ALBERT

Description: Background: Less-fit patients with acute myeloid leukemia (AML) or high-risk myelodysplasia (MDS) age 60 years and older constitute the majority of patients with AML/MDS but are not well represented in clinical trials. DNA-methyltransferase inhibitor (HMA) monotherapy (e.g. azacitidine or decitabine) is usual. Overall response rates (ORR) are low; improvement in overall survival relative to supportive care alone is modest, highlighting the critical need for efficient identification of effective novel therapies. Blocking programed cell death protein-1 (PD-1) signaling with nivolumab may increase the sensitivity of AML cells to azacitidine and improve outcomes and is the focus of one arm of the S1612 trial. Signaling through PD-1 contributes to tumor immune evasion and growth in AML [Chen, Cancer Biol Ther 2008]. Increased expression of PD-1 (~40% of AML), is associated with poor HMA response [Ørskov, Oncotarget 2015]. A single center azacitidine/nivolumab non-randomized phase II study in relapsed/refractory AML reported ORR of 33% (23/70), including 22% complete remission/complete remission with incomplete hematologic recovery [Daver, Cancer Discovery 2018]. About 25% of the patients developed grade 2-4 immune toxicities; nivolumab immune-related adverse events led to treatment discontinuation in nearly 1 in 7 patients. Study Design and Methods:The S1612 trial [NCT03092674] is a platform randomized phase II/III clinical trial with a common azacitidine control arm (CA) and two currently active experimental arms (EA). Therapy is intended for community setting: azacitidine/nivolumab; and azacitidine/midostaurin. The innovative design utilizes a phase II go/no-go decision comparing each EA with the CA independently when there are 100 pts/arm and 104 deaths on the EA and CA combined. EAs will proceed to phase III if the null hypothesis (HR=1) is rejected in favor of the EA (15% one-sided alpha). When the two currently active EAs complete phase II accrual, a third EA (decitabine/cytarabine) will open. The CA stays open the entire length of the trial and only concurrently randomized patients will be compared across arms. If an EA proceeds to phase III, 200 additional patients (300 total patients) will be accrued. Phase III analysis occurs 1.5 years after accrual or at 414 deaths (in the respective EA and CA), whichever comes first. The phase III tests the null hypothesis with 4.5% two-sided alpha and 83% power for each EA to detect an improvement in median OS from 10.4 to 15.6 months. Eligible pts are age ≥60 years, newly diagnosed AML with ≥ 20% blasts or myelodysplastic syndrome with excess blasts-2 (MDS-EB-2); deemed by the treating physician unfit for standard cytotoxic chemotherapy; and no prior HMA permitted. Trial in Progress Issues:Between December 2017 and October 2018, 113 patients were screened and 78 randomized to study treatment (median/range age: 75/61-86 years; median/range performance status 1/0-3). Two concerns challenged this trial: 1) required administration of 7-day azacitidine at the enrolling sites created a burden for this population and 2) an early excess grade 5 toxicity signal in the azacitidine/nivolumab arm compared with the control arm. Without a control comparison, this safety signal likely would have been missed. Strategies to address these concerns were developed by the study team. Discussion with the sponsor and US Food and Drug Administration (FDA) focused on allowance of standard-of-care protocol-directed azacitidine administration in the patient's primary care doctor's office rather than at the oncology center. Because of the toxicity concern, the trial was placed on partial clinical hold for further evaluation and possible nivolumab-arm eligibility changes, along with new surveillance and pre-emptive action including prompt steroid initiation for suspected immune-related toxicities. The S1612 trial highlights special concerns when enrolling vulnerable populations onto leukemia clinical trials, and the importance of collaborative strategies including with the FDA to preserve clinical trial integrity for patient benefit. It also demonstrates the efficiency this novel platform design has for therapeutic investigation and, importantly, very early identification of serious toxicity. Updates on accrual and resolution and of these issues will be presented. Disclosures Hay: Kite: Research Funding; Gilead: Research Funding; AbbVie: Research Funding; Janssen: Research Funding; MorphoSys: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Roche: Research Funding; Novartis: Research Funding. Assouline:Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria. Walter:Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; New Link Genetics: Consultancy; Agios: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Seattle Genetics: Research Funding; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; Amgen: Consultancy. Foran:Agios: Honoraria, Research Funding. Radich:TwinStrand Biosciences: Research Funding; Novartis: Other: RNA Sequencing. Othus:Celgene: Other: Data Safety and Monitoring Committee; Glycomimetics: Other: Data Safety and Monitoring Committee. Erba:Astellas Pharma: Consultancy; Amgen: Consultancy; Amgen: Consultancy; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Pfizer: Consultancy; Pfizer: Consultancy; ImmunoGen: Consultancy, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; Astellas Pharma: Consultancy; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Michaelis:Pfizer: Equity Ownership, Research Funding; Incyte: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; TG Therapeutics: Consultancy, Research Funding; JAZZ: Other: Data Safety Monitoring Board, uncompensated, Research Funding; BMS: Research Funding; Bioline: Research Funding; ASTEX: Research Funding; Janssen: Research Funding; Millenium: Research Funding; Macrogeneics: Research Funding. OffLabel Disclosure: Off label experimental combination therapies in newly diagnosed AML/MDS will be discussed, including nivolumab and azacitidine.

