ALBERT

Description: Background: After long-term treatment with tyrosine kinase inhibitors (TKIs), an important proportion of patients with chronic myeloid leukemia (CML) achieve and maintain a deep molecular response (DMR) that allows them to stop treatment indefinitely. However, approximately 50% of these patients on treatment-free remission (TFR) experience relapse by undetermined reasons. It has been described that TKIs may induce a potent antileukemic response that conditions the outcome of the discontinuation. Our objective was to analyze different immune parameters that could be used as biomarkers of safer treatment discontinuation. Objectives: To determine the modulation of immune biomarkers that could be related to current treatment with TKIs on patients with CML ("On TKI") or to successful TFR in patients that maintain DMR after treatment withdrawal ("Off TKI") or to relapse after TFR on patients that lost DMR. Materials & methods: We analyzed by flow cytometry the peripheral blood mononuclear cells (PBMCs) from 45 patients with CML "On TKI" for at least 9 months (imatinib (11), nilotinib (9), dasatinib (20) or bosutinib (5)), 17 patients "Off TKI" for at least 7 months who kept DMR at the moment of sampling (last TKI before TFR: imatinib (7), nilotinib (6), dasatinib(4)), 7 patients "Off TKI" for at least 1 year and 4 months who relapsed during TFR (samples from 3 patients were taken previous to TKI reintroduction (on relapse); samples from 4 patients were taken after they restarted treatment with TKIs ("On TKI" relapse), 4 patients with recent diagnosis of CML still untreated, and 20 healthy donors as basal control. Results: 1) Patients characteristics are shown in table 1. 2) Treatment with TKIs induced an increase of 8.6±1.2% ((p4%; CD86+

Description: INTRODUCTION: In chronic myeloid leukemia (CML) patients in chronic phase (CML-CP), BCR-ABL levels ≤10% at 3 months measured by RT-qPCR (IS) has been consistently correlated with probabilities to obtain an optimal response at 12 months. Monitoring molecular response with automated cartridge-based detection system GeneXpert BCR-ABL (Cepheid®) method has shown an optimal correlation with standardized BCR-ABL (IS) EUTOS method in patients with complete cytogenetic response (CCyR). However, is not known if both methods are also equivalent when measuring BCR-ABL levels above 1%, and therefore, the utility of GeneXpert in order to evaluate response at 3 months must be confirmed. AIMS: To validate the predictive value of molecular response at 3 months with GeneXpert method METHODS: We have studied 125 new consecutive CML-CP patients treated with tyrosine kinase inhibitors (TKIs) followed in 13 centers. Median age at diagnosed was 55 years. The percentage of low, intermediate and high risk Sokal groups were 42%, 40% and 18% . First line treatment was imatinib (IM), nilotinib (NI), dasatinib (DA) or bosutinib (BO) in 58%, 28%, 13% and 1% of the patients, respectively. BCR-ABL level was measured by GeneXpert platform, where all necessary steps to measure BCR-ABL levels are automatically performed. ABL was used as gene control. The study was approved by the Ethics Committee. RESULTS: Median follow up was 43 months. The proportion of patients that achieved CCyR by 12 months, analyzed by intention to treat, was 84% (108/123). Probabilities for each specific TKI were 78%, 93%, 100% and 100% for IM, NI, DA and BO respectively. 23% (96/125) of patients required treatment changed due to resistance or intolerance. Treatment discontinuation probabilities were 32%, 11%, 5% and 0% for IM, NI, DA and BO respectively. Only 4% (5/125) did not achieve an optimal response at 3 months (BCR-ABL ≤10%), which is significant lower compare to results obtain with historical series when using EUTOS IS method. 10% cut-off at 3 month was unable to identify patients that achieved an optimal response in further evaluations. By 12 months, this cutoff did not correlate with probabilities to obtain CCyR (50% vs 86% (p=0.1) or major molecular response (MMR) (60% vs 79% (p=0.21)). In order to find a cutoff that could correlate with optimal response at 12 months, we used a receiver operating characteristic curve to identify the optimal cutoff in transcript level that would allow us to classify the patients as high risk or low risk with maximal sensitivity and specificity for each individual outcome. At 3 months, patients with transcript levels ≤ 1.6% had significantly better probabilities to obtain an optimal response by 12 months, with 81% and 94% sensitivity and specificity for CCyR. With this new cutoff, probabilities for CCyR and MMR at 12 months were 98% vs 54% (p

Description: Introduction: Bosutinib is approved for newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML) and CML resistant or intolerant to prior therapy. Efficacy and safety of first-line bosutinib and imatinib were assessed in older vs younger patients in the ongoing phase 3 BFORE trial (NCT02130557). Methods: In all, 536 patients were randomized 1:1 to receive bosutinib or imatinib (400 mg once daily). We compared outcomes in patients aged ≥65 years (older group) vs

