Imatinib Arm Research Articles

ENESTnd Update: Nilotinib (NIL) Vs Imatinib (IM) In Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) and The Impact Of Early Molecular Response (EMR) and Sokal Risk At Diagnosis On Long-Term Outcomes

ENESTnd Update: Nilotinib (NIL) Vs Imatinib (IM) In Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) and The Impact Of Early Molecular Response (EMR) and Sokal Risk At Diagnosis On Long-Term Outcomes

Four-Year (Yr) Follow-Up Of Patients (Pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) Receiving Dasatinib Or Imatinib: Efficacy Based On Early Response

Four-Year (Yr) Follow-Up Of Patients (Pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) Receiving Dasatinib Or Imatinib: Efficacy Based On Early Response

Peripheral Arterial Occlusive Disease (PAOD) In Patients (Pts) Receiving Dasatinib: Experience Across Multiple Clinical Trials

BackgroundThe introduction of BCR-ABL inhibitors revolutionized the treatment of chronic myeloid leukemia (CML) which is now a manageable, chronic disease. As BCR-ABL inhibitors are used more widely and for longer, some distinctly different or late occurring adverse events (AEs) have become apparent from clinical studies and literature reports (e.g. pulmonary arterial hypertension, PAOD). PAOD has been described in a varying percentage of pts receiving nilotinib across the ENESTnd phase 3 trial of nilotinib versus imatinib (1.2%) and the literature (0.5%–12.5%). Arterial thrombotic events have also been reported in pts receiving ponatinib (11%). To assess whether PAOD may be a class effect, a pooled database of over 2700 pts in clinical trials of dasatinib was assessed. MethodsBristol-Myers Squibb clinical trial safety databases were examined using specific search-terms to identify cases of PAOD or PAOD-related events based on the mapped MedDRA preferred terms. In total, 11 clinical trials of first-line (n=2) and second-line (n=9) single-agent dasatinib in pts with CML (any phase) or Philadelphia chromosome-positive acute lymphoblastic leukemia were evaluated. Dasatinib 100 mg once daily (QD) was received in first-line trials while doses received in second-line trials varied: 15–240 mg QD or twice daily (BID), 20 mg BID, 50 mg BID, 70 mg BID, 100 mg QD, 140 mg QD. ResultsAcross 11 clinical trials, 2705 pts received dasatinib with a cumulative 5890 pt years exposure. 6 pts (0.2%) were identified with either PAOD (n=1) or a PAOD-related event (n=5). See Table for details. In the dasatinib and imatinib arms of the phase 3 DASISION study (the only study with an imatinib control arm using the standard 400 mg QD dose) no cases of PAOD or related events were identified. For the 6 pts receiving dasatinib with PAOD or a related event the median age was 67.5 years (range: 54.0–80.0). All pts received dasatinib following imatinib resistance (n=4) or intolerance (n=2) after 20.0 months median duration of prior imatinib therapy (range: 2.4 – 53.1). Pts received dasatinib treatment for a median of 39.1 months (range: 9.9 – 74.4); 5/6 received a starting dose of 70 mg BID. All of the 6 PAOD or related events were grade 3 or lower in severity; no grade 4 or serious AEs were reported. None of the 6 pts discontinued dasatinib due to PAOD or a related event. Dose interruptions occurred in 2/6 pts; the remaining pts continued to receive dasatinib. All pts had risk factors for PAOD including cardiovascular events (n=3) such as coronary/ischemic heart disease, tricuspid regurgitation, hypertension, and heart failure; endocrine/metabolic events (n=2) such as obesity and diabetes mellitus; or other events such as hyperlipidemia (n=1). 3/6 pts were or had been smokers. PAOD or related events were newly diagnosed in 5/6 pts; 1 pt with femoral artery occlusion had a prior history of right leg angioplasty indicating a preexisting condition (pt 5 in the Table). Common concomitant medications included acetylsalicylic acid (n=3) and erythropoietin (n=3). ConclusionThe incidence of PAOD in pts receiving dasatinib is low and as expected for the target population. In the dasatinib clinical trials assessed here, PAOD occurred in pts who had received prior imatinib treatment and had significant predisposing risk factors for PAOD. These results suggest that PAOD is most likely not an effect of dasatinib treatment. In conclusion, confronting possible vascular AEs, pt baseline risk factors, AE profiles, and off-target profiles of therapeutic alternatives should be considered individually when choosing the most appropriate BCR-ABL inhibitor. Disclosures:le Coutre:Pfizer: Honoraria; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Hughes:Ariad: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Mahon:Ariad: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Kim:Ilyang: Research Funding, Speakers Bureau; Ariad: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau, Support for travel to meetings Other. Steegmann:Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Shah:Bristol-Myers Squibb: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Wallis:Bristol-Myers Squibb: Employment. Cortes:Novartis: Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria, Research Funding; Tragara: Membership on an entity's Board of Directors or advisory committees; Ambit: Research Funding; Astellas: Research Funding; Incyte: Research Funding; Arog: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Research Funding.

Nilotinib Or High-Dose Imatinib Compared With Standard-Dose Imatinib In Early Chronic Phase CML Patients Who Have Suboptimal Molecular Responses To Standard-Dose Imatinib: Including Updated Data From RE-Nice Study

