Should nilotinib replace imatinib as first line treatment of chronic myeloid leukemia in chronic phase (CML-CP)?

Should nilotinib replace imatinib as first line treatment of chronic myeloid leukemia in chronic phase (CML-CP)? http://test.metromomsblog.org/wp-content/uploads/2010/02/tortoise-and-the-hare.jpg D. Van Nguyen, Pharm.D. PGY2 Oncology Pharmacy Resident South Texas Veterans Affairs Health System, San Antonio, TX Division of Pharmacotherapy, University of Texas at Austin College of Pharmacy, TX Pharmacotherapy Education and Research Center, UTHSCSA, TX October 8, 2010 Learning objectives: Outline the epidemiology, pathophysiology, standard treatment, and monitoring parameters for CML Understand the limitations of current treatment options Assess clinical trials supporting the use of imatinib and nilotinib as first-line treatment for in CML-CP Formulate evidence-based conclusions

Chronic Myeloid Leukemia Epidemiology 1-3 CML accounts for approximately 15% of all leukemias The annual incidence is about 5000 new cases Risk increases with age Median age at diagnosis is 55 years Affect both genders equally Only identifiable risk factor for CML is exposure to high-dose radiation Myeloproliferative disease resulting from a specific genetic mutation 2,4 Figure 1. Chronic myeloid leukemia. Adapted from Clarke FM. N Engl J Med. 2004;351:635 Pathophysiology 2,4 Characterized by the presence of the Philadephia (Ph+) chromosome and BCR-ABL transcript in leukemic cells 90% of CML are Ph+ Nguyen DV 2 of 17

A translocation between chromosome 9 and 22, t(9:22) (q34q11) fusion of abelson (ABL) gene on chromosome 9 and the break-point cluster (BCR) gene on chromosome 22 The fusion product BCR-ABL encodes for the BCR-ABL protein BCR-ABL protein has constitutively activated tyrosine kinase activity Uncontrolled myeloproliferation Decreased apoptosis Altered cellular adhesion Defective DNA repair Clinical presentation 2,4 Signs and symptoms LUQ abdominal pain Weight loss Fatigue Figure 2. Mechanism of CML. Savage GD, et al. N Engl J Med. 2002;346:685 Nguyen DV 3 of 17

Laboratory Leukocytosis, thrombocytosis, anemia Increased granulocytes Increased uric acid and lactase dehydrogenase (LDH) Decreased alkaline phosphatase Physical exam Splenomegaly Diagnosis 2-5 Bone marrow Hypercellular Myeloid to erythroid ratio at least 10 to 1 Normal is 3 to 1 Cytogenetics Gold standard for diagnosis t(9,22) Ph+ Reverse transcriptase polymerase chain reaction (RT-PCR) BCR-ABL transcripts Prognosis 6-8 Triphasic Chronic accelerated blast Table 1. M.D. Anderson Cancer Center CML criteria 6 Phase Criteria Chronic (CP) <15% blasts in the peripheral blood or bone marrow <20% basophils in the peripheral blood or bone marrow <30% blasts + promyelocytes Accelerated (AP) >15% blasts in the peripheral blood or bone marrow >30% blasts and promyelocytes in the peripheral blood >20% peripheral blood basophils Platelet < 100 x 10 9/ L Clonal evolution Blast (BP) At least 30% blasts in the peripheral blood or bone marrow Extramedulary involvement (except hepatosplenomegaly) Abbreviations: CML-chronic myeloid leukemia; CP-chronic phase; AP-accelerated phase; BP-blast phase More than 90% of newly diagnosed patients are in chronic phase Progression from chronic to blast phase increases with time 5-10% in the first 2 years 20-25% after two years Nguyen DV 4 of 17

Risk stratification Calculated based on age, platelet count, peripheral blast, and spleen size Hasford score places fewer people in the high-risk category vs. Sokal score Table 2. Median survival (months) based on risk stratification Risk Sokal score (1984) 7 Hasford score (1998) 8 Low 50-60 102 Intermediate 36-40 80-95 High 24-30 45-60 No current risk stratification system derived from TKI therapy Monitoring Parameters 5 Table 3. European LeukemiaNet monitoring parameters Response Definition Hematologic Cytogenetic CHR CCR PCR mcr mincr None Plt <450x10 9 /L WBC <10x10 9 /L No immature granulocytes Basophils <5% Non palpable spleen No Ph+ metaphases 1-35% 36-65% 66-95% >95% Molecular CMR Undetectable BCR-ABL mrna transcripts by real time quantitative and/or nested PCR in 2 consecutive samples MMR BCR-ABL to ABL ratio less than or equal to 0.1% Abbreviations: CHR-complete hematologic response; CCR-complete cytogenetic response; PCR-partial cytogenetic response; mcr-minor cytogenetic response; mincr-minimal cytogenetic response; CMR-complete molecular response; MMR-major molecular response Evolution of treatment 2,9,10 Busulfan Effective in lowering white blood count (WBC) No effect on disease progression Significant toxicity Hydroxyurea Better tolerated than busulfan Effective in lowering WBC and reducing splenomegaly No effect on disease progression Allogeneic stem cell transplant Only curative option 3-5 year survival rate of 40-80% Limited by transplant related mortality (5-50%) and lack of suitable donor Nguyen DV 5 of 17

Interferon alpha (TNFα) Naturally occurring glycoprotein found to be effective in CML in 1980 High rate of hematologic response (40-80%) Minimal complete cytogenetic response (5-25%) Median survival : 60-90 months Poor safety profile Tyrosine kinase inhibitors (see appendix 1) 2,3,9,11-13 Mechanism of action Blocks the binding of ATP to the BCR-ABL tyrosine kinase and inhibit the tyrosine kinase activity of BCR-ABL mediated signaling pathways Induced inactivation of downstream pathways results in reduction of excessive myeloid cell proliferation Imatinib and nilotinib binds to the inactive conformation of BCR-ABL tyrosine kinase Figure 3. Mechanism of tyrosine kinase inhibitor. Adapted from An X, et al. Leukemia Research 2010;34:1255-68 First generation: imatinib FDA approved in 2003 for first-line treatment Currently the standard first-line treatment Second-generation: nilotinib More potent than imatinib FDA approved in 2007 for second-line treatment On June 2010, FDA approved for first-line Nguyen DV 6 of 17

Imatinib International Randomized Study of Interferon and STI571 (IRIS) 14 Objective To compare the efficacy of imatinib versus interferon alfa and low-dose cytarabine in newly diagnosed CML-CP Design Prospective, multicenter, open-label, phase 3, randomized, controlled Methods Inclusion Adults with newly diagnosed Ph+ CML in chronic phase Previously untreated (except hydroxyurea, anagrelide, or both) Eastern Cooperative Oncology Group (ECOG) <3 Adequate organ function Exclusion Breast-feeding or pregnant Uncontrolled serious medical conditions Undergone major surgery within the preceding four weeks Seropositive for HIV History of another cancer within the previous five years (except basal-cell carcinoma or cervical carcinoma in situ) Treatment Stratefied according to Sokal and Hasford score Arm 1: imatinib 400 mg PO daily Arm 2: interferon alfa and low-dose cytarabine (I+C) Gradual dose escalation of interferon alfa to a target of 5 mu/m 2 as tolerated Once maximum dose of interferon alfa was achieved, cytarabine 20 mg/m 2 /d SC x 10 days every month Dose modification allowed if no CHR within 3 months or minor CR at 12 months Double imatinib dose (400 mg BID) or increase cytarabine to 40 mg/day x 15 days each month Crossovers No or loss of response, increase WBC, or treatment intolerance End points Primary Progression-free survival (PFS) Death from any cause during treatment Development of AP/BP Loss of complete hematologic response (CHR) Loss of major cytogenetic response (MCR) Doubling of WBC Secondary Rate of CHR Rate of MCR Safety and tolerability Statistics Intent-to-treat analysis of primary endpoint Rates of hematologic and cytogenetic response were estimated according to Kaplan- Meier method Treatment effect was evaluated with the log-rank test Nguyen DV 7 of 17

