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| Ref Type | Journal Article | ||||||||||||
| PMID | (33563661) | ||||||||||||
| Authors | Pikman Y, Tasian SK, Sulis ML, Stevenson K, Blonquist TM, Apsel Winger B, Cooper TM, Pauly M, Maloney KW, Burke MJ, Brown PA, Gossai N, McNeer JL, Shukla NN, Cole PD, Kahn JM, Chen J, Barth MJ, Magee JA, Gennarini L, Adhav AA, Clinton CM, Ocasio-Martinez N, Gotti G, Li Y, Lin S, Imamovic A, Tognon CE, Patel T, Faust HL, Contreras CF, Cremer A, Cortopassi WA, Garrido Ruiz D, Jacobson MP, Dharia NV, Su A, Robichaud AL, Saur Conway A, Tarlock K, Stieglitz E, Place AE, Puissant A, Hunger SP, Kim AS, Lindeman NI, Gore L, Janeway KA, Silverman LB, Tyner JW, Harris MH, Loh ML, Stegmaier K | ||||||||||||
| Title | Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory, or High-Risk Leukemias: A Report from the LEAP Consortium. | ||||||||||||
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| Abstract Text | Despite a remarkable increase in the genomic profiling of cancer, integration of genomic discoveries into clinical care has lagged behind. We report the feasibility of rapid identification of targetable mutations in 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on a prospective clinical trial conducted by the LEAP Consortium. Eighteen percent of patients had a high confidence Tier 1 or 2 recommendation. We describe clinical responses in the 14% of patients with relapsed/refractory leukemia who received the matched targeted therapy. Further, in order to inform future targeted therapy for patients, we validated variants of uncertain significance, performed ex vivo drug-sensitivity testing in patient leukemia samples, and identified new combinations of targeted therapies in cell lines and patient-derived xenograft models. These data and our collaborative approach should inform the design of future precision medicine trials. SIGNIFICANCE: Patients with relapsed/refractory leukemias face limited treatment options. Systematic integration of precision medicine efforts can inform therapy. We report the feasibility of identifying targetable mutations in children with leukemia and describe correlative biology studies validating therapeutic hypotheses and novel mutations. See related commentary by Bornhauser and Bourquin, p. 1322 . This article is highlighted in the In This Issue feature, p. 1307 . | ||||||||||||
| Molecular Profile | Treatment Approach |
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
|---|---|---|---|---|---|
| FLT3 | A680V | missense | gain of function | FLT3 A680V lies within the N-terminal kinase domain of the Flt3 protein (PMID: 15976757). A680V results in autophosphorylation of Flt3 (ASH, 2015, abstract no. 87) and leads to IL-3 independent growth in culture (PMID: 33563661). |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| FLT3 I836del | acute myeloid leukemia | predicted - sensitive | Azacitidine + Sorafenib + Venetoclax | Case Reports/Case Series | Actionable | In a clinical study, combination treatment with Vidaza (azacitidine), Nexavar (sorafenib) and Venclexta (venetoclax) resulted in continued remission from Cytosar-U (cytarabine), Novantrone (mitoxantrone), and Nexavar (sorafenib) treatment in an acute myeloid leukemia patient harboring FLT3 I836del (PMID: 33563661; NCT02670525). | 33563661 |
| NRAS Q61R | acute biphenotypic leukemia | no benefit | Trametinib | Case Reports/Case Series | Actionable | In a clinical study, Mekinist (trametinib) treatment was well tolerated and led to an initial decrease of peripheral blasts in a pediatric patient with mixed phenotype acute leukemia harboring NRAS Q61R who had previously undergone a stem cell transplant, but patient experienced progressive disease after 2 months, and died soon after (PMID: 33563661; NCT02670525). | 33563661 |
| FLT3 F594_W603dup | acute myeloid leukemia | predicted - sensitive | Gilteritinib | Case Reports/Case Series | Actionable | In a clinical study, Xospata (gilteritinib) treatment led to decreased disease burden (<10%) in an acute myeloid leukemia patient harboring FLT3 F594_W603dup (PMID: 33563661; NCT02670525). | 33563661 |
| FLT3 I836del | acute myeloid leukemia | predicted - sensitive | Cytarabine + Mitoxantrone + Sorafenib | Case Reports/Case Series | Actionable | In a clinical study, combination treatment with Cytosar-U (cytarabine), Novantrone (mitoxantrone), and Nexavar (sorafenib) treatment in an acute myeloid leukemia patient harboring FLT3 I836del led to remission with negative minimal residual disease (PMID: 33563661; NCT02670525). | 33563661 |
| NRAS G13D | B-cell acute lymphoblastic leukemia | no benefit | Everolimus | Case Reports/Case Series | Actionable | In a clinical study, a pediatric patient with relapsed B-cell acute lymphoblastic leukemia harboring NRAS G13D, who also harbored SETD2 L1778fs* and an IKZF1 deletion, was treated with Afinitor (everolimus) in combination with chemotherapy and experienced persistent disease, and the patient died 6 months later (PMID: 33563661; NCT02670525). | 33563661 |
| FLT3 A680V | hematologic cancer | sensitive | Gilteritinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing FLT3 A680V were sensitive to treatment with Xospata (gilteritinib) in culture, demonstrating decreased cell viability and decreased Flt3 phosphorylation (PMID: 33563661). | 33563661 |