chromosome-like ALL with cryptic ETV6-NTRK3 rearrangement.
Journal Blood advances
Vol 4
Issue 1
Date 2020 Jan 14
URL
Abstract Text Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) is a subtype of Ph-negative ALL that molecularly resembles Ph-positive ALL. It shares the adverse prognosis of Ph-positive ALL, but lacks the BCR-ABL1 fusion oncogene. Instead, Ph-like ALL is associated with alternative mutations in signaling pathways. We describe a case of Ph-like ALL that harbored 2 genomic alterations, which activated signaling, an NRASGly12Asp mutation, and an ETV6-NTRK3 rearrangement. Initially, the NRAS mutation was detected at high frequency, whereas the gene fusion was only detectable with a targeted next-generation sequencing-based fusion assay, but not by fluorescence in situ hybridization analysis. The disease failed to respond to multiagent chemotherapy but investigational CD19-directed chimeric antigen receptor T-cell therapy resulted in a complete remission. However, the leukemia relapsed after 6 weeks. Intriguingly, the NRAS mutation was extinguished during the chimeric antigen receptor T-cell therapy and did not contribute to the relapse, which was instead associated with a rise in ETV6-NTRK3. The relapsed leukemia progressed with further chemo- and immunotherapy but was controlled for 6 weeks with substantial leukemic cytoreduction using the TRK inhibitor larotrectinib. Unfortunately, recovery of normal hematopoiesis was only marginal and the patient eventually succumbed to infections. These results demonstrate that larotrectinib has clinical activity in ETV6-NTRK3-associated Ph-like ALL.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ETV6 - NTRK3 B-lymphoblastic leukemia/lymphoma with BCR-ABL1 predicted - sensitive Larotrectinib Case Reports/Case Series Actionable In a clinical case study, Vitrakvi (larotrectinib) treatment resulted in significant suppression of leukemic cells and clinical benefit in a patient with relapsed Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia associated with an expansion of a subclone harboring ETV6-NTRK3 fusion (PMID: 31905241). 31905241
NRAS G12D B-lymphoblastic leukemia/lymphoma with BCR-ABL1 predicted - sensitive Anti-CD19 CAR T cells Case Reports/Case Series Actionable In a clinical case study, an investigational CD19-directed CAR T cells therapy resulted in rapid elimination of leukemic cells, including a subclone harboring NRAS G12D, in a patient with relapsed Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia, the NRAS G12D subclone remained undetectable at disease progression 6 weeks after treatment (PMID: 31905241). 31905241