Description: Abstract 3551 Background: With intensive chemotherapy, many acute myeloid leukemia (AML) patients will enter complete remission (CR). Empirically, the bone marrow is typically examined 14 days after initiating induction therapy, and re-treatment is commonly considered if significant residual blasts remain. However, many patients receiving single induction will enter CR without additional therapy despite substantial amounts or residual marrow blasts on day 14, leaving considerable uncertainty about the value of early marrow assessments. An emerging alternative approach to predict the efficacy of induction therapy includes the assessment of peripheral blood blast (PBB) dynamics. Rapid clearance of PBB, determined either by review of manual differential counts or flow cytometry is predictive of CR (likelihood of 76–90%) and overall survival. We investigated whether mathematical modeling of early PBB dynamics using automated complete blood cell (CBC) counts and the manual differential could further refine our ability to predict CR. Patients and Methods: We identified 111 adult patients with circulating PBB who underwent curative-intent, single-cycle induction chemotherapy for newly diagnosed AML between April 1999 and December 2011. Therapy regimens included “7+3”-like (56.8%), and regimens of similar/higher (29.7%) or lower (13.5%) intensity. PBBs were quantified as WBC count from the automated CBC times percentage of blasts by manual differential (100 cells). Cytogenetic abnormalities, NPM1/Flt3 status, day 14 and recovery bone marrow data were extracted from patient records. In the 62 patients with 〉3 measurable PBB counts, the rate of PBB clearance was calculated by fitting an exponential decay curve to the data points of absolute PBB counts, starting on day 1 of chemotherapy. This subgroup of patients had similar baseline parameters as the whole group, including age, WBC count at diagnosis, cytogenetic risk, percent of secondary AML, therapy regimens were similar, and CR rates were identical (69 vs. 68%). Results: An exponential decay curve [N(t) = N0×e-xt, with x=decay constant] resulted in an excellent goodness of fit of early PBB dynamics (mean r2=0.93). Rapid PBB clearance was highly predictive of CR achievement, with an optimal cut-off of x=1.4 (corresponding to a 4.2-log reduction in tumor burden if maintained over the course of a weeklong chemotherapy) based on the receiver operating characteristic (ROC) curve. All but 1 of the 27 patients with x〉1.4 achieved CR (positive predictive value [PPV]=96%) the only non-responder with x〉1.4 had a combination of negative prognostic factors including secondary AML, unfavorable cytogenetics, older age, and lower intensity treatment. PPV of PBB clearance rate of 96% for predicting CR compared favorably to alternative previously published approaches such as day of PBB clearance or percentage of day 14 bone marrow blasts (84 and 85% respectively in our study). Day 14 marrow assessments did not add prognostic information in 26/27 patients who had fast PBB clearance rate (x〉1.4). In univariate analyses, CR achievement was significantly correlated with a higher PBB clearance rate, younger age, primary AML, more favorable cytogenetics, and treatment intensity. In multivariate analyses including age, primary vs. secondary AML, cytogenetics, type of therapy, and PBB clearance rate (57 patients), only the PBB clearance rate remained statistically significantly associated with CR achievement. Importantly, information from CBC differentials is routinely available in most institutions and associated costs are low. Unlike determination of the exact day of PBB clearance that coincides with profound cytopenia, the PBB clearance rate is measured while PBB are still abundant, rendering the latter method less prone to sampling and observer errors. Conclusion: our findings suggest that early marrow assessment may not be necessary in AML patients who experience rapid PBB clearance upon induction treatment initiation as they have an almost 100% chance of achieving CR. Disclosures: Vainstein: Neumedicines Inc: Employment.

