Higher Rates Of Major Molecular Response Research Articles

With up to 8 Years of Therapy, Asciminib (ASC) Monotherapy Demonstrated Continued Favorable Efficacy, Safety, and Tolerability in Patients (Pts) with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase (Ph+ CML-CP) without the T315I Mutation: Final Results from the Phase 1 X2101 Study

CONCLUSIONS Tyrosine kinase inhibitors (TKIs) have extended the life expectancy for pts with CML, approximating that of the general population, and established BCR::ABL1-targeted therapies as the standard of care for CML. However, multi-TKI resistance and intolerance remain challenges that may lead to treatment (Tx) discontinuation. ASC is the first and only approved BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP) with higher selectivity for ABL, reducing off-target effects seen with TKIs. A follow-up analysis (median exposure: 4.2 y) of the phase 1 ASC study in pts with CML-CP without T315I after receiving ≥2 TKIs demonstrated durable efficacy and favorable tolerability, with nearly one-third of pts achieving deep molecular response by cutoff (Jan 6, 2021). Here we present final end-of-study (EOS) efficacy and safety results from the phase 1 ASC study in pts with CML-CP without the T315I mutation (cutoff: Mar 14, 2023). This analysis included adults with Ph+ CML-CP without the T315I mutation and an ECOG performance status of 0-2 who had relapsed disease or were refractory to or intolerant of ≥2 prior TKIs. Pts received ASC monotherapy at starting doses of 10-200 mg twice daily (BID) or 80-200 mg once daily (QD). The study started with dose escalation to estimate the maximum tolerated dose (MTD), followed by expansion to establish safety and tolerability of ASC. Dose adjustments were allowed if pts did not tolerate the dosing schedule. The EOS was declared when all pts completed ≥64 wks within the study or discontinued Tx; pts continuing to receive ASC at the EOS were provided continued access to ASC. A total of 115 pts were enrolled between Apr 2014 and Mar 2023. Across all starting doses, the median exposure duration was 5.9 y, with a maximum exposure of 8.4 y; 112 pts (97.4%) had received ≥2 prior TKIs and 82 (71.3%) had received ≥3 prior TKIs. By data cutoff, 70 pts (60.9%) who completed the study on ASC were provided continued access to ASC. Among 45 pts who ended Tx early, 15 (13.0%) and 8 (7.0%) ended due to adverse events (AEs) and disease progression, respectively. Efficacy of ASC at EOS was sustained and consistent with previous reports, with the majority of pts (65.1%) achieving major molecular response (MMR) by the cutoff. While most responses were observed by wk 48, cumulative MMR rates continued to increase up to wk 144 (Figure 1). The median time to MMR (range) was 58.3 (2-360) wks among pts who achieved MMR but were not in MMR at screening. Among the 56 pts who achieved MMR, 50 maintained or improved the response up to data cutoff. At wks 24, 48, and 96, respectively, 18.9%, 17.9%, and 23.6% of pts achieved MR 4 and 13.2%, 15.1%, and 18.9% achieved MR 4.5. Safety and tolerability of ASC improved with longer durations of exposure. The most frequent all-grade AEs included arthralgia (40.9%), increased lipase (39.1%), fatigue (38.3%), and headache (38.3%), and only 13.0% of pts experienced AEs leading to Tx discontinuation. Even with longer durations of Tx, AEs were less likely to occur after the first year on ASC (Figure 2). The safety and tolerability of ASC remained consistent with prior analyses; there were no new or worsening safety issues compared with those already known for ASC and no new on-Tx deaths. The MTD of ASC was not reached. Based on safety, tolerability, efficacy, and pharmacokinetic data, ASC 40 mg BID was selected as the recommended dose for expansion in adults with CML-CP without the T315I mutation. In this final analysis of the phase 1 ASC trial in pts with CML-CP without the T315I mutation, ASC continued to show favorable efficacy and sustained safety and tolerability over a median exposure duration of 5.9 y, with a maximum exposure of 8.4 y. Pts achieved high rates of MMR with nearly one-fourth of pts achieving deep molecular responses at wk 96, demonstrating durable efficacy of ASC over time. Even with longer exposures, the risk of AEs did not increase and there were no new or worsening safety issues. With ASC, most AEs occurred early, and no new late-emerging safety issues were seen, supporting ASC as a safe and tolerable long-term Tx, highly clinically relevant in the management of resistant/intolerant CML-CP. Based on results from this and the ASCEMBL study, 40 mg BID and 80 mg QD have since been approved for use in this pt population.

Asciminib: the first-in-class allosteric inhibitor of BCR::ABL1 kinase.

The prognosis of patients with chronic phase (CP) chronic myeloid leukemia (CML) has significantly improved due to the development of potent BCR::ABL1 tyrosine kinase inhibitors (TKIs). However, approximately 15‒20% of patients ultimately experience treatment failure due to resistance or intolerance to TKI therapy. As the prognosis of patients in whom multiple TKIs fail remains poor, an optimal therapeutic approach is required to treat the condition. Asciminib, an allosteric inhibitor that targets ABL1 myristoyl pocket, has been approved by the Food and Drug Administration for use in patients with CP-CML resistant or intolerant to ≥2 prior TKIs or those with T315I mutation. In a phase 1 trial, asciminib monotherapy showed a relatively favorable safety profile and potent efficacy in patients with and without the T315I mutation. In a subsequent phase 3 trial, asciminib treatment was associated with a significantly higher major molecular response rate and lower discontinuation rate than bosutinib in patients with CP-CML for whom two previous TKIs failed. Several clinical trials are being performed in various clinical settings to evaluate the role of asciminib as a frontline treatment for newly diagnosed CP-CML, either as a single agent or in combination with other TKIs as a second-line or additive treatment to improve treatment-free or deep remission. This review summarizes the incidence, available therapies, and outcomes of patients with CP-CML who experienced treatment failure, the mechanism of action, preclinical and clinical data, and ongoing trials for asciminib.

Monitoring and Improving Adherence to Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia: A Systematic Review.

PurposeSuboptimal adherence to tyrosine kinase inhibitors (TKIs) is a widely recognized issue compromising the disease control and survival of patients with chronic myeloid leukemia (CML). A recently published review by Heiney et al reported inconclusive findings on the effects of a broad range of adherence enhancing interventions. The current systematic review aimed to identify studies that evaluated adherence-enhancing interventions implemented by healthcare professionals and determine their effect on CML patients’ medication adherence and clinical outcomes.MethodsA systematic literature search was performed in 5 databases for articles published between 2002 and 2021. Studies that compared adherence enhancing interventions implemented by healthcare professionals with a comparison group were included. Relevant data on study characteristics were extracted. Medication adherence and clinical outcomes between intervention and control arms were compared.ResultsNine studies were included in two randomised controlled trials, four cohort studies, and three before-and-after comparison studies. All the included studies incorporated complex interventions, including intensive education or consultation with pharmacists, nurses or multidisciplinary team, in combination with one or more other strategies such as structured follow-up, written materials or video, psychotherapy, medication reminder or treatment diary, with the overall goal of monitoring and improving TKI adherence. Most (7 out of 9) studies demonstrated significantly better adherence to TKIs in the intervention group than the comparison group. The relative proportion of participants who adhered to TKIs ranged from 1.22 to 2.42. The improvement in the rate of TKI doses taken/received ranged from 1.5% to 7.1%. Only one study showed a significant association between intervention and clinical outcomes, with a 22.6% higher major molecular response rate and improvement in 6 out of 20 subscales of health-related quality-of-life.ConclusionComplex interventions delivered by healthcare professionals showed improvement in adherence to TKIs in CML patients. Further studies are required to clarify the cost-effectiveness of adherence-enhancing interventions.

