scholarly journals Prognostic Significance of Baseline FLT3-ITD Mutant Allele Burden in Acute Myeloid Leukemia Treated with Intensive Chemotherapy with/without Sorafenib

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3983-3983 ◽  
Author(s):  
Fevzi Yalniz ◽  
Hagop M. Kantarjian ◽  
Tapan M. Kadia ◽  
Guillermo Garcia-Manero ◽  
Keyur Patel ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Mutant Allele ◽  
Optimal Cutoff ◽  
Allele Burden ◽  
Genetics Research ◽  
Group 2 ◽  
Allelic Burden ◽  
Group 1

Abstract Background Internal tandem duplication (ITD) mutation of the FMS-like tyrosine kinase-3 (FLT3) receptor gene occurs in about 25% patients with acute myeloid leukemia (AML) and confers a poor prognosis. Several studies have reported that a higher mutant allelic burden is associated with a worse prognosis. Methods Adult patients with FLT3-ITD mutated AML treated at our institution from January 2001 to January 2018, who had quantified FLT3-ITD allele burden, were identified. Patients with acute promyelocytic leukemia and core-binding factor AML were excluded.Patients were assigned into 2 groups; Group 1 included patients who received idarubicin and cytarabine (IA) containing induction and Group 2 included patients who received sorafenib in addition to IA containing regimens at induction. Mutant allelic burden was expressed as the ratio of area under the peak of mutant allele to total FLT3. Relapse free survival (RFS) for patients achieving complete response (CR)/CR with incomplete recovery (CRi) was defined as time from CR/CRi to relapse or death. Overall survival (OS) was defined as time from treatment to death. Patients were censored at last follow up. Time from therapy to allogeneic hematopoietic cell transplant (AlloHCT) was handled as a time-dependent variable. The optimal cutoff of mutant FLT3-ITD allelic burden was defined as the cutoff to divide the whole cohort with the highest statistical significance. Results A total of 183 patients withFLT3-ITD mutated AML were identified including 104 (57%) in Group 1 and 79 (43%) in Group 2. Baseline characteristics are summarized in Table 1. The median age was 52 years (range, 17-64). The median allelic burden of mutant was 33% (range, 0.3% to 88%). This was comparable between the two groups (p=0.6). The CR/CRi rates following induction for Group 1 vs Group 2 were 85% vs 99%, respectively (p=0.004). Overall, 111 (61%) patients received an AlloHCT, at any time during the follow up, more frequently in Group 2 than in Group 1 (67% vs 56%, respectively, p=0.1). The median RFS for Group 1 and 2 were 12 and 45 months, respectively (p=0.02); the median OS was 17 months in Group 1 and has not been reached in Group 2 (p=0.008) (Table 2). The optimal mutant allele burden cutoff for OS and RFS in the entire cohort was 1.55% (p=0.002) confirming the adverse effect of FLT3-ITD even at low level. The cutoff was 6.9% in Group 1, with no optimal cutoff value in Group 2 (Figure 1) confirming the value of sorafenib inFLT3-ITD mutated AML. When censored for AlloHCT; the FLT3-ITD cutoff for OS and RFS was 60% and 60% in the entire group. For Group 1 the cutoff values where 59% and 7.9% for OS and RFS, respectively. For Group 2 the cutoff values were 46% and 46%, respectively (Figure 2). On multivariate analysis, AlloHCT (HR 0.52; 95%CI 0.33-0.82; p=0.005), sorafenib (HR 0.6; 95%CI 0.38-0.93; p=0.02) and white blood cell count (HR 1.005; 95%CI 1.002-1.009) were independent predictors of OS with no impact by cytogenetics, concurrent NPM1, TP53, FLT3-D835 mutations or the FLT3-ITD allelic burden. Conclusion Although a higher FLT3-ITD allele burden is associated with a worse RFS and OS in patients with FLT3-ITD mutated AML treated with IA-based chemotherapy, it is no longer prognostic when sorafenib is added to the therapeutic regimen. Addition of sorafenib to intensive chemotherapy as well as AlloHSCT are associated with a significant improvement in OS on multivariate analysis. Disclosures Kadia: Novartis: Consultancy; BMS: Research Funding; Takeda: Consultancy; Celgene: Research Funding; Celgene: Research Funding; Jazz: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy; BMS: Research Funding; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Abbvie: Consultancy. Sasaki:Otsuka Pharmaceutical: Honoraria. Daver:BMS: Research Funding; ImmunoGen: Consultancy; Karyopharm: Consultancy; Sunesis: Research Funding; Novartis: Consultancy; Otsuka: Consultancy; Karyopharm: Research Funding; Novartis: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Sunesis: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; ARIAD: Research Funding; Alexion: Consultancy; Kiromic: Research Funding. DiNardo:Medimmune: Honoraria; Bayer: Honoraria; Abbvie: Honoraria; Celgene: Honoraria; Agios: Consultancy; Karyopharm: Honoraria. Pemmaraju:Affymetrix: Research Funding; SagerStrong Foundation: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding. Short:Takeda Oncology: Consultancy. Bose:Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; CTI BioPharma: Research Funding; Blueprint Medicines Corporation: Research Funding; Pfizer, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding; Novartis: Consultancy, Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Sunesis: Honoraria; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Orsenix: Honoraria; Sunesis: Honoraria; Orsenix: Honoraria; Abbvie: Research Funding; Jazz: Honoraria; Bristol-Myers Squibb: Research Funding; Abbvie: Research Funding; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria.

scholarly journals The Impact of Clonal Hematopoiesis of Indeterminate Potential on Survival in Patients with Newly Diagnosed Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4359-4359
Author(s):  
Koji Sasaki ◽  
Rashmi Kanagal-Shamanna ◽  
Guillermo Montalban-Bravo ◽  
Rita Assi ◽  
Kiran Naqvi ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Next Generation ◽  
Risk Of Death ◽  
Genetics Research ◽  
The Impact ◽  
Generation Sequencing

Abstract Introduction: Clearance of detected somatic mutations at complete response by next-generation sequencing is a prognostic marker for survival in patients with acute myeloid leukemia (AML). However, the impact of allelic burden and persistence of clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations on survival remains unclear. The aim of this study is to evaluate the prognostic impact of allelic burden of CHIP mutations at diagnosis, and their persistence within 6 months of therapy. Methods: From February 1, 2012 to May 26, 2016, we reviewed 562 patients with newly diagnosed AML. Next-generation sequencing was performed on the bone marrow samples to detect the presence of CHIP-associated mutations defined as DNMT3A, TET2, ASXL1, JAK2 and TP53. Overall survival (OS) was defined as time period from the diagnosis of AML to the date of last follow-up or death. Univariate (UVA) and multivariate Cox proportional hazard regression (MVA) were performed to identify prognostic factors for OS with p value cutoff of 0.020 for the selection of variables for MVA. Landmark analysis at 6 months was performed for the evaluation of the impact of clearance of CHIP, FLT3-ITD, FLT3D835, and NPM1 mutations. Results: We identified 378 patients (74%) with AML with CHIP mutations; 134 patients (26%) with AML without CHIP mutations. The overall median follow-up of 23 months (range, 0.1-49.0). The median age at diagnosis was 70 years (range, 17-92) and 66 years (range, 20-87) in CHIP AML and non-CHIP AML, respectively (p =0.001). Of 371 patients and 127 patients evaluable for cytogenetic in CHIP AML and non-CHIP AML, 124 (33%) and 25 patients (20%) had complex karyotype, respectively (p= 0.004). Of 378 patients with CHIP AML, 183 patients (48%) had TET2 mutations; 113 (30%), TP53; 110 (29%), ASXL1; 109 (29%), DNMT3A; JAK2, 46 (12%). Of 378 patients, single CHIP mutations was observed in 225 patients (60%); double, 33 (9%); triple, 28 (7%); quadruple, 1 (0%). Concurrent FLT3-ITD mutations was detected in 47 patients (13%) and 12 patients (9%) in CHIP AML and non-CHIP AML, respectively (p= 0.287); FLT3-D835, 22 (6%) and 8 (6%), respectively (p= 0.932); NPM1 mutations, 62 (17%) and 13 (10%), respectively (p= 0.057). Of 183 patients with TET2-mutated AML, the median TET2 variant allele frequency (VAF) was 42.9% (range, 2.26-95.32); of 113 with TP53-mutated AML, the median TP53 VAF, 45.9% (range, 1.15-93.74); of 109 with ASXL1-mutated AML, the median ASXL1 VAF was 34.5% (range, 1.17-58.62); of 109 with DNMT3A-mutated AML, the median DNMT3A VAF was 41.8% (range, 1.02-91.66); of 46 with JAK2-mutated AML, the median JAK2 VAF was 54.4% (range, 1.49-98.52). Overall, the median OS was 12 months and 11 months in CHIP AML and non-CHIP AML, respectively (p= 0.564); 16 months and 5 months in TET2-mutated AML and non-TET2-mutated AML, respectively (p <0.001); 4 months and 13 months in TP53-mutated and non-TP53-mutated AML, respectively (p< 0.001); 17 months and 11 months in DNMT3A-mutated and non-DNMT3A-mutated AML, respectively (p= 0.072); 16 months and 11 months in ASXL1-mutated AML and non-ASXL1-mutated AML, respectively (p= 0.067); 11 months and 12 months in JAK2-murated and non-JAK2-mutated AML, respectively (p= 0.123). The presence and number of CHIP mutations were not a prognostic factor for OS by univariate analysis (p=0.565; hazard ratio [HR], 0.929; 95% confidence interval [CI], 0.722-1.194: p= 0.408; hazard ratio, 1.058; 95% confidence interval, 0.926-1.208, respectively). MVA Cox regression identified age (p< 0.001; HR, 1.036; 95% CI, 1.024-1.048), TP53 VAF (p= 0.007; HR, 1.009; 95% CI, 1.002-1.016), NPM1 VAF (p=0.006; HR, 0.980; 95% CI, 0.967-0.994), and complex karyotype (p<0.001; HR, 1.869; 95% CI, 1.332-2.622) as independent prognostic factors for OS. Of 33 patients with CHIP AML who were evaluated for the clearance of VAF by next generation sequencing , landmark analysis at 6 months showed median OS of not reached and 20.3 months in patients with and without CHIP-mutation clearance, respectively (p=0.310). Conclusion: The VAF of TP53 and NPM1 mutations by next generation sequencing can further stratify patients with newly diagnosed AML. Approximately, each increment of TP53 and NPM1 VAF by 1% is independently associated with 1% higher risk of death, and 2% lower risk of death, respectively. The presence of CHIP mutations except TP53 does not affect outcome. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Short:Takeda Oncology: Consultancy. Ravandi:Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Sunesis: Honoraria; Xencor: Research Funding; Jazz: Honoraria; Seattle Genetics: Research Funding; Abbvie: Research Funding; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria; Abbvie: Research Funding; Jazz: Honoraria; Xencor: Research Funding; Orsenix: Honoraria; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria. Kadia:BMS: Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Celgene: Research Funding. DiNardo:Karyopharm: Honoraria; Agios: Consultancy; Celgene: Honoraria; Medimmune: Honoraria; Bayer: Honoraria; Abbvie: Honoraria. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding.

Prognosis Impact of Positive Minimal Residual Disease By Flow Cytometry Prior to Transplant According to the Cut-Off Threshold in Patients with Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 15-16
Author(s):  
Claudia Nunez-Torron ◽  
Fernando Martin Moro ◽  
Juan Marquet Palomanes ◽  
Miguel Piris-Villaespesa ◽  
Ernesto Roldan ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Residual Disease ◽  
Allogeneic Transplant ◽  
Group 3 ◽  
Baseline Characteristics ◽  
Group 2 ◽  
Minimal Residual ◽  
Group 1

Introduction: Patients with Acute Myeloid Leukemia (AML) and positive Minimal Residual Disease (MRD) prior to allogeneic transplant are currently considered to be a group at high risk of relapse. Multiparameter flow cytometry is a standard technique to measure MRD, and generally we use a 0.1% threshold for positivity. The clinical significance of those patients with an MRD levels &gt;0% but &lt;0.1% is uncertain and it is recommended to define the prognosis of this subgroup. Material and methods: We performed a single-center retrospective analysis of 88 patients transplanted between 2012 and 2020. All patients achieved complete remission (CR) with or without hemoperipheral recovery prior to allogeneic transplant. We have divided our cohort into three groups according to MRD state by flow cytometry: Group 1 patients with negative MRD, Group 2 patients with MRD level &gt;0% but &lt;0.1% and Group 3 patients with MRD ≥ 0.1%. The baseline characteristics of each group were compared using the Chi2 test. The survival analysis was performed through Kaplan-Meier method and the risk was calculated with Cox regression. The Overall Survival (OS) was defined as the time from transplantation to death and the Relapse-Free Survival (RFS) as the time from transplantation to either relapse or death. P&lt;0.05 was defined as statistically significant difference. Results: The baseline characteristics of our cohort are reflected in Table 1. We did not find statistical significant differences except for the response to induction. The median follow-up of the entire cohort was 13.5 months (range 6-43.5). The 4-year RFS (4y-RFS) was 47% and the 4-year OS (4y-OS) 50%. The 4y-RFS was 52.5% in Group 1 vs 59% in Group 2 vs 30% in Group 3. The 4y-OS was 60% in Group 1 vs 60% in Group 2 vs 31% in Group 3 (Image 1). The Hazard Ratio (HR) for RFS and OS comparing Group 1 vs Group 2 was 0.9 [95% CI ((0.3-2.5)] and 1.1 [95% CI (0.4-3)] respectively. The HR for the RFS and OS comparing Group 1 vs 3 was 1.2 [95% CI (0.9-1.7)] and 1.2 [95% CI (0.8-1.6)]. We have stratified patients according to the European LeukemiaNet risk classification. In Group 1, the 4y-RFS was 79% in patients with Favorable Risk (FR) vs 55% in those with Intermediate Risk (IR) and 53% in patients with Adverse Risk (AR) [HR 1.2, 95% CI (0.6-2.3)] and the 4y-OS was 79% vs 54% vs 53% respectively [HR 1.3, 95% CI (0.6-2.5)]. In Group 2, the 4y-RFS was 100% in those with FR vs 83% in IR vs 33% in AR [HR 3.9, 95% CI (0.4-30)] and the 4y-OS was 100% vs 82% vs 36% respectively [HR 4, 95% CI (0.5-32%)]. In Group 3, the 4y-RFS in patients with FR was 82% vs 0% in IR vs 0% in AR [HR 2.1, 95% CI (1.1-4.1)] and the 4y-OS was 82% vs 0% vs 0% respectively [HR 1.6, 95% CI (0.8-3.3)] (Image 2). Conclusions: In our cohort, positive MRD &gt;0.1% prior to transplant identified a group with worse RFS and OS compared to those with negative MRD or positive MRD level &gt;0% but &lt;0.1%. Positive MRD &gt;0.1% is especially relevant in the IR and AR groups of the European LeukemiaNet risk classification. In the AR subgroup even any detectable level of positive MRD could identify patients with unfavorable post-transplant OS and RFS outcomes. We must establish post-transplant strategies in these patients to improve survival. Disclosures Garcia-Gutiérrez: Pfizer: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Incyte: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding.

Impact of Second-Generation Tyrosine Kinase Inhibitors As Second Line Treatment for Patients with Chronic Myeloid Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3780-3780 ◽  
Author(s):  
J Valentin Garcia-Gutierrez ◽  
Pilar Herrera ◽  
Lorena L Abalo ◽  
Maria Dolores Rey ◽  
Maria Calbacho ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Second Generation ◽  
Kinase Inhibitors ◽  
Salvage Treatment ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Group 2 ◽  
Group 1

