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Management of Patients with Newly Diagnosed Chronic Myeloid Leukemia: Opportunities and Challenges
Management of Patients with Newly Diagnosed Chronic Myeloid Leukemia: Opportunities and Challenges Elias Jabbour, Jorge Cortes, Susan O’Brien, Mary Beth Rios, Francis Giles, Hagop Kantarjian
Abstract Chronic myelogenous leukemia (CML) is a progressive and often fatal hematopoietic neoplasm characterized by the presence of the Philadelphia chromosome. This arises from a balanced translocation between chromosomes 9 and 22, creating the bcr-abl fusion gene. It is often stated that the only proven curative option is allogeneic stem cell transplantation, which is indicated for only a limited subset of patients. The Bcr-Abl tyrosine kinase inhibitor imatinib represented a major advance over conventional CML therapy. After imatinib treatment, > 90% of patients had a complete hematologic response, and 70%-80% had a complete cytogenetic response. With 5 years of follow-up, the data are very encouraging and exhibit a major change in the natural history of the disease. The understanding of some of the mechanisms of resistance to imatinib has led to a rapid development of new agents that might overcome this resistance. The outlook today for patients with CML is much brighter than that of a few years ago.
Clinical Lymphoma & Myeloma, Vol. 7, Suppl. 2, S51-S57, 2007 Key words: Cytogenetic response, Immunotherapy, Myeloid blast crisis, Myelosuppression, Stem cell transplantation, Tyrosine kinase inhibitors
Introduction Chronic myeloid leukemia (CML) is a rare disease. Although its incidence is low, its prevalence is increasing. In the United States, there are approximately 4570 new cases of CML each year.1 The annual incidence of CML is 1.5 cases per 100,000 adults. 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 might become 200,000-300,000 cases in the United States. Chronic myeloid leukemia is the first malignant disease for which a direct gene link has been found. The BcrAbl oncoprotein is an abnormal, non–membrane-bound, constitutively active tyrosine kinase (TK).2 This oncoprotein is translated from the bcr-abl protooncogene. A reciprocal translocation involving the bcr gene (chromosome 22) and the abl protooncogene (chromosome 9) creates this oncogene.3 Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston Submitted: Oct 25, 2006; Revised: Jan 18, 2007; Accepted: Jan 22, 2007 Address for correspondence: Hagop Kantarjian, MD, Department of Leukemia, Unit 428, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 Fax: 713-794-4997; e-mail: [email protected]
This reciprocal translocation between chromosomes 9 and 22 (t[9,22][q34;q11]) is known as the Philadelphia (Ph) chromosome and is present in 95% of patients with CML.4 Numerous signal transduction pathways, including Ras/Raf/ mitogen activated protein kinase, phosphatidylinositol 3-kinase, signal transducer and activator of transcription–5/Janus kinase, and Myc, are activated by the Bcr-Abl TK.3,5 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 TK and its associated pathways.6 The treatment of CML has evolved greatly over the past few years. Imatinib is now well established as the standard therapy. For many years, stem cell transplantation (SCT) and interferon-α (IFN-α) were the major therapeutic choices. Longterm survival and possibly cure was achieved with both of these modalities.7,8 Although SCT is still a valid treatment option for some patients, IFN-α has been replaced in CML first-line therapy by imatinib. Imatinib is a potent and selective TK inhibitor (TKI) that has become standard therapy for patients with all stages of CML.9 A complete cytogenetic response (CCyR) can be achieved in 50%-60% of patients treated in chronic phase after failure of IFN-α10,11 and in > 80% of those receiving imatinib as first-
Dr Jabbour is a member of the Speaker’s Bureau for Novartis Oncology and Bristol-Myers Squibb. Dr Cortes has received research support from Breakthrough Therapeutics, Novartis Oncology, Johnson & Johnson, Schering-Plough, Bristol-Myers Squibb, and ChemGenex Pharmaceuticals. He is also a member of the Speaker’s Bureau for Novartis Oncology and Celgene. Dr O’Brien has received research support from Genentech BioOncol, Berlex, and Biogen Idec. Dr Rios is a member of the Speaker’s Bureau for Bristol-Myers Squibb and has received other remuneration from Novartis. Dr Giles has received research support from Novartis Oncology, Bristol-Myers Squibb, Merck, SGX Pharmaceuticals, Amgen, and Pfizer. Dr Kantarjian has received research support from Bristol-Myers Squibb, Novartis Oncology, and MGI Pharma. This article includes discussion of investigational and/or unlabeled uses of drugs, including the use of nilotinib, p210 multipeptide vaccine, nonpeptide PR1 vaccine, and a heat-shock protein–70–based vaccine in the treatment of CML.
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Management of Chronic Myeloid Leukemia
Time (Months)
Complete Hematologic Response (%)
Major Cytogenetic Response (%)
Complete Cytogenetic Response (%)
12
96
85
69
18
97
88
76
24
97
90
80
60
98
92
87
line therapy.12,13 Responses are durable in most patients treated in early chronic phase, particularly among those who have major molecular responses (eg, ≥ 3-log reduction in transcript levels).14,15 Herein, we will review the current information regarding treatment of patients with newly diagnosed chronic phase CML, issues of imatinib dose schedules, imatinib toxicity, management of adverse events, monitoring of minimal residual disease, and data regarding other strategies, mainly the novel TKIs and vaccines.
Imatinib Imatinib is an orally bioavailable 2-phenylaminopyrimidine with targeted inhibitory activity against the constitutively active TK of the Bcr-Abl chimeric fusion protein. Imatinib inhibits other kinases, such as c-Kit, platelet-derived growth factor–α and platelet-derived growth factor–β, and abl-related gene.16,17 Imatinib has become the standard therapy for CML because of its remarkable activity and mild toxicity profile.
Efficacy Data Phase I/II Clinical Trials In a phase I dose-finding study in patients who were intolerant to or in whom IFN-α–based therapy failed, daily doses of 25-1000 mg were investigated.18 Cytogenetic responses among patients receiving doses < 250 mg daily were rare compared with 98% of patients receiving a dose of ≥ 300 mg daily who displayed a complete hematologic response, including 54% who had a cytogenetic response. A dosage of 400 mg daily was selected for a subsequent phase II study, including 454 patients in late chronic phase disease that was intolerant or in which IFN-α–based therapy had failed.19 The updated results showed complete hematologic responses in 96% and CCyRs in 55%. After a median follow-up of 5 years, the overall survival rate was 79%. These results are in concordance with results from our single-institution study. Among 261 patients treated, 73% had a major cytogenetic response (MCyR; 63% complete).20 With a median follow-up of 45 months, 86% of patients were alive, of whom 80% were progression free. More than 90% of patients who had a CCyR maintained a major response. The Bcr-Abl/Abl ratio by nested polymerase chain reaction (PCR) was < 0.05% in 31% of patients and undetectable in 15% of patients. Two hundred thirty-five patients with accelerated phase disease were treated in a phase II open-label study, 77 patients
Figure 1 Survival of Patients with Early Chronic Phase CML Treated at the University of Texas M. D. Anderson Cancer Center Compared with Patients Treated with Imatinib 100
Patient Survival (%)
Table 1 Responses to First-Line Imatinib in 5-Year Update: IRIS Phase III Trial, N = 38224
Year Imatinib 1990-2000 1982-1989 1975-1981 1965-1974
80
60
Total Dead 276 14 960 357 365 266 132 127 123 122
40
20
0
3
6
9
12
15
Year(s) from Referral
at 400 mg daily and 158 patients at 600 mg daily.21 Median duration of treatment was 18 months. Response rates (RRs) in accelerated phase CML were higher with the 600 mg dose group than with 400 mg: the hematologic RRs were 75% versus 64% and the MCyR rates were 31% versus 19%. Two hundred sixty patients with myeloid blast crisis were treated, 37 patients at 400 mg daily and 223 patients at 600 mg daily.22 The hematologic RR was higher in untreated than in treated patients (36% vs. 22%, respectively), and with 600 mg versus 400 mg (33% vs. 16%). Rates of MCyR were also higher with 600 mg versus 400 mg (17% vs. 8%).
