Major Molecular Response Rates Research Articles

The Strategy of Early Nilotinib Switch Based on Failure to Achieve Optimal Molecular Targets on Imatinib May Not Overcome the Negative Impact of a Low OCT-1 Activity in De-Novo CP-CML Patients

Abstract 1690 Background:We have previously identified that low OCT-1 activity (OA) is a poor prognostic indicator in CP-CML patients treated with imatinib (IM). Importantly, a very low OA (OA≤4ng/200,000 cells) is associated with a significant risk of poor molecular response, kinase domain mutations and transformation. The TIDEL II strategy of early intervention, via dose escalation and/or switch to nilotinib (NIL) may reduce the incidence of poor response/therapeutic failure in CP-CML patients, particularly those with very low OA. Methods:Patients in Cohort I (n=105) of the TIDEL II trial were switched to NIL for either IM intolerance, or failure to demonstrate a clinical benefit from IM dose escalation which was triggered by failure to achieve time dependent molecular targets: ≤10% BCR-ABL by 3 m, ≤1% BCR-ABL by 6 m or ≤0.1% BCR-ABL by 12 m. In Cohort II (n=105) patients failing to achieve these molecular targets were switched directly to NIL without prior IM dose intensification. All patients, where possible, had OA measured at diagnosis. Only therapeutic changes prior to 24 months, and patients with a minimum of 6 months exposure to NIL are considered in this analysis. Results:(Table 1) Cohort I: Median follow-up 30 months. The overall rate of major molecular response (MMR) by 12 months was 66%. There was a significant difference in the rate of MMR between patients with low OA (n=49) compared to those with higher OA (n= 54): 49% vs 76%, p=0.007. The overall rate of MMR by 24 months was 81%. Again, patients with low OA (n=46) achieved MMR at a significantly lower rate compared to those with higher OA (n=54): 65% vs 91%, p= 0.003. Thirty patients have switched to NIL, 19/30 because of IM intolerance (av. time on IM 8.5m.) and 11/30 because of molecular target failure (av. time on IM 12.8m). 14/14 intolerant patients not in MMR at the time of switch have achieved MMR on NIL with an average log reduction of 2.8, and 9/18 have achieved CMR. In contrast, 1/9 patients switched for molecular target failure has achieved MMR on NIL, with an average log reduction of 0.65. Importantly, 3/19 withdrew from study due to CML related events.Table 1:Comparison of the parameters associated with NIL switch.Ave time (m) on IM (range)Ave time (m) on NIL (range)Ave log reduction on NILOA median (sd)Cohort 1Intol (n=18)8.5 (3–16.4)15 (6–21)2.85.1 (2.57)Target failure (n=11)12.8 (3.6–17.7)9 (6–21)0.652.5 (1.41)P value0.0280.203<0.0010.007Cohort IIIntol (n=11)4.4 (2–7.3)*9 (6–12)*2.89π5.3π (2.37)Target failure (n=11)5.1 (2.1–11.8)*9 (6–12)π0.95π2.8π (1.81)P value0.5110.6490.0070.003p values within each cohort are as shown. p values between cohort 1 and 2 are indicated with symbols:*p<0.01:πp>0.05.Cohort II: Median follow-up 12 months. To date, 22/105 patients have switched to NIL and have a minimum of 6 months follow-up: 11 for intolerance and 11 for molecular target failure. All patients switched for intolerance achieved and/or maintained MMR on nilotinib, with an average log reduction of 2.89. In contrast, 1/11 patients switched for molecular target failure achieved MMR, with an average log reduction of 0.95 and CCyR has been achieved in 5/10 patients not previously in CCyR. 2/11 of these patients have withdrawn from study.There was a significant difference in the time of switch to NIL, and the length of imatinib exposure between the 2 cohorts for intolerance, and a significant difference between the cohorts in the length of IM exposure for patients with target failure. However, this did not translate to a significant difference in molecular response between the 2 cohorts, suggesting the length of prior IM exposure is not a determinant of subsequent NIL response.Importantly in both cohorts, the OA of those patients switched to NIL based on molecular target failure was significantly lower than that of those who switched for intolerance (p=0.007 and p=0.003) and those patients remaining on IM (p=0.004). Conclusion:Switch to NIL significantly improves response in IM intolerant patients. The majority of patients who switch for molecular target failure on IM do not subsequently achieve MMR on NIL. This suggests that a low OA may delineate a group of CP-CML patients intrinsically insensitive to TKI therapy, for whom switch to NIL either following IM dose intensification (Cohort 1) or as a primary strategy (Cohort II) may not result in an improvement in response. A different first-line strategy may be more effective for this poor risk subgroup. Disclosures:White:Novartis Pharmaceuticals: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Slader:Novartis Pharmaceuticals: Employment, Equity Ownership. Yeung:Novartis Pharmaceuticals: Research Funding; BMS Oncology: Research Funding. Osborn:Novartis Pharmaceuticals: Research Funding; BMS Oncology: Research Funding. Mills:Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Sponsorship to professional meetings; BMS Oncology:. Hughes:Novartis: 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; ARIAD: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Nilotinib Shows Safety and Efficacy in Older Patients (≥ 65 years) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase Comparable with That in Younger Patients with Chronic Myeloid Leukemia in Chronic Phase: Results From ENESTnd,

Abstract 3768 Background: Data from the phase 3, randomized multicenter ENESTnd trial have demonstrated the superiority of nilotinib over imatinib after 24 months (mo) of follow-up, with significantly higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR), and significantly lower rates of progression to accelerated phase/blast crisis (AP/BC). The current subanalysis evaluated the efficacy and safety of nilotinib 300 mg twice daily (Nil300) and nilotinib 400 mg twice daily (Nil400) in older (≥ 65 years [yrs] at study entry) patients (pts) with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) with a minimum follow-up of 24 mo. Methods: In ENESTnd, 846 pts stratified by Sokal risk score were randomized 1:1:1 to Nil300 (n = 282), Nil400 (n = 281), or imatinib 400 mg once daily (n = 283). Pts with impaired cardiac function or ECOG performance status > 2 were excluded. Rates of CCyR and MMR by 24 mo, progression to AP/BC on treatment, and safety were evaluated according to age group ( 60 msec from baseline in older pts and 3 in nilotinib-treated pts 500 msec did not occur in any pt treated with nilotinib on study. Periodic echocardiograms were done, and there were no decreases of > 15% in left ventricular ejection fraction from baseline in any pt treated with nilotinib on study. There were 4 cases of ischemic heart disease reported in older pts (1/35 [3%] on Nil300; 3/25 [12%] on Nil400) and 7 cases in pts Disclosures: Larson:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Bunworasate:Novartis Pharmaceutical: Research Funding. Turkina:Novartis: Consultancy, Honoraria; BMS: Honoraria. Goldberg:Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding. Dorlhiac-Llacer:Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding. Saglio:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis Pharmaceutical: Consultancy, Speakers Bureau; Pfizer: Consultancy. Hochhaus:Ariad: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Yu:Novartis: Employment, Equity Ownership. Gallagher:Novartis: Employment, Equity Ownership. Clark:Bristol Myers Squibb: Honoraria, Research Funding; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau. Hughes:Bristol Myers Squibb: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity9s Board of Directors or advisory committees.

Impact of Dose Reductions and Interruptions Due to Adverse Events (AEs) on Efficacy in Newly Diagnosed Chronic Myeloid Leukemia in ChronicPhase (CML-CP) Patients (pts) Receiving Either Dasatinib (D) or Imatinib(IM): Analysis of the DASISION Trial

