Affiliation of authors: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
Correspondence to: Richard J. Jones, MD, Bunting-Blaustein Cancer Research Building, 1650 Orleans St., Rm. 207, Baltimore, MD 21231 (e-mail: rjjones{at}jhmi.edu)
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INTRODUCTION |
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IMATINIB IN CHRONIC MYELOID LEUKEMIA: A MODEL OF TARGETED THERAPY |
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Imatinib was developed as part of a program to identify drugs that block the unregulated activities of the protein kinases expressed in many cancers. Imatinib is a potent and relatively selective inhibitor of the Abl tyrosine kinases, including Bcr-Abl (3). Moreover, imatinib has demonstrated striking selective activity against CML cell lines and clinical progenitors in vitro, inhibiting more than 90% of CML progenitor cell growth at concentrations (110 µM) that have little activity against normal hematopoietic progenitors. The clinical activity of imatinib has mirrored its in vitro activity. Many CML patients who are interferon resistant enter complete cytogenetic remissions with imatinib (4), and even those with accelerating disease can achieve excellent responses after imatinib therapy (5). Results from a large, multicenter, randomized study comparing imatinib to interferon plus cytarabine indicate that the most dramatic responses to imatinib are in newly diagnosed CML patients (6). With a median follow-up of 19 months, 76% of patients who received imatinib had a complete cytogenetic response, compared with 14% of patients who received interferon plus cytarabine. Imatinib was also tolerated better than interferon plus cytarabine; however, there was no survival difference between the two study arms (6).
In May 2001, imatinib was initially approved by the Food and Drug Administration as a second-line therapy for CML; the interim results of the multicenter randomized trial (6) led to its recent approval as a first-line therapy for CML. In addition, the new National Comprehensive Cancer Network guidelines for the treatment of CML no longer recommend interferon as the standard of care; only imatinib is recommended as a first-line therapy for patients not undergoing allogeneic transplantation (7). This recommendation was made despite the short follow-up with imatinib relative to the natural history of CML (6) and the established track record of interferon (8). Not only has interferon been proven to prolong the survival of CML patients, but the 10%20% of patients who achieve a complete cytogenetic remission with interferon have a median survival greater than 10 years, and some of these patients may actually be cured (8). The prevailing wisdom is that the high early-response rates with imatinib will ultimately translate into improved survivals. However, a recent report (9) has suggested that most of the patients who achieved the best responses with imatinib (polymerase chain reaction negativity for the BCR-ABL fusion transcript) may now be showing evidence of disease progression; although the long-term clinical significance of this finding is currently unclear, it raises some concerns about the durability of responses to imatinib.
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RESISTANCE TO IMATINIB |
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CANCER STEM CELLS AND TARGETED THERAPY |
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CML was the first recognized, and remains the best studied, example of a stem cell malignancy. However, cancer stem cells that are biologically distinct from the differentiated cells that characterize the disease have been demonstrated in acute myeloid leukemia (AML) (19), acute lymphocytic leukemia (ALL) (20), myelodysplastic syndrome (21), breast cancer (22), and multiple myeloma (23). It is possible that most malignancies arise from a rare population of cancer stem cells (24), which may have profound implications for the development of targeted anticancer therapies in general. For example, gemtuzumab ozogamicin (Mylotarg), an anti-CD33 monoclonal antibody conjugated to the cytotoxic agent calicheamicin, has been approved for patients with relapsed AML and is currently being studied in newly diagnosed AML patients. Although most AML cells express the myeloid antigen CD33, the leukemic stem cells in most cases of AML phenotypically resemble immature hematopoietic stem cells (19) and do not express antigens that are specific for more differentiated blood cells, including CD33 (25,26). Similarly, monoclonal antibody conjugates directed against the B cell antigen CD19 expressed by most ALL cells are being studied in ALL patients (27,28). Yet it appears that many cases of ALL also originate from a hematopoietic stem cell that does not express CD19 (20). Therapies that target mature cancer cells may produce clinical improvements and dramatic responses, but they are unlikely to produce long-term remissions if the rare cancer stem cells responsible for maintaining the disease are also not targeted.
It is also possible that therapy directed against targets uniquely expressed by cancer stem cells could be prematurely abandoned if clinical activity is judged solely by standard response criteria. For example, rituximab, a monoclonal antibody against the B cell antigen CD20, has excellent activity in B cell lymphomas and may contribute to curing some patients with these diseases (29). However, its activity in multiple myeloma has been disappointing (30), despite emerging evidence that this disease arises from CD20-positive postgerminal center B cells. These rare myeloma stem cells differentiate into the malignant plasma cells that characterize the disease but that usually do not express CD20 (23,31). The parameters typically used to measure clinical response in myeloma (i.e., monoclonal immunoglobulin levels and the percentage of plasma cells in the bone marrow) primarily measure the effect of treatment on the terminally differentiated plasma cells. However, rituximabs activity would primarily be against myeloma stem cells, analogous to interferons possible activity in CML (18), and the long survival of the malignant plasma cells could obscure such activity. It is possible that a longer duration of rituximab treatment may ultimately have demonstrated clinical responses according to standard criteria by inhibiting new myeloma cell production for a sufficient period of time to allow myeloma plasma cells to undergo spontaneous apoptosis (23).
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DRUG DEVELOPMENT FOR CANCER: ARE WE OFF TARGET? |
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REFERENCES |
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Manuscript received November 26, 2003; revised February 9, 2004; accepted February 17, 2004.
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