ALBERT

Description: Objectives To analyze the molecular response during the first trimester of nilotinib therapy in newly diagnosed CML-CP patients. Hypothesis The values of BCR-ABL ratios during the first trimester of nilotinib treatment, and the kinetic of their descent, could be predictive of molecular response thereafter. Patients ENEST1st (NCT01061177) is an open-label study of nilotinib 300 mg twice daily in adults with newly diagnosed BCR-ABL+ CML-CP. Imatinib pretreatment was not allowed. Methods BCR-ABLIS and BCR-ABL/GUS ratios were measured previously to nilotinib, and fortnightly thereafter until the 3rd month (m), and at 6, 12 and 18 m. Sokal, Euro and Eutos scores were calculated with data at diagnosis. BCR-ABL values were centrally measured in an ELN-EUTOS certified laboratory. Molecular response was classified by ELN2013 recommendations. As the linearity of values of BCR-ABL using ABL as control is questionable, when ratios are higher than 10%, only baseline BCR-ABL/GUS ratios were used when analyzing the molecular response using GUS as control. The kinetic of the descent was calculated using the ratio of a given time compared with that of an earlier time, and measuring slopes. Logistic regressions and ROC analysis have been used, calculating positive and negative predictive values (PPV and NPV) Results 61 patients were included. 1 patient was excluded of the analysis because of lack of molecular data (baseline). Out of 60 patients, 10 abandoned during the first 18 m because of AE’ s. Those patients have been classified as non-responders after the time they went off-study. Risk distribution: Sokal (L, I, H): 57%, 32%, 11.7% Euro: 52%, 45%, 3%) Eutos (L, H): 92%, 8%). Outcomes and Molecular response: No patient died or transformed during the follow-up. MR4.5 at 18 M has been obtained in 30% of the patients. The ELN 2013 molecular milestones for optimal response at 3,6,12 and thereafter were obtained in 97%, 93%, 83%, and 70%, respectively.(Table) Predictive variables of response: (Table). Major molecular response (²0.1%) (BCR-ABL/ABL, BCR-ABL/GUS). At 3MBaseline BCR-ABL/GUS ratios were significantly different between responders and non-responders (22,1±23,1 vs 41,5± 38,1, p=0.05). For both control genes, the multivariate analysis disclosed that the independent and significant variable was the ratio at 45d. The ROC analysis disclosed a cut-off of 3.28 (PPV: 83% NPV: 80%). [OR: 20(4.4- 90) p

Description: Abstract 991 Smoldering Multiple Myeloma (SMM) is an asymptomatic proliferative disorder of plasma cells (PCs) defined by a serum monoclonal component (MC) of 30 g/L or higher and/or 10% or more plasma cells in the bone marrow (BM). There are several risk factors predicting high-risk of progression to symptomatic disease: 〉10% of PCs in BM, serum MC 〉30g/L, 〉95% aberrant PCs by immunophenotyping, or abnormal free-light chains. Standard of care of SMM is no treatment until progression disease. In this phase III trial, SMM patients at high-risk of progression were randomized to receive Len-dex as induction followed by Len alone as maintenance vs no treatment in order to evaluate whether the early treatment prolongs the time to progression (TTP) to symptomatic disease. The high-risk population was defined by the presence of both 〉PC 10% and MC 〉30g/L or if only one criterion was present, patients must have a proportion of aberrant PCs within the total PCsBM compartment by immunophenotyping of 95% plus immunoparesis. Len-dex arm received an induction treatment consisting on nine four-weeks cycles of lenalidomide at dose of 25 mg daily on days 1–21 plus dexamethasone at dose of 20 mg daily on days 1–4 and 12–15 (total dose: 160mg), followed by maintenance until progression disease with Lenalidomide at dose of 10 mg on days 1–21 every two months (amended in May 2010 into monthly). The 124 planned patients were already recruited, and 118 were evaluable (six patients didn't meet inclusion criteria). According to baseline characteristics, both groups were well balanced. On an ITT analysis (n=57), based on IMWG criteria, the overall response rate during induction therapy was 81%, including 56% PR, 11% VGPR, 7% CR and 7% sCR. 51 patients have completed the nine induction cycles, and the ORR was 87%, including 12% VGPR, 8% CR and 8% sCR. After a median of 7 cycles of maintenance therapy (1-21), the sCR increased to 12%. After a median follow-up of 22 months (range: 5–42), six patients progressed to symptomatic disease in the Len-dex arm: four of them during maintenance therapy and the other two progressed 3 and 8 months after early discontinuation of the trial due to personal reasons. In addition, twelve patients have developed biological progression during maintenance, and dex was added according to the protocol. In nine of them, the addition of dex was able to control again the disease without CRAB symptoms (median of 11 months). In the therapeutic abstention arm, 28 out of 61 patients (46%) progressed to active MM. The estimated hazard ratio was 6·2 (95%CI= 2·6-15), corresponding to a median TTP from inclusion of 25 months for the not treatment arm vs median not reached in the treatment arm (p

Description: Introduction: Over half of patients with chronic myeloid leukemia (CML) in sustained deep molecular remission do not lose the major molecular response (MMR) after stopping treatment with tyrosine kinase inhibitors (TKI). This strategy is safe in controlled clinical trials, but there is scarce information on its applicability in the real-life setting. We aimed to assess if treatment cessation was feasible in clinical practice in a large nationwide series of CML patients from Spain. Methods: This retrospective study comprised a series of 236 patients in chronic-phase CML who discontinued TKI treatment outside of clinical trials between April 2009 and February 2018 in 33 Spanish institutions. Inclusion criteria were: a) TKI treatment duration 〉3 years; b) sustained MR4.5 in 〉4 consecutive determinations (one single point in MR4 was acceptable) during 〉2 years; c) molecular monitoring in a reference laboratory expressing the results on the International Scale (IS). Patients who had undergone allogeneic hematopoietic stem-cell transplantation were excluded. Molecular relapse was defined as consecutively detectable BCR-ABL1 transcripts showing a ≥1 log increase or loss of MMR in any single sample. Treatment-free remission (TFR) was estimated by the method of Kaplan-Meier and defined as the time from TKI discontinuation to the date of restarting therapy for any reason or, if treatment was not restarted, the date of last contact. Incidence of molecular relapse was calculated using the cumulative incidence function with resumption of TKI treatment in the absence of molecular relapse and death in MMR as competing events. Analysis of factors predicting molecular relapse was done by the method of Fine and Gray. Results: Table 1 shows the main characteristics of the series. Median follow-up from treatment discontinuation was 21.5 months, and 5 patients died in MMR due to CML unrelated causes. TKI therapy was reinitiated due to molecular relapse (MMR loss: n=52, increase 〉1 log in BCR-ABL transcript level at two consecutive assessments without losing MMR: n=12), patient preference (n=2), and severe withdrawal syndrome (n=1). One additional patient lost MMR after 20 months from treatment cessation but decided not to be retreated, with spontaneous recovery of MMR. The probability of TFR at 4 years was 64% (95% Confidence Interval [CI]: 55%-72%)(Figure 1). The cumulative incidence of molecular recurrence was 33% (95% CI: 26%-38%) at 3 years (Figure 2). Forty-nine relapses (75% of total) occurred in the first 6 months. The latest MMR loss was detected 30 months after treatment stop. One patient restarted treatment 44 months after TKI discontinuation due to ≥1 log increase in BCR-ABL1 transcripts in two consecutive samples without losing MMR. In univariate analysis, duration of TKI treatment of less than 5 years (P=0.005) and time in RM4.5 shorter than 4 years before TKI discontinuation (P=0.003) were both significantly associated with a higher incidence of molecular recurrence. No patient progressed to the advanced phases of CML. At the time of restarting treatment, the median BCR-ABL1 IS was 0.3%, with this value being 〉5% in only 7 instances. Most patients (81%) received the same TKI that they were taking before the trial of treatment cessation. Median follow-up after treatment resumption was 20 months. Among the 64 patients who restarted treatment due to molecular relapse, 46 of 52 cases regained MMR after a median time of 3 months, and 47 of 64 regained MR4.5 after a median time of 5 months. Response status at last control was: MR4.5 (n=196), MR4 (n=15), MMR (n=14), complete cytogenetic response (n=10), and other (n=1). Fifty-one patients (22%) developed musculoskeletal or joint pain after treatment cessation. In patients stopping imatinib, a significant increase in Hb levels, leukocyte counts, total lymphocyte counts, platelet counts, and cholesterol levels was observed. At 6 months, an increase in Hb level 〉2 g/dL was observed in 47% of patients with anemia. By contrast, nilotinib discontinuation was not followed by any relevant change in laboratory values. Conclusions: Our results confirm that treatment discontinuation is feasible and safe in clinical practice in Spain. Duration of TKI treatment of less than 5 years and a time in RM4.5 shorter than 4 years before TKI discontinuation were significantly associated with a higher incidence of molecular recurrence. Disclosures Hernandez Boluda: Incyte: Consultancy; Novartis: Consultancy. García Gutiérrez:Incyte: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Ferrer Marin:Incyte: Consultancy; Novartis: Consultancy, Research Funding. Cervantes:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hospital Clinic Barcelona: Employment.

Description: Abstract 1121 Poster Board I-143 The Spanish Registry on CML ( RELMC ) is a multicentric, hospital-based cancer registry whose aim is to describe what is the actual treatment received by patients with CML in Spain, its outcome, and the variables which influence it. Aim To study the variables which could influence the outcome in newly diagnosed CML patients treated with Imatinib, including classic and new variables, such as phosphate serum levels, which are diminished in a substantial number of patients ( Osorio et al,2007) Patients 207 CP-CML patients, newly diagnosed, were included in 17 Spanish hospitals. Sex: 131 M,76F( 63%,37%). Age: Median: 51,5 (18,7-87,5).The risk group distribution was as follows: Sokal L/I/H: ((47%;35%;18%). Hasford ( 44%,49%,7%). The variables studied at diagnosis were sex, Sokal and Hasford group. During the treatment: dose of Imatinib, anemia, neutropenia, thrombocytopenia and hypophosphatemia. Results Median follow up of the series have been 19,1 months. Among 207 patients, frequency values for anemia, neutropenia, and thrombocytopenia were 21%, 29% and 11%, respectively. Ninety-one patients had serum phosphate measured during the treatment. Among them, 49(54%) had hypophosphatemia. Complete hematologic response ( CHR) was obtained in 94,6%.No significant association was found between Sokal or Hasford group and the achievement of complete HR. Complete cytogenetic response (CCR ) was obtained in 73%. A significant association was found between obtaining CCR and Low or intermediate Hasford group (p=0,013) or having hypophosphatemia during the treatment ( p=0,04). The probability of obtaining CCR was higher in patients having hypophosphatemia in the 9th month of therapy (Log Rank (Mantel-Cox) Chi2: 6,21 (p=0,013).Patients who had hypophosphatemia during the treatment also showed a trend for higher probability of CCR (p=0,096). Major and complete molecular response (MMR, CMR) were obtained in 71% and 48%, respectively. MMR was significant worse in Hasford high-risk patients (Pearson Chi-Square:6,909 (p=0,009), and the probability of MMR was higher in patients developing hypophosphatemia ( p=0,175). Regarding CMR, Hasford high risk had a significant association with worse rate of CMR (Chi-Square: 4,419; p=0,036. Also, the probability of CMR was significantly higher in patients having hypophosphatemia ( p=0,045). Conclusion In our series, Hasford risk system has a stronger predictive value than the Sokal classification. It is interesting to note that half of our patients had hypophosphatemia during the treatment with Imatinib. Intriguingly, having low serum levels of phosphate during treatment is associated with better response, and it invites to further study of the biological basis of this finding and its relevance as prognostic variable. This study has received the grant PI07/91015 from the Instituto de Salud Carlos III. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 1935 Smoldering Multiple Myeloma (SMM) is an asymptomatic proliferative disorder of plasma cells (PCs) defined by a serum monoclonal component (MC) of 30 g/L or higher and/or 10% or more plasma cells in the bone marrow (BM), but no evidence of end-organ damage. There are several risk factors predicting high-risk of progression to symptomatic disease (〉50% at 2 years): 〉10% of PCs in BM, serum MC 〉30g/L, 〉95% aberrant PCs by immunophenotyping, or abnormal free-light chains. Standard of care of SMM is close follow-up without treatment until progression disease. Several trials have evaluated the role of early treatment with convencional agents (melphalan), bisphosphonates and novel agents (thalidomide, anti-IL1a), with no clear benefit, but they didn't focus on high-risk patients. In this phase III trial, SMM patients at high-risk of progression were randomized to receive Len-dex as induction followed by Len alone as maintenance vs no treatment in order to evaluate whether the early treatment prolongs the time to progresión (TTP) to symptomatic disease. The high risk population was defined by the presence of both 〉PC 10% and MC 〉30g/L or if only one criterion was present, patients must have a proportion of aberrants PCs within the total PCsBM compartment by immunophenotyping of 95% plus immunoparesis. Len-dex arm received an induction treatment consisting on nine four-weeks cycles of lenalidomide at dose of 25 mg daily on days 1–21 plus dexamethasone at dose of 20 mg daily on days 1–4 and 12–15 (total dose: 160mg), followed by maintenance until progression disease with Lenalidomide at dose of 10 mg on days 1–21 every two months (ammended in May 2010 into monthly). The 124 planned patients were recruited between October 2006 and June 2010, and 118 were evaluables (three in Len-dex and three in therapeutic abstention arm didn't meet inclusion criteria). This second interim analysis was planned when all patients were recruited. According to baseline characteristics, both groups were well balanced. On an ITT analysis (n=57), based on IMWG criteria, the overall response rate during induction therapy was 75%, including 51% PR, 12% VGPR, 5% CR and 7% sCR. If we select the group of 33 patients who completed the nine induction cycles, the ORR was 91%, including 15% VGPR, 9% CR and 9% sCR. After a median of 8 cycles of maintenance therapy (1-15), the sCR increased to 16%. After a median follow-up of 16 months (range:1-33), four patients progressed to symptomatic disease in the Len-dex arm: two of them during maintenance therapy after 24 and 28 months from inclusion and the other two progressed 3 and 8 months after early discontinuation of the trial due to personal reasons. In addition, nine patients have developed biological progression during maintenance, but in all but one of these, Len has been able to control the disease without CRAB symptoms (median of 9·5 months (1-18)). In the therapeutic abstention arm, 21 out of 61 patients progressed to active MM. The estimated hazard ratio was 6·7 (95%CI= 2·3-19·9), corresponding to a median TTP from inclusion of 25 months for the not treatment arm vs median not reached in the treatment arm (p

Description: Abstract 1237 Background: The RELMC is a multicentric, 17-hospitals-based cancer registry whose aim is to describe the treatments received by patients with CML, their outcomes, and the variables that influence treatment choices. Aim: To study the response and survival outcomes, in newly diagnosed CML patients treated with Imatinib (Im) as first line treatment. Patients and methods: 249 newly diagnosed CML patients have been included. They are distributed in the following subgroups according to treatments received Im400. 166 patients received only Im400. Result: A summary of response and outcome is included in Table 1. Complete cytogenetic response with regards to the best response, the CCyR rate was lower in patients with Im400-HDIm-2GTKI (60%) and Im400-2GTKI (62%). The rates were 84% in Im400, 83% in Im400-HDIm and 85% in HDIm; P Chi2 8,381(a) p=0,079. The CCyR cumulative incidence was also lower in patients with Im400-HDIm-2GTKI and Im400-2GTKI in comparison to the other groups, although second line response was faster in patients who changed to 2GTKI after Im400. The frequency of CCyR as best response in the Hasford high risk patients was low in all groups (66%,50%,50%,50&55%). Major molecular response MMR as best response was lower in patients with Im400-HDIm-2GTKI (50%) and Im400-2GTKI (47%). The rates were 83%, 81% and 77% in the Im400, Im400-HDIm and HDIm groups respectively; P Chi2 19,4(a)p=0,001. The MMR cumulative incidence was higher in the HDIm group, lower in those treated with Im400-HDIm-2GTKI, and intermediate and similar in the other three groups. MMR as best response in the Hasford high risk patients was also low in all groups (60%, 75%, 50%, 50% & 33%). Complete molecular response regarding best response, the CMR rate was lower in patients with Im400-HDIm-2GTKI (37,5%), Im400-2GTKI (31,6%) and Im400-HDIm (34%). In the other groups, the rate was 48% (Im400), and 72% (HDIm); P Chi2 17,4(a) p=0,002. The CMR cumulative incidence was higher in the HDIm group, and nil in those treated with Im400-HDIm-2GTKI. Salvage therapy after suboptimal response (SR) or Failure (F). Two-thirds of patients with SR or F were able to obtain an optimal response and avoid transformation with a timely therapy change. All but one of the options (Im400-HDIm-2GTKI group) were similarly effective. Survival: 6 patients progressed (2,4%) (4 AP, 2 BC), and died; 6 patients changed to allo BMT and were censored; 6 patients died of non-CML related causes. Conclusion: Disclosures: Palomera: Janssen Cilag: Honoraria. Steegmann:Bristol-Myers Squibb: Honoraria, Participated in advisory boards, Research Funding; Novartis: Participated in advisory boards, Research Funding.

Description: Background: Cytarabine (Ara C) is considered the most effective chemotherapeutic agent in acute myeloid leukemia (AML) treatment. Several studies suggest that single nucleotide polymorphisms (SNPs) within the genes involving metabolic pathway of Ara C could influence in treatment outcomes, although their clinical relevance remains undetermined. Methods: The SNPs of cytarabine pathway (DCK: rs2306744, rs11544786, rs4694362; CDA: rs2072671, rs3215400, rs532545, rs602950; NT5C2: rs11598702; RRM1: rs9937; NME1: rs2302254) were evaluated in 225 adult patients at initial diagnosis from AML using a mass spectrometry-based multiplex genotyping assay (Sequenom®). All patients received induction chemotherapy consisting of idarubicin plus cytarabine (PETHEMA 99, 2007 and 2010 trials). Efficacy of first induction cycle was evaluated comparing complete remission (CR) vs. partial remission (PR) or resistance (patients dying during induction excluded); and overall survival (OS). Induction death was defined as patients dying during induction against CR, excluding these patients with PR or resistance. Based on WHO grading scale, toxicities were grouped as binary variables (grades 0-1 vs. 2-4; or 0 vs. 1-4), assigning the maximum grade of all the specific toxicities within that group (evaluated in all patients). Genotypes were studied with co-dominant model. Association between variables was assessed using linear and logistic regression adjusting for age, gender, cytogenetic risk, ECOG, leukocyte and platelet count, hemoglobin, creatinine, bilirubin, albumin and LDH level at diagnosis (R® version 3.1.2). Kaplan-Meier method and Cox proportional were employed to OS estimates with the same covariates. Results: The median age of patients was 51.1 years (16-78 years). The variant allele of DCK SNP rs2306744, enzyme that catalyzes the limiting first phosphorylation in activation of Ara C, showed higher CR (OR:6.3; 95%CI 1.3-31.1; P=0.024), as well as higher mucositis (OR:3.3; 95%CI 1.1-10.0; P=0.038). CDA is the main inactivating enzyme of Ara C. The variant allele of rs602950 was related to higher CR (OR:3.0; 95%CI 1.02-8.8; P=0.045) and OS at 5 years (HR:0.4; 95%CI 0.2-0.9; P=0.012; Figure 1) and the variant homozygous of rs2072671 to higher OS at 5 years (HR:0.3; 95%CI 0.1-0.96; P=0.018; Figure 2), whereas the wild-type allele of rs532545 was associated to higher OS at 3 years (HR:1.5; 95%CI 1.01-2.4; P=0.039; Figure 3). In addition, variant alleles of rs532545 and rs602950 were related to skin toxicity (OR:2.2; 95%IC 1.1-4.3; P=0.033; OR:2.1; 95%IC 1.01-4.5; P=0.047, respectively). Variant allele of RRM1 (rs9937), enzyme directly associated with Ara C sensitivity, was associated to induction death (OR:0.2; 95%IC 0.03-0.9, P= 0.034). Variant allele of NT5C2 (rs11598702), responsible of nucleotide pools balance, showed higher hepatotoxicity (OR: 4.1; 95%IC 1.1-14.5; P=0.032). Conclusions: This study reveals the influence in Ara C efficacy of DCK and CDA polymorphisms in AML adult patients, previously suggested in other studies. In addition, novel associations between SNPs in metabolic Ara C genes and toxicities were detected. Further studies with larger population are needed to validate these associations. Figure 1 Figure 1. Figure 3 Figure 3. Figure 2 Figure 2. Disclosures Boluda: Instituto de Investigación Sanitaria La Fe: Employment.

Description: BACKGROUND: Despite the excellent prognostic of chronic myeloid leukemia (CML) patients since the introduction of tyrosine kinase inhibitors (TKIs), approximately 50% of patients that are treated with TKIs will discontinue first line treatment due to lack of efficacy or intolerance. Once patients need a second line treatment, a considerable proportion of patients will need third or even fourth line therapy during further evolution. At this moment, there is a lack of data about real benefit of this group of patients. We have recently published our experience of 30 CML patients treated with bosutinib in 4th line. We present an update of the study where we have increased the number of patients, and the follow-up. The aim of this study is to present safety and efficacy data CML chronic phase patients treated with bosutinib in 4th line. METHODS: We have collected data from 59 CML patients treated with bosutinib in 4th line after resistance or intolerance to IM, NI and DA. 51 patients have been treated under the Spanish compassionate use program (36 centers) and 10 patients were treated in a single institution from United Kingdom. Median age of patients at diagnosis was 53 years. The percentage of low, intermediate and high risk Sokal groups were 47%, 37% and 16%. Median time TKIs exposure before bosutinib was 9 years. The most common indication (30/59) was intolerant to DA and NI. Patients' dispositions and main line characteristics are shown in table 1. RESULTS: Median follow-up was 14.3 months. All patients started bosutinib at 500mg/d, median dose of was 450mg/d. Overall probabilities to either achieve or maintain previous response were 96% (57/59), 62% (37/59), 40% (24/59) and 17% (10/59) for complete hematological response (CHR), complete cytogenetic response (CCyR), major molecular response (MMR) and MR4.5 respectively. However, probabilities to obtain responses (in patients without response evaluated at baseline) were 27% (7/26), 26% (12/45) and 12% (7/55) for CCyR, MMR and MR4.5. As expected, probabilities to obtain CCyR were lower for patients resistant to DA and NI patients than for patients intolerant to DA and NI (8% VS 44%). Event free survival (EFS) and progression free survival (PFS) probabilities were 50% and 83% by 27 month. Treatment was discontinued in 20/58 (34%), most frequent reasons being adverse events 9/59(15%), lack of efficacy 5/59 (8.5%), disease progression 2/59 (3.4%) and death 1/59 (1.7%). Two patients discontinued due to stem cell transplantation. The adverse events that led to treatment discontinuation were pleural effusion (3), diarrhea (2), rash, renal impairment, auricular fibrillation and liver enzyme elevation one patient each. Overall, bosutinib was well tolerated. Grade 3-4 hematological toxicities were 3%, 6% and 6% for anemia, thromboctytopenia and neutropenia. Most common non hematological side effects were diarrhea (39%, nauseas 13% and liver alterations 14% and pleural effusion 14%. CONCLUSIONS: Little is known about the therapeutic role of Bosutinib in 4th line. The series presented here is, to our knowledge, the largest being presented. Bosutinib seems to be an appropriate treatment option for patients resistant or intolerant to three prior TKIs. Table 1. IM+NI-I+DA-R (N=4) IM+NI-R+DA-R (N=18) IM+NI-I+DA-I (N=30) IM+NI-R+DA-I (N=7) Total (N=59) Sex, N (%) Male 2 (50) 11 (61.1) 16 (53.3) 2 (28.6) 31 (52.5) Median age of diagnosis, yr (range) 57.32 (50-64) 49.19 (23-73) 54.95 (21-89) 48.87 (26-68) 53.15 (21-89) Median age of Bosutinib initiation, yr (range) 69.13 (61-70) 62.27 (39-79) 64.85 (25-90) 64.79(35-74) 63.7 (25-9) Median follow up, months (range) 18.5(7.8-34.1) 8.4(1.22-36.1) 16.3(0.5-34.7) 23.4(3.3-28.9) 14.3(0.7-36.1) SOKAL Index at diagnosis, N (%) High 2(50.0) 4 (23.5) 1 (4.3) 1 (20) 8 (16.3) Intermediate 1 (25.0) 5 (29.4) 10(43.5) 2 (40) 18 (36.7) Low 1 (25.0) 8 (47.1) 12 (52.2) 2 (40) 23 (46.9) Median Time from first TKI to BOS, (yr, range) 10.3 (4.8-11.9) 9.3 (2.0-11.4) 8.8 (0.7-13.6) 8.2 (5.1-12.3) 8.8 (0.7-13.6) Median duration of prior therapy, months (range) Imatinib 38.8 (11.8-69.8) 32.6 (6.3-96.8) 26.2 (1.6-102.6) 23.1 (8.3-66.8) 28.8 (1.6-102.6) Dasatinib 21.5 (12.6-75) 21.8 (7.7-69) 31.4 (0.4-87.1) 23.7 (10.3-53.6) 23.44 (0.4-87.1) Nilotinib 19.1 (2.1-46.2) 16.7 (5-65.6) 8.9 (0.2-58.5) 30.9 (6.9-49.3) 14.3 (0.2-65.6) BOS: bosutinib, IM, imatinib; DA, dasatinib; NI, nilotinib, I: Intolerance, R: Resistant, Yr: year Disclosures García-Gutiérrez: Ariad: Consultancy; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Milojkovic:Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Boque:Novartis: Honoraria; BMS: Honoraria; Celgene: Honoraria. Casado:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Jiménez:Pfizer: Consultancy, Honoraria. Giraldo:Pfizer: Consultancy. Steegmann:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Description: Introduction: TKIs introduction in the treatment of chronic myeloid leukemia (CML) has offered an outstanding improvement in prognosis, especially in survival. Data about TKIs were obtained from clinical trials but little is known about their translation to real life. In addition, clinical trials are mainly based on efficacy analysis to just one line of therapy, rather than treatment sequences (due to failure or intolerance). Objectives: To analyze the long-term survival of patients outside clinical trials in response to TKI treatment, describing the pattern of sequential treatments the patients actually received. Patients and methods: CML patients in first chronic phase, treated with TKIs (imatinib, nilotinib, dasatinib) either as monotherapy or in sequence, outside clinical trials. The setting was a multicentric, hospital-based registry. Survival and their potentially associated variables were studied. Results: Demographics, risk and treatment distribution: 696 patients (423 men, 273 women) with a median age at diagnosis of 41y (14-94y) were included with a follow up of 85±7 months (m) from diagnosis, 78±6.6 m from first treatment, and 69±6 m from first TKIs; 106 patients (15%) were over 70y. The risk distributions were as follows: Sokal: low (L) 48%, intermediate (I) 38% and high (H) 13%; Euro score: L 51%, I 45% and H 4%; EUTOS L: 91% and H 9%; EUTOS LT: L 68%, I 25% and H 7%. Treatment groups were the following: Group 1: IFN alpha and then imatinib or 2¼ GTKIs (176 patients); Group 2: imatinib only (340 patients); Group 3: imatinib and then nilotinib, dasatinib or both due to failure or intolerance (131 patients) and Group 4: 2¼GTKIs in first line (49 patients). Survival: Estimated survival by 10 years was 80%. Ninety-one patients have died (27 due to unknown reasons, 33 due to progression or BMT, 7 due to second neoplasias and 21 due to cardiac or neurological disease). Variables associated with survival: In the univariate survival analyses (log rank test) either from diagnosis, first therapy or first TKIs, the Sokal, Eutos, Euro and EUTOS LT scores as well as age over 70y were the only statistically significant variables associated with survival.