Dasatinib Pts Research Articles

Real-World Analysis of the Clinical and Economic Burden of Later Line in Chronic Myeloid Leukemia Patients in Italy

BackgroundThe use of real-world data in oncology is gaining increasing interest, as it can provide valuable insights into treatments and related outcomes in routine daily oncology practice, thus integrating the evidence coming from clinical trials. The study aims to describe the characteristics of patients (pts) with chronic myeloid leukemia (CML) in 2 nd or ≥3 rd tyrosine kinase inhibitors (TKI) lines of therapy, analyze their drug utilization and evaluate healthcare direct costs for the Italian National Health Service in order to estimate the impact of disease burden.MethodsThis retrospective observational analysis was based on administrative databases covering around 15.3 million subjects in Italy. All adult pts with prescription of the TKIs bosutinib (BOS), dasatinib (DAS), imatinib (IMA), nilotinib (NIL), ponatinib (PON) in 2 nd or ≥3 rd line of therapy during 01/2015-12/2018 were included. Specifically, those with IMA, DAS or PON prescription were enrolled if they also presented ≥1 CML hospitalization or previous prescription for NIL or BOS or ≥1 BCR-ABL1 RQ-PCR test without hospitalization for acute lymphoid leukemia. Pts enrolled in clinical trials were not captured. Index date was 1 st prescription date for a TKI in 2 nd or ≥3 rd line. Comorbidities were assessed by hospitalization diagnosis codes and/or presence of specific drugs as proxy of diagnosis. Mean annual healthcare resource costs were evaluated during follow-up (from index date to end of study) in terms of drugs other than TKI (excluded), visits, tests, hospitalizations (overall and comorbidity-related during treatment).ResultsOverall, 491 pts in 2 nd and 144 in ≥3 rd line were included. In each calendar year from 2015 to 2018, the incidence of pts who entered a 2 nd line changed from 22.6% to 28.7%, whereas the ≥3 rd line fluctuated from 37% to 46.7%. An increment of 97.6% was observed in the number of pts treated in ≥3 rd line from 2015 to 2018 (figure 1). As 2 nd line, 40.9% was represented by DAS, 28.9% NIL, 12.2% BOS, 10.2% PON and 7.8% IMA. Mean age ranged from 56.1 (PON) to 68.2 (BOS) years. At baseline, hypertension was the most reported comorbidity (from 64.1% for NIL to 91.7% for BOS), followed by metabolic (from 27.9% in DAS pts to 63.2% for IMA) and blood count (from 28.4% for DAS to 58.0% for PON) alterations. Among pts in ≥3 rd line, 26.3% received imatinib, 22.2% PON, 18.8% NIL, 16.7% BOS, 16% DAS. Mean age was 57 years for NIL, 64.8 PON and 69.5 BOS pts. Same trend of comorbidities was reported in the ≥3 rd line cohort, with hypertension detected in all pts starting BOS to a minimum of 65.2% pts in DAS group, followed by blood count alteration (34.8% for DAS to 59.4% for PON) and metabolic alterations (37.0% for NIL to 50.0% for BOS). Baseline cardiovascular comorbidities were present in 22.8% of pts starting a 2 nd line and in 35.4% of pts starting ≥3 rd line. After a median follow up of 3.0 and 2.6 years, 13% and 19% of pts died in 2 nd and ≥3 rd lines, respectively, around 40% in both lines discontinued their treatment. Median time to discontinuation was 5.5 (95%CI: 4.7-6.2) (2 nd line) and 4.3 (95%CI: 3.2-5.2) (≥3 rd line) years. Mean number of annual hospitalizations was 0.6 (from 0.4 for NIL to 1.1 for PON) in 2 nd line, and 0.5 (from 0.4 for IMA and NIL to 0.7 for PON) in ≥3 rd line. Total mean annual costs/pts (TKI excluded) were of €10,168 (PON), €6,106 (BOS), €5,086 (DAS), €4,779 (NIL) and €3,905 (IMA), with hospitalizations comorbidity-related accounting for €3,245 among PON, €2,820 BOS, €1,739 NIL, €1,573 DAS and €1,448 IMA pts. Mean annual costs per lines are shown in figure 2.ConclusionsThis real-world study provided a demographic and clinical profile of CML pts in 2 nd and ≥3 rd TKI lines and described drug utilization and resource consumption in the Italian clinical practice setting. An increase of pts treated with TKIs in ≥3 rd line was reported, reflecting the availability of multiple TKIs over the years; moreover, a highly comorbid population suggests an increasingly complex CML management. Our results underlined a heavy clinical and economic burden for pts in 2 nd or ≥3 rd lines, especially in terms of comorbidities, treatment discontinuation and hospitalizations suggesting the need of novel therapeutic options for management of later lines CML. [Display omitted] DisclosuresBreccia: Novartis: Consultancy; Pfizer: Consultancy; BMS: Consultancy; INCYTE: Consultancy; Abbvie: Consultancy. Chiodi: Novartis: Current Employment. Valsecchi: Novartis Farma SpA: Current Employment. Rendace: Novartis Farma S.p.A.: Current Employment. Coco: Novartis Farma S.p.A.: Current Employment. Premoli: Novartis Farma SpA: Current Employment.

Treatment Characteristics and Deep Molecular Response in Chronic Phase - Chronic Myeloid Leukemia Patients Treated with Second-Line Nilotinib or Dasatinib: A Multi-Country Retrospective Chart Review Study

BackgroundAchievement of deep molecular response (i.e., MR4.5, BCR-ABL1 ≤0.0032% on international scale, or 4.5-log reduction) is an important goal of tyrosine kinase inhibitor (TKI) treatment for patients (pts) with chronic myeloid leukemia (CML). Pts achieving a sustained MR4.5 are potential candidates for treatment-free remission. However, data on MR4.5 after TKI therapy outside of clinical trial setting are limited, especially in second-line TKI treatment setting.ObjectiveThis study aims to describe pt and treatment characteristics by regions and investigate frequency and time to achieving MR4.5 in pts with chronic phase (CP)-CML treated with second-line nilotinib or dasatinib in 10 countries, categorized into two regions, Europe [France, Germany, Italy, Netherlands]/Australia and Latin America - LATAM [Argentina, Brazil, Chile, Colombia, and Mexico]).MethodsOnline physician panel approach was used to recruit oncologists (N=172) globally to conduct physician-based chart reviews. To increase the representativeness of physician sample, each physician was allowed to review up to four patients, and was instructed to select these pts via randomization scheme. Eligible pts were diagnosed with CP-CML at age ≥18 years, initiated second-line nilotinib or dasatinib between 1/1/11 and 7/1/15, and had ≥12 months of follow-up since initiating the first-line or second-line TKI. A multivariate Fine and Gray's extension of Cox proportional hazards model was used to assess time to first recorded MR4.5 for nilotinib vs dasatinib as second-line therapy. The model accounted for competing-risk event of TKI resistance and random effect of country clustering of data, and was adjusted for age, gender, Sokal risk score at CML diagnosis, prior hydroxyurea use, first-line TKI agent (1st vs 2nd generation TKI), first-line TKI treatment duration, and reasons for first-line TKI discontinuation. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were reported.ResultsThe study included 285 pts treated with nilotinib (N=138[48%]) or dasatinib (N=147[52%]) as second-line TKI, including 111 nilotinib and 117 dasatinib pts from Europe/Australia (80%), and 27 nilotinib and 30 dasatinib pts from LATAM (20%). Median follow-up time was 19.5 and 18.9 months for nilotinib and dasatinib in both regions, respectively. In Europe/Australia, 85% of pts had received imatinib as first-line TKI, and in LATAM, 96% (Table 1). In Europe/Australia, 85% of pts discontinued first-line TKI due to ineffectiveness (per treating physician) and 16% due to toxicity; corresponding percentages were 79% and 23% in LATAM. Median (range) age at second-line TKI initiation was 58 (18-88) years in Europe/Australia vs 49 (22-77) in LATAM. In Europe/Australia, more second-line nilotinib (21%) than dasatinib (10%) pts had high-risk Sokal score at CML diagnosis. Compared to Europe/Australia, more pts in LATAM had a high-risk Sokal score in both the nilotinib (30%) and dasatinib (27%) cohorts.The raw proportion of pts achieving first recorded MR4.5 by 24 months of second-line TKI therapy was 34% for nilotinib and 31% for dasatinib. After controlling for country clustering effects and baseline covariates, adjusted multivariate Cox model showed that nilotinib was associated with a significantly higher rate of achieving MR4.5 (HR=1.37, 95% CI [1.12, 1.67], p<0.01) than dasatinib. Additionally, high-risk Sokal score was significantly inversely associated with achieving MR4.5 (HR=0.34, 95% CI [0.14, 0.81], p=0.01) while discontinuing first-line TKI due to resistance (HR=0.57, 95% CI [0.30, 1.08], p=0.08) reached borderline statistical significance at the two-sided α-level of <0.10 (Figure 1). MR4.5 outcome will be reported by regions in the presentation.ConclusionThis retrospective chart review study shows some variations in pt and treatment characteristics across regions. A significant percentage of second-line TKI pts can reach MR4.5 after failure to first-line TKI. In addition, this study suggests that second-line nilotinib may be associated with a higher rate of MR4.5 than dasatinib in this setting. Given its retrospective and observational nature, our results should be taken with caution as this study is susceptible to unmeasured confounding and biases. Rigorous clinical assessment in a prospective setting is needed to conclusively compare rates of achieving MR4.5 in ptstreated with nilotinib versus dasatinib. [Display omitted] DisclosuresCortes:ARIAD: Consultancy, Research Funding; Teva: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Sun Pharma: Research Funding; BMS: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Huynh:Novartis Pharmaceuticals Corporation: Research Funding. Mendelson:Novartis Pharmaceuticals Corporation: Employment. Brandt:Novartis Pharmaceuticals Corporation: Employment. Dalal:Novartis Pharmaceuticals Corporation: Employment. Dersarkissian:Novartis Pharmaceuticals Corporation: Research Funding; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding. Cortina:Novartis Pharmaceuticals Corporation: Employment. Narkhede:Novartis Pharmaceuticals Corporation: Research Funding. Duh:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding.

Comparison of Healthcare Resource Utilization and Costs Related to Infections between Patients Newly Diagnosed with Chronic Myeloid Leukemia Treated with Dasatinib and Nilotinib As First-Line Therapy in the United States

Introduction:In the past decade, targeted inhibition of BCR-ABL1 with tyrosine kinase inhibitor therapies (TKIs) has become the standard-of care for treatment of chronic myeloid leukemia (CML). Second-generation TKIs, including dasatinib and nilotinib, have been shown to be more effective treatment options over imatinib and are approved as first-line therapies for newly diagnosed patients (pts) with Philadelphia chromosome positive CML in chronic phase (CP) and as second-line therapies for pts in CP and accelerated phase resistant to or intolerant to prior therapy. Although TKIs have been demonstrated to prolong overall and progression-free survival, there is evidence that TKIs may be associated with an increased risk of infections. This risk of infections can occur with or without neutropenia and is potentially due to an immunosuppressive effect from off-target activity of the treatment (Reinwald 2016). The real-world healthcare resource utilization (HRU) and costs related to infections have not been well studied, particularly in pts diagnosed with CML treated with second generation TKIs. To address this gap, this study compared HRU and costs of pts receiving dasatinib or nilotinib in first-line therapy for CML, with a focus on infection-related economic outcomes.Methods:Adult pts newly diagnosed with CML who were initiated on dasatinib or nilotinib as first-line therapy on/after October 2010 were identified from 2 large US administrative claims databases (2006-2016). First-line TKI initiation was defined as the index date, the 6-month period before the index date was defined as the baseline period, and pts were observed from index date until the end of first-line TKI therapy (i.e., discontinuation, switch, end of data availability/continuous health plan enrollment). HRU, including inpatient (IP) days, emergency room (ER) visits, and days with outpatient (OP) services, and associated healthcare costs from a payers' perspective (USD 2016) were measured during first-line TKI therapy. All-cause HRU and costs and those related to infections of any type, identified using diagnosis recorded in medical claims, were compared between dasatinib and nilotinib pts using multivariate regression models.Results:A total of 1,156 dasatinib and 677 nilotinib pts met the sample selection criteria. Mean age was 52 years and 54% were male in both cohorts (p>.05). Mean TKI therapy duration was 13.6 months for dasatinib and 15.5 months for nilotinib (p=.014).On average, dasatinib pts had 2.7 all-cause IP days annually, where 1.4 (52%) were related to infections; nilotinib pts had 1.3 all-cause IP days annually, where 0.6 (46%) were related to infections. Dasatinib pts had 90% more all-cause IP days (adjusted IRR=1.9; p=.003) and 2 times more IP days related to infections (adjusted IRR=2.1; p=.020) than nilotinib pts (Figure 1). On average, dasatinib pts had 0.7 all-cause ER visits annually, where 0.2 (29%) were related to infections; nilotinib pts had 0.6 all-cause ER visits annually where 0.1 (16%) were related to infections. Dasatinib pts had 30% more all-cause ER visits (adjusted IRR=1.3; p=.041); 2 times more ER visits related to infections (adjusted IRR=2.1; p<.001) than nilotinib pts (Figure 1). On average, dasatinib pts had 27.5 days with all-cause OP services annually, where 1.6 (6%) were related to infections; nilotinib pts had 26.0 all-cause days with OP services annually where 1.5 (6%) was related to infections (difference not statistically significant).On average, the annual all-cause total cost was $157,767 for dasatinib pts with $37,110 (24%) for medical service costs and $120,657 (76%) for pharmacy costs. Of this total cost, $10,943 (7%) was related to infections. On average, the annual all-cause total cost was $136,290 for nilotinib pts with $24,508 (18%) for medical service costs and $111,782 (82%) for pharmacy costs. Of this total cost, $7,620 (6%) was related to infections. Dasatinib pts incurred higher all-cause total costs by $17,265 per patient per year compared to nilotinib pts (adjusted cost difference; p=.004); where $6,572 (38%) of the difference was related to infections (adjusted cost difference; p=.004; Figure 1). Overall, among pts with infection, the average cost related to infection during first-line TKI therapy was $9,637.Conclusion:Dasatinib was associated with higher HRU and healthcare costs, particularly related to infections, compared to nilotinib. [Display omitted] DisclosuresSeiter:Novartis: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Latremouille-Viau:Analysis Group, Inc.: Employment; Novartis: Other: Analysis Group, Inc. has received consulting fees from Novartis. Guerin:Novartis: Other: I am an employee of Analysis Group, which received consulting fees from Novartis; AbbVie Inc.: Other: I am an employee of Analysis Group, which received consulting fees from AbbVie ; Analysis Group, Inc: Employment. Ndife:Novartis Pharmaceuticals Corporation: Employment. Habucky:Novartis: Employment. Joseph:Novartis Pharmaceuticals Corporation: Employment; Pfizer: Other: stock/stock options; Amgen: Other: stock/stock options; Express Scripts: Other: stock/stock options. Pivneva:Analysis Group, Inc: Employment; Novartis: Other: Analysis Group, Inc. has received consulting fees from Novartis. Gagnon-Sanschagrin:Novartis: Other: Analysis Group, Inc. has received consulting fees from Novartis; Analysis Group, Inc.: Employment. Tang:Novartis: Employment, Equity Ownership.

Cardiovascular Hospitalization in Patients Treated with Dasatinib or Nilotinib in Simplicity, an Observational Study of Chronic-Phase Chronic Myeloid Leukemia (CP-CML) Patients in Routine Clinical Practice

Introduction: The combined effect of cardiovascular (CV) risk and tyrosine kinase inhibitor (TKI) therapy may contribute to the incidence of CV events in patients (pts) with chronic phase chronic myeloid leukemia (CP-CML). CV events can affect the overall clinical outcomes and survival of CML patients, and hospitalization due to CV events is costly; analyzing the rates and risks of CV hospitalization in pts with CML receiving TKI therapy may help to inform treatment decisions and risk mitigation strategies and to minimize costs. SIMPLICITY (NCT01244750) is an ongoing observational study of CP-CML pts in routine clinical practice receiving first-line (1L) TKIs since 2010 in the US and Europe, exploring TKI use and management patterns in clinical practice. This analysis aims to evaluate rates of CV-related hospitalization and estimate related costs in pts treated with the second-generation TKIs dasatinib (DAS) and nilotinib (NIL).Methods: CV hospitalizations were identified retrospectively from events reported by SIMPLICITY investigators over the course of treatment with DAS or NIL, from the start of treatment (any line of therapy) to 30 days after the end of that line of therapy, or prior to the start of a subsequent line of TKI therapy, whichever was sooner. Pts were followed for a maximum of five years. Owing to the observational nature of SIMPLICITY, patients were not matched between cohorts and adjustments for covariates were not made. Kaplan-Meier methods with the log-rank test were used to estimate time to first CV hospitalization. Statistical comparisons were made using t-tests and the Mann-Whitney U test for continuous variables and chi square for categorical variables.Results: Overall, 825 pts received DAS (n=417) or NIL (n=408) as 1L therapy; 376 pts received DAS (n=214) or NIL (n=162) as second-line (2L) therapy; and 124 pts received DAS (n=63) or NIL (n=61) as third-line (3L) therapy. See table for patient baseline demographics and comorbidities. No significant differences were noted between the DAS and NIL cohorts. Median age was similar between the DAS and NIL groups at 56.2 and 54.1 years. At baseline, both groups had similar CV comorbidities. A significantly greater number of pts were treated in the US vs Europe (p=0.017).Investigators reported that, during 1L DAS and NIL therapy, 43% (n=357) of pts experienced a CV disorder: 45.3% (n=189) of DAS pts and 41.2% (n=168) of NIL pts (DAS vs NIL, p=0.28). Numbers of CV-related hospitalizations occurring during DAS and NIL therapy were 16 and 36, respectively, translating to 12.6 and 27.4 CV-related hospitalizations per 1000 pt years. Across 1L, 2L, and 3L (referred to here as ‘all lines‘) of DAS and NIL therapy, 31 and 51 CV-related hospitalizations occurred, translating to 16.7 and 28.8 CV-related hospitalizations per 1000 pt years, respectively. The three most common CV-related reasons for hospitalization were congestive cardiac failure, atrial fibrillation and myocardial infarction. The figure shows Kaplan-Meier curves of time to first CV-related hospitalization for 1L therapy, for five years of follow-up. CV-related hospitalization at 5 years of follow-up was 5% for pts on 1L DAS, 7.5% for pts on 1L NIL, 5.7% for all lines of DAS and 8.5% for all lines of NIL. Durations of hospital stay related to CV disorders for pts on 1L DAS and 1L NIL were 68 days and 263 days, translating to 53.3 and 199.8 days in hospital per 1000 pt years. Durations of hospital stay related to CV disorders for pts on all lines of DAS and NIL were 107.4 days and 226.1 days, translating to 53.3 and 199.8 days in hospital per 1000 pt years. Incremental cost differences based on mean estimates will be presented.Conclusions: CV disorders and related hospitalizations were frequently seen in patients with CP-CML in SIMPLICITY. In these patients, NIL was associated with a rate of CV hospitalization up to double that associated with DAS and lengthier hospital stay. Owing to the survival benefits conferred by TKIs, it is critical to minimize and manage complications that may arise in treated pts; potential for greater morbidity and healthcare cost should be considered when making decisions about TKIs to use in individual pts, particularly those with preexisting CV comorbidities. [Display omitted] DisclosuresMauro:Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding. Chen:Bristol-Myers Squibb: Employment. Cortes:Novartis: Consultancy, Research Funding; Arog: Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding. Gambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Sen:ICON PLC: Employment. Gajavelli:Bristol-Myers Squibb: Employment. Davis:Bristol-Myers Squibb: Employment. Michallet:Octapharma: Membership on an entity's Board of Directors or advisory committees; Chugai: Consultancy; Novartis: Research Funding.

Tyrosine Kinase Inhibitor (TKI) Switching Patterns during the First 12 Months in Simplicity, an Observational Study of Chronic-Phase Chronic Myeloid Leukemia (CP-CML) Patients (Pts) in Routine Clinical Practice

Introduction:SIMPLICITY (NCT01244750) is an ongoing observational study of CP-CML pts in routine clinical practice receiving first-line (1L) imatinib (IM) prior to 2010 (retrospective) or 1L IM, dasatinib (DAS) or nilotinib (NIL) since 2010 (prospective) in the US and Europe.Methods: This analysis was designed to identify baseline characteristics associated with TKI switching in pts pooled from the prospective and retrospective cohorts. Pts were characterized as ’early switchers’ (who discontinued 1L TKI and switched to a second-line [2L] TKI within 3 months of TKI initiation) or ’late switchers’ (who discontinued 1L TKI and switched to a 2L TKI between 3 and 12 months after TKI initiation). A comparator group of ’non-switcher’ pts did not discontinue 1L TKI within 12 months of TKI initiation; ’early non-switchers’ did not switch 1L TKI within the first 3 months and ’late non-switchers’ did not switch 1L TKI between 3 and 12 months after TKI initiation. Logistic regression analysis was used to identify factors associated with early vs. late switching (gender, age at diagnosis ≥65 years, 1L TKI, region, reason for discontinuation).Results: By March 07 2016, 1494 pts were enrolled at 197 sites in 7 countries. Within 12 months of initiating 1L TKI 238 pts (16%) had switched to 2L TKI. Of switchers, 31% and 69% were early and late, respectively. Of the overall cohort, 1189 pts were early non-switchers and 1146 were late non-switchers. Most early switchers received IM as 1L TKI (49%), followed by NIL (32%) and DAS (19%); most late switchers received IM (56%), followed by DAS (26%) and NIL (18%). Fewer early non-switchers than switchers received IM as 1L TKI (43%), followed by NIL (28%) and DAS (28%); fewer late non-switchers than switchers received IM (44%), followed by DAS (28%) and NIL (28%). Most switchers were female; a higher proportion of female switchers was early vs. late (63% vs. 52%, respectively). In comparison, 43% of pts in both non-switching groups were female. Median ages of early and late switchers were 54 (interquartile range [IQR]: 46-68) and 58 (IQR: 46-69) years, respectively; median ages of early and late non-switchers were 56 (IQR: 46-68) and 56 (IQR: 45-67) years, respectively.Logistic regression analysis showed that pts who switched due to intolerance had greater odds of switching early compared with those who switched due to resistance (odds ratio = 3.49; 95% confidence interval: 1.11-10.98; p=0.0323). Among the 238 pts who switched 1L TKI, the main reason for 1L TKI discontinuation was intolerance (early switchers: 76%; late switchers: 71%; Figure).The most common intolerances leading to changes in early and late switchers varied by 1L TKI. Most common for IM early switchers (n=26) was general disorders/administration site conditions (including fatigue, edema, pain) and skin/subcutaneous disorders; for IM late switchers (n=53), gastrointestinal (GI) disorders, general disorders/administration site conditions and skin/subcutaneous disorders. Most common for DAS early switchers (n=10) was GI disorders; for DAS late switchers (n=36), respiratory/thoracic/ mediastinal disorders. Most common for NIL early switchers (n=19) was GI disorders; for NIL late switchers (n=25), GI disorders, general disorders/administration site conditions and skin/subcutaneous disorders.TKI resistance less commonly contributed to 1L TKI discontinuation. Primary and acquired resistance were seen in higher proportions of late than early switchers (Figure). In late switchers, primary resistance was a more common reason for discontinuation in IM pts vs. DAS pts or NIL pts (22%, 5% and 4%, respectively). Acquired resistance was only reported as a reason for discontinuation in IM-treated pts (early switchers: 0.3%; late switchers: 11%).Conclusions: Of pts switching or discontinuing 1L TKI in the first 12 months of therapy, around one third switched within the first 3 months; compared with late switchers and non-switchers these pts were more likely to be younger and female. TKI intolerance was the main reason for switching and was significantly associated with early switching. Resistance was a less common reason for changing TKI therapy and was seen more frequently after 3 months and among pts treated with IM. More research is necessary to make definitive conclusions about comparisons between TKI groups, given the small numbers of pts in the TKI cohorts and the non-controlled nature of the trial. [Display omitted] DisclosuresGoldberg:COTA Inc: Employment; Novartis: Consultancy; Neostem: Equity Ownership; Pfizer: Honoraria; Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Michallet:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria. Hehlmann:Bristol-Myers Squibb: Consultancy; Novartis: Research Funding; German CML-Group: Research Funding. Zyczynski:Bristol-Myers Squibb: Employment. Foreman:ICON Clinical Research: Employment. Calimlim:ICON Clinical Research: Employment. Paquette:Incyte: Consultancy, Honoraria; Novartis: Consultancy; Ariad: Consultancy. Gambacorti:Pfizer: Honoraria, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Zagorska:Bristol-Myers Squibb: Employment. Rong:Bristol-Myers Squibb: Employment. Mauro:BMS: Consultancy; Ariad: Consultancy; Pfizer: Consultancy; Novartis: Consultancy.

Treatment Patterns and Healthcare Costs in Newly Diagnosed Patients with Chronic Myeloid Leukemia Receiving Dasatinib or Nilotinib As First-Line Therapy in the United States: A Retrospective Claims Database Analysis

Background: To date, no studies have directly compared the treatment patterns and economic outcomes of dasatinib and nilotinib as 1st-line therapy for Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP). This study aimed to address this gap using retrospective claims data. Method: Newly diagnosed adult pts with CML who received dasatinib or nilotinib as 1st-line therapy were identified from 2 large US administrative claims databases (Q1/2010 - Q4/2014). Pts with continuous health plan coverage for ≥6 months before (baseline period) and ≥1 month after the 1st-line TKI initiation (index date) were classified as dasatinib or nilotinib pts based on the 1st-line TKI. Pts were excluded from the study if they were enrolled in a clinical trial, had a stem-cell transplant, received chemotherapy (except hydroxyurea), had a metastatic cancer/solid tumor or end stage renal disease during the baseline period. Dose adjustment (dose decrease/increase of ≥20mg for dasatinib and ≥100mg for nilotinib vs the initial dose) were measured from the index date to treatment discontinuation (i.e., treatment gap of ≥60 days) or end of follow-up. Treatment adherence was measured using proportion of days covered (PDC) during a 6- and 12-month period following index date among pts with continuous health plan coverage during these periods. Treatment discontinuation, switching to another TKI, and healthcare resource utilization (HRU) and costs (pharmacy+medical costs; per person per month: PPPM; USD 2014) were measured from index date to end of follow-up. Outcomes were compared between cohorts using multivariate regression analyses adjusting for potential confounding factors identified at baseline/index date (age, gender, CML complexity, CCI, starting dose, and health plan type). Results: A total of 604 dasatinib and 418 nilotinib pts met the sample selection criteria with average follow-up of 17 months in both cohorts. Pts in dasatinib and nilotinib cohorts did not significantly differ in age (mean=51 vs 52, respectively; p=.114), sex (46% female in both cohorts; p=.834), and comorbidities (mean CCI=1.4 vs 1.5, respectively; p=.600). In dasatinib pts, 91% started with 100mg/day, 3% with Conclusions: Based on retrospective claims data, this study shows that dasatinib was associated with an increased risk of dose decrease despite majority of pts starting on the recommended dose, an increase risk of switching to another TKI, and higher total healthcare costs compared to nilotinib pts. No difference in adherence, discontinuation, and HRU was found. The study showed the association between nilotinib versus dasatinib as first-line therapy in CML patients and outcomes, not causation. The proportion of CML patients in accelerated phase or blast crisis by cohort at the first-line TKI initiation and its impact on results is unknown but was assumed to be marginal. Disclosures Chen:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Latremouille-Viau:Janssen-Cilag GmbH, Janssen-Ortho, Inc., Merck Frosst Canada, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Janssen Scientific Affairs, LLC, Centocor Ortho Biotech: Consultancy, Other: Dominick Latremouille-Viau is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations; AbbVie Inc., Alcon Laboratories, AstraZeneca, Bayer Healthcare Pharmaceuticals, LLC, Celgene Corporation, Forest Laboratories, Inc., Genentech, Inc., GlaxoSmithKline: Consultancy, Other: Dominick Latremouille-Viau is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations; Pfizer Canada, Inc., Savient Pharmaceuticals, Inc., Shire Pharmaceuticals Inc., Takeda Global Research & Development Center, Inc.,Takeda Pharmaceuticals U.S.A., Inc.: Consultancy, Other: Dominick Latremouille-Viau is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations. Guerin:GlaxoSmithKline, Janssen Scientific Affairs, Janssen-Ortho, Inc., Merck & Co., Inc., Merck Frosst Canada, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ogilvy Renault, Ortho-Clinical Diagnostics, Inc., Otsuka America Pharmaceutical, Inc.,: Consultancy, Other: Annie Guerin is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations; Pfizer Canada, Inc., RXD AbbVie Inc., Alcon Laboratories, Bayer Healthcare Pharmaceuticals, LLC, Celgene Corporation, Cempra Inc., Centocor Ortho Biotech, Cooley LLP, Cyberonics, Inc., DLA Piper, Eli Lilly & Company, Forest Laboratories, Inc., Genentech, Inc.,: Consultancy, Other: Annie Guerin is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations. Nitulescu:Novartis Pharmaceuticals Corporation, Sunovion Pharmaceuticals Inc., AbbVie Inc., Otsuka America Pharmaceutical, Inc., Shire Pharmaceuticals Inc., Genentech, Inc., GlaxoSmithKline, Merck Frosst Canada: Consultancy, Other: Roy Nitulescu is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations. Gagnon-Sanschagrin:Novartis Pharmaceuticals Corporation, Genentech, Inc., AbbVie Inc., Takeda Pharmaceuticals U.S.A., Inc.: Consultancy, Other: Patrick Gagnon-Sanschagrin is an employee of Analysis Group Inc, which has received consultancy fees from the listed organizations.

Comparison of Treatment Changes for Patients with Chronic Myelogenous Leukemia in Chronic Phase Switched From Imatinib to Nilotinib or Dasatinib As Second-Line Therapy

AbstractAbstract 4443 Background:Nilotinib and dasatinib are two therapies approved by the US Food and Drug Administration for pts with Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase (Ph+ CML-CP) who are resistant or intolerant to 1st-line imatinib. Although these therapies were shown to be generally effective and tolerable, sometimes they are not, requiring treatment changes (e.g., discontinuation, dose modification, and drug holidays). To date, no head-to-head study has been conducted to compare treatment changes between 2nd-line nilotinib and dasatinibin clinical practice. Methods:Through an online chart abstraction form, participating community physicians retrospectively submitted de-identified information on Ph+ CML-CP pts ≥ 18 years old who switched after 10/28/2007 from imatinib to 2nd-line nilotinib or dasatinibwith at least 30 days of follow-up. When multiple pts met the selection criteria, pts were selected randomly by physicians. Pts enrolled in clinical trials or with concurrent malignancies were excluded. Information was collected on clinical characteristics and therapy changes in 2nd-line treatment, including dose modification (increase or decrease), drug holiday, and discontinuation of current therapy with or without switch to a 3rd-line therapy. Reasons for therapy changes were also collected, and treatment changes were classified as due to (1) lack of effectiveness if reasons included progression to accelerated phase or blast crisis, failure to achieve satisfactory response, or loss of satisfactory response; (2) intolerance if reasons included adverse events; (3) other reasons, including non-adherence, vacation, pregnancy, or economic reasons. Rates of treatment changes were compared between treatment groups using chi-square tests. Results:122 hematologists and oncologists provided information on 597 pts (301 nilotinib pts and 296 dasatinib pts). The median follow-up was 11 months (range 1–54 months) for pts on nilotinib and 10 months (range 1–56 months) for those on dasatinib. The two groups had similar age, sex, race, and comorbidities. Overall, treatment change was infrequent for both nilotinib and dasatinib patients (10% vs. 13%, p=0.40), but nilotinib pts had significantly fewer dose increases vs. dasatinib pts (0.0% vs. 1.4%, p=0.04), and they tended to have fewer drug holidays (1.7% vs. 4.4%, p=0.05). When treatment changes were classified by reason for change, nilotinib pts were less likely to change treatment due to lack of effectiveness vs. dasatinib pts (2.0% vs. 5.1%, p=0.04). Further, among pts who discontinued, fewer nilotinib pts discontinued due to lack of effectiveness (29% vs. 61%, p=0.03). Nilotinib and dasatinib pts had similar rates of treatment changes due to intolerance or other reasons, except for drug holiday, where nilotinib pts had fewer events than dasatinibpts (0% vs. 1.7%, p=0.02). The table below summarizes the changes in treatment by reason for treatment change. Conclusions:For Ph+ CML-CP pts on 2nd-line nilotinib or dasatinib, pts on nilotinib were less likely than those on dasatinibto change treatment due to lack of effectiveness.NilotinibDasatinibP-value(n=301)(n=296)Treatment change due to lack of effectiveness, n (%)6 (2.0)15 (5.1)0.04Discontinuation with or without switch to 3rd-line6 (2.0)14 (4.7)0.06Dose increase0 (0.0)4 (1.4)0.04Treatment change due to intolerance, n (%)11 (3.7)11 (3.7)0.97Discontinuation with or without switch to 3rd-line2 (0.7)3 (1.0)0.64Drug holiday0 (0.0)5 (1.7)0.02Dose decrease9 (3.0)3 (1.0)0.09Treatment change due to other reasons, n (%)18 (6.0)13 (4.4)0.38Discontinuation with or without switch to 3rd-line13 (4.3)6 (2.0)0.11Drug holiday5 (1.7)8 (2.7)0.38 Disclosures:Macalalad:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Chen:Novartis Oncology: Employment, Own stock in Novartis Other. Guerin:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Luo:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Wu:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Griffin:Novartis: Consultancy, Research Funding.

Clinical Significance of Deeper Molecular Responses with Four Modalities of Tyrosine Kinase Inhibitors As Frontline Therapy for Chronic Myeloid Leukemia

AbstractAbstract 164▪▪This icon denotes a clinically relevant abstract Background:The achievement of a major molecular remission (MMR) after imatinib therapy in pts with chronic myeloid leukemia (CML) in chronic phase (CP) predicts for decreased risk of events, but has little impact in overall survival (OS) among patients with complete cytogenetic response (CCyR). Deeper molecular responses (MR), including undetectable transcripts, are frequently sought in patients with CML treated with tyrosine kinase inhibitors (TKI), but the prognostic significance of these responses is not known. Objectives:To determine the long-term clinical significance of achieving deeper level of MR achieved after therapy with TKI for CML in CP. Methods:Pts were included in clinical trials for initial therapy for CML with one of the following modalities: imatinib 400mg/day (IM400), imatinib 800mg/day (IM800), nilotinib (NILO) and dasatinib (DASA). We defined the level of MR as MMR, MR4, MR4.5 and undetectable transcripts (UND), corresponding to an ABL/BCR-ABL ratio (International Scale) of ≤0.1%, ≤0.01%, ≤0.0032%, and undetectable transcripts (minimum sensitivity 4.5-log), respectively. Results:A total of 495 pts were treated: 83 pts with IM400, 204 with IM800, 106 with NILO and 102 with DASA. At presentation leukocyte counts were higher in the NILO group (41.5 vs 22.2, 27.5 and 27×109/L for IM400, IM800 and DASA pts). All other patient characteristics were equally distributed across the 4 treatment groups. After a median follow-up of 73 months (2 to 142), complete cytogenetic response (CCyR) was achieved in 88%. CCyR rates for IM400, IM800, NILO and DASA pts were 82%, 88%, 90% and 90%, respectively. Best level of MR for the entire population was: <MMR in 17% of pts, MMR in 13%, MR4 in 5%, MR4.5 in 19%, UND in 44%. In IM400 pts MR was <MMR in 28% of pts, MMR in 10%, MR4 in 8%, MR4.5 in 14%, UND in 40%. In IM800 pts MR was <MMR in 14% of pts, MMR in 8%, MR4 in 5%, MR4.5 in 19%, UND in 54%. In NILO pts MR was <MMR in 18% of pts, MMR in 20%, MR4 in 7%, MR4.5 in 22%, UND in 33%. In DASA pts MR was <MMR in 18% of pts, MMR in 18%, MR4 in 7%, MR4.5 in 23%, UND in 39%. There was a trend for earlier achievement of MR with NILO: median times to MMR, MR4, MR4.5 and UND were 12, 17.4, 17.9 and 25.1 months, respectively, for IM400 pts; 5.8, 8.7, 11.8 and 23.7 months, respectively, for IM800 pts; 5.7, 7, 8.3 and 16.4 months, respectively, for NILO pts; 5.7, 8.8, 17.4 and 27.2 months, respectively, for DASA pts. To analyze the relationship between the degree of MR and clinical outcome we excluded pts not achieving a CCyR as their best response since the clinical significance of CCyR is well known. For the remaining 438 pts, the depth of molecular remission was inversely correlated with the risk of losing CCyR (19%, 16%, 11%, 7%, 2% in pts with <MMR, MMR, MR4, MR4.5 and UND, respectively) or losing MMR (31%, 42%, 24%, 2%, respectively), as well as the risk of events (22%, 20%, 15%, 12%, 3%, respectively), transformation (3%, 5%, 0%, 1%, 0%, respectively), or death (25%, 11%, 8%, 6%, 4%, respectively). The 6-year OS for pts with <MMR, MMR, MR4, MR4.5 and UND is 74%, 84%, 95%, 96% and 99%, respectively (p<.0001); transformation-free survival (TFS) is 95%, 93%, 100%, 99% and 100%, respectively (p<.014); event-free survival (EFS) is 74%, 74%, 86%, 89% and 99%, respectively (p<.0001). To adjust for the lead-time to achieve deeper responses, we then calculated OS, TFS and EFS rates at 6 years according to the depth of molecular response at 18 or 24 months. Results are summarized in table 1. Conclusion:Most patients treated with TKI as initial therapy for early CP CML achieve a MR during the course of treatment. BCR-ABL transcripts become undetectable in a significant fraction of them. Achieving a MMR or better at 18 months or 24 months is associated with significantly superior 6-years OS, TFS and EFS. These result suggest that deeper molecular responses (MMR and beyond) are associated with clinical benefit, with a particularly good outcome for those achieving undetectable transcript levels.Table 1Survival at 6 years by level of molecular response at 18- and 24-month landmarks.OutcomeMolecular response at 18 monthsp-valueNo MRMMRMR4MR4.5UND6-years OS93%98%97%95%100%.1536-years TFS90%100%100%100%100%.036-years EFS78%94%97%93%100%<.0001OutcomeMolecular response at 24 monthsNo MRMMRMR4MR4.5UND6-years OS92%97%100%97%100%.0186-years TFS90%100%100%100%100%.0576-years EFS80%90%97%95%100%<.0001 Disclosures:Off Label Use: Imatinib, dasatinib and nilotinib frontline for chronic phase chronic myeloid leukemia on clinical trial. Kantarjian:Bristol-Myers Squibb: Research Funding; Ariad: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Jabbour:Pfizer: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Ravandi:Bristol-Myers-Squibb: Research Funding. Cortes:Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Dasatinib or imatinib (IM) in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): Two-year follow-up from DASISION.

6510 Background: In the randomized phase III DASISION trial of dasatinib v IM in newly diagnosed CML-CP, dasatinib showed higher and faster rates of complete cytogenetic response (CCyR) and major molecular response (MMR) (Shah Blood 2010 116 abs 206). Methods: Pts received dasatinib 100 mg once daily (QD) (n=259) or IM 400 mg QD (n=260). Primary endpoint was confirmed CCyR (cCCyR; CCyR on 2 consecutive tests) by 12 mos. Results: After 19.7 mos’ median follow-up (range 0.1–31.4), 81% and 80% remained on dasatinib and IM. 18-mo response rates for dasatinib v IM were: cCCyR 78% v 70%, P=0.0366; CCyR 84% v 78%, P=0.0932; and MMR 56% v 37%, P<0.0001. MMR occurred more often with dasatinib in all Hasford groups. For dasatinib v IM, 13% v 7% had a BCR-ABL level ≤0.0032%. In time to response analyses, dasatinib pts were 1.8-/1.5-fold more likely to have MMR/CCyR (both P<0.0001). For dasatinib v IM, 6 (2.3%) v 9 (3.5%) pts transformed to accelerated/blast phase (AP/BP) on study; 1 other pt transformed 183 days after discontinuing dasatinib. For dasatinib v IM, 18-mo rates (follow-up ongoing) were overall survival: 96% v 98%; progression-free survival (no AP/BP or loss of response): 95% v 94%; failure-free survival (ELN 2006 criteria): 93% v 90%; and maximum clinical benefit (no progression, failure or intolerance): 87% v 86%. Drug-related adverse events (AEs) are shown (Table). Grade 3/4 nonhematologic AE rates were ≤1%. Pleural effusions seen only with dasatinib (2% gr 1, 9% gr 2, <1% gr 3) did not seem to impact efficacy. Most cytopenias (75%) arose within 4 mos. Gr 3/4 lab abnormality rates were ≤3% except hypophosphatemia (dasatinib 5%, IM 24%). For dasatinib v IM, 56% v 39% had dose interruption, 25% v 14% had dose reduction and 6% v 4% discontinued due to drug-related AEs. Minimum 24-mo follow-up will be presented. Conclusions: At 18 mos, dasatinib continues to show superior efficacy over IM and acceptable tolerability, supporting first-line dasatinib use in newly diagnosed CML-CP. % Dasatinib n=258 IM n=258 Nonhematologic ≥15%, all grades Fluid retention Superficial edema Pleural effusion 23 10 12 43 36 0 Diarrhea 18 19 Nausea 9 21 Myalgia 22 38 Rash 11 17 Hematologic, gr 3/4 Anemia 11 7 Neutropenia 22 20 Thrombocytopenia 19 10

A Randomized Phase II Trial of Dasatinib 100 Mg Vs Imatinib 400 Mg In Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP): The S0325 Intergroup Trial

AbstractAbstract LBA-6 Background.The optimal tyrosine kinase inhibitor (TKI) for patients (pts) with newly diagnosed CML-CP is unknown. While dasatinib (DAS) is a more potent TKI in vitro than imatinib (IM), it is unclear if this will translate into improved long-term clinical outcomes for pts with newly diagnosed CML-CP. In this open-label phase II trial pts with newly diagnosed CML-CP were randomized to IM 400 mg po qd or DAS 100 mg po qd by four North American cooperative groups (SWOG, ECOG, CALGB, NCIC-CTG). The primary endpoint was >4 log reduction in BCR-ABL transcript at 12 months (mos). The study design, with 240 evaluable pts, provided >90% power to detect a difference in this endpoint of >20 percentage points (two-sided alpha=5%). Patients.253 pts were randomized (12/2006 to 2/2009). Seven were ineligible, primarily due to diagnosis other than CML-CP, or nonevaluable because they received no protocol treatment or withdrew consent. Pretreatment characteristics were balanced between the arms. Treatment outcomes.Outcomes of the 246 included pts (age 18–90, median 49; 60% male; 35% / 30% with Hasford intermediate / high risk) are shown in Table 1. Eighteen DAS (15%) and 13 IM 400mg (11%) pts discontinued study drug because of a variety of toxicities. Eleven pts (3 DAS [2%], 8 IM 400mg [7%]) discontinued due to refusal, and 36 others (12 DAS [10%], 24 IM 400mg [20%]) for other reasons, most often physician or pt concerns about inadequate response, recurrence or progression. Molecular response at 12 months was deeper in the DAS arm (median 3.3 log reduction in BCR-ABL transcript level vs 2.8 with IM 400mg; Wilcoxon P=0.048), although the proportions achieving >4 log or >4.5 log reductions did not differ significantly (molecular response at 12 mos was based on 189 rather than the planned 240 pts, but this provided >80% power to detect a difference of >20 percentage points). The rates of hematologic CR (HemCR) and cytogenetic CR (CCyR) were not significantly higher with DAS, though 11% and 5% of DAS and IM 400mg pts were not adequately assessed for HemCR, and CCyR data were only available for 51% of pts. Overall survival (OS) and progression-free survival (PFS) were similar in the two arms, with very few deaths, relapses or progressions. Among pts with HemCR, 2-year relapse-free survival was 97% in the DAS arm, 95% in the IM 400mg arm. Toxicity.There were no fatal toxicities. The most common grade 3 and 4 toxicities were hematologic, including thrombocytopenia (<50×109/L) in 18% and 8% of DAS and IM 400mg pts, respectively (P=0.024). A variety of grade 4 non-hematologic toxicities were reported for 6% of DAS pts but no IM 400mg pts. An additional 30% and 17% of DAS and IM 400mg pts had a variety of grade 3 non-hematologic toxicities, while another 57% and 79% had non-hematologic grade 1–2 toxicities. Pleural effusion of any grade was reported for 11% and 2% of DAS and IM 400mg pts (P=0.0017); <2% in either arm were grade 3. Deaths.Seven pts have died, all >8 months after entering the study. Three DAS pts died: one at 8 months after progression to blast crisis, one from lung cancer diagnosed 10 months after DAS started, and one in an automobile accident. Two IM 400mg pts died of CML, and two others (ages 70 and 75 at treatment start) of cardiac arrest unrelated to CML or treatment. Conclusions.Both IM 400mg and DAS are highly effective and generally well-tolerated therapies for newly diagnosed CML-CP. DAS induced deeper molecular responses at 12 months, but not significantly higher rates of >4 log or >4.5 log reduction in BCR-ABL, compared to IM 400mg. 12-month PFS and OS were similar between the two arms, with very few events so far. DAS was associated with more grade 3–4 toxicity. Clinical follow-up is continuing to study whether the short-term deeper molecular response seen with DAS will translate into improved long-term outcomes. Disclosures:Radich:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy. Kopecky:Bristol-Myers Squibb: Research Funding. Kamel-Reid:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Larson:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Emanuel:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Genzyme: Consultancy. Lipton:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Deininger:Bristol-Myers Squibb: Advisory Board, Consultancy, Research Funding; Novartis: Advisory Board, Consultancy. Druker:MolecularMD: Equity Ownership; Novartis: Clinical Trial Funding; Bristol-Myers Squibb: Clinical Trial Funding.

Dasatinib or high-dose imatinib for patients with chronic myelogenous leukemia chronic-phase (CML-CP) resistant to standard- dose imatinib: 2-year follow-up data from START-R

7012 Background: Resistance to imatinib is a well-recognized problem in CML-CP. Dasatinib is 325-fold more potent than imatinib against BCR-ABL in vitro is effective in imatinib-resistant CML patients. Prior to dasatinib, imatinib dose escalation to 800 mg/day was the primary option for resistance to standard-dose imatinib. Methods: In this global Phase II study, 150 patients (pts) with CML-CP resistant to imatinib 400–600 mg/d were randomized 2:1 to dasatinib 70 mg BID (n=101) or imatinib 800 mg/d (n=49). The primary endpoint of the study was major cytogenetic response (MCyR) at 12 wks. Crossover was permitted for confirmed progression, lack of MCyR at 12 wks, or intolerance despite dose reduction. MCyR rates at 12 weeks were 36% vs 29%; p=0.4025. Two-year follow-up is now presented. Results: With a minimum follow-up (LPFV to database closure) of 24 mos, MCyR rates were (53% vs 33%, p=0.017) for pts receiving dasatinib and high-dose imatinib, respectively; the difference being attributable to complete cytogenetic responses (44% dasatinib vs 18% imatinib, p=0.0025). Major molecular responses (MMR) were also more frequent with dasatinib (29% vs 12%, p=0.028). Duration of MCyR was greater with dasatinib; 90% of dasatinib pts maintained MCyR at 18 mos vs 74% of imatinib pts. Analysis of progression-free survival at 24 mos favored dasatinib (86% vs 65%, p=0.0012); results were consistent irrespective of the prior imatinib dose received (400 mg/d, p=0.0562; 600 mg/d, p=0.0033). Time to treatment failure also favored dasatinib (proportion of pts without failure at 24 mos: 59% vs 18% p<0.0001). Grade 3–4 non-hematologic toxicity was minimal for both treatment groups. Grade 3–4 cytopenia was more frequent with dasatinib. Discontinuation attributable to toxicity occurred in 22% of pts receiving dasatinib and 20% treated with imatinib. Conclusions: With an extended follow-up of 24 mos, the overall benefit-risk assessment favors dasatinib over high-dose imatinib in CML-CP pts with resistance to 400–600 mg imatinib. The current labelled dose of 100 mg QD was approved based on a subsequent Phase III dose optimization study which showed comparable efficacy with improved tolerability compared with 70 mg BID. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb, Novartis

Incidence of grade 3/4 adverse events in imatinib resistant/intolerant chronic phase CML (CP-CML): A comparison of nilotinib and dasatinib

17501 Background: Toxicities of new treatments may increase the care and resources required to manage patients (pts). The objective of this study was to compare the rates of Grade 3/4 AEs reported for nilotinib and dasatinib, the second generation tyrosine kinase inhibitors (TKIs) in imatinib resistant/intolerant CP-CML pts in preparation for an economic analysis. Methods: A systematic literature review was conducted to identify published articles, registration documents, or abstracts of clinical trials in CP-CML for nilotinib 400 mg bid and dasatinib 70 mg bid. The base case incidence rates were selected from the most rigorous sources, specifically data from the dasatinib product label and the nilotinib phase II trial, both populations having a median drug exposure of slightly &gt;5 months. The AEs selected for the comparison were based on frequency (&gt;5%) and/or high likelihood of incurring incremental costs for medical treatment/monitoring. The full ranges for the incidence of AEs (if available) were summarized from other papers/abstracts for sensitivity analyses in future economic analyses. Results: The Grade 3/4 hematologic AEs were the most common AEs (table below) and were ∼2 times higher for dasatinib than for nilotinib. Common Grade 3/4 biochemistry abnormalities included lipase elevations in 5% of nilotinib pts (1 pt developed a Grade 1/2 pancreatitis; no Grade 3/4 pancreatitis) and hypophosphatemia in 11% of dasatinib pts. Rates of Grade 3/4 non-hematologic AEs such as pleural effusion, GI bleeding, arrhythmia, and pneumonia/infection were &gt;2–7 times higher for dasatinib than nilotinib, though they occurred in &lt;5% of the population. Conclusions: The toxicity profiles of the second generation TKIs for imatinib resistant/intolerant CP-CML appear to be different and favor nilotinib with its reduced rates of Grade 3/4 AEs. Further analysis is required to understand the cost impact to health care payers of the differences in safety profiles among the new TKIs. [Table: see text] No significant financial relationships to disclose.

Dasatinib (SPRYCEL®) vs Escalated Dose of Imatinib (im) in Patients (pts) with Chronic Phase Chronic Myeloid Leukemia (CP-CML) Resistant to Imatinib: Results of the CA180-017 START-R Randomized Study.

Pts with CML resistant to im have few therapeutic options. A growing body of evidence suggests that treatment outcomes can be improved with increased potency of BCR-ABL inhibition. Escalating the dose of im to 800mg/day (d) can overcome some cases of im-resistance, but tolerability and durability of response are significant issues. Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL, SRC, and other kinases that is approximately 300 times more potent than im in vitro. Dasatinib has been shown to be effective and safe in pts with CML resistant or intolerant to im, leading to recent FDA approval. START-R is an international trial of dasatinib 70mg twice daily (BID) and im 800mg/d in pts with CP-CML resistant to prior im 400–600mg/d. Crossover was allowed upon confirmed progression or intolerance despite dose reduction (grade 3/4 non-hematologic toxicity). Dasatinib dose escalation to 90mg BID was allowed for inadequate response at 12 wks, and dose reduction to 50 or 40mg BID for toxicity. Dose reduction of im to 600mg/d was allowed for patients who had not previously received that dose. Major cytogenetic response (MCyR) rate at 12 weeks was the primary endpoint. From Feb–Nov 2005, 150 pts were randomized (2:1), 101 to dasatinib, 49 to im. MCyR to prior im had been seen in 28% of dasatinib and 29% of im pts. With a minimum follow-up of 10 mo, complete hematologic response (CHR) rate was 92% (93 dasatinib pts) vs 82% (40 im pts), and MCyR rate was 48% dasatinib vs 33% im. Of importance, the primary difference was the complete cytogenetic response (CCyR) rate of 35% (35/101) dasatinib vs 16% (8/49) im, suggesting that dasatinib can achieve deeper responses in this patient population. Of pts with no prior CyR to im, 44% (17/39) achieved a MCyR with dasatinib vs 7% (1/15) with higher dose im. MCyR rates of 40% to dasatinib and 20% to im were achieved in pts with baseline im-resistant BCR-ABL mutations, with 47% of dasatinib pts vs 0 im pts with difficult-to-treat P-loop mutations achieving a MCyR. Pts with no prior CyR to im were able to achieve MCyR with dasatinib, but dose escalation of im was not effective. 23% dasatinib pts vs 80% im pts had treatment failure (TF, defined as progression, lack of response, crossover for intolerance, or off treatment). Median time to TF was not reached for dasatinib, and was 3.5 mo (95% CI: 3.3-3.8) for im. 61 pts discontinued the initially assigned treatment, of whom 50 (12 dasatinib; 38 im) crossed over after progression, no response, or intolerance. Of 45 post-crossover pts (38 dasatinib; 7 im), 17 (45%) dasatinib pts achieved MCyR, but no (0%) im pts with 800mg/d achieved MCyR after crossover following dasatinib. Grade 3/4 non-hematologic toxicity was minimal in both arms. All grades of superficial edema and fluid retention were more common with im than dasatinib (41% im vs 15% dasatinib; and 43% im vs 28% dasatinib respectively), whereas pleural effusion was 13% (3% grade 3/4) dasatinib vs 0 im. Cytopenia was more frequent and severe with dasatinib. This is the first clinical trial in pts with CML to include both im and dasatinib arms. Based on nearly 1 year of follow-up, dasatinib clearly appears to be more effective in achieving MCyR than high-dose im in pts who fail 400–600mg/d im. An update with molecular response data and detailed mutational analysis will be presented.

Dasatinib (D) vs high dose imatinib (IM) in patients (pts) with chronic phase chronic myeloid leukemia (CP-CML) resistant to imatinib. Results of CA180017 START-R randomized trial

6507 Background: High dose imatinib (800 mg/day) has been shown to have efficacy in a subset of CML patients with resistance to IM, although the durability of responses is not well-established. Dasatinib (BMS-354825) is a novel, highly potent, oral multi-targeted kinase inhibitor of BCR-ABL and SRC with activity against 18/19 imatinib resistant BCR-ABL mutants tested in vitro. Methods: START-R is a multicenter randomized (2:1 ratio) trial of D 70 mg twice daily (bid) and IM 800 mg/day in pts with CP-CML resistant to prior IM 400 to 600 mg/day. Cross-over was allowed for lack of response or intolerance (grade 3–4 non hematologic toxicity). D dose escalation to 90 mg bid was allowed for inadequate response at 12 wks, and dose reduction to 50 or 40 mg bid for drug toxicity. IM dose reduction to 600 mg/day was allowed. Evaluations consisted of weekly blood counts for the first 12 wks, bone marrow cytology and cytogenetics every 12 wks. The primary endpoint was major cytogenetic response (MCyR) rate at wk 12. Results: From February 2005 to November 2005, 150 pts were randomized of whom the first 36 pts (D 22, IM 14) are reported. Median age was 57 yrs, with 12 males and 24 females. Treatment groups were balanced with respect to CML characteristics; median time from initial diagnosis was 61 months for D and IM; prior interferon 64% and 79%; no prior CyR on IM 36% and 57%. BCR-ABL mutations were documented in 10 D pts and 1 IM pt. Dose reductions were required in 8 D pts and 1 IM pt. Complete hematologic response was documented in 21 D and 13 IM pts. MCyR rate at 12 wks was 45% for D and 21% for IM (7 complete for D and 1 for IM). With a 95% CI on the difference between D and IM was - 9.9 to +51.2. Two (9%) D and 11 (79%) IM pts crossed over for intolerance (1 D and 6 IM) or no MCyR (1 D and 5 IM). Grade 3–4 neutropenia or thrombopenia occurred in 8 and 9 dasatinib pts and in 8 and 2 IM pts. Most common grade 1–2 non-hematologic toxicities in D and IM groups were diarrhea (7 and 1 pts), nausea (7 and 7 pts), and facial/peripheral edema (8 and 7 pts). Conclusions: Dasatinib was effective in pts with CP-CML resistant to IM 400 to 600 mg/day. Preliminary data suggest that D is more effective and better tolerated than high dose IM. An updated analysis of all randomized pts will be presented. [Table: see text]