Seminars in Hematology
Volume 40, Issue 1 , Pages 50-58, January 2003

Imatinib alone and in combination for chronic myeloid leukemia☆☆☆

Howard Hughes Medical Institute, Oregon Health & Science University Cancer Institute, Portland, OR.

Article Outline

Abstract 

Imatinib mesylate (STI571, Gleevec, Glivec; Novartis, Basel, Switzerland) has profoundly changed the management of chronic myeloid leukemia (CML). The unprecedented efficacy of a drug that specifically acts on the causative lesion in a malignant disorder is a proof of principle for the concept of molecular targeted therapy. This article will review the development of imatinib as a new therapy for CML. Data regarding the use of higher than the standard dose of 400 mg of imatinib and combinations of imatinib with other antileukemic agents will be discussed in the context of emerging data regarding resistance mechanisms. Semin Hematol 40:50-58. Copyright 2003, Elsevier Science (USA). All rights reserved.

 

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Bcr-Abl as a therapeutic target 

The Bcr-Abl tyrosine kinase is a well-validated therapeutic target in chronic myeloid leukemia (CML). Present in 95% of patients with CML, Bcr-Abl has been demonstrated to be a leukemogenic oncogene in animal studies and is considered the causative molecular abnormality of CML. Bcr-Abl functions as a constitutively activated tyrosine kinase, impacting numerous signaling pathways, as described by Barnes and Melo in this issue. However, all of the transforming activities of Bcr-Abl are dependent on its tyrosine kinase activity.31 Thus, an inhibitor of the Bcr-Abl kinase would be predicted to be an effective and selective therapeutic agent for CML.

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Development of imatinib 

Having identified an appropriate target, the next task was to design an inhibitor of this enzyme. Scientists at Ciba-Geigy (now Novartis) identified a 2-phenylaminopyrimidine as a weakly potent and nonspecific kinase inhibitor. A series of related compounds was then synthesized and, using structure-activity relationships, optimized against a variety of targets.3, 10 STI571 (signal transduction inhibitor), one of many compounds developed in this program, was found to be a potent inhibitor of the platelet-derived growth factor receptor (PDGF-R) and the Abl tyrosine kinases. Further testing revealed that it was relatively selective for the Abl tyrosine kinases, including Bcr-Abl, c-Abl, v-Abl, and Arg (Abl-related gene).3, 38 Besides the Abl and PDGF-R alpha and beta tyrosine kinases, the only other tyrosine kinase inhibited by STI571 is c-Kit.10 STI571 (formerly CGP57148, now imatinib mesylate, Glivec, or Gleevec; Novartis, Basel, Switzerland) emerged as the lead compound for clinical development based on its superior in vitro selectivity against CML cells and its drug-like characteristics, including pharmacokinetic and formulation properties.10

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Preclinical studies 

Initial studies of imatinib showed that it specifically inhibited the in vitro proliferation of Bcr-Abl–expressing cells and colony formation using CML patient samples.14 Imatinib, at concentrations of 1 and 10 μmol/L, kills or inhibits the proliferation of all Bcr-Abl–expressing cell lines tested to date.1, 3, 4, 5, 16 In contrast, a variety of immortalized or transformed cell lines that do not express Bcr-Abl are unaffected by exposure to imatinib. In mice imatinib had in vivo activity against Bcr-Abl–expressing cells. Initial experiments failed to eradicate Bcr-Abl–expressing tumors14; however, subsequent experiments, using a thrice-daily administration schedule that allowed continuous exposure to imatinib, achieved eradication of tumors.30 This result suggested that continuous exposure to imatinib would be important for optimal antileukemic effects. These promising preclinical data led to the initiation of human clinical trials.

