Introduction: Tyrosine kinase inhibitor (TKI) therapy can result in the adverse events of prolong... more Introduction: Tyrosine kinase inhibitor (TKI) therapy can result in the adverse events of prolonged anemia, thrombocytopenia and/or leukopenia via c-kit blockade in hematopoietic stem cells. Previous studies have reported that even low-grade adverse events could impair a patient's health-related quality of life. One of the benefits of TKI discontinuation is to allow patients to live drug-free, thereby preventing drug-related adverse events including cytopenias. The Canadian tyrosine kinase inhibitor (TKI) discontinuation trial has reported 59.1% and 21.5% molecular relapse-free survival (mRFS) rates after first and second attempts at treatment free remission (TFR) with imatinib (IM) or Dasatinib (DA) discontinuation, respectively. In the present study, we attempted to analyze the impact of TKI discontinuation on changes in hematological parameters, and its impact on TFR success after TKI discontinuation. Methods and materials: Throughout the trial, we have collected the hematoloigc parameters at 22 timepoints in 131 patients. These included Hb level, WBC count with differentials, and platelet count during IM discontinuation (7 times), DA rechallenge (10 times), and DA discontinuation (5 times). Results: With IM discontinuation, most of the hematological parameters showed a significant improvement within 3 months: Hb level rise by +10.47g/L (+8.86%; p=1.67x10-22), WBC count rise by +1.43x109/L (+30.08%; p=2.03x10-16), neutrophil rise by +0.99x109/L (36.76%; p=4.48x10-11), lymphocyte rise by +0.24x109/L (+20.64%; p=6.72x10-9), monocyte rise by +0.13x109/L (+35.9 0%; p=3.33x10-14), platelet count rise by +22.65 x109/L (+12.76%; p=1.03x10-7). Eosinophil counts were not significantly changed (p=0.475). With DA rechallenge, mixed changes were observed in hematologic parameters within 1 month: Hb level significant dropped by 11.57g/L (-8.26%; p=6.38x10-14) and platelet counts also showed a decreasing trend (-9.39x109/L or -4.57%; p=0.07), while significant increases were noted in lymphocyte (+0.41x109/L or +22.22%; p=0.00027), and monocyte counts (+0.14x109/L or +14.29%; p=0.001). No significant changes were noted in WBC counts (+0.32x109/L or +1.64%; p=0.234), neutrophil counts (-0.18x109/L or -10.42%; p=0.285), or eosinophil counts (+0.03 x109/L or 0%; p=0.185). With DA discontinuation, the Hb level rebounded by +7.08g/L within 3 months (+9.45%; p=0.0003). However, there was no significant change in the other parameters 3 months after DA discontinuation, including WBC (p=0.841), neutrophil (p=0.309), lymphocyte (p=0.995), monocyte (p=0.451), eosinophil (p=0.826) and platelet counts (p=0.533). When the changes in hematologic parameters were analyzed in correlation with mRFS, there was no association of those parameter changes with RFS after DA discontinuation. However, associations of mRFS following IM discontinuation were noted as follows: higher mRFS after IM discontinuation was observed in the group with a smaller change in Hb level (≤+1.17%, p=0.004), lymphocyte count (≤+1.06%; p=0.006), and monocyte count (≤+1.43%; 0.005) compared to those with a larger change. In other words, the group showing a rebounded Hb level after IM discontinuation showed a lower mRFS rate compared to those in whom the Hb did not rebound. A lower mRFS was noted in the group with a smaller change in neutrophil count (≤+1.07%) compared to those with a larger change (p=0.008), implying that the group with rebounded neutrophil count showed a higher mRFS compared to those not. Multivariate analysis confirmed: 1) IM treatment duration longer than 8.75 years is associated with a decrease in loss of molecular response by 13% per year (p=0.001, HR 0.871), 2) Hb level rebound above 22gm/L showed 2.8 times higher risk of molecular relapse (p=0.021, HR 2.801), 3) rebound rise of neutrophil count by 1.075% or above reduced the risk of molecular relapse by 52% (p=0.06, HR 0.485). Conclusion: Further research is warranted to explore the functional role of the hematopoietic stem cell fraction following prolonged TKI therapy in CML patients. Hematopoiesis in Ph-negative cell population could contribute to TFR after TKI discontinuation. Figure Disclosures Busque: ExCellThera: Patents & Royalties; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy. Savoie:BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Keating:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Seattle Genetics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Delage:Celgene: Honoraria, Research Funding;…
Introduction: The Canadian tyrosine kinase inhibitor (TKI) discontinuation trial has reported a 5... more Introduction: The Canadian tyrosine kinase inhibitor (TKI) discontinuation trial has reported a 59.1% and 21.5% molecular relapse-free survival (RFS) rate after first attempt of treatment free remission (TFR1) with imatinib (IM) discontinuation and after a 2nd attempt of TFR (TFR2) with dasatinib (DA) discontinuation, respectively. Throughout the first and second attempts of TKI discontinuation, the kinetics of BCR-ABL qPCR transcript rise were very similar after TFR1 and TFR2. This prompts us to have a better understanding of the dynamics of BCR-ABL qPCR rise after TKI discontinuation. Methods and materials: This prospective clinical trial (BMS CA180-543, Clinicaltrial.gov NCT#02268370) has 3 phases: 1) IM discontinuation phase, 2) DA rechallenge phase, 3) DA discontinuation phase. We have analyzed the monthly BCR-ABL1 qPCR value and doubling time (DT) in the first 6 months following IM discontinuation. The qPCR level before IM discontinuation or the qPCR level from the prior month was used as a baseline. DT at each measurement was calculated as x = ln(2)/K, where x is the DT and k is the fold BCR-ABL1 change from the previous value divided by the number of days between each measurement. The distribution of DT for all patients was assessed at each timepoint of DT measurement within the first 6 months. In order to define the best cut-off levels of BCR-ABL1 qPCR and DT showing the best risk stratification power throughout the first 6 months, DT values were collected and analyzed for molecular relapse-free survival (RFS) from the time of DT measurement. Then, a binary recursive partitioning method was applied using RFS which is calculated from the time of each DT measurement. Based on the DT cut-off value, the group was divided into 2 groups. The RFS was compared according to the groups. Results: As of March 25, 2019, out of 131 patients enrolled, 58 patients (44.3%) lost a molecular response. The 6- and 12-months' molecular relapse-free survival (mRFS) rate was estimated as 59.1% (50.1-67.0%) and 56.8 % (47.8-64.8%), respectively. BCR-ABL1 qPCR transcript level after IM discontinuation showed a rapid rise between the first 2-4 months, followed by a gradual rise after 4 months. The proportion of the patients showing DT less than 12.71 days but above 0 was 3.8% at 1 mo, 25.2% at 2 mo, 15.3% at 3 mo, 12.2% at 4 mo, 2.3% at 5 mo and 2.3% at 6 mo, respectively. DT values were collected and analyzed for molecular RFS from the time of DT measurement. Binary recursive partitioning method was applied and provided 12.71 days as the best DT cutoff value to stratify the patients according to the RFS from the time of each DT measurement. In other words, the patients having DT less than 12.71 days but above 0 at any time within the first 6 months had a higher risk of failing the TFR attempt, while those with DT equal to or over 12.71 days at any time has a lower risk of losing TFR after IM discontinuation. The best result was reported in the group with stable BCR-ABL qPCR transcript level. A rapid incline of BCR-ABL qPCR transcript level was observed 2-4 months after IM discontinuation. According to the DT measured at 2 months, the group with DT less than 12.71 days but above 0 showed the lowest mRFS rate of 5.0% (0.9-14.8%) at 12 months (HR 5.74), compared to the group with DT equal to/over 12.71 days (12 months' mRFS 47.4% [23.2-68.3%]) or the group with DT equal to/less than 0 days (12 months' mRFS 87.5% [77.3-93.3%]; p<0.001 [i.e. 3.5x10-32]). Decision tree analysis was performed including 4 variables such as DT below 12.71 days, DT equal to or below 0 days, total IM treatment duration and MR4 response duration. The first node was DT below 12.71 days, and the second was DT equal to/less than 0 days. Total IM duration or MR4 duration were not identified as significant in the decision tree analysis. Multivariate analysis confirmed that grouping based on the DT at 2 months is an independent risk factor for TFR. The group with DT below 12.71 but above 0 showed 5.74 times higher risk of losing TFR after IM discontinuation independent of the total duration of IM treatment. Conclusion: DT with cut off value of 12.71 days at 2 months based on the BCR-ABL1 qPCR transcript level measured in the first 6 months after IM discontinuation is predictive of TFR failure after IM discontinuation. Figure Disclosures Busque: ExCellThera: Patents & Royalties; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy. Savoie:Pfizer: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Keating:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Seattle Genetics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an…
BACKGROUND: Multiparameter flow cytometry (MFC) has increasingly been used for measurable residua... more BACKGROUND: Multiparameter flow cytometry (MFC) has increasingly been used for measurable residual disease (MRD) assessment in patients with acute myeloid leukemia (AML), while next-generation sequencing (NGS)-based MRD monitoring tool is in clinical development for its application. Clonal hematopoiesis (CH), in which leukemia-associated somatic mutations gene are present in individuals with no apparent hematologic disease, adds a challenge in the detection of MRD. In patients with AML, CH could be potentially pre-leukemic, while persistent mutations in DNMT3A, TET2 orASXL1 (DTA) in remission marrow are usually removed from the analysis of residual leukemic cells. However, reports suggest that persistent DTA mutations in remission may be correlated with an increased relapse risk. In the patients with DTA mutations, the use of NGS for MRD monitoring is limited or modified due to the presence of CH clone in the remission marrow. We evaluated whether MFC-MRD can be adjunctive to predic...
