Rates Of MMR Research Articles

Complete Molecular Remission (CMR 4.5) of CML Is Induced Faster by Dose – Optimized Imatinib and Predicts Better Survival - Results From the Randomized CML-Study IV

AbstractAbstract 67Dose optimized imatinib (IM) at doses of 400– 800mg has been shown to induce faster and deeper cytogenetic and molecular – responses than standard IM (400mg/day). Since complete molecular remission (CMR 4.5) identifies a subgroup of patients who may stay in remission even after discontinuation of treatment, it was of interest to analyse whether CMR 4.5 is reached faster with dose optimized IM and whether CMR 4.5 correlates with survival.CMR 4 and CMR 4.5 are defined as ≤ 0.01% BCR-ABL IS or ≥ 4. log reduction and ≤ 0.0032% BCR-ABL IS or ≥ 4.5 log reduction, respectively, from IRIS baseline as determined by real-time PCR. CML-Study IV is a five arm randomized study of IM 400 mg vs IM 400 mg + IFN vs. IM 400 mg + Ara C vs. IM after IFN failure vs. IM 800 mg. In the IM 800 arm, a 6 weeks run in period at IM 400 mg was followed by a dose increase to 800 mg and then by a dose reduction according to tolerability. Grade 3 or 4 adverse effects (AE) were to be avoided. From July 2002 to March 2012 a total of 1551 patients with newly diagnosed chronic phase CML were randomized of whom 1525 were evaluable. Median age was 52 years, 88% were EUTOS low risk, 12% high risk, 36% were Euro score low risk, 52% intermediate and 12% high risk, 38% were Sokal low risk, 38% intermediate and 24% high risk. 113 patients were transplanted, 246 received 2nd generation TKI. 152 patients have died, 90 of CML or unknown reasons, 62 of not directly CML-related causes.After a median observation time of 67,5 months 6 years OS was 88.2% and PFS 85.6%. CCR, MMR, CMR 4 and CMR 4,5 were achieved significantly faster with dose optimized IM (400 – 800 mg). No significant differences in remission rates were observed between IM 400 mg and the combination arms IM 400 mg + IFN and IM 400 mg + Ara C, whereas IM after IFN failure thus far yielded significantly slower response rates. After 4 years CCR rates were for IM 400, IM 400 + IFN, IM 400 + Ara C, IM 400 after IFN, and IM 800, 80%, 75%, 73%, 59% and 80%, respectively, MMR rates 84%, 77%, 82%, 61% and 88%, CMR 4 rates 57%, 55%, 55%, 40% and 65%, and CMR 4.5 rates 40%,42%, 42%, 28% and 52%, respectively. CMR 4 was reached after a median of 27 months with IM 800 and 41.5 months with IM 400. CMR 4.5 was reached after a median of 41.5 months with IM 800 and 63 months with IM 400. EUTOS low risk patients reached all remissions faster than EUTOS high risk patients. The differences of CMR 4 rates between IM 800 and IM 400 at 3 years were 13% and at 4 years 8%, and of CMR 4.5 rates at 3 years 10% and at 4 years 13%. Grade 3 and 4 AE were not different between IM 400 and dose optimized IM 800.Independent of treatment approach, CMR 4 and more clearly CMR 4.5 at 3 years predicted better OS and PFS, if compared with patients without CMR 4 or CMR 4.5, respectively. CMR 4 and 4.5 were stable. After a median duration of CMR 4 of 3.7 years only 4 of 792 patients with CMR 4 have progressed. Life expectancy with CMR 4 and 4.5 was identical to that of the age matched population.We conclude that dose optimized IM induces CMR 4.5 faster than IM 400 and that CMR 4 and CMR 4.5 at 3 years are associated with a survival advantage. Dose optimized IM may provide an improved therapeutic basis for unmaintained treatment discontinuation in patients with CML. Disclosures:Hehlmann:Novartis: Research Funding. Müller:Novartis, BMS: Consultancy, Honoraria, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Hochhaus:Novartis, BMS, MSD, Ariad, Pfizer: Consultancy Other, Honoraria, Research Funding.

Switch to nilotinib versus continued imatinib in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with detectable BCR-ABL after 2 or more years on imatinib: ENESTcmr 12-month (mo) follow-up.

6505^ Background: Nilotinib induced significantly faster and deeper molecular responses vs imatinib in the ENESTnd trial. Achieving these deeper molecular responses may increase patient eligibility for future TKI discontinuation studies. Methods: CML-CP pts (N = 207) who achieved a complete cytogenetic response but were still BCR-ABL positive by RQ-PCR after ≥ 24 mo on imatinib were randomized 1:1 to receive nilotinib 400 mg BID (n = 104) or to continue their imatinib dose (400 or 600 mg QD [n = 103]). The primary endpoint was confirmed CMR (undetectable BCR-ABL by RQ-PCR with a sample sensitivity of ≥ 4.5 logs in 2 consecutive samples). Other endpoints included molecular responses (MMR ≤ 0.1%IS, MR4 ≤ 0.01%IS, and MR4.5 ≤ 0.0032%IS) and BCR-ABL ratio over time. Results: Rate of confirmed CMR was higher in the nilotinib arm vs imatinib by 12 mo (12.5% vs 5.8%) (Table). Rate of CMR (undetectable BCR-ABL in at least 1 sample) by 12 mo was significantly higher on nilotinib vs imatinib (23.1% vs 10.7%; P = .02). Rates of MMR, MR4, MR4.5, and CMR were also superior in pts switched to nilotinib, and these pts had significantly shorter times to achieve these responses. Imatinib-treated pts had minimal evidence of improvement in molecular response vs a median 0.5-log reduction in BCR-ABL by 12 mo for the nilotinib cohort. With 12-mo follow-up, 84% of pts remained on nilotinib and 96% on imatinib. The nilotinib safety profile was consistent with prior studies. Both drugs were well tolerated. Conclusions: Twice as many pts achieved deeper molecular responses after switching to nilotinib vs staying on imatinib. [Table: see text]

Nilotinib versus imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd 3-year (yr) follow-up (f/u).

6509^ Background: In ENESTnd, nilotinib significantly reduced progression to AP/BC and demonstrated superior rates of MMR, MR4, and MR4.5 vs imatinib with f/u of 2 yrs. Methods: 846 pts with Ph+ CML-CP were randomized to nilotinib 300 mg BID (n = 282), nilotinib 400 mg BID (n = 281), or imatinib 400 mg QD (n = 283). Here, we report 3-yr f/u data. Results: Both nilotinib doses continued to demonstrate significantly higher rates of MMR, MR4, and MR4.5 vs imatinib. In a landmark analysis, pts with BCR-ABL transcript levels ≤ 10% at 3 months (mo) had a higher probability of achieving MMR by 1 and 2 yrs vs pts with transcript levels > 10%. No new progressions occurred on treatment since the 2-yr analysis; rates of progression to AP/BC including events on treatment (n = 2, 3, 12) and those occurring both on treatment and after discontinuation (n = 9, 6, 19) were significantly lower for nilotinib 300 mg BID and nilotinib 400 mg BID vs imatinib, respectively. At 3 yrs, OS considering only CML-related deaths was significantly higher for nilotinib vs imatinib. The safety profiles of nilotinib and imatinib were similar to those at 2 yrs. Conclusions: 3-yr f/u confirms the superiority of nilotinib vs imatinib and an acceptable tolerability profile for the treatment of pts with newly diagnosed Ph+ CML-CP. [Table: see text]

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.

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.

Kinetics of Molecular Response with Different Tyrosine Kinase Inhibitors (TKI) Used As Frontline Therapy in Chronic Myeloid Leukemia-Chronic Phase (CML CP),

Abstract 3784▪▪This icon denotes a clinically relevant abstract Background:TKI are standard therapy for patients with CML CP. Imatinib was first established as frontline therapy and more recently dasatinib and nilotinib have shown improved rates and speed of response. Early molecular response has been associated with improved long-term outcome (Blood 2009; 113: 6315), thus the kinetics and rates of molecular response are important predictors of long-term outcome. Aim:To determine the kinetics and rates of molecular response with different TKIs used as initial therapy for patients with CML CP. Methods:We evaluated all pts treated with frontline TKIs (imatinib standard dose or high dose, dasatinib and nilotinib) in consecutive or parallel trials. Cytogenetic and molecular responses were assessed at least every 3 months for the first 12 months, then every 6 months, and were defined using the recommendations of European LeukemiaNet. Molecular responses were defined using international scale. Survival was calculated by the Kaplan-Meier method. Results:Of the 485 pts treated, 73 received imatinib 400mg; 208 imatinib 800mg; 99 dasatinib, and 105 nilotinib. Median age was 48 years (15–86) and median time from diagnosis to TKI therapy was 1 mo (1–13). The median follow-up for each group were 109 months (mo) with imatinib 400, 69 mo with imatinib 800, 30 with dasatinib and 25 mo with nilotinib. Nineteen pts with clonal evolution, but otherwise in CP, were included. Sokal risk score was high in 7%, intermediate in 24% and low in 69%. Cumulative rates of complete cytogenetic response (CCyR) were: imatinib 400mg 87%; imatinib 800mg 91%; dasatinib 96%; and nilotinib 94%. The rate of MMR with imatinib 400mg was 73%, with imatinib 800mg 87%, dasatinib 86%, and nilotinib 88%. Rates of CMR (BCR-ABL/ABL ≤0.0032% IS) were 51%, 71%, 61% and 62%. Median time to achieve MMR and CMR were: imatinib 400mg, 12 mo (3–60) and 18 mo (3–60); imatinib 800mg, 6 mo (3–60) and 9 mo (3–60); dasatinib, 6 mo (3–36) and 12 mo (3–54), and nilotinib 6 mo (3–48) and 6 mo (3–42). The median transcript levels at 3, 6, 12, 18, 24 and 36 mo by treatment arm are shown in table 1. The rates of MMR and CMR at 36 mo for imatinib 400mg were 58% and 34%. Corresponding rates for imatinib 800mg were 87% and 59%; for dasatinib 87% and 54%; and for nilotinib 90% and 63%. We then assessed the probability of achieving MMR and CMR at 12 mo according to the BCR-ABL/ABL levels at earlier timepoints. Two of 9 (22%) evaluable pts with transcript level >10 at 3 mo achieved a MMR at 12 mo but none achieved a CMR. In contrast, 31/52 (60%) evaluable pts with transcript level >1–10 at 3 mo, achieved a MMR at 12 mo and 4 (8%) achieved a CMR. Similarly, pts with level >0.1–1 at 3 mo, 72/129 (56%) evaluable pts achieved a MMR and 29 pts (22%) a CMR at 12 months. For each individual TKI, a similar trend was noted where a higher transcript level (>10; >1–10; >0.1–1) at 3 mo was associated with a decline in achieving a MMR and CMR at 12 mo (MMR- imatinib 400mg: 0%; 50%; 67%, imatinib 800mg: 0%; 62%; 80%, dasatinib: 33%; 67%; 71%, nilotinib: 100%; 50%, 88%, CMR-imatinib 400mg: 0%, imatinib 800mg: 0%; 8%; 10%, dasatinib:0%; 17%; 29%, nilotinib: 0%; 0%; 32%). The probability of transformation to AP/BP by transcript levels at 3 mo (>10; >1–10; >0.1–1, ≤0.1) was 0%, 3%, 2% and 1% for the overall population, with similar trends for the different therapies.Table 1Median transcript levels by treatment arm3 mo6 mo12 mo18 mo24 mo36 moImatinib 4000.20050.33600.03990.00840.00300.0079Imatinib 8000.18100.01830.00840.00490.00440.0027Dasatinib0.21500.03360.01400.00700.00320.0032Nilotinib0.16100.02100.01050.00320.00320.0032 Conclusion:New TKI provide a faster improvement in molecular response among pts with CML CP receiving TKI as initial therapy. Early responses are equally predictive of long-term outcome across all treatment options. Disclosures:Kantarjian:Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Cortes:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; ChemGenex: ChemGenex is now Cephalon, Inc., Consultancy, Research Funding; Deciphera: Research Funding.

A Phase IIIb Multicentre Open-Label Study of Nilotinib in Adult Patients with Newly Diagnosed BCR-ABL Positive Chronic Myeloid Leukemia (CML) in Chronic Phase (CP): A European Clinical Initiative with EUTOS Collaboration for Standardisation of Molecular Remission

Abstract 2759 BACKGROUND Nilotinib, a highly potent, selective inhibitor of BCR-ABL, is now approved for frontline treatment of Philadelphia chromosome positive (Ph+) CP CML. ENEST1st (Evaluating Nilotinib Efficacy and Safety trial as first line treatment) is a phase IIIb, open-label study of nilotinib in adult patients with newly diagnosed CP CML (ClinicalTrials.gov NCT01061177). The primary study aim is to establish the rate of molecular remission with a sensitivity of 4 log (MR 4 ) rate through EUTOS (European Treatment and Outcomes Study) laboratories to improve the sensitivity and standardisation of RT-PCR for low level BCR-ABL detection and further refine the working definition of deep molecular response. The attainment of sustained MR 4 will identify a patient population potentially eligible to join studies of tyrosine kinase inhibitor discontinuation in CP CML. METHODS 806 patients (pts) with newly diagnosed BCR-ABL+ CML-CP, diagnosed within 6 months, were to be treated with nilotinib 300 mg BID for a study period of 24 months. The primary study endpoint is MR 4 rate at 18 months, initially defined as undetectable BCR-ABL transcripts by quantitative RT- PCR in a peripheral blood sample of at least 10 ml with a minimum sensitivity of 1:10,000. Molecular monitoring was performed by 13 EUTOS laboratories with conversion factors to the International Scale to facilitate standardised measurement. Key secondary endpoints include: rate of progressions to accelerated phase (AP) or blast crisis (BC) in year 1 and 2; rate of events in patients achieving MR 4 at 1 year; rate of MMR ( st IA), and when a subsequent 400 pts had also reached 6 months of study treatment and the first 200 pts had 18 months follow up. Additionally, 11 translational and correlative science sub studies were performed. RESULTS The 1 st IA results are as follows: Baseline demographics: 208 pts were recruited in 102 sites in 15 countries. Median age was 53 years, median time from diagnosis 1.1 months (range 0.07–5.39). 39.0% pts were female, 91.8% had typical b2a2 or b3a2 BCR-ABL transcripts, 71.2% had been previously treated. 37.6% with standard dose imatinib (maximum of 12 weeks) and 55.1% with hydroxyurea. 34.0%, 37.2% and 17.8% pts were classified as Sokal low, intermediate and high risk. 80.4% and 9.3% pts were classified as EUTOS score low and high risk. The median dose intensity was 600 mg/day. 29.8% pts experienced a dose interruption of a median cumulative duration of 14 days. Rate of MMR by 3 and 6 months was 22.5% and 50.3%. MMR by 3 and 6 months was 43.9% and 61.1% for EUTOS low risk and 17.6% and 41.2% for EUTOS high risk pts. Quality control of molecular responses beyond MMR is ongoing. Adverse events (AE) were mostly grade 1 and 2, mainly rash (22.4%), pruritus (17.1%), alopecia (11.7%), fatigue (11.7%), headache and nausea (10.2%) which were usually manageable with appropriate dose interruptions/reduction. Grade 3–4 hematological AE rates were low, with thrombocytopenia and neutropenia reported in 5.3 and 3.5% pts respectively. The incidence of treatment –related Grade 3–4 non-hematological AEs was low, with lipase increase and hyperbilirubinaemia reported in 2.4% and 1.5% pts respectively. 8.8% patients reported study drug related SAEs. 7.8% and 0.5% of pts showed a prolongation of QTcF above 450ms and 500ms respectively. At 6 months, 88.8% pts remain on study, 14 pts (6.8%) have discontinued due to AE (3 discontinued due to hyperbilirubinemia), 1 due to abnormal laboratory value, 5 withdrew consent, 1 died due to a metastatic neoplasm, and 2 discontinued due to protocol violations. No pt has progressed during the first 6 months of study. Methodological improvements in RT-PCR have allowed refinement of the working definition of MR 4 as either (i) detectable disease ≤0.01% BCR-ABL IS or (ii) undetectable disease in cDNA with ≥10,000 ABL transcripts. CONCLUSIONS Results of the ENEST1st first IA with over 100 pt years of nilotinib treatment demonstrate nilotinib9s efficacy and safety to be similar to that reported in other front line trials. Through methodological improvements of RT-PCR, a network of EUTOS laboratories are now able to define and measure MR 4 in a standardised and validated manner. Disclosures: Giles: Novartis: Consultancy, Honoraria, Research Funding. Rosti: Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Ossenkoppele: Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria. Tulliez: Novartis: Investigator in Novartis Study. Stentoft: Novartis: Investigator in Novartis Study. Giagounidis: Novartis: Investigator in Novartis Study. Nobile: Novartis: Investigator in Novartis Study. le Coutre: Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria. Gattermann: Novartis: Honoraria, Research Funding. Griskevicius: Novartis: Investigator in Novartis Study. Cross: Novartis: Research Funding. Hill: Novartis: Employment. Schuld: Novartis: Employment. Pellegrino: Novartis: Employment. Magazzu: Novartis: Employment. Hochhaus: Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding.

Upfront Imatinib Therapy in CML Patients with Rapid Switching to Nilotinib for Failure to Achieve Molecular Targets or Intolerance Achieves High Overall Rates of Molecular Response and a Low Risk of Progression - An Update of the TIDEL-II Trial

Abstract Abstract 451FN2 Background: While nilotinib and dasatinib produce faster responses than imatinib as first-line therapy in de novo Chronic Phase Chronic Myeloid Leukemia (CP-CML), an equally effective strategy may be to selectively use these more potent tyrosine kinase inhibitors (TKIs) only in patients who fail to achieve stringent early molecular targets or are intolerant. Aim: To update the molecular outcome and survival of patients in the TIDEL-II study. Method: TIDEL-II is a multicentre, single arm prospective ALLG trial for de novo CP-CML adult patients with two sequential cohorts each of 105 patients. All patients started on imatinib (IM) 600mg OD. Patients with IM trough levels &lt;1000ng/mL on day 22 were dose escalated to 800mg OD (IM800). All patients were monitored for achievement of time-dependent molecular targets - BCR-ABL RQ-PCR of 10%, 1% and 0.1% IS at 3, 6 and 12 months (mo) respectively. Patients in cohort I who failed to meet these targets had dose escalation to IM800. Those patients who again failed to achieve these targets after a further 3 mo were switched to nilotinib 400mg BID (NIL). Patients in cohort 2 who failed their time dependent targets switched to NIL directly without escalating to IM800. In both cohorts, switching to NIL was also permitted for grade III/IV or persistent grade II non-haematological toxicity or loss of response. Primary end point was MMR at 12 mo (BCR-ABL '0.1%IS), with CMR4.5 being a secondary end point (BCR-ABL ≤0.0032%IS). Results: At 12 mo 69% of patients achieved MMR. With median follow up (f/u) of 20mo, AP/BC progression occurred in 5 cases (2.4%) ( Table 1). The 3 mo molecular response was highly correlated with the MMR at 12mo and progression events (table 2). COHORT 1: Using intention to treat analysis (ITT) with median follow-up of 30 mo the rate of MMR at 12 and 24 mo is 66% and 81% respectively (n=105); CMR4.5 was 12% and 24%, respectively. In total, 34/105 (32%) patients switched to NIL, 12 for failure to achieve molecular targets, 19 for intolerance and 3 for loss of response. Only 2/12 patients who failed to meet targets on IM have subsequently achieved MMR on NIL (median f/u on NIL 14 mo). Fourteen patients switched for intolerance when not in MMR, and 9 subsequently gained MMR (64%) (median f/u on NIL 19 mo). Two patients progressed to AP/BC, both in the first 12 mo in patients taking IM. One progression related death and one fatal myocardial infarction (on NIL) have been reported. Fourteen (13%) of patients remain on IM800. COHORT 2: With a median f/u of 12 mo the rates of MMR and CMR4.5 at 12 mo (n=50) were 72% and 16%, respectively (ITT). To date, 35/105 patients, (33%) have switched to NIL, of which 23 switched for failure to meet molecular targets. Subsequently, 3/23 (13%) have achieved MMR (median 6 mo on NIL). Eleven patients have switched to NIL for intolerance, 7 of them not in MMR at time of switch; 6/7 reached MMR in the subsequent 6 mo (median 5 mo on NIL). Seven patients (7%) remain on IM800. Three patients progressed to AP/BC (3%), 2 on IM and 1 on NIL. Three deaths were reported (3%), 1 from cardiac causes and 1 from stroke, both patients on IM at the time; and 1 from CML progression. Relatively short f/u precludes a meaningful comparison of results between the 2 cohorts. Conclusion: The TIDEL-II strategy has achieved a higher rate of MMR at 12 mo of 69% compared to 47% achieved with the strategy of IM intensification previously utilised in the TIDEL-I study. The improvement in molecular response is mostly attributable to improved responses in patients intolerant of IM as deeper responses were uncommon with patients who failed their early molecular targets despite intensification of kinase inhibition. Molecular response at 3 mo is highly correlated with response and progression events, underscoring the importance of early molecular targets. Disclosures: Yeung: Novartis Pharmaceuticals: Research Funding; BMS Oncology: Research Funding. Osborn:Novartis Pharmaceuticals: Research Funding; BMS Oncology: Research Funding. White:Novartis Pharmaceuticals: Research Funding. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding. Slader:Novartis Pharmaceuticals: Employment, Equity Ownership. Hiwase:CSL: Research Funding. Schwarer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria; Hospira: Membership on an entity's Board of Directors or advisory committees. Arthur:Novartis Pharmaceuticals: Honoraria; BMS Oncology: Honoraria. Ross:Novartis: Honoraria, Research Funding. Mills:Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Sponsorship to professional meetings; BMS Oncology: Sponsorship to professional meetings. Hughes:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS Oncology: Research Funding.

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.

Frontline Tyrosine Kinase Inhibitors (TKI) As Initial Therapy for Patients with Chronic Myeloid Leukemia in Accelerated Phase (CML-AP),

Abstract 3779▪▪This icon denotes a clinically relevant abstract Background:Some patients (pts) with chronic myeloid leukemia (CML) present with features of accelerated phase (AP) at the time of diagnosis. Imatinib, dasatinib, and nilotinib are standard initial tyrosine kinase inhibitor (TKI) therapy for pts with CML in chronic phase (CP). For pts with accelerated phase CML (CML-AP), data is available mostly on treatment after failing previous therapies, and there is no available data on nilotinib and dasatinib as initial therapy for CML-AP. Aim:To describe efficacy of imatinib, dasatinib, and nilotinib as initial therapy for patients with CML-AP. Methods:Frontline TKI therapy was administered on consecutive or parallel clinical trials to 58 CML pts who presented with features of AP at the time of diagnosis, defined as blasts ≥15% (n=8), basophils ≥20%, (n=22), platelets <100×109/L (n=3), cytogenetic clonal evolution (n=22), or more than 1 feature (n=3). 36 pts received imatinib. 22 pts received a second generation TKI (2GTKI) (desatinib, n = 5 or nilotinib, n= 17). Results:A total of 58 pts were treated. Median age was 46 years (range 22 to 81). Pt characteristics were similar in all 4 treatment groups. With a median follow-up of 32 months (range 2 to 125), a complete hematologic response (CHR) was achieved in 93%, a partial cytogenetic response (PCyR) in 2 %, and a complete cytogenetic response (CCyR) in 82%. The rate of CCyR for evaluable patients treated with imatinib was 75%, and with 2GTKIs, 95%. Major molecular responses (MMR, BCR-ABL/ABL ≤0.1% IS) were achieved in 68% including complete molecular responses (CMR, BCR-ABL/ABL ≤0.0032% IS) in 49%. MMR rates for pts treated with imatinib were 66%, and with 2GTKIs, 71%. The median time to achieve a CCyR was 3 months, and a MMR, 9 months. The 12-month rate of CCyR was 74% with imatinib and 83% with 2GTKIs. The 12-month MMR rate was 52% for imatinib and 67% for 2GTKIs. Patients with clonal evolution as the only criterion for CML-AP had a 91% rate of CCyR compared to 76 % for those with other criteria (p=0.168). At 24 months from the start of therapy, event free survival (EFS) for all patients was 90% (imatinib 90%; 2GTKI 90%). 24-month transformation free survival (TFS) (survival free from transformation to blast phase) was 92% (imatinib 94%, 2GTKIs 90%). Overall survival at 24 months was 100% with both imatinib and 2GTKI’s. We also analyzed the impact of early response on long-term outcome. The TFS rate at 24 months for those achieving a 12-month CCyR was 100% compared to 56% for those not achieving such responses. TFS was 100% for those with a MMR at 18 months and 60% for those without a MMR at 18 months. In total, 4 patients have transformed to BP. None of the patients who transformed had achieved CCyR by 12 months. At last follow-up, 34 patients remain on therapy. Reasons for discontinuation were treatment failure/disease progression in 8, toxicity in 1, and other reasons in 15. Conclusion:Patients with CML who present with features of AP at the time of diagnosis have an excellent outcome with TKIs, particularly 2GTKI. Those with clonal evolution as the only manifestation of AP have a particularly favorable outcome. TKIs should be considered standard initial therapy for patients with AP at the time of diagnosis. Disclosures:Kantarjian:Novartis: Consultancy; Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding. Quintas-Cardama:Novartis: Consultancy; BMS: Consultancy. Ravandi:BMS: Honoraria; BMS: Honoraria; Bristol Meyers-Squibb: Research Funding. Jabbour:Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

Clinical Significance of Myelosuppression Associated with the Use of Dasatinib and Nilotinib As Initial Therapy in Chronic Phase (CP) of Chronic Myeloid Leukemia (CML)

Abstract 2761 Background:Frontline treatment with tyrosine kinase inhibitors (TKIs) has improved prognosis for patients with chronic myelogenous leukemia (CML). Myelosuppression is the most common adverse event (AE) seen during therapy with frontline second generation TKIs, dasatinib and nilotinib. The impact that grade 3/4 myelosuppression has on future outcome has not been described. Aim: To define the patient characteristics and clinical significance of myelosuppression associated with the use of dasatinib or nilotinib as initial therapy for CML. Methods: From August 2005, 204 patients (pts) diagnosed with CML-CP were treated with dasatinib (n=99) or nilotinib (n=105) in parallel trials. Prior imatinib exposure of less than 4 weeks was allowed. Complete blood counts (CBC) and differentials were done weekly in the first month, every 1–2 months up to the first year, every 3–4 months in the second year, and every 4–6 months thereafter. Results:A total of 44 (42%) pts developed grade 3/4 myelosuppression (MS) defined under CTCAE v4.0 criteria as hemoglobin (Hb)<8g/dL (n=5), absolute neutrophil count (ANC)<1×109/L (n=32), and platelet count (Plt)<50×109/L (n=21); 12 (30%) developed more than one cytopenia. MS occurred in 30 pts on dasatinib (anemia 13%, neutropenia 73%, thrombocytopenia 40%), and 14 pts on nilotinib (7%,71%,64%, respectively). Comparing patient characteristics between those who experienced myelosuppression vs. no myelosuppression, there was no significant difference in age, prior imatinib therapy, percent Ph positivity, or baseline hematologic parameters. There was a trend for more pts in the intermediate Sokal risk category among pts with MS.Of the 44 patients with MS, 39 (89%) experienced the event for the first time within 3 months from initiation of therapy. Five (11%) experienced the event after the first 3 months of treatment: 2 eventually came off study (one for resistance and the other for disease progression, both on nilotinib), and 3 (all on dasatinib) continued on therapy, able to achieve CMR. Complications associated with MS included hospitalization in 2 pts (one for pneumonia, and another for flu and prolonged QTc); 6 (14%) required antibiotics; 2 (5%) required blood transfusions; and 2 (5%) required growth factors (erythropoietin). MS led to TKI dose reduction in 9% of all pts treated (41% of those with MS), including 13% of those on dasatinib, and 5% of those on nilotinib. Dose reduction resolved MS in most instances. Recurrence of MS was seen in 10 pts, 2 of whom had progression of disease to blast phase/AML. The outcome of pts with MS is described in table 1 compared to those without MS. Patients with MS had a significantly lower rate of CCyR, MMR, CMR and EFS compared to those without MS.Table 1OutcomesMSNo MSP valueCCyR84960.019MMR77900.025CMR47660.01936 mo EFS76930.01336 mo TFS98990.34436 mo OS1001000.484 Conclusion:MS is a common AE among pts receiving therapy with dasatinib or nilotinib as initial therapy for CML that frequently leads to dose reductions, and is associated with an inferior outcome. Whether the worse outcome reflects decreased dose intensity, or whether the outcome and decreased tolerance to therapy reflect an intrinsic difference in disease biology remains to be determined. Disclosures:Kantarjian:BMS: Research Funding; Novartis: Research Funding. Quintas-Cardama:Novartis: Consultancy; BMS: Consultancy. Jabbour:Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Ravandi:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

Effect of Nilotinib (NIL) on Molecular Response in Chronic Myelogenous Leukemia - Chronic Phase (CML-CP) Patients (pts) with a Suboptimal Molecular Response to Imatinib (IM)–ENABL Study Update

Effect of Nilotinib (NIL) on Molecular Response in Chronic Myelogenous Leukemia - Chronic Phase (CML-CP) Patients (pts) with a Suboptimal Molecular Response to Imatinib (IM)–ENABL Study Update

P1-287 Maternal mortality rate in Kurdistan Province Western Iran from 2002 to 2007; an epidemiologic survey

IntroductionNowadays 1500 mothers die due to complications of pregnancy and delivery in the world. This study is aimed to evaluation the frequency of maternal mortality rate and its associated causes...

Comparison of nilotinib and imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd 24-month follow-up.

6511 Background: Nilotinib demonstrated superiority vs imatinib in ENESTnd at 12 months (mo). Here, we present data with a minimum follow-up (f/u) of 24 mo. Methods: 846 CML-CP pts were randomized to receive nilotinib 300 mg bid (n = 282), nilotinib 400 mg bid (n = 281), or imatinib 400 mg qd (n = 283). Primary endpoint was major molecular response (MMR, ≤ 0.1% BCR-ABLIS) at 12 mo. Here, we report MMR by 24 mo, overall best molecular response (CMR4 and CMR4.5), progression to AP/BC, progression-free survival (PFS), and overall survival (OS). Results: With minimum 24-mo f/u, response rates were significantly higher for nilotinib vs imatinib. MMR rates remained superior for nilotinib across all Sokal risk groups. Achievement of CMR4 and CMR4.5 were significantly higher for nilotinib vs imatinib. There continued to be significantly fewer progressions to AP/BC on treatment, including clonal evolution (CE), on nilotinib 300 (n = 2) and 400 mg bid (n = 5) vs imatinib (n = 17). At 24 mo, OS remained similar in all groups, but there were fewer CML-related deaths on both nilotinib 300 (n = 5) and 400 mg bid (n = 3) vs imatinib (n = 10). Both drugs were well tolerated. Discontinuation due to adverse events/lab abnormalities was 9% for nilotinib 300 mg bid, 13% for nilotinib 400 mg bid, and 10% for imatinib. Conclusions: Nilotinib continues to demonstrate superior efficacy with significantly improved disease control vs imatinib for the treatment of pts with newly diagnosed CML-CP. Nilotinib 300 mg bid (n = 282) Nilotinib 400 mg bid (n = 281) Imatinib 400 mg qd (n = 283) MMR, % By 24 mo 71* p < .0001* 67* p < .0001* 44 Best molecular response at any time, % ≤ 0.01% IS (CMR4) 44 p < .0001* 36 p < .0001* 20 ≤ 0.0032% IS (CMR4.5) 26 p < .0001* 21 p = .0004* 10 Freedom from progression to AP/BC, (%) Estimated rate at 24 mo Excluding CE 99.3 p = .0059** 98.1 p = .0196** 95.2 Including CE 99.3 p = .0003** 97.3 p = .0089** 93.2 PFS, % Estimated rate at 24 mo OS, % 98.0 p = .0736** 97.7 p = .0437** 95.2 Estimated OS rate at 24 mo 97.4 p = .6485** 97.8 p = .2125** 96.3 Estimated OS rate of CML- related death at 24 mo 98.9 p = .1930** 98.9 p = .0485** 96.7 * Cochran-Mantel-Haenszel test stratified by Sokal vs imatinib. ** Log-rank test stratified by Sokal vs imatinib.

Selective Escalation of Imatinib Therapy and Early Switching to Nilotinib In De Novo Chronic Phase CML Patients: Interim Results From the TIDEL-II Trial

AbstractAbstract 209 Background:Although the majority of chronic phase (CP) Philadelphia positive (Ph+) chronic myelogenous leukemia (CML) patients (pts) achieve good disease control with imatinib, some pts demonstrate suboptimal responses. Early dose escalation or switching to nilotinib, a more potent BCR-ABL kinase inhibitor, as soon as suboptimal molecular response is recognised may improve response and disease outcome. Aim:To optimise clinical and molecular outcomes in Ph+ CML using imatinib (IM) as frontline therapy with selective IM dose escalation based on pharmacokinetic (PK) results and switching to nilotinib (NIL) in case of suboptimal response, or IM-intolerance. Method:TIDEL-II is a multicentre, single arm prospective ALLG trial in de novo CP-CML pts with 2 separate sequential cohorts. In Cohort I, pts are treated with IM 600mg/d up-front, aiming for BCR-ABL RQ-PCR target values of ≤ 10%, 1%, and 0.1% IS (major molecular response, MMR) at 3, 6, and 12 months respectively. Pts who do not reach these treatment targets are classified as suboptimal responders. Dose escalation to 800mg/d or maximal tolerated dose occurs if trough IM level is <1000ng/mL at day 22, or for suboptimal response. A switch to NIL (400mg bid) is triggered if molecular targets are still not met 3 months after IM escalation, or for loss or response, or for IM intolerance (Grade III/IV or persistent Grade II non-haematological toxicity). Results:105 pts were assessed with median follow up of 18.9 months (range: 9–33) in cohort I. For pts with a minimum of 12 months follow up (n=80), complete cytogenetic response (CCR), MMR and complete molecular response (CMR)# rates at 12 months were 92%, 66% and 11% respectively. BCR-ABL levels at 3 months were predictive of MMR at 12 months, but not for CMR due to small pt numbers (Table 1). For pts who failed to achieve BCR-ABL of ≤10% at 3 months, the 12 month MMR rate was 25% (vs 5% in TIDEL-I where pts were also started on IM 600mg/d and suboptimal responders were dose escalated to IM 800mg/d). Of the 105 pts, 16 pts dose escalated IM due to a day 22 IM blood level <1000ng/mL, after which 2/16 switched to NIL (1 suboptimal, 1 intolerant); all achieved CCR. Twelve pts dose escalated for suboptimal response, 7 subsequently switched to NIL for again failing treatment targets. In all, 21/105 pts (20%) switched to NIL: 7 for suboptimal response and 14 for intolerance. The median time to switching and the median pre-switch prescribed IM dose were 468 days & 800mg/d for the suboptimal group; and 183 days & 600mg/d for the intolerant group respectively. Of these, 20/21 achieved or remained in CCR. At the time of switching to NIL, 19/21 pts were not in MMR. With a median follow-up of 295 days post switch to NIL, 9/12 intolerant pts (75%) achieved MMR, whereas 1/7 suboptimal IM responders (14%) achieved MMR (median follow up after switching: 286 days). Only 7/105 pts (7%) discontinued treatment: 4 for non-compliance, 1 pt with a T315I mutation and 2 pts with blast crisis (BC). Progression to BC was associated with detectable mutations: 1 pt with 4 different mutations including T315I and 1 pt with H396P mutation. The progression rate to AP/BC was 2%. The overall mutation rate was 5/105 (5%). The 2 pts who progressed and the pt who discontinued when a T315I mutation was detected were among the 28 pts with BCR-ABL values >1.0% at 3 months. In contrast, no resistant mutations were detected or transformations occurred in the 49 pts with BCR-ABL values ≤1.0% at 3 months. Conclusion: A strategy of selective intensification of BCR-ABL inhibitor therapy based on molecular response and PK values resulted in a 66% MMR rate by 12 months. Despite a minority of pts (20%) requiring a switch to NIL, this has enhanced the rate of MMR by 12 months when compared to IM intensification alone as seen in TIDEL-I where the rate of MMR and CMR by 12 months was 47% and 9% respectively. The IM intolerant pts demonstrated excellent response rates after switching to NIL. To date, the results from TIDEL-II compare favourably with other frontline strategies with regards to response and transformation rates. Disclosures:Yeung:Novartis Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding. Osborn:Novartis Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding. White:Novartis Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding. Branford:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Slader:Novartis Pharmaceuticals: Employment, Equity Ownership. Ross:Novartis Pharmaceuticals: Honoraria, Research Funding. Mills:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hughes:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Meyers Squibb: Honoraria, Research Funding; Ariad: Honoraria.

Efficacy and Safety of Nilotinib In Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients (Pts) with Type 2 Diabetes In the ENESTnd Trial.

AbstractAbstract 3430 Background:Nilotinib is a potent and selective BCR-ABL kinase inhibitor. In the randomized, multicenter phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Philadelphia chromosome-positive CML pts) trial, nilotinib demonstrated superior efficacy, including significantly lower rates of progression on treatment to the accelerated or blastic phases of CML vs imatinib. It was previously reported that nilotinib treatment may lead to transient hyperglycemia in some pts receiving second-line nilotinib (400 mg twice daily [bid]) for resistance or intolerance to imatinib. The objective of this prospective analysis was to determine the effects of frontline nilotinib therapy on glucose metabolism in a subset of pts from ENESTnd with preexisting type 2 diabetes, and to evaluate the efficacy and safety of nilotinib therapy in these pts. Methods:Changes from baseline in glucose metabolism parameters including fasting blood glucose (FBG), insulin, C-peptide, and HbA1c levels at 12 months were assessed in the diabetic subset of pts. Changes in body weight were also assessed. Results:A total of 836 pts were included in the safety analysis of ENESTnd (279, 277, and 280 pts in the nilotinib 300 mg bid, nilotinib 400 mg bid, and imatinib arms, respectively) with a median follow-up of 18 months. In this population, all grade hyperglycemia occurred in 38%, 42%, and 22% of pts in the nilotinib 300 mg bid, 400 mg bid, and imatinib arms, respectively (grade 3/4 in 6%, 4%, and 0%). Importantly, no patient from any treatment arm discontinued study due to hyperglycemia and there were no diabetic serious adverse events (eg, diabetic ketoacidosis, hyperosmolar events, and/or hospitalization due to diabetes). The subset of pts with preexisting type 2 diabetes (n = 57; 23, 18, and 16 pts in the nilotinib 300 mg bid, nilotinib 400 mg bid, and imatinib arms, respectively) was analyzed for glucose metabolism parameters and efficacy. Median age was higher (approximately 60 years) in this subset of pts compared to the entire pt population (approximately 47 years). At study entry, 68% (39/57) of pts were on diabetes medications; 18% (7/39) of whom were on insulin. The majority of diabetic pts (74%) did not have a change in diabetes therapy on study. Changes in glucose metabolism parameters were minimal (Table), and no meaningful changes in body weight or HbA1c were noted in any arm. In the subset of pts with preexisting type 2 diabetes, response rates were similar to the overall population, with MMR rates by 12 months of 69.6%, 55.6%, and 25%, and CCyR rates by 12 months of 69.6%, 77.8%, and 68.8% in the nilotinib 300 mg bid, nilotinib 400 mg bid, and imatinib arms, respectively. No pt in the diabetic subset has progressed to advanced disease. Overall, 8, 5, and 6 diabetic pts discontinued nilotinib 300 mg bid, nilotinib 400 mg bid, and imatinib, respectively. Of these, 3, 5, and 4 pts discontinued due to an adverse event or laboratory abnormality unrelated to diabetes. One diabetic pt in each of the nilotinib arms experienced an ischemic heart disease event (grade 1 or 2). Two diabetic pts died, 1 due to intestinal obstruction and 1 due to suicide, both in the nilotinib 300 mg bid arm. Conclusions:Hyperglycemia occurring during nilotinib treatment was usually mild, transient, manageable and did not lead to treatment discontinuation in patients with or without preexisting type 2 diabetes. Moreover, the efficacy and safety of nilotinib in this subset of pts was similar to the overall population in ENESTnd. These data suggest that nilotinib is efficacious and well-tolerated in pts with type 2 diabetes. Disclosures:Saglio:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Larson:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Hughes:Ariad: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding. Marin:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Kalaycio:Novartis: Honoraria, Speakers Bureau. Gallagher:Novartis Pharma AG: Employment, Equity Ownership. Kayath:Novartis: Employment. Zheng:Novartis: Employment, Equity Ownership. Kantarjian:Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding.

Specific Drug Transporter Genotypes Are Significantly Associated with Increased Rates of Major and Complete Molecular Responses In Newly Diagnosed Chronic Myeloid Leukemia Patients Treated with Imatinib – A TOPS Correlative Substudy

AbstractAbstract 670The availability of multiple options for chronic myeloid leukemia (CML) treatment is not paralleled by the availability of biological predictors of outcome allowing to identify patients (pts) who are more likely to benefit from dasatinib or nilotinib rather than imatinib (IM). Pharmacogenetics has proven a potential source of biomarkers given the known influence of polymorphisms in key genes encoding drug transporters and metabolizing enzymes on drug delivery – hence effectiveness. In CML, only two studies had so far explored this field, but both were conducted in heterogeneous populations including pts at different stages of disease, not all receiving IM first-line. We thus aimed to investigate a panel of 20 single nucleotide polymorphisms (SNPs) in ABCB1, ABCG2, SLC22A1, OATP1A2, OCTN1, CYP3A4 and CYP3A5 genes that can be hypothesized to influence IM transport and metabolism in 189 newly diagnosed CML pts enrolled in the TOPS phase III trial (Cortes et al, J Clin Oncol 2010). Pts selection was exclusively based on availability of written informed consent and sufficient amount of archived material. Median age was 46 years; male to female ratio was 103 to 86; 156 (83%) pts were Caucasian and 23 (12%) were Asian; low, intermediate and high Sokal risk pts were 84 (44.4%), 65 (34.4%) and 40 (21.2%), respectively. Baseline demographic/clinical features did not differ significantly from those of the overall population. Treatment outcomes (complete cytogenetic response [CCyR]; major molecular response [MMR] and complete molecular response [CMR]) were compared according to i) each candidate genotype ii) summary measures based on combinations of SNPs in the same gene and iii) summary measures based on combinations of SNPs in functionally related genes (uptake; efflux). CC genotype in OCTN1 had a favorable impact on the achievement of MMR at 12 months (MMR@12m; P = 0.03). With respect to the summary measures, combination of SNPs in the SLC22A1 gene was significantly correlated with MMR@12m (P = 0.03). When considering summary measures of uptake and efflux, the former was found to be associated with both MMR@12m and CMR@12m (P = 0.003 and P = 0.01, respectively). A separate analysis limited to Caucasian pts (n=156) yielded similar results (Table 1). In addition, the analysis in the Caucasian subgroup evidenced a significant association between the CC genotype in ABCB1 rs60023214 and MMR@12m (P = 0.005) (Table 1). Cumulative incidence plots based on the Kaplan-Meier method were also analyzed in the overall population and in Caucasians, with comparable results. Representative plots are shown in Figure 1. There was evidence for difference among MMR cumulative incidence curves for 2 single SNPs and 2 score measures. Presence of the major allele in OCTN1 (CC) and of the minor allele in CYP3A4 rs2740574 (GG) were associated with increased MMR rate (P = 0.028 and P = 0.042, respectively, in the overall population and P = 0.027 and P = 0.038, respectively, in Caucasians). Similarly, an increase in the number of favorable alleles in the SLC22A1 gene was associated with increased MMR rate (P = 0.030 and P = 0.043 in the overall population and in Caucasians, respectively). In addition, the combination of favorable alleles in the genes involved in IM uptake was associated with increased rates of both MMR and CMR (P = 0.004 and P = 0.015, respectively, in the overall population and P = 0.005 and P = 0.009, respectively, in Caucasians). Our results suggest that SNP genotyping might be helpful in selecting pts who are more likely to benefit from first-line use of more potent inhibitors. Further assessment of the SNPs here identified in larger series of pts is warranted.Table 1Summary of significant associationsOverall population (n=189)Caucasians (n=156)Gene, rsOutcomePHazard ratio[95% CI]PHazard ratio[95% CI]OCTN1 - rs1050152MMR@12m0.030.78 (0.63, 0.98)0.030.77 (0.60, 0.97)ABCB1 (MDR1) - rs60023214CMR@12m0.060.71 (0.49, 1.02)0.0050.56 (0.37, 0.84)SLC22A1 (hOCT1) - SNP combinationMMR@12m0.031.24 (1.02, 1.50)0.041.24 (1.00, 1.54)Uptake - SNP combinationMMR@12m0.0031.21 (1.06, 1.37)0.0051.24 (1.06, 1.44)Uptake - SNP combinationCMR@12m0.011.30 (1.05, 1.61)0.011.37 (1.08, 1.74) [Display omitted] Supported by Novartis Oncology, Clinical Development, TOPS Correlative Studies Network Disclosures:Hughes:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria. White:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding. Saglio:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Rosti:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Hatfield:Novartis: Employment. Martinelli:Novartis: Consultancy, Honoraria; BMS: Honoraria; Pfizer: Consultancy.

Analysis of Outcomes In Adolescents and Young Adults (AYA) with Chronic Myeloid Leukemia (CML) Treated with Upfront Tyrosine Kinase Inhibitors (TKI)

AbstractAbstract 1234 Background:Outcomes in CML have dramatically improved since the introduction of upfront treatment with first (imatinib) and second generation (dasatinib, nilotinib) TKIs. The median age of diagnosis of CML is approximately 67 years (yrs). However, there is a small, but significant group of patients (pts) diagnosed with CML at a significantly younger age, especially those age 15–21, or AYA pts. Historically, stem cell transplantation was employed as an initial treatment strategy in many CML AYA pts. Little is known about the outcomes of this AYA group of CML pts in the TKI era. Objective:To determine the characteristics and outcomes of CML AYA pts in the era of upfront treatment with TKI. Methods:We reviewed the records of all CML pts treated at our institution on clinical protocols with upfront TKI treatments from July 2000-April 2010. AYA pts were defined as age 15–21. No pts receiving upfront SCT were included in this analysis. Result:A total of 435 CML pts have been prospectively followed on protocol from 7/2000-4/2010. Patients were included in sequential or parallel trials with identical inclusion criteria: 1) Imatinib (281 pts), 2) Nilotinib (78 pts), and 3) Dasatinib (76 pts). The median age of the entire cohort was 48 yrs (15-85 yrs). Median follow up time for the entire cohort was 67 months (mo) (2-116 mo) with median treatment time 49 mo (0.1-114.9 mo). We identified 13 AYA pts for analysis in this study. There were no significant differences between the AYA pts and the older pts with regard to baseline splenomegaly, platelet count, or blast counts. There was an expected trend for more AYA patients being in the low Sokal risk group (as age is one of the factors in Sokal risk), but it was not statistically significant. The only significant differences between AYA pts and older pts was median baseline Hemoglobin levels (11.3 g/dL in AYA group vs 12.4 g/dL in older group, p=0.04) and in baseline median WBC (6.8 × 109/L for AYA group vs 28.2 × 109/L in older group, p=0.02). In the AYA group: 2 pts have had stem cell transplants (SCT) after failing upfront TKI. Only one pt has died (pt experienced TKI resistance and then developed GVHD after cord blood transplant) in the AYA group. Eight of total 13 AYA pts have been taken off TKI (2 TKI resistance, 2 lost to follow-up, 3 toxicity of TKI, 1 SCT). For comparison of outcomes by age group of AYA pts and for pts >21 yrs, see Table 1 below:Table 1Age <= 21 (n=13)Age >21 (n=422)P valueTotalSokal risk at rx, no (%)Low12 (92)288 (68)0.24300 (69)Intermediate1 (8)105 (25)106 (24)High029 (7)29 (7)CCyR, no (%)7 (64)384 (93)0.008391/425 evaluable (92)Median time to CCyR (mo)333 (2-64)MMR, no (%)7 (64)359 (87)0.0497366/424 evaluable (86)Median time to MMR (mo)966 (2-78)CMR, no (%)1 (9)160 (39)0.06161/424 evaluable (38)Median time to CMR (mo)At 12 mo2424 (3-84)Event Free Survival (EFS) (IRIS) at 5-yr (%)79900.26 (log-rank)TFS at 5-yr (%)100940.51Overall survival (OS) at 5-yr (%)88930.9 Conclusions:At median follow up of 67 months and med treatment time of 49 months, we found the rate of CCyR was significantly higher in older pts compared to AYA pts, and trended towards significance favoring older pts with rates of MMR and CMR (as shown in Table 1). The EFS, TFS, and OS among the two groups showed no significant differences. Although these are small numbers of AYA pts, the observation of higher MMR, CCyR and CMR rates in older, rather than younger, pts is unexpected. The factors that contribute to this observation need to be determined (eg, compliance). Additional observations in this patient population are warranted to better define their outcome and make proper treatment recommendations. Disclosures:Off Label Use: Dasatinib as treatment for upfront, frontline treatment of CML. Kantarjian:BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Verstovsek:Incyte Corporation: Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau. Wierda:GlaxoSmithKline: Honoraria, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cortes:Pfizer: Consultancy, Research Funding; BMS: Honoraria, Research Funding; Novarits: Honoraria, Research Funding.

Early Switching From Imatinib to Nilotinib In CML Patients Failing to Achieve Early Molecular Targets May Not Be An Effective Approach In Patients with Very Low OCT-1 Activity: A TIDEL II Sub-Study

AbstractAbstract 356We have previously demonstrated that CML patients with very low OCT-1 activity (Quartile 1 (Q1)<4 ng/200,000 cells) have significantly poorer outcomes with respect to response, mutation development, progression, and survival than patients with higher OCT-1 activity(OA). We have also demonstrated that the influx pump OCT-1 is associated with the active uptake of imatinib, but not nilotinib (NIL), into target CML cells. Hence, if the prognostic significance of OA primarily reflects IM transport we predicted that patients with very low OA who had poor initial responses to imatinib, should respond well when switched to NIL. In the Tidel II study CML-CP patients are treated with 600mg/day imatinib (IM) upfront and are dose escalated to 400mg BID or switched to NIL 400mg BID for either intolerance (Grade III/IV or persistent Grade II non-haematological toxicity) or failure to meet pre defined molecular targets. These targets are early markers of sub-optimal response, but not IM failure: failure to achieve <10% BCR-ABL IS by 3 months, <1% by 6 months and <0.1% by 12months. Hence this study is designed to enable early efficacious intervention in the case of poor response, to prevent frank therapeutic failure. In this study we examine the cohort of patients who have switched to NIL and compare their response on NIL to that achieved on IM. To date 63 patients on this trial have greater than 12 month molecular follow up, and OA quantified. 26/63 patients have OA<4ng/200,000 cells. As demonstrated in Table 1, and in keeping with previous findings, patients with low OA have significantly poorer rates of MMR by 12 months, and higher rates of study discontinuation when compared to patients with ≥4.0ng/200,000 (high OA). Importantly the study design of Tidel II has enabled the more careful assessment of therapeutic intervention. Of note 23% of patients with low OA had a dose increase and 42% switched to nilotinib because of failure to meet pre-stated milestones. This compares with only 8% of remaining patients being dose increased and 14% switching to NIL(p=0.007).Table 1:Showing the response of patients within the two OCT-1 Activity Groups.MMR by 12 moMutationsOff StudyIncreased dose 400mg BID IMMMR on 400mg BID IMSwitched to NILMMR on NIL<4.0ng/200,000 cells n=2637%19%19%23%16.6%42%10%≥4.0ng/200,000 cells n=3781%0%2.7%8.1%100%13.5%100%p=<0.0010.0060.0370.1410.050.0070.007With a median follow up after switching to NIL of 12 months (Low OA R=6-21 high OA R=9-12 p=0.887) all patients with high OA, not previously in MMR (n=4), achieved MMR within 6 months. In contrast 1/10 low OA patients not previously in MMR achieved MMR on NIL. Interestingly, not all patients with low OA were switched to NIL because of sub-optimal IM response. Four of this cohort were intolerant to 600mg IM (one of these 4 achieved MMR), while all patients in the high OA cohort were switched because of intolerance. This implies that a low OA is not overcome with early switch to NIL, despite NIL transport being unrelated to OCT-1. This may be due to other intrinsic factors, possibly related to leukaemia biology and majority cell type for which the OA assay may be a surrogate measure. Alternatively, the poor response to imatinib in low OA patients has facilitated the activation of other resistance mechanisms, that in turn lead to a poor response after switching implying that patients with low OA may require upfront treatment with a TKI that is OCT-1 independent. Importantly only 1 of the patients on NIL had a mutation prior to switching, with another patient transforming to blast crisis with a T315I mutation while on NIL. Thus the presence of kinase domain mutations does not explain these findings. Conclusions:Low OA is associated with poor response to IM. Here we show that the MMR rate for patients with low OA was not substantially improved by the TIDEL II treatment strategy. This is despite the protocol allowing for early dose escalation or switch for suboptimal response. This preliminary data suggests that patients with low OA may have more generalized insensitivity to kinase inhibitor therapy which is not simply related to drug transport. These are important findings in the setting of multiple TKIs being available, and suggest that in patients with very low OA a regimen of selective TKI intensification may not be the optimal approach. Disclosures:White:Novartis: Honoraria, Research Funding; BMS: Research Funding. Slader:Novartis Pharmaceuticals: Employment, Equity Ownership. Osborn:Novartis Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding. Mills:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hughes:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria.

Measles-Mumps-Rubella Revaccination; 18 Months vs. 4-6 Years of Age: Potential Impacts of Schedule Changes

The policy of administering the second dose of measles-mumps-rubella (MMR) vaccine (MMR(2)) has recently changed in Iran, at age 1.5 years instead of 4-6 years previously. The effects of such a change on the immune status of the individual are evaluated in this study. Totally 249 and 228 children aged 18 months and 4- to 6-year-olds, respectively, with a documented receipt of primary MMR vaccine at the age of ≥ 1 year were enrolled. Before, and 4-6 weeks after MMR(2) administration, anti-MMR IgG antibody levels were measured using ELISA method. IgM antibody levels were also assessed in measles-rubella seronegative children that responded to MMR(2). Collected data for each component from both age groups were compared by using Fischer's exact probability and chi-square tests. Before revaccination, measles seroimmunity rate was similar between the two groups, but rates to mumps and rubella were significantly higher in younger children-measles: 74 vs. 78.3%; mumps: 82.3 vs. 68.4% and rubella: 75% vs. 67%, respectively. After administration of MMR(2), all seroimmune subjects were IgG boosted. Except for rubella, older seronegative children showed significantly higher seroconvertion rate to MMR(2) and seroprevalence rates increased in vaccinees--measles: 98.2 vs. 94%, mumps: 97 vs. 94.4% and rubella: 87 vs. 92.4%, respectively. Only few measles-rubella seronegative children showed IgM response to MMR(2). This study showed that the majority of younger children were susceptible to MMR infection before revaccination. Earlier age policy provides more protection against MMR in preschool-aged children. Rubella strain seems to be less potent than reported.