Description: Background Adults with newly diagnosed or relapsed acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS) typically receive intensive chemotherapy to achieve disease remission. Generally, these patients remain hospitalized until blood count recovery due to the risk for infections and bleeding during pancytopenia. However, a recent small pilot study at our institution suggested that early discharge (ED) following induction/salvage therapy for MDS/AML may be safe and may reduce cost. We therefore conducted a phase 2 study to test this care strategy in a larger cohort of patients (NCT01235572). Methods Patients aged 18-75 years with high-risk MDS or AML (other than acute promyelocytic leukemia) were enrolled before or during induction or salvage chemotherapy and provided with outpatient care teaching. Patients were considered eligible for ED if they fulfilled the following medical and logistic criteria: ECOG performance status of 0-1, adequate organ function; no active bleeding; agreeable to close outpatient follow-up; reliable caregiver; and residency within 60 minutes of the outpatient clinic. Patients who met medical but not logistic criteria served as inpatient controls. If readmitted, ED was again possible if all medical/logistic criteria were met. Patients remained on protocol until blood count recovery, additional chemotherapy was administered, or a maximum of 45 days. Our goal was to compare the number of early deaths, healthcare costs and resource utilization among ED patients versus inpatient controls. Safety was monitored with early stopping if the early death rate was 〉7% in the ED group, with a predefined interim analysis after 30 patients. All data are provided as median (range). Results One hundred and seven eligible patients were enrolled over a 2-year period. Two patients died during chemotherapy. Twenty-seven patients failed to meet medical ED criteria after completion of chemotherapy and were taken off study, mostly due to poor performance status. Eighteen patients, age 51.4 (22-70) years, met medical but not logistic ED criteria and served as controls; they were followed for 14 (9-41) days, with 7 patients taken off study at the time of hospital discharge before blood count recovery. Sixty patients, age 51.6 (22-71) years, met all ED criteria and were discharged upon completion of induction (n=19) or salvage (n=41) chemotherapy for AML (n=50) or MDS (n=10). A median number of 1 (1-3) readmission occurred in 53 of these patients, primarily for neutropenic fever; 8 patients were readmitted twice and 3 patients were readmitted 3 times prior to coming off study. Overall, ED patients spent 12.8 (0-38) and 7.5 (0-33) days as out- and inpatients, respectively, for a total of 62.7% (0-100%) of the study time spent as outpatients. ED patients required 0.41 (0-1.9) clinic visits and 0.13 (0-0.66) physician visits per outpatient day. Duration of IV antibiotics was similar in ED and control patients (10 [0-40] vs 12 [0-40] days; p=0.38) as was number of red blood cell transfusions (0.27 [0.0-0.94] vs 0.29 [0.08-0.548] units/study day; p=0.21). In contrast, ED patients required fewer platelet transfusions (0.21 [0.09-1.25] vs 0.33 [0.21-0.80] units/ study day; p=0.02). Six patients in the ED group required between 1-6 days of intensive care unit (ICU) care (p= 0.17 for the difference in ICU days between discharges and controls). Three deaths occurred in the ED group during the study period: two of sepsis (2 and 7 days after readmission), and one of fungal sinusitis (11 days after readmission). The median daily total professional and facility charges, dated from the day of re-evaluation until removal from protocol, were significantly lower for patients discharged early compared to inpatient controls: $3,871 [$360.86-$13,361] vs $6,283 [$4,868-$11,898], p

Description: Introduction Mangement of AML typically calls for a bone marrow aspirate 7-10 days after completion of induction therapy with standard or high-dose cytarabine (HiDAC)-containing regimens (day 14 marrow). If this marrow contains 〉5-10% blasts, National Comprehensive Cancer Network guidelines recommend a second course of induction therapy. However, nearly 70% of patients who have persistent blasts in a day 14 marrow do not begin reinduction within 1 week. Additionally, at least in patients given higher doses of cytarabine as part of induction therapy, blast counts often continue to decrease between days 14 and 21, and many such patients will achieve complete remission (CR) without a second induction. These findings call into question the value of a day 14 marrow. Methods Our database contained 154 patients with newly diagnosed AML or MDS with 10-19% blasts seen in our hospital from 2008-2013. Patients lived at least 21 days after receiving induction therapy with regimens containing standard-dose cytarabine (114 patients, typically given “3+7” ) or high-dose cytarabine (40 patients). The treatments were not given on protocol, thus granting physicians discretion to determine when to examine the marrow. Marrow exams performed between days 10 and 17 after starting induction were considered a “day 14 marrow.” Response was assessed at least 21 days from the start of the initial induction course. Our goals were (1) to identify pretreatment factors (described below) associated with the decision to obtain a day 14 marrow and (2) to determine the influence obtaining a day 14 marrow had on the likelihood of CR on course 1, after accounting, by multivariable logistic regression, for age, cytogenetic risk (SWOG criteria), pretreatment blast % (morphologic count in marrow; peripheral blood if no marrow available), and type of AML (de novo vs. secondary). Results 116 of 154 patients (75%) had a day 14 marrow. Patients who had and did not have a day 14 marrow were similarly-aged (average 53 in both groups), had similar pretreatment blast percentages (52% vs 47%, respectively), and had a similar proportion with de novo AML (66% vs 68%). Patients who had a day 14 marrow more often received 3+7 (79% of standard-dose cytarabine patients had a day 14 marrow vs 65% of HiDAC, p=0.06). Only 60% of patients with favorable risk cytogenetics had a day 14 marrow vs 79% of patients with intermediate or unfavorable risk (p=0.03). Considering the 3+7 group separately, only a higher pretreatment blast count predicted the likelihood of a day 14 marrow (53% with a day 14 marrow vs 38% without, p=0.02). No factors were predictive in the HiDAC group. As expected, favorable cytogenetics were associated with a higher CR rate while age, pretreatment blast %, and de novo vs secondary AML did not influence CR. After accounting for these covariates, there was no difference in the rate of CR between patients who did and did not have a day 14 marrow (66% vs 74%, p=0.61). The same was true when standard and high-dose cytarabine were analyzed separately (p=0.80 and 0.26, respectively). 18 patients with a day 14 marrow had resistant disease and received a second induction course; of these, two achieved CR. Likewise, two patients without a day 14 marrow were reinduced for resistant disease, and one entered CR. While the response to the second induction was not included in the analysis, results would not be expected to vary significantly given the CR rates with the second course. Conclusions These results suggest that while patients are more likely to have a day 14 marrow if they have intermediate- or poor-risk cytogenetics and receive 3+7, the decision to obtain a day 14 marrow does not lead to a higher CR rate. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Current treatment options for R/R AML are highly inadequate. CD33 is expressed in 〉99% of AML cases. BiTE®s have been effective in R/R Acute Lymphoblastic Leukemia. AMG 330 is a BiTE® that binds CD33 and CD3 on T cells, facilitating T-cell destruction of CD33+ cells. The objectives of this ongoing study are to evaluate the safety, pharmacokinetics, and pharmacodynamics of AMG 330 in R/R AML and to estimate the maximum tolerated dose. Methods: This was a phase 1 dose escalation study evaluating AMG 330 as a continuous IV infusion in patients with R/R AML, with single-patient cohorts for the first 3 doses and subsequently 3-6 patients per cohort (NCT#02520427). Response was per revised IWG criteria with the addition of complete response (CR) with partial hematologic recovery. After completing the first cycle without dose-limiting toxicity (DLT), up to 5 additional cycles could be given for benefit. After the 30 μg/day (d) cohort, risk mitigation measures for cytokine release syndrome (CRS) were