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The Oncologist, Vol. 9, No. 3, 259–270, June 2004
© 2004 AlphaMed Press

Optimizing Treatment of Chronic Myeloid Leukemia: A Rational Approach

Richard M. Stone

Dana-Farber Cancer Institute, Boston, Massachusetts, USA

Correspondence: Richard M. Stone, M.D., Dana-Farber Cancer Institute, 44 Binney Street, Room D-840, Boston, Massachusetts 02115, USA. Telephone: 617-632-2214; Fax: 617-632-2933; e-mail: rstone{at}partners.org


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Current Options for CML...
 Resistance to Imatinib
 Current Approach to...
 Summary and Conclusions
 References
 
After completing this course, the reader will be able to:

  1. Discuss the rationale for using imatinib as front-line therapy for chronic phase CML.
  2. Interpret the results of the phase III trial comparing imatinib with interferon-alfa plus Ara-C in chronic-phase CML.
  3. Evaluate various options for CML treatment including imatinib, oral chemotherapy, interferon-based approaches, and allogeneic stem cell transplantation.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Current Options for CML...
 Resistance to Imatinib
 Current Approach to...
 Summary and Conclusions
 References
 
Imatinib mesylate, a novel, molecularly targeted agent for the treatment of chronic myeloid leukemia (CML), has expanded the management options for this disease and provided a paradigm for the treatment of other cancers. Imatinib is a potent, specific inhibitor of BCR-ABL, the constitutively active protein tyrosine kinase critical to the pathogenesis of CML. A randomized, phase III comparison of imatinib with interferon-alfa plus cytarabine as initial treatment for newly diagnosed chronic-phase CML, which demonstrated significantly higher rates of disease response with less toxicity, better quality of life, and a significantly longer progression-free survival time, provided the most persuasive data supporting a major role for imatinib. Currently, allogeneic stem cell transplantation is the only treatment modality with long-term data demonstrating curative potential in CML. An option for less than half of CML patients and associated with substantial morbidity and mortality, transplantation may still be appropriate initial therapy for certain patients. Busulfan and hydroxyurea have no demonstrable effect on disease natural history. The interferon-plus-cytarabine combination can induce durable cytogenetic remissions and was previously the CML pharmacotherapy standard of care, but it is often poorly tolerated. Imatinib is now indicated as first-line therapy for CML in all phases.

Key Words. Leukemia, myeloid, chronic • Stem cell transplantation • Antineoplastic agents • Imatinib • Interferon-alfa


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Current Options for CML...
 Resistance to Imatinib
 Current Approach to...
 Summary and Conclusions
 References
 
Chronic myeloid leukemia (CML) is a clonal proliferative malignancy originating from a pluripotent hematopoietic stem cell [1–3]. Until recently, the therapeutic armamentarium for CML has been limited to allogeneic stem cell transplantation (SCT), conventional chemotherapy with such agents as busulfan (BUS) and hydroxyurea (HU), and treatment with interferon-alfa (IFN)-based regimens [4]. All these options have major drawbacks with respect to efficacy and tolerability.

The introduction of imatinib mesylate (Gleevec®, Glivec® formerly STI571; Novartis Pharma AG; Basel, Switzerland), a potent and specific inhibitor of the BCR-ABL tyrosine kinase, has caused rapid change in the management of patients with CML. The development of this rationally designed, molecularly targeted agent was made possible by the identification of a consistent chromosomal abnormality, termed the Philadelphia chromosome (Ph), in patients with CML [5]. This abnormality is a reciprocal translocation between the long arms of chromosomes 9 and 22, leading to the generation of the BCR-ABL fusion oncogene and its protein product, the constitutively active BCR-ABL tyrosine kinase [3, 6]. BCR-ABL tyrosine kinase activity is sufficient to cause leukemia [7–9], and is thus a logical target for imatinib intervention.

Preclinical studies demonstrated that imatinib specifically killed BCR-ABL-dependent cell lines and was orally bioavailable [2]. Phase I/II clinical testing in patients with chronic-phase (IFN-intolerant or -refractory), accelerated-phase, and blast-phase CML subsequently demonstrated unprecedented efficacy and safety results [4, 10–17]. On the basis of these findings, the phase III International Randomized Interferon vs STI571 (IRIS) study was undertaken to compare imatinib with the combination of IFN plus cytarabine (IFN/Ara-C) as initial therapy for newly diagnosed chronic-phase disease [18]. The original impetus for this trial was to determine whether the high rate of cytogenetic response in advanced chronic-phase patients noted in the phase II trial translated into disease-free and overall survival benefits. The results showed that imatinib monotherapy was superior—based on a greater cytogenetic response, slower progression to the advanced phase, and better tolerability—to the IFN-based regimen. Imatinib is now approved for the first-line treatment of CML and is the preferred pharmacotherapeutic agent [19].

Physicians and patients face key questions concerning CML management as findings continue to be reported from ongoing studies. Two of these questions are the focal points of this review. First, what is the appropriate place of the various modalities currently available for the treatment of CML? Second, given that imatinib therapy has been demonstrated to be the current gold standard for drug therapy [19], should patients receiving an IFN-based regimen be switched to imatinib?


   CURRENT OPTIONS FOR CML TREATMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Current Options for CML...
Resistance to Imatinib
 Current Approach to...
 Summary and Conclusions
 References
 
Allogeneic Stem Cell Transplant
Currently, allogeneic SCT is the only treatment with known curative potential in CML, but it is an option for only about 40% of the patients with this disease [19]. Long-term survival rates associated with human leukocyte antigen (HLA)-matched related-donor transplants range from 50%–75% in patients with chronic-phase CML (Table 1Go). Survival rates after transplantation during the accelerated phase are approximately 50% lower, and 5-year survival rates are <20% for patients who receive transplants during blast crisis [20, 21]. Approximately 75%–90% of patients in complete hematologic remission following transplantation test negative for residual leukemia as measured by reverse transcriptase polymerase chain reaction (RT-PCR) amplification of BCR-ABL transcripts [22, 27]. The significance of the presence of RT-PCR amplified transcripts following SCT is somewhat controversial, but this finding may augur a clinical relapse.


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  		Table 1. Results of allogeneic bone marrow transplantation in patients with CML in chronic phase
 
The success of SCT is age dependent when total body irradiation (TBI)-based conditioning regimens are used. Results are optimal for patients younger than 21 years, and there is a steady drop-off in survival with each successive decade [20, 28, 29]. In contrast, recent data suggest that preparative regimens using pharmacokinetically targeted busulfan (BUS) and cyclophosphamide without TBI may yield superior survival rates with no age effect in patients up to 65 years [19, 30–32]. However, less than half of all patients with CML are younger than 60 years [19]. The risk for relapse after allogeneic transplant in CML is about 20%. Many patients who relapse respond to donor leukocyte infusions (so-called adoptive immunotherapy) [33, 34].

SCT additionally carries a significant risk of treatment-related morbidity and mortality. The probability of SCT-related death has been reported to range from 20%–40% [4]. A related HLA-matched donor can be found for fewer than 30% of CML patients [20, 21]. Transplants from unrelated or non HLA-matched donors have higher mortality risks. Use of an allograft from an HLA-matched unrelated donor (URD) can be considered if the patient does not have an HLA-identical sibling, but this option has historically been limited by donor availability and by greater toxicity (due mainly to the effects of graft-vs-host disease [GVHD]) than with related-donor transplants [35, 36]. However, recent reports suggest that results with URD molecularly matched transplants in selected younger patients can approach those achieved with related-donor transplants [35, 36].

Pre-SCT conditioning therapy results in regimen-related toxicity that is moderate to severe in most cases [4, 37]. TBI can have long-term effects, such as cataracts, growth retardation, and secondary malignancy [20]. Moderate-to-severe acute GVHD and chronic GVHD occur in as many as 63% and 75% of patients, respectively, and are the cause of death in 2%–13% [4]. With an HLA-matched donor and the use of current prophylactic measures, the rate of grade 3 or grade 4 acute GVHD now approaches 35% [4, 35]. After SCT, patients are at risk for death from such complications as bacterial, fungal, or cytomegalovirus infection and interstitial pneumonitis, although the use of ganciclovir and fluconazole as well as other improvements in postprocedural care have led to better outcomes in recent years [4, 35]. In summary, while allogeneic SCT is associated with a high cure rate (up to 70% if performed in early chronic phase), its acceptance is hindered by treatment-associated morbidity and mortality as well as the availability of less toxic approaches to therapy. A reduction in treatment-related mortality with reduced-intensity conditioning allogeneic transplants may represent a critical improvement in the immunotherapeutic approach to CML relative to standard allogeneic transplants if initial reports of high response rates are confirmed with longer follow-up [38].

Chemotherapy
The alkylating agent BUS, introduced in the 1950s, was shown to reduce elevated white blood cell counts and disease-related signs and symptoms in a majority of patients with CML [39]. However, this agent causes serious adverse effects, including myelosuppression as well as pulmonary, hepatic, and cardiac fibrosis [4, 39, 40]. Hydroxyurea (HU), a ribonucleotide reductase inhibitor, has demonstrated a more rapid onset of action and better side-effect profile than BUS [39]. However, like BUS, HU monotherapy does not produce cytogenetic remission or significantly delay the onset of accelerated-phase or blast-crisis CML [3], and its effects are primarily palliative. Adverse effects associated with HU therapy include nausea and other gastrointestinal reactions, myelosuppression, skin atrophy, and drug fever [10, 41–43]. Long-term therapy can produce a lichenoid dermopathy [44], lower-extremity ulcers [45–50], cutaneous squamous cell carcinoma [51], gangrene of the toes [52], vasculitis [41, 53], and life-threatening pulmonary reactions [42, 54].

The plant alkaloid homoharringtonine (HHT) has been shown to have efficacy in treating CML both as monotherapy and when administered with Ara-C [55, 56]. However, at high doses and with short infusion schedules, HHT has been associated with serious cardiovascular complications, such as hypotension and arrhythmias [55].

Interferon-alfa
Treatment with recombinant IFN can induce hematologic and cytogenetic remissions in patients with CML [57, 58]. In studies in which IFN was administered as monotherapy or in combination with Ara-C, major cytogenetic responses (MCRs) were reported in 10%–46% of patients with chronic-phase CML, and 22%–87% had complete hematologic responses (CHRs) (Table 2Go) [4]. In patients with advanced disease, IFN demonstrated considerably less activity [40].


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  		Table 2. Results of IFN therapy in patients with CML in chronic phase
 
In the largest noncomparative study of IFN as a single agent to treat chronic-phase CML, the median duration of remission was 52 months, with a median survival of 66 months for the entire cohort [59]. Comparative trials have shown a modest statistically significant longer survival time for patients given IFN, versus conventional chemotherapy with BUS or HU (Table 3Go). Survival time was longer for patients who achieved MCRs than for those who did not, but only 5%–10% of IFN-treated patients had sustained, complete disappearance of Ph+ cells [3, 64].


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  		Table 3. Comparison of results of IFN therapy versus chemotherapy in patients with CML in chronic phase
 
In attempts to improve upon the rate and duration of response, IFN has been tested in combination with chemotherapeutic agents. In a randomized trial of IFN/Ara-C (n = 360) versus IFN alone (n = 361) in the treatment of patients with newly diagnosed CML, 12-month rates of CHR (66% vs 55%; p = 0.003) and MCR (41% vs 24%; p < 0.001) were significantly higher for patients given Ara-C [62]. Survival was also significantly better when the regimen included Ara-C, but major toxicities caused 26% of the patients receiving IFN/Ara-C to discontinue therapy [62].

Long-term follow-up data for 512 patients treated with IFN-based therapies between 1981 and 1995 confirm the results of previous studies [63]. A total of 140 patients (27%) achieved complete cytogenetic response (CCR), which was durable (median of 10.6 years) in 44 patients (31%) or approximately 10% of all the IFN-treated patients. RT-PCR testing of bone marrow samples from a subset of patients in CCR suggested that molecular response correlated with cytogenetic response. Measured from the date of the first CCR, 10-year MCR rates were 100% for patients with persistently negative RT-PCR results (n = 20), 76% for those with transiently negative results (n = 18), and 46% for those with only positive results (n = 32) (p < 0.001). The 10-year survival rate was 78% among the 140 patients who achieved CCRs; among the total of 78 patients monitored by RT-PCR, only two had died of CML-specific causes at last follow-up (median follow-up duration for all CCR patients was 128 months), and those two had remained RT-PCR positive [63].

The correlation between CCR and survival is further supported by a recent analysis of studies of IFN therapy that showed that the best therapeutic results were obtained in low-risk patients (i.e., risk ratio <0.8 based on Sokal risk score) who achieved CHRs within 3–6 months of the initiation of IFN treatment, MCRs within 1 year, and CCRs thereafter [65]. Approximately 50% of the patients who achieved CCRs with IFN therapy became long-term survivors. Therefore, CCR can be regarded as an early surrogate marker for long-term survival in IFN-treated CML patients [63, 65]. As with any such marker, it may be difficult to determine whether the response, per se, predicts a better outcome, or whether it mainly defines a better risk group of patients.

IFN therapy is associated with substantial toxicity. The majority of patients receiving IFN-based treatment experience an initial influenza-like syndrome of fever, chills, myalgias, malaise, and headache, as well as nausea, vomiting, or diarrhea [4, 40, 59]. Adverse effects occurring later are dose limiting in up to 20% of patients and include persistent fatigue, weight loss, neurotoxicity, depression, insomnia, alopecia, marrow hypoplasia, and occasional immune-mediated complications [12, 40, 62]. CML patients with pretreatment neurologic or psychiatric diagnoses are at a significantly greater risk for the development of severe neuropsychiatric toxicities during therapy with IFN/Ara-C [12]. Overall, 10%–25% of patients discontinue therapy with IFN-based regimens because of intolerance [4, 11, 62].

Imatinib
Imatinib is a novel antineoplastic agent that specifically inhibits the BCR-ABL tyrosine kinase [2]. Unlike IFN, which has a poorly understood mechanism of action in CML [3, 66], imatinib has a well-characterized and clinically measurable mechanistic basis for its activity [13].

In phase I studies, administration of imatinib at doses of 300 mg or more daily to chronic-phase patients in whom IFN therapy had failed or was not tolerable resulted in CHRs in 98% (53/54), which were sustained in 96% (51/53) of those patients during follow-up that ranged from 17–468 days (median of 265 days) [13]. Further, 55% (21/38) of the patients in blast crisis responded to imatinib; 33% of the responders (7/21) continued to receive therapy and were in remission over an observation period of up to 1 year [14].

The high rates of response were confirmed in phase II studies of imatinib in the treatment of chronic-phase, accelerated-phase, and myeloid-blast-crisis CML [15–17], prompting expedited regulatory approval of the drug. Results of the phase II trials are summarized in Table 4Go.


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  		Table 4. Efficacy of imatinib in CML: phase II trial results
 
A recent study of 36 patients with chronic-phase CML who started imatinib therapy at a dosage of 400 mg twice daily after failure of IFN showed that the high dose resulted in improvements in cytogenetic and molecular responses [67]. Twenty-four of 27 evaluable patients (89%) achieved CCRs, and 18 of 32 evaluable patients (56%) had molecular remissions (BCR-ABL transcripts undetectable in 41%) as demonstrated by quantitative RT-PCR testing. The median duration of follow-up was 15 months. The side-effect profile was similar to that in trials with the standard 400 mg/day dosage of imatinib for CML in chronic phase. In another study, dose escalation to 600 mg/day or 400 mg twice a day was effective in overcoming disease relapse or refractoriness in patients with chronic-phase CML who initially received 400 mg/day of imatinib after failure of IFN therapy [68].

Treatment with imatinib was well tolerated in all trials, including the high-dose studies. The most frequently reported adverse effects included edema, nausea, diarrhea, muscle cramps, and rash [13–15]. The majority of adverse events were mild to moderate. In a small percentage of patients (<1% in chronic phase; 3% in blast crisis), generalized fluid retention occurred, including pulmonary edema, pleural or pericardial effusion, ascites, or anasarca [69]. Myelosuppression was more common in patients with advanced CML and in those receiving higher imatinib doses; however, cytopenia did not necessarily require withdrawal of therapy or dose reduction [15–17, 69]. In the phase II study of imatinib in myeloid blast-crisis patients, only grade 1 or grade 2 edema was more frequent in the 600-mg than in the 400-mg dose group [17]. The incidences and severities of all other toxicities were comparable in the two groups.

To investigate whether imatinib therapy could modify disease natural history in CML, a phase III study, the IRIS trial, compared imatinib (400 mg/day) with IFN (target dose of 5 MU/m2/day s.c.) plus Ara-C (20 mg/m2/day s.c. for 10 days per month) in the initial treatment of newly diagnosed CML in chronic phase [18]. In that open-label, multicenter trial, 1,106 patients were randomized 1:1 to one of the two regimens. Crossover to the alternative arm was permitted for drug intolerance or treatment failure.

Patients treated with imatinib had significantly higher rates of CHR and CCR than those treated with IFN (Table 5Go) [18]. The estimated rate of freedom from progression at 18 months was also significantly greater in the imatinib (96.7%) than in the IFN (91.5%) treatment group (p < 0.001).


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  		Table 5. Imatinib versus IFN-based therapy for newly diagnosed CML in chronic phase—best observed responses in the IRIS trial [18]
 
Imatinib was significantly better tolerated than the combination regimen in the IRIS study [18]. Of the 553 patients in the IFN arm, 318 (57.5%) crossed over to the imatinib arm, 136 (43%) because of treatment intolerance. In contrast, only 11 imatinib-treated patients (2%) crossed over, four because of treatment intolerance. The side-effect profiles of imatinib and IFN in the IRIS study were consistent with those in previous studies of these agents. Compared with the imatinib-treated patients, the patients who received IFN/Ara-C had higher rates of hematologic adverse events and serum transaminase elevations as well as a much higher likelihood of grade 3 and grade 4 toxicities overall [18]. Quality of life (QOL) was also significantly better with imatinib, as demonstrated by a significant decline in QOL scores among patients in the IFN treatment arm compared with a preservation of baseline scores among those in the imatinib arm (p < 0.001) [70].

Imatinib monotherapy resulted in a significantly greater likelihood of molecular response than did the IFN/Ara-C combination in the IRIS trial [71]. A previous study of IFN-treated patients demonstrated that levels of BCR-ABL transcripts correlated inversely with remission duration [72]. In the IRIS trial, 32% of imatinib-treated patients had >3 log reductions in RT-PCR measured BCR-ABL transcript levels at the time of CCR, whereas none of the IFN-treated patients demonstrated a similar reduction. After 12 months of therapy, 39% of imatinib-treated patients were estimated to have at least a 3 log reduction in BCR-ABL, versus 2% of all IFN-treated patients (p < 0.001). Of 18 patients given imatinib who were monitored for more than 12 months after CCR, 94% had >3 log reductions in their leukemia burden.

Improvements in the rate and rapidity of major responses were observed in a separate study of imatinib therapy in patients with previously untreated chronic-phase CML that included an 800-mg/day treatment group [73]. Among the patients given that dose, 90% (103/114) achieved CCRs, 63% (71/112) had a RT-PCR-measured BCR-ABL/ABL ratios <0.05%, and BCR-ABL was undetectable by PCR in 28% after a median follow-up period of 15 months. The response rates for the historical control group of patients in that study who received 400 mg/day of imatinib were 74% (37/50) with CCRs and 56% (26/46) with BCR-ABL/ABL ratios <0.05%. Compared with 400-mg imatinib, high-dose imatinib was associated with achievement of significantly better CCRs (p = 0.0005). There was a somewhat higher rate of myelosuppression in the 800-mg treatment group.

Results of the IRIS study reported to date demonstrate that imatinib monotherapy is significantly more effective and better tolerated than IFN/Ara-C. Superior outcomes were seen in molecular, cytogenetic, and hematologic response rates; progression-free survival; and QOL. Additional data on disease-free and overall survival are awaited as follow-up continues.


   RESISTANCE TO IMATINIB
Top
 Learning Objectives
 Abstract
 Introduction
 Current Options for CML...
 Resistance to Imatinib
Current Approach to...
 Summary and Conclusions
 References
 
Although imatinib is unquestionably effective in treating CML, some patients ultimately relapse with resistant disease. Resistance may develop through several mechanisms, the most common of which is reactivation of BCR-ABL kinase activity within the leukemic cells by either point mutations [74–76] or gene amplification [74, 77, 78]. Point mutations within the tyrosine kinase binding site can prevent imatinib from binding by interrupting critical contact points between imatinib and the protein or by inducing a conformation to which imatinib cannot bind [79]. In vitro studies have demonstrated that some mutants (e.g., T315I) have 1 or 2 log higher 50% inhibitory concentration (IC50) values for imatinib compared with wild-type BCR-ABL [80, 81], whereas others have slightly higher IC50 values [82]. These findings suggest that, depending on the mutation present, dose escalation may be an effective strategy for restoring responsiveness to imatinib [82].

Persistent BCR-ABL kinase activity despite imatinib therapy may also be related to overexpression of the BCR-ABL protein [82]. In some cases, gene amplification has been demonstrated [74, 83]. As is the case with some mutations, dose escalation may restore responsiveness to imatinib in patients with increased BCR-ABL expression as an underlying cause of resistance [82]. Other possible causes of resistance include elevated levels of the multidrug resistance protein 1 [78]; imatinib binding to alpha 1 acid glycoprotein [84]; and additional molecular abnormalities other than BCR-ABL, which may prevent apoptosis of the malignant clone despite effective BCR-ABL kinase inactivation by imatinib [78]. Currently, efforts are continuing to further elucidate the mechanisms of imatinib resistance and develop strategies (e.g., combination with other therapeutic agents) that will expand the usefulness of imatinib.


   CURRENT APPROACH TO PHARMACOTHERAPY OF CML
Top
 Learning Objectives
 Abstract
 Introduction
 Current Options for CML...
 Resistance to Imatinib
 Current Approach to...
Summary and Conclusions
 References
 
The range of options for the management of CML widened considerably with the introduction of imatinib. With imatinib now established as the first-line pharmacotherapy for newly diagnosed CML, a key consideration is how to incorporate it into the treatment of patients who are candidates for SCT [19, 69]. One approach is to administer imatinib initially to all patients with a new diagnosis of CML while they are being evaluated for a transplant (Fig. 1Go). Peggs and Mackinnon [19] have recommended that patients younger than 60 years of age who have incomplete cytogenetic responses to first-line imatinib therapy and have suitable donors undergo transplantation. For inadequately responding patients without donors, an increase in the imatinib dose, with or without the addition of other agents (e.g., IFN, Ara-C), can be considered [19]. The choices are less clear for patients who respond adequately to imatinib and have HLA-matched donors. The 10%–15% of patients at low risk for death from transplantation (i.e., young patients with sibling donors) could be considered for immediate SCT [19]. Transplantation among higher-risk patients might be reserved for those who show signs of disease progression on imatinib. For patients with advanced CML or Ph+ acute lymphoblastic leukemia, induction of a second chronic phase by using imatinib, with its low levels of toxicity, may make SCT an option [69]. However, until long-term survival data are available for imatinib-treated patients, decision making regarding transplant candidates with CML, particularly newly diagnosed cases, will present a challenge. Patients with potential transplant donors who are receiving imatinib should be monitored closely. While the exact monitoring schedule is unclear, an approach that includes annual bone marrow sampling (to screen for secondary cytogenetic abnormalities) and semiannual assessments of disease burden (e.g., peripheral blood fluorescence in situ hybridization for BCR-ABL or quantitative PCR if cytogenetically negative) seems a reasonable minimum. In such patients, the lack of an MCR or loss of a hematologic or chromosomal response should be considered grounds for proceeding to SCT.



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  		Figure 1. Algorithm for treating CML in patients less than 60 years old. Reproduced with permission from Peggs and Mackinnon [19].

 
Should patients who are currently receiving HU or IFN-based treatments be switched to treatment with imatinib? The available evidence suggests a strong rationale for making such a recommendation, particularly for HU-treated and IFN-nonresponsive patients. Achievement of a CCR is associated with 5- to 10-year survival rates of approximately 50%–80% and has been a consistent early marker of survival prolongation in CML patients treated with IFN-based regimens [20, 30, 62–64, 85]. Trials of chemotherapy with HU or BUS demonstrated that they do not produce cytogenetic remissions [3, 4]. In the IRIS trial, 8.5% of patients achieved CCRs with IFN-based first-line treatment, compared with 73.8% of patients given imatinib [18]. Among patients who crossed over from the imatinib to the IFN/Ara-C arm (n = 11), none achieved cytogenetic responses, whereas 39.6% of the patients who crossed over from the IFN regimen to imatinib (n = 318) achieved CCRs. These data clearly indicate that patients who do not achieve and maintain CCRs with IFN-based therapy should be considered as candidates for imatinib treatment.

