ALBERT

Description: 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.

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

Description: Introduction: Early reduction of BCR-ABL transcript level has been associated with improved outcomes in CML treatment. Inability to achieve early molecular response(MR) at 3 months (M3〉10%) is considered a predictor factor for unfavourable outcome. However, the kinetics of BCR-ABL transcript level reduction measured at early time points have shown to be an independent predictor of response.The aim of this analysis was to determine whether the "M3-M6" status is critical to categorize CML patients (pts) focusing in high-risk group. Method: Molecular monitoring was performed in all pts prior treatment (M0), at months 3 (M3), 6 (M6), 12 (M12) and every 6 months thereafter, applying Q-PCR method according international recommendations. Results of BCR-ABL1 transcript level were reported on the international scale as IS-BCR-ABL %. Optimal responses: M3≤10%, M6≤1%, M12≤0,1%. Deep responses (MR4.0): ≤0,01% or undetectable/10.000 ABL copies. Results: A total of 70 CML pts were included, median age 49 (19-82), female 39%. First line treatment: sustained branded 81% and generic 19% TKIs. Imatinib 59%, Dasatinib and Nilotinib 41%. Sokal risk score: low (L) 51%, intermediate (In) and high (H) 49%. Optimal responses at molecular milestones: 75% at M3, 72% at M6, 61% at M12 and 53% pts achieved MR4.0. Event-free survival (EFS) was evaluated according to time point M3: M3≤10% group had significantly better EFS compared with the M3〉10% (96% vs 70%; P=0.028). M3-M6 status defined 4 groups of pts: M3≤10%-M6≤1%, M3≤10%-M6〉1%, M3〉10%-M6≤1%, M3〉10%-M6〉1%. Molecular response evolution by M3-M6 status is described in Table 1. EFS stratified by groups according to combined M3-M6 responses showed significant differences: 92% for group 1, 87% for group 2, 68% for group 3, 54% for group 4. (P=0.002). M6 time point was shown to be critical in 32 high-risk pts (H+In): 17 pts with M6 ≤1% showed significant differences in MR4.0 achievement compared to 15 pts with M6 〉1% (82% vs 27% P=0.02). Better EFS was observed in this high-risk group under branded vs generic TKIs treatment (97% vs 54% P=0.04). Statistical differences in deep responses and MMR at M12 were observed between branded and generic TKIs independently of Sokal risk (P=0.06, P=0.02). Conclusions: M3≤10% pts showed a favourable evolution with better EFS than M3〉10% group. However not all patients with M31%. In pts with M3 〉10% and optimal response at M6 also showed higher MR4.0 rate. Our study supports that M6 is a crucial endpoint to predict MMR at M12 and deep responses in CML pts.Pts with M3≤10% without optimal response at M6 (〉1%) had a worse evolution than those slow responders who showed M3〉10% and M6≤1%.High-risk pts are still a challenge, observing better outcomes in those under branded TKIs treatment. The M3-M6 status would be a prognostic marker of responses and EFS in chronic phase CML pts treated with TKIs. Our data support the critical role of M6 response in non-optimal M3〉10% pts and intermediate and high risk Sokal score. Treatment adherence is mandatory for achieving and sustaining optimal responses. This multicentric Argentine study, reinforces the importance of clinical follow-up and molecular monitoring under IS standardization at early time points. Education on early molecular monitoring with adequate resources must continue to be an objective in our region. Table 1 Table 1. Disclosures Pavlovsky: Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau. Moiraghi:Novartis: Speakers Bureau; Bristol: Speakers Bureau. Varela:Novartis: Speakers Bureau; Bristol: Speakers Bureau. Enrico:Novartis: Honoraria, Patents & Royalties; Bristol Myers squib: Speakers Bureau. Brodsky:International PNH Registry: Other: -; Alexion Pharma Argentina: Speakers Bureau. Pavlovsky:Novartis: Speakers Bureau; Janssen: Speakers Bureau; Bristol Myers Squib: Speakers Bureau.

Description: BCR-ABL transcript levels (IS%BCR-ABL) in CML patients (pts) allow to define molecular response (MR) to TKIs. MR at 3 months (M3〉10%) is the strongest predictor of bad outcome and a point of divergence for changing therapy. Emerging biomarkers are being proposed in order to optimize prognosis in addition to initial MR and other clinical markers. The rate of BCR-ABL decline measured as halving time (HT) for transcript level reduction (RT0.5) at month 3 in 1GTKI (imatinib) treated pts, and the fractional clearance as a relative BCR-ABL ratio (RR3) during the first 3 months in 2GTKI (dasatinib) treated pts were recently proposed as predictive markers of outcome. Optimal responses (OR) were defined upon %ISBCR-ABL values at 3, 6 and 12 months: M3 ≤10%, M6 ≤1% y M12 ≤0,1%. Early time point prognostication could allow better outcome predictions and rapid therapeutic interventions. Aim: to determine whether the rate of BCR-ABL decline as HT and the BCR-ABL transcripts reduction as relative ratio at M3 from baseline, have predictive value in CML pts treated with 2GTKIs. Method: BCR-ABL transcript level was measured by Q-PCR according international recommendations and results were reported as BCR-ABL/ABL on the international scale (IS BCR-ABL %). Molecular monitoring was performed prior treatment (M0) and at months 3 (M3), 6 (M6), 12 (M12) and every 6 months thereafter. RT0.5 from baseline to M3 was calculated as the time to halve by considering an exponential model of reduction during the period. The median RT0.5 and quartiles, were calculated to define rapid declines as those HT in the lowest quartile. RR3 was determined as a relative ratio of transcript clearance at M3 from baseline. The median RR3and quartiles, were considered to define high BCR-ABL clearance as those in the highest quartile. Fisher statistical test was used to determine whether the proportions of good responses were statistically different depending on the decline rate. Results: A total of 77 CML pts were included, first line treatment: Dasatinib (D) 28%, Nilotinib (N) 32% and Imatinib (I) 40%. Sokal risk score was available in 70% pts: low (L) 67%, intermediate (In) 22% and high (H) 11%. Molecular assessment: prior therapy M0 (90%), M3 (60%), M6 (79%), M12 (78%) and M0+M3+M12(39%). Deep responses (MR4.0) were considered as IS%BCR-ABL0,1% and without MR4.0. All of these pts showed RT0.5 〉13d and RR3

Description: Background: Since the introduction of Imatinib (IM), the treatment of chronic myeloid leukemia (CML) experienced its most important change. As this drug became the first line for the treatment of CML, we learned that under-dosing was associated with a delay in achieving cytogenetic response and the development of acquired resistance. Last year we presented a case-control study that analyzed how compliance affects the cytogenetic response to Imatinib. This is an update of that data. Materials and Methods: Twenty-four patients with newly diagnosed Ph (+) chronic phase CML (CP-CML) were included and followed for 24 months. Patients received 400mg of IM and were asked to note down all taken doses, and reasons for non-compliance. Follow up visits were scheduled every 28–30 days and prescriptions were filled in order to last for only 30 days. During each visit, the medication was counted and non-adherence reasons were determined. Adverse events were graded according to the CTC and modifications in the Imatinib dose were only allowed with related adverse events with a CTC score ≥3. As a control group, we matched each case with a Phi + CP-CML patient from our data base of the same sex and similar age as the case patient. All control patients had to have complete information about dosing and response. They all received initial treatment with IM 400mg; thereafter, dose was adjusted according to each physician’s criteria. Compliance was measured as: mg prescribed/mg taken during the study period. Results: Twenty-four patients, 14 males median age 56 yo (range: 24–83), were included in the study. Three were lost to follow up, leaving only twenty-one for analysis of compliance. At the end of the first year, all patients had complete hematological response. Compliance during these 12 months was 96.1, which is clearly superior to the 80% reported in the setting of clinical trials. All patients had a complete hematological response, 89.9 achieved a major cytogenetic response (MCyR) and 87.4 a complete cytogenetic response (CCyR), compared to 60 of the control group with a MCyR (p=0.027) and 57.8 a CCyR (p=0.025). During the second year, four patients lost CCyR, three responded to an increase in IM dose and one progressed to an accelerated phase and died. Compliance fell slightly during this period to 90.86% which was reflected in 81.66% CCyR, which was still statistically higher than the 54% of major responses in the control group (p=0.033). In both groups, none of the patients not achieving MCyR at 12 months achieved MCyR at 24 months. Hematological toxicity was more frequently observed within the first 6 months of treatment and after the increase in dosage. Severity and incidence of adverse events were similar in both groups, and were the main reasons for interruption or reduction of IM dose in the control group. The only additional difference besides compliance between the two groups was the average IM dose prescribed during the duration of the study (cases group: 430mg – control group: 330mg). Conclusions: Adherence to Imatinib is associated with an improvement in cytogenetic response that can be seen even at two years after the start of therapy. Since outcome and development of resistance seem to be associated with compliance to therapy, emphasis should be put on maintaining treatment at an adequate dose for as long as possible.

