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Patients with chronic myeloid leukemia in chronic phase (CML-CP) resistant/intolerant to ≥2 tyrosine kinase inhibitors (TKIs) are at high risk of experiencing poor outcomes because of disease biology and inadequate efficacy and/or safety of current therapies. Asciminib, a first-in-class BCR-ABL1 inhibitor Specifically Targeting the ABL Myristoyl Pocket (STAMP), has the potential to overcome resistance/intolerance to approved TKIs. In this phase 3, open-label study, patients with CML-CP previously treated with ≥2 TKIs were randomized (2:1) to receive asciminib 40 mg twice daily vs bosutinib 500 mg once daily. Randomization was stratified by major cytogenetic response (MCyR) status at baseline. The primary objective was to compare the major molecular response (MMR) rate at week 24 for asciminib vs bosutinib. A total of 233 patients were randomized to asciminib (n = 157) or bosutinib (n = 76). Median follow-up was 14.9 months. The MMR rate at week 24 was 25.5% with asciminib and 13.2% with bosutinib. The difference in MMR rate between treatment arms, after adjusting for MCyR at baseline, was 12.2% (95% confidence interval, 2.19-22.30; 2-sided P = .029). Fewer grade ≥3 adverse events (50.6% vs 60.5%) and adverse events leading to treatment discontinuation (5.8% vs 21.1%) occurred with asciminib than with bosutinib. The study showed a superior efficacy of asciminib compared with that of bosutinib, together with a favorable safety profile. These results support the use of asciminib as a new therapy in patients with CML-CP who are resistant/intolerant to ≥2 prior TKIs. This trial was registered at www.clinicaltrials.gov as #NCT03106779.

The results of long-term follow-up of patients (pts) with chronic myeloid leukemia (CML) do not lose their importance. Data from routine clinical practice are of particular interest. The use of 1 st (imatinib, IM) and 2nd generation TKI (2G TKI) led to a significant increase in survival, so the probability of death associated with CML could be significantly lower than the probability of death due to common causes of death other than CML. To analyze the overall survival (OS) and causes of mortality in CML pts treated in routine clinical practice in Russian Federation for a long period (>15 years) of time. The long-term follow-up data of the Russian part of the European LeukemiaNet (ELN) OSP EUTOS multicenter observational study were evaluated. The analyzed cohort consisted of 678 Ph/BCR-ABL-positive CML pts from 35 regions of Russia diagnosed in 2002-2006 with IM therapy initiation ≤6 months (mo) after diagnosis. Median (Me) age was 47(range 18-81) years (y), 47% males. Chronic phase, accelerated phase and blast crisis at diagnosis was in 631 (93%), 41(6%) and 6(1%) pts, respectively. The annual number of newly diagnosed pts was as follows: 2002 - 15 pts, 2003 - 38 pts, 2004 - 46 pts, 2005 - 206 pts, 2006 - 302 pts. The last update for 209 pts was done in Jun. 2021; last contact for 100 pts - in 2020, for 39pts - in 2019, for the other - before 2018. The date of the last contact/death could not be established for 14 pts. Statistical analysis included 661 pts, the OS was evaluated by Kaplan-Mayer method using the SAS 9.4 package. In total, 331 (50%) pts of the analyzed cohort were alive with the Me follow-up of 180 (range 2-232) mo or 15 y (range 2 mo-19,3 y). All pts started therapy with IM with 25% switched to 2G TKI in subsequent therapy lines. In total, 218 (66%) pts achieved MR4, 183 (55%) pts got MMR; 46 (21%) of these pts with deep molecular response (DMR) were observed in hematology centers of Moscow. The 15-y OS in the total cohort was 63% (CI 59-70%)(fig.1). The OS by age groups was as follows: 18-40yy-75% (CI 73-82%), 40-60yy- 63% (CI 59-70%), 60-80yy- 37% (CI 30-45%). The most complete information was provided by Moscow centers (2 centers, 113 pts). The 15-y OS of pts receiving treatment in Moscow was significantly higher vs pts from other regions (32 centers, 548 pts): 75% vs 60%, p=0,0030 (fig.2). The mortality in the whole cohort of 661 pts was 35% (233 pts). Of these 233 pts, 112(48%) pts deaths were due to CML progression to AP or BP (including non-compliant cases); 3pts (1,5%) died after allogenic stem cell transplantation (infection complications); the cause of death was unknown in 50 (21,5%) pts. The highest death rate from CML progression was at 4-9 y of follow-up. Deaths caused by concomitant diseases were in 68 (29%) pts: coronary artery disease/myocardial infarction/heart failure in 42 (62%) of 68 pts, acute ischemic stroke in 10 (15%) pts, second malignancies (Cr- cancer) in 10 (15%) pts (lung tumor, metastatic esophageal Cr, stomach Cr, brain tumor, sigmoid colon Cr, rectal colon Cr, melanoma, renal Cr, breast tumor, other hematological malignancies), accidents - 1 pt, liver cirrhosis - 2 pts, in 2 cases - respiratory virus infections complicated with pneumonia, 1 pt died due to Covid-19. Conclusions. The long-term follow-up of the multicenter study EUTOS OSP in 35 regions of Russian Federation allows not only to characterize the 15-y OS in CML pts but also provides the long-term outlook of the routine clinical practice. Probably, better OS of CML patients receiving treatment in Moscow (2 centers) may be related to organizational issues of interaction with the federal center, better monitoring and timely switching to 2G TKI therapy. The organization and support of multicenter studies may improve the situation with the treatment of diseases of the blood system. Figure 1 Figure 1. Disclosures Chelysheva: Novartis Pharma: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Vinogradova: Pharmstandart: Speakers Bureau; Novartis Pharma: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Lomaia: Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Pharmstandard: Honoraria. Voloshin: Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; Pfizer: Consultancy; Biacad: Consultancy, Speakers Bureau. Turkina: Pharmstandart: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Novartis Pharma: Speakers Bureau.

Introduction Data on the effectiveness and safety of new vaccines against COVID-19 in patients (pts) with hematological diseases are just beginning to accumulate. We planned to obtain such information for pts with chronic myeloid leukemia (CML) during vaccination. Objective. To evaluate the antibodies formation and adverse events (AEs) after vaccination against COVID-19 in pts with CML Materials and methods. All pts with CML diagnosis who applied to the National Research Center for Hematology (NRCH, Moscow, Russia) for outpatient or remote consultations were suggested to prospectively report the AEs after getting a vaccination against COVID-19 by the most frequently used vector-based vaccine GamCovidVac (Sputnik V). Two vaccine components with the interval of 21 days were given at the vaccination facilities, as prescribed. At least after 3 weeks after the 2 nd injection, pts were advised to perform a blood test for the specific antibodies against spike (S) protein of SARS-CoV-2. A semi-quantitative test detecting the SARS-CoV-2 S1 subunit (RBD) IgG antibodies by enzyme-linked immunoassay (ELISA) kit was used in the clinic. The results were considered positive with the cutoff index >1,1. The use of any other lab tests detecting antibodies to S protein of SARS-CoV-2 was acceptable as well. Results. In total, 66 pts with chronic phase of CML received a vaccination by Sputnik V in the 7 months period (from 18.12.2020 to 20.07.2021). Me age was 54 years (range 29 - 89 years), 34 (52%) were males. Median (Me) CML duration was 8 years (from the moment of diagnostics up to 20 years). Fifty one (77%) pt received TKI therapy and 15 (23%) were off-therapy at the time of vaccination, including 12 (18%) in a treatment-free remission and 3 (4,5%) pts in the process of diagnosis. Deep and major molecular response (MMR) was in 46 (70%) and 7 (11%) pts, respectively. Two (3%) pts had a molecular response MR2, 11 (17%) had no MR2. Eight (12%) pts had a history of COVID-19 manifestation prior to vaccination. Me time for testing for the antibodies was 27 days (range 5-77) after the 2 nd vaccine injection. The tests were done in 44 (67%) of pts and revealed positive by any of the test systems in 42 (95%) pts. ELISA test was used in 30 (45%) pts and was positive in 25 (83%) of 30 pts. Me cutoff index in the positive samples was 7,7 (range 1,1 - 12) and corresponded to the value observed in healthy people after vaccination (medical stuff, data not shown). In all 3 pts with the history COVID 19, the index of positivity was above the Me value (Fig. 1, 2). Other test systems were used in 14 (21%) pts, in all 14 (100%) the antibodies were found. In 3 of 5 patients with the cutoff index A weak reverse correlation of the antibody levels with the time after vaccination was noted ( r = - 0,39, p = 0,033). A very weak reverse correlation with age was observed ( r = - 0,28, p = 0,127) (Fig. 1, 2). No AEs after the vaccination were observed in 25 (38%) pts while 41 (62%) pts reported the AEs and 7 (10%) pts did not report their reactions. The AEs were as follows: local pain/discomfort in the injection site in 19 (29%) pts, weakness and/or drowsiness in 20 (30%), fever and/or chills in 16 (24%), other reactions in 8 (12%) including headache, heartbeat, lower back pain, pain in limbs, activation of herpes infection. Conclusion: The single center study revealed no unusual or unexpected AEs in CML pts after the vaccination against COVID-19 by Sputnik V vaccine. The proportion of CML pts with specific antibodies after was 95% which is close to the published results of the 3rd phase study. No significant correlation was found with age (r = -0,28, p = 0,127), however, the absence or very low antibody levels were detected in individual patients aged about 60-70 years. This data raise a question of a necessity for a non-specific protection (masks, respirators, distance etc) and probably considering additional vaccination in some elderly persons. The duration of a humoral response against COVID-19, protective antibody titer and connection with clinical outcomes in CML pts need further evaluation in parallel with a common population. Figure 1 Figure 1. Disclosures Chelysheva: Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Novartis Pharma: Speakers Bureau. Petrova: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau. Gurianova: Pfizer: Speakers Bureau. Turkina: Pharmstandart: Speakers Bureau; Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau.

INTRODUCTION: Asciminib is the first BCR-ABL1 inhibitor that potently inhibits kinase activity of the BCR-ABL1 oncoprotein by Specifically Targeting the ABL Myristoyl Pocket (STAMP). The primary analysis from ASCEMBL, a randomized, phase 3 trial, demonstrated that asciminib has superior efficacy and a better safety and tolerability profile than bosutinib (BOS) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) after ≥2 prior ATP-binding tyrosine kinase inhibitors (TKIs). The major molecular response (MMR) rate at wk 24 was 25.5% with asciminib vs 13.2% with BOS; the difference in MMR rates, after adjusting for major cytogenetic response status at baseline, was 12.2% (95% CI, 2.19-22.30; 2-sided P=.029). Grade ≥3 adverse events (AEs) were reported in 50.6% and 60.5% of pts receiving asciminib and BOS, respectively, and AEs leading to discontinuation in 5.8% and 21.1%, respectively. After a median follow-up of 19.2 months (or 7.5 months' additional follow-up since the primary analysis), we report updated efficacy and safety results from ASCEMBL. METHODS: Adults with CML-CP treated with ≥2 prior TKIs were randomized 2:1 to asciminib 40 mg twice daily (BID) or BOS 500 mg once daily (QD). Eligible pts must have experienced treatment failure (lack of efficacy) per 2013 European LeukemiaNet recommendations for second-line TKI therapy or intolerance of the most recent TKI at screening. Pts intolerant of their most recent TKI were eligible only if they had BCR-ABL1 on the International Scale >0.1% at screening. Pts with known BOS-resistant T315I or V299L mutations were ineligible. The cutoff date for the current analysis was January 6, 2021. RESULTS: A total of 233 pts were randomized to receive either asciminib (n=157) or BOS (n=76). At cutoff, all randomized pts had completed their wk 48 visit or had discontinued earlier. Treatment was ongoing in 89 (56.7%) and 17 (22.4%) pts on asciminib and BOS, respectively; the most common reason for treatment discontinuation was lack of efficacy in 37 (23.6%) and 27 (35.5%) pts, respectively (Table 1). By wk 48, the cumulative incidence of MMR was 33.2% with asciminib and 18.6% with BOS, showing that the difference between the 2 treatment arms observed by wk 24 in the primary analysis was maintained with longer follow-up (Figure 1). The cumulative incidence of BCR-ABL1IS ≤1% by wk 48 in patients without this level of response at baseline was 50.8% with asciminib and 33.7% with BOS. The difference in deep molecular responses (MRs) favoring asciminib vs BOS persisted by wk 48: MR 4 (BCR-ABL1IS ≤0.01%) and MR 4.5 (BCR-ABL1IS ≤0.0032%) rates were 14.0% and 9.6% with asciminib and 6.6% and 2.6% with BOS, respectively. With a longer duration of exposure in the asciminib arm, the safety and tolerability profile in the current analysis remains similar to that at the primary analysis. Median duration of exposure was 67.1 wk (range, 0.1-162.1 wk) for asciminib and 29.7 wk (range, 1.0-149.3 wk) for BOS. By the cutoff date, 91.0% of pts on asciminib and 97.4% of pts on BOS reported ≥1 all-grade AE; 54.5% and 67.1% of pts, respectively, reported ≥1 grade ≥3 AE. No additional fatal events were reported since the primary analysis. Fewer pts in the asciminib (7.1%) than BOS (25.0%) arm experienced AEs leading to treatment discontinuation (Table 2). The most common AEs leading to treatment discontinuation included thrombocytopenia (3.2%) and neutropenia (2.6%) in the asciminib arm and increased alanine aminotransferase (5.3%) and neutropenia (3.9%) in the BOS arm. CONCLUSIONS: Resistant/intolerant CML-CP after 2 lines of TKI treatment remains BCR-ABL1 dependent. The novel STAMP inhibitor asciminib demonstrates continued superior efficacy and a limited adverse event profile; myelosuppression, while more prominent, appears to be early and disease related. Secondary resistance based on loss of MMR is rare. Overall, after a median follow-up of 19.2 months, the positive benefit-risk profile of asciminib vs BOS continues to support the use of asciminib as a new therapy in this heavily pretreated pt population. This study is sponsored by Novartis. Figure 1 Figure 1. Disclosures Mauro: Sun Pharma / SPARC: Research Funding; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy. Minami: Takeda: Honoraria; CMIC: Research Funding; Astellas: Honoraria; Ono: Research Funding; Pfizer Japan Inc.: Honoraria; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria. Rea: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hochhaus: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Lomaia: Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Pharmstandard: Honoraria. Voloshin: Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; Pfizer: Consultancy; Biacad: Consultancy, Speakers Bureau. Turkina: Pharmstandart: Speakers Bureau; Novartis Pharma: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau. Kim: Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; ILYANG: Research Funding; Takeda: Research Funding. Apperley: Bristol Myers Squibb, Novartis: Honoraria, Speakers Bureau; Incyte, Pfizer: Honoraria, Research Funding, Speakers Bureau. Cortes: Sun Pharma: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Fogliatto: AstraZeneca: Speakers Bureau. Kim: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Paladin: Honoraria, Research Funding; Bristol-Meier Squibb: Research Funding. le Coutre: Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria; Bristol Myers Squibb: Honoraria. Saussele: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Pfizer: Honoraria; Roche: Honoraria. Hughes: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Incyte: Honoraria. Chaudhri: Abbvie: Honoraria; Novartis: Honoraria; Astra Zeneca: Honoraria. Chee: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Garcia Gutierrez: Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Kapoor: Novartis: Current Employment, Current equity holder in publicly-traded company. Allepuz: Novartis: Current Employment, Current equity holder in publicly-traded company. Quenet: Novartis: Current Employment. Bédoucha: Novartis: Current Employment. Boquimpani: Pinth Pharma: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jansen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Introduction Despite the availability of vaccination against COVID 19 for all population categories since January 2021, it is moving slowly in Russia. Patients (pts) with chronic myeloid leukemia (CML) usually lead a normal life with social interactions. In the context of the COVID 19 pandemic, we find it important to identify the factors of adherence to vaccination and clarify the concerns. Objective: To determine the proportion of CML pts willing to consider vaccination against COVID 19, adherence factors and reasons for not vaccinating. Materials and methods. A survey on the attitude to vaccination against COVID 19 was prospectively carried out among all pts with CML consulted at the outpatient department of National Research Center for Hematology (Moscow, Russia) who agreed to participate. The key questions included considerations for and against vaccination, socio-demographic and clinical characteristics, lifestyle, comorbidities and history of COVID 19. Results. Within 4 months (from March 15 to July 19, 2021), 172 CML pts completed the questionnaire. CML chronic phase, advanced phase and blast crisis were in 167 (97%), 4 (2%) and 1(1%) respectively. In total, 141 (82%) pts were on therapy with 1 st, 2 nd and >3 rd therapy line in 77 (55%), 33 (23%) and 31 (22%) pts, respectively. Thirty one (18%) had no therapy: 6 (3.5%) newly diagnozed, 25 (14.5%) in a treatment-free remission. A deep and major molecular response was in 77 (45%) and 30 (17%) pts, respectively. Presence and absence of molecular response MR2 was in 20 (12%) and 45 (26%) pts respectively. The median age of pts was 46 years (range 19-82), 75(44%) were males. Married 108 (63%), 70 (41%) lived with elderly relatives, 35 (20%) with children. A higher education was in 123 (72%) pts, 123 (72%) could not work remotely and 46 (27%) had interactions to people by work. Any comorbidity was in 89 (52%) pts, 42(24%) had >1 concomitant disease, 48 (28%) had cardiovascular diseases, 44 (26%) had an obesity. A history of COVID 19 was in 41 (24%) pts and in the close circle of 74 (43%) pts. Vaccination was supported by 94(55%) pts (with 29 (17%) already vaccinated) and not supported by 76 (44%) pts, 2 (1%) pts did not answer. Among those supporting vaccination vs not supporting there was significantly more males (52% vs 33%, p=0,012), married pts (73% vs 49%, p The two most common reasons to avoid vaccination were the fear of complications in 37(49%) pts and waiting for additional data in 19(25%) (Fig.1). Notably, 7 (9%) pts considered CML as a contraindication to vaccination. Among those supporting vaccination, 55(59%) preferred to choose the GamCovidVac (Sputnik V) vaccine, 20(21%) had no preference (Fig.2). Out of 32 pts who gave the rationale for the Sputnik V choice 19(59%) noted its best availability, study or popularity (Fig.3). Among 23 pts with additional questions 12 (52%) wondered about the possibility of vaccination with CML diagnosis and 6 (26%) asked help with a vaccine choice. Conclusion: Despite access to vaccines against COVID 19 with proven efficacy and safety, almost half of CML pts (44%) do not support vaccination. Socio-demographic factors such as gender, education, marriage status appeared to be significant for this decision. Considering the frequent concerns of the possibility of vaccination with CML diagnosis as well as the fear of complications, hematologists should provide a relevant clarifying information on these issues. Figure 1 Figure 1. Disclosures Chelysheva: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau; Pharmstandart: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Petrova: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau. Gurianova: Pfizer: Speakers Bureau. Kokhno: Novartis Pharma: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Turkina: Novartis Pharma: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau.

Background: The problem of resistance and intolerance to 2nd generation tyrosine kinase inhibitors (2G TKIs) in patients (pts) with chronic myeloid leukemia (CML) currently remains relevant. Ponatinib has demonstrated a high effectiveness and may be an option in CML pts with resistance or intolerance to available TKIs but the high incidence of vascular adverse events (AEs) limits its broad use. A STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor asciminib has demonstrated a superiority over bosutinib in CML pts previously treated with 2 or more TKIs (Phase III Study). Asciminib is available in Russia under the Managed Access Program (MAP) approved by Novartis. Aim: to present the first results of the use of asciminib in clinical practice under the MAP program in Russia. Methods: In total 46 CML pts from 3 Russian clinics were enrolled into the MAP program and received asciminib from September 2019 to June 2021 (1 pt started asciminib in a cinical trial and was transferred to MAP later). We analyzed therapy results of 32 pts who received asciminib for at least 3 months. Patient recruitment, dosing regimen, response monitoring, and toxicity control were performed according to the MAP treatment plan. Complete cytogenetic response (CCyR), major molecular response (MMR) and deep molecular response (MR4) rates were assessed by cumulative incident function (CIF). Differences between the subgroups were considered significant with p value ≤ 0.05 by the Gray's test. Results: Baseline characteristics: male: 41%; Меdian (Me) age 54 years (range 26-81); Me duration of CML before asciminib was 8 years (range 2-24); 23 pts were in chronic phase (CP) CML, 7 and 2 pts had a history of accelerated phase (AP) and blast crisis (BC), respectively, but were in a second CP at baseline. Nineteen (59%) pts had BCR-ABL mutations, 10 pts (31%) had BCR-ABLt315i clones, 7 (22%) pts had at least two mutations. Eight (25%) pts had additional chromosomal abnormalities (ACAs). Twenty one (66%) pts received ≥4 TKIs, 14 (44%) pts had a history of ponatinib treatment. Me duration of asciminib treatment at the time of analysis was 7 months (range 4-24), 4 (12.5%) pts discontinued asciminib due to lack of efficacy; all pts were alive. The initial asciminib dose was 40 BID in 22 (69%) pts and 200 mg BID in 10 (31%) pts. CCyR, MMR and MR4 at the time of analysis was achieved in 32% (8/25), 34% (10/29) and 17% (5/30) pts, respectively (considering pts without this kind of response at baseline). The 6 month CIF of CCyR, MMR and MR4 was 27%, 24% and 19%, respectively. Univariate analysis was performed in 29 pts without MMR at baseline evaluating the following factors of 6 month MMR achievement: initial dose of asciminib, CML phase, presence of BCR-ABL mutations and ACAs, best molecular response on previous TKIs, molecular response at the time of asciminib starting, history of ponatinib treatment, number of TKIs and duration of TKI therapy before asciminib. The duration and number of TKIs, the history of advanced phases, BCR-ABL kinase domain mutations and ACAs did not significantly effect on MMR rate (tab.1). BCR-ABL Fourteen (44%) of 32 pts had AEs of any grade and 7 (22%) had AEs of grade 3-4 (hematological AEs -6 (19%), non-hematological AE- 1 (3%)) (tab.2). Conclusion: Asciminib has shown promising efficacy and a good toxicity profile in a cohort of highly pre-treated CML pts and should be considered as a therapeutic option for CML pts resistant or intolerant to other TKIs. Figure 1 Figure 1. Disclosures Turkina: Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau; Novartis Pharma: Speakers Bureau. Lomaia: Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Pharmstandard: Honoraria. Petrova: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau. Chelysheva: Novartis Pharma: Speakers Bureau; Pharmstandart: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau. Gurianova: Pfizer: Speakers Bureau.