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Clinical trials 

Phase I studies 

A standard dose-escalation, phase I study of imatinib began in June 1998 at three centers in the United States. The study population consisted of CML patients in chronic phase, refractory or resistant to interferon-α–based therapy or intolerant of this drug.13 At later stages of the study, patients with CML in blast crisis and patients with Ph chromosome–positive acute lymphoblastic leukemia (ALL) were also enrolled.12 Imatinib was well tolerated with minimal side effects. Despite dose escalation from 25 mg to 1,000 mg in 14 cohorts of patients, a maximally tolerated dose could not be defined. Imatinib was administered once daily and pharmacokinetics showed a half-life of 13 to 16 hours. Significant clinical benefits were observed at daily doses above 300 mg. Among chronic-phase patients who had failed therapy with interferon, 53 of 54 (98%) treated with ≥300 mg/d achieved a complete hematologic response (CHR) and 96% of these responses lasted beyond 1 year.13 Among myeloid blast crisis patients, 21 of 38 (55%) treated at doses ≥300 mg/d responded, with 18% having responses lasting longer than 1 year.12

Phase II studies 

The success of the phase I studies prompted phase II trials; single-agent imatinib was tested further in interferon-refractory and interferon-intolerant patients, as well as in accelerated-phase patients and patients with CML in myeloid blast crisis and Philadelphia chromosome–positive ALL. More than 1,000 patients were accrued at 30 centers in six countries over 6 to 9 months. Results from these trials, with 18 months of follow-up, have been published and are summarized in Table 1.25, 39, 43, 46

Table 1. Phase II results with imatinib
Chronic Phase (IFN failure)25Accelerated Phase46Blast Crisis43
CHR95%34%8%
MCR60%24%16%
CCR41%17%7%
Disease progression11%40%80%

Abbreviations: IFN, interferon; CHR, complete hematologic response; MCR, major cytogenetic response (Ph+ metaphases ≤ 35%); CCR, complete cytogenetic response.

Five hundred thirty-two chronic-phase patients who were refractory to or intolerant of interferon-α were treated with an imatinib dose of 400 mg daily. Eligibility criteria in this study allowed inclusion of patients with up to 15% blasts and 15% basophils in the marrow or peripheral blood. Median duration of disease was 34 months and median duration of previous interferon therapy was 14 months. Ninety-five percent of patients achieved a CHR, with the median time to CHR of less than 1 month. Imatinib induced major cytogenetic responses (≤35% Ph-positive metaphases) in 60% of patients, with a complete cytogenetic response rate of 41%. With a median follow-up of 18 months, the estimated progression-free survival was 89%. Only 2% of patients discontinued therapy due to adverse events.25 A major cytogenetic response at 3 months was associated with a higher rate of progression-free survival. Baseline features that independently predicted a high rate of major cytogenetic responses were the absence of blasts in the peripheral blood, hemoglobin greater than 12 g/dL, less than 5% blasts in the marrow, CML disease duration of less than 1 year, and a prior cytogenetic response to interferon.

Results of the phase II study in accelerated-phase patients were equally impressive.46 Accelerated phase was defined as 15% to 30% blasts or greater than 30% blasts plus promyelocytes in the peripheral blood or marrow, greater than 20% peripheral basophils, or a platelet count less than 100 × 109/L unrelated to therapy. Among 235 patients enrolled, 82% showed some form of hematologic response, with 34% achieving a CHR. Twenty-four percent of patients achieved a major cytogenetic response, with 17% attaining a complete response. Estimated 12-month progression-free and overall survival rates were 59% and 74%. Again, these results were achieved without substantial toxicity.46

Results of the phase II study treating 260 myeloid blast crisis patients with imatinib showed an overall response rate of 52% with sustained hematologic responses, lasting at least 4 weeks, in 31% of patients. Eight percent of patients achieved a complete remission (CR; defined as < 5% blasts) with peripheral blood recovery.43 Another 4% of patients cleared their marrows to less than 5% blasts but did not meet the criteria for CR due to persistent cytopenias. Lastly, 18% of patients either returned to chronic phase or had partial responses. Major cytogenetic responses were seen in 16% of patients, with 7% having complete responses. Median survival was 6.9 months. Twenty percent of patients were still alive at 18 months with a suggestion of a plateau on the survival curve. These results compare favorably to historical controls treated with chemotherapy for myeloid blast crisis in which the median survival is approximately 3 months. The majority of patients with Ph-positive ALL responded to single-agent imatinib (29 of 48 patients or 60%). However, the duration of response was relatively short with a median estimated time to disease progression of only 2.2 months.39

Phase III study 

A phase III randomized study compared imatinib at 400 mg/d to interferon plus cytarabine (Ara-C) in 1,106 newly diagnosed chronic-phase CML patients enrolled from June 2000 to January 2001; 553 patients were randomized to each treatment. Baseline characteristics were well balanced for all features evaluated, including age, white blood cell count, Sokal and Euro score, and time from diagnosis. With a median follow-up of 14 months, patients randomized to imatinib had statistically significant better results than patients treated with interferon plus Ara-C in all parameters measured (Table 2), including rates of CHR, major and complete cytogenetic responses, tolerance of therapy, and freedom from disease progression.9