(figure 1). In the multivariate analysis (Cox model), only Sokal and Eutos LT scores, and age over 70y were independent variables. Patients older than 70 years at diagnosis had a 50% probability of survival by 8 years. It is worth mentioning that, although the probability of overall survival from diagnosis was higher in the group receiving imatinib after IFN alpha, this difference was not seen when measuring the probability of survival after the first treatment o first TKI. This is probably explained by the higher proportion of low-risk score in patients having had previous IFN. Whereas the cause of death was progression in half of the patients aged equal or less than 70 years, in patients older than 70 years, two third of the deaths were not related to progression of CML. Conclusions: 1.These results show that the probability of survival by 10 years is roughly 80%, and extend the findings of our previous work showing that this probability is not different across different sequential treatments (imatinib before IFN, alone or switched to 2»GTKis due to intolerance o failure)(1). This fact emphasizes the rescue potential of available TKI therapies. 2. We have validated for the first time the Eutos LT score in real life population. 3. Patients over 70 years have shorter survival due to reasons different than progression, opening an interesting field of research, and a non-negligible room of improvement. Figure 1 (1)Casado LF, et al Cancer Med. 2015 Mar 10. Figure 1. (1)Casado LF, et al Cancer Med. 2015 Mar 10. Disclosures Casado Montero: BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Steegmann:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

Description: Abstract 3762 Introduction: In late 2009 it was published the second version of the international recommendations for CML monitoring and treatment with Imatinib and other tyrosine kinase inhibitors(TKI) (Bacarrani M et al JCO 2009). Although widely distributed and discussed, there has not been any report describing the adherence of hematologists to those guidelines, or analyzing the differential outcomes in the setting outside clinical trials. Objectives: To study the association between the compliance to ELN 09 recommendations in every timepoint, and the response to TKI treatment. Methods and patients: CML patients in first chronic phase, treated upfront with imatinib, outside clinical trials. The adherence to ELN 09 in the given timepoint was classified, as orthodox if, monitoring and treatment were done accordingly, and heterodox, if monitoring or treatment were done disaccordingly. Study variables: Best complete cytogenetic response (CCyR) and major molecular response (MMR) with Imatinib and second line TKI, and progression rates. Besides, we analyzed the association between response grades considering the value obtained in the precedent timepoint. Results: 374 patients (229 men, 145 women) were included. The Sokal risk distribution was: low (L): 138(39%), intermediate (I): 172 (48%), and high (H): 44(12%). Correspondent values for Euro score were 170(48%), 165(47%) y 19(5%). EUTOS score: L: 294(91%), H: 30(9%). Median age: 52 years (15–88). Median follow-up 59.3 months (0,6–131,9). A summary of the results is shown in Table 1. Most of the patients were evaluated on time (73–90%), and 2/3 of the patients were monitored and managed in an orthodox way in the specific timepoints. The rate of CCyR and MMR were significantly higher in patients managed in an orthodox way. In contrast, progression rates were significantly higher only in those patients whose management was heterodox at 3 months. Besides, a better response at any given timepoint was associated with better ulterior responses. Conclusions: Our results reinforce the use of ELN 09 recommendations, showing that those patients whose monitoring and treatment is done according to these recommendations have a higher probability of response. An orthodox management in the first trimester of treatment is specially important, because it is associated with a lower progression rate. Disclosures: Casado: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Martínez-López:Celgene: Honoraria. Steegmann:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau.