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Phase II study of nilotinib in patients with relapsed or refractory Philadelphia chromosome—positive acute lymphoblastic leukemia

Leukemia volume 27, pages 1411–1413 (2013)Cite this article

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The t(9;22)(q34;q11) translocation, known as the Philadelphia chromosome (Ph), is present in ∼15–30% of adult patients with acute lymphoblastic leuremia (ALL).1 This translocation results in the formation of breakpoint cluster region-Abelson (BCR-ABL) fusion gene and subsequent expression of the constitutively active 190-kDa BCR-ABL protein tyrosine kinase, which is distinct from the 210 kDa form of BCR-ABL observed in chronic myeloid leukemia (CML).1 Before the development of BCR-ABL tyrosine kinase inhibitors (TKIs), chemotherapy and allogeneic stem cell transplantation (alloSCT) were the standard treatments for patients with Ph+ ALL. Relapse rates were high and long-term survival rates were low with these approaches. Imatinib combined with chemotherapy is now considered frontline treatment for Ph+ ALL.1 For patients with Ph+ ALL who relapse following initial therapy, treatment with a second-generation BCR-ABL TKI may be an effective option.2 Nilotinib was designed to inhibit BCR-ABL activity more potently and with greater specificity than imatinib.3 In addition to being more potent than imatinib against the wild-type 190- and 210 kDa BCR-ABL proteins, nilotinib has activity against all known imatinib-resistant BCR-ABL mutants except T315I.4 In a phase I study of nilotinib in patients with imatinib-resistant Ph+ CML or ALL, 2 of 13 (15.4%) patients with Ph+ ALL responded to nilotinib.5 Here, we present the safety and efficacy of nilotinib in patients with refractory ALL treated on a Phase II study when all patients had either at least 24 months of treatment or were off study.

Patients aged ⩾18 years with Ph+ ALL were eligible if they had relapsed or were refractory to the standard therapy, had adequate performance status, and normal cardiac, renal, and hepatic function. Patients with minimal residual disease (MRD) were eligible only if there was an indication of evolving relapse on the basis of increasing BCR-ABL transcript levels.6 The study was conducted in accordance with the Declaration of Helsinki, and all patients provided written informed consent according to the institutional guidelines. Nilotinib monotherapy was administered at a dosage of 400 mg twice daily (800 mg/day).

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Acknowledgements

Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. The authors thank Erinn Goldman, PhD, Cornel Phillip, PhD and Karen Miller-Moslin, PhD, for medical editorial assistance with this paper.

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Authors and Affiliations

  1. Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt, Germany

    O G Ottmann

  2. Department of Medicine and Cancer Research Center, University of Chicago, Chicago, IL, USA

    R A Larson

  3. Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    H M Kantarjian

  4. Department of Medicine, Charité—Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany

    P D le Coutre

  5. Department of Hematology–Oncology, University of Bologna, Bologna, Italy

    M Baccarani

  6. Department of Medicine, Universitätsklinikum Jena, Jena, Germany

    A Hochhaus

  7. Department of Medicine, Seoul St Mary’s Hospital, Seoul, South Korea

    D W Kim

  8. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

    X Fan & S Novick

  9. HRB Clinical Research Facilities, National University of Ireland, Galway and Trinity College, Dublin, Ireland

    F J Giles

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  1. O G Ottmann
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Correspondence to F J Giles.

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Competing interests

OGO, RAL, HMK, PDLeC, MB, AH, DWK and FJG acted as a consultant for, and received research funding from Novartis, XF and SN are employees of Novartis Pharmaceuticals.

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Ottmann, O., Larson, R., Kantarjian, H. et al. Phase II study of nilotinib in patients with relapsed or refractory Philadelphia chromosome—positive acute lymphoblastic leukemia. Leukemia 27, 1411–1413 (2013). https://doi.org/10.1038/leu.2012.324

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