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Background: Most adult patients with ALL will achieve a complete hematologic remission following frontline therapy, but approximately 40% of patients will subsequently have evidence of MRD. This status describes the presence of leukemia cells in the bone marrow, which cannot be detected by conventional methods and is recognized as an independent negative prognostic factor for disease relapse and survival. An SLR was conducted to evaluate evidence comparing clinical outcomes following SCT among patients who are MRD+ vs. MRD- prior to transplant. Methods: Medline, Embase, and Central databases were systematically searched with keywords for ALL and MRD to identify relevant literature on adults undergoing transplants according to MRD status published through 5/8/2018. Oncology conferences were also searched for relevant data presented between 2014─2018. Results: 30 primary studies were identified that reported outcomes following SCT in ALL patients with MRD results available prior to transplant. Clinical outcome comparisons between MRD+ and MRD- patients were most commonly reported (27/30 studies). Comparisons between MRD+ and MRD- patients universally suggested that those with MRD+ status prior to SCT had lower survival rates at all time points reported relative to patients who were MRD- with an exception of one study, evaluating patients treated with salvage therapy, which favored MRD+ in survival gains with a non-significant difference between MRD+ and MRD- groups (Table 1). The available hazard ratio (HR) on overall survival consistently indicated that patients with MRD+ status before transplant were more likely to die after SCT as patients who are MRD- (HRs for OS: 1.51-2.646) (Figure 1). MRD+ status was also associated with higher likelihood of disease progression, (HRs for PFS: 2.15 to 2.8). Six studies reported data on mean or median survival; median OS after SCT ranged from 1.98 months to 17 months among MRD+ patients compared with 17 months to 67 months among those with MRD- status. This translated to median OS difference ranging from -8 to -50 months for the MRD+ vs. MRD- patients. Data indicated that patients who are MRD- at time of transplant also experienced longer median event-free survival (EFS) (median EFS difference was -8 months for MRD+ vs. MRD- in two studies) and longer median relapse-free survival (RFS) (median RFS MRD+ vs. MRD- of -40.5 months in one study). While 12 studies reported data on the proportion of patients who relapsed after SCT, timepoints were not consistently reported and population sizes varied widely. Among all studies reporting this data, 16% to 100% of MRD+ patients relapsed after SCT, while 0% to 50% of MRD- patients experienced a relapse after SCT. Only four studies reported complete remission (CR); 35.6% to 86%of MRD+ patients achieved CR after SCT, while 100% of MRD- patients maintained CR after SCT based on one study. Conclusion: This systematic literature review found consistent evidence of markedly worse transplant outcomes among patients with MRD+ vs. MRD-, including shorter median survival (OS, RFS and EFS), higher risks of death and relapse events and lower likelihood to achieve hematologic remission. Therapies that can eradicate MRD among adult ALL patients can potentially improve the outcomes of SCT in these critically ill patients. Disclosures Turner: Evidera: Employment. Shah:Amgen, Inc.: Employment, Equity Ownership. Martin:Evidera: Employment. Cong:Amgen, Inc.: Employment, Equity Ownership. Stein:Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau.

Blinatumomab (BT), a CD19/CD3 bispecific T-cell engager (BiTE) antibody recently approved for treatment of relapsed/refractory acute lymphoblastic leukemia (r/r ALL), has resulted in a 40-50% complete response (CR)/CR with incomplete count recovery (CRi) rate and frequent cytokine release syndrome (CRS) events. While extent of disease burden has been identified as a key predictor of disease response, there have been no studies to date evaluating the impact of single nucleotide polymorphisms (SNPs) in cytokine genes on disease response or CRS after treatment with BT. Here, we evaluated the possible association between cytokine SNPs, disease response, and/or CRS in r/r ALL patients with receiving BT. A total of 82 patients (consecutive case-series) received BT between 2012 and 2017 at City of Hope. Of these, 68 patients had archived DNA samples available for study and analysis. Genotyping was done using Illumina's Omni 5-4 bead array, which interrogates more than 4.2 million SNPs. Array processing was done following manufacturer's recommendations and arrays were scanned by Illumina's iScan instrument. Beeline software and Genome Studio (Illumina) were used for analysis of scanned images and to generate the genotyping calls and quality control reports, respectively. Our analysis focused on the following cytokine genes of interest (known to be associated with autoimmune diseases/graft-versus-host disease): IL-1B, IL-2, IL-6, IL-7R, IL-10, IL-11, IL-12, IL-17A, IL-23R, TNF-α, TGF-β, and IFN-γ. Two modes of inheritance (dominant and recessive) were considered whenever appropriate. Univariate analyses of SNPs, response and CRS were performed using Fisher's exact test. P values were not adjusted for multiple hypothesis testing due to the exploratory nature of the analyses. In our cohort, median age of patients at BT treatment was 34 years old (range: 7-85), with 32 females (39%) and 50 males (61%). Patients' race/ethnicity included 49 Hispanic (60%), 20 non-Hispanic Caucasians (24%), 9 Asians (11%), and 3 African Americans (3%). All patients had primary refractory (n=16) or relapsed disease status (1st relapse: n=38, 2nd or subsequent relapse: n=27) with median lines of prior therapy of 2 (range: 0-5). Cytogenetic abnormalities included Ph+ALL in 11 patients, while 50 patients had other cytogenetic abnormalities and 15 had normal cytogenetics. Bone marrow blasts of >50% at BT treatment was detected in 45 patients, and 22 patients had a history of or active extra-medullary involvement. After BT treatment, 37 patients (45%) achieved CR/CRi with a median duration of 9.5 months (range: 1-37), 54 patients (66%) experienced CRS (grade 1: n=35, grade 2: n=14, and grade 3: n=5), and 9 patients developed neurotoxicity. Lastly, the peak C-reactive protein level (median/range) was 17 mg/L (range: 1-392). By univariate analysis, disease response (CR/CRi) to BT was significantly associated with the following cytokine SNPs: IL2 rs2069762 [48.3% (T/T-G/T: n=60) Vs. 0% (G/G; n=7), p=0.016], IL17A rs3819024 [30.8% (A/A; n=39) Vs. 58.6% (A/G-G/G; n=29), p=0.027], and IL17A rs4711998 [54.5% (A/A: n=33) Vs. 29.4% (A/G-G/G: n=34), p=0.049]. (Table 1) These three cytokine SNPs and two additional SNPs with p-values between 0.05 and 0.1 (IL7R rs1494555, IL17A rs8193036) were evaluated by multivariable analysis, adjusted for >50% bone marrow blasts, which was associated with lower rate of CR/CRi (33% vs. 63% with In conclusion, to our knowledge this is the first study to demonstrate a possible association between treatment response to BT and cytokine genetic polymorphisms. Our hypothesis-generating data suggest a potential role of IL17 and IL2 in BT response and justify a larger confirmatory study, which may lead to personalized BT immunotherapy for B-ALL. Disclosures Stein: Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

Background: In the phase 3 TOWER study, patients with relapsed or refractory (r/r) Philadelphia chromosome-negative (Ph-) B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) who received bispecific T-cell engager (BiTE®) antibody construct blinatumomab had improved overall survival (OS; median, 7.7 vs 4.0 months; P=0.01;) and health-related quality of life (HRQoL) compared with those who received standard of care (SOC) chemotherapy (Kantarjian H, et al. N Engl J Med. 2017;376:836-847; Topp MS, et al. Blood. 2018;131:2906-2914). In this subgroup analysis of TOWER, we assessed the HRQoL between patients with low versus high baseline disease burden (low versus high bone marrow blast levels) who received blinatumomab or SOC chemotherapy. Methods: Patients (N=405) with r/r Ph- BCP ALL were randomized 2:1 to receive 2 cycles of induction blinatumomab by continuous intravenous infusion (n=271) or SOC (n=134). Those in remission could receive up to 3 consolidation cycles; 12 months of maintenance was allowed for those who received up to 3 consolidation cycles and had bone marrow response. HRQoL was assessed using the EORTC QLQ-C30 Questionnaire on days 1 (baseline), 8, and 15; on day 29 of cycle 1; days 1, 15, and 29 of consolidation; and at the safety follow-up. The questionnaire included 1 global health status scale, 5 functioning scales, 3 symptom scales, and 6 single-symptom items. For global health status and functioning scales, a higher score indicates better HRQoL; for symptom scales/items, a lower score indicates better HRQoL. A 10-point change was viewed as the minimum clinically important difference in EORTC QLQ-C30 (Zikos E, et al. EORTC. 2016). HRQoL was assessed in patient subgroups by screening the bone marrow aspirates for low blast levels ( Results: In total, 342 patients (blinatumomab, n=247; SOC, n=95) had ≥1 HRQoL result: low blasts, n=87 (blinatumomab, n=64; SOC, n=23); high blasts, n=255 (blinatumomab, n=183; SOC, n=72). The EORTC QLQ-C30 analysis set included all randomized subjects with a nonmissing baseline result and at least 1 nonmissing post-baseline result of any EORTC QLQ-C30 scale/item. There was no statistically significant difference in baseline HRQoL scores between the high and low blasts groups; however, the high blasts group had worse HRQoL overall. Baseline HRQoL scores were also similar between blinatumomab arm and SOC arm for each group. Global health status was improved by blinatumomab regardless of baseline blast level; however, this effect was somewhat greater in the low blasts group. When the function scores worsened, the extent of worsening was almost always smaller for blinatumomab versus SOC, particularly in the high blasts group. Functioning status scores tended to stay the same or worsen with both blinatumomab and SOC regardless of blast level, except emotional scores, which improved with blinatumomab regardless of blast level (Figure 1). Symptom scores generally improved with blinatumomab but not with SOC, particularly in patients with high blasts (Figure 2). TTD analyses showed that hazard ratios favored blinatumomab over SOC, particularly in patients with high blasts (Table). Conclusions: Blinatumomab improved HRQoL in patients with r/r Ph- BCP ALL and delayed the time to clinically meaningful deterioration in HRQoL compared with SOC. The treatment effects of blinatumomab versus SOC on HRQoL were particularly larger among patients with high disease burden. Download : Download high-res image (708KB) Download : Download full-size image Disclosures Stein: Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau. Zimmerman: Amgen Inc.: Employment, Equity Ownership. Dombret: Novartis: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; Ambit (Daiichi Sankyo): Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria, Other: Travel expenses; Celgene: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Immunogen: Consultancy, Honoraria; Shire-Baxalta: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharma: Consultancy, Honoraria, Research Funding; Ariad (Incyte): Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Roche/Genentech: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau. Topp: F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Boehringer Ingelheim: Research Funding. Franklin: Amgen Inc.: Employment, Equity Ownership. Cong: Amgen, Inc.: Employment, Equity Ownership. Zhang: Amgen Inc.: Employment, Equity Ownership. Schuh: Pfizer: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Teva: Consultancy; Amgen Inc.: Consultancy; Otsuka: Consultancy; Jazz: Consultancy; Shire: Consultancy.

Introduction: Acute myeloid leukemia (AML) is a highly aggressive form of leukemia that results a poor survival outcome. Currently, diagnosis and prognosis are based on invasive single-point bone marrow biopsies (iliac crest). Although non-invasive positron emission tomography (PET) imaging has been developed for almost all solid tumors and some hematological malignancies, there is currently no non-invasive imaging specific to AML available, representing an unmet clinical need. About 85% of AML cells express CD33, and expression levels of CD33 has been correlated with poor survival outcomes (Pollard et al., Blood (2012)), making it an ideal candidate for immuno-PET. Therefore, our primary goal is to develop anti-CD33 immuno-PET for detecting CD33+ AML. The secondary goal is to assess the feasibility of CD33 PET image-guided external beam targeted radiation delivery in combination with chemotherapy (AraC). Methods: Murine anti-human CD33 monoclonal antibody clone p67.6 was conjugated to DOTA and radiolabeled with Cu-64 for imaging studies. In vivo PET-CT imaging and bio distribution of 64Cu-DOTA-anti-CD33 in vivo was carried out in NSG mice bearing CD33+ (MV4-11, HL60) AML cells. CD33-negative MM1s cells (multiple myeloma) were used as negative control. The AML and MM bearing mice were injected with 64Cu-DOTA-anti-CD33 (100 µCi/10 µg) and serial PET imaged at 24-48 h. We developed a functional total marrow irradiation (fTMI) treatment, where mice received total marrow irradiation (TMI) (2 Gy) and boost radiation (2 Gy) to regions with increased CD33 activity, followed by 2 days of AraC (40 mg/kg) and 24h later a bone marrow transplant. Furthermore, a humanized anti-human CD33 monoclonal antibody was generated and tested for immunogenicity against CD33 in AML cell lines and patient samples for future clinical studies. Results: PET-CT imaging and biodistribution studies of 64Cu-DOTA-anti-CD33 clearly indicates a CD33+ PET signal in the femur, tibia, humerus joints, L spine and spleen in AML-bearing mice, but not in multiple myeloma-bearing mice or in cold anti-CD33-DOTA treated leukemic mice (Figure 1A and B). Our new imaging method was able to detect CD33+ AML with a favorable sensitivity (71.4%) and specificity (100%). Based on detailed whole-body 3D imaging and validated with biodistribution studies, we discovered preferential regions in the skeletal system with differential CD33 activity, indicating the spatial heterogeneity of AML. CD33+ PET intensity was observed in the following descending order: femur≥lspine>humerus>tibia (Figure 1C). Next, using the PET-CT images, we targeted these CD33-active regions using the fTMI treatment plan. We have developed a unique irradiation system which allows targeting only skeletal tissues while sparing major organs like gut, lung and liver, unlike conventional total body irradiation (TBI). This approach will also provide an opportunity to escalate doses to specific regions in the body without damaging other unintended targets. The fTMI (2 Gy TMI and 2 Gy boost) treatment plan increased the medial survival of the mice to 43 days versus that of untreated control mice (26 days) or AraC treated mice (33 days) Figure(1D). Since the preclinical study was carried out using murine anti-CD33 antibody clone p67.6, we further tested the newly generated humanized anti-human-CD33 monoclonal antibody. This humanized antibody detects CD33 in both AML cell lines and human patient sample (Fig 1E). Conclusion: This study is the first to use an anti-CD33 monoclonal antibody for non-invasive immuno-PET-based imaging for AML detection, showing high sensitivity and specificity. This whole body imaging may be useful for AML diagnosis not only in the entire skeletal system, but also in the extramedullary organs, and for longitudinal monitoring of treatment response. Unlike conventional TBI, Image-guided fTMI along with conventional chemotherapy may result in an improved prognosis, as unintended major organs are spared from radiation. Disclosures Vallera: GT Biopharma: Consultancy, Research Funding. Stein:Celgene: Speakers Bureau; Amgen Inc.: Speakers Bureau.

Several prognostic models have been developed to predict survival outcomes and response in patients with myelofibrosis (MF). MIPSS70 prognostic system, developed by incorporation of all the key clinical characteristics, cytogenetics, and mutational factors into one system, has recently been revised to MIPSS70+ v2.0 with refinements in degrees of anemia, cytogenetics, and HMR. While allogeneic hematopoietic cell transplantation (alloHCT) is the only curative treatment for patients with MF, limited data exists on the impact of molecular markers on transplant outcomes. Here, we evaluated the transplant outcome in MF patients who uniformly received fludarabine/melphalan (FluMel) conditioning at City of Hope and assessed the impact of cytogenetics, somatic mutations on transplant outcomes based on a 72 gene next-generation sequencing (NGS) panel and MIPSS 70+ v2.0. A total of 110 consecutive MF patients (primary: n=58, secondary: n=52) without prior acute leukemic transformation, underwent alloHCT between 2004 and 2017. Median age at the time of transplant was 58.5 years (range: 38-72 years) with median interval from diagnosis of primary or secondary MF to HCT of 15.2 months (range: 1.6-332.5 months). AlloHCT donors were matched related (n=51), matched unrelated (n=44), and mismatched unrelated (n=15). Intermediate-2 and High risk by DIPSS accounted for 83 (76%) of patients at the time of transplant. Tacrolimus/Sirolimus-based GVHD prophylaxis was used in 100 (91%) patients, and 16 had splenectomy prior to alloHCT. Pre-transplant DNA sample were available for 93 patients and cytogenetics information was available for 106 patients; among which 60 had abnormal cytogenetics. Based on recently developed revised cytogenetic risk stratification on transplant outcomes, we identified 67 patients (61%) in favorable, 24 (22%) in unfavorable, and 15 (14%) in very high risk groups. Median number of 2 mutations were detected with at least one mutation in 95% (n=88) of patients. JAK2 V617F was the most common alteration noted in 54 (58.1%) patients. Other common mutations were ASXL1 (n=41, 44%), CALR type 1 (n=15, 16.1%), TET2 (n=12, 13%) SRSF2 and DNMT3A (each n=10, 11%). No detectable mutations were found in 5 (5.4%) patients. HMR genes (ASLX1, EZH2, IDH1/2, SRSF2, and U2AF1) were identified in 48 patients (52%), with 30 patients (32%) carrying one and 18 patients (19%) carrying more than 1 HMRs. With a median follow-up of 63.7 months (range: 11.9-158.5), 5 year overall survival (OS) and non-relapse mortality (NRM) were 65% (95% CI: 54-73) and 17% (95%CI: 10%-24%), respectively. Detailed transplant outcomes were previously reported (Ali et al. American Society of Hematology. Vol. 130. Atlanta, GA: Blood; 2017:199) (Figure 1a). On multivariable analysis, unfavorable and VHR cytogenetic changes had significantly shorter OS and PFS (p=0.001 and 0.008), and relapse risk (p=0.035) (Figure1b). Triple negative status (p=0.063), HMR (p=0.73), and more than 1 HMR (p=0.59) did not significantly impact survival post-HCT. (Figure1c) Similarly, CALR type 1 (p=0.42), and ASXL1 (p=0.29) mutations also did not impact survival after HCT. Only CBL mutation was significantly associated with lower OS (HR=2.64, 95% CI: 1.09-6.38, p=0.032) and lower DFS (HR=4.35, 95% CI: 1.83-10.36, p In summary, we are presenting one of the largest single center experiences of FluMel-based alloHCT for MF patients, demonstrating revised cytogenetic changes and MIPSS70+ v2.0 accurately predicts transplant outcomes, thus would better inform physicians and patients in discussing and decision making about alloHCT. Figure. Figure. Disclosures Ali: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Khaled:Juno: Other: Travel Funding; Alexion: Consultancy, Speakers Bureau; Daiichi: Consultancy. Salhotra:Kadmon Corporation, LLC: Consultancy. Stein:Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly aggressive hematologic malignancy with a historical overall survival (OS) of ~8-14 months from diagnosis and no approved therapies or standard of care. Tagraxofusp (Elzonris™; SL-401) is a novel targeted therapy directed to the interleukin-3 receptor-α (CD123), a target expressed on BPDCN and other malignancies. Tagraxofusp was granted Breakthrough Therapy Designation for the treatment of patients with BPDCN, and a rolling Biologics License Application (BLA) submission to the U.S. Food and Drug Administration (FDA) was completed in June 2018. Detailed results from the pivotal trial of tagraxofusp in BPDCN will be presented. Methods: This pivotal Phase 2 clinical trial is a multicenter, open label, non-randomized, single-arm trial designed to determine safety and efficacy of tagraxofusp in patients with BPDCN. In Stage 1 (lead-in), first line (1L) and relapsed/refractory (r/r) patients with BPDCN received tagraxofusp as a daily IV infusion at 7, 9, or 12 mcg/kg/day on days 1-5 of a 21-day cycle. Patients with BPDCN enrolled in subsequent stages received tagraxofusp at the dose determined in Stage 1 (12 mcg/kg). Stage 2 (expansion) enrolled 1L and r/r patients, and Stage 3 (pivotal, confirmatory) enrolled only 1L patients. Results: 45 patients with BPDCN (Stages 1 and 2, n=32; Stage 3, n=13) were enrolled at 7 sites in the US, including 32 (71%) patients as 1L. Median age was 70 years (range, 22-84); 82% male. Median follow-up for all 1L patients treated at 12 mcg/kg (n=29) was 13.8 months (range 0.2-37.4+). The most common treatment-related adverse events (TRAEs) at 12 mcg/kg in 148 patients treated in four clinical trials with tagraxofusp were transaminitis (44%), hypoalbuminemia (44%), and thrombocytopenia (26%). Capillary leak syndrome (CLS), all grades, occurred in 17% of patients across all indications at 12 mcg/kg; 0.7% (1/148) and 1.6% (3/182) of cases resulted in death across all indications at 12 mcg/kg and all doses, respectively. The Stage 3 pivotal cohort met its primary endpoint with a 54% (7/13) rate of CR+CRc (95% CI: 25.1, 80.8). Across Stages 1, 2 and 3, in 1L patients dosed at 12 mcg/kg (n=29), ORR was 90% (26/29) with a 72% (21/29) rate of CR+CRc+CRi (ORR=overall response rate; CR=complete response; CRc=clinical CR: absence of gross disease with minimal residual skin abnormality; CRi=CR with incomplete hematologic recovery). 45% (13/29) of first-line patients treated with 12 mcg/kg were bridged to stem cell transplant (SCT) (10 allo+3 auto). In r/r patients, ORR was 69% (9/13) with a 38% (5/13) rate of CR+CRc+CRi. Additional patient follow-up will be provided. Conclusions: The pivotal trial of tagraxofusp was the largest prospectively designed, multi-center trial specifically dedicated to patients with BPDCN. This study has met its primary endpoint, and also demonstrated high response rates that were generally achieved early in the course of treatment and maintained over multiple cycles of therapy. Safety profile demonstrated most common toxicities of transaminitis, hypoalbuminemia, and thrombocytopenia; occurrence of CLS was the most serious TRAE, which was overall manageable in this population. Patients with BPDCN are being enrolled in an additional cohort, Stage 4, to ensure ongoing access. Tagraxofusp is also being evaluated in other trials including in patients with chronic myelomonocytic leukemia (CMML) and myelofibrosis (MF). Disclosures Pemmaraju: celgene: Consultancy, Honoraria; SagerStrong Foundation: Research Funding; stemline: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; novartis: Research Funding; abbvie: Research Funding; samus: Research Funding; daiichi sankyo: Research Funding; plexxikon: Research Funding; Affymetrix: Research Funding. Lane:N-of-one: Consultancy; Stemline Therapeutics: Research Funding. Sweet:Agios: Consultancy; Jazz: Speakers Bureau; BMS: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy; Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Astellas: Consultancy; BMS: Honoraria; Phizer: Consultancy; Agios: Consultancy; Celgene: Honoraria, Speakers Bureau; Phizer: Consultancy. Stein:Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau. Vasu:Boehringer Ingelheim Inc: Membership on an entity's Board of Directors or advisory committees. Blum:Tolero: Research Funding; Forma: Research Funding; Astellas: Consultancy; Xencor: Research Funding; Boehringer Ingelheim: Research Funding; Pfizer: Consultancy. Rizzieri:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: 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. Wang:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Pfizer: 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. Duvic:Guidepoint Global: Consultancy; Eisai: Research Funding; Allos: Research Funding; Clinical Care Options: Consultancy; Array Biopharma: Consultancy, Honoraria; Spatz Foundation: Research Funding; Defined Health: Consultancy; Medivir AB: Membership on an entity's Board of Directors or advisory committees; MiRagen Therapeutics: Consultancy; MEDACorp: Consultancy; Taiwan Liposome Company LTD: Consultancy; Medscape: Other: Speaker/Preceptor; Concert Pharmaceuticals, Inc.: Consultancy; Kyowa Hakko Kirin, Co: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Huya Bioscience Int'l: Consultancy; Shape: Research Funding; Kiniksa Pharmaceuticals: Consultancy; Soligenix, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Corp: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cell Medica Inc.: Consultancy, Honoraria; Dr. Reddy's Laboratories (A.K.A. Promius Pharma): Consultancy; Huron Consulting Group: Consultancy; Aclaris Therapeutics Int'l Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; UT MD Anderson Cancer Center: Employment; The Lynx Group: Consultancy; Evidera, Inc.: Consultancy; Mallinckrddt Pharmaceuticals (formerly Therakos): Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; American Council on Extracorporeal Photopheresis (ACE): Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogics: Research Funding; Precision Oncology, LLC: Membership on an entity's Board of Directors or advisory committees; Oncoceuticals: Research Funding; Jonathan Wood & Associates: Other: Speaker; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rhizen Pharma: Research Funding. Spence:Stemline Therapeutics: Consultancy. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership. Bergstein:Stemline Therapeutics: Employment, Equity Ownership. Chen:Stemline Therapeutics: Employment, Equity Ownership. Dunn:Stemline Therapeutics: Employment, Equity Ownership. McDonald:Stemline Therapeutics: Employment, Equity Ownership. Sloan:Stemline Therapeutics: Consultancy. Konopleva:Stemline Therapeutics: Research Funding.

Allogeneic hematopoietic stem cell transplant (alloHCT) remains the only potentially curative treatment for patients with myelodysplastic syndrome (MDS). However, this treatment is associated with significant risk of transplant-related mortality/morbidity such as graft-versus-host disease, infections, and regimen-related toxicities. Since there has been no "randomized" trial comparing between patients undergoing or not undergoing transplantation, the relative benefit of this treatment, particularly in elderly patients, is largely unknown. Retrospective comparative studies are significantly limited by the inherent selection bias of healthier/well-supported patients in the alloHCT group. Therefore, a critical knowledge gap exists regarding the survival outcome of MDS patients who are transplant eligible yet did not undergo alloHCT due to lack of suitable donors or other reasons. Herein, we retrospectively identified a consecutive case-series of 73 patients with MDS (excluding CMML), who were considered alloHCT candidates, based on initiation of an official donor search from 2005 to 2015, yet did not proceed with alloHCT. Median age at time of donor search was 60 years (range: 20-79) with the majority (63%) being male. Classifications of MDS were single or multi-lineage dysplasia (n=20), excess blast (n=39), MDS unclassified (n=6) or other/unknown classification (n=8). The cohort included 51 de novo MDS and 14 therapy-related MDS (t-MDS). Per International Prognostic Scoring System (IPSS) 29 patients (39.7%) were Intermediate (Int)-1, 14 (19.2%) were Int-2, and 23 (31.5%) were high risk at the time of donor search (Table 1). Reasons for no alloHCT were lack of donor (n=29), persistent/progressive disease (n=9), patient choice (n=13), or infections/complications after initiating the donor search (n=18). Treatments of these patients included chemotherapy (n=14), hypomethylating agents (n=61) and supportive care (n=23). Of the 73 patients, 15 (20.5%) had disease progression to acute leukemia at 1 year. There were 38 deaths with the median OS of 26.2 months (95%CI: 17.3-48.3 months). The 2-year probability of OS was 51% (95%CI: 36.7-62.9%). We next compared outcomes of these MDS patients who had a donor search without subsequent HCT to a consecutive case-series of MDS patients who underwent alloHCT from matched related and unrelated donors (cord blood and haploidentical transplants were excluded) during the same time period (n=276) at our center (Aldoss et al. Haematologica 2017). Patient demographics and MDS disease characteristics were similar between the two groups (Table 1). Median number of days from HLA typing to HCT were 168. By Kaplan-Meier method, OS (from the time of donor search) was significantly better for the alloHCT group (74% at 2-years) compared with non-HCT group (51% at 2-years), log-rank P In conclusion, using a unique cohort of patients who were referred for a donor search, our study in real-world practice demonstrates that transplant eligible MDS patients (at the time of donor search) who do not undergo alloHCT have worse survival outcomes compared to those undergoing transplantation. A prospective biologic assignment study is currently underway by the BMT CTN (#1102) to more definitively determine the impact and relative benefits of alloHCT in patients (≥50 years old) with Int2/high-risk de novo MDS. Disclosures Khaled: Alexion: Consultancy, Speakers Bureau; Daiichi: Consultancy; Juno: Other: Travel Funding. Salhotra:Kadmon Corporation, LLC: Consultancy. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Stein:Celgene: Speakers Bureau; Amgen Inc.: Speakers Bureau.

The prevalence of vancomycin-resistance Enterococci colonization (VRE-C) in patients undergoing allogeneic hematopoietic cell transplantation (aHCT) is between 23-40%. Pre-HCT VRE-C is shown to be associated with high risks of VRE bloodstream infection (VRE-BSI), non-relapse mortality (NRM) and lower overall survival. Recent studies investigating the association between VRE-C and risk of acute graft-versus-host disease (aGVHD) after aHCT has demonstrated conflicting results, possibly due to the heterogeneous transplant conditioning and GVHD prophylactic regimens. Here, we sought to examine the VRE-C prevalence and determine its impact on aHCT outcomes, in patients receiving tacrolimus and sirolimus (T/S) as aGVHD prophylaxis. To explore the association between pre-HCT VRE-C and transplant outcomes, we retrospectively reviewed medical records of a cohort of 1074 consecutive patients who underwent aHCT at City of Hope from 2014 to 2017. Patients with stool culture screening within 30 days pre-aHCT (n=862) were identified from the microbiology database and were grouped as VRE-C and non-colonized (VRE-NC). Data was not available on VRE-C in 185 patients and they were not included in analysis. Overall survival (OS) and progression-free survival (PFS) were examined by Kaplan-Meier curves and log-rank tests. Non-relapse mortality (NRM), VRE-BSI, and GVHD rates of the 2 groups were compared by cumulative incidence rates and Gray's test. Multivariate analyses were performed when adjusting for prognostic factors. Two-sided P value of ≤0.05 was considered significant. Of the 862 evaluated patients, 68 had VRE-C (7.9% prevalence). Median age of patients in VRE-C and VRE-NC groups were 53 and 55 years, respectively. Gender distribution, transplant indications, stem cell source, proportion of unrelated donors, GVHD prophylaxis with T/S and other clinical variables including intensity of conditioning regimen and HCT-CI were similar between the two groups (Table 1) . Karnofsky performance status (KPS) of 90-100 and 70-80 were seen in 40% and 53% of patients with VRE-C compared to 47% and 48% of VRE-NC patients (p=0.12). Overall, VRE-BSI episodes were rare (n=7) with 4 patients in VRE-C (6.1%) and 3 patients in VRE-NC (0.4 %); p At a median follow-up duration of 19.4 months (range: 2.7-48.4), similar 1-year OS was achieved in both groups (67.4% in VRE-C and 76.5% in VRE-NC; p=0.11) but 1 year PFS was significantly lower in the VRE-C cohort (55.6% Vs. 69.4%; p=0.038). Higher NRM was achieved in the VRE-C cohorts on days +100 and +365 (11.8% Vs. 7.2% and 25.1% Vs. 14.4%, respectively, p=0.041). (Figure 1) There were no differences in rates of day 100 aGVHD (grades II-IV) (Figure 2) and relapse rates at 12 months between the two groups. Conditioning regimen intensity, donor type, KPS, and primary diagnosis were significantly associated with NRM. When these variables were included in the multivariate model, VRE-C was found to be independently associated with higher NRM (HR=1.82, 95%CI: 1.12-2.93; p=0.015). In conclusion, in our cohort of patients receiving predominantly T/S-based aGVHD prophylaxis, no association was detected between VRE-C and aGVHD incidence. Higher rate of VRE-BSI in the VRE-C group is in accordance with published data, albeit lower rates of VRE-BSI was seen in our cohort. VRE-C contributed to higher NRM at days 100 and 365 post-aHCT and was an independent risk factor for poor HCT outcomes Since VRE-C is a potentially modifiable risk factor, our data supports continued efforts for specific interventional strategies (i.e. antimicrobial stewardship) to reduce drug resistant bacterial colonization, and for clinical research to reverse the impact of VRE-C, such as the use of agents, which may modulate gut microbiome. Disclosures Salhotra: Kadmon Corporation, LLC: Consultancy. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Stein:Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Dadwal:AiCuris: Research Funding; Gilead: Research Funding; MERK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Research Funding.

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, Conclusions: Preliminary data of AMG 330 dosed up to 480 μg/d provide encouraging early evidence of tolerability and anti-leukemic activity in heavily pre-treated patients with R/R AML. Expected CRS was mitigated through step-up dosing, corticosteroid pretreatment, IV fluids, tocilizumab, and drug interruption if needed; most patients had short periods of CRS which responded well to treatment. A 2-step approach will be used in the future to quickly achieve the target dose and optimize clinical response. Regarding pharmacodynamics, to date, 2 CRs and 2 CRis have been observed at target doses of 120 and 240 μg/d. As nearly all patients were substantially cytopenic at baseline, it is challenging to evaluate the impact of AMG 330 on cytopenias. Of note, both CR patients had a complete recovery of blood counts after one cycle of treatment. These promising data validate the use of the BiTE® platform to target CD33. Figure Figure. Disclosures Ravandi: Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Xencor: Research Funding; Jazz: Honoraria; Orsenix: Honoraria; Xencor: Research Funding; Jazz: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Orsenix: Honoraria; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau. Stein:Celgene: Speakers Bureau; Amgen: Speakers Bureau. Walter:Amphivena Therapeutics: Consultancy, Equity Ownership, Other: Clinical trial support, Research Funding; Aptevo Therapeutic: 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; Boehringer Ingelheim Pharma GmbH & Co. KG: Consultancy; Pfizer: Consultancy; Amgen Inc.: Other: Clinical trial support, Research Funding; Actinium Pharmaceuticals, Inc.: Other: Clinical trial support, Research Funding. Paschka:Amgen: Other: Travel support; Jazz: Speakers Bureau; Bristol-Meyers Squibb: Other: Travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Travel support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Travel support; Astex: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Travel support. Ossenkoppele:Celgene: Honoraria, Research Funding; Roche: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Karyopharm: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Genmab: Research Funding; Johnson & Johnson: Consultancy, Honoraria, Research Funding. Yang:Amgen Inc.: Employment, Equity Ownership. Mehta:Amgen Inc.: Employment, Equity Ownership. Subklewe:Roche: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Introduction: Blinatumomab, a CD19/CD3 bi-specific T-cell engager monoclonal antibody that re-directs CD3-positive T cells towards CD19-positive B cells, has shown promise in the treatment of R/R B-cell precursor acute lymphoblastic leukemia (B-ALL), with superior survival rates compared to salvage chemotherapy. However, many patients do not respond or subsequently relapse, and the mechanisms underlying resistance are unclear. The goals of this study were to characterize the genomic features associated with response to blinatumomab. Methods: We studied 29 patients (pts; median age 28, range 18-70) with R/R B-ALL who were treated with up to 5 cycles of blinatumomab, and predominantly of Hispanic ancestry (66%). Overall, 17 pts (59%) achieved remission with blinatumomab whilst 12 showed no response. Among the 17 responders, 7 (41%) subsequently relapsed or progressed during treatment. We analyzed leukemic blasts obtained before and after blinatumomab treatment whenever available: pre-blinatumomab R/R (n=28), post-blinatumomab refractory (n=5), post-blinatumomab relapsed (n=3) (Figure 1). Leukemia and matched remission samples were studied using transcriptome sequencing (n=34), whole genome sequencing (n=28), whole exome sequencing (n=19) and Infinium Omni2.5Exome-8 (SNP array, n=19). Results: Seventeen of 29 pts (59%) were Ph-like ALL. Twelve of 17 Ph-like ALL pts had high CRLF2 expression, among these we identified P2RY8-CRLF2 (n=4) and IGH-CRLF2 (n=8). Within the remaining 5 Ph-like ALL cases, two pts harbored NUP214-ABL1, two IGH-EPOR and one TERF-JAK2. Fifteen of the 17 (88%) Ph-like ALL cases were of Hispanic ancestry. The prevalence of other known subtypes was relatively low: BCR-ABL1 7%, hypodiploid 7%, KMT2A 3%, TCF3-PBX1 3% and B-other 21%. We observed a high response rate of 83.3% (10/12 cases) in Ph-like_CRLF2 pts, whilst the frequency of response was 60% (3/5, including two IGH-EPOR) for Ph-like_non-CRLF2 pts, and 33% (4/12) for the other subtypes (Ph-like ALL vs. others, P=0.029) (Figure 1). Unsupervised hierarchical clustering of pre-blinatumomab samples identified 3 clusters based on response to blinatumomab: cluster 1 contained non-responders, clusters 2 and 3 were largely made up of responders. By gene expression profiling using CIBERSORT we found reduced infiltration of cytotoxic CD8+ T-cells in cluster 1 compared to clusters 2 and 3 (6.1% vs. 14.9%, P=0.014), which was inversely correlated with the presence of CD4+ T cells (17.9% vs. 11.5%). GSEA showed enrichment for the IFNγ response, JAK-STAT signaling, chemokine and cytokine signaling in responders. In non-responders, differential gene expression analysis identified up-regulation of the H3K4 demethylase KDM5B, an oncogene associated with progression and chemoresistance of glioma and neuroblastoma. We observed a high frequency of alterations affecting B-lymphoid development (IKZF1, PAX5 and EBF1) in the pre-blinatumomab samples (20 of 22, 91%), which were maintained during progression or relapse. The frequency of B-lymphoid alterations did not differ significantly between responders and non-responders (13 of 14, 93% vs. 7 of 8, 88%). Alterations affecting the cell cycle (CDKN2A/B, TP53, RB1) were observed at a high frequency in pre-blinatumomab samples (15 of 22, 68%), with CDKN2A/B deletions enriched in responders compared to non-responders (11 of 14, 79% vs. 2 of 8, 25%; P=0.026). We also observed a high prevalence of alterations affecting epigenetic modifiers (ARID1B, CREBBP, KDM6A, KMT2D, TRRAP, SMARCA4) in pre-blinatumomab samples (17 of 22, 77%), with no difference between responders and non-responders (10 of 14, 71% vs. 7 of 8, 88%; P=0.61). Of the post-blinatumomab R/R samples available for study (n=8), CD19 expression was negative (n=1), dim (n=2) or positive (n=5). In contrast to previous reports of CD19 escape in CAR T-cell treated patients, there was no evidence of aberrantly spliced CD19 mRNA species, CD19 mutation or deletion in the three negative/dim cases. Conclusion: We show that a heightened immune response through the infiltration of cytotoxic T-cells and activation of IFNγ and JAK-STAT signaling in leukemic cells is an important determinant of response to blinatumomab. Importantly, blinatumomab is a valid therapeutic approach for patients harboring high-risk CRLF2 and EPOR-rearrangements. CD19 escape is not associated with genetic alterations at the CD19 locus. Figure. Figure. Disclosures Stein: Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau. Mullighan:Loxo Oncology: Research Funding; Cancer Prevention and Research Institute of Texas: Consultancy; Amgen: Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Abbvie: Research Funding. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

BACKGROUND: Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) are observed in approximately 4% of patients with myelodysplastic syndrome (MDS) and have been linked with increased transformation to acute myeloid leukemia. Ivosidenib (AG-120), an oral, potent, targeted, small-molecule inhibitor of the mutant IDH1 protein (mIDH1), is a therapeutic candidate for the treatment of patients with mIDH1 MDS. Through inhibition of mIDH1, ivosidenib suppresses the production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To report safety and efficacy data from patients with relapsed or refractory (R/R) MDS enrolled in the first-in-human, phase 1, dose escalation and expansion study of ivosidenib in patients with mIDH1 advanced hematologic malignancies (NCT02074839). METHODS: This ongoing study is evaluating the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib. Trial enrollment was completed on 08May2017. In dose escalation, patients received single-agent ivosidenib orally once daily (QD) or twice daily in 28-day cycles. The MTD was not reached and 500 mg QD was selected as the dose to be tested in expansion. Expansion Arm 3 enrolled patients with mIDH1 advanced hematologic malignancies, including MDS. The overall response rate (ORR) for MDS was defined as complete remission (CR) + partial remission + marrow CR. Exploratory biomarker assessments included baseline co-occurring mutations (next-generation sequencing panel for hematologic malignancies) and mIDH1 variant allele frequency (VAF) in bone marrow mononuclear cells (BEAMing Digital PCR; lower limit of detection for mIDH1, 0.02-0.04%). Here, we present safety and efficacy data for patients with MDS in expansion Arm 3 and in dose escalation whose starting dose was 500 mg QD. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) received ivosidenib, including 12 patients with MDS (9 from expansion and 3 from escalation) whose starting dose was 500 mg QD. Baseline characteristics for these 12 patients were: 9 men/3 women; median age, 72.5 years (range, 52-78) and 42% were ≥75 years of age; median number of prior therapies, 1 (range, 1-3). As of 10Nov2017, 7 of 12 (58.3%) patients remained on treatment and 5 (41.7%) had discontinued (one for allogeneic stem cell transplantation). The median duration of exposure to ivosidenib was 11.0 months (range, 3.3-31.1). The most common adverse events (AEs) of any grade, irrespective of causality, occurring in ≥20% of the 12 patients were back pain (n=4, 33.3%) and anemia, decreased appetite, diarrhea, dyspnea, fatigue, hypokalemia, pruritus, and rash (n=3, 25.0% each). The majority of these AEs were grade 1-2 and reported as unrelated to treatment. No AEs led to permanent discontinuation of treatment. IDH differentiation syndrome (IDH-DS) was observed in 2 of 12 (16.7%) patients; the events were grade 1 and 2, respectively. Of the 12 patients with MDS receiving ivosidenib 500 mg QD, 5 achieved CR (41.7%; 95% CI 15.2%, 72.3%) and 6 achieved marrow CR (50.0%), resulting in an ORR of 91.7% (95% CI 61.5%, 99.8%). The median durations of CR and overall response were not estimable at the time of the data cutoff. The percentages of patients who remained in CR and response at 12 months were 60.0% and 61.4%, respectively. Among 5 patients who were transfusion dependent at baseline, 4 became transfusion independent for at least 56 days on treatment. Baseline co-occurring mutations and changes in mIDH1 VAF levels on ivosidenib therapy will be presented. CONCLUSION: In patients with mIDH1 R/R MDS, ivosidenib monotherapy was well tolerated and induced durable remissions and transfusion independence. These findings support the role of ivosidenib as an effective, oral, targeted treatment for patients with mIDH1 R/R MDS. Disclosures DiNardo: Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Watts:Jazz Pharma: Consultancy, Speakers Bureau; Takeda: Research Funding. Stein:Celgene: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Bayer: Consultancy. de Botton:Agios: Research Funding; Celgene: Honoraria, Research Funding. Fathi:Takeda: Consultancy, Honoraria; Jazz: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Astellas: Honoraria; Seattle Genetics: Consultancy, Honoraria; Agios: Honoraria, Research Funding. Stein:Amgen: Speakers Bureau; Celgene: Speakers Bureau. Foran:Agios: Research Funding; Xencor, Inc.: Research Funding. Stone:AbbVie: Consultancy; Agios: Consultancy, Research Funding; Cornerstone: Consultancy; Orsenix: Consultancy; Fujifilm: Consultancy; Sumitomo: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Ono: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Consultancy; Jazz: Consultancy; Merck: Consultancy; Astellas: Consultancy; Arog: Consultancy, Research Funding; Argenx: Other: Data and Safety Monitoring Board; Amgen: Consultancy. Patel:France Foundation: Honoraria; Dava Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tallman:Cellerant: Research Funding; BioSight: Other: Advisory board; ADC Therapeutics: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; AROG: Research Funding; Orsenix: Other: Advisory board. Choe:Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership. Dai:Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Kapsalis:Agios: Employment, Equity Ownership. Hickman:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership, Patents & Royalties. Attar:Agios: Employment, Equity Ownership.

BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) mutations are seen in 6-10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120), an oral, potent, targeted inhibitor of the mutant IDH1 protein (mIDH1), is a therapeutic candidate for mIDH1 AML. Ivosidenib suppresses production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To determine the safety and efficacy of single-agent ivosidenib in patients with untreated AML enrolled in the first-in-human, phase 1, dose escalation and expansion study of patients with mIDH1 advanced hematologic malignancies (NCT02074839). METHODS: This ongoing study assesses the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib. Enrollment completed on 08May2017. In dose escalation, patients received single-agent ivosidenib orally once daily (QD) or twice daily in 28-day cycles. MTD was not reached; 500 mg QD was selected as the dose for expansion cohorts. Overall response rate (ORR) was defined as complete remission (CR) + CR with incomplete hematologic or platelet recovery + partial response + morphologic leukemia-free state. CR with partial hematologic recovery (CRh) was defined as CR except absolute neutrophil count >0.5 × 109/L [500/µL] and platelet count >50 × 109/L [50,000/µL]). Exploratory biomarker assessments included baseline co-occurring mutations (next-generation sequencing panel for hematologic malignancies) and mIDH1 variant allele frequency (VAF) in bone marrow mononuclear cells (BEAMing Digital PCR; lower limit of detection for mIDH1, 0.02-0.04%). Here, we present data for all patients with untreated AML whose starting dose was 500 mg QD. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) received ivosidenib, including 34 patients with untreated AML (9 from dose escalation, 25 from expansion) who received ivosidenib 500 mg QD. Baseline characteristics for these 34 patients were: 19 male/15 female with median age 76.5 years (range 64-87); 56% were ≥75 years of age; 79% had secondary AML and 53% had prior MDS; 41% had ≥1 hypomethylating agent for antecedent hematologic disorder. As of 10Nov2017, 9 of 34 (26.5%) patients remained on treatment. Three (8.8%) patients discontinued treatment for allogeneic stem cell transplantation. Median duration of exposure to ivosidenib was 4.3 months (range 0.3-29.1). Treatment was well tolerated; the most common adverse events (AEs) (n=34) of any grade, irrespective of causality, occurring in ≥20% of patients were diarrhea (50.0%), fatigue (44.1%), nausea (38.2%), decreased appetite (32.4%), leukocytosis (26.5%), anemia (26.5%), peripheral edema (26.5%), dyspnea (23.5%), thrombocytopenia (23.5%), hypomagnesemia (23.5%), constipation (20.6%), dizziness (20.6%), and insomnia (20.6%). The majority of AEs were grade 1-2 and reported as unrelated to treatment. IDH differentiation syndrome (IDH-DS) was seen in 6 of 34 (17.6%) patients, and was grade ≥3 in 3 (8.8%); ivosidenib was held due to IDH-DS in 3 patients (8.8%), but IDH-DS did not lead to permanent treatment discontinuation or death. CR rate was 26.5% (95% CI 12.9%, 44.4%), CR+CRh rate was 41.2% (95% CI 24.6%, 59.3%), and ORR 58.8% (95% CI 40.7%, 75.4%; 20/34 patients). Median durations of CR, CR+CRh, and overall response were not estimable (lower bound of 95% CI 4.2, 6.5, and 4.2 months, respectively); 12-month durations of response were 75.0%, 56.4%, and 54.3%, respectively. Of patients who were transfusion dependent at baseline, 38.1% became transfusion independent for ≥56 consecutive days on treatment. Longitudinal mIDH1 VAF data were available for 23 patients with untreated AML in expansion: IDH1 mutation clearance was seen in 6 of 11 patients who achieved CR+CRh, including 3 of 7 patients with CR and 3 of 4 with CRh. The relationship between baseline co-occurring mutations and response will be presented. CONCLUSION: Ivosidenib monotherapy was well tolerated in patients with untreated mIDH1 AML, and induced durable remissions and transfusion independence in a molecularly defined, poor prognosis, elderly patient population with high rates of secondary AML, and prior hypomethylating agent exposure. These results support the role of ivosidenib as an effective, oral, targeted treatment for patients with untreated mIDH1 AML who are not eligible for intensive chemotherapy. Disclosures Roboz: Argenx: Consultancy; Orsenix: Consultancy; Jazz Pharmaceuticals: Consultancy; Cellectis: Research Funding; Sandoz: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; Celgene Corporation: Consultancy; Bayer: Consultancy; Otsuka: Consultancy; Novartis: Consultancy; Orsenix: Consultancy; Pfizer: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; Otsuka: Consultancy; Novartis: Consultancy; Eisai: Consultancy; AbbVie: Consultancy; Celltrion: Consultancy; Astex Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Cellectis: Research Funding; Janssen Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Roche/Genentech: Consultancy; Astex Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Sandoz: Consultancy; Eisai: Consultancy; Argenx: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy; Aphivena Therapeutics: Consultancy. DiNardo:Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Stein:Agios: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. de Botton:Agios: Research Funding; Celgene: Honoraria, Research Funding. Mims:Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Altman:Pfizer: Other: payment to the institution to conduct clinical trial work; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: payment to the institution to conduct clinical trial work; Agios: Other: Payment to the institution to conduct the trial ; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bayer: Other: payment to the institution to conduct clinical trial work; GSK: Other: payment to the institution to conduct clinical trial work; Epizyme: Other: payment to the institution to conduct clinical trial work; Ariad: Other: payment to the institution to conduct clinical trial work; Boeringer Ingelheim: Other: payment to the institution to conduct clinical trial work; Immune Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Incyte: Other: payment to the institution to conduct clinical trial work; Astellas Pharma: Other; FujiFilm: Other: payment to the institution to conduct clinical trial work; Syros: Membership on an entity's Board of Directors or advisory committees; Cyclacel: Other: payment to the institution to conduct clinical trial work; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celator: Other: payment to the institution to conduct clinical trial work; Genetech: Other: Payment to the institution to conduct clinical trial work. Arellano:Cephalon: Research Funding. Mannis:Agios: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; NKarta: Membership on an entity's Board of Directors or advisory committees. Pollyea:Gilead: Consultancy; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Curis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stein:Celgene: Speakers Bureau; Amgen: Speakers Bureau. Uy:GlycoMimetics: Consultancy; Curis: Consultancy. Watts:Jazz Pharma: Consultancy, Speakers Bureau; Takeda: Research Funding. Fathi:Astellas: Honoraria; Seattle Genetics: Consultancy, Honoraria; Boston Biomedical: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Takeda: Consultancy, Honoraria; Agios: Honoraria, Research Funding. Kantarjian:Orsenix: Honoraria; Novartis: Research Funding; Immunogen: Honoraria; BMS: Honoraria, Research Funding; Astex: Research Funding; ARIAD: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria; AbbVie: Honoraria; Pfizer: Honoraria, Research Funding. Tallman:AbbVie: Research Funding; BioSight: Other: Advisory board; AROG: Research Funding; Daiichi-Sankyo: Other: Advisory board; Orsenix: Other: Advisory board; ADC Therapeutics: Research Funding; Cellerant: Research Funding. Choe:Agios: Employment, Equity Ownership. Dai:Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Kapsalis:Agios: Employment, Equity Ownership. Hickman:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership, Patents & Royalties. Attar:Agios: Employment, Equity Ownership. Stone:Merck: Consultancy; Cornerstone: Consultancy; AbbVie: Consultancy; Orsenix: Consultancy; Ono: Consultancy; Fujifilm: Consultancy; Otsuka: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Jazz: Consultancy; Astellas: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Arog: Consultancy, Research Funding; Sumitomo: Consultancy; Novartis: Consultancy, Research Funding; Amgen: Consultancy; Agios: Consultancy, Research Funding; Pfizer: Consultancy.

The Philadelphia (Ph) chromosome or t(9;22) results in the generation of a fusion gene, namely BCR/ABL1, which encodes a chimeric protein with aberrant tyrosine kinase activity that drives leukemia cell growth and survival. This molecular/cytogenetic aberration occurs in ~20%-30% of ALL cases and confers poor prognosis. Ph+ ALL patients (pts) are often referred for allogeneic hematopoietic stem cell transplantation (alloHCT), although more recently BCR-ABL-specific tyrosine-kinase inhibitors (TKIs) and immunotherapeutic approaches seemingly induced long-term remission in some patients. Nevertheless, it is still a challenge to determine which Ph+ ALL of the pts could be treated more conservatively without alloHCT. Thus identification of new prognostic biomarkers and/or therapeutic targets may be helpful. Regulation of short non-coding microRNAs(miRNAs) associated with initiation and progression of acute leukemia has been reported. miR-142(both miR-142-3p and miR-142-5p) is expressed at a relatively high level in hematopoietic tissue, and plays a role in myeloid lineage differentiation. In fact, low miR-142-3p expression was associated with myeloid differentiation failure, and miR-142 mutations was reported to promote acute myeloid leukemia (AML). More recently, Kramer et al demonstrated a role of miR-142 in lymphopoiesis by showing that miR-142 deficiency impaired B cell production in a miR-142 knock-out(ko) mouse model (Blood. 2015). Here, we first investigated if miR-142 levels were altered in ALL pts. Analysis of a publically available miRNA expression dataset(GSE23024) showed lower level of miR-142-3p, but not miR-142-5p in Ph+ ALL pts(n=10) vs. healthy donors(n=7;p=0.0093); while no significant differences were observed in Ph- pre-B ALL pts(n=61) vs. healthy donors (n=7). In ALL Tg(P190-BCR/ABL) transgenic mice(Ph+ ALL; Nature. 1990), we found bone marrow (BM) miR-142-3p level to be ~2.3-fold lower than those in the wild-type (wt) controls(p=0.036). Compared to wt mice, Ph+ ALL mice showed significantly lower miR-142-3p level in all the immunophenotypically identified BM lymphoid subpopulations, including progenitor B (pro-B, B220+CD19+CD43+IgM-,~19.1-fold lower,p Disclosures Stein: Celgene: Speakers Bureau; Amgen Inc.: Speakers Bureau. Jin:The National Natural Science Foundation of China: Research Funding; College of Medicine, Zhejiang University: Employment.