All patients who received at least one dose of study drug were included in the safety analysis Results N = 1106 Imatinib (n=533) I+C (n=533) Similar characteristics at baseline Mean follow-up : 19 months Progression-free survival At 12 months: 96.6% in imatinib vs. 79.9% in I+C (P<0.001) At 18 months: 92.1% vs. 73.5% (no P value) Figure 4. Kaplan-Meier estimate of progression-free survival. Adapted from O Brien S, et al. Eng J Med 2003;348:994-1004 Responses Statistically significant difference in CHR and MCR between imatinib and I+C (P<0.0001) Table 4. Rates of best observed hematologic and cytogenetic responses 14 Initial treatment Crossover treatment Response Imatinib (N=553) I+C (N=553) Imatinib to I+C (N=11) I+C to Imatinib (N=318) Percent (95% CI) CHR 95.3 (93.2-96.9) 55.5 (51.3-59.7) 27.3 (6-61) 82.4 (77.7-86.4) MCR 85.2 (81.9-88) 22.1 (18.7-25.8) 0 (0-28.5) 55.7 (50-61.2) CCR 73.8 (69.9-77.4) 8.5 (6.3-11.1) 0 (0-28.5) 39.6 (34.2-45.2) PCR 11.4 (8.9-14.3) 13.6 (10.8-16.7) 0 (0-28.5) 16 (12.2-20.5) Abbreviations: I+C-interferon alfa and cytarabine; CHR-complete hematologic response; MCR-major cytogenetic response; CCR-complete cytogenetic response; PCR-partial cytogenetic response Nguyen DV 8 of 17

No difference in estimated overall survival at 18 months 97.2% in imatinib vs. 95.1% in I+C (P = 0.16) Adverse events Most common in imatinib group (30%-50%) Superficial edema Elevated liver enzymes Nausea, diarrhea Muscle cramps, musculoskeletal pain Rash, fatigue, HA Most common in I+C (30-80%) Elevated liver enzymes Musculoskeletal and joint pain Nausea, diarrhea, constipation Pyrexia, insomnia, depression, rigors Grade 3 or 4 Table 5. Rate of most common grade 3 or 4 adverse effects (%) 14 Adverse Effect Imatinib (n=551) I+C (n=533) Fatigue 1.1 24.4 Depression 0.4 12.8 Neutropenia 14.3 25 Thrombocytopenia 7.8 16.5 Strengths Adequately powered, randomized study Patients were stratified using appropriate criteria Imatinib was compared to standard therapy at the time that the study was conducted Weaknesses High crossover rate prevented true assessment of overall survival between the two arms Although the study duration was adequate to show short-term benefit, it was too short to show long-term benefit Molecular response of IRIS 15 At least 3-log reduction of BCR-ABL transcript among those who achieved CCR at 12 months 39% imatinib vs. 2% I+C, P < 0.001 Progression free survival Table 6. Correlation between response and PFS 15 Response at 12 months PFS at 24 months (%) CCR and MMR 100 CCR and <MMR 95 <CCR, no MR 85 Abbreviations: PFS-progression free survival; CCR-complete cytogenetic response; MMR-major molecular response; MRmolecular response Nguyen DV 9 of 17

Eight-year follow up of IRIS 16 55% (n=304) remained on imatinib treatment Estimated event-free survival (EFS) was 81% Freedom from progression to AP/BC was 92% None of the patient who achieved MMR at 12 months progressed to AP/BC Estimated OS was 85% 93% when based on CML-related deaths and those prior to stem cell transplant only Patients with partial CR at 6 months and 12 months were more likely to achieve a stable CCR than have an event At 6 months: 63% stable CCR vs. 17% estimated event rate At 12 months: 57% stable CCR vs. 20% estimated event rate No P-value reported 86% achieved MMR No new unreported adverse effect Suboptimal or failure to imatinib (see appendix 2) 5,17,19,18 Imatinib intolerance Poor compliance Imatinib resistance 17 Incidence is about 2-4% annually Rate decline after two years of continuous treatment Table 7. Annual rate of imatinib resistance Year 1 2 3 4 5 6 Rate (%) 3.3 7.5 4.8 1.5 0.8 0.4 Mechanisms of imatinib resistance (figure 5) 19 Drug efflux Plasma-protein binding BCR-ABL domain mutations Several mutants have been identified Some are sensitive to second-generation TKIs T315I mutants are resistant to all approved TKIs Activation of downstream pathways (eg. SCR family) BCR-ABL gene amplification Nguyen DV 10 of 17