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: Introduction: The diagnostic criteria for polycythemia vera (PV) has recently been updated by the World Health Organization (WHO). The criterion for erythrocytosis has been modified downwards: hemoglobin (hb)〉 16.5 g/dL or hematocrit (hto)〉 49% in men and hb〉 16 g/dL or hto〉 48% in women. This reduction increases the potential number of patients that would be test for JAK2 V617F mutation if PV is suspected. The V617F mutation in the JAK2 gene is present in 95% of cases of PV. It is estimated that the prevalence of this mutation in the general population is around 0.2%. Our aims are to determine the prevalence of JAK2 V617F in individuals with erythrocytosis according to WHO2016 criteria and to find prognostic factors that could help to identify patients with PV. Methods: We prospectively studied all hemograms performed in our laboratory during 7 nonconsecutive days. Variables studied were hb, hto, leukocytes, neutrophils, platelets, MCV, MCH, MCHC and RDW. JAK2 V617F mutation was studied in all males that had hb〉 16.5 g/dl or hto〉 49% or females that had hb〉 16 g/dl or hto〉 48%. JAK2 V617F mutation was studied by PCR assay in which an amplification control fragment and the JAK2 mutant allele were simultaneously amplified. All positive samples were confirmed by quantitative real-time PCR in a reference laboratory. Positive results were considered when the JAK2 V617F allele ratio was ≥ 0.7. The variables collected were correlated with the result of the JAK2 test in a univariate way. The T-Student test was used for the quantitative variables and the Chi-square test for the categorical variables. For the cell count variables, the Mann-Whitney U test was used. Results: A total of 15366 HG were analyzed. 1271 (8.3%) met the inclusion criteria for erythrocytosis. JAK2 V617F was performed on 1001 samples (270 samples were not suitable for the PCR assay due to low quality). Twelve samples (1.2%) were positive for JAK2 V617F mutation. However, 5 samples were excluded due to a known diagnosis of myeloproliferative neoplasm. Therefore, finally prevalence of JAK2 V617 mutation in 996 patients that met WHO erythrocytosis criteria was 0.8% (8/996). Medians for all parameter studied for each group are shown in table 1. In order to find out parameters that could increase the incidence probabilities to identify patients with JAK2 V617F we performed an univariate analysis of the variables included, according to JAK2 mutational status. We found that patients with JAK2 V617F had higher levels of leukocytes, neutrophils, platelets and RDW than patients with negative JAK2 (p

Description: INTRODUCTION: In patients with so called "late suboptimal responses" (patient with complete cytogenetic response (CCyR) without major molecular response (MMR) after 18 months of imatinib) , the role of dasatinib has not been evaluated. Dasatinib has unique immunomodulatory effects especially on the proliferation and activation of T- and NK-cells. Yet, how dasatinib affects the migration of lymphocytes is unknown. DASAPOST is the first clinical trial evaluating efficacy and safety of dasatinib in patients with late suboptimal response (now considered as ELN2013 as warning). Another aim is to correlate new immunological aspects related to dasatinib and its possible correlation with responses. METHODS: We are presenting results of first 18 patients enrolled in the phase II DASAPOST study (NCT01802450). Main inclusion criteria were patients treated with late suboptimal response by ELN09 (CCyR without MMR after 18 months of treatment. Sokal risk groups were (L/I/H) 22.5%, 50% and 22.5%. All BCR-ABL/ABL (IS) measurements were centralized in an EUTOS laboratory. An exhaustive lymphocyte migration study was done, including immunophenotipying pre and post samples (CD 45, CD3,CD8, CD16, CXCR3, CXCR4, CD56 and CCR7), migration assay (chemokines CXCL10, CCL19+CCL21 and CXCL12) and CXCL10 plasma concentration measured by ELISA. RESULTS: - Clinical: Median follow up was 288 days (100-380). Three out of 18 (16%) patients had discontinued dasatinib due to side effects (pancreatitis, pleural effusion and low grade, persistant side effects (fever, arthralgias, anemia and astenia). All patients have been evaluated at 3 months, 17 at 6 months and 11 at 12 months. Cumulative incidences by ITT of MMR by 3 and 6 months were 50% and 81%. Cumulative incidences by ITT of MR4.5 by 3 and 6 months were 18% and 25%, respectively. - Inmunological: Dasatinib intake induced a significant increase of NK-cells and decrease of percentage of T-cells. Further, it increased CD8+ T cells, while reducing the proportion of CD4+ T-cells among the total T-cells. With the first dose of dasatinib (to),the percentage of CCR7 was lower in CD4+ and CD8+ T-cells in the post-samples. Lymphocyte migration was studied with transwell assays. At t0, post-samples showed a reduced migratory capacity towards the chemokines CCL19 and CCL21 in both CD4+ and CD8+ T-cell subsets. Patients were classified as mobilizers (n=14) or non-mobilizers (n=3) depending on whether they experienced an increase in the absolute lymphocyte counts after the first intake of dasatinib or not, showing different lymphocyte distribution and migratory capacity. In order to study the long term effects of dasatinib, we calculated the fold change (FC) of absolute lymphocyte counts pre- and post-dasatinib intake. Patients were divided into two groups based on whether in the 3 months samples (t3) had a higher ("increase group") or a lower ("decrease group") FC compared with t0. The migratory capacity of these two groups was studied in basal conditions and towards CCL19+CCL21 or CXCL10. We found no differences in basal migration in the "increase "group, while, the basal migration in the "decrease" group was quite promoted at t0 and t3. Further, migration towards CCL19+21 in post-samples is even more inhibited in "increase" patients at t3, whereas in the "decrease" patients the inhibition is diminished. The patients were divided into two groups based on the achievement of MMR at t3. At t0 both patient groups had similar migratory capacity, however, at t3, responders maintained significantly impaired migratory capacity to CCL19+21, compared with non-responders. CONCLUSIONS: Our study shows, for the first time to our knowledge, that in patients treated with Imatinib and with late warning responses, switch to Dasatinib induced MMR in 83% of the patients, although 16% discontinued treatment because of toxicity. We reported for the first time that dasatinib has significant effects on lymphocyte migration, and these are associated with early response. Disclosures García-Gutierrez: Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Casado:Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Sánchez-Guijo:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau. Boque:Celgene: Honoraria; BMS: Honoraria; Novartis: Honoraria. Muñoz-Calleja:BMS: Research Funding. 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: Young patients (age 〈 60 years) with essential thrombocythemia (ET) and no history of thrombosis are considered at low risk of thrombosis and therefore managed on a conservative approach with antiplatelet therapy or even without any treatment. JAK2 V617F and CALR exon 9 mutations are the most frequent molecular alterations observed in ET, with CALR-positive ET being considered a distinct clinical entity due to its higher platelet counts and lower incidence of thrombosis as compared with JAK2 V617F-positive ET. There is some evidence supporting a role for antiplatelet therapy in JAK2 V7617F-positive neoplasms. However, the role of antiplatelet therapy in CALR-positive ET has not been studied. The aim of the present study was to assess the effect of antiplatelet therapy in the primary prevention of thrombosis in patients with CALR-positive ET without indication of cytoreductive therapy. For such purpose, 240 patients (107 males, 133 females) diagnosed with ET at a median age of 42 years (range 13-59) were included in a multicenter retrospective study. Initial treatment consisted of antiplatelet therapy (n=109) or careful observation (n=108), whereas 23 patients received cytoreduction since diagnosis and were excluded. During a median follow up of 8 years, 137 patients were started on cytoreductive therapy because of the following indications: age 〉 60 years (n=10), thrombosis (n=10), bleeding (n=2), microvascular symptoms (n=18), extreme thrombocytosis (n=89), and others (n=8). Median time free of cytoreductive therapy was 3.2 years. Thrombosis-free survival restricted to the time of cytoreductive therapy abstention was calculated using the Kaplan-Meier method. Variables attaining a significant level at the univariate analysis were included in a Cox proportional hazard model. During the period of abstention of cytoreductive therapy, a total of 10 thrombotic events and 8 major bleeding episodes were registered. The probability of thrombosis at 3 years was 5% in patients managed with careful observation and 1% in those receiving antiplatelet therapy (p = 0.2). At multivariate analysis, antiplatelet therapy did not result in a lower risk of thrombosis after correction for age, sex and presence of cardiovascular risk factors. Interaction studies did not identify any subgroup of patients that benefited from antiplatelet therapy in thrombosis prevention. Regarding major bleeding, patients receiving antiplatelet therapy experienced a higher rate than those managed on observation (3-year probability of major bleeding, 5.5% and 0%, respectively, p=0.05). At multivariate analysis, antiplatelet therapy was associated with a tendency towards and increased risk of major bleeding (HR: 7.7, 95%CI: 0.9-66.2, p=0.06) independently of platelet count at diagnosis, age and gender. In conclusion, CALR-mutated low-risk ET patients under cytoreductive therapy abstention may not obtain a clear benefit from antiplatelet therapy since the increase in the rate of bleeding may offset the reduction in the rate of thrombosis Disclosures García-Gutierrez: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Gilead: Honoraria; Sanofi: Honoraria, Speakers Bureau; Shire: Speakers Bureau. Cervantes:Sanofi-Aventis: Consultancy; Novartis: Consultancy, Speakers Bureau; CTI-Baxter: Consultancy, Speakers Bureau. Vannucchi:Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Description: Imatinib treatment has radically changed the prognosis of patients with CML. However, around 23-32% of patients discontinue this therapy due to lack of efficacy. Second generation TKI are available, which exhibit greater potency, so there is scope to further improve the strategy of selection of the appropriate TKI in the first line setting. Measurement of PTCH1 expression at diagnosis has been proposed as a useful strategy to tailor first line therapy as patients with low PTCH1 expression showed a worse outcome. Signalling via SMO is inhibited by non-Hedgehog ligated PTCH1 in Hedgehog pathway. SMO and PTCH1/SMO expression ratio has also been related to response to imatinib. Our aim was to corroborate imatinib outcome prediction in a different cohort and compare the prognostic power of PTCH1, SMO and PTCH1/SMO. We have retrospectively studied 101 pre-treatment samples of patients who received first-line imatinib from 14 Spanish centres. Clinical data were recorded in the Spanish CML Registry (RELMC). Informed consent was signed by every patient. Predesigned assays for PTCH1, SMO and GUSB (control gene) were used in single qPCR reactions in duplicates and run in an ABI 7900. Receiver operating characteristic (ROC) curves were plotted for PTCH1, SMO and PTCH1/SMO expression ratio and the area under curve (AUC) was used to compare its capacity to predict imatinib failure free survival (IFFS). For the measurement with higher AUC a threshold was set to divide patients with high and low expression. TKI failure was defined as loss of CCyR, progression to advanced phase disease, death or change in treatment from imatinib due to lack of efficacy. Secondary endpoints were: probability of achieving

Description: Background: Current European LeukemiaNet (ELN) recommendations (ELN 2013) endorse closely monitoring, due to risk of failure, for patients with so called late warning response (patients with complete cytogenetic response without major molecular response after 12 months of treatment). In this situation, for patients initially treated with imatinib, previous studies have shown a benefit of treatment change to nilotinib in terms of the achievement of deeper molecular responses. However, the role of treatment change to dasatinib in this group of patients have not been evaluated. DASAPOST is the first clinical trial evaluating efficacy and safety of dasatinib in patients with late warning responses. Methods: We are presenting results of the 18 patients enrolled in the phase II, open, multicenter DASAPOST study (NCT01802450). Main inclusion criteria were patients previously treated with imatinib with late suboptimal response by ELN2009 (CCyR without MMR after 18 months of treatment). The primary end point was rate of MMR by 6 moths after treatment change to dasatinib. Secondary end points were rate of MMR by 12 months, rate of deep molecular responses, progression free survival and safety of treatment change. Results were expressed as the proportion of patients who achieved molecular responses in the intention-to-treat (ITT) population, considering as failure if the evaluation was not performed in a specific time point. All BCR-ABL/ABL (IS) measurements were centralized in an EUTOS laboratory. Results: From April 2013 to May 2015, 18 patients were enrolled in 12 Spanish centers. Median age was 59 years (39-77). The ratio of men to women was 13/5, and the risk groups according to Sokal Score were 48%, 30% and 22% for low, intermediate and high risk, respectively. Median time from diagnosis to treatment change to dasatinib was 2.6 years (1.6-23) and median time while on imatinib to achieve CCyR 1.4 years (0.2-12). Median exposure to imatinib was 2.4 years (1.6-14). Seventy-two percent of the patients achieved MMR by 6 months (primary endpoint). Rates of MMR and deeper molecular responses at different time points are shown in table 1. Of interest 9/18 patients (50%) achieved MR4 by 12 months. Treatment change to dasatinib was safe, with only 3 study discontinuations (16%), due to adverse events (AE) and 4 serious AE (congestive heart failure, acute gastroenteritis, pyelonephritis and pancreatitis (only congestive heart failure was related to dasatinib). Most commonly reported (〉5%) drug-related AEs are shown in table 1. Conclusions: Our study shows, for the first time, that in patients treated with imatinib and with late warning responses, switching to Dasatinib induced MMR in 2 out every 3 patients, and MR4 in half of the patients by 6 months, with a good safety profile. Table 1 Most commonly reported (〉5%) drug-related AEs Table 1. Most commonly reported (〉5%) drug-related AEs Table Table. Disclosures García-Gutierrez: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Casado:Ariad: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria. Sánchez-Guijo:Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol-Myers-Squib: Consultancy, Honoraria. Martinez-Lopez:BMS: Research Funding. Steegmann:Ariad: Honoraria, Other: Research funding for the Spanish CML Group; Pfizer: Honoraria, Other: Research funding for the Spanish CML Group; BMS: Honoraria, Other: Research funding for the Spanish CML Group; Novartis: Honoraria, Other: Research funding for the Spanish CML Group.