Journal of Clinical Oncology, Vol 20, Issue 1
(January), 2002: 325-334
© 2002 American Society for Clinical Oncology
STI571: A Paradigm of New Agents for Cancer Therapeutics
By Michael J. Mauro,
Michael O’Dwyer,
Michael C. Heinrich,
Brian J. Druker
From the Leukemia Program, Division of Hematology and Medical Oncology, Oregon Health Sciences University and Veterans Affairs Medical Center, Portland, OR.
Address reprint requests to Brian J. Druker, MD, Oregon Health Sciences University, L592, 3181 SW Sam Jackson Park Rd, Portland, OR 97201; email: drukerb{at}ohsu.edu
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ABSTRACT
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ABSTRACT: STI571 exemplifies the successful development of a rationally designed, molecularly targeted therapy for the treatment of a specific cancer. This article reviews the identification of Bcr-Abl as a therapeutic target in chronic myelogenous leukemia and the steps in the development of an agent to specifically inactivate this abnormality. Issues related to clinical trials of molecularly targeted agents are discussed, including dose selection, optimizing therapy, and predicting response, as are possible mechanisms of resistance to STI571. Lastly, the potential use of STI571 in other malignancies and the translation of this paradigm to other malignancies are explored.
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INTRODUCTION
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OVER THE LAST SEVERAL decades, a wealth of knowledge has emerged regarding the molecular events involved in human cancer. Through our understanding of signaling pathways regulating cellular growth, cell cycle, and programmed cellular death, numerous targets for anticancer agents have emerged. Perhaps the best example of the unraveling of the molecular pathogenesis of a human malignancy and development of a therapy that targets this pathogenetic event is chronic myelogenous leukemia (CML). This malignancy also exemplifies how the confluence of several lines of investigations can result in significant advances. Specifically, the investigations into chromosomal or genetic changes in cancer, the study of transforming retroviruses leading to the discovery of oncogenes, the availability of molecular techniques to map genes, and the biochemical evaluation of protein phosphorylation leading to the discovery of tyrosine kinases have all contributed to the identification of the Bcr-Abl oncogene as the causative abnormality of CML and development of a drug specifically designed to inactivate this enzyme. This review will trace these discoveries and discuss some of the lessons learned in the clinical development of a molecularly targeted agent and the implications for translating this success to other malignancies.
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CML: CLINICAL FEATURES
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CML is a clonal hematopoietic stem-cell disorder with an annual incidence of one to two cases per 100,000 per year. The chronic, or stable, phase of the disease is characterized by excess numbers of myeloid cells. Within an average period of 4 to 6 years, the disease transforms through an accelerated phase to an invariably fatal acute leukemia, also known as blast crisis, as the leukemic clone progressively loses the capacity for terminal differentiation.1,2
Current treatment choices for CML include stem-cell transplantation and hydroxyurea-based or interferon-alfa–based regimens, with allogeneic stem-cell transplantation being the only proven curative therapy for CML.3 However, the average age of onset of CML is greater than 50 years of age; this factor, combined with the inability to identify suitably matched donors in all cases, limits this option to a minority of patients. Thus, fewer than 20% of CML patients are cured with current treatment options.1,2
GENETIC CHANGES IN CANCER CELLS
In 1960, Nowell and Hungerford4 described a consistent chromosomal abnormality in CML patients, an acrocentric chromosome that was thought to be a chromosomal deletion. This was the first example of a chromosomal abnormality linked to a specific malignancy. As chromosomal banding techniques improved, it became apparent that the abnormality was a shortened chromosome 22. Rowley5 later clarified that the shortened chromosome, the so-called Philadelphia (Ph) chromosome, was the product of a reciprocal translocation between the long arms of chromosomes 9 and 22, t(9:22)(q34;q11).
ONCOGENES, CANCER, AND GENE MAPPING
The study of transforming retroviruses led to the recognition that mutations in normal cellular genes could be oncogenic. One such retrovirus, the Abelson leukemia virus (v-Abl), initially described in 1970, led to the cloning of its normal cellular homolog, c-Abl, that mapped to the long arm of chromosome 9.6 However, when samples from CML patients were examined, it was apparent that c-Abl had been translocated to chromosome 22 into a region historically known as the breakpoint cluster region, or bcr.7,8
Bcr-Abl, TYROSINE KINASE ACTIVITY, AND CML
After the discovery of the translocation of c-Abl to chromosome 22 in CML patients, Northern blots using Abl probes demonstrated a larger than normal Abl mRNA in CML patients.9 Shortly thereafter, a fusion protein, termed Bcr-Abl, was found to be produced by the chimeric mRNA resulting from the 9:22 chromosomal translocation.10,11 This discovery provided an important link to the field of oncogenes and biochemistry of protein kinases, as it had previously been recognized that v-Abl possessed a novel kinase activity, the ability to phosphorylate tyrosine residues.12 Thus, Bcr-Abl was similarly found to have increased tyrosine kinase activity as compared with c-Abl, and the kinase activity of Bcr-Abl is known to be essential for its ability to transform cells.13,14
ANIMAL MODELS OF CML
In 1990, two experimental approaches demonstrated the ability of Bcr-Abl, as the sole oncogenic abnormality, to cause leukemia. In one set of experiments, transgenic mice that express Bcr-Abl were shown to develop a rapidly fatal acute leukemia.15 Using a different approach, a Bcr-Abl–expressing retrovirus was used to infect murine bone marrow. These Bcr-Abl–expressing marrow cells were used to repopulate irradiated mice. The transplanted mice developed a variety of myeloproliferative disorders, including a CML syndrome.16,17 Both of these approaches clearly demonstrated the leukemogenic potential of Bcr-Abl; however, even in these models, it was still possible that secondary changes were required for leukemia to develop. Recently, Huettner et al18 placed Bcr-Abl under the control of a tetracycline-repressible promoter. Mice expressing this transgene develop a reversible leukemia dependent on the presence or absence of tetracycline, and this even more clearly demonstrates the leukemic potential of Bcr-Abl as a sole oncogenic abnormality.
Bcr-Abl AND LEUKEMIA
The Ph chromosome can be detected in approximately 90% of patients with CML. However, when molecular testing for Bcr-Abl is performed, over 95% of CML patients will have evidence of this abnormality.8 Thus, it is possible to have translocations that are not detectable using standard cytogenetic techniques. On a practical level, patients with typical features of CML should have samples sent for fluorescent in situ hybridization analysis for Bcr-Abl gene rearrangements, reverse-transcriptase polymerase chain reaction for Bcr-Abl mRNA, or immunoblotting for Bcr-Abl protein. In addition to CML, the Bcr-Abl fusion gene is found in approximately 20% of adult patients with acute lymphoblastic leukemia (ALL) and 5% of pediatric ALL patients.2 Virtually all CML patients and half of the adult ALL patients express a 210-kd Bcr-Abl protein (p210). In the other half of the adult Ph+ ALL patients and the majority of pediatric Ph+ ALL patients, a slightly smaller mRNA and protein are generated, termed p185 or p190 (Fig 1).
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Fig 1. Common CML and Ph+ ALL breakpoints: In CML and Ph+ ALL, a break occurs between the first and second exon of c-Abl. In CML, bcr breakpoints occur after the second or third exon, whereas in Ph+ ALL, breaks can occur after the first exon.
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Bcr-Abl SIGNALING AND CML PATHOGENESIS
The past decade has seen significant advances in determining the signaling pathways that are activated by Bcr-Abl kinase activity (Fig 2). Numerous substrates and binding partners have been identified, and current efforts are directed at linking these pathways to the specific pathologic defects that characterize CML.8 The pathologic defects identified in CML cells include increased proliferation or decreased apoptosis of a hematopoietic stem or progenitor cell, which leads to a massive increase in myeloid cell numbers, and because patients have circulating immature myeloid progenitors, it has been postulated that there is a defect in adherence of myeloid progenitors to marrow stroma. An example of a cellular pathway that links to an increased proliferative rate is activation of the ras pathway. Protection from programmed cell death may be mediated in part through STAT-5 upregulation of the antiapoptotic molecule BCLXL and phosphorylation of and inactivation of the pro-apoptotic molecule BAD by AKT.8 CML cells also exhibit reduced adhesion to fibronectin, possibly as a downstream effect of Crkl phophosphorylation.8 Despite the seemingly endless expansion of the list of pathways activated by Bcr-Abl and the increasing complexity that is being revealed in these pathways, all of the transforming functions of Bcr-Abl are dependent on its tyrosine kinase actvity.14
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Fig 2. Model of Bcr-Abl function: A few of the many pathways known to be activated by Bcr-Abl are depicted along with the possible links of these pathways to known physiologic abnormalities characteristic of CML. Abbreviations: SH, src homology domain; Y, tyrosine residue; PPPP, proline-rich region.
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Bcr-Abl AS A THERAPEUTIC TARGET
From the above discussion, it should be clear 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 (Fig 3).
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Fig 3. (A) The constitutively active Bcr-Abl tyrosine kinase functions by transferring phosphate from ATP to tyrosine residues on various substrates to cause excess proliferation of myeloid cells characteristic of CML. (B) STI571 blocks the binding of ATP to the Bcr-Abl tyrosine kinase, thus inhibiting kinase’s activity.
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DEVELOPMENT OF AN Abl-SPECIFIC TYROSINE KINASE INHIBITOR
Tyrosine kinases, such as Bcr-Abl, catalyze the transfer of phosphate from adenosine triphosphate (ATP) to tyrosine residues on substrate proteins, and these tyrosine phosphorylated proteins induce the phenotypic changes characteristic of CML. All protein kinases use ATP as a phosphate donor, and there is a high degree of conservation among kinase domains, particularly in the ATP binding sites.19 Thus, it was thought that inhibitors of ATP binding would lack sufficient target specificity to be clinically useful. However, in 1988, Yaish et al20 published a series of compounds, known as tyrphostins, that demonstrated that specific tyrosine kinase inhibitors could be developed. Starting in the late 1980s, scientists at Ciba Geigy (now Novartis) under the direction of N. Lydon and A. Matter, performed high-throughput screens of chemical libraries searching for compounds with kinase inhibitory activity. From this time-consuming approach, a lead compound of the 2-phenylaminopyrimidine class was identified. This lead compound had low potency and poor specificity, but from this starting point, a series of related compounds was synthesized. Through analysis of the relationship between structure and activity, this series of compounds was optimized to inhibit a variety of targets.21 One series of compounds, optimized against the platelet-derived growth factor receptor (PDGF-R), showed equipotent activity against the Abl tyrosine kinase. Of the several compounds generated from this program, STI571 (formerly CGP57148, now Glivec, Gleevec, [Novartis, Basel, Switzerland] or imatinib mesylate) emerged as the lead compound for clinical development based on its superior in vitro selectivity against CML cells and its drug-like properties, including pharmacokinetic and formulation properties.21
PRECLINICAL STUDIES
A series of experiments initiated in our laboratory showed that STI571 was a potent and relatively selective inhibitor of the Abl tyrosine kinases, including Bcr-Abl.22 The concentrations of STI571 that resulted in a 50% reduction in substrate phosphorylation and cellular tyrosine phosphorylation induced by Bcr-Abl were 0.025 µmol/L and 0.25 µmol/L, respectively. Besides the PDGF-R, the only other tyrosine kinase that we have found to be inhibited by STI571 is c-kit.23 In vitro studies of STI571 showed specific inhibition of the proliferation of myeloid cell lines containing Bcr-Abl.22 Colony-forming assays from CML patients showed a marked decrease (92% to 98%) in the number of Bcr-Abl colonies, with no inhibition of normal colony formation using STI571 1 µmol/L. Deininger et al24 reported similar results, and others have shown that prolonged exposure to STI571 in long-term marrow cultures has a sustained inhibitory effect on CML progenitors with little toxicity to normal cells.25 Further experiments showed that both p185- and p210-expressing cells are sensitive to STI571.26,27 Dose-dependent inhibition of tumor growth was seen in animals inoculated with Bcr-Abl–expressing cells, treated daily with STI571; however, this dosing schedule failed to eradicate the tumors.22 Le Coutre et al28 subsequently showed that a three-times-per-day dosing schedule with oral administration of STI571 effectively eradicated Bcr-Abl–dependent tumors in nude mice. Since the half-life of STI571 is mice is approximately 4 hours, it seems likely that continuous exposure to STI571 is required for optimal antileukemic effects.
CLINICAL TRIALS: CHRONIC PHASE OF CML
Based on the efficacy of STI571 in a variety of preclinical models and an acceptable animal toxicology profile, phase I clinical trials with STI571 were begun in June 1998 at Oregon Health Sciences University, the University of California Los Angeles, and M.D. Anderson Cancer Center. The initial study was a dose escalation study designed to establish the maximum-tolerated dose (MTD), with a secondary end point of clinical efficacy.29 Patients with Ph+ CML were eligible if therapy with interferon-alfa had failed and they were in the chronic phase of the disease, defined as less than 15% blasts. Patients had to be off all antileukemia therapy for at least 1 week before starting STI571 and were required to have a WBC count of at least 20,000/mm3. STI571 was administered as once-daily oral therapy and no other cytoreductive agents were allowed. From this phase I study, it was determined that the half-life of STI571 is 13 to 16 hours,30 which suggests that once-daily administration is appropriate. Patients were treated continuously at their initial dose unless severe toxicity or disease progression developed.
Eighty-three patients were enrolled onto 14 dose levels ranging from 25 to 1,000 mg. Patients ranged in age from 19 to 76 years, with the median age being 55 years. Interferon failed in 44% of patients because of the lack of a hematologic response to interferon after 3 months of treatment or loss of a complete hematologic remission. Another 39% were eligible due to lack of a cytogenetic response after 1 year of interferon therapy or loss of a cytogenetic response. Lastly, 17% of patients were enrolled because of intolerance of interferon. The median duration of disease at study entry was 3.8 years, and one third of patients had signs of early progression to the accelerated phase, with increased blasts or basophils in the peripheral blood or marrow.29
Most patients were asymptomatic while receiving therapy with STI571, and no dose-limiting toxicity was encountered. The most common reported side effects were occasional nausea (particularly if STI571 was taken on an empty stomach), periorbital edema, muscle cramps, skin rashes, and diarrhea, with most of these being grade 1 toxicities. Grade 2 or 3 myelosuppression was observed at a dose  300 mg in 16 (30%) of 54 patients.29 The myelosuppression might be consistent with a therapeutic effect, as the Ph+ clone contributes the majority of hematopoiesis in these patients.
Hematologic responses, defined as a 50% decrease in the WBC count from baseline, maintained for at least 2 weeks, were achieved in all patients treated with 140 mg or greater of STI571. Once doses of 300 mg or greater were reached, 53 (98%) of 54 patients achieved a complete hematologic response, defined as a normal WBC count and platelet count with no circulating immature myeloid cells, maintained for at least 4 weeks.29 Lowering of the WBC count was typically seen within the first 2 to 3 weeks of therapy, with achievement of normal WBC counts in 3 to 6 weeks. Normal WBC counts have been maintained in 51 of 53 patients with a median duration of follow-up of 310 days. At doses of STI571 300 mg, cytogenetic responses were seen within 5 months in 17 (53%) of 31 patients, with 31% of patients achieving a major (< 35% Ph+) cytogenetic response and 10% achieving a complete cytogenetic response.29 Cytogenetic responses tend to occur relatively early as compared with interferon therapy, with most patients having major cytogenetic responses within 5 months of therapy. However, some patients do have later cytogenetic responses, and most patients with cytogenetic responses maintain these responses. Although the follow-up on this group of patients is relatively short, these data indicate that an Abl-specific tyrosine kinase inhibitor has significant activity in CML, even in interferon-refractory patients.
PHASE I STUDIES: CML BLAST CRISIS AND Ph+ ALL
Given the effectiveness of STI571 in chronic-phase patients in whom interferon had failed, the phase I studies were expanded to include CML patients in myeloid and lymphoid blast crisis and patients with relapsed or refractory Ph chromosome-positive ALL.31 Patients were treated with daily doses of 300 to 1,000 mg of STI571. Twenty-one (55%) of 38 patients with myeloid blast crisis had a response to therapy, as defined by a decrease in percentage of marrow blasts to less than 15%. Seventeen (45%) of 38 cleared their marrows of blasts (< 5%), with four of these patients (11%) meeting criteria for a complete remission with full recovery of peripheral blood counts. Seven patients in myeloid blast crisis remain on therapy, with less than 5% marrow blasts, with or without recovery of peripheral blood counts, and follow-up between 101 and 349 days.31
Of 20 patients with Ph+ ALL or lymphoid blast crisis of CML, 14 (70%) responded. Eleven (55%) of 20 completely cleared their marrow of blasts, with four patients (20%) meeting criteria for a complete hematologic response. Unfortunately, all but one of the lymphoid phenotype patients relapsed between days 45 and 117.31 Thus, STI571 has significant single-agent activity in Bcr-Abl–positive acute leukemias, but resistance to STI571 can occur, at least in more advanced stages. However, these studies demonstrate that in the majority of cases, the leukemic clone in Bcr-Abl–positive acute leukemias, including CML blast crisis, remains at least partially dependent on Bcr-Abl kinase activity for survival. It also suggests that for at least the blast phase of CML and Ph+ ALL, STI571 should be used in conjunction with other therapies, such as standard induction chemotherapy regimens. Since a large percentage of blast crisis patients clear their marrows of blasts and the outcome of stem-cell transplantation is improved if patients are returned to a second chronic phase, STI571 could also be used as a bridge to stem-cell transplantation.
CURRENT STATUS OF CML CLINICAL TRIALS
After the success of the phase I studies, phase II studies were begun in late 1999. These studies included chronic-phase patients who were refractory to or intolerant of interferon; patients were treated with STI571 at a dose of 400 mg/d. CML patients in advanced phases of the disease (accelerated phase and blast crisis) were also treated with STI571 at a dose of 600 mg in these phase II studies. These studies accrued 532 chronic-phase, 235 accelerated-phase, and 260 myeloid blast crisis patients at 30 centers in six countries. An early analysis of the phase II data confirmed the phase I results, with accelerated-phase responses intermediate between the chronic and blast crisis responses.32-34 Remarkably complete cytogenetic remissions were seen in 14% of patients in the accelerated phase and in 6% of blast crisis patients. Follow-up of patients in these studies is ongoing to determine the longevity of these responses. A phase III randomized study comparing STI571 with interferon and cytarabine in newly diagnosed patients, to establish whether STI571 is superior to the current standard of care in those patients not undergoing allogeneic stem-cell transplantation, has also completed enrollment.
INTEGRATION OF STI571 INTO CML TREATMENT ALGORITHMS
The rapid success of STI571 has already rendered many chronic-phase CML treatment algorithms obsolete. The major issue is whether STI571 should be offered as upfront therapy instead of allogeneic stem-cell transplantation, given the known mortality from transplantation. As the duration of follow-up with STI571 is relatively short, predictions regarding the potential use of STI57I range widely. However, at present, allogeneic stem-cell transplantation remains the only treatment known to cure CML. As is it unknown whether initial treatment with STI571 will compromise the outcome of transplantation, it is difficult to know whether delaying transplantation for a trial of STI571 in a younger patient is advisable. In the absence of firm data, individual decisions regarding the choice and timing of transplantation will continue to depend on factors such as patient age, availability of a well-matched donor, individual prognostic factors, and, of course, patient preference. For patients who are not candidates for transplantation, STI571, at least from the early studies, is an attractive alternative. Our current algorithm is to recommend stem-cell transplantation to younger patients with suitably matched donors and nontransplant therapies to older patients or patients who lack donors. The age cutoff for these recommendations depends in part on whether patients present with low- or high-risk features for disease progression to blast phase35 and on an assessment of the risk of transplant mortality,36 as discussed in greater detail elsewhere.37 For now, clinical trials with STI571, if available, are recommended for patients who are not undergoing transplantation.
OTHER THERAPEUTIC TARGETS FOR STI571
In addition to inhibiting the Abl kinase, STI571 inhibits the PDGF-R and c-kit tyrosine kinases.21,23,38 Given the utility of STI571 in CML, it is logical to try STI571 in other diseases where these kinases are activated (Table 1). The PDGF-R is activated as a consequence of its fusion to the Tel transcription factor in a subset of patients with chronic myelomonocytic leukemia.39 STI571 has shown in vitro and in vivo inhibition of leukemic cell lines expressing Tel–PDGF-R, supporting the use of STI571 in this indication.26,40 Glioblastomas have been reported to have autocrine activation of PDGF-R, and recent studies using glioblastoma cell lines suggest that STI571 could have utility in this malignancy.41 Numerous other malignancies have also been reported to have autocrine activation of PDGF-R, including non–small-cell lung, breast, and prostate cancer and a variety of sarcomas; however, the data supporting a role for PDGF-R activation in these diseases are less compelling.42 Nevertheless, clinical trials with STI571 in these diseases could be envisioned to test this hypothesis. Lastly, PDGF-R activation may have a role in a variety of fibrotic disorders, such as myelofibrosis and pulmonary and hepatic fibrosis.43 Given the acceptable toxicity profile, an exploration of the activity of STI571 in these disorders may also be warranted.
c-kit is expressed in a variety of human tumors, including mastocytosis/mast cell leukemia, germ cell tumors, small-cell lung cancer, gastrointestinal stromal tumors (GISTs), acute myelogenous leukemia, neuroblastoma, melanoma, ovarian cancer, and breast cancer. As with the PDGF-R, the precise role of c-kit expression in the pathogenesis of the majority of these tumors is poorly defined. The exceptions to this are GIST and mastocytosis/mast cell leukemia, where activating mutations of c-kit are likely critical pathogenetic events. In GIST, c-kit is activated by mutation in the majority of cases.44-47 Early clinical results with STI571 seem quite promising in this tumor, which has previously been highly refractory to chemotherapy.48-50 The results with STI571 in GIST demonstrate that targeting the critical molecular pathogenetic lesions will also be successful in solid tumors.
The majority of cases of systemic mastocytosis have a mutation of aspartic acid 816 to valine (D816V), in the kinase domain of c-kit, which results in activation of c-kit. Unfortunately, the kinase activity of the D816V mutant isoform was recently shown to be resistant to STI571,51 probably because this mutation induces conformational changes in the activation loop of c-kit that prevent the binding of STI571. Thus, STI571 is unlikely to be useful in this disorder. Autocrine activation of c-kit has been reported in small-cell lung cancer, but the precise role of c-kit activation in the pathogenesis of small-cell lung cancer is less clear. Two groups have recently reported activity of STI571 against small-cell lung cancer cell lines,52,53 and clinical trials with STI571 in this indication are planned.
DOSE SELECTION
In the phase I clinical trials of STI571, an MTD of STI571 was never reached. Even among those closely associated with the phase I studies, there was a lack of consensus about when to discontinue dose escalation. Some investigators thought no cap on the dose should be considered except the MTD, particularly since studies in solid tumors were planned and since penetration of STI571 into solid tumors might require higher doses. Others thought alternate end points, such as optimal therapeutic response, or pharmacokinetic end points could be used. In evaluating pharmacokinetic end points, it was known from preclinical studies that continuous exposure of cells to STI571 doses of 1 µmol/L or higher resulted in maximal cell killing.21 In the phase I clinical trials, a trough level of 1 µmol/L was reached at a dose level of 300 mg, which corresponds to a threshold for significant therapeutic benefits.30 Thus, pharmacokinetic parameters could have been used to predict therapeutic responses. Similarly, an analysis of responses in WBCs and platelets over time suggested that doses of 400 to 600 mg were on the plateau of a dose-response curve.30 Thus, an analysis of optimal therapeutic responses led to a similar conclusion that doses greater than 300 mg should be chosen for phase II trials. However, the analysis of optimal therapeutic responses may not always be available from early clinical trials.
When using molecularly targeted agents, it would seem more reasonable to consider maximal inhibition of the target as the therapeutic end point. In the case of CML and a Bcr-Abl inhibitor, the obvious choice would be to assess for maximal inhibition of the Bcr-Abl kinase activity. An analysis of Bcr-Abl kinase inhibition, performed by assaying for decreases in phosphorylation of the Bcr-Abl substrate, Crkl, have shown that a plateau in inhibition is seen above 250 mg.29 Additional experiments are being conducted to determine the percentage of Bcr-Abl kinase activity that is being inhibited at these dose levels.54 Once again, there are certain advantages in CML in that the tumor cells are easily accessible and that the kinase itself or its substrates could be monitored for inhibition. These types of assays will clearly be more problematic for solid tumors but will likely be necessary to determine the penetration of agent into the tumor. In the absence of specific assays, information about intracellular drug levels in tumor samples would also be a useful surrogate. This type of data, regarding maximal kinase inhibition, could be particularly useful in explaining response variability and could also be used to individualize patient dosing.
MECHANISMS OF RELAPSE
The activity in blast crisis patients demonstrates that the leukemic clone remains at least partially dependent on Bcr-Abl kinase activity for survival. However, these trials also point out that resistance to STI571 as a single agent is a reality. The assays described above for kinase inhibition could also be useful in analyzing patterns of relapse. For example, one could separate patients into two categories at relapse, those with persistent inhibition of the Bcr-Abl kinase and those with reactivation of the Bcr-Abl kinase at relapse (Fig 4). Patients with persistent inhibition of the Bcr-Abl kinase would be predicted to have additional molecular abnormalities besides Bcr-Abl driving the growth and survival of the malignant clone. In contrast, patients with persistent Bcr-Abl kinase activity or reactivation of the kinase would be postulated to have resistance mechanisms that either prevent STI571 from reaching the target or render the target insensitive to Bcr-Abl. In the former category are mechanisms such as drug efflux or protein binding of STI571. In the latter category would be mutations of the Bcr-Abl kinase that render Bcr-Abl insensitive to STI571 and amplification of the Bcr-Abl protein.
Several publications examining cells lines that express Bcr-Abl have shown that the most common mechanism of STI571 resistance was Bcr-Abl gene amplification.55-57 However, other resistant cell lines did not have detectable Bcr-Abl gene amplification, and at least one resistant cell line showed overexpression of the multidrug resistance P-glycoprotein.56 Lastly, there has been a suggestion from animal studies that protein binding of STI571 could be responsible for relapse.58 However, samples from relapsed patients have decreased cellular sensitivity to STI571, suggesting that resistance is due to intrinsic cellular properties rather than protein binding of drug. Analysis of a small number of blast crisis patients who relapsed while receiving STI571 have shown either Bcr-Abl amplification or Bcr-Abl kinase domain mutations.59 Additional studies are ongoing to determine whether these or other mechanisms are present in the majority of patients who relapse while receiving therapy with STI571.
OPTIMIZING THERAPY WITH STI571 AND CIRCUMVENTING RESISTANCE
CML is a disease that exemplifies the concept of multistage tumor progression. Early in the course of the disease, it is likely the Bcr-Abl is the sole molecular abnormality. Over time, the leukemic clone accumulates additional molecular changes as the disease progresses toward blast crisis. Thus, it is possible that in patients with early disease, STI571 as a single agent could eradicate the leukemic clone. However, as the disease advances, it would seem more likely that combinations of STI571 with other agents would be required, and by the time the blast phase is reached, combinations would absolutely be required.
Historically, development of resistance to single agents is the general rule. Additionally, Bcr-Abl is known to render cells resistant to chemotherapeutic agents, although the mechanism of resistance remains unclear.60,61 In vitro evidence demonstrates that treatment of cells expressing Bcr-Abl with STI571 reverses this chemotherapy resistance. Additive or even synergistic antiproliferative effects between STI571 and other antileukemic agents, including interferon-alfa, daunorubicin, and cytarabine, have also been observed in vitro.62 Similar results were seen with etoposide and cytarabine.63 Such studies provide a strong rationale for combining STI571 with other active agents, both in advanced disease as well as chronic-phase disease. In chronic-phase patients, future studies will be designed to determine whether the addition of interferon or cytarabine to STI571 will improve survival. In accelerated-phase and blast crisis patients, STI571 will be tried in combination with a variety of antileukemic agents (Table 2). For blast crisis or Ph+ ALL, using STI571 similarly to all-trans-retinoic acid in acute promyelocytic leukemia would seem a reasonable paradigm. Other uses for STI571 might include treatment of patients relapsing after stem-cell transplantation as an alternative to donor lymphocyte infusions, as an adjunct to autologous stem-cell transplantation, and possibly as an in vitro purging agent for autologous stem-cell transplantation STI571.
One of the tasks for the future will be to predict response patterns of patients. This will include predictions based on individual genetic factors that might influence parameters, such as drug metabolism, as well as the genetic makeup of the tumor, as described above. Current techniques to predict responses use pretreatment clinical features that are likely poor surrogate markers for specific genetic alterations in tumors. Microarray techniques that survey the gene expression pattern of tumors have already been demonstrated to distinguish subgroups with different clinical outcomes from a larger group of apparently clinically homogenous patients.64,65 Thus, the ideal situation would be to predict specific response patterns of patients before treatment and treat patients with the minimally toxic but effective therapy. It is also likely that microarray experiments could yield insight into the molecular mechanism of relapse and identify future targets for therapy.
TRANSLATING THE SUCCESS OF STI571 TO OTHER MALIGNANCIES
The clinical trials with STI571 are a dramatic demonstration of the potential of targeting molecular pathogenetic events in a malignancy. As this paradigm is applied to other malignancies, it is worth remembering that Bcr-Abl and CML have several features that were critical to the success of this agent. One feature is that Bcr-Abl tyrosine kinase activity has clearly been demonstrated to be critical to the pathogenesis of CML. Thus, not only was the target of STI571 known, but the target is the critical factor required for the development of CML. Another important feature is that as with most malignancies, treatment earlier in the course of the disease yields better results. Specifically, the response rate and durability of responses have been greater in chronic-phase patients than in blast-phase patients. Thus, for maximal utility as a single agent, the identification of crucial, early events in malignant progression is the first step in reproducing the success with STI571 in other malignancies. An equally important issue is the selection of patients for clinical trials based on the presence of an appropriate target. Again, in the CML experience, patients with activation of Bcr-Abl were easily identifiable by the presence of the Ph chromosome. In this regard, as reagents to analyze molecular end points are developed, these same reagents should be useful in identifying appropriate candidates for treatment with a specific agent. When all of these elements are put together, a critical pathogenetic target that is easily identifiable early in the course of the disease, remarkable results with an agent that targets this abnormality can be achieved. The obvious goal is to identify these early pathogenetic events in each malignancy and to develop agents that specifically target these abnormalities.
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Submitted April 10, 2001;
accepted October 5, 2001.
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TOP
ABSTRACT
INTRODUCTION