Background: In the phase 3 TOWER study, patients with relapsed or refractory (r/r) Philadelphia chromosome-negative (Ph-) B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) who received bispecific T-cell engager (BiTE®) antibody construct blinatumomab had improved overall survival (OS; median, 7.7 vs 4.0 months; P=0.01;) and health-related quality of life (HRQoL) compared with those who received standard of care (SOC) chemotherapy (Kantarjian H, et al. N Engl J Med. 2017;376:836-847; Topp MS, et al. Blood. 2018;131:2906-2914). In this subgroup analysis of TOWER, we assessed the HRQoL between patients with low versus high baseline disease burden (low versus high bone marrow blast levels) who received blinatumomab or SOC chemotherapy. Methods: Patients (N=405) with r/r Ph- BCP ALL were randomized 2:1 to receive 2 cycles of induction blinatumomab by continuous intravenous infusion (n=271) or SOC (n=134). Those in remission could receive up to 3 consolidation cycles; 12 months of maintenance was allowed for those who received up to 3 consolidation cycles and had bone marrow response. HRQoL was assessed using the EORTC QLQ-C30 Questionnaire on days 1 (baseline), 8, and 15; on day 29 of cycle 1; days 1, 15, and 29 of consolidation; and at the safety follow-up. The questionnaire included 1 global health status scale, 5 functioning scales, 3 symptom scales, and 6 single-symptom items. For global health status and functioning scales, a higher score indicates better HRQoL; for symptom scales/items, a lower score indicates better HRQoL. A 10-point change was viewed as the minimum clinically important difference in EORTC QLQ-C30 (Zikos E, et al. EORTC. 2016). HRQoL was assessed in patient subgroups by screening the bone marrow aspirates for low blast levels ( Results: In total, 342 patients (blinatumomab, n=247; SOC, n=95) had ≥1 HRQoL result: low blasts, n=87 (blinatumomab, n=64; SOC, n=23); high blasts, n=255 (blinatumomab, n=183; SOC, n=72). The EORTC QLQ-C30 analysis set included all randomized subjects with a nonmissing baseline result and at least 1 nonmissing post-baseline result of any EORTC QLQ-C30 scale/item. There was no statistically significant difference in baseline HRQoL scores between the high and low blasts groups; however, the high blasts group had worse HRQoL overall. Baseline HRQoL scores were also similar between blinatumomab arm and SOC arm for each group. Global health status was improved by blinatumomab regardless of baseline blast level; however, this effect was somewhat greater in the low blasts group. When the function scores worsened, the extent of worsening was almost always smaller for blinatumomab versus SOC, particularly in the high blasts group. Functioning status scores tended to stay the same or worsen with both blinatumomab and SOC regardless of blast level, except emotional scores, which improved with blinatumomab regardless of blast level (Figure 1). Symptom scores generally improved with blinatumomab but not with SOC, particularly in patients with high blasts (Figure 2). TTD analyses showed that hazard ratios favored blinatumomab over SOC, particularly in patients with high blasts (Table). Conclusions: Blinatumomab improved HRQoL in patients with r/r Ph- BCP ALL and delayed the time to clinically meaningful deterioration in HRQoL compared with SOC. The treatment effects of blinatumomab versus SOC on HRQoL were particularly larger among patients with high disease burden. Disclosures Stein: Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau. Zimmerman:Amgen Inc.: Employment, Equity Ownership. Dombret:Novartis: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; Ambit (Daiichi Sankyo): Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria, Other: Travel expenses; Celgene: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Immunogen: Consultancy, Honoraria; Shire-Baxalta: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharma: Consultancy, Honoraria, Research Funding; Ariad (Incyte): Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Roche/Genentech: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau. Topp:F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Boehringer Ingelheim: Research Funding. Franklin:Amgen Inc.: Employment, Equity Ownership. Cong:Amgen, Inc.: Employment, Equity Ownership. Zhang:Amgen Inc.: Employment, Equity Ownership. Schuh:Pfizer: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Teva: Consultancy; Amgen Inc.: Consultancy; Otsuka: Consultancy; Jazz: Consultancy; Shire: Consultancy.

The combination of venetoclax and hypomethylating agents (HMA) has demonstrated potent activity in acute myeloid leukemia (AML), both in newly diagnosed patients (pts) and those with relapsed/refractory (r/r) disease. We analyzed the association between response to therapy and leukemic somatic mutations, cytogenetics, and other pertinent patient- and leukemia-related features in a large series of newly diagnosed and r/r AML in adults treated with venetoclax in combination with HMA at City of Hope between October 2016 and May 2018. We identified 107 evaluable adults with AML treated with the combination of venetoclax and HMA. Sixty-one (57%) pts had r/r AML at the time of initiating treatment (median prior lines of therapy: 2; range: 1-10), while 46 (43%) were treated in the frontline setting. The median age of pts was 68 years (range: 19-86). AML was de novo in 57 (53%), therapy-related in 23 (21%) and secondary in 27 (25%) pts. Thirty-six (34%) pts had prior exposure to HMA, and 21 (20%) pts had relapsed following prior allogeneic hematopoietic cell transplantation (HCT). The majority of treated pts had unfavorable (52%) or intermediate-risk (39%) AML based on combined cytogenetics and molecular profiles. The most common detected somatic mutations (majority by next generation sequencing) were FLT3 (17%), followed by DNMT3A (15%), RAS and TET2 (each 14%), RUNX1 (13%), TP53 (12%), and IDH1/2 (11%). Most pts received decitabine in combination with venetoclax (N=97, 91%); only 10 (9%) pts received 5-azacitidine together with venetoclax. Complete remission (CR)/CR with incomplete hematologic recovery (CRi) was achieved in 57 (53%) pts after a median of 2 (range 1-4) cycles. For 36 pts who achieved CR/CRi and had available minimal residual disease (MRD) assessment by multicolor flow cytometry (MFC), 23 (64%) became MRD-. CR/CRi was higher in pts carrying favorable- or intermediate-risk AML compared to poor-risk AML (100% vs. 60% vs. 45%, P=0.029). CR/CRi was 48% in those with complex cytogenetics (N = 31), 45% in monosomal karyotype (N = 22), 36% in KMT2A gene rearrangement (N = 11), 74% in normal karyotype (N = 19), and 25% in inversion 3 (N =4). The CR/CRi rate was not significantly different between newly diagnosed or r/r AML (61% vs. 48%, P = 0.17), nor was there a difference associated with AML type (de novo vs. therapy-related vs. secondary, P= 0.26), patient age (> or ≤ 65 years) at time of therapy (P = 0.13), prior allogeneic HCT (P = 0.29), prior administration of HMA (P = 0.37) and the type or schedule (5- or 10-day decitabine) of HMA (P = 0.52). In multivariate analysis, only favorable- or intermediate-risk cytogenetics was associated with better CR/CRi (P = 0.036). CR/CRi was also comparable regardless of the presence or absence of various analyzed somatic AML mutations. However, in recursive partitioning analysis of detectable somatic mutations and response to therapy, the combined lack of RAS, TP53 and RUNX1 mutations was linked to an improved rate of CR/CRi. When AML cases were stratified into functional gene alteration subgroups (according to the TCGA data set), there was no significant difference in CR/CRi according to the presence or absence of certain functional genes/fusions. Median overall survival (OS) for all pts was 12.5 months and was 14.6 months for pts who achieved CR/CRi, in contrast to 4.6 months for non-responders (P We report remarkable activity with venetoclax and HMA across various high-risk genetics and clinical features in AML patients. Prospective studies are warranted to compare this combination directly with chemotherapy in all AML subsets. This is particularly true for high risk AML where response to conventional chemotherapy is poor. Disclosures Ali: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Salhotra:Kadmon Corporation, LLC: Consultancy. Khaled:Alexion: Consultancy, Speakers Bureau; Juno: Other: Travel Funding; Daiichi: Consultancy. Stein:Celgene: Speakers Bureau; Amgen Inc.: Speakers Bureau. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

7042Background: Ivosidenib (IVO; AG-120) and enasidenib (ENA; AG-221) are oral inhibitors of mIDH1 and mIDH2 proteins. In vitro, mIDH inhibitor + AZA combinations enhance cell differentiation and a...

7044Background: In BCP-ALL, blinatumomab has demonstrated efficacy in two phase 2 trials: MT 103 -203 (Gokbuget et al, Blood 2017) in minimal residual disease (MRD) and MT 102 – 211 in relapsed/ref...

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. Disclosures Stein: Pfizer: Consultancy, Other: Travel expenses; GSK: Other: Advisory Board, Research Funding; Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; Constellation Pharma: Research Funding; Seattle Genetics: Research Funding; Celgene Corporation: Consultancy, Other: Travel expenses, Research Funding; Novartis: Consultancy, Research Funding. DiNardo: AbbVie: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Mims: Novartis: Honoraria. Savona: Amgen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Equity Ownership; Incyte Corporation: Consultancy, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stein: Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy. Fathi: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medimmune: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Stone: Amgen: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Agios: Consultancy; Ono: Consultancy; Astellas: Consultancy; Arog: Consultancy; Jazz: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Fuji Film: Consultancy; Sumitomo: Consultancy. Pollyea: Agios, Pfizer: Research Funding; Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis: Membership on an entity's Board of Directors or advisory committees. Odenike: Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; CTI/Baxalta: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Döhner: Agios: Honoraria; Seattle Genetics: Honoraria; Arog Pharmaceuticals: Honoraria, Research Funding; Celator: Honoraria; Amgen: Honoraria; Abbvie: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Sunesis: Honoraria; Pfizer: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Research Funding; Astex Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schiller: Celator/Jazz: Research Funding. Gupta: Celgene: Employment, Equity Ownership. Nabhan: Agios: Employment, Equity Ownership. Zhang: Agios: Employment, Equity Ownership. Almon: Agios: Employment, Equity Ownership. Cooper: Agios: Employment, Equity Ownership.

Background: Enasidenib (AG-221) is an oral, selective inhibitor of mIDH2 proteins. Results from the AG221-C-001 phase 1/2 dose-escalation and expansion study of enasidenib monotherapy showed an overall response rate (ORR) of 40.3% and median overall survival (OS) of 9.3 months in patients with m IDH2 relapsed or refractory (R/R) AML (Stein, Blood, 2017). Like patients with R/R AML, older patients with untreated AML who are not candidates for standard induction therapy due to advanced age, poor performance status, comorbidities, poor-risk cytogenetics, or other factors, pose a therapeutic challenge. Treatment options for these patients are limited and outcomes are poor. Reported here are clinical outcomes for older patients with previously untreated m IDH 2 AML who received enasidenib monotherapy in the AG221-C-001 study (NCT01915498). Methods: The phase 1 dose-escalation and expansion portions of the study included patients aged ≥ 60 years with previously untreated AML who were not candidates for standard treatment and had ECOG PS scores of 0-2. Patients in the dose-escalation phase received enasidenib doses of 50-650 mg/day, and all patients in the expansion phase received enasidenib 100 mg/day, in continuous 28-day treatment cycles. ORR included complete remission (CR), CR with incomplete count recovery (CRi/CRp), partial remission (PR), and morphologic leukemia-free state (MLFS), per modified IWG 2003 response criteria for AML. OS was defined as the time from first dose to death from any cause. Event-free survival (EFS) was defined as the time from first dose to relapse, progressive disease (PD), or death, whichever came first. Safety was assessed by treatment-emergent adverse event (TEAE) reporting and TEAEs were graded for severity per CTCAE version 4.0. Results: Of 239 patients in the phase 1 dose-escalation and study expansion, 37 patients (15.5%) had previously untreated m IDH2 AML. At data cutoff (14 Oct 2016), 4 patients with previously untreated AML (11%) remained on-study: 3 patients in CR, and 1 patient with stable disease at cycle 13. Median age was 77 years (range 58-87); 62% of patients were aged ≥ 75 years (Table 1). Median number of enasidenib treatment cycles was 6 (range 1-23) and median follow-up was 7.9 months (range 0.5-23.7). Seven patients (19%) attained CR, with a median time to CR of 5.6 months (range 3.4-12.9) (Table 2). ORR was 37.8% (95%CI 22.5, 55.2). The median duration of CR was not reached (NR) (95%CI 3.7, NR) and median duration of any response was 12.2 months (2.9, NR) (Table 2). Three patients proceeded to transplant; at data cutoff, all 3 patients remained in remission. Among all 37 patients, median OS was 10.4 months (95%CI 5.7, 15.1) and median EFS was 11.3 months (3.9, NR). Median OS for responding patients (n=14) was 19.8 months (95%CI 10.4, NR) and for non-responders was 5.4 months (2.8, 12.4). The most frequent TEAEs (any grade or cause) were fatigue (43%), nausea (41%), and decreased appetite (41%). The most frequent treatment-related TEAEs were hyperbilirubinemia (30%) and nausea (22%) (Table 3). The only serious treatment-related TEAEs reported for more than 1 patient were IDH differentiation syndrome (n=3, 8%) and tumor lysis syndrome (n=2, 5%). Treatment-related TEAEs led to dose modification for 3 patients (8%), dose interruption for 7 patients (19%), and treatment discontinuation for 1 patient (3%). Conclusions: Enasidenib induced hematologic responses in these older patients with previously untreated m IDH2 AML who were not candidates for standard treatment. Approximately 1 in 5 of these patients attained CR and 1 in 3 patients had a response with enasidenib monotherapy. Responses were durable: at a median of 7.9 months of follow-up, median CR duration was not reached and median duration of any response was > 1 year. Median OS and EFS were also promising (10.4 months and 11.3 months, respectively). Rates of treatment-related TEAEs were low and only 1 patient discontinued treatment due to a TEAE. These results suggest enasidenib may benefit older adults with m IDH2 AML who are not fit to receive cytotoxic chemotherapy. These encouraging findings have prompted follow-up studies of enasidenib in older patients with previously untreated m IDH2 AML, such as the Beat AML Master Trial (NCT03013998). Disclosures Pollyea: Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis: Membership on an entity's Board of Directors or advisory committees; Agios, Pfizer: Research Funding. De Botton: Servier: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Agios: Honoraria, Research Funding. DiNardo: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding. Kantarjian: Bristol-Meyers Squibb: Research Funding; Amgen: Research Funding; Novartis: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding; Delta-Fly Pharma: Research Funding. Collins: BMS: Research Funding; Arog: Research Funding; Agios: Research Funding; Celgene Corporation: Research Funding. Stein: Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy. Xu: Celgene Corporation: Employment, Equity Ownership. Tosolini: Celgene Corporation: Employment, Equity Ownership. Gupta: Celgene Corporation: Employment, Equity Ownership. Agresta: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Stein: Seattle Genetics: Research Funding; GSK: Other: Advisory Board, Research Funding; Constellation Pharma: Research Funding; Celgene Corporation: Consultancy, Other: Travel expenses, Research Funding; Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; Pfizer: Consultancy, Other: Travel expenses; Novartis: Consultancy, Research Funding.

BACKGROUND: Recurrent isocitrate dehydrogenase (IDH) 1 mutations are observed in 6-10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120), a potent, selective, oral, small-molecule inhibitor of the mutant IDH1 (mIDH1) protein, is a promising therapeutic candidate for the treatment of patients with mIDH1 AML. Through inhibition of mIDH1, ivosidenib suppresses the abnormal production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To report safety and efficacy data from the first-in-human phase 1 study of ivosidenib in patients with mIDH1 advanced hematologic malignancies including relapsed/refractory (R/R) AML (NCT02074839). This is the first report of data from the 4 expansion cohorts, with a total of 258 patients treated on study. METHODS: The ongoing phase 1 study assesses the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib in mIDH1 hematologic malignancies. Enrollment was completed on May 8, 2017. During dose escalation, patients received ivosidenib as a single agent orally once daily (QD) or twice daily (BID) in 28-day cycles. The MTD was not reached and 500 mg QD was selected as the recommended dose to be tested in 4 expansion cohorts: R/R AML (Arms 1 and 4, where Arm 1 patients are those with relapse after transplantation, second or later relapse, resistance to initial induction or reinduction treatment, or relapse within 1 year of initial treatment, and Arm 4 patients have R/R AML but are not eligible for Arm 1); untreated AML (Arm 2); and other advanced hematologic malignancies including myelodysplastic syndrome (MDS) (Arm 3). Updated safety data will be presented for all patients. Efficacy outcomes will be presented for all R/R AML patients treated at 500 mg QD across the dose escalation and expansion cohorts who received their first dose of ivosidenib at least 6 months prior to the analysis cut-off date of May 12, 2017, as well as for the poorest prognosis Arm 1 subset. Efficacy data for all treated patients from the other expansion cohorts (untreated AML and other advanced hematologic malignancies including MDS) will also be presented. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) were treated with ivosidenib. As of May 12, 2017, 62 of 258 (24%) patients were continuing on treatment. The median duration of exposure to ivosidenib was 3.5 months (range 0.1-33.5). Twenty-two (8.5%) patients discontinued treatment to proceed to allogeneic stem cell transplantation. Treatment was well tolerated; the most common adverse events (AEs) (n=258) of any grade irrespective of causality occurring in ≥20% of patients were diarrhea (33%), leukocytosis (30%), nausea (30%), fatigue (29%), febrile neutropenia (25%), dyspnea (24%), anemia (23%), QT prolongation (23%), peripheral edema (22%), pyrexia (21%), and decreased appetite (20%). The majority of these AEs were grades 1-2 and reported as unrelated to treatment. Differentiation syndrome (DS) was observed in 29 of 258 (11.2%) patients, including grade ≥3 DS in 14 (5.4%); study drug was held owing to DS in 11 patients (4.3%), and no instances of DS led to permanent treatment discontinuation or death. The primary efficacy endpoint for R/R AML is the CR+CRh rate, i.e., the rate of complete remission (CR according to modified IWG 2003 criteria plus CR with partial hematologic recovery, defined as CR except absolute neutrophil count >0.5 × 109/L [500/µL] and platelet count >50 × 109/L [50,000/µL]). Among 125 Arm 1 R/R AML patients receiving ivosidenib 500 mg QD across dose escalation and expansion who received their first dose at least 6 months prior to the analysis cutoff date, the CR+CRh rate was 30.4% (95% CI 22.5%, 39.3%), including CR in 27 (21.6%) and CRh in 11 (8.8%) patients. Median duration of CR+CRh was 8.2 months (95% CI 5.5, 12.0), and duration of CR was 9.3 months (95% CI 5.6, 18.3). The overall response rate (CR+CRi/CRp+PR+MLFS) was 41.6% (95% CI 32.9%, 50.8%) (52/125 patients). CONCLUSION: Ivosidenib monotherapy is well tolerated in patients with mIDH1 AML and other advanced hematologic malignancies. In a high-risk, molecularly defined R/R AML patient population with unmet medical need, ivosidenib induced durable remissions and improved patient outcomes. These findings support the role of ivosidenib as an effective, oral, targeted treatment for patients with mIDH1 AML. Disclosures DiNardo: Celgene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. De Botton: Pfizer: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Servier: Honoraria; Agios: Honoraria, Research Funding. Stein: GSK: Other: Advisory Board, Research Funding; Constellation Pharma: Research Funding; Seattle Genetics: Research Funding; Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; Celgene Corporation: Consultancy, Other: Travel expenses, Research Funding; Pfizer: Consultancy, Other: Travel expenses; Novartis: Consultancy, Research Funding. Roboz: AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy; Cellectis: Research Funding. Mims: Novartis: Honoraria. Pollyea: Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis: Membership on an entity's Board of Directors or advisory committees; Agios, Pfizer: Research Funding. Altman: Syros: Consultancy; NCCN: Other: Educational speaker; BMS: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Ceplene: Consultancy; Janssen Pharmaceuticals: Consultancy; Novartis: Consultancy; ASH: Other: Educational speaker. Collins: Celgene Corporation: Research Funding; Agios: Research Funding; Arog: Research Funding; BMS: Research Funding. Mannis: Curis: Honoraria; Juno: Research Funding; Agios: Research Funding; Amgen: Honoraria. Uy: GlycoMimetics: Consultancy; Novartis: Consultancy, Other: Travel Suppport; Boehringer Ingelheim: Consultancy. Fathi: Juno: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Medimmune: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stein: Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy. Erba: Celgene: Consultancy, Other: Chair, Scientific Steering Committee , Speakers Bureau; Incyte: all research support paid to University of Alabama, Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Daiichi Sankyo: Consultancy, Other: all research support paid to University of Alabama, Research Funding; ImmunoGen: Consultancy, Other: all research support paid to University of Alabama, Research Funding; MacroGen: Consultancy; Ono: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Sunesis: Consultancy; Millennium/Takeda: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Agios: Other: all research support paid to University of Alabama, Research Funding; Juno: Other: all research support paid to University of Alabama, Research Funding; Astellas: Other: all research support paid to University of Alabama, Research Funding; Celator: Other: all research support paid to University of Alabama, Research Funding; Janssen: Other: all research support paid to University of Alabama, Research Funding; Glycomimetics: Other: Chair, Data and Safety Monitoring Committee. Traer: ImmunoGen: Consultancy; Tolero: Consultancy; Notable Labs: Equity Ownership. Stuart: Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Consultancy, Honoraria; Agios: Research Funding; Celator/Jazz: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel Support, Research Funding; Bayer: Research Funding; Novartis: Research Funding; Incyte: Research Funding; ONO: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; MedImmune: Research Funding; Cantex: Research Funding; Astellas: Research Funding. Arellano: Cephalon Oncology: Research Funding. Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees. Yen: Agios: Employment, Equity Ownership. Kapsalis: Agios: Employment, Equity Ownership. Liu: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Goldwasser: Agios: Employment, Equity Ownership. Agresta: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Attar: Agios: Employment, Equity Ownership. Stone: Novartis: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Fuji Film: Consultancy; Jazz: Consultancy; Astellas: Consultancy; Pfizer: Consultancy; Arog: Consultancy; Ono: Consultancy; Agios: Consultancy; Sumitomo: Consultancy. Kantarjian: ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Delta-Fly Pharma: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Novartis: Research Funding.

