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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.

Background Approximately 5–20% of chronic myeloid leukemia (CML) patients demonstrate primary resistance or intolerance to imatinib. None of the existing predictive scores gives a good prognosis of TKI efficacy. Gene polymorphisms, expression and microRNAs are known to be involved in the pathogenesis of TKI resistance in CML. The aim of our study is to find new molecular markers of TKI therapy efficacy in CML patients. Methods Newly diagnosed patients with Ph+ CML in chronic phase were included in this study. Optimal and non-optimal responses to TKI were estimated according to ELN 2013 recommendation. We performed genotyping of selected polymorphisms in 62 blood samples of CML patients, expression profiling of 33 RNA samples extracted from blood and miRNA profiling of 800 miRNA in 12 blood samples of CML patients. Results The frequencies of genotypes at the studied loci did not differ between groups of patients with an optimal and non-optimal response to TKI therapy. Analysis of the expression of 34,681 genes revealed 26 differently expressed genes (p

The ENESTop study evaluated treatment-free remission (TFR) in patients with chronic myeloid leukemia (CML) in chronic phase who had received ≥3 years of tyrosine kinase inhibitor therapy and achieved sustained deep molecular response only after switching from imatinib to nilotinib. After 1-year nilotinib consolidation, 126 patients attempted TFR. At 48 weeks (primary analysis), 57.9% (73/126) were in TFR. In the present analysis at 5 years, 42.9% (54/126) were in TFR. Since the 48-week analysis, among patients who left the TFR phase, 58% (11/19) did not have a loss of molecular response and discontinued for other reasons. Of the 59 patients who reinitiated nilotinib upon loss of major molecular response (MMR) or confirmed loss of MR4, 98.3% regained MMR, 94.9% regained MR4, and 93.2% regained MR4.5. Overall adverse event rates decreased over the 5 years of TFR. In patients reinitiating nilotinib, there was a cumulative increase in cardiovascular events with longer nilotinib exposure. No disease progression or CML-related deaths were reported. Overall, these results confirm the durability and safety of TFR for patients receiving second-line nilotinib. Cardiovascular risk should be carefully managed, particularly when reinitiating treatment after TFR.

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/.

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.

To assess the results of following up patients with chronic myeloid leukemia (CML) and a deep molecular response (MR) without tyrosine kinase inhibitor (TKI) therapy.The reasons for TKI discontinuation in 70 patients with CML and a deep MR of more than 1 year's duration were adverse events, pregnancy, and patients' decision. Information was collected retrospectively and prospectively in 2008-2016.The median follow-up after TKI therapy discontinuation was 23 months (2 to 100 months). At 6, 12 and 24 months after TKI therapy discontinuation, the cumulative incidence of major MR (MMR) loss was 28, 41 and 48%, respectively; the survival rates without TKI therapy were 69, 50, and 39%, respectively. MMR loss was noted in 28 (88%) patients at 12 months; it was not seen without TKI therapy at 2-year follow-up. Deaths due to CML progression were absent. The Sokal risk group was a reliable factor influencing MMR loss (p ≤ 0.05). The cumulative recovery rate for deep MR after resumption of TKI use was 73 and 100% at 12 and 24 months, respectively, with a median follow-up of 24 months (1 to 116 months). Deep MR recovered at a later time when the therapy was resumed more than 30 days after MMR loss.Safe follow-up is possible in about 50% of the patients with CML and stable deep MRs without TKI therapy. The introduction of this approach into clinical practice requires regular molecular genetic monitoring and organizational activities. Biological factors in maintaining remission after TKI discontinuation need to be separately studied.Цель исследования. Оценка результатов наблюдения больных хроническим миелолейкозом (ХМЛ) с глубоким молекулярным ответом (МО) без терапии ингибиторами тирозинкиназ (ИТК). Материалы и методы. Причинами отмены ИТК у 70 больных ХМЛ с длительностью глубокого МО более 1 года служили нежелательные явления, беременность, собственное решение больных. Сбор информации осуществлялся ретроспективно и проспективно в 2008-2016 гг. Результаты. Медиана времени наблюдения после отмены терапии ИТК составила 23 мес (от 2 до 100 мес). Кумулятивная частота потери большого молекулярного ответа (БМО) после прекращения терапии ИТК через 6, 12 и 24 мес составила 28, 41 и 48% соответственно, выживаемость без терапии ИТК - 69, 50 и 39% соответственно. У 28 (88%) пациентов потеря БМО отмечена в течение 12 мес; после 2 лет наблюдения без терапии ИТК потери БМО не отмечалось. Летальные исходы от прогрессии ХМЛ отсутствовали. Группа риска по Sokal являлась достоверным фактором, влияющим на потерю БМО (p≤0,05). Кумулятивная частота восстановления глубокого МО после возобновления приема ИТК составляла 73 и 100% через 12 и 24 мес соответственно при медиане наблюдения 24 мес (от 1 до 116 мес). Восстановление глубокого МО наблюдалось позднее при возобновлении терапии более, чем через 30 дней после потери БМО. Заключение. Примерно у 50% больных ХМЛ со стабильным глубоким МО возможно безопасное наблюдение без терапии ИТК. Для внедрения этого подхода в клиническую практику необходимы обеспечение регулярного молекулярно-генетического контроля и организационные меры. Биологические факторы сохранения ремиссии после отмены ИТК нуждаются в отдельном изучении.

Summary The Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Extending Molecular Responses (ENESTxtnd) study was conducted to evaluate the kinetics of molecular response to nilotinib in patients with newly diagnosed chronic myeloid leukaemia in chronic phase and the impact of novel dose-optimization strategies on patient outcomes. The ENESTxtnd protocol allowed nilotinib dose escalation (from 300 to 400 mg twice daily) in the case of suboptimal response or treatment failure as well as dose re-escalation for patients with nilotinib dose reductions due to adverse events. Among 421 patients enrolled in ENESTxtnd, 70·8% (95% confidence interval, 66·2–75·1%) achieved major molecular response (BCR-ABL1 ≤ 0·1% on the International Scale) by 12 months (primary endpoint). By 24 months, 81·0% of patients achieved major molecular response, including 63·6% (56 of 88) of those with dose escalations for lack of efficacy and 74·3% (55 of 74) of those with dose reductions due to adverse events (including 43 of 54 patients with successful re-escalation). The safety profile of nilotinib was consistent with prior studies. The most common non-haematological adverse events were headache, rash, and nausea; cardiovascular events were reported in 4·5% of patients (grade 3/4, 3·1%). The study was registered at clinicaltrials.gov (NCT01254188).

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.

Context Chronic myeloid leukemia (CML) patients (pts) receive a long-term treatment with tyrosine kinase inhibitors (TKI) in standard doses. A new approach with reduced dose TKI use is desirable for the CML pts with adverse effects (AE) or with a high risk of AE, particularly in pts with major molecular response (MMR) and deep molecular response (DMR) receiving second generation TKI (2GTKI). Objective To evaluate the stability of MMR in CML pts after dose reduction of 2GTKI. Patients We included 36 pts taking 2GTKI, all in chronic phase, in retrospective analyses. Median (Me) age was 47 years (range 22-71). Me therapy duration was 42.5 months (mo). MMR was in 7 (19%) pts, DMR in 29 (81%) pts. Me duration of MMR was 21.5 mo at the time of dose reduction. The AEs were in 21 (58%) pts before the dose reduction. Interventions The dose reduction of nilotinib and dasatinib was done in 28 (78%) and 8 (22%) pts. Initial dose of nilotinib was 800, 600 and 400 mg in 18 (64%), 8 (28%) and 2 (7%) pts. The dose of nilotinib was reduced to 600, 400, 300, and 200 mg in 1 (4%), 21 (75%), 2 (7%) and 4 (14%) pts. The initial dose of dasatinib was 140 mg in 1 (12.5%) and 100 mg in 7 (87.5%) pts, and the reduced dose was 70 and 50 mg in 2 (25%) and 6 (75%) pts. Results Me follow-up after 2GTKI dose reduction was 13 mo. The MMR loss occurred in 3 pts with MMR duration 3, 6 and 8 mo at the time of dose reduction. Survival without MMR loss at 12 mo was 96% (CI 89% -100%) and 64% (CI 23-100%) in the DMR and MMR cohort. MMR was regained in all pts after the standard dose therapy was recommenced. The toxicity after dose reduction was resolved in 19 (90%) of 21 pts with the previously observed AE. Conclusions This option allows reduction of the drug toxicities and prevents the potential AE of TKI therapy. In January 2020 in Russia, the prospective clinical trial was started in order to evaluate a relapse-free survival after discontinuation of therapy with the previous 12-months two-stage phase of TKI dose reduction.

Chronic myeloid leukemia (CML) is usually diagnosed in chronic phase, yet there is a small percentage of patients that is diagnosed in accelerated phase or blast crisis. Due to this rarity, little is known on the prognosis of these patients. Our aim was to identify prognostic factors for this cohort. We identified 283 patients in the EUTOS population-based and out-study registries that were diagnosed in advanced phase. Nearly all patients were treated with tyrosine kinase inhibitors. Median survival in this heterogeneous cohort was 8.2 years. When comparing patients with more than 30% blasts to those with 20-29% the hazard ratio (HR) was 1.32 (95%-confidence interval (CI): [0.7 - 2.6]). Patients with 20-29% had a significantly higher risk than patients with less than 20% blasts (HR: 2.24, 95%-CI: [1.2 - 4.0], p = 0.008). We found that the blast count was the most important prognostic factor; however, age, hemoglobin, basophils and other chromosomal aberrations should be considered as well. The ELTS score was able to define two groups (high risk vs. non-high risk) with an HR of 3.01 (95%-CI: [1.81 - 5.00], p

7009 Background: BOS is approved for Philadelphia chromosome (Ph)+ CML resistant/intolerant to prior therapy and newly diagnosed Ph+ CP CML. In a phase 1/2 study, second-line BOS showed durable efficacy and manageable toxicity in pts with imatinib-resistant (IM-R) or -intolerant (IM-I) Ph+ CP CML. Methods: This final efficacy and safety analysis of the phase 1/2 study and extension study was based on ≥10 y of follow-up (FU). Ph+ CP CML pts who received BOS starting at 500 mg/d after prior treatment (Tx) with imatinib only were included. Results: 19% of pts were on BOS at y 10, and 13% were still on BOS at study completion after ≥10 y; 19% completed ≥10 y of FU. Median duration of Tx and FU were 26 and 54 mo, respectively. Median (range) dose intensity was 436 (87–599) mg/d. The most common primary reasons for permanent Tx discontinuation were lack of efficacy (unsatisfactory response or disease progression; 27%) and adverse events (AEs; 26%). In pts with a valid baseline assessment, cumulative complete cytogenetic response (CCyR), major molecular response (MMR) and MR4 rates (95% CI), respectively, were 50% (43–56), 42% (35–49) and 37% (30–44) (IM-R: 48% [41–56], 46% [37–55] and 39% [31–48]; IM-I: 53% [41–64], 36% [25–48] and 33% [22–45]). Responses were durable, with estimated probabilities of maintaining CCyR, MMR and MR4 > 50% after ≥10 y (Table). At 10 y, cumulative incidence of on-Tx progression/death was 24% and Kaplan-Meier (K-M) overall survival 72% (Table); 55 deaths (IM-R: n = 41; IM-I: n = 14) occurred on study, none BOS-related. Any grade Tx-emergent AEs (TEAEs) in ≥40% of pts were diarrhea (86%), nausea (46%) and thrombocytopenia (42%). Pleural effusion, cardiac and vascular TEAEs occurred in 13%, 12% and 11% of pts, respectively. 28% of pts had AEs leading to permanent Tx discontinuation; most common (≥2% of pts) were thrombocytopenia (6%), neutropenia (2%) and alanine aminotransferase increased (2%). Conclusions: These 10-y data are consistent with prior results of durable efficacy and manageable toxicity with second-line BOS and support long-term BOS use in CP CML pts after imatinib failure. Clinical trial information: NCT00261846 and NCT01903733. [Table: see text]

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.

Aim To define the prognostic factors for molecular relapse-free survival (MRFS) after TKI discontinuation in the Russian CML population. Methods The base for the analysis was the Russian multicenter prospective study RU-SKI on the discontinuation of TKI in patients (pts) with CML and deep molecular response (DMR). Ninety-eight CML pts with chronic-phase, TKI therapy for at least three years and a stable DMR (BCR-ABL Results Three-year MRFS rate was 51%. Baseline pts characteristics: male - 50%; median (Me) age at TKI cessation 46 years (range, 22 to 80); Me duration of TKI therapy 8.3 years (range, 3 to 16.2); Me duration of DMR 3.2 years (range, 2 to 10.7). Therapy before treatment cessation: imatinib in 67 (68.4%) pts, second-generation (2G) TKI in 31 (31.6%) pts. Me follow-up time after TKI cessation was 40 mo (range, 28 to 57). Probability of MRFS (1st stop) was 53% after 36 mo of follow-up. Length of DMR, duration of therapy and depth of molecular response were found to be significant factors with p ≤ 0.05. We have found that the duration of TKI therapy, and not the duration of DMR, has an independent prognostic value for the Russian CML population due to the lack of molecular monitoring data at early stages of the disease. No difference in 36 months MRFS was observed in 1st-line imatinib (55%) compared with 1st-line 2G TKI (70%; p=0.26) and 2nd-line 2G TKI (39%; p=0,09) groups. However, significantly shorter treatment duration was observed in pts treated with 1st-line 2G TKI (Me=41.5 mo) vs imatinib (Me=96.4 mo), p Conclusion Longer treatment duration and depth of DMR before cancellation at least MR 4.5 are associated with durable TFR. Our study showed that the MRFS rate is not significantly improved with the use of 1st-line 2G TKI in comparison with 1st-line imatinib.

Introduction Duration of treatment with tyrosine kinase inhibitors (TKI) is an important favorable prognostic factor for treatment-free remission (TFR) and deep molecular response (DMR) in patients (pts) with chronic myeloid leukemia (CML). Aim To analyze the impact of first-line treatment duration with imatinib and 2G TKI on molecular relapse-free survival (MRFS) in CML pts with sustained DMR. Patients and methods In total, 174 CML pts in chronic phase with ≥3 years treatment duration and sustained DMR (MR4-MR5, BCR-ABL IS 0.1%). Median (Me) age of pts was 43 (range 21-86) years; 39% were males. Me TKI treatment duration was 86 months (IQR 57-125 mo), Me DMR duration was 45 (IQR 29-66 mo). Imatinib, 2G TKI in first-line and 2G TKI in second-line were discontinued in 116 (66.7%), 15(8.6%) (11 nilotinib, 3 dasatinib, 1 bosutinib) and 43 (24.7%) (34 nilotinib, 9 dasatinib) pts respectively. Results Me follow-up time after treatment cessation was 33 months (range 1-133). MRFS at 6, 12, 24 and 36 months was 62% (CI: 55-70%), 53% (CI: 45-60%), 50% (CI: 42-57%) and 48% (CI: 40-56%) respectively. Treatment duration and MR4.5 vs MR4 were significant for MRFS both in univariate (p=0.009 and p=0.015) and multivariate analysis (p=0.017 and p=0.037). No difference in 36 months MRFS was observed for imatinib (47% (CI: 42-60%)), first-line 2G TKI (59% (CI: 33-84%) p=0.58) and second-line 2G TKI (47% (CI: 32-63%) p=0.97) groups. However, significantly shorter treatment duration was observed in first-line 2G TKI group (Me=44 mo (IQR 40-52 mo)) vs imatinib (Me=93 mo (IQR 69-127 mo)), p Conclusion The 2G TKI as a first-line seem to be an effective option to reduce the treatment duration before TFR in CML pts although MRFS rate was not significantly improved in our study.

Breastfeeding in patients with chronic myeloid leukaemia (CML) who take tyrosine kinase inhibitors (TKIs) is not recommended but interruption of TKI treatment may cause the loss of remission. We observed the kinetics of the leukaemic clone in 3 women with CML in accordance with treatment interruptions for pregnancy and breastfeeding. The concentrations of nilotinib and imatinib in maternal milk were measured when the breastfeeding period was over. Nilotinib transfer into human breast milk was demonstrated for the first time and had a maximum concentration (Cmax) 129 ng/ml after 4 hours of the drug intake at a dose of 400 mg. The Cmax of imatinib in maternal milk ranged from 420 to 1411 ng/ml after 4-8 hours of the drug intake at a dose of 400-600 mg. Breastfeeding without TKI treatment may be safe with molecular monitoring, but preferably in those patients with CML who have durable deep molecular response.

Background Treatment-free remission (TFR)-that is, stopping tyrosine kinase inhibitor (TKI) therapy without loss of response-is an emerging treatment goal in chronic myeloid leukemia (CML). Objective To evaluate TFR after discontinuation of second-line nilotinib therapy. Design Single-group, phase 2, open-label study. (ClinicalTrials.gov: NCT01698905). Setting 63 centers in 18 countries. Patients Adults with CML in chronic phase who received TKI therapy for at least 3 years (>4 weeks with imatinib, then ≥2 years with nilotinib) and achieved MR4.5 (BCR-ABL1 ≤0.0032% on the International Scale [BCR-ABL1IS]) while receiving nilotinib entered a 1-year consolidation phase. Those with sustained MR4.5 during consolidation were eligible to enter TFR. Interventions Patients received nilotinib during consolidation; those who entered TFR stopped treatment. Patients with loss of major molecular response (MMR) (BCR-ABL1IS ≤0.1%) or confirmed loss of MR4 (BCR-ABL1IS ≤0.01%) during TFR reinitiated nilotinib treatment. Measurements Proportion of patients without loss of MMR, confirmed loss of MR4, or treatment reinitiation within 48 weeks of stopping treatment (primary end point). Results 163 patients who had switched from imatinib to nilotinib (for reasons including resistance, intolerance, and physician preference) enrolled in the study and entered the consolidation phase. Of these patients, 126 met the criteria for entering the TFR phase, and 73 (58% [95% CI, 49% to 67%]) and 67 (53% [CI, 44% to 62%]) maintained TFR at 48 weeks (primary end point) and 96 weeks, respectively. Of the 56 patients who reinitiated nilotinib therapy, 55 regained MMR or better and 52 regained MR4.5. None had CML progression to accelerated phase or blast crisis. Musculoskeletal pain was more frequent during the first 48 weeks after nilotinib discontinuation. Limitation The study included a heterogeneous patient population and was not designed to compare outcomes between patients continuing and those stopping treatment. Conclusion TFR seems achievable in patients with sustained MR4.5 after switching to nilotinib. Primary funding source Novartis Pharmaceuticals Corporation.

Long‐term efficacy and safety of bosutinib (≥4 years follow‐up from last enrolled patient) were evaluated in an ongoing phase 1/2 study in the advanced leukemia cohort with prior treatment failure (accelerated‐phase [AP, n = 79] chronic myeloid leukemia [CML], blast‐phase [BP, n = 64] CML, acute lymphoblastic leukemia [ALL, n = 24]). Fourteen AP, 2 BP, and 1 ALL patient remained on bosutinib at 4 years (vs. 38, 8, 1 at 1 year); median (range) treatment durations: 10.2 (0.1–88.6), 2.8 (0.03–55.9), 0.97 (0.3–89.2) months. Among AP and BP patients, 57% and 28% newly attained or maintained baseline overall hematologic response (OHR); 40% and 37% attained/maintained major cytogenetic response (MCyR) by 4 years (most by 12 months). In responders at 1 versus 4 years, Kaplan‐Meier (KM) probabilities of maintaining OHR were 78% versus 49% (AP) and 28% versus 19% (BP); KM probabilities of maintaining MCyR were 65% versus 49% (AP) and 21% versus 21% (BP). Most common AEs (AP, BP) were gastrointestinal (96%; 83%), primarily diarrhea (85%; 64%), which was typically low grade (maximum grade 1/2: 81%; 59%) and transient; no patient discontinued due to diarrhea. Serious AEs occurred in 44 (56%) AP and 37 (58%) BP patients, most commonly pneumonia (n = 9) for AP and pyrexia (n = 6) for BP; 11 and 13 died within 30 days of last dose (2 considered bosutinib‐related [AP] per investigator). Responses were durable in ∼50% AP responders at 4 years (∼25% BP patients responded at year 1, suggesting possible bridge‐to‐transplant role in BP patients); toxicity was manageable.Am. J. Hematol. 90:755–768, 2015. © 2015 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.

Both favorable pregnancy outcomes and fetal abnormalities have been associated with the use of tyrosine kinase inhibitors (TKIs) during pregnancy. The placental transfer of TKIs in humans is poorly understood. We observed women with chronic myeloid leukemia who used imatinib or nilotinib during the late pregnancy stages. The newborns had no birth abnormalities. We evaluated the drug concentrations in maternal blood, umbilical cord blood, and placental samples collected during labor. We found limited placental transfer of the TKIs. The fetal/maternal concentration ratio ranged from 0.5 to 0.58 for nilotinib and from 0.05 to 0.22 for imatinib. The placental/maternal ratio was higher for imatinib than for nilotinib. Theoretical pharmacokinetic modeling of passive placental crossing was insufficient to predict the in vivo data because the calculated fetal/maternal ratio was close to 1 for both drugs. We propose that active placental transport contributes to fetal protection against TKI exposure during pregnancy.

Bosutinib is an orally active, dual Src/Abl tyrosine kinase inhibitor for treatment of chronic myeloid leukemia (CML) following resistance/intolerance to prior therapy. Here, we report the data from the 2-year follow-up of a phase 1/2 open-label study evaluating the efficacy and safety of bosutinib as second-line therapy in 288 patients with chronic phase CML resistant (n = 200) or intolerant (n = 88) to imatinib. The cumulative response rates to bosutinib were as follows: 85% achieved/maintained complete hematologic response, 59% achieved/maintained major cytogenetic response (including 48% with complete cytogenetic response), and 35% achieved major molecular response. Responses were durable, with 2-year estimates of retaining response >70%. Two-year probabilities of progression-free survival and overall survival were 81% and 91%, respectively. The most common toxicities were primarily gastrointestinal adverse events (diarrhea [84%], nausea [45%], vomiting [37%]), which were primarily mild to moderate, typically transient, and first occurred early during treatment. Thrombocytopenia was the most common grade 3/4 hematologic laboratory abnormality (24%). Outcomes were generally similar among imatinib-resistant and imatinib-intolerant patients and did not differ with age. The longer-term results of the present analysis confirm that bosutinib is an effective and tolerable second-line therapy for patients with imatinib-resistant or imatinib-intolerant chronic phase CML. http://ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00261846","term_id":"NCT00261846"}}NCT00261846. Am. J. Hematol. 89:732–742, 2014. © 2014 The Authors American Journal of Hematology Published by Wiley Periodicals, Inc.

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.

7005 Background: In the ENESTop study (NCT01698905) of TFR in pts with CML-CP who achieved a sustained deep molecular response (MR) with 2L NIL, 57.9% remained in TFR 48 wks after stopping NIL (primary endpoint). Analyses at 144 wks showed durability of TFR. Data from longer follow-up (192 wks) evaluating the maintenance of TFR are reported. Methods: Pts treated with ≥2 y NIL after > 4 wks imatinib (≥3 y total) and achieving MR4.5 ( BCR-ABL1IS ≤0.0032%) on NIL were eligible. After a 1 y consolidation, pts with no confirmed loss of MR4.5 could attempt TFR. NIL was resumed upon loss of major MR ( BCR-ABL1IS ≤0.1%) or confirmed loss of MR4 ( BCR-ABL1IS ≤0.01%). At the data cut-off (Sep 24 2018), all pts had completed ≥192 wks of TFR, resumed NIL, or discontinued the study. Results: By the data cut-off, of 126 pts entering TFR, 56 were ongoing, 59 had resumed NIL, and 11 had discontinued. TFR rate at 192 wks was 46.0% (58/126; 95% CI, 37.1–55.1%); all but 1 of the 58 pts were in MR4.5. Only 1/61 pts in TFR at 144 wks lost response by 192 wks (confirmed loss of MR4); another 2 pts discontinued due to serious AE (polycythemia vera) and pt/guardian decision, respectively. Of 59 pts who resumed NIL, 56 (94.9%) and 55 (93.2%) regained MR4 and MR4.5, respectively. 40/56 pts (71.4%) who regained MR4 had stable MR4 at 96 wks (12 discontinued < 96 wks, and 4 remained on study with < 96 wks, after regaining MR4); 37/55 pts (67.3%) who regained MR4.5 had stable MR4.5 at 96 wks (12 discontinued < 96 wks, and 6 remained on study with < 96 wks, after regaining MR4.5). There were no disease progressions, deaths due to CML, or new deaths since the 144-wk analysis. The 192 wk treatment-free survival rate was 50.3% (95% CI, 41.2–58.7%). Of 62 pts who remained in TFR for > 144 wks, 11.3%, 53.2%, 21.0%, 14.5% and 3.2% had musculoskeletal pain AEs during consolidation and each subsequent 48 wk period of TFR. Among 59 pts who resumed NIL, most common AEs were hypertension (20.3%) and arthralgia (13.6%); the majority of AEs were grade 1/2. Conclusions: Results demonstrate long-term durability and safety of TFR following 2L NIL, with no disease progressions or CML-related deaths, and musculoskeletal pain AEs were transient. Clinical trial information: NCT01698905.

The introduction of tyrosine kinase inhibitors (TKI) in the treatment of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) has revolutionized the outcome, but the prognosis of the disease is still based on prognostic systems that were developed in the era of conventional chemotherapy and interferon (IFN)-alfa. A new prognostic score including only two variables, spleen size and basophils, was developed for the prediction of complete cytogenetic response (CCyR) and progression-free survival (PFS). The score was based on a large series of patients who were enrolled in prospective multicenter studies of first-line imatinib treatment. The prognostic value of the EUTOS (European Treatment and Outcome Study for CML) score has now been tested in an independent, multicenter, multinational series of 1288 patients who were treated first-line with imatinib outside prospective studies. It was found that also in these patients, the EUTOS prognostic score was predictive for CCyR, PFS and overall survival (OS). In addition, the prognostic value of the score was reported to be significant in seven of the eight other independent studies of almost 2000 patients that were performed in Europe, the Americas and Asia. The EUTOS risk score is a valid tool for the prediction of the therapeutic effects of TKI, particularly imatinib.

Myeloproliferative disease associated with FGFR1 rearrangement (8p11), which is included in the 2008 WHO Classification of Myeloid Neoplasms, is a rare and extremely aggressive abnormality. The paper describes a clinical case of a 39-year-old female patient who was detected to have leukocytosis (as high as 47.2·109/l), absolute eosinophilia (as high as 3.1·109/l), and enlarged peripheral lymph nodes during her visit to a doctor. The bone marrow (BM) showed the changes typically encountered in myeloproliferative disease with eosinophilia. The patient was found to have t(8;13)(p11;q12) translocation associated with the rearrangement of the FGFR1 gene located at the 8p11 locus. Molecular and cytogenetic examinations failed to reveal BCR-ABL chimeric transcript, Jak2 V617F mutation, and deletions and translocations involving PDGFRA (4q12) and PDGFRB (5q32-33). The similar changes in the karyotype were also found in the lymph node cells. The undertaken treatment with hydroxyurea and the tyrosine kinase inhibitor dasatinib turned out to be ineffective. The patient underwent allogeneic BM transplantation from a HLA-identical sibling. Graft rejection occurred 6 months later. Allogeneic BM transplantation from the same donor (100% donor chimerism; FGFR1/8р11 translocation was not detected), which was complicated by the development of chronic graft-versus-host reaction, was performed again in March 2015. The patient is being followed up and continues to receive immunosuppressive therapy.Миелопролиферативное заболевание, ассоциированное с реаранжировкой гена FGFR1 (8р11), включенное в классификацию миелоидных новообразований ВОЗ, 2008 г., - редко встречающаяся патология, протекающая чрезвычайно агрессивно. Приведено клиническое наблюдение 39-летней пациентки, у которой при обращении к врачу выявлены лейкоцитоз (до 47,2·109/л), абсолютная эозинофилия (до 3,1·109/л), увеличение периферических лимфатических узлов. В костном мозге (КМ) наблюдались изменения, характерные для миелопролиферативного заболевания с эозинофилией. У больной выявлена транслокация t(8;13)(p11;q12), связанная с перестройкой гена FGFR1, расположенного в локусе 8p11. При молекулярном и цитогенетическом исследованиях химерный транскрипт BCR-ABL, мутация V617F гена Jak2, делеции и транслокации с вовлечением локусов генов PDGFRA (4q12) и PDGFRB (5q32-33) не обнаружены. Аналогичные изменения кариотипа выявлены и в клетках лимфатического узла. Предпринятое лечение больной гидроксимочевиной и ингибитором тирозинкиназ дазатинибом оказалось неэффективным. Выполнена трансплантация аллогенного КМ от сиблинга, совместимого по HLA. Спустя 6 мес произошло отторжение трансплантата. В марте 2015 г. проведена повторная аллотрансплантация КМ от того же донора (100% донорский химеризм, транслокация FGFR1/8р11 не выявляется), осложнившаяся развитием хронической реакции трансплантат против хозяина. Пациентка остается под наблюдением, продолжает получать иммуносупрессивную терапию.

The European Treatment and Outcome Study (EUTOS) population-based registry includes data of all adult patients newly diagnosed with Philadelphia chromosome-positive and/or BCR-ABL1+ chronic myeloid leukemia (CML) in 20 predefined countries and regions of Europe. Registration time ranged from 12 to 60 months between January 2008 and December 2013. Median age was 55 years and median observation time was 29 months. Eighty percent of patients were treated first line with imatinib, and 17% with a second-generation tyrosine kinase inhibitor, mostly according to European LeukemiaNet recommendations. After 12 months, complete cytogenetic remission (CCyR) and major molecular response (MMR) were achieved in 57% and 41% of patients, respectively. Patients with high EUTOS risk scores achieved CCyR and MMR significantly later than patients with low EUTOS risk. Probabilities of overall survival (OS) and progression-free survival for all patients at 12, 24 and 30 months was 97%, 94% and 92%, and 95%, 92% and 90%, respectively. The new EUTOS long-term survival score was validated: the OS of patients differed significantly between the three risk groups. The probability of dying in remission was 1% after 24 months. The current management of patients with tyrosine kinase inhibitors resulted in responses and outcomes in the range reported from clinical trials. These data from a large population-based, patient sample provide a solid benchmark for the evaluation of new treatment policies.

Eur J Clin Invest 2012; 42 (9): 1016–1026 Abstract Background Tyrosine kinase inhibitors (TKIs) have dramatically changed the treatment of chronic myeloid leukaemia (CML). Results from ongoing phase 3 trials with nilotinib [Efficacy and Safety in Clinical Trials—Newly Diagnosed Patients (ENESTnd)] and dasatinib [Dasatinib Versus Imatinib Study in Treatment-Naive CML-CP Patients (DASISION)] in newly diagnosed patients with CML in chronic phase have demonstrated that these TKIs resulted in significant improvements in responses vs. imatinib. Design The Developmental Therapeutics Consortium (DTC) systematically reviewed the published literature to provide a comparative analysis of the ENESTnd and DASISION trial designs and data reported on each study. Results The recent approval of nilotinib and dasatinib based on these two pivotal studies offers physicians the option to optimise frontline treatment based on a patient’s comorbidities, risk factors and tolerability profiles. Although nilotinib and dasatinib provide effective therapeutic options for the frontline treatment of CML, the lack of an evidenced-based, side-by-side comparison makes it difficult to directly compare these agents. Conclusions Despite potential bias from differences in patient populations and study design, indirect cross-trial comparisons to determine the relative effectiveness of these agents will be performed by physicians. This DTC report provides a comprehensive summary of the study designs, protocols and results of the ENESTnd and DASISION trials, which will assist physicians in making informed decisions on the best treatment approach for their patients.

Nilotinib has shown favorable safety in patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic (CML-CP) or accelerated phase (CML-AP) who failed prior imatinib, and superior efficacy over imatinib in newly diagnosed Ph+ patients with CML-CP. Reported here are the efficacy and safety data for patients in CML-AP (n = 181) or blast crisis (CML-BC) (n = 190; myeloid BC, 133; lymphoid BC, 50; unknown, seven) enrolled in an expanded access phase IIIb study. Non-hematologic adverse events were mostly mild to moderate. Drug-related myelosuppression was generally manageable with dose reductions or interruptions and infrequently led to discontinuation of nilotinib. Drug-related grade 3/4 elevations in serum bilirubin and lipase were infrequent. While an analysis of efficacy was not the primary objective of this study, significant hematologic and cytogenetic responses were observed. These results support the safety and efficacy of nilotinib in patients with advanced CML in AP and BC.

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: Nilotinib is a selective, potent BCR-ABL inhibitor. Previous studies demonstrated the efficacy and safety of nilotinib in Philadelphia chromosome-positive chronic myeloid leukemia patients in chronic phase (CML-CP) or accelerated phase who failed prior imatinib. METHODS: This expanded access trial further characterized the safety of nilotinib 400 mg twice daily in patients with CML-CP (N = 1422). RESULTS: In this large, heavily pretreated population, nilotinib demonstrated significant efficacy, with complete hematologic response and complete cytogenetic response achieved in 43% and 34% of patients, respectively. Responses were rapid, mostly occurring within 6 months, and were higher in patients with suboptimal response to imatinib, with 75% and 50% achieving major cytogenetic response and complete cytogenetic response, respectively. At 18 months, the progression-free survival rate was 80%. Most patients achieved planned dosing of 400 mg twice daily and maintained the dose >12 months. Nonhematologic adverse events (AEs) were mostly mild to moderate and included rash (28%), headache (25%), and nausea (17%). Grade 3 or 4 thrombocytopenia (22%), neutropenia (14%), and anemia (3%) were low and managed by dose reduction or brief interruption. Grade 3 or 4 elevations in serum bilirubin and lipase occurred in 4% and 7% of patients, respectively. The incidence of newly occurring AEs decreased over time. Of patients who experienced a dose reduction because of AEs and attempted a re-escalation, 87% successfully achieved re-escalation to the full dose. CONCLUSIONS: This large study confirms that nilotinib was well tolerated and that grade 3 or 4 AEs occurred infrequently and were manageable through transient dose interruptions. Cancer 2012;. © 2011 American Cancer Society.

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: 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.

7003Background: TFR is a new treatment goal in CML. In the ENESTop study (NCT01698905) in pts with CML-CP who sustained a deep molecular response with 2L nilotinib, 57.9% and 53.2% remained in TFR ...

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.

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.

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.

7054Background: The ENESTop (NCT01698905) study explores the discontinuation of NIL therapy in pts who achieved sustained MR4.5 (BCR-ABL1IS≤ 0.0032%) after switching from imatinib (IM) to NIL. Methods: The single-arm phase 2 study enrolled pts with CML-CP treated with tyrosine kinase inhibitor (TKI) for ≥ 3 y (including IM for > 4 wk followed by NIL for ≥ 2 y) and achieved MR4.5 on NIL. On study, pts continued NIL for 1 y (consolidation phase [CONS]). After 1 y, pts without confirmed loss of MR4.5 (consecutive BCR-ABL1IS > 0.0032%), were eligible to stop NIL (TFR). RQ-PCR was monitored every 12 wk in CONS and every 4 wk during first 48 wk of TFR. Upon confirmed loss of MR4 (consecutive BCR-ABL1IS > 0.01%) or loss of MMR (BCR-ABL1IS> 0.1%), NIL was re-initiated (ReRx). Primary endpoint was the proportion of pts with successful TFR (neither loss of MMR nor confirmed loss of MR4 by 48 wk of TFR) after a ≥ 48 wk follow up (data cutoff, 26 Nov 2015). Results: Of the 163 pts in CONS, 126 entered TFR (median dur...

Imatinib mesylate (imatinib) is a new generation preparation that is now successfully used for treatment of cancer, particularly for chemotherapy of chronic myeloid leukemia (CML). Imatinib inhibits the activity of chimeric kinase BCR-ABL, which is responsible for the development of CML. The goal of this study was to investigate the role of a multidrug resistance protein, P-glycoprotein (Pgp), in the evolution of CML treated with imatinib. We demonstrate here that although imatinib is a substrate for Pgp, cultured CML cells (strain K562/i-S9), overexpressing active Pgp, do not exhibit imatinib resistance. Studies of CML patients in the accelerated phase have shown variations in the number of Pgp-positive cells (Pgp+) among individual patients treated with imatinib. During treatment of patients with imatinib for 6-12 months, the number of Pgp-positive cells significantly increased in most patients. The high number of Pgp+ cells remained in patients at least for 4.5 years and correlated with active Rhodamine 123 (Rh123) efflux. Such correlation was not found in the group of imatinib-resistant patients examined 35-60 months after onset of imatinib therapy: cells from the imatinib-resistant patients exhibited efficient Rh123 efflux irrespectively of Pgp expression. We also compared the mode of Rh123 efflux by cells from CML patients who underwent imatinib treatment for 6-24 months and the responsiveness of patients to this therapy. There were significant differences in survival of patients depending on the absence or the presence of Rh123 efflux. In addition to Pgp, patients' cells expressed other transport proteins of the ABC family. Our data suggest that treatment with imatinib causes selection of leukemic stem cells characterized by expression of Pgp and other ABC transporters.

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: 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.

The described case of FIP1L1-PDGFRА-positive myeloproliferative disease is characterized by an atypical aggressive course to develop severe specific complications as injuries to the brain, heart, lung, and intestine. Pathogenetic therapy with imatinib could stabilize a patient's state, but failed to produce a complete hematological response. Switching from imatinib to dasatinib could produce sustained clinical, hematological, and molecular remissions.Представленный случай позитивного по FIP1L1-PDGFRA миелопролиферативного заболевания отличался нетипичным агрессивным течением с развитием тяжелых специфических осложнений в виде поражений головного мозга, сердца, легких, кишечника. Патогенетическая терапия иматинибом позволила стабилизировать состояние больной, но полный гематологический ответ не получен. После замены иматиниба дазатинибом достигнута стойкая клинико-гематологическая и молекулярная ремиссия.

Purpose To determine the maximum-tolerated dose (MTD), efficacy, safety, and pharmacokinetics of oblimersen sodium in patients with advanced chronic lymphocytic leukemia (CLL). Patients and Methods Eligible patients had relapsed or refractory CLL after treatment with fludarabine. Oblimersen was administered at doses ranging from 3 to 7 mg/kg/d as a 5-day continuous intravenous infusion in cycle 1 and as a 7-day continuous intravenous infusion in subsequent cycles every 3 weeks in stable or responding patients. Results Forty patients were enrolled and treated (14 patients in phase I and 26 patients in phase II). Dose-limiting reactions in phase I included hypotension and fever, and the MTD for phase II dosing was established at 3 mg/kg/d. Two (8%) of 26 assessable patients achieved a partial response. Other evidence of antitumor activity included ≥ 50% reduction in splenomegaly (seven of 17 patients; 41%), complete disappearance of hepatomegaly (two of seven patients; 29%), ≥ 50% reduction of lymphadenopathy (seven of 22 patients; 32%), and ≥ 50% reduction in circulating lymphocyte counts (11 of 22 patients; 50%). Adverse events included transient hypotension, fever, fatigue, night sweats, diarrhea, nausea, vomiting, hypokalemia, and cough. Plasma concentrations of oblimersen (parent drug) and its major metabolites were variable. Renal clearance represented only a small portion of total parent drug clearance. Conclusion Dosing with oblimersen sodium in patients with CLL is limited by development of a cytokine release syndrome that is characterized by fever, hypotension, and back pain. Oblimersen sodium has modest single-agent activity in heavily pretreated patients with advanced CLL, and further evaluation of its activity in combination with cytotoxic drugs is warranted.