BackgroundIn chronic myeloid leukemia (CML), achievement of optimal responses by time point has improved long-term outcomes. In IRIS study, patients who achieved major molecular response (MMR) at 18 months had event-free survival (EFS) benefit, compared to those who achieved complete cytogenetic response (CCyR) without MMR. However, the best treatment for these patients is still not confirmed. By the previous studies, sustaining standard-dose of imatinib (IM) is expected to yield less than 20 percent of additive MMR. In this study, we investigated the efficacy of switching to nilotinib (NIL) versus high-dose IM versus standard-dose IM for patients with suboptimal molecular response to IM as first-line therapy. MethodsEarly chronic phase (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 IM therapy at a daily dose of 400 mg were enrolled in RE-NICE study, and informed consents were obtained from all patients. In NIL arm, patients received 400 mg BID (800 mg/day) and in high-dose IM arm, patients received 800 mg/day administrated as 400 mg BID. Primary endpoint is to evaluate the cumulative MMR rates by 12 months, and secondary endpoints are to evaluate the cumulative MMR, MR4.0 and undetectable molecular residual disease (UMRD) rates during further 24 month follow-up. The efficacy of switching to NIL or high-dose IM were compared with that of the patients who maintained standard-dose of IM. Patients with standard-dose IM were selected with the same inclusion criteria and maintained standard-dose IM after enrollment period. To compare the efficacy among three groups, MMR rate, MR4.0 and undetectable molecular residual disease (UMRD) rates by 12 months were analyzed. Safety profiles also be assessed. 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. ResultsWith a data cut-off date of 15 Jul 2013, a total of 52 patients were randomized into NIL arm (n = 26) or high-dose IM arm (n = 26) and 16 patients were included in standard-dose IM group. With a median follow-up of 21 months (range, 1-36) in NIL arm and high-dose IM arm, all patients have maintained CCyR without progression to advanced disease, and progressive decrease in BCR-ABL1 transcript levels was observed in all patients. With a median follow-up of 12 months (range, 1-60), all patients in standard-dose IM group have maintained CCyR without progression to advanced disease. Cumulative incidence (CI) of MMR by 12 months showed no significant difference between NIL arm and high-dose IM arm (41.1% vs 28.8, P = 0.334). Only in NIL arm, 2 in 26 (8%) achieved confirmed MR4.0 and UMRD. By 12 months, 10 in 26 (39%), 7 in 26 (27%) and 3 in 16 (19%) patients achieved MMR, in NIL arm, high-dose IM arm and standard-dose IM group respectively. Overall, the patients treated with high-dose IM showed toxicities more frequently, such as leucopenia, anemia, Thrombocytopenia, edema, fatigue, dyspnea and decreased phosphate. In addition, 14 patients in high-dose IM arm have cross-over to NIL treatment due to lack of response (n=11) and intolerance (n=3), and the median duration of NIL treatment was 23 months (range, 2-36 months). Among them, 6 (43%) patients have achieved MMR with a median NIL treatment duration of 12 months (range, 0-18). ConclusionsThese results demonstrate that early switching to NIL or dose escalation of IM could be recommended, considering the results of standard dose of IM in suboptimal molecular responders. When the tolerability of treatment was considered for switching to NIL or high-dose IM, NIL may be preferred. Through further clinical investigation on a large patient population and longer period observation, the efficacy and safety of early intervention of suboptimal molecular response using NIL or dose escalation of IM will be needed. Updated data with longer follow-up duration will be presented in the meeting. Disclosures:No relevant conflicts of interest to declare.

Randomized phase III trial of imatinib (IM) rechallenge versus placebo (PL) in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) after failure of at least both IM and sunitinib (SU): RIGHT study.

LBA10502 Background: To palliate and prolong disease control after failure of all available treatment in advanced GIST, resumption of IM dosing has been commonly practiced based on evidence of rapid GIST progression after discontinuation of all TKIs. We evaluated the efficacy of IM rechallenge in pts with advanced GIST following failure of all TKIs. Methods: Eligible pts had metastatic and/or unresectable GIST with prior benefit from first-line IM (defined as disease control for > 6 months), progressive disease (PD) on first-line IM, PD on or intolerance to SU, and ECOG performance status 0-3. Pts were randomized 1:1 to receive best supportive care with either IM 400 mg po once daily or PL. At the time of PD, pts were unblinded and allowed to cross-over to open-label IM. The primary endpoint was progression-free survival (PFS) determined by blinded external radiology review according to RECIST v1.0. Secondary endpoints included overall survival (OS), time to progression, disease control rate (DCR) at 12 weeks, and safety. Results: Between July 2010 and January 2013, 81 pts were randomized (IM: 41, PL: 40) at a single Korean center. All baseline characteristics were balanced between the arms and 40% of pts received ≥ 3 prior TKIs. The planned final analysis in March 2013 demonstrated that the primary endpoint was met, with significantly greater PFS for pts randomized to IM vs. PL : 1.8 vs. 0.9 months, respectively (p=0.002), hazard ratio (HR) 0.45 (95% CI, 0.27-0.76). DCR at 12 weeks was 32% for IM vs. 5% for PL (p=0.003). With 92.5 % of PL pts rapidly crossing over to IM, median OS was 8.2 months for IM vs. 7.5 months for PL (HR of 0.99, p=0.982). The most common treatment-emergent AEs (> grade 3) during double-blind period in the IM arm included anemia (29%), fatigue (10%), and hyperbilirubinemia (7%). Conclusions: Rechallenge of IM significantly improves PFS and DCR in pts with advanced GIST after failure of at least IM and SU, likely by continuous kinase inhibition of the bulk of disease clones which retain IM sensitivity. However, TKI-resistant clones continue to progress leading to relatively brief duration of benefit. Clinical trial information: NCT01151852.

Switching patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with residual disease on long-term imatinib (IM) to nilotinib (NIL): ENESTcmr 24-mo follow-up.

7053^ Background: The 12-mo results of ENESTcmr demonstrated that switching pts on IM with sustained BCR-ABL positivity to NIL leads to faster, deeper molecular responses (MRs)vs remaining on IM. These deeper molecular responses (MR4.5 [BCR-ABL ≤ 0.0032%IS] or greater) are a prerequisite to enter most treatment-free remission studies. Here, we report 24-mo f/u of ENESTcmr. Methods: Philadelphia chromosome–positive CML-CP pts (N = 207) who achieved a complete cytogenetic response, but had detectable BCR-ABL transcripts after ≥ 2 y on IM, were randomized to receive NIL 400 mg twice daily (BID; n = 104) or continue their IM dose (400/600 mg once daily [QD]; n = 103). Results: By 24 mo, significantly more pts achieved confirmed undetectable BCR-ABL (by RQ-PCR with ≥ 4.5 log sensitivity in 2 consecutive samples) with a switch to NIL vs continuing IM (22.1% vs 8.7%; P = .0087). The increase in the rate of undetectable BCR-ABL from mo 12 to 24 was higher for pts on NIL vs IM (9.6 vs 2.9 percentage points). In pts without MR4.5 at baseline (BL), MR4.5 was achieved by 24 mo in 42.9% vs 20.8% of pts (NIL vs IM; P = .0006). In pts without major molecular response (MMR; ≤ 0.1%IS) at BL, MR4.5 was achieved by 24 mo in 29.2% vs 3.6% of pts (P = .016). No progressions to accelerated phase/blast crisis or deaths occurred on study since the 12-mo f/u. Event-free survival at 24 mo was 96.6% vs 92.8% in the NIL and IM arms, respectively. Discontinuations due to adverse events occurred in 11.5% and 2.9% of pts in the NIL and IM arms. The NIL safety profile was consistent with prior switch studies. Conclusions: By 24 mo, significantly more pts achieved deeper responses (MR4.5and undetectable BCR-ABL) with switch to NIL vs remaining on IM, and the difference between arms in these endpoints increased between 12 and 24 mo. Clinical trial information: NCT00760877. [Table: see text]

A phase II randomized study of adjuvant imatinib versus high-dose interferon alpha-2b for resected high-risk c-kit mutated melanoma.

e20027 Background: Imatinib, a selective inhibitor targeting Abl as well as C-Kit and the platelet-derived growth factor receptor, has been tested for the efficacy and toxicities in metastatic melanoma patients harboring mutations in C-Kit gene. High-dose interferon for one year (HDI) is the FDA approved adjuvant therapy for patients (pts) with high-risk melanoma. This study (NCT01782508) aims to see whether imatinib is more effective than interferon alfa-2b in adjuvant therapy for patients with C-Kit mutated melanomas. Methods: This study enrolled C-Kit mutated(exon 9,11 or 13)pts who were high risk (stage IIB to stage IIIC) and randomized them to receive either imatinib (400mg daily for a year) or HDI (interferon a-2b 15X106 U/m2 d1–5/wX4w + 9X106U tiwX48w) in the absence of disease progression or unacceptable toxicity. 40 pts of each group were planned to enroll. Routine tests including blood tests, medical history updates, physical exams and Brain/Chest/Abdomen/Pelvic CT were performed every 2 months. The endpoints were recurrence-free survival (RFS) and overall survival. Results: Through Jan 2013,7 pts were recruited F3 in imatinib arm and 4 in HDI arm. The three pts received imatinib haven’t had recurrence or metastasis. The RFS were 6m+ (Exon 11: W577S), 5m+ (Exon 11: L576P), 5m+ (Exon 11: L576P) respectively. Two pts have already had lung or regional lymphnode at 4 months (Exon 13: K642E) and 5 months (Exon 11: V560D) in the HDI arm. The other two pts (both Exon 11: 579 insert) in the HDI arm were still disease free for 6 months. The toxicities were consistent with the usual reported studies. Conclusions: In the C-Kit mutated melanoma pts, it’s promising that imatinib may provide more beneficial effect than HDI for high-risk melanomas. (Supported by the National Natural Science Foundation of China (30973483, 81172196, 81102068.) Clinical trial information: NCT01782508.

High-dose imatinib versus high-dose imatinib in combination with intermediate-dose cytarabine in patients with first chronic phase myeloid leukemia: a randomized phase III trial of the Dutch-Belgian HOVON study group

Despite the revolutionary change in the prognosis of chronic myeloid leukemia (CML) patients with the introduction of imatinib, patients with resistant disease still pose a considerable problem. In this multicenter, randomized phase III trial, we investigate whether the combination of high-dose imatinib and intermediate-dose cytarabine compared to high-dose imatinib alone, improves the rate of major molecular response (MMR) in newly diagnosed CML patients. This study was closed prematurely because of declining inclusion due to the introduction of second generation tyrosine kinase inhibitors and only one third of the initially required patients were accrued. One hundred nine patients aged 18-65years were randomly assigned to either imatinib 800mg (n = 55) or to imatinib 800mg in combination with two successive cycles of cytarabine 200mg/m(2) for 7days (n = 54). After a median follow-up of 41months, 67% of patients were still on protocol treatment. The MMR rate at 12months was 56% in the imatinib arm and 48% in the combination arm (p = 0.39). Progression-free survival was 96% after 1year and 89% after 4years. Four-year overall survival was 97%. Adverse events grades 3 and 4 were more common in the combination arm. The addition of intermediate-dose of cytarabine to imatinib did not improve the MMR rate at 12months. However, the underpowering of the study precludes any definitive conclusions. This trial is registered at www.trialregister.nl (NTR674).

Outcome of Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Based On Early Molecular Response and Factors Associated with Early Response: 4-Year Follow-up Data From Enestnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients)

Abstract Abstract 167 Background: In the ENESTnd study, nilotinib significantly reduced progression to accelerated phase/blast crisis (AP/BC) and demonstrated superior rates of deep molecular response vs imatinib. Data from ENESTnd demonstrated that significantly more patients achieved early molecular response of both < 10% and < 1% BCR-ABLIS at both 3 and 6 months on nilotinib vs imatinib. Here, we report landmark analyses based on BCR-ABL transcript levels at 3 and 6 months using data with a minimum follow-up of 3 years and also provide data on factors associated with poor early molecular response; data based on longer follow-up of 4 years will be presented. Methods: The nilotinib 300 mg twice daily (BID; n = 282) and imatinib 400 mg once daily (QD; n = 283) arms from ENESTnd were used for this analysis. Patients were grouped based on BCR-ABL transcript levels of ≤ 1%, > 1% to ≤ 10%, and > 10% at 3 months (n = 258 and n = 264 patients with available PCR samples at 3 months in the nilotinib and imatinib arms, respectively) and at 6 months (n = 257 and n = 256 patients with available PCR samples at 6 months in the nilotinib and imatinib arms, respectively). Rates of major molecular response (MMR; ≤ 0.1% BCR-ABLIS) and molecular response with a 4.5-log reduction in BCR-ABL transcript levels (MR4.5, ≤ 0.0032%IS) as well as rates of progression-free survival (PFS) and overall survival (OS) were evaluated among patients grouped according to their BCR-ABL transcript levels at 3 and 6 months. Data on selected baseline characteristics and dose intensity were also assessed. Results: Among evaluable patients at 3 months, 9% of patients (n = 24) in the nilotinib arm vs 33% (n = 88) in the imatinib arm had BCR-ABL transcript levels of > 10%; among evaluable patients at 6 months, 3% of patients (n = 7) in the nilotinib arm vs 16% (n = 40) in the imatinib arm had BCR-ABL transcript levels of > 10%. Patients with a BCR-ABL transcript level of > 10% had a lower probability of future MMR or MR4.5 as well as poorer PFS and OS compared with patients who had BCR-ABL transcript levels ≤ 10% at 3 months (Table). Results were similar based on 6-month landmark analyses. In patients with > 10% BCR-ABL transcript levels at 3 months, the average dose intensity of nilotinib within the first 3 months was 474 mg/day compared with 600 mg/day for patients with ≤ 10% BCR-ABL transcript levels; the average dose intensity of imatinib within the first 3 months was the same (400 mg/day) for patients with both ≤ 10% and > 10% BCR-ABL levels at 3 months (Table). Patients with > 10% BCR-ABL transcript levels at 3 months were also more likely to have high Sokal risk, larger spleen size, and additional chromosomal abnormalities compared with patients with ≤ 10% BCR-ABL transcript levels at 3 months. Other factors associated with early response and further data on long-term outcomes are being assessed and will be presented with a minimum follow-up of 4 years. Conclusions: Fewer patients in the nilotinib arm vs the imatinib arm had BCR-ABL transcript levels > 10% at 3 and 6 months. Reasons for poor early response appeared to be related, at least in part, to baseline factors and dose intensity. Early molecular response at 3 and 6 months correlated with future MMR and MR4.5as well as an increased probability of PFS and OS. Nilotinib frontline therapy allows more patients to achieve deeper responses earlier, associated with improved long-term outcomes vs imatinib. Disclosures: Hochhaus: BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Hughes:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; CSL: Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Guilhot:Celgene: Consultancy; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Ariad: Honoraria. Al-Ali:Novartis: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Sanofi-Aventis: Consultancy, Honoraria. Rosti:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Speakers Bureau. Kemp:Novartis Pharmaceuticals Corp: Employment. Fan:Novartis Pharmaceuticals Corp: Employment. Hoenekopp:Novartis Pharma AG: Employment, Equity Ownership. Larson:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy; Ariad: Consultancy, Research Funding. Kantarjian:Novartis Pharmaceuticals Corp: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding.

ABCG2 Polymorphism Is Associated with Lower Major Molecular Response Rates in CML Patients Treated with 400 Mg Imatinib but Not in Patients Treated with 600 Mg Imatinib.

AbstractAbstract 2465 BackgroundThis study was designed to identify single nucleotide polymorphisms (SNPs) associated with probability of achieving a major molecular response (MMR) in chronic phase CML patients (pts) treated with imatinib. We used a non-commercial, pharmacogenetics-dedicated DNA chip containing 16561 SNPs covering 1916 candidate genes. We tested an exploratory cohort of pts treated with imatinib first line or after interferon therapy and then extended our finding in a validation set of pts included in the French SPIRIT trial (C Preudhomme, NEJM 2011) and randomized to the 400 mg or the 600 mg imatinib arm. Patients and methodsConstitutive DNA samples from 312 pts were analyzed: samples from 91 pts in the exploratory set and 221 pts in the validation set (SPIRIT trial: 120 pts within the 400 mg imatinib arm and 101 pts within the 600 mg imatinib arm). We analyzed the expression of BCR-ABL/ABL standardized ratio as a function of the time elapsed since imatinib initiation for each patient using nonlinear (spline) interpolation and then derived the delay to achieve MMR or time of follow-up. With this method, we obtained a cumulative incidence curve of MMR in both groups. Relevant SNPs were identified using a COX model adjusted for covariates (sex, two first principal components and Sokal score when available). SNP with FDR (False Discovery Rate) below 30% in the exploratory cohort where subsequently investigate in the SPIRIT trial groups. ResultsPatient characteristics such as age, sex, Sokal score were homogeneous between exploratory and validations sets as well as within both arms of the SPIRIT trial. We confirmed the prognostic value of the Sokal score in term of cumulative incidence of MMR (CI-MMR) in both sets of pts (CI-MMR was 83%, 67% and 56% for low, intermediate and hight Sokal risk groups respectively, additive log rank, p < 0.001), as well as the significant improvement of CI-MMR within the SPIRIT trial for pts assigned to the 600 mg daily imatinib arm as compared to the 400 mg daily arm (CI-MMR was 80% in the 600 mg imatinib arm compared to 61% in 400 mg/day arm, log rank, p = 0.008). CI-MMR was similar between exploratory set and the 400 mg/day arm of the SPIRIT trial (63% vs 61%, log rank, p = 0.56) and higher in the 600 mg arm of the SPIRIT trial compared to the exploratory set: 80% vs 63% (log rank, p < 0.001), consistent with dose received in the exploratory set (imatinib 400 mg/d).Association study shows that 10 SNPs identified pts with significantly different probability to achieve MMR within the two first year of therapy (FDR less than 30% p < 0,01) in the exploratory cohort three of which belong to ABCG2 gene. In the SPIRIT trial (n=221), only two SNPs from ABCG2 locus were significantly associated with a higher probability of achieving MMR. We then analyzed separately both arms of the SPIRIT trial. All tree ABCG2-SNPs identified in the exploratory set of pts were significantly associated with CI-MMR in the 400 arm at the 5% level. In contrast, none of them were confirmed in the 600 mg arm. In order generalize our results and to get closer to the underling molecular structure of genotypes markers we performed haplotyping at locus of ABCG2 gene. Multivariate analysis distinguished two minor haplotypes (haplotype 1 and 3) linked to MMR achievement in pts receiving 400 mg/day of imatinib (from exploratory set and SPIRIT, n=211). Haplotypes 1 had G-C-G and haplotype 2 had G-T-G at rs12505410, rs13120400 and rs2725252 respectively and their frequencies were 26 and 6% respectively. Collapsing these haplotypes yielded a surrogate dominant marker highly associated to CI-MMR in this group (p < 0.001, figure 1A) whereas in the SPIRIT 600 mg arm, this phenomenon did not hold anymore (p=0.25, figure 1B). Interestingly, CI-MMR in the 400 mg/day harboring a copy of minor haplotypes (1 or 3) was comparable to the CI-MMR observed in pts receiving 600 mg/d imatinib lacking of at least one copy of the two minor haplotypes (75% vs 70% respectively, p=0.99) or whatever haplotype they had (75% vs 80%, p=0.37). ConclusionThe ABCG2 gene product is a well-known protein involved in drug absorption in the bowel. Polymorphism of the ABCG2 gene has been implicated in drugs absorption including imatinib. We here confirm that ABCG2 haplotypes could distinguish patients at a lower probability to achieve MMR. We report for the first time that this unfavorable pharmacologic effect can be overcome in vivo by increasing imatinib daily dose from 400 mg to 600 mg. [Display omitted] Disclosures:Rousselot:BMS, Novartis: Research Funding. Guilhot:ARIAD: Honoraria.

Incidence of Hyperglycemia by 3 Years in Patients (Pts) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Nilotinib (NIL) or Imatinib (IM) in ENESTnd

Abstract Abstract 1686 Background: ENESTnd established the superior efficacy of frontline NIL vs IM in pts with CML-CP. An association between NIL treatment and hyperglycemia has been previously reported. NIL-mediated increases in fasting plasma glucose levels (FGLs) have been shown to be reversible, with levels returning to normal on treatment discontinuation; in contrast, IM has been shown to decrease FGLs in pts with diabetes (Breccia M, Alimena G. Leuk Res. 2009;33:871–875). Here, we report the incidence of hyperglycemia and related glycemic outcomes with NIL and IM by 3 y in ENESTnd. Methods: Pts were randomized to receive NIL 300 mg twice daily (BID; n = 282), NIL 400 mg BID (n = 281), or IM 400 mg once daily (QD; n = 283). This analysis included randomized pts who had ≥1 dose of study drug and no drug treatment for diabetes mellitus /prediabetes at baseline (BL; 264, 262, and 267 pts in the NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively); pts with treated diabetes at BL (15, 15, and 13 pts, respectively) were excluded. Hyperglycemia was defined as FGL ≥1.1 g/L, prediabetes as FGL ≥1.1 g/L to &lt; 1.26 g/L or glycated hemoglobin (HbA1C) ≥5.7% to &lt; 6.5%, and diabetes as FGL ≥1.26 g/L or HbA1C ≥6.5%. These criteria represent a combination of World Health Organization and American Diabetes Association guidelines. Results: At BL, median age and mean body mass index (BMI) were similar across the 3 arms (Table). In the NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively, 34.9%, 35.5%, and 37.8% of pts had untreated prediabetes at BL, and 6.1%, 6.1%, and 3.4% of pts had untreated diabetes at BL. Median time on treatment in the 3 arms was similar (≈ 3 y). Cumulative incidence of hyperglycemia by 3 y was higher with NIL vs IM (Table). By 3 y, grade 3/4 hyperglycemia was reported in 6 (2.3%), 7 (2.7%), and 0 pts on NIL 300 mg BID, NIL 400 mg BID, and IM, respectively; no pt discontinued due to hyperglycemia. Median time to hyperglycemia was longer with NIL 300 mg BID than with NIL 400 mg BID. From BL to 3 y, there were minimal changes in mean BMI and mean HbA1C in all 3 arms; greater increases in mean fasting insulin were observed with NIL vs IM. Excluding pts with diabetes at BL, 20.1%, 22.8%, and 8.9% of pts developed diabetes by 3 y, and 48.8%, 51.6%, and 50.0% developed prediabetes by 3 y (NIL 300 mg BID, NIL 400 mg BID, and IM, respectively). Relatively few pts required antidiabetic medication by 3 y. Based on a multivariate analysis, prediabetes at BL was a risk factor for development of hyperglycemia in all 3 treatment arms (P =.0252.0004, and.0296 [NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively]). Age &gt; 60 y at BL was a risk factor for NIL 300 mg BID (P =.0183) and IM (P =.0010) but was not a risk factor for NIL 400 mg BID (P =.6001). Dyslipidemia (P =.0455) at BL was identified as an additional risk factor for development of hyperglycemia on IM in the multivariate analysis. Conclusions: In ENESTnd, the incidence of hyperglycemia by 3 y was higher with NIL vs IM. However, most events were low grade, HbA1C levels remained stable over time, and few pts required antidiabetic medication. The underlying mechanism of action driving NIL-mediated hyperglycemia is unknown, but the increases in fasting insulin observed suggest NIL therapy is associated with insulin resistance. NIL-treated pts with CML-CP and BL risk factors for diabetes should be monitored closely. Disclosures: Delphine: Novartis: Honoraria; BMS: Honoraria; Teva: Honoraria. Gautier:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Breccia:Novartis: Honoraria; BMS: Honoraria; Celgene: Honoraria. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Hughes:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; CSL: Research Funding. Kantarjian:Novartis Pharmaceuticals Corp: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Kemp:Novartis Pharmaceuticals Corp: Employment. Gao:Novartis: Employment. Piccolo:Novartis Pharma AG: Employment. Larson:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy; Ariad: Consultancy, Research Funding. Hochhaus:BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding.

Enestnd 4-Year (y) Update: Continued Superiority of Nilotinib Vs Imatinib in Patients (pts) with Newly Diagnosed Philadelphia Chromosome–Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Abstract Abstract 1676 Background: Pts treated with nilotinib in the ENESTnd phase 3 trial achieved higher and faster rates of major molecular response (MMR, ≤ 0.1% BCR-ABLIS), deeper molecular responses (MR4, ≤ 0.01%IS and MR4.5, ≤ 0.0032%IS), significantly lower rates of progression to accelerated phase/blast crisis (AP/BC), and fewer CML-related deaths compared with imatinib by 1, 2, and 3 y. Here, we report data with a minimum follow-up of 3 y; efficacy and safety data based on longer follow-up of 4 y will be presented to further assess the impact of nilotinib vs imatinib in pts with newly diagnosed Ph+ CML-CP. Methods: Adult pts (N = 846) 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, progression-free survival (PFS), and overall survival (OS) were evaluated. Results: Significantly higher rates of MMR, MR4, and MR4.5 by 3 y were achieved in nilotinib- vs imatinib-treated pts (Table). Nilotinib led to the achievement of higher rates of molecular responses regardless of Sokal risk group or age. The difference in the rates of both MR4 and MR4.5 continued to be significantly higher for nilotinib, with the difference in favor of nilotinib increasing from 1 to 3 y (MR4: 9%-14% difference by 1 y, 18%-24% difference by 3 y; MR4.5: 6%-10% difference by 1 y, 13%-17% difference by 3 y). Among patients who achieved MMR, more pts achieved MR4 or MR4.5 on nilotinib 300 mg BID (68%) and nilotinib 400 mg BID (62%) compared with imatinib (49%). No pt in any arm progressed after achieving MR4.5. Significantly fewer pts progressed to AP/BC on nilotinib vs imatinib (Table). No new progressions occurred on core treatment between the 2-y and 3-y analyses. When events occurring after treatment discontinuation were included, the rates of progression to AP/BC were also significantly lower with nilotinib vs imatinib (Table). Nearly twice as many pts had emergent mutations on imatinib (n = 21) vs either nilotinib arm (n = 11 in each arm), with 5 pts overall developing mutations between 2 and 3 y. OS remained similar in all groups at 3 y, but fewer CML-related deaths occurred in both the nilotinib 300 mg BID (n = 5) and 400 mg BID (n = 4) arms vs imatinib (n = 14). Both drugs were well tolerated. Few new adverse events (AEs) and laboratory abnormalities were observed between 2 and 3 y. Rates of discontinuation due to AEs were 10%, 14%, and 11% in the nilotinib 300 mg BID, nilotinib 400 mg BID, and imatinib arms, respectively. Conclusions: Nilotinib continues to demonstrate superiority vs imatinib, yielding faster and deeper molecular responses and a significantly decreased risk of progression. Results of ENESTnd support the use of nilotinib as a standard of care option in newly diagnosed adult pts with Ph+ CML-CP and should be considered to replace imatinib as the standard-of-care frontline therapy for patients with Ph+ CML-CP. Disclosures: Kantarjian: Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Kim:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ARIAD: Research Funding; II-Yang: Research Funding. Clark:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: 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. Reiffers:BMS: Expense reimbursement for travel expenses Other; Novartis: Expense reimbursement for travel expenses, Expense reimbursement for travel expenses Other. Nicolini:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria. Hughes:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; CSL: Research Funding. Hochhaus:BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Kemp:Novartis Pharmaceuticals Corp: Employment. Fan:Novartis Pharmaceuticals Corp: Employment. Waltzman:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Larson:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy; Ariad: Consultancy, Research Funding.

Assessment of Early Molecular Response As a Predictor of Long-Term Clinical Outcomes in the Phase 3 BELA Study

Abstract 69 Bosutinib (BOS) is an oral, dual Src/Abl kinase inhibitor. In the randomized, phase 3 BELA trial, BOS 500 mg/d demonstrated clinical activity in newly diagnosed (≤6 mo) chronic phase chronic myeloid leukemia (CP CML) and manageable toxicity distinct from that of imatinib (IM) 400 mg/d. This analysis of the BELA trial investigated reduction in Bcr-Abl/Abl ratio at Months 3, 6, and 9 as early predictors of long-term outcomes. Baseline characteristics were well balanced between treatment arms. Dose escalation to 600 mg/d occurred in 6% of patients (pts) on BOS and 18% of pts on IM. The most common reason for BOS discontinuation was toxicity (24% vs 7% on IM), and for IM was progressive disease (13% vs 4% on BOS). Data included a minimum follow-up of 24 mo. In the intent-to-treat population, the rate of major molecular response (MMR; Bcr-Abl/Abl ratio ≤0.1% on International Scale [IS]) was higher at all time points for BOS versus IM, with a significantly shorter median time to MMR for BOS (48 wks) versus IM (73 wks; P In both arms, a Bcr-Abl/Abl ratio ≤10% versus >10% at Months 3, 6, and 9 was predictive of significantly higher cumulative rates of MMR and CCyR by both 12 mo and 24 mo (Table). The rates of MMR by 12 and 24 mo were generally highest among pts with a Bcr-Abl/Abl ratio ≤1% at Month 3, 6, and 9 in both arms. A similar trend was generally observed for on-treatment event-free survival (EFS; included death, transformation to accelerated/blast phase, increased white blood cell count without complete hematologic response [CHR], or loss of CHR or CCyR) and overall survival (OS) at 24 mo (Table). In the BOS arm, Kaplan-Meier estimates at 24 mo were significantly higher with a Bcr-Abl/Abl ratio ≤10% versus >10% for EFS at Months 3, 6, and 9, and for OS at Months 3 and 9. Furthermore, Kaplan-Meier estimates of EFS and OS at 24 mo were significantly higher for pts with Bcr-Abl/Abl ratio ≤10% versus >10% at Months 6 and 9 in the IM arm. Within each treatment arm, estimated rates of EFS and OS at 24 mo generally appeared similar for pts with reduction of Bcr-Abl/Abl ratio ≤1% versus ≤10% at early time points. In summary, a Bcr-Abl/Abl ratio ≤10% versus >10% at Months 3, 6, and 9 was associated with higher rates of MMR and CCyR by later time points in both arms. A lower Bcr-Abl ratio was also predictive of EFS after 24 mo of follow-up except for IM at Month 3, and of OS except for IM at Month 3 and BOS at Month 6. However, because of the very limited number of EFS and OS events and the relatively few pts with a Bcr-Abl/Abl ratio >10% (particularly in the BOS arm at Months 6 [n = 12] and 9 [n = 6]), longer follow-up in the BELA trial is needed to fully characterize the predictive properties of early reductions in Bcr-Abl/Abl ratio on long-term EFS and OS. Disclosures: Brummendorf:Bristol Myer Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Patent on the use of imatinib and hypusination: Patents & Royalties. Kantarjian:Pfizer Inc: Research Funding. Gambacorti-Passerini:Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy. Guilhot:Celgene, Bristol Myers Squibb: Consultancy. Akard:Pfizer, Novartis, Merck, Bristol Myers Squibb: Research Funding; Novartis, BMS, Eisai, Millenium, Celgene: Speakers Bureau. Pavlov:Pfizer Inc: Employment, Equity Ownership. Gogat:Pfizer Inc: Employment, Equity Ownership. Duvillie:Pfizer Inc: Employment. Shapiro:Pfizer Inc: Employment, Equity Ownership. Cortes:Novartis, Bristol Myers Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding.

Assessment of Patient Reported Outcomes (PROs) From the Enestnd Trial with Minimum Follow-up of 36 Cycles.

AbstractAbstract 3166 Background:In ENESTnd, nilotinib (NI) significantly reduced progression and demonstrated superior molecular response rates vs. imatinib (IM) in patients newly diagnosed with Philadelphia chromosome positive chronic phase chronic myelogenous leukemia (CML-CP). Additionally, fewer NI patients discontinued therapy vs. IM (Table 1). Previously reported 24-month analyses of PROs indicated similar health-related quality of life (HRQoL) and functioning mean scores between the treatment arms, and scores similar to general population norms. Aim:To evaluate the PROs for patients in ENESTnd with minimum follow-up of 36 cycles and to understand cohort-level (per treatment arm) HRQoL outcomes Methods:In ENESTnd, nNewly diagnosed CML-CP patients were randomized to NI 300 mg twice daily (BID), NI 400 mg BID, or IM 400 mg once daily (QD). HRQoL was assessed using the Functional Assessment of Cancer Therapy – Leukemia (FACT-Leu) and the Short Form 36 Health Survey (SF-36). The FACT-Leu has two components: a) the FACT-General (FACT-G) which measures physical, social/family, emotional, and functional well-being and b) a 17-item leukemia specific subscale. The SF-36 assesses eight domains (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health) that enable a mental component score (MCS) and physical component score (PCS). Questionnaires were administered at enrollment and end of cycles 3, 12, 24, and 36. Mixed effects models for longitudinal data were used to compare trends over time between treatment arms. Study discontinuation prevented collection of PROs from patients with inadequate response or intolerance to treatment. Pattern-mixture models were fit to attempt to control for missing PRO data resulting from discontinuation or other reasons. Separately, missing data were imputed consistently across arms for cohort-level analysis of the FACT-Leu subscale so mean cohort scores could be reported (Table 1). Results:In both mixed effects and pattern-mixture models, FACT-Leu subscale, FACT-G, and SF-36 scores (PCS and MCS) were similar across treatment arms over time. Of the patients remaining on study and completing PRO questionnaires, SF-36 PCS and MCS scores at cycle 36 in all arms were comparable to the general US population; FACT-G scores were slightly better (Table 2). In the cohort-level analysis with imputation according to reason, IM FACT-Leu subscale scores began to trend increasingly lower vs. NI arms beginning at day 168 (Figure 1). By day 1008, the IM arm mean score is 10% and 13% lower than the NI 300 mg and NI 400 mg arms, respectively (Figure 1). Higher rates of discontinuation in the IM arm are the main factors that lead to the HRQoL deficit. Conclusions:In ENESTnd, patients who respond to and tolerate treatment have consistent HRQoL that is comparable to the general population. Cohort-level analysis indicates that discontinuation rates due to inadequate response and intolerance must be considered when determining the HRQoL across the entire cohort. These results suggest that in a population of newly diagnosed patients with CML-CP, NI results in higher HRQoL than IM. These findings may have particularly important implications for payers and policy makers when evaluating treatment options.Table 1IM 400mg QD (n=283) (%)NI 300mg BID (n=282) (%)NI 400mg BID (n=281) (%)Imputed FACT-LEUbStill on treatment61.870.973.7MeanDisease progression3.50.71.40Suboptimal response/treatment failure4.21.82.814Adverse events/lab abnormalities11.09.914.214Death0.41.40.40Other a6.77.86.414aIncludes abnormal test result(s), condition no longer requires study drug, consent withdrawn, lost to follow-up, administrative problems, protocol deviationbImputed values per time point, 14 represents the lowest recorded scoreTable 2Mean (SD)IM 400mg QD (n=152)NI 300mg BID (n=176)NI 400mg BID (n=185)General US Pop.SF-36 PCS49.1 (9.0)47.9 (9.5)49.1 (8.2)49.6 (10.0)cSF-36 MCS51.3 (9.6)50.2 (9.7)49.9 (9.0)50.5 (9.9)cFACT-G86.0 (15.7)84.5 (15.4)85.1 (15.0)80.1 (18.1)dFACT-Leu subscale54.7 (9.4)54.9 (8.9)55.4 (8.5)NAcFor ages 45–54 (http://www.sf-36.org/research/sf98norms.pdf)dEval Health Prof 2005; 28:192–211. [Display omitted] Disclosures:Beaumont:Novartis: Research Funding. Magestro:Novartis: Employment. Coombs:Novartis: Employment. Fan:Novartis Pharmaceuticals Corp: Employment. Kemp:Novartis Pharmaceuticals Corp: Employment. Waltzman:Novartis: Employment.

Nilotinib Versus High-Dose Imatinib in Early Chronic Phase CML Patients Who Have Suboptimal Molecular Responses to Standard-Dose Imatinib: Updated Data From RE-Nice Study

AbstractAbstract 3775 Background.In chronic myeloid leukemia (CML), achievement of optimal responses by time point has improved long-term outcomes. In contrast, several clinical studies investigating the clinical implications of suboptimal response showed that patients with suboptimal responses tend to have poor long-term outcomes. In IRIS study, patients who achieved major molecular response (MMR) at 18 months had event-free survival (EFS) benefit, compared to those who achieved complete cytogenetic response (CCyR) without MMR. However, the best treatment for these patients is still not confirmed. By the previous studies, sustaining standard-dose of imatinib (IM) is expected to yield less than 20 percent of additive MMR. In this prospective study, we investigated whether switching to nilotinib (NIL) or high-dose IM may be more effective for patients with suboptimal molecular response to IM as first-line therapy. Methods.Early chronic phase (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 IM therapy at a daily dose of 400 mg were enrolled in this clinical trial, and informed consents were obtained from all patients. In NIL arm, patients received oral dose of 400 mg BID (800 mg/day) and in high-dose IM arm, patients received 800 mg/day administrated as 400 mg BID. Primary endpoint is to evaluate the cumulative MMR rates by 12 months, and secondary endpoints are to evaluate the cumulative MMR, MR4.0 and undetectable molecular residual disease (UMRD) rates during further 24 month follow-up. Safety profiles will also be assessed. 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. Results.With a data cut-off date of 10 Jul 2012, a total of 43 patients were randomized into NIL arm (n = 22) or high-dose IM arm (n = 21). With a median follow-up of 15 months (range, 1–36), all patients have maintained CCyR without progression to advanced disease, and progressive decrease in BCR-ABL1 transcript levels was observed in all patients. Cumulative incidence (CI) of MMR by 12 months showed no significant difference between NIL arm and high-dose IM arm (37.8 ± 11.9% vs 34.8 ± 10.6%, P = 0.789). In NIL arm, 3 in 22 (14%) and 2 in 22 (9%) patients achieved MR4.0 and UMRD, respectively, and in high-dose IM arm, 1 in 21 (5%) patients achieved MR4.0. Overall, the patients treated with high-dose IM showed toxicities more frequently, such as fatigue, dyspnea and decreased phosphate. In addition, 10 patients in high-dose IM arm have cross-over to NIL treatment due to lack of response (n=9) and intolerance (n=1), and the median duration of NIL treatment was 14 months (range, 7–26 months). Among them, 5 (50%) patients have achieved MMR with a median NIL treatment duration of 12 months (range, 3–18). Conclusions.These results demonstrate that early switching to NIL or dose escalation of IM could be recommended, considering the results of standard dose of IM in suboptimal molecular responders. When the tolerability of treatment was considered for switching to NIL or high-dose IM, NIL may be preferred. Through further clinical investigation on a large patient population and longer period observation, the efficacy and safety of early intervention of suboptimal molecular response using NIL or dose escalation of IM will be needed. Updated data with longer follow-up duration will be presented in the meeting. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Bosutinib Versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Results From the BELA Trial

Bosutinib is an oral Src/Abl tyrosine kinase inhibitor. The phase III Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia (BELA) trial compared bosutinib with imatinib in newly diagnosed, chronic-phase chronic myeloid leukemia (CML). A total of 502 patients were randomly assigned 1:1 to bosutinib 500 mg per day or imatinib 400 mg per day. The complete cytogenetic response (CCyR) rate at 12 months was not different for bosutinib (70%; 95% CI, 64% to 76%) versus imatinib (68%; 95% CI, 62% to 74%; two-sided P = .601); therefore, the study did not achieve its primary end point. The major molecular response (MMR) rate at 12 months was higher with bosutinib (41%; 95% CI, 35% to 47%) compared with imatinib (27%; 95% CI, 22% to 33%; two-sided P < .001). Time to CCyR and MMR was faster with bosutinib compared with imatinib (two-sided P < .001 for both). On-treatment transformation to accelerated/blast phase occurred in four patients (2%) on bosutinib compared with 10 patients (4%) on imatinib. A total of three CML-related deaths occurred on the bosutinib arm compared with eight on the imatinib arm. The safety profiles of bosutinib and imatinib were distinct; GI and liver-related events were more frequent with bosutinib, whereas neutropenia, musculoskeletal disorders, and edema were more frequent with imatinib. This ongoing trial did not meet its primary end point of CCyR at 12 months, despite the observed higher MMR rate at 12 months, faster times to CCyR and MMR, fewer on-treatment transformations to accelerated/blast phase, and fewer CML-related deaths with bosutinib compared with imatinib. Each drug had a distinct safety profile.

Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION)

AbstractDasatinib is a highly potent BCR-ABL inhibitor with established efficacy and safety in imatinib-resistant/-intolerant patients with chronic myeloid leukemia (CML). In the phase 3 DASISION trial, patients with newly diagnosed chronic-phase (CP) CML were randomized to receive dasatinib 100 mg (n = 259) or imatinib 400 mg (n = 260) once daily. Primary data showed superior efficacy for dasatinib compared with imatinib after 12 months, including significantly higher rates of complete cytogenetic response (CCyR), confirmed CCyR (primary end point), and major molecular response (MMR). Here, 24-month data are presented. Cumulative response rates by 24 months in dasatinib and imatinib arms were: CCyR in 86% versus 82%, MMR in 64% versus 46%, and BCR-ABL reduction to ≤ 0.0032% (4.5-log reduction) in 17% versus 8%. Transformation to accelerated-/ blast-phase CML on study occurred in 2.3% with dasatinib versus 5.0% with imatinib. BCR-ABL mutations, assessed after discontinuation, were detected in 10 patients in each arm. In safety analyses, fluid retention, superficial edema, myalgia, vomiting, and rash were less frequent with dasatinib compared with imatinib, whereas pleural effusion and grade 3/4 thrombocytopenia were more frequent with dasatinib. Overall, dasatinib continues to show faster and deeper responses compared with imatinib, supporting first-line use of dasatinib in patients with newly diagnosed CML-CP. This study was registered at ClinicalTrials.gov: NCT00481247.

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.

Favorable Therapeutic Responses in Newly Diagnosed CML-CP Patients Induced by Dasatinib Are Reflected At the CD34+CD38+ Progenitor Cell but Not At the CD34+CD38− Stem Cell Level: Results From Randomized NordCML006 Study

Abstract 784 Background:In vitro studies have suggested that CML stem cells are resistant to tyrosine kinase inhibitors (TKIs), but in vivo effects in patients have not been prospectively assessed. Furthermore, the inter-individual variation of the leukemic stem cell pool at diagnosis and its possible prognostic value is unknown. Patients:46 newly diagnosed CML-CP patients were randomized 1:1 to receive either dasatinib 100 mg or imatinib 400 mg QD. The primary endpoint was a comparison of the proportion of Ph+ cells in CD34+CD38− and CD34+CD38+ compartment at 6 months between the study arms. Key secondary endpoints were the fraction of Ph+ cells in the stem cell compartments at 1 and 3 months, and molecular and cytogenetic responses at 3, 6, 12 and 18 months. Experimental endpoints included the percentage of Ph+ cells in the stem cell compartment at diagnosis and its correlation with therapeutic response. Results:One patient in the imatinib arm and none in the dasatinib arm progressed to blast crisis within first 12 months. 4/22 of dasatinib patients have discontinued the treatment due to side-effects (mainly pleural effusion) and 1 patient due to insufficient response. 3/24 imatinib patients have discontinued the therapy (1 blast crisis, 1 side-effects, 1 other malignancy).Early cytogenetic responses were superior in the dasatinib arm: the median percentage of Ph+ cells in the bone marrow was 81% (imatinib) vs. 70% (dasatinib) at 1 month (p=0.15) and 5% vs. 0% at 3 months (p=0.0085). At 12 months all dasatinib (n=20) and 19/20 imatinib patients were in CCyR (results based on patients on treatment at 12 months).MMR rate was significantly higher in the dasatinib arm already at 6 months (70% vs. 20%, p=0.002) and similarly at 9 (75 vs. 26%, p=0.004) and 12 months (88% vs. 40%, p=0.009). Undetectable BCR-ABL1 transcripts (at least CMR4) were observed in 20% of the dasatinib patients at 6 months compared to none in the imatinib arm (p=0.11) and 44% in the dasatinib arm at 12 months compared to 7% in the imatinib arm (p=0.037).The median percentage of Ph+ cells, as measured by FISH (1000 cells analyzed), in the CD34+CD38− fraction at diagnosis was 79% (range 1–100%) compared to 96% (range 50–100%) in CD34+CD38+ fraction. The proportion of Ph+ cells in CD34+CD38− fraction correlated with WBC count (r=0.50, p<0.001), splenomegaly (r=0.43, p=0.0055), anemia (r=-0.44, p=0.004) and blood blast percentage (r=0.57, p=0.0001) at diagnosis. There was also a significant correlation between Ph+ cells in CD34+CD38− fraction at diagnosis and cytogenetic response at 1 (r=0.63, p<0.0001), 3 (r=0.48, p=0.0025) and 6 months (r=0.36, p=0.0271). Furthermore, leukemic stem cell burden at diagnosis correlated significantly with BCR-ABL1 transcript levels at 3 (r=0.54, p=0.0005), 6 (r=0.42, p=0.0088) and 9 months (r=0.40, p=0.0123). All patients who were not in MMR at 18 months, had >79% of Ph+ cells in CD34+CD38− fraction at diagnosis.During TKI therapy, the proportion of Ph+ cells decreased rapidly in the stem cell fractions. At 1 month, the median proportion of Ph+ cells was 14% and 56% in CD34+CD38− and CD34+CD38+ fractions compared to 69% in whole BM (p<0.0001, n=38). At 3 months, the respective numbers were 0.40%, 0.20% and 0.80% (p=0.087, n=33) and at 6 months 0%, 0% and 0.1% (p=0.23, n=41).Dasatinib-treated patients had significantly lower proportion of Ph+ cells in CD34+CD38+ fraction at 3 months than imatinib patients (0.05% vs. 0.68%, p=0.0318). A similar trend was also observed at 1 month (24% vs. 69%, p=0.05), but no difference existed at 6 months. In CD34+CD38− fraction the proportions of Ph+ cells did not differ significantly at 1 (11 vs. 17%, p=0.91), 3 (0.2 vs. 0.3%, p=0.44) or 6 months (0 vs. 0%, p=0.75). Conclusions:In comparison to imatinib, dasatinib induced superior therapeutic responses with remarkably high MMR and CMR rates. This was associated with a faster reduction of Ph+ cells at the progenitor CD34+CD38+ cell level. Surprisingly, both drugs rapidly depleted Ph+ cells from the more primitive CD34+CD38− compartment.The proportion of Ph+ stem cells at diagnosis varied significantly among individual patients and bore prognostic value. Patients with a low proportion of Ph+ leukemic stem cells at diagnosis achieved faster and better cytogenetic and molecular responses. The leukemic stem cell burden at diagnosis may be a biomarker predicting treatment outcome and reflecting key biological factors in CML. Disclosures:Mustjoki:Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Richter:Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Dybedal:Novartis: Travel support. Fioretos:Cantargia AB: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Qlucore AB: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Weiss Bjerrum:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy. Simonsson:Novartis, BMS, Merck, Pfizer: Consultancy, Honoraria. Porkka:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Hjorth-Hansen:Novartis: Honoraria; Bristol-Myers Squibb: Honoraria.

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.