Background: Not everyone with CML responds optimally to TKI-therapy, especially those with BCR::ABL1T315I. PF-114 is a 4 th-generation oral tyrosine kinase-inhibitor (TKI) active against wild-type and mutated BCR::ABL1 isoforms including BCR::ABL1T315I. We present final results of a phase-1 study (NCT02885766). Methods: 3+3 dose-escalation study to determine maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary objectives included safety and efficacy based on haematological, cytogenetic and molecular response criteria. Adverse events (AEs) were graded using NCI-CTCAE v4.03. Results: 51 subjects (5 with accelerated phase CML, 46 - with chronic CML), 23 males, were studied. Daily doses were 50-600 mg/d given once daily continuously. Median age was 50 y (range, 29-82 y). Median CML duration pre-study was 10 y (range, 0.3-23 y). 16 subjects had BCR::ABL1T315I. 25 subjects received ≥ 3 prior TKIs. Median follow-up was ≥ 31 mo and median exposure, 6 mo (range, 0.4-52). Therapy was ongoing in 7 subjects at study termination. Others discontinued because of progression (n = 20), AEs (n = 2), consent withdrawal (n = 5), entry into another study (n = 3) or other reasons (n = 14). The MTD was 600 mg with the grade-3 psoriasis-like skin AE as the DLT. There were no vascular occlusive events or deviations of ankle-brachial index. Complete haematologic response (CHR) was achieved in 14 of 30 subjects, major cytogenetic response (MCyR) in 15 of 44 subjects, complete cytogenetic response (CCyR) in 11 of 50 subjects and major molecular response (MMR) in 8 of 51 subjects. Median duration of CHR was 12 mo and has not been reached for MCyR, CCyR and MMR. The best safety/efficacy dose was 300 mg/d with 6 of 9 subjects achieving a MCyR, 5, a CCyR and 4, MMR. 5 of 16 subjects with BCR::ABL1T315I responded, including 4 achieving a MCyR, 2, a CCyR and 1, a MMR. 2 of 6 subjects failing ponatinib achieved a CHR. Conclusion: PF-114 was safe and effective in subjects failing ≥ 2 TKIs and those with BCR::ABL1T315I including those failing ponatinib. The PF-114 dose for further study is 300 mg/d. Disclosures Turkina: Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau; Novartis Pharma: Speakers Bureau. Vinogradova: Bristol Myers Squibb: Speakers Bureau; Novartis Pharma: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau. Lomaia: Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Pharmstandard: Honoraria. Chelysheva: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Pharmstandart: Speakers Bureau. Petrova: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau. Cortes: Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Baccarani: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ottmann: Fusion: Honoraria; Incyte: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Novartis: Honoraria. Mikhailov: Fusion Pharma: Current Employment. Novikov: Fusion Pharma: Current Employment. Shulgina: Fusion Pharma: Current Employment. Chilov: Fusion Pharma: Current Employment.

Background: The ENESTop study (NCT01698905) evaluates treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with sustained deep molecular response following second-line (2L) treatment with nilotinib (NIL). In the primary analysis, 57.9% of pts remained in TFR 48 weeks after stopping NIL and previous analysis at ≥3.7 years showed durability of TFR. The present analysis first assessed long-term TFR outcomes at ≥5 years and then a post-hoc analysis evaluated rates of regain of molecular response following NIL re-initiation in pts with loss of major molecular response (MMR) or confirmed loss of MR4.0 at a follow-up of 5 years. Methods: Eligible pts had received ≥3 years of treatment (including >4 weeks of imatinib followed by ≥2 years of NIL) and had achieved MR4.5 (BCR-ABL1IS ≤0.0032%) on NIL. Pts without confirmed loss of MR4.5 after 1 year of consolidation treatment (CONS) could attempt TFR. NIL was re-initiated upon loss of MMR (BCR-ABL1IS >0.1%) or confirmed loss of MR4.0 (BCR-ABL1IS >0.01% in 2 consecutive assessments). By data cut-off (29 Jan 2020) pts had completed ≥5 years of TFR, resumed NIL, or discontinued the study. Results: At the data cut-off, of the 126 pts who entered TFR, 52 remained in TFR, 59 had resumed NIL and 15 had discontinued the study. At 5 years, the TFR rate was 42.9% (54/126; 95% CI, 34.1-52.0). Compared with pts in TFR at the end of the 3.7-year follow-up, an additional 4 pts were not in TFR at the 5-year follow-up, none due to loss of response: 2 pts discontinued TFR due to pt/guardian decision, 1 pt had an ischemic stroke and died in the post-treatment follow-up phase, and 1 pt was lost to follow-up. The MR4.5 rate at 5 years after starting TFR was 37.3% (47/126, 95% CI: 28.9-46.4). 11 pts with MR4.5 at 5 years had a temporary loss of MR4.5 while 36/126 (28.6%) maintained stable MR4.5 for 5 years. The estimated treatment-free survival (TFS) rate at 5 years was 49.4% (95% CI: 40.3-57.9). Of the 59 pts who resumed NIL, 58 (98.3%) regained MMR. The only pt who did not regain MMR stopped retreatment at 20 weeks and withdrew from the study. 56 (94.9%) pts regained MR4.0 and 55 (93.2%) regained MR4.5 (Figure). The median time to regain MR4.5 was 2.9 months (range: 0.9-22.5). Baseline characteristics between pts who resumed NIL due to loss of MMR (n=34) or confirmed loss of MR4.0 (n=25)were similar; more pts with loss of MMR had a low Sokal relative risk score at diagnosis (44.1% vs 16.0%) and pts with loss of MMR had a shorter median time from achievement of MR4.5 until TFR entry (27.9 vs 40.1 months). In pts with confirmed loss of MR4.0, 25/25 (100.0%) and 24/25 (96.0%) regained MR4.0 and MR4.5 within the first 48 weeks of NIL re-initiation, respectively. In pts with loss of MMR, 33/34 (97.1%), 31/34 (91.2%) and 30/34 (88.2%) regained MMR, MR4.0 and MR4.5 within the first 48 weeks of NIL re-initiation, respectively. The median time to regain MR4.5 for pts who resumed NIL due to confirmed loss of MR4.0 or loss of MMR was 2.0 months (range: 0.9-4.6) and 3.6 months (range: 1.6-22.5), respectively. There were no cases of disease progression or death due to underlying CML. For pts remaining in TFR >3.7 years (n=58), the rates of all-grade adverse events (AEs) were 50.0% in the fifth 48 weeks of TFR compared with 55.2% in the fourth 48 weeks. The musculoskeletal pain AE rate was high during the first 48 weeks of TFR (53.4%) but by the fifth 48 weeks of TFR was lower (6.9%) than during CONS (10.3%). In pts who resumed NIL (n=59), the rate of all-grade AEs was higher (94.9%) than during CONS (77.9%, n=163). Overall all-grade AE rates were similar between pts re-initiating NIL due to loss of MMR (94.1%) or confirmed loss of MR4.0 (96.0%), with the most common AEs being hypertension (26.5% vs 32.0%), arthralgia (20.6% vs 8.0%), constipation (11.8% vs 20.0%) and hyperglycemia (26.5% vs 0%). Conclusions: These results illustrate the long-term (up to 5 years) durability and safety of TFR in pts with CML-CP following 2L NIL. The majority of pts requiring NIL re-treatment rapidly regained MMR, MR4.0 or MR4.5. The faster rate of regain in pts resuming NIL due to confirmed loss of MR4.0 likely reflects earlier intervention but could also suggest a slower tempo of relapse and possibly more favorable biology. Subgroup analysis should be interpreted with caution due to small base sizes. No new or unexpected safety signals were observed. Disclosures Mahon: ARIAD: Honoraria; Novartis Pharma: Honoraria, Research Funding; Pfizer: Honoraria; BMS: Honoraria. Clementino:EMS: Other: Financial support for congress. Fominykh:Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Lipton:Takeda: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria. Turkina:Pfizer: Honoraria; Novartis Pharma: Honoraria; BMS: Honoraria. Moiraghi:Novartis: Speakers Bureau; BMS: Speakers Bureau. Nicolini:Sun Pharma Ltd: Consultancy; Incyte: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Takahashi:Pfizer Japan Inc.: Honoraria, Research Funding; Novartis Pharma KK: Honoraria, Research Funding; Bristol-Myers Squibb Company: Honoraria. Sacha:Incyte: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Kim:Sun Pharma.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Fellague-Chebra:Novartis: Current Employment, Current equity holder in publicly-traded company, Research Funding. Tiwari:Novartis: Current Employment. Bouard:Novartis: Current Employment. Hughes:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background The criteria of molecular relapse in different treatment-free remission (TFR) trials in patients (pts) with chronic myeloid leukemia (CML) varied. In the early trials molecular relapse was defined as loss of deep molecular response (DMR) including MR4 loss. In recent ELN guideline (Hochhaus et al, 2020) major molecular response (MMR) loss was a criterion of molecular relapse. We consider it reasonable to evaluate the role of MR4 loss in connection with MMR loss and time of treatment-free observation and to describe the pattern of minimal residual disease (MRD) in this context. Aim To evaluate the role of MR4 loss on further MMR loss in CML pts during early and late period after TKI cessation and to describe the pattern of MRD during TFR. Patients and methods In total 98 CML pts with chronic phase who had received therapy by any TKI ≥3 years (yrs) with sustained DMR (at least MR4 or BCR-ABL ≤0.01% by international scale (IS)) during ≥2 yrs) were enrolled into the prospective TFR study RU-SKI. The BCR-ABL level (IS) was evaluated by RQ-PCR monthly during the first 6 months (mo) after TKI cessation, every 2 mo from 6 to 12 mo and every 3 mo thereafter. MR4 loss was considered if BCR-ABL was >0,01% and 0,1%). Molecular relapse free survival (MRFS) was evaluated by Kaplan-Meier method, log-rank test was used for comparison. Results Меdian (Me) time after TKI discontinuation was 40 mo (range 28-57). MMR loss and MR4 loss was observed in 48(49%) and 38(39%) pts respectively. In 42(87%) pts MMR loss was observed within first 6 mo after treatment cessation. MRFS at 36 mo was 51% (95% CI 41 - 61%). No MMR loss occurred in 10(26%) pts with MR4 loss while 28(74%) pts with MR4 loss subsequently lost MMR. The MRFS after the first documented MR4 loss was 29% (95% CI 15 - 44%) and 24% (95% CI 10,5 - 38%) at 12 and 24 mo respectively. MRFS at 24 mo was significantly higher in pts with late MR4 loss (>3 mo) than in pts with early MR4 loss ( The pattern of MRD in 50 pts who continued a treatment-free observation after TKI cessation was represented by 3 main variants: 1) stable undetected MRD in 17(34%) pts; 2) transient short-term or long-term fluctuations without MR4 loss in 23(46%) pts; 3) fluctuations with transient MR4 loss but without MMR loss in 10(20%) pts (figure 2). Interestingly, 8 of 10 pts with MR4 fluctuations subsequently achieved MRD-negative status. Conclusion We confirmed that MR4 loss after TKI cessation in most cases (74%) preceded the molecular relapse which was considered as MMR loss. However, the MRFS was significantly higher in pts with late MR4 loss than in those with early MR4 loss during the first 3 mo of TKI cessation and comparable with MRFS in the whole pts cohort. We found that only 34% pts who maintained a molecular remission had stable undetected MRD while 66% of pts had fluctuations of MRD during TFR. About a quarter of pts (26%) with MR4 loss could remain in TFR and achieve the MRD-negative status. We support the importance of regular MRD monitoring both in early and late terms during TFR observation to benefit for the safety of the pts. Disclosures Chelysheva: Novartis: Other: performed lectures; Fusion Pharma: Consultancy. Shukhov:Novartis: Consultancy, Other: performed lectures; Pfizer: Consultancy, Other: performed lectures. Ionova:BMS: Other: principal investigator of the observational studies sponsored by BMS; Takeda: Other: principal investigator of the observational studies sponsored by Takeda. Turkina:Pfizer: Honoraria; Novartis Pharma: Honoraria; BMS: Honoraria.

Introduction: Asciminib, unlike all approved TKIs that bind to the ATP site of the BCR-ABL1 oncoprotein, is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor with a new mechanism of action. BOS, an ATP-competitive TKI, has shown clinical efficacy in pts who received ≥2 TKIs and in newly diagnosed CML, in prospective clinical trials. We asked if asciminib could provide superior efficacy to BOS beyond 2nd line, based on the clinical activity of asciminib monotherapy in heavily pretreated pts with CML in a phase 1 study. Methods: Adults with CML-CP previously treated with ≥2 TKIs were randomized 2:1 to asciminib 40 mg twice daily (BID) or BOS 500 mg once daily (QD). Randomization was stratified by major cytogenetic response (MCyR; Ph+ metaphases ≤35%) status at baseline. Pts intolerant of their most recent TKI were eligible if they had BCR-ABL1IS >0.1% at screening (19 pts with BCR-ABL1IS Results: A total of 233 pts with CML-CP was randomized to receive asciminib 40 mg BID (n=157) or BOS 500 mg QD (n=76). Fewer pts on asciminib discontinued their last TKI due to lack of efficacy and fewer received ≥3 prior lines of TKI therapy (Table 1). At cutoff, treatment was ongoing in 97 (61.8%) and 23 (30.3%) pts, respectively; the most common reason for treatment discontinuation was lack of efficacy (asciminib, 33 [21.0%] pts; BOS, 24 [31.6%]) (Table 1). Lack of efficacy was most frequently BCR-ABL1 >10% or Ph+ >65% after 6 months of therapy (asciminib 10.8%, BOS 25.0%). Among the 24 pts who discontinued BOS due to lack of efficacy, 22 switched to asciminib. At baseline, ≥1 BCR-ABL1 mutation was present in 12.7% pts on asciminib (most common: F359C/V) and 17.1% on BOS (most common: M244V, F317L). Median duration of follow-up was 14.9 months from randomization to cutoff. Median duration of exposure was 43.4 wks (range, 0.1-129.9) for asciminib and 29.2 wks (range, 1.0-117.0) for BOS; median relative dose intensity was 99.7% (87-100) and 95.4% (74-100). MMR rate at 24 wks was 25.5% with asciminib and 13.2% with BOS, meeting the primary objective. The between-arm common treatment difference for MMR at 24 wks, after adjustment for MCyR status at baseline, was 12.2% (95% CI, 2.19-22.3: 2-sided P=.029). Among those pts who achieved MMR, median time to MMR was 12.7 wks and 14.3 wks with asciminib and BOS, respectively. At 24 wks, more pts on asciminib (17 [10.8%] and 14 [8.9%]) than on BOS (4 [5.3%] and 1 [1.3%]) achieved deep molecular response (MR4 and MR4.5, respectively). CCyR rate at 24 wks was 40.8% with asciminib vs 24.2% with BOS. Preplanned subgroup analysis showed that the MMR rate at 24 wks was superior with asciminib than BOS across most major demographic and prognostic subgroups, including in pts who received ≥3 prior TKIs, in those who discontinued the prior TKI due to treatment failure, and regardless of baseline cytogenetic response (Figure). Grade ≥3 adverse events (AEs) occurred in 50.6% and 60.5% of pts receiving asciminib and BOS, respectively. The proportion of pts who discontinued treatment due to AEs was lower with asciminib (5.8%) than BOS (21.1%). Grade ≥3 AEs and AEs requiring dose interruption and/or adjustments were reported less frequently with asciminib than BOS (Table 2). Most frequent grade ≥3 AEs (occurring in >10% of pts in any treatment arm) with asciminib vs BOS were thrombocytopenia (17.3%; 6.6%), neutropenia (14.7%; 11.8%), diarrhea (0%, 10.5%), and increased alanine aminotransferase (0.6%, 14.5%). On-treatment deaths occurred in 2 pts (1.3%) on asciminib (ischemic stroke and arterial embolism, 1 pt each) and 1 pt (1.3%) on BOS (septic shock). Conclusions: In this first controlled study comparing treatments for resistant/intolerant (R/I) pts with CML, asciminib, a first-in-class STAMP inhibitor, demonstrated statistically significant and clinically meaningful superiority in efficacy compared with BOS (primary objective), deeper MR rates, and a favorable safety profile. These results support the use of asciminib as a new treatment option in CML, particularly in R/I pts who received ≥2 prior TKIs. Disclosures Hochhaus: Novartis: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding. Boquimpani:Novartis: Speakers Bureau. Rea:BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Minami:Pfizer Japan Inc.: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria. Lomaia:Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Voloshin:Novartis: Honoraria, Speakers Bureau. Turkina:Pfizer: Honoraria; Novartis Pharma: Honoraria; BMS: Honoraria. Kim:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Sun Pharma.: Research Funding. Apperley:Bristol Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau. Cortes:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Immunogen: Research Funding; Merus: Research Funding; Sun Pharma: Research Funding. Abdo:Novartis: Honoraria; Takeda: Honoraria. Kim:Paladin: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Research Funding. le Coutre:Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Saussele:Novartis: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria. Hughes:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chee:Novartis: Other: Travel support for attendance at investigator meeting. García Gutiérrez:Novartis Pharma AG: Consultancy, Honoraria, Other: travel/accommodations/expenses, Research Funding; Pfizer: Honoraria, Other: travel/accommodations/expenses, Research Funding; Incyte: Consultancy, Honoraria, Other: travel/accommodations/expenses, Research Funding. Sasaki:Pfizer Japan: Consultancy; Otsuka: Honoraria; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Aimone:Novartis: Current Employment. Allepuz:Novartis: Current Employment. Quenet:Novartis: Current Employment. Bédoucha:Novartis: Current Employment. Mauro:Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Sun Pharma/SPARC: Research Funding.

Background: A success of the tyrosine kinase inhibitors (TKI) therapy in patients (pts) with chronic myeloid leukemia (CML) allowed to set a new goal: a treatment-free remission (TFR). A stable and long-lasting deep molecular response (DMR) is required for a successful TKI discontinuation. The number of CML pts with stable DMR increases on late terms of TKI therapy. With the relationship to this new goal it is relevant to evaluate the proportion of the potential candidates for TKI discontinuation in accordance with the country-specific features of the CML pts population in routine clinical practice. Aim :To characterize the cohort of CML pts treated in routine clinical practice in Russian Federation and to evaluate the proportion of CML pts eligible for TFR. Methods: The analyzed cohort consisted of 197 pts from 6 regions of Russia covering the population of 10 million inhabitants. All pts with CML diagnosed from 01.10.2009 to 31.12.2012 were included into the prospective multicenter EUTOS Population Based Study (EUTOS PBS). Median (Me) age was 50 (18-82)years, 49% were males. Chronic phase, accelerated phase and blast crisis was diagnosed in 93,4%, 6% and 0,6% pts respectively. Imatinib as a 1st line was used in 97% pts. The 2nd generation TKIs (TKI2) were used as 1st and 2nd -3rd line in 3% and 12% pts respectively; imatinib failure was the main reason of switch to TKI2. Overall survival (OS) and cumulative (CI) of DMR were evaluated and adjusted to the new ELTS (EUTOS long-term-survival) score. A proportion of pts with sustained DMR eligible for TFR was calculated. DMR was considered as BCR-ABL2 years and TKI therapy >3 years. Results:Me follow-up in Russian CML pts cohort of EUTOS PBS was 77 (0,7 - 107) months (mo). The ELTS score available in 179 pts was low, intermediate and high in 86(48%), 50(28%) and 43(24%) pts accordingly. The 7-year OS was 76% in total cohort (figure 1a). The 7-year OS in low, intermediate and high ELTS group was 87%, 68% and 55% respectively (p=0,001). Me time of DMR achievement was 38mo (11,2 - 89 mo). The 7-year CI of DMR was 62%. The CI of 7-year DMR achievement in ELTS low, intermediate and high group was 62%, 42% and 38% respectively with significant difference between low and non-low score pts (p= 0,001) (figure 1b). The data for the molecular response at data cut-off April 2019 were available in 114/123 pts who were alive and treated by TKIs with Me time 85 (range 65 - 105) mo. DMR, major molecular response (MMR, (BCR-ABL >0,01%- 0,1% IS) and no MMR (BCR-ABL> 0,1% IS) was in 76 (66,7%), 8 (7%) and 30 (26,3%) pts respectively. A sustained DMR was in 38 (50%) of 76 pts or 19% of the total cohort of 197 pts. Conclusion: A significant proportion of CML pts reach a sustained DMR on late terms of TKI therapy. In total 19% of CML pts in Russian part of the EUTOS PBS study can be eligible to treatment-free observation after 7 years of TKI therapy. The low ELTS score predicts better survival and better chance of DMR achievement. The evaluation of the TFR perspective in routine clinical practicein important from diagnosis to late terms of treatment. Disclosures Chelysheva: Novartis: Consultancy, Honoraria; Fusion Pharma: Consultancy. Vinogradova:Novartis: Consultancy; Fusion Pharma: Consultancy. Turkina:Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; fusion pharma: Consultancy; Novartis: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy.

Background The data on quality of life (QoL) in chronic myeloid leukemia (CML) patients (pts) with deep molecular response (DMR) in the treatment-free remission (TFR) studies are limited. The influence of comorbidities on QoL in CML pts before and after tyrosine kinase inhibitors (TKIs) discontinuation has not been studied. Aim We aimed to study the impact of comorbidities on QoL in CML pts before and after the stop therapy by TKIs. Patients and methods The chronic phase (CP) CML pts who had received therapy by any TKI ≥3 years (yrs) with sustained DMR (BCR-ABL ≤0.01% IS) during ≥2 yrs were enrolled into the prospective TFR study RU-SKI. A regular qPCR with BCR-ABL IS evaluation was performed after TKI cessation. TKI were resumed in pts with major molecular response loss (MMR loss, BCR-ABL>0,1%). The QoL was evaluated by RAND SF-36 questionnaire at baseline before TKI stop and at 1, 3, 6, 12 mo during TFR. Eight functional scales were assessed: physical functioning, role limitations physical, bodily pain, general health perceptions, energy/vitality, social functioning, role limitations emotional, mental health. The Integral QoL Index (IQoLI) was calculated based on the scales. Mann-Whitney test, paired Wilcoxon test χ2 were used for the statistical analysis. Molecular relapse free survival (MRFS) was evaluated by Kaplan-Meier method, log-rank test was used for comparison. Results The analysis was performed in the group of 97 CML pts. Median (Me) age was 47±14.5 (yrs), 48.5% were males. The TKI before treatment cessation were as follows: imatinib and second-generation (2G) TKIs in 67 (70%) and 30 (30%) pts accordingly; 9 (30%) pts received 2G TKIs in 1st line and 21 (70%) pts in 2nd line. Me time of observation was 25 mo (range 12-42). Comorbidities were present in 81 pts (82%) at baseline. The most frequent comorbidities were cardiovascular (38.4%), gastroenterological (29.3%) and musculoskeletal disorders (27.3%). First we compared baseline QoL in 2 pts groups: group 1 - pts with acute comorbidity status at baseline (n=42), group 2 - pts with stable comorbidity status (n=29) and with no comorbidity (n=16). QoL in group 1 was significantly worse by all functional scales, except mental health (p Then we evaluated QoL at 3 mo after TKI stop in 72 available pts, as acute status comorbidity remained in 30 pts. The majority of pts exhibited QoL improvement or stabilization by all SF-36 scales. The most pronounced positive changes were observed by SF-36 scales in pts with acute comorbidity status (group 1).The proportion of pts with QoL improvement at 3 mo after TKI stop was higher in group 1 as compared to group 2 by physical functioning (57% vs 29%), role physical functioning (30% vs 5%) and social functioning (40% vs 24%), p MRFS at 24 mo was 62% (CI 46-77%) and 45% (CI 32-58%) in groups 1 and 2 respectively, with no significant differences between the groups (p=0.107). Conclusion CML pts with DMR and acute comorbidity status had a worse QoL before TKI therapy cessation compared to pts without comorbidity or with comorbidity in remission. The majority of pts exhibited QoL improvement or stabilization in early terms after TKI stop. Pts with acute comorbidity status had more pronounced positive QoL changes after treatment cessation than other pts. Possible explanation is that TKI therapy could increase the clinical symptoms manifestation by overlapping with the treatment toxicity effects. The molecular relapse rate was similar in pts with and without acute comorbidity status. Thus, comorbidity is not a factor which may have negative impact on the outcomes of stop TKI therapy in CML pts. Disclosures Ionova: Takeda, BMS: Other: Principal Investigator of IISR, Research Funding. Chelysheva:Novartis: Consultancy, Honoraria; Fusion Pharma: Consultancy. Shukhov:Novartis: Consultancy; Pfizer: Consultancy. Turkina:Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; fusion pharma: Consultancy; Novartis: Consultancy, Speakers Bureau.

Pregnancy in CML patients (pts) is becoming a reality due to the increase in information from published cases or larger multicentric database (GIMEMA and ELN). Interferon (IFN) has been used during pregnancy, but little is known about the use of tyrosine kinase inhibitors (TKIs), which should be stopped early due to their teratogenic effects. Female pts can ideally plan a pregnancy if they are in a deep, stable, molecular response (DMR=MR≥ 4, ≤0.01%IS) and treatment free remission (TFR) parameters are satisfied. Molecular remission can be maintained throughout the pregnancy, but how to proceed if the remission is rapidly lost, or if the patient is not in DMR, or when CML is discovered during pregnancy? To address these questions, we analyzed more than 300 pregnancies registered through the ELN database. Pts completing pregnancy were grouped as follow: 1) pts diagnosed with CML while pregnant 2) pts in DMR 3) pts with ≤MR3 (≥ 0.1%IS) In 47 patients CML was diagnosed during pregnancy, 21 during the 1st trimester, 15 in the 2nd , and 11 in the 3rd (range 3-38 wk). Sixteen patients were not treated until delivery, 15 were treated with IFN; 19 with Imatinib (IM), 12 in the 2nd trimester (>16 wk), and 7 in the 3rd. Forty-eight children were born (one set of twins). Three were preterm (35-37 wk), and one pregnancy is ongoing. No births defects were observed. Seven newborns had a low birth weight (< 2.5 Kg) 6 of them were exposed to IM at late pregnancy and 3 were preterm. Follow-up was uneventful. The majority of pts achieved ≥ MR3 after starting TKI. Two pts died: 1 in blast crisis (BC) after 9 years, but she was not adherent to treatment; 1 of transplant complication (resistant to>2TKI). Seventy five pts had 80 pregnancies in DMR. Six were in TFR (no therapy) for more than 12 mo, while 8 stopped TKI in order to conceive (2-8 mo before conception). Twenty two pts were treated during pregnancy: 12 with TKI (8 IM, 4 nilotinib, NIL) 1 in the 1st trimester (never stopped IM), 7 in the 2nd and 4 in the 3rd; 10 pts received IFN. Eighty one children were born (6 patients had 2 pregnancies, 1 had twins) with one baby born preterm (wk 35). No births defects were observed and two pregnancies are ongoing. Fifty eight pregnancies were carried without any CML treatment. Twenty six maintained DMR, 28 ≤ MR3 and considered in "treatment free pregnancy" (TFP), and 5 had >10% transcript levels at delivery, considered as high tumor burden (HTB). None of the patients progressed after pregnancy, 4 patients maintained TFR. Four patients did not return to MR3 Pts belonging to ≤MR3 do not satisfy TFR criteria, and were discouraged from starting a pregnancy. However 95 pregnancies (90 pts) were reported; 29 had stopped TKI prior to conception (5 of them had HTB at pregnancy onset). Fifty eight (61%) were treated with IFN (20), TKIs (35), or HU (3). Thirteen patients were treated with IM during 1st trimester (10 throughout the pregnancy). Among the untreated pts, 6 were surprisingly in DMR at delivery, 20 were in TFP, and 11 had HTB. Two babies were born with polydactyly and hypospadias (IFN treatment since 1st trimester), and 2 exhibited a non-closed foramen ovale (IM during 2-3rd trimester) which was considered unlikely to be related to treatment. Four pts progressed in BC and died after pregnancy but all were not compliant to therapy. This is the first, large, multicenter report focusing on treatment during pregnancy. Results suggest that CML patients can pursue a normal life including planning a family, with several caveats. Based on the different situations examined, treatment with IFN is confirmed safe. In contrast TKIs should not be used during pregnancy. Selected TKIs, specifically IM and NIL which have little placental transfer, can be started after organogenesis. Pts at onset can delay therapy without jeopardizing the future CML outcome. If therapy during pregnancy is deemed necessary, IFN can induce and maintain hematologic remission, or, if introduced earlier, preserve molecular remission after TKI interruption, while TKIs can reduce HTB. Caution should be taken when considering stopping TKI prior to conception due to the possibility of losing response, while an early stop (at first positive pregnancy test, 4-5 wk) could be considered. Detailed results, mother and child follow up and practical management will be presented. Disclosures Abruzzese: BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Turkina:Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; fusion pharma: Consultancy. Apperley:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kim:Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Il-Yang co.: Research Funding; Takeda: Research Funding. Garcia-Gutiérrez:Novartis: Honoraria, Other: Advisory Committees. Mauro:Novartis Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; Takeda: Consultancy. Milojkovic:Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Moriaghi:novartis: Speakers Bureau; BMB: Speakers Bureau; Takeda: Speakers Bureau. Nicolini:Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Sun Pharma Ltd: Consultancy. Rea:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Incyte Biosciences: Honoraria. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Shacham:novartis: Consultancy. Trawinska:Novartis: Consultancy, Honoraria. Chelysheva:Fusion Pharma: Consultancy; Novartis: Consultancy, Honoraria. OffLabel Disclosure: informations on the use of interferon and/or TKIs (imatinib, nilotinib) during pregnancy.

Background: PF-114 is a 4th-generation oral tyrosine kinase-inhibitor (TKI) active against wild-type and mutated BCR-ABL1 isoforms including BCR-ABL1T315I. We present data from a phase-1 study in patients with chronic or accelerated phase chronic myeloid leukaemia (CML) failing ≥2 TKIs or with BCR-ABL1T315I (NCT02885766) with ≥6 months therapy. Methods: 3+3 dose-escalation study to determine maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary objectives included safety and efficacy based on haematological, cytogenetic, and molecular criteria. Adverse events (AEs) were graded using NCI-CTCAE v4.03. Results: 51 patients were enrolled. Daily doses were 50 mg (n=3), 100 mg (n=3), 200 mg (n=9), 300 mg (n=11), 400 mg (n=12), 500 mg (n=3), 600 mg (n=6), 750 mg (n=4) given continuously. Median age was 50 years (range, 29-82 years). Median CML duration pre-study was 10 years (range, 0.3-23 years). All patients had baseline ECOG performance scores 0-1. Twelve patients had BCR-ABL1T315I. Patients were heavily pre-treated: 25 received ≥3 prior TKIs; 5 patients with BCR-ABL1T315I received 1 prior TKI. Interim analysis was conducted at follow-up of ≥6 months (cut-off date January 16th 2019). Therapy was ongoing in 17 patients at doses 200 mg (n=4), 300 mg (n=9), 400 mg (n=3) and 600 mg (n=1) with median duration of exposure of 7,4 (range, 4,6-26), 9,2 (range, 7,4-26), 9,2 (range, 8,3-9,2) and 9,2 months. Other patients discontinued because of progression (n=18), adverse events (n=6), consent withdrawal (n=4), participation in another study (n=3) or other reasons (n=3). The MTD was 600 mg with the grade-3 psoriasis-like skin lesions the DLT, which occurred during the first 28 days of treatment. Reversible grade-3 skin toxicity occurred in 11 patients at doses ≥400 mg. There were no other drug-related non-hematologic grade-3 toxicities except 1 grade-3 toxic hepatitis at 400 mg and there were no detectable effects on ankle-brachial index or vascular occlusive events. The best safety/efficacy dose was 300 mg/d with 6 of 11 patients achieving a major cytogenetic response (MCyR) and 4 of them - a major molecular response (MMR). Higher doses were less effective probably because of toxicity-related therapy interruptions and discontinuations. Five of 12 patients with BCR-ABL1T315I responded, 3 of which achieved a complete hematologic response and 4 achieved MCyR. Conclusion: PF-114 was safe and effective in patients with CML failing ≥2 TKIs or with BCR-ABL1T315I. The most effective dose was 300 mg/d. Five of 12 patients with BCR-ABL1T315I responded. A pivotal study is beginning. Disclosures Turkina: Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; fusion pharma: Consultancy; Novartis: Consultancy, Speakers Bureau. Vinogradova:Novartis: Consultancy; Fusion Pharma: Consultancy. Lomaia:Novartis: Other: Travel Grant;Lecture fee; Pfizer: Other: Travel Grant. Shukhov:Pfizer: Consultancy; Novartis: Consultancy. Chelysheva:Novartis: Consultancy, Honoraria; Fusion Pharma: Consultancy. Shikhbabaeva:Novartis: Consultancy; Fusion Pharma: Consultancy. Shuvaev:Fusion Pharma: Consultancy; Novartis: Consultancy; Pfize: Honoraria; BMS: Consultancy. Cortes:Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; BiolineRx: Consultancy; Sun Pharma: Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding. Baccarani:Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Takeda: Consultancy. Ottmann:Roche: Honoraria; Pfizer: Honoraria; Fusion Pharma: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Mikhailov:Fusion Pharma: Employment. Novikov:Fusion Pharma: Employment. Shulgina:Fusion Pharma: Employment. Chilov:Fusion Pharma: Consultancy.

Introduction. Stromal microenvironment of the bone marrow (BM) is essential for normal hematopoiesis; the very same cells are involved in the interaction with the leukemic stem cells. The aim of the study was to reveal the alterations in stromal microenvironment of patients in debut and after the therapy using multipotent mesenchymal stromal cells (MSC) as a model. Methods. MSC of patients with acute myeloid leukemia (AML, N=32), acute lymphoblastic leukemia (ALL, N=20), chronic myeloid leukemia (CML, N=19), and diffuse large B-cell lymphoma without BM involvement (DLBCL, N=17) were isolated by standard method from the patients' BM. Each BM sample was acquired during diagnostic aspiration after the informed signed consent was obtained from the patient. Groups of BM donors comparable by age and gender were used as controls for each nosology. Gene expression was analyzed with real-time RT-PCR. The significance of differences was evaluated with Mann-Whitney U-test. Results. The results of gene expression analysis are summarized in Table. The expression of genes regulating hematopoietic stem and precursor cells (JAG1, LIF, IL6) was significantly upregulated in MSC of the patients in debut, except for DLBCL. The latter was characterized with upregulation of osteogenic marker gene SPP1 and downregulation of FGFR1 gene. The upregulation of the expression of genes regulating proliferation of stromal cells (PDGFRA, FGFR1) and adipogenic marker gene (PPARG) was common for AML and CML. Both acute leukemias were characterized by the upregulation of genes associated with inflammation and regulation of hematopoietic precursors (CSF1, IL1B, IL1BR1) and by the downregulation of chondrogenic differentiation marker gene (SOX9). CML and DLBCL demonstrated the upregulation of FGFR2. BM of the DLBCL patients did not contain any malignant cells; nevertheless, stromal precursors from the BM were significantly affected. This indicates the distant effects of DLBCL malignant cells on the patients' BM. Myeloid malignancies seem to affect MSC more profoundly then lymphoid ones. Effect of leukemic cells on stromal microenvironment in case of myeloid leukemia was more pronounced. The treatment significantly affected gene expression in MSC of patients. In all studied nosologies the IL6 gene expression was upregulated, which may reflect the inflammation processes ongoing in the organism. The expression of LIF was upregulated and ICAM1, downregulated in MSCs of AML, ALL, and CML patients. In the MSC of patients with AML, who had received the highest doses of cytostatic drugs to achieve remission, a significant decrease in the expression of most studied genes was found. In patients with ALL with long-term continuing treatment in combination with lower doses of drugs, IL1B expression was increased, while the decrease in expression was detected for a number of genes regulating hematopoietic stem cells (SDF1, TGFB1), differentiation and proliferation (SOX9, FGFR1, FGFR2). Treatment of CML patients is based on tyrosine kinase inhibitors in doses designed for long-term use, and is less damaging for MSC. The upregulation of TGFB1, SOX9, PDGFRA genes and downregulation of IL1B gene was revealed. MCS of DLBCL patients, unlike the other samples, were analyzed after the end of treatment. Nevertheless, significant upregulation of IL8 and FGFR2 genes was found. Thus, both the malignant cells and chemotherapy affect stromal precursor cells. The changes are not transient; they are preserved for a few months at least. MSCs comprise only a minor subpopulation in the BM in vivo. When expanded in vitro, they demonstrate significant changes between groups of patients and healthy donors. Conclusions. Leukemia cells adapt the stromal microenvironment. With different leukemia, the same changes are observed in the expression of genes in MSC. MSC of patients with acute forms have a lot of changes which coincide among these two diseases. MSC of AML patients are most affected both in debut and after the therapy. Treatment depends on the nosology and in varying degrees changes the MSC. This work was supported by the Russian Foundation for Basic Research, project no. 17-00-00170. Disclosures Chelysheva: Novartis: Consultancy, Honoraria; Fusion Pharma: Consultancy. Shukhov:Novartis: Consultancy; Pfizer: Consultancy. Turkina:Bristol Myers Squibb: Consultancy; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; fusion pharma: Consultancy.

Bosutinib, a dual Src/Abl kinase inhibitor, has shown potent activity against chronic myeloid leukemia (CML). In this phase 1/2 study we evaluated bosutinib in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. Part 1 was a dose-escalation study to determine the recommended starting dose for part 2; part 2 evaluated the efficacy and safety of bosutinib 500 mg once-daily dosing. The study enrolled 288 patients with imatinib-resistant (n = 200) or imatinibintolerant (n = 88) CML and no other previous kinase inhibitor exposure. At 24 weeks, 31% of patients achieved major cytogenetic response (primary end point). After a median follow-up of 24.2 months, 86% of patients achieved complete hematologic remission, 53% had a major cytogenetic response (41% had a complete cytogenetic response), and 64% of those achieving complete cytogenetic response had a major molecular response. At 2 years, progression-free survival was 79%; overall survival at 2 years was 92%. Responses were seen across Bcr-Abl mutants, except T315I. Bosutinib exhibited an acceptable safety profile; the most common treatment-emergent adverse event was mild/moderate, typically self-limiting diarrhea. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (9%), rash (9%), and vomiting (3%). These data suggest bosutinib is effective and tolerable in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. This trial was registered at http://www.clinicaltrials.gov as NCT00261846.

Background It is reasonable to incorporate quality of life (QoL) assessment into the comprehensive evaluation of treatment outcomes in chronic myeloid leukemia (CML) patients (pts) with deep molecular response (DMR) who enter the treatment-free remission (TFR) phase and stop therapy by tyrosine kinase inhibitors (TKIs). QoL assessment was included into the design of Russian prospective multicenter trial RU-SKI along with the clinical outcomes evaluation. Aim To study QoL in chronic phase (CP) CML pts with DMR before stopping TKI treatment and during TFR observation. Materials and methods The study has been conducted within the clinical approbation supported by the Ministry of Health of RF. The CML CP pts with therapy by any TKI ≥ 3 years (yrs) and stable DMR (BCR-ABL ≤0.01% IS) during ≥2 yrs were enrolled. Pts who met these criteria and had previous resistance to any TKI were also eligible. TKIs were resumed in case of major molecular response loss (MMR, BCR-ABL>0,1%). The QoL questionnaires RAND SF-36 and EORTC QLQ C30 were filled out by the pts before stopping TKI treatment and at 1, 3, 6 and 12 months (mo) after treatment discontinuation. The comparison group consisted of healthy persons matched by age and gender to CML CP pts (n=97). The Mann-Whitney test, paired Wilcoxon test and Generalized Estimation Equations (GEE) with adjustment to age, gender, the risk group according to Sokal score and duration of TKI treatment were used for the statistical analysis. Results QoL assessment was performed in all 99 CML CP pts who were enrolled into the trial during a period from Aug 2015 till Dec 2017. The TKIs before treatment cessation were as follows: imatinib and second-generation (2G) TKIs were used in 69(70%) and 30(30%) pts accordingly. 2G TKIs were used in 9(30%) and in 21(70%) pts as 1st and 2nd line accordingly. Mean age was 47±14.5 yrs, 48.5% were males, 12.1% had high Sokal risk score. The physical functioning of CML pts before stopping TKI treatment compared to the healthy controls was significantly worse (p0.05). Conclusion The QoL in CML CP pts with DMR on TKI treatment is slightly worse and physical functioning is significantly lower as compared to healthy controls. The positive changes of the role functioning along with TKI treatment-related symptoms decrease were revealed in pts who maintained stable MMR during 12 mo of TFR. No changes in QoL and no new symptoms were found in pts who reinitiated treatment before and after TKIs interruption. The results of QoL assessment may contribute to optimization of the treatment strategies of CML patients with DMR. Disclosures Chelysheva: Fusion Pharma: Other: provided consultations ; Bristol Myers Squibb: Other: provided consultations and performed lectures; Novartis: Other: provided consultations and performed lectures. Shukhov:Bristol Myers Squibb: Other: provided consultations and performed lectures ; Novartis: Other: provided consultations and performed lectures . Turkina:Novartis: Other: provided consultations; Bristol Myers Squibb: Other: provided consultations; Phizer: Other: provided consultations; Fusion Pharma: Other: provided consultations. Ionova:Takeda: Research Funding; BMS: Research Funding.

Background: PF-114 mesylate is a 4th-generation oral tyrosine kinase-inhibitor (TKI) active against wild-type and mutated BCRABL1 isoforms including those with a BCRABL1T315I. We present data from a phase-1 study in subjects with chronic or accelerated phase chronic myeloid leukaemia (CML) failing ≥2 TKIs or who have BCRABL1T315I (NCT02885766). Methods: 3+3 dose-escalation design to determine maximum tolerated dose (MTD) followed by expanded cohorts for doses ≤MTD. The primary objective was to determine the MTD and identify dose-limiting toxicities (DLTs) during cycle 1 (28 days). Secondary objectives included safety and anti-CML activity based on hematological, cytogenetic, and molecular criteria. Adverse events (AEs) were assessed and graded using NCI-CTCAE v4.03. Results: 51 subjects were enrolled as of June 26, 2018. Daily doses were 50 mg (n=3), 100 mg (n=3), 200 mg (n=9), 300 mg (n=11), 400 mg (n=12), 500 mg (n=3), 600 mg (n=6), 750 mg (n=4) given on a continuous QD schedule. Median age was 50 years (range, 29-82 years). Median interval from diagnosis to study-entry was 10 years (range, 0-23 years). Subjects had baseline ECOG performance scores Conclusion: MTD of PF-114 is 600 mg with skin toxicity as the DLT. The best safety/efficacy ratio was seen at doses of 200 and 300 mg which are being studied in expanded cohorts and soon in a phase-2 study. Disclosures Turkina: Novartis: Other: provided consultations; Bristol Myers Squibb: Other: provided consultations; Phizer: Other: provided consultations; Fusion Pharma: Other: provided consultations. Shukhov:Novartis: Other: provided consultations and performed lectures ; Bristol Myers Squibb: Other: provided consultations and performed lectures . Chelysheva:Bristol Myers Squibb: Other: provided consultations and performed lectures; Fusion Pharma: Other: provided consultations ; Novartis: Other: provided consultations and performed lectures. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding. Ottmann:Novartis: Consultancy; Pfizer: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Fusion Pharma: Consultancy, Research Funding. Mikhailov:Fusion Pharma: Employment. Novikov:Fusion Pharma: Employment. Shulgina:Fusion Pharma: Employment. Chilov:Fusion Pharma: Employment.

Background: A large number of tyrosine kinase inhibitors (TKI) discontinuation studies has shown that about 50% of chronic myeloid leukemia (CML) patients (pts) after TKI cessation lose a major molecular response (MMR) and should return to therapy. Despite the fact that, after TKI resumption, almost all patients re-achieve deep molecular remission, facilitating a more accurate selection process for therapy cessation remains topical. Aim: Develop a prognostic model for the better selection of CML patients for TKI discontinuation. Methods: The base for the training set was the Russian multicenter prospective study RU-SKI on the discontinuation of TKI in pts with CML and deep molecular response (DMR). Ninety-eight CML pts with chronic phase (CP), TKI therapy for at least three years and a stable DMR (BCR-ABL0.1%). We used the Kaplan-Meier method for calculating the probability of TFR. Univariate analyses were performed using the log-rank test to identify prognostic factors for TFR. Variables found to be significant at the p Results: Baseline characteristics of the training set (n=91): male: 48%; median (Mе) age at TKI cessation 46 years (range 22 to 80); Me duration of TKI therapy 8.3 years (range three to 16.2); Me duration of DMR 3.2 years (range two to 10.7). Therapy before treatment cessation: imatinib in 63 (69%) pts, second-generation (2G) TKI in 28 (31%) pts. Me follow-up time after TKI cessation was 14 mo (range three to 36). Probability of TFR was 55% after 12 mo of follow-up. We analyzed the following factors: age, gender, history of previous resistance to imatinib, type and line of TKI, duration of therapy, length of DMR, depth of molecular response before cancellation, Sokal risk group. Age, Sokal risk group, duration of therapy and depth of molecular response were found to be independently significant factors and included in the survival prognostic model (Table 1). 73% (n=66) of pts scored 5.5 points or less and were assigned to the low risk group. The probability of TFR was 64% and 33% for the low risk and high risk groups, respectively (p=0.001) (Figure 1). Baseline characteristics of validation set (n=48): male: 36%; Ме age at TKI cessation 46 years (range 22 to 76); Me duration of TKI therapy six years (range 3.5 to 13.2); Me duration of DMR 2.8 years (range two to 10). Therapy before treatment stopped: imatinib in 31 (65%) pts, 2G TKI in 17 (35%) pts. Me follow-up time after TKI cessation was 36 mo (range six to 116). Probability of TFR was 47% after 30 mo of follow-up. In the validation set, 77% (n=37) of pts were assigned to the low risk group. The probability of TFR was 56% and 18% for the low risk and high risk groups, respectively (p=0.007) (Figure 2). Conclusion: RU-SKI prognostic model is effective in prediction of successful TFR and can be used for better selection of CML pts for TKI discontinuation. Disclosures Shukhov: Novartis: Other: provided consultations and performed lectures ; Bristol Myers Squibb: Other: provided consultations and performed lectures . Chelysheva:Novartis: Other: provided consultations and performed lectures; Fusion Pharma: Other: provided consultations ; Bristol Myers Squibb: Other: provided consultations and performed lectures. Turkina:Novartis: Other: provided consultations; Bristol Myers Squibb: Other: provided consultations; Phizer: Other: provided consultations; Fusion Pharma: Other: provided consultations.

Background Chronic myeloid leukemia (CML) diagnosed during pregnancy is a rare situation with no standard treatment schemes. If a pregnancy is prolonged weighting the risks/benefits of therapy or observation without therapy is a complicated task. If a pregnancy is terminated a possibility of a further childbirth has to be judged. The course of the disease, treatment options and possible outcomes need to be known in these patients (pts) in the era of tyrosine kinase inhibitors (TKIs). Aim To describe pregnancy outcomes, therapy and follow-up in women with CML diagnosed during pregnancy in the era of TKIs Methods We made a search in the databases of pregnancy cases in CML pts after 2003 year, since the first TKI imatinib became available. The data were obtained from observational studies: CML pregnancy registries of Russian hematology society and ELN. Clinical and demographic characteristics of pts, therapy, monitoring, pregnancy outcomes and follow-up were analyzed. Results. We found that 48 of 199 women with CML and pregnancy were diagnosed as having CML during pregnancy in years 2006-2018. Median (Me) age at CML diagnosis was 26 years (range 19-39). All pts had a chronic phase of CML. Sokal score was low in 34(71%), intermediate in 9(19%) high in 4(8%) and not known in 1(2%) pt. CML was diagnosed during 1st, 2ndand 3rd trimester of pregnancy in 26(54%), 11(23%) and 11(23%) females, respectively. Elective abortion was done in 14 (29%) pts, 1(2%) pt had a miscarriage. All 15 pts started TKI therapy shortly after delivery. Me observation time after labour was 52 months (range 4-139). Imatinib (IM) and nilotinib (NIL) were used as 1st line therapy in 14 and 1 pt accordingly. Five pts were switched from IM to a second line TKI due to resistance in 3 pts and to physician choice in 2 pts. Deep molecular response (DMR or BCR-ABL≤0,01% IS) and major molecular response (MMR or BCR-ABL≤0,1% IS) was achieved in 6 and 5 pts. No molecular response 2 (MR2 or BCR-ABL≤1%) was reported in 4 pts with the follow-up of 24-184 months. One pt died due to CML progression in BC (resistant to IM, T315I mutation, relapsed after allogenic bone marrow transplant (BMT), pre ponatinib availability). Pregnancy was carried out in 33(71%) pts: in 11 of 26 pts with CML diagnosed at 1st trimester and in all 22 pts diagnosed at 2nd-3rd trimester. Pregnancy ended in labour in 32 pts while in 1 pt pregnancy was ongoing pregnancy (week 26th) at the time of evaluation. No therapy for whole pregnancy was in 14 pts: 1, 5 and 8 of them were diagnosed in 1st, 2nd and 3rd trimester accordingly. Therapy during pregnancy was started in 19 pts: 10, 6 and 3 pts with CML diagnosed in 1st, 2nd and 3rd trimester accordingly. Five pts got interferon (IFN) in 1st trimester and 3 of 5 were switched to IM in 2nd-3rd trimester. Four pts got hydroxyurea (HU) for 5-7 days in 1st-2nd trimester prior to any other therapy. Fourteen pts with no therapy in 1st trimester started therapy at late pregnancy: IM since 2nd-3rd trimester in 10 pts, HU in 3rd trimester in 1 pt. A total of 13 pts got IM with Me time of IM start at 18 weeks (range 16-35). Me time of observation after delivery was 52 months (range 4-139). Me time of delay in TKI administration after diagnosis was 7 weeks (range 1-51) and in total 12(36%) of 33 pts got IFN or HU before TKI. TKIs used as 1st line were as follows: IM, dasatinib and NIL in 30, 1 and 1 pts accordingly. Nine pts were further switched from IM to TKI2 as 2nd line due to resistance/suboptimal response. DMR and MMR was achieved in 11 and 17 pts accordingly, MR2 in 5 pts, no MR2 in 1 pt with short follow-up (4 months), 4 pts were too early to evaluate. Two pts were resistant to 2 lines of TKIs and died from disease progression; one of them had a BMT failure and 1 pt was non-compliant. Thirty three children were born (one twins): 17 boys and 16 girls, no births defects were observed. Seven newborns had a low birth weight ( Eleven pts later had 13 pregnancies which ended in childbirth within Me 5 years (1-9 years) Conclusion CML may be diagnosed at any pregnancy stage and pregnancy termination/prolongation should be judged individually. A normal childbirth may take place including cases with use of IM at late pregnancy. It is reasonable to adjust therapy options to pregnancy trimester and to avoid potential teratogenic drugs at 1st trimester. A careful follow-up and timely monitoring of these cases is needed. Disclosures Chelysheva: Fusion Pharma: Other: provided consultations ; Bristol Myers Squibb: Other: provided consultations and performed lectures; Novartis: Other: provided consultations and performed lectures. Abruzzese:Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy. Rea:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Kim:BMS: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Ilyang: Research Funding. Chabaeva:Russian Foundation for Basic Research grant 18-015-00399 A: Research Funding. Kulikov:Russian Foundation for Basic Research grant 18-015-00399 A: Research Funding. Turkina:Novartis: Other: provided consultations; Bristol Myers Squibb: Other: provided consultations; Phizer: Other: provided consultations; Fusion Pharma: Other: provided consultations.

Introduction: The effective therapy of PDGFRA- and PDGFRB-myeloid/lymphoid neoplasms with eosinophilia in the era of tyrosine kinase inhibitors (TKI) allows to achieve a complete hematologic response (CHR) and a molecular response (MR). The long-term duration of the MR makes it reasonable to evaluate the eligibility of various TKI maintenance regimens by analogy with Ph'-positive chronic myelogenous leukemia. Objective: to evaluate the results of maintenance imatinib therapy in patients with PDGFRA-positive neoplasm. Patients and Methods: Between November 2003 and March 2018, imatinib was used in 42 patients with a PDGFRA-positive neoplasm (male:female=40:2, median age 39 years). The initial dose of imatinib was 100 mg per day. CHR was considered as normalization of complete blood counts and disappearance of clinical symptoms and complaints caused by to the disease. The MR was estimated by the qualitative RT-PCR method. The achievement of MR was noted in case of the absence of FIP1L1-PDGFRA transcript expression in bone marrow/peripheral blood cells. The preservation of stable CHR and stable MR was the indication for switching to a maintenance (supportive) regimen. The frequency of imatinib use during the maintenance regimen was reduced from 100 mg daily to 100 mg every other day or 100 mg twice a week. All patients receiving imatinib within a reduced dose regimen underwent regular clinical and laboratory monitoring. Results: CHR was obtained in 95% (40/42) of patients. The MR was evaluated in 37 patients. The MR achievement was obtained in 87% (32/37) patients. The reduction of the frequency of imatinib intake according to the above scheme was carried out in 1(53%) 7 out of 32 patients with stable CHR and MR at different time points after the therapy start. Patients who received imatinib in a supportive regimen were conditionally divided into 2 groups. The first group included 13(77%) patients in whom CHR was maintained; the repetitive molecular tests in 11 patients of this group confirmed the preservation of MR. The median follow-up of patients before transfer to a supportive regimen was 30 months (from 12 to 65 months). The median duration of the maintenance regimen at the time of presentation was 29 months (1.5 months to 99 months). The second group included 4(23%) of 17 patients with the loss of response to treatment during the maintenance regimen. The duration of imatinib therapy in the full-dose regimen prior to switch to a supportive regimen was 8, 13, 21 and 26 months and it was significantly less than in the first group of patients. The loss of MR and CHR was observed in 2 patients during the first 5 months after the change of the therapy regimen. Only a loss of MR without CHR loss was observed in the other 2 patients 3 and 11 months after the dose reduction of imatinib. Conclusions: Preserving a stable CHR and MR in patients with PDGFRA-positive neoplasm receiving imatinib makes it possible to transfer the patients to a maintenance regimen of imatinib 100 mg twice a week. We suggest that a continuous imatinib use in a dose 100 mg daily for at least 3 years is necessary in order to have a stable CHR and MR and to be eligible for switching to a supportive treatment regimen. Disclosures Chelysheva: Novartis: Other: provided consultations and performed lectures; Bristol Myers Squibb: Other: provided consultations and performed lectures; Fusion Pharma: Other: provided consultations . Shukhov:Novartis: Other: provided consultations and performed lectures ; Bristol Myers Squibb: Other: provided consultations and performed lectures . Turkina:Novartis: Other: provided consultations; Bristol Myers Squibb: Other: provided consultations; Phizer: Other: provided consultations; Fusion Pharma: Other: provided consultations.

Bosutinib is an orally active, dual SRC/ABL tyrosine kinase inhibitor (TKI) approved for treating adult patients with chronic phase, accelerated phase (AP), or blast phase (BP) Philadelphia chromosome-positive (Ph+) CML with resistance or intolerance to prior therapy. In an open-label, phase 1/2 study (NCT00261846), second-line bosutinib demonstrated durable hematologic and cytogenetic responses and good tolerability in patients with Ph+ CP CML who were imatinib resistant (IM-R) or imatinib intolerant (IM-I) (Cortes, Am J Hematol, 2016). Here we report a 96-month update of this study and its ongoing extension study (NCT01903733). Adult patients with Ph+ CP CML who were resistant or intolerant to first-line imatinib were included in this analysis. 195 IM-R and 89 IM-I patients received bosutinib starting at 500 mg/d. Median age (range) was 53 yr (18-91 yr), time from CML diagnosis was 3.7 yr (0.1-15.1 yr), treatment duration was 25.6 mo (0.2-133 mo), and follow-up duration was 53.7 mo (0.5-133 mo). Bosutinib dose was increased to 600 mg/d in 13% of patients. For the last enrolled IM-R and IM-I patients, time from first dose of bosutinib to data cutoff was 96.5 mo and 94.2 mo, respectively. At 8 yr, 26% of patients were still receiving bosutinib. Major cytogenetic response (MCyR) was achieved by 60% of patients in both groups (Table). Median duration of MCyR was not reached as of the minimum follow-up, and the Kaplan-Meier probability of maintaining MCyR at 8 yr was 60% (IM-R) and 75% (IM-I). Complete cytogenetic response (CCyR) was achieved by 49% (IM-R) and 51% (IM-I) of patients. Median duration CCyR was not reached as of the minimum follow-up, and the Kaplan-Meier probability of maintaining CCyR at 8 yr was 57% (IM-R) and 69% (IM-I) of patients. On-treatment transformation to accelerated phase or blast phase occurred in 7% (IM-R) and 2% (IM-I) of patients with no new events since the 5-yr follow-up. The cumulative incidence of on-treatment progression or death at 8 yr was 28% (IM-R) and 11% (IM-I), respectively (Table). Overall survival at 8 yr on study was 75% for the IM-R group and 87% for the IM-I group. Dose delays due to adverse events (AEs) occurred in 133 (68%) and 76 (85%) of IM-R and IM-I patients, resulting in median cumulative treatment delays of 25 d and 27 d, respectively. Dose reductions due to AEs occurred in 93 (48%) and 54 (61%) of IM-R and IM-I patients, respectively. Median cumulative duration of dose reduction was 357 d and 267 d, and median time to dose reduction was 49 d and 54 d in the IM-R and IM-I cohorts, respectively. By 8 yr, treatment was discontinued in 141 (72%) and 69 (78%) of IM-R and IM-I patients, respectively. The most common reasons for discontinuation were disease progression (23%) and AEs (16%) in the IM-R cohort, and AEs (42%) and patient request (13%) in the IM-I cohort. In the IM-R cohort, the most frequent AEs leading to permanent treatment discontinuation were thrombocytopenia (4%), increased ALT (2%), and diarrhea (2%). In the IM-I cohort the most frequent AEs leading to permanent treatment discontinuation were thrombocytopenia (11%), neutropenia (5%), increased ALT (3%), and rash (3%). Among the 40 patients (21%) in the IM-R cohort who died on study, the most frequent reasons for death were disease progression (12%) and AEs unrelated to study drug (7%). For the 11 patients (12%) in the IM-I cohort who died on study, the most frequent reasons were disease progression (7%) and unknown (3%). No patients died due to an AE related to study drug and 13 patients (5%) died within 30 days of last dose. Five subjects died since the 5-yr follow-up; 3 within 30 days of last dose. These long-term (8-yr) data are consistent with previous findings associating second-line bosutinib therapy with similar rates of durable major cytogenetic responses in the majority of patients with imatinib-resistant and imatinib-intolerant CP CML. Most AEs could be managed through temporary treatment interruptions and dose reductions. Disclosures Brümmendorf: Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Gambacorti-Passerini: BMS: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Pagnano: Roche: Speakers Bureau; Amgen: Consultancy; Bristol-Meirs Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy. Aguiar: Pfizer: Employment, Equity Ownership. Leip: Pfizer: Employment, Equity Ownership. Cortes: Teva: Research Funding; Pfizer: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Sun Pharma: Research Funding; ARIAD: Consultancy, Research Funding.

Background: PF-114 mesylate is a novel third generation oral tyrosine kinase inhibitor (TKI) that blocks native and mutated Bcr-Abl isoforms, including the gatekeeper mutant T315I, which is uniformly resistant to all approved first- and second generation TKIs. At the present time extensive pre-clinical studies of PF-114, including mechanism of action, kinase profiling, in vitro and in vivo efficacy, safety pharmacology, ADME, and toxicology studies in mice, rats and dogs have been completed and supported initiation of phase I clinical trial of PF-114 mesylate in patients with chronic or accelerated phase Ph+ CML who are resistant to at least one of the second generation TKIs or intolerant to previous treatment with TKIs or who have T315I mutation in the BCR-ABL gene (NCT02885766). Methods: The trial represents a classical 3+3 design of dose escalation till the maximum tolerated dose (MTD) followed by the expanded cohorts planned for dose(s) below the MTD. The total expected enrollment is 44 patients. Escalating doses of single-agent PF-114 mesylate were administered orally on a continuous once daily (QD) dosing schedule. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary objective was to study the dose-limiting toxicities (DLTs) occurring in cycle 1 of treatment and determine the MTD. Secondary objectives included safety, anti-CML activity (based on hematologic, cytogenetic, and molecular assessments), pharmacodynamic and pharmacogenetic properties. Adverse events (AEs) were assessed and graded according to NCI-CTCAE v4.03. Results: At data cutoff, 4-dose cohorts - 50 mg, 100 mg, 200 mg and 400 mg have completed cycle 1 and 500 mg cohort has started cycle 1 of treatment. Overall 18 patients (8 males) had been treated at the following QD doses: 50 mg (n = 1), 200 mg (n = 5), 400 mg (n = 11), 500 mg (n = 1), and the MTD has not yet been reached. A total of 7 patients with T315I mutation were included into the trial thus far. Median age was 50.5 years (range, 32-66 years). Median time from diagnostics to treatment was 11.5 years (range, 16-1 years) All patients had baseline Eastern Cooperative Oncology Group performance status 0-1. Patients were heavily pretreated; 9 (50%) had received ≥ 3 prior TKIs, 6 (33%) had received 2 prior TKIs and 3 (17%) patients with T315I had received 1 prior TKI. In 11 patients, treatment is ongoing at doses 200-500 mg QD, with median duration of exposure of 8 months (range, 2-12 months), and 7 patients discontinued (disease progression [n = 5], AEs [n = 2]). Preliminary data suggest PF-114 pharmacokinetics is dose-proportional. At the end of cycle 1 of study therapy, no drug-related adverse events greater than grade 1 in severity were observed in patients treated at the 50 mg, 100 mg and 200 mg dose levels. At the dose of 400 mg QD, a single DLT case of grade 3 erythematous rash was observed. Most common grade 2/3 AEs on 400 mg QD were dermatologic toxicity (4/11), neutropenia (1/11). No deterioration of the ankle-brachial index (ABI), which is being prospectively measured, or vascular occlusive events were observed so far. The patient with recurrent pleural effusions on previous treatment with dasatinib did not reveal effusions after 11 cycle of therapy; the patient with ischemic stroke on previous treatment with nilotinib did not reveal cardio-vascular events after 9 cycles. To date, no SAEs have been reported. Overall, during the period of 3 cycles, major cytogenetic response (CyR) have been obtained in 4 of 11 patients who completed 3 cycles (2 cases of complete CyR in and 2 cases of partial CyR). Of those patients who revealed cytogenetic response two patients have T315I mutation. Pharmacodynamic and pharmacogenetic assessments are underway. Conclusion: PF-114 mesylate exhibits antitumor activity in a heavily pretreated subgroup of patients with resistant forms of CML including cases with T315I mutation. The evaluation of the safety profile continues. The dose escalation stage of the current phase 1 study continues, while the including of patients into the expanded cohorts with doses below the MTD has already started. Disclosures Chelysheva: Fusion Pharma LLC: Consultancy. Nemchenko: Fusion Pharma LLC: Consultancy. Zaritskey: Janssen: Consultancy; Novartis: Consultancy, Speakers Bureau. Shuvaev: Fusion Pharma LLC: Consultancy. Novikov: Fusion Pharma LLC: Employment. Shulgina: Fusion Pharma LLC: Employment. Chilov: Fusion Pharma LLC: Employment, Patents & Royalties.

As a group of more than 100 experts in chronic myeloid leukemia (CML), we draw attention to the high prices of cancer drugs, with the particular focus on the prices of approved tyrosine kinase inhibitors for the treatment of CML. This editorial addresses the multiple factors involved in cancer drug pricing and their impact on individual patients and health care policies, and argues for the need to (1) lower the prices of cancer drugs to allow more patients to afford them and (2) maintain sound long-term health care policies.

Background. The tyrosine kinase inhibitors (TKI) are the standard therapy for patients with chronic myeloid leukemia (CML) in chronic phase. However, six years after the diagnosis, only 50%-60% of CML patients are treated with the initial dosage of Imatinib, while the remained patients require a different dosage or treatment. One of the causes of resistance to TKI is additional chromosome aberrations in Ph+ cells (ACA) and BCR-ABL1 kinase domain (KD) mutations. Patients with KD mutations, (especially with mutations affecting P-loop and T315 codon) and patients with ACA in addition to the Ph-chromosome have significantly inferior unfavorable outcomes. To the best of our knowledge, the presence and the prognostic role of the two major resistance mechanisms in CML patients during TKI treatment had not been performed in combination before. The aim of our study was to evaluate the long-term impact of the simultaneous presence of BCR-ABL1 KD mutations and ACA in Ph+ cells in newly diagnosed CML patients on TKI treatment results. Patients and methods.We analyzed charts of 30 patients with ACA in Ph+ cells, who were diagnosed with CML between 2005 and 2015. All patients received only TKI treatment. There were 14 females (47%) and 16 males (53%) with a median age of 47 years (range, 20-75). Patients' distribution for Sokal risk groups was as follows: low 6 (20%), intermediate 10 (33%), high 14 (47%) patients. Five (17%) patients had high-risk EUTOS score. Twenty-three patients had been diagnosed in the chronic phase and 7 (23%) - had the accelerated phase. Twenty-six (87%) patients started treatment with Imatinib 400 mg QD, 3 patients started with Nilotinib 400 mg BID and 1 patient started with Dasatinib 100 mg QD. The "major-route" ACA was detected in 16 (53%) CML patients. Sixteen (53%) patients had ACA at the time of initial CML diagnosis. We investigated the influence of ACA and KD mutations on overall survival (OS) and CML-related death with the Cox regression method and Fine and Gray regression model. Probabilities of OS were estimated using the Kaplan-Meier method, survival times were compared with log-rank test. Cumulative incidence probability (CIP) of "death due to CML" were estimated with cumulative incidence function (causes of death unrelated to CML had to be considered as competing risks), difference between groups was assessed with Gray's test. All analyses were performed according to the intention-to-treat principle. Results. The median follow-up from diagnosis was 77 months (range, 14-124), from ACA emergence - 51 months (3-124). Six (20%) patients died at the moment of the analysis data, 5 (17%) of them had CML progression. The combination of BCR-ABL1 KD mutations and ACA (ACA+mut) was found in 6 (20%) patients. Five different mutations (T315I, E355G, G250E, D363Y, E279K) were identified and one patient had double mutations (F359C and T315I). Forty-six percent (12/26) of Imatinib first-line treated patients were switched to second-line therapy (Dasatinib and Nilotinib), subsequently 12% (3/26) of patients were switched to Dasatinib as third-line. Among the 2nd TKI first-line treated patients: 2 (50%) were switched from Nilotinib to Dasatinib. The multivariate regression analysis had shown that the combination of BCR-ABL1 KD mutations with ACA had a prognostic significance for OS (p=0.003) and a cumulative incidence of death due to CML (p=0.0005) from the moment of ACA emergence. We also studied the influence of these factors influence on OS and CIP of death due to CML from date of diagnosis. ACA+mut co-existence (n=6) was statistically significant (p=0.02) only for CIP of death due to CML, but not for OS. On the next step, we compared the impact of combination BCR-ABL1 KD mutations with ACA on OS and CIP death due to CML following the emergence of ACA. As shown in Figure 1, patients with ACA+mut (n=6) had a lower 4-year survival rate (28%) than patients with only ACA - 95% (n=24), p Conclusion. Our study demonstrated the significance of simultaneous presence of BCR-ABL1 KD mutations and ACA for TKI therapy outcome. CML patients with a combination of BCR-ABL1 KD mutations and ACAs conferred an inferior survival and can be viewed as the poor prognostic group. Figure 1 Figure 1. Disclosures Fominykh: Novartis Pharma: Honoraria; BMS: Honoraria. Shuvaev:Pfizer: Honoraria; BMS: Honoraria; Novartis pharma: Honoraria. Shukhov:Novartis Pharma: Honoraria; BMS: Honoraria. Chelysheva:Novartis: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Turkina:Pfizer: Honoraria; Novartis Pharma: Honoraria; BMS: Honoraria.

Chronic myeloid leukemia (CML) is characterized by the presence of the chimeric tyrosine kinase BCR-ABL in all leukemic cells. This non-specific enzyme promotes uncontrolled cell proliferation and genome instability. Tyrosine kinase inhibitors (TKI) help most of the people to achieve long standing remission, however up to 20% of patients develop slow response or even primary resistance to the therapy. In this work we focused on copy number variation (CNV) in glutathione transferases (GSTs) and cytochromes (CYPs) as possible predictors of the response rate to TKI. Thirty one CML patient with optimal response and 16 with therapy failure were enrolled in the study. Patient were grouped according to ELN2013 recommendations: BCR-ABL10% and/or Ph+ >35% at 6 months of TKI therapy for the failures. We found that these two groups of patients had differed frequencies of wild type and mutated genes: CYP1A2, CYP2A6, CYP2C19, CYP2C9, CYP2D6, CYP2E1, CYP3A4, CYP3A5, GSTM1, GSTP1, GSTT1 (p< 0.0013). Validation in the additional group of 15 CML patients showed that the test allows to predict failures and responders (p=0.02) with high accuracy: positive and negative predictive value 83% and 78%; sensitivity and specificity 71% and 88%. Disclosures Chelysheva: Novartis: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Shukhov:BMS: Honoraria; Novartis Pharma: Honoraria. Turkina:BMS: Honoraria; Novartis Pharma: Honoraria; Pfizer: Honoraria. Kutsev:Novartis: Speakers Bureau; Pfizer: Speakers Bureau.