BACKGROUND: Acute myeloid leukemia (AML) is a highly heterogeneous group of diseases with variabl... more BACKGROUND: Acute myeloid leukemia (AML) is a highly heterogeneous group of diseases with variable response to therapy. Several factors have a prognostic impact for an outcome. Despite intensive chemotherapy and hematopoietic stem cell transplant (HCT), a significant proportion of patients eventually relapse, indicating that morphological assessment is not adequate due to limitations in sensitivity, requiring a better tool for assessment of remission. METHODS: A retrospective analysis was performed in AML patients who achieved first complete remission (CR1) and the outcomes compared according to the performance of HCT, and multi-color flow cytometry (MFC)-based measurable residual disease (MRD) status (defined as negative if patients achieved 0.1% or less) assessed at the time of CR1. In order to take account of the time interval from the MFC-MRD assessment to HCT, we applied a Mantel-Byar test for overall (OS) and relapse-free survival (RFS), considering time-to-HCT as a time-depen...
The impact of adverse risk genetic profiles on outcomes in acute myeloid leukemia (AML) patients ... more The impact of adverse risk genetic profiles on outcomes in acute myeloid leukemia (AML) patients following allogeneic hematopoietic stem cell transplantation (HCT) has not been fully elucidated. Accordingly, we have profiled somatic mutations at diagnosis using next-generation sequencing (NGS) in 178 AML patients who received allogeneic HCT. NGS revealed 598 somatic mutations in 165/178 patients (92.7%). Frequently mutated genes include DNMT3A, TET2, NPM1, RUNX1, IDH2, and FLT3. Commonly detected cytogenetic profiles include normal karyotype, trisomy 8, monosomal karyotype (MK), deletion 5, complex karyotype (CK), and monosomy 7. In univariate analyses, TP53 mutation, MK, CK, and monosomy 7 were associated with decreased overall survival (OS), relapse-free survival (RFS), and a higher relapse incidence (RI). We defined adverse molecular-genetic profile as harboring at least one of the molecular/genetic abnormalities of TP53 mutation, MK, CK, monosomy 7, and deletion 5. The patients harboring adverse molecular-genetic profile (n = 30) showed a lower 2-year OS (24.9% vs. 57.9%; p = 0.003), RFS (23.7% vs. 57.9%; p = 0.002), and higher RI (47.2% and 17.2%; p = 0.001) after HCT when compared to patients without those lesions. Multivariate analysis confirmed adverse molecular-genetic profile as an independent prognostic factor, associated with decreased OS (HR 2.19), RFS (HR 2.23), and higher RI (HR 2.94).
Introduction: The introduction of next-generation sequencing (NGS) has expedited the discovery of... more Introduction: The introduction of next-generation sequencing (NGS) has expedited the discovery of novel genetic lesions in acute myeloid leukemia (AML), thereby allowing better risk stratification with respect to overall survival (OS). We have previously reported that AML patients with PTPN11 and NPM1 mutations had longer OS following chemotherapy, while those carrying mutations in ASXL1, JAK2, RUNX1, TP53 and SRSF2 had a shorter OS (Daher-Reyes,ASH 2018). Little is known, however, regarding the impact of genetic profiles (somatic mutations and cytogenetic abnormalities) at initial AML diagnosis on the treatment outcomes following allogeneic hematopoietic stem cell transplantation (HCT). Methods & Patients: We enrolled AML patients who had available NGS data at time of initial diagnosis as part of the AGILE project between February 2015 and December 2018, and who subsequently underwent allogeneic HCT. NGS was performed on DNA samples isolated from peripheral blood or bone marrow sam...