put in place, including step-dosing and pretreatment with a single dose of corticosteroids. The modified treatment regimen consisted of an initial run-in dose of 10 μg/d × 4d followed by the target dose. A 2-step regimen was then tested, ie 10 μg/d, 60 μg/d, and then the target dose, for a treatment duration of 14d or 28d, followed by 1-4 weeks off treatment. Results: As of June 14, 2018, 35 patients had enrolled in 12 dose cohorts with a target dose range of 0.5-480 μg/d in this ongoing study. Over half (20/35, 57%) of patients were male and the median age was 58 (range: 18-80) years; 14/35 (40%) have previously received a stem cell transplant. Median AML disease duration at baseline was 1.3 (range: 0.3-9.6) years, median proportion of blasts at baseline was 37% (range: 3%-95%), and the median # of prior treatments was 4 (range: 1-15). Median baseline ANC was 0.2 (range: 0-8.6) × 109/L. Patients received a median of 1 (range: 1-6) cycle with AMG 330; 31/35 (89%) patients discontinued treatment for disease progression (n=24), adverse events (AEs; n=5, 2 treatment-related), and patient request (n=2). One patient completed the maximum of 6 cycles allowed and 3 patients are still receiving study drug. Serious AEs (SAEs) were seen in 23/35 (66%) patients (treatment-related in 15 patients); SAEs seen in 〉1 patient included CRS (n=11), febrile neutropenia (n=6), pneumonia (n=4), leukopenia (n=3), thrombocytopenia (n=2), and subdural hematoma (n=2); 1 patient died on study due to AML progression (not treatment-related). One patient each in the 10 μg/d and 30 μg/d cohorts (no lead-in) experienced severe CRS; CRS signs and symptoms resolved in 1d with corticosteroids, vasopressors, and IV fluids, and interruption of AMG 330. There were DLTs of grade 2 CRS and grade 4 ventricular fibrillation with a target dose of 480 μg/d; the target dose was then decreased to 240 μg/d. Two patients had a CR at a target dose of 240 μg/d (lead-in of 10 μg/d→60 μg/d); 1 patient each at target doses of 120 μg/d and 240 μg/d had a CRi and 1 patient who received 1.5 μg/d had a morphologic leukemia-free state (MLFS,

Description: Key Points Patients with abnl(17p) AML have a poor outcome after allogeneic hematopoietic stem cell transplantation.

Description: Background: SL-401 is a novel targeted therapy directed to the interleukin-3 receptor (CD123), a target overexpressed on acute myeloid leukemia (AML) blasts and AML cancer stem cells (CSCs), and a variety of additional hematologic malignancies. While conventional chemotherapy can induce remission in a majority of treatment-naive AML patients, relapse rates remain high. Outcomes are particularly poor when minimal residual disease (MRD), as determined by genetic and/or flow cytometric analyses, remains after therapy, with high rates of relapse and short disease-free survival. Conceivably, a therapy directed at lowering MRD burden may improve long-term outcomes. Given the association of MRD with CD123+ AML CSCs, SL-401 is being evaluated in patients with AML in first or second complete remission (CR1 or CR2, respectively) with high risk of relapse including persistent MRD. Preliminary results are reported here. Methods & Results: This multicenter, single-arm Phase 2 trial of AML patients in CR1 or CR2 with high risk of relapse includes a lead-in (stage 1) and expansion (stage 2). In stage 1, patients (MRD+ or MRD-) receive SL-401 as a daily IV infusion at 7, 9, or 12 ug/kg/day for days 1- 5 of a 28 day cycle in a 3x3 design. In stage 2, patients (MRD+ only) receive SL-401 at the dose determined in stage 1. Presence of MRD for eligibility requires either molecular (by cytogenetics, FISH, PCR, or next-generation sequencing of AML-associated mutations) or multiparameter flow cytometry (MFC) evidence of persistent abnormalities in the setting of morphologic CR. In stage 2, MRD assessment will include MFC of bone marrow aspirates conducted at a central laboratory for uniformity. Objectives include characterization of SL-401 safety with determination of the maximum tolerated or tested dose, and preliminary assessment of efficacy including changes in MRD burden and response duration. As of 7/27/16, stage 1 has been completed and stage 2 is open for enrollment. Nine patients (stage 1) received SL-401 (7 ug/kg, n=3; 9 ug/kg, n=3; 