Imatinib treatment is administered orally and is generally well tolerated. In contrast, IFN must be given by subcutaneous injection and is associated with considerable toxicities. Discontinuation of IFN-based treatment owing to intolerance or diminished QOL occurred in up to 25% of patients in reported series [4, 11, 62]. In the IRIS study, <1% of imatinib-treated patients, versus 19% of IFN/Ara-C–treated patients, crossed over to the alternative therapy because of intolerance at a median of 6 months of follow-up [86]. At 14 months, 1.3% of the imatinib-treated patients and 39% of the IFN/Ara-C-treated patients had crossed over [87] and, at 19 months, 2% and 57.5%, respectively, had crossed over, with 43% of crossovers from IFN to imatinib caused by intolerance [18]. Thus, compliance and QOL considerations suggest that treatment with imatinib is preferable to IFN-based therapy.

Should only those IFN-treated patients who do not respond to or cannot tolerate IFN be switched to imatinib? Because achievement of a CCR is associated with a longer survival time, consideration can be given to switching patients who achieve CHRs but not CCRs during IFN therapy. For the 5%–10% of patients who may obtain long-term CCRs with IFN-based therapy [3], it is presently unclear whether switching to imatinib is advantageous. While toxicity, compliance, and QOL considerations generally favor the use of imatinib, long-term clinical data are not yet available.

For all CML patients treated with imatinib, continuous and adequate dosing is essential for optimal results [69]. The recommended dosage of imatinib is 400 mg/day for patients with chronic-phase CML and 600 mg/day for patients with advanced disease. Higher dosages may increase the rate of CCR and the reduction of BCR-ABL transcript levels in patients with chronic-phase disease [67, 73], as well as improve cytogenetic and hematologic responses in patients with advanced CML [16, 17]. In the absence of long-term data and a definitive demonstration by sensitive testing (RT-PCR) that a complete molecular remission has been achieved, imatinib therapy should be continued in patients with CCRs induced by this agent.


   SUMMARY AND CONCLUSIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Current Options for CML...
 Resistance to Imatinib
 Current Approach to...
 Summary and Conclusions
References
 
The introduction of imatinib has heralded a new era in the treatment of CML. Recent phase III study data confirm that, in comparison with IFN-based therapy, treatment with imatinib in patients with newly diagnosed CML results in significantly higher hematologic and cytogenetic response rates, greater reductions in levels of molecular disease markers, better tolerability and QOL, and significantly longer progression-free survival times. Given the previous findings from IFN trials that achievement of a CCR is associated with long-term survival and that reduced levels of BCR-ABL transcripts correlate with prolonged remission duration, the phase III results with imatinib are highly encouraging.

Based on the results of the IRIS trial, imatinib was recently approved by U.S. and European regulatory authorities as first-line treatment for patients with a new diagnosis of CML and is the pharmacotherapy of choice for this cancer. To define the relative roles of imatinib and SCT, longer follow-up is needed.

Imatinib has been shown to induce higher rates of cytogenetic remission than IFN and also to offer a superior QOL. In light of the association between a CCR and survival seen in studies of IFN, consideration of a switch to imatinib is warranted for IFN-treated patients who do not obtain CCRs with IFN.


   ACKNOWLEDGMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Current Options for CML...
 Resistance to Imatinib
 Current Approach to...
 Summary and Conclusions
 References
 
Dr. Stone receives funding from Novartis Pharmaceuticals for his participation in their speaker’s bureau and also as a consultant.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Current Options for CML...
 Resistance to Imatinib
 Current Approach to...
 Summary and Conclusions
 References
 

  1. Fialkow PJ, Jacobson RJ, Papayannopoulou T. Chronic myelocytic leukemia: clonal origin in a stem cell common to the granulocyte, erythrocyte, platelet and monocyte/macrophage. Am J Med 1977;63:125–130.[CrossRef][Medline]
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  5. Nowell P, Hungerford D. A minute chromosome in human chronic granulocytic leukemia. Science 1960;132:1947.[Free Full Text]
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Received October 7, 2003; accepted for publication March 4, 2004.




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