EBioMedicine (Oct 2024)

Phosphoproteomics predict response to midostaurin plus chemotherapy in independent cohorts of FLT3-mutated acute myeloid leukaemiaResearch in context

  • Weronika E. Borek,
  • Luis Nobre,
  • S. Federico Pedicona,
  • Amy E. Campbell,
  • Josie A. Christopher,
  • Nazrath Nawaz,
  • David N. Perkins,
  • Pedro Moreno-Cardoso,
  • Janet Kelsall,
  • Harriet R. Ferguson,
  • Bela Patel,
  • Paolo Gallipoli,
  • Andrea Arruda,
  • Alex J. Ambinder,
  • Andrew Thompson,
  • Andrew Williamson,
  • Gabriel Ghiaur,
  • Mark D. Minden,
  • John G. Gribben,
  • David J. Britton,
  • Pedro R. Cutillas,
  • Arran D. Dokal

Journal volume & issue
Vol. 108
p. 105316

Abstract

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Summary: Background: Acute myeloid leukaemia (AML) is a bone marrow malignancy with poor prognosis. One of several treatments for AML is midostaurin combined with intensive chemotherapy (MIC), currently approved for FLT3 mutation-positive (FLT3-MP) AML. However, many patients carrying FLT3 mutations are refractory or experience an early relapse following MIC treatment, and might benefit more from receiving a different treatment. Development of a stratification method that outperforms FLT3 mutational status in predicting MIC response would thus benefit a large number of patients. Methods: We employed mass spectrometry phosphoproteomics to analyse 71 diagnosis samples of 47 patients with FLT3-MP AML who subsequently received MIC. We then used machine learning to identify biomarkers of response to MIC, and validated the resulting predictive model in two independent validation cohorts (n = 20). Findings: We identified three distinct phosphoproteomic AML subtypes amongst long-term survivors. The subtypes showed similar duration of MIC response, but different modulation of AML-implicated pathways, and exhibited distinct, highly-predictive biomarkers of MIC response. Using these biomarkers, we built a phosphoproteomics-based predictive model of MIC response, which we called MPhos. When applied to two retrospective real-world patient test cohorts (n = 20), MPhos predicted MIC response with 83% sensitivity and 100% specificity (log-rank p < 7∗10−5, HR = 0.005 [95% CI: 0–0.31]). Interpretation: In validation, MPhos outperformed the currently-used FLT3-based stratification method. Our findings have the potential to transform clinical decision-making, and highlight the important role that phosphoproteomics is destined to play in precision oncology. Funding: This work was funded by Innovate UK grants (application numbers: 22217 and 10054602) and by Kinomica Ltd.

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