Abstract 2768 Background:24-month follow-up of pts with newly diagnosed CML-CP in the DASISION trial demonstrated both a high rate of complete cytogenetic response (CCyR) with dasatinib (D) and higher and faster rates of major molecular response (MMR) with D over imatinib (IM), supporting the use of D 100 mg once daily as a first-line treatment option for newly diagnosed CML-CP. Discontinuations due to adverse events (AEs) occurred in 7% with D and 5% with IM. Median dose intensity for D and IM were 99.5 mg/day and 400 mg/day, respectively (Kantarjian JCO 2011:29;Abs 6510). A retrospective analysis of pts from DASISION was performed to evaluate the impact of dose reductions and interruptions due to AEs on efficacy of D or IM in newly diagnosed CML-CP. Methods:Pts with newly diagnosed CML-CP received D 100 mg QD (N=258) or IM 400 mg QD (N=258). The primary endpoint was confirmed CCyR by 12 months. In DASISION, up to two dose reductions were permitted for AEs; dose reduction levels were 80 mg/50 mg for D and 300 mg/200 mg for IM. Dose interruptions were permitted for management of AEs. Upon resolution or improvement of AEs to ≤ Grade 1, pts could resume therapy at an appropriate dose based on initial severity of the AE. Efficacy was evaluated for pts with or without dose reductions and/or interruptions due to AEs at any time. Efficacy was also evaluated for pts with first dose interruption and/or reduction due to AEs within ≤6 or >6 months of their first dose who remained on treatment for at least 6 months, in order to reduce selection bias of pts with longer duration of therapy. Pts with dose reduction and/or interruption for reasons other than AEs (dosing error, medical procedure) were excluded from all analyses. Results:134 D pts (52%) and 92 IM pts (36%) had dose reduction and/or interruption for AE management at the DASISION 24-month update. First dose reduction and/or interruption due to non-hematologic AEs occurred in 59 (23%) D and 40 (16%) IM pts and hematologic AEs in 75 (29%) D and 52 (20%) IM pts. Pts with dose reduction and/or interruption for reasons other than AE management were excluded, including 21 (8%) D pts and 19 (7%) IM pts. The median duration of first dose interruption due to AEs was approximately 2 weeks on both arms. CCyR and MMR rates with D were comparable whether pts did or did not have their dose reduced and/or interrupted at any time (Table). D pts who had dose reduction and/or interruption had generally higher rates of responses than IM pts overall and in those without an IM dose reduction and/or interruption. The timing of dose reduction and/or interruption appeared to have a potential impact as response rates were higher when dose reduction and/or interruption occurred >6 months after the first dose of either drug (Table). CCyR and MMR rates with D remained higher than with IM when dose reduction and/or interruption occurred ≤6 months from first dose. Similarly, both CCyR and MMR were higher for D than with IM if dose reduction and/or interruption occurred >6 months from the first dose. Conclusions:Results of this analysis suggest that CML-CP pts receiving dasatinib achieved similar response rates despite dose modification for the management of AEs. Data for pts with and without dose reduction and/or interruption due to AEs are consistent with DASISION 24-months results, showing higher rates of response with dasatinib than with imatinib.All TreatedNo Dose R and/or IDose R and/or I due to AEaD N=258IM N=258D n=103IM n=147D n=134IM n=92CCyR by 12 mo221 (86%)191 (74%)89 (86%)111 (76%)107 (80%)59 (64%)CCyR by 24 mo223 (86%)213 (83%)90 (87%)126 (86%)112 (84%)69 (75%)MMR by 12 mo119 (47%)73 (28%)50 (49%)43 (29%)55 (41%)21 (23%)MMR by 24 mo165 (64%)120 (47%)71 (69%)66 (45%)76 (57%)41 (45%)2-year PFS94%92%94%90%93%93%2-year OSc95%95%97%93%94%98%R and/or I due to AE ≤6 Months After 1st DosebR and/or I due to AE >6 Months After 1st DoseD n=90IM n=61D n=34IM n=24CCyR by 12 mo76 (84%)39 (64%)29 (85%)18 (75%)CCyR by 24 mo80 (89%)47 (77%)30 (88%)20 (83%)MMR by 12 mo35 (39%)14 (23%)20 (59%)7 (29%)MMR by 24 mo53 (59%)26 (43%)23 (68%)15 (63%)2-year PFS96%96%93%90%2-year OSc98%98%97%100%AE = adverse event; I = interruption; R = reductionaPatients with dose R and/or I due to reasons other than AEs were excluded (21 D, 19 IM)bPatients on treatment ≤6 months were excluded (10 D, 7 IM)cSurvival data remain immature; all patients will be followed for 5 years Disclosures:Kantarjian:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Quintas-Cardama:Bristol-Myers Squibb: Honoraria. Guilhot:Novartis: Honoraria; Bristol-Myers Squib: Honoraria; Pfizer: Honoraria; Celgene: Honoraria. Zhu:Bristol-Myers Squibb: Employment. Hong:Bristol-Myers Squibb: Employment, Equity Ownership. Cain:Bristol-Myers Squibb: Employment, Equity Ownership. Cortes:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

Efficacy of Nilotinib Versus High-Dose Imatinib in Early Chronic Phase CML Patients Who Have Suboptimal Molecular Responses to Standard-Dose Imatinib (RE-NICE Multicenter Study)

Abstract 2765In CML, achievement of major molecular response (MMR) is a significant prognostic factor as it has been shown to be associated with longer duration of complete cytogenetic response (CCyR) and long-term progression-free survival. In IRIS study, patients who achieved both CCyR and MMR showed higher progression-free survival rates, compared to those who had CCyR without MMR. Higher doses of imatinib are expected to yield higher CCyR and MMR rates, compared to standard dose of imatinib, and second-generation tyrosine kinase inhibitor, nilotinib also produces high CCyR and MMR rates in patients with CP CML who are resistant to imatinib. In this prospective study, the efficacy of nilotinib and high-dose imatinib was investigated in suboptimal molecular responders who received standard-dose imatinib as first-line therapy. Early CP CML patients who have achieved CCyR but no MMR after at least 18 months and up to 24 months (≥ 18 to ≤ 24 months) on first-line imatinib therapy at a daily dose of 400 mg were enrolled in this clinical trial, and informed consents were obtained from all patients prior to participation. In nilotinib arm, patients received oral dose of 400 mg BID (800 mg/day), and patients received 800 mg/day administrated as 400 mg BID in imatinib dose-escalation arm. To assess the drug efficacy, cytogenetics and RQ-PCR analysis were performed at regular intervals, and baseline mutational analysis was conducted for every patient with subsequent mutational analyses performed in patients demonstrating either lack of response or disease progression. Primary endpoint is to evaluate the cumulative MMR rates by 12 months, and secondary endpoints are to evaluate the cumulative CMR rates and time to and duration of MMR and CMR during further 24 month follow-up. Progression-free survival and safety profiles will also be assessed as secondary endpoints. Patients showing lack of response (lack of complete hematologic response (CHR) at 6 months, increasing WBC, no major cytogenetic response (MCyR) at 24 months), loss of response (loss of CHR or MCyR) or severe intolerance to treatment were allowed to crossover to the alternative treatment arm. With a data cut-off date of 18 Jul 2011, a total of 30 patients were randomized into nilotinib arm (n =13) or imatinib arm (n = 17), and 6 patients have crossed-over to nilotinib arm due to lack of response. With a median follow-up of 11 months (range, 0.2–28 mos), all patients have maintained CCyR without progression to advanced disease, and progressive decrease in BCR-ABL transcript levels was observed in all patients. Cumulative MMR rates at 20 months were significantly higher in nilotinib arm compared to imatinib dose-escalation arm (59.00% vs. 27.40%, P = 0.047), and patients treated with nilotinib also showed faster molecular response rates, with 5 patients achieving MMR within 3 months of nilotinib therapy. At the last follow-up, 7/13 (53.85%) and 2/11 (18.18%) patients achieved MMR in nilotinib arm and in high-dose imatinib arm, respectively, with 1 patient in nilotinib arm achieving 4-log reduction of BCR-ABL transcripts. Although toxicity was observed more frequently in imatinib dose-escalation arm, all patients currently maintain the initial dose (except 1 patient who interrupted imatinib therapy due to neurosurgical operation), and based on the toxicity data, no additional or serious adverse events were developed except for pre-existing toxicities before randomization. These preliminary results demonstrate that early intervention using nilotinib or dose escalation of imatinib could be recommended in suboptimal molecular responders, with nilotinib being more preferable. Through further clinical investigation on a large patient population and longer period of observation, efficacy and safety of early intervention of suboptimal molecular response using nilotinib or dose escalation of imatinib will be assessed. Updated data with longer follow-up duration will be presented in the meeting. Disclosures:Woodman:Novartis: Employment, Equity Ownership. Szczudlo:Novartis: Employment, Equity Ownership. Kim:Novartis: Employment.