Comparison of Hepatotoxicity Associated With New BCR-ABL Tyrosine Kinase Inhibitors vs Imatinib Among Patients With Chronic Myeloid Leukemia

Although BCR-ABL fusion oncoprotein tyrosine kinase inhibitors (BCR-ABL TKIs) can substantially improve the survival rate of chronic myeloid leukemia (CML), they are clinically accompanied by severe hepatotoxicity. To compare the relative risk (RR) of hepatotoxicity of new-generation BCR-ABL TKIs with that of imatinib, and to provide an overall assessment of the clinical benefit. PubMed, Embase, Cochrane library databases, and ClinicalTrials.gov were searched for clinical trials published between January 2000 and April 2020. Study selection was conducted independently by 2 investigators according to the inclusion and exclusion criteria published previously in the protocol: only randomized phase 2 or phase 3 clinical trials that compared bosutinib, dasatinib, nilotinib, or ponatinib with imatinib were included. Among the 2666 records identified, 9 studies finally fulfilled the established criteria. Two investigators extracted study characteristics and data independently using a standardized data extraction form. Data were extracted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. When substantial heterogeneity was observed, pooled estimates were calculated based on the random-effect model; otherwise, the fixed-effect model was used. Data extracted included study characteristics, baseline patient information, interventions and data on all-grade and high-grade (grades 3 and 4) elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, overall survival, and major molecular response (MMR). The RRs and 95% CIs were calculated using the inverse variance method. Nine trials involving 3475 patients were analyzed; the median (range) age was 49 (18-91) years; 2059 (59.2%) were male patients. Increased risks were observed for each new-generation TKI except for dasatinib. Patients receiving new-generation TKIs were more likely to experience all grades of ALT elevation (pooled RR, 2.89; 95% CI, 1.78-4.69; P < .001) and grades 3 and 4 ALT elevation (pooled RR, 4.36; 95% CI, 2.00-9.50; P < .001) compared with those receiving imatinib. Patients receiving new-generation TKIs were also more likely to experience all grades of AST elevation (pooled RR, 2.20; 95% CI, 1.63-2.98; P < .001) and grades 3 and 4 AST elevation (pooled RR, 2.65; 95% CI, 1.59-4.42; P < .001) compared with those receiving imatinib. New-generation TKIs were associated with a significantly higher rate of MMR at 1 year compared with imatinib (pooled RR, 1.59; 95% CI, 1.44-1.75; P < .001). No statistical difference in overall survival at 1 year was found between new-generation TKIs and imatinib (pooled RR, 1.00; 95% CI, 1.00-1.01; P = .33). When compared to imatinib, bosutinib, nilotinib, and ponatinib had higher relative risks of hepatotoxicity. Treatment with new-generation TKIs was associated with a higher MMR rate at 1 year but not with 1-year overall survival.

Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: 12-Month Patient-Reported Outcomes from the BFORE Trial

Introduction: Since many patients with chronic phase chronic myeloid leukemia (CP CML) achieve long-term survival, health-related quality of life (HR-QOL) as assessed by PROs is an important consideration. Bosutinib is a SRC/ABL tyrosine kinase inhibitor approved for Philadelphia chromosome-positive CML treatment in adults resistant or intolerant to prior therapy. In the BFORE trial (NCT02130557) of bosutinib versus imatinib a significantly higher major molecular response rate at 12 months (the primary endpoint) occurred with bosutinib. Here we report initial PRO results from BFORE.Methods: BFORE is an ongoing, multinational, phase 3, open-label study in patients with newly diagnosed CP CML. Patients are randomized 1:1 to bosutinib 400 mg once daily or imatinib 400 mg once daily. PROs, assessed as exploratory endpoints, included functional status using the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) and the European Quality of Life-5 Dimensions-Visual Analog Scale (EQ-5D-VAS) instruments. Assessments were conducted at baseline and every 3 to 6 months, to continue for up to 5 years after treatment initiation. Outcomes at month 12 are reported herein.Results: Bosutinib and imatinib mean FACT-Leu scores were similar at baseline and at month 12 (Table). At month 12, significant improvement from baseline in FACT-Leu total score was observed for both bosutinib (mean change 3.1, P=0.0425) and imatinib (mean change 4.8, P=0.0008). For bosutinib at month 12, all FACT-Leu combined and subscale scores demonstrated either improvement (emotional well-being; leukemia symptoms; FACT-Leu total score) or maintenance (physical, functional, social well-being; FACT-General total score; trial outcome index).Bosutinib and imatinib mean EQ-5D-VAS scores were similar at baseline and at month 12 (Table). At month 12, significant improvement in mean EQ-5D-VAS was observed for both bosutinib (mean change 4.4, P=0.0014) and imatinib (mean change 9.3; P <0.0001). Additional FACT-Leu and EQ-5D analyses yielded similar findings. For example, mean [SD] Functional Health Status as measured using the EQ-5D Utility Score was similar between groups at baseline (bosutinib: 0.688 [0.2710] and imatinib: 0.657 [0.2929]) and improved from baseline for subjects in both treatment arms, with comparable scores seen at Month 12 (bosutinib: 0.722 [0.2953] and imatinib: 0.724 [0.2717]).Conclusion: In the BFORE trial of first-line CP CML therapy, PROs for bosutinib indicated improvement or maintenance of HRQoL at month 12, with effects comparable to those observed for imatinib, the standard of care for first-line CML treatment. These exploratory PRO results indicate fewer symptoms, better HRQoL, and improved functional health status at month 12 relative to baseline for both therapies. [Display omitted] DisclosuresCortes:ARIAD: Consultancy, Research Funding; Sun Pharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Teva: Research Funding. Gambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Deininger:Novartis: Consultancy, Research Funding; Incyte: Consultancy; ARIAD: Consultancy; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; BMS: Consultancy, Research Funding; Celgene: Research Funding; Gilead: Research Funding. Mauro:Bristol-Myers Squibb: Consultancy. Chuah:Chiltern: Honoraria; BMS: Honoraria, Other: Travel; Novartis: Honoraria; Avillion: Honoraria. Kim:Il-Yang: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Milojkovic:ARIAD: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria. le Coutre:Incyte: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria, Research Funding; ARIAD: Honoraria. García Gutiérrez:BMS: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Reilly:Avillion LLP: Employment. Jeynes-Ellis:Avillion LLP: Employment, Equity Ownership. Crescenzo:Pfizer: Employment, Equity Ownership. Mamolo:Pfizer: Employment, Equity Ownership. Reisman:Pfizer: Employment. Bardy-Bouxin:Pfizer: Employment, Equity Ownership. Hochhaus:Novartis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Ariad: Research Funding; MSD: Research Funding; BMS: Research Funding. Brümmendorf:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Real-World Effectiveness of First-Line (1L) Dasatinib Versus 1L Imatinib in Newly Diagnosed Patients with Chronic Phase Chronic Myeloid Leukemia (CP-CML)

