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Background: Registry data in chronic myeloid leukemia (CML) complement clinical trial data, and can help determine how closely real world clinical practice adheres to guidelines. Several reports addressing this issue have suggested adherence to monitoring guidelines varies. However, no Canadian data on this topic has been published to date. To provide insight into this issue, we present data from the British Columbia (BC), Saskatchewan (SK), Ontario (ON) and Quebec (QC) CML registries. Methods: Data on cytogenetic and molecular monitoring were analyzed for CML patients treated with first-line imatinib from 2001-2015 in the BC registry, 2009-2014 in the SK registry and 2001-2014 in the ON registry. From 2006, clinicians in BC and SK were advised to follow the European LeukemiaNet (ELN) monitoring recommendations. Molecular monitoring of BCR-ABL for these provinces was conducted at the BC Cancer Agency Molecular Genetics Laboratory according to standard practices. In ON, clinicians were not advised to follow any particular guidelines and molecular and cytogenetic tests were conducted by the Hamilton Regional Laboratory Medicine Program using contemporary standards. In QC, province-specific guidelines were in place beginning in 2012 (see www.gqr-lmc-nmp.ca for specific guidance). Treatment patterns for patients treated with first-line imatinib from BC, SK and QC were analyzed for the 2001-2015, 2001-2014 and 2002-2012 time periods, respectively. Results: Monitoring data were collected for 234, 58 and 104 patients from BC, SK and ON, respectively. As shown in table 1, adherence to monitoring recommendations in Canada was 70% to 80% at 12 months. Treatment data were available for 234 BC patients, 73 SK patients, and 223 QC patients. Data on adherence to treatment recommendations were available for 58 SK patients diagnosed with CML and treated with first-line imatinib between 2009 and 2014. Of these 58 patients, over a quarter (n=15) experienced treatment failure or failed to meet ELN milestones without a change in therapy. Smaller proportions of patients receiving first-line imatinib therapy in BC and QC remained on imatinib therapy (see table 2). Discussion and Conclusions: These data suggest there is room for improvement with regards to adherence to CML monitoring and treatment recommendations in Canada. However, assessment of adherence to recommendations and inter-provincial comparisons are limited by the fact that monitoring and treatment guidelines have evolved over the data collection time period, as well as by differences in data collection strategies. For instance, in the ON registry, monitoring at the 3-month time point may be lower as testing was not typically conducted at 3 months in ON during the early 2000s. The opposite pattern observed in BC (with higher testing rates at 3 months dropping off by 18 months) may be attributable to the strict time period definition, with more patients receiving testing outside of the 4-week window after 1 year or more on treatment. In spite of these limitations, data collection through these registries continues to improve our understanding of real world CML populations and its management in Canada, as well as to spur initiatives aimed at improving CML care. This study was sponsored by Bristol-Myers Squibb. Professional medical writing and editorial assistance was provided by MedPlan Communications Inc. and was funded by Bristol-Myers Squibb. Disclosures Hillis: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria; Celgene: Consultancy. Busque:Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Stakiw:Roche: Research Funding; BMS: Honoraria; Novartis: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Jansen: Honoraria, Speakers Bureau. Forrest:BMS: Consultancy, Research Funding; Ariad: Honoraria, Speakers Bureau.

Imatinib mesylate (IM) given orally at a daily dose of 400 mg was the standard of care as initial therapy for patients with chronic myeloid leukemia (CML) in the chronic phase (CML-CP), before 2ndTKI era. Treatment guidelines by European Leukemia Net (ENL) propose dose escalation based on clinical assessments of disease response in 2006. Preclinical data and results of single-arm studies raised the suggestion that better results could be achieved with a higher dose. However, randomized study to compare high-dose IM (800 mg) with the standard dose (400 mg) as front-line in all CML high-risk patients did not support the extensive use of high-dose IM. To improve the results of CML therapy, another alternative strategy is a dose-escalation based on more aggressive clinical assessments of disease response in comparison with the standard ELN proposed. In 2007, we conducted a prospective randomized study to compare different dose escalation programs; the standard-dose escalation program proposed by ENL (Group A) and the aggressive dose escalation program (Group B) among newly diagnosed patients with CML-CP. The aggressive dose escalation program consisted of the following interventions. If the patients do not obtained a complete cytogenetic response at 3 months or do not reach a major molecular response (MR3, IS=0.1%), IM is increased from standard dose of 400mg daily to 600 mg daily. The primary endpoint is the rate of major molecular response at 12 months, which is a surrogate for long-term progression-free survival (PFS). It is also a surrogate for complete molecular response, which is pointed out recently to be the condition for treatment free survival. Total 248 patients entered to this study between June 16 2007 and June 15, 2011. Median age was 49 years old (range 15-69); 86 were female and 162 were male. Sokal score index was high-risk in 46 patients, intermediate-risk in 77 and low-risk in the remaining. White blood cell count at diagnosis was 43X10^9/L in median (10-881 in range). There was no significant difference between Group A (N=126) and Group B (N=127) according to these factors. Overall survival was 100%, 98% and 98% at 1, 2 and 3 years after treatment, respectively. Three patients developed blast crisis during 3 years (day 177, 272, 481) and all received hematopoietic stem cell transplantation (HSCT). Two other patients who had no cytogenetic response also received HSCT. Eleven patients (4.5%, Group A, N=8, Group B, N=3) failed to achieve complete hematological remission. The overall complete cytogenetic response (CCR) rate at 6 months after the treatment was better in Group B (89%) than in Group A (79%) with borderline significance (p=0.05, Fisher's exact test). However, the overall CCR rate at 12 months was 92% in both groups. At 12 months, MR3 was achieved in 61% and 64% of patients in Group A and Group B, respectively (p=0.69). Also, at 24 months, MR3 was achieved in 91% and 87% of patients in Group A and Group B, respectively. At 3 months, plans called for 8 and 45 patients to increase the dose of IM to 600 mg in Group A and B, respectively; however, only 4 and 27 patients followed the protocol. At 6 months, 10 and 55 patients were to increase the dose of IM to 600 mg in Group A and B, respectively; however, only 2 and 24 patients followed this protocol. The main reason was intolerance of IM. Among the patients who were to increase the dose at 3 and 6 months, 53% of those who could do according to the protocol achieved MR3 at 12 months, while only 16% of patients failed to increase (p=0.08). Eighty patients experienced drug discontinuation during 1 year. The incidence of discontinuation was 37% in Group B, whereas it was 29% in Group B (p=0.18). A substantial part of patients withdrew from this study; however, there was no difference between Groups (A 20%, B 21%). This is the first randomized study to compare two different dose escalation programs. The aggressive dose escalation program showed a better early cytogenetic response than the standard-dose escalation program, but, failed to evidence a better molecular response in a later period. Higher efficacy of high dose IM might be cancelled by the more frequently discontinuation of IM in this group. This study concluded that aggressive dose escalation is not recommended and careful management of drug dose according to patients' condition (residual leukemia, adverse effect, emotion) might be the best way for better outcome, which is applicable to new generation TKIs. Disclosures Miyamura: Nippon Shinyaku CO, LT: Honoraria; Pfizer Inc: Honoraria; Novartis Pharmaceutical: Honoraria; Alexion Pharmaceutical Inc: Honoraria. Usui:Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Research Funding. Nakaseko:BMS: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; NOVARTIS: Honoraria. Fujita:Chugai Pharmaceutical Co.,LTD: Honoraria. Okumura:Novartis Pharma: Honoraria. Hatta:Novartis Pharma: Honoraria. Naoe:Astellas Pharma Inc.: Research Funding; Kyowa-Hakko Kirin Co.,Ltd.: Honoraria, Patents & Royalties, Research Funding; Celgene K.K.: Honoraria, Research Funding; Amgen Astellas BioPharma K.K.: Honoraria; Chugai Pharmaceutical Co.,LTD.: Honoraria, Patents & Royalties; TOYAMA CHEMICAL CO.,LTD.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding; CMIC Co., Ltd.: Research Funding; Fujifilm Corporation: Honoraria, Patents & Royalties, Research Funding; Sumitomo Dainippon Pharma Co.,Ltd.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Nippon Boehringer Ingelheim Co., Ltd.: Honoraria, Research Funding; Pfizer Inc.: Research Funding.

Introduction: Nilotinib is a second-generation TKI that exhibits significant efficacy as first- or second-line treatment in patients with CML. Superior rates of deeper molecular responses were achieved with nilotinib vs. imatinib in patients newly diagnosed with CML in chronic phase in the ENESTnd trial. In addition, the 24-month analysis of the ENESTcmr study demonstrated that switching to nilotinib after a minimum of 2 years on imatinib led to increased rates of MR4.5 by 24-month vs. remaining on imatinib (42.9% on nilotinib vs. 20.8% on imatinib). Although our CMR study revealed that ABCG2 421C/A genotype was an independent predictor of CMR in imatinib-treated CML patients (Shinohara et al, Haematologica, 2013), a relationship between ABCG2 421C/Agenotypes and CMR rate has not been observed in CML-CP patients treated with Nilotinib until now. The purpose of this study is to evaluate the efficacy of nilotinib in patients with CML-CP who have achieved a MMR with imatinib. In addition, the correlation of deeper molecular responses with clinical, immunological, and pharmacokinetic parameters in CML-CP patients was evaluated. Methods: Patients with CML-CP who had achieved MMR but still had persistent BCR-ABL positivity by RQ-PCR on imatinib were eligible. Nilotinib will be taken twice daily (600 mg/day) for 2 years. Thirty-five institutions in STAT study group participated. The study was conducted in accordance with the principles of the Declaration of Helsinki. Informed consent was written by all patients according to institutional guidelines. The study was approved by all institutional review boards and registered with ClinicalTrials.gov (number UMIN000005903). The primary objective of this multicenter phase II, single arm, open-label clinical study was to identify the MR4.5 rate at 24 months after the initiation of nilotinib treatment. The molecular response was evaluated according to the International Scale RQ-PCR upon study entry and every 3 months thereafter. Nilotinib trough concentrations were determined using high-performance liquid chromatography.Genotyping of SLC22A1 (156T>C, 480G>C, 1022C>T, and 1222A>G), ABCB1 3435T>C, ABCG2 421C>A, and the *6, *27 and *28 alleles of UGT1A1 were performed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Flow cytometry-based analysis of peripheral blood T cell subsets was performed using a whole blood lysis technique. Results: Between July 2011 and December 2012, 80 Japanese patients were recruited, and 74 patients were evaluated in the study. The median age was 54.5 years. The ratio of men to women was 52:22. The median duration of imatinib treatment was 62.5 months (range, 13.3-131.1 months). All patients showed MMR at the time of entry into the study and the median time to MMR on imatinib therapy was 20.2 months (range, 4.6-92.1 months). The median duration of treatment was 17.9 months (range, 0.5-25.1 months) for nilotinib 300 mg twice daily. Dose reduction and interruption were seen 17.1% and 18.4% in safety data set (N=76), respectively. The patients achieving deeper molecular responses increased over time (Figure1). The rates of MR4 in the evaluable patients were 69% and 73% at 12 and 24 months, respectively, and the rates of MR4.5 were 28% and 49% at 12 and 24 months, respective. Comparison of the clinical backgrounds, pharmacokinetic, pharmacogenomic, and immunological parameters (NK cells, NK activity, and cytokines) in patients with MR4.5 at 24 months (n=33) and without (n=41) is performed. Age, sex, Sokal risk score, prior IFN therapy, duration of imatinib treatment and time to MMR were not significant predictive factors for achieving MR4.5 at 24 months. The mean nilotinib plasma trough concentration was not significantly different in both groups either (Table1). However, the frequency of patients with ABCG2 421A allele was significantly higher in patients with MR4.5 than without (OR 7.056, 95%CI 2.040-24.406, P =0.002). This finding suggested that the ABCG2 421A allele was associated with a higher intracellular retention and therefore, higher nilotinib exposure than the wild-type genotype. Conclusion: We confirmed that switching to nilotinib led to deeper molecular responses in CML patients with persistent residual disease on long-term imatinib therapy. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Nakaseko: Otsuka: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Takahashi:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Masis: Consultancy; Astellas: Speakers Bureau; Sysmex: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees. Nishiwaki:Novartis: Research Funding, Speakers Bureau.

Background: For molecular assessment in CML, NCCN and European LeukemiaNet had defined the cut-off values. Until now the gold standard for BCR-ABL quantification is the real time quantitative polymerase chain reaction (RQ-PCR), and this technique has a limited sensibility to MR4.0 or MR4.5 in the majority of laboratories worldwide. There are several discontinuation studies for CP-CML patients under imatinib therapy who achieved and sustained at least MR4.0 during 2 years or more, and the fact of achieve a deeper response and the time during this response had been the major factors for good outcomes in these studies, now situated in around 40% of success. The droplet digital PCR (ddPCR), and other kind of digital PCR as the nanofluidic ddPCR, had showed more sensitivity for detect minimal amounts of BCR-ABL transcripts in patients with undetectable BCR-ABL transcripts by RQ-PCR, leading a window for investigation in this field. Aims: to evaluate the usefulness of the ddPCR in detect the presence of transcripts of BCR-ABL in patients with CP-CML under TKI therapy compared with RQ-PCR. Material & methods: A total of 54 samples from 32 patients with CP-CML under TKI therapy were analyzed. Sampling was performing obtaining one sample in EDTA for RQ-PCR and other in a TempusTM tube for ddPCR. The RNA was obtained from peripheral blood using TempusTM Spin RNA isolation kit according manufacturer recommendations. The analysis by ddPCR for each sample was done using 5 μg of the obtained RNA and processed in Qx100 Droplet Digital PCR, Biorad; using primers and probes described by Gabert et al., 2003 using ABL1 for control; the results was analyzed using QuantaLife Biorad software and expressed in absolute copies of BCR-ABL and in ratio BCR-ABL/ABL1. Only experiments with >32,000 copies of ABL1 were considered as valid for ddPCR to consider at least MR4.5. The use of a dual-determination in the same experiment with the ddPCR; one for BCR-ABL and other for ABL1 permit us to relativize the experiment and create results expressed in ratios easy to compare with the results obtained during the analysis by RQ-PCR for the same samples. Period of Study: August-2013 to Jun 2014. Results: The final analysis shows that 26 of the 54 analyzed samples presents values of BCR-ABL/ABL1 ratio within MR4.0 or more in the RQ-PCR test, of them 15 with MR4.5 values and 11 with MR4.0. However only 13 (50%) shows ratio values according to MR4.5/4.0 in the ddPCR analysis. The other 13 samples were compatible to MR3.0 or inferior. The samples that for RQ-PCR obtained values of MR4.5 or more (15), in only 6 (40%) a MR3.0 or inferior value of ratio were obtained by ddPCR, however in samples with values of MR4.0 by RQ-PCR (11), the proportion of samples with MR3.0 or inferior was higher, 63.6% (7 samples). See Table 1. The rest of the samples (28) the molecular results were within MR3.0 or inferior response values by RQ-PCR and for ddPCR this was confirmed, except in 3 samples in with ddPCR show a MR4.0 or superior response value. This led us to hypothesize that the use of ddPCR for confirms the response of the patients with MR4.0 or superior would improve the follow-up of the patients, and the success ratio for discontinuation. Comments: The ddPCR offers a new way to assess CP-CML patients, in especially in patients with >MR4.0 molecular response, and would offer a more accurately tool to select patient for discontinuation trials. Actually around 60% of patients who discontinues therapy lost MR4.0 or MR4.5 at 6 months, in our cohort, 50% of samples classified as MR4.0 for RQ-PCR had MR3.0 or less by ddPCR and would not be suitable for discontinuation trials; maybe if we use ddPCR as the standard for select patient to discontinuation less patients will lost the response. Table 1. Molecular response correlation between RQ-PCR and ddPCR ddPCR(RM4.0) Total RQ-PCR (RM4.0) 7 (63.6%) 4 (36.4%) 11 RQ-PCR (RM4.5) 6 (40.0%) 9 (60.0%) 15 Total 13 13 26 Disclosures No relevant conflicts of interest to declare.

As more patients are being treated with imatinib (formerly STI 571), cutaneous reactions[1][1],[2][2] are being recognized as very common among the side effects of the drug, ranging from mild macular erythema to widespread papulous lesions, that sometimes are pruriginous and cause discomfort to the

Imatinib has become standard therapy for patients with chronic myelogenous leukemia (CML). A complete cytogenetic response can be achieved in 75% to 90% of patients treated in early chronic phase,[1][1],[2][2] and a fraction of patients have undetectable levels of BCR-ABL by polymerase chain

Abstract 3754 Background Imatinib (IM) has dramatically improved the prognosis of chronic myeloid leukaemia (CML) patients. Some of them will achieve a so-call complete molecular remission (CMR) that allows when it is sustained treatment discontinuation without relapse. Aims Aims of this study were i) to evaluate the frequency of CMR in IM de novo CML-CP patients, ii) to identify baseline and ongoing predictive factors of CMR in patients who had achieved a complete cytogenetic response (CCyR) on IM therapy, iii) to assess if achieving a CMR with IM frontline therapy is associated with a better event and progression-free survival. Methods Unselected CML chronic phase patients under frontline IM therapy were considered. CMR was defined as undetectable BCR-ABL transcript with sensitivity of at least 4·5 log on two consecutive analyses at least two months apart. Event-free survival (EFS) referred to survival without loss of complete hematologic response, loss of complete CCyR, detection of a BCR-ABL domain kinase point mutation associated with a high level of IM resistance, progression to accelerated or blastic phase, death of any cause on or off therapy, off treatment for toxicity. Progression-free survival (PFS) referred to survival without events previously described with the exception of treatment cessation for toxicity. EFS and PFS and overall survival were measured from the date of the first CCyR on therapy to the date of event. Among patients who failed to achieve a CMR, patients with a follow-up lower than the observed median time to CMR and without any reported event were excluded for the identification of predictive factors of CMR and survival studies . Results 266 patients diagnosed with CML-CP and treated with IM frontline were included between July 2000 and June 2010. The median age was 56 years (range 17–89), 160 (60%) were male. 86% of the patients received an initial IM daily dose of 400 mg. Sixty-five (24%) patients had IM dose increase to at least 600 mg. The median follow-up was 4,43 years (range 0.79–10 .8). At the time of the analysis 88 (33%) patients had stopped IM. Two hundred and thirty three patients achieved a CCyR while on IM. Among them, 35 (13%) had a CCyR without major molecular response (MMR), 133 (50%) a CCyR with MMR without CMR, 65 (24%) a CCyR with CMR. The median time to CMR was 32.7 months (range 2.6 to 87.9). Forty six out of the 65 patients (70%) were still in CMR at the last follow-up with a median duration of CMR of 35.4 months (range, 4.1 to 91.5 months). For patients who achieved a CMR, the probability of remaining in CMR at two years is 68%. Twelve out of 35 patients of the CCyR+MMR- group, 41 out of 133 patients of the CCyR+MMR+CMR- group had a follow-up below the observed median time to CMR and without any reported event during follow-up were excluded for the identification of CMR predictive factors and survival studies. In multivariate analysis, spleen enlargement below the costal margin at diagnosis was negatively associated with the achievement of a CMR (HR:0.354 CI95%:0.192–0.654; p=0.0009) while shorter time from IM start to the first CCyR (CCyR before or after 12 months, HR:0.5; IC95%:0.27–0.95; p=0.034) and MMR (before or after 12 months; HR:0.2147;IC95%:0.092–0.5; p=0.00038) were strongly associated with the probability of achieving a CMR. Patients who achieved a CMR had a better EFS and PFS than those with CCyR irrespective of MMR status (95.2% vs 64.7% vs 27.7% p=0.00124; 98.4% vs 82.3% vs 56% p=0.0335) (figures 1a and 1b). Overall survival was not different between the 3 groups. Conclusion This study points out that once patients achieve a CCyR on IM therapy, achieving a further deeper molecular response is associated with a better EFS and PFS, CMR confering the best outcome. Disclosures: Etienne: Novartis: Consultancy, 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; Pfizer: Membership on an entity's Board of Directors or advisory committees. Nicolini:Novartis Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; ARIAD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mahon:Novartis Pharma: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy.

Abstract 2763 Approximately 50% of CP CML patients achieve complete molecular response (CMR) at 6–7 years of first-line imatinib therapy. Although imatinib therapy is effective in CML patients and a substantial portion of patients achieve CMR with prolonged imatinib therapy, up to 10^7 leukemic cells can still be present in the absence of detectable BCR-ABL in RQ-PCR assay due to the sensitivity limit of current RQ-PCR technology. The recent data from STIM (Stop Imatinib) trial showed that the probability of persistent CMR at 12 month follow-up after imatinib discontinuation was 41%, and the conclusion was that imatinib can be safely discontinued, at least in some patients with persistent CMR. However, it is still not clearly defined whether discontinuation of imatinib therapy can be safely employed in patients with sustained CMR. In our prospective study, we examined if imatinib therapy can be safely discontinued in CML patients with sustained CMR4.5 according to strict PCR sensitivity criteria, and CMR4.5 was defined as undetectable BCR-ABL using RQ-PCR assay with at least 4.5-log sensitivity. CML patients who were treated with imatinib for more than 3 years and whose BCR-ABL was undetectable in RQ-PCR for at least 2 years were enrolled in this study. Our primary objectives were to evaluate the probability of persistent CMR4.5 at 12 month follow-up after discontinuation, and to measure the duration of persistent CMR4.5 after discontinuation. The secondary objective was to evaluate the probability of major molecular response (MMR) loss and the time taken to lose MMR at 12 month follow-up after discontinuation. In patients with loss of MMR, the probability of re-achieving MMR/CMR4.5 and the time taken to re-achieve MMR/CMR4.5 after imatinib resumption were also evaluated. After discontinuation, molecular response was monitored using RQ-PCR assay every month up to 6 month follow-up, every 2 months up to 12 month follow-up, and every 3 months thereafter. Digital PCR methodology with higher sensitivity compared to RQ-PCR assay was also applied before discontinuation and every year after discontinuation for more accurate estimation of BCR-ABL transcript levels. In case of relapse, defined as loss of MMR on 2 consecutive assessments, imatinib therapy was re-introduced and molecular response after resumption was observed using both RQ-PCR and digital PCR assays. As of data cut-off date of 15 Jul 2011, 20 patients (13 females, 7 males) who were diagnosed in Seoul St. Mary's Hospital between 20 Mar 1996 and 25 Apr 2005 were enrolled in this study with a median follow-up of 7 months (range, 2–9), and informed consents were obtained from all patients prior to participation. With a median age of 44 years (range, 25–67), the percentages of patients with low, intermediate and high Sokal risk scores were 30%, 30% and 15%, respectively with unknown Sokal risk scores in 25%. Ten patients (50%) received SCT and/or interferon therapy prior to imatinib therapy, while 10 patients (50%) received first-line imatinib therapy. The median time on imatinib therapy and the median duration of sustained CMR4.5 were 91 months (range, 40–112) and 60 months (range, 23–104), respectively, prior to discontinuation. Since discontinuation of imatinib therapy, all of 20 patients remained off therapy at the last follow-up with persistent CMR4.5 in 18 patients (90%) and loss of CMR in 2 patients (10%). Although loss of CMR was observed in 2 patients, both patients have not resumed imatinib therapy as MMR was maintained at the last follow-up. Our preliminary data show lower relapse rate after discontinuation compared to previous discontinuation studies. Strict PCR sensitivity criteria should be employed to assess the accurate measurement of BCR-ABL transcript levels prior to discontinuation, and then it might be possible to safely stop imatinib therapy in CML patients with stable CMR4.5. Through further clinical investigation on a large patient population and longer period of observation, more concrete conclusion can be made regarding the outcome of imatinib discontinuation. Updated data with longer follow-up duration will be presented in the meeting. Disclosures: No relevant conflicts of interest to declare.

Abstract 3762 Introduction: The EUTOS Score was developed and validated as a prognostic tool for the achievement of complete cytogenetic response (CCR) at 18 months for chronic phase (CP) CML patients under imatinib therapy. The score identifies high-risk patients not reaching CCR at 18 months with a positive predictive value of 34% and a specificity of 92% using only two variables, peripheral blood basophils and spleen size at diagnosis (Hasford et al. Blood 2011). We sought to evaluate the clinical impact of the EUTOS score to predict molecular response. Therefore, we analyzed the EUTOS score with patients from the German CML-Study IV, a randomized 5-arm trial (imatinib 400 mg vs. imatinib 800 mg vs. imatinib in combination with interferon alpha vs. imatinib in combination with araC vs. imatinib after interferon failure). Results: From July 2002 to December 2010, 1,502 patients with BCR-ABL positive CML in CP were randomized. 129 patients with imatinib after interferon alpha and 36 other patients had to be excluded (14 due to incorrect randomization or withdrawal of consent, 22 with missing baseline information). 1,337 patients were evaluable for overall and progression-free survival (OS and PFS), 1,252 for molecular responses. 749 of these patients were part of the score development sample. Therefore cytogenetic analyses are not described here. By EURO score, 36% of patients (n=475) were low risk, 51% (n=681) intermediate risk, and 12% (n=167) high risk. The EUTOS score was low risk in 88% (n=1163) and high risk in 12% (n=160). The high-risk patients differed between the two scores: EUTOS high-risk patients were classified according to EURO score in 12% as low (n=19), in 45% as intermediate (n=68) and in 43% as high risk (n=73). Patients with high, intermediate, and low risk EURO score achieved MMR in 22, 16, and 13 months and CMR4 (BCR-ABL Patients with high risk EUTOS score achieved deep molecular responses (MMR and CMR4) significantly later than patients with low risk EUTOS score (MMR: median 21.0 vs. 14.8 months, p The proportions of patients achieving MMR at 12 months were significantly lower in the EUTOS high-risk group than in the EUTOS low-risk group (30.8% vs. 50.6%, p OS after 5 years was 85% for high and 91% for low risk patients (p=n.s.), PFS was 85% and 90%, respectively. Conclusions: The EUTOS score clearly separates CML patients also according to MMR and CMR4 (MR4). The new EUTOS score should be used in future trials with tyrosine kinase inhibitors in CML. Disclosures: Neubauer: Novartis: Honoraria, Research Funding; Roche: Research Funding. Kneba:Hoffmann La Roche: Honoraria. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Hochhaus:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, 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; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. German CML Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; BMBF: Research Funding; EU: Research Funding; Roche: Research Funding; Essex: Research Funding.

Abstract 3426 Imatinib mesylate (IM) has shown remarkable efficacy for the treatment of Chronic Myeloid Leukemia (CML) patients (pts) in the chronic phase of the disease. However, while most individuals achieve an optimal response to conventional IM therapy, approximately 30% either fail IM or develop intolerance to the drug. Thus, there is a growing need for biological parameters predictive of IM response (at diagnosis or during the first months of therapy) in order to recognize pts with a more aggressive disease that should receive alternative treatments. We examined the outcomes of the first 193 CML pts accrued to the observational SCREEN (Sicily and Calabria CML REgional ENterprise) multicenter non-sponsored study, and analyzed the responses of this unselected population. Pts characteristics were as shown in Table 1. All subjects received IM 400 mg daily. Median follow-up was 26 months (range 3–60). Complete hematological (CHR), cytogenetic (CCyR) and major molecular responses (MMR) were rated according to the European Leukemia Net 2006 guidelines. Peripheral blood samples were used for BCR-ABL determination by quantitative real-time polymerase chain reaction according to the International standardized Scale (IS). To identify parameters predictive of IM response, pts were stratified according to clinical and molecular responses or BCR-ABL transcript levels at diagnosis and analyzed for their outcome on an intention to treat basis. At 12 months, cumulative incidences of CHRs, CCyRs and MMRs were 100%, 82% and 43%, respectively. At 24 months, incidences of CCyR and MMR increased to 87% and 67%. According to the ELN criteria, 121 pts (62%) achieved an optimal response; 36 pts (19%) had a suboptimal response; 32 pts (17%) failed IM because of either primary (20 pts) or secondary (12 pts) resistance. Only 4 pts (2%) were intolerant to IM. Kaplan-Meyer estimates for overall, progression-free, event-free and failure-free survival at 60 months were 99%, 96% 80% and 72%. When we clustered all subjects in optimal responders (ORs) and suboptimal/resistant (S/R) pts and correlated response to therapy with various molecular characteristics we found that the amount of BCR-ABLIS transcripts at diagnosis predicted response to IM. Indeed, the median amount of BCR-ABLIS at diagnosis displayed by patients that failed IM or achieved a suboptimal response was significantly higher (104.154IS) than that of patients obtaining an optimal response (53.478IS; p=0.000611). As WBC counts were not significantly different between ORs and S/R pts (p=0.2065), increased amounts of BCR-ABLIS transcripts were probably representative of the aggressiveness of the leukemic clone. We also observed that pts displaying >10% BCR-ABLIS after 3 or 6 months of IM had a significantly lower chance of achieving a CCyR compared to pts with BCR-ABLIS levels lower than 10% (p Table 1. Characterisitics of CML pts included in the SREEN study Age (median yrs) 54 (range 24–90) Sex (M/F) 108/85 WBC × 109/L (median) 64.8 (range 3.4–718.0) Hb (g/dL) 12.1 (range 7.5–17.0) PLT × 109/L (median) 330.0 (range 67.0–1690.0) Organomegaly % 58 Sokal risk stratification % 49 Low/36 Intermediate/15 High Ph+ % (diagnosis) 96 ACA % (diagnosis) 7 BCR-ABL transcript variants % 38 e13a2/53 e14a2/9 other BCR-ABLIS % (median at diagnosis) 58.641 Disclosures: No relevant conflicts of interest to declare.

Abstract 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 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 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.

Abstract 4476 At present, the main goal of chronic myeloid leukemia (CML) therapy is to obtain complete cytogenetic response (CCyR) which is strongly associated with patient's survival. The second main factor for good prognosis after CCyR achievement is its stability. The aim of this study was to reveal factors, influencing the stability of CCyR in CML chronic phase (CML-CP) patients on Imatinib (IM) therapy in routine clinical practice. Patients and methods: In patients database of St-Petersburg and Leningrad region there are 235 CML-CP patients, who received IM for 12 months or more. Eligibility criteria for analysis were as follow: IM start dosage 400 mg/day, CCyR, which was confirmed by at least 2 consecutive cytogenetic analysis with 0% Ph+ cells in at least 20 metaphases. Patients in CCyR with IM therapy interruptions more than 3 months were censored at the date of last cytogenetic analysis. Results: 115 patients from our database were found to eligible for analysis. The median age at the diagnosis was 48 years (16-76 years). Male/female ratio was 50/65. The median time from diagnosis to IM treatment was 7 months (0.1-108 months), 55 patients begun the IM treatment in early CML-CP (≤ 6 months since diagnosis). 64, 38 and 13 patients had low, intermediate and high Sokal scores respectively. There were no differences between patients in early and late CML-CP. 56 (48,7%) patients before IM were treated with interferon. The median observation time on IM treatment was 56 months (16-88 months). Overall estimated probability of CCyR loss was 16%, rate 12.1% (14/115). In 10 patients CCyR was lost within major CyR. The estimated overall survival (all causes of death) was 78% (death rate 4.3% (5/115)), and only 1 death was CML-related. The probability of CCyR loss was not depend on previous interferon therapy and was equal in both groups -16%. The rate of CCyR loss was 15.3% (9/59) vs 8.9% (5/56) in pts with or without interferon pretreatment respectively. Sokal scores also didn't influence CCyR stability: CCyR loss rates were 10.9% (7/64), 13.2% (5/38), 15.4% (2/13) for low, intermediate and high risks, respectively (p>0.1). Probabilities of CCyR loss in different ages groups were similar: 13% (rate 8% (4/50)) vs 18% (rate 15.4% (10/65)) in patients older and younger than 50 years old, respectively (p>0.1). CCyR loss was less frequent in early CML-CP 10% (rate 3.6% (2/55)) then in late CML-CP 21% (20% (12/60)), p=0.032. For more thoroughly analysis, patients in late CML-CP were divided in subgroups related to duration of CML before IM initiation: >6 and ≤12 months, >12 and ≤60 and more than 60 months. Probabilities of CCyR loss in this groups were 22% (rate 20% (3/15)), 27% (rate 25.7% (9/35)) and 0% (rate 0% (0/10)), respectively (p Among patients, who lost CCyR, only 2/14 (14%) patients progressed to blast crisis. One of them was treated with chemotherapy followed by allo-SCT. At present, he is still alive in CCyR and complete molecular response. Another patient with blast transformation was treated by high dose IM with chemotherapy. There is no response and patient died due to progressive disease. From other patients: CCyR was re-obtained in 7 patients - in 5 patients on IM (2 pts on the same dose and 3 pts after IM dose escalation) and in 2 pts on second generation TKIs. One patient after IM dose escalation is not yet evaluable. Other 3 patients didn't respond either high dose IM or second generation TKIs, but are still alive in CML-CP. One patient lost from follow up. Conclusions: Patients in CML-CP with CCyR has very good prognosis. Very few patients progressed and dead during several years. There are two factors, which influence the probability of CCyR loss: initiation of IM in early CP and CCyR in first year of treatment are favorable to good prognosis for CCyR durability. Disclosures: No relevant conflicts of interest to declare.

Abstract 3439 Introduction: The European LeukemiaNet (ELN) recommendations for the management of chronic phase chronic myeloid leukemia (CP-CML) have provisionally defined criteria for suboptimal and failure to second-generation tyrosine kinase inhibitors (TKIs) (Baccarani et al., J Clin Oncol. 27 (35):6041-51, 2009). We tested the significance of these definitions in 3 studies of dasatinib after imatinib failure. Methods: Data from 1150 treated patients (pts) included in the 3 studies [CA180-013 (n=387); dasatinib only arm of CA180-017 (n=101); CA180-034 (n=662)] were analyzed. For the purpose of this analysis, we modified the 2009 ELN recommendations to add an optimal response category as shown in Table 1. Background: The median age of the pts included in this analysis was 56 yrs (range, 18–85) and the median duration of CML in these pts was 58 months (range, 0.9–250.8). Thirty-eight percent of the pts had received imatinib at a dose > 600mg/day and 45% had been on imatinib therapy >3 yrs. Twenty-four percent of pts included in this analysis had demonstrated imatinib-intolerance. Thirty-five percent of pts had mutations before the start of dasatinib therapy (5% had T315l). Results: Rates of optimal response at 3, 6 and 12 months were 51%, 44% and 36%. Rates of suboptimal response at 3, 6 and 12 months were 7%, 16% and 27%. Rates of failure response at 3, 6 and 12 months were 29%, 34% and 37%. Rates of warning response at 3 and 6 months were 12% and 6%. The starting dose of dasatinib did not influence these response rates. The group defined as suboptimal at 12 months (of whom 52% had already achieved CCyR) had a higher probability of achieving CCyR within 2 yr (83%) compared to the groups defined as suboptimal at 6 months (69%) or 3 months (51%). This suboptimal group at 12 months also had a higher 2 yr progression-free survival (PFS) (92%) compared to the suboptimal groups at 6 months (82%) and 3 months (80%). The probability of achieving an MMR within 2 yr was slightly higher in pts defined as optimal at 6 months (80%) vs. those at 3 months (71%). However, the probability of achieving an MMR within 2 yr showed minimal change for the suboptimal (31-35%) or the failure (5%) response groups defined at 3, 6 and 12 months. The pts with a warnings response had a profile that was intermediate between suboptimal and failure response. Table 2 summarizes 2 yr outcomes based on response. Conclusions: These results suggest that the 2009 ELN provisional response definitions may be helpful in predicting long term outcomes in pts receiving second-line dasatinib therapy. In this cohort of pts, optimal responders identified themselves rapidly as did pts with failure. However, the outcome of pts defined as suboptimal at 12 months appeared more favorable than that of pts defined as suboptimal at 3 and 6 months. This, in addition to the higher proportion of pts classified as suboptimal at 12 months, compared to those classified as suboptimal at 3 and 6 months, may suggest that the ELN defined cut-off between optimal vs. suboptimal at 12 months (i.e. MMR) may need to be modified in order to make the prognosis for suboptimal response more consistent across different time points. Pts classified in the warnings category at 3 and 6 months had an outcome intermediate between those with suboptimal and failure response. Disclosures: Cortes: Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Shah:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Ariad: Consultancy. LeCoutre:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Kantarjian:Novartis Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding. Jabbour:GlaxoSmithKline: Research Funding. Bahceci:Bristol-Myers Squibb: Employment. Chen:Bristol-Myers Squibb: Employment. Lambert:Bristol-Myers Squibb: Employment. Guilhot:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy.

Abstract 3414 We have previously shown that adherence to imatinib therapy is the single most important factor determining the degree of molecular response achieved by CML patients (Marin et al, JCO 2010). We now study the relation between adherence to imatinib and the probabilities of losing CCyR and of imatinib failure in patients receiving long term therapy. We measured the adherence to imatinib in 87 consecutive chronic phase CML patients who had received imatinib 400 mg day as first line therapy for a median of 59.7 months before enrolment, all of whom were in complete cytogenetic response (CCyR). Adherence levels were monitored during a 3-month period using microelectronic monitoring devices (MEMS, see below) and patients were followed subsequently for a median of 15 months. Data from the patients were censored in March 2010, when our previous work was published, to ensure that the results of this study were not influenced by possible changes in a patient's behavior. MEMS is an electronic device fitted into the cap of a normal looking medication bottle that automatically records each time the bottle is opened. MEMS are considered as the ‘gold standard' for measuring adherence. We also measured the imatinib plasma level, the presence of kinase domain mutations and the following factors assessed at diagnosis: demographic data, hemoglobin, leukocytes, Sokal risk group, BCR-ABL1 transcript type, hOCT1 transcript levels, and the presence of the 1236C>T polymorphism in ABCB1. The study protocol was approved by the Research Ethics Committee and patients gave written informed consent to participate. Adherence was defined as the quantity of imatinib actually taken divided by the amount prescribed expressed at a percentage. The median adherence was 97.6% range 24–100%). In 23 (26.4%) patients adherence was ≤90% (median 76%) and in 12 (13.8%) ≤80% (median 63%). During the follow up 7 (8%) patients lost their CCyR, and 12 (13.8%) discontinued the imatinib therapy (7 because of loss of CCyR, 2 because of failure to achieve MMR and 3 because of side effects). In multivariate analysis the adherence rate was the only independent predictor for loss of cytogenetic response (RR=0.95, p=0.0001) and discontinuation of imatinib therapy (RR= 0.97, p=0.009). When we categorized the adherence rate as (≤90% or >90%) we found that at 18 months the 23 patients with an adherence rate ≤90% had a higher probability of losing the CCyR (26.8% vs 1.5%, p=0.0002) and a lower probability of remaining on imatinib (64.5% vs 90.6%, p=0.006) than the 64 patients with an adherence rate >90% (Figure). In summary we have shown that poor adherence to imatinib is the principal factor contributing to the loss of cytogenetic responses and treatment failure in Patients on long term therapy. Figure Figure. Disclosures: Marin: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding.

Abstract 1113 Poster Board I-135 Currently, imatinib (IM) 400 mg daily is the frontline therapy for patients with CP-CML. In an attempt to improve the therapeutic response to IM, the Spanish collaborative PETHEMA group undertook a study of early optimization of therapy, in which 210 adult patients newly diagnosed with CP-CML (< 3 months from diagnosis) were included. Median age was 44 (range: 18-71) years and distribution by Sokal groups: low risk 56%, intermediate risk 28%, and high risk 16%. Hydroxyurea was permitted before IM. Patients initially received IM 400 mg daily for 3 months and then those failing to achieve a complete hematologic response (CHR) had the dose increased (to 600 and then 800 mg daily), while the remainder were maintained on 400 mg daily for three more months. At 6 months, depending on cytogenetic response, patients were kept on IM 400, if they had achieved a complete cytogenetic response (CCyR), or randomized to receive higher IM doses (600 and then 800 mg) or IM 400 plus low dose interferon (IFN, 3 million units 3 times a week) in case that a CCyR had not been attained by that time. In patients already in CCyR at 6 months, the IM dose was increased if a major molecular response (MMolR) according to the international scale had not been achieved at 18 months, whereas in patients not in CCyR and randomized at 6 months, a switch to a second generation TKI (dasatinib or nilotinib) was permitted if a CCyR was not achieved at one year of randomization. At standard intervals, cytogenetic response was assessed in bone marrow by chromosome banding analysis and molecular response determined in peripheral blood by RT-Q-PCR performed in three reference laboratories. At the time of the analysis, median follow-up was 48.3 (range: 1.2-73) months. Median time from diagnosis to IM start was 0.5 (range: 0-2.8) months; 72% of patients started IM within one month from diagnosis. At 3 months of treatment, 4 patients had not achieved a CHR; two of them failed to achieve a favorable response following the increase in the IM dose. At 6 months, a CCyR was obtained in 79% of patients; of the 41 patients not in CCyR, 9 could not be randomized because of toxicity (n= 3) or withdrawal of consent (n=6), 17 were assigned to higher IM dose, and 15 to IM 400 + IFN, but only 9 of the latter actually started IFN. Due to the scarce number of patients randomized, no comparison could be established between the two arms. Overall, cumulative incidence of response at 3 years was: CHR 98.6%, CCyR 90%, and MMolR 82%. Based on an intention-to-treat analysis, CCyR was 70% at 18 months. With current follow-up, only 5 patients have died and 9 have progressed to the accelerated or blastic phases (AP/BP). At 5 years, overall survival rate is 97.5%, survival free from AP/BP 95.5%, survival free from failure (including death, progression to AP/BP and the lack of achievement or the loss of a previously obtained CHR and CCyR) 82%, and event-free survival (including the above plus the permanent IM discontinuation for any reason) 80%. Twenty-seven patients (12.8% of the overall group) had grade 3-4 hematological toxicity and 26 (12.4%) grade 3-4 nonhematological side effects, in most cases during the first year of treatment. The presentresults show the benefit of prompt institution and early optimization of IM therapy in patients with newly diagnosed CP-CML. Disclosures Cervantes: Novartis: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau.

Abstract 859 Background Imatinib (IM) has greatly improved survival rates in chronic myeloid leukemia* (*CML). However, all patients (pts) must continue treatment for an unknown period of time. A pilot study of the first pts who discontinued IM therapy was previously reported (Rousselot et al. Blood 2007;109:58–60). The multicentre study Stop Imatinib (STIM) was initiated in July 2007 in order to evaluate the persistence of complete molecular remission (CMR) after stopping IM, and to determine the factors that could be associated with CMR persistence. Methods Inclusion criteria were IM treatment duration of at least 3 years and sustained CMR. Sustained CMR was defined as BCR-ABL/ABL levels below a detection threshold corresponding to a 5-log reduction (undetectable signal using RQ-PCR) for at least 2 years. Molecular relapse, defined as RQ-PCR positivity, was taken into account if confirmed in two successive assessments. In cases of molecular relapse, pts were re-challenged with IM at 400 mg daily. Results From the pilot study, 8 among 15 patients are still in CMR with a median follow up of 42 months (range 37-49). The number of patients enrolled in the STIM study was 69. 34 patients had received interferon alpha (IFNa) prior to IM and 35 pts were de novo. Median follow-up (range) was 17 months (6-24). 37 pts relapsed (loss of CMR) within the first 6 months and two patient relapsed after more than 6 months (M7 ,M18). At M12, the probability of remaining in CMR was 45% (95% CI: 33-56%). For previously treated with IFN (n=34) this probability was 44% (95% CI: 27-59%) versus 46% (95% CI: 29-61%) for de novo pts (p=0.93, overall). All patients in molecular relapse were sensitive again after imatinib re-challenge (decreasing BCR-ABL level, achievement CMR again). Male pts had a better probability of survival without molecular relapse (p=0.02) and a trend was observed for the low Sokal risk group (p = 0.06). Peripheral NK cells counts prior to IM discontinuation were significantly lower in relapse pts (mainly cytotoxic cells CD56dim) as compared to the non relapse pts(p=0.005). Conclusions We have confirmed that CMR can be sustained after discontinuation of imatinib with a long follow-up, particularly in male patients and in pts with cytotoxic NK cells in their peripheral blood. Using stringent criteria, it is possible to stop treatment in patients with sustained CMR, even in those treated with IM as a single agent. (ClinicalTrials.gov number, NCT00478985 [ClinicalTrials.gov]) Disclosures: Mahon: Amgen: Honoraria; Novartis Pharma: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria. Guilhot:Novartis Pharma: Consultancy, Honoraria; BMS: Consultancy, Honoraria.

