Imatinib molecular biology to therapy

From the above discussion, it should be clear that the BCR-ABL possesses many characteristics of an ideal therapeutic target. It is expressed in the majority of patients with CML and it has been shown to be the cause of CML. BCR-ABL functions as a constitutively activated tyrosine kinase and mutagenic analysis has shown that this activity is essential for the transforming function of the protein. Thus, an inhibitor of the BCR-ABL kinase would be predicted to be an effective and selective therapeutic agent for CML (Figure 7.4).

Imatinib mesylate (Gleevec, Glivec, formerly STI571) is a relatively specific inhibitor of the BCR-ABL tyrosine kinase. Other tyrosine kinases inhibited by imatinib include the platelet-derived growth factor receptor KIT, and ARG (ABL-related gene). Preclinical data showed significant specific activity against BCR-ABL-expressing cell lines in vitro and in vivo. In addition, imatinib could select for the growth of BCR-ABL-negative hematopoietic cells from CML patient samples in colony-forming assays and long-term marrow cultures.

Based on the favorable preclinical data, imatinib was tested in Phase I and II clinical trials in CML patients. These studies

CML CML

Fig. 7.4 Schematic representation of the mechanism of action of the BCR-ABL tyrosine kinase and its inhibition by imatinib

CML CML

Fig. 7.4 Schematic representation of the mechanism of action of the BCR-ABL tyrosine kinase and its inhibition by imatinib showed that imatinib has significant activity in all phases of CML, and the results of the Phase II trials are summarized in Table 7.1. In chronic-phase patients who had failed interferon, 96% achieved a CHR with an imatinib dose of 400 mg per day. Imatinib induced major cytogenetic responses (<35% Philadelphia chromosome-positive metaphases) in 64% of patients, with a complete cytogenetic response rate of 48%. The estimated progression-free survival at 24 months was 87%. Cytogenetic responses have been durable and correlate with improved progression-free and overall survival. Thus, once a patient achieves a major cytogenetic response, it is estimated that, 24 months later, 91% of these patients will not have progressed. Achievement of a major cytoge-netic response was associated with a statistically significant improvement in overall survival. For example, if patients achieve a major cytogenetic response within 12 months, the estimated survival at 24 months was 99%, compared with 86% for patients with less than a major cytogenetic response (P < 0.001). Baseline features that independently predicted a high rate of major cytogenetic responses were the absence of blasts in the peripheral blood, a hemoglobin concentration above 12 g/dl, fewer than 5% blasts in the marrow, CML disease duration of less than 1 year, and a prior cytogenetic response to interferon-a.

Table 7.1 Phase II results with imatinib.

Chronic phase (IFN failure)

Accelerated phase

Blast crisis

CHR MCR CCR

Disease progression*

IFN, interferon; CHR, complete hematological response; MCR, major cytogenetic response (Philadelphia chromosome-positive metaphases <35%); CCR, complete cytogenetic response; *at 24 months.

In the Phase II trial in the accelerated phase, patients were required to have 15-30% blasts or more than 30% blasts plus promyelocytes in the peripheral blood or marrow, greater than 20% peripheral basophils, or a platelet count less than 100 x 109/L, unrelated to therapy. With follow-up of up to 3 years, 83% of patients showed some form of hematological response, 40% of patients achieving a CHR. Twenty-eight percent of patients achieved a major cytogenetic response, with 20% complete responses. In this study, significantly improved outcomes for responses and survival were observed for patients treated with 600 mg per day of imatinib compared with patients treated with 400 mg per day.

In patients with myeloid blast crisis, the overall response rate to imatinib was 52%, with sustained hematological responses lasting at least 4 weeks in 31% of patients. Nine percent of patients achieved complete remission (fewer than 5% blasts) with peripheral blood recovery and another 4% of patients cleared their marrows to less than 5% blasts but did not meet the criteria for complete remission because of persistent cytopenia. Finally, 18% of patients either returned to the chronic phase or had partial responses. Major cytogenetic responses were seen in 16% of patients, 7% having complete responses. Median survival was 6.9 months, with an estimated survival of 17% at 24 months. The baseline features predictive of prolonged survival were a platelet count at least 100 x 109/ L, peripheral blood blasts fewer than 50% and a hemoglobin concentration of at least 10 g/dl. For patients with all three of these features, the median survival was 21 months. However, if patients had none of these features their median survival was only 4 months. Patients with a CHR or marrow blasts less than 5% at 2 months had a median survival of more than 24 months and their survival was significantly longer than that of patients who either returned to the chronic phase or had no response. These results with single-agent imatinib compare favorably with historical controls treated with chemotherapy for myeloid blast crisis, in which the median survival is approximately 3 months. However, the high relapse rates suggest either that imatinib should be viewed as a bridge to allogeneic stem cell transplantation or that patients should be enrolled in clinical trials combining imatinib with other agents.

In patients with Philadelphia chromosome-positive ALL, 29/48 (60%) responded to single-agent imatinib. Unfortunately, the duration of response was relatively short, with a median estimated time to disease progression of only 2.2 months.

A Phase III randomized study, comparing imatinib at 400 mg per day with interferon-a plus Ara-C in newly diagnosed patients with chronic-phase CML, enrolled 1106 patients between June 2000 and January 2001. Five hundred fifty-three patients were randomized to each treatment. Baseline characteristics were well balanced for all features evaluated, including age, white blood count, Sokal and Euro

Table 7.2 Phase III results of imatinib versus interferon-a plus cytarabine (Ara-C) for newly diagnosed chronic phase CML patients.

Imatinib 400 mg Interferon + Ara-C

Intolerance 3% 31%

Progressive disease 3% 8.5%

Ara-C, cytosine arabinoside; CHR, complete hematological response; MCR, major cytogenetic response (Philadelphia chromosome-positive metaphases <35%); CCR, complete cytogenetic response. 'Intolerance' means intolerance leading to discontinuation of first-line therapy. 'Progressive disease' indicates progression to accelerated phase or blast crisis. All differences are highly statistically significant (P < 0.001). Median follow up is 18 months.

score, and time from diagnosis. With a median follow-up of 19 months, patients randomized to imatinib had statistically significant better results than patients treated with interferon-a plus Ara-C in all parameters measured (Table 7.2) including rates of CHR, major and complete cytogenetic responses, tolerance of therapy, and freedom from disease progression. Despite the fact that 76% of patients randomized to imatinib achieved a complete cytogenetic response, the majority of these patients had detectable leukemia, as analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) for BCR-ABL transcripts. When analyzed by log reduction in BCR-ABL transcript levels, 39% of patients achieved at least a three-log reduction in BCR-ABL levels, but only 13 and 3% achieved a four- and five-log reduction, respectively.

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