Introduction: The safety and efficacy of 1L dasatinib and 1L imatinib was established in the pivotal DASISION and IRIS trials; however, limited real-world evidence exists for the comparative effectiveness of these agents among US patients with CP-CML treated in routine clinical practice. As such, real-world data are needed to assess the outcomes of imatinib- and dasatinib-treated patients in a pragmatic setting. Additionally, recent data suggest that second generation tyrosine kinase inhibitors (TKIs), including dasatinib, may be beneficial in certain CP-CML populations, which may be underrepresented in clinical trials (e.g., high risk, elderly, or high body mass index [BMI]). This study examined the real-world clinical response rates and time to response associated with 1L dasatinib or 1L imatinib among patients with CP-CML, as well as in subgroups defined by Sokal risk, age, and BMI. Methods: A retrospective, observational, US multi-site cohort study was conducted among adults with newly diagnosed Philadelphia chromosome-positive CP-CML treated with 1L dasatinib or 1L imatinib between January 2014 and September 2018. Patients had at least 1 year of follow-up after 1L initiation and did not have another malignancy or treatment as part of any clinical trial for CML. Oncologists collected data from eligible patient charts, including patient characteristics, treatment details, response to dasatinib or imatinib, and survival. Response was classified as major molecular response (MMR) and deep molecular response (DMR: 4.5-log reduction in BCR-ABL1 transcript levels) by physician report. Patient characteristics and outcomes were summarized using descriptive statistics for dasatinib and imatinib; results were reported in aggregate and stratified by Sokal risk (low and intermediate/high), age (&amp;lt; 65 and ≥ 65 years old), and BMI (low/normal [&amp;lt; 25 kg/m2] and high [≥ 25 kg/m2]). Comparisons were made by chi-square or Fisher's exact test for categorical variables, t-test or Wilcoxon test for continuous variables, log-rank test for overall survival (OS), and Cox proportional hazard models using Fine and Gray's method to account for competing risks in estimating differences in time to response across groups. Results: Among the patients treated with 1L dasatinib (n = 309) and 1L imatinib (n = 304), median follow-up time was 27.4 and 28.9 months, respectively. Most patients initiated dasatinib at 100 mg (82%) or imatinib at 400 mg (95%). Dose reductions were more common among dasatinib patients vs imatinib (15% vs 7%, P &amp;lt; 0.01), though fewer dasatinib-treated patients discontinued for any reason (15% vs 28%, P &amp;lt; 0.01). Higher rates of MMR were seen in dasatinib vs imatinib patients (79% vs 65%, P &amp;lt; 0.01) and median time to MMR was shorter with dasatinib vs imatinib (11.9 vs 14.7 months, P &amp;lt; 0.01). Similarly, higher rates of DMR were seen among dasatinib vs imatinib patients (44% vs 25%, P &amp;lt; 0.01) along with a shorter median time to DMR with dasatinib vs imatinib (30.3 vs 66.1 months, P &amp;lt; 0.01). Among patients with intermediate/high Sokal risk, as well as those &amp;lt; 65 years old, rates of MMR and DMR were higher and achieved earlier with dasatinib vs imatinib (all P &amp;lt; 0.01) (Table). Low-risk patients treated with dasatinib had higher rates of DMR vs imatinib (60% vs 32%, P = 0.01). Among patients ≥ 65 years old, rates of MMR and DMR were numerically higher with dasatinib vs imatinib, though differences were not significant at α = 0.05. Across both BMI strata, rates of MMR and DMR were higher with 1L dasatinib vs 1L imatinib (all P &amp;lt; 0.05). In the overall population, dasatinib patients had superior OS compared to those treated with imatinib (98% vs 89%, P &amp;lt; 0.01). Conclusions: In real-world clinical practice, a greater proportion of patients with CP-CML treated with 1L dasatinib achieved MMR and DMR and also achieved these responses earlier vs 1L imatinib. These clinically meaningful improvements were also observed across patient subgroups stratified by Sokal risk, age, and BMI. These findings from real-world US data were consistent with DASISION, demonstrating that dasatinib yields better outcomes among patients with CP-CML, with the novel findings of improved OS and improved outcomes in certain subgroups, including a higher rate of DMR among low-risk patients. Disclosures Klink: Cardinal Health: Current Employment, Current equity holder in publicly-traded company. Keating:Bristol Myers Squibb: Current Employment. Brokars:Bristol Myers Squibb: Current Employment. Kee:Bristol Myers Squibb: Current Employment. Copher:Bristol Myers Squibb: Current Employment. Stwalley:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Feinberg:Cardinal Health: Current Employment. Jabbour:Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding.

Relationship between molecular response and quality of life with bosutinib or imatinib for chronic myeloid leukemia

Patients with newly diagnosed chronic phase chronic myeloid leukemia (CP CML) can be effectively treated with tyrosine kinase inhibitors (TKIs) and achieve a lifespan similar to the general population. The success of TKIs, however, requires long-term and sometimes lifelong treatment; thus, patient-assessed health-related quality of life (HRQoL) has become an increasingly important parameter for treatment selection. Bosutinib is a TKI approved for CP CML in newly diagnosed adults and in those resistant or intolerant to prior therapy. In the Bosutinib Trial in First-Line Chronic Myelogenous Leukemia Treatment (BFORE), bosutinib demonstrated a significantly higher major molecular response rate compared with imatinib, with maintenance of HRQoL (measured by the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) questionnaire), after 12 months of first-line treatment. We examined relationships between molecular response (MR) and HRQoL. MR values were represented by a log-reduction scale (MRLR; a continuous variable). A repeated-measures longitudinal model was used to estimate the relationships between MRLR as a predictor and each FACT-Leu domain as an outcome. Effect sizes were calculated to determine strength of effects and allow comparisons across domains. The majority of FACT-Leu domains (with the exception of social well-being and physical well-being) demonstrated a significant relationship with MRLR (p < 0.05). Our results showed variable impact of clinical improvement on different dimensions of HRQoL. For patients who achieved MR5, emotional well-being and leukemia-specific domains showed the greatest improvement, with medium differences in effect sizes, whereas social well-being and physical well-being had the weakest relationship with MR.

Impact of Diarrhea on Health-Related Quality of Life: Analysis of the Phase 3 BFORE Trial of Bosutinib Vs Imatinib for Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia

Introduction: In the ongoing phase 3 BFORE trial (NCT02130557), a significantly higher major molecular response rate at Month 12 was seen with bosutinib vs imatinib in patients with newly diagnosed chronic phase chronic myeloid leukemia (CP CML), and bosutinib treatment was accompanied by improvement or maintenance of health-related quality of life (HRQoL), as assessed by the patient-reported Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) instrument. Diarrhea is a common side effect of bosutinib and occurred more frequently in bosutinib- vs imatinib-treated patients in the primary analysis of the BFORE trial (all grades: 70.1% vs 33.6%). Here, the impact of diarrhea, specifically on HRQoL, was assessed in patients receiving bosutinib or imatinib in the BFORE trial.Methods: Patients with CP CML were randomized 1:1 to receive first-line bosutinib or imatinib. HRQoL was analyzed in the modified intent-to-treat (mITT) population, comprised of Philadelphia chromosome-positive patients with typical BCR-ABL transcripts. The FACT-Leu consists of the 27-item FACT-General (FACT-G) scale with 4 domains (physical, social, emotional, and functional well-being) and the 17-item leukemia-specific subscale; higher scores and changes in scores indicate better HRQoL. Patients completed questionnaires at baseline, every 3 months for the first 2 years and every 6 months thereafter while on treatment, and at treatment completion. In this post hoc analysis, FACT-Leu scores from the first 12 months of treatment were analyzed in patients with diarrhea (any event during treatment) or chronic diarrhea (event lasting ≥28 days). Longitudinal analyses were conducted and standardized effect sizes were calculated to characterize the strength of effect on the FACT-Leu scores for the diarrhea and chronic diarrhea subgroups. Standardized effect sizes of approximately 0.1, 0.2, 0.5, and 0.8 (in absolute values) were considered trivial, small, medium, and large, respectively.Results: In the mITT population (bosutinib: n=246; imatinib: n=241), 163 (66.3%) patients in the bosutinib arm and 74 (30.7%) in the imatinib arm had diarrhea and were evaluable for HRQoL; 34 (13.8%) and 20 (8.3%), respectively, had chronic diarrhea (≥28 days). Among patients who developed diarrhea, the FACT-Leu total score and most subscale scores improved from baseline to Month 12 in both treatment arms, although changes were generally not significant (P>0.05) and could be interpreted as small or trivial, based on effect size (Table). For patients with diarrhea in the bosutinib arm, changes from baseline in the leukemia-specific subscale could be characterized as small improvements starting at Month 6 of treatment; in the imatinib arm, an improvement was not seen until Month 12, and all changes could only be characterized as trivial (Figure). Among patients with chronic diarrhea, the changes from baseline at Month 12 were not significant for all FACT-Leu total or subscale scores in the bosutinib arm and could be interpreted as small or trivial; in the imatinib arm, changes from baseline in all FACT-Leu scores were numerically negative and nonsignificant with the exception of the physical well-being domain (P<0.01), which had a large effect size (Table). For patients with chronic diarrhea in the bosutinib arm, improvements in the leukemia-specific subscale at Month 3 through Month 9 could be characterized as small; in the imatinib arm, a deterioration was seen at Month 3 through Month 12, and changes could be considered small at Months 9 and 12 (Figure).Conclusions: In this post hoc analysis of the BFORE trial, HRQoL was not negatively affected by diarrhea or chronic diarrhea in the bosutinib arm. Although the analysis is limited by the small number of patients, chronic diarrhea during treatment with imatinib appeared to have a greater impact on HRQoL than chronic diarrhea during treatment with bosutinib, based on the magnitude of the effect sizes and direction of changes, particularly for physical well-being. These data suggest that patients with CP CML treated with bosutinib can preserve or slightly improve HRQoL during therapy, regardless of the presence of diarrhea or chronic diarrhea. [Display omitted] DisclosuresBrümmendorf:Merck: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy. Mamolo:Pfizer: Employment, Equity Ownership. Reisman:Pfizer: Employment, Equity Ownership. Bushmakin:Pfizer: Employment, Equity Ownership. Cappelleri:Pfizer: Employment, Equity Ownership. Crescenzo:Pfizer: Employment. DeAnnuntis:Pfizer Inc: Employment, Equity Ownership. Viquiera:Pfizer: Employment, Equity Ownership. Cortes:Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding.

Improved Adherence Rates and Clinical Outcomes of an Integrated, Closed-Loop, Pharmacist-Led Oral Chemotherapy Management Program.

To address the growing use of oral anticancer therapy, an integrated, closed-loop, pharmacist-led oral chemotherapy management program was created within an academic medical center. An integrated, closed-loop, pharmacy-led oral chemotherapy management program was established. From September 2014 until June 2015, demographic information, rates of adherence, patient understanding of treatment, pharmacist interventions, patient and provider satisfaction, and molecular response rates in patients with chronic myeloid leukemia (CML) were collected. After full implementation, 107 patients were enrolled in our oral chemotherapy management program from September 2014 until June 2015. All patients were educated before starting oral chemotherapy, and using pre- and postassessment tests, comprehension of oral chemotherapy treatment increased from 43% to 95%. Patient-reported adherence was 86% and 94.7% for the GI/breast and malignant hematology patient populations, respectively, and these were validated with medication possession ratio, revealing adherence rates of 85% and 93.9% for the GI/breast and malignant hematology patient populations, respectively. A total of 350 encounters with a clinical pharmacist and 318 adverse effects were reported, which led to 235 interventions. This program led to a higher major molecular response rate (83%) in our CML population compared with published clinical trials (average major molecular response rates, 40% and 60% with 1- and 2-year follow-up, respectively). An innovative model was developed and resulted in improved patient knowledge regarding oral chemotherapy, improved adherence rates that exceeded nationally established thresholds, and superior major molecular response outcomes for patients with CML compared with published literature. As a result, this model has produced the gold standard in managing patients receiving oral chemotherapy.

Trough concentration and ABCG2 polymorphism are better to predict imatinib response in chronic myeloid leukemia: a meta-analysis.

The present study aimed to conduct a series of meta-analyses to investigate the influence of imatinib trough concentration (C0), as well as ABCB1 and ABCG2 polymorphisms, on the clinical response in patients with chronic myeloid leukemia (CML). A literature search was conducted using the PubMed and Cochrane electronic databases to locate relevant papers from 2003 onward. Then, an initial meta-analysis of 14 studies involving 2184 patients was conducted to understand the effect of imatinib mesylate (IM) C0 on clinical outcome in CML patients. Subsequently, a series of meta-analyses were performed, including up to 23 studies with 2577 patients, on the effect of genetic polymorphisms of ABCB1 and ABCG2 on the clinical response to IM. Meta-analysis revealed that patients who achieved a major molecular response (MMR) have a significantly higher IM C0 than those who failed to achieve an MMR. We also found that the patients who achieved a complete cytogenic response (CCyR) have a significantly higher IM C0 than those who did not achieve a CCyR. However, no significant difference in IM C0 was found between the complete molecular response and non-complete molecular response groups. Additional analysis showed that ABCG2 421 variant A allele was significantly associated with a higher rate of MMR and overall response, especially in Asian patients. Meta-analysis did not reveal a correlation between ABCB1 C3435T and C1236T polymorphisms with any clinical response to IM. However, the G2677T/A polymorphism could play a role in IM response in the recessive model. This meta-analysis demonstrates that there was a significant correlation between the IM trough concentration and clinical responses, especially MMR and CCyR, in CML patients. Furthermore, we found that the probability of successful treatment was correlated with the ABCG2 C421A polymorphism, at least within the Asian population. We failed to determine an association between ABCB1 polymorphisms and IM response, although the G2677T/A polymorphism might be involved. However, further large-scale investigations using more sensitive genotyping methods would be required to confirm this.

Clinical Application of Artificial Intelligence in Patients with Chronic Myeloid Leukemia in Chronic Phase

▪IntroductionArtificial intelligence (AI) has been applied to a wide range of daily activities to assist in decision-making. Randomized clinical trials can compare the efficacy of treatment between patient groups. However, the best treatment decision for each individual patient, with their own clinical and biological features, and in the context of comparable treatment options, is more difficult to predict. The integrated consideration of various prognostic features can reach the point beyond human recognition. An AI-assisted approach may help with decision-making in complex clinical situations. The aim of this study is to introduce a prototype of AI to predict outcome such as achievement of major molecular response (MMR) within 1 year of the start of tyrosine kinase inhibitor (TKI).MethodsResponse data for 630 patients with newly diagnosed CML-CP in consecutive prospective clinical trials of frontline imatinib (n=73; NCT00048672), high-dose imatinib (n=208; NCT00038469 and NCT00050531), nilotinib (n=148; NCT00129740), dasatinib (n=150; NCT00254423), and ponatinib (n=51; NCT01570868) were analyzed. After multiple imputation for missing variables, neural network analysis with a multilayer perceptron model using the statistically significant variables by stepwise multivariate analysis was performed to predict the cumulative incidence of MMR within 1 year. The hyperbolic tangent and softmax activation function were used to create the architecture of hidden layers and output layers, respectively. Batch training with scaled conjugate gradient optimization algorithm with learning parameters (initial Lambda of 0.0000005, initial Sigma of 0.00005, interval center of 0, and interval offset of ±0.5) was used to train the neural network. To evaluate the accuracy of prediction, the entire cohort was randomly divided into training dataset (70%) and test dataset (30%). The correct prediction in the test dataset was repeatedly assessed 1,000 times to validate this approach. The whole cohort was subsequently used to create the AI model for MMR prediction, and was divided into two cohorts based on the prediction by the AI; AI-predicted response, and AI-predicted nonresponse. Hypothetical choice of TKI was assumed to rank the selection of TKI among imatinib 400 mg/day, imatinib 800 mg/day, dasatinib, nilotinib, and ponatinib to calculate the estimated percentage of MMR within 1 year for each patient. The Kaplan-Meier method with a log-rank test was used for failure-free survival (FFS), transformation-free survival (TFS), event-free survival (EFS), and overall survival (OS). To balance baseline patient characteristics between cohorts, propensity score matching after propensity score calculation by logistic regression was performed with nearest neighbor matching method with a caliper of 0.20. Exact matching was used for the type of cytogenetic, transcript, and TKI.ResultsOf 630 patients treated, 464 (74%) achieved MMR within 1 year. The stepwise multivariate analysis identified the selection of TKI, type of transcript, white blood cell count, albumin, and spleen size at diagnosis were the predictors for MMR within 1 year. Neural network analysis with a multilayer perceptron model is shown in figure 1. Through repeated random selection for training set (70%) and test set (30%), the mean correct prediction for MMR within 1 year was 77.4% (95% confidence interval [CI], 74.2-80.5), and 76.9% (95% CI, 71.4-82.3), respectively. Of 630 patients, the neural network model predicted 539 patients (86%) as responders, and 91 patients (14%) as nonresponders (table 1). Before propensity score matching, the AI-response cohort had higher rates of CCyR, MMR, MR4, MR4.5, and CMR as well as FFS, TFS, EFS, and OS compared to those of the AI-nonresponse cohort (figure 2). After propensity score matching, 25 patients in each cohort were identified, and the baseline differences were minimized (table 1). The AI-response cohort had higher rates of MMR, MR4, and FFS than those of AI-non-response cohort (figure 2).ConclusionAI with a multilayer perceptron model can predict target outcome. Incorporation of additional clinical and biological variables may improve the prediction rates to suggest the best treatment option in each patient with CML-CP. Such strategy is ongoing. [Display omitted] [Display omitted] [Display omitted] DisclosuresKantarjian:ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Ravandi:BMS: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Konopleva:AbbVie: Research Funding; Genentech: Research Funding. Wierda:Novartis: Research Funding; Abbvie: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Daver:Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; BMS: Research Funding; Otsuka: Consultancy, Honoraria; Sunesis: Consultancy, Research Funding; Karyopharm: Honoraria, Research Funding; Ariad: Research Funding.

Personalized Daily Doses of Imatinib By Therapeutic Drug Monitoring Increase the Rates of Molecular Responses in Patients with Chronic Myeloid Leukemia. Final Results of the Randomized OPTIM Imatinib Study

▪BackgroundImatinib mesylate (IM) at 400 mg/d remains a standard for first line therapy in patients (pts) with newly diagnosed chronic phase CML (CP-CML). A sub analysis of the IRIS study (Larson et al. Blood, 2008) demonstrated that pts with high IM trough levels achieved higher rates of major molecular response (MMR). The level of 1000 ng/ml was established as the [C]min value threshold to predict molecular response (Picard et al. Blood, 2007).We conducted a randomized trial to evaluate the value of IM dose optimization based on the monitoring of [C]min levels in newly diagnosed CP-CML pts (OPTIM-imatinib trial, EudraCT number 2008-006854-17).Patients and MethodsPts diagnosed with CP- CML for less than 3 months, not previously treated or treated with IM for less than 3 months were eligible and treated with IM 400 mg/d. IM [C]min was determined by chromatography-tandem mass-mass spectrometry 15 days after enrollment. Pts with a [C]min < 1000 ng/ml were randomized between a dose-increase strategy aiming to reach the threshold of 1000 ng/ml (arm A1) versus standard IM management (arm A2). Pts with [C]min levels ≥1000 ng/ml were observed (arm A3). All pts were managed according to the ELN 2009 recommendations (amended with ELN 2013 recommendations). IM [C]min levels were assessed monthly in A1 and A2 and every 3 months in A3. BCR-ABLIS was assessed every 3 months. The primary end-point was MMR rates at 12 months.ResultsOne hundred thirty nine pts were enrolled. Median follow-up was 31 months. Median age was 64y (25 to 88y), sex ratio (M/F) was 1.4 and Sokal score distribution was 21%, 41% and 38% for high, intermediate and low categories respectively, equally distributed in the 3 arms. In 6 pts the initial [C]min was not assessed (3 were intolerant and 3 declined the dosage). Thus 133 pts were studied. In 86 pts (65%), initial [C]min value was < 1000 ng/ml. These pts were randomized between A1 (43 pts) and A2 (43 pts). [C]min was ≥1000 ng/ml in the 47 remaining pts followed in A3. Table 1 shows the significant improvement of the median IM [C]min after dose adjustment in A1 (p<0.0001) as compared to standard management in A2. Correspondingly, IM daily dose increased in A1 (p<0.0001) to reach a mean value of 600 mg/d. In the experimental A1 arm, the distribution of IM doses at 12 months was 13% for 500 mg/d, 30% for 600 mg/d, 34% for 800 mg/d whereas 16% of the pts remained at 400 mg/d and 7% were dose decreased at 300 mg/d.During follow-up, a similar proportion of pts with AE was observed in A1 (58%) and A2 (51%). Eight SAE related to IM were equally distributed in A1, A2 and A3. Cumulative incidences of treatment discontinuation were comparable in the 3 arms (overall, 18.8% by 12 months and 34.1% by 24 months). Reasons for discontinuation were not similar in A1 and A2 with a trend for more treatment failures in A2 as compared to A1 (60% versus 18%, p=0.08). At 12 months, MMR was achieved in 27 out of 43 pts (63%; 95%CI 49-77) in A1 as compared to 16 out 43 pts (37%; 95%CI 23-51) in A2 (p=0,031). The rates of MMR were not statistically different between A1 and A3 (p=0.12).ConclusionsOnly 1/3 of pts on IM400 were correctly dosed and may not require systematic high dose IM. Two-thirds of the pts were not exposed enough to IM at standard dose and may benefit from individualized strategies. A tailored dose adjustment based on pharmacology resulted in higher MMR rate at 12 months (63% vs 37%), a magnitude in line with the results previously reported with second generation tyrosine kinase inhibitors or high dose IM front line. Our results may provide a strong rational to early personalize the use of IM and IM generic formulations in order to optimize the outcome for each patient.This study was supported by a grant from the French Department of Health (Programme Hospitalier de Recherche Clinique).Table 1Median [C]min (ng/ml; (95% CI))Initial AssessmentM3M6M9M12A1591; (508-654)838; (746-922)1001; (748-1261)1062; (918-1221)1013; (830-1277)A2651; (558-797)605; (487-786)591; (517-722)605; (460-720)646; (576-894)A31314; (1199-1514)1032; (899-1143)1002; (784-1205)935; (737-1073)1000; (846-1098)Mean IM daily dose (mg/d; (95% CI))InclusionM3M6M9M12A1400538; (508-568)611; (563-658)607; (545-668)600; (535-665)A2400395; (387-402)392; (383-401)391; (381-401)391; (381-401)A3400400; (400-400)398; (385-410)389; (376-402)382; (370-395) DisclosuresRousselot:BMS: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Consultancy. Johnson-Ansah:BMS: Speakers Bureau; Hybrigenics SA: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau. Huguet:PFIZER: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding. Legros:Novartis: Research Funding, Speakers Bureau; ARIAD: Speakers Bureau; BMS: Speakers Bureau. Gardembas:Novartis: Speakers Bureau. Coiteux:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau. Deau:BMS: Honoraria. Mahon:ARIAD: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

Gender and BCR-ABL transcript type are correlated with molecular response to imatinib treatment in patients with chronic myeloid leukemia.

Achieving a major molecular response (MMR) is the goal of imatinib therapy for chronic myeloid leukemia. However, the association between gender, BCR-ABL transcript type, and age with MMR is not well understood and often controversial. We retrospectively analyzed 166 patients who have been treated with imatinib for up to 10 yr. Men had a lower MMR rate than women (63.3% vs. 81.6%, P = 0.006) and a shorter time to relapse (median 354 vs. 675 d, P = 0.049), while patients with b3a2 or with both b3a2 and b2a2 break point transcripts had higher MMR rate than those with b2a2 (81.8%, 77.1% vs. 60.7%, P = 0.023 for b3a2 vs. b2a2, P = 0.043 for both vs. b2a2). A striking difference was found between men with b2a2 and women with both b2a2 and b3a2 in terms of MMR rate (43.8% vs. 88.9%), MMR rate within 6 months (7.1% vs. 62.5%) and the time to MMR (median d 493 vs. 159, P = 0.036). Both gender and BCR-ABL transcript, but not age, were significantly associated with the molecular response. Men with b2a2 represent a less favorable group in their response to imatinib treatment and may need alternative therapy regimen and closer monitoring.

The Association Of Dasatinib-Induced Lymphocytosis With Treatment Outcome In Patients With Chronic Myeloid Leukemia (CML)

The Association Of Dasatinib-Induced Lymphocytosis With Treatment Outcome In Patients With Chronic Myeloid Leukemia (CML)

Cytogenetic and Molecular Responses At 3 Months Are Associated with A Better Outcome in Early Chronic Phase (ECP) Chronic Myeloid Leukemia (CML) Patients Treated with Nilotinib.

Abstract 2797 Background: Nilotinib is a second-generation tyrosine kinase inhibitor that demonstrated higher and faster responses and lower progression rates compared to imatinib in ECP CML patients. Early cytogenetic and molecular responses have been associated with a better outcome in patients treated with imatinib, dasatinib, or nilotinib frontline. In particular, BCR-ABL transcript level 4.5 (>4.5 log reduction in BCR-ABL transcript level) with dasatinib (Marin D et al, Blood 2012); increased CCyR rate by 1 year, MMR rate by 2 years, and better progression-free survival (PFS) at 2 years, with dasatinib (DASISION; Hochhaus A et al, ASH 2011, abs. 2767); increased MMR rate by 1 year, and better PFS and overall survival (OS), with nilotinib (ENESTnd; Hochhaus A et al, EHA 2012, abs. 584). Here we report a landmark analyses based on BCR-ABL transcript level and cytogenetic response at 3 months to evaluate their impact on subsequent response and outcome in an independent cohort of patients treated with nilotinib-based regimens in Italy (CML Italian Registry of Nilotinib). Methods: The CML Italian Registry of Nilotinib includes 215 patients, enrolled in 2 multicenter phase II studies conducted by the GIMEMA CML WP (ClinicalTrials.gov. NCT00481052 and NCT00769327) or treated at the Dpt. of Hematology and Oncology, Bologna University Hospital, with nilotinib 300 mg BID or 400 mg BID as initial treatment. The median age was 53 years (range 18–86). The median follow-up was 29 months (range: 18–47 months). At 3 months 196/215 (91%) and 189/215 (88%) patients were evaluable for the molecular and cytogenetic response, respectively. BCR-ABL transcript levels were: 2 1% in 88%; > 1% to 2 10% in 11%; > 10% in 1%; given the very low proportion of patients with a BCR-ABL > 10% (n. 2), to the purpose of these analyses, patients have been divided into 2 groups, with a transcript level 2 1% (n. 173, 88%), or > 1% (n. 23, 12%). Cytogenetic response was: CCyR 84%; partial cytogenetic response (PCyR) 9%; less than PCyR 7%. We analyzed the rate of MMR at 1 year, and the failure-free survival (FFS, according to ELN 2009 definitions), PFS (transformation to accelerated or blastic phase), and OS (any death included) according to the BCR-ABL transcript levels and to the cytogenetic response at 3 months. Results: Of the 2 patients with a BCR-ABL transcript level > 10% at 3 months, 1 progressed to blastic phase at 1 year, while the other one obtained a CCyR at 6 months and a MMR at 24 months. Patients with BCR-ABL 2 1% at 3 months had a higher rate of MMR at 12 months with respect to those with a transcript level > 1% (79% vs. 35%, p 2 1%) at 3 months correlated with a better FFS and PFS and a similar OS at 3 years. Patients with a MCgR and CCyR at 3 months had higher rates of MMR at 12 months (77% and 79%, respectively) vs. patients with less than a MCyR or less than a CCyR (46% and 57%, respectively) (p=0.02 and 0.019, respectively). Patients in MCgR at 3 months had a better FFS and PFS, but similar OS with respect to patients not in MCgR. Conclusion: In our national experience, where 42 centers are represented with at least 1 patient, a very small proportion of patients treated frontline with nilotinib failed to achieve a reduction to . The cut-off of 1% of BCR-ABL at 3 months in our experience is a reliable surrogate marker of response at 1 year (MMR) and outcome (PFS and FFS), along with the level of cytogenetic response achieved. These patients with > 1% of BCR-ABL at 3 months are characterized by a higher propensity to fail the treatment and to progress. Consequently, they deserve a close monitoring and, for those not achieving the expected cytogenetic and molecular responses later on (at 6–12 months), an optimization of the dose of nilotinib or a treatment modification is advised. Acknowledgments: European LeukemiaNet, University of Bologna, BolognAIL, COFIN. Disclosures: Gugliotta: Novartis: Consultancy, Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria. Castagnetti: Novartis: Consultancy, Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria. Breccia: Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Abruzzese: Bristol Myers-Squibb and Novartis: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Soverini: Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; ARIAD: Consultancy. Saglio: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Martinelli: Novartis: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers-Squibb: Consultancy, Honoraria, Speakers Bureau. Baccarani: ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Rosti: Novartis Pharma: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau.

Bosutinib Versus Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia – BELA Trial: 24-Month Follow-up

Abstract 455 Introduction:Bosutinib (SKI-606) is an orally active, dual competitive inhibitor of the Src and Abl tyrosine kinases. The phase 3 BELA study compared bosutinib with imatinib in patients (pts) with newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML). Methods:Pts were randomized 1:1 to open-label oral bosutinib 500 mg/d (n = 250) or imatinib 400 mg/d (n = 252) and stratified by Sokal score risk group (low, medium, high) and geographical region. The primary efficacy endpoint was complete cytogenetic response (CCyR) at 12 mo in the intent-to-treat population. Key secondary and exploratory efficacy endpoints included major molecular response (MMR) at 12 mo, time to CCyR and MMR, duration of CCyR and MMR, time to and incidence of transformation to accelerated/blast phase (AP/BP) CML, event-free survival (EFS), and overall survival. Safety analyses included all treated pts. Results:The median treatment duration was 19.3 mo for bosutinib and 19.5 mo for imatinib; 67% and 74% of pts, respectively, are still receiving therapy. The primary reason for discontinuation of bosutinib was toxicity (23%), while the primary reason for discontinuation of imatinib was disease progression (13%). Rates of CCyR and MMR are shown in the table. The rate of cumulative CCyR by 18 mo was 79% in both arms, and the cumulative rate of MMR by 18 mo was 55% in the bosutinib arm versus 45% in the imatinib arm. Median time to CCyR was faster for bosutinib versus imatinib (12.7 vs 24.6 wk); median time to MMR was also faster for bosutinib versus imatinib (36.9 vs 72.3 wk). Transformation to AP/BP CML while on treatment occurred in 4 (2%) pts on bosutinib and 13 (5%) pts on imatinib. On-study deaths from any cause occurred in 6 (2%) pts receiving bosutinib versus 13 (5%) pts receiving imatinib, and included 5 (2%) and 9 (4%) pts, respectively, who died due to CML progression. Median on-treatment EFS and overall survival were not yet reached for either arm. At 18 mo, the Kaplan-Meier estimates of EFS were 95% for bosutinib versus 91% for imatinib, and the estimates of overall survival were 99% versus 95%, respectively. Bosutinib was associated with higher incidences compared with imatinib of gastrointestinal events (diarrhea [69% vs 22%, respectively], vomiting [32% vs 14%], pyrexia [18% vs 10%], and abdominal pain [13% vs 7%]). In contrast, bosutinib was associated with lower incidences of edema (peripheral edema [4% vs 11%] and periorbital edema [1% vs 14%]) and musculoskeletal events (myalgia [5% vs 11%], muscle cramps [4% vs 22%], and bone pain [4% vs 10%]). Fewer pts on bosutinib experienced grade 3/4 laboratory abnormalities of neutropenia (11% vs 24% with imatinib), while the incidences of grade 3/4 anemia and thrombocytopenia were similar between treatment arms (8% with anemia and 14% with thrombocytopenia). Grade 3/4 liver function test abnormalities occurred more frequently with bosutinib versus imatinib (increased alanine aminotransferase [23% vs 4%] and aspartate aminotransferase [12% vs 3%]). Although common with bosutinib, gastrointestinal events and liver function test abnormalities were typically transient, managed with dose modifications, and not life threatening. Conclusions:The study did not meet the primary endpoint (CCyR at 12 mo); early discontinuation of bosutinib due to adverse events may have contributed to this observed lack of difference. However, bosutinib did result in a higher rate of MMR at 12 mo, faster times to MMR and CCyR, fewer events of transformation to AP/BP CML, and fewer overall and CML-related deaths compared with imatinib, suggesting superiority of bosutinib in pts with newly diagnosed CP CML. In addition, the 18-mo estimates for both EFS and OS currently favor bosutinib. Bosutinib and imatinib were each associated with acceptable but distinct toxicity profiles. Based on these results, bosutinib may offer a new therapeutic option for pts with newly diagnosed CP CML. Minimum of 24 mo of follow-up will be presented for all pts.TableResponseBosutinib (n = 248)Imatinib (n = 250)CCyRAt 3 moa50%25%At 6 moa59%49%At 9 mo63%55%At 12 mo70%68%At 18 mo62%67%MMRAt 3 moa7%3%At 6 moa28%11%At 9 moa35%19%At 12 moa41%27%At 18 mo46%38%aStatistically significant (P value <0.05). P values were based on a Cochran-Mantel-Haeszel test stratified by site and geographic region; all time points, with the exception of Month 12, were exploratory. Disclosures:Cortes:Pfizer Inc: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Guilhot:CHU de Poitiers: Employment; Pfizer Inc: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria. Duvillie:Pfizer Inc: Employment. Powell:Pfizer Inc: Employment, Equity Ownership. Countouriotis:Pfizer Inc: Employment. Gambacorti-Passerini:Pfizer Inc: Honoraria, Research Funding; BMS: Research Funding; Novartis: Honoraria; Biodiversity: Honoraria.

Pharmacokinetics of Dasatinib as a First Line Therapy In Newly Diagnosed CML Patients (OPTIM dasatinib trial): Correlation with Safety and Response.

AbstractAbstract 3432 Introduction.Dasatinib 100 mg QD is now validated as a first line option in patients with chronic myelogenous leukaemia in chronic phase (CML in CP). Our hypothesis was that significant adverse events observed with dasatinib including fluid retention, pleural effusions and grade 3–4 cytopenias, may be driven by the level of the residual dosage of dasatinib (Cmin). We initiated an optimization study based on the monitoring of dasatinib plasma levels (Cmin and Cmax) in patients with CML in chronic phase newly diagnosed and treated with dasatinib as front line therapy. Patients and methods.Patients aged 18 years old or more were eligible if they were diagnosed with CML in CP for less than 3 months without having being exposed to tyrosine kinase inhibitors. Dasatinib was initiated at the daily dose of 100 mg QD. Dasatinib daily dose adaptation was randomized in patients with a Cmin over 3nM. For all other patients, dasatinib was given at the dose of 100 mg QD. The pharmacokinetic (PK) evaluation (Cmin and Cmax measurements) was performed after 7 to 10 days of therapy and then every 15 days in the treatment adaptation arm (until a level of Cmin under 3nM) and every 3 months therafter as in the non-adapted arm. Cmax was assessed 2 hours after dasatinib intake. Results.The results of the first 78 patients included in the trial from May 2009 to May 2010 are reported. Median age was 47 years (19 – 77) with a sex ratio M/F of 1.85. The Sokal score distribution was 51.9%, 30.7% and 17.4% for Low, intermediate and high risk respectively. Median Cmin and Cmax values were 2.1 nM (range 0.2–18.7) and 107.6 nM (range 20.5–353) at first PK analysis. The median Cmin value was significantly lower in patients with age <47y compared to patients >47y (1.6 nM versus 2.8 nM, p=0.0028). By contrast, the median Cmax value was comparable in both age groups. Efficacy analysis was performed on the 53 patients with a 3 months follow-up and on the 36 patients with a 6 months follow-up. The complete cytogenetic response (CCR) rates at 3 and 6 months were 83.3% and 90.9% respectively. At 3 and 6 months, the major molecular response (MMR) rates were 15.1% and 69.4%. All patients in cytogenetic failure had high Sokal score values (p=0.023). Median PK values at months 3 and 6 were not statistically different compared to initial PK values, suggesting a stable exposure to the treatment with time. With a median follow-up of 7.2 months, the rate of significant adverse events was 11.5%. Fluid retention (n=2) and pleural effusion (n=1) were observed in patients with high Cmin values (mean 3.7 nM). A trend was observed between the Cmax and response at month 3 (CCR, p=0.05 and MMR, p=0.08). Patients with lymphocytosis may have a higher MMR rate (p=0.07). Conclusion.Dasatinib 100 mg QD as first line therapy in CP CML provided a high rate of MMR and CCR rates. Pharmacokinetic parameters of dasatinib were different in aged patients. A trend was observed first between Cmax and responses and second between Cmin and fluid retention or pleural effusion. A complete analysis with correlation to response and safety will be presented on more patients with 6 and 12 months follow-up. Disclosures:Rousselot:Bristol Myers Squibb: Research Funding. Off Label Use: Dasatinib as first line therapy for CML.

High-dose imatinib improves cytogenetic and molecular remissions in patients with pretreated Philadelphia-positive, BCR-ABL-positive chronic phase chronic myeloid leukemia: first results from the randomized CELSG phase III CML 11 "ISTAHIT" study

Imatinib 400 mg/day is the standard treatment for patients with chronic phase chronic myeloid leukemia. Recent reports suggested higher and more rapid cytogenetic and molecular responses with higher doses of imatinib. In this prospective international, multicenter phase III study, 227 patients with pre-treated Philadelphia chromosome-positive, BCR-ABL-positive chronic myeloid leukemia were randomized to a standard-dose imatinib arm (400 mg/day) or a high-dose imatinib arm (800 mg/day for 6 months followed by 400 mg/day as maintenance therapy). In this planned interim analysis hematologic, cytogenetic and molecular responses as well as toxicity were evaluated. Compared to the standard-dose, high-dose imatinib led to higher rates of major and complete cytogenetic responses at both 3 months (major: 21% versus 37%, P=0.01; complete: 6% versus 25%, P<0.001) and 6 months (major: 34% versus 54%, P=0.009; complete: 20% versus 44%, P<0.001). This was paralleled by a significantly higher major molecular response rate at 6 months in the high-dose imatinib arm (11.8% versus 30.4%; P=0.003). At 12 months, the rates of major cytogenetic response (the primary end-point) were comparable between the two arms (57% versus 59%). In contrast to non-hematologic toxicities, grade 3/4 hematologic toxicities were more common in the high-dose arm. Cumulative complete cytogenetic response rates were higher in patients without dose reduction in the high-dose arm (61%) than in the patients with no dose reduction in the standard-dose arm (36%) (P=0.014). This is the first randomized phase III trial in patients with pre-treated chronic phase chronic myeloid leukemia demonstrating improvements in major cytogenetic response, complete cytogenetic response and major molecular response rates with high-dose imatinib therapy (ClinicalTrials.gov Identifier: NCT00327262).

Phase III, Randomized, Open-Label Study of Daily Imatinib Mesylate 400 mg Versus 800 mg in Patients With Newly Diagnosed, Previously Untreated Chronic Myeloid Leukemia in Chronic Phase Using Molecular End Points: Tyrosine Kinase Inhibitor Optimization and Selectivity Study

To evaluate the safety and efficacy of initial treatment with imatinib mesylate 800 mg/d (400 mg twice daily) versus 400 mg/d in patients with newly diagnosed chronic myeloid leukemia in chronic phase. A total of 476 patients were randomly assigned 2:1 to imatinib 800 mg (n = 319) or 400 mg (n = 157) daily. The primary end point was the major molecular response (MMR) rate at 12 months. At 12 months, differences in MMR and complete cytogenetic response (CCyR) rates were not statistically significant (MMR, 46% v 40%; P = .2035; CCyR, 70% v 66%; P = .3470). However, MMR occurred faster among patients randomly assigned to imatinib 800 mg/d, who had higher rates of MMR at 3 and 6 months compared with those in the imatinib 400-mg/d arm (P = .0035 by log-rank test). CCyR also occurred faster in the 800-mg/d arm (CCyR at 6 months, 57% v 45%; P = .0146). The most common adverse events were edema, gastrointestinal problems, and rash, and all were more common in patients in the 800-mg/d arm. Grades 3 to 4 hematologic toxicity also occurred more frequently in patients receiving imatinib 800 mg/d. MMR rates at 1 year were similar with imatinib 800 mg/d and 400 mg/d, but MMR and CCyR occurred earlier in patients treated with 800 mg/d. Continued follow-up is needed to determine the clinical significance of earlier responses on high-dose imatinib.