Description: INTRODUCTION: Ponatinib is a potent TKI indicated in T315I mutated CML and not mutated CML resistant to other drugs. Deep responses were reported in PACE trial in patients who had failed all other TKIs in chronic and advanced phase CML with acceptable toxicity profile. Ponatinib use is authorized in United States and Europe but compassionate use allows access in Argentina with no previous reports of local results. OBJECTIVE: To analyze a cohort of CML resistant patients treated with ponatinib: clinical characteristics, outcome and adverse events. MATERIALS AND METHDOS: Retrospective, multicentric, observational, descriptive study. Data was collected from charts review of patients with resistant CML treated with ponatinib at 8 different centers. Mutational status was reported. Frequency of Complete Hematologic Response (CHR), Complete Cytogenetic Response (CCgR) and Major Molecular Response (MMR) at 3, 6 and 12 months, adverse events and death were analyzed. RESULTS Twenty three patients were included with median follow-up from CML diagnosis 119 months (m) (IQR: 12-215) and 6 m (IQR: 2-21) from ponatinib first dose. Median age at CML diagnosis was 41 year-old (5-61). At the moment of ponatinib first dose 74% (17/23) patients were in chronic phase (CP), 13% (3/23) in accelerated phase and (AP) and 13% (3/23) in blast crisis (BC). Ponatinib was indicated as second line treatment in 4% (1/23), third line treatment in 9% (2/23), fourth line 83% (19/23) and fifth line 4% (1/23). Mutations were detected in 83% (19/23) patients with presence of T315I mutation in 44% (10/23). Median time from mutation detection to ponatinib start was 6 m (1-12). Ponatinib dose was 45 mg/d in 48% (11/23) and 55% (6/11) of these patients required dose reduction, 52% (12/23) received 30mg/d. Treatment have been discontinued in 8% (2/23) due to safety reasons. All patients in CP with evaluable response achieved CHR with median time to CHR of 1m, 27% (3/11) achieved CCgR, and 18% (2/11) obtained MMR by 3 m y 6 m, and 37% (3/8) by 12 m. Of patients in AP/BC 83% (5/6) achieved no molecular response and only 1patient have received ponatinib associated with standard chemotherapy, obtained MR4.5 and underwent unrelated bone marrow transplantation and is alive --- months after BC T315I mutated CML. Disease progression occurred in 6% (1/17). Death occurred in 4/23 (17%) all advanced phase at start of ponatinib. Adverse events are reported in table 1:Table 1.ADVERSE EVENTINCIDENCETOXICITY GRADEHematologic21% (5/23)1-2- 3Dermatologic13% (3/23)1-2-3Hypertension9% (2/23)2- 3Mialgia4% (1/23)3Palpitations4% (1/23)2Hipertriglyceridemia4% (1/23)4Hepatotoxicity4% (1/23)2Disnea4% (1/23)3Arterial Thrombosis4% (1/23)4Grade 4 toxicities occurred in 2 patients receiving 30 mg/d. Arterial thrombosis was the cause of death of one patient and cardiac toxicity mandated drug interruption in another. CONCLUSION: This is the first report of ponatinib use in daily practice in Argentina.Response rates are lower than those reported in the literature. Drug was safe with low discontinuation rates although severe cardiac toxicity occurred as reported. Time to first dose in Argentina may be a relevant factor to explain the lower rates of response in patients who have failed other ITKs. Disclosures Varela: Bristol Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Enrico:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Pavlovsky:Novartis: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau. Bengio:Bristol Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Pavlovsky:Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Moiraghi:Bristol Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau.

Description: Chronic myeloid leukemia (CML) is specifically associated with the t(9;22)(q34;q11) reciprocal translocation giving rise to the Philadelphia chromosome and the subsequent formation of the BCR/ABL1 fusion gene, encoding a constitutively active tyrosine kinase. Advances in targeted therapies in chronic phase CML, notably the use of tyrosine kinase inhibitors (TKIs) such as imatinib mesylate (IM), have achieved successful treatment outcomes. However, some patients fail to achieve optimal response, and a substantial proportion of patients develop resistance to IM, which is frequently associated with mutations in the ABL kinase domain. Although BCR/ABL1 fusion oncogene is a key molecular marker involved in the pathogenesis and the clinical course of CML, molecular or cellular events that initiate leukemogenesis or drive translocation of the BCR/ABL1 genes are incompletely understood and little is known about individual susceptibility to this disease. Moreover, it is still unclear whether BCR/ABL1 oncoprotein alone is sufficient to explain the full range of clinical responses to ITKs. There is mounting evidence that genetic factors may play an important role in susceptibility to CML and variability in drug responsiveness. Polymorphic variants of several genes are linked to variations in expression, function, drug disposition and drug response and are potential factors accounting for susceptibility to complex diseases or drug resistance as they can uniquely influence the quality and quantity of gene product. Association studies have been performed to identify genetic variants associated with CML susceptibility and progression, but data are lacking for Argentina. In the present study, we determined the distribution of polymorphisms on TP53 tumor suppressor gene, drug transporter (ABCB1) and drug-metabolizing (glutathione-S-transferases, GSTs) genes to identify markers of susceptibility and pharmacogenetic response in Argentinian patients with CML. Genomic DNA samples from peripheral blood of 141 patients (69 females/72 males, median age 50.8 ± 1.3 years,) treated with IM and 141 age and sex matched healthy controls were evaluated. IM therapy failure was defined by cytogenetics and qRT-PCR in 2 consecutive studies, finding 76 cases that fail treatment. All individuals provided their informed consent according to institutional guidelines and the study was approved by the Ethics Committee of our Institution. GSTM1 and GSTT1 gene deletion polymorphisms and single nucleotide polymorphisms (SNPs) in GSTP1 (313A〉 G), TP53 (215C〉 G) and ABCB1 (3435C〉 T, 1236 C〉 T and 2677G〉T/A) were determined using PCR-based methods. BCR/ABL1 transcript level was analyzed using RT-PCR and ABL1 mutations were identified by RT-PCR and sequencing. Comparison of genotypes between patients and controls as well as regarding clinical parameters was performed by logistic regression. The Kaplan-Meier curves were analyzed using the log-rank test. The level of significance was p