Abstract Abstract 3780 Background: Imatinib has shown an outstanding improvement in the prognosis of chronic myeloid leukemia (CML) patients. Nevertheless, some of them have proven to be resistant or intolerant to imatinib. For these patients, second-generation tyrosine kinase inhibitors (TKIs) are available. These drugs may be indicated in different circumstances as primary or second resistance, suboptimal responses or intolerance.The real benefits of second-generation TKIs as salvage treatment are surely in dependence with the indication in each case and are, therefore, difficult to evaluate. Second-generation TKIs are being evaluated as first line treatment compared to imatinib with quite favourable outcomes so long, but have not yet been compared with a strategy combining imatinib followed by second-generation TKIs for patients with previous unfavourable responses. Aims: Evaluate the real benefit of second-generation TKIs in second line treatment for CML patients regardless of the indication for its use. Study groups and methods: We have studied 98 patients treated with imatinib as first tyrosin kinase inhibitor (TKI) in our centre. These patients have been classified according whether second-generation TKIs were available or not. Group 1 includes 60 patients treated since 2001 to 2005, when the only salvage treatment was an increased imatinib dose, chemotherapy or allogenic stem cell transplantation. Group 2 includes 38 patients treated since 2005 until today. In the second group second-generation TKIs (dasatinib or nilotinib) were used according to the indications mentioned above. Follow up period was 39 months and 32 months for group 1 and 2 respectively. Sokal risk index was high in 14% and 16%; intermediate 42 % and 40%; and low in 44% and 44 % for group 1 and 2 respectively. Results: The use of second-generation TKIs as second line resulted in significant benefit to patients in terms of responses. Complete cytogenetic responses (CCR) at any time were achieved in 73% and 86% for patients in group 1 and 2 (p=.09). Probability of the achievement of mayor molecular responses (MMR) was 42% vs 71% for group 1 and 2 respectively [p=.009; ratio=0.3 (0.1–0.7)]. Response rates at the last follow up for group 1 and 2 were: MMR: 33% vs 62%; CCR: 68% vs 94% and failure 32% vs 6% (p=.008). Progression free survival (including all the patients who started treatment) was 88% vs 94% for group 1 and 2 respectively. We found no correlation among responses and some prognostic factors (Sokal index, mutations at the TK domain or imatinib plasma levels). Imatinib doses were increased in 21 patients (35%) in group 1 (reasons for increasing doses were failure in 14 patients and suboptimal responses in 7 patients). 10 patients (26%) in group 2 received second-line TKIs as second line treatment (4 because imatinib failure, 3 by suboptimal responses and 3 due to intolerance). Conclussions: The use of second-generation TKIs as salvage has improved the responses of CML patients treated with TKIs. Once the second-generation TKIs has shown benefit compared to imatinib in first line treatment, this therapeutic strategy should be compared vs the use of imatinib followed of second-line TKIs for patients without optimal responses to imatinib. Disclosures: Montalban: Red Temática de Investigación Cooperativa en Cancer (RETICC): Research Funding; Asociación Española contra el Cancer: Research Funding.

scholarly journals Preliminary Safety and Efficacy Results with an Intermittent Schedule of the PI3kδ Inhibitor ME-401 Alone or in Combination with Rituximab for B-Cell Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2893-2893 ◽  
Author(s):  
Andrew D. Zelenetz ◽  
Jacob D. Soumerai ◽  
Deepa Jagadeesh ◽  
Nishitha Reddy ◽  
Anastasios Stathis ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Objective Response ◽  
Intermittent Schedule ◽  
Safety And Efficacy ◽  
Group 2 ◽  
Grade 3 ◽  
Expansion Cohort ◽  
Group 1

Abstract Background: ME-401, a potent and selective oral PI3kδ inhibitor, achieved a high rate of early and durable responses in patients with follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) when administered once daily in 28-day cycles on a continuous schedule (CS) in a dose escalation Phase 1b study (Soumerai et al, ASCO 2018:#7519). The most common adverse events (AEs) were the delayed onset (beyond Cycle 2) of grade 3 diarrhea and rash, which were reversible with drug interruption and/or corticosteroids. These delayed AEs were thought to be due to pathway inhibition in regulatory T cells (Treg) leading to a disruption in immune homeostasis. We hypothesized that an intermittent schedule (IS) beyond Cycle 2 might mitigate or reduce the incidence of significant delayed AEs. The IS tested was selected based on the kinetics of Treg repopulation, and consists of ME-401 administered on days 1-7 of a 28-day cycle. We report preliminary results of this strategy. Methods: Group 1 included 31 patients with relapsed FL (n = 22) or CLL/SLL (n = 9) who received ME-401 on a CS at doses ≥60 mg per day. 11/29 patients (38%) who received >2 cycles of therapy had developed delayed grade 3 AEs on CS and could be re-challenged with either the CS or IS (from December 2017 onward) following recovery from toxicity. The other 18/29 patients (62%) had not developed a grade 3 AEs of interest on CS and, beginning in December 2017, were switched to IS after a median of 26 weeks (range, 8-49) of daily dosing. Group 2 included 15 patients with relapsed FL (n = 9), diffuse large B-cell lymphoma (n = 4), marginal zone lymphoma (MZL, n = 1), and CLL (n = 1) who received rituximab 375 mg/m2 x 8 doses over 6 months and ME-401 at 60 mg daily x 2 cycles then switched to the IS. Group 3 includes 30 patients with relapsed FL/CLL/SLL enrolling in an expansion cohort of ME-401 alone at 60 mg daily x 2 cycles then switching to IS. Results: Group 1: Of the 11 patients who developed a delayed grade 3 AE on CS, 6 were never re-challenged, 2 were re-challenged with CS with recurrence of their AE, and 3 were re-challenged with IS without recurrence of their AE. Of the 18 patients switched to the IS, and with a median follow-up of 5.2 months (range, 2.3-6.6) on IS, 3 developed grade 3 diarrhea on IS, 2 in the first cycle and 1 in the second cycle after the switch to IS, of whom 2 have been re-treated with IS for 1+ and 5+ months without recurrence of the AE. One patient was not evaluable for response due to discontinuation on Day 28 for personal reasons and 27/30 (90%) evaluable patients achieved an objective response. With a median follow-up of 9.4 months (range, 2.2-17.5) from enrollment, only 2/27 (7%) responders had disease progression (PD) on CS and were discontinued. Of the 18 patients who were switched to IS, only 1 SLL patient with a partial response (PR) achieved on CS developed PD on IS and was successfully rescued with switch back to CS. Another CLL patient in PR on CS had 10% increase in SPD from nadir in Cycle 5 on the IS and was switched back to CS. Group 2: 10/15 patients have completed 2 cycles of daily dosing at the time of analysis and were systematically switched to IS. With a median follow-up of 3.4 months (range, 1.5-5.7) on IS, only 1/10 patients developed delayed grade 3 diarrhea in the first cycle after switch to IS. 7/10 patients (70%) with FL/MZL achieved an objective response and no PD was reported with a median follow-up of 5.2 months (range, 3.1-7.5) from enrollment. Conclusions: Preliminary data suggest that switching to an intermittent schedule consisting of ME-401 administered on days 1-7 of a 28-day cycle following 2 cycles of continuous daily dosing was associated with a low rate of delayed grade 3 AEs and was associated with preservation of response in the vast majority of patients. All delayed grade 3 AEs of interest on IS occurred within 1-2 cycles of switching from CS to IS, suggesting that these might have represented a delayed effect of daily dosing. IS may also be a suitable re-treatment strategy in patients with delayed AEs on CS. Safety and efficacy data for the expansion cohort of 30 patients treated with ME-401 at 60 mg for 2 cycles then switched to IS will be presented at the meeting. A randomized study comparing CS and IS in FL is planned. Disclosures Zelenetz: Abbvie: Research Funding; Celgene: Consultancy; AstraZeneca: Consultancy; Novartis/Sandoz: Consultancy; Amgen: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding. Reddy:MEI Pharma: Research Funding. Stathis:Oncology Therapeutic Development: Research Funding. Ghalie:MEI Pharma: Employment, Equity Ownership; Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy.

