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New Agents to Treat CML Post TKI Failure

Leukemia Insights - Spring 2011

Multiple strategies to overcome TKI failure are under investigation. Post imatinib failure, nilotinib and dasatinib are both FDA approved and continue to show sustained efficacy, with almost half of patients with imatinib failure being able to achieve a CCyR17-18. However, in patients in whom imatinib has failed because of the presence of the T315I mutation and in patients who have failed 2 TKIs, there are no currently available standard options. For these patients, new agents are being developed and early results seem promising.

Ponatinib (AP24534)

Ponatinib is one of the most promising agents for treatment of T315I mutation. Ponatinib is an orally available multi-TKI designed using a structure-based approach as a pan-BCR-ABL inhibitor19. Ponatinib potently inhibits the enzymatic activity of BCR-ABL-T315I, the native enzyme, and all other tested mutants. It also prevents the emergence of resistant mutants at concentrations of 40 nM. In a phase 1 clinical trial of AP24534 at doses from 2-60 mg in 60 patients with CML (44 with CP, 7 AP and 9 BP), complete hematologic response (CHR) was achieved or maintained in 95% of patients treated in CP; major hematologic responses were also achieved in 35% of patients treated in advanced stages of the disease19. More importantly, 25 of 38 (66%) evaluable patients treated in CP achieved a MCyR, including 20 (53%) CCyR. All 9 patients with T315I mutations in CP achieved MCyR  with 89% of them achieving CCyR. The most common drug-related adverse events were elevations of lipase and amylase at a dose of 60 mg daily. Grade 3 or 4 thrombocytopenia occurred in 9% of patients, with no grade 3-4 drug-related neutropenia. Currently, our institution is testing Ponatinib in a phase II, multinational study focusing on patients who have failed dasatinib and/or nilotinib therapies including a subset of patients with the T315I mutation.


While second generation BCR-ABL inhibitors dasatinib and nilotinib both inhibit many imatinib-resistant mutations, neither drug is effective against the T315I mutation. DCC-2036 is a new tyrosine kinase inhibitor that overcomes imatinib resistance by binding to a different domain on the BCR-ABL protein thus avoiding interaction with the mutated regions most commonly associated with resistance. DCC-2036 retained full potency against the T315I mutant kinase in preclinical studies and therefore warrants testing in patients who have failed prior TKI therapies or who have the T315I mutation and are diagnosed with either Ph+ CML or Ph+ ALL. DCC-2036 is also active against wild type BCR-ABL and other mutants commonly seen after imatinib failure20. Early results in our phase I clinical trial of DCC-2036 suggest evidence of clinical benefit.


Abnormalities of Janus Kinase (JAK) function have been associated with a number of hematological disorders. For example, chromosomal translocations resulting in TEL-JAK2 constructs lead to the constitutive activation of STAT5, IL-3-independent cellular proliferation, and leukemogenesis. The translocation t(9;12)(p24;p13) results in the fusion of the kinase catalytic region of JAK2 with the transcription factor TEL generating the constitutively active TEL-JAK2. Similarly, infection with oncogenic viruses such as type I human T-cell lymphotrophic virus and Abelson murine leukemia viruses results in enhanced kinase activity of JAKs, possibly accounting for their leukemogenic potential.

Abnormalities of the JAK-STAT pathways have been described in a variety of leukemias, and their inhibition can be a goal for leukemia therapy. Recent reports suggest that JAK2 activation is critical in maintaining the leukemic stem cell in CML.

INCB018424 phosphate is an inhibitor of the JAKs that is currently being developed for treatment of myeloproliferative disorders21. Our current study is examining the potential role of this drug in CML. Patients with CML who are resistant to at least 2 TKIs and have no standard stem cell transplant option are eligible as well as patients with relapse/refractory CML in blast crisis.

Hedgehog Inhibitors

Extensive evidence has been developed for a role for Hedgehog (HH) signaling, including the Smoothened transmembrane protein (Smo), in the maintenance and proliferation of CML stem cells. Using a variety of models, activation of Smo was demonstrated in Bcr-Abl+ cells, and their proliferation was shown to be more dependent on Smo than that of normal hematopoietic stem cells22. Conversely, inhibition of HH signaling reduced self-renewal in vitro, in vivo, and in murine retransplantation models.

Additionally, reduction of stem cells (defined as clonal progenitors developing during long-term culture) by Smo inhibition was demonstrated in CML patient samples22. Recently, the importance of Smo signalling in CML stem cell function was independently demonstrated23; constitutive Smo expression increased whereas conditional deletion reduced this population. In a recent preclinical study, the combination of nilotinib plus the Smo inhibitor LDE225 was reported to provide supra-additive inhibition of primitive CML stem cells24. Thus, the combination of TKI with HH inhibitor provides an important opportunity to potentially cure patients with CML. The sequential combination of TKI and HH inhibitor is planned at our institution for patients with minimal residual disease and/or suboptimal response to TKI. We are currently conducting a phase I study of the hedgehog inhibitor PF-04449913 for patients with CML (and other hematologic malignancies) who have failed prior therapy. The first portion of the study tests this agent by itself. In the second portion of the study, we will combine this agent with a tyrosine kinase inhibitor.

© 2014 The University of Texas MD Anderson Cancer Center