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The Evolution of Tyrosine Kinase Inhibitor Therapy: Improving Outcomes in Patients with Newly Diagnosed Chronic Myelogenous Leukemia

JHOP - December 2011 VOL 1, NO 4 - Drug Therapies
Natalie J. Greisl, PharmD
Christopher A. Fausel, PharmD, BCPS, BCOP

Chronic myelogenous leukemia (CML) is a hematologic malignancy initiated by a translocation event that results in the fusion of the breakpoint cluster region (BCR) of chromosome 22 with the Abelson leukemia oncogene (ABL) tyrosine kinase on chromosome 9 in bone marrow stem cells. This chromosomal abnormality is known as the Philadelphia (Ph) chromosome.1,2

The dysregulation of ABL kinase activity transforms the stem cell, resulting in the production of undifferentiated blasts as opposed to normally differentiated white blood cells. Left untreated, CML progresses through an indolent chronic phase to a lethal phase of blast crisis within 3 to 5 years.1

Before the advent of tyrosine kinase inhibitor (TKI) therapy, median survival for patients who had progressed to advanced disease—the accelerated phase— ranged from 6 to 39 months.3,4 For patients in blast crisis, survival was from 2 to 8 months.5,6

Historically, conventional cytotoxic agents such as busulfan and hydroxyurea were used to control peripheral blood counts but did not prevent the progression of disease.1,7 Therapy would become less effective after 3 to 5 years of treatment, after which the disease would transform to accelerated phase or blast crisis. Interferon (IFN)-alpha was the first therapy that was demonstrated to increase overall survival (OS) in CML, and survival was marginally increased with the addition of low-dose cytarabine.8

A transformative discovery in cancer therapeutics was the characterization of the adenosine triphosphate (ATP) binding site on the BCR-ABL tyrosine kinase, and its role in imatinib-mediated inhibition of that kinase.9 Imatinib, a BCR-ABL TKI, became standard first-line therapy when it was shown to be superior to IFN-alpha plus cytarabine therapy.10 However, mutations in the BCR-ABL tyrosine kinase binding site induce imatinib resistance in some patients, necessitating active second-line therapy, which led to the development and the US Food and Drug Administration (FDA) approval of 2 second-generation TKIs—dasatinib and nilotinib. As discussed below, these 2 agents have been shown to achieve cytogenetic remissions and molecular responses in patients with CML who are intolerant of or whose disease is refractory to imatinib.

This review discusses the advances in the pharmacotherapy of chronic-phase CML (CML-CP) and highlights the clinical data regarding the use of dasatinib and nilotinib in patients with newly diagnosed disease.

The Pre-Imatinib Era
Busulfan was a frontline treatment for CML when in 1963 a clinical trial demonstrated its superiority over 6- mercaptopurine therapy during an era when the goal of therapy for patients with CML was limited to normalization of the white blood cell count.11 Hydroxyurea, originally synthesized almost a century earlier, was found to have antileukemic effects in mice and was subsequently investigated as a therapy for CML.12

Metabolic experiments in that study suggested that hydroxyurea inhibited DNA synthesis, thereby blocking the proliferation of transformed blasts. Additional clinical studies demonstrated that hydroxyurea improved survival in patients with CML by extending the length of the chronic phase.13,14 As recently as 1993, the median survival for a patient with CML-CP taking hydroxyurea as a frontline medication was approximately 5 years.14 Busulfan and hydroxyurea have minimal potential to induce cytogenetic response and do not alter the disease course of CML.13,14

In the 1980s, IFN-alpha, a nonspecific, immune-modulating agent, advanced into clinical trials for the treatment of patients with CML. In randomized clinical trials, IFN-alpha demonstrated efficacy by its ability to induce at least partial hematologic responses in 55% to 86% of patients, at least minor cytogenetic responses of 10% to 52%,8,15-18 a 12% to 20% absolute improvement in the 5- year survival rate, and an increase in median OS of 1 to 2 years over previous therapies.19

IFN-alpha has a considerable toxicity profile that includes flulike symptoms along with arthralgia and myalgia and depression.8,20