scholarly journals Real Life Study on Allogeneic Hematopoietic Cell Transplantation Practice According to International Guidelines and Its Impact on Survival in Acute Myeloid Leukemia French Population

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4133-4133
Author(s):  
Loic Abed ◽  
Morgane Mounier ◽  
Marie Robin ◽  
Stephanie Nguyen Quoc ◽  
Nicole Raus ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Therapeutic Strategy ◽  
Hematopoietic Cell Transplantation ◽  
Real Life ◽  
Cancer Registries ◽  
Response To Treatment ◽  
Group 2 ◽  
Acute Myeloid ◽  
Group 1

Abstract Introduction Allogeneic Hematopoietic Cell Transplantation (allo-HCT) has proved its efficiency in reducing Acute Myeloid Leukemia (AML) recurrence, although it was associated with high rates of complications especially in older patients. The worldwide number of allo-HCT has increased within 35 years, from 10.000 transplantations before 1985 to over a million in 2012. The decision to perform transplantation depends on the estimated risk-benefit ratio. High-risk prognostic factors include cytogenetics, age at diagnosis, presence of comorbidities and the response to treatment. By using combination of risk factors, international recommendations have been published to harmonize AML care and maximize the benefit of using allo-HCT. The principal aim of this study is to describe real life AML care management in all consecutive patients diagnosed and registered on 3 regional cancer registries in France, to analyze their outcome after different therapeutic strategies, following or not the international recommendations. Method This retrospective study included all AML patients diagnosed between January 2012 and December 2016 reported to the French population data-based of regional cancer registries specialized in hematological malignancies. Allo-HCT data were extracted from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) registry. Two groups of patients were defined according to the treatment received: i) group 1, patients who have received the best recommended care including allo-HCT considering HLA compatibility and best donor choice or best conventional treatment according to therapeutic guidelines based on individuals and clinical characteristics from The American Society for Blood and Marrow Transplantation guidance; ii) group 2, patients who received a treatment outside the recommendations. To study the impact of therapeutic decision on overall survival, a case-control study was performed using a one for one matching between group 1 and group 2. An exact matching on individual and disease characteristics (cytogenetic risk, Charlson score class, age group at diagnosis, subtype AML and response to treatment) allowed to pair-match patients following or not the international recommendations for therapeutic strategy. Net survival was estimated until five-year using non-parametric Pohar-Perme estimator (survival distribution compared using Grafféo test). Results A total of 1039 AML patients diagnosed from 2012 to 2016 were identified, 449 (43 %) received a curative treatment and 540 patients a non-curative treatment (hypomethylating agents, low dose of cytarabine or other palliative treatment, best supportive care combined to no effective treatment). Based on available clinical data, 430 patients were included in the study. Group 1 included 296 patients (68%), 167 males and 129 females with 54 receiving allo-HCT (32 geno-identical and 22 unrelated). Group 2 included 134 patients (31%), 72 males and 62 females with 94 receiving allo-HCT (14 geno-identical, 50 unrelated and 30 mismatched). In patients for whom allo-HCT represented the best option according to the recommendations (Figure B, n = 44), a very significant lower survival was observed in patients who did not receive allo-HCT when they were compared to patients who received allo-HCT, with a 5 year-overall survival probability of 7 % and 50 % respectively (p= 0.019). In patients for whom allo-HCT was not recommended (Figure A, n = 42), we did not observe any significant difference of survival between patients transplanted or not. Conclusion This analysis shows the importance of allo-HCT decision in AML patients, especially when following international guidelines. Although individual risks factors have been previously studied, our analysis sums up theses factors and allow to understand the importance of integrating allo-HCT in the therapeutic strategy of AML and to re-evaluate current practices and its impact on patient outcome. Figure 1 Figure 1. Disclosures Pigneux: Roche: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Amgen: Consultancy; Novartis: Consultancy, Research Funding. Forcade: Novartis: Other: travel grant. Mohty: Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Sanofi: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria. Dulery: Novartis: Honoraria; Takeda: Consultancy; Gilead: Other: Travel support and registration fees for scientific meetings .

scholarly journals Prognosis of Acute Myeloid Leukemia with Myelodysplasia-Related Changes According to the Different Subgroups of the WHO 2016 Classification in Patients Candidates to Intensive Chemotherapy

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 30-31
Author(s):  
Claudia Nunez-Torron ◽  
Juan Marquet Palomanes ◽  
Valentín Garcia-Gutiérrez ◽  
Adolfo Saez ◽  
Alejandro Luna ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Intensive Chemotherapy ◽  
Consolidation Therapy ◽  
Complex Karyotype ◽  
History Of ◽  
Baseline Characteristics ◽  
Group 2 ◽  
Acute Myeloid ◽  
Group 1

Introduction: In the WHO 2016 classification, within the category of Acute Myeloid Leukemia with Myelodysplasia-Related Changes (AML-MRC), 3 subgroups are distinguished: 1) AML with Defining Cytogenetic Abnormality (AML-DCA) 2) AML with Previous History of MDS or MDS/MPN (AML-PHM) and 3) AML with Multilineage Dysplasia (AML-MD). The prognostic impact of significant Multilineage Dysplasia in patients without accompanying adverse cytogenetics or a history of prior hematologic malignancy is currently unclear. Objectives: To analyze the impact of MD as a classification criterion of AML-MRC compared to the rest of AML-MRC subgroups in terms of survival. To analyze if there are characteristics in global cohort that could us to predict worse survival outcomes. Material and methods: We performed a retrospective analysis of 48 patients candidates to intensive chemotherapy treated in a single center between 2013 and 2019. We divided our cohort into 2 groups 1) AML-MD and 2) AML-DCA + AML -PHM. The baseline characteristics of each group were compared using the Chi2 test. The survival analysis was performed through Kaplan-Meier method and the risk was calculated with Cox regression. The Overall Survival (OS) was defined as the time from diagnosis to death and the Event-Free Survival (EFS) as the time from diagnosis to either relapse or death. P&lt;0.05 was defined as statistically significant difference. Results: The baseline characteristics of the global cohort are reflected in Table 1. The median follow-up of the entire population was 15 months (0-77). The median OS and EFS were 18 months and 11 months, respectively. The median OS was 14 months in group 1 vs 19 months in group 2 with a Hazard Ratio (HR) of 0.9 (95% CI 0.3-2.2, p = 0.8). The median EFS in Group 1 was 10 months vs 14 months in group 2 (HR 0.9 95% CI (0.4-2.1), p = 0.9) (Image 1). In global cohort, 11 patients had a complex karyotype at diagnosis. The median OS in these patients was 23 vs 16 months in those with other cytogenetic alterations or normal karyotype (HR 0.8 (95% CI (0.3-2.1), p = 0.8) and EFS 14 vs 10 months [HR 1.1 (95% CI (0.5-2.5), p = 0.6]. 34 patients received transplantation (HSCT) as consolidation therapy (33 allogeneic, 1 autologous). In transplanted patients the median OS was 26 months vs 4 months in those that did not consolidate with transplant [HR 4.5 (95% CI 2-10, p &lt;0.0001] and the EFS 14 months vs 3 months [HR = 4.2, 95% CI (2-8.5), p = &lt;0.001] (Image 2). We performed a multivariate analysis including AML-DM vs AML-DCA + AML -PHM, complex karyotype, European LeukemiaNet classification at diagnosis, response to induction and consolidation with transplantation vs not received transplantation. The variables with a significant HR for EFS were not received transplantation as consolidation therapy [HR 2.8, 95% CI (1.2-6.1), p = 0.01] and the response to induction [HR 1.6, 95% CI (1.05-2.4), p = 0.3]. The only variable with a significant HR for OS was consolidation with transplantation (HR 3.3 (CI 95 % 1.4-8), p &lt;0.01). Conclusions: patients with AML-MRC are a high-risk group in terms of OS and EFS. Although allogeneic transplantation in these patients improves survival, the prognosis remains poor. In our cohort, morphological dysplasia without cytogenetic criteria or previous hematological neoplasia identified a high-risk subgroup with similar results to the other two subgroups. The results in the AML-MD subgroup are currently controversial, so we probably need to better characterize this subgroup in future studies. Disclosures Garcia-Gutiérrez: Incyte: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding.

Changes of JAK2 V617F Allele Burden Over Time in Patients with Polycythemia Vera or Essential Thrombocythemia: A Retrospective Study of 172 Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1892-1892
Author(s):  
Elisabetta Antonioli ◽  
Alessandra Carobbio ◽  
Lisa Pieri ◽  
Alessandro Pancrazzi ◽  
Paola Guglielmelli ◽  
...  
Keyword(s):  
Jak2 V617f ◽  
Repeated Measure ◽  
Interval Time ◽  
Allele Burden ◽  
Group 3 ◽  
Group 2 ◽  
Over Time ◽  
Group 1 ◽  
Median Interval

Abstract Abstract 1892 Poster Board I-915 There are conflicting results about quantitative modifications of V617F allele burden in patients (pts) with myeloproliferative neoplasms (MPN) who are either therapy-naive or are treated with hydroxyurea (HU). In a retrospective single center study in 48 pts with polycythemia vera (PV) or essential thrombocythemia (ET) the granulocyte JAK2V617F allele burden remained stable over time (median follow-up was 34 months for PV and 23 for ET) irrespective of the pts being treated or not with cytotoxic therapy (Theocharides A et al, Haematologica 2008). Conversely, another study in 25 patients reported a significant reduction of V617F allele burden (>30% of baseline level) after HU therapy in 52% of the pts, becoming indetectable in 3 of them (Girodon F et al, Haematologica 2008). The aim of this study was to evaluate any modifications of JAK2V617F allele burden during long-term follow-up in patients with PV or ET and the effects of HU treatment. This two-center (Firenze and Bergamo) retrospective study concerned 172 patients with a diagnosis of PV or ET according to the WHO criteria. The only study inclusion criteria were the presence of JAK2V617F mutation and the availability of at least two sequential blood samples drawn at an interval time of at least 6 months. The JAK2-V617F allele load was measured by sensitive quantitative RT-PCR in granulocyte DNA according to the method of Lippert et al (Blood 2006). Differences between median values of JAK2 V617F allele burden were tested by the Wilcoxon matched-pairs signed-ranks test. Repeated measure test for JAK2 V617F mean change over time, irrespective of diagnosis, was also calculated to investigate a significant variance among ordered time measures. There were 103 pts with PV and 69 with ET; median age was 56 yr (range, 15–84), females were 49%. The median interval time between the baseline and follow-up sample in the whole pt population was 27 months (range 6–60), 26 and 28 months for ET and PV, respectively. The median patient follow-up was 3 years (range 0.5–25); no evolution to myelofibrosis or acute leukemia was recorded. According to previous reports, the mean V617F burden was significantly greater in PV than in ET pts (50 ± 26% and 32 ± 18%, respectively; p <0.0001). Sixty-nine pts (41 PV, 28 ET) remained untreated during follow-up (Group 1), whereas 103 received HU; of the latter, 60 pts were already on treatment at the time of first genotyping (Group 2) whereas 43 patients were chemotherapy-naive and started HU after the first blood sampling (Group 3). In Group 1 pts, the median interval between 1st and 2nd sample was 26 months (range 6–60)for PV pts and 24 mo (range 6–59) for ET pts. The JAK2 V617F allele burden was 47.7±22.3% and 48.3±18.9% in the 1st and 2nd sample in PV pts, respectively, and 25.2±13.1% and 28.6±13.5% in case of ET pts, without any significant difference. In pts included in Group 2, the median interval between 1st and 2nd sample was 28 months (range 6–54) for PV pts and 28 mo (range 6–60) for ET pts. The JAK2 V617F allele burden was 55.1±29.2% and 60.3±25.6% in the 1st and 2nd sample in PV pts, respectively, and 36.3±21.7% and 40.7±22.9% in case of ET pts (P=.039). Considering PV and ET pts together, there was a statistically significant increase of V617F allele burden over time from 47.9±28.0% in the 1st sample to 52.8±26.3% in the 2nd (P= .023, repeated measure test). Among pts of Group 3, the median interval time between 1st and 2nd sample was 32 months (range 10–48) for PV pts and 24 mo (range 7–58) for ET pts. The JAK2 V617F allele burden was 47.0±26.2% and 45.5±20.8% in the 1st and 2nd sample in PV pts, respectively, and 37.3±16.2% and 33.3±15.0% in case of ET pts (P= .024). In conclusion, within the observation period of this study we found no evidence for a time-dependent increase of V617F allele burden in untreated PV and ET pts, although we cannot exclude that these results might be related to the relatively short follow-up. Accordingly, in a previous study in ET pts we found that the mutant allele burden increased significantly after 10 years from diagnosis (Carobbio A et al., Exp Hematol, 2009). Furthermore, we observed a very modest reduction of V617F allele burden in HU newly treated ET patients, while in previously treated PV and ET patients the allele burden actually increased over time, suggesting that HU has very little if any likelihood to impact on the size of mutant hematopoietic cell clone. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Acute Myeloid Leukemia with Myelodisplasia-Related Changes (AML-MRC) Defined Only By Morphological Findings May Not Represent a Poor Prognosis AML

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2612-2612
Author(s):  
Ana Pérez ◽  
Olga Salamero ◽  
Helena Pomares ◽  
Maria Julia Montoro ◽  
Montserrat Arnan Sangerman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Poor Prognosis ◽  
Advisory Committees ◽  
Group 3 ◽  
Group 2 ◽  
Acute Myeloid ◽  
Group 1

According to the 2016 WHO classification, AML-MRC encompasses an heterogeneous group of acute myeloid leukemias (AML) comprising: AML emerged from a previous myelodysplastic syndrome (MDS) or myeloproliferative /myelodysplastic disease (group 1), AML with MDS-defining cytogenetic abnormalities (group 2), or acute myeloid leukemia (AML) with dysplasia in at least 2 cell lineages without the above mentioned (group 3). In spite that AML-MRC has been considered a high-risk entity with poor prognosis, little is known on the relationship of clinical and biological characteristics with outcomes in these three groups. The aim of this study was to describe the clinical and biological characteristics of patients with AML-MRC and analyze their prognostic variables and outcomes. We retrospectively analyzed AML-MRC cases diagnosed between January-2009 and December- 2018 in two institutions. Descriptive variables were studied to compare the three AML-MRC groups. AML cytogenetic risk and response were defined according to the European Leukemia Net recommendations. Overall survival (OS) was considered as the time from the diagnosis to the last visit. Survival analysis were performed with Kaplan Meier method and comparisons with the log-rank test. Among 575 cases of AML identified, 186 (32.3%) met AML-MRC criteria and were included in the study. The main patient characteristics are shown in Table1. Median age was 72 (range, 22-88) years and 32% were female. Adverse karyotype was present in 29% of patients, being more prevalent in the AML-MRC group 2. Sixty one patients (33%) received an intensive chemotherapy approach and 36 (19%) an allogeneic stem cell transplantation. Patients in group 3 exhibit a higher probability of achieving a complete response than groups 1 and 2 (Table 2). After a median follow-up for survivors of 28.5 months (range, 5-130), 149 (80%) died in this period. Three years Overall Survival (OS) for patients in groups 1, 2 and 3 was 3 (0-117), 5 (0-93) and 10 (0-130) months, respectively (p=0.012) (Figure 1). Type of treatment (intensive, non intensive or best supportive care) and cytogenetic risk also showed impact on OS. Multivariant analysis adjusting these factors showed that patients in group 3 also presented better OS than patients in group 1 (HR=0,42 [IC95% 0,18-0,84], p=0,02), both with around a 30% of patients with adverse cytogenetics. To conclude the present study suggests that group 3 of AML-MRC, for which the diagnosis is based solely on morphologic findings, showed better prognosis than the other groups. A more detailed molecular characterization might contribute to improve prognostic stratification of this heterogeneous AML entity, particularly in patients with non-high risk cytogenetics. Disclosures Salamero: Pfizer: Honoraria; Daichii Sankyo: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Valcárcel:Jazz Pharmaceuticals: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: spouse is an employee in the company, Speakers Bureau; Pfizer: Honoraria. Bosch:AstraZeneca: Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals Clinical relevance of IDH1/2 mutant allele burden during follow-up in acute myeloid leukemia. A study by the French ALFA group

Haematologica ◽  
2018 ◽  
Vol 103 (5) ◽  
pp. 822-829 ◽  
Author(s):  
Yann Ferret ◽  
Nicolas Boissel ◽  
Nathalie Helevaut ◽  
Jordan Madic ◽  
Olivier Nibourel ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Relevance ◽  
Myeloid Leukemia ◽  
Mutant Allele ◽  
Allele Burden ◽  
Acute Myeloid

Switching to a Second Generation TKI in Chronic Myeloid Leukemia Patients with Late Suboptimal Response with Imatinib Obtained Better Molecular Responses That the “Watch and Wait” Approach. an Experience of a Multicenter Registry in Patients Outside Clinical Trials

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3768-3768
Author(s):  
J Valentin Garcia-Gutierrez ◽  
Begoña Maestro ◽  
Luis Felipe Casado ◽  
Manuel Perez-Encinas ◽  
Isabel Massague ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Second Generation ◽  
Molecular Response ◽  
Treatment Change ◽  
Molecular Responses ◽  
Group 2 ◽  
Group 1

Abstract Abstract 3768 Introduction: Tyrosine kinase inhibitors (TKIs) have dramatically changed chronic myeloid leukemia prognostic. The European Leukemia Net guidelines are widely used for patients treated with TKIs. While strategies for patients with optimal response and failure after imatinib are clear, there are doubts about the best treatment option for patients with suboptimal response (SubR), specially for late SubR (patients with complete cytogenetic response (CCyR) but not mayor molecular response (MMR) after 18 months of treatment). Patients with MMR seem to have better outcomes than patients with CCyR but not MMR, but at this time, there are few data showing the benefits of treatment change in this group of patients. Aims: To identify the benefits of treatment change in patients with late SubR, outside clinical trials, in the setting of a multicenter hospital-based registry. Patients and methods: We have studied retrospectively a group of 488 CML chronic phase patients treated with imatinib as first TKI, identifying 96 patients (19%) with SubR criteria (following the ELN recommendations) after 18 months of treatment. These patients have been classified according to the strategy followed by their physician after SubR identification. Group 1 includes 65 patients (67%) continuing with imatinib (either initial dose or higher dose) and group 2 includes 31patients (33%) that were changed to second generation TKI (2GTKI: dasatinib or nilotinib). Sokal risk index was high in 17% and 9%; intermediate 44 % and 41%; and low in 39% and 50 % for group 1 and 2, respectively. 31% and 30% of patients had received interferon prior to imatinib. Molecular response was analyzed after 12 months of identifying late SubR (for group 1) or after switching to 2GTKI, for group 2. Results: The use of 2G TKIs resulted in significant benefit to patients in terms of improving molecular responses. Complete molecular responses (CMR) and MMR rates were 3.8% vs 27% and 41.5% vs 69% for group 1 and 2 respectively (p=0.006). Time for the achievements the best molecular responses was significantly lower for patients receiving second generation TKI (4.1 vs 20.2 months, p=0.004). Probabilities of treatment failure, defined as loss of CCR, were also higher in patients remaining with imatinib (15.4% vs 5.7% (p=0.12). Progression free survival was 93.8% vs 97.2% (p=0.18) for group 1 and 2 respectively. Changing treatment for late SubR patients was also safe, and only 17% of patients needed to switch to another TKI due to intolerance. Conclusions: In CML patients treated with Imatinib with late SubR, and outside clinical trials, switching to second generation TKI increased probabilities of achievement a deeper molecular response, with a good safety profile. Disclosures: Casado: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Steegmann:Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau.

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