Dasatinib Versus Imatinib Research Articles

Real-World Effectiveness of Dasatinib Versus Imatinib in Newly Diagnosed Patients With Chronic Myeloid Leukemia

IntroductionLimited data exist comparing dasatinib with imatinib in clinical practice. This study assessed real-world outcomes associated with first-line (1L) dasatinib or imatinib treatment of chronic myeloid leukemia (CML). Patients and MethodsThis retrospective, observational, United States multisite cohort study analyzed electronic medical record data from adults with Philadelphia chromosome-positive (Ph+) CML in the chronic phase (CML-CP) after 1L dasatinib or imatinib between January 2014 and September 2018. Rates of and times to major molecular response (MMR) and deep molecular response (DMR) were assessed overall and in subgroups (low vs. intermediate/high risk, aged <65 vs. ≥65 years, low/normal vs. high body mass index [BMI]). ResultsThe dasatinib cohort (n = 309) experienced higher rates of MMR (n = 304, 79% vs. 65%, P < .001) and DMR (44% vs. 25%, P < .001) vs. the imatinib cohort with shorter median times to MMR (11.9 vs. 14.7 months, P < .001) and DMR (30.3 vs. 66.1 months, P < .001). Patients with intermediate-/high-risk disease and those aged <65 years had higher MMR and DMR rates and achieved response earlier with dasatinib (P < .01). Patients with low-risk disease treated with dasatinib had higher rates of DMR (60% vs. 32%, P = .01). Across BMI strata, rates of MMR and DMR were higher with dasatinib (P < .05). ConclusionsPatients with CML-CP treated with 1L dasatinib achieved higher rates of, with shorter times to, MMR and DMR versus 1L imatinib. These clinically meaningful improvements were observed across subgroups.

Comparison of Generic Dasatinib Versus Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia with Reference to Early Molecular Response: Results from a Single-Center, Randomized Controlled Study from India

Background: Chronic myeloid leukemia (CML) is the commonest leukemia in adult population in India. The advent of tyrosine kinase inhibitors (TKI) targeting BCR-ABL1 fusion transcript in CML has dramatically improved survival of CML patients. Generic formulations of imatinib mesylate have been the mainstay of TKI therapy in Indian CML patients for more than a decade, due to prohibitive costs of 2nd generation TKIs and poor socio-economic status of majority of patients. However, with the availability of generic dasatinib in India since March 2021, the cost of dasatinib therapy has become comparable to that of generic imatinib treatment, thereby enabling more extensive use of dasatinib as first-line TKI therapy in CML patients in India. Achievement of early molecular response (EMR) after 3 months of first-line TKI therapy, defined as blood BCR-ABL1 transcript level ≤ 10% [international scale (IS)], has emerged as an important predictor of favorable long-term outcome in CML-CP. There is scarcity of data on efficacy & safety of generic formulations of dasatinib vis-à-vis generic imatinib in CML-CP patients in India, which the present study has attempted to explore at a tertiary care hospital in India. Objectives: The objectives of the study were to compare early molecular response (EMR) [defined as BCR-ABL1 transcript level ≤ 10%, I.S.] at 3 months of therapy with generic dasatinib versus generic imatinib in newly diagnosed CML-CP patients and to compare treatment-related adverse effects in the two groups. Methods: This randomized controlled study enrolled newly diagnosed CML-CP patients after obtaining institutional ethics committee approval & informed consent. Inclusion Criteria:Newly diagnosed patients with chronic phase CML.Age ≥ 12 years. Exclusion Criteria:Patients with de novo accelerated phase or blast phase CML.Pregnancy & lactation.Patients with pre-existing pleural effusion, grade ≥ 3 lung disease, or pulmonary arterial hypertension.Patients with angina, or grade ≥ 3 cardiac disease [as defined by the New York Heart Association (NYHA) criteria] at diagnosis.Patients with prolonged QTc interval (> 480 msec) at baseline. The EUTOS long-term survival (ELTS) risk score was calculated at diagnosis. Patients were randomized to one of the two following treatment groups: Group A: Dasatinib 100 mg p.o. once daily (60 mg/m2/day for age <18 years). Group B: Imatinib 400 mg p.o. once daily (340 mg/m2/day for age < 18 years). Follow up & monitoring of patients was done every 2 weekly till completion of 3 months of TKI therapy, followed by assessment of hematological response & molecular response as per standard criteria. Results: A total of 61 consecutive CML patients were screened between June 2021 and March 2022, out of which 54 patients with confirmed diagnosis of CML-CP were enrolled in the study and were randomized to receive generic dasatinib or generic imatinib as first-line therapy and were followed up for 3 months for EMR and complete hematological response (CHR). Four patients were lost to follow up and data was analyzed for 50 patients for whom EMR results at 3 months was available. Out of these 50 patients, 24 patients received dasatinib & 26 patients received imatinib. The median age of patients was 33 years (range 18-64 years), with male: female ratio of 1.3: 1. Achievement of CHR was documented in 96% of patients in both dasatinib & imatinib treatment arms. EMR at 3 months was achieved in overall 72% patients in study [19/24 patients (79%) in dasatinib arm & 17/26 patients (65%) in imatinib arm]. However, the difference was not statistically significant (p = 0.27). Notably, EMR rates in ELTS intermediate-risk group was 86% in dasatinib arm versus 42% in imatinib arm, and EMR rates in ELTS high-risk group was 82% in dasatinib arm versus 57% in imatinib arm (p = 0.33). The incidence of grade 3-4 adverse events was not significantly different in the two treatment groups. The patient characteristics & treatment results are summarized in Table 1 & Figure 1. Conclusion: The results of the present study suggested that generic formulations of dasatinib were well-tolerated and were associated with improved early molecular response rates compared to generic imatinib in CML-CP patients in India. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CML-081: Effect of Comorbidities on Response Outcomes with First-Line Tyrosine Kinase Inhibitors (TKIs), Dasatinib Versus Imatinib, in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Exploratory Post Hoc Analysis of DASISION

Background: Five-year follow-up of the open-label, phase 3 DASISION study (NCT00481247) demonstrated faster and deeper molecular responses with dasatinib versus imatinib as first-line therapy for CML-CP. NCCN guidelines recommend considering comorbidities when selecting first-line TKI therapy. This exploratory post hoc analysis of DASISION investigates the effect of comorbidities on responses with dasatinib versus imatinib. Design: Patients with newly diagnosed CML-CP were randomized to 100mg dasatinib (n=259) or 400mg imatinib (n=260) QD. Charlson Comorbidity Index (CCI) was retrospectively calculated for each patient at diagnosis; data were retrospectively stratified by CCI categories (2-4, 5-6, and ≥7 [high burden]). Major molecular response (MMR) and MR4.5 were compared between treatments using unstratified Cochran-Mantel-Haenszel tests. Time to response was evaluated using Kaplan-Meier methodology with HRs based on Cox proportional hazards models and P-values from unstratified log-rank tests. Results: Baseline characteristics were mostly balanced between treatments. Fourteen (3%) patients had CCI 2-4, 260 (50%) had 5-6, and 245 (47%) had ≥7. Responses were numerically greater with dasatinib versus imatinib for CCI 2-4 (MMR: 85.7% versus 57.1%, P=0.2542; MR4.5: 71.4% versus 14.3%, P=0.0374) and ≥7 (MMR: 70.8% versus 64.0%, P=0.2552; MR4.5: 45.0% versus 39.2%, P=0.3589), and significantly higher for CCI 5-6 (MMR: 81.1% versus 64.8%, P=0.0033; MR4.5: 42.4% versus 29.7%, P=0.0329). Median time to MMR (months) was significantly shorter with dasatinib than imatinib for CCI 5-6 (15.0 versus 24.0; HR, 1.64; P=0.0006) and ≥7 (12.0 versus 21.4; HR, 1.41; P=0.0279). Grade 3/4 treatment-related adverse events (TRAEs; dasatinib versus imatinib): 0% versus 14% (CCI 2-4), 8% versus 9% (CCI 5-6), 24% versus 13% (CCI ≥7). Frequency of grade 3/4 TRAEs leading to discontinuation was similar: 0% versus 0%, 1% versus 1%, 8% versus 7%. No deaths occurred for CCI 2-4; similar percentage of patients died between treatments for CCI 5-6 and ≥7. Conclusions: Dasatinib was effective across all CCI groups, consistent with previous findings, suggesting that comorbidities do not negatively affect TKI activity. These findings highlight the benefits of first-line dasatinib in patients with CML-CP and elevated comorbidity burden. Funding: Bristol Myers Squibb. Previous presentation: 62nd ASH Annual Meeting, December 5-8, 2020; republished with permission of Elsevier Inc.

