ALBERT

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: 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: 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: Introduction P210 BCR-ABL translocation resulting from rearrangements within the major breakpoint cluster region (M-BCR), either e13a2 or e14a2, is the molecular hallmark of chronic myeloid leukemia (CML). However, some CML patients may harbor atypical BCR-ABL rearrangements such e1a2 P190 BCR-ABL which involves the minor breakpoint cluster region (m-BCR). Response to therapy with tyrosine kinase inhibitors (TKI) and outcome of such atypical patients is not well defined. Objective To evaluate response to TKI therapy of CML patients with the atypical e1a2 P190 BCR-ABL translocation. Patients and Methods Since 2009, 4 patients with CML in chronic phase and with atypical e1a2 P190 BCR-ABL rearrangement have been recruited in various institutions belonging to the Hematological Molecular Biology Group (GBMH) of the Spanish Society of Hematology (SEHH). Patient characteristics, treatments administered and response to therapy for the 4 patients is shown in Table 1. BCR-ABL transcripts were revealed at diagnosis by quantitative PCR followed by conventional agarose electrophoresis of PCR products. Molecular follow-up of BCR-ABL transcripts throughout treatment was performed by quantitative PCR following the guidelines of the European Leukemia Net. Results One patient received treatment (HU and INF+araC) prior to TKI (Pat. 1; Table 1). All 4 patients received Imatinib as initial TKI treatment. Two of the patients treated with Imatinib (Pat. 1,2) obtained a complete molecular response (CMR) and the other 2 (Pat. 3,4) only achieved a complete hematological response (CHR) as best response (Table 1). All patients had to switch to a second generation TKI (3 Nilotinib and 1 Dasatinib) due to intolerance to Imatinib (n=1; Pat. 1) or resistance (n=3; Pat. 2-4). The patient who received Dasatinib as second line TKI (Pat. 3) only achieved a partial hematologic response (PHR) and was changed to Nilotinib as third line TKI, achieving CHR after which the patient entered in blast crisis and died 36 months after diagnosis (Table 1). Overall, only 1 (Pat. 1) out of the 4 patients included in the present study achieved a sustained molecular response with Imatinib. At last follow-up, among the 4 patients included in the study, all 4 had needed a change of TKI, 1 had died due to disease progression (Pat. 3) and only 2 of them retained a molecular response (Pat. 1,2). Conclusion CML patients harboring atypical e1a2 P190 BCR-ABL transcripts show a poor response and short-lived responses to TKI therapy and therefore should be identified as high-risk patients at diagnosis. These patients must be closely monitored during therapy with TKI and should be treated upfront with a second generation TKI or even be considered for allogeneic SCT in the early phase of the disease. Paper presented on behalf of the Hematological Molecular Biology Group (GBMH) of the Spanish Society of Hematology (SEHH). AJ-V and IB contributed equally to this work. Disclosures: No relevant conflicts of interest to declare.

Description: Study Rationale The present study with ponatinib is based on previous studies on the potential role of imatinib discontinuation, to achieve a stable treatment-free remission (TFR) of patients with Philadelphia-positive Chronic Myeloid Leukemia (CML). As ponatinib has shown to induce deeper molecular responses compared with imatinib, the rationale is that ponatinib treatment could increase the proportion of patients who could discontinue treatment successfully. Purpose The purpose is to determine the successful TFR within the first 48 weeks following cessation of treatment in patients who achieved MR4 on imatinib, and maintained MR4 on ponatinib, after a switch from imatinib. Eligible patients have been previously treated with imatinib as unique tyrosine kinase inhibitor (TKI) therapy, for at least 4 years, and have documented MR4 (at least 12 months) at the time of ponatinib to study entry. Objectives The Primary Objective is to evaluate the proportion of patients without confirmed loss of MR4 or loss of MMR (do not require confirmation). The Key Secondary Objectives are: To evaluate the proportion of patients without confirmed loss of MR4 or loss of MMR within 72 and 96 weeks following ponatinib cessation.To estimate progression-free survival (PFS) from the date of ponatinib cessation to the date of the earliest event. Treatment-free survival (TFS) defined as a lack of any of the following: loss of MMR, confirmed loss of MR4, re-start of imatinib treatment, progression of AP/BP, or death from any cause.Overall survival (OS), defined as the time from the date of cessation of ponatinib therapy to the date of death from any cause.Proportion of patients who regain MR4 within 48 weeks of imatinib treatment re-initiation, following confirmed loss of MR4 within 48 weeks subsequent to ponatinib cessation.Kinetics of BCR-ABL transcript level (IS) after re-start of imatinib therapy. Other Secondary Objectives include adverse events, laboratory data for hematology, biochemistry, and urinary test, vital signs and ECGs. Exploratory Objectives include phenotypic and genotypic biomarkers, as well as functional analysis of cytotoxic cell activation. Plasma monitoring of ponatinib levels will also be performed. Study Design This is a single-arm, open label study, open label study in 40 patients who achieved and maintained MR4, to determine the rate of successful TFR in both gender patients, treated with 15 mg/day of ponatinb for 48 weeks. Ten Spanish sites will participate. The study has two main phases: ponatinib consolidation (48 weeks) and ponatinib TFR phase (96 weeks). Inclusion criteria are patients who had received a minimum of 4 years imatinib as unique TKI therapy, have documented MR4 at least 12 months prior to study entry, and will continue with MR4 before the discontinuation of ponatinib. After stopping ponatinb (TFR phase), BCR-ABL wil be monitored every 4 weeks during the first 48 weeks, and every 12 weeks during the last period of 48 weeks. Exclusion criteria include patients with transplant, atypical transcripts, CML treatment resistant mutation, or having cardiovascular or pancreatitis diseases. Figure 1: Current State of the Study First Visit First Patient: 17 JUL 2019 Patients Enrolled: 4 Patients Recruited: 3 Screening Failure: 0 In Screening: 1 patient Figure 1 Disclosures Sanchez-Guijo: Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Honoraria; Roche: Honoraria. Hernandez Boluda:Incyte: Other: Travel expenses paid. Steegmann:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: 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: Background and objective. An important proportion of patients with polycythemia vera (PV) and essential thrombocythemia (ET) are diagnosed in the seventh and eighth decades of life. Because of the chronic course of PV and ET and the advanced age of patients, many will actually die from age-related ailments instead of the myeloproliferative neoplasm, so the disease's impact on life-expectancy remains largely unknown. This registry‐based study was aimed at investigating the excess mortality attributable to PV and ET in a large series of patients diagnosed and managed according to modern criteria. Methods. We queried the databases of the Spanish Group for Chronic Myeloproliferative Neoplasms (GEMFIN) to retrieve patients diagnosed with PV or ET after 1980. Criteria for diagnosis and treatment modalities were the internationally recommended ones in each period. Excess mortality was defined as the complementary of the ratio between the actuarial survival observed in the cohort of patients and the expected survival derived from the general Spanish population matched to the patients by age, sex, and calendar year at diagnosis, and was estimated by the Dickman's method (Stat Med 2004;23:51). Spanish life-tables stratified by age, sex, and calendar year were obtained from the Human Mortality Database (www.mortality.org). Results. A total of 3,268 patients were included in the study (PV: 1,731; ET: 1,537). Median age (interquartile range) and sex distribution in the PV and ET groups were 67 (55-75) years, 48% females, and 62 (48-74) years, 61% females, respectively. At the study closing date, 270 (16%) patients with PV and 202 (13%) with ET had died. Estimated median survival was 20.2 years for PV patients and 23.8 years for ET patients. Transformation into acute myeloid leukemia/myelodysplastic syndrome was diagnosed in 76 (4.4%) patients with PV and 63 (4.1%) with ET. Three hundred and seventy-one patients (170 ET, 201 PV) had one or more episodes of thrombosis over the course of the disease. No significant excess mortality attributable to ET was detected at 20 years from diagnosis (figure 1a). In PV, mortality did not significantly deviate from matched general population until 18 years from diagnosis (figure 1b). In both diseases, excess mortality significantly increased after the first recorded thrombotic event (figure 1c). Conclusion. From the population viewpoint, ET and PV do not carry an increased excess mortality until late in the second follow-up decade or later. Nevertheless, appearance of a thrombotic event significantly increases the subsequent excess mortality. Figure 1 Figure 1. Disclosures Hernandez Boluda: Incyte: Consultancy; Novartis: Consultancy. Ferrer Marin:Novartis: Consultancy, Research Funding; Incyte: Consultancy. Gómez-Casares:Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau. 