Background: ENESTop (NCT01698905) is an ongoing, single-arm, phase 2 study evaluating treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) who achieved sustained molecular response 4.5 (MR4.5; BCR-ABL1 ≤ 0.0032% on the International Scale [BCR-ABL1IS]) on second-line nilotinib (NIL). In the primary analysis, 57.9% (95% CI, 48.8%-66.7%) of pts who stopped NIL maintained TFR (no loss of major molecular response [MMR; ie, BCR-ABL1IS > 0.1%], confirmed loss of MR4 [ie, consecutive BCR-ABL1IS > 0.01%], or treatment reinitiation) at 48 weeks. Adverse events (AEs) were reported in 73.8% of pts during the first 48 weeks of TFR vs 77.0% during the year prior to stopping treatment. The incidence of musculoskeletal pain-related AEs was higher during TFR (42.1% vs 14.3%). To assess the potential effect of stopping NIL on quality of life (QOL), pt-reported outcomes were assessed before and during TFR. Methods: ENESTop enrolled adult pts with CML-CP with ≥ 3 years of prior tyrosine kinase inhibitor (TKI) therapy (> 4 weeks of imatinib [IM], then ≥ 2 years of NIL). Pts must have achieved sustained MR4.5 on NIL after switching from IM. Enrolled pts entered a 1-year NIL treatment consolidation phase; those without confirmed loss of MR4.5 (ie, consecutive BCR-ABL1IS > 0.0032%) entered the TFR phase and stopped NIL. Pts with loss of MMR or confirmed loss of MR4 during the TFR phase reinitiated NIL. QOL was assessed via questionnaires completed by pts at specified time points. The MD Anderson Symptom Inventory for CML (MDASI-CML) questionnaire assessed, for a defined set of symptoms, the levels of severity and interference with daily life on a scale of 0 to 10, with 0 being the lowest level. The EQ-5D-5L questionnaire assessed problems experienced by pts (no, slight, moderate, severe, or extreme [ie, interfering with functioning] problems) in 5 dimensions: mobility, self-care, usual activities, anxiety/depression, and pain/discomfort; additionally, overall level of health was assessed on a scale of 0 to 100 using the EQ VAS, with 0 being the lowest level. Results: Of 163 enrolled pts, 126 met the criteria for stopping NIL in the TFR phase; of these 126, 53 had loss of MMR or confirmed loss of MR4, of whom 51 reinitiated NIL. Among pts who completed each questionnaire at week 48 of the consolidation phase, week 12 of the TFR phase, or week 48 of the TFR phase, mean MDASI-CML severity scores were 1.7, 1.5, and 1.2, respectively; mean MDASI-CML interference scores were 1.7, 1.6, and 1.4, respectively; and mean EQ VAS scores were 82.2, 78.8, and 82.3, respectively (Table). Among pts with sustained TFR and scores at both week 48 of the consolidation phase and week 12 or 48 of the TFR phase, minimal changes were observed in MDASI-CML and EQ VAS scores during TFR vs week 48 of the consolidation phase. Among pts who reinitiated NIL, mean MDASI-CML severity and interference scores and mean EQ VAS scores at 24 weeks after the start of retreatment were 1.6, 1.5, and 78.8, respectively; changes in scores between week 24 after treatment reinitiation and week 48 of the consolidation phase were minimal among pts with scores at both time points. Among pts who completed the EQ-5D-5L questionnaire, the proportions who reported problems (any level of severity) in the 5 dimensions were generally similar across time points, although problems with mobility and pain/discomfort were more common during TFR vs week 48 of the consolidation phase, particularly at week 12 of the TFR phase (Table). Conclusion: Changes in QOL after stopping NIL, as assessed using these questionnaires, were minimal. This may be related to pts having a relatively high QOL prior to stopping treatment given that they had tolerated ≥ 3 years of TKI therapy, including ≥ 2 years of NIL, prior to enrollment. Despite the higher incidence of musculoskeletal pain-related AEs observed during TFR (42.1% vs 14.3%), the overall QOL was generally similar between the TFR and consolidation phases. This suggests that these AEs did not have a significant negative impact on QOL. Longer follow-up in ENESTop will be needed to further evaluate trends in QOL after stopping second-line NIL. Disclosures Mahon: NOVARTIS PHARMA: Honoraria, Research Funding; BMS: Honoraria; ARIAD: Honoraria; PFIZER: Honoraria. Boquimpani:BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Takahashi:Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria. Shuvaev:Novartis pharma: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Lipton:Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Turkina:Novartis Pharma: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Moiraghi:NOVARTIS: Speakers Bureau; BMS: Speakers Bureau. Nicolini:Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria. Sacha:Pfizer: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Fellague-Chebra:Novartis: Employment. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Brandt:Novartis: Employment. Gnanasakthy:Novartis: Consultancy, Equity Ownership, Research Funding. Jin:Novartis: Employment, Equity Ownership. Hughes:Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background: ENESTop, an ongoing, single-arm, phase 2 study (ClinicalTrials.gov, NCT01698905), is the first trial specifically evaluating treatment-free remission (TFR; ie, stopping tyrosine kinase inhibitor [TKI] treatment without a loss of response) in patients with chronic myeloid leukemia in chronic phase (CML-CP) who achieved a sustained deep molecular response after switching from imatinib (IM) to nilotinib (NIL). Of 126 patients in ENESTop who were eligible to stop NIL, 57.9% (95% CI, 48.8%-66.7%) maintained TFR at 48 weeks. Here we present results from a subgroup analysis based on reasons for switching from IM to NIL, categorized as intolerance, resistance, and physician preference. Methods:Eligible patients were adults with CML-CP who received ≥ 3 years of total TKI therapy (> 4 weeks of IM, followed by ≥ 2 years of NIL) and achieved a sustained MR4.5 (BCR-ABL1 ≤ 0.0032% on the International Scale [BCR-ABL1IS]) on NIL therapy; patients with a documented MR4.5 at the time of switch from IM to NIL were not eligible. Enrolled patients continued NIL treatment in a 1-year consolidation phase, and those without confirmed loss of MR4.5 (ie, consecutive BCR-ABL1IS > 0.0032%) were eligible to stop NIL in the TFR phase. Patients with loss of major molecular response (MMR; ie, BCR-ABL1IS > 0.1%) or confirmed loss of MR4 (ie, consecutive BCR-ABL1IS > 0.01%) during the TFR phase reinitiated NIL treatment. The primary endpoint was the proportion of patients who maintained TFR (ie, no loss of MMR, confirmed loss of MR4, or treatment reinitiation) at 48 weeks after stopping NIL. In this post hoc analysis, rates of TFR at 48 weeks after stopping NIL and a Kaplan-Meier (KM) analysis of treatment-free survival (TFS; defined as the time from the start of TFR to the earliest occurrence of any of the following: loss of MMR, confirmed loss of MR4, reinitiation of NIL due to any cause, progression to accelerated phase/blast crisis, death due to any cause) were evaluated in subgroups of patients who switched from IM to NIL due to intolerance, resistance, or physician preference. These categories were determined by grouping the reasons for switching from IM to NIL, as reported by the investigators, based on relatedness to safety (intolerance), loss of response/treatment failure (resistance), and the physician's clinical judgment (physician preference); individual reasons included within each category are presented in the Figure. Results:A total of 125 patients who entered the TFR phase were included in this analysis; 1 patient who was found to have had atypical transcripts was excluded. Among these 125 patients, the reasons for switching to NIL were categorized as intolerance in 51 patients (40.8%), resistance in 30 patients (24.0%), and physician preference in 44 patients (35.2%). The proportion of patients who maintained TFR at 48 weeks after stopping NIL was generally similar across the 3 subgroups: 30 of 51 (58.8%; 95% CI, 44.2%-72.4%) in the intolerance subgroup, 16 of 30 (53.3%; 95% CI, 34.3%-71.7%) in the resistance subgroup, and 27 of 44 (61.4%; 95% CI, 45.5%-75.6%) in the physician preference subgroup. KM analysis of TFS showed that in all 3 subgroups, the majority of TFS events occurred within the first 24 weeks after stopping NIL (Figure). There were no notable differences in the kinetics of TFS events among subgroups. The KM-estimated median duration of TFS was not reached by the data cutoff date in all 3 subgroups. Conclusion: Primary analysis from ENESTop showed that among patients with CML-CP who achieved a sustained MR4.5after switching from IM to NIL, 57.9% of those who stopped NIL maintained TFR at 48 weeks. In the present analysis, TFR was maintained at 48 weeks after stopping NIL by > 50% of patients in the intolerance, resistance, and physician preference subgroups, with generally similar results across subgroups. These findings suggest that the rate of successful TFR following second-line NIL does not differ based on the reasons for switching from IM to NIL. Figure. Figure. Disclosures Hughes: Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Australasian Leukaemia and Lymphoma Group (ALLG): Other: Chair of the CML/MPN Disease Group. Boquimpani:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau. Takahashi:Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria. Shuvaev:Pfizer: Honoraria; BMS: Honoraria; Novartis pharma: Honoraria. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Lipton:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Turkina:Pfizer: Honoraria; Novartis Pharma: Honoraria; BMS: Honoraria. Moiraghi:BMS: Speakers Bureau; NOVARTIS: Speakers Bureau. Nicolini:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; Ariad pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sacha:BMS: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria. Kim:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding. Fellague-Chebra:Novartis: Employment. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Krunic:Novartis: Employment, Equity Ownership. Jin:Novartis: Employment, Equity Ownership. Mahon:BMS: Honoraria; PFIZER: Honoraria; NOVARTIS PHARMA: Honoraria, Research Funding; ARIAD: Honoraria.

Introduction. Implementation of target therapy in chronic myelogenous leukemia (CML) treatment allowed saving life for majority of CML patients. First and second generation tyrosine kinase inhibitors (TKI) usage experience showed that part of patients can achieve deep molecular responses. Clinical trials of treatment cessation in CML patients with deep molecular response demonstrated that substantial proportion of patients can be free from drug with predictable relapse risk and safe treatment re-initiation. This approach is interesting due to sustained increasing number of CML patients and avalanche like increment of budget burden because of continuous expensive TKI therapy. The aim of our study was to assess potential budget impact of successful TKI cessation in CML patients with long-lasting deep molecular response. Materials and methods. Pharmacoeconomical modelling of CML diagnostic and treatment process including treatment free remission (TFR). Markov chain approach was implemented to construct models for non-stop therapy and TFR in patients with sustained molecular response 4 logs (MR4.0) (Fig 1). Treatment re-initiation was considered in case of major molecular response loss. The total number of CML patients in Russia was 6500; annual rate of newly diagnosed CML cases was 800 (in accordance with Russian CML Registry data). The patient consent rate to TFR inclusion was assumed as 80%. Transition rates were chosen from clinical trials and own experience. Cost-utility analysis of first and second generation TKI apply was performed. Simulation of clinical and economical consequences was done on national level. Five-year (2015-2020) time horizon was used. To simplify presentation of our results we recalculated costs to US dollars. Results. Our analysis showed that by year 2020 the estimated total CML patient number in Russia will be about 11000 patients with total direct yearly CML cost 109 mln $. TFR approach can decrease budget burden from 109 to 95 mln $ yearly and the total evaluated money saving during years 2015-2020 period in Russia will be 67 mln $ with complement cost-utility data (Fig 2). Conclusion. Annual CML cost will increase due to increment of CML patients number. Nevertheless, TFR strategy in CML patients with long-lasting deep molecular response under continuous molecular monitoring can significantly decrease the healthcare budget burden. TFR approach has the advantage over sustained therapy on financial cost and efficacy of its use. Disclosures Turkina: Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Novartis Pharma: Consultancy.

Introduction: The in-study and out-study sections of the European Treatment and Outcome Study (EUTOS) registry comprise data on imatinib-treated adult patients with chronic myeloid leukemia (CML) who were prospectively enrolled in clinical studies or registries between 2002 and 2006. All patients diagnosed with chronic-phase Philadelphia chromosome-positive CML were eligible for analysis. The new EUTOS long-term survival (ELTS) score was developed in 2,205 in-study patients (Blood 2014; 124(21):153). Its purpose is the discrimination of three risk groups with clinically significantly different probabilities of dying from CML. The score was validated in 1,120 out-study patients. Aims: Up to now, many investigators still apply the Sokal score for the prognostic discrimination of CML-patients treated with tyrosine kinase inhibitors (TKIs). The Sokal score allocated more than 20% of chronic-phase patients to the high-risk group while it was 12% with the new ELTS score. Long-term outcome with tyrosine kinase inhibitors (TKIs) suggests that the allocation of more than 20% chronic-phase CML patients into a high-risk group is too pessimistic. The focus of this analysis was the comparison of risk group allocations and prognosis between the two scores. Methods: Survival time was calculated from the date of start of treatment to death or to the latest follow-up date. Survival was censored at the time of allogeneic stem cell transplantation in first chronic phase. Cumulative incidence probabilities (CIPs) of dying of CML were compared with the Gray test and overall survival probabilities with the log-rank test. As "death due to CML", only death after confirmed disease progression was regarded. Progression was defined in accordance with the recommendations of the ELN (Baccarani et al, Blood 2013). Level of significance was 0.05. Results: Both registries combined, the 3,325 patients had a median observation time of 6.1 years. Six-year overall survival probability was 91% (95% confidence interval (CI): 89-92%). Death was due to CML in 142 of 309 deceased patients (46%).The 6-year CIP of dying of CML was 4% (CI: 4-5%). From low to high risk groups, the Sokal score resulted in 6-year CIPs of 3% (n=1358 (41%), CI: 2-4%), 4% (n=1209 (36%), CI: 3-5%), and 8% (n=758 (23%), CI: 6-11%) and the ELTS score in 6-year CIPs of 2% (n=2030 (61%), CI: 2-3%), 6% (n=898 (27%), CI: 4-7%), and 13% (n=397 (12%), CI: 10-17%). Of the 758 patients allocated to high risk by the Sokal score, the ELTS score classified 165 (22%) as low risk and 265 (35%) as intermediate risk. Compared to the 328 high-risk patients (43%) according to both scores (6-year CIP of dying: 13%, CI: 9-17%), the CIPs of dying were significantly lower for the 165 low-risk patients (p=0.0062, 6-year CIP: 5%, CI: 2-9%) and for the 265 intermediate-risk patients (p=0.0050, 6-year CIP: 5%, CI: 3-9%). These 430 Sokal high but ELTS non-high-risk patients (6-year OS: 89%. CI: 86-92%) showed significantly higher OS probabilities than the 328 Sokal and ELTS high-risk patients (p=0.030, 6-year OS: 81%. CI: 76-85%). Of the 2030 patients identified as low risk by the ELTS score, the Sokal score allocated 603 (30%) to the intermediate- and 165 (8%) to the high-risk group. Without significant CIP differences to the latter group, at 6 years, the CIP of dying was 2% (CI: 1-3%) in the 1262 low-risk and also 2% in the 603 intermediate-risk patients (CI: 1-3%). The OS probabilities of the 768 non-low-risk patients according to the Sokal score (6-year OS: 93%. CI: 91-95%) were not significantly different from the 1262 classified as low-risk by both scores (6-year OS: 95%. CI: 93-96%). Conclusions: To be able to perform comparisons between the various prognostic groups suggested by the Sokal and the EUTOS survival score with a reasonable power, data of in- and out-study samples were combined. The Sokal score allocated an absolute difference of 12% (n=430) more patients to the high-risk groups than the EUTOS survival score. As these patients had significantly and clinically relevantly lower CIPs and higher OS probabilities, the allocation of the Sokal score was not appropriate. Contrarily, the long-term outcome of 768 patients assessed as low-risk by the ELTS and non-low-risk by the Sokal score was not different from the outcome of 1262 assesses as low-risk patients by both scores. For prognosis of long-term survival outcome, the use of the EUTOS survival score is recommended. Disclosures Pfirrmann: BMS: Consultancy, Honoraria; Novartis Pharma: Consultancy, Honoraria. Hasford:Novartis: Research Funding. Saussele:Novartis Pharma: Honoraria, Other: Travel grant, Research Funding; BMS: Honoraria, Other: Travel grant, Research Funding; ARIAD: Honoraria; Pfizer: Honoraria, Other: Travel grant. Turkina:Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Novartis Pharma: Consultancy. Prejzner:Novartis Pharma: Honoraria; BMS: Honoraria. Steegmann:Novartis Pharma: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Simonsson:Novartis Pharma: Research Funding. Zaritskey:University of Heidelberg: Research Funding; Novartis: Consultancy. Zackova:Novartis Pharma: Consultancy; Bristol Myers Squibb: Consultancy. Janssen:Novartis: Research Funding; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; ARIAD: Consultancy. Cervantes:Novartis: Consultancy, Speakers Bureau; Sanofi-Aventis: Consultancy; CTI-Baxter: Consultancy, Speakers Bureau. Hehlmann:Novartis Pharma: Research Funding; BMS: Consultancy. Baccarani:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Speakers Bureau.

Background: In the pivotal Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) study, frontline NIL 300 mg and 400 mg twice daily (BID) resulted in higher rates of deep molecular response and lower rates of disease progression than imatinib in pts with CML-CP. In the ENEST-Extending Molecular Responses (ENESTxtnd) study, the kinetics of molecular response to NIL 300 mg BID and novel dose optimization strategies were evaluated. Methods: ENESTxtnd was a 24 months (mo), phase 3b study of de novo pts with CML-CP within 6 mo of diagnosis. Primary endpoint was rate of major molecular response (MMR; BCR-ABL1 ≤ 0.1% on the International Scale [IS]) by 12 mo. Initial dose for all pts was NIL 300 mg BID. Dose escalation to NIL 400 mg BID was permitted for pts with suboptimal response (SoR) or treatment failure. Dose reduction to NIL 450 mg once daily (QD) was performed as required by the protocol; reescalation was permitted following adverse event (AE) improvement. Successful reescalation was defined as ≥ 4 weeks of NIL 300 mg BID with no dose adjustments for any AE. Rates of overall survival (OS; considering all deaths during the study) and progression-free survival (PFS; considering events during study treatment) were estimated by Kaplan-Meier analysis. Results: A total of 421 pts (median age, 48 y; males, 53.7%) were enrolled. Median time on study treatment was 23.7 mo; 328 pts (77.9%) completed 24 mo of treatment, and 93 pts (22.1%) discontinued early due to AEs (n = 43), consent withdrawal (n = 7), disease progression (n = 6), protocol deviation (n = 6), loss to follow-up (n = 5), death (n = 4), pregnancy (n = 2), or other reasons (n = 20). Of the 92 pts (21.9%) dose-escalated, 88 (20.9%) were dose-escalated due to lack of efficacy (SoR, 83, 19.7%; treatment failure, 5, 1.2%) and 4 due to dosing error; 11 pts were dose-escalated at 3 mo. Of the dose-escalated pts, 5 and 9 pts discontinued due to SoR and treatment failure, respectively. A total of 144 pts (34.2%) had dose reductions, dose reduction due to AEs were reported in 74 pts; 106 pts attempted to reescalate to NIL 300 mg BID, and 92 successfully reescalated. Median duration of exposure of all pts was 23.2 mo and median actual dose intensity was 598.8 mg/d (range, 150-760 mg/d). At 12 mo, 306, 33, 16, and 7 pts were on NIL 300 mg BID, 400 mg BID, 450 mg QD, and other doses respectively; 59 pts had discontinued prior to 12 mo. Of the 306 pts on NIL 300 mg BID at 12 mo, 136 did not have any dose modification (interruption/reduction/escalation) prior to 12 mo and 170 had ≥1 dose modification. Of the 170 pts, 88 had ≥ 1 dose reduction followed by reescalation to 300 mg BID. Among the 16 pts on a reduced dose at 12 mo, 4 later re-escalated to NIL 300 mg BID. The cumulative MMR rate (95% CI) was 70.8% (66.2%-75.1%) by 12 mo and 81.0% (76.9%-84.6%) by 24 mo (figure). Of the 88 pts with dose escalation due to lack of efficacy, 63.6% achieved MMR by 24 mo (Table 1). Of the 144 pts with dose reduction, 75.7% achieved MMR by 24 mo, including 78 of 92 pts (85%) who successfully reescalated to NIL 300 mg BID (Table 2). The cumulative rate of complete cytogenetic response by 24 mo was 74.1 %. Ten pts had PFS events on treatment (progression, n = 6; death, n = 4), and 9 deaths were reported at any time on study and during follow-up 2 due to CML; 1 each due to cardiorespiratory arrest, intestinal infarction, acute leukemia, increased intracranial pressure, accident, suicide, and unknown). The estimated rates (95% CI) of PFS and OS at 24 mo were 97.0% (95.1%-98.8%) and 97.6% (96.1%-99.2%), respectively. The most common nonhematologic drug-related AEs of any grade were rash (15.4%), headache (10.5%), and nausea (10.2%), and new or worsening grade 3/4 laboratory abnormalities were lipase abnormalities (14.5%), neutropenia (11.9%), and thrombocytopenia (10.5%). Cardiovascular events were observed in 19 pts (4.5%), including ischemic heart disease (n = 14), ischemic cerebrovascular events (n = 1), and peripheral artery disease (n = 5). Conclusion: Dose-optimized frontline NIL resulted in rapid reductions in BCR-ABL1IS levels andvery few progressions or deaths. Most pts achieved MMR by 24 mo, including > 60% of pts who were dose-escalated due to lack of efficacy and > 80% of pts who were successfully reescalated after dose reduction. The safety profile of NIL was consistent with previous studies. These results support the use of NIL 300 mg BID, with dose optimization as necessary, in pts with newly diagnosed CML-CP. Disclosures Hughes: ARIAD: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Off Label Use: The indicated label for newly diagnosed CML chronic phase patients is 300 mg twice daily. This abstract discusses modifications of this dose.. Salvino:Novartis: Research Funding. Shortt:Novartis, Bristol Meyers Squibb: Honoraria, Other: Sponsorship to attend conferences, Speakers Bureau. Quach:Celgene Corp, ONYX, Janssen, Takeda, Novartis, BMS: Honoraria, Research Funding. Pavlovsky:Novartis - Bristol: Speakers Bureau. Louw:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Unrestricted educational grant, Research Funding, Speakers Bureau. Shih:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Turkina:Novartis International AG: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy. Meillon:Novartis, Bayer, BMS, Pfizer, AMGEN: Honoraria, Speakers Bureau. Jin:Novartis: Employment. Khanna:Novartis: Employment. Dalal:Novartis: Employment, Equity Ownership. Lipton:Ariad: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Background Using oftyrosine kinase inhibitors (TKIs) in women with chronic myeloid leukemia (CML) at pregnancy is risky due to possible teratogenecity. Absence of TKIs for whole pregnancy is risky for remission loss and disease progression. Particular situations may warrant TKI usage at pregnancy for potential benefits despite potential risks although no precise indications have been developed. Rareness of cases and ethical issues make significant difficulties in decision making. Aim To develop and evaluate the treatment approach for CML and pregnancy considering leukemic burden and pregnancy terms. Materials and methods During years 2011-2015 we monitored prospectively 29 cases of pregnancy in 28 women with CML chronic phase developing the treatment scheme step by step (picture 1). In 16 cases molecular response (MR) at pregnancy start was the following: MR4 in 8 cases (BCR-ABL 0,01%), MR2 in 3 cases (BCR-ABL0,01%). In 13 cases leukemic burden at pregnancy start was high: 6 cases without complete hematologic remission (CHR) including 5 newly diagnosed, 7 cases with BCR-ABL>1% and CHR. All women insisted to keep pregnancy in spite of risks. We recommended 1) immediate discontinuation of TKIs if they were taken 2) monthly follow-up of complete blood count (CBC) and BCR-ABL level by reverse quantitative polymerase chain reaction (RQ-PCR) 3) careful evaluation for developmental defects 4)possibility of using TKIs in cases of high leukemic burden starting from 15th pregnancy week as comparatively safe late term when main organogenesis is completed and blood-placental barrier (BPB) exists knowing that TKIs have limited BPB crossing ability. High leukemic burden was considered BCR-ABL>1% as this level correlates with complete cytogenetic response (CCyR) absence and increased progression risk. The absence and/or loss of CHR was crucial to warrant TKIs. Alternative approaches including interferon, leukapheresis and staying without treatment were weighted in all cases. Dasatinib (DAS) was avoided due to multitargeted action, high fetal/maternal (F:M) concentrations and known possibility of hydrops fetalis. All patients were informed about possible risks at every stage of pregnancy. Results In 19 of 29 cases TKIs taken at conception were discontinued at 4th -10th week: imatinib (IM) in 17 and nilotinib (NIL) in 2. Evaluation for BCR-ABL level was done regularly but not monthly. Practically significant timepoints for BCR-ABL evaluation were pregnancy start, week 15th and pregnancy end. In 17 cases TKIs were reinitiated or started first: 4 newly diagnosed cases, 2 with CHR loss, 11 with BCR-ABL>1% (high level at pregnancy start or MR loss). The TKIs taken were IM in 14 cases (dose 400 mg), NIL in 3 (1-400 mg, 1-600 mg 1- 800mg). In 1 woman NIL was taken from week 10th due to CHR loss and resistance to IM. In 12 other cases no TKIs were reinitiated at pregnancy as 11 had BCR-ABL In 24 cases TKIs were continued after delivery. Five women with MR3-MR4 at pregnancy end prolonged off-treatment period for breastfeeding being on regular PCR control. All 5 newly diagnosed women got an optimal response on IM. In 3 woman switch from IM to TKI2 was needed after delivery. The 29 pregnancy outcomes were: 27 deliveries (1 woman twice), 1 spontaneous abortion on week 5th (IM stopped from week 4th), 1 non-developing pregnancy terminated at week 20th (IM at conception, intrauterine infection, normal fetus). All newborns had no birth defects. Eight children were born preterm (weeks 31-37), 7 of them had been exposed to TKIs after week 15th. Further development was without deviations, median follow-up 23 months (range 1 -52), including 17 children exposed to TKIs at late terms. In 5 cases the F:M concentration ratio was studied for IM and NIL ranging from 0,12 to 0,3. Conclusion Treatment approach considering leukemic burden and pregnancy terms may help to avoid treatment interventions in favorable situations and warrantinterests of both mother and child when treatment initiation is necessary.This approach can expand chances for woman with CML to have children. Possible risks should be understood by patient and physician. Management of CML at pregnancy in case of huge leukemic mass remains a complicated task, pregnancy in CML should be safely planned at deep remission. Figure 1. Figure 1. Disclosures Chelysheva: Bristol Myers Squibb: Honoraria; Novartis Pharma: Consultancy, Honoraria. Turkina:Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Novartis Pharma: Consultancy.

Background. About 70% of chronic myeloid leukemia (CML) patients achieve early molecular response (BCR-ABLIS2 10% at 3-months) that lead to 5-years overall survival close to 95%. However, CML patients remain heterogeneous group and several studies in recent years were aimed to personalize treatment based on individual patients' characteristics. Our group previously put forward a hypothesis about the prognostic value of individual BCR-ABL declinerate in the first three months of CML therapy1,2. The ratio BCR-ABL at 3 months to baseline had chosen as 0.1 as best cut-off value to predict MMR at 12 months. The aims of this study were to validate our prognostic method in larger group of patients and compare these results according to CML prognostic scores. Patients and methods. Fifty-five patients (median age, 52 years; range 19-84; 24 male and 31 female) with chronic phase CML were included in the study. Patients' distribution for Sokal risk groups were as follows: low-30 / intermediate-15 / high-10. Six patients had EUTOS high-risk. Forty-two patients started treatment with Imatinib 400 mg/day, 12 patients started with Nilotinib 600 mg/day and 1 patient started with Dasatinib 100 mg/day. Median BCR-ABL transcript levels was 41.38% at diagnosis, range 3.39-3185.36% (IS). The ratio of BCR-ABL levels at 3 months to baseline for each patient was calculated. In addition, we calculated ratio of BCR-ABL levels at 3 months to BCR-ABL levels at 1 month for 13 patients. Comparison was made of the predictive sensitivity to achieve early molecular response at 3 months (10% by IS) and according to prognostic CML scores (Sokal and EUTOS). We also assessed positive likelihood ratio (LR) value for the probability of achieving MMR between patients' stratification methods. Statistical analysis was conducted with Fisher exact test and sensitivity-specificity analyses. Results. Twenty-six out of 34 patients (76.5%) with ratio of BCR-ABL levels at 3 months to baseline below than 0.1 achieved MMR at 12 months, while only 9 of 21 patients (42.9%) with ratio more than 0.1 had optimal response (LR = 1.86 (1.05 - 3.29); p=0.003). Ratio of BCR-ABL levels at 3 months to 1 month showed much better results with the same (0.1) cut-off value - 5 out of 6 patients (83.3%) with ratio BCR-ABL at 3 months to 1 month below than 0.1, while only 1 patient (14.3%) with ratio more than 0.1 achieved optimal response (LR = 5.83 (0.92 - 37.08); p=0.05), respectively. Application of early molecular response at 3 months (10% by IS) yielded worse discrimination results: 34 of 47 (72.3%) patients with BCR-ABL level ²10% at 3 months, whereas 2 of 8 (25%) patients with BCR-ABL >10% had MMR at 1 year (LR = 1.38 (1.01 - 1.89); p=0.78), respectively. CML prognostic scores results had the following sensitivity-specificity results: for Sokal - low-risk 23 of 30 (76.7%), intermediate-risk 9 of 15 (60%) and 3 of 10 (30%) high-risk patients achieved MMR at 1 year (LR (low+intermediate)/high = 1.41 (1.00 - 1.97); p=0.03); for EUTOS-score - low-risk 34 of 49 (69.4%) and only 1 of 6 (16.7%) high-risk patients had achieved MMR at 12 months (LR = 1.30 (1.00 - 1.68); p=0.02). Furthermore, application of our ratio cut-off value among patients with BCR-ABL level ²10% at 3 months allowed us to revealed additional 6 high-risk patients have not reached MMR at 1 year of therapy (Table 1). Conclusion. Our study showed that individual rates of BCR-ABL decline from baseline to 3 months and to 1 month had better LR than CML prognostic scores (Sokal, EUTOS) or early molecular response achievement (BCR-ABL levels ²10% at 3 months) and might be useful as an optimized predictors of outcome for CML patients (MMR at 1 year of treatment). 1 Fominykh M., ShuvaevV., Martynkevich I. et al. ELN Frontiers Meeting ÇWhere science meets clinical practiceÈ 16-19 October, 2014, Berlin, Germany. Abstract book: 11. 2 Shuvaev V., Fominykh M., Martynkevich I. et al. Blood (56th ASH Annual Meeting Abstracts), 2014; 124 (21): 5529. Figure 1. The patient numbers of achieving MMR at 12 months of therapy in various stratification groups with sensitivity-specificity characteristics Figure 1. The patient numbers of achieving MMR at 12 months of therapy in various stratification groups with sensitivity-specificity characteristics Disclosures Chelysheva: Novartis Pharma: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria. Turkina:Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Novartis Pharma: Consultancy.

Background. The aim of chronic myeloid leukemia (CML) treatment with tyrosine kinase inhibitors (TKI) is not only effectiveness, but also safety. Long treatment duration makes the analysis of most significant complications very important. Pleural effusion (PE) is an important adverse event of dasatinib therapy with largely unclear cause. The optimal management of recurrent PE is unknown and the analysis of its treatment results is actual. Aim. To describe the characteristics of patients with recurrent PE at prolonged dasatinib treatment and to suggest the strategy of their management. Methods. Follow-up data of 23 CML late chronic phase patients at dasatinib therapy after imatinib failure in 2 clinical studies: phase II study comparing dasatinib 140 mg and imatinib 800 mg daily (N = 12) and phase III dasatinib dose-optimizing study in patients with imatinib-resistant or intolerant patients (N = 11). M:F ratio was 7:16. Median age at the beginning of dasatinib - 48 years (26-68), median CML duration - 11 years (4,1-19,2). The reason for TKI change was imatinib resistance: cytogenetic (N = 17) and hematological (N = 6). Results. Median duration of dasatinib treatment - 40 months (10-107); 13 patients (56,3%) are alive, 10 patients (43,5%) have died because of progression of CML. In 19 patients (82,6%) dasatinib treatment was stopped because of: blastic transformation - 6 (26,1%), hematological resistance - 3 (13,1%), cytogenetic resistance - 5 (21,7%), PE - 5 (21,7%). Four patients are still on dasatinib treatment with median duration 8,8 years (8,7-8,9), 3 of them retain complete/major molecular response. The best responses were: complete hematological response in 21 (91,3%), complete cytogenetic response - in 8 (34,8%), major molecular response - in 6 (26,1%) patients. Overall 8-year survival was 55,1%, progression-free survival - 55,4%, event-free survival - 26,1%. PE was observed in 11 (47,8%) patients, in 8 of them (72,7%) - recurrent. In one patient the prolonged PE was associated with fibrosis of adjacent lung and pleura. Median time to PE was 34 (6-83) months. In cases of PE dasatinib was interrupted (mean duration 21 d) and diuretics were started. Six patients (54,5%) also received corticosteroids. Five patients (45,6%) were treated with thoracocentesis. In recurrent PE the dasatinib dosage was decreased. The dasatinib discontinuation in 4 patients with recurrent PE has led to loss of major molecular response in 2 of them; in other 2 it is retained for 6,5 and 1,5 years. Event-free 8-year survival was 36,4% in patients with PE, 16,7% - without it. Discussion. The response rate in patients with PE was not worse, than in those without it. Most often PE begins at 3rd year of treatment; later events were only relapses. Among risk factors of PE 2 patients had arterial hypertension and hypercholesterinemia, 3 patients were > 65 yrs. The significantly high PE on rate (48%) was linked to high initial dasatinib dosage (> 100 mg/d) and bid prescription. We have not observed cases of absolute lymphocytosis due to large granular lymphocytes proliferation. The continuation of treatment generally leads to recurrences of effusion. According to our experience, once arising PE tends to recur. The compensation can be maintained with continuous treatment with diuretics. The prolonged PE may lead to fibrosis of adjacent lung and pleura. Prolonged treatment interruptions and decreased doses can cause treatment failure. The role of corticosteroids is unclear. Conclusion. Our experience in recurrent PE management at dasatinib treatment allow to recommend the usage of alternative TKI in patients with poor treatment response, and discontinuation of treatment in patients with deep molecular response with close monitoring of residual disease by PCR. Disclosures Turkina: Novartis International AG: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy.

Introduction Clinical studies clearly show that treatment with tyrosine-kinase inhibitors (TKI) greatly improve the prognosis of patients with CML. Detailed treatment recommendations have since been deduced from clinical trial results by the European LeukemiaNet (Blood 122:872-884). However, little is known about whether these achievements can also be transferred to routine health care. This work investigates if all CML patients are treated in agreement with current standards and wether they achieve outcomes at least as good as those in clinical trials. Methods The web-based registry aimed to collect all newly diagnosed adult patients with chronic phase Ph+ and/or BCR-ABL1+ CML in 20 countries or pre-specified regions covering ~ 92.5 million inhabitants. Overall 2904 patients were registered between 2008 and 2012. Cytogenetic and molecular responses were analyzed using cumulative incidences considering death and progression as competing risks. Survival was analyzed using Kaplan-Meier curves and log rank tests. Results 2342 patients were diagnosed in chronic phase and had follow-up data available. The median age was 55 years (range: 18 to 99 years) and 53% were male; 11% of the patients were at high risk of not achieving complete cytogenetic remission (CCyR) at 18 months according to the EUTOS score. According to the Euro score 10% of the patients were in the high risk group, 51% in the intermediate and 39% in the low risk group. 18% were included in clinical trials. Treatment data of 1701 patients were contributed from 15 countries (85% of 2042 patients registered in those countries). As a first-line therapy 80% of patients received imatinib 15% nilotinib, 3% dasatinib and 3% hydroxyurea (HU). Of the patients receiving nilotinib or dasatinib 56% had been enrolled into clinical trials. There were no significant differences between female and male patients regarding the first-line therapy. More than half of the patients who were treated with HU alone were aged 70 or older. Time to first CCyR is known for 62% of patients. Median time to first CCyR was 10 months; after 12 months 57% (95% CI 54%-60%) and after 18 months 76% (95% CI 74%-79%) had achieved CCyR. Time to first CCyR differed significantly regarding the EUTOS score. Median time to first CCyR was 9 months for the low and 13 months for the EUTOS high risk group (p < 0.0001). After 18 months 78% (95% CI 75%-80%) of patients in the low and 69% (95% CI 60%-76%) of patients in the high risk group had achieved CCyR. The patients' age did not have major influence on the time to first CCyR (p=0.8974, median time to first CCyR: 18 to 39 years: 9 months, 40-65 years: 9 months, older than 65 years: 11 months). Time to first major molecular remission (MMR) could be calculated for 54% of patients. Median time to first MMR was 15 months. Cumulative incidence of MMR after 12 months was 41% (95% CI 38%- 44%). The median observation time of living patients was 29 months. 187 patients died (8%). Probability of OS for all patients at 12, 24 and 30 months was 97% (95% CI 96% - 97%), 94% (95% CI 93% - 95%) and 92% (95% CI 90% - 93%), respectively. 108 patients progressed of whom 62 subsequently died, while 125 patients died without prior progression. Probability of PFS for all patients at 12, 24 and 30 months was 95% (95% CI 94% - 96%), 92% (95% CI 91% - 93%) and 90% (95% CI 88% - 91%), respectively. Of the 187 patients who died, 33% died after progression. 67% died without prior progression. The probability of progression and subsequent death was 1% (95% CI 1% - 2%) after 12 months and 2% (95% CI 2% - 3%) after 24 months. The probability of dying without prior progression was 2% (95% CI 2% - 96%) after 12 months and 4% (95% CI 3% - 5%) after 24 months. Discussion The EUTOS population based registry provides the first unselected sample of adult Ph+ and/or BCR/ABL1+ adult CML patients in Europe. It shows that in Europe the success reported from commercial and academic studies is transferred to the general population. The majority of patients were treated first-line with imatinib, which was the only TKI approved for first-line use by the EMA during most of the registration period. Probabilities of PFS and OS in the registry are comparable to those in clinical trials. The importance of calculating both overall survival and leukemia-related survival is highlighted, since many patients die from different causes related or unrelated to leukemia and to treatment, but without progression. Disclosures Hoffmann: Novartis Oncology Europe: Research Funding. Baccarani:PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hasford:Novartis: Research Funding. Lindoerfer:Novartis Oncology Europe: Research Funding. Burgstaller:Novartis: Honoraria; Mundipharma: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; AOP Orphan Pharmaceuticals: Honoraria, Research Funding. Mayer:Novartis: Consultancy, Other: funding of travel, accomodations or expenses, Research Funding; BMS: Consultancy, Other: funding of travel, accomodations or expenses, Research Funding. Koskenvesa:GSK: Consultancy; Pfizer: Consultancy; Ariad: Other: funding of travel, accomodations or expenses; BMS: Consultancy, Other: funding of travel, accomodations or expenses; Novartis: Consultancy, Research Funding. Castagnetti:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. Griskevicius:Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Sacha:Angelini: Consultancy; Adamed: Consultancy; Novartis: Consultancy; BMS: Consultancy. Hellmann:Novartis: Consultancy, Other: funding of travel, accomodations or expenses, Research Funding, Speakers Bureau; BMS: Consultancy, Other: funding of travel, accomodations or expenses, Speakers Bureau. Turkina:Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Novartis Pharma: Consultancy. Zaritskey:University of Heidelberg: Research Funding; Novartis: Consultancy. Sninska:Novartis: Consultancy. Simonsson:Novartis Pharma: Research Funding. Saussele:Novartis Pharma: Honoraria, Other: Travel grant, Research Funding; ARIAD: Honoraria; Pfizer: Honoraria, Other: Travel grant; BMS: Honoraria, Other: Travel grant, Research Funding. Hochhaus:ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Hehlmann:BMS: Consultancy; Novartis Pharma: Research Funding.

Introduction: in the last 10 years the number of tyrosine kinase inhibitors (TKI) used to treat patients with chronic myeloid leukemia (CML) significantly increased. The basic principle of therapy was also changed, now it is aimed at early induction of deep response (ELN, NCCN). The treatment results in clinical practice may vary widely and depend on the effectiveness of the entire complex TKI, based on timely evaluation of residual leukemic clone. Objective: To characterize the TKI treatment results and monitoring of residual leukemic clone in clinical practice in CML patients in the Russian Federation (RF). Methods: The observational study "Russian registry of chronic myeloid leukemia management in routine clinical practice" (CSTI571ARU06 LLC) was launched in November 2011 by Novartis. Patients with Ph'+ CML were enrolled into study after signing the informed consent. Thus the study has a retrospective part (4626 patients) and prospective group of 1828 CML patients. By February 2015, the Registry contained information about 6466 patients from 110 centers of 80 regions of the RF. The annual increase of newly registered CML cases ranged from 493 to 694 people per year or 10-13% of the total number of patients included in the Registry on the treatment of CML in 2012- 2014. Characteristics of patients in the Registry: median duration of the disease was 71 months (from 0.2 to 343 months); median age at registration time and CML diagnosis was 49.5 years (range 2 - 94 years); male 43%. The biggest number of cases was diagnosing with patients aged 50-69 years old, which is 50% out of all the registered patients. It is important to note that the number of female patients aged 50 years old and older (39.1% in total, out of the overall number of CML cases) prevails the same male patients age group (25.6% of the cases). Chronic phase was in 93.6% of patients, accelerated phase and blast crisis- 5.6% and 0.6% cases, accordantly. Sokal risk group's ratio was 50%/31%/19% for low, intermediate and high risk, respectively. Results: The data for the analysis were available for 5632 patients (93% of CML patients in the Registry). The 1st line TKI therapy was Imatinib (IM)- in 4908 of the 5632 patients (87%), including the advanced phases of CML; in 71 and 14 patients the 1st line treatment was nilotinib and dasatinib respectively(totally 1%). The percentage of patients receiving TKI-2 ranged from 10 to 35% in different regions of RF. In 2006, the diagnosis CML was confirmed by the data of karyological analysis only with 42% of the patients, but it should be pointed out that currently cytogenetic and/or molecular-based analysis has been conducted at least once with 99% of the patients. Thus, the data presented in Registry of CML treatment provides grounds to state that almost all the patients have had their diagnosis verified within routine clinical practice. The presented data demonstrate the amount of work done to obtain such results during the previous ten-year period. We evaluated cytogenetic monitoring (CyM)/molecular monitoring (MM) frequency during years 2013-2014. Two or more studies per year of cytogenetic CyM/MM were done only 20% of 40 patients per year (2320 persons); with 50% (2960 in 2013, 1203 in 2014) of patients CyM/MM was performed once; no studies have been done in 489 patients in 2013 and 3580 patients in 2014. There was a trend of increasing of molecular studies to evaluate minimal residual disease:1829 MM vs 491 CyM in 2013 and 1028 MM vs 179 CyM in 2014. The absence of optimal response (ELN2013) was observed in 887 patients on different TKIs: (759patients on IM: in 732 patients with the duration of IM therapy over 12months and in 27 patients-less than 12months. Change of treatment to 2nd line was performed in 639 (12%) patients. The death occurred in 373 (6.2%) patients, no data of the living status was in 50 (0.8%) cases. According to the Registry data, death due to the CML progression was in 99 cases (26%). Conclusions: The observational study "Russian registry of chronic myeloid leukemia management in routine clinical practice" is the largest registry of hematological diseases in Russia, providing information about CML patients receiving TKI therapy more than 10 years. The introduction of information technologies to analyze a large amount of data is an essential component to improve the quality of medical care. The evaluation of therapy results can give objective information of the TKI 1st and 2nd generations requirement. Disclosures Turkina: Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Novartis Pharma: Consultancy. Golenkov:Novartis: Consultancy.

Introduction: Most of the knowledge about treatments and outcome of CML patients originates from clinical studies. To get new and unbiased insights in the epidemiology, treatment and outcome of CML, the EUTOS population-based registry of newly diagnosed CML patients was established, - as part of the European Treatment and Outcome Study (EUTOS) for CML. The aim was to collect the data of all adults with newly diagnosed CML, irrespective of treatment and of enrolment in studies. Patients and Methods: The EUTOS population-based registry collected data of newly diagnosed CML patients, 18 years or older, over a specified period of time from 2008 till 2012 living in defined regions. The data were collected by 22 study groups in 20 European countries. Data were gathered via a web-based CRF-system. For comparison we used the already published data from five Company-sponsored registration studies IRIS (O’Brien et.all, NEJM, 2003), TOPS (Cortes et al, JCO, 2009) ENESTnd (Saglio et al, NEJM, 2010), DASISION (Kantarjian et al, NEJM, 2010) and BELA (Cortes et al, JCO, 2012), from three Investigator-sponsored studies GIMEMA (Castagnetti et al, JCO, 2010 and Gugliotta et al, Blood, 2011), French SPIRIT (Preudhomme et al, NEJM, 2010) and German CML IV (Hehlmann et al, JCO, 2011) and from two single referral centers HAMMERSMITH (De Lavallade et al, JCO, 2008) and MDA (Jain et al, Blood, 2013). Results: Till 15.05.2014 2978 patients were registered in the EUTOS Population-based registry. 94.3% of the patients were diagnosed in chronic phase (CP), 3.6% in accelerated phase (AP), and 2.2% in blastic phase (BP). For the calculation of the prognostic scores 361 patients had to be excluded because they were pretreated. For the comparison we used 2350 patients in Chronic Phase with laboratory values before any treatment. 54% of the patients in the EUTOS Population-based registry were male, less than in all studies (56.6 - 60.6%). The median age at diagnosis was 56 years, higher than in all studies (46 - 55). In EUTOS the proportion of patients more than 60 years and more than 65 years old was 40.4 % and 21.9 % respectively. Similar data were rarely reported in all other studies. Median value of the spleen size below costal margin was 0. 46.1% of the patients had a palpable spleen and 15.2% had a spleen size ≥ 10 (spleen size is always reported in cm under costal margin in this abstract). The % of palpable spleen is only reported by IRIS, 25.0% and by the FRENCH Spirit group, 49.8%. The median spleen is only reported by GIMEMA, 2.0. Spleen size ≥ 10 is reported by IRIS, 6.0%, ENESTnd, 12.4% and HAMMERSMITH 25.5%. While the median values for Platelets and Hemoglobin show no big differences, the median WBC in EUTOS is 83.9 x109/l and in the Company-sponsored registration studies: IRIS 18-20 x109/l , in ENESTnd 23-26 x109/l, in DASISION 23-25 x109/l , and in BELA 22-23 x109/l, in the Investigator-sponsored studies: GIMEMA 55 x109/l , in the FRENCH SPIRIT 83-104 x109/l , in the GERMAN CML IV 75-91 x109/l , and in the single referral center study HAMMERSMITH 140 x109/l, clearly indicating that in company-sponsored, registration studies, the reported values of the WBC were not recorded prior to any treatment. The median values for Blasts, Basophils and Eosinophils show also not so big differences. The % of Sokal low risk patients is in EUTOS with 34.5% lower than in all studies (35.2 - 60%) with the exception of HAMMERSMITH 28.9%. Discussion: The EUTOS Population-based registry provides the first European wide real-world series of patients with newly diagnosed Ph+, BCR-ABL+ CML. The age and sex distribution and some baseline characteristics such as Sokal Score as well as median WBC count in the EUTOS population-based registry are different from many prospective studies. This should be taken in due consideration before extrapolating the results of treatment studies to real life. Spleen size, which is known as an important value for prediction, is only very rarely reported in clinical studies. With further follow-up, this registry will provide a population-based insight on treatment, survival, and causes of death. Disclosures Baccarani: Novartis, BMS, Pfizer, Ariad: Consultancy, Honoraria, Speakers Bureau. Hoffmann:Novartis: Research Funding. Rosti:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Castagnetti:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy. Saussele:Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria. Steegmann:Novartis, BMS, Pfizer: Honoraria, Research Funding. Mayer:Ariad: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Turkina:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Zaritskey:Novartis: Consultancy. Clark:Novartis Pharmaceuticals Corporation: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Porkka:BMS: Honoraria; BMS: Research Funding; Novartis: Honoraria; Novartis: Research Funding; Pfizer: Research Funding. Hehlmann:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding. Hasford:Novartis: Research Funding. Lindoerfer:Novartis: Research Funding.

