From the Division of Hematology & Oncology, Oregon Health & Science University Cancer Institute, Portland, OR
Author's disclosure of potential conflicts of interest is found at the end of this article.
Supported in part by NHLBI grant HL082978–01 and the Leukemia & Lymphoma Society.
Address reprint requests to Michael W.N. Deininger, MD, PhD, Hematology and Medical Oncology, L592, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239; e-mail: deininge{at}ohsu.edu
Overview: Imatinib has revolutionized the treatment for chronic myeloid leukemia, providing a paradigm for other types of cancer. However, much remains to be done. Some of the issues may represent general problems associated with molecularly targeted cancer therapy. Significant progress has been made with respect to managing imatinib resistance, for which second-line ABL kinase inhibitors provide an excellent option. To exploit the potential of these new drugs, early recognition of failure is pivotal because advanced disease is still difficult to manage, particularly blast crisis, when the "biologic age" of the disease is advanced (Fig. 4). There is a glimmer of hope that patients with BCR-ABL addicted disease may benefit from inhibitor combinations that include an anti-T315I active agent; however, rare exceptions aside, the only curative option for advanced disease is allogeneic stem cell transplant. Fortunately, for the majority of patients, we are dealing with minimal residual disease. Although this is not life-threatening, the need for continued, life-long therapy is unpleasant for patients with side effects. At this point, we only have a limited understanding as to why imatinib fails to eradicate the chronic myeloid leukmia stem cells. However, there is the possibility or even the suspicion that these cells may not be BCR–ABL-dependent. If so, they would be innately resistant to imatinib and its successors, and annihilating the leukemic clone would require an approach that is mechanistically different from targeting BCR-ABL kinase activity. Chronic myeloid leukemia remains a challenging disease.
View larger version (33K):
[in a new window]
[PowerPoint Slide for Teaching]
Fig. 4. A virtual model of CML. The disease age is a composite measure of disease duration and the disease's ability to acquire mutations in addition to BCR-ABL, loosely correlated with clinical disease stages of chronic phase (CP), accelerated phase (AP), and blast crisis (BC). At a young age, imatinib is capable of inducing durable response, although it does not eradicate the disease. When the disease ages, kinase domain mutations are acquired that must be controlled by a second-line ABL inhibitor. If T315I is present, then lasting responses require combinations with an anti-T315I inhibitor. Ultimately, BCR–ABL-independent clones become more prevalent, which renders the disease resistant to all BCR-ABL inhibitors. Reproduced with permission from O'Hare et al.19