12ug/kg, n=3). The median age was 63 years (range: 51-78 years); 6 males and 3 females were treated; 8 patients were in CR1 and 1 patient was in CR2 at enrollment. The 12 ug/kg dose level was the highest tested dose with no DLTs; MTD was not reached. The most common treatment-related AEs, all grades, were thrombocytopenia (3/9; 33%) and hypoalbuminemia (3/9; 33%); the most common ≥ grade 3 treatment-related AE was thrombocytopenia (1/9; 11%); there was no DLT. Patients treated at all doses received 1+ to 5+ cycles (ongoing) of SL-401, including 3 MRD+ patients treated at 7 ug/kg (n=1) or 9 ug/kg (n=2) who received 1-5 cycles, and 1 MRD+ patient treated at 12 ug/kg who is receiving ongoing SL-401 for 4+ cycles. For all 3 patients treated at 12 ug/kg (MRD+, n=1; MRD-, n=2), 2 patients remain on SL-401 and have received 1+ and 4+ cycles (both ongoing); one other patient treated at 12 ug/kg discontinued the study because of infection unrelated to study drug. Notably, the one MRD+ patient treated at 12 ug/kg (ongoing at 4+ cycles) had marked MRD reduction as determined by MFC at the local institution; this patient is being considered for stem cell transplant (SCT). Conclusions: Stage 1 is complete without DLT or MTD, and stage 2 (expansion) is open to enroll AML patients in CR1 or CR2 who are MRD+ at the highest tested dose of 12 ug/kg. The safety profile has been similar to that observed in other SL-401 clinical studies, with no unexpected AEs. Targeting MRD with SL-401 has the potential to reduce this chemo-resistant cell population and offer improved long-term outcomes for AML patients in remission with high risk of relapse. Updated data will be presented. Clinical trial information: NCT02270463. Disclosures Lane: N-of-1: Consultancy; Stemline Therapeutics: Research Funding. Sweet:Pfizer: Speakers Bureau; Karyopharm: Honoraria, Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau. Wang:Immunogen: Research Funding; Incyte: Speakers Bureau. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Carraway:Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau; Baxalta: Speakers Bureau. Prebet:celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Chen:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Lindsay:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Stone:Novartis: Consultancy; Juno Therapeutics: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Karyopharm: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Xenetic Biosciences: Consultancy. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Konopleva:Cellectis: Research Funding; Calithera: Research Funding.

Description: Background: Patients with AML harboring FLT3 mutations have poor clinical outcomes. Furthermore, FLT3 mutations frequently co-occur with other driver mutations, such as NPM1 with DNMT3A, WT1, and RUNX1, that are associated with poor prognosis. Crenolanib is a highly potent and specific type-I FLT3 inhibitor, which has shown promising safety and efficacy in combination with chemotherapy. Here we report the outcomes of newly diagnosed FLT3 mutated AML patients treated with crenolanib and intensive 7 + 3 based chemotherapy (NCT02283177) by baseline genomic profile. Methods: Patients were treated on clinical trial with 7+3 induction chemotherapy combined with crenolanib, consolidation with high-dose cytarabine (HiDAC) combined with crenolanib, and/or allo-HCT followed by crenolanib maintenance. Of 44 pts enrolled and treated, 36 had sequencing performed at baseline. The median survival follow-up for these patients was 20.7 months with data cut off July 25, 2018. A post hoc analysis was performed to assess the impact of genomic profile on patient outcomes using published data from the German-Austrian AML Study Group as a historical control. Results: Concurrent FLT3-ITD, NPM1, and DNMT3A mutations ("triple mutant") were present in 10 pts. These patients demonstrated improved OS with crenolanib treatment compared with historical controls. Similarly, patients with FLT3-ITD and WT1 mutations (n = 6) showed dramatically improved outcomes, with no deaths occurring by 18 months. Patients with FLT3 (ITD or TKD) and RUNX1 mutations (n = 10) also had improved OS. Conclusions: This analysis suggests that adding a potent pan-FLT3 inhibitor can overcome the poor prognostic implication of