Poster: CML-081: Effect of Comorbidities on Response Outcomes With First-Line Tyrosine Kinase Inhibitors (TKIs), Dasatinib Versus Imatinib, in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Exploratory Post Hoc Analysis of DASISION

Poster: CML-081: Effect of Comorbidities on Response Outcomes With First-Line Tyrosine Kinase Inhibitors (TKIs), Dasatinib Versus Imatinib, in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Exploratory Post Hoc Analysis of DASISION

Impact of Comorbidities on Response Outcomes in Patients with Chronic Myeloid Leukemia in Chronic Phase Treated with First-Line Dasatinib Versus Imatinib: Exploratory Post Hoc Analysis of DASISION

Impact of Comorbidities on Response Outcomes in Patients with Chronic Myeloid Leukemia in Chronic Phase Treated with First-Line Dasatinib Versus Imatinib: Exploratory Post Hoc Analysis of DASISION

Association of High Body Mass Index with Response Outcomes in Patients with CML-CP Treated with Dasatinib Versus Imatinib in the First Line: Exploratory Post Hoc Analysis of the Phase 3 DASISION Trial

Association of High Body Mass Index with Response Outcomes in Patients with CML-CP Treated with Dasatinib Versus Imatinib in the First Line: Exploratory Post Hoc Analysis of the Phase 3 DASISION Trial

Dasatinib Versus Imatinib in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Who Have Not Achieved an Optimal Response to 3 Months of Imatinib Therapy: Dascern

Introduction: Treatment with dasatinib, a second-generation tyrosine kinase inhibitor (TKI), has resulted in high rates of cytogenetic and molecular responses for pts with CML-CP, both as initial therapy and after failure of other therapies. A reduction in BCR-ABL1 transcript levels to ≤ 10% on the International Scale (IS) at 3 mo is associated with an improved probability of deep molecular responses and superior progression-free and overall survival (PFS and OS). In DASISION, considerably more pts treated with dasatinib achieved BCR-ABL1 ≤ 10% IS compared to imatinib. BCR-ABL1 ≤ 10% IS at 3 mo is considered an optimal response by international guidelines; however, approximately one-third of pts with CML-CP on first-line (1L) imatinib will not achieve this threshold. Clinical studies exploring the potential benefit of early switching to dasatinib in pts with less than optimal responses on initial imatinib treatment have not been reported.Methods: DASCERN (NCT01593254) is a randomized, open-label, international phase 2b trial in adult pts with CML-CP who had achieved complete hematologic response (CHR) but who had BCR-ABL1 > 10% IS at 3 mo after initial treatment with 400 mg imatinib once daily (QD). Imatinib must have been started within 6 mo of the initial CML-CP diagnosis. Pts were randomized 2:1 to receive 100 mg dasatinib QD or continue imatinib at ≥ 400 mg daily with the option for dose escalation. Pts initially randomized in the imatinib cohort who met European LeukemiaNet 2013 failure criteria after randomization and without dasatinib-resistant mutations were crossed over to the dasatinib arm. The primary endpoint in DASCERN is the rate of MMR (BCR-ABL1 < 0.1% IS) at 12 mo after day 1 initiation of 1L imatinib (9 mo after randomization). Secondary endpoints include time to MMR, OS, and PFS (progression was defined as transformation to accelerated/blast phase or death). Tertiary endpoints include safety and tolerability profile of both treatment arms and cytogenetic response over time.Results: All 260 randomized pts (dasatinib: n = 174; imatinib: n = 86) had a minimum follow-up of ≥ 12 mo from the last pts 1st visit (Sokal scores: 28% low, 30% intermediate, 24% high, 18% unknown; median age 37 y [range 18-82, 95% were < 65 y]; 78% male; 73% Asian). All pts had e13a2 or e14a2 transcript types. At the time of analysis, 84% of pts were continuing in the study. Median daily dose was 100 mg QD (range 26-142) for dasatinib and 400 mg QD (range 129-825) for imatinib. Median treatment duration was 111 wk (774 d) in the dasatinib arm and 68 wk (477 d) in the imatinib arm; 42 (49%) imatinib-randomized pts crossed over to dasatinib. Rate of MMR at 12 mo in the intent-to-treat population was 29% (95% confidence interval [CI] 22, 36) for dasatinib and 13% (95% CI 7, 22) for imatinib (P = 0.005); median time to MMR was 14 mo (range 12-18) for dasatinib vs 20 mo (range 14-26) for imatinib (P = 0.053). No differences in the rate of progression or OS were observed between treatment arms. No new safety signals were observed for either treatment arm and the early switch to dasatinib did not increase the toxicity rate. Treatment-emergent pleural effusion (PE; any grade) occurred in 11 (6%) pts randomized to dasatinib and 3 (7%) imatinib-randomized pts who crossed over to dasatinib; treatment-emergent PE grade 3/4 occurred in 1 (1%) pt randomized to dasatinib and 2 (5%) pts randomized to imatinib who crossed over to dasatinib. Hematologic toxicity was similar between treatment arms: neutropenia grade 3/4 occurred in 18 (11%) pts randomized to dasatinib and 12 (29%) pts randomized to imatinib who crossed over to dasatinib; thrombocytopenia grade 3/4 occurred in 18 (11%) pts randomized to dasatinib and in 7 (17%) pts randomized to imatinib who crossed over to dasatinib. Two dasatinib-treated pts discontinued due to hematologic toxicity (1 neutropenia, 1 thrombocytopenia).Conclusions: Early results from DASCERN show that pts with suboptimal responses to imatinib at 3 mo who switched to dasatinib had a significantly increased rate of MMR at 12 mo compared to pts who remained on imatinib. Longer follow-up is required to assess the impact of early switching on PFS and OS, and achievement of deep molecular responses. DisclosuresCortes:Astellas Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Takeda: Research Funding. Kim:BMS: Research Funding; Ilyang: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Savona:Boehringer Ingelheim: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Martin Regueira:Bristol-Myers Squibb: Employment, Equity Ownership. Sy:Bristol-Myers Squibb: Employment. Gurnani:Bristol-Myers Squibb: Employment.

Final Study Results of the Phase 3 Dasatinib Versus Imatinib in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Trial (DASISION, CA180-056)

▪Background: The randomized, phase 3 DASISION trial demonstrated improved efficacy with dasatinib compared with imatinib in treatment-naïve CML-CP patients (pts). Dasatinib was also well tolerated, and demonstrated a faster response at 3 months. Here, we report the results of the final, 5-year analysis of DASISION.Methods: Pts with newly diagnosed CML-CP were randomized to receive dasatinib 100 mg once daily (n=259) or imatinib 400 mg once daily (n=260) as previously reported. The primary endpoint was confirmed complete cytogenetic response (cCCyR) by 12 months. Long-term efficacy and safety data from pts with the predefined minimum 5 years of study treatment are presented.Results: Sixty-one percent of dasatinib-treated pts and 63% of imatinib-treated pts were still on their initial study therapy at study end. Cytogenetic and molecular response rates continued to be higher for dasatinib compared with imatinib (intent-to-treat population). Specifically, the rate of cCCyR by 5 years was higher with dasatinib versus imatinib (83% vs 78%, P=.187), as were the rates of major molecular response (MMR; BCR-ABL ≤0.1%; 76% vs 64%, P=.002) and MR4.5 (BCR-ABL ≤0.0032% IS; 42% vs 33%, P=.025) by 5 years. Time to cCCyR (hazard ratio [95% confidence interval]=1.46 [1.20–1.77], P=.0001) and MMR (hazard ratio [95% confidence interval]=1.54 [1.25–1.89], P<.0001) in all randomized pts were faster with dasatinib (Figure 1). Transformations to both accelerated (AP) and blast phase (BP) CML were reported on study or after discontinuation with fewer cases overall for dasatinib (n=12/259; 4.6%) compared with imatinib (n=19/260; 7.3%). Five-year progression-free survival (PFS) and overall survival (OS) rates were similar across treatment arms (PFS: 85% [dasatinib], 86% [imatinib]; OS: 91% [dasatinib], 90% [imatinib]). A higher proportion of pts on dasatinib achieved BCR-ABL ≤10% at 3 months (84%) compared with those on imatinib (64%). For pts who achieved BCR-ABL ≤10% versus >10% at 3 months, improved PFS, OS, and lower rates of transformation to AP/BP have been previously reported and were maintained at 5 years for dasatinib (PFS: 89% vs 72%, P=.0014; OS: 94% vs 81%, P=.0028; transformation n=6/198 [3%] vs n=5/37 [14%]) and imatinib (PFS: 93% vs 72%, P<.0001; OS: 95% vs 81%, P=.0003; transformation: n=5/154 [3%] vs n=13/85 [15%]). Between 4 and 5 years, the number of mutations increased slightly in dasatinib-treated pts (12 pts at 4 years; 15 pts at 5 years), and the spectrum remained the same. No new, unexpected safety events were identified in either treatment arm at 5 years. However, the total incidence of pleural effusion continued to increase each year in dasatinib-treated pts (29% overall). Most cases of pleural effusion were grade 1/2 (n=67/74), and the median time to first grade 1/2 pleural effusion was 114 weeks (range, 4–299 weeks). Discontinuation of dasatinib due to pleural effusion occurred in only 15 pts (6% overall; 20% of pts who experienced a pleural effusion). Arterial ischemic events overall were not common, occurring in 12 pts (5%) on dasatinib and 6 pts (2%) on imatinib. Cardiovascular (CV) ischemic events and transient ischemic attack were reported in 10 and 2 dasatinib-treated pts, respectively. CV ischemic and peripheral arterial occlusive events were reported in 4 and 2 imatinib-treated pts, respectively. Of the pts with overall arterial ischemic events, 8 pts on dasatinib and 3 pts on imatinib had a history and/or risk factors for atherosclerosis. Fourteen dasatinib-treated pts experienced pulmonary hypertension by 2D echocardiogram, with right heart catheterization (RHC) performed in 1; 6 discontinued therapy. No pts were diagnosed with World Health Organization Group 1 pulmonary arterial hypertension (confirmed by RHC).Conclusion: At 5 years, dasatinib 100 mg once daily has demonstrated superior outcome compared to imatinib 400 mg once daily as initial therapy for CML. This is manifested by a faster time to cytogenetic and molecular responses, with more pts achieving BCR-ABL ≤10% at 3 months, sustained higher cumulative rates of response, and a lower rate of transformation. The 5-year rates of PFS and OS were equal in both arms. After 5 years, no new safety signals have been reported. These consistent results suggest that dasatinib offers meaningful advantages for pts with newly diagnosed CML-CP and remains a standard of care in this setting. [Display omitted] DisclosuresCortes:ARIAD, BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Saglio:Novartis: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; Pfizer: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; ARIAD: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; BMS: Consultancy, Fees for occasional speeches Other. Baccarani:Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Kantarjian:ARIAD: Research Funding; Pfizer: Research Funding; Amgen: Research Funding. Mayer:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Shah:Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding. Chuah:Bristol-Myers Squibb: Honoraria; Novartis: Honoraria. Bradley-Garelik:Bristol-Myers Squibb: Employment. Manos:Bristol-Myers Squibb: Employment. Hochhaus:Novartis: Research Funding; BMS: Research Funding; MSD: Research Funding; Ariad: Research Funding; Pfizer: Research Funding.

PCN63 The Relative Value of Dasatinib Versus Imatinib as First-Line Treatment for Chronic Myeloid Leukemia

PCN63 The Relative Value of Dasatinib Versus Imatinib as First-Line Treatment for Chronic Myeloid Leukemia

Developmental Therapeutics Consortium report on study design effects on trial outcomes in chronic myeloid leukaemia

Tyrosine kinase inhibitors (TKIs) have dramatically changed the treatment of chronic myeloid leukaemia (CML). Results from ongoing phase 3 trials with nilotinib [Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd)] and dasatinib [Dasatinib Versus Imatinib Study in Treatment-Naive CML-CP Patients (DASISION)] in newly diagnosed patients with CML in chronic phase have demonstrated that these TKIs resulted in significant improvements in responses vs. imatinib. The Developmental Therapeutics Consortium (DTC) systematically reviewed the published literature to provide a comparative analysis of the ENESTnd and DASISION trial designs and data reported on each study. The recent approval of nilotinib and dasatinib based on these two pivotal studies offers physicians the option to optimise frontline treatment based on a patient's comorbidities, risk factors and tolerability profiles. Although nilotinib and dasatinib provide effective therapeutic options for the frontline treatment of CML, the lack of an evidenced-based, side-by-side comparison makes it difficult to directly compare these agents. Despite potential bias from differences in patient populations and study design, indirect cross-trial comparisons to determine the relative effectiveness of these agents will be performed by physicians. This DTC report provides a comprehensive summary of the study designs, protocols and results of the ENESTnd and DASISION trials, which will assist physicians in making informed decisions on the best treatment approach for their patients.

Impact of treatment end point definitions on perceived differences in long-term outcome with tyrosine kinase inhibitor therapy in chronic myeloid leukemia.

Different definitions of progression-free survival (PFS) and event-free survival (EFS) may result in perceived differences in outcomes with tyrosine kinase inhibitor (TKI) therapies in chronic myelogenous leukemia (CML). We analyzed the outcome of 435 patients with early chronic-phase, Philadelphia chromosome-positive CML treated with imatinib (n = 281), nilotinib (n = 78), and dasatinib (n = 76) using definitions of PFS and EFS used in the International Randomized Study of Interferon Versus STI571 (IRIS), Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENEST-nd), Dasatinib Versus Imatinib Study in Treatment-Naïve CML Patients (DASISION), and MD Anderson Cancer Center (MDACC) trials. Definitions for EFS-IRIS, time without progression in ENEST-nd, PFS-DASISION, and EFS-MDACC were as previously reported. The EFS-MDACC considered an event any instance of toxicity or death from any cause on or off therapy (if not counted before death as progression/event). Of the 435 patients, 123 (28%) were taken off TKI therapy (resistance/loss of response, n = 33; blastic phase on TKI therapy, n = 6; intolerance/toxicity, n = 29; other causes, n = 55). Thirty-three patients (7.6%) have died; eight patients died on TKI therapy, two patients died within 60 days of being off TKIs, and 23 patients died after being off TKIs for more than 60 days. Of the 33 deaths, 19 deaths (eight deaths on TKI, two deaths within 60 days, and nine deaths off for resistance/relapse/transformation) would be counted as progression/events on the IRIS/ENEST-nd/DASISION studies, whereas 14 deaths would be censored at time off TKI. On the basis of the four definitions used by IRIS, ENEST-nd, DASISION, and MDACC trials, the corresponding 5-year PFS/EFS rates were 96%, 90%, 89%, and 81%. Uniform definitions of PFS and EFS are needed to compare the long-term efficacy and potential use of different TKIs in CML.

Dasatinib Versus Imatinib In Patients with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) In the DASISION Trial: 18-Month Follow-up

AbstractAbstract 206 Background:Dasatinib is 325-fold more potent than imatinib in vitro against unmutated BCR-ABL, and is an established second-line treatment for patients (pts) with CML-CP who are resistant, intolerant or have a suboptimal response to imatinib. The Phase 3 DASISION study compares dasatinib with imatinib as initial treatment for pts with newly diagnosed CML-CP. After a minimum of 12 months (mos) of follow-up, dasatinib 100 mg once daily demonstrated significantly higher and faster rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared to imatinib 400 mg once daily (Kantarjian, H, et al. N Engl J Med 2010;362:2260). Eighteen-mo follow-up data are presented here. Methods:519 pts with newly diagnosed CML-CP (median disease duration of 1 mo) stratified by Hasford risk were randomized to either dasatinib 100 mg once daily (n=259), or imatinib 400 mg once daily (n=260). The study design and endpoints have been described previously. All analyses were based on intention-to-treat pts. Results:Median treatment duration at the present analysis was 18 mos for each drug, with 81% of pts in the dasatinib arm and 80% in the imatinib arm still remaining on study drug. Median dose intensity was 99 mg/d for dasatinib and 400 mg/d for imatinib. Efficacy and safety results in the present analysis were consistent with those reported previously after 12 mos of follow-up. The rate of confirmed CCyR (cCCyR, CCyR on consecutive analyses at least 1 mo apart) by 18 mos continued to be higher for dasatinib than for imatinib (78% vs 70%); P=0.0366). Based on time-in-cCCyR (a measure of durability) analysis involving all randomized pts, dasatinib-treated pts were 28% less likely to experience a progression event (as defined by European LeukemiaNet 2006) after achieving a cCCyR or never achieving a cCCyR compared to those on imatinib. The MMR rate at any time was superior for dasatinib compared to imatinib (57% vs 41%, P=0.0002). Based on time-to-response analysis, pts on dasatinib were 1.84-fold more likely to achieve a MMR than those on imatinib (HR=1.84, P <0.0001). Rates of cCCyR in dasatinib-treated pts with low, intermediate and high risk were 92, 71 and 73%, respectively. The corresponding rates in the imatinib arm were 72, 71 and 64%. Rates of MMR in dasatinib-treated pts with low, intermediate and high risk were 63, 56 and 51%, respectively. The corresponding rates in the imatinib arm were 48, 40 and 30%. A BCR-ABL transcript level of ≤ 0.0032% was achieved in 13% dasatinib-treated and 7% imatinib-treated pts. Rates of progression-free survival at 18 mos were 94.9% for dasatinib and 93.7% for imatinib; the corresponding overall survival rates were 96.0% and 97.9%, respectively. Six pts (2.3%) in the dasatinib arm and 11 (4.3%) in the imatinib arm discontinued due to treatment failure as defined by 2006 European LeukemiaNet criteria. Six pts (2.3%) on dasatinib and 9 (3.5%) on imatinib had a transformation to accelerated or blast phase. Discontinuation of treatment due to drug-related adverse events (AEs) was infrequent for both dasatinib (6%) and imatinib (4%). Non-hematologic AEs (all grades) in ≥10% of pts (dasatinib vs imatinib) were fluid retention (23% vs 43%), diarrhea (18% vs 19%), nausea (9% vs 21%), vomiting (5% vs 10%), muscle inflammation (4% vs 19%), myalgia (6% vs 12%), musculoskeletal pain (12% vs 16%), fatigue (8% vs 11%) and rash (11% vs 17%). While superficial edema was less frequent with dasatinib than with imatinib (10% vs 36%), pleural effusion was seen only with dasatinib (12% vs 0%: grade 1, 2%; grade 2, 9%; grade 3, <1%), and did not impact the efficacy. Non-hematologic grade 3/4 AEs were infrequent in either arm (≤1%). Grade 3/4 cytopenias (dasatinib vs imatinib) were anemia (11% vs 7%), neutropenia (22% vs 20%) and thrombocytopenia (19% vs 10%). Two pts (0.8%) on dasatinib and 3 (1.2%) on imatinib had grade 3/4 bleeding. Cytopenia was the reason for discontinuation in 6 pts on the dasatinib arm (2.3%) and 3 on the imatinib arm (1.2%). Conclusions:After 18 mos of follow-up, dasatinib 100 mg once daily continues to demonstrate superior efficacy compared to imatinib. Dasatinib also continues to be generally well tolerated. These results support the potential use of dasatinib as initial treatment for pts with newly diagnosed CML-CP. Disclosures:Shah:Bristol-Myers Squibb, Novartis and Ariad: Membership on an entity's Board of Directors or advisory committees. Kantarjian:BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Hochhaus:Novartis, Bristol-Myers Squibb: Consultancy, Research Funding. Cortes:Brostol-Myers Squibb, Novartis and Wyeth: Honoraria. Bradley-Garelik:Bristol-Myers Squibb: Employment, Equity Ownership. Zhu:Bristol-Myers Squibb: Employment. Baccarani:Novartis, Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Safety and Efficacy of Dasatinib Versus Imatinib by Baseline Cardiovascular Comorbidity In Patients with Chronic Myeloid Leukemia In Chronic Phase (CML-CP): Analysis of the DASISION Trial

AbstractAbstract 2286 Background:BCR-ABL kinase inhibitors dasatinib, nilotinib and imatinib have become the therapeutic mainstay for patients (pts) with CML-CP. It has been suggested that baseline comorbid conditions be considered in choosing BCR-ABL inhibitors as second-line treatment for pts with CML post-imatinib failure. Cardiovascular (CV) disease is an important comorbid condition in some pts with CML-CP (median age, ∼ 60 years) and can play a critical role in treatment decisions. The DASISION trial is a large Phase 3 study comparing dasatinib with imatinib as initial treatment in pts with newly diagnosed CML-CP and has demonstrated superior efficacy of dasatinib after a minimum of 12 months (mos) of follow-up (Kantarjian, H, et al. N Engl J Med 2010;362:2260-70). We assessed if baseline CV conditions impacted the efficacy and safety of these agents when used as initial treatment for CML-CP. Methods:Five hundred nineteen pts with newly diagnosed CML-CP (median disease duration of 1 mo) were randomized to either dasatinib 100 mg once daily (n = 259) or imatinib 400 mg once daily (n = 260). Complete cytogenetic response (CCyR), major molecular response (MMR) and drug-related adverse events (AEs) were analyzed in pts with CV conditions and in those without. Pts with myocardial infarction (MI) within 6 mos, uncontrolled angina within 3 mos, congestive heart failure (CHF) within 3 mos, congenital prolonged QT syndrome, QTc interval of > 450 msec or ventricular arrhythmias were excluded. Pts with CV conditions including hypertension, MI > 6 mos prior to the start of treatment, uncontrolled angina > 3 mos prior to the start of treatment, CHF > 3 mos prior to the start of treatment, unstable angina (UA), left ventricular (LV) dysfunction, coronary artery disease (CAD), peripheral artery disease (PAD), transient ischemic attack (TIA), stroke and QTc interval of ≤ 450 msec were not excluded. Results:Across the 2 treatment arms, there were 85 pts (16%) with ≥ 1 baseline CV condition, 42 of whom had ≥ 2. Of the 85 pts, 69 (35 dasatinib; 34 imatinib) reported having baseline hypertension and 16 (8 dasatinib; 8 imatinib) reported other baseline CV conditions (some pts reported more than 1 CV condition) including LV dysfunction (n = 6), CAD (including clinically documented CAD, prior MI and unstable angina; n = 15), PAD (n = 11), and cerebral artery disease (including prior stroke and TIA, n = 8). The distribution of CV conditions was balanced across the 2 treatment arms. Safety profiles of dasatinib and imatinib in pts with baseline CV conditions were generally similar to those in pts without (Table). Notably, fluid retention including superficial edema and pleural effusion appeared to have occurred more frequently in pts with baseline CV conditions compared to those without. Pleural effusions were all grade 1 or 2, and manageable by dose interruption and/or reduction. In both arms, the 12-mo rates of CCyR and MMR in pts with baseline CV comorbidities were similar to the corresponding rates in pts without (Table). Safety and efficacy profiles of pts with hypertension and pts with CV conditions other than hypertension were also generally similar to those in pts without any CV condition. Conclusions:Although fluid retention and cardiac AEs were more common in patients with any baseline CV condition, overall these data show no substantial impact of baseline CV conditions on the general safety and efficacy of dasatinib or imatinib as initial treatment for CML-CP. Disclosures:Saglio: Brostol-Myers Squibb and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hochhaus: Brostol-Myers Squibb and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cortes: Brostol-Myers Squibb, Novartis and Wyeth: Consultancy, Honoraria. Kantarjian: BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Baccarani: Brostol-Myers Squibb and Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bradley-Garelik: Bristol-Myers Squibb: Employment, Equity Ownership. Dejardin: Bristol-Myers Squibb: Employment, Equity Ownership. Shah: Bristol-Myers Squibb, Novartis and Ariad: Membership on an entity's Board of Directors or advisory committees.

Cost-Effectiveness Analysis in Canada of Dasatinib Versus Imatinib for the Treatment of Chronic Myelogenous Leukemia in Patients with Imatinib Resistance.

Objective: To estimate the cost-utility of dasatinib versus high-dose imatinib (HDI, imatinib 800mg/day) for chronic myelogenous leukemia (CML) in patients with resistance to imatinib at standard doses.Methods: We adapted to the Canadian setting a Markov model with a monthly cycle length that followed hypothetical patients until death. Cost effectiveness was evaluated during three phases of CML: chronic (86% of Ontario patients in 2006), accelerated (9%) and blast crisis (5%). Efficacy of dasatinib and HDI (cytogenetic and hematologic response) and adverse events (AEs) were taken from randomized trials. Canadian costs of medications, laboratory tests, professional fees, hospitalizations, and AEs were obtained from published sources. Societal utility scores were estimated from a Canadian time trade-off study. Analyses were performed from the perspective of the Ontario Ministry of Health. Costs (2006 CDN$) and outcomes (QALYs) were discounted at 5% annually after the first year. Univariate and probabilistic sensitivity analyses were carried out to quantify uncertainty for the incremental cost-effectiveness ratios (ICERs).Results: Dasatinib dominated HDI in chronic phase patients with additional QALYs (3.92 vs. 3.47) and a lower lifetime cost ($379,678 vs. $444,934). The ICERs of dasatinib vs. HDI in accelerated and blast phase were $88,098/QALY and $173,922/QALY respectively. The higher cost/QALY of dasatinib in the advanced phases is explained primarily by the increased predicted survival of dasatinib patients and therefore the longer duration of drug therapy for these patients. Parameters with the greatest influence on results were the time horizon, drug costs and utility values. The interpretation of results remained robust in univariate and probabilistic sensitivity analyses.Conclusion: From an economic perspective dasatinib is an attractive treatment choice for the majority of imatinib resistant CML patients and provides better value for money than HDI.