A study comparing therapy with IFN-alpha mono - therapy and IFN-alpha plus cytarabine in patients with recently (≤6 months) diagnosed CML-CP showed that the 3-year OS increased from 79.1% among patients receiving IFN-alpha alone to 85.7% among those receiving IFN-alpha plus cytarabine.8 In addition, combination therapy increased the percentage of patients who achieved a major cytogenetic response (MCyR) from 24% to 41%.8 Allogeneic stem-cell transplant (SCT) is the only proved option for achieving cure in CML. After a 3- to 5-year follow-up, disease-free survival of patients with good prognostic factors undergoing transplant from human leukocyte antigen (HLA)-matched related donors can be as high as 78%; it ranges from 46% in patients aged >40 years to 61% in patients aged <30 years, for HLA-matched unrelated donors.21,22

Because of age limitations, the limited availability of appropriately matched donors, and the toxicities associated with treatment, only 30% of patients with CML meet the eligibility criteria for allogeneic SCT, precluding its widespread use.23-26 Furthermore, in addition to long-term complications, such as infections and secondary malignancies, late relapses have been seen as long as 14 years or more after transplant.27-29

The Imatinib Era The introduction of imatinib, a multikinase inhibitor with high specificity for the inhibition of BCR-ABL activity, revolutionized the treatment of CML.30 Imatinib was developed from a small-molecule library in a screening for inhibitors of protein tyrosine kinases.31 Imatinib competes with ATP for binding to the BCR-ABL tyrosine kinase in a region known as the phosphate-binding loop (P-loop).9 The interaction of imatinib with the BCR-ABL tyrosine kinase is conformationally sensitive; only the closed conformation of the P-loop serves as a binding site. Cell-culture studies confirmed that imatinib inhibited the growth of CML blasts in vitro.31

Imatinib was studied in a phase 1 dose-escalation trial that examined 83 patients with CML-CP in whom IFN-alpha therapy had failed.32 Patients were successively assigned to dosing groups ranging from 25 mg to 1000 mg daily. All doses were well tolerated, and the most common adverse events (AEs) reported were nausea, myalgia, edema, and diarrhea.32 Of the 54 patients who received a dose of 300 mg or more, 98% achieved complete hematologic response, 54% achieved cytogenic response, and 13% achieved complete cytogenic response (CCyR).32

In a second analysis of this study, patients with CML who had progressed to blast crisis also responded to imatinib, but to a lesser extent.33 A total of 38 patients with CML were in myeloid blast crisis and 20 patients either had Ph-positive (Ph+) acute lymphoblastic leukemia (ALL) or were in lymphoid blast crisis. Although 21 of the 38 patients (55%) in myeloid blast crisis responded with a decrease in blasts in the marrow, only 4 (19%) of them achieved complete hematologic response. Although 70% of the patients with ALL/lymphoid blast crisis responded to imatinib, the disease subsequently relapsed in virtually all the responders.33

In a phase 2 study, 454 patients with CML-CP in whom IFN-alpha therapy had failed were treated with oral imatinib 400 mg once daily.34 Complete hematologic response was achieved by 95% of the patients and MCyR was achieved by 60% of patients. After a mean follow-up of 18 months, 89% of the patients remained in chronic phase and 95% were still alive. Intolerable AEs led to imatinib discontinuation in only 2.1% of the patients. The most common AEs consisted of superficial edema, nausea, and muscle cramps.34

In the IRIS (International Randomized Study of Interferon Versus STI571) study, a phase 3, open-label, randomized, controlled trial, imatinib was compared directly with IFN-alpha plus cytarabine as frontline treatment for newly diagnosed CML.10 A total of 553 patients received 400 mg imatinib daily; the IFN-alpha plus cytarabine group (N = 553) received gradually escalating doses of IFN-alpha, up to 5 million U/m2 of body surface area daily. When the maximum tolerated dose was reached, subcutaneous low-dose cytarabine was added to the regimen for 10 days monthly.10

The study design allowed patient crossover from IFNalpha plus cytarabine to imatinib if patients showed no response to treatment, lost response, or had an AE; a majority of the patients (57.5%) crossed over to the imatinib group, and more than one third (43%) who crossed over did so because of intolerance of IFN-alpha.10