adverse mutations co-occurring with mutated FLT3. These data support the combination of crenolanib with chemotherapy to improve the overall outcome of FLT3 mutated AML with diverse mutational profiles. Hence, a randomized trial has been initiated of standard chemotherapy combined with either crenolanib or midostaurin in newly diagnosed patients with FLT3-mutant AML (NCT03258931). Table. Table. Disclosures Goldberg: AROG: Research Funding; Pfizer: Research Funding; Celgene: Research Funding; Abbvie: Research Funding. Collins:Arog Pharmaceuticals: Research Funding; Celgene Corporation: Research Funding; Bristol Myers Squibb: Research Funding; Agios: Research Funding. Stone:Ono: Consultancy; Novartis: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Argenx: Other: Data and Safety Monitoring Board; Arog: Consultancy, Research Funding; Merck: Consultancy; Fujifilm: Consultancy; Jazz: Consultancy; Orsenix: Consultancy; Astellas: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; AbbVie: Consultancy; Amgen: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Sumitomo: Consultancy; Cornerstone: Consultancy. Walter:Actinium Pharmaceuticals, Inc: Other: Clinical Trial support , Research Funding; Amgen Inc: Other: Clinical Trial Support, Research Funding; Amphivena Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Aptevo Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Covagen AG: Consultancy, Other: Clinical Trial Support, Research Funding; Boehringer Ingelheim Pharma GmbH & Co. KG: Consultancy; Pfizer, Inc: Consultancy; Seattle Genetics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding. Wang:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Jazz: Speakers Bureau; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau. Tallman:AROG: Research Funding; AbbVie: Research Funding; Orsenix: Other: Advisory board; Daiichi-Sankyo: Other: Advisory board; ADC Therapeutics: Research Funding; Cellerant: Research Funding; BioSight: Other: Advisory board.

Description: BACKGROUND: The median age for diagnosis of acute myeloid leukemia (AML) is 68 years. Elderly patients are often ineligible for intensive chemotherapy and have limited treatment options. Venetoclax (Ven), an oral agent that targets the antiapoptotic protein, BCL-2, has demonstrated high rates of remission (〉60%) when administered in combination with low-dose cytarabine (LDAC), and could represent a potent therapeutic option for patients ineligible for intensive chemotherapy. METHODS: This open-label, phase 1/2 study (NCT02287233) evaluated the safety and efficacy of venetoclax in combination with LDAC in patients with previously untreated AML who were ineligible for intensive chemotherapy due to comorbidities or age. Patients had an Eastern Cooperative Oncology Group (ECOG) performance score of 0-2, had adequate hepatic and renal function, and were enrolled from December 2014 to May 2017. In the dose escalation portion of the study, 600 mg venetoclax was determined to be the recommended phase 2 dose (RPTD). Venetoclax was initiated at 50 or 100 mg daily and dose escalated over 4-5 days to reach the RPTD. In subsequent 28 day cycles, venetoclax was administered at 600 mg on all days. LDAC (20 mg/m2 daily) was subcutaneously administered on days 1-10 of each cycle. At the beginning of the study, concominant strong and moderate CYP3A inhibitor use was prohibited; however, as additional safety and pharmacokinetic data became available, their use was allowed with appropriate venetoclax dose adjustments. Time to first response, rates of complete remission (CR), CR with incomplete blood count recovery (CRi), CR with partial hematologic recovery (CRh), duration of response, achievement of transfusion independence, overall survival (OS) and adverse events (AEs) were evaluated. Minimal residual disease (MRD) was evaluated centrally by multicolor flow cytometry at a cutoff of 10-3 leukemic cells. RESULTS: Data cutoff was November 8, 2017. Of 82 patients treated with 600 mg of venetoclax, 65% were male, 95% white race, 60% had intermediate and 32% had poor cytogenetic risk, and 49% had secondary AML (of whom 60% had prior HMA exposure). Transfusion dependence for red blood cells (RBC) and platelets within 8 weeks prior to venetoclax treatment was 65% (53/82) and 28% (23/82) of patients, respectively. Most common grade ≥3 AEs across all patients were febrile neutropenia (43%), thrombocytopenia (38%), neutropenia (27%), and anemia (27%). Laboratory evidence of grade 3 tumor-lysis syndrome (TLS) was observed in two patients; both patients achieved the target dose of venetoclax. Forty seven percent of patients received moderate (40%) or strong (7%) CYP3A inhibitors for at least 7 days (predominantly azole antifungals); no relevant differences in serious adverse event rates were observed. Key efficacy results are shown in the Table. Median time to first response was 1.4 months, and 54% and 46% of patients achieved CR/CRi and CR/CRh, respectively. The rates of CR/CRi for patients with secondary and de novo AML were 35% and 71%, respectively; median DOR for those with secondary and de novo AML was 8.1 and 11.6 months, respectively. Patients with selected genetic mutations achieved the following rates of CR/CRi: TP53, 30%; IDH1/2, 72%; FLT3, 44%; NPM1, 89%. MRD response below 10-3 cutoff was achieved by 32% of patients with CR/CRi; median OS has not yet been reached for these patients. Among patients that were RBC or platelet transfusion dependent at baseline, 49% (26/53) and 65% (15/23), respectively, achieved transfusion independence while on venetoclax therapy. CONCLUSIONS: Venetoclax in combination with LDAC led to rapid, deep, and durable responses in patients with AML who were ineligible for intensive chemotherapy. Venetoclax plus LDAC demonstrated an improved CR rate (26% vs. 8%), CR/CRi rate (54% vs. 11%) and median overall survival (10 months vs. 5 months) compared to the historical rates with LDAC alone. Furthermore, a majority of patients achieved transfusion independence during venetoclax therapy. Strong and moderate CYP3A inhibitors, including azole antifungals, were safely coadministered with appropriate venetoclax dose adjustments. These results demonstrate that venetoclax, in combination with LDAC, represents an effective therapeutic option for patients with AML who are not suitable for standard induction therapy. Disclosures Wei: Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Strickland:Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Consultancy; Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis Pharmaceuticals: Consultancy, Research Funding. Fiedler:Amgen: Consultancy, Other: Meeting attendance, Patents & Royalties, Research Funding; ARIAD/Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Gilead: Other: Meeting attendance; GSO: Other: Meeting attendance; Teva: Other: Meeting attendance; JAZZ pharma: Other: Meeting attendance; Daiichi Sankyo: Other: Meeting attendance. Lin:Jazz Pharmaceuticals: Honoraria. Walter:Actinium Pharmaceuticals, Inc: Other: Clinical Trial support , Research Funding; Amgen Inc: Other: Clinical Trial Support, Research Funding; Amphivena Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Aptevo Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Covagen AG: Consultancy, Other: Clinical Trial Support, Research Funding; Seattle Genetics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Pfizer, Inc: Consultancy; Boehringer Ingelheim Pharma GmbH & Co. KG: Consultancy. Hong:Genentech Inc/Roche: Employment, Other: Ownership interests PLC. Chyla:AbbVie, Inc: Employment, Equity Ownership. Popovic:AbbVie Inc: Employment, Equity Ownership. Fakouhi:AbbVie, Inc: Employment, Equity Ownership. Xu:AbbVie, Inc: Employment, Equity Ownership. Hayslip:AbbVie: Employment, Equity Ownership. Roboz:Bayer: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; AbbVie: Consultancy; Orsenix: Consultancy; Cellectis: Research Funding; Aphivena Therapeutics: Consultancy; Otsuka: Consultancy; Roche/Genentech: Consultancy; Astex Pharmaceuticals: Consultancy; Orsenix: Consultancy; Roche/Genentech: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Eisai: Consultancy; Celgene Corporation: Consultancy; Sandoz: Consultancy; Novartis: Consultancy; Celgene Corporation: Consultancy; Cellectis: Research Funding; Argenx: Consultancy; Jazz Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Sandoz: Consultancy; Janssen Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Celltrion: Consultancy; Aphivena Therapeutics: Consultancy; Argenx: Consultancy; Celltrion: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Eisai: Consultancy.