Background: In pts with newly diagnosed CML-CP, NIL 300 mg twice daily (BID) is generally well tolerated and results in high rates of molecular response and low rates of disease progression. The kinetics of molecular response achieved with NIL, as assessed by local laboratories, and the potential for NIL dose optimization are being investigated in Evaluating Nilotinib Efficacy and Safety in Clinical Trials—Extending Molecular Reponses (ENESTxtnd). Here, we present results from a preplanned interim analysis of ENESTxtnd based on the first 50% of pts who completed 12 mo of treatment or discontinued early. Methods: Adults from 18 countries (Algeria, Argentina, Australia, Brazil, Canada, Egypt, India, Israel, Lebanon, Malaysia, Mexico, Oman, Russia, Saudi Arabia, South Africa, Taiwan, Thailand, and Tunisia) within 6 mo of diagnosis with Philadelphia chromosome–positive (Ph+) or Ph-negative CML-CP were enrolled. Initial treatment for all pts was NIL 300 mg BID. Molecular responses were assessed at local laboratories. The primary endpoint was rate of major molecular response (MMR; BCR-ABL ≤ 0.1% on the International Scale [IS]) by 12 mo. NIL dose escalation to 400 mg BID was recommended for pts with BCR-ABLIS > 10% at 3 mo or later, lack of MMR at 12 mo, loss of MMR, or treatment failure. Dose reduction to NIL 450 mg once daily was recommended for grade 2-4 nonhematologic adverse events (AEs) and grade 3/4 hematologic AEs other than anemia. In pts with dose reduction due to AEs, dose reescalation was recommended (successful reescalation: ≥ 4 wk of treatment with NIL 300 mg BID with no dose adjustments for any AE). Results: Among 211 pts included in this analysis, median age was 49 y (range, 18-86 y) and median time from diagnosis to enrollment was 30 d (range, 0-170 d); 110 pts (52.1%) were male. Previous CML therapies included hydroxyurea (n = 153), imatinib (≤ 2 wk; n = 9), anagrelide (n = 4), interferon (n = 1), and other therapies (n = 3). By the data cutoff (March 5, 2013), 38 pts (18.0%) discontinued treatment (due to AEs [n = 19], loss to follow-up [n = 4], protocol deviation [n = 2], administrative problems [n = 2], withdrawal of consent [n = 1], disease progression [n = 1], death [n = 1; raised intracranial pressure; pt had a cerebrovascular accident before study entry], or other reasons [n = 8]). Median time on study treatment was 13.8 mo (range, 0-22 mo). Overall, 63 pts (29.9%) had a dose reduction, and 47 attempted to reescalate to 300 mg BID; among these, 37 (78.7%) successfully reescalated. Twenty-eight pts (13.3%) dose-escalated to NIL 400 mg BID due to lack of efficacy, including 10 of 15 pts with BCR-ABLIS > 10% at 3 mo. After dose escalation, 6 pts had dose interruptions due to AEs. Of pts who dose-escalated due to suboptimal response or treatment failure, 4 later discontinued due to suboptimal response (BCR-ABLIS > 1% at 6 mo [n = 1]; no MMR at 12 mo [n = 1]) or treatment failure (Ph+ > 35% at 12 mo [n = 2]). Among all pts, median actual dose intensity was 600 mg/d (range, 165-759 mg/d). By 12 mo, 152 pts achieved MMR in IS-standardized assessments and 1 additional pt achieved MMR in a non-IS assessment, for a total MMR rate by 12 mo of 72.5% (99.52% CI, 63.1%-80.7%). Among pts with a dose reduction, 42 of 63 (66.7%) achieved MMR by 12 mo; among those who attempted to reescalate to NIL 300 mg BID, 30 of 37 pts (81.1%) with successful reescalation and 4 of 10 pts (40.0%) without successful reescalation achieved MMR by 12 mo. Among pts with dose escalation to NIL 400 mg BID due to lack of efficacy, 6 of 28 (21.4%) achieved MMR by 12 mo. Median BCR-ABLIS levels decreased over time (Figure), with a median value of 0.03% (range, 0.00%-177.18%) at 12 mo. Most pts (n = 120; 56.9%) achieved complete cytogenetic response by 6 mo. Drug-related nonhematologic AEs of any grade reported in ≥ 10% of pts were rash (17.5%), headache (11.4%), nausea (10.9%), and pruritus (10.4%). New or worsening grade 3/4 laboratory abnormalities reported in ≥ 10% of pts were elevated blood lipase (13.3%), thrombocytopenia (13.3%), and neutropenia (12.8%). One pt died > 28 d after the last dose of study treatment due to acute myeloid leukemia. Conclusion: Dose-optimized NIL was well tolerated and resulted in rapid achievement of MMR in most pts. Among pts with lack of efficacy on NIL 300 mg BID, some achieved MMR after dose escalation to NIL 400 mg BID. Most pts with temporary NIL dose reductions due to AEs who attempted to dose-reescalate were able to successfully resume treatment with NIL 300 mg BID. Figure 1 Figure 1. Disclosures Hughes: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Shortt:Novartis: Attendance at CML expert forum, Travel sponsorship (conference attendance). Other, Honoraria; BMS: Honoraria, Travel sponsorship (conference attendance)., Travel sponsorship (conference attendance). Other. Quach:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pavlovsky:Novartis: Speakers Bureau; BMS: Speakers Bureau. Louw:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Meillon:Bayer: Honoraria, Speakers Bureau; Pfizer/BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Shih:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Turkina:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Hwang:Novartis: Employment. Nidamarthy:Novartis Healthcare Pvt. Ltd. India: Employment. Dalal:Novartis: Employment. Lipton:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Consultancy, Research Funding.

Introduction As there are only few data available about the incidence, the stage of disease at diagnosis, the treatment and the outcome of chronic myeloid leukemia (CML) in Europe the European Treatment and Outcome Study (EUTOS) for CMLcollected such data in 27 European countries. The population-based registry was set up by EUTOS to further explore the epidemiology, characteristics, treatment and outcomes of CML in Europe. The present work focused on the estimation of incidence of CML in Europe, in the single countries participating in the registry and the comparison to existing incidence estimations from the US. Patients and Methods The EUTOS population-based registry aimed to document all newly diagnosed adult patients with Ph+ and/or BCR-ABL+ CML at any stage nationwide or in prespecified regions within countries of Europe. Croatia, Cyprus, Estonia, Latvia, Lithuania, Slovakia, Slovenia and Sweden were observed in total while for Austria, the Czech Republic[H1] , France, Germany, Italy, the Netherlands, Poland, Russia, Serbia, Spain, Sweden and the United Kingdom specified regions were selected. Population data from the United Nations database were used for calculations in countries that were observed nationwide, while the study groups provided the population numbers of the specified regions for countries that were observed partially only. The registration periodvaried between 12 and 60 months in the different countries, from January 2008 to December 2012, registration area covered over 92.5 million inhabitants overall. Raw and standardized incidenceswere calculated for the countries and regions and adjusted to the registration period. For standardization the Old Europe Standard Population was used (Waterhouse et al IARC 1976). The registry and the standard population were truncated so only patients from 20 years on were included for the calculation of standardized rates. To compare and validate the EUTOS estimations we chose the data of the Surveillance Epidemiology and End Results Program (SEER) which cover about 28% of the US population. The data were collected from 2007 to 2011. Results There were 2,936 patients registered into the EUTOS population-based registry. Raw incidences per 100,000 inhabitants per year ranged from 0.72 in Poland to 1.39 in Italy. The overall raw incidence for all countries was 1.02, with 0.90 in females and 1.14 in males. Estimations of standardized incidences ranged from 0.72 in the UK to 1.29 in Italy. Overall standardized incidence was 0.99, with 0.86 in females and 1.12 in males. Age specific incidences rose with age group. While the incidence in the 18 to 40 years old population was as low as 0.52 (0.61 in males and 0.42 in females) it increased to 1.61 (2.18 in males and 1.26 in females) in the population from 70 years up. Comparing the SEER data to our EUTOS results very similar incidences can be observed up to age group 55-59 years. From that age group up the SEER incidence estimations are considerably higher. The overall standardized SEER incidences ranged around 1.7 per 100,000 for the years observed. The higher rates can be explained by different inclusion criteria of the registries: While EUTOS includes only Ph+ and/or BCR/ABL+ patients, the SEER has more open inclusion criteria. Also patients without information on Ph-status, BCR-ABL1 negative patients and patients diagnosed with chronic myelomonocytic leukemia are included. Discussion The EUTOS population based registry is the first paneuropean prospective study of incidence of CML in Europe. For the first time data about the incidence of CML are available now for most European countries. Raw and standardized incidences from the EUTOS registry fit in well with earlier findings of study groups from countries like the UK (Bhayat et al., BMC Cancer 2009; 9; 252) (Phekoo et al Haematologica 2006), Sweden (Höglund et al Blood 2013), Germany (Nennecke et al Bundesgesundheitsblatt 2014) and France (Corm et al J Clin Oncol 2008) that range between 0.7 and 1.1 per 100,000 inhabitants. Thus the estimation of incidence over all regions participating in the EUTOS project can serve as a robust estimation of the incidence of CML in Europe. [H1]Wurde zwar voll beobachtet, zwei Regionen wurden aber ausgeschlossen, da sie nicht garantieren konnten pop-based gewesen zu sein! Disclosures Hoffmann: Novartis: Research Funding. Lindoerfer:Novartis: Research Funding. Castagnetti:Novartis, BMS,: Consultancy, Honoraria; Pfizer: Consultancy. Griskevicius:NOvartis: Research Funding. Steegmann:Novartis, BMS, Pfizer: Honoraria, Research Funding. Hehlmann:Novartis, BMS: Research Funding. Hasford:Novartis: Research Funding. Baccarani:Novartis, BMS, Pfizer, Ariad: Consultancy, Honoraria, Speakers Bureau.

Objectives and background: Introduction of tyrosine kinase inhibitor (TKI) for the treatment of chronic myeloid leukemia (CML) led to favorable outcome in the majority of patients.About 70% of patients with early molecular response (BCR-ABLIS ≤ 10% at 3-months) have 5-year overall survival of 95%. Nonetheless, CML patients remain heterogeneous group and several studies in recent years were aimed to personalize treatment based on individual patients’ characteristics. One of them was the study by B. Hanfstein et al. (2014), which showed good prognostic potential of 0.35 ratio BCR-ABL level at 3 months to absolute transcript level at diagnosis[1]. In this study, GUS was used as control gene, but at present ABL is normalization gene for BCR-ABL quantification worldwide. One of the obstacles to use of baseline BCR-ABL/ABL level is a distortion of the results of its measurement (non-linearity) due to the mixture of BCR-ABL with normal ABLgene. During the first month of therapy there takes place a rapid tumor mass reduction. The aims of our study were to assess potential of ratio BCR-ABL level at 3 months to baseline and ratio BCR-ABL level at 3 months to 1 month using ABLas control gene to predict optimal response related to individual patient’s tumor characteristic. Methods: Forty-three patients (median age, 50 years; range 24-84; 17 male and 26 female) with chronic phase CML were included in the study, Sokal risk groups were low-23 / intermediate-10 / high-10; 8 patients had EUTOS high-risk. Thirty-one patients started treatment with Imatinib 400 mg/day, 11 patients started with Nilotinib 600 mg/day and 1 patient started with Dasatinib 100 mg/day. Median BCR-ABLIS transcript levels was 18.886% at diagnosis, range 3.390-3185.361%. In all patients BCR-ABL levels were monitored at diagnosis and at 3, 6 and 12 months of treatment, additionally 10 patients from this group had BCR-ABL levels evaluation at 1 month. The ratio of BCR-ABL levels at 3 months to baseline for each patient was calculated. In addition, we calculated ratio of BCR-ABL levels at 3 months to BCR-ABLlevels at 1 month for 10 patients. We performed ROC curve analysis to establish the best cut-off value to predict MMR achievement as optimal treatment results at 12 months. Then we compared predictive sensitivity of our ratio cut-off and early molecular response at 3 months (10% by IS). Statistical analysis was conducted with ROC analysis and Fisher exact test. Results: The ratio BCR-ABL at 3 months to baseline as 0.1 had chosen as best cut-off value (sensitivity 83.33 CI 62.6-95.3; specificity 66.67 CI 34.9-90.1) to predict MMR at 12 months. Nineteen out of 23 patients (82.6%) with ratio below than 0.1 achieved MMR at 12 months, while only 9 of 20 patients (45%) with ratio more than 0.1 had optimal response (hazard ratio = 0.2625; p=0.013). Ratio of BCR-ABL levels at 3 months to BCR-ABL levels at 1 month also showed good results with the same cut-off value – 5 out of 6 patients (83.3%) with ratio BCR-ABL at 3 months to 1 month below than 0.1 achieved MMR, while patients with ratio more than 0.1 none achieved optimal response (p=0.0238). Application of early molecular response at 3 months (10% by IS) yielded worse discrimination results: 25 of 35 (73.9%) patients with BCR-ABL ≤10% at 3 months had achieved MMR at 12 months, whereas 3 of 8 (37.5%) patients with BCR-ABL level >10% had MMR at 1 year (p=0.1036). Moreover application of our cut-off value among patients with BCR-ABL level ≤10% at 3 months allowed us to revealed additional 4 high-risk patients have not reached MMR to a 1 year of therapy. Conclusions: Our study demonstrated that the individual BCR-ABL decline rate from baseline to 3 months might be useful prognostic marker that allowed detecting more patients at risk who had no MMR at 1 year of treatment and ABL should be used as control gene. Also the study showed that the individual ratio of BCR-ABL level at 3 months to 1 month might be studied as more predictive landmark for change of TKI treatment even among these patients that have BCR-ABLlevels ≤10% at 3 months. References: 1. B. Hanfstein, V. Shlyakhto, M. Lauseker et al. Velocity of early BCR-ABL transcript elimination as an optimized predictor of outcome in chronic myeloid leukemia (CML) patients in chronic phase on treatment with imatinib. Leukemia. 2014 May 6. doi: 10.1038/leu.2014.153. Disclosures No relevant conflicts of interest to declare.

Background. Isolated hyperbilirubinemia mostly of indirect bilirubin fraction is diagnosed in patients with polymorphism of UGT1A1 gene (Gilbert's syndrome), mainly homozygous genotype (TA)7/(TA)7 which encodes the enzyme uridinediphosphoglycosyltransferase 1 (UDP-GT) in hepatocytes. Hyperbilirubinemia is also frequent laboratory abnormality in chronic myeloid (CML) patients treated by nilotinib. Connection of hyperbilirubinemia with UGT1A1 polymorphism in CML patients on nilotinib therapy requires understanding and studying. Aims. To estimate the correlation between polymorphism of UGT1A1 gene and frequency of hyperbilirubinemia in patients with CML treated by nilotinib. Methods. We estimated biochemical parameters in a group of 100 patients treated by nilotinib: bilirubin, transaminases (AST, ALT), persistence of hyperbilirubinemia and biochemical parameters normalization. We also considered patients’ anamnesis for hepatitis and estimated those laboratory abnormalities in previous imatinib therapy as 98 of 100 patients received nilotinib second line after imatinib. Me time of observation on nilotinib therapy was 36.7 months (range 1 – 94.5). Men/women ratio was 45/55. Promoter region of the UGT1A1 gene was studied by allele specific polymerase chain reaction (AS-PCR). Results. Hyperbilirubinemia due to the indirect bilirubin fraction was observed in 84 (84%) of 100 patients. Of those 84 patients hyperbilirubinemia grade 1 was in 41 (49%), grade 2 in 33 (39%), grade 3 in 10 (12%). Normal genotype (TA)6/(TA)6 was in 71 (71%) patients, heterozygous genotype (TA)6/(TA)7 in 19 (19%), homozygous genotype (TA)7/(TA)7 in 10 (10%) patients. Frequency of hyperbilirubinemia grade 1-3 in patients depending on genotype is presented in table1. Figure 1 Figure 1. Hyperbilirubinemia grade 1 was associated mostly with normal genotype patients, grade 2 with normal and abnormal genotype, grade 3 with abnormal and homozygous genotype (9 of 10 patients). In 1 patient with normal genotype grade 3 hyperbilirubinemia was due to intracellular hemolysis approved by laboratory tests. One patient with heterozygous form (TA6/TA7) and normal bilirubin was on nilotinib Hyperbilirubinemia on previous imatinib treatment was in 29 (35,7%) of 82 patients with second line nilotinib: grade 1 in 25 (86.2%) of 29 patients (homozygous genotype TA7/TA7 in 5 of 25), grade 2 in 4 (13.8%) of 29 patients (all with homozygous genotype TA7/TA7). Normal bilirubin levels were in 55(46,3%) of 82 patients on previous imatinib therapy. One patient with TA7/TA7 genotype received nilotinib as first line. Bilirubin levels normalized in 48 (57.2%) of 84 patients during 1 to 3 months and persisted in 36 (42.8%). In 8(9,5%) of 84 patients transient ALT and AST elevation was observed: grade 1(1), grade 2 (5) grade 3-4(2); it was resolved and only isolated hyperbilirubinemia was observed later on. In 2 of 84 patients hepatitis C was diagnosed. No treatment discontinuation was done due to hyperbilirubinemia. Summary/Conclusion. In CML patients on nilotinib treatment Grade 3 hyperbilirubinemia as well as previous history of hyperbilirubinemia any grade on imatinib can be a sign of homozygous genotype TA7/TA7. Lower grades of hyperbilirubinemia occur both in patients with normal and abnormal heterozygous genotype. Other reasons for hyperbilirubinemia (hemolysis, hepatitis) should be assessed. No connection of UGT1A1 polymorphism and transaminase (ALT,AST) elevation was established. Disclosures Chelysheva: Bristol-Myers Squibb: Consultancy, Honoraria; Novartis International AG: Consultancy, Honoraria. Turkina:Bristol-Myers Squibb: Consultancy, Honoraria; Novartis International AG: Consultancy, Honoraria.

Introduction: Most surrogate endpoints are based on periodical measurement and the assessment of event time uses data censored by both sides. Kaplan-Maier (KM) estimators are calculated from right censored data and as result they are biased and sensitive to irregularity in measurements. High rate of missing data and irregularity is a common problem for registries. Interval Censorship Estimators (ICE) are relative complex but more reliable and robust than KM. Cytogenetic response is a major prognostic factor for long-term results of therapy of chronic myeloid leukemia (CML) and is often used as surrogate endpoint. The challenge of ICE usage instead of KM’s for cytogenetic response estimation is illustrated on real data from the registry of patients with CML. Methods and data source: We compare data in 2 studies of similar population of CML patients. The studies are distinguished by the design and completeness of data. First one is retrospective, second is prospective controlled registry population study. For evaluation of time to event characteristics two estimators were used and compared: classical KM estimators and ICE estimators based on Turnbul’s algorithm, realized as SAS Macro [1]. The EUropean Treatment Outcome Study (EUTOS) is a registry based international investigation started in June 2007 running for 3 years. The aim is to study the epidemiology of CML. The first part of the study is OUT Study section (EUTOS-OSP) with retrospectively collect data form patients who are not included into the local or international clinical trials. The second part of EUTOS study is online registry so called Population Based Sections (PBS EUTOS) aimed to estimate incidence of CML in EUROPE. Results: For the analysis we made 2 data sets. First one includes data of 508 patients with 2005-2008 years of diagnosis from study EUTOS-OSP collected retrospectively from 36 regions of Russian. Median age at diagnosis was 49,3 years, range from 18 to 82, 47,6% of men, 6.7% in AC,BC phase, 29,3% at high risk by Sokal. Second set includes data of all 200 patients of PBS EUTOS study prospectively collected form 6 regions of Russia in 2008-2012 years. Median age at diagnosis was 50,4 years, range from 16 to 82, 50,8% of men, 6.0% in AC,BC phase, 31,7% at high risk by Sokal. Progression free survival (PFS) and complete cytogenetic responds (CCyR) probability were calculated by traditional KM method in OSP and PBS data sets. Also ICE estimations of the CCyR was done in this data sets. The 3-year PFS was estimated as 89.6% in OSP set and 88.8% in PBS set (fig. 1). KM estimations gives median time to CCyR =17.5 months in OSP and 12 months in PBS group, delta=5.5 moths (fig.2), if ICE estimations is used median time to CCyR =12 month in OSP, 8.5 month in PBS group, delta=3.5 moths (fig.3). The difference of CCyR between OSP and PBS was much less on fig.3 than on fig.2. The completeness of cytogenetic data in both studies was quite distinguishing. Percentages of patients with reported cytogenetic tests were following: in 6±3 month – 333/497 (67%) in OSP and 151/174 (87%) in PBS, in 24±3 month – 254/470 (54%) in OSP and 52/79 (66%) in PBS. Figure 1. KM estimations PFS in OSP (dash line) and PBS (solid line) sets Figure 1. KM estimations PFS in OSP (dash line) and PBS (solid line) sets Figure 2. KM estimations of CCyR in OSP (dash line) and PBS (solid line) sets. Figure 2. KM estimations of CCyR in OSP (dash line) and PBS (solid line) sets. Figure 3. ICE estimations of CCyR in OSP (dash line) and PBS (solid line) sets. Figure 3. ICE estimations of CCyR in OSP (dash line) and PBS (solid line) sets. Long term results of studies are almost identical (p=0.3, fig.1) although the KM estimations of response rates are essentially different (p Conclusions: Irregularity of time assessment of surrogate endpoints and missing data may lead to bias of classical estimations and then to wrong interpretations. The challenge of ICE usage instead of KM is illustrated on real data from CML registries. ICE estimations showed to be reliable and robust in comparison to classic right censored estimations. 1. References: So Y., Johnston G. Kim S.H.: // Analyzing Interval-Censored Survival Data with SAS® Software. SAS Global Forum 2010. Disclosures No relevant conflicts of interest to declare.

Background The experience of usage of second line tyrosine kinase inhibitors (TKI2) in chronic myeloid leukemia (CML) patients in routine clinical practice in Russian Federation is still limited. Therefore the information about long-term therapy results and adverse events (AEs) is very important. Aim To provide information about the results of TKI2 nilotinib treatment in patients with chronic phase (CP) CML. To evaluate the long-term hematological and non-hematological AEs. Materialsandmethods Follow-up data of 37 CML CP patients treated by nilotinib 2nd line after imatinib failure due to resistance (28 [76%]) or intolerance (9 [24%]) were obtained and analyzed. The patients formerly participated in clinical trial ENACT after which continued treatment in routine clinical practice. A median CML observation prior to the nilotinib treatment was 66 months (range 7.9 to 148.1). Hematological, cytogenetic and molecular responses and AEs were evaluated with a median follow-up of 40 months (range 1.2 to 76.7). Results At the moment of evaluation 15 (41%) of 37 patients continue nilotinib treatment, 12 of 15 have been treated by nilotinib for more than 5 years. Nilotinib dose is 800 mg daily for all but one patient with 400 mg dose daily reduced due to constitutional hyperbilirubinemia. Nilotinib was discontinued in 22 (59%) of 37 patients: in 4 of 22 due to cytogenetic resistance, in 9 of 22 due to hematologic relapse, in 7 of 22 due to AEs. Two of 22 patients with concomitant atherosclerosis and diabetes diagnosed before nilotinib treatment died because of cardiovascular events. Efficacy Complete hematological remission (CHR), major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) were obtained in 34 (92%), 26 (70%) and 18 (48%) consequently. Major molecular response (MMR) and complete molecular response (CMR) was achieved in 16 (43%) and 9 (24%) consequently. Currently 10 (27%) patients have stable CCyR, 5 of those 10 have stable CMR lasting more than 5 years in 2 of these 5. Disease progression No cases of progression to accelerated phase (AP) and blast crisis (BC) before treatment discontinuation were observed. Hematologic relapses were within CP. Deaths due to CML progression were not observed on nilotinib treatment. Hematological AEs Grade 3-4 thrombocytopenia was observed in 8 (22%) patients, grade 3-4 neutropenia was observed in 5 (14%) and grade 3 anemia was observed in 1 (3%) patient. Non-hematological AEs The most common AE was rash (12 [32%] patients), in some cases with pruritus and xerodermia. The hemorrhagic syndrome was observed in 4 (11%) patients, associated with grade 3-4 thrombocytopenia only in 2 patients. The other 2 patients had uterine bleeding with questionable connection to therapy. Neither QT prolongation nor other abnormalities were revealed by ECG. As to laboratory findings: hyperbilirubinemia occurred in 33 (89%) patients, mostly due to indirect fraction, 5 of those 33 had hyperbilirubinemia grade 3. ÀL” and AST elevation (all grades) was observed in 26 (70%) and in 20 (54%) patients respectively, grade 3-4 was observed in 3 (8%) patients. Grade 1 hyperglycemia occurred in 7 (19%) patients, grade 3 hyperglycemia was observed in 1 (3%) patient with concomitant type 2 diabetes. All AEs were manageable according to general rules. No life-threatening AEs were diagnosed. Summary The results of long-term nilotinib 2nd line therapy are satisfactory for patients who achieved stable CCyR. Low level of high grade toxicity AEs was observed on nilotinib treatment, no new kinds of AEs appeared during long-term treatment. Disclosures: Bykova: Federal State Budgetary Institution Hematology Research Center of Health Ministry of Russia, Moscow, Russian Federation : Employment. Gusarova:Novartis International AG : Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Federal State Budgetary Institution Hematology Research Center of Health Ministry of Russia, Moscow, Russian Federation : Employment. Chelysheva:Novartis International AG : Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Federal State Budgetary Institution Hematology Research Center of Health Ministry of Russia, Moscow, Russian Federation : Employment. Turkina: Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

Background Frontline nilotinib 300 mg twice daily (BID) provides superior efficacy vs imatinib in pts with CML-CP, with good tolerability. Evaluating Nilotinib Efficacy and Safety in Clinical Trials—Extending Molecular Reponses (ENESTxtnd) is evaluating the kinetics of molecular response to frontline nilotinib 300 mg BID in pts with newly diagnosed CML-CP, as assessed in national and local laboratories, and is also the first study to evaluate the safety and efficacy of nilotinib dose optimization (including dose re-escalation in pts who require dose reductions due to adverse events [AEs] and dose increase in pts with less than optimal response). Here, we present results of a preplanned, interim analysis (IA) based on the first 20% of pts who completed 12 mo of treatment or discontinued early. Methods ENESTxtnd (NCT01254188) is an open-label, multicenter, phase 3b clinical trial of nilotinib 300 mg BID in adults with CML-CP newly diagnosed within 6 mo of study entry. The primary endpoint is rate of MMR by 12 mo. Molecular responses were monitored by real-time quantitative polymerase chain reaction (RQ-PCR) at local laboratories at baseline, at 1, 2, and 3 mo, and every 3 mo thereafter. Bone marrow cytogenetic analyses were performed locally at baseline, 6 mo, and end of study. Dose reductions were allowed for grade ≥ 2 nonhematologic AEs and grade 3/4 hematologic AEs. Pts with dose reductions could attempt to re-escalate (successful re-escalation defined as ≥ 4 wk on nilotinib 300 mg BID with no dose adjustments for any AE) and remain on study. Dose increase to nilotinib 400 mg BID was allowed in cases of BCR-ABL > 10% on the International Scale (BCR-ABLIS) at 3 mo or later, no major molecular response (MMR; BCR-ABLIS ≤ 0.1%) at 12 mo, loss of MMR, or treatment failure. Results This IA includes 85 pts treated in 12 countries (Argentina, Australia, Brazil, Canada, Israel, Lebanon, Mexico, Malaysia, Saudi Arabia, Thailand, Taiwan, and South Africa). Median age was 49 y (range, 19-85 y), and 58% of pts were male. Median time since diagnosis was 35 days (range, 2-157 days). Prior to study entry, 64 pts (75%) received hydroxyurea, and 3 pts (4%) received imatinib (all for ≤ 2 wk). At the data cutoff, 68 pts (80%) had treatment ongoing, and the remaining 17 had discontinued due to AEs/laboratory abnormalities (n = 8; nonhematologic AEs [n = 5], biochemical abnormalities [n = 2], and hematologic abnormalities [n = 1]), loss to follow-up (n = 2), administrative problems (n = 2), intolerance to the protocol-proposed dose (n = 2), suboptimal response (n = 1), withdrawal of consent (n = 1), or protocol deviation (n = 1). Median time on treatment was 13.8 mo (range, 1 day-18 mo). Median actual dose intensity of nilotinib was 597 mg/day (range, 165-756 mg/day), and 85% of pts had an actual dose intensity of > 400 mg/day to ≤ 600 mg/day. Of 30 pts with dose reductions due to AEs, 19 (63%) successfully re-escalated to nilotinib 300 mg BID. Nine pts (11%) dose escalated to nilotinib 400 mg BID due to lack of efficacy. The primary endpoint of MMR by 12 mo was achieved by 57 pts (67%; 99.89% CI, 49%-82%). Complete cytogenetic response by 6 mo was achieved by 48 pts (56%). Median BCR-ABLIS decreased over time, with a median value of 0.05% (range, 0.00%-41.36%) at 12 mo (Figure). Most pts (91%) achieved early molecular response (BCR-ABLIS ≤ 10% at 3 mo). Of the 8 pts (9%) with BCR-ABLIS > 10% at 3 mo (4 of whom were then dose escalated), 3 achieved MMR by 12 mo (1 of whom had been dose escalated). By the data cutoff, no pt had progressed to accelerated phase/blast crisis (AP/BC), and there had been no deaths on study. Nilotinib was well tolerated, with a safety profile similar to that seen in other frontline studies. Drug-related nonhematologic AEs (≥ 10% of pts) were rash (31%), constipation (13%), and headache (13%). Newly occurring or worsening grade 3/4 hematologic or biochemical abnormalities (≥ 10% of pts) were neutropenia (17%), thrombocytopenia (17%), increased lipase (13%), and increased bilirubin (12%). Conclusions These results demonstrate that dose-optimized nilotinib affords high rates of molecular response in pts with newly diagnosed CML-CP. Further, they support the feasibility of nilotinib dose re-escalation in pts who require temporary dose reductions due to AEs, with 63% of dose-reduced pts able to successfully re-escalate to nilotinib 300 mg BID and safely continue therapy. Disclosures: Lipton: Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Meillon:Bayer: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria. Louw:Novartis: Congress attendance support Other, Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Congress attendance support, Congress attendance support Other, Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Pavlovsky:Novartis: Research Funding, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Jin:Novartis: Employment. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Woodman:Novartis: Employment, Equity Ownership. Hughes:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; CSL: Research Funding. Turkina:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria.

Introduction In some cases of the cytogenetic analysis patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) there are increase frequency non-clonal disorders (“cytogenetic noise”) in combination with complex (≥ 3 chromosomal aberration) clonal disorders. It is not infrequently manifested in the form of superinstability of the karyotype. In this case every aberrant cell is genetic different from each other. It is obvious that super unstable karyotype has a poor prognosis even more than complex clonal disorders, since due to the high genetic instability is a strong possibility of mutations that cause resistance to chemotherapy. In other words, the high level of “cytogenetic noise” on background of complex clonal disorders can be used as a marker of highly aggressive course of AML and MDS. The aim of our study was to determine the effect of superinstability of the karyotype on the current and prognosis of AML and MDS. Methods Thus, 157 patients with cytogenetic survey from register of AML and MDS by Kirov Research Institute of Heamatology were included in our research. They are 73 men, 84 women have the age from 21 to 81 (Me 55) years. Among them 34 patients have MDS and 123 – AML excluding promyelocytic leukemia. Chromosomal aberration were determined from bone marrow aspirate by standard cytogenetic method (GTG-method). Was evaluated at least 20 metaphase cells. Results Among MDS patients the prevalence of superinstability of the karyotype was 29%, while among AML – only 4%, χ2=16.9, p Conclusion A chromosomal superinstability of tumor cells that greatly enhances the aggressiveness of the current AML and MDS, leading to chemotherapy resistance and dramatically reduces the overall survival patients. Superinstability of the karyotype determines the group of patients untreatable by standard chemotherapy. The allogeneic bone marrow transplantation need in these cases. Disclosures: No relevant conflicts of interest to declare.

Abstract 4431 The European Treatment Outcome Study (EUTOS) is register based international investigation started in June 2007. [1] The aim is to study the epidemiology of CML and to gain insight into the ‘real world’ treatment of patients with CML. Population base section (EUTOS-PBS) is the prospective study directed mostly to epidemiology aims. Russian part of the EUTOS-PBS registry collect data of newly diagnosed patients lived in 7 large regions of about 10 millions of population totally. EUTOS-PBS inclusion criteria are following: newly diagnosed CML (Ph +/BCR-ABL) started form 1st October 2009, age: older than 18. Russian CML group includes additional protocol for collection data for patients with clinical symptoms of CML. These patients are included into the roster table and after laboratory confirmation are enrolled into the main phase of the study. Thus, 174 patients were included in pre-phase, 142 (82%) had the diagnosis of CML which was confirmed by cytogenetic/molecular-genetic tests (Ph +/BCR-ABL +), 32 (18%) was not confirmed as CML. Among them 87% (n = 20) - have other Ph–negative chronic myeloproliferative diseases, and also acute leukemia (n = 1), cancer (n = 1), chronic inflammatory processes (n = 1). 142 patients with CML are 73 men, 69 women have the age from 18 to 82 (Me 49) years. 136 (96%) of patients are in the chronic phase, 6 (4%) -in the phase of acceleration, nobody in a blast ñrisis. The standard frequency analysis with adjustment to the standard population of WHO was carried out to estimate distribution. The results was presented in the table 1. As shown registered morbidity in 6 regions is not varied so much: source incidence is 0,58 (0,44–0,69); standardized on WHO incidence is: 0,7 (0,57 – 0,85); per 100 thousands per year. Estimated registered morbidity of CML in Russian regions are in 1.5–2 times less, than published morbidity in western countries. The analysis of the incidence in age stratums (table 2) shows that there is no much growth of age morbidity as expected. It obviously points to low detectability of new CML incidents in senior age categories (are more senior 60 years). This fact is probably the main reason of low total registered morbidity. Tabl.1. Incidence rate of new CML cases in 6 regions of Russia Region population (mln.) N CML for 100000. in year Standard of WHO Mordovia Republic 0.87 14 0.69 0.85 Kirov region 1.46 18 0.53 0.6 Perm territory 2.77 45 0.68 0.8 Bryansk region 1.35 17 0.53 0.65 Irkutsk region 2.55 36 0.56 0.68 Zabaikal's territory 1.36 12 0.44 0.57 Total 10.13 142 0.58 0.7 Table 2.CML incidence in age groups Age groups Male Female Maleandfemale 18–29 0.65 0.57 0.61 30–39 0.86 0.39 0.62 40–49 0.50 0.57 0.54 Conclusion: The CML incidence in Russia regions is underestimated. The main reason is an insufficient CML diagnostic screening in the senior age groups of population. References. 1. http://www.eutos.org/content/registry/documents/documents/e940/infoboxContent941/CML-Registry_February09.pdf Disclosures: Vinogradova: BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Chelysheva:Novartis Pharma: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; MSD: Speakers Bureau. Senderova:Novartis: Consultancy. Turkina:Novartis Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Abstract 3779 Bosutinib (BOS) is an oral, dual Src/Abl kinase inhibitor with minimal inhibitory activity against PDGFR or c-KIT. This open-label, phase 1/2 study evaluated BOS in patients (pts) with chronic phase chronic myeloid leukemia (CP CML) following imatinib resistance (IM-R) or intolerance (IM-I). Pts aged ≥18 y with IM-R (n = 195) or IM-I (n = 91) CP CML received oral BOS 500 mg/d. Of 286 pts, 53% were male, median age was 53 y (range, 18–91 y), and median time from CML diagnosis was 3.7 y (range, 0.1–15.1 y). Median treatment duration was 24.6 mo (range, 0.2–72.3 mo); median BOS dose intensity was 443 mg/d (range, 61–600 mg/d); 12% of pts received dose escalation to BOS 600 mg/d. Minimum time from last enrolled pt's first dose was 38 mo; 42% of pts are still receiving BOS. A confirmed complete hematologic response (CHR) was attained/maintained by 167/194 (86%) IM-R and 77/91 (85%) IM-I pts with a valid baseline assessment; Kaplan-Meier (KM)–estimated probabilities of maintaining a CHR at 3 y were 65% and 83%. A major cytogenetic response (MCyR) was attained/maintained by 106/182 (58%) IM-R and 49/82 (60%) IM-I pts with a valid baseline assessment. A complete cytogenetic response (CCyR) was attained/maintained by 88/182 (48%) and 42/82 (51%) evaluable pts. Among evaluable pts without a CCyR at baseline, 101/177 (57%) IM-R and 39/71 (55%) IM-I pts achieved a MCyR including 83 (47%) IM-R and 33 (47%) IM-I pts who achieved a CCyR. The KM-estimated probability of maintaining a MCyR at 3 y was 71% for IM-R and 88% for IM-I pts. Of 210 pts with baseline mutation status assessed, 78 (37%) pts had 42 unique Bcr-Abl kinase domain mutations (P loop, 9% of pts; non-P loop, 30% of pts), including 9 (4%) pts with the T315I mutation. Responses to BOS were seen across different Bcr-Abl baseline mutations, including those associated with resistance to other TKIs, but were low (22% for both CHR and MCyR) among pts with T315I. When pts with T315I at baseline were excluded, response rates for the remaining pts with ≥1 mutation were 93% for CHR and 62% for MCyR. Eighteen of 68 pts evaluated at baseline and treatment discontinuation had ≥1 new Bcr-Abl mutation (T315I, n = 8; V299L, n = 3; E255V, E450A, E450G, G250E, K378E, L273M, and M244V, n = 1 each); 15 of these 18 pts had discontinued due to disease progression or lack of efficacy. On-treatment transformation to accelerated or blast phase CML occurred in 10 (5%) IM-R and 2 (2%) IM-I pts. KM-estimated on-treatment progression-free survival (PFS) at 3 y was 72% for IM-R pts and 89% for IM-I pts. KM-estimated overall survival (OS) at 2 y was 88% for IM-R and 98% for IM-I pts (3-y OS not provided as results may be unreliable since per study protocol pts were followed for OS for only 2 y after BOS discontinuation). There were 34 (12%) deaths on study, with 5 deaths occurring within 30 d of the last BOS dose. Most deaths were due to disease progression (n = 17 [6%]) or an adverse event (AE) unrelated to BOS (n = 12 [4%]); only 1 treatment-related death occurred (due to febrile neutropenia 78 d after the last BOS dose in the IM-R group). Four additional deaths were due to unknown causes ≥136 d after the last BOS dose. The most frequent non-hematologic treatment-emergent AEs (TEAEs; all grades/grade 3/4) were diarrhea (85%/10%), nausea (46%/1%), vomiting (37%/4%), rash (36%/9%), pyrexia (26%/1%), abdominal pain (25%/1%), and fatigue (25%/1%). Diarrhea was predominantly grade 1/2 in severity, had an early onset (median time to first event of 2 d [range, 1–1,330 d]), and was typically transient (median event duration of 1 d [range, 1–830 d]). Grade 3/4 on-treatment hematologic and non-hematologic lab abnormalities in ≥10% of pts included thrombocytopenia (25%), neutropenia (18%), lymphocytopenia (16%), anemia (14%), hypermagnesemia (11%), alanine transaminase elevation (11%), and hypophosphatemia (10%). Toxicities were manageable with medications and/or BOS dose modification; 45% of IM-R and 57% of IM-I pts had ≥1 dose reduction, and 66% of IM-R and 84% of IM-I pts had ≥1 dose interruption. AEs led to BOS discontinuation in 32 (16%) IM-R and 37 (41%) IM-I pts; the most common reason was thrombocytopenia. Overall, the rates of TEAEs and BOS discontinuation due to AEs showed little increase from the prior 24-mo analysis. In conclusion, BOS therapy continues to demonstrate durable efficacy and manageable toxicity in pts with CP CML following IM-R or IM-I after a minimum of 36 mo of follow-up, emphasizing the therapeutic potential of BOS in this population. Disclosures: Cortes: Novartis, Bristol Myer Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding. Kantarjian:Pfizer Inc: Research Funding. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Turkina:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Brümmendorf:Bristol Myer Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Patent on the use of imatinib and hypusination: Patents & Royalties. Schafhausen:Bristol Myers Squibb, Novartis, Pfizer: Consultancy, Honoraria. Porkka:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Leip:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment, Equity Ownership. Besson:Pfizer Inc: Employment. Gambacorti-Passerini:Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy.

Abstract 4447 Background: High efficiency of imatinib (IM) in CML therapy has been proven in clinical trials. However, the outcomes of CML treatment by IM in clinical practice are not covered in the literature. Objectives: To evaluate the results of CML treatment by TKI in clinical practice in the Russian Federation. Patients and treatment: The data analysis from 28 administrative regions of theRussian Federation was performed. The selection of regions was based on the quality of the data from CML pts registry. 524 CML pts were included in this study. Inclusion criteria were: Ph/bcr-abl-positive CML diagnosed in 2002– 2006, age of pts ≥ 18 years (y), initiation of IM therapy ≤ 6 months (mo) from the date of diagnosis. Median (Me) age was 47(18 – 81) y, sex ratio (M/F (%)) 250/274 (48/52) pts, Me time from diagnosis to IM treatment was 2.4(0 – 6) mo. Pretreatment: Hydrea 398 (76%) pts; Mielosan 3 (0.5%) pts, chemotherapy 21(4%)pts, IFN-α 30 (5.7%) pts. Me follow-up since the beginning of CML treatment was 55.2 (1 – 108) mo (*6 pts have not data on the date of analysis). In Chronic Phase (CP) were 478 (91.2%) pts, in Accelerated Phase (AP) - 40 (7.6%) pts and in Blast Crisis (BC) - 6 (1.2%). Sokal risk stratification, %: 52 low (L)/22 intermediate (Int)/26 high(H) (78 pts with no baseline data. Statistical analysis was performed using a package SAS9.1.3. Result: 427 (89%) from 478 CP CML pts were alive on May2011, 51(11%) pts were died. In this cohort of CP CML pts 5-year Overall Survival (OS) and Progression Free Survival (PFS) to AP/BC were 89% and 95% respectively (Me 56.4 (1 – 108) mo). The slow achievement of complete hematologic response (CHR) and complete cytogenetic response (CCyR) should be noted. On the IM therapy, 48% pts have achieved CHR by 3 mo only and 86% pts have achieved CHR by 12 mo (Me 3.2 (0.1 – 85) mo); CCyR at any time was achieved in 77% of pts, but by 12 mo – in only 40% of pts (Me 15 mo (0.7 – 75). There was no clear evidence of the dependence of OS rate from % of Ph’-positive cells in bone marrow after 6, 12, 18 and 36 mo were not received (p>0.5 in all cases). Analysis of molecular response (MR) was performed in 338 (70%) pts (not standardized rtPCR method): major MR was achieved in 241 (71%) pts (Me 42 (6–86) mo), complete MR - in 172 (50%) pts (Me 53(6–100) mo). OS by Sokal in pts with L and Int risk groups was identical and better than in pts with H, consistent with 90 and 83%, respectively (p=0.04). The probability of CCyR by Sokal were 85, 80 and 70% for the L, Int and H risk of disease progression, respectively (p=0,0002). IM therapy is still ongoing in 362 (85%) pts in doses 400/600/800mg/day-54%/33%/13%, respectively. 41(10%) pts were switched to 2nd line TKI (25 pts to Nilotinib, 10 pts- Dasatinib, 6 pts-Bosutinib). In total, 51 (11%) pts died (21 pts with progression to AP/BC, 30pts with associated diseases). Conclusion: The research program EUTOS enabled Russian hematologists to cooperate with an international research group (ELN) and this cooperation allows to improve the quality of CML treatment, monitoring MRD and data collection in the Russian CML registry. The analysis of data shows high rates of OS and PFS in CP CML, despite the delay of CHR and CCyR achievement. In clinical practice the low significanse of Sokal risk criteria and the absence of the influence of cytogenetic response achievement on OS was established that differ from clinical trial data and that may be due to a non-standardized approach to treatment and retrospective data collection. Disclosures: Turkina: Novartis: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Kulikov:Novartis: statistical tasks. Kutsev:Novartis: Research Funding, Speakers Bureau. Golenkov:Novartis: Speakers Bureau. Ivanova:Novartis: Honoraria, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Pospelova:Novartis: Research Funding, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Konstantinova:Novartis: Speakers Bureau. Lazareva:Novartis: Research Funding, Speakers Bureau, work with CML Registry. Khoroshko:Novartis: Speakers Bureau.

Abstract 3768 Background: Data from the phase 3, randomized multicenter ENESTnd trial have demonstrated the superiority of nilotinib over imatinib after 24 months (mo) of follow-up, with significantly higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR), and significantly lower rates of progression to accelerated phase/blast crisis (AP/BC). The current subanalysis evaluated the efficacy and safety of nilotinib 300 mg twice daily (Nil300) and nilotinib 400 mg twice daily (Nil400) in older (≥ 65 years [yrs] at study entry) patients (pts) with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) with a minimum follow-up of 24 mo. Methods: In ENESTnd, 846 pts stratified by Sokal risk score were randomized 1:1:1 to Nil300 (n = 282), Nil400 (n = 281), or imatinib 400 mg once daily (n = 283). Pts with impaired cardiac function or ECOG performance status > 2 were excluded. Rates of CCyR and MMR by 24 mo, progression to AP/BC on treatment, and safety were evaluated according to age group (< 65 vs ≥ 65 yrs) in the 2 nilotinib arms. Safety data are reported for any pt who received ≥ 1 dose of nilotinib (n = 279, Nil300; n = 277, Nil400). Results: 36 pts (13%) and 28 pts (10%) were ≥ 65 yrs old in the Nil300 and Nil400 arms, respectively. Of the pts aged ≥ 65 yrs, 51/64 (80%) had an ECOG performance status of 0 at baseline and 60/64 (94%) had intermediate or high Sokal risk scores. Of the older pts, 8 (22%) on Nil300 and 6 (21%) on Nil400 had type 2 diabetes at baseline. CCyR rates by 24 mo were 83% and 68% among older pts treated with Nil300 and Nil400, respectively, and 87% for pts aged < 65 yrs in each nilotinib arm. By 24 mo, MMR was achieved by 72% and 61% of older pts on Nil300 and Nil400, respectively; in pts aged < 65 yrs, the respective rates were 71% and 67%. All 5 pts who progressed to AP/BC on treatment (2 on Nil300 and 3 on Nil400) were aged < 65 yrs. The frequency of grade 3/4 hematologic adverse events (AEs) was low in older pts; no pts had grade 3/4 neutropenia and only 1 older pt reported grade 3/4 thrombocytopenia in each nilotinib arm (Table). Transient, asymptomatic lipase elevations were reported in 11% and 16% of older pts treated with Nil300 and Nil400, and 7% of younger pts in each arm. Hyperglycemia occurred in 23% and 16% of older pts on Nil300 and Nil400, respectively, and 4% of younger pts in each arm; regardless of age, no pt discontinued study due to hyperglycemia. Among the 12 older pts with grade 3/4 hyperglycemia (8 on Nil300; 4 on Nil400), 9 pts had type 2 diabetes at baseline. There were no QTcF increases of > 60 msec from baseline in older pts and 3 in nilotinib-treated pts < 65 yrs old (1 on Nil300; 2 on Nil400). QTcF prolongation of > 500 msec did not occur in any pt treated with nilotinib on study. Periodic echocardiograms were done, and there were no decreases of > 15% in left ventricular ejection fraction from baseline in any pt treated with nilotinib on study. There were 4 cases of ischemic heart disease reported in older pts (1/35 [3%] on Nil300; 3/25 [12%] on Nil400) and 7 cases in pts < 65 yrs of age (4/244 [2%] on Nil300; 3/252 [1%] on Nil400). No sudden deaths occurred on study. Discontinuation occurred in approximately 25% of older and younger pts with Nil300, of which, 6% and 9%, respectively, were due to AEs/lab abnormalities. Discontinuation from study with Nil400 was 46% in older pts and 19% in younger pts; of which, 36% and 10% were due to AEs/lab abnormalities. Conclusions: Older pts treated with nilotinib demonstrated high rates of cytogenetic and molecular responses and low rates of progression. Nilotinib was generally well tolerated by older pts. In older pts, Nil300 had numerically higher rates of CCyR and MMR and was generally better tolerated (as evidenced by fewer AEs and discontinuations) vs Nil400. These data support the use of Nil300 in older pts with newly diagnosed CML-CP. Disclosures: Larson: Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Bunworasate:Novartis Pharmaceutical: Research Funding. Turkina:Novartis: Consultancy, Honoraria; BMS: Honoraria. Goldberg:Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding. Dorlhiac-Llacer:Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding. Saglio:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis Pharmaceutical: Consultancy, Speakers Bureau; Pfizer: Consultancy. Hochhaus:Ariad: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Yu:Novartis: Employment, Equity Ownership. Gallagher:Novartis: Employment, Equity Ownership. Clark:Bristol Myers Squibb: Honoraria, Research Funding; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau. Hughes:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees.