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Although total duration of tyrosine kinase inhibitor (TKI) therapy and of molecular response at 4 log reduction or deeper (MR4) correlates with treatment-free remission (TFR) success after TKI discontinuation, the optimal cut-off values of the duration remain unresolved. Thus, 131 patients were enrolled into the Canadian TKI discontinuation study. The molecular relapse-free survival (mRFS) was defined from imatinib discontinuation till molecular recurrence, that is, major molecular response (MMR) loss and/or MR4 loss. We evaluated mRFS at 12 months after imatinib discontinuation, analyzed it according to the imatinib treatment duration and MR4 duration, and calculated P value, positive (PPV) and negative predictive value (NPV) in the yearly cut-off period of time. The shortest cut-off was sought that met the joint criteria of a P value ≤ 0·05, PPV ≥ 60% and NPV ≥ 60%. We propose six years as the shortest imatinib duration cut-off with a P value 0·01, PPV 68% and NPV 62%: The patients treated with imatinib duration ≥ 6 years showed a superior mRFS rate (61·8%) compared to those with less treatment (36·0%). Also, 4·5 years MR4 duration as the shortest cut-off with a P value 0·003, PPV 63% and NPV 61%: those with MR4 duration ≥ 4·5 years showed a higher mRFS rate (64·2%) than those with a shorter MR4 duration (41·9%).

The doubling time (DT) of the BCR-ABL1 quantitative polymerase chain reaction (qPCR) transcript level reflects the re-growing fraction of leukaemic cells after discontinuation of tyrosine kinase inhibitor (TKI). The present study analyzed monthly DT within six months after imatinib discontinuation in 131 patients. Monthly DT 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 optimal DT value was determined as 12·75 days at two months using a recursive partitioning method. The patients were stratified into three groups: the high-risk group (DT12·75 days but0, with rapidly proliferating chronic myeloid leukaemia (CML) cells; n = 26) showed the lowest molecular relapse-free survival (mRFS) of 7·7% at 12 months, compared to 53·6% in the intermediate-risk group (DT≥12·75 days, with slowly proliferating CML cells; n = 16) or 90·0% in the low-risk group (DT≤0, i.e., without proliferating CML cells; n = 71; P 0·001). Monthly assessment of DT helps identify high-risk patients for treatment-free remission failure with an imminent risk of molecular recurrence, and to define low-risk patients who can be spared the frequent monitoring of monthly molecular tests.

While second generation tyrosine kinase inhibitors (2GTKIs) are highly effective therapies for chronic myeloid leukemia (CML), a significant minority of patients who initiate a 2GTKI will require a switch to an alternative TKI. The long-term outcomes of those who require a change in therapy after front-line 2GTKI therapy are largely undescribed. Here we describe the clinical outcomes associated with switch to an alternative TKI after first-line therapy with a 2GTKI. Of 232 patients who initiated a 2GTKI during the study period, 76 (33 %) switched to an alternative TKI. Reasons for switching included intolerance (79 %) and resistance (21 %). Among the 60 patients who switched due to intolerance, 53 (88 %) were able to achieve or maintain a major molecular response (MMR) with 5-year progression-free survival (PFS) 90.5 % (95 % CI 90.4-90.6 %). Amongst the 16 patients who switched due to resistance, 8 patients (50 %) were able to achieve MMR with 5-year PFS 80.4 % (95 % CI 80.2-80.6 %). Most patients who switched due to intolerance remained on their second-line TKI. Approximately 25 % of patients who initiate first-line 2GTKI in a real world setting will ultimately switch to an alternate TKI due to intolerance. Patients who switch for intolerance continue to enjoy excellent clinical outcomes.

Background: The Canadian tyrosine kinase inhibitor (TKI) discontinuation trial, named "Treatment Free Remission Accomplished By Dasatinib " (NCT#02268370), has reported 56.8% molecular relapse-free survival (mRFS) rate at 12 months after imatinib (IM) discontinuation. MMR loss occurred quickly after IM discontinuation, typically within 2-4 months, while those who lost MR4 on two consecutive measurements tended to lose their molecular response more gradually. BCR-ABL transcript doubling time (DT) after TKI discontinuation is a reciprocal concept to transcript halving time following TKI therapy. Due to inter-individual differences in DT after TKI discontinuation, DT can be used as a potential biomarker to identify those patients at high-risk for TFR failure when measured before they experience a clinically significant event of molecular relapse. The present study has not only evaluated the kinetics of BCR-ABL transcript rise after IM discontinuation, but also explored the predictive/prognostic role of DT of BCR-ABL transcript level as an early predictor of TFR failure. Patients and methods: Changes of BCR-ABL1 transcript level in each patient were assessed monthly by estimating the number of days required for BCR-ABL1 to double from the previous expression level/measurement, termed the DT. Based on the BCR-ABL1 qPCR value taken monthly in the first 6 months after IM discontinuation, DT was calculated monthly, 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. K was determined as follows: K = [ln(b) - ln(a)]/t, where a is the BCR-ABL1 value of the previous measurement, b is the BCR-ABL1 at the relevant time point, and t is the number of days between measurements. The baseline qPCR level from the prior month to TKI discontinuation was referenced. The distribution of DT was assessed at each time point of DT measurement within the first 6 months. In order to define cut-off levels for BCR-ABL1 qPCR and DT for the first 6 months, multiple statistical parameters were taken into account including positive (PPV) and negative predictive value (NPV), accuracy and F1 score of DT value, resulting in the DT value of 12.75 days at 2 months as the optimal cut-off value of DT value. Patients were stratified into the 3 groups based on the DT value of 12.75 days at 2 months after IM discontinuation. The high-risk group was defined as the patients showing DT < 12.75 days but above 0, i.e. rapidly proliferating CML cells, implying a high risk for TFR failure with a shorter DT. The intermediate-risk group was defined as those patients with DT ≥ 12.75 days, i.e. more slowly proliferating CML cells implying intermediate risk for TFR failure. The low-risk group was defined as patients showing DT of zero or below, i.e. no increase in the size of the pool of cells expressing BCR-ABL, implying a low risk for TFR failure. The mRFS was analyzed for each of these risk groups at 6 monthly intervals after TKI discontinuation. Results: We compared the DT values of the patients that failed TFR with those from the patients who maintained their molecular response at last follow-up. The DT values at 2 months were much shorter in patients who failed TFR after IM cessation (median 8.32 days) compared to those who maintained molecular response (median 20.7 days; p The DT value of 12.75 days was defined as the optimal value for DT at 2 months with the NPV, PPV, accuracy and F1 score of 80.90%, 96.43%, 84.62% and 0.75, respectively, as the -log10(p-value), accuracy and F1 score reached a plateau at a DT of 12.75 days as presented in the Figure A. At a DT value of 12.75 days at 2 months after IM discontinuation, patients were stratified into 3 groups: high- (n=26), intermediate- (n=16) and low-risk groups (n=71; Figure B). With respect to mRFS rate, the high-risk group showed 7.7% mRFS rate at 12 months compared to 53.6% in the intermediate-risk group or 90.0% in the low-risk group (p Conclusion: Monthly assessment of DT based on the monthly BCR-ABL qPCR is useful to identify the patients with an imminent risk of molecular recurrence after IM cessation for TFR. Figure Disclosures Bence-Bruckler: Merck: Membership on an entity's Board of Directors or advisory committees. Keating:Takeda: Honoraria, 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; Seattle Genetics: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees; Taiho: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Busque:Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Delage:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lipton:BMS: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding. Leber:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Treadwell: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda/Palladin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees.

SUMMARY Myelofibrosis is characterized by progressive splenomegaly, cytopenias and debilitating constitutional symptoms. It has the worst prognosis and poorest quality of life of all the chronic myeloproliferative neoplasms. Allogeneic stem cell transplantation is the only curative therapy, but it carries high treatment-related risks and is thus available to only a small subset of patients. All other interventions merely palliate either anemia or splenomegaly. Ruxolitinib, a JAK1/2 inhibitor, has recently been shown to be effective in reducing splenomegaly and improving constitutional symptoms to a degree that has not been achieved with conventional therapy. However, treatment with ruxolitinib can often worsen anemia, and its ability to change the natural history of myelofibrosis has not been definitively established.

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; Novartis: Honoraria, Research Funding. Liew:Novartis: Consultancy, Honoraria. Leber:Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Introduction: The Canadian trial entitled "Treatment Free Remission Accomplished By Dasatinib" (BMS CA180543, NCT#02268370) is ongoing since Jan 2015, and has completed accrual of 131 patients. The study was designed to determine if using dasatinib (DA) can lead to a successful treatment-free remission (TFR) after failing a first attempt of TKI discontinuation following imatinib (IM) treatment. The preliminary results (ASH 2018) indicate: 1) The 6-month molecular relapse-free survival (mRFS) rate is estimated as 58.0%; 2) DA re-treatment is feasible and safe, with achievement of excellent rates of MMR and MR4; 3) The estimated TFR2 rate after DA discontinuation was 21.5±8.5% at 6 months [7.9-39.5%]). Herein, we report the 4-year follow-up results with updated TFR2 after second TFR attempt following DA discontinuation. Methods and materials: This prospective clinical trial has 3 phases: 1) IM discontinuation phase, 2) DA rechallenge phase, 3) DA discontinuation phase. Molecular relapse is defined as an increase in BCR-ABL transcript level above MR4.0 on 2 consecutive occasions, or an increase in BCR-ABL transcript level above MR3.0 on a single occasion. 100mg daily of DA is started if molecular relapse is confirmed and is discontinued 12 months after achieving MR4 following a 2nd TFR attempt. Results: As of Jun 25, 2019, 58 (44.3%) of 131 enrolled patients experienced molecular relapse after IM discontinuation with a mRFS rate of 59.1% [50.1-67.0%] and 56.8% [47.8-64.8%] at 6 and 12 months, respectively. TFR using loss of MMR as an event was 69.8% at 6/12 months. Of the 58 patients who lost response, 53 patients (91.4%) lost response within 6 months after IM discontinuation: 7 (10.1%) lost response within 2 months, 20 (34.5%) within 3 months, 14 (24.1%) within 4 months, 9 (15.5%) within 5 months, and 3 (5.2%) within 5-6 months. Beyond 6 months, 5 patients (15.5%) lost response within 7, 8, 10, 20, 21 months, respectively. Only two patients experienced late relapse occuring 15 months after IM discontinuation. 54 patients started DA, of whom 49 patients (90.7%) achieved MR4.5 on DA. Median time to MMR, MR4 and MR4.5 was 0.94, 1.95, and 2.48, respectively. The incidence of MMR, MR4 and MR4.5 at 3 months was 99.0% (86.3-99.0%), 91.5% (78.4-96.7%), and 76.6% (60.9-86.0%), respectively. 32/49 patients receiving DA attained MR4.5, and discontinued DA for a 2nd TFR attempt (TFR2). 25/32 (78.1%) of these patients lost molecular response at a median of 3.67 months after DA discontinuation. The estimated TFR2 after DA discontinuation was 18.5% at 6 months [6.8-34.7%], TFR2 using loss of MMR as a definition of molecular relapse was 20.4% [7.6-37.4%], while TFR2 using two consecutive losses of MR4 was 25.4% [9.4%-45.2%]. Two patients continued to attain deep molecular response at MR4.2 and undetectable level (equivalent to MR5.5) beyond 18 months after DA discontinuation. At last follow-up of Jun 25, 2019, 30 patients are still being monitored on trial on IM discontinuation (n=20), DA rechallenge (n=4) or DA discontinuation phases (n=6). With a median follow-up duration of 36 months, risk factor analyses were performed using Cox's proportional hazard regression model suggesting a strong correlation of mRFS with total duration of IM treatment prior to IM discontinuation (p Conclusion: The 4-year follow-up results suggests that DA rechallenge after failing a first IM discontinuation attempt for TFR was safe, feasible and well tolerated. It was effective in most cases rapidly regained at least MR4. Based on the two cases who successfully discontinued DA more than 18 months after DA consolidation following achievement of deep molecular response, second generation TKI therapy after imatinib discontinuation failure is a feasible option. Further follow-up is strongly warranted in order to reach a clear conclusion on this issue. Disclosures Busque: ExCellThera: Patents & Royalties; Paladin: Consultancy; Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy. Savoie:Pfizer: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Keating:Sanofi: Membership on an entity's Board of Directors or advisory committees; 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. Delage:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Liew:Novartis: Consultancy, Honoraria. Leber:Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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 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 entity's Board of Directors or advisory committees. Delage:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Liew:Novartis: Consultancy, Honoraria. Leber:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

7056 Background: BETi have been shown to regulate NF-κB, MYC, BCL2, and TGF-β signaling, important drivers of marrow fibrosis. Preclinical studies have suggested that combined BETi and JAK2 inhibition synergistically reduce MF-related splenomegaly, bone marrow fibrosis and the malignant allele burden (Kleppe, 2018). CPI-0610 is a selective and potent oral BETi, being evaluated in the first study of a BETi in MF. Methods: Phase 2 trial with 3 arms: CPI-0610 monotherapy (Arm 1) or RUX + CPI-0610 “add-on” (Arm 2) in pts who have progressed/ had an inadequate response to RUX, or CPI-0610 + RUX in JAK inhibitor-naïve pts with anemia (Arm 3). Arms 1 and 2 are stratified: transfusion dependence (TD) yes: A/no: B. The primary objectives are to evaluate the effect of CPI-0610 on transfusion dependence (TD, 1A and 2A) and spleen volume (1B, 2B and 3). A Simon two-stage design: if 2 responses are seen will advance to the 2nd stage. Results: 4 pts enrolled in Arm 1, 14 pts in Arm 2, no pts accrued to Arm 3 yet. Median age: 69 years (46-83), gender: 9 male pts; 11 pts received ≥1 prior therapy besides RUX. JAK2/MPL/CALR mutations: 17/18 pts, ≥3 mutations: 10 pts, ASXL1 mutations: 11 (61%) pts. Hemoglobin 3/uL). Most common adverse events were mild diarrhea, nausea/vomiting; and reversible and non-cumulative thrombocytopenia. Conclusions: CPI-0610 is a well-tolerated, and an effective therapeutic agent for the treatment of MF. Collectively, these data indicate that CPI-0610 +/- RUX might have disease modifying effects. Updated data will be provided. Clinical trial information: NCT02158858.

We conducted a retrospective study assessing FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor) as first-line treatment in 56 newly diagnosed acute myeloid leukemia patients considered ineligible for anthracycline-based treatment due to advanced age, significant comorbidities, or pre-existing cardiac disease. The median age was 69 (21-80); 46% received FLAG for pre-existing cardiac disease and others due to age (32%), non-cardiac comorbidities (20%), or previous anthracycline exposure (2%). The induction mortality was 16% and, among evaluable patients, 48% achieved a complete remission after the first induction course with an additional patient achieving a remission after a second course for a total complete remission rate of 50%. Four patients proceeded to an allogeneic stem cell transplant including two with pre-existing cardiac disease. Among non-transplanted patients, the relapse rate (RR) was 47%. When censored at time of stem cell transplant, the median relapse-free survival was 14.7 months. The median overall survival was 9.3 months with 1- and 2-yr survivals of 44% and 22%, respectively. There was no difference in clinical outcomes between patients treated with FLAG for cardiac reasons vs. other reasons. In conclusion, FLAG is a useful alternative to anthracycline-based induction for Acute myeloid leukemia in those with significant comorbidities including pre-existing cardiac disease.

Most guidelines suggest that only the bone marrow aspirate (BMA) is necessary to assess residual disease following intensive chemotherapy for Acute Myeloid Leukemia (AML) with the bone marrow trephine biopsy (BMTB) recommended in cases of a poor quality BMA. We performed a retrospective study evaluating this in a cohort of patients receiving intensive chemotherapy for AML. Residual disease was assessed by morphological examination of the BMA and BMTB±immunohistochemistry. Of the 647 marrows 32.6% were interim marrows performed prior to peripheral count recovery, 41.7% were end of induction (EOI) marrows and the remaining were 'other marrows'. The BMA and BMTB findings were concordant in 92.8% of cases. The BMTB led to a change in diagnosis from 'no leukemia' to 'residual leukemia' in 5.2% of interim, 3.7% of EOI and 2.4% of 'other' marrows. The BMA alone had a sensitivity of 86.8% in detecting residual leukemia and of 82.3%, 82.5% and 94.2% for interim, EOI and 'other marrows', respectively. Despite the high concordance between the BMA and the BMTB the poor sensitivity of the BMA in detecting residual leukemia, particularly at EOI, may lead to an overestimation of the complete remission rates which may have therapeutic and clinical trial implications.

We analyzed the outcome of 46 patients with acute lymphoblastic leukemia (ALL) who relapsed following treatment with a pediatric-based protocol; 34 received intensive re-induction chemotherapy, with a CR2 rate of 62%, median overall survival (OS) 7.8 months, median relapse-free survival 5.2 months and one year OS 19%. Allogeneic HSCT was performed in 8 patients in CR2/3, with a median OS 2.2 months. OS was superior in patients who relapsed after completion of chemotherapy, compared to those relapsing on treatment. The outcome of adult ALL relapsing after treatment was therefore poor, and novel salvage strategies are needed to improve outcomes.

Introduction: A Canadian tyrosine kinase inhibitor (TKI) discontinuation trial is ongoing to determine if using dasatinib (DA) can lead to a successful treatment-free remission (TFR) after failing a first attempt of TKI discontinuation after imatinib (IM) treatment. The preliminary result indicate : 1) The 6-month molecular relapse-free survival (mRFS) rate is estimated as 58.0%; 2) DA re-treatment is feasible and safe, with achievement of excellent rates of MMR and MR4. We report here the preliminary analysis of the TFR rate at 6 months after DA discontinuation for the second TFR attempt. 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. Molecular relapse is defined as an increase in BCR-ABL transcript level < MR4.0 on 2 consecutive occasions, or a single increase in BCR-ABL transcript level < MR3.0. 100mg daily of DA is started if molecular relapse is confirmed and is discontinued 12 months after achieving > MR4 for a 2nd TFR attempt. The null hypothesis was a TFR2 rate of 17.5% while the alternative hypothesis was a TFR2 rate of 35.0% and the study was designed to reject our null hypothesis if > 28% of patients remain in TFR after DA discontinuation. Results: As of Jun 15, 2018, 53 (40.4%) of 131 enrolled patients experienced molecular relapse after IM discontinuation with a mRFS rate of 58.0% at 12 months (95% CI, 42.1-71.0%). Of the 53 patients who lost response, 51 patients received DA. The incidence of MMR, MR4 and MR4.5 at 3 months was 97.7%, 89.9%, and 84.6%, respectively. 25/ 51 patients receiving DA attained MR4.5 for 12 months or longer and discontinued it for a 2nd TFR attempt (TFR2). 21/25 (84.0%) of these patients lost molecular response at a median of 3.7 months after DA discontinuation. The estimated TFR2 rate after DA discontinuation was 21.5±8.5% at 6 months (95% CI [7.9-39.5%], Fig 1A). Thus we cannot reject our null hypothesis based on this result. For risk factor analysis for maintaining TFR2, the variables analysed included Sokal risk score, IM duration, MR4/MR4.5 duration, monthly doubling time after IM discontinuation, time to molecular relapse after IM discontinuation, molecular relapse pattern after IM discontinuation (MMR loss vs MR4 loss), and BCR-ABL1 qPCR value prior to DA discontinuation. 1) Time to molecular relapse after IM discontinuation correlates with TFR2 (p 2) Molecular relapse pattern after IM discontinuation correlates with TFR2. The group who had loss of MMR after IM discontinuation lost molecular response faster after DA discontinuation (n=19; median 3.0 months) compared to those with two consecutive losses of MR4(n=6; 6.43 months; p=0.0435, HR 2.991; Fig 3B). 3) The group with 5.5 log reduction or deeper in BCR-ABL1 qPCR transcripts prior to DA discontinuation (n=19) showed a TFR2 rate of 28.7% at 6 months (median TFR2 duration of 4.04 months) versus 0% in the group with qPCR transcript level between 4.5 and 5.4 log reduction (n=6, median TFR2 duration of 2.89 months; p=0.017; Fig 3C). We did not identify any other risk factor for molecular relapse after DA discontinuation . The expansion kinetics of the leukemic clone after DA discontinuation is similar to that after IM discontinuation. Conclusion: These preliminary results suggest that rechallenge with DA after failing a first IM discontinuation attempt for TFR is well tolerated and effective as most cases rapidly regained at least MR4. However, more strict criteria should be considered for TFR2 attempt, including achievement of a 5.5 log reduction or deeper in BCR-ABL1 qPCR levels prior to the 2nd TKI discontinuation attempt, and a MR4 duration of more than 12 months. Disclosures Kim: Pfizer: Consultancy; Paladin: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Busque:BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy. Savoie:Pfizer: Consultancy; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Bence-Bruckler:Lundbeck: Membership on an entity's Board of Directors or advisory committees. Delage:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Liew:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Laneuville:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Paladin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lipton:Bristol-Myers Squibb: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Leber:Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Polycythemia vera (PV) is a clonal stem cell disorder characterized by erythrocytosis and associated with burdensome symptoms, reduced quality of life, risk of thrombohemorrhagic complications, and risk of transformation to myelofibrosis and acute myeloid leukemia. The discovery of the JAK2 V617 mutation marked a significant milestone in understanding the pathophysiology of the disease and subsequently the diagnostic and therapeutic approaches. The current diagnostic criteria for PV are based on hemoglobin level and presence of the JAK2 V617 mutation. The treatment is geared toward prevention of thrombotic events, normalization of blood counts, control of disease-related symptoms, and potential prolongation of survival. Cytoreductive therapy is indicated in patients at increased risk of thrombosis. Hydroxyurea (HU) remains the most commonly used first-line cytoreductive therapy and is superior to phlebotomy in reducing risk of arterial and venous thrombosis. Interferon (IFN) is used either at failure of HU or in selected patients as first-line therapy. The results of pegylated IFN in phase 2 studies appear encouraging, with molecular responses occurring in some patients. Ongoing phase 3 studies of HU versus pegylated IFN will define the optimal first-line cytoreductive therapy for PV. A recent phase 3 trial has shown the superiority of the JAK1/2 inhibitor ruxolitinib in comparison to best available treatment in HU-intolerant or -resistant patients. The therapeutic landscape of PV is likely to change in the near future. In this report, we assess the potential impact of the changing landscape of PV management on daily practice.

Using multiple validated self-report instruments, we evaluated the health-related quality of life (HRQoL) of 29 adult ALL patients a median of 28 months after completing a pediatric-based treatment regimen. Global health was similar to normative data, but leukemia survivors had lower cognitive and social function, and reported more financial difficulty. Fatigue and pain affected 83% and 53% of patients, respectively, and both showed significant inverse correlation with overall health and all functional scales. Vincristine-related peripheral neuropathy was reported by 43%. Although therapy-related symptoms were persistent, long-term ALL survivors have a global HRQoL similar to the general population.

Introduction: Multiple studies have shown that tyrosine kinase inhibitor (TKI), usually imatinib (IM), can be successfully discontinued in chronic myeloid leukemia (CML) patients, achieving a 40-50% treatment free remission (TFR) rate. However, the remaining 60% of patients require reintroduction of TKI therapy. We have designed this study to answer the question if a second generation TKI, i.e. dasatinib, should be used after failing the first attempt of TKI discontinuation with IM. This prospective study attempts to evaluate whether the use of dasatinib after failure of a 1st attempt of TKI discontinuation with IM could improve TFR rate after a 2nd attempt of TKI discontinuation. Methods and materials: This is a prospective clinical trial (BMS CA180-543, Clinicaltrial.gov NCT#02268370) including all major CML centers across Canada (n=12). The primary objective is to determine the proportion of patients who remain in molecular remission (defined as maintaining ≥MR4.0) after dasatinib discontinuation following achieving ≥MR4.5. The present study has 3 phases: 1) IM discontinuation phase, 2) dasatinib rechallenge phase, 3) dasatinib discontinuation phase. A total of 135 patients is planned to be enrolled over 18-24 months. Key inclusion criteria include: 1) CML in chronic phase (CP), 2) total duration of IM therapy of minimum of 3 years, 3) total duration of MR4.5 or deeper response over 2 years with 2 consecutive confirmed MR4.5 or deeper response at the central lab with 3 months interval. Key exclusion criteria include prior allogeneic stem cell transplant or prior accelerated or blastic phase CML. Molecular recurrence was defined as an increase in BCR-ABL transcript level above MR4.0, on at least two consecutive occasions, or a single increase in BCR-ABL transcript level above MR3.0. Dasatinib is started at a dose of 100mg daily once molecular recurrence is confirmed. Results: The study was launched on March 2015. As of June 22 2016, 110 patients were entered into screening phase of whom 16 patients were not qualified due to 1) fluctuating transcripts (n=8) or 2) consent withdrawal (n=8). Two patients withdrew consent after losing their molecular response following IM discontinuation before starting dasatinib. Finally 75 patients were enrolled into IM discontinuation phase with 17 additional patients on screening in awaiting enrollment (Figure A). Of 67 patients evaluable for molecular relapse, 21 patients (31.3%) lost molecular response defined as loss of major molecular response (MMR; n=18) and loss of MR4 on 2 consecutive tests (n=3). The 6-month relapse free survival (RFS) rate was estimated as 58.0% (42.1-71.0%), while TFR rate using loss of MMR as an event was 64.7% (48.7-76.7%) at 6 months (Figure B) Of 21 patients who lost molecular response, 20 patients underwent dasatinib rechallenge phase, 14 of which were treated with dasatinib for at least 1 month and evaluated at least once with monthly BCR-ABL transcript monitoring (Figure C). Twelve patients achieved MMR at a median time of 56 days. The median time to achieve MR4.5 was 84 days. The incidence of MMR and MR4.5 at 3 months was 100% each (Figure D). Cox's proportional hazard regression model suggested strong correlation of RFS with total duration of IM therapy prior to IM discontinuation (p=0.001), duration of MR4 maintenance (p=0.004) or MR4.5 maintenance (p=0.006) prior to IM discontinuation, but not with time to achieve MR4 (p=0.289) or MR4.5 (p=0.330). Recursive partitioning method also defined the best cutoff for those variables: The group treated with IM for over 8.9 years (n=35) had RFS rate 81.1% vs 21.0% in those treated for less than 8.9 years (n=32; p Conclusion: Preliminary results of this Canadian TKI discontinuation trial show a RFS rate of 58-65% after IM discontinuation in CP-CML patients who attained MR4.5 for over 2 years, similar to other TKI discontinuation studies. Dasatinib can be safely administered in CML patients who lost molecular response after IM discontinuation with 100% of MMR rate at 3 months. Prolonged duration of IM treatment, or duration of MR4/MR4.5 maintenance with IM therapy could predict the chance of TFR success, but not time to achievement of MR4/MR4.5. Disclosures Bence-Bruckler: Lundbeck: Membership on an entity's Board of Directors or advisory committees. Savoie:Amgen: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy; Lundbeck: Consultancy. Busque:Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Delage:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Laneuville:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Paladin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Liew:BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Xenocostas:Janssen Inc.: Research Funding. Kamel-Reid:BMS: Research Funding. Leber:BMS Canada: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background: The use of tyrosine kinase inhibitors (TKIs) in the treatment of Philadelphia chromosome (Ph+) or BCR-ABL positive acute lymphoblastic leukemia (ALL) has improved remission rates allowing more eligible patients to proceed on to allogeneic hematopoietic stem cell transplantation (alloHSCT). Since many patients relapse following alloHSCT, some guidelines have recommended TKIs post alloHSCT (Couban, 2014, Giebel, 2016). Although some studies have demonstrated the benefits of this strategy, others have indicated that, owing to the immunomodulatory effects of TKIs, this approach may be harmful, leading to higher relapse rates. Given this uncertainty, we conducted a systematic review and meta-analysis of published studies comparing the outcomes of patients post alloHSCT who did or did not receive TKIs. Methods: We searched MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, ACP Journal Club, Scopus and conference abstracts focusing on the period during which TKIs were available (2000 to March 2016). Studies were included if they were retrospective or prospective cohort/randomized studies of adult patients with Ph+ or BCR-ABL+ ALL who underwent alloHSCT and received post-transplant TKIs. Studies that did not include a comparative group of patients who did not receive TKIs, duplicate studies, abstracts later published and studies of only pediatric patients were excluded from further analyses. Two reviewers with ALL expertise independently evaluated all abstracts and performed study selection. Results: The literature search identified 868 unique references, 195 of which were reviewed in detail. Seven studies, 6 retrospective and 1 prospective, comprising 1441 patients met all inclusion criteria (Table 1). Three studies contained one or more pediatric patients and four included patients beyond first complete remission including some with hematological relapse at the time of alloHSCT. All studies had a mix of donor sources including matched related, matched unrelated, mismatched related and mismatch unrelated. Pre-transplant conditioning was myeloablative in 3, reduced intensity in 1 and a combination of the two in the remaining 3 studies. TKIs were administered prophylactically (prior to hematological or minimal residual disease relapse) or pre-emptively (prior to hematological relapse). Data on the TKI used was not available in one study. Amongst the remaining 6 studies, imatinib at 400 - 600mg was the most commonly used TKI with dasatinib being used in 3 studies and nilotinib in 1 study. TKIs were initiated 0.5 - 60 months after alloHSCT and continued for 1-64 months after initiation. Overall, 346 patients received a TKI post alloHSCT while 1095 patients did not. Using a fixed effects model there was no difference in the relapse free survival (HR =0.838, 95% CI 0.678 - 1.036, p=0.102) or overall survival (HR=0.868, 95% CI 0.675 - 1.117, p=0.27) for those who received a TKI compared to those who did not. In contrast, there was a significant increase in relapse rates for those who were treated with TKI post-HSCT (HR 1.204, 95% CI 1.044 - 1.387, p=0.011). Conclusions: While there are compelling theoretical reasons to recommend TKIs post alloHSCT (Couban, 2014), this meta-analysis suggests that their use is not associated with improvements in overall survival or relapse free survival and may be associated with higher relapse rates. However, given the heterogeneous nature of the studies, these results must be viewed with caution. Nonetheless, the results are compelling and highlight the need for larger prospective controlled studies evaluating the role of TKI post alloHSCT in patients with Ph+ ALL. Disclosures Liew: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees.

Background: The diagnosis of acute myeloid leukemia (AML), response to treatment and disease recurrence are most commonly assessed with bone marrow studies. Recommendations from leading experts (Bain, 2001) and guidelines of the European LeukemiaNET (Dohner, 2010) and the National Comprehensive Cancer network (O’Donnell, 2012) suggest that only the bone marrow aspirate (BMA) is necessary to assess residual disease while the trephine biopsy (TB) is necessary only when an aparticulate BMA is obtained. In contrast, guidelines of the International Council for Standardization in Hematology (Lee, 2008) suggest that BMA and the TB should be routinely performed together as they provide complementary information. Due to these conflicting recommendations we sought to determine whether the TB provides additional sensitivity for the detection of residual leukemia following intensive chemotherapy for AML. Methods: A single centre retrospective chart review was conducted of bone marrow studies of all AML patients who had received intensive chemotherapy from 2004 – 2013. Those lacking a TB were excluded. Residual disease was assessed by morphological examination of the BMA and TB +/- immunostaining but minimal residual disease (MRD) analysis was not performed. Results: 598 bone marrow studies from 227 patients were evaluated. The median age of the patients was 54.6 (range 18 -77) with 70% age < 60. Forty-four percent were female. Cytogenetics were favorable in 30 (13%), intermediate in 146 (64%), high-risk in 44 (19%) and failed in 7 (3%) of the patients. Of the 598 bone marrow samples 198 (33%) were interim marrows performed 14 days following initiation of induction or re-induction chemotherapy (D14 marrow), 251(42%) were recovery marrows following induction/re-induction chemotherapy (EOI marrow) and 149 (25%) were during follow-up. The BMA was considered to be acellular/hypocellular in 31%, hemodilute in 16.4% and aparticulate/pauciparticulate in 27.3% of samples. As per guidelines > 200 cells were counted in 99.8% of the aspirate samples to ascertain remission status. The median length of the TB segments was 1.85 cm (0.2 – 7.0 cm) and it was considered inadequate in 12.7%, of good or excellent quality in 24.9% and adequate for residual disease assessment in the remainder of cases. Approximately 19 % of TB samples had mild to significant hemorrhagic artifact. The bone marrow cellularity could not be assessed in 1.2% of samples but was patchy in 0.5%, aplastic in 2.8%, hypocellular in 36%, normocellular in 23.6%, hypercellular in 23.2%, packed in 6% and was not described in 6.7% of the cases. Residual leukemia was identified in 33.1% of BMA and in 33.3% of TB samples. The BMA and the TB findings were concordant in 562 of 598 (94%) of cases. In 3.5% (21) of cases residual leukemia was seen in the TB but not the BMA whereas in 2.5% (15) of cases the BMA detected residual disease but the TB failed to do so. The TB led to a change in diagnosis from ‘No Leukemia’ to ‘Residual Disease’ in 5.1% of D14 marrows, 3.6% of EOI marrows and in 1.3% of follow-up marrows with no statistically significant difference between the groups (p=0.178). There was no relationship between a change in diagnosis and whether patients received an anthracycline or a non-anthracycline based chemotherapy regimen (4.4% vs. 3.2%, p=1.0). The TB, however, led to a change in diagnosis more commonly in patients with favorable risk karyotype relative to those with intermediate risk karyotype (20% vs. 6.2%, p= 0.02) but not relative to those with unfavorable risk karyotype (20% vs. 13.6%, p=0.53). Hemodilute bone marrow samples were more likely to have a TB related change in diagnosis relative to undilute samples (8.2% versus 2.6%, p=0.01) as were aparticulate/pauciparticulate samples relative to particulate samples (8% vs. 1.9%, p=0.00046). However, in multivariate analysis, only an aparticulate/pauciparticulate sample was associated with TB related change in diagnosis (p=0.015, OR = 3.6). Conclusions: Our data demonstrate that, following intensive chemotherapy, the BMA alone may fail to identify residual leukemia particularly when the BMA is aparticulate/pauciparticulate. In these situations the TB provides additional sensitivity for the detection of residual disease. Further studies are required to evaluate the need for the TB in particulate samples when combined with MRD analysis. Disclosures No relevant conflicts of interest to declare.

BACKGROUND: Anthracycline based treatment for acute myeloid leukemia (AML) can be associated with significant morbidity and mortality amongst older patients or those with significant co-morbidities. Furthermore, for patients with previous anthracycline exposure or preexisting cardiac disease anthracyclines pose an increased risk of cardiotoxicity. For such patients intensive treatment options are limited. The FLAG (fludarabine, cytarabine and filgrastim) regimen is a non-anthracycline based chemotherapy useful for relapsed/refractory AML and as initial therapy for “fit” eligible patients. We present our experience using FLAG as first line therapy in a cohort of newly diagnosed AML patients with advanced age, significant co-morbidities or preexisting cardiac disease. METHODS: A single institution retrospective chart review was undertaken of patients treated with FLAG as frontline therapy from 2004 – 2013 with follow-up until June 2014. All patients were considered ineligible for standard ‘3+7’ treatment by the attending physician. RESULTS: Over the study period 56 patients received FLAG. Due to patient refusal or induction complications bone marrow assessments to ascertain remission status were not performed in 10 patients – to minimize bias these patients were evaluated for toxicity and overall survival (OS) but excluded from complete remission (CR) and relapse free survival (RFS) analysis. Of the 56 patients, 68% were males. The median age was 69 (21 – 80) with 79% aged ≥ 60 and 43% aged ≥ 70. Fifty-five percent (31) of the patients had primary AML and cytogenetics were favorable in 5% (3), intermediate in 66% (37), poor-risk in 21% (12) and failed in 7% (4). Forty-six percent (26) were treated with FLAG due to preexisting cardiac disease and others due to advanced age (20%), poor performance status (16%), co-morbidities (16%) or previous anthracycline exposure (2%). The ages of patients treated with FLAG due to cardiac disease or other reasons was similar (63.5 years vs. 66.9 years, p=0.27). Amongst patients with cardiac disease a pre-chemotherapy cardiac evaluation revealed wall motion abnormalities in 39% and an ejection fraction (EF) ranging from 33% - 81% with a borderline (≤ 50-51%) EF in 46%. Febrile neutropenia was observed in 82% (46) of patients, 27% (15) required intensive care support and the induction mortality was 16% (9). Amongst patients evaluated for a CR (46/56), 48% (22/46) obtained a CR. Although a CR was seen in 100% (3/3), 46% (15/33) and 37% (3/8) of patients with favorable, intermediate and poor-risk cytogenetics respectively there was no statistically significant difference (p=0.22) between groups. A CR was obtained in two additional patients following a second course of FLAG for an overall CR rate of 52% (24/46). Of these 24 patients, 8 (33.3%) received no additional treatment while 16 (66.7%) received consolidative chemotherapy. Of 10 eligible patients, 4 proceeded to an allogeneic stem cell transplant (allo-SCT) including two with preexisting cardiac disease. Of patients not transplanted 50% (10/20) eventually relapsed. There was no difference in relapse rates for those receiving FLAG for age/co-morbidities vs. cardiac disease (60% vs. 40%, p= 0.66) or for patients age The median OS for the 56 patients was 278 days with 1 and 2 year survivals of 44% and 22% respectively. The median OS for patient’s age < 60 was higher than those age ≥ 60 (1102 days vs. 218 days, p=0.009) but there was no difference in the OS between patients treated with FLAG for cardiac disease and those treated for other reasons (305 days vs. 254 days, p=0.202). The median survival of patients with favorable, intermediate and unfavorable risk cytogenetics was 523 days, 311 days and 87 days respectively but this was not statistically significant (p=0.25) likely due to limited patient numbers. Conclusions: The FLAG regimen is a non-anthracycline based regimen that may serve as an alternative to the standard ‘3+7’ induction for AML in older adults or those with significant co-morbidities including preexisting cardiac disease. It is associated with comparable remission rates and overall survival in older patients. In addition, it may allow some patients with preexisting cardiac disease to proceed to allo-SCT. Disclosures No relevant conflicts of interest to declare.

Abstract 1424 Although induction chemotherapy can achieve complete remission (CR) in 60 – 80% of younger patients with acute myeloid leukemia (AML), most patients eventually relapse; therefore, the search for risk stratification methods that take into account response to therapy is warranted. Multiparameter flow cytometry (MFC) is more sensitive than conventional morphology and can detect residual leukemic cells (minimal residual disease, MRD) at a level of 1 AML cell in 103 – 104 non-leukemic cells. However, the prognostic significance of the presence of MRD by MFC after induction chemotherapy remains controversial, as is the timing of MRD testing after induction or consolidation chemotherapy (San Miguel et al, Blood 2001). The objective of this study is to evaluate whether MRD detectable by MFC after induction chemotherapy for AML predicts patient overall survival (OS) and progression-free survival (PFS) in patients undergoing conventional chemotherapy. Methods: All patients with newly diagnosed AML in Alberta between 2002 and 2010 were retrospectively reviewed. Patients were included in this study if they had evidence of an aberrant “leukemia-associated immunophenotype” (LAIP) by 5-colour MFC at diagnosis, underwent induction chemotherapy and had post-induction bone marrow assessment for MRD. Exclusion criteria included: diagnosis of acute promyelocytic leukemia, allogeneic transplantation in first complete remission (CR), or lack of outcomes information. Prognostic markers planned prospectively for inclusion in the analysis included age>60y, presence of secondary leukemia therapy-related or following prior hematologic disease, and cytogenetic risk group (Grimwade et al, Blood 2010). All patients were classified into one of three groups: those in CR without MRD, those in CR with any level of detectable MRD by MFC, and patients with no response (NR) to induction. Results: Of 199 patients diagnosed with AML during this time period, 84 met the inclusion criteria and were included in this analysis. CR was achieved in 55 patients without evidence of MRD, and CR with presence of MRD was identified post-induction in 17 patients. NR to induction was seen in 12 patients. In the MRD group compared to the CR group, age >60 years was seen in 41% vs 35% of patients, secondary leukemia in 14% vs 14%, and by cytogenetic risk groups 41% vs 71% had intermediate risk, 35% vs 16% had good risk and 24% vs 13% had poor risk disease, respectively. All deaths were due to relapsed leukemia except 1 patient in the NR group, 1 with MRD and 5 patients in CR after induction. There was no difference seen in outcomes with secondary AML (N=5) between groups. There was no difference in predicted OS (p Figure 1 ) and progression-free survival at 5 years (CR 27.7%, MRD18.8%, p=0.66) within this small sample size, although both groups have significantly better outcomes than those with refractory disease. There is a trend to better survival in patients in patients in CR compared to those with MRD. Age and cytogenetic risk group remain highly significant predictors of patient outcomes regardless of the presence of MRD, CR or NR after induction. Table 1 . Univariate analysis of MRD status and prognostic variables in AML patients undergoing chemotherapy Factor Definition 5 year OS HR 95% CI Log rank p value Response to Induction CR vs MRD 52% vs 41.2% 1.634 0.742–3.597 0.222 CR vs NR 52% vs 8.3% 25.641 7.519–90.909 Age (yrs) 60 55.5% vs 23.9% 2.090 1.143–3.823 0.017 Cytogenetic Risk Group Favourable vs Intermediate 86.7% vs 43.5% 2.982 1.380–6.444 0.005 Favourable vs High 86.7% vs 0% 21.73 7.247–65.16 Download : Download high-res image (31KB) Download : Download full-size image Conclusion: Within a small group of patients, MRD presence after induction chemotherapy in patients in morphologic CR was not predictive of OS or PFS, although a trend is suggested toward improved OS in patients in CR. Conventional cytogenetic risk groups and age >60 years are more highly predictive of patients outcomes than presence of MRD for patients within all response groups. Disclosures: Geddes: Calgene Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding.