PURPOSE: We report the 5-year analysis from the phase III Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients (DASISION) trial, evaluating long-term efficacy and safety outcomes of patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with dasatinib or imatinib. PATIENTS AND METHODS: Patients with newly diagnosed CML-CP were randomly assigned to receive dasatinib 100 mg once daily (n = 259) or imatinib 400 mg once daily (n = 260). RESULTS: At the time of study closure, 61% and 63% of dasatinib- and imatinib-treated patients remained on initial therapy, respectively. Cumulative rates of major molecular response and molecular responses with a 4.0- or 4.5-log reduction in BCR-ABL1 transcripts from baseline by 5 years remained statistically significantly higher for dasatinib compared with imatinib. Rates for progression-free and overall survival at 5 years remained high and similar across treatment arms. In patients who achieved BCR-ABL1 ≤ 10% at 3 months (dasatinib, 84%; imatinib, 64%), improvements in progression-free and overall survival and lower rates of transformation to accelerated/blast phase were reported compared with patients with BCR-ABL1 greater than 10% at 3 months. Transformation to accelerated/blast phase occurred in 5% and 7% of patients in the dasatinib and imatinib arms, respectively. Fifteen dasatinib-treated and 19 imatinib-treated patients had BCR-ABL1 mutations identified at discontinuation. There were no new or unexpected adverse events identified in either treatment arm, and pleural effusion was the only drug-related, nonhematologic adverse event reported more frequently with dasatinib (28% v 0.8% with imatinib). First occurrences of pleural effusion were reported with dasatinib, with the highest incidence in year 1. Arterial ischemic events were uncommon in both treatment arms. CONCLUSION: These final results from the DASISION trial continue to support dasatinib 100 mg once daily as a safe and effective first-line therapy for the long-term treatment of CML-CP.

Jorge E Cortes and Hagop M Kantarjian The University of Texas MD Anderson Cancer Center Houston TX; Neil P Shah University of California San Francisco School of Medicine San Francisco CA; Brigid Bradley Garelik and George Manos Bristol Myers Squibb Princeton NJ; Giuseppe Saglio University of Turin Turin; Michele Baccarani S Orsola Malpighi Hospital University of Bologna Bologna Italy; Jiří Mayer University Hospital Brno and Central European Institute of Technology Masaryk University Brno Czech Republic; Concepción Boqué Institut Català d'Oncologia Hospital Duran i Reynals L'Hospitalet Barcelona Spain; Charles Chuah Singapore General Hospital Duke National University of Singapore Medical School Singapore; Luis Casanova Instituto Nacional de Enfermedades Neoplásicas Lima Perú;and Andreas Hochhaus Universitätsklinikum Jena Jena Germany

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J Clin Oncol. 2017 Feb 10;35(5):567. doi: 10.1200/JCO.2016.69.5940. PubMed

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J Clin Oncol. 2017 Feb 10;35(5):567-568. doi: 10.1200/JCO.2016.70.2944. PubMed

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Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260–2270. PubMed

Bristol-Myers Squibb: Sprycel (dasatinib) [prescribing information]. Princeton, NJ, Bristol-Myers Squibb Company, 2015.

Cortes JE, Hochhaus A, Kim DW, et al. Four-year (yr) follow-up of patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) receiving dasatinib or imatinib: Efficacy based on early response. Blood. 2013;122:653. (abstr)

Hochhaus A, Kantarjian H. The development of dasatinib as a treatment for chronic myeloid leukemia (CML): From initial studies to application in newly diagnosed patients. J Cancer Res Clin Oncol. 2013;139:1971–1984. PubMed PMC

Jabbour E, Kantarjian HM, Saglio G, et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION) Blood. 2014;123:494–500. PubMed PMC

Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION) Blood. 2012;119:1123–1129. PubMed PMC

Alvarado Y, Kantarjian H, O’Brien S, et al. Significance of suboptimal response to imatinib, as defined by the European LeukemiaNet, in the long-term outcome of patients with early chronic myeloid leukemia in chronic phase. Cancer. 2009;115:3709–3718. PubMed PMC

Branford S, Kim DW, Soverini S, et al. Initial molecular response at 3 months may predict both response and event-free survival at 24 months in imatinib-resistant or -intolerant patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase treated with nilotinib. J Clin Oncol. 2012;30:4323–4329. PubMed PMC

Hanfstein B, Müller MC, Hehlmann R, et al. Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML) Leukemia. 2012;26:2096–2102. PubMed

Hughes TP, Hochhaus A, Branford S, et al. Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: An analysis from the International Randomized Study of Interferon and STI571 (IRIS) Blood. 2010;116:3758–3765. PubMed PMC

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. PubMed

Jabbour E, Kantarjian HM, O’Brien S, et al. Front-line therapy with second-generation tyrosine kinase inhibitors in patients with early chronic phase chronic myeloid leukemia: What is the optimal response? J Clin Oncol. 2011;29:4260–4265. PubMed PMC

Marin D, Hedgley C, Clark RE, et al. Predictive value of early molecular response in patients with chronic myeloid leukemia treated with first-line dasatinib. Blood. 2012;120:291–294. PubMed

Marin D, Ibrahim AR, Lucas C, et al. Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J Clin Oncol. 2012;30:232–238. PubMed PMC

Marin D, Milojkovic D, Olavarria E, et al. European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood. 2008;112:4437–4444. PubMed PMC

Neelakantan P, Gerrard G, Lucas C, et al. Combining BCR-ABL1 transcript levels at 3 and 6 months in chronic myeloid leukemia: Implications for early intervention strategies. Blood. 2013;121:2739–2742. PubMed PMC

Quintás-Cardama A, Kantarjian H, Jones D, et al. Delayed achievement of cytogenetic and molecular response is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving high-dose or standard-dose imatinib therapy. Blood. 2009;113:6315–6321. PubMed PMC

Wang L, Pearson K, Ferguson JE, et al. The early molecular response to imatinib predicts cytogenetic and clinical outcome in chronic myeloid leukaemia. Br J Haematol. 2003;120:990–999. PubMed

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;90:850–858. PubMed

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. PubMed

Hughes T, Deininger M, 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. PubMed PMC

Ludwig H, Bolejack V, Crowley J, et al. Survival and years of life lost in different age cohorts of patients with multiple myeloma. J Clin Oncol. 2010;28:1599–1605. PubMed

National Cancer Institute: Common Terminology Criteria for Adverse Events v3.0, August 2006. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf.