Introduction: The Canadian tyrosine kinase inhibitor (TKI) discontinuation trial has reported a 5... more Introduction: The Canadian tyrosine kinase inhibitor (TKI) discontinuation trial has reported a 59.1% and 21.5% molecular relapse-free survival (RFS) rate after first attempt of treatment free remission (TFR1) with imatinib (IM) discontinuation and after a 2nd attempt of TFR (TFR2) with dasatinib (DA) discontinuation, respectively. Throughout the first and second attempts of TKI discontinuation, the kinetics of BCR-ABL qPCR transcript rise were very similar after TFR1 and TFR2. This prompts us to have a better understanding of the dynamics of BCR-ABL qPCR rise after TKI discontinuation. Methods and materials: This prospective clinical trial (BMS CA180-543, Clinicaltrial.gov NCT#02268370) has 3 phases: 1) IM discontinuation phase, 2) DA rechallenge phase, 3) DA discontinuation phase. We have analyzed the monthly BCR-ABL1 qPCR value and doubling time (DT) in the first 6 months following IM discontinuation. The qPCR level before IM discontinuation or the qPCR level from the prior month...
Introduction: Tyrosine kinase inhibitor (TKI) therapy can result in the adverse events of prolong... more Introduction: Tyrosine kinase inhibitor (TKI) therapy can result in the adverse events of prolonged anemia, thrombocytopenia and/or leukopenia via c-kit blockade in hematopoietic stem cells. Previous studies have reported that even low-grade adverse events could impair a patient's health-related quality of life. One of the benefits of TKI discontinuation is to allow patients to live drug-free, thereby preventing drug-related adverse events including cytopenias. The Canadian tyrosine kinase inhibitor (TKI) discontinuation trial has reported 59.1% and 21.5% molecular relapse-free survival (mRFS) rates after first and second attempts at treatment free remission (TFR) with imatinib (IM) or Dasatinib (DA) discontinuation, respectively. In the present study, we attempted to analyze the impact of TKI discontinuation on changes in hematological parameters, and its impact on TFR success after TKI discontinuation. Methods and materials: Throughout the trial, we have collected the hematolo...
Acute myeloid leukemia (AML) is a clinically and biologically heterogeneous disease. Traditionall... more Acute myeloid leukemia (AML) is a clinically and biologically heterogeneous disease. Traditionally, cytogenetic analysis has been the backbone for prognostication and treatment decisions. Outcomes vary between age groups with older adults generally having a poorer prognosis. Next Generation Sequencing (NGS) has expedited the discovery of novel genetic lesions in AML to better predict response to intensive chemotherapy and overall survival (OS). The aims of our study were to describe the genetic profile of older adults with AML and to determine its impact on treatment response and survival. We included all new patients with a diagnosis of AML (≥20% blasts in peripheral blood or bone marrow; acute promyelocytic leukemia and myeloid sarcoma were excluded), treated at Princess Margaret Cancer Centre between February 2015 and August 2017. NGS was performed on DNA isolated from peripheral blood or bone marrow samples at diagnosis. Analysis was performed using the TruSight Myeloid Sequenci...
Key Points DNMT3A R882, TET2, ASXL1, and SRSF2 mutations identified at the time of diagnosis are ... more Key Points DNMT3A R882, TET2, ASXL1, and SRSF2 mutations identified at the time of diagnosis are associated with delayed count recovery. Persistence of preleukemic mutations in remission at high variant allele frequency is associated with delayed count recovery.
There is a paucity of data regarding the impact of mutations on outcomes in accelerated-phase (AP... more There is a paucity of data regarding the impact of mutations on outcomes in accelerated-phase (AP) and blast-phase (BP) myeloproliferative neoplasms (MPNs). Moreover, it is unknown whether mutational status affects survival, as seen in chronic-phase MPNs. Therefore, we performed a retrospective analysis of all patients treated at our institution with AP/BP MPNs (N = 122; AP = 14; BP = 108) to comprehensively describe the mutational profile and correlate with clinical outcomes. Targeted sequencing with a 54-gene panel was performed. Forty-four patients were treated with intensive therapy, 27 with nonintensive therapy, and 51 with best supportive care (BSC). The most common mutation was , occurring in 55% of subjects; was found in 13% of patients and in 6%. Thirty-two (26%) patients were triple negative. Other frequently mutated genes were (30%), (25%), (22%), (20%), and (17%). Mutations in 1, 2, 3, and ≥4 genes were seen in 15%, 13%, 25%, and 46% of patients, respectively. There was ...
Introduction: Tyrosine kinase inhibitor (TKI) therapy can result in the adverse events of prolong... more Introduction: Tyrosine kinase inhibitor (TKI) therapy can result in the adverse events of prolonged anemia, thrombocytopenia and/or leukopenia via c-kit blockade in hematopoietic stem cells. Previous studies have reported that even low-grade adverse events could impair a patient's health-related quality of life. One of the benefits of TKI discontinuation is to allow patients to live drug-free, thereby preventing drug-related adverse events including cytopenias. The Canadian tyrosine kinase inhibitor (TKI) discontinuation trial has reported 59.1% and 21.5% molecular relapse-free survival (mRFS) rates after first and second attempts at treatment free remission (TFR) with imatinib (IM) or Dasatinib (DA) discontinuation, respectively. In the present study, we attempted to analyze the impact of TKI discontinuation on changes in hematological parameters, and its impact on TFR success after TKI discontinuation. Methods and materials: Throughout the trial, we have collected the hematoloigc parameters at 22 timepoints in 131 patients. These included Hb level, WBC count with differentials, and platelet count during IM discontinuation (7 times), DA rechallenge (10 times), and DA discontinuation (5 times). Results: With IM discontinuation, most of the hematological parameters showed a significant improvement within 3 months: Hb level rise by +10.47g/L (+8.86%; p=1.67x10-22), WBC count rise by +1.43x109/L (+30.08%; p=2.03x10-16), neutrophil rise by +0.99x109/L (36.76%; p=4.48x10-11), lymphocyte rise by +0.24x109/L (+20.64%; p=6.72x10-9), monocyte rise by +0.13x109/L (+35.9 0%; p=3.33x10-14), platelet count rise by +22.65 x109/L (+12.76%; p=1.03x10-7). Eosinophil counts were not significantly changed (p=0.475). With DA rechallenge, mixed changes were observed in hematologic parameters within 1 month: Hb level significant dropped by 11.57g/L (-8.26%; p=6.38x10-14) and platelet counts also showed a decreasing trend (-9.39x109/L or -4.57%; p=0.07), while significant increases were noted in lymphocyte (+0.41x109/L or +22.22%; p=0.00027), and monocyte counts (+0.14x109/L or +14.29%; p=0.001). No significant changes were noted in WBC counts (+0.32x109/L or +1.64%; p=0.234), neutrophil counts (-0.18x109/L or -10.42%; p=0.285), or eosinophil counts (+0.03 x109/L or 0%; p=0.185). With DA discontinuation, the Hb level rebounded by +7.08g/L within 3 months (+9.45%; p=0.0003). However, there was no significant change in the other parameters 3 months after DA discontinuation, including WBC (p=0.841), neutrophil (p=0.309), lymphocyte (p=0.995), monocyte (p=0.451), eosinophil (p=0.826) and platelet counts (p=0.533). When the changes in hematologic parameters were analyzed in correlation with mRFS, there was no association of those parameter changes with RFS after DA discontinuation. However, associations of mRFS following IM discontinuation were noted as follows: higher mRFS after IM discontinuation was observed in the group with a smaller change in Hb level (≤+1.17%, p=0.004), lymphocyte count (≤+1.06%; p=0.006), and monocyte count (≤+1.43%; 0.005) compared to those with a larger change. In other words, the group showing a rebounded Hb level after IM discontinuation showed a lower mRFS rate compared to those in whom the Hb did not rebound. A lower mRFS was noted in the group with a smaller change in neutrophil count (≤+1.07%) compared to those with a larger change (p=0.008), implying that the group with rebounded neutrophil count showed a higher mRFS compared to those not. Multivariate analysis confirmed: 1) IM treatment duration longer than 8.75 years is associated with a decrease in loss of molecular response by 13% per year (p=0.001, HR 0.871), 2) Hb level rebound above 22gm/L showed 2.8 times higher risk of molecular relapse (p=0.021, HR 2.801), 3) rebound rise of neutrophil count by 1.075% or above reduced the risk of molecular relapse by 52% (p=0.06, HR 0.485). Conclusion: Further research is warranted to explore the functional role of the hematopoietic stem cell fraction following prolonged TKI therapy in CML patients. Hematopoiesis in Ph-negative cell population could contribute to TFR after TKI discontinuation. Figure Disclosures Busque: ExCellThera: Patents & Royalties; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy. Savoie:BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Keating:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Seattle Genetics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Delage:Celgene: Honoraria, Research Funding;…