Multidrug Resistance Gene (MDR1) C3435T Polymorphism and Imatinib Response in Patients with Chronic Myeloid Leukemia

Abstract 1692 Background:There has been a remarkable improvement in the management of chronic myeloid leukemia (CML) after imatinib mesylate (IM) became available in the market, but there is still a group of patients who are resistant to imatinib. Although point mutations in the BCR-ABL kinase domain is the most common mechanism for resistance in patients with CML receiving tyrosine kinase inhibitor (TKI) therapy, there are several mechanisms that can play a role in the resistance to TKIs. Multi drug resistance gene (MDR1) [ABCB1 (ATP-binding cassette, sub-family B (MDR/TAP), member 1) ] product is an ATP-driven efflux pump contributing to the pharmacokinetics of drugs that are P-glycoprotein (P-gp) substrates and to the multidrug resistance of cancer cells. More than 50 single nucleotide polymorphisms (SNPs) have been identified concerning the MDR1 gene, and SNP polymorphisms may affect the expression and function of the P-gp. The SNPs T1236C, G2677T/A, and C3435T are the most common variants in the coding region of ABCB1. Imatinib is a substrate of P-gp-mediated efflux, and P-gp mediated drug efflux can play a role in IM resistance. So identifying these SNPs may allow to predict the drug disposition and responses to IM in CML patients. The aim of the study was to identify the C3435T SNP variants, and the associations between MDR1 C3435T polymorphism and IM efficacy in our CML patients. Methods:Between December 2010 and March 2011, 110 chronic phase (CP) CML patients who consecutively visited our outpatient clinic were enrolled in this study. Hematologic, cytogenetic and molecular response patterns to IM as well as the association between MDR1 C3435T polymorphism and responses to imatinib were evaluated in our patient cohort. MDR1 C3435T polymorphisms were detected by real-time polymerase chain reaction (RT-PCR). We could assess complete cytogenetic response (CCyR) and major molecular response (MMR) in one hundred and six patients (96%) among these 110 patients. The differences in genotype frequencies in all patients taking imatinib treatment was determined by using the chi-square test. All tests were two-sided, and p <0.05 was considered as statistical significant. This study was approved by the local research ethics committee, and written informed consent was obtained from the patients. Results:59 patients were male (54%), and fifty-one were female (46%). Median age was 50.5 years (range, 19–84 years). 37.6% of the patients were low, 45% were intermediate, and 17.4% were high risk according to Sokal risk score. The CCyR rate was 71%, and MMR rate was 60%. The frequencies of MDR1 3435 CC, CT, and TT genotypes were 22.5%, 55%, and 22.5%, respectively. No statistically significant difference was observed between the frequencies of the genotypes according to gender. The CCyR rates in patients with CC, CT, and TT genotypes were 88%, 62%, and 75%, respectively (Figure 1). The patients with CC genotype had significantly higher CCyR rates when compared to patients having CT/TT and CT genotypes (p =0.04 and p =0.023, respectively) (Table 1). The patients with CC, CT, and TT genotypes did not differ significantly between each other regarding the MMR rates. There were no significant difference between the C3435T genotypes and second generation TKI usage regarding both CCyR and MMR. [Display omitted] [Display omitted] Conclusion:Before starting IM therapy, the individual patientÕs MDR1 gene polymorphism pattern can be important in determining the treatment strategy in patients with CML. Among our patient cohort, the patients with CC genotype had significantly higher CCyR rates than patients with CT/TT and CT genotypes. Up to now, there are a few studies in CML patients with different results regarding MDR1 gene polymorphisms, and since racial differences can be seen in the frequencies of MDR1 gene polymorphisms, further studies in larger series are needed to define the genetic polymorphisms with therapeutic relevance in patients on imatinib. Disclosure:This study was supported by Istanbul University Research Fund. Disclosures:No relevant conflicts of interest to declare.

EUTOS Score Is Not Predictive for Survival and Outcome in Patients (pts) with Chronic Myeloid Leukemia in Early Chronic Phase (CML-CP) Treated with Tyrosine Kinase Inhibitors (TKIs) At MD Anderson Cancer Center (MDACC),

Abstract 3769 Background:Until recently, prognosis of pts with CML treated with TKI was based on scores developed in the chemotherapy and interferon era. Hasford and colleagues [Blood. 2011;(118):686–692] have identified the EUTOS score, using the percentage of basophils and spleen size, as a significant tool to predict the probability of achieving 18-month complete cytogenetic response (CCyR) and progression-free survival in patients treated with imatinib. Aims:To validate the EUTOS score in an independent MDACC cohort of pts, with early CML-CP treated with standard-dose imatinib, high-dose imatinib, dasatinib, and nilotinib, and its ability to predict transformation-free survival (TFS), event-free survival (EFS) and overall survival (OS). Methods:465 consecutive pts with newly diagnosed CML–CP (0 – 6 months from diagnosis to TKI treatment) were treated with imatinib 400 mg daily (n=71), imatinib 800 mg daily (n=208), and 2nd TKIs (n=186; dasatinib n=88, nilotinib n=98) in sequential phase II trials. Entry criteria were similar for all trials. EUTOS score = (7 x basophils %) + (4 x spleen cm BCM). A EUTOS score of >87 indicates high-risk and ≤87 low-risk. Results:465 pts with CML-CP were assessed. Median age was 47 years (range, 15–85). Median time from diagnosis to TKI therapy was 1 month (range, 0 to 6). 319 (69%), 112 (24%), and 34 (7%) pts were in low, intermediate, and high-Sokal score category, respectively. Median basophils percentage at baseline was 3 (range, 0 to 19). Median splenomegaly size was 0 cm (range, 0 to 30). 118 pts (25%) received previous cytoreduction therapy. Median follow-up was 117 months (range, 16 to 130) for pts receiving standard-dose imatinib, 88 months (range, 4 to 118) for those receiving high-dose imatinib, and 30 months (range, 3 to 69) for those receiving 2nd TKI. The overall CCyR rates were 87%, 91%, and 95%, respectively. The 4-year EFS, TFS, and OS rates for the whole group were 84%, 94%, and 95%, respectively. Overall, of the 465 pts, 427 (92%) were in low EUTOS score category (Table 1). Pts with low EUTOS score had higher rates of CCyR at anytime compared to pts with high EUTOS score (93% versus 81%, p=0.02). This difference was mainly significant among pts receiving 2nd TKI (p=0.03) while it was not different among pts receiving imatinib (p=0.27). There was no difference in the rates of major molecular response (85% versus 81%, p=0.48) between pts with low and high EUTOS score. There was no difference in TFS, EFS, and OS rates between pts with low and high EUTOS score, overall and among specific therapy (Table 1). Conclusion:Eight percent of pts with CML-CP treated at MDACC are of high EUTOS score. In this population, the EUTOS score was not predictive for overall MMR, TFS, EFS, and OS.ParameterOverallLow EUTOS scoreHigh EUTOS scorep-valueN=465427 (92%)38 (8%)CCyR (%)Overall (evaluable=454)9293810.02 Imatinib9091820.27 400 mg87861001.0 800 mg9192790.082nd TKI9596800.03MMR (%)Overall (evaluable=452)8585810.48 Imatinib8485820.76 400 mg78771001.0 800 mg8687790.302nd TKI8686800.464-year EFS (%)Overall8484810.71 Imatinib8182720.20 400 mg7880500.34 800 mg8283760.292nd TKI89881000.164-year TFS (%)Overall9494970.51 Imatinib9393940.33 400 mg8990670.47 800 mg94931000.462nd TKI97971000.534-year OS (%)Overall95951000.88 Imatinib94941000.75 400 mg93921000.34 800 mg95941000.322nd TKI99991000.64 Disclosures:Cortes:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

The Incidence of Bcr-Abl Mutations and Their Impact on Clinical Outcome in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia Patients Treated with Bosutinib Versus Imatinib in the BELA Trial

