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JAK inhibitor therapy for myelofibrosis: critical assessment of value and limitations

Leukemia volume 25, pages 218–225 (2011)Cite this article

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Abstract

The discovery of JAK2V617F has rejuvenated interest in Janus kinase (JAK)-signal transducer and activator of transcription (STAT), both as an oncogenic pathway and a drug target in BCR-ABL1-negative myeloproliferative neoplasms (MPN). However, the complexity of these diseases in terms of both clonal structure and mutation repertoire makes it unlikely that JAK inhibitor therapy will replicate what has been achieved with imatinib in chronic myeloid leukemia. Consistent with this view, JAK inhibitor therapy in myelofibrosis has not yet produced complete or partial remissions. However, most patients treated with a JAK2 (TG101348) or JAK1/2 (INCB018424) inhibitor experienced substantial improvement in constitutional symptoms and reduction in spleen size; the mechanism of action for INCB018424 includes anti-JAK1-mediated downregulation of proinflammatory cytokines. These observations complicate the choice of primary end points in clinical trials that would be robust enough to support regulatory approval. TG101348 and INCB018424 are the vanguard of JAK inhibitor therapy in myelofibrosis, but newer JAK inhibitors might have a broader spectrum of activity; preliminary results with CYT387 suggest responses in both anemia and splenomegaly. Outstanding issues regarding these drugs include identification of the optimal dosing strategy, their role (if any) in the treatment of polycythemia vera or essential thrombocythemia, and the potential for combining them with other therapeutic agents.

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Acknowledgements

AP's effort for this project was partly supported by the Henry J. Predolin Foundation.

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Authors and Affiliations

  1. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    A Pardanani & A Tefferi

  2. Dipartimento di Area Critica Medico-Chirurgica, UF di Ematologia, Università degli Studi, Azienda Ospedaliera-Universitaria Careggi, Istituto Toscano Tumori, Firenze, Italy

    A M Vannucchi

  3. Hematology Division, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico S Matteo, University of Pavia, Pavia, Italy

    F Passamonti

  4. Hematology Department, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain

    F Cervantes

  5. Hematology Department of Ospedali Riuniti di Bergamo, Bergamo, Italy

    T Barbui

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AP has received a research grant from Cytopia Inc.

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Pardanani, A., Vannucchi, A., Passamonti, F. et al. JAK inhibitor therapy for myelofibrosis: critical assessment of value and limitations. Leukemia 25, 218–225 (2011). https://doi.org/10.1038/leu.2010.269

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