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: Transformation to secondary myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PV) and essential thrombocythemia (ET), the two more indolent Ph-negative myeloproliferative neoplasms (MPN). Once transformed, survival is remarkably shorted. Chronic inflammation plays a critical role in the progression of MPN, driving clonal expansion toward end stage disease. Importantly, MPN are characterized by the production of inflammatory cytokines, by both malignant and non-malignant clone. Inflammation and cancer share a common pathway, i.e. NF-κB. Interestingly, miR-146a regulates TLR/NF-κB pathway through the inhibition of its targets, IRAK1 and TRAF6, decreasing the production of cytokines. Based on: i) miR-146a-/- mice develop an MF-like phenotype with aging; and ii) miR-146a polymorphism (miRSNPs) rs2431697, influences its expression levels (50% decrease in TT individuals); we hypothesized that lower miR-146a-5p levels associated to this miRSNPs may result in high risk to develop MF. Objective: To evaluate the association of rs2431697 with MF transformation and to study the molecular mechanisms beyond this association. Methods: We genotyped rs2431697 in 938 patients (312 MF, 299 PV, and 327 ET) recruited from 13 tertiary Spanish institutions belonging to GEMFIN and 600 controls. The levels of miR-146a and IRAK1 were evaluated by qRT-PCR in total blood RNA of homozygous patients (TT=30, CC=25) with PV or ET and in healthy subjects (TT=7, CC=7). In miR-146a-/- mice, 2 and 9 months old, we evaluated spleen size and cellularity: degree of fibrosis in bone marrow (H&E and silver staining); and STAT3 and pSTAT3 in granulocytic lysates by western blot. Results: Association analysis, taken controls as reference, showed that TT genotype (associated in the literature with low levels of mir-146a) is associated to MF with an OR of 1.36 (1.01-1.82, p=0.04). Among MF patients, the subgroup with the greatest differences was the one of secondary MF (OR = 1.47, CI: 0.98-2.20) (Table 1 a,b). Next, we compared the genetic frequencies of rs2431697 SNPs between the secondary MF patients and the population in risk. Confirming our hypothesis, we observed an enrichment of TT genotype in the post-PV/TE MF group (n=132) compared to the PV+TE group (n=626) (OR=1.51; p

Description: Backgroung: In chronic myeloid leukemia (CML) patients, 3-month BCR-ABL1 levels ≤10% measured using conventional RQ-PCR (IS) have consistently been correlated with further outcomes. Monitoring molecular responses using the Xpert BCR-ABL1 MonitorTM PCR system has demonstrated an optimal correlation with standardized RT-qPCR (IS), however, it is not known whether both methods are also equivalent when measuring BCR-ABL1 levels higher than 10%. We previously showed how the cutoff of 10% was not correlate with subsequent responses when using Xpert BCR-ABL1 in a cohort of 125 consecutive CML patients treated with imatinib (58%) and second generation TKI (2GTKI) (42%) as frontline treatment. By contrast, by using a receiver operating characteristic curve, a new cutoff of 1.5% was correlated with probabilities to achieve complete cytogenetic response (CCR) and major molecular response (MMR. The aim of this study is to validate the new cutoff of 1.5% at 3 months in patients treated with second generation 2GTKI. Methods: We have studied 57 new consecutive CML-CP patients treated 2GTKI from from Andalusian CML Group Registry. BCR-ABL1 transcript quantification was performed using the automated method Xpert BCR-ABL1 Monitor™, Cepheid, aligned to the 0.1% BCR-ABL1 ratio according to the standards of the World Health Organization. The samples were not centrally collected. All analyses were performed on an intention-to-treat basis unless otherwise stated. The proportions of patients who achieved MMR and CCyR after first-line treatment for 1 year and the response at 3 months were compared by applying Pearson's chi-square test or Fisher's exact test The study was approved by the Ethics Committee. Results: The median age at diagnosed was 48 years (18-74). The ratio of men to women was 59/41, and the risk groups according to Sokal Score were 48%, 30% and 22% for low, intermediate and high risk, respectively. Median follow up was 38 months (3-56). First-line treatment consisted of nilotinib and dasatinib in 58% and 42% of patients, respectively. Overall, the probability of achieving CCyR and MMR at 12 months was 92% (48/52) and 82% (39/47), respectively. Ten patients (17%) required treatment changes as a result of resistance (n=3), not achieving MMR (n=3) or intolerance (n=4). No patients progressed to advanced phases, and only 1 patient died during follow-up (not CML related). The overall median value of BCR-ABL1 at 3 months was 0.16%. Consistent with the original cohort of patients treated with first-line 2GTKI, all patients achieved a BCR-ABL1 level ≤10% at 3 months; therefore, this cutoff did not predict further evolution. We classified this new cohort based on the new cutoff observed in the primary population (BCR-ABL1 level at 3 months ≤1.5%); 77% of patients achieved BCR-ABL1 levels ≤1.5%, whereas 23% of patients did not. This cutoff also predicted the probability to obtain MMR by 12 months (91% vs. 44% (p=0.025). Conclusions: We have shown that when using the current version of GeneXpert, a BCR-ABL1cutoff of 10% at 3 months may underestimate the probability of not achieving an ulterior optimal response. We have shown that a new cutoff of 1.5% at 3 months can better identify patients with lower risk to achieve an optimal response at 12 months. This information should be taken into considerations when using this practical and widespread platform to monitor CML patients. Disclosures García Gutiérrez: Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Ramirez:Bristol-Myers-Squibb: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Roche: Honoraria. Steegmann:BMS: Honoraria, Other: Research funding for the Spanish CML Group; Pfizer: Honoraria, Other: Research funding for the Spanish CML Group; Novartis: Honoraria, Other: Research funding for the Spanish CML Group; Ariad: Honoraria, Other: Research funding for the Spanish CML Group.

Description: Introduction: Tyrosine kinase inhibitor (TKI) discontinuation is being investigated in pts with CML-CP with sustained DMR (defined here as MR4.5 or BCR-ABL1 ≤ 0.0032% on the International Scale [IS]), with the goal of treatment-free remission (TFR). Successful TFR has been reported previously for pts enrolled in DASFREE (CA180-406/NCT01850004), which showed that 48% of CML-CP pts with DMR for ≥ 1 year were able to stop dasatinib and maintain major molecular response (MMR) 12 months after discontinuation. Here we present updated results from pts followed for a minimum of 18 months, in order to understand the durability of TFR beyond 12 months. Methods: DASFREE is a phase 2, open-label, single-arm study in adult pts with CML-CP on dasatinib for ≥ 2 years as 1st-line or subsequent therapy. Eligible pts had dasatinib-induced DMR (MR4.5) confirmed at a local lab for ≥ 1 year prior to enrollment, with a 1-log reduction in BCR-ABL1 from baseline within 3-6.5 months of starting dasatinib. MR4.5 was confirmed at a central lab twice within 3 months prior to dasatinib discontinuation (screening phase). BCR-ABL1 was monitored centrally after discontinuation every month in the 1st year, then every 3 months. Pts resumed dasatinib at their previous dose if MMR was lost. The primary endpoint is the rate of MMR 12 months after dasatinib discontinuation. Secondary endpoints include BCR-ABL1 kinetics, molecular relapse-free survival (MRFS; no loss of MMR), relapse-free survival (RFS; no loss of MMR, complete cytogenetic response, or complete hematologic response, or progression to accelerated/blast phase [AP/BP] CML), rate of transformation to AP/BP, progression-free survival, and overall survival. Exploratory analyses include frequency of adverse events (AEs) after discontinuation and during dasatinib treatment, and MMR after reinitiating dasatinib. Results: In total, 84 pts enrolled between February 2014 and June 2016 discontinued dasatinib; all had ≥ 18 months of follow-up after discontinuation at the time of this analysis. Pt characteristics were previously reported (the majority [64%] had low Sokal scores; no pt had prior interferon; 37 pts were on 1st-line dasatinib, 47 on subsequent lines of dasatinib). At 18 months after discontinuation, the RFS rate was 48% (95% CI 37-58) in all pts (Figure), 54% (95% CI 38, 70) in 1st-line pts, and 42% (95% CI 28, 57) in pts who received subsequent-line therapy. With longer follow-up, 1 additional pt lost MMR at 18 months following discontinuation. Of the 45 pts who lost MMR and restarted treatment, 44 regained MMR (1 pt discontinued after only 1 molecular assessment) in a median of 2 months (range 1-4) and 42 regained MR4.5 in a median of 3 months (range 2-18). Analyses of baseline pt characteristics revealed that for the 40 pts who did not lose MMR after discontinuation, 15 (37.5%) were able to maintain MR4.5. Additionally, the median time in prior MR4.5 was 28 months (range 13-116) for all pts, and was similar for 1st-line pts who maintained (27 months [range 13-56]) or lost MMR (27 months [range 15-68]) at 12 months. With longer follow-up, AEs (any cause) identified were consistent with previous reports and were found to be similar on and off treatment: 8 (10%) pts off treatment and 8 (18%) pts on treatment experienced grade 3/4 AEs of any cause after restarting dasatinib (4.4% were drug related). No transformation events or deaths occurred. Of the 13 reported withdrawal events occurring in 8 (9.5%) pts, 10 were resolved (5 off treatment, 5 resolved after restarting treatment due to loss of MMR) after a median of 5 months (range 1-12) after onset. One pt discontinued after restarting dasatinib due to malignancy unrelated to treatment. In addition to efficacy and safety data, multivariate analyses evaluating prognostic factors for MMR will be presented. Conclusions: Additional follow-up of pts enrolled in DASFREE revealed that TFR remained durable at 18 months after discontinuing dasatinib. AEs reported here were consistent with the known safety profile of dasatinib, and withdrawal was well tolerated. Collectively, this trial, the largest dasatinib discontinuation trial to date, continues to support the feasibility and practicality of TFR in pts with CML-CP in DMR treated with dasatinib in the 1st line and beyond. Figure. Figure. Disclosures Shah: ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding. García Gutiérrez:Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Larson:Bristol-Myers Squibb: Consultancy; Takeda: Speakers Bureau. Saussele:Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria. Rea:Incyte: Honoraria; Bristol-Myers Squibb: 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; Pfizer: Honoraria. Mahon:Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Levy:Takeda (Millennium Pharmaceuticals, Inc.): Consultancy. Gómez-Casares:Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau. Pane:Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy. Nicolini:Incyte: Consultancy, Honoraria, Speakers Bureau; Sun Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Mauro:Pfizer: Consultancy; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding. Sy:Bristol-Myers Squibb: Employment. Martin Regueira:Bristol-Myers Squibb: Employment, Equity Ownership. Lipton:ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

Description: Introduction The clinical characteristics, treatment, cardiovascular events (CVE) and evolution of patients diagnosed with JAK2 V617F positive essential thrombocythemia (ET) with low allele burden (LAB) are scarcely studied. Its presence in people without a confirmed diagnosis of malignant hemopathy is called clonal hematopoiesis of uncertain significance (CHIP) and confers higher risk of developing CVE. The objective of this study was to compare the clinical characteristics and CVE of a series of JAK2 V617F-positive ET patients with 5%. Treatments received by both groups were not significantly different. None of the patients from both groups progressed to AML, whereas 1/48 vs. 6/137 of patients evolved to MF. Median follow-up of patients with LAB and HAB was 3.4 years [0.1-17.7] and 4.3 years [0.1-27.8], respectively (Table 1). Conclusions In these series of ET patients from the GEMFIN group, patients with LAB had significantly lower median platelet count at diagnosis and less CVE after diagnosis than patients with HAB, although CVRF and IPSET scores and treatment approach were similar. The clinical behavior of LAB patients may resemble that of individuals with CHIP. The therapeutic algorithm of ET patients with LAB may be somehow different than that of patients with HAB and therefore, might be revised. Disclosures Bellosillo: Astra-Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biocartis: Honoraria; Merck-Serono: 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; Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffman â€"La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; ThermoFisher: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; BMS: Honoraria. Hernandez Boluda:Incyte: Other: Travel expenses paid. Pérez:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.