Phase III Clinical Trial The prospective International Randomized Trial of IFN plus Cytarabine Versus Imatinib (STI-571; IRIS) study of 1106 patients with newly diagnosed CML in chronic phase established the superiority of imatinib 400 mg daily over IFN-α and low-dose cytarabine.23 The complete hematologic RRs were 95% versus 55%; the CCyR rates were 76% versus 15%; and the progression-free survival rates at 18 months were 97% versus 91% (P < 0.001). The molecular RRs were also significantly better, with estimated major molecular RRs of 40% versus 2% at 12 months. A 5-year update of the IRIS study continued to show positive results (Table 1).24 Three hundred eighty-two patients remained on imatinib first-line therapy. The cumulative complete hematologic response, MCyR, and CCyR rates were 98%, 92%, and 87%, respectively. The estimated 5-year event-free survival was 83%; only 6.3% of patients experienced progression to accelerated and blastic phases. The overall annual progression rate has decreased to 0.9% in the fifth year of therapy, compared with 1.5%, 4.8%, and 7.5% in the past 3 years, suggesting that disease progression might be diminished in the following years. The estimated 5-year survival rate was 89%; excluding non-CML deaths, it was 95%. The intensity
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Elias Jabbour et al of the cytogenetic response after 12 months and 18 months of imatinib therapy has important implications regarding survival without transformation. The estimated 5-year survival rate in patients not having an MCyR at 12 months was significantly less (81%) than those who had an MCyR (complete, 97%; partial, 93%; P < 0.001). At 18 months of therapy, the estimated 5-year survival rate for patients not having a CCyR was significantly less than those who had CCyR (99% vs. 90%; P < 0.001).24 There was a continuous improvement in the rate of molecular response. The rate of major molecular response improved from 44% at 1 year of therapy to 68% at 4 years of therapy.25 This study did not document a survival advantage for imatinib because of the crossover design. Studies comparing the survival of patients treated with imatinib with historical cohorts treated with IFN-α–based therapy demonstrated the anticipated survival advantage.26-28 Figure 1 shows the survival of patients treated at our institution 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 IFN therapy, and in 4%-5% of patients in accelerated blastic phase.20-23 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%-6%, superficial edema in 1%-6%, hemorrhage in 1%19%, and musculoskeletal pain in 2%-9%. Severe fluid retention appeared to be dose related and was more common in the elderly and in the advanced phase studies with an imatinib dosage of 600 mg daily. 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 < 0.5% of patients. A recent report suggested that imatinib is cardiotoxic and can lead to severe left ventricular dysfunction and heart failure.29 Imatinib therapy as a causal factor of congestive heart failure was shown to be uncommon and was mainly seen in elderly patients with preexisting cardiac conditions.30 Among 1276 patients treated at 1 institution, 22 patients (1.8%; median age of 70 years) were identified as having symptoms that could be attributed to congestive heart failure. 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%). Eleven of the 22 patients continued imatinib therapy with dose adjustments and management for the congestive heart failure symptoms with no further complications.30
Table 2 Nonhematologic Adverse Events Side Effects
Treatment
Nausea, Vomiting, and Diarrhea
Antiemetics, antidiarrhea
Bone Aches
Antiinflammatory Calcium, Gatorade®, quinine
Muscle Cramps Skin Rashes
Avoid sun; steroids; I/R
Liver Dysfunction
I/R; steroids
Weight Gain
–
Edema, Fluid Retention, and CHF Cardiac Toxicity (Rare)
Diuretics Diuretics; CHF treatment; I/R
Abbreviations: CHF = congestive heart failure; I/R = dose interruptions/reductions
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 (filgrastim for neutropenia, oprelvekin [interleukin 11] for thrombocytopenia, erythropoietin, or darbepoetin 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 2-3 months of therapy. A brief treatment interruption is often sufficient to allow recovery, and most patients will not require dose reductions. 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 In the dose-finding phase I study of imatinib, the maximum tolerated dose was not identified. Because of the good responses obtained at the dose of 300-400 mg daily and because the blood concentration of imatinib at 400 mg daily was consistently higher than that required to inhibit 50% of Bcr-Abl TK activity in vitro,39,40 that dose was chosen for subsequent studies. Imatinib 600 mg daily was more effective than 400 mg for patients in advanced-stage disease.21,22 Treatment of patients with CML in late chronic phase after IFN-α failure with imatinib 400 mg twice daily resulted in a CCyR rate of 90%, compared with 48% in historical controls treated with standard dose therapy. In addition, 56% of patients had a major molecular response, including 41% with undetectable levels.41 Several imatinibresistant mutations might confer relative rather than absolute resistance to imatinib, which could be overcome with higher dose imatinib.42 In patients with previous hematologic and cytogenetic resistance to 400 mg of imatinib daily, increasing the dose to 800 mg resulted in a complete hematologic RR of 65% and a complete cytogenetic RR of 18%.43 Several phase II studies of high-dose imatinib in previously untreated patients with chronic phase CML documented higher rates of CCyR (up to 95%) and of molecular response, particularly ≥ 4-log reduction
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Management of Chronic Myeloid Leukemia in transcript levels.13,44-46 When compared with historical patients treated with standard dose, patients treated with highdose imatinib had higher rates of earlier CCyR (90% vs. 78%; P = 0.03). The cumulative incidences of major molecular response and complete molecular response were significantly better with high-dose imatinib (P < 0.0001 and P < 0.005, respectively).47 Progression-free survival and time to transformation were also significantly better.
Monitoring of Treatment Effect and Minimal Residual Disease on Imatinib Most patients have a CCyR with imatinib. Achievement of molecular response has become the endpoint of anti-CML strategies and led to redefining the therapeutic goals in CML.48 The long-term significance of molecular monitoring in CML is best exemplified in the setting of SCT, in which detection of high Bcr-Abl transcripts confers higher risk of relapse.49 The IRIS trial showed that a reduction of Bcr-Abl transcripts level by ≥ 3 logs below a standard baseline value correlated with better progression-free survival.15 Another study reported that achieving a major molecular response within the first 12 months of therapy was predictive of durable cytogenetic remission.14 The lack of consistency in reporting Bcr-Abl transcript levels has been a source of debate. A consensual proposal suggests harmonizing the differing methodsv for measuring Bcr-Abl transcripts by using a conversion factor, in which individual laboratories can express Bcr-Abl transcript levels on internationally agreed scales. 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.50 For practical purposes, a major molecular response can be defined as a reduction of Bcr-Abl/Abl transcripts to ≤ 0.1%.27 After a patient has had a CCyR, real-time PCR should be performed every 3-6 months and a routine cytogenetic analysis every 12 months. The latter test might detect clonal evolution and chromosomal abnormalities occurring in normal metaphases.
