Optimal First-Line Treatment of Chronic Myeloid Leukemia: How to Use Imatinib and What Role for Newer Drugs?

May 1, 2007

The development of imatinib mesylate (Gleevec), a tyrosine kinase inhibitor targeted against the causative Bcr-Abl protein in chronic myeloid leukemia (CML), has resulted in hematologic and cytogenetic remissions in all phases of CML. Following imatinib treatment, more than 90% of patients obtain complete hematologic response, and 70% to 80% achieve a complete cytogenetic response. With 5 years of follow-up, the data are very encouraging, exhibiting a major change in the natural history of the disease. The understanding of at least some of the mechanisms of resistance to imatinib has led to a rapid development of new agents that may overcome this resistance. Combination strategies are currently being investigated in preliminary clinical studies and may prove to be useful. Overall, there are an increasing number of treatment options now available for patients with CML.

The development of imatinib mesylate (Gleevec), a tyrosine kinase inhibitor targeted against the causative Bcr-Abl protein in chronic myeloid leukemia (CML), has resulted in hematologic and cytogenetic remissions in all phases of CML. Following imatinib treatment, more than 90% of patients obtain complete hematologic response, and 70% to 80% achieve a complete cytogenetic response. With 5 years of follow-up, the data are very encouraging, exhibiting a major change in the natural history of the disease. The understanding of at least some of the mechanisms of resistance to imatinib has led to a rapid development of new agents that may overcome this resistance. Combination strategies are currently being investigated in preliminary clinical studies and may prove to be useful. Overall, there are an increasing number of treatment options now available for patients with CML.

Chronic myeloid leukemia (CML) is a rare disease. Although its incidence is low, its prevalence is increasing. In the United States, there are approximately 4,500 new cases of CML per year.[1] The annual incidence of CML is 1.6 cases per 100,000 adults.[1] The median age at diagnosis is 55 years. With an estimated survival rate of 90% at 5 years and an annual mortality rate of 2%, the prevalence of CML in 20 years may become 200,000 to 300,000 cases in the United States. CML is characterized by a balanced genetic translocation, involving a fusion of the Abelson oncogene (ABL) from chromosome 9q34 with the breakpoint cluster region (BCR) on chromosome 22q11.2, t(9;22)(q34;q11.2), the Philadelphia chromosome (Ph). The molecular consequence of this translocation is the generation of a BCR-ABL fusion oncogene, which in turn translates into a Bcr-Abl oncoprotein. This most frequently has a molecular weight of 210 kD (p210Bcr/Abl) and has increased tyrosine kinase activity, which is essential to its transforming capability.[2,3]

FIGURE 1


Pathways Activated by Bcr-Abl

Numerous signal transduction pathways, including Ras/Raf/mitogen activated protein kinase (MAPK), phosphatidylinositol 3 kinase, STAT5/Janus kinase, and Myc, are activated by the Bcr-Abl tyrosine kinase (Figure 1).[4,5] Perturbation of these pathways results in uncontrolled cell proliferation and reduced apoptosis. Understanding the CML pathophysiology resulted in the development of novel drugs targeting Bcr-Abl tyrosine kinase and its associated pathways.

The treatment of CML has evolved greatly over the past few years. Imatinib mesylate is now well established as the standard therapy. For many years, stem cell transplantation (SCT) and interferon-alpha were the major therapeutic choices. Long-term survival and possibly cure could be achieved with both of these modalities.[6,7] While SCT is still a valid treatment option for some patients, interferon-alpha has been replaced in CML front-line therapy by imatinib.

Imatinib mesylate is a potent and selective tyrosine kinase inhibitor that has become standard therapy for patients with any stage of CML.[3] A complete cytogenetic response can be achieved in 50% to 60% of patients treated in chronic phase after failure to respond to interferon-alpha[8,9] and in over 80% of those receiving imatinib as first-line therapy.[10,11] Responses are durable in most patients treated in early chronic phase, particularly among those who achieve major molecular responses (eg, ≥ 3-log reduction in transcript levels).[12,13]

Here we will review the current information regarding treatment of patients with newly diagnosed chronic phase CML, issues of imatinib dose schedules, imatinib toxicity and management of adverse events, monitoring of minimal residual disease, and the place of the new tyrosine kinase inhibitors in the front-line therapy arsenal of patients with newly diagnosed CML in chronic phase.

Imatinib: Front-Line Standard of Care in CML

Imatinib is an orally bioavailable 2-phenylaminopyrimidine with targeted inhibitory activity against the constitutively active tyrosine kinase of the Bcr-Abl chimeric fusion protein. Imatinib inhibits other kinases, such as c-kit, platelet-derived growth factor receptor (PDGFR)-alpha and -beta, and Abl-related gene.[14,15] Imatinib has become the standard therapy for CML because of its remarkable activity and mild toxicity profile.

Preclinical studies established that imatinib potently inhibits ABL and the related protein-tyrosine kinase ARG as well as the kinase activity of members of the class III family of receptor tyrosine kinases including KIT, PDGFRs and the macrophage colony-stimulating factor receptor CSF-1R (cFMS).[16-20] Inhibition of BCR-ABL protein-tyrosine kinase activity with imatinib blocks intracellular oncogenic signal transduction pathways.[3,21]

IRIS Trial

The efficacy of imatinib was demonstrated in the phase III International Randomized Study of Interferon and STI571 (IRIS) trial, in which treatment with imatinib at 400 mg daily was compared with combined interferon-alpha/cytarabine in patients with newly diagnosed chronic phase CML (N = 1,106).[22] After a median follow-up of 19 months, imatinib was found to be significantly better than interferon-alpha-based treatment, as shown by rates of complete hematologic response (95% vs 56% of patients; P < .001) and major cytogenetic response (≤ 35% Ph-positive cells in metaphase; 85% vs 22% of patients; P < .001). Major molecular response rates (at 12 months, 40% vs 2%) and progression-free survival were also superior with imatinib.[13,22] Adverse events reported in the imatinib group were generally mild to moderate, and included superficial edema, nausea, muscle cramps, and rashes, and grade 3/4 events were uncommon except for neutropenia (14%) and thrombocytopenia (8%).[22] Adverse event rates of all types were higher in the combination-therapy group.

TABLE 1


Best Responses in Patients Remaining on First-Line Imatinib Therapy: 5-yr Update of the Phase III IRIS Trial

A 5-year update of the IRIS study continued to show positive results (Table 1).[23] A total of 382 patients remained on imatinib front-line therapy. The cumulative best complete hematologic response, major cytogenetic response, and complete cytogenetic response rates were 98%, 92%, and 87%, respectively. The estimated 5-year event-free survival was 83%; only 6.3% of patients progressed to accelerated and blastic phases. The overall annual progression rate has declined to 0.9% in the fifth year of therapy, compared with 1.5%, 4.8%, and 7.5% in the previous 3 years, suggesting that disease progression may be diminished in the following years. The estimated 5-year survival rate was 89%; excluding non-CML deaths, it was 95%. The intensity of the cytogenetic response after 12 and 18 months of imatinib therapy has important implications regarding survival without transformation. The estimated 5-year survival rate in patients not achieving a major cytogenetic response at 12 months was significantly lower (81%) than those who achieved major cytogenetic response (complete, 97%; partial, 93%; P < .001).

FIGURE 2


Survival of Chronic Myeloid Leukemia

At 18 months of therapy, the estimated 5-year survival rate for patients not achieving a complete cytogenetic response was significantly less than for those who achieved a complete cytogenetic response (99% vs 90%; P < .001).[23] The investigators found a continuous improvement in the rate of major molecular response, which rose from 53% at 1 year to 80% at 4 years of therapy (P < .001).[23] This study did not document a survival advantage for imatinib because of the crossover design. Studies comparing the survival of imatinib-treated patients with historical cohorts treated with interferon-alpha-based therapy demonstrated the anticipated survival advantage.[9,24,25] Figure 2 shows the survival of patients treated at M. D. Anderson Cancer Center since 1965 by year of therapy.

Safety Data

Most adverse events with imatinib therapy were mild to moderate in severity. Treatment was discontinued for adverse events in 3.1% of newly diagnosed patients, in 4% of patients in chronic phase after failure of interferon therapy, and in 4% to 5% of patients in accelerated-blastic phase.[10,26-28] The most frequently reported adverse events (all grades) were superficial edema (59%-76%), nausea (47%-73%), muscle cramps (28%-62%), vomiting (21%-58%), diarrhea (39%-57%), musculoskeletal pain (40%-49%), and rash (37%-47%). Severe adverse experiences (grade 3/4) included severe fluid retention (eg, pleural effusion, pulmonary edema, and ascites) in 1% to 6%, superficial edema in 1% to 6%, hemorrhage in 1% to 19%, and musculoskeletal pain in 2% to 9%. Severe fluid retention appeared to be dose-related and was more common in the advanced-phase studies with imatinib dosages of 600 mg/d, and in the elderly.

Grade 3/4 laboratory abnormalities included neutropenia (3%-48%), anemia (< 1%-42%), thrombocytopenia (< 1%-42%), and hepatotoxicity (3%-6%). Treatment was discontinued permanently because of liver function abnormalities in less than 0.5% of patients.

Recently, imatinib was reported to be associated with cardiotoxicity and congestive heart failure, although this toxicity is rare.[29] Among 1,276 patients treated at one institution, 22 patients (1.8%), with a median age of 70 years, were identified as having symptoms that could be attributed to congestive heart failure.[30] At the time these events were reported, 8 were considered possibly or probably related to imatinib. Eighteen patients had previous medical conditions predisposing to cardiac disease: congestive heart failure (6 patients, 27%), diabetes mellitus (6 patients, 27%), hypertension (10 patients, 45%), coronary artery disease (8 patients, 36%), arrhythmia (3 patients, 14%) and cardiomyopathy (1 patient, 5%). Of the 22 patients, 11 continued imatinib therapy with dose adjustments and management for congestive heart failure symptoms with no further complications.

Management of Adverse Events

Myelosuppression, the most common adverse event with imatinib, is managed with dose interruptions and modifications.[31] The use of hematopoietic growth factors (granulocyte colony-stimulating factor [filgrastim, Neupogen] for neutropenia, oprelvekin [interleukin 11, Neumega] for thrombocytopenia, epoetin alfa [Epogen, Procrit] or darbepoetin [Aranesp] for anemia) has been reported to be safe and effective in patients with recurrent or persistent cytopenias.[32-38] Myelosuppression is frequently seen during the first 2 to 3 months of therapy. A brief treatment interruption is often sufficient to allow recovery, and most patients do not require dose reductions.

TABLE 2


Nonhematologic Adverse Events With Imatinib Therapy

Nonhematologic adverse events are relatively common but mild with imatinib, and can be managed easily with supportive care measures (Table 2). Early intervention is important to avoid more significant problems, unnecessary treatment interruptions, and dose reductions.

Imatinib Dose Schedules

The optimal dose of imatinib is not clearly defined. In the dose-finding phase I study, the maximum tolerated dose was not identified. Because of the good responses obtained at doses of 300 to 400 mg daily, particularly in patients in chronic phase, and because the blood concentration of imatinib at 400 mg daily was consistently higher than that required to inhibit 50% of BCR-ABL tyrosine kinase activity in vitro,[39,40] that dose was chosen for subsequent studies. Imatinib at 600 mg daily was more effective than 400 mg for patients in accelerated-blastic phase disease.[27,28] Among patients with CML in late chronic phase in whom interferon-alpha failed, treatment with imatinib at 400 mg twice daily resulted in a complete cytogenetic response rate of 90%, compared with 48% in historical matched controls treated with standard-dose therapy. In addition, 56% of patients had a major molecular response, including 41% with undetectable levels.[41] The toxicity profile was similar to that of imatinib at 400 mg, although there was a higher rate of grade 3/4 myelosuppression.

In patients with both prior hematologic and cytogenetic resistance to 400 mg of imatinib daily, increasing the dose to 800 mg resulted in a complete hematologic response rate of 65% and a complete cytogenetic response rate of 18%.[42] Several phase II studies, using high-dose imatinib in patients with previously untreated CML in chronic phase, have documented complete cytogenetic response rates of up to 95% and higher rates of molecular responses, particularly at the level of a 4-log or greater reduction in transcript levels.[9,43-45]

When compared with historical matched cohorts of patients treated with standard-dose therapy, patients treated with high-dose imatinib had higher rates of complete cytogenetic response (91% vs 76%, P = .002). Moreover, these occurred earlier, with 88% achieving this response after 6 months of therapy vs 56% with standard-dose therapy (P < .00001). The cumulative incidences of major molecular response and complete molecular response were significantly better with high-dose imatinib.[46] Progression-free and transformation-free survivals were significantly better in the high-dose group (P = .02 and .005). Results from ongoing randomized studies will determine whether the positive results obtained with high-dose imatinib will translate into prolonged progression-free and/or overall survival.

Monitoring Imatinib Therapy and Minimal Residual Disease

Given that most patients achieve a complete cytogenetic response with imatinib, achievement of molecular response has become the endpoint of anti-CML strategies and has led to the redefinition of therapeutic goals in CML. The IRIS trial showed that a reduction of BCR-ABL transcript levels by 3 or more logs below a standard baseline value correlated with progression-free survival.[13] In addition, one study reported that achieving a major molecular response within the first 12 months of therapy is predictive of durable cytogenetic remission.[12] However, the lack of consistency in reporting BCR-ABL transcript levels has been a source of debate.

A recent consensual proposal suggests harmonizing the differing methodologies for measuring BCR-ABL transcripts by using a conversion factor, whereby individual laboratories can express BCR-ABL transcript levels using scales that are internationally agreed upon: Results will be converted by comparing analysis of standardized reference samples with a value of 0.1% corresponding to major molecular response in all laboratories.[47] For practical purposes, a major molecular response can be defined as a reduction of BCR-ABL/ABL transcripts to 0.1% or less.[47] After a patient has achieved a complete cytogenetic response, real time polymerase chain reaction (RT-PCR) should be performed every 3 months and a routine cytogenetic analysis of bone marrow, every 12 months. This latter test may permit the detection of clonal evolution and chromosomal abnormalities occurring in normal metaphases.

Significance of Cytogenetic Abnormalities

Following treatment for CML, chromosome abnormalities have been detected in cells that do not contain the Ph chromosome. In most cases, these have followed imatinib treatment,[48-54] although isolated cases have been detected with interferon-alpha treatment.[32,33] Estimates of incidence from retrospective studies (> 100 imatinib-treated patients) range from 1.6% to 6.4%,[27-29,31] with a rate of 3.4% (34/1,001) reported in the largest study to date.[30]

The most commonly reported chromosomal changes associated with imatinib are trisomy 8 and monosomy 7, and changes may occur transiently in some patients. Risk factors identified for Ph-negative abnormalities include previous exposure to cytarabine or idarubicin[26] and shorter interval (≤ 1 year) from disease diagnosis to initiation of imatinib treatment.[33] Chromosomal changes have been detected following both imatinib monotherapy and imatinib treatment after previous therapy.

The prognostic significance of Ph-negative abnormalities remains unclear. Although some investigators have suggested an association between Ph-negative abnormalities and myelodysplasia,[26] this relationship has not been found in other studies.[29-31] In addition, it is not known if chromosome abnormalities are induced by imatinib, or if the disappearance of Ph-positive cells following cytogenetic responses to imatinib enables other chromosomal abnormalities to be observed. One study, however, has demonstrated that imatinib induces chromosome aberrations in vitro in a dose-dependent manner.[34]

Imatinib Resistance and Monitoring of Mutations

Various mechanisms have been proposed to explain resistance to imatinib. A small proportion of cases are thought to result from increased expression of Bcr-Abl kinase through gene amplification.[58,59] Resistance might also result from decreased intracellular drug concentrations caused by drug efflux proteins[60,61] or imatinib binding by plasma proteins.[62,63] Clonal evolution might contribute to imatinib resistance.[59] Lyn and Hck are overexpressed in imatinib-resistant patient isolates and cell lines, suggesting that Src family kinases may be involved in BCR-ABLindependence and progression to imatinib resistance.[64-66] However, approximately 35%-45% of cases of imatinib resistance arise because of mutations in the BCR-ABL kinase domain.[59,67]

Clinically relevant BCR-ABLmutations disrupt critical contact points between imatinib and the Bcr-Abl protein or induce structural alternations that prevent imatinib binding, often by inducing a transition from the inactive to the active conformation of the protein, to which imatinib is unable to bind.[68,69] This illustrates the disadvantages of the high specificity of imatinib for wild-type Bcr-Abl in its inactive conformation. With continued imatinib treatment, resistant mutants are selected and eventually outgrow drug-sensitive leukemic cells. The number of different BCR-ABL mutations identified has steadily increased. Clusters of mutations have been described in different areas of the Bcr-Abl molecule, and include the ATP binding site (P-loop), the imatinib binding site, the activation loop (controlling kinase activation), and the catalytic domain.[68,69] The first mutation to be identified, T315I,[58] is of particular importance, as will be discussed below.

Some BCR-ABL mutations result in a highly resistant phenotype in vitro, whereas others remain relatively sensitive, meaning that resistance can be overcome by increasing the imatinib dose.[59,70-74] Higher rates of mutations have been identified in patients who have received extended treatment, patients who did not achieve a major cytogenetic response, and those with more advanced disease.[75,76] It has also been suggested that mutations in the P-loop are associated with a poor prognosis,[75,77,78] although this has been contradicted in a separate analysis.[76] Kinase domain mutations screening for patients in chronic phase is indicated in cases of hematologic or cytogenetic resistance/relapse,[47] or if there is an increase in BCR-ABL transcript ratio of 1 log or greater.[79] Kinase domain mutations should be investigated in any patients presenting in advanced-phase disease.

Duration of Imatinib Therapy

The optimal duration of imatinib therapy is unknown. The current recommendation is to continue treatment indefinitely unless the patient experiences unacceptable toxicity or treatment failure. There is no evidence to support the concept that imatinib can safely be discontinued even after transcript levels become undetectable. Most patients who have discontinued imatinib therapy have experienced molecular or cytogenetic relapse even after sustained undetectable levels of BCR-ABL for significant periods of time.[80-82] Rousselot et al reported on 12 patients who discontinued imatinib after maintaining undetectable BCR-ABL levels for 24 months or longer; six are still PCR-negative after a median follow-up of 18 months (range: 9-24 months).[83] Of these 12 patients, 10 had been treated with interferon-alpha, suggesting that interferon-alpha immunomodulatory effects may account for the sustained and prolonged molecular responses observed upon therapy discontinuation. It has been suggested that the earliest, probably quiescent, progenitor cells in CML are insensitive to imatinib in vitro.[84] It is conceivable that these progenitors might trigger proliferation of CML once the inhibitory pressure of imatinib is eliminated.

Second-Generation Tyrosine Kinase Inhibitors

TABLE 3


Summary of Outcomes From the Dasatinib Phase II Clinical Development Program

Novel more potent tyrosine kinase inhibitors have been developed to overcome imatinib resistance. Dasatinib (Sprycel), an orally bioavailable dual Bcr-Abl and Src inhibitor, is now approved for the treatment of CML and Ph-positive acute lymphocytic leukemia after imatinib failure.[85] Dasatinib has been clinically assessed in one dose-ranging study and five subsequent studies involving more than 900 imatinib-resistant or -intolerant patients (the START program). Data from the dose-ranging study suggested that dasatinib treatment was associated with a high level of efficacy and durability.[85] Results from the START program demonstrated that treatment with dasatinib at 70 mg twice daily resulted in hematologic and cytogenetic responses across all phases of CML in both imatinib-intolerant and -resistant patients (Table 3).[86-90]

TABLE 4


Summary of Outcomes From Nilotinib Phase II Trials

Nilotinib (Tasigna) is an oral potent and selective Bcr-Abl inhibitor in advanced clinical trials.[91] In a phase I dose-escalation study (n = 119), nilotinib showed activity in patients with imatinib-resistant CML.[91] Nilotinib has also been examined in three ongoing phase II studies conducted in patients with CML and imatinib resistance or intolerance. Data are currently available from 145 patients who received nilotinib at 400 mg twice daily. Nilotinib has demonstrated clinical activity in all phases of CML; complete hematologic responses were recorded in 69%, 16%, and 4% of patients with chronic, accelerated, and blastic phase disease, respectively, and major cytogenetic responses were recorded in 46%, 28%, and 29% of patients (Table 4).[92-94]

Both agents have been investigated in patients with newly diagnosed CML. Preliminary results were recently reported for 14 patients with newly diagnosed CML treated with nilotinib at 400 mg twice daily.[95] A major cytogenetic response was observed in all patients at 3 months (complete in 13 and partial in 1); the complete cytogenetic response rate was 100% in all evaluable patients at 6 months (n = 13) and 9 months (n = 11). Major molecular response rates, at 6 and 9 months, were significantly higher with nilotinib compared to historical data with standard-dose and high-dose imatinib.[95] In another study, 24 patients with newly diagnosed CML in chronic phase were treated with dasatinib at 100 mg daily or 50 mg twice daily. The complete cytogenetic response rates at 6 and 9 months were, respectively, 73% and 95%; more favorable as compared with historical data in patients treated with standard-dose and high-dose imatinib.[96]

Two other novel agents, bosutinib (SKI-606) and INNO-406 (NS-187),[97,98] are being investigated in phase I/II clinical trials. Both compounds will eventually be explored in the front-line setting.

Stem Cell Transplantation

Because of the success of Bcr-Abl inhibitors, SCT has changed from being a preferred first-line therapy to a second- or third-line option. Despite this, SCT remains an important treatment option that offers the potential for disease cure, although this needs to be balanced with potential risks, including graft-vs-host disease, life-threatening infections, and secondary malignancy.[99,100]

Recent reports provide the best estimates of current outcomes following SCT. Data have been analyzed from 131 chronic phase CML patients receiving allogeneic SCT (bone marrow or peripheral blood) from related donors at a single institution in the United States between 1995 and 2000.[101] The estimated probability of disease-free survival at 3 years was 78%, with survival estimated at 86% and relapse estimated at 8%.

The Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT) recently provided updated data.[102] Among all European patients receiving SCT for CML between 2000 and 2003 (n = 3,018), the 2-year survival rate was 61%, transplant-related mortality was 30%, and relapse rate was 22%. However, in patients transplanted in first chronic phase from a human leukocyte antigen (HLA)-identical sibling, 2-year survival was 74%, transplant-related mortality was 22%, and relapse rate was 18%. These data illustrate that outcome following SCT is highly dependent on defined risk factors. In the EBMT study, favorable risk factors were identified as sibling donor, treatment at early disease stage, younger recipient age (< 20 vs 20-40 vs > 40), and less than 12 months from diagnosis to transplantation.[102,103]

If successful, SCT can have long-term results. In a 10-year study of patients receiving allogeneic bone marrow from siblings (46 in first chronic phase, 43 in advanced phases), mean time to hematologic or cytogenetic relapse was 7.7 years, and 46% (13/28) of long-term survivors never relapsed.[104]

Related vs Unrelated Donors

REFERENCE GUIDE

Therapeutic Agents
Mentioned in This Article

Bosutinib (SKI-606)
Cytarabine
Darbepoetin (Aranesp)
Dasatinib (Sprycel)
Epoetin alfa (Epogen, Procrit)
Granulocyte colony-stimulating factor (filgrastim, Neupogen)
Idarubicin
Imatinib mesylate (Gleevec)
INNO-406 (NS-187)
Interferon-alpha
Nilotinib (Tasigna)
Oprelvekin (interleukin 11, Neumega)

Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.

Although SCT outcomes are better with related donors, one-half to two-thirds of patients do not have a suitable HLA-matched sibling. This has led to assessment of treatment with unrelated HLA-matched donors.[105] One study has compared results from 2,464 unrelated donor bone marrow transplants with 450 HLA-identical, sibling donor transplants performed at National Marrow Donor Program institutions in the United States between 1988 and 1999.[106] In the unrelated donor group, 63% were matched at HLA-A, -B, and -DRB1 alleles.

Multivariate analysis demonstrated a significantly increased risk of graft failure and acute graft-vs-host disease following transplant from an unrelated as opposed to a related donor. In addition, survival and disease-free survival were significantly worse for unrelated donor recipients. However, for those with chronic phase disease undergoing transplantation within 1 year of diagnosis, the 5-year disease-free survival rate was similar or only slightly inferior. Hematologic relapse was uncommon in both groups and occurred with similar frequency (8%-9%). Several studies have confirmed that complete donor-recipient matching across HLA-A,-B,-C,-DRB1, and -DQB1 alleles can significantly reduce the incidence of graft-vs-host disease and the risk of mortality.[107]

Modifying SCT Outcome

Reduced-intensity conditioning prior to SCT has been used to try and increase tolerability and decrease mortality. This approach takes advantage of a graft-vs-leukemia effect, whereby CML cells are eliminated by donor cells instead of ablative chemotherapy. Although long-term follow-up is not yet available, early results from small studies suggest that rates of survival and disease-free survival may be high.[108,109]

Although donor leukocyte infusions are extremely useful for treating disease relapses in SCT recipients,[110] accumulating evidence demonstrates that imatinib is also useful in this regard.[111-114] In addition, current evidence suggests that prior imatinib treatment does not adversely affect SCT outcome.[115]

Immunotherapy and Residual Disease

The observation of a graft-vs-leukemia effect following SCT suggests that immunotherapy aimed at CML is an approach worth investigating. Because the BCR-ABL fusion protein represents a unique tumor-specific antigen, vaccination using peptides based on the BCR-ABL junction point may be useful, especially in helping to reduce residual disease levels after maximal responses to imatinib have been achieved.[116,117] Two recent clinical studies of vaccination, using peptides derived from the BCR-ABL fusion region, have demonstrated that patients develop a functional immune response to these peptides.[118,119] In one study, vaccination of nine patients who had achieved stable but incomplete cytogenetic responses (median Ph-positive level: 10%) on imatinib resulted in improved cytogenetic responses, including a complete cytogenetic response in five patients. In addition, three patients achieved a complete molecular response.

Conclusions

Imatinib has provided treatment benefits for a large number of patients with CML. Long-term outcomes after 5 years of follow-up are encouraging and suggest a major change in the history of the disease. Adequate management, proper follow-up, and opportune intervention with imatinib dose increases in patients with suboptimal responses can maximize the benefit. The availability of highly potent tyrosine kinase inhibitors has broadened the treatment armamentarium in CML. Long-term treatment of CML may require a combination of tyrosine kinase inhibitors, farnesyl transferase inhibitors, and, possibly, compounds with other mechanisms of action-both conventional and targeted. Vaccines to stimulate patient immunity may control and eliminate residual disease. Overall, treatment options are increasing for patients with CML, and this is likely to continue in the future.

Financial Disclosure:Dr. Cortes receives research grants from Novartis and Bristol-Myers Squibb.

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