Figure 5. Mechanisms of resistance to tyrosine kinase inhibitors. Adapted from Krause SD, Van Etten AR. N Engl J Med. 2005;353:172-87 Treatment strategies High-dose imatinib as first line Overcoming drug efflux and plasma protein binding The randomized phase 3 Tyrosine Kinase Inhibitor Optimization and Selectivity study (TOPS) 20 400 mg vs. 800 mg of imatinib in newly diagnosed CML-CP CCR at 12 months: 66% vs. 70% (P=0.002) MMR at 12 months: 40% vs. 46% (NS) Higher rate of neutropenia, thrombocytopenia, rash, diarrhea, myalgia, edema, and dypsnea in the 800-mg imatinib group Baccarani et al 21 400 mg vs. 800 mg imatinib in newly diagnosed CML-CP CCR and MMR at 12 months: no difference Limitations of using high-dose imatinib as first line Inconsistent efficacy Higher rate of adverse event Nilotinib 22 30 times more potent than imatinib Active against most imatinib-resistant mutants Cellular transport independent of human organic cation transporter 1 (hoct1) Nguyen DV 11 of 17

Nilotinib Nilotinib as second line 4,22,23 Table 8. Results of trials evaluating nilotinib as second-line therapy Kantarjian et al 24 Le Coutre et al 25 No. of patient 321 137 Follow-up duration (months) 19 11 CHR (%) 91 31 MCR (%) 59 32 CCR (%) 41 20 Abbreviations: CHR-complete hematologic response; MCR-major cytogenetic response; CCR-complete cytogenetic response Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) study 24 Objective To compare the efficacy and safety of nilotinib versus imatinib in patients with newly diagnosed Ph+ CML-CP Design Phase 3, randomized, open-label, multicenter Methods Inclusion Adults with newly diagnosed Ph+ CML-CP No prior treatment with a TKI or any medical treatment for CML for more than 2 weeks Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 Adequate organ function Exclusion Impaired cardiac function Currently taking warfarin, CYP3A4 inducers or inhibitors, or any medication with the potential to prolong QT interval Treatment Stratified according to Sokal risk score Arm 1: Nilotinib 300 mg PO BID Arm 2: Nilotinib 400 mg PO BID Arm 3: Imatinib 400 mg PO once daily Imatinib dose escalation to 400 mg BID was permitted if suboptimal response or treatment failure Dose escalation of nilotinib and crossover were not permited End points Primary Rate of MMR at 12 months Secondary Rate of CCR by 12 months Others Progression to AP or BP Adverse events Statistics Intention-to-treat analysis of primary end point A 2-sided Cochran-Mantel-Haenszel test was used at a 5% level to test statistical significance of response rates Nguyen DV 12 of 17

Major molecular response (%) Time-to-event comparisons were estimated using Kaplan-Meier curves and compared using the log-rank test Safety analysis included all patients who received at least 1 dose of study drug Results N = 846 Nilotinib 300 (n =282) vs. nilotinib 400 (n=281) vs. imatinib (n=283) No difference in baseline characteristics or Sokal risk score Duration 14 months for all treatment groups Treatment is ongoing; pending 5-years follow-up MMR 60 50 P<0.001 P<0.001 40 30 20 10 0 3 months 6 months 9 months 12 months Nilotinib 300 9 33 44 44 Nilotinib 400 5 30 38 43 Imatinib 1 18 22 22 Figure 6. Rates of major molecular response. Adapted from Saglio G, et al. N Engl J Med 2010;362:2251-9 Median time to first MMR Nilotinib 300: 8.6 months Nilotinib 400: 11 months Imatinib: median not yet achieved No P value reported CCR at 12 months (Nilotinib 300 vs. nilotinib 400 vs. imatinib) 80% vs. 78% vs. 65% (P<0.001 for both comparisons) Progression to AP/BP at 12 months (Nilotinib 300 vs. nilotinib 400 vs. imatinib) Nilotinib 300 vs. imatinib: <1% (n=2) vs. 4% (n=11), P=0.01 Nilotinib 400 vs. imatinib: <1% (n=1) vs. 4% (n=11), P=0.004 No patient who had a MMR progressed to AP/BP at 12 months Adverse events Most common in nilotinib (30-70%) Rash, pruritis Elevated total bilirubin, liver enzymes Hyperglycemia Nguyen DV 13 of 17

Most common in imatinib (30-45%) Nausea Increased alkaline phosphatase Decreased phosphate Grade 3 or 4 Table 9. Rate of most common grade 3 or 4 adverse effect (%) 24 Adverse Effect Nilotinib 300 Nilotinib 400 Imatinib Neutropenia 12 10 30 Thrombocytopenia 10 12 9 Anemia 3 3 5 Increased total bilirubin 4 8 <1 Increased ALT 4 9 2 Strengths Adequately powered Patients were stratified using appropriate criteria Compared to current standard therapy Weaknesses Longer follow-up needed to confirm response durability (pending results) No report of compliance Although MMR was shown to predict PFS for imatinib, there is no data validating this surrogate endpoint for nilotinib. Summary IRIS established imatinib as standard first-line therapy Eight year follow-up data of IRIS confirmed the durable efficacy and safety of imatinib Nilotinib is active against most imatinib-resistant mutations ENESTnd showed improved response rates and shorter time to response for nilotinib vs. imatinib Correlation between early response and durability of response was based on imatinib data Nilotinib is more potent than imatinib Discussion Standard time to response based on imatinib might not be applicable to nilotinib Remaining questions What are the long-term benefits of achieving an early response with nilotinib? Could earlier exposure to nilotinib result in new mutations that are resistant to all TKIs? What is the overall long-term clinical impact of using nilotinib as first-line therapy? Benefit of response vs. risk of resistance and unknown long-term effect Conclusions Imatinib remains a reasonable, effective, and safe therapeutic option for newly diagnosed CML-CP Long-term follow-up of the ENESTnd study is needed to confirm the benefit of using nilotinib as firstline therapy in CML-CP Until longer follow up data is available, nilotinib should not replace imatinib as first-line treatment of CML-CP Nguyen DV 14 of 17

Appendix A Table 11. TKIs approved for first-line therapy of CML-CP 11-13 Imatinib (Gleevec) Nilotinib (Tasigna) Mechanism of action Binds to inactive conformation of BCR-ABL Binds to the inactive conformation of the BCR-ABL protein 30x more potent than imatinib Dosage 400 mg daily 300 mg BID Dose adjustments Hepatic: 25% decrease in severe impairment Renal: Initial 50% decrease in moderate to severe impairment; may titrate up as tolerated Other: 50% decrease if use with a strong CYP450 inducer Hepatic: 25%-33% initial dose reduction for mild to moderate impairment, 50% dose reduction for severe impairment Renal: none Other: adjustments indicated for QT prolongation, neutropenia, thrombocytopenia according to abnormal values Administration Orally with food Orally on an empty stomach Common adverse effects Edema, n/v/d/dyspepsia (improved when taken with food), muscle cramps, musculoskeletal pain, rash, fatigue Rash, pruritus, HA, n/v/c/d, fatigue, myalgia, dyspepsia, nasopharyngitis, arthralgia, pyrexia, upper urinary tract infection, cough, myelosuppression Metabolism CYP450 (mostly CYP3A4) CYP450 Excretion Biliary Biliary Drug interaction CYP450 inducers and inhibitors may alter level Increase APAP level Strong CYP450 inducers may alter level The drug is an inhibitor of CYP3A4, 2C8, 2C9, 2D6. It is also an inducer of CYP2B6, 2C8, and 2C9 Contraindication None Hypokalemia, hypomagnesemia, long QT syndrome Availability Scored tablets: 100 mg and 400 mg Hard capsules: 150 mg and 200 mg Abbreviations: TKIs-tyrosine kinase inhibitors; MOA-mechanism of action; CML-CP-chronic myeloid leukemia in chronic phase; BIDtwice daily; CYP450 cytochrome P450; d/n/v-diarrhea/nausea/vomiting; HA-headache; c-constipation; APAP-acetaminophen Nguyen DV 15 of 17