Significance of Cytogenetic Abnormalities Approximately 5% of patients who have a cytogenetic response develop karyotypic abnormalities in Ph-negative cells. These do not represent clonal evolution because they occur in cells without the Ph chromosome and should not be considered as part of the definition of accelerated phase. The significance of these events is currently unknown.51 The most common cytogenetic abnormalities include trisomy 8, monosomy 5 or 7, and deletion 20q.52-55 These abnormalities frequently regress spontaneously, and patients with these abnormalities have similar long-term outcome as patients without such abnormalities. However, occasional cases of progression to acute myeloid leukemia or myelodysplastic syndrome have been reported,56 mainly in patients with a deletion of chromosome 7 and/or other complex abnormalities, but also in patients with isolated trisomy 8, warranting a careful follow-up.
Imatinib Resistance and Monitoring of Mutations Despite the benefit of imatinib compared with previous treatments, some patients might develop resistance,57 with a reported annual relapse rate of 4% in newly diagnosed patients in chronic phase.58 Multiple mechanisms of resistance to imatinib, Bcr-Abl dependent and Bcr-Abl independent, have been identified; one of the best characterized is mutations in bcr-abl fusion gene (30%-50% of patients with imatinib resistance).59 Clinically relevant mutations disrupt critical contact points between imatinib and Bcr-Abl or induce a transition from the inactive to the active configuration, to which imatinib is unable to bind.57,60 Numerous bcr-abl mutations have been identified. Not all mutations have the same biochemical and clinical properties: some bcr-abl mutations result in a highly resistant phenotype in vitro; others are relatively sensitive, and resistance might be overcome by imatinib dose increase.59,61-64 The T315I mutation and some mutations affecting the so-called P-loop of Bcr-Abl confer a greater level of resistance to imatinib and to the novel TKIs.65,66 Kinase domain mutation screening for patients in chronic phase is indicated in cases of hematologic or cytogenetic resistance/relapse65 or if there is an increase in bcr-abl transcript ratio of ≥ 1 log.67Kinase domain mutations should be investigated in any patients presenting in advanced phase disease.
Duration of Therapy with Imatinib The optimal duration of imatinib therapy is unknown. The current recommendation is to continue treatment indefinitely unless there is 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 sustaining undetectable levels of Bcr-Abl for significant periods of time.68-70 Rousselot et al reported on 12 patients who discontinued imatinib after maintaining undetectable Bcr-Abl levels for ≥ 24 months; 6 are still PCR negative after a median follow-up of 18 months (range, 9-24 months).71 Ten of these 12 patients had been treated with IFN-α, suggesting that IFN-α immunomodulatory effects might 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.72 It is conceivable that these progenitors might trigger proliferation of CML when the inhibitory pressure of imatinib is eliminated.
Imatinib and Pregnancy The effects of imatinib on fertility, pregnancy, and lactation are known mostly from animal studies with imatinib. Male rats administered imatinib 70 days before mating had a decrease in testicular and epididymal weights and in sperm motility. Imatinib was teratogenic in rats when administered during organogenesis at doses > 100 mg/kg, which is equivalent to a dose of 800 mg daily in adults based on body surface
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Elias Jabbour et al area. Female rats administered imatinib doses of ≥ 45 mg/kg experienced postimplantation loss, with no fetal loss at doses < 30 mg/kg. At doses > 100 mg/kg, total fetal loss occurred in all animals. There is limited information on the potential effect that imatinib could have on the developing fetus. The outcome of 19 pregnancies involving 18 patients (10 women and 8 men) who conceived while receiving imatinib for the treatment of CML was recently reported.73 All female patients discontinued therapy immediately upon recognition of the pregnancy. Three pregnancies (involving 2 women and 1 man) ended in spontaneous abortion, and 1 patient had an elective abortion. All other pregnancies were uneventful. Two of the 16 (12%) babies had minor abnormalities at or shortly after birth that were surgically repaired. All babies have continued normal growth and development. Among female patients (N = 10) who interrupted therapy, 5 of 9 in complete hematologic remission at the time of treatment interruption eventually lost complete hematologic response, and 6 of 10 experienced an increase in Ph chromosome–positive metaphases. At a median of 18 months after resuming therapy with imatinib, 8 patients (44%) had a cytogenetic response (complete in 3 patients). Although there is no evidence that a brief exposure to imatinib during conception and pregnancy adversely affects the developing fetus, most patients lose their response after treatment interruption. Therefore, patients receiving imatinib should be advised to practice adequate contraception.
Stem Cell Transplantation Imatinib is now recommended as initial treatment for most patients with newly diagnosed chronic phase CML. Allogeneic SCT (ASCT) is recommended in case of failure, and could be considered in case of suboptimal response, particularly in younger patients with full match-related donor.48 Previous treatment with imatinib was shown not to be associated with an increase of transplantation-related morbidity and mortality.74,75
Immunotherapy and Residual Disease Immune-mediated suppression of the CML clones is evidenced by the graft-versus-leukemia effect in eradicating CML cells after ASCT76 and by maintenance of durable remissions after discontinuation of IFN-α therapy in a subset of patients.8,77 This led to the development of vaccine strategies that elicit specific immune responses directed at CML-restricted tumor antigens. At least 3 approaches of vaccine therapy are being developed. The first approach is to use tumor-specific antigens. In 1 study, 12 patients with CML in complete or partial remission (PR) on IFN-α were vaccinated with a mixture of junction peptides: 2 patients had a transient response (1 molecular response and 1 CCyR).78 In a subsequent phase II study, 4 of 14 patients (29%) vaccinated had a decrease in Ph-positive cells, 2 of them while on IFN-α (n = 1) or imatinib (n = 1).79 Three patients (21%) treated for molecular relapse after ASCT had a transient complete molecular response (2 patients received concurrent donor leukocyte infusions). Bocchia and
colleagues vaccinated 16 patients with stable residual disease after > 12 months of imatinib therapy (n = 10) or 24 months of IFN therapy (n = 6) with a peptide vaccine derived from the sequence p210-b3a2.80 Five of 9 patients on imatinib had a CCyR after vaccination and 3 had a complete molecular response. Of 6 patients on IFN-α, 5 had improvement in cytogenetic response and 2 of them had a CCyR. The second approach is the use of PR1, derived from proteinase 3 and presented through human leukocyte antigen–A2.1. In 1 study, 3 of 10 patients with CML treated with the nonapeptide PR1 had cytogenetic improvement, and 1 had a CCyR.81 The third approach, using the heat-shock protein–based vaccines, was assessed in 11 patients with CML who did not have an MCyR response after 6 months of imatinib therapy: 5 patients had an MCyR, and 2 of them had a molecular remission.82 Overall, these data suggest that immunotherapy might have a role in the management of CML, particularly at the stage of minimal residual disease.
Novel Approaches Novel, more potent TKIs have been developed to overcome imatinib resistance.6 Dasatinib, 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.83Nilotinib is an oral potent and selective Bcr-Abl inhibitor in advanced clinical trials.84 Both agents have been investigated in patients with newly diagnosed CML. Preliminary results on 14 patients with newly diagnosed CML and treated with nilotinib 400 mg twice daily were recently reported.82 Major cytogenetic response was observed in all patients at 3 months (complete in 13 and partial in 1), and all 7 evaluable patients were in CCyR at 6 months.85 The rates of CCyR at 3 months and 6 months were significantly better than with imatinib 400 mg and 800 mg.
Conclusion and Future Perspectives The introduction of imatinib has marked an important and revolutionary step in the management of CML. The longterm 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 maximize the benefit. The availability of highly potent TKIs has broadened the treatment armamentarium in CML. Long-term treatment of CML might require a combination of TKIs, farnesyltransferase inhibitors, and possibly compounds with other mechanisms of action, both conventional and targeted. Vaccines to stimulate patient immunity might control and eliminate residual disease. With these strategies, the treatment prospects of patients with CML are very hopeful.
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Management of Chronic Myeloid Leukemia chronic myeloid leukaemia. Acta Haematol 2002; 108:180-202. 4. Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973; 243:290-293. 5. Mughal TI, Goldman JM. Chronic myeloid leukemia: why does it evolve from chronic phase to blast transformation? Front Biosci 2006; 11:198-208. 6. Jabbour E, Cortes J, Kantarjian H. Novel tyrosine kinase inhibitors in chronic myelogenous leukemia. Curr Opin Oncol 2006; 18:578-583. 7. Thomas ED, Clift RA, Fefer A, et al. Marrow transplantation for the treatment of chronic myelogenous leukemia. Ann Intern Med 1986; 104:155-163. 8. Kantarjian HM, O’Brien S, Cortes J, et al. Complete cytogenetic and molecular responses to interferon-alpha-based therapy for chronic myelogenous leukemia are associated with excellent long-term prognosis. Cancer 2003; 97:1033-1041. 9. Goldman JM, Melo JV. Chronic myeloid leukemia—advances in biology and new approaches to treatment. N Engl J Med 2003; 349:14511464. 10. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002; 346:645-652. 11. Kantarjian HM, Cortes JE, O’Brien S, et al. Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia after failure of interferon-{alpha}. Blood 2004; 104:1979-1988. 12. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348:994-1004. 13. Kantarjian H, Talpaz M, O’Brien S, et al. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood 2004; 103:2873-2878. 14. Cortes J, Talpaz M, O’Brien S, et al. Molecular responses in patients with chronic myelogenous leukemia in chronic phase treated with imatinib mesylate. Clin Cancer Res 2005; 11:3425-3432. 15. Hughes TP, Kaeda J, Branford S, et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 2003; 349:1423-1432. 16. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996; 2:561-566. 17. Beran M, Cao X, Estrov Z, et al. Selective inhibition of cell proliferation and Bcr-Abl phosphorylation in acute lymphoblastic leukemia cells expressing Mr 190,000 Bcr-Abl protein by a tyrosine kinase inhibitor (CGP-57148). Clin Cancer Res 1998; 4:1661-1672. 18. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the Bcr-Abl tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344:1031-1037. 19. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002; 346:645-652. 20. Kantarjian HM, Cortes JE, O’Brien S, et al. Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia after failure of interferon-alpha. Blood 2004; 104:1979-1988. 21. Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 2002; 99:1928-1937. 22. Sawyers CL, Hochhaus A, Feldman E, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 2002; 99:3530-3539. 23. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348:994-1004. 24. Druker BJ, Guilhot F, O’Brien S, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355:2408-2417. 25. Goldman JM, Hughes T, Radich J, et al. Continuing reduction in level of residual disease after 4 years in patients with CML in chronic phase responding to first-line imatinib in the IRIS study. Blood 2005; 106:51a
(Abstract #163). 26. Kantarjian HM, O’Brien S, Cortes J, et al. Imatinib mesylate therapy improves survival in patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia in the chronic phase. Comparison with historic data. Cancer 2003; 98:2636-2642. 27. Kantarjian HM, Talpaz M, O’Brien S, et al. Survival benefit with imatinib mesylate versus interferon alpha-based regimens in newly diagnosed chronic phase chronic myelogenous leukemia. Blood 2006; 108:1835-1840. 28. Roy L, Guilhot J, Kranhke T, et al. Survival advantage from imatinib compared to the combination interferon-{alpha} plus cytarabine in chronic phase CML: historical comparison between two phase III trials. Blood 2006; 108:1478-1484. 29. Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006; 12:908-916. 30. Atallah E, Durand JB, Kantarjian H, et al. Congestive heart failure is a rare event in patients receiving imatinib therapy. Blood 2006; 108:609a (Abstract #2146). 31. Deininger MW, O’Brien SG, Ford JM, et al. Practical management of patients with chronic myeloid leukemia receiving imatinib. J Clin Oncol 2003; 21:1637-1647. 32. Quintas-Cardama A, Kantarjian H, O’Brien S, et al. Granulocytecolony-stimulating factor (filgrastin) may overcome imatinib-induced neutropenia in patients with chronic-phase chronic myelogenous leukemia. Cancer 2004; 100:2592-2597. 33. Mauro MJ, Kurilik G, Balleisen S, et al. Myeloid growth factors for neutropenia during imatinib mesylate therapy for CML: preliminary evidence of safety and efficacy. Blood 2001; 98:139a (Abstract #584). 34. Marin D, Marktel S, Foot N, et al. G-CSF reverses cytopenia and may increase cytogenetic responses in patients with CML treated with imatinib mesylate. Blood 2002; 100:782a (Abstract #3093). 35. Ault P, Kantarjian H, Welch MA, et al. Interleukin 11 may improve thrombocytopenia associated with imatinib mesylate therapy in chronic myelogenous leukemia. Leuk Res 2004; 28:613-618. 36. Cortes J, O’Brien S, Quintas A, et al. Erythropoietin is effective in improving the anemia induced by imatinib mesylate therapy in patients with chronic myeloid leukemia in chronic phase. Cancer 2004; 100:2396-2402. 37. Mauro MJ, Blasdel C, O’Dwyer ME, et al. Erythropoietin for anemia during imatinib mesylate (STI571) therapy for CML: preliminary evidence of safety and efficacy. Proc Am Soc Clin Oncol 2002; 21:27a (Abstract #106). 38. Ault P, Kantarjian H, Kurzrock R, et al. Use of darbepoetin alfa for the treatment of anemia occurring during imatinib therapy for CML: preliminary evidence of safety and efficacy. Proc Am Soc Clin Oncol 2003; 22:613 (Abstract #2467). 39. Peng B, Hayes M, Resta D, et al. Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. J Clin Oncol 2004; 22:935-942. 40. Schmidli H, Peng B, Riviere GJ, et al. Population pharmacokinetics of imatinib mesylate in patients with chronic-phase chronic myeloid leukaemia: results of a phase III study. Br J Clin Pharmacol 2005; 60:35-44. 41. Cortes J, Giles F, O’Brien S, et al. Result of high-dose imatinib mesylate in patients with Philadelphia chromosome-positive chronic myeloid leukemia after failure of interferon-α. Blood 2003; 102:83-86. 42. O’Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinibresistant Abl kinase domain mutants. Cancer Res 2005; 65:4500-4505. 43. Kantarjian H, Talpaz M, O’Brien S, et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 2003; 101:473-475. 44. Hughes TP, Branford S, Matthews J, et al. Trial of higher dose imatinib with selective intensification in newly diagnosed CML patients in chronic phase. Blood 2003; 102:31a. 45. Cortes J, Giles F, Salvado A, et al. High-dose (HD) imatinib in patients with previously untreated chronic myeloid leukemia (CML) in early chronic phase (CP): preliminary results of a multicenter community based trial. J Clin Oncol 2005; 23:564a. 46. Rosti G, Martinelli G, Castagnetti F, et al. Imatinib 800 mg: preliminary results of a phase II trial of the GIMEMA CML working party in intermediate sokal risk patients and status-of-the-art of an ongoing multinational, prospective randomized trial of imatinib standard dose (400 mg daily) vs high dose (800 mg daily) in high sokal risk patients. Blood 2005; 106:320a (Abstract #1098).
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Elias Jabbour et al 47. Aoki E, Kantarjian H, O’Brien S, et al. High-dose imatinib mesylate treatment in patients (pts) with untreated early chronic phase (CP) chronic myeloid leukemia (CML): 2.5-year follow-up. J Clin Oncol 2006; 24(18 suppl):345s (Abstract #6535). 48. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006; 108:1809-1820. 49. Radich JP, Gehly G, Gooley T, et al. Polymerase chain reaction detection of the Bcr-Abl fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia: results and implications in 346 patients. Blood 1995; 85:2632-2638. 50. Hughes TP, Deininger MW, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting Bcr-Abl transcripts and kinase domain mutations and for expressing results. Blood 2006; 108:28-37. 51. Loriaux M, Deininger M. Clonal cytogenetic abnormalities in Philadelphia chromosome negative cells in chronic myeloid leukemia patients treated with imatinib. Leuk Lymphoma 2004; 45:2197-2203. 52. Fayad L, Kantarjian H, O’Brien S, et al. Emergence of new clonal abnormalities following interferon-alpha induced complete cytogenetic response in patients with chronic myeloid leukemia: report of three cases. Leukemia 1997; 11:767-771. 53. Medina J, Kantarjian H, Talpaz M, et al. Chromosomal abnormalities in Philadelphia chromosome-negative metaphases appearing during imatinib mesylate therapy in patients with Philadelphia chromosomepositive chronic myelogenous leukemia in chronic phase. Cancer 2003; 98:1905-1911. 54. Bumm T, Muller C, Al-Ali HK, et al. Emergence of clonal cytogenetic abnormalities in Ph- cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood 2003; 101:1941-1949. 55. Jabbour E, Kantrjian H, O’Brien S, et al. Chromosomal abnormalities in Philadelphia chromosome (Ph)-negative metaphases appearing during imatinib mesylate therapy in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood 2005; 106:1090. 56. Kovitz C, Kantarjian H, Garcia-Manero G, et al. Myelodysplastic syndromes and acute leukemia developing after imatinib mesylate therapy for chronic myeloid leukemia. Blood 2006; 108:2811-2813. 57. Shah NP. Loss of response to imatinib: mechanisms and management. Hematol Am Soc Hematol Educ Program 2005; 183-187. 58. Hochhaus A, Hughes T. Clinical resistance to imatinib: mechanisms and implications. Hematol Oncol Clin N 2004; 18:641-656. 59. Hochhaus A, Kreil S, Corbin AS, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 2002; 16:2190-2196. 60. Deininger M, Buchdunger E, Druker BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 2005; 105:2640-2653. 61. Shah NP, Nicoll JM, Nagar B, et al. Multiple Bcr-Abl kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002; 2:117-125. 62. von Bubnoff N, Schneller F, Peschel C, et al. BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study. Lancet 2002; 359:487-491. 63. Corbin AS, Buchdunger E, Pascal F, et al. Analysis of the structural basis of specificity of inhibition of the Abl kinase by STI571. J Biol Chem 2002; 277:32214-32219. 64. Azam M, Latek RR, Daley GQ, et al. Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of Bcr-Abl. Cell 2003; 112:831-843. 65. Hughes TP, Deininger MW, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detect-
66. 67.
68. 69. 70. 71. 72. 73. 74. 75.
76. 77. 78.
79. 80.
81. 82. 83. 84. 85.
ing Bcr-Abl transcripts and kinase domain mutations and for expressing results. Blood 2006; 108:28-37. Jabbour E, Kantarjian H, Jones D, et al. Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia 2006; 20:1767-1773. Branford S, Rudzki Z, Parkinson I, et al. Real-time quantitative PCR analysis can be used as a primary screen to identify patients with CML treated with imatinib who have Bcr-Abl kinase domain mutations. Blood 2004; 104:2926-2932. Cortes J, O’Brien S, Kantarjian H. Discontinuation of imatinib therapy after achieving a molecular response. Blood 2004; 104:2204-2205. Mauro MJ, Druker BJ, Maziarz RT. Divergent clinical outcome in two CML patients who discontinued imatinib therapy after achieving a molecular remission. Leukemia Research 2004; 28:71-73. Ghanima W, Kahrs J, Dahl TG III, et al. Sustained cytogenetic response after discontinuation of imatinib mesylate in a patient with chronic myeloid leukaemia. Eur J Haematol 2004; 72:441-443. Rousselot P, Huguet, F, Rea D, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukaemia in complete molecular remission for more than two years. Blood 2007; 109:58-60. Graham SM, Jorgensen HG, Allan E, et al. Primitive quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 2002; 99:319-325. Ault P, Kantarjian H, O’Brien S, et al. Pregnancy among patients with chronic myeloid leukemia treated with imatinib. J Clin Oncol 2006; 24:1204-1208. Oehler VG, Gooley T, Snyder DS, et al. The effects of imatinib mesylate treatment before allogeneic transplant for chronic myeloid leukemia. Blood 2006. [Epub ahead of print] Jabbour E, Cortes J, Kantarjian HM, et al. Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after Bcr-Abl kinase mutation-related imatinib failure. Blood 2006; 108:1421-1423. Barrett J. Allogeneic stem cell transplantation for chronic myeloid leukemia. Semin Hematol 2003; 40:59-71. Guilhot F, Lacotte-Thierry L. Interferon-alpha: mechanisms of action in chronic myelogenous leukemia in chronic phase. Hematol Cell Ther 1998; 40:237-239. Pinilla-Ibarz J, Cathcart K, Korontsvit T, et al. Vaccination of patients with chronic myelogenous leukemia with bcr-abl oncogene breakpoint fusion peptides generates specific immune responses. Blood 2000; 95:1781-1787. Cathcart K, Pinilla-Ibarz J, Korontsvit T, et al. A multivalent bcr-abl fusion peptide vaccination trial in patients with chronic myeloid leukemia. Blood 2004; 103:1037-1042. Bocchia M, Gentili S, Abruzzese E, et al. Effect of a p210 multipeptide vaccine associated with imatinib or interferon in patients with chronic myeloid leukaemia and persistent residual disease: a multicentre observational trial. Lancet 2005; 365:657-662. Qazilbash MH, Weider E, Rios R, et al. Vaccination with the PR1 leukemia-associated antigen can induce complete remission in patients with myeloid leukemia. Blood 2004; 104:77a (Abstract #259). Li Z, Qiao Y, Laska E, et al. Combination of imatinib mesylate with autologous leukocyte-derived heat shock protein 70 vaccine for chronic myelogenous leukemia. Proc Am Soc Clin Oncol 2003; 22:166 (Abstract #664). Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006; 354:2531-2541. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006; 354:2542-2551. Jabbour E, Giles F, Cortes J, et al. Preliminary activity of AMN107, a novel potent oral selective Bcr-Abl tyrosine kinase inhibitor, in newly diagnosed Philadelphia chromosome (Ph)-positive chronic phase chronic myelogenous leukaemia (CML-CP). J Clin Oncol 2006; 24(18 suppl):358s (Abstract #6591).
Clinical Lymphoma & Myeloma Vol 7 Suppl 2 March 2007 • S57
Abstract Chronic myelogenous leukemia (CML) is a progressive and often fatal hematopoietic neoplasm characterized by the presence of the Philadelphia chromosome. This arises from a balanced translocation between chromosomes 9 and 22, creating the bcr-abl fusion gene. It is often stated that the only proven curative option is allogeneic stem cell transplantation, which is indicated for only a limited subset of patients. The Bcr-Abl tyrosine kinase inhibitor imatinib represented a major advance over conventional CML therapy. After imatinib treatment, > 90% of patients had a complete hematologic response, and 70%-80% had a complete cytogenetic response. With 5 years of follow-up, the data are very encouraging and exhibit a major change in the natural history of the disease. The understanding of some of the mechanisms of resistance to imatinib has led to a rapid development of new agents that might overcome this resistance. The outlook today for patients with CML is much brighter than that of a few years ago.
Clinical Lymphoma & Myeloma, Vol. 7, Suppl. 2, S51-S57, 2007 Key words: Cytogenetic response, Immunotherapy, Myeloid blast crisis, Myelosuppression, Stem cell transplantation, Tyrosine kinase inhibitors
Introduction Chronic myeloid leukemia (CML) is a rare disease. Although its incidence is low, its prevalence is increasing. In the United States, there are approximately 4570 new cases of CML each year.1 The annual incidence of CML is 1.5 cases per 100,000 adults. 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 might become 200,000-300,000 cases in the United States. Chronic myeloid leukemia is the first malignant disease for which a direct gene link has been found. The BcrAbl oncoprotein is an abnormal, non–membrane-bound, constitutively active tyrosine kinase (TK).2 This oncoprotein is translated from the bcr-abl protooncogene. A reciprocal translocation involving the bcr gene (chromosome 22) and the abl protooncogene (chromosome 9) creates this oncogene.3 Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston Submitted: Oct 25, 2006; Revised: Jan 18, 2007; Accepted: Jan 22, 2007 Address for correspondence: Hagop Kantarjian, MD, Department of Leukemia, Unit 428, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 Fax: 713-794-4997; e-mail: [email protected]
This reciprocal translocation between chromosomes 9 and 22 (t[9,22][q34;q11]) is known as the Philadelphia (Ph) chromosome and is present in 95% of patients with CML.4 Numerous signal transduction pathways, including Ras/Raf/ mitogen activated protein kinase, phosphatidylinositol 3-kinase, signal transducer and activator of transcription–5/Janus kinase, and Myc, are activated by the Bcr-Abl TK.3,5 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 TK and its associated pathways.6 The treatment of CML has evolved greatly over the past few years. Imatinib is now well established as the standard therapy. For many years, stem cell transplantation (SCT) and interferon-α (IFN-α) were the major therapeutic choices. Longterm survival and possibly cure was achieved with both of these modalities.7,8 Although SCT is still a valid treatment option for some patients, IFN-α has been replaced in CML first-line therapy by imatinib. Imatinib is a potent and selective TK inhibitor (TKI) that has become standard therapy for patients with all stages of CML.9 A complete cytogenetic response (CCyR) can be achieved in 50%-60% of patients treated in chronic phase after failure of IFN-α10,11 and in > 80% of those receiving imatinib as first-
Dr Jabbour is a member of the Speaker’s Bureau for Novartis Oncology and Bristol-Myers Squibb. Dr Cortes has received research support from Breakthrough Therapeutics, Novartis Oncology, Johnson & Johnson, Schering-Plough, Bristol-Myers Squibb, and ChemGenex Pharmaceuticals. He is also a member of the Speaker’s Bureau for Novartis Oncology and Celgene. Dr O’Brien has received research support from Genentech BioOncol, Berlex, and Biogen Idec. Dr Rios is a member of the Speaker’s Bureau for Bristol-Myers Squibb and has received other remuneration from Novartis. Dr Giles has received research support from Novartis Oncology, Bristol-Myers Squibb, Merck, SGX Pharmaceuticals, Amgen, and Pfizer. Dr Kantarjian has received research support from Bristol-Myers Squibb, Novartis Oncology, and MGI Pharma. This article includes discussion of investigational and/or unlabeled uses of drugs, including the use of nilotinib, p210 multipeptide vaccine, nonpeptide PR1 vaccine, and a heat-shock protein–70–based vaccine in the treatment of CML.
Clinical Lymphoma & Myeloma Vol 7 Suppl 2 March 2007 • S51
Management of Chronic Myeloid Leukemia
Time (Months)
Complete Hematologic Response (%)
Major Cytogenetic Response (%)
Complete Cytogenetic Response (%)
12
96
85
69
18
97
88
76
24
97
90
80
60
98
92
87
line therapy.12,13 Responses are durable in most patients treated in early chronic phase, particularly among those who have major molecular responses (eg, ≥ 3-log reduction in transcript levels).14,15 Herein, we will review the current information regarding treatment of patients with newly diagnosed chronic phase CML, issues of imatinib dose schedules, imatinib toxicity, management of adverse events, monitoring of minimal residual disease, and data regarding other strategies, mainly the novel TKIs and vaccines.
Imatinib Imatinib is an orally bioavailable 2-phenylaminopyrimidine with targeted inhibitory activity against the constitutively active TK of the Bcr-Abl chimeric fusion protein. Imatinib inhibits other kinases, such as c-Kit, platelet-derived growth factor–α and platelet-derived growth factor–β, and abl-related gene.16,17 Imatinib has become the standard therapy for CML because of its remarkable activity and mild toxicity profile.
Efficacy Data Phase I/II Clinical Trials In a phase I dose-finding study in patients who were intolerant to or in whom IFN-α–based therapy failed, daily doses of 25-1000 mg were investigated.18 Cytogenetic responses among patients receiving doses < 250 mg daily were rare compared with 98% of patients receiving a dose of ≥ 300 mg daily who displayed a complete hematologic response, including 54% who had a cytogenetic response. A dosage of 400 mg daily was selected for a subsequent phase II study, including 454 patients in late chronic phase disease that was intolerant or in which IFN-α–based therapy had failed.19 The updated results showed complete hematologic responses in 96% and CCyRs in 55%. After a median follow-up of 5 years, the overall survival rate was 79%. These results are in concordance with results from our single-institution study. Among 261 patients treated, 73% had a major cytogenetic response (MCyR; 63% complete).20 With a median follow-up of 45 months, 86% of patients were alive, of whom 80% were progression free. More than 90% of patients who had a CCyR maintained a major response. The Bcr-Abl/Abl ratio by nested polymerase chain reaction (PCR) was < 0.05% in 31% of patients and undetectable in 15% of patients. Two hundred thirty-five patients with accelerated phase disease were treated in a phase II open-label study, 77 patients
Figure 1 Survival of Patients with Early Chronic Phase CML Treated at the University of Texas M. D. Anderson Cancer Center Compared with Patients Treated with Imatinib 100
Patient Survival (%)
Table 1 Responses to First-Line Imatinib in 5-Year Update: IRIS Phase III Trial, N = 38224
Year Imatinib 1990-2000 1982-1989 1975-1981 1965-1974
80
60
Total Dead 276 14 960 357 365 266 132 127 123 122
40
20
0
3
6
9
12
15
Year(s) from Referral
at 400 mg daily and 158 patients at 600 mg daily.21 Median duration of treatment was 18 months. Response rates (RRs) in accelerated phase CML were higher with the 600 mg dose group than with 400 mg: the hematologic RRs were 75% versus 64% and the MCyR rates were 31% versus 19%. Two hundred sixty patients with myeloid blast crisis were treated, 37 patients at 400 mg daily and 223 patients at 600 mg daily.22 The hematologic RR was higher in untreated than in treated patients (36% vs. 22%, respectively), and with 600 mg versus 400 mg (33% vs. 16%). Rates of MCyR were also higher with 600 mg versus 400 mg (17% vs. 8%).
Phase III Clinical Trial The prospective International Randomized Trial of IFN plus Cytarabine Versus Imatinib (STI-571; IRIS) study of 1106 patients with newly diagnosed CML in chronic phase established the superiority of imatinib 400 mg daily over IFN-α and low-dose cytarabine.23 The complete hematologic RRs were 95% versus 55%; the CCyR rates were 76% versus 15%; and the progression-free survival rates at 18 months were 97% versus 91% (P < 0.001). The molecular RRs were also significantly better, with estimated major molecular RRs of 40% versus 2% at 12 months. A 5-year update of the IRIS study continued to show positive results (Table 1).24 Three hundred eighty-two patients remained on imatinib first-line therapy. The cumulative complete hematologic response, MCyR, and CCyR rates were 98%, 92%, and 87%, respectively. The estimated 5-year event-free survival was 83%; only 6.3% of patients experienced progression to accelerated and blastic phases. The overall annual progression rate has decreased to 0.9% in the fifth year of therapy, compared with 1.5%, 4.8%, and 7.5% in the past 3 years, suggesting that disease progression might be diminished in the following years. The estimated 5-year survival rate was 89%; excluding non-CML deaths, it was 95%. The intensity
S52 • Clinical Lymphoma & Myeloma Vol 7 Suppl 2 March 2007
Elias Jabbour et al of the cytogenetic response after 12 months and 18 months of imatinib therapy has important implications regarding survival without transformation. The estimated 5-year survival rate in patients not having an MCyR at 12 months was significantly less (81%) than those who had an MCyR (complete, 97%; partial, 93%; P < 0.001). At 18 months of therapy, the estimated 5-year survival rate for patients not having a CCyR was significantly less than those who had CCyR (99% vs. 90%; P < 0.001).24 There was a continuous improvement in the rate of molecular response. The rate of major molecular response improved from 44% at 1 year of therapy to 68% at 4 years of therapy.25 This study did not document a survival advantage for imatinib because of the crossover design. Studies comparing the survival of patients treated with imatinib with historical cohorts treated with IFN-α–based therapy demonstrated the anticipated survival advantage.26-28 Figure 1 shows the survival of patients treated at our institution 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 IFN therapy, and in 4%-5% of patients in accelerated blastic phase.20-23 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%-6%, superficial edema in 1%-6%, hemorrhage in 1%19%, and musculoskeletal pain in 2%-9%. Severe fluid retention appeared to be dose related and was more common in the elderly and in the advanced phase studies with an imatinib dosage of 600 mg daily. 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 < 0.5% of patients. A recent report suggested that imatinib is cardiotoxic and can lead to severe left ventricular dysfunction and heart failure.29 Imatinib therapy as a causal factor of congestive heart failure was shown to be uncommon and was mainly seen in elderly patients with preexisting cardiac conditions.30 Among 1276 patients treated at 1 institution, 22 patients (1.8%; median age of 70 years) were identified as having symptoms that could be attributed to congestive heart failure. 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%). Eleven of the 22 patients continued imatinib therapy with dose adjustments and management for the congestive heart failure symptoms with no further complications.30
Table 2 Nonhematologic Adverse Events Side Effects
Treatment
Nausea, Vomiting, and Diarrhea
Antiemetics, antidiarrhea
Bone Aches
Antiinflammatory Calcium, Gatorade®, quinine
Muscle Cramps Skin Rashes
Avoid sun; steroids; I/R
Liver Dysfunction
I/R; steroids
Weight Gain
–
Edema, Fluid Retention, and CHF Cardiac Toxicity (Rare)
Diuretics Diuretics; CHF treatment; I/R
Abbreviations: CHF = congestive heart failure; I/R = dose interruptions/reductions
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 (filgrastim for neutropenia, oprelvekin [interleukin 11] for thrombocytopenia, erythropoietin, or darbepoetin 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 2-3 months of therapy. A brief treatment interruption is often sufficient to allow recovery, and most patients will not require dose reductions. 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 In the dose-finding phase I study of imatinib, the maximum tolerated dose was not identified. Because of the good responses obtained at the dose of 300-400 mg daily and because the blood concentration of imatinib at 400 mg daily was consistently higher than that required to inhibit 50% of Bcr-Abl TK activity in vitro,39,40 that dose was chosen for subsequent studies. Imatinib 600 mg daily was more effective than 400 mg for patients in advanced-stage disease.21,22 Treatment of patients with CML in late chronic phase after IFN-α failure with imatinib 400 mg twice daily resulted in a CCyR rate of 90%, compared with 48% in historical controls treated with standard dose therapy. In addition, 56% of patients had a major molecular response, including 41% with undetectable levels.41 Several imatinibresistant mutations might confer relative rather than absolute resistance to imatinib, which could be overcome with higher dose imatinib.42 In patients with previous hematologic and cytogenetic resistance to 400 mg of imatinib daily, increasing the dose to 800 mg resulted in a complete hematologic RR of 65% and a complete cytogenetic RR of 18%.43 Several phase II studies of high-dose imatinib in previously untreated patients with chronic phase CML documented higher rates of CCyR (up to 95%) and of molecular response, particularly ≥ 4-log reduction
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Management of Chronic Myeloid Leukemia in transcript levels.13,44-46 When compared with historical patients treated with standard dose, patients treated with highdose imatinib had higher rates of earlier CCyR (90% vs. 78%; P = 0.03). The cumulative incidences of major molecular response and complete molecular response were significantly better with high-dose imatinib (P < 0.0001 and P < 0.005, respectively).47 Progression-free survival and time to transformation were also significantly better.
Monitoring of Treatment Effect and Minimal Residual Disease on Imatinib Most patients have a CCyR with imatinib. Achievement of molecular response has become the endpoint of anti-CML strategies and led to redefining the therapeutic goals in CML.48 The long-term significance of molecular monitoring in CML is best exemplified in the setting of SCT, in which detection of high Bcr-Abl transcripts confers higher risk of relapse.49 The IRIS trial showed that a reduction of Bcr-Abl transcripts level by ≥ 3 logs below a standard baseline value correlated with better progression-free survival.15 Another study reported that achieving a major molecular response within the first 12 months of therapy was predictive of durable cytogenetic remission.14 The lack of consistency in reporting Bcr-Abl transcript levels has been a source of debate. A consensual proposal suggests harmonizing the differing methodsv for measuring Bcr-Abl transcripts by using a conversion factor, in which individual laboratories can express Bcr-Abl transcript levels on internationally agreed scales. 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.50 For practical purposes, a major molecular response can be defined as a reduction of Bcr-Abl/Abl transcripts to ≤ 0.1%.27 After a patient has had a CCyR, real-time PCR should be performed every 3-6 months and a routine cytogenetic analysis every 12 months. The latter test might detect clonal evolution and chromosomal abnormalities occurring in normal metaphases.
Significance of Cytogenetic Abnormalities Approximately 5% of patients who have a cytogenetic response develop karyotypic abnormalities in Ph-negative cells. These do not represent clonal evolution because they occur in cells without the Ph chromosome and should not be considered as part of the definition of accelerated phase. The significance of these events is currently unknown.51 The most common cytogenetic abnormalities include trisomy 8, monosomy 5 or 7, and deletion 20q.52-55 These abnormalities frequently regress spontaneously, and patients with these abnormalities have similar long-term outcome as patients without such abnormalities. However, occasional cases of progression to acute myeloid leukemia or myelodysplastic syndrome have been reported,56 mainly in patients with a deletion of chromosome 7 and/or other complex abnormalities, but also in patients with isolated trisomy 8, warranting a careful follow-up.
Imatinib Resistance and Monitoring of Mutations Despite the benefit of imatinib compared with previous treatments, some patients might develop resistance,57 with a reported annual relapse rate of 4% in newly diagnosed patients in chronic phase.58 Multiple mechanisms of resistance to imatinib, Bcr-Abl dependent and Bcr-Abl independent, have been identified; one of the best characterized is mutations in bcr-abl fusion gene (30%-50% of patients with imatinib resistance).59 Clinically relevant mutations disrupt critical contact points between imatinib and Bcr-Abl or induce a transition from the inactive to the active configuration, to which imatinib is unable to bind.57,60 Numerous bcr-abl mutations have been identified. Not all mutations have the same biochemical and clinical properties: some bcr-abl mutations result in a highly resistant phenotype in vitro; others are relatively sensitive, and resistance might be overcome by imatinib dose increase.59,61-64 The T315I mutation and some mutations affecting the so-called P-loop of Bcr-Abl confer a greater level of resistance to imatinib and to the novel TKIs.65,66 Kinase domain mutation screening for patients in chronic phase is indicated in cases of hematologic or cytogenetic resistance/relapse65 or if there is an increase in bcr-abl transcript ratio of ≥ 1 log.67Kinase domain mutations should be investigated in any patients presenting in advanced phase disease.
Duration of Therapy with Imatinib The optimal duration of imatinib therapy is unknown. The current recommendation is to continue treatment indefinitely unless there is 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 sustaining undetectable levels of Bcr-Abl for significant periods of time.68-70 Rousselot et al reported on 12 patients who discontinued imatinib after maintaining undetectable Bcr-Abl levels for ≥ 24 months; 6 are still PCR negative after a median follow-up of 18 months (range, 9-24 months).71 Ten of these 12 patients had been treated with IFN-α, suggesting that IFN-α immunomodulatory effects might 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.72 It is conceivable that these progenitors might trigger proliferation of CML when the inhibitory pressure of imatinib is eliminated.
Imatinib and Pregnancy The effects of imatinib on fertility, pregnancy, and lactation are known mostly from animal studies with imatinib. Male rats administered imatinib 70 days before mating had a decrease in testicular and epididymal weights and in sperm motility. Imatinib was teratogenic in rats when administered during organogenesis at doses > 100 mg/kg, which is equivalent to a dose of 800 mg daily in adults based on body surface
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Elias Jabbour et al area. Female rats administered imatinib doses of ≥ 45 mg/kg experienced postimplantation loss, with no fetal loss at doses < 30 mg/kg. At doses > 100 mg/kg, total fetal loss occurred in all animals. There is limited information on the potential effect that imatinib could have on the developing fetus. The outcome of 19 pregnancies involving 18 patients (10 women and 8 men) who conceived while receiving imatinib for the treatment of CML was recently reported.73 All female patients discontinued therapy immediately upon recognition of the pregnancy. Three pregnancies (involving 2 women and 1 man) ended in spontaneous abortion, and 1 patient had an elective abortion. All other pregnancies were uneventful. Two of the 16 (12%) babies had minor abnormalities at or shortly after birth that were surgically repaired. All babies have continued normal growth and development. Among female patients (N = 10) who interrupted therapy, 5 of 9 in complete hematologic remission at the time of treatment interruption eventually lost complete hematologic response, and 6 of 10 experienced an increase in Ph chromosome–positive metaphases. At a median of 18 months after resuming therapy with imatinib, 8 patients (44%) had a cytogenetic response (complete in 3 patients). Although there is no evidence that a brief exposure to imatinib during conception and pregnancy adversely affects the developing fetus, most patients lose their response after treatment interruption. Therefore, patients receiving imatinib should be advised to practice adequate contraception.
Stem Cell Transplantation Imatinib is now recommended as initial treatment for most patients with newly diagnosed chronic phase CML. Allogeneic SCT (ASCT) is recommended in case of failure, and could be considered in case of suboptimal response, particularly in younger patients with full match-related donor.48 Previous treatment with imatinib was shown not to be associated with an increase of transplantation-related morbidity and mortality.74,75
Immunotherapy and Residual Disease Immune-mediated suppression of the CML clones is evidenced by the graft-versus-leukemia effect in eradicating CML cells after ASCT76 and by maintenance of durable remissions after discontinuation of IFN-α therapy in a subset of patients.8,77 This led to the development of vaccine strategies that elicit specific immune responses directed at CML-restricted tumor antigens. At least 3 approaches of vaccine therapy are being developed. The first approach is to use tumor-specific antigens. In 1 study, 12 patients with CML in complete or partial remission (PR) on IFN-α were vaccinated with a mixture of junction peptides: 2 patients had a transient response (1 molecular response and 1 CCyR).78 In a subsequent phase II study, 4 of 14 patients (29%) vaccinated had a decrease in Ph-positive cells, 2 of them while on IFN-α (n = 1) or imatinib (n = 1).79 Three patients (21%) treated for molecular relapse after ASCT had a transient complete molecular response (2 patients received concurrent donor leukocyte infusions). Bocchia and
colleagues vaccinated 16 patients with stable residual disease after > 12 months of imatinib therapy (n = 10) or 24 months of IFN therapy (n = 6) with a peptide vaccine derived from the sequence p210-b3a2.80 Five of 9 patients on imatinib had a CCyR after vaccination and 3 had a complete molecular response. Of 6 patients on IFN-α, 5 had improvement in cytogenetic response and 2 of them had a CCyR. The second approach is the use of PR1, derived from proteinase 3 and presented through human leukocyte antigen–A2.1. In 1 study, 3 of 10 patients with CML treated with the nonapeptide PR1 had cytogenetic improvement, and 1 had a CCyR.81 The third approach, using the heat-shock protein–based vaccines, was assessed in 11 patients with CML who did not have an MCyR response after 6 months of imatinib therapy: 5 patients had an MCyR, and 2 of them had a molecular remission.82 Overall, these data suggest that immunotherapy might have a role in the management of CML, particularly at the stage of minimal residual disease.
Novel Approaches Novel, more potent TKIs have been developed to overcome imatinib resistance.6 Dasatinib, 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.83Nilotinib is an oral potent and selective Bcr-Abl inhibitor in advanced clinical trials.84 Both agents have been investigated in patients with newly diagnosed CML. Preliminary results on 14 patients with newly diagnosed CML and treated with nilotinib 400 mg twice daily were recently reported.82 Major cytogenetic response was observed in all patients at 3 months (complete in 13 and partial in 1), and all 7 evaluable patients were in CCyR at 6 months.85 The rates of CCyR at 3 months and 6 months were significantly better than with imatinib 400 mg and 800 mg.
Conclusion and Future Perspectives The introduction of imatinib has marked an important and revolutionary step in the management of CML. The longterm 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 maximize the benefit. The availability of highly potent TKIs has broadened the treatment armamentarium in CML. Long-term treatment of CML might require a combination of TKIs, farnesyltransferase inhibitors, and possibly compounds with other mechanisms of action, both conventional and targeted. Vaccines to stimulate patient immunity might control and eliminate residual disease. With these strategies, the treatment prospects of patients with CML are very hopeful.
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