Abstract 3290 Poster Board III-1 There is a great variability in the degree of molecular responses achieved by chronic myeloid leukemia (CML) patients treated with imatinib. These different levels of molecular response could reflect different degrees of adherence to therapy. We measured the adherence to imatinib therapy in 87 consecutive CML chronic phase patients who had received imatinib 400 mg day as first line therapy for a median of 59.7 months before enrolment (range 25–104) and therefore all them were in complete cytogenetic response. Adherence levels were monitored during a 3-month period using microelectronic monitoring devices (MEMS) and were related to levels of molecular response. MEMS consist of an electronic device fitted in the cap of a normal looking medication bottle that automatically records each time the bottle is opened. MEMS are considered as the ‘gold standard' for measuring adherence. We also measured the imatinib plasma level, the presence of TKD mutations and the following prognostic factors measured at diagnosis: hOCT1 transcripts level, polymorphism 1236C>T in ABCB1, Sokal risk group, hemoglobin, leukocytes , BCR-ABL1 transcript type and BCR1-ABL1 ratio and demographic data. The study protocol was approved by the Research Ethics Committee and patients gave written informed consent to participate. The median adherence rate was 97.6% (range 22.6–103.8%). In 23 (26.4%) patients adherence was ≤90% (median 76%) and in 12 (13.8%) ≤80% (median 63%). We found a strong association between adherence rate (≤90% or >90%) and the 6-year probability of major molecular response (MMR) (28.4% vs 94.5%, p Disclosures: Mahon: Novartis: Consultancy, Research Funding. Apperley:Novartis: Consultancy, Honoraria. Rezvani:Novartis: Consultancy, Honoraria, Research Funding. Marin:Novartis: Consultancy, Research Funding.

Diagnosis of chronic myeloid leukemia (CML) is based on detection of the BCR-ABL gene or Philadelphia chromosome, and the BCR-ABL tyrosine kinase inhibitor imatinib has been the standard therapy for CML patients. Although imatinib therapy is effective in CML, it is still unclear whether imatinib can be safely discontinued without relapse. This study was designed to investigate the outcome of 26 CML patients after discontinuation of imatinib and to determine whether intermittent imatinib therapy can be employed in CML patients. Between May 2001 and Jun 2007, 555 patients have been treated with imatinib in St Mary’s Hospital of the Catholic University of Korea, and 26 patients discontinued imatinib when they achieved either complete cytogenetic response (CCyR) or complete molecular response (CMR). These 26 patients were diagnosed as Philadelphia positive (Ph+) CML between November 1995 and May 2002, and 22 patients were in chronic phase (CP) and 4 patients were in accelerated phase (AP) at diagnosis. The median age was 35 years (22–56), and 12 patients (46%) were female and 14 (54%) were male. Among 26 patients, 7 received interferon prior to imatinib therapy and 7 underwent SCT. Five patients received both interferon and SCT before imatinib therapy, and the remaining 7 patients received the imatinib as a front line therapy. Imatinib was started at oral dose of 400mg and 600mg daily for patients in CP and AP, respectively, and when they achieved CCyR or CMR, imatinib was discontinued after informed consent of the patient. In case of cytogenetic or molecular relapse, patients in all phases were retreated with imatinib at 400mg daily. Bone marrow (BM) or peripheral blood (PB) samples were obtained at regular intervals from diagnosis for hematologic response (HR), cytogenetic response (CyR) and molecular response (MR) monitorings. Eleven patients discontinued imatinib when they achieved CCyR, and 15 patients discontinued imatinib after achieving CMR. After the median duration of 7 month (4–48) observation without imatinib therapy, hematologic, cytogenetic and molecular relapses occurred in 4, 7 and 10 patients, respectively, and imatinib at oral dose of 400mg daily was reintroduced to all patients except 2 who continued to remain in CMR after imatinib discontinuation. Except 1 patient who expired and 2 patients who are in persistent molecular remission, all of 23 patients are maintaining the best response achieved after imatinib resumption with a median duration of 38 months (16–58). In conclusion, although imatinib cannot be discontinued completely, intermittent therapy can be considered for the treatment of CML patients. Intermittent imatinib treatment should not be restricted to CP patients who achieve CMR, and AP patients or patients with CCyR also can be considered for intermittent imatinib treatment. We will continue the follow-up of the patients enrolled in this study, and long-term study of intermittent imatinib treatment with expanded pool of patients will enable us to determine the accurate consequences of discontinuation of imatinib and intermittent imatinib treatment.

Background: Results from the International Randomized Study of Interferon and STI571 (IRIS) trial showed that achievement of a CCyR is prognostically relevant for long-term survival in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP). With the advent of next generation tyrosine kinase inhibitors (TKIs), there is a need to understand factors that may influence long term outcomes. Here we analyze whether time to achievement of a CCyR affects long term outcomes. Methods: The relationship between time to CCyR and long-term outcomes was examined for 551 imatinib-treated patients with newly diagnosed CML-CP at the 6-year follow up of the IRIS trial. As evaluations included non-responders, landmark analyses were conducted in which only pts who were treated for ≥1 year were included (n=509). Patients were stratified according to time to achieving a CCyR as follows: ≤6 months (n=265), >6≤12 months (n=99), >12≤18 months (n=34), >18 months (n=49), or no CCyR during imatinib treatment (n=62). In each category patients were assessed for duration of cytogenetic response, event free survival (EFS; any event while on study), freedom from progression to accelerated phase (AP) or blast crisis (BC), and overall survival (OS). Results: In the 447 patients who were treated for at least 1 year and achieved a CCyR ( Conclusion: Long-term outcomes on imatinib for patients in CML-CP are independent of time to achieve CCyR. Therefore, achievement of a “late” CCyR does not increase the potential for progression or portend a worse overall survival for patients treated with imatinib. Figure Figure

The purpose of the registry is to collect existing cases of pts who failed imatinib therapy. Since the drug has been registered most of information on safety and efficacy were collected through clinical trials. Thus the true rate of failure is currently unknown. Members of the European LeukemiaNet agreed to establish a subregistry with the aim of collecting these cases. Failure is defined as efficacy failure i.e. no hematological response (HR) or cytogenetic response (CyR), unsatisfactory response, loss of response, according to the European Guidelines criteria (Baccarani et al, Blood 2006) and documented toxicity leading to discontinuation of imatinib. Objectives are to describe the sub-categories of failure and main toxicities, demographic patterns, clinical and biological profiles of pts (at diagnosis, at the beginning of imatinib therapy, at time of failure), dose and duration of imatinib therapy until failure was recorded, therapeutic decision after failure, and survival status. Eligibility criteria: To be included in the Registry, pts who failed imatinib therapy must be 18 years old or more with Ph+ CML in chronic phase at the onset of imatinib therapy. Pts are eligible, being included in prospective studies or not. Data collection: based on notification, data is prospectively centralized and quality controlled. The planned period for registration is 2005–2007 and 1000 cases are expected. Final analyses will be conducted overall, by groups: imatinib first line/not first line and by categories of failures. Results: As of July, 2006, 378 pts,(M: 56%, F 44%), were recorded. Median age at diagnosis was 51 (range 12–80). Participating countries were: Austria (4 pts), Denmark (13), Finland (18), France (236), Germany (39), Israel (34), Italy (10), Netherlands (11), Spain (13). Thirty seven percent of pts were never included in prospective studies at the time of failure. Reason for registration was no or unsatisfactory response in 30% of the cases including no complete HR (2%), not any CyR (12%), no major CyR (16%). Loss of responses occurred in 41% of the cases including hematological relapse (6%) cytogenetic relapse or progression (12%), progression to accelerated phase or blast crisis (23%). Discontinuation because of toxicity was recorded in 13% of the cases. Sixteen percent of the pts presented toxicity combined with unsatisfactory response. Policy: The IFP sub-registry is supported by a grant from the 6th European framework program “LifeSciHealth”. This collaborative study is linked with the European CML Registry (Work Package 4). This study is conducted in accordance with principles and guidelines of the European Community and Helsinki protocol and was approved by French authorities. In conclusion, this registry has been successfully established and already provides important information on subcategories of imatinib failure pts.

44 patients of CML (in chronic phase) were evaluated for their hematological, cytogenetic and molecular response (by doing quantitative PCR- for bcr-abl/abl), over a period of last 4 years. The toxicity profile of these patients was also evaluated. The mean age of study group was 54.5 years, with a male: female ratio of 1.8:1 (28 males and 16 females). 13/44 (29.3%) patients were treated with interferon prior to imatinib therapy, while the rest (31) were started on imatinib (400mg/day) upfront. 43/44 (97.7%) patients achieved a complete hematological response. 1 patient who did not respond to imatinib therapy had long duration of disease (111 months). 24/44 (54.6%) had complete cytogenetic response, 4 (9.1%) had major and 5 (11.3%) had minor cytogenetic response. 7/44 (15.9%) had hematological relapse while on Imatinib therapy. 3/44 (6.8%) had cytogenetics / molecular relapse only. Out of the 13 patients who had received prior interferon, 4 developed hematological relapse and of these 4 patients, 1 developed blast crisis and other 3 are in accelerated phase. 3/31 (9.7%) patients who received imatinib therapy upfront developed hematological relapse, while 6/31 (19.2%) developed cytogenetic/molecular relapse including the 3 patients who developed hematological relapse. A median of 17 months of imatinib therapy was given in patients who did not receive prior interferon. 36/44 (81%) developed hypopigmentation 19/44 (43%) had fluid retention, 9/44 (20%) had muscle cramps and 3/44 (6.8%) developed myelosupression. The relapse rate in patients of CML in chronic phase is more in those who have received interferon prior to imatinib therapy (37.7%). At a median follow up of 17 months the relapse rate in patients who received imatinib de novo was 19.2%.

In Japan Adult Leukemia Study Group (JALSG) clinical trial, imatinib was used as initial therapy for 171 patients with chronic myelogenous leukemia. We measured levels of BCR-ABL transcripts in the blood of all patients in this trial before and 1, 2, 3, 6 and 12 months after the treatment. Levels of BCR-ABL transcripts were measured by a quantitative real-time polymerase-chain-reaction assay. Results were expressed copy number of BCR-ABL per 1 microgram of RNA. Median number of BCR-ABL transcript was 106,478 at diagnosis and 61328, 24213, 4981, 331 and 98 at 0, 1, 2, 3, 6, 12 months after the treatment, respectively. Three log reductions were obtained 0%, 35.5% and 50.9% of patients at 3, 6 and 12 months of the treatment. Half reduction time between 0 and 1 month (0M–1M) is 1.3 M. In the next month (1M–2M), it is 0.75M and those between 2–3 and 3–4.5 months are 0.44 and 0.51. Thereafter, reduction speed is down because half reduction time is 1.5 between 4.5 and 6 months. After 6 months half time is 4.1months. This reduction curve shows the. Exponential decline value per day are 1.8%, 3.1% and 5.2% during first, second and third month, respectively. Thereafter exponential decline value is decreasing as 4.4% (3M–4.5M), 1.5% (4.5M–6M) and 0.6% (6–12M). In the previous study reported that, successful therapy leads to a biphasic exponential decline of leukemic cells (Nature435:1267–1270, 2005). The first slope is determined by calculating the exponential decline between 0 and 3 months; mean value of 0.05 per day was observed. While the second slope showed 0.008 per day. Our observation suggests that imatinib leads to a triphasic exponential decline of leukemic cells; between 0 and 2 months, much slower declining curve in comparison with between 2–6 months.

We analyzed clinical and molecular follow-up of 16 patients with chronic myeloid leukemia (CML) relapsing after allogeneic stem cell transplantation (SCT). The median interval between allogeneic SCT and relapse was 26 months (7–162). Two patients had failed treatment with donor lymphocyte infusions prior to Imatinib; four patients had received therapy with IFN alpha. All patients were treated with Imatinib (400 or 600 mg/daily). One patient had received Imatinib before allogeneic SCT. The overall complete hematological (CHR) and cytogenetic responses (CCyR) were 100% for all patients either relapsed in CP or AP. All patients achieved complete molecular response (CMR), intended as 3 logs reduction of BCR-ABL/B2M within 18 months; 8/16 patients obtained a CMR within three months, independently of the phase of the disease at of relapse. Median follow-up after start of Imatinib therapy was 24 months (range 6–36). Chimerism status evaluated in 9 patients showed conversion to full donor chimerism after therapy in all but one of them. Imatinib has significant activity against CML in relapse after allogeneic bone marrow transplantation with durable cytogenetic and molecular remissions obtainable in all patients.

Most patients (pts) with CML in chronic phase treated with imatinib achieve a major cytogenetic (CG) remission, and increasing numbers of pts are achieving molecular responses. To determine the clinical significance of molecular responses in these pts, we analyzed the results of quantitative PCR monitoring among 280 pts with CML in CP who achieved a complete CG remission with imatinib therapy (117 after IFN-α failure, 163 previously untreated). Pts have been followed for a median of 31.2 mo (range, 3 to 52 mo). The median BCR-ABL/ABL ratio before the start of therapy was 37.43 (range, 0.004 to 170.53). A major molecular response (i.e., BCR-ABL/ABL ratio 1.0 (p=0.0001). The probability of cytogenetic relapse is particularly high for patients who never achieved a major molecular remission. We conclude that achieving a major molecular response, particularly within the first year of therapy with imatinib, is predictive of a durable cytogenetic remission and should be the goal of therapy with imatinib. Increasing transcript levels after achieving a complete CG response predict for a relapse in patients who did not achieve a major molecular response.

High rates of complete cytogenetic response (CCR), the availability of sensitive methods to detect residual disease, and direct therapeutic consequences are leading motives to integrate regular molecular monitoring into the standards for the management of patients (pts) with chronic myeloid leukemia (CML). We sought to determine long-term dynamics of BCR-ABL mRNA expression levels in 132 CML pts (75 m, 57 f, median age 51, range 20–71 yrs) recruited into the IRIS study in 17 German centers. Pts were randomized to receive imatinib (n=69) or interferon α+Ara-C (IFN, n=63). Due to intolerance or lack of response 41 pts crossed over from IFN to imatinib. Response to therapy was sequentially monitored by conventional cytogenetics from bone marrow metaphases (n=806). BCR-ABL transcripts were determined in 1414 peripheral blood samples by quantitative real time RT-PCR (RQ-PCR) using the LightCycler technology. In case of low level (

Cutaneous reactions to imatinib therapy are increasingly being recognized, with up to 21% of patients experiencing mild to moderate reactions at doses of 600 mg and higher.[1][1] A recent case report of Stevens-Johnson syndrome complicating the use of imatinib[2][2] expressed caution in the