Introduction: The Canadian tyrosine kinase inhibitor (TKI) discontinuation trial has reported a 5... more Introduction: The Canadian tyrosine kinase inhibitor (TKI) discontinuation trial has reported a 59.1% and 21.5% molecular relapse-free survival (RFS) rate after first attempt of treatment free remission (TFR1) with imatinib (IM) discontinuation and after a 2nd attempt of TFR (TFR2) with dasatinib (DA) discontinuation, respectively. Throughout the first and second attempts of TKI discontinuation, the kinetics of BCR-ABL qPCR transcript rise were very similar after TFR1 and TFR2. This prompts us to have a better understanding of the dynamics of BCR-ABL qPCR rise after TKI discontinuation. Methods and materials: This prospective clinical trial (BMS CA180-543, Clinicaltrial.gov NCT#02268370) has 3 phases: 1) IM discontinuation phase, 2) DA rechallenge phase, 3) DA discontinuation phase. We have analyzed the monthly BCR-ABL1 qPCR value and doubling time (DT) in the first 6 months following IM discontinuation. The qPCR level before IM discontinuation or the qPCR level from the prior month was used as a baseline. DT at each measurement was calculated as x = ln(2)/K, where x is the DT and k is the fold BCR-ABL1 change from the previous value divided by the number of days between each measurement. The distribution of DT for all patients was assessed at each timepoint of DT measurement within the first 6 months. In order to define the best cut-off levels of BCR-ABL1 qPCR and DT showing the best risk stratification power throughout the first 6 months, DT values were collected and analyzed for molecular relapse-free survival (RFS) from the time of DT measurement. Then, a binary recursive partitioning method was applied using RFS which is calculated from the time of each DT measurement. Based on the DT cut-off value, the group was divided into 2 groups. The RFS was compared according to the groups. Results: As of March 25, 2019, out of 131 patients enrolled, 58 patients (44.3%) lost a molecular response. The 6- and 12-months' molecular relapse-free survival (mRFS) rate was estimated as 59.1% (50.1-67.0%) and 56.8 % (47.8-64.8%), respectively. BCR-ABL1 qPCR transcript level after IM discontinuation showed a rapid rise between the first 2-4 months, followed by a gradual rise after 4 months. The proportion of the patients showing DT less than 12.71 days but above 0 was 3.8% at 1 mo, 25.2% at 2 mo, 15.3% at 3 mo, 12.2% at 4 mo, 2.3% at 5 mo and 2.3% at 6 mo, respectively. DT values were collected and analyzed for molecular RFS from the time of DT measurement. Binary recursive partitioning method was applied and provided 12.71 days as the best DT cutoff value to stratify the patients according to the RFS from the time of each DT measurement. In other words, the patients having DT less than 12.71 days but above 0 at any time within the first 6 months had a higher risk of failing the TFR attempt, while those with DT equal to or over 12.71 days at any time has a lower risk of losing TFR after IM discontinuation. The best result was reported in the group with stable BCR-ABL qPCR transcript level. A rapid incline of BCR-ABL qPCR transcript level was observed 2-4 months after IM discontinuation. According to the DT measured at 2 months, the group with DT less than 12.71 days but above 0 showed the lowest mRFS rate of 5.0% (0.9-14.8%) at 12 months (HR 5.74), compared to the group with DT equal to/over 12.71 days (12 months' mRFS 47.4% [23.2-68.3%]) or the group with DT equal to/less than 0 days (12 months' mRFS 87.5% [77.3-93.3%]; p<0.001 [i.e. 3.5x10-32]). Decision tree analysis was performed including 4 variables such as DT below 12.71 days, DT equal to or below 0 days, total IM treatment duration and MR4 response duration. The first node was DT below 12.71 days, and the second was DT equal to/less than 0 days. Total IM duration or MR4 duration were not identified as significant in the decision tree analysis. Multivariate analysis confirmed that grouping based on the DT at 2 months is an independent risk factor for TFR. The group with DT below 12.71 but above 0 showed 5.74 times higher risk of losing TFR after IM discontinuation independent of the total duration of IM treatment. Conclusion: DT with cut off value of 12.71 days at 2 months based on the BCR-ABL1 qPCR transcript level measured in the first 6 months after IM discontinuation is predictive of TFR failure after IM discontinuation. Figure Disclosures Busque: ExCellThera: Patents & Royalties; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy. Savoie:Pfizer: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Keating:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Seattle Genetics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an…
BACKGROUND: Multiparameter flow cytometry (MFC) has increasingly been used for measurable residua... more BACKGROUND: Multiparameter flow cytometry (MFC) has increasingly been used for measurable residual disease (MRD) assessment in patients with acute myeloid leukemia (AML), while next-generation sequencing (NGS)-based MRD monitoring tool is in clinical development for its application. Clonal hematopoiesis (CH), in which leukemia-associated somatic mutations gene are present in individuals with no apparent hematologic disease, adds a challenge in the detection of MRD. In patients with AML, CH could be potentially pre-leukemic, while persistent mutations in DNMT3A, TET2 orASXL1 (DTA) in remission marrow are usually removed from the analysis of residual leukemic cells. However, reports suggest that persistent DTA mutations in remission may be correlated with an increased relapse risk. In the patients with DTA mutations, the use of NGS for MRD monitoring is limited or modified due to the presence of CH clone in the remission marrow. We evaluated whether MFC-MRD can be adjunctive to predic...
BACKGROUND: Acute myeloid leukemia (AML) is a highly heterogeneous group of diseases with variabl... more BACKGROUND: Acute myeloid leukemia (AML) is a highly heterogeneous group of diseases with variable response to therapy. Several factors have a prognostic impact for an outcome. Despite intensive chemotherapy and hematopoietic stem cell transplant (HCT), a significant proportion of patients eventually relapse, indicating that morphological assessment is not adequate due to limitations in sensitivity, requiring a better tool for assessment of remission. METHODS: A retrospective analysis was performed in AML patients who achieved first complete remission (CR1) and the outcomes compared according to the performance of HCT, and multi-color flow cytometry (MFC)-based measurable residual disease (MRD) status (defined as negative if patients achieved 0.1% or less) assessed at the time of CR1. In order to take account of the time interval from the MFC-MRD assessment to HCT, we applied a Mantel-Byar test for overall (OS) and relapse-free survival (RFS), considering time-to-HCT as a time-depen...
The impact of adverse risk genetic profiles on outcomes in acute myeloid leukemia (AML) patients ... more The impact of adverse risk genetic profiles on outcomes in acute myeloid leukemia (AML) patients following allogeneic hematopoietic stem cell transplantation (HCT) has not been fully elucidated. Accordingly, we have profiled somatic mutations at diagnosis using next-generation sequencing (NGS) in 178 AML patients who received allogeneic HCT. NGS revealed 598 somatic mutations in 165/178 patients (92.7%). Frequently mutated genes include DNMT3A, TET2, NPM1, RUNX1, IDH2, and FLT3. Commonly detected cytogenetic profiles include normal karyotype, trisomy 8, monosomal karyotype (MK), deletion 5, complex karyotype (CK), and monosomy 7. In univariate analyses, TP53 mutation, MK, CK, and monosomy 7 were associated with decreased overall survival (OS), relapse-free survival (RFS), and a higher relapse incidence (RI). We defined adverse molecular-genetic profile as harboring at least one of the molecular/genetic abnormalities of TP53 mutation, MK, CK, monosomy 7, and deletion 5. The patients harboring adverse molecular-genetic profile (n = 30) showed a lower 2-year OS (24.9% vs. 57.9%; p = 0.003), RFS (23.7% vs. 57.9%; p = 0.002), and higher RI (47.2% and 17.2%; p = 0.001) after HCT when compared to patients without those lesions. Multivariate analysis confirmed adverse molecular-genetic profile as an independent prognostic factor, associated with decreased OS (HR 2.19), RFS (HR 2.23), and higher RI (HR 2.94).
Introduction: The introduction of next-generation sequencing (NGS) has expedited the discovery of... more Introduction: The introduction of next-generation sequencing (NGS) has expedited the discovery of novel genetic lesions in acute myeloid leukemia (AML), thereby allowing better risk stratification with respect to overall survival (OS). We have previously reported that AML patients with PTPN11 and NPM1 mutations had longer OS following chemotherapy, while those carrying mutations in ASXL1, JAK2, RUNX1, TP53 and SRSF2 had a shorter OS (Daher-Reyes,ASH 2018). Little is known, however, regarding the impact of genetic profiles (somatic mutations and cytogenetic abnormalities) at initial AML diagnosis on the treatment outcomes following allogeneic hematopoietic stem cell transplantation (HCT). Methods & Patients: We enrolled AML patients who had available NGS data at time of initial diagnosis as part of the AGILE project between February 2015 and December 2018, and who subsequently underwent allogeneic HCT. NGS was performed on DNA samples isolated from peripheral blood or bone marrow sam...
Introduction: The Canadian tyrosine kinase inhibitor (TKI) discontinuation trial has reported a 5... more Introduction: The Canadian tyrosine kinase inhibitor (TKI) discontinuation trial has reported a 59.1% and 21.5% molecular relapse-free survival (RFS) rate after first attempt of treatment free remission (TFR1) with imatinib (IM) discontinuation and after a 2nd attempt of TFR (TFR2) with dasatinib (DA) discontinuation, respectively. Throughout the first and second attempts of TKI discontinuation, the kinetics of BCR-ABL qPCR transcript rise were very similar after TFR1 and TFR2. This prompts us to have a better understanding of the dynamics of BCR-ABL qPCR rise after TKI discontinuation. Methods and materials: This prospective clinical trial (BMS CA180-543, Clinicaltrial.gov NCT#02268370) has 3 phases: 1) IM discontinuation phase, 2) DA rechallenge phase, 3) DA discontinuation phase. We have analyzed the monthly BCR-ABL1 qPCR value and doubling time (DT) in the first 6 months following IM discontinuation. The qPCR level before IM discontinuation or the qPCR level from the prior month...
Introduction: Tyrosine kinase inhibitor (TKI) therapy can result in the adverse events of prolong... more Introduction: Tyrosine kinase inhibitor (TKI) therapy can result in the adverse events of prolonged anemia, thrombocytopenia and/or leukopenia via c-kit blockade in hematopoietic stem cells. Previous studies have reported that even low-grade adverse events could impair a patient's health-related quality of life. One of the benefits of TKI discontinuation is to allow patients to live drug-free, thereby preventing drug-related adverse events including cytopenias. The Canadian tyrosine kinase inhibitor (TKI) discontinuation trial has reported 59.1% and 21.5% molecular relapse-free survival (mRFS) rates after first and second attempts at treatment free remission (TFR) with imatinib (IM) or Dasatinib (DA) discontinuation, respectively. In the present study, we attempted to analyze the impact of TKI discontinuation on changes in hematological parameters, and its impact on TFR success after TKI discontinuation. Methods and materials: Throughout the trial, we have collected the hematolo...
Acute myeloid leukemia (AML) is a clinically and biologically heterogeneous disease. Traditionall... more Acute myeloid leukemia (AML) is a clinically and biologically heterogeneous disease. Traditionally, cytogenetic analysis has been the backbone for prognostication and treatment decisions. Outcomes vary between age groups with older adults generally having a poorer prognosis. Next Generation Sequencing (NGS) has expedited the discovery of novel genetic lesions in AML to better predict response to intensive chemotherapy and overall survival (OS). The aims of our study were to describe the genetic profile of older adults with AML and to determine its impact on treatment response and survival. We included all new patients with a diagnosis of AML (≥20% blasts in peripheral blood or bone marrow; acute promyelocytic leukemia and myeloid sarcoma were excluded), treated at Princess Margaret Cancer Centre between February 2015 and August 2017. NGS was performed on DNA isolated from peripheral blood or bone marrow samples at diagnosis. Analysis was performed using the TruSight Myeloid Sequenci...
Key Points DNMT3A R882, TET2, ASXL1, and SRSF2 mutations identified at the time of diagnosis are ... more Key Points DNMT3A R882, TET2, ASXL1, and SRSF2 mutations identified at the time of diagnosis are associated with delayed count recovery. Persistence of preleukemic mutations in remission at high variant allele frequency is associated with delayed count recovery.
There is a paucity of data regarding the impact of mutations on outcomes in accelerated-phase (AP... more There is a paucity of data regarding the impact of mutations on outcomes in accelerated-phase (AP) and blast-phase (BP) myeloproliferative neoplasms (MPNs). Moreover, it is unknown whether mutational status affects survival, as seen in chronic-phase MPNs. Therefore, we performed a retrospective analysis of all patients treated at our institution with AP/BP MPNs (N = 122; AP = 14; BP = 108) to comprehensively describe the mutational profile and correlate with clinical outcomes. Targeted sequencing with a 54-gene panel was performed. Forty-four patients were treated with intensive therapy, 27 with nonintensive therapy, and 51 with best supportive care (BSC). The most common mutation was , occurring in 55% of subjects; was found in 13% of patients and in 6%. Thirty-two (26%) patients were triple negative. Other frequently mutated genes were (30%), (25%), (22%), (20%), and (17%). Mutations in 1, 2, 3, and ≥4 genes were seen in 15%, 13%, 25%, and 46% of patients, respectively. There was ...
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Papers by Georgina Daher-Reyes