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Limited clinical activity of nilotinib and sorafenib in FIP1L1-PDGFRA positive chronic eosinophilic leukemia with imatinib-resistant T674I mutation

Leukemia volume 26, pages 162–164 (2012)Cite this article

Imatinib induces rapid and durable complete hematologic and molecular remissions in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. Primary resistance has not yet been reported and secondary resistance seems to be rather rare. In a German-wide registry, we currently oversee the clinical course of 57 patients who have been treated with imatinib for a median of 36 months (range 1–82) at doses ranging between 100 mg every other day and 400 mg/day. Recently, we identified the first case of secondary resistance in a 50-year-old male patient, 7 months after imatinib 400 mg/day was started. The patient presented in hematologic relapse with leukocytosis (37 × 109/l, 71% eosinophils), anemia (Hb 9.8 g/dl), thrombocytopenia (37 × 109/l) and splenomegaly. The karyotype was normal, but reverse transcription-PCR with primers covering the juxtamembrane and tyrosine kinase domains of platelet-derived growth factor receptor A (PDGFRA) (exons 11–18) and subsequent sequence analysis identified a C>T change that predicts a T674I mutation in the ATP-binding region of PDGFRA (PDGFRAT674I).

Including the case presented here, seven cases of secondary resistance to imatinib have now been reported in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia.1, 2, 3, 4, 5, 6, 7 We analyzed the clinical and molecular characteristics from four patients with a T674I mutation,1, 3, 5, 7 one patient with a D842V mutation6 and one patient with a T674I mutation, followed by a D842V mutation (Table 1).4 All patients were male, the median age at diagnosis was 39 years (range 25–67). Imatinib had been administered at doses of 100 mg every other day (1/5), 100 mg/day (2/5) or 400 mg/day (2/5); in two cases, the dose of imatinib had been not reported. The median time to imatinib resistance was 5 months (range 2–9). Marrow blasts were increased in five of seven patients, suggesting accelerated/blast phase. Four patients died, three of them within 5 months after diagnosis of secondary resistance to imatinib (time interval was not reported in the fourth patient).3, 4, 6, 7

Table 1 Clinical and molecular characteristics of FIP1L1-PDGFRA positive CEL patients with secondary resistance to imatinib due to PDGFRA point mutations
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Acknowledgements

This work was supported by the ‘Deutsche José Carreras Leukämie-Stiftung e.V.’ (AR R09/29f), Germany.

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Authors and Affiliations

  1. III. Medizinische Klinik, Universitätsmedizin Mannheim, Mannheim, Germany

    G Metzgeroth, P Erben, M Teichmann, W-K Hofmann & A Reiter

  2. Medizinische Klinik II, Klinikum der Goethe-Universität, Frankfurt am Main, Germany

    H Martin & S Mousset

  3. Pathologisches Institut, Ludwig-Maximilians-Universität München, München, Germany

    C Walz

  4. Hämatologische Gemeinschaftspraxis, Frankfurt, Germany

    T Klippstein

  5. Abteilung Hämatologie/Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany

    A Hochhaus

  6. Wessex Regional Genetics Laboratory, Salisbury, UK

    N C P Cross

  7. Human Genetics Division, University of Southampton School of Medicine, Southampton, UK

    N C P Cross

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Metzgeroth, G., Erben, P., Martin, H. et al. Limited clinical activity of nilotinib and sorafenib in FIP1L1-PDGFRA positive chronic eosinophilic leukemia with imatinib-resistant T674I mutation. Leukemia 26, 162–164 (2012). https://doi.org/10.1038/leu.2011.181

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