Post ASH speaker abstracts 2018


Abstracts to support presentations from Mike Dennis and Jonathan Kell

Flow Cytometric Minimal Residual Disease As Risk Stratification Tool in Younger Adults with NPM1 Wild Type Standard Risk Acute Myeloid Leukemia

Result Type: Paper
Number: 468
Presenter: Sylvie Freeman
Program: Oral and Poster Abstracts
Session: 613. Acute Myeloid Leukemia: Clinical Studies: Advances in Frontline Therapy: Induction, Consolidation, and Maintenance

Sylvie D Freeman, MBChB, DPhil1*, Robert K. Hills, DPhil2, Paul Virgo3*, Naeem Khan, PhD4*, Stephen Couzens5*, Richard James Dillon, MA, PhD, MRCP, FRCPath6, Laura Upton7*, Lars Kjeldsen, MD8, Ian Thomas7*, David Grimwade9*, Alan K. Burnett, MD10 and Nigel H. Russell, MD11

1Institute of Immunology and Immunotherapy, University of Birmingham, Cheltenham, United Kingdom
2Centre for Trials Research, College of Biomedical & Life Sciences, Cardiff University, Cardiff, United Kingdom
3Pathology Sciences, North Bristol NHS Trust, Bristol, United Kingdom
4University of Birmingham, Birmingham, United Kingdom
5University Hospital of Wales, Cardiff, United Kingdom
6Kings College London, London, United Kingdom
7Centre for Trials Research, Cardiff University, Cardiff, United Kingdom
8Rigshospitalet, Copenhagen University Hospital, Horsholm, DNK
9King’s College London, London, United Kingdom
10Cardiff University, Cardiff, United Kingdom
11Centre for Clinical Haematology, Nottingham University Hospital (City Hospital Campus), Nottingham, United Kingdom


Response to induction therapy is a powerful prognostic indicator in acute myeloid leukemia (AML). Measurable/minimal residual disease (MRD) assays are being increasingly incorporated into response assessment; however, their value as a surrogate for long-term outcome remains unclear because of assay limitations and the effect of post remission therapies. This is particularly the case for the molecularly heterogeneous NPM1 wild type standard risk patients for whom treatment decisions, including predicting the benefit of allogeneic stem cell transplantation (SCT), are particularly challenging. We investigated the effect on outcome of MRD status compared to other response criteria after each cycle of induction for NPM1wild type (wt) standard risk patients and other risk groups in a cohort of younger AML patients.

Patients and Methods: As part of the UK NCRI AML17 trial (ISRCTN55675535) for patients with AML or high risk MDS up to the age of 60, prospective flow cytometric MRD (MFC-MRD) monitoring was performed after each course of induction. Any level of MRD detected was considered MRD+ (sensitivity thresholds: ~0.02% by tracking diagnostic leukemic aberrant phenotypes/LAIP, ~0.05-0.1% by “different-from normal” blast LAIP). Clinicians were not informed of MFC-MRD results. Following cycle 1 of induction with daunorubicin/ara-C based therapy, patients were allocated a risk group by a validated score (comprising cytogenetics, WBC, age, secondary disease, blast response to cycle 1 and mutation status). Standard risk patients including ITD wt/NPM1 wt received a second daunorubicin/ara-C induction with some proceeding to SCT after 1 or 2 consolidation cycles (high dose ara-C).

Results: 2450 non APML patients, median age 51, randomised 4/09 to 12/14, contributed data. For the total cohort, 5 year overall survival (OS) excluding early deaths was 52% for those achieving CR/CRi vs 31% for those not in CR (p<.001). Post cycle 1 (C1) responses were categorised as resistant disease (RD), partial remission (PR) and CR/CRi by clinicians, with CR/CRi subdivided by MFC-MRD assay into MRD+ and MRD-. RD vs PR vs MRD+ vs MRD- frequencies were 15% vs 14% vs 40% vs 31% for all patients with response data (n=1443), 5% vs 7% vs 45% vs 43% for good / standard risk (n=785), 10% vs 8% vs 47% vs 35% NPM1 wt standard risk (n=320). Post C1 response was prognostic for survival: OS for RD vs PR vs MRD+ vs MRD- were 25% vs 36% vs 43% vs 63% all patients; 33% vs 49% vs 51% vs 70% good/standard risk and 28% vs 38% vs 47% vs 59% NPM1 wt standard risk. (p<.0001 throughout). For NPM1 wt standard risk as well as good/standard risk patients adjusted analyses confirmed significant OS differences between C1 RD vs PR or MRD+ but not PR vs MRD+. Results were similar when censored at SCT. Post C1 best response was CRi for 39/446 MRD- vs 49/575 MRD+ overall (11/111 vs 8/149 for NPM1 wt standard risk). C1 CRi was associated with reduced OS overall (39% vs 53% CR, p=.002) and in MRD+ (19% vs 45% CR, p=.001) but not for MRD- patients. OS for NPM1wt standard risk MRD+ was 25% CRi vs 43% CR (p=0.4). No significant difference was detected for 5 year cumulative incidence of relapse (CIR). The effect on outcomes of MRD status post cycle 2 (C2) for the 806 patients in CR/CRi with MFC-MRD data appeared greater (relapse HR 1.88(1.50- 2.36), p<0.001; OS HR 1.77(1.41-2.22) p<0.001) than C1 (relapse HR 1.70(1.40- 2.06), p<0.001; OS HR 1.50(1.23-1.84) p<0.001). MRD+ levels of ≥0.1% predicted highest CIR in NPM1wt standard risk patients at C1 (CIR 71%) and C2 (CIR 89%) but any MRD+ at C2 reduced OS (32% vs 63% MRD-, p=0.003) and OS censored at any SCT (35% vs 88%). The effect of CR vs CRi was smaller post C2 although outcomes were still worst in CRi/MRD+ve patients. Of 204 NPM1 wt standard risk patients with C2 MRD data 83 had an allograft (44 in CR1: 29 MRD-, 15 MRD+). In Mantel-Byar analyses, although numbers were small, there was a suggestion that transplant could be considered in MRD +ve (HR 0.72 (0.31-1.69)) but not MRD -ve patients (HR 1.68 (0.75-3.85); p-value for interaction p=0.16). Conclusion: MRD status by MFC refines response criteria at induction time-points to differentiate NPM1 wild type standard risk patients with poor outcome and helps define a group of patients who may benefit from SCT in CR1.

Prospective Molecular MRD Detection By NGS: A Powerful Independent Predictor for Relapse and Survival in Adults with Newly Diagnosed AML

Result Type: Paper
Number: LBA-5
Presenter: Tim Grob
Program: General Sessions
Session: Late-Breaking Abstracts Session

Mojca Jongen-Lavrencic, MD, PhD1Tim Grob, MD1*, Francois G. Kavelaars1*, Adil S.A. Al Hinai1*, Annelieke Zeilemaker1*, Claudia A.J. Erpelinck-Verschueren1*, Yvette Norden2*, Rosa Meijer, PhD2*, Bart J. Biemond, MD, PhD3*, Carlos Graux4*, Marinus van Marwijk Kooij, MD, PhD5*, Markus G. Manz, MD6, Thomas Pabst, MD, PhD7, Violaine Havelange, MD, PhD8*, Jakob R. Passweg, MD, PhD9*, Gert J. Ossenkoppele, MD, PhD10, Gerrit Jan Schuurhuis, PhD10*, Mathijs A. Sanders, PhD1*, Bob Löwenberg, MD, PhD1 and Peter J.M. Valk, PhD1

1Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands
2HOVON Data Center, Erasmus University, Rotterdam, Netherlands
3Hematology, Academic Medical Center, Amsterdam, Netherlands
4Université catholique de Louvain, CHU UCL Namur (site Godinne), Godinne, Belgium
5Isala Hospital, Zwolle, Netherlands
6Department of Hematology and Oncology, University and University Hospital Zurich, Zurich, Switzerland
7Department of Medical Oncology, Inselspital, University Hospital and University of Bern, Bern, Switzerland
8St. Luc, Bruxelles, Belgium
9Division of hematology, University Hospital Basel, Basel, Switzerland
10Cancer Center Amsterdam, Department of Hematology, VU University Medical Center, Amsterdam, Netherlands


Introduction: Although the majority of Acute Myeloid Leukemia (AML) patients achieve a complete morphological remission (CR) after induction therapy, relapse rates remain high. Molecular Minimal Residual Disease (MRD) detection by PCR-based technologies has been shown to improve relapse prediction but has been restricted to specific genetically-defined subsets of AML only. Next-Generation Sequencing (NGS) has the advantage that it allows for the assessment of a broad range of disease-related gene mutations in a single assay. Residual leukemia-specific mutations in bone marrow in morphological CR after induction therapy are supposed to represent the source of relapse. However, persistent mutations may also represent clonal hematopoiesis, analogous to age-related clonal hematopoiesis of indeterminate potential (CHIP) present in healthy individuals. It is currently unknown which and to what extent the persisting somatic mutations after induction therapy contribute to AML relapse. Here, we present a comprehensive study, detailing the value of molecular MRD detection by NGS, in a large prospective cohort of newly diagnosed AML.