Appendix B Table 11. European LeukemiaNet response evaluation criteria to imatinib 5 Optimal Suboptimal response Failure At 3 months CHR + mcr No CR <CHR At 6 months PCR <PCR No CR At 12 months CCR PCR <PCR At 18 months MMR <MMR <CCR Any time during treatment Stable or improving MMR Loss of MMR or obtain mutations Loss of CHR, loss of CCR, or obtain mutations Abbreviations: CHR-complete hematologic response; mcr-minor cytogenetic response; CR-cytogenetic reponse; PCR-partial cytogenetic response; CCR-complete cytogenetic response; MMR-major molecular response Appendix C Table 12. Risk score equations 7,8 Sokal risk score equation Hasford risk score equation Exp 0.0116 x (age in years 43.4) + 0.0245 x (spleen -7.51) + 0.188x [(platelet count/700) 2 0.563] + 0.0887 x (blast cells 2.10) 0.666 when age >49 + (0.042 x spleen) + 1.09656 when platelet count >1500 x 10 9/ L + (0.0584 x blast cells) + 0.20399 when basophils >3% + (0.0413 x eosinophils x 100 References 1. Clarke FM. Chronic myeloid leukemia identifying the Hydra s heads. N Engl J Med. 2004;351:635 2. Druker JB, Lee JS. Chronic leukemias. In: DeVita TV, Jr, Hellman S, Rosenberg AS, eds. Cancer Principles & Practice of Oncology. Philadelphia, PA: Lippincott William & Wilkins; 2005:2121-31 3. Kantarjian H, Cortes J, Rosee P, Hochhaus A. Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase. Cancer 2010;116:1419-30 4. An X, Tiwari A, Sun Y, Ding P, et al. BCR-ABL tyrosine kinase inhibitors in the treatment of Philadephia chromosome positive chronic myeloid leukemia: a review. Leukemia Research 2010;34:1255-68 5. Baccarani M, Cortes J, Pane F. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 2009;27:6041-51 6. Kantarjian H, Deisseroth A, Kurzrock R, et al. Chronic myelogenous leukemia: a concise update. Blood. 1993:82:691-703 7. Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in good risk chronic granulocytic leukemia. Blood 1984;63:789-99 8. Hasford J, Pfirrmann M, Hehlmann R, et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. J Natl Cancer Inst 1998;90:850-8 9. Coutre P, Schwarz M, Kim Theo. New development in tyrosine kinase inhibitor therapy for newly diagnosed chronic myeloid leukemia. Clin Cancer Res 2010;16(6):1771-80 10. Garcia-Manero G, Faderi S, O Brien S, et al. Chronic myelogenous leukemia: a review and update of therapeutic strategies. Cancer 2003;98:437-57 11. Novartis. Tasigna (nilotinib). [Package insert]. East Hanover, NJ:2009 12. Bristol-Myers Squibb. Sprycel (dasatinib). [Package insert]. Princeton, NJ:2009 13. Novartis. Gleevec (imatinib). [Package insert]. East Hanover, NJ:2010 Nguyen DV 16 of 17

14. O Brien S, Guilhot F, Larson R, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase myeloid leukemia. N Eng J Med 2003;348:994-1004 15. Hughes PT, Kaeda J, Brandford S, et al. Frequency of major molecular response to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. J Engl J Med. 2003;349:1423-32 16. Deininger, Michael, O'Brien, et al. International Randomized Study of Interferon Vs STI571 (IRIS) 8- Year Follow up: Sustained Survival and Low Risk for Progression or Events in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib. ASH Annual Meeting Abstracts. 2009;114:1126 17. Hochhaus A, O Brien SG, Guilhot F, et al. Six-year follow-up of patients receiving imatinib for the firstline treatment of chronic myeloid leukemia. Leukemia 2009;23:1054-1601 18. Stein B, Smith BD. Treatment options for patients with chronic myeloid leukemia who are resistant to or unable to tolerate imatinib. Clin Ther 2010;32:804-820 19. Krause SD, Van Etten AR. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005;353:172-87 20. Cortes J, Baccarini M, Guilhot F, et al. A phase III, randomized, open-label study of 400 mg versus 800 mg of imatinib mesylate (IM) in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase (CML-CP) using molecular endpoints: 1-year results of TOPS (Tyrosine Kinase Inhibitor Optimization and Selectivity) Study [abstract]. Blood 2008;112:130-1. Abstract 335 21. Baccarini M, Castagnetti F, Simonsson B, et al. Cytogenetic and molecular response to imatinib in high risk (Sokal) chronic myeloid leukemia (CML): results of European LeukemiaNet prospective study comparing 400 mg and 800 mg front line [abstract]. Blood 2008;112:75. Abstract 185 22. Kantarjian H, Giles F, Bhalla K. Nilotinib in chronic myeloid leukemia patients in chronic phase (CML- CP) with imatinib (IM) resistance or intolerance: longer follow-up results of phase II study. J Clin Oncol 2009;27:7029 [meeting abstract] 23. Le Coutre PD, Giles F, Hochhaus A, et al. Nilotinib in chronic myeloid leukemia patients in accelerated phase (CML-AP) with imatinib (IM) resistance or intolerance) who are resistant or intolerant to imatinib. J Clin Oncol 2009;27:7057 [meeting abstracts]. 24. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010;362:2251-9 Nguyen DV 17 of 17