Simonneau G, Gatzoulis MA, Adatia I, et al: Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 62:D34-D41, 2013 (suppl) PubMed

Valent P, Hadzijusufovic E, Schernthaner GH, et al. Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. Blood. 2015;125:901–906. PubMed

Hjorth-Hansen H, Stenke L, Söderlund S, et al. Dasatinib induces fast and deep responses in newly diagnosed chronic myeloid leukaemia patients in chronic phase: Clinical results from a randomised phase-2 study (NordCML006) Eur J Haematol. 2015;94:243–250. PubMed PMC

O’Brien SG, Hedgley C, Adams S, et al. Spirit 2: An NCRI randomised study comparing dasatinib with imatinib in patients with newly diagnosed CML. Blood. 2014;124:517. (abstr)

Radich JP, Kopecky KJ, Appelbaum FR, et al. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood. 2012;120:3898–3905. PubMed PMC

Sasaki K, Strom SS, O’Brien S, et al. Relative survival in patients with chronic-phase chronic myeloid leukaemia in the tyrosine-kinase inhibitor era: Analysis of patient data from six prospective clinical trials. Lancet Haematol. 2015;2:e186–e193. PubMed PMC

Paquette R, Mauro M, Simonsson B, et al: Cardiovascular (CV)-related hospitalization in patients with chronic-phase chronic myeloid leukemia (CP-CML) in SIMPLICITY, a prospective observational study. Haematologica 100:E1099, 2015 (abstr)

Pemmaraju N, Kantarjian HM, O'Brien S, et al: Phase II clinical trial results of dasatinib for frontline therapy in patients with chronic myeloid leukemia (CML) in chronic phase (CP). Blood 124:4565, 2014 (abstr)

Hughes TP, Saglio G, Quintás-Cardama A, et al. BCR-ABL1 mutation development during first-line treatment with dasatinib or imatinib for chronic myeloid leukemia in chronic phase. Leukemia. 2015;29:1832–1838. PubMed PMC

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. PubMed

Cohen MH, Williams G, Johnson JR, et al. Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res. 2002;8:935–942. PubMed

Yilmaz M, Lahoti A, O’Brien S, et al. Estimated glomerular filtration rate changes in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. Cancer. 2015;121:3894–3904. PubMed PMC

Shah NP, Wallis N, Farber HW, et al. Clinical features of pulmonary arterial hypertension in patients receiving dasatinib. Am J Hematol. 2015;90:1060–1064. PubMed

Novartis: Tasigna (nilotinib) prescribing information. East Hanover, NJ, Novartis Pharmaceuticals Corporation, 2015.

ARIAD: Iclusig (ponatinib) prescribing information. Cambridge, MA, ARIAD Pharmaceuticals, 2015.

Quintás-Cardama A, Kantarjian H, O’Brien S, et al. Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol. 2007;25:3908–3914. PubMed

Saglio G, le Coutre P, Cortes J, et al. The observed and expected incidence of cardiovascular ischemic events in dasatinib-treated patients across a clinical trial program. Blood. 2014;124:4534. (abstr)

le Coutre PD, Hughes TP, Mahon F-X, et al: Low incidence of peripheral arterial disease in patients receiving dasatinib in clinical trials. Leukemia 10.1038/leu.2015.352 [epub ahead of print on December 21, 2015] PubMed PMC

Eliasson L, Clifford S, Barber N, et al. Exploring chronic myeloid leukemia patients’ reasons for not adhering to the oral anticancer drug imatinib as prescribed. Leuk Res. 2011;35:626–630. PubMed

Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol. 2010;28:2381–2388. PubMed PMC

Noens L, van Lierde MA, De Bock R, et al. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: The ADAGIO study. Blood. 2009;113:5401–5411. PubMed

Ibrahim AR, Eliasson L, Apperley JF, et al. Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy. Blood. 2011;117:3733–3736. PubMed PMC

Noens L, Hensen M, Kucmin-Bemelmans I, et al. Measurement of adherence to BCR-ABL inhibitor therapy in chronic myeloid leukemia: Current situation and future challenges. Haematologica. 2014;99:437–447. PubMed PMC

Asciminib add-on to imatinib demonstrates sustained high rates of ongoing therapy and deep molecular responses with prolonged follow-up in the ASC4MORE study

Clinical efficacy and safety of first-line nilotinib or imatinib therapy in patients with chronic myeloid leukemia-Nationwide real life data

The EUTOS long-term survival (ELTS) score is superior to the Sokal score for predicting survival in chronic myeloid leukemia

European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia

Imatinib dose reduction in major molecular response of chronic myeloid leukemia: results from the German Chronic Myeloid Leukemia-Study IV

Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants

Prognostic discrimination based on the EUTOS long-term survival score within the International Registry for Chronic Myeloid Leukemia in children and adolescents

Evaluation of cardiovascular ischemic event rates in dasatinib-treated patients using standardized incidence ratios