Methods: 482 AML patients (<65 years) were treated with 2 cycles of standard induction chemotherapy followed by consolidation in HOVON-SAKK clinical trials ( NGS was performed to detect mutations in a panel of 54 genes frequently mutated in myeloid malignancies (Illumina) at diagnosis and in bone marrow in morphological CR after completion of induction therapy. Thompson-Tau outlier testing was performed to reliably detect persisting mutations above background error rates. The primary and secondary endpoints of the study were relapse and overall survival, respectively. To establish and subsequently test our definition of NGS MRD, the cohort was split into a representative training (n=283) and validation cohort (n=147). The Cumulative Incidence of Relapse (CIR) was estimated with competing-risks regression analyses according to the method of Fine & Gray. The Cox proportional hazard model was used to calculate overall survival estimates. P-values <0.05 were considered significant. Results: In 430 out of 482 (89.2%) AML patients somatic driver mutations were present at diagnosis. In 51.4% of subjects persisting mutations were detected in bone marrow in morphological CR at highly variable variant allele frequencies (VAF 0.0002-0.47), predominantly persisting in DNMT3A (78.7%), TET2 (54.2%) and ASXL1 (51.6%). These persistent mutations in DNMT3A, TET2 and ASXL1 (DTA) in the training cohort did not associate with the incidence of relapse at any VAF cut-off, indicating a stage of clonal hematopoiesis rather than a condition of impending relapse. In contrast, in the subset of AML patients with persisting DTA mutations, a significant correlation with relapse was observed when any other persistent non-DTA mutation was considered (training cohort: 5-years CIR 76.4% vs. 39.4%; p=0.002). In the training cohort NGS MRD, as defined by persistent non-DTA mutations, was found to be highly associated with the risk of relapse (SHR:1.85 [95%CI 1.27-2.70]; p=0.001), which was confirmed in the validation set (SHR:2.81 [95%CI 1.64-4.79]; p<0.001) (Fig. 1). In fact, NGS MRD was significantly associated with CIR when the training and validation series were combined (5-years CIR 58.3% versus 33.9% (p<0.001)) (Fig. 2). In addition, NGS MRD predicted for reduced survival in both cohorts (training: HR:1.64 [95%CI 1.12-2.42]; p=0.012 and validation: HR:3.08 [95%CI 1.87-5.08]; p<0.001). Finally, multivariable analysis including the data of all 430 AML patients, with adjustment for age, WBC, ELN2017 risk and number of induction cycles needed to achieve CR, revealed that NGS MRD expresses profound independent prognostic significance for relapse (SHR:1.89 [95%CI:1.34-2.65]; p<0.001) and overall survival (HR:1.64 [95%CI:1.18-2.27]; p=0.003). In sensitivity analysis with time-dependent correction for allogeneic stem cell transplantation NGS MRD remained highly prognostic for relapse and survival. Conclusions: In an unprecedentedly large prospective study including training and validation cohorts, targeted NGS MRD detection is established as a powerful and independent predictor for relapse and survival. NGS MRD is applicable in virtually all newly diagnosed adults with AML while persistent CHIP-related mutations lack prognostic value.

An Analysis of Maintenance Therapy and Post-Midostaurin Outcomes in the International Prospective Randomized, Placebo-Controlled, Double-Blind Trial (CALGB 10603/RATIFY [Alliance]) for Newly Diagnosed Acute Myeloid Leukemia (AML) Patients with FLT3 Mutations

Result Type: Paper
Number: 145
Presenter: Richard Larson
Program: Oral and Poster Abstracts
Session: 615. Acute Myeloid Leukemia: Commercially Available Therapy, excluding Transplantation: Innovative AML Treatment with Approved Agents

Richard A. Larson, MD1, Sumithra J Mandrekar, PhD2*, Ben L. Sanford, MS3*, Kristine Laumann2*, Susan M. Geyer, PhD4*, Clara D. Bloomfield, MD5, Christian Thiede, MD6, Thomas W Prior, MD7*, Konstanze Dohner, MD8*, Guido Marcucci, MD9, Francesco Lo-Coco, MD 10, Rebecca B. Klisovic, MD7*, Andrew Wei, MBBS, PhD, FRACP, FRCPA11, Jorge Sierra12, Miguel A. Sanz, MD13, Joseph M. Brandwein, MD, FRCPC14, T. M. M de Witte, MD, PhD15, Dietger Niederwieser, MD16, Frederick R. Appelbaum, MD17, Bruno C Medeiros, MD18, Martin S. Tallman, MD19, Jurgen Krauter, MD20*, Richard F. Schlenk, MD21, Arnold Ganser, MD22, Hubert Serve23, Gerhard Ehninger, MD24, Sergio Amadori, M.D.25, Hartmut Döhner, MD26 and Richard M. Stone, MD27

1University of Chicago Comprehensive Cancer Center, Chicago, IL
2Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN
3Alliance Statistics and Data Center, Duke University, Durham, NC
4Health Informatics Institute, University of South Florida, Tampa, FL
5Division of Hematology and Comprehensive Cancer Center, the Ohio State University, Columbus, OH
6Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der TU Dresden, Dresden, Germany
7Comprehensive Cancer Center, Ohio State University, Columbus, OH
8University Hospital of Ulm, Ulm, Germany
9Division of Hematopoietic Stem Cell and Leukemia Research, Gehr Family Center for Leukemia Research, Beckman Research Institute at City of Hope, Duarte, CA
10University of Rome Tor Vergata, Rome, ITA
11Haematology, The Alfred Hospital, Melbourne, AUS
12Hospital de la Santa Creu i Sant Pau, Hematology Department, University of Barcelona, Barcelona, Spain
13Hospital Univ. La Fe, Valencia, ESP
14Division of Hematology, University of Alberta, Edmonton, AB, Canada
15Radboud University Medical Centre, Nijmegen, Netherlands
16Department of Hematology, University of Leipzig, Leipzig, Germany
17Fred Hutchinson Cancer Research Ctr., Seattle, WA
18Stanford University School of Medicine, Stanford, CA
19Division of Hematologic Oncology, Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY
20Department of Internal Medicine III, Municipal Hospital of Braunschweig, Braunschweig, Germany
21University of Ulm, Heidelberg, Germany
22Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
23Goethe University of Frankfurt, Frankfurt, Germany
24Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
25Tor Vergata University Hospital, Rome, Italy
26Department of Internal Medicine III, Ulm University, Ulm, Germany
27Dana-Farber Cancer Institute, Boston, MA


Background: Midostaurin (M) is an oral, multi-targeted, small molecule FLT3 inhibitor that has single agent activity in both internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutant (mut) FLT3 AML. This randomized, double-blinded phase III trial demonstrated a statistically significant overall survival (OS) benefit when M was added to induction and consolidation chemotherapy followed by one year of maintenance compared to standard chemotherapy in patients (pts) with activating FLT3 mutations (Stone et al. NEJM 2017). In this unplanned subset analysis, we sought to evaluate the contribution of the maintenance treatment to overall outcomes.

Methods: Between 5/2008 and 10/2011, 3277 previously untreated AML pts (exclusive of APL) age 18-60 years were screened at one of 7 academic labs. 717 pts were randomized for the duration of therapy to M or placebo (P), stratified by FLT3 mut subtype (TKD vs ITD low allelic ratio 0.05-0.7 vs high ratio >0.7). Induction consisted of daunorubicin and cytarabine plus M or P (50 mg orally twice daily, d8-21). Re-treatment with a second course was allowed if residual AML was noted on a d21 marrow exam. Pts achieving complete remission (CR) received 4 cycles of high-dose cytarabine plus M or P (d8-21) followed by 12 4-week cycles (336 days) of maintenance with M or P (50 mg orally twice daily). Allogeneic transplantation (SCT) was allowed, and 182 pts discontinued study drug and underwent SCT in CR1. Landmark disease-free survival (DFS) analyses were performed to understand the impact of M vs P on the subset of CR pts who started maintenance (defined as time from start of maintenance to the first of death or relapse, where pts alive and disease-free were censored at the time they completed the planned maintenance or discontinued study drug early). Landmark DFS analyses were also performed to understand the long-term impact of M vs P on the subset of CR pts who completed all protocol treatment (i.e., time from end of all planned maintenance to the first of death or relapse).

Results: All pts are off treatment. Median follow-up is 59 months from enrollment. Data were frozen in March 2016. A CR was achieved within the protocol-specified 60 days by 403 pts (CR60; 56%) with no significant difference between arms (212/360 (59%; 95% CI, 54-64%) on the M arm and 191/357 (54%; 48-59%) on P) (Fisher’s p=0.15); an additional 101 pts achieved CR after 60 days but were excluded from this analysis of maintenance therapy. 174 of the 403 CR60 pts began maintenance therapy still in CR1. Pts remained on their originally assigned double-blind treatment arm, and were not re-randomized. Pretreatment characteristics for these 174 pts were balanced with no significant differences between the maintenance arms (Table); however, they were slightly older, significantly less female, and had more favorable FLT3 mut status and cytogenetics than the 543 pts who did not start maintenance and/or lacked CR60. Adherence to full doses was high on both arms during maintenance (90% for M; 92% for P). Maintenance was well tolerated, and median duration of exposure was the same on both arms (336 days). Discontinuation due to adverse events was infrequent (8% for M; 6% for P). Events during maintenance were reported in 31 pts on M (30%; 30 relapses, 1 death) and 22 pts on P (32%; all relapses). Using a landmark analysis (Figure 1), DFS was not different between the 2 arms during the 12 cycles of maintenance (HR=0.83 for M vs P [95% CI, 0.48-1.43]; p=0.49). At the end of the maintenance portion of the trial, 60 pts (57%) remained on the M arm and 44 (64%) on the P arm. There were 16 post-maintenance DFS events (all relapses) on the M arm and 9 DFS events on the P arm (7 relapses, 2 deaths): 6/35 (17%) with FLT3-TKD, 15/51 (29%) with ITD-low, and 4/18 (22%) with ITD-high (X2, p=0.4) Using a landmark analysis from the end of maintenance (Figure 2), there was no difference in DFS between the 2 arms (HR=1.4 [95% CI, 0.63-3.3]; p=0.38). DFS at 1-year from end of maintenance was 75% [95% CI, 62-84%] for M and 91% [95% CI, 77-96%] for P. There was no difference between the arms in OS from the time starting maintenance (HR=0.96 for M [95% CI, 0.58-1.59]; p=0.86).

Conclusions: The results from this unplanned post-hoc subset analysis of the CALGB 10603/RATIFY trial do not allow conclusions on the value of maintenance therapy. Midostaurin was well-tolerated, but the definitive impact of maintenance strategies with midostaurin will need to be addressed by randomization.

Phase 1/2 Study of Venetoclax with Low-Dose Cytarabine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia Unfit for Intensive Chemotherapy: 1-Year Outcomes

Result Type: Paper
Number: 890
Presenter: Andrew Wei
Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Novel Therapies for Elderly Patients with AML

Andrew Wei, MBBS, PhD, FRACP, FRCPA1, Stephen A. Strickland, MD, MSCI2, Gail J. Roboz, MD3, Jing-Zhou Hou, MD, PhD4, Walter Fiedler, MD5, Tara L. Lin, MD6, Roland B. Walter, MD, PhD7, Anoop Enjeti, MD, MRCP, FRCPA, MClin Epid, GradCert Bioethics8, Brenda Chyla, PhD9*, Relja Popovic, PhD9*, Kaffa Fakouhi9*, Pooja Shah9*, Martin Dunbar, DRPH, MS9*, Tu Xu, PhD10*, Mack Mabry, MD9 and John Hayslip, MD, MSCR9

1The Alfred Hospital and Monash University, Melbourne, Australia
2Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN
3Weill Cornell Medical College, New York
4University of Pittsburgh Medical Center Cancer Center, Pittsburgh
5Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
6University of Kansas Medical Center, Kansas City, KS
7Department of Medicine/Division of Hematology, Fred Hutchinson Cancer Research Center, Seattle, WA
8Haematology Department, Calvary Mater Hospital Newcastle and School of Medicine and Public Health, University of Newcastle, Callaghan, Australia
9AbbVie Inc, North Chicago, IL
10AbbVie Inc., North Chicago, IL


Background: Older patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy are unlikely to achieve remission with available therapy and have unacceptably short survival. Venetoclax (VEN) is a small molecule inhibitor of BCL-2 that achieved remission rates of >60% combined with low-dose cytarabine (LDAC). Presented are long-term outcomes, including 1-year overall survival (OS) and biomarker analyses.

Methods: This phase 1b/2, open-label study (NCT02287233) evaluates the safety and preliminary efficacy of orally administered VEN combined with LDAC in patients ≥65 years with previously untreated AML (except for hydroxyurea). Patients were ineligible for intensive chemotherapy because of comorbidity or other factors and had an ECOG performance score of 0-2, with adequate hepatic and renal function. Exclusion criteria were acute promyelocytic leukemia, active CNS involvement with AML, concominant use of moderate or strong CYP3A inhibitors, or prior treament with cytarabine for a preexisting myeloid disorder. Prior treatment for myelodysplastic syndrome (MDS) was allowed. In cycle 1, VEN was started at 50 mg/day PO and increased over a 5-day ramp-up to reach the designated cohort dose of 600 or 800 mg/day on day 6, which was continued through day 28. In subsequent cycles, the desingated dose of VEN 600 or 800 mg/day was administered on days 1-28. LDAC 20 mg/m2/day SQ was given on days 1-10 of each cycle. Preliminary efficacy was assessed as the overall response rate (ORR, which included complete remission [CR], CR with incomplete blood count recovery [CRi], and partial remission [PR]). Adverse events (AEs) and laboratory values were monitored. Exploratory analysis of biomarkers (eg, cytogenetics, molecular markers) was performed to identify potential predictors of clinical outcomes.

Results: Data cutoff was May 30, 2017. All 71 patients were enrolled ≥1 year prior (46 [65%] male; median age, 74 years [range, 66-87 years]): 10 received VEN 800 mg and 61 received VEN 600 mg, the recommended phase 2 dose. Thirty-three patients (47%) had a history of antecedent hematologic disorder (AHD), most commonly MDS. Among 61 patients given VEN 600 mg, median time on VEN treatment was 6 months (range, <1 to 21 months). Thirty-eight (62%) of these patients achieved CR/CRi with a median duration of CR/CRi of 14.9 months (95% CI, 5.6 months to not reached [NR]; Figure). Best responses were 26% CR, 36% CRi, and 2% PR. Median OS was 11.4 months (95% CI, 5.7-15.7 months); the observed 12-month OS was 46% (95% CI, 33-58%). Only 1 patient has subsequently undergone bone marrow transplantation. Treatment-emergent grade 3/4 AEs (in ≥20% of 61 patients) were thrombocytopenia (59%), neutropenia (46%), febrile neutropenia (36%), anemia (28%), and decreased WBC count (26%). One case (2%) of tumor lysis syndrome occurred. Serious AEs (in ≥3 of 61 patients) were febrile neutropenia (20%), malignant neoplasm progression (13%), lung infection/pneumonia (13%), and sepsis (7%). The 30-day mortality rate was 3%; causes of death were disease progression (n=1) and lung infection (n=1). Common recurrent mutations in 53 patients who received VEN 600 mg are shown in the Table. All patients with an NPM1 mutation (including 3 with a co-mutation in FLT3-ITD) achieved CR/CRi. Patients with DNMT3A, FLT3-ITD, and SRSF2mutations had CR/CRi rates of ≥75%, whereas those with TP53 mutations had the lowest CR/CRi rates of 44%. For patients with CR/CRi, median OS was 18.4 months (95% CI, 13.5 months to NR). The 12-month OS rate for patients in the 600-mg VEN cohort who achieved CR/CRi was 70.4% from Kaplan-Meier estimates, with 11 deaths. Among 19 patients who received study treatment ≥12 months, 17 remain alive. The longest, ongoing, disease-free follow-up after treatment completion is 12 months. Conclusions: The safety profile of VEN 600 mg/day plus LDAC was acceptable for elderly patients with treatment-naive AML who were ineligible for intensive chemotherapy. After ≥1 year of follow-up, the observed median OS was 11.4 months. This cohort included 44% (27/61) of patients with AHDs. Corelations of specified AML mutations with response and duration should be confirmed in later trials. Due to the observced CR/CRi rate of 62%, extended duration of response, and encouraging OS in a cohort of patients with particularly poor-risk features, the 600-mg dose of VEN combined with LDAC is being tested in an ongoing phase 3 study.

Preliminary Results of a Phase 1 Study of Flotetuzumab, a CD123 x CD3 Bispecific Dart® Protein, in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome

Result Type: Paper
Number: 637
Presenter: John Godwin
Program: Oral and Poster Abstracts
Session: 613. Acute Myeloid Leukemia: Clinical Studies: Novel Therapies for AML and APL

Geoffrey L. Uy, MD1John Godwin, MD2, Michael P Rettig, PhD3, Norbert Vey4, Matthew C. Foster, MD5, Martha L. Arellano, MD6, David A. Rizzieri, MD7, Max S. Topp, MD8, Gerwin Huls, MD, PhD9, Bob Löwenberg, MD, PhD10, Giovanni Martinelli, MD11, Stefania Paolini, MD, PhD12*, Fabio Ciceri, MD13*, Matteo Giovanni Carrabba, MD13*, Carmen Ballesteros-Merino, PhD2*, Carlo B Bifulco, MD2*, Helene Lelièvre, PhD, PharmD14*, Ross La Motte-Mohs, PhD15*, Daner Li, MS15*, Jichao Sun, PhD15*, Kenneth Jacobs, MD15*, Karen Spohn, BS15*, Nadia Lonsdale, BA15*, Kathy Tran15*, Jan Baughman, MPH15*, Michele Shannon, PhD15*, Bernard Fox, PhD2*, Ezio Bonvini, MD15, Jon Wigginton15*, Jan Davidson-Moncada, MD15 and John F DiPersio, MD, PhD16

1Washington University School of Medicine, Saint Louis, MO
2Providence Cancer Center, Portland, OR
3Division of Oncology, Washington University School of Medicine, Saint Louis, MO
4Clinical Hematology, Paoli-Calmettes Institute, Marseille, France
5Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC
6Emory University School of Medicine, Atlanta, GA
7Dept. of Medicine, Div. of Hematological Malignancies & Cellular Therapy, Duke University Medical Center, Durham, NC
8Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
9Department of Hematology, University Medical Center Groningen, Groningen, Netherlands
10Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands
11Institute of Hematology “L. e A. Seragnoli”, Dep. of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
12Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
13Vita-Salute San Raffaele University, Milano, Italy
14Centre de Recherche en Cancérologie de Marseille, Servier, Suresnes, France
15MacroGenics, Inc., Rockville, MD
16Department of Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, MO


Background: Acute myeloid leukemia (AML) blast and leukemic stem cells highly express CD123, which is associated with high-risk disease and disease progression. CD123 expression on normal hematopoietic stem cells is minimal, enabling a strategy of preferential ablation of AML with a CD123-targeted approach. Flotetuzumab (MGD006/S80880) is a novel T-cell redirecting (CD123 x CD3) bispecific DART® protein being tested in a phase 1 study in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

Methods: This phase 1 dose-escalation study is designed to define the safety profile, maximum tolerated dose and schedule (MTDS), and preliminary anti-leukemic activity of flotetuzumab. Relapsed/refractory (R/R) AML or intermediate-2/high-risk MDS patients (pts) are treated on 28-day cycles at doses from 3-1000ng/kg/day on one of 2 dosing schedules (4-day on/3-day off or a continuous 7-day on schedule). To mitigate cytokine-release syndrome (CRS), a one-step lead-in dose (LID) (100ng/kg/day for 4 days) or two-step LID (30 ng/kg/day for 3 days followed by 100ng/kg/day for 4 days) was instituted during Cycle 1/Week 1 (C1W1), followed by the cohort target dose (300-1000ng/kg/day) on either of the dosing schedules on W2-4. Cycle 2 and beyond, all pts were treated on a 4-day on/3-day off schedule at the cohort target dose for a maximum of 12 cycles, with 2 cycles after a complete response or complete remission with incomplete blood count recovery. Steroid-sparing, anti-cytokine therapy was used, if clinically indicated, to manage CRS symptoms. Disease status was assessed by International Working Group (IWG) criteria. Samples were collected for pharmacokinetics, anti-drug antibodies (ADA) and cytokine analysis, including IL-2, IL-6, IL-8, IL-10, TNF-alpha, IFN-gamma and GM-CSF.

Results: 45 pts with R/R AML/MDS (89% AML and 11% MDS) have been treated with flotetuzumab, median age of 64 (29-84), and 44% female. The MTDS has been reached at 500ng/kg/day. Overall flotetuzumab has demonstrated manageable toxicity; drug-related adverse events ≥G3 were observed in 20/45 (44%) pts; infusion-related reaction/CRS (IRR/CRS), the most common toxicity, was observed in 34/45 (76%) pts (G3 in 6/45, 13%). The most frequent CRS symptoms were pyrexia (15), chills (10), tachycardia (10), and hypotension (4). Cytokine levels were higher in pts with CRS than in pts without (median IL-6, 116.2 vs. 67.9 pg/mL; IL-8, 191.1 vs. 144.6 pg/mL; IL-10, 867.6 vs. 348.7 pg/mL) and were generally higher with increasing CRS grade. A two-step LID during week 1 appeared to decrease the severity of CRS grade (mean grade reduction 0.54) compared to pts that received a one-step LID during cycle 1. In addition, lower median peak cytokine levels are observed with two-step LID during W1 and after achieving W2 target dose. Fourteen pts treated at the threshold 500 ng/kg/day dose cohort and beyond (700ng/kg/day dose cohort) have completed at least one cycle of treatment and had a post-treatment bone marrow (BM) biopsy. Anti-leukemic activity was documented in 57% (8/14) pts, 6/14 reached IWG criteria (3 CR, 1 CRi, 1 MLF, 1 PR) for an overall response rate (ORR) of 43%, and 2 pts had stable disease and bone marrow (BM) blast reduction of 20 and 25% from baseline, respectively. Blast reduction occurred rapidly, often within one cycle of therapy, and extended beyond flotetuzumab discontinuation. Multispectral immunohistochemistry analysis of BM samples showed flotetuzumab in situ with a significant increase (in CD-8 T cells (1.58-fold increase, p=0.0013). Consistent with T-cell activation, CD-25, CD-69 and PD-1 upregulation on both CD-4 and CD-8 T-cells was also observed in peripheral blood samples.

Conclusions: Flotetuzumab in R/R AML and MDS demonstrated evidence of anti-leukemic activity (ORR 43%) with a manageable safety profile. This program advances an immune-activating agent in treating AML and continues to enroll patients in cohort expansion (24 AML and 24 MDS patients at the MTDS) in the US and Europe. NCT02152956.