Abstract 2769In the phase 3 BELA study, bosutinib was associated with superior rates of major molecular response (MMR) at 12 months, faster times to MMR and complete cytogenetic response (CCyR), fewer on-treatment events of transformation to accelerated/blast phase CML, and fewer overall deaths on study when compared with imatinib; each agent was associated with an acceptable but distinct safety profile. However, clinical resistance to TKIs commonly results from development of Bcr-Abl mutations. Therefore, we investigated the incidence of Bcr-Abl mutations and their impact on clinical outcome in the BELA trial.Newly diagnosed patients (pts) with CP CML were randomized to bosutinib 500 mg/day (n = 250) or imatinib 400 mg/day (n = 252). Direct sequencing of Bcr-Abl kinase domain (10%-20% sensitivity) in a central laboratory was employed at baseline (bosutinib, n = 237; imatinib, n = 241) as well as at treatment discontinuation (bosutinib, n = 62; imatinib, n = 49).The median age was 48 years (range, 19–91 years) in the bosutinib arm and 47 years (range, 18–89 years) in the imatinib arm. Based on a minimum of 18 months from the last pt randomized, median treatment duration was 22.0 months for both treatment arms; 33% (n = 81) of pts in the bosutinib arm and 26% (n = 66) of pts in the imatinib arm have discontinued treatment. The primary reason for discontinuation of bosutinib was treatment-related toxicity (22% vs 6% with imatinib), while the primary reason for discontinuation of imatinib was disease progression (13% vs 4% with bosutinib); all other reasons for discontinuation were reported for ≤3% of pts in either arm.At baseline, already present Bcr-Abl polymorphisms were equally distributed among the 2 arms (bosutinib, n = 24; imatinib, n = 17). The most common baseline polymorphisms were E499E (bosutinib, n = 18; imatinib, n = 10), 499E/E or 499E/E variant (bosutinib, n = 3; imatinib, n = 1), and T83T (bosutinib, n = 0; imatinib, n = 4); additional polymorphisms detected in at least one of the treatment arms included E197K, K247R, T240T, and Y320C.As of the database snapshot, 81 pts had discontinued treatment in the BOS arm compared with 66 pts in the IM arm, of which 62 (77%) pts in the BOS arm and 49 (74%) pts in the IM arm had a sample collected at treatment discontinuation. Of these, 37/62 (60%) pts in the BOS arm did not have a detectable mutation and 28/49 (57%) pts in the IM arm did not have a detectable mutation.Four (6%) pts had a detectable mutation in the BOS arm (T315I [n = 2], E255K, and V299L [n = 1 each]) compared with 10 (21%) pts in the IM arm (G250E [n = 2], M244V [n = 2], Q252H, Y253H, E255K, M244V/M351T, D276G/H396R, and D276G/T277A/T315I [n = 1 each]) at the time of treatment discontinuation. In the BOS arm, 1 pt with the V299L mutation achieved CCyR (time to CCyR of 254 days). In the IM arm, 1 pt with the G250E mutation achieved both CCyR and MMR (time to response of 252 days for both) and 2 pts with the M244V and D276G/T277A/T315I mutations achieved CCyR (times to CCyR of 254 and 340 days, respectively). Treatment failure was experienced by 2/4 pts in the BOS arm with a mutation (E255K and T315I) compared with 7/10 pts in the IM arm (M244V [n = 2], G250E, Q252H, Y253H, M244V/M351T, and D276G/H396R). An on-treatment event of transformation to accelerated/blast phase CML was experienced by 2/4 pts in the BOS arm (E255K and T315I) versus 5/10 pts in the IM arm (G250E, Q252H, Y253H, M244V/M351T, and D276G/H396R). Among pts with a new mutation detected at treatment completion, 2 deaths were reported in each treatment arm; all 4 deaths occurred after discontinuation of study treatment.In conclusion, baseline and emergent Bcr-Abl kinase domain mutations were detected in both treatment arms, with polymorphisms at the E499 position the most common. In this analysis, imatinib was associated with a higher rate of progressive disease compared with bosutinib among pts with new mutations at treatment discontinuation; a similar trend has been observed in the overall study population. Additional follow-up will allow for more complete mutational analysis. Disclosures:Kim:Pfizer Inc: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding. Cortes:Pfizer Inc: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Wong:Pfizer Inc: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; GSK: Research Funding; Bayer: Honoraria, Research Funding; Sanofi: Research Funding; Biogen Idec: Honoraria, Research Funding; Roche: Research Funding; Leo Pharma: Honoraria. Duvillie:Pfizer Inc: Employment. Powell:Pfizer Inc: Employment, Equity Ownership. Countouriotis:Pfizer Inc: Employment. Brümmendorf:Pfizer Inc: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; BMS: Consultancy, Honoraria.

Clinical or Sub-Clinical Pancreatitis (PA) Associated with Nilotinib (Nb) As Frontline for Chronic Myelogenous Leukemia (CML)

Abstract 4443 Background:Nilotinib is now standard therapy in chronic phase (CP) CML, both as initial therapy and after imatinib failure. One of the adverse effects of nilotinib is the increase in serum amylase and/or lipase levels with or without clinical pancreatitis.The mechanism by which nilotinib increases serum pancreatic enzymes is not clear. Nilotinib is able to inhibit the non-receptor tyrosine kinase c-abl with high affinity. It is possible that c-abl inhibition might interfere with the molecular mechanisms regulating pancreatic cell death, inducing pancreatic damage. Nilotinib may release calcium from the intracellular acinar stores which regulate exocrine pancreatic secretion, or it may promote the accumulation of fatty acid inside the pancreatic acinar cells which disturbs exocytose. (JOP. J Pancreas (Online) 2010 May 5; 291–293). Purpose:To understand the frequency, risk factors and management strategy for patients who develop pancreatitis (clinical or subclinical) during nilotininb frontline therapy for CML. Method:We reviewed the records of 105 CML patients treated at our institution on a clinical trial from 7/2005 to 7/2011 with nilotinib 400 mg twice daily as initial therapy for CML in chronic phase. Results:The median age for the total population was 52 yrs (range, 17 to 89), and 63 were males (60%). Thirteen (12%) pts experienced pancreatitis at least once, most frequently asymptomatic (ie, grade 1). Pancreatitis episodes occurred 28 times (2 episodes were grade 3, 2 episodes were grade 4, 10 episodes were grade 2, and 14 episodes were grade 1). Thirteen episodes (47%) occurred at a dose of 200 mg daily, 4 (14%) at 400 mg daily, and 11 (39%) at 800 mg daily. In 3 instances total bilirubin was also elevated (2 grade 2 and 1 grade 4). One patient experienced recurrent elevations (16 episodes) of lipase and amylase despite dose reduction to 200mg once daily. Concurrent use of hydrochlorothiazide and moderate alcoholic intake were identified as risk factors associated with pancreatitis in the patient who experienced recurrent episodes. Diabetes was identified as a risk factor for pancreatitis in other 4 pts. Twenty four episodes (86%) were characterized by an elevation of lipase and amylase without any clinical symptoms. In four instances, patients experienced a moderate abdominal pain without other symptoms of pancreatitis. In 3 instances, imaging (ultrasound and/or CT scan) demonstrated normal pancreases. Management of pancreatitis included transient nilotinib interruption in most instances. In most patients, lipase and amylase values returned to normal within 14 days of stopping nilotinib. Three patients eventually required change from nilotinib to other tyrosine kinase inhibitors (TKI) (imatinib 2, dasatinib 1) without recurrence of pancreatitis. One of these pts switched to imatinib because of recurrent pancreatitis and the other 2 were switched because of nilotinib toxicities (liver and cardiac toxicity). At the time of pancreatitis episodes, 54% had achieved complete cytogenetic response (CCyR), and 8% complete molecular response (CMR). Rates of (CCyR) were 92% and 94% in patients who experienced and who did not experience pancreatitis, respectively. Rates of major molecular response (MMR) were 100%and 87% in patients who experienced and who did not experience pancreatitis, respectively. Rates of complete hematologic response (CHR) were 100% and 98% in patients who experienced and who did not experience pancreatitis, respectively. The 3-year event-free survival (EFS), treatment- free survival (TFS), and overall survival (OS) rates were 100% in patients who experienced and 93%, 97%, and 100% in patients who did not experience pancreatitis, respectively. Conclusion:Pancreatitis associated with nilotinib is most frequently grade 1 and 2 (asymptomatic enzyme elevation). Close monitoring and timely intervention may allow patients to continue therapy and achieve the desired clinical benefit. Rarely, pancreatitis may require treatment discontinuation. Disclosures:Cortes:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Deciphera: Research Funding.

Efficacy and Safety of Dasatinib in Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) with Imatinib Resistance or Intolerance

Abstract 4444 Background:Dasatinib is highly potent BCR-ABL inhibitor, with 325-fold higher potency than imatinib and a 16-fold higher potency than nilotinib in vitro. Across a series of phase II and III trials with more than 2 years of follow-up, dasatinib has demonstrated durable efficacy in patients with CML following resistance or intolerance to imatinib. We conducted a phase II study to evaluate the efficacy and safety of dasatinib in patients with imatinib resistance or intolerance in the Japanese population. Methods:54 CML- CP patients (median age 63.5 years) with resistance, intolerance or a suboptimal response to imatinib were submitted to dasatinib 100mg once daily. Efficacy and safety were assessed using rates of major molecular response (MMR)/ complete molecular response (CMR) or drug-related adverse events (AEs) respectively. All analyses were based on the intension-treat principle. Results:Until now, the results of 32 patients, who passed more than 12 months, have been analysed. The median time since of prior imatinib therapy was 19.2 months with 57.4 % being imatinib-resistant and 42.6 % imatinib-intolerant. The incidence of MMR (primary endopoint) and complete molecular response at 12 months was 59.3 % (95% confidence interval, 45.0 – 72.4 %), and 24.1 % patients, respectively. Progression to the accelerated or blastic phase had not been observed. All patients with baseline samples tested for mutations, and different mutations were not observed. Non-hematological AEs were mostly grade 1/2. Grade 3/4 non-hematological AEs were infrequent, including increased AST (1.9%), and increased creatinine (1.9%), respectively. Grade 1/2 fluid retention adverse events were shown in 10 patients, including 2 patients with edema, and 9 patients with pleural effusion. Grade 3/4 hematological toxicities including anemia (1.9%), neutropenia (14.8%), and thrombocytopenia (9.3 %) were shown, and 13 patients have permanently discontinued treatment due to adverse effects. Conclusions:Dasatinib treatment results in high rate of molecular response in CML-CP patients with resistance or intolerance to imatinib, and approximately 60% of evaluated patients who switched to dasatinib achieved MMR at 12 months. Importantly, among all patients who achieved molecular response, 24.1 % patients achieved CMR. Dasatinib at a dose of 100 mg once daily was generally well-tolerated, and had better efficacy for patients with CML-CP post imatinib failure. Disclosures:No relevant conflicts of interest to declare.

Nilotinib Versus Imatinib in Patients (pts) with Newly Diagnosed Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENESTnd 36-Month (mo) Follow-up

Abstract 452 Background: In ENESTnd, pts treated with nilotinib demonstrated higher and faster rates of major molecular response (MMR, ≤ 0.1% BCR-ABLIS), deeper molecular response (MR4, ≤ 0.01%IS and MR4.5, ≤ 0.0032%IS), and complete cytogenetic responses (CCyR) along with significantly lower rates of progression to AP/BC and fewer CML-related deaths compared with imatinib by 12 and 24 mo. Here, we report data with a minimum follow-up of 24 mo; however, efficacy and safety data based on considerably longer follow-up of ≥ 36 mo will be presented. As demonstrated in IRIS and other imatinib trials, most pts who progress on imatinib do so within the first 3 years of therapy. Thus, this 36-mo update of ENESTnd will be important to further verify the benefits of nilotinib in newly-diagnosed pts. Methods: 846 adult pts with newly-diagnosed Ph+ CML-CP were randomized to nilotinib 300 mg twice daily (BID) (n = 282), nilotinib 400 mg BID (n = 281), or imatinib 400 mg once daily (QD) (n = 283). MMR, MR4, MR4.5, time to progression to AP/BC on treatment, progression-free survival (PFS) on treatment, and overall survival (OS) were evaluated. Results: By 24 mo, both doses of nilotinib demonstrated significantly higher rates of MMR, MR4, and MR4.5 vs imatinib (Table). Nilotinib-treated pts achieved median BCR-ABLIS levels of 0.09% (300 mg BID) and 0.10% (400 mg BID) by 12 mo, while this level of reduction was not observed before 24 mo on imatinib. More pts with CCyR achieved MMR at 12 and 24 mo with either dose of nilotinib vs imatinib (Table). Regardless of Sokal risk, rates of MMR and MR4.5 were higher for nilotinib at both doses vs imatinib (Table). Progression to AP/BC (excluding clonal evolution [CE]) on treatment was significantly lower for nilotinib vs imatinib (2 pts and 3 pts with nilotinib 300 mg BID [P = .0059] and 400 mg BID [P =.0196]), respectively vs 12 pts with imatinib). After achieving CCyR, 4 pts treated with imatinib progressed to AP/BC and 2 pts treated with nilotinib 400 mg BID progressed after achieving both CCyR and MMR (1 also achieved MR4). No pt who achieved MR4.5 progressed at any time. All but 1 pt who progressed to AP/BC on treatment were in the intermediate and high Sokal risk groups; 1 pt treated with nilotinib 400 mg BID progressed in the low Sokal risk group who had an E255V mutation at progression. When considering progression events of pts after discontinuation of treatment, an additional 7, 2, and 6 events (excluding CE) were observed with nilotinib 300 mg BID, nilotinib 400 mg BID and imatinib, respectively. Twice as many pts had emergent mutations on imatinib (n = 20) vs nilotinib (n = 10 on 300 mg BID; n = 8 on 400 mg BID). At 24 mo, OS remained similar in all groups, but there were fewer CML-related deaths in both nilotinib 300 mg BID (5 pts) and nilotinib 400 mg BID (3 pts) arms vs imatinib (10 pts). Both drugs were well tolerated and few new adverse events (AEs) and lab abnormalities were observed between 12- and 24-mo of follow-up. Nilotinib 300 mg BID had the fewest discontinuations due to AEs/lab abnormalities (9% vs 13% and 10% with nilotinib 400 mg BID and imatinib, respectively). Conclusions: With a minimum follow-up of 24 mo, nilotinib continued to demonstrate superiority vs imatinib with faster and deeper molecular responses and a significantly decreased risk of progression. These data support the use of nilotinib as a standard of care option in newly-diagnosed adult pts with Ph+ CML-CP. Disclosures: Saglio:Novartis Pharmaceutical: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Pfizer: Consultancy. Off Label Use: Nilotinib is a safe and effective treatment for patients with CML. LeCoutre:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria. Pasquini:Novartis: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Nakamae:Novartis: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau. Flinn:nOVARTIS: Research Funding. Hochhaus:Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hughes:Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Larson:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Gallagher:Novartis: Employment. Yu:Novartis: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Kim:BMS: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

Alternating Nilotinib 400 mg twice daily and Imatinib 400 mg once daily as Frontline Treatment of Ph+ Chronic Myeloid Leukemia. A Phase 2 Multicentric Study of the GIMEMA CML Working Party

Abstract 453 Background:Imatinib (IM) 400 mg daily is the standard treatment for Ph+ Chronic Myeloid Leukemia (CML) in early Chronic Phase (ECP). Nilotinib (NIL) is a 2nd generation tyrosine kinase inhibitor (TKI) with superior efficacy to IM (phase 3 ENESTnd trial). NIL has been approved for the frontline treatment of CML in many countries. The treatment with more than one TKI, according to the principles of cancer polychemotherapy, may improve the response rates and may decrease the frequency of drug-resistance. The combination of different TKIs is potentially toxic, difficult to be explored in the ECP setting. The sequential administration of IM and NIL is worth to be investigated because a significant proportion of CML patients treated with a single TKI as monotherapy develops primary or secondary resistance. Aims:To evaluate the response (either cytogenetic and molecular) and the outcome of ECP Ph+ CML patients treated with the sequential administration of NIL and IM. Methods:A phase 2 study was conducted by the GIMEMA CML WP (ClinicalTrials.gov. NCT00769327). NIL was administered first because it has a more rapid therapeutic effect. Schedule: NIL 400 mg twice daily for 3 months; IM 400 mg daily for the next 3 months; then, NIL and IM turning every 3 months, for a total duration of 24 months (study core). The 3-month rotation schedule was respected, irrespectively of temporary discontinuations. The primary end-point was the Complete Cytogenetic Response (CCgR) rate at 12 months. If the conventional cytogenetic analysis resulted not evaluable, a FISH analysis was performed. If one of the 2 drugs was permanently discontinued for adverse event (AE), the patient remained in study, continuing the treatment with the other drug (except for cardiac AEs). Definitions: Major Molecular Response (MMR): BCR-ABL/ABL ratio < 0,1%IS; failure: according to 2009 ELN recommendations; event: failure, permanent discontinuation of both drug for any reason, patient refusal. All the analysis were performed according to the ITT principle. Results:123 patients have been enrolled in 38 italian hematologic Centers; median age 56 years (range 18–84); 33% low, 45% intermediate and 22% high Sokal score; median follow-up 21 months (at least 12 months observation, 24 months by November 2011). The cumulative CCgR rate by 12 months was 87%; CCgR at each milestone: 68% at 3 months, 73% at 6 months, 67% at 12 months (primary efficacy variable). The cumulative MMR rate by 12 months was 82%, while the rates of MMR at 3, 6 and 12 months were 59%, 62% and 60%, respectively. The discrepancies between cumulative response rates and response at each timepoint were mainly due to the number of patients not evaluable at each timepoint (10% of cytogenetic analysis not evaluable at 12 months) and to protocol discontinuation in stable CCgR and/or MMR. The incidence of hematologic AEs was low. Non-hematologic AEs or lab abnormalities grade > 2 observed in >5 % of patients were as follows: NIL - skin rash, pruritus, bilirubin increase, transaminase increase, lipase increase; IM - fluid retention, periorbital edema. AEs were manageable with appropriate dose adaptations. Four patients (3%) showed a prolongation of the QTcF above 450 msec (none above 500 msec). At the end of the first 12 months, 95 patients (77%) remained on study: 6 and 3 on NIL and IM monotherapy, respectively, 86 on sequential treatment with both drugs; 15% of patients permanently reduced the NIL dose to 400 mg daily and 9% of patients permanently reduced the IM dose to 300 mg daily. During the first year, 28 patients (23%) experienced an event: 10 treatment failure (8%); 2 death in CP (2%); 16 refusal, protocol violation or AE (13%). Six out of the 10 patients who failed the treatment progressed to advanced phase (3 patients: detection of a T315I mutation). Conclusions:The cumulative response rates achieved with a sequential administration of NIL and IM seem to be superior to the historical data of IM alone. The response rates at each timepoint, lower than expected, were probably due to the high number of not evaluable patients and to the number of patients not continuing the study despite a stable CCgR/MMR. However, if compared to the excellent results of 2nd generation TKI as monotherapy in ECP CML (single and randomized trials), the present analysis do not support an alternating schedule of NIL and IM as frontline treatment of ECP CML. Acknowledgments:European LeukemiaNet, COFIN, Bologna University, BolognAIL Disclosures:Castagnetti:Novartis Pharma: Honoraria; Bristol-Myers Squibb: Honoraria. Rosti:Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Soverini:Novartis: Consultancy; ARIAD: Consultancy; Bristol-Myers Squibb: Consultancy. Martinelli:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding.