Table 2. Phase III trial results of imatinib versus interferon plus cytarabine for newly diagnosed chronic-phase CML patients9
Imatinib 400 mgIFN + Ara-C
CHR96%67%
MCR83%20%
CCR68%7%
Intolerance*0.7%23%
Progressive disease†1.5%7%
*Intolerance leading to discontinuation of first-line therapy. † Progressive disease to accelerated phase or blast crisis.

NOTE. All differences are highly statistically significant, P < .001.

Abbreviation: Ara-C, cytarabine.

Given the significant difference in percentage of patients with disease progression to accelerated phase or blast crisis, 7% with interferon versus 1.5% with imatinib, it seems likely that this will translate into a survival benefit. A remaining question is the durability of the responses to imatinib.

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Side effects of therapy 

Imatinib has generally been well tolerated with grade 3 or 4 nonhematologic toxicities being uncommon. The toxicities observed in newly diagnosed chronic-phase patients are summarized in Table 3.

Table 3. Nonhematologic toxicities with imatinib in newly diagnosed chronic-phase CML patients9
Adverse EventAll Grades (%)Grades 3/4 (%)
Superficial edema53.20.9
Nausea42.50.4
Muscle cramps35.41.1
Musculoskeletal pain33.62.7
Rash31.92.0
Fatigue30.71.1
Diarrhea30.31.3
Headache28.50.4
Joint pain26.72.2
Abdominal pain23.42.0
Myalgia20.91.5
Nasopharyngitis19.20
Hemorrhage18.90.7
Dyspepsia15.10
Vomiting14.70.9
Pharyngolaryngeal pain14.20.2
Dizziness13.20.5
Cough12.50.2
Upper respiratory tract infection12.50.2
Pyrexia11.80.5
Weight increase11.60.7
Insomnia11.40
Depression8.90.5
Constipation7.60.7
Rigors6.90
Anxiety6.50.2
Dyspnea6.51.3
Pruritus6.50.2
Influenza-like illness6.40
Night sweats6.40.2
Anorexia4.70
Sweating increase3.30
Alopecia2.20
Common grade 1 or 2 toxicities include fluid retention, nausea, muscle cramps, rashes, fatigue, and diarrhea. Practical aspects of management of these symptoms have been reviewed elsewhere.11 Myelosuppression is more common in advanced-phase than in chronic-phase patients (Table 4) and imatinib induced prolonged aplasia in 1% of blast crisis patients.43
Table 4. Myelosuppression in the phase II and III studies with imatinib
NeutropeniaThrombocytopenia
Grade 3 (ANC < 1.0 × 109/L)Grade 4 (ANC < 0.5 × 109/L)Grade 3 (<50 × 109/L)Grade 4 (<10 × 109/L)
Chronic phase (newly diagnosed)911%2%7%0.5%
Chronic phase (IFN failure)2527%8%19%1%
Accelerated phase4623%35%31%12%
Blast crisis4316%48%29%33%

Abbreviation: ANC, absolute neutrophil count.

In contrast, patients with gastrointestinal stromal tumors treated with 400 or 600 mg/d of imatinib had rates of grade 3/4 neutropenia and thrombocytopenia of 5% and less than 1%, demonstrating the specificity of this side effect to leukemia patients.6

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Rationale for attempts to improve on imatinib monotherapy at 400 mg/d 

Despite the lack of long-term follow up data, imatinib at 400 mg daily has emerged as the preferred therapy for newly diagnosed CML patients who do not undergo allogeneic stem cell transplantation. However, only a minority (5% to 10%) of imatinib-treated patients achieve a molecular remission, that is, negative by reverse-transcriptase polymerase chain reaction (RT-PCR) for Bcr-Abl transcripts (B. Druker, unpublished data). Relapses in patients with more advanced disease have been common and it is likely that resistance to imatinib will emerge in chronic-phase patients. Combinations of imatinib with chemotherapy are an obvious choice for patients with advanced-phase disease and this topic is discussed elsewhere in this issue. If one accepts that chronic-phase patients who do not achieve durable molecular remissions are at risk of relapse, then it is clear that there is much room for improvement. Options that have shown promise thus far include higher doses of imatinib, and combinations of imatinib with interferon-α or Ara-C. Early results of these treatments as compared to 400 mg/d of imatinib are summarized in Table 5.

Table 5. Comparison of cytogenetic responses in newly diagnosed chronic-phase CML patients
Cytogenetic Responses
6 Months9 Months
MajorCompleteMajorComplete
Imatinib 400 mg976%51%81%63%
Imatinib + PEG-IFN3576%44%86%48%
Imatinib + Ara-C (F. Guilhot, personal communication)74%57%80%57%
M.D. Anderson24
Imatinib 400 mg80%52%
Imatinib 800 mg83%65%

NOTE. Cytogenetic responses are reported at 6 and 9 months for comparative purposes.

Abbreviation: PEG-IFN, pegylated interferon.

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Higher doses of imatinib 

The dose of 400 mg/d of imatinib for the chronic-phase studies was selected based on responses seen in the phase I study and a lack of sufficient safety data for higher doses. As additional safety data from the phase I study emerged, advanced-phase patients were treated with 600 mg/d. Thus, in the phase II study of accelerated disease, 77 patients were treated with 400 mg and 158 patients with 600 mg of imatinib.46 In the phase II study of myeloid blast crisis patients, 36 patients were treated with 400 mg and 223 patients with 600 mg.43 Retrospective analysis of prognostic factors in the accelerated-phase patients showed that the 400- and 600-mg cohorts were well matched. In both studies, there was a trend towards higher hematologic and major cytogenetic response rates in patients treated with 600 mg of imatinib (Table 6).

Table 6. Results with imatinib at 400 mg versus 600 mg per day in advanced-phase patients
Accelerated Phase46Blast Crisis43
400 mg600 mg400 mg600 mg
HR65%71%9%35%
CHR27%37%3%14%
MCR16%28%6%18%
TTP8 moNot reached
(P = .002)
12-mo survival65%78% (P = .014)

Abbreviations: HR, hematologic response; CHR, complete hematologic response; MCR, major cytogenetic response; TTP, time to progression.

In the accelerated-phase study, patients treated with 600 mg had a statistically significant improvement in time to disease progression and survival.46

A subsequent study also treated accelerated-phase patients with 600 mg daily of imatinib. As opposed to the accelerated protocol cited above, patients who otherwise had chronic-phase features but had cytogenetic abnormalities besides a single Ph chromosome, were defined as accelerated. Fifteen such patients with this definition of accelerated phase were enrolled at Oregon Health & Science University and had a median disease duration of 45 months. With a median follow-up of 12 months, the major cytogenetic response rate was 80% (12 of 15), with a complete cytogenetic response rate of 67% (10 of 15). None of these patients has relapsed.36 Although the study was small, the results for these relatively poor-prognosis patients compare favorably with the 12-month results in newly diagnosed CML patients treated with 400 mg of imatinib.

The experience with doses higher than 600 mg/d is limited. In chronic-phase patients in the phase II study who failed to achieve a cytogenetic response following 1 year of imatinib therapy, dose escalation to 800 mg/d has been allowed. Limited experience suggests that up to one third of patients will achieve a major cytogenetic response with dose escalation (B. Druker, unpublished data). Investigators at M.D. Anderson Cancer Center have recently reported results in newly diagnosed chronic-phase CML patients treated daily with 400 versus 800 mg of imatinib.24 There was a trend towards higher cytogenetic responses in the 800-mg dose cohort (Table 5). Toxicity was similar to that reported in the phase I study, which demonstrated that daily doses of 800 mg and higher were less well tolerated than 600 mg.13 In particular, there was a higher incidence of fluid retention, rashes, and muscle cramps. Daily dosing above 800 mg has generally not been used, as this was defined as the maximally tolerated dose in a European Organization for Research and Treatment of Cancer (EORTC) study of patients with gastrointestinal stromal tumors.50 At 1,000 mg/d, the dose-limiting toxicities were nausea, vomiting, edema, and rashes.

These data suggest that doses higher than 400 mg/d may yield improved responses. However, in the accelerated and blast crisis studies, the main impact of higher doses was on time to progression and survival. As the response rates for newly diagnosed chronic-phase CML patients are already quite high, this implies that comparative studies of higher dose imatinib therapy in this patient population will require time to progression or survival as endpoints. Alternatively, rates of molecular remissions, if they correlate with improved survival, may be a useful early endpoint.

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Imatinib in combination with interferon-α 

As imatinib and interferon are the two most active forms of nontransplant therapy available for patients with CML, this combination is an obvious choice for testing. In vitro data demonstrated additive or synergistic antiproliferative effects of the combination of imatinib with interferon using Bcr-Abl–positive cell lines and in colony-forming assays using CML patient samples.23, 32, 47 Based on these data, several phase I/II pilot studies with this combination are in progress.

A phase I dose-escalation study using imatinib with regular interferon enrolled 14 chronic-phase CML patients.37 Imatinib was administered as a single agent at 400 mg daily for 2 weeks prior to adding a specified dose of interferon. During the dose-escalation period, no patient was able to maintain a dose of 400 mg/d of imatinib plus 5 MU of interferon daily, primarily due to hematologic toxicity. Therefore, the current starting dose in a phase II study for newly diagnosed patients is 400 mg of imatinib daily with 3 MU of interferon daily. Side effects and responses have been similar to those in a larger study described below.

A second phase I/II study combined imatinib with pegylated interferon (PEGIntron, Schering-Plough, Kenilworth, NJ). As of December 2001, 49 patients with chronic-phase CML had been entered into PISCES (PEGIntron and Imatinib Combination Evaluation Study); the median age is 52.5 years, with 32 newly diagnosed patients (<6 months since diagnosis).35 Imatinib was administered for 2 weeks prior to adding a specified dose of interferon. After 6 months of treatment, the major cytogenetic response rate was 73.3% (n = 22) overall and 82.4% (n = 14) in the newly diagnosed patients (CR, 36.7% and 41.2%, respectively) (Table 5). Of the 22 patients achieving a major cytogenetic response, 55% were taking either 200 mg of imatinib plus 0.25 μg/kg/wk PEGIntron (n = 8) or 200 mg imatinib plus 0.5 μg/kg/wk PEGIntron (n = 4). In the phase I study, only one of seven (14%) patients treated with 200 mg/d of imatinib had a cytogenetic response, suggesting that the combination of imatinib with interferon has improved activity over imatinib alone. Myelosuppression was common, with 30 of 49 patients experiencing grade 3/4 neutropenia within the first month on study while taking 400 mg imatinib plus 0.5 μg/kg/wk PEGIntron. Based on this, the recommended dose for phase II/III studies is 400 mg of imatinib with 0.25 μg/kg/wk PEGIntron. Grade 1/2 adverse events were common and included flu-like symptoms/fatigue (45%), increased liver transaminases (transient) (55%), musculoskeletal pain (39%), edema (33%), headache (33%), and nausea (33%). Grade 3/4 adverse events were rare, with febrile neutropenia and joint/muscle pain experienced by 6% of patients. These data indicate that the combination of imatinib plus interferon can be administered safely, but whether improved results can be obtained will require a large, prospective, randomized study.

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Imatinib in combination with Ara-C 

In vitro data have also demonstrated additive or synergistic antiproliferative effects for the combination of imatinib with Ara-C using Bcr-Abl–positive cell lines and in colony-forming assays using CML patient samples.15, 47, 49 Based on these data, phase I/II studies of this combination are in progress.

A phase I study of the combination of imatinib plus low-dose Ara-C was initiated in chronic-phase CML patients who failed to respond to interferon.8 Twenty-two patients were divided into four cohorts. Imatinib was given daily at 400 or 600 mg and Ara-C administered on days 14 to 28 with cycles repeated every 28 days. The maximally tolerated dose was 400 mg of imatinib daily with 20 mg/m2 of Ara-C given for 2 of every 4 weeks. Myelosuppression at the highest dose level necessitated dose reductions in all patients such that no patient remained on treatment with 600 mg plus 20 mg/m2 of Ara-C. With a median follow-up duration of 300 days, the CHR rate was 86% and the major cytogenetic response rate was 32%. This compares favorably with the results reported in phase I and II studies of imatinib alone and served as the impetus for a phase II study of this combination in newly diagnosed patients.

A phase II study was initiated in France to assess the tolerability and the efficacy of imatinib in combination with Ara-C. Imatinib was administered at a daily fixed dose of 400 mg in combination with Ara-C at 20 mg/m2 on days 14 to 28 days with cycles repeated every 28 days. From June to August 2001, 30 previously untreated chronic-phase CML patients within 6 months of diagnosis were recruited. The median age was 48 years (range, 22 to 81 years). After 6 months of treatment, 24 of 30 (80%) patients had achieved a major cytogenetic response, 17 (57%) of whom achieved a complete cytogenetic response (Table 5; F. Guilhot, personal communication). The dose of Ara-C was reduced to a median of 77% to 91% of the expected dose (range, 48% to 108%) and the median dose of imatinib was 400 mg, demonstrating that the dose of 400 mg was not affected by the addition of low-dose Ara-C. Grade 3/4 nonhematologic toxicities included nausea (1.1%), rashes (2.1%), abdominal pain (1.5%), and weight increase (1.6%). Common grade 1/2 adverse events included nausea (51%), muscle cramps (38.7%), periorbital edema (27.6%), vomiting (22%), diarrhea (20.3%), rashes (17%), weight increase (16.7%), myalgias (13.9%), arthralgias (12.6%), and dyspepsia (13.5%). Grade 3/4 neutropenia and thrombocytopenia occurred in 35% and 20% of patients, but were rarely associated with infectious or bleeding complications.

Based on the phase II data with higher doses of imatinib and the combinations of imatinib with interferon and Ara-C, a prospective, randomized phase III trial has been designed. This study will compare standard therapy for newly diagnosed chronic-phase CML patients treated with 400 mg of imatinib per day to higher dose therapy versus imatinib at 400 mg per day with interferon versus 400 mg per day of imatinib with low-dose Ara-C. This study is expected to be activated by the end of 2002.

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Other combinations and resistance to imatinib 

In vitro combinations of imatinib with various antileukemic agents have been investigated and are summarized in Table 7. These studies used various Bcr-Abl–positive cell lines and some studies also reported on colony-forming assays using primary patient cells. A consistent observation from these studies is that increased synergy is observed at higher levels of Bcr-Abl kinase inhibition.27, 49 The implication of this is that full doses of imatinib might be required to achieve optimal therapeutic responses in combination regimens.

Table 7. Summary of conventional chemotherapeutic agents that have been tested in combination with imatinib
Combined DrugSynergyAdditivityAntagonism
Ara-C✓✓
Carboplatin✓
Corticosteroids✓
Etoposide✓
Idarubicin✓
IFN✓✓
Mafosfamide✓
Mitoxantrone✓
Treosulfan✓
Vincristine✓
Nimustine hydrochloride ✓
Busulfan ✓
4-OH-cyclophosphamide ✓
Daunorubicin ✓
Doxorubicin ✓
Fludarabine ✓
Gemcitabine ✓
Taxotere ✓
Thiotepa ✓
Cladribine ✓
Hydroxyurea ✓✓
Methotrexate ✓
Topotecan ✓

NOTE. Included are all published results in the studies of Topaly et al,49 Thiesing et al,47 and Kano et al.23 Joint action studies were performed using myeloid or lymphoid CML blast crisis cell lines or using Bcr-Abl–negative cell lines with engineered Bcr-Abl expression.

In addition to the compounds listed in Table 7, many novel agents have shown activity against Bcr-Abl–expressing cell lines, and their activity in combination with imatinib is summarized in Table 8.

Table 8. Summary of novel antileukemic agents in combination with imatinib
AgentMolecular Mechanism(s)References
17-AAGhsp90 chaperone function inhibition48
AdaphostinTyrosine kinase inhibition33
AG490Tyrosine kinase inhibition45
As2O3Induction of mitochondrial damage, Bcr-Abl downregulation28, 40
Bestatin, actinoninAminopeptidase inhibition42
DecitabineDNA hypomethylation27
HomoharringtonineInhibition of protein synthesis23
LeptomycinNuclear entrapment of Bcr-Abl51
PD184352MAPK kinase inhibition53
Wortmannin, LY294002PI3-kinase inhibition26
PS341Proteasome inhibition17
SCH66336, L-744,832Farnesyl transferase inhibition22, 48
TRAILInduction of apoptosis34
Trichostatin AHistone deacetylase inhibition27

Abbreviations: As2O3, arsenic trioxide; hsp90, heat-shock protein 90; PS341, proteasome inhibitor 341; MAPK, mitogen-activated protein kinase, 17-AAG, allylamino-17-demethoxygeldanamycin; TRAIL, tumor necrosis factor-α–related apoptosis-inducing ligand.

More details on the activity of these agents is contained in a review by La Rosee et al.29

Although many of the combinations will be tested in clinical trials, based on single-agent activity, more rational combinations would be based on known mechanisms of resistance. In the largest studies of resistance or relapse, several consistent themes emerge. In primary resistance, that is, for patients who do not respond to imatinib therapy, Bcr-Abl–independent mechanisms are most common.19 In contrast, the majority of patients who relapse on therapy with imatinib reactivate the Bcr-Abl kinase. In these studies, greater than 50% and perhaps as many as 90% of patients with hematologic relapse have Bcr-Abl point mutations in at least 13 different amino acids scattered throughout the Abl kinase domain (Fig 1).2, 19, 20, 41, 44, 52

  • View full-size image.
  • Fig. 1. 

    Schematic of point mutations in the Abl kinase domain. The Abl kinase domain, from amino acid 240 to 500, is shown with the adenosine triphosphate (ATP) binding domain (P), the catalytic domain (C), and the activation loop (A). Numbers below the kinase domain designate amino acids that are mutated in patients who relapsed on therapy with imatinib. Vertical lines above the kinase domain indicate the number of times each amino acid has been found to be mutated, as compiled from several sources.2, 19, 20, 44, 52 (Adapted from Shah et al,44 with permission of Elsevier Science.)

Other patients have amplification of Bcr-Abl at the genomic or transcript level.19

It should be noted that the studies described above represent a minority of CML patients, who had advanced-phase disease. The majority of patients diagnosed with CML will be in the chronic phase, most will obtain a complete cytogenetic response with imatinib, and very few have relapsed. However, only a minority attain a molecular remission. It is assumed that if these patients relapse, similar mechanisms will be operative. However, the more pressing question is the mechanism of molecular resistance: why do residual leukemia cells persist? Quiescent stem cells may be insensitive to imatinib.18, 21 If this is true, then management of this group of patients may differ substantially from patients with relapses.

Regardless, in relapsed patients, the Bcr-Abl kinase remains a good target. Abl kinase inhibitors with specificity that differs from imatinib have already been synthesized.7, 33, 45 Whether these compounds will inhibit some or all of the Bcr-Abl mutations that have been described needs to be determined. It is conceivable that several inhibitors, analogous to cocktails of protease inhibitors for human immunodeficiency virus, would be necessary and that the appropriate inhibitors would be chosen based on the molecular profile of mutations present in individual patients. Given that Bcr-Abl kinase activity has been reactivated in relapsed patients, it might also be useful to target downstream signaling pathways, such as Raf/MEK/ERK, PI3-kinase, AKT, or ras. For example, two groups recently reported in vitro sensitivity of imatinib-resistant Bcr-Abl–positive cell lines to a farnesyl transferase inhibitor.22, 48 Moreover, this compound sensitized cells to imatinib, even imatinib-resistant cell lines.22 Alternatively, strategies to increase Bcr-Abl protein degradation using agents such as geldanamycin, 17-AAG, or arsenic trioxide might be useful.28, 40, 48

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Conclusion 

Imatinib is a highly effective therapy for CML, yet numerous questions remain. Despite a complete cytogenetic response rate of 68% in newly diagnosed chronic-phase patients, the durability of these responses in unknown. Whether combinations of imatinib with other therapies can increase the molecular remission rate and whether this will prolong survival is also unknown. How best to integrate imatinib with stem cell transplantation is a topic of ongoing debate.

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References 

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☆ Supported by grants from the National Cancer Institute, The Leukemia and Lymphoma Society, Burroughs Wellcome Fund, T. J. Martell Foundation, and the Doris Duke Charitable Foundation.

☆☆ Address reprint requests to Brian J. Druker, MD, Oregon Health & Science University, L592, 3181 SW Sam Jackson Park Rd, Portland, OR 97239.

PII: S0037-1963(03)70042-0

Seminars in Hematology
Volume 40, Issue 1 , Pages 50-58, January 2003

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