Venetoclax (Ven) with Azacitidine (Aza) for Untreated Elderly Acute Myeloid Leukemia (AML) Patients (Pts) Unfit for Induction Chemotherapy: Single Center Clinical Experience and Mechanistic Insights from Correlative Studies

Result Type: Paper
Number: 181
Presenter: Daniel Pollyea
Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis III

Daniel A. Pollyea, MD1, Brett M. Stevens, Ph.D.2*, Amanda Winters, MD, PhD3*, Mohd Minhajuddin, PhD4*, Jonathan A Gutman, MD4, Enkhtsetseg Purev, MD, PhD5, Clayton Smith, MD, FRCPC4, Diana Abbott, PhD6* and Craig T. Jordan, Ph.D.5*

1Division of Hematology, University of Colorado Denver, Aurora, CO
2Division of Hematology, Department of Medicine, University of Colorado, Aurora, CO
3Department of Pediatrics, University of Colorado, Aurora, CO
4Division of Hematology, University of Colorado, Aurora, CO
5Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
6Division of Hematology, University of Colorado School of Medicine, Aurora, CO


Introduction: There is no effective standard of care for older AML pts who are unfit for induction. We explored the combination of the BCL-2 inhibitor venetoclax (ven) with azacitidine (aza) for this population in a multi center phase 1b study (NCT02203773), and report clinical results from our center, as well as mechanistic insights regarding the activity of this regimen derived from correlative studies performed with our pt samples.

Methods: The dose escalation/expansion trial combined aza or decitabine, at the standard dose and schedule, with ven daily in older AML pts unfit for induction. Our institution enrolled into the aza arm. Pts were eligible if ≥65 and with adequate organ function. Response assessments employed International Working Group (IWG) criteria; if a morphologic remission was achieved without count recovery, delay of the subsequent cycle by up to 14 days was permitted, with growth factors per institutional guidelines, and best response was upgraded if counts improved in this timeframe. Minimal residual disease (MRD) testing was performed by digital droplet PCR (ddPCR) with a sensitivity of 0.01%. Mass cytometry was performed using CyTOF.

Results: 33 pts enrolled and received at least 1 day of therapy. 23 received 400 mg venetoclax, 9 received 800 and 1 received 1200 (Table 1). 2 elected to come off study after <7 days; both died of AML. Median follow up time using reverse Kaplan-Meier was 351 days (95% CI 146, 468). The overall response rate (ORR), defined as complete response (CR) + CR with incomplete count recovery (CRi) + partial response (PR) + morphologic leukemia free state (MLFS), was 30/33 (91%); 19 (58%) had a CR, 9 (27%) had a CRi, 1 had a PR and 1 had a MLFS. Only 1 pt who completed >1 week of therapy did not respond (resistant disease). No variables tested predicted outcomes in the 31 pts who had >1 week of therapy (Table 2); 5/5 with monosomal karyotype, 5/5 with FLT3 and 2/2 with TP53 responded. 3 proceeded to transplant; none have relapsed after 14, 8 and 4 months. 4/33 (12%) relapsed; only 1 relapse occurred in a patient who continued on therapy, after 13 months. 3/4 relapsed after coming off study for a hip fracture (N=1), personal decision (N=1) and development of mastocytosis (N=1). The median response duration has not occurred; mean is 484 days (std error 44). Median progression free survival (PFS) has not occurred; mean is 294 days. Median overall survival (OS) has not occurred; mean is 376 days (Figure 1).

We used ddPCR to measure MRD in all pts with amenable mutations (N=18). Of these, 14 have completed ≥1 cycle with ≥3 months of follow-up, and were analyzed for MRD. 3 achieved MRD negativity; 1 who remains on therapy (cycle 16, 453 days), and surprisingly, 2 who discontinued therapy, for personal reasons and cytopenias, after 1 and 6 cycles. They remain in MRD negative CR and CRi after 24 and 16 months. Another who achieved a CR and discontinued therapy after 3 cycles for personal reasons has also had no further therapy for 25 months and continues to be in CR with borderline MRD detectability (0.024%).

Detailed temporal analysis of 2 pts who achieved a CR and CRi using CyTOF and single cell RNA-seq methods showed rapid and extensive targeting of primitive AML cell types (Figure 2, not all data shown). This data indicates effective targeting of the AML stem cell population. Ongoing functional studies using xenograft models will corroborate direct targeting of AML stem cells.

Conclusion: Ven with aza is a highly active regimen for untreated elderly AML pts who are not candidates for induction chemotherapy; all but 1 pt who stayed on study for >1 week achieved an IWG response, primarily CR/CRi. There were no serious adverse events related to ven and very few significant related adverse events. Responses were durable with few relapses, particularly for pts who remained on treatment; 3 pts who elected to stop all therapy have had no recurrence with considerable follow up. MRD detection with ddPCR reveals the depth of response possible with aza+ven; several pts in long term follow up have achieved MRD negative remissions, including 2 who discontinued all therapy after 6 months or less with no subsequent treatment for 24 and 16 months. Median PFS and OS were not reached with median follow up time of nearly 1 year. The universality, depth and durability of responses, coupled with the CyTOF and single cell RNA-seq data, suggest this regimen effectively targets the leukemia stem cell population.

Mutant Isocitrate Dehydrogenase (mIDH) Inhibitors, Enasidenib or Ivosidenib, in Combination with Azacitidine (AZA): Preliminary Results of a Phase 1b/2 Study in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)

Result Type: Paper
Number: 639
Presenter: Courtney DiNardo
Program: Oral and Poster Abstracts
Session: 613. Acute Myeloid Leukemia: Clinical Studies: Novel Therapies for AML and APL

Courtney D. DiNardo, MD, MSc1, Anthony S. Stein, MD2, Amir T. Fathi, MD, MD, BS3,4, Pau Montesinos, MD, PhD5*, Olatoyosi Odenike, MD6, Hagop M. Kantarjian, MD7, Richard M. Stone, MD3,8, Daniel O. Koralek, PhD9*, Jason Van Oostendorp, M.Sc.10*, Jing Gong, PhD10*, Ira Gupta, MD10* and Paresh Vyas, DPhil, FRCP, FRCPath, MRCP, MRCPath11

1The University of Texas MD Anderson Cancer Center, Houston, TX
2City of Hope Comprehensive Cancer Center, Duarte, CA
3Harvard Medical School, Boston, MA
4Massachusetts General Hospital, Boston, MA
5Hospital Universitari i Politècnic La Fe, Valencia, Spain
6University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL
7Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
8Dana-Farber Cancer Institute, Boston, MA
9Agios Pharmaceuticals, Inc., Cambridge, MA
10Celgene Corporation, Summit, NJ
11MRC Molecular Haematology Unit and Oxford Biomedical Research Centre, University of Oxford and Oxford University Hospitals, Oxford, United Kingdom


Background: Enasidenib (AG-221) and ivosidenib (AG-120) are oral, small-molecule inhibitors of mIDH2 and mIDH1 proteins, respectively, both shown preclinically to reduce aberrant 2-HG levels and promote myeloid differentiation. As monotherapies, enasidenib and ivosidenib induce clinical responses in patients (pts) with mIDH relapsed/refractory AML. AZA monotherapy prolonged survival vs conventional care in older pts with newly diagnosed (ND) AML (10.4 vs 6.5 months, respectively; P = 0.101). AZA reduces DNA methylation by inhibiting DNA methyltransferases, and mIDH inhibitors indirectly reduce DNA methylation by suppressing 2-HG and restoring function to α-ketoglutarate-dependent TET family enzymes. In vitro, combinations of mIDH inhibitors + AZA showed synergistic effects on releasing differentiation block in mIDHleukemia models, providing a clinical rationale for combining these agents for treatment (Tx) of AML. Herein we report initial results of the phase 1b portion of an ongoing phase 1b/2 study of mIDH inhibitors + AZA combinations in pts with ND-AML (NCT02677922).

Methods: Eligible pts with mIDH ND-AML were aged ≥18 years and ineligible for intensive chemotherapy per investigator assessment. Pts with mIDH2 AML received enasidenib in dose-escalation cohorts of 100 or 200 mg QD and pts with mIDH1 AML received ivosidenib 500 mg QD, each in continuous 28-day cycles. All patients also received SC AZA 75 mg/m2/day x 7 days/cycle. Safety was assessed by Tx-emergent adverse event (TEAE) reporting. Efficacy was assessed per IWG criteria for AML; overall response rate (ORR) included complete remission (CR), CR with incomplete count recovery (CRi/CRp), partial remission (PR), and morphologic leukemia-free state (MLFS).

Results: At data cutoff (9 May 2017), 13 pts had received ≥1 dose of enasidenib 100 mg (n=3) or 200 mg (n=3) + AZA, or ivosidenib 500 mg (n=7) + AZA. Ten pts (77%) remained on-study: 2 pts in the enasidenib 100 mg + AZA arm, 2 pts in the enasidenib 200 mg + AZA arm, and 6 pts in the ivosidenib 500 mg + AZA arm.

Enasidenib: Median age was 68 years (Table 1). Four pts had de novo AML and 2 pts had secondary AML (sAML). Median number of enasidenib Tx cycles overall was 6.5 (range 1-9). Two pts discontinued Tx due to progressive disease (PD), including 1 pt in the 200 mg arm who later died from a lung infection. The most common (>2 pts) TEAEs were hyperbilirubinemia and nausea (n=3 each). Tx-related TEAEs (any grade) in >1 enasidenib-treated pt were nausea and vomiting (n=2 each). Grade 3-4 TEAEs (any cause) are shown in Table 2. Three serious TEAEs in 1 pt were considered Tx-related: hyperbilirubinemia, febrile neutropenia, and a thromboembolic event in the leg. For enasidenib-treated pts, ORR was 3/6 at data cutoff. In the enasidenib 100 mg + AZA arm, the best responses on-study were 2 CRs; 1 pt had PD. In the enasidenib 200 mg + AZA arm, 1 pt achieved PR and 2 pts maintained stable disease (SD).

Ivosidenib: Median age was 81 years (Table 1). Six pts had de novo AML and 1 pt had sAML. Median number of ivosidenib Tx cycles was 4 (range 1-11). TEAEs (any grade) occurring in >2 pts were fatigue (n=6), nausea (5), and constipation (5). Tx-related TEAEs occurring in >1 pt were nausea (n=4) and fatigue (5). The only serious grade 3-4 TEAE occurring in >1 pt was pneumonia (n=2), from which 1 pt died on-study. Neither pneumonia event was considered Tx-related (Table 2). ORR was 3/5; all 3 responders attained CR and 2 pts maintained SD. The remaining 2 pts entered the study in March 2017 and had no response data available at data cutoff.

Conclusions: Enasidenib or ivosidenib + AZA combination regimens were generally well tolerated in pts with ND-AML, with 10 of the initial 13 pts remaining on-study at data cutoff, and only 2 discontinuations due to PD. The most common TEAEs with all regimens were grade 1 and 2 GI events and indirect bilirubin increases (likely due to off-target inhibition of UGT1A1 enzyme). Preliminary efficacy results with these combination regimens are encouraging, with 5 CRs and 1 PR on-study. Based on clinical activity and tolerability, the 100 mg enasidenib dose and 500 mg ivosidenib dose will move forward for further study in combination regimens. Evaluation of mIDH inhibitors + AZA continues in 2 currently enrolling randomized studies, including the expansion phase of the current study and the phase 3 AGILE study of ivosidenib + AZA (NCT03173248), to further assess the safety and clinical efficacy of these regimens.

Ivosidenib or Enasidenib Combined with Standard Induction Chemotherapy Is Well Tolerated and Active in Patients with Newly Diagnosed AML with an IDH1 or IDH2 Mutation: Initial Results from a Phase 1 Trial

Result Type: Paper
Number: 726
Presenter: Eytan Stein
Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Emerging Molecularly-Targeted Therapies in AML

Eytan M. Stein, MD1, Courtney D. DiNardo, MD, MSc2, Alice S. Mims, MD, MSCR3, Michael R. Savona, MD4, Keith Pratz, MD5, Anthony S. Stein, MD6, Amir T. Fathi, MD, MD, BS7, Richard M. Stone, MD8, Daniel A. Pollyea, MD9,10, Olatoyosi Odenike, MD11, Bob Löwenberg, MD, PhD12, Hartmut Döhner, MD13*, Gary Schiller, MD14, Ira V. Gupta, MD15, Salah Nabhan16*, Vickie Zhang, PhD16*, Caroline Almon, MS16*, Michael Cooper, MD16 and Martin S. Tallman, MD17

1Division of Hematologic Oncology, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY
2The University of Texas MD Anderson Cancer Center, Houston, TX
3Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
4Vanderbilt-Ingram Center, VUMC, Nashville, TN
5Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD
6Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA
7Massachusetts General Hospital Cancer Center, Boston, MA
8Dana-Farber Cancer Institute, Boston, MA
9University of Colorado Cancer Center, Aurora, CO
10Division of Hematology, University of Colorado Denver, Aurora, CO
11University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL
12Erasmus University Medical Centre, Rotterdam, Netherlands
13Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
14David Geffen School of Medicine, UCLA, Los Angeles, CA
15Celgene Corporation, Summit, NJ
16Agios Pharmaceuticals, Inc., Cambridge, MA

17Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY

Background: Mutations in isocitrate dehydrogenase (IDH)1 or IDH2 are seen in ~15–20% of patients with acute myeloid leukemia (AML). Mutant IDH (mIDH) reduces α-ketoglutarate to 2-hydroxyglutarate (2-HG), leading to histone hypermethylation and a block in myeloid differentiation, and may also exert leukemogenic effects by inducing dependence on BCL2 and inhibiting homologous recombination. Ivosidenib (AG-120) and enasidenib (AG-221) are oral inhibitors of mIDH1 and mIDH2, respectively, that as monotherapy are associated with robust overall response rates in patients with relapsed/refractory AML. We are assessing the safety and preliminary efficacy of ivosidenib or enasidenib in combination with standard induction chemotherapy.

Methods: In this open-label, multicenter, phase 1 study (NCT02632708), eligible patients with newly diagnosed mIDH1 or mIDH2 AML are treated with standard induction chemotherapy (daunorubicin 60 mg/m2/day or idarubicin 12 mg/m2/day x 3 days with cytarabine 200 mg/m2/day x 7 days) in combination with either ivosidenib 500 mg once daily (for mIDH1) or enasidenib 100 mg once daily (for mIDH2). After induction, patients may receive ≤4 cycles of consolidation chemotherapy while continuing the mIDH inhibitor. Patients who either complete or are ineligible for consolidation may continue on maintenance ivosidenib or enasidenib for ≤2 years from the start of induction. Patients may be removed from the study at any point for an allogeneic hematopoietic stem cell transplant (HSCT); these patients do not receive maintenance therapy post-transplant.

Results: As of Apr 18, 2017, 65 patients had been treated: 27 with ivosidenib (median age 60 years, range 24–76) and 38 with enasidenib (median age 63 years, range 32–76, Table 1). Of the 38 patients with mIDH2, 19 (50%) had secondary AML (sAML; arising after myelodysplastic syndrome or another antecedent hematologic disorder, or after exposure to genotoxic injury) compared with 9/27 (33%) with mIDH1. Ivosidenib or enasidenib combined with induction chemotherapy was generally well tolerated. One dose-limiting toxicity was observed (persistent grade 4 thrombocytopenia without leukemia on Day 42 in an enasidenib- and daunorubicin/cytarabine-treated patient). The most frequent grade ≥3 nonhematologic treatment-emergent adverse events during induction therapy, regardless of attribution, in ivosidenib-treated patients were febrile neutropenia (56%), alanine aminotransferase increased (11%), aspartate aminotransferase increased (11%), and colitis (11%); and in enasidenib-treated patients were febrile neutropenia (63%), hypertension (11%), colitis (8%), and maculopapular rash (8%; Table 2). Thirty- and 60-day mortality rates were both 7% in ivosidenib-treated patients, and were 5% and 8%, respectively, in enasidenib-treated patients. Median times for ANC recovery to ≥500/µL were 28 and 34 days for ivosidenib- and enasidenib-treated patients, respectively, and for platelet recovery to >50,000/µL were 28 and 33 days for ivosidenib- and enasidenib-treated patients, respectively. In enasidenib-treated patients with sAML there was an increased time to platelet count recovery (median 50 days). Among 23 efficacy-evaluable ivosidenib-treated patients, a response of CR, CRi, or CRp was achieved in 12/14 (86%) patients with de novo AML and 4/9 (44%) patients with sAML. Among 37 efficacy-evaluable enasidenib-treated patients, a response of CR, CRi, or CRp was achieved in 12/18 (67%) patients with de novo AML and 11/19 (58%) patients with sAML (Table 3). Seven ivosidenib-treated and 14 enasidenib-treated patients received ≥1 cycle of consolidation therapy; 6 ivosidenib-treated and 8 enasidenib-treated patients proceeded to HSCT.

Conclusion: Ivosidenib or enasidenib in combination with standard AML induction therapy is generally well tolerated. The slower platelet recovery observed in patients with mIDH2 sAML may reflect the reduced normal hematopoietic reserve in sAML patients; nevertheless, alternative dosing schedules for enasidenib with induction chemotherapy are being explored to see if delayed platelet recovery can be mitigated. Response rates thus far are encouraging, especially in patients with sAML, many of whom had received hypomethylating agent therapy. To further understand the quality of responses, analyses of minimal residual disease by mutational clearance are underway.

Oral Arsenic Plus Retinoic Acid Versus Intravenous Arsenic Plus Retinoic Acid for Non-High Risk Acute Promyelocytic Leukemia: A Multicenter Randomized Controlled Trials

Result Type: Paper
Number: 641
Presenter: Honghu Zhu
Program: Oral and Poster Abstracts
Session: 613. Acute Myeloid Leukemia: Clinical Studies: Novel Therapies for AML and APL

Honghu Zhu1*, Depei Wu, MD 2, Xi Zhang, MD, PhD3*, Lin LIU4*, Jun Ma5*, Zonghong Shao, MD6, Hanyun Ren, MD, PhD7,8*, Jianda Hu, Prof MD PhD9, Kailin Xu, MD., PhD10*, Jing-Wen Wang11*, Yongping Song12*, Mei-Yun Fang13*and Xiao-Jun Huang, MD1

1Peking University People’s Hospital, Beijing, China
2the First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou, China
3Department of Hematology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China
41 Youyi Road, Yuzhong District, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
5Harbin Institute of Hematology and Oncology, Heilongjiang, CHN
6Tianjin Medical University, Tianjin, China
7Department of Hematology, Peking University First Hospital, Beijing, China
8Department of Hematology, Peking University First Hospital, Xicheng District, Beijing, China
9Department of Hematology, Union Hospital, Fujian Medical University, Fuzhou, China
10Department of Hematology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, China
11Department of Hematology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
12Henan Cancer Hospital, Zhengzhou, China
13the First Affiliated Hospital, Dalian Medical University, Dalian, China


Objective: Intravenous arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA) without chemotherapy is the standard of care for non high-risk acute promyelocytic leukemia (APL), resulting in cure rates exceeding 95%. Pilot study of treatment with oral arsenic named the Realgar-Indigo naturalis formula (RIF) plus ATRA without chemotherapy has shown high efficacy, convenient and economical. This randomized, multicenter, phase 3 noninferiority trial was designed to test the efficacy and safety of an oral RIF and ATRA compared with intravenous ATO for newly diagnosed non high-risk APL patients.

Methods: We conducted a phase 3, multicenter trial comparing RIF plus ATRA with ATO plus ATRA in patients with non high-risk APL (white-cell count, ≤10×109 per liter) between 2014 and 2017. In all, 109 patients were randomly assigned (2:1) to oral RIF (60 mg/kg) plus ATRA (25 mg/m2) or ATO (0.16mg/kg) plus ATRA (25 mg/m2) as induction therapy until complete hematologic remission. Postremission therapy included RIF or ATO on a schedule of 4 weeks on and 4 weeks off and ATRA on a schedule of 2 weeks on and 2 weeks off for 7 months.

The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival (EFS) at 2 years in the two groups was not greater than 10%.

Results: Complete remission was achieved in all 69 patients in the RIF-ATRA group who could be evaluated (3 withdraw during the induction) and in 34 of 36 patients in the ATO-ATRA group (2 died and another one withdraw during the induction) (100% vs. 94.4%, p = 0.12).

The median follow-up was 32 months. Two-year EFS rates were 97.1% in the RIF-ATRA group (n=69) and 94.4% in the ATO-ATRA group (n=36). The EFS rate difference was 2.7% (95% CI,-5.8% to11.1%). The lower limit of the 95%CI for EFS rate difference was greater than-10% noninferiority margin, confirming noninferiority (noninferiority P=0.0017). There is no difference about relapse rate and overall survival between two groups (all p >0.05).

Conclusions: RIF plus ATRA is not inferior to ATO plus ATRA in the treatment of patients with non high-risk APL (Chinese Clinical Trial Registry number, ChiCTR-TRC-13004054).

Preliminary Results from a Phase 1 Study of Gilteritinib in Combination with Induction and Consolidation Chemotherapy in Subjects with Newly Diagnosed Acute Myeloid Leukemia (AML)

Result Type: Paper
Number: 722
Presenter: Keith Pratz
Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Emerging Molecularly-Targeted Therapies in AML

Keith Pratz, MD1, Mohamad Cherry, MD, MS2, Jessica K. Altman, MD3, Brenda W. Cooper, MD4, Jose Carlos Cruz, MD5, Joseph G. Jurcic, MD6, Mark J. Levis, MD, PhD7, Tara L. Lin, MD8, Alexander E. Perl, MD9, Nikolai A. Podoltsev, MD, PhD10, Gary Schiller, MD11, Chaofeng Liu, PhD, MBA12* and Erkut Bahceci, MD12

1Johns Hopkins University, Baltimore, MD
2Stephenson Cancer Center, Oklahoma, OK
3Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL
4Adult Hematologic Malignancies & Stem Cell Transplant Section, Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, OH
5Adult Blood & Marrow Stem Cell Transplant, Texas Transplant Physician Group, San Antonio, TX
6Department of Medicine, Columbia University Medical Center, New York, NY
7Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD
8University of Kansas, Westwood, KS
9Division of Hematology/Oncology, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA
10Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT
11David Geffen School of Medicine, UCLA, Los Angeles, CA
12Astellas Pharma Global Development, Northbrook, IL


Background: Gilteritinib is a novel, potent, highly-selective oral fms-like tyrosine kinase 3 (FLT3)/AXL inhibitor with clinical activity in relapsed/refractory (R/R) AML with activating FLT3-ITD and -TKD mutations. In such patients, once-daily gilteritinib ≥80 mg/day, as a single agent, elicited a response rate of 52% and median overall survival (OS) of 31 weeks (Perl AE, et al. Lancet Oncol. 2017.). Here we examined the safety/tolerability and antitumor activity of gilteritinib combined with front-line intensive chemotherapy in newly diagnosed AML patients.

Methods: The primary objective of this open-label, dose-escalation/expansion Phase 1 study (NCT02236013) was to assess the safety/tolerability profile (including dose-limiting toxicities [DLTs] and maximum tolerated dose [MTD]) of gilteritinib when combined with 7+3 induction and high-dose cytarabine (HiDAC) consolidation, and administered as single-agent maintenance therapy in subjects aged ≥18 years with newly diagnosed AML. Assessment of antitumor effects of this combination therapy was an exploratory objective. Dose escalation followed a 3+3 design where successive cohorts of 3–6 subjects received gilteritinib doses of 40, 80, or 120 mg/day. Dose-escalation decisions were made based on DLTs that occurred during remission induction. A DLT was defined as any grade ≥3 non-hematologic or extramedullary toxicity (with exceptions) or hematologic toxicity that occurred after the first gilteritinib dose and did not resolve by Day 42 of the last induction cycle or before initiation of consolidation therapy. Subjects received up to 2 cycles of a 7+3 induction regimen (cytarabine 100 mg/m2/day, days 1–7 plus idarubicin 12 mg/m2/day, days 1–3) plus once-daily oral gilteritinib, which was initially administered on days 1-14 but was subsequently changed to administration on days 4–17 at the designated dose. During consolidation, subjects received cytarabine (1.5 g/m2 every 12 hours, days 1, 3, and 5) and once-daily gilteritinib (days 1–14) at the induction dose, for up to 3 cycles. Subjects in the dose-expansion cohort, received gilteritinib at the recommended expansion dose established during dose escalation. After consolidation, subjects received maintenance therapy with once-daily gilteritinib (28-day cycles; up to 26 cycles).

Results: As of July 9, 2017, 50 subjects had been enrolled (n=17, dose-escalation cohort; n=33, dose-expansion cohort); 49 had received at least 1 dose of gilteritinib. Most subjects were male (67.3%; n=33); median age was 59 years (range, 23–77 years). Of the 48 subjects with known FLT3 mutation status, 23 (47.9%) were FLT3mut+, of whom 15 (65.2%) had internal tandem duplications. During dose-escalation, 2 subjects in the 40 mg/day cohort who had received gilteritinib on days 1-14 experienced DLTs (neutropenia, thrombocytopenia, and decreased ejection fraction). After gilteritinib induction schedule modification, no additional DLTs were observed. The MTD was not reached; gilteritinib 120 mg/day was chosen as the recommended expansion dose. Grade ≥3 treatment-emergent adverse events (TEAEs) occurring in ≥10% of subjects were febrile neutropenia (53.1%), thrombocytopenia (18.4%), neutropenia (16.3%), decreased platelet count (12.2%), sepsis (10.2%), and decreased white blood cell count (10.2%). Serious drug-related TEAEs occurring in >1 subject were febrile neutropenia (16.3%), sepsis (6.1%), and decreased ejection fraction (4.1%). The end of treatment investigator-reported composite complete remission (CRc) rate for all subjects was 71.4% and 57.1% achieved complete remission (Table). In FLT3mut+ and FLT3 mutation-negative (FLT3mut−) subjects, end-of-treatment CRc rates were 91.3% and 56%, respectively. Among subjects who received ≥80 mg/day gilteritinib (n=40), end-of-treatment CRc rates were 90% (n=18/20) for FLT3mut+ and 60% (n=12/20) for FLT3mut− subjects. Median OS and duration of response have not been reached. For the total study population, median event-free survival (EFS) was 327 days and median disease-free survival (DFS) was 297 days; FLT3mut+ subjects had a longer median EFS (327 days) and DFS (134 days) than FLT3mut− subjects (EFS, 80 days; DFS, not estimable).

Conclusions: In subjects with newly diagnosed AML, gilteritinib combined with intensive chemotherapy was well tolerated (MTD >120 mg/day) with seemingly high response rates in FLT3mut+ subjects.

Remissions of Acute Myeloid Leukemia and Blastic Plasmacytoid Dendritic Cell Neoplasm Following Treatment with CD123-Specific CAR T Cells: A First-in-Human Clinical Trial

Result Type: Paper
Number: 811
Presenter: Lihua Budde
Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Novel Targeted and Immune-based Approaches in the Treatment of AML

Lihua Budde, MD, PhD1, Joo Y Song, MD1*, Young Kim, MD1*, Suzette Blanchard, PhD1*, Jamie Wagner, BS1*, Anthony S. Stein, MD1, Lihong Weng, MD1*, Marissa Del Real, PhD1*, Rochelle Hernandez1*, Emanuela Marcucci1*, Jennifer K Shepphird, PhD1*, Xiuli Wang, PhD1*, Brent Wood, MD PhD2*, Guido Marcucci, MD1, Christine E Brown, PhD1* and Stephen J. Forman, MD, FACP1

1City of Hope, Duarte, CA
2Department of Laboratory Medicine and Division of Hematopathology, University of Washington, Seattle, WA


The current treatment of relapsed or refractory AML is associated with low rates of complete response (CR) and considerable complications. As a result, only a minority of patients (pts) proceed to allogeneic hematopoietic stem cell transplantation (alloHSCT) with curative intent. Furthermore, outcomes for AML pts with disease relapse after alloHSCT are dismal. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and incurable blood cancer with a median survival of <18 months and no standard of care. Thus, there are clear unmet therapeutic needs in both these conditions. CD123 is overexpressed on AML blasts and leukemic stem cell (LSC)-enriched cell subpopulations compared to normal hematopoietic stem cells and myeloid progenitors. High levels of CD123 expression is also one of the diagnostic hallmarks for BPDCN. All these features make CD123 an attractive target for T cell based adoptive immunotherapy. We have previously demonstrated preclinically the anti-AML activity of CD123-chimeric antigen receptor (CAR) T cell therapy (Mardiros, Blood 2013). The CD123CAR contains an anti-CD123 single-chain variable fragment, an optimized IgG4 CH2CH3 linker, a CD28 co-stimulatory domain, and a CD3 zeta signaling domain and is used to engineer T cells for patients enrolled on a single center, first-in-human phase I dose escalation clinical trial open at our Institution (NCT02159495). The primary objective is to test the safety and activity of escalating doses of CD123CAR T cells for patients with relapsed or refractory AML (cohort 1) and BPDCN (cohort 2). Donor-derived or autologous T cells from leukapheresed peripheral blood mononuclear cells were lentivirally transduced with the CD123CAR vector. Prior to T cell infusion, all patients undergo a lymphodepleting regimen including fludarabine 25–30 mg/m2 daily for 3 days and cyclophosphamide 300 mg/m2 daily for 3 days. Pts receive a single dose of CD123CAR T cells with an option for a second infusion if they continue to meet safety and eligibility criteria and still have CD123+ disease. To date, 14 patients have been enrolled and 7 treated (6 AML, 1 BPDCN).

All 6 patients in the AML cohort had refractory AML following alloHSCT, and a median of 4 (range: 4–7) prior lines of therapy. Of the 2 pts treated at dose level (DL) 1 (50M CAR+ T), 1 achieved a morphologic leukemic-free state, which lasted 2 months. She received a second infusion 3 months later with subsequent blast reduction from 77.9% to 0.9% (flow cytometry) after 35 days. Of the 4 pts on DL 2 (200M CAR+ T), 1 achieved CR and became transfusion independent. She proceeded to a second alloHSCT on day 70. Restaging on day +161 post-transplant showed she has remained in MRD-negative CR with good engraftment and 100% donor chimerism. Another pt with CR prior to treatment remained in CR at day 28 and has proceeded to a second alloHSCT. The remaining 2 patients had reductions in blast counts, but did not achieve remission. All toxicities were reversible and manageable: cytokine release syndrome (CRS; 4 grade 1, 1 grade 2); 1 adenoviral pneumonia requiring intubation; and 1 grade 3 rash due to drug hypersensitivity. There were no dose limiting toxicities and no treatment-related cytopenias. One pt with prior alloHSCT had mild recurrent cutaneous GVHD, which occurred after the completion of CAR T treatment. Correlative studies including T cell persistence and CD123 expression are underway and will be reported.

In the BPDCN cohort, 1 pt has been treated so far, a 74-year-old man with a persistent bulky subcutaneous mass after clinical trial treatment with a CD123 antibody-drug conjugate. Following lymphodepletion, he received a single dose of 100M autologous CD123CAR T cells and continues to be in CR at 60 days post-infusion. Skin biopsies at the tumor site on days 14 and 28 showed no evidence of disease. Restaging work-up at day 28 revealed disease-free bone marrow, no new masses by CT scan, normalized blood counts, and complete resolution of clinical symptoms. The pt tolerated the treatment well with no CRS or neurologic toxicity.

In this first-in-human clinical trial of CD123CAR T cell therapy, we have demonstrated the feasibility and safety of targeting CD123. We have also observed promising anti-leukemic activity in both AML and BPDCN. Importantly, no myeloablative effects have been observed, supporting further testing of this immunotherapeutic strategy in both transplant eligible and ineligible patients.