Number Needed to Treat (NNT) and Cost Estimation to Achieve a Major Molecular Response in Newly Diagnosed Chronic-phase cronic Myeloid Leukemia in Brasil: 24-months follow-up

Abstract 4216 Background:The use of imatinib (IM) has greatly improved the outcome of patients with Ph+ chronic myeloid leukemia (CML), with a good balance of potency and exposure that translated into clinical efficacy for many patients. However, patient responses to IM can be variable with factors such as blood plasma levels and OCT-1 transporter activity influencing responses (Larson, 2008; White, 2010). Some patients do not reach complete cytogenetic response (CCyR) and others may have intolerable side effects. Loss of response to IM and disease progression occur mainly in the first 3 years of treatment, and the rate of overall survival is affected as a consequence. Molecular monitoring is the most sensitive measure of CML disease burden and Major Molecular Response (MMR) is associated with an extremely low rate of disease progression (Hughes, 2008). Objectives: (1) To estimate the ‘Number Needed to Treat’ (NNT) to achieve one MMR by 24 months. (2) To provide a relative measure of the cost of attaining treatment objective defined by MMR and hematologic adverse events (AEs) with 2 novel targeted therapies in the treatment of newly diagnosed CP-CML from the Brazilian Public Health Care System (SUS) perspective. Methods: MMR and AE data were evaluated from two phase 3 studies comparing IM 400mg once daily with DAS 100mg (Hochhaus, Haematologica. 2011; abstract 1011) and the other with NIL 300mg twice daily (Hochhaus, Haematologica. 2011, abstract 484) in newly diagnosed CP-CML patients. MMR rates by 24 months were used to calculate the NNT as the inverse of the MMR rate. The costs of managing neutropenia (R$8137), thrombocytopenia (R$599) and anemia (R$232) were estimated from SUS perspective in local currency (2008 BRL) using administrative databases, literature and survey with clinical experts. The costs of managing the AEs were then multiplied by the incidence of the AEs. Results: The number of newly diagnosed Ph+ CML-CP patients needed to treat to achieve 1 MMR with nilotinib (NNT=1,41) is 38% lower than imatinib in the ENESTnd study (Table 1). The dasatinib NNT of 1,56 is 28% lower than imatinib in the DASISION study (table 2). Lower NNT represents more effective therapy. The NNT analysis highlights that CML treatment with NIL600mg or DAS100mg provides greater efficacy when each are compared with IM400mg in the studies, and that Nilotinib NNT of 1,41 in the ENESTnd study is the most efficient in producing MMR among BCR-ABL inhibitors. DASISION study results demonstrate dasatinib produced more hematologic events, resulting in an estimated 14% higher cost of managing these adverse events compared to imatinib (table 2). ENESTnd study results demonstrate nilotinib produced lower incidence of hematologic events than imatinib, providing savings around 40% lower than imatinib in hematologic AE grade 3 or 4 management (table1). Conclusion: Although comparisons between published studies have some limitations, such an approach may be useful in the absence of direct comparative data. The NNT findings in this 24-months analysis and the differential cost of managing AEs in each treatment from this evaluation suggests that nilotinib provides better clinical outcomes and would result in lower costs for hematologic AE management from the perspective of the Brazilian Public Health Care System when compared to Imatinib. [Display omitted] [Display omitted] Disclosures:Alves:Novartis: Employment. Coombs:Novartis: Employment. Ruiz:Novartis: Employment. Valentim:Novartis: Employment. Lemos:Novartis: Employment.

Dasatinib and Imatinib-Induced Reductions in BCR-ABL Transcript Levels Below 10% At 3 Months Are Associated with Improved Responses in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Analysis of Molecular Response Kinetics in the DASISION Trial

Abstract▪2767▪This icon denotes a clinically relevant abstract Background:In the randomized phase 3 DASISION trial in patients (pts) with newly diagnosed CML-CP, dasatinib showed superior efficacy over imatinib (IM), including higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR) at 24 months, and acceptable tolerability (Hochhaus et al. Haematologica 96: 2011 [Suppl 2; abstract 1011]). Previous studies have shown that molecular response after 3 months of imatinib therapy is predictive for treatment failure and transformation (Hanfstein et al, ASH 2010, abstract 360). Here, an analysis of BCR-ABL kinetics in pts from DASISION after a minimum 24 months of follow-up and a 3-month landmark analysis are presented. Methods:Pts with CML-CP diagnosed within 3 months were randomized to receive dasatinib 100 mg once daily (QD; n=259) or IM 400 mg QD (n=260). Levels of BCR-ABL b2a2 and b3a2 transcripts in peripheral blood were assessed using real-time quantitative PCR by a central independent laboratory (MolecularMD, Portland, OR). For the current analysis, pts with atypical BCR-ABL transcripts were excluded (5 in the dasatinib arm, 3 in the imatinib arm). MMR was defined as a BCR-ABL transcript level of ≤0.1% on the international scale (IS) (≥3-log reduction from the standardized baseline). For PCR negative samples an at least 4.5 log test sensitivity was confirmed. The following events were considered in the progression-free survival (PFS) analysis: increasing WBCs, loss of complete hematologic response or major cytogenetic response, transformation to accelerated/blast phase (AP/BP), or death. Results:In the dasatinib vs imatinib arms, 24-month cumulative response rates were MMR in 65% vs 47%, BCR-ABL ≤0.01% (MR4, ≥4-log reduction) in 29% vs 19%, and BCR-ABL ≤0.0032% (MR4.5, ≥4.5-log reduction) in 17% vs 9%, respectively. The advantage in MMR rates for dasatinib over imatinib was maintained between 12 and 24 months (18–19% difference). Median time to MMR in all pts irrespective of response (calculated by competing risk analysis) was 20 months shorter for dasatinib compared with imatinib (15 vs 35 months). The median BCR-ABL transcript level decreased faster in the dasatinib arm compared with the imatinib arm (Table). By 3 months, 84% vs 64% of evaluable pts in the dasatinib vs imatinib arms, respectively, had achieved a BCR-ABL level ≤10%. Compared with pts who had not achieved this degree of response, a landmark analysis found that pts who had achieved BCR-ABL ≤10% at 3 months had a higher probability of achieving CCyR by 12–18 month and MMR by 18–24 months, a higher probability of 24-month PFS, and a lower probability of transformation to AP/BP, both in the dasatinib and imatinib arms (Table). Probabilities of subsequent CCyR and MMR among pts who had a BCR-ABL level ≤10% at 3 months showed a higher trend in dasatinib-treated pts compared with imatinib-treated pts. Conclusions:In pts with newly diagnosed CML-CP, first-line dasatinib results in faster and deeper molecular responses compared imatinib. For pts treated with either dasatinib or imatinib, BCR-ABL reduction to ≤10% at 3 months is associated with increased likelihood of achieving CCyR by 12 months and MMR by 24 months, decreased progression to AP/BP, and increased PFS at 24 months.Table:Molecular kinetics with dasatinib and imatinib, and landmark analysis of response/outcome based on achieving a BCR-ABL level ≤10% at 3 monthsDasatinib 100 mg QD armImatinib 400 mg QD armMedian BCR-ABL level, %3 months1.265.516 months0.301.0112 months0.130.3918 months0.060.1524 months0.040.09BCR-ABL at 3 months (evaluable patients)≤1% (n=112)>1–10% (n=86)≤10% (n=198)>10% (n=37)≤1% (n=32)>1–10% (n=122)≤10% (n=154)>10% (n=85)CCyR by 12 months, n110 (98%)81 (94%)191 (96%)10 (27%)31 (97%)107 (88%)138 (90%)38 (45%)MMR by 24 months, n99 (88%)51 (59%)150 (76%)6 (16%)28 (88%)73 (60%)101 (66%)16 (19%)AP/BP at any time, n2 (2%)1 (1%)3 (2%)3 (8%)0 (0%)4 (3%)3 (3%)8 (9%)PFS at 24 months*96%98%97%83%100%95%96%85%*PFS rates were obtained from Kaplan-Meier estimates. PFS included death from any cause as a progression event. Disclosures:Hochhaus:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Pfeizer: Consultancy. Chuah:Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Pavlovsky:Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Bradley Garelick:Bristol-Myers Squibb: Employment. Lambert:Bristol-Myers Squibb: Employment. Shah:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy; Ariad: Consultancy, Research Funding.

Analysis of the GeneXpert System on the International Multicentre ICORG 08–02 Phase II Study of Nilotinib 300mg BID as Frontline Treatment in Patients with Early Chronic Phase Chronic Myeloid Leukemia (ECPCML),

Abstract 3774 BACKGROUND/METHODS:Data from the ENESTnd phase III trial showed superiority of nilotinib over imatinib leading to accelerated approval of nilotinib as initial treatment of ECPCML at a dose of 300mg BID. ICORG, the All-Ireland Cooperative Oncology Research Group, has been coordinating an international open-label, single stage, multicenter, investigator-initiated phase II study (ClinicalTrials.gov NCT00809211) of the safety and efficacy of nilotinib 300 mg BID in previously untreated patients with ECPCML. The primary study endpoint is the complete cytogenetic response (CCyR) rate at 6 months; secondary endpoints include the kinetics of molecular response, determined by RQ-PCR at baseline and 3 monthly from start of treatment as well as an evaluation of a novel rapid turnaround PCR system “GeneXpert” with IS BCR-ABL1/ABL1 RQ-PCR. The study closed to accrual with 61 patients (median age 54 years [range 20 –77]) enrolled; 53% have low risk Sokal score, 25% intermediate and 22% high risk. Median follow up is currently 12 months (range 1–30) and by November 2011 all patients will have had at least 6 months follow up. RESULTS:At the time of this analysis, 6 and 12 month follow up data were available in 43 and 31 patients, respectively. By intention to treat analysis, 41/43 (95%) have achieved CCyR within 6 months with all patients still on treatment at 12 months achieving CCyR. 26/43 (60%) and 25/31 (81%) of patients have achieved a major molecular response (MMR) (BCR-ABL1/ABL1 IS ≤ 0.1%) within 6 and 12 months, respectively, with 16/31 (52%) and 11/31 (35%) patients on treatment at least 12 months achieving BCR-ABL1/ABL1 IS ≤ 0.01% and ≤ 0.0032%, respectively. Sokal risk had no apparent effect on response with 12/16 (75%) low risk and 13/15 (87%) intermediate/high risk patients achieving MMR within 12 months, p=0.65. Thus far 4/6 (67%) high risk Sokal patients achieved BCR-ABL1/ABL1 IS ≤ 0.0032% within 12 months. No patients have suffered CML progression to date. 53 patients remain on study. Six patients have been removed from study due to adverse events: 4 patients due to persistent drug-related toxicity; 2 patients non drug-related events (death due to progressive multiple system atrophy and colorectal carcinoma, respectively). In addition, one patient was enrolled but never received study drug and an additional patient was lost to follow up. Treatment was generally well tolerated and toxicities easily managed. Haematologic toxicity was minimal with grade III/IV thrombocytopenia seen in 3 (5%) patients and only a single patient (2%) each with grade III/IV neutropenia and anemia, respectively. The most common grade III/IV non-haematologic toxicity was lipase elevation, seen in 14/61 (23%). No cases of acute pancreatitis were seen. Other grade III/IV non-hematologic toxicities were uncommon (< 5% patients). While treatment was interrupted at least once in 36/59 (61%) patients, the median duration of interruptions was short (5 days). At last follow up 49/59 (83%) of patients were taking ≥ 300mg BID. The study evaluation of the “GeneXpert” PCR system consisted of paired BCR-ABL1/ABL1 measurements performed by RQ-PCR methodologies aligned to International Standard (IS) and by the Xpert BCR-ABL Monitor system on 36 evaluable patients at diagnosis and at 128 subsequent three-monthly time-points. In patients expressing e13a2 or e14a2 BCR-ABL1 transcripts, both techniques had comparable results at diagnosis: IS median BCR-ABL1/ABL1 41.0% vs 44.0% median BCR-ABL1/ABL1 on the Xpert BCR-ABL Monitor. In the 122 paired analyses, correlation between methodologies, without automated system IS conversion, over a five log range (IS BCR-ABL1/ABL1 100–0.001%) was favourable (r2=0.845), however a progressive decline in correlation was noted with each decreasing log IS BCR-ABL1/ABL1 level. No significant difference was observed between the Xpert BCR-ABL Monitor and IS RQ-PCR in identifying MMR (44.3% vs 41.8%). CONCLUSION:In ECPCML, nilotinib 300mg BID induces high rates of CCyR and MMR with a substantial fraction of patients achieving responses in the range of complete molecular response (CMR). This regimen's toxicity is modest. The GeneXpert system provides a reliable and rapid means of assessing CML patients' response to tyrosine kinase inhibitor (TKI) therapy. Development of a reagent lot-specific conversion factor to the IS would enhance GeneXpert's applicability in monitoring TKI therapy in patients with CML. Disclosures:O'Dwyer:Novartis: Honoraria, Research Funding. Giles:Novartis: Consultancy, Honoraria, Research Funding. le Coutre:Novartis: Honoraria, Research Funding, Speakers Bureau. Nagler:Novartis: Honoraria, Research Funding. Egan:Novartis: Employment. Conneally:Novartis: Honoraria.

Pegylated Interferon a2a (PegIFN) At the Dose of 45μg Per Week in Combination with Imatinib 400mg Is the Recommended Initial Dose for Patients (pts) with Chronic Phase Chronic Myeloid Leukemia (CML-CP): Results From the French SPIRIT Trial of the French CML Group (FI LMC)

Abstract 456 Background:The SPIRIT phase III randomized multicenter open-label prospective trial was designed to compare 4-arm, imatinib 400 mg versus imatinib 600 mg versus imatinib 400 mg + cytarabine at a dose of 20 mg/m2/day in cycles of 28 days, versus imatinib 400 mg + PegIFN at an initial dose of 90 μg/week. The planned molecular analysis after 1 year based on the outcome of 636 pts resulted in a highly significant improvement of superior molecular response (SMR) (0.01 % Bcr-Abl/Abl on IS) of the combination imatinib 400mg-PegIFN (N Engl J Med, 2010). Accrual within the imatinib 600 mg and imatinib 400 mg-cytarabine has been stopped. In the initial cohort of 171 pts who had been treated less than 4 months with the 2 combined agents, major molecular response (MMR: 0.1%) rate was 48%, SMR rate was 23%, and undetectable molecular residual disease (UMRD) was 8%. By contrast, in pts receiving the combined agents longer than 12 months, MMR, SMR and UMRD rates were 82%, 49% and 20% respectively. In order to improve tolerability of the combination, initial dose of PegIFN has been reduced to 45μg/week. The current analysis focuses on the tolerability and efficacy of the reduced dose of PegIFN as compared to the initial planned dose of 90μg/week. Patients and methods: As of December 31st 2010, date for closing accrual, 789 pts have been included, 445 pts within the imatinib 400mg and imatinib 400mg+PegIFN arms. The high proportion of PegIFN discontinuation during the first year prompted an amendment that recommended reducing the initial dose down to 45ug/week at enrolment. For these pts the weekly dose of PegIFN was increased up to 90μg after 2 months of treatment with the combination of PegIFN 45μg plus Imatinib 400mg, if the hematological and non-hematological tolerance was acceptable. Out of the 221 pts assigned to imatinib plus PegIFN, 171 received 90μg and 50 received 45μg/week of PegIFN, both groups being similar with a median age of 51 and 48 years respectively. Molecular biology was centralized, samples being collected every 4 months, with a karyotype recommended yearly. Data of parameters of effectiveness and tolerance were collected even after stopping treatment protocol. Adverse events (AE) considered for the analysis are those which led for PegIFN dose adjustment. Results. At the time of the analysis, 30% of pts were still on PegIFN. Table 1 describes the AE which occurred during the two consecutive periods of the trial (before and after the amendment).AE before the amendment (n=171)AE after the amendment (n=50)All grade (%)G1-2 (%)G3-4 (%)All grade (%)G1-2 (%)G3-4 (%)Hematologic toxicity681454451827Flu-like syndrome752422Skin toxicity725220Neuropsychiatric syndrome954624Liver toxicity10.50.5624other312624Hematologic toxicity was predominant within the PegIFN arm (68% pts suffering all grade including 54% with G3-4) leading to 40% of permanent discontinuation of PegIFN. However, only a small proportion of neuropsychiatric syndrome (including depression, chronic fatigue and insomnia) and flu-like syndrome were observed and no cardiac event occurred with PegIFN at the dose of 45μg/week. Rate of all grade hematologic toxicity decreased from 68% to 45% of pts after the amendment. Of interest the reduced dose of PegIFN had a significant impact on the adherence to the treatment. During the first 6 months before and after the amendment, 40% and 10% of pts discontinued PegIFN respectively. Thus after the amendment 90% received at least 6 months of PegIFN. Of note the reduced dose of 45μg/week resulted in a similar response rate as compared to the initial planned dose of 90μg. The MMR rates at 6 months were before and after the amendment 36.3% (95%CI: 29.1–49.3) and 36% (95%CI: 22.0–50.8) respectively. The corresponding number for SMR rates at 6 months were 9.9% (95%CI: 5.9–15.4) and 10% (95%CI: 3.3–21.8) respectively. Finally for 222 pts, imatinib 400mg alone resulted in less responses at 6 months with MMR and SMR rate of 19.3% (95CI: 14.3–25.0) and 5.8% (95CI:3.1–0.7) respectively. The combination of imatinib and PegIFN has been shown in this trial as an effective combination for increasing the rate of molecular responses compared to imatinib alone. The lower dose of PegIFN (45 mg/week) resulted in less early toxicity. It will allow the combination to be given together for a longer period of time and preserve the increased antitumor efficacy. An update with a minimum of 12 months of follow-up of the 50 pts will be presented. Disclosures:Off Label Use: Pegylated form of interferona2a.

Determinants and Impact of Treatment Interruptions and Nonadherence to Imatinib Therapy in Patients with Chronic Myeloid Leukemia in a South Brazilian Cohort

Abstract 4425Adherence to imatinib therapy has proven to be a major determinant of treatment results, but the degree of impact and the determinants of nonadherence are still contradictory. There is no information regarding adherence to imatinib therapy in the Brazilian public health system. The aims of this study were to identify the characteristics related to treatment interruptions and nonadherence and to examine how these interruptions affect treatment responses and survival. Materials and MethodsWe conducted a retrospective study in a cohort of patients (pts) with CP-CML enrolled in 14 Hematology centers in South Brazil. All pts received imatinib 400mg as first or second-line therapy. Early-imatinib treatment was considered when imatinib started before 12 months (mo) from diagnosis. Patient evaluation and response criteria followed the ELN recommendations. The ACE-27 (Adult Comorbidity Evaluation-27) is a 27 item comorbidity index for patients with cancer and assign weights from 1 to 3 based on the dysfunction grade of each condition (mild, moderate and severe, respectively). An ACE-27 score was applied to each patient. Imatinib suspensions were considered if superior to 20 days at any point during therapy. Two levels of analysis were performed: all kinds of interruptions (nonadherence and toxicity) and only nonadherence ones. Information for nonadherence was taken from medical and pharmacy registers (pt self-report, missing scheduled appointments and pill counts). ResultsWe analyzed data from 185 pts with CP-CML diagnosed since 1990. The median age at diagnosis was 48 yr (4 – 85) and 55% were male. The median time from diagnosis to imatinib was 7 mo (0 – 178) and 71% pts were early-imatinib treated. Prior therapy with interferon was used in 70% pts. The median of follow-up was 47 mo. Treatment interruption was observed in 63/185 patients (34%) and was related to toxicities in 35/63 pts (55%) and to nonadherence in 28/63 pts (45%). The adherence rate was 85%. In a multivariate analysis, only late-onset imatinib treatment (Odds Ratio [OR]=36,05; p<0,001) and severe comorbidity (OR=27,05; p=0,03) were associated with higher risk of interrupting imatinib for any reason. The only variable associated with nonadherence was late-onset imatinib treatment (OR=14,76; p<0,001). Although not statistical significant, male and comorbidity showed a tendency to be linked with nonadherence (Table 1). Nonadherent pts, compared with adherent ones, had lower complete cytogenetic response (CCyR) rates at 12 mo (39% and 65%; p=0,004, respectively; Figure 1) and lower major molecular response (MMR) rates at 18 mo (9,5% and 35%; p=0,002, respectively; Figure 2). Finally, treatment interruption had a relevant negative impact on EFS in 4 yr. In the group that had treatment interruption, EFS was 52%, compared with 78,5% in the group without interruptions (p=0,002; Figure 3). Analysis performed only on nonadherence treatment interruption groups showed no significant difference (53% and 71%; p=0,15, respectively). [Display omitted] ConclusionsIn this cohort, a substantial proportion of pts failed to take imatinib properly, decreasing the chances of disease control. The late onset of imatinib therapy correlates with lower adherence, so front-line imatinib therapy should be started as soon as possible. Special attention should be given to pts with severe comorbidities, as they are more prone to suffer side effects or to lack adherence. Finally, pts who interrupted treatment had lower CCyR, MMR and EFS.Clinical and patient characteristics related to nonadherence Disclosures:No relevant conflicts of interest to declare. [Display omitted] [Display omitted]

The achievement of an early complete cytogenetic response is a major determinant for outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors

AbstractWe analyzed the association between achievement of early complete cytogenetic response (CCyR) and event-free survival (EFS) and overall survival (OS) in patients with newly diagnosed chronic myeloid leukemia in chronic phase treated with imatinib 400 mg (n = 73), or imatinib 800 mg daily (n = 208), or second- generation tyrosine kinase inhibitors (n = 154). The overall CCyR rates were 87%, 91%, and 96%, respectively (P = .06); and major molecular response (MMR) rates were 77%, 87%, and 89%, respectively (P = .05). Their 3-year EFS rates were 85%, 92%, and 97% (P = .01), and OS rates were 93%, 97%, and 100% (P = .18), respectively. By landmark analysis, patients with 3-, 6-, and 12-month CCyR had significantly better outcome: 3-year EFS rates of 98%, 97%, and 98% and OS rates of 99%, 99%, and 99%, respectively, compared with 83%, 72%, and 67% and 95%, 90%, and 94%, in patients who did not achieve a CCyR. Among patients achieving CCyR at 12 months, the depth of molecular response was not associated with differences in OS or EFS. In conclusion, second tyrosine kinase inhibitors induced higher rates of CCyR and MMR than imatinib. The achievement of early CCyR remains a major determinant of chronic myeloid leukemia outcome regardless of whether MMR is achieved or not.

Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia

AbstractBiologic and clinical observations suggest that combining imatinib with IFN-α may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission either to receive a combination of pegylated IFN-α2b (Peg–IFN-α2b) 50 μg weekly and imatinib 400 mg daily (n = 56) or to receive imatinib 400 mg daily monotherapy (n = 56). The primary endpoint was the major molecular response (MMR) rate at 12 months after randomization. In both arms, 4 patients (7%) discontinued imatinib treatment (1 because of blastic transformation in imatinib arm). In addition, in the combination arm, 34 patients (61%) discontinued Peg–IFN-α2b, most because of toxicity. The MMR rate at 12 months was significantly higher in the imatinib plus Peg–IFN-α2b arm (82%) compared with the imatinib monotherapy arm (54%; intention-to-treat, P = .002). The MMR rate increased with the duration of Peg–IFN-α2b treatment (< 12-week MMR rate 67%, > 12-week MMR rate 91%). Thus, the addition of even relatively short periods of Peg–IFN-α2b to imatinib markedly increased the MMR rate at 12 months of therapy. Lower doses of Peg–IFN-α2b may enhance tolerability while retaining efficacy and could be considered in future protocols with curative intent.

Imatinib Is Effective in Children With Previously Untreated Chronic Myelogenous Leukemia in Early Chronic Phase: Results of the French National Phase IV Trial

Imatinib is the standard of care in adults with chronic myeloid leukemia (CML) in chronic phase (CP). Only a few studies to assess efficacy in children have been performed. We report on the results of the French prospective trial (ClinicalTrials.gov identifier NCT00845221) conducted in children and adolescents with newly diagnosed CML in CP. A total of 44 patients from age 10 months to 17 years with newly diagnosed CML in CP received daily imatinib 260 mg/m(2). Progression-free survival, responses, and tolerance were evaluated. With a median follow-up times of 31 months (range, 11 to 64 months), the estimated progression-free survival rate at 36 months was 98% (95% CI, 85% to 100%). A complete hematologic response was achieved in 98% of the patients. The rates of complete cytogenetic response (CCyR) and major molecular response (MMR) were 61% and 31% at 12 months, respectively. During follow-up, CCyR and MMR were achieved in 36 children (77%) and 25 children (57%), respectively. Overall, 30% of the patients discontinued imatinib, mainly because of unsatisfactory response. The most common adverse events were neutropenia and musculoskeletal events. Imatinib is effective in children with CML in CP with response rates similar to rates reported in adults. The adverse effects are acceptable, but longer follow-up studies are required to fully assess the long-term impact.

Optimizing the selection of kinase inhibitors for chronic myeloid leukemia patients

Long-term follow-up of clinical studies has demonstrated the efficacy of imatinib therapy in newly diagnosed chronic phase-chronic myeloid leukemia patients (CML). However, recent updates of two separate randomized Phase III studies demonstrated higher complete cytogenetic and major molecular response rates with dasatinib and nilotinib compared with imatinib 400 mg/day. Hence, for newly diagnosed chronic phase-CML patients there are multiple treatment options, including standard-dose imatinib, high-dose imatinib, and combination therapy of imatinib and interferon, dasatinib and nilotinib. This article critically analyzes the current literature and provides guidelines for the management of newly diagnosed CML. Disease and therapy-related prognostic factors, which may aid in the selection of therapeutic strategies to enable optimal treatment outcomes, are discussed. In addition, we provide commentary on the therapeutic options for patients who fail imatinib therapy.