Patients with Chronic Myeloid Leukemia (CML) who develop resistance to imatinib have poor clinical outcomes. The disease stage at the time of imatinib failure is an important prognostic factor for this outcome. Specifically, although patients with advanced-stage CML, particularly those in blast-crisis at the time of imatinib failure, had a high rate of cytogenetic response to second-line tyrosine kinase inhibitors (TKIs), these responses were not durable in most instances. In contrast, patients who remained in chronic-phase (CML-CP) at the time of imatinib failure substantially benefited from second-line TKIs, achieving PFS and OS that appear favorable compared to historical data of patients treated with non-TKI therapeutic modalities. Because the prognosis for those in chronic-phase is significantly better than patients who have progressed to accelerated- or blast-phase, it is important to examine the clinical status of patients at the time of TKI failure. This study examined the clinical status of patients in the START-C trial (CA180-013) at the time of disease progression after imatinib and dasatinib therapy. Progression was defined as: loss of complete hematologic response (CHR), loss of major cytogenetic response (MCyR), increasing WBC count, development of accelerated- or blast- phase CML, or death due to any cause. Of 387 participants, 322 (83%) were progression-free at the 2-year follow-up. Of the 65 patients with any criteria for progression as defined above, 46 subjects had progressive disease (loss of MCyR = 14, loss of CHR = 14, increasing WBC counts = 8, development of accelerated-phase CML = 10). The remaining 19 patients died. Thus, only 10 out of 65 (15%) progression events were due to the development of advanced disease and 36 patients (55%) remained in chronic-phase despite a loss or lack of therapeutic response to imatinib and subsequent dasatinib. In summary, 2.6% (10/387) of all patients analyzed transitioned to accelerated-phase CML after first- and second-line therapy. Importantly, development of blast-crisis CML was also not observed in our study population. In a 5-year follow-up of the IRIS trial comparing imatinib to interferon as first-line therapy, a projected 17% of subjects relapsed and 7% developed advanced-phase disease after imatinib. Despite the fact that patients analyzed in our study sequentially failed both imatinib and dasatinib, most remained in chronic-phase after dasatinib failure and are expected to benefit from additional therapeutic options.

Disclosures: Cortes:Bristol-Myers Squibb: Research Funding. Mauro:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. O’Brien:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Borthakur:Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Matloub:Bristol- Myers Squibb: Employment, Equity Ownership; GlaxoSmithKline: Equity Ownership. Sinha:Bristol-Myers Squibb: Employment, Equity Ownership. Liu:Bristol-Myers Squibb: Employment, Equity Ownership. Kantarjian:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding.

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