The analyzed results did not account for outcomes in patients who crossed over to alternative therapies. The imatinib arm demonstrated greater complete hematologic response (95.3% vs 55.5%, respectively; P <.001), MCyR (85.2% vs 22.1%; P <.001), and CCyR (73.8% vs 8.5%; P <.001) compared with the IFN-alpha plus cytarabine arm. At 12 months, progression-free survival (PFS) was 96.6% for the imatinib group and 79.9% for the IFN-alpha group (P <.001).10 The 5-year follow-up demonstrated an increase in CCyR to 82% and OS of 89%.35 Only 6% of the patients randomized to imatinib progressed to accelerated-phase or blastphase CML, and these progression events occurred primarily within the first 2 to 3 years of treatment.35

Two important analyses performed in the 5-year follow- up of the IRIS study demonstrated the association of response at 12 months with long-term disease outcomes. In the first analysis, 97% of 350 patients who achieved CCyR by 12 months of imatinib treatment had not progressed to accelerated-phase or blast-phase CML during the 5-year follow-up.35 Of the 139 patients who achieved CCyR and a major molecular response (MMR)—defined as ≥3-log reduction in BCR-ABL transcripts—at 12 months, 100% remained free of progression to accelerated phase or blast phase at 5 years. AEs decreased over time, and their general profile did not change.35

The results at 8-year follow-up were presented in 2009.36 The estimated event-free survival (81%) and OS (85% when all causes are considered, 93% considering only CML-related deaths) continue to remain high and stable. No new toxicities were identified, and only 1 patient had disease progression.36

Some patients develop resistance to imatinib primarily in response to the emergence of cells containing BCR-ABL mutations unresponsive to imatinib. Most of these mutations occur in the kinase domain of the fusion protein.37 In addition, for some patients, the AEs are not tolerable and preclude the use of imatinib.

The Post-Imatinib Era
The second-generation TKIs dasatinib and nilotinib were initially studied as treatment alternatives for patients with imatinib-resistant or -intolerant CML. Dasatinib and nilotinib are capable of inhibiting most BCR-ABL mutations, with the exception of the T315I mutation, which is resistant to all currently available TKIs.38,39 The safety and efficacy of nilotinib and dasatinib were first established in the second-line setting in patients with imatinib-resistant or -intolerant CML.

Nilotinib
Nilotinib (originally known as AMN107) was rationally designed through close examination of the crystal structure of the imatinib/BCR-ABL tyrosine kinase complex.40 Nilotinib binds to the closed-loop structure of the BCR-ABL tyrosine kinase. However, additional interaction sites between the BCR-ABL tyrosine kinase and nilotinib allow the drug to bind with a much greater affinity than imatinib. The potency of nilotinib for inhibition of the wild-type BCRABL is 20 to 40 times greater than that of imatinib, and its potency for inhibition of many BCR-ABL mutations is much greater than that of imatinib.41

Although nilotinib binds to the BCR-ABL tyrosine kinase with high affinity, its binding to other tyrosine kinases is largely reduced and is generally not significant at clinical doses.42 Nilotinib’s greater selectivity versus imatinib is seen in its higher affinity for the BCR-ABL tyrosine kinase, its similar inhibition of platelet-derived growth factor and c-KIT receptor tyrosine kinases, and its lack of activity against a wide range of other protein kinases, including the C-Src oncogene.40

The efficacy and safety of nilotinib were initially reported in an open-label, phase 2 study of patients with imatinib-resistant or -intolerant CML-CP.43 At 6 months of follow-up, 48% of the patients achieved MCyR and 31% achieved CCyR. The estimated 1-year OS was 95%: nilotinib was well tolerated in these patients. In response to these positive data, nilotinib received FDA approval in 2007 for second-line treatment of CML-CP.

At 24 months of follow-up, 46% of patients achieved CCyR with nilotinib therapy, 56% of whom achieved an MMR.44 The estimated PFS rate was 64%, and OS was 87% at 24 months, with no changes in the safety profile.44

The efficacy and safety of nilotinib in the frontline setting were evaluated in a phase 2 trial of 51 patients with newly diagnosed CML-CP.45 By 3 months, 90% of the patients achieved CCyR; by 6 months, that percentage increased to 96%. At 12 months, 81% of the patients achieved an MMR. The estimated event-free survival at 24 months was 90%; transformation-free survival was 98%.45

The most common AEs were increased liver transaminase activity or bilirubin levels, skin rash, fatigue, hyperglycemia, neutropenia, anemia, and thrombocytopenia.45 Most AEs were grade 1 or 2. Grade 3 and 4 AEs included elevation of bilirubin, lipase, or amylase levels. Cardiac events were rare; 2 patients developed hypertension, and 2 developed a prolonged corrected QT (QTc) interval; none of these AEs was grade 3 or 4.45

A second phase 2 trial was conducted by the GIMEMA (Gruppo Italiano Malattie e Matologiche dell’Adulto) CML Working Party to investigate nilotinib as a first-line therapy in 73 patients with newly diagnosed CML.46 All patients achieved complete hematologic response within 3 months. By 6 months, 96% achieved CCyR, and by 12 months 85% achieved an MMR. AEs were similar to those observed in the previous trial.45,46 A recent 3-year analysis demonstrated the durability of nilotinib responses in patients with newly diagnosed CML, without any new safety concerns.47

Table 1
Nilotinib versus Imatinib: Treatment Discontinuation and Adverse Events in the ENESTnd Study
View larger version

Nilotinib has been compared with imatinib in the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients) trial, a phase 3 open-label study (Table 1).48 A total of 846 patients with newly diagnosed CML-CP were randomized in a 1:1:1 ratio into 3 arms: nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, or imatinib 400 mg once daily (the control arm). The primary end point was MMR at 12 months.48

At data cutoff, the MMR rates for the 300-mg and 400-mg nilotinib arms were 57% and 54%, respectively, compared with 30% in the imatinib arm.48 The median time to MMR, as estimated by a Kaplan-Meier analysis, was shorter for the 300-mg nilotinib (8.6 months) and 400-mg nilotinib (11.0 months) groups compared with the imatinib arm (median not yet reached).48

Complete molecular response (defined as <0.0032% of baseline transcripts on the International Standard) at the data cutoff was 13% and 12%, respectively, for the nilotinib 300-mg and 400-mg arms and 4% for the imatinib arm.48 CCyR rates by 12 months were significantly greater in the 2 nilotinib arms compared with the imatinib arm (80% with nilotinib 300 mg and 78% with 400 mg vs 65% with imatinib; P <.001 for both comparisons).48

Progression to accelerated-phase or blast-phase CML occurred in 11 patients (4%) receiving imatinib compared with 3 patients (<1%) receiving nilotinib (2 in the 300-mg arm and 1 in the 400-mg arm).48 Although no patient who attained an MMR had progressed, 3 patients receiving imatinib who had achieved CCyR progressed. Nilotinib was superior to imatinib in terms of the time to progression (P = .01 for the 300-mg group and P = .004 for the 400-mg group compared with the imatinib-treated group).48

Overall, grade 3 or 4 nonhematologic AEs were uncommon. The incidence of nausea, diarrhea, vomiting, muscle spasm, and edema were higher in the imatinib arm, whereas rash, headache, pruritus, and elevated liver enzymes were higher in the nilotinib arms.48 No patient had a QTc longer than 500 milliseconds or a decreased left-ventricular ejection fraction. Grade 3 or 4 hematologic abnormalities occurred within the first 2 months of therapy for both treatments.48

Recently, results of a 24-month analysis were presented, demonstrating that the responses observed with nilotinib were durable; no new safety concerns emerged with longer follow-up.49 In mid-2010, this trial led to the approval of nilotinib for the treatment of newly diagnosed CML-CP in treatment-naïve patients.

Dasatinib
Dasatinib (originally known as BMS-354825) was identified through a screening of a small-molecule library for inhibitors of the C-Src kinase.50 The affinity of dasatinib for the BCR-ABL fusion gene is 325-fold higher than that of imatinib.42 Dasatinib can bind to open and closed conformations of the BCR-ABL tyrosine kinase as well as to most BCR-ABL mutations. In addition, dasatinib has inhibitory activity against the C-Src kinase, c-KIT, and the platelet-derived growth factor receptors.42,50

The efficacy and safety of dasatinib were demonstrated in a phase 2 study involving patients with imatinib-resistant or -intolerant CML-CP.51 At 8 months of treatment, 90% of the patients achieved complete hematologic response, 52% achieved an MCyR, and the PFS rate was 92%. Dasatinib was well tolerated, and there was no crossintolerance with imatinib.51 Follow-up at 15 months indicated 91% of patients achieved complete hematologic response and 59% maintained or attained MCyR; PFS was 90%, and OS was 96%.52

A recently published phase 2 study established the safety and efficacy of dasatinib in the frontline setting. 53 A total of 62 patients were randomized to receive 100 mg once daily or 50 mg twice daily until either disease progression or an unacceptable AE occurred. The primary end point was an MMR in <40% of the treatment group within 12 months (the average response rate for imatinib).53

Efficacy was similar for the 2 dosages. At 3 months, 82% of the patients achieved a CCyR, and 24% achieved an MMR. By 12 months, 98% of the patients achieved CCyR and 71% achieved an MMR. Complete molecular response was achieved by 7% of the patients; however, this was lost by 30 months.53

Muscle and joint pain, fatigue, rash, headache, and diarrhea were the most common nonhematologic AEs. Grade 3 and 4 nonhematologic AEs consisted of fatigue (6%), joint and muscle pain (6%), peripheral neuropathy (5%), dyspnea (5%), and memory impairment (5%). Pleural effusion occurred in 13% of the patients; 2% of these events were grade 3 in severity. Hematologic toxicities included neutropenia (63%), anemia (81%), and thrombocytopenia (69%).53

The DASISION (Dasatinib versus Imatinib Study in Treatment-Naïve CML Patients) trial examined frontline treatment with dasatinib in comparison with imatinib.54 A total of 519 patients with newly diagnosed CML-CP were randomized to 1 of 2 arms: dasatinib 100 mg daily or imatinib 400 mg daily. The primary end point was a confirmed CCyR by 12 months. Confirmation required 2 measures of CCyR, at least 28 days apart.54 Of the patients receiving dasatinib, 77% achieved confirmed CCyR versus 66% of imatinibtreated patients (P = .007). The rate of MMR, a secondary end point, was 46% versus 28%, respectively, at 12 months of follow-up (P <.001).54

An examination of the subpopulation of patients in each arm who had achieved CCyR showed a greater MMR rate with dasatinib than with imatinib (54% vs 39%, respectively; P = .002).54 Progression to accelerated phase or blast phase occurred in 5 patients (1.9%) in the dasatinib arm and in 9 patients (3.5%) in the imatinib arm. At 12 months, the estimated rates of PFS were indistinguishable for the 2 groups (96% vs 97%, respectively). The OS was 97% for the dasatinib arm and 99% for the imatinib arm.54

AEs for the 2 treatment groups were primarily grade 1 and 2; however, the pattern of specific AEs was distinct for the 2 treatments. Nausea, vomiting, muscle inflammation, rash, and fluid retention occurred more frequently in the imatinib group.54 Pleural effusion, headache, and cytopenias were more frequent in the dasatinib group. Gastrointestinal or other bleeding events occurred in 5% of patients in the dasatinib and imatinib arms. One patient in each group had a QTc interval longer than 500 milliseconds.54

Table 2
Dasatinib versus Imatinib: Treatment Discontinuation and Adverse Events in the DASISION Study Dasatinib 100 mg once daily (N = 258) Imatinib 400
View larger version

The recently reported 18-month DASISION results showed that cytogenetic and molecular responses remained higher in the dasatinib arm than in the imatinib arm and were associated with no new safety concerns (Table 2).55 Since 2006, dasatinib has been available for the treatment of imatinib-resistant or -intolerant CML-CP, CML in blast phase, or CML in accelerated phase. In October 2010, dasatinib received FDA approval for the treatment of newly diagnosed CML-CP. The 2011 National Comprehensive Cancer Network guidelines recommend the use of imatinib, nilotinib, or dasatinib as treatment options for patients with newly diagnosed CML-CP.56

Table 3
Oral Dosages, Interactions, and Adverse Reactions of Tyrosine Kinase Inhibitors0
View larger version

Perhaps the most important differentiator between the 2 second-generation TKIs dasatinib and nilotinib is their safety profile. Compared with imatinib, nilotinib showed a relative increase in rash, headache, and pruritus, whereas dasatinib showed a relative increase in pleural effusion, headache, and cytopenia (Table 3).

Future Therapies
Aurora kinase inhibitors, such as VX-68057 and PHA-739358,58 inhibit the BCR-ABL T315I mutation, as well as other mutations. The investigational agent bosutinib has been evaluated in a phase 2 trial of 288 patients with CML-CP who had been previously treated with imatinib.59 After a median of 24.2 months of follow-up, 53% achieved an MCyR—the primary end point of the trial—and 41% achieved CCyR.

Of the patients who achieved CCyR, 64% attained an MMR. The drug was well tolerated, and the most frequently reported AE was gastrointestinal toxicity. Notably, bosutinib is not active against BCR-ABL mutations with the T315I mutation.59

AP24534 (ponatinib)—a second investigational drug that has activity in inhibiting BCR-ABL T315I—is being studied in a phase 2 trial of 320 patients with CML-CP, CML in accelerated phase, or CML in blast phase and Ph+ ALL.60 The study will include patients with CML or ALL resistant to or intolerant of nilotinib or dasatinib or who have the T315I mutation. As these newer agents accumulate additional clinical experience, the prospect for additional treatment options for patients with CML refractory to first-line treatment will be expanded.

Conclusions
The improvement in outcomes with imatinib therapy has ushered in a new era of CML management and provided the impetus for the further development of targeted therapies for cancer. The improved efficacy of nilotinib and dasatinib in achieving MMR and CCyR with early follow-up suggests a potential change in the first-line treatment of CML. There are no prospective head-to head studies comparing the efficacy and safety of dasatinib and nilotinib in either the first-line or second-line treatment settings, making a direct comparison infeasible.

The post-imatinib era for first-line treatment of CML is emerging, but long-term follow-up is needed to confirm the optimal therapy for newly diagnosed CML. Because of the relatively immature data in frontline therapy with second- generation TKIs, it is unknown whether an increase in the rates of CCyR and MMR translate into improvement in long-term freedom from disease progression and whether the toxicities associated with nilotinib and dasatinib will decrease over time, as was observed in the IRIS study with imatinib. Careful analysis is necessary to elucidate the potential resistance profiles that may emerge for dasatinib and nilotinib.

The emergence of second-generation TKIs for first-line treatment of CML has raised the question of what the optimal treatment standard is for second-line therapy. The impact of TKI therapy on the role of allogeneic SCT is still being investigated. It is not yet known whether the administration of TKIs after allogeneic SCT will improve long-term disease control or treat relapsed Ph+ disease; however, work in this area is ongoing.61,62

Acknowledgments
Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. We thank Robert Scheinman, PhD, and Patricia Segarini, PhD, of Percolation Communications LLC, for their medical editorial assistance.

References

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  3. Karanas A, Silver RT. Characteristics of the terminal phase of chronic granulocytic leukemia. Blood. 1968;32:445-459.
  4. Kantarjian HM, Dixon D, Keating MJ, et al. Characteristics of accelerated disease in chronic myelogenous leukemia. Cancer. 1988;61:1441-1446.
  5. Coleman M, Silver RT, Pajak TF, et al. Combination chemotherapy for terminal- phase chronic granulocytic leukemia: cancer and leukemia group B studies. Blood. 1980;55:29-36.
  6. Vallejos CS, Trujillo JM, Cork A, et al. Blastic crisis in chronic granulocytic leukemia: experience in 39 patients. Cancer. 1974;34:1806-1812.
  7. Kalidas M, Kantarjian H, Talpaz M. Chronic myelogenous leukemia. JAMA. 2001;286:895-898.
  8. Guilhot F, Chastang C, Michallet M, et al. Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. French Chronic Myeloid Leukemia Study Group. N Engl J Med. 1997;337:223-229.
  9. Schindler T, Bornmann W, Pellicena P, et al. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science. 2000;289:1938-1942.
  10. O’Brien SG, Guilhot F, Larson RA, et al, for the IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronicphase chronic myeloid leukemia. N Engl J Med. 2003;348:994-1004.
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