Background: Enasidenib (AG-221) and ivosidenib (AG-120) are oral, small-molecule inhibitors of mIDH2 and mIDH1proteins, 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 m IDH 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 m IDH leukemia 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 m IDH ND-AML were aged ≥18 years and ineligible for intensive chemotherapy per investigator assessment. Pts with m IDH2 AML received enasidenib in dose-escalation cohorts of 100 or 200 mg QD and pts with m IDH1 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. Disclosures DiNardo: Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding. Stein: Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy. Fathi: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Medimmune: Consultancy, Membership on an entity's Board of Directors or advisory committees. Montesinos: Celgene Corporation: Honoraria, Research Funding. Odenike: Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; CTI/Baxalta: Membership on an entity's Board of Directors or advisory committees. Kantarjian: Bristol-Meyers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Stone: Fuji Film: Consultancy; Ono: Consultancy; Abbvie: Consultancy; Amgen: Consultancy; Agios: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Astellas: Consultancy; Arog: Consultancy; Jazz: Consultancy; Sumitomo: Consultancy. Koralek: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Van Oostendorp: Celgene Corporation: Employment, Equity Ownership. Gong: Celgene Corporation: Employment, Equity Ownership. Gupta: Celgene Corporation: Employment, Equity Ownership. Vyas: Celgene Corporation: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau.

Background Although secondary acute leukemias and myelodysplasia are the known complications of adjuvant chemotherapy for breast cancer, the treatment outcome of these secondary malignancies is presently unclear. We examined the clinical and pathological features as well as the treatment results of a series of patients with acute leukemia/myelodysplasia arising after adjuvant chemotherapy for breast cancer. Patients and methods Patients referred to our institution during a 5-year period for treatment of acute leukemia/myelodysplasia and who had received adjuvant chemotherapy for breast cancer are included. Leukemia-free survival for the whole group and for patients who underwent hematopoietic stem cell transplantation (HSCT) was estimated. Results Fifteen women (14 with acute leukemia and one with myelodysplasia) were identified. Seven of 15 patients had received an anthracycline, cyclophosphamide and a taxane. Ten patients developed acute leukemia/myelodysplasia with a latency period of 2 years or less from initiation of chemotherapy. Although mixed-lineage leukemia (MLL) rearrangement was the commonest chromosomal abnormality (8 of 15 patients), various other chromosomal abnormalities were also detected. Twelve of 15 patients underwent HSCT (11 allogeneic and one autologous). Eleven of these 12 patients who underwent HSCT were in remission at a median follow-up of 20.4 months (range 4.4–53.3 months). Conclusion Durable remissions can be achieved in patients who develop acute leukemia/myelodysplasia secondary to adjuvant chemotherapy for breast cancer and are able to undergo allogeneic HSCT. Our results indicate that HSCT should be an early consideration in the management of such patients who are suitable candidates for the procedure.

Background:Over the years, the prognosis following treatment of a primary cancer has significantly improved. However, the growing population of these cancer survivors has led to the realization of multiple longterm complications secondary to their treatment. One of the most devastating long-term complications is the development of a second malignancy. CaseReports:We report here the case of a 34-year-old man who developed stage IIB node-positive breast cancer almost 15 years following total body irradiation and allogeneic hematopoietic cell transplantation for acute lymphoblastic leukemia. To our knowledge, this is only the second report of a male breast cancer following allogeneic bone marrow transplantation (BMT). Conclusion:Survivors of primary cancer need lifelong monitoring for complications from their initial therapy.

We assessed late mortality in 1479 individuals who had survived 2 or more years after allogeneic hematopoietic cell transplantation (HCT). Median age at HCT was 25.9 years and median length of follow-up was 9.5 years. The conditional survival probability at 15 years from HCT was 80.2% (SE = 1.9%) for those who were disease-free at entry into the cohort, and the relative mortality was 9.9 (95% confidence interval, 8.7-11.2). Relative mortality decreased with time from HCT, but remained significantly elevated at 15 years after HCT (standardized mortality ratio = 2.2). Relapse of primary disease (29%) and chronic graft-versus-host disease (cGVHD: 22%) were the leading causes of premature death. Nonrelapse-related mortality was increased among patients older than 18 years at HCT (18-45 years: relative risk [RR] = 1.7; 46+ years: RR = 3.7) and among those with cGVHD (RR = 2.7), and was lower among patients who received methotrexate for GVHD prophylaxis (RR = 0.5). HCT survivors were more likely to report difficulty in holding jobs (odds ratio [OR] = 13.9), and in obtaining health (OR = 7.1) or life (OR = 9.9) insurance compared with siblings. This study demonstrates that mortality rates remain twice as high as that of the general population among 15-year survivors of HCT, and that the survivors face challenges affecting their health and well-being.

Total body irradiation (TBI) is an important part of bone marrow transplantation conditioning regimens. In TBI, dose escalation is difficult, because of associated normal organ toxicities. A method to deliver a more targeted dose of TBI preferentially to sites of greatest tumor burden is needed to reduce the dose to normal organs, reduce toxicities, and permit dose escalation. The purpose of this study was to evaluate, through a dosimetric analysis, the potential advantages and feasibility of selectively delivering targeted myeloablative doses of radiation to bone and marrow using a recently developed image-guided tomographic intensity-modulated radiation therapy delivery system (helical tomotherapy). Whole-body computed tomography datasets from 3 patients, age 5, 20, and 53 years, were used for treatment planning studies to evaluate 2 targeted TBI strategies: total marrow irradiation (TMI), in which the target region was defined as the skeletal bone, and total marrow and lymphoid irradiation (TMLI), in which the target regions were defined as bone, major lymph node chains, liver, spleen, and sanctuary sites, such as brain. Organ doses and dose distributions were compared with those in conventional TBI. A 1.7- to 7.5-fold reduction in median organ doses was observed with TMI and TMLI compared with conventional TBI. With this more targeted approach, a dose-volume histogram analysis predicted the potential to escalate the dose to bone (and containing marrow) up to 20 Gy, while maintaining doses to normal organs at lower levels than in conventional TBI to 12 Gy. Results were similar for the adult and pediatric patients, indicating that this form of targeted TBI will be applicable to most patients regardless of frame size. TMI to 10 Gy was delivered as part of a tandem transplant regimen to the 53-year-old patient with multiple myeloma. Clinical results confirmed the treatment planning predictions. After TMI, the patient experienced the expected blood count nadir, followed by successful engraftment. Grade 2 nausea and grade 1 emesis occurred only briefly on day 2 of TMI. Skin erythema, oral mucositis, esophagitis, and enteritis were not observed. This report demonstrates the feasibility and potential dosimetric advantages of selectively delivering myeloablative doses of radiation to bone and marrow using an image-guided tomographic intensity-modulated radiation therapy delivery system. Organ doses are substantially lower than those associated with standard TBI and predict the potential to significantly reduce associated toxicities and allow for dose escalation. The results also suggest that this form of targeted TBI may have potential advantages over other forms of targeted TBI, such as radioimmunotherapy or bone-seeking radionuclide therapy. Ongoing clinical trials will define the maximum TMI and TMLI doses achievable and define the potential advantages and limitations of this new approach for patients undergoing hematopoietic stem cell transplantation.

We conducted a phase 1/2 trial of high-dose 90Y-ibritumomab tiuxetan in combination with high-dose etoposide (VP-16) 40 to 60 mg/kg (day -4) and cyclophosphamide 100 mg/kg (day -2) followed by autologous stem cell transplantation (ASCT) in 31 patients with CD20+ non-Hodgkin lymphoma (NHL). Patients underwent dosimetry (day -21) with 5 mCi (185 MBq) 111In-ibritumomab tiuxetan following 250 mg/m2 rituximab, followed a week later by 90Y-ibritumomab tiuxetan to deliver a target dose of 1000 cGy to highest normal organ. Bone marrow biopsy was done on day -7 to estimate radiation dose and stem cells were reinfused when the radiation dose was estimated to be less than 5 cGy. The median 90Y-ibritumomab tiuxetan dose was 71.6 mCi (2649.2 MBq; range, 36.6-105 mCi; range, 1354.2-3885 MBq). Histology included follicular lymphoma (n = 12), diffuse large B-cell (n = 14), and mantle cell (n = 5). The median number of prior chemo-therapy treatments was 2. The treatment was well tolerated. The median times to reach an absolute neutrophil count greater than 500/μL and platelet count more than 20 000/μL were 10 days and 12 days, respectively. There were 2 deaths and 5 relapses. At a median follow-up of 22 months, the 2-year estimated overall survival and relapse-free survival rates are 92% and 78%, respectively. We conclude that high-dose 90Y-ibritumomab tiuxetan can be combined safely with high-dose etoposide and cyclophosphamide without an increase in transplant-related toxicity or delayed engraftment. (Blood. 2005;106:2896-2902)

We assessed late mortality in 854 individuals who had survived 2 or more years after autologous hematopoietic cell transplantation (HCT) for hematologic malignancies. Median age at HCT was 36.5 years, and median length of follow-up was 7.6 years. Overall survival was 68.8% ± 1.8% at 10 years, and the cohort was at a 13-fold increased risk for late death (standardized mortality ratio [SMR] = 13.0) when compared with the general population. Mortality rates approached those of the general population after 10 years among patients at standard risk for relapse at HCT (SMR = 1.1) and in patients undergoing transplantation for acute myeloid leukemia (AML; SMR = 0.9). Relapse of primary disease (56%) and subsequent malignancies (25%) were leading causes of late death. Relapse-related mortality was increased among patients with Hodgkin disease (HD; relative risk [RR] = 3.6), non-Hodgkin lymphoma (NHL; RR = 2.1), and acute lymphoblastic leukemia (ALL; RR = 6.5). Total body irradiation (RR = 0.6) provided a protective effect. Nonrelapse-related mortality was increased after carmustine (RR = 2.3) and with use of peripheral blood stem cells (RR = 2.4). Survivors were more likely to report difficulty in holding jobs (RR = 9.4) and in obtaining health (RR = 7.7) or life insurance (RR = 8.4) when compared with siblings. Although mortality rates approach that of the general population after 10 years in certain subgroups, long-term survivors of autologous HCT continue to face challenges affecting their health and well-being.

In an attempt to decrease toxicity in high-risk patients undergoing unrelated donor hematopoietic stem cell transplantation (URD HSCT), we tested a combination of cyclosporine (CSP) and mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis with the reduced-intensity conditioning regimen fludarabine/melphalan (Flu/Mel). A total of 22 adult patients with advanced myeloid (n=15) and lymphoid (n=7) malignancies were treated. All patients received Flu 25 mg/m2 for 5 days and Mel 140 mg/m2, with CSP 3 mg/kg daily and MMF 15 mg/kg three times a day. The median age was 49 years (range 18-66). Durable engraftment was seen in all but one patient with myelofibrosis. The 1-year nonrelapse mortality was 32%, 27% from GVHD. The cumulative incidence of acute GVHD grade 2-4 and 3-4 was 63 and 41%, respectively. With a median follow-up of 18 months, the disease-free survival (DFS) and overall survival (OS) are 55 and 59%, respectively. For patients with AML and MDS (n=14), the DFS and OS is 71%. For patients undergoing a second transplant (n=14), the DFS and OS is 57%. In conclusion, this regimen is associated with acceptable toxicity but high rates of GVHD in high-risk patients undergoing URD HSCT. Encouraging disease control for patients with advanced myeloid malignancies was observed.

The prognosis of patients with primary refractory acute myelogenous leukemia (AML) is poor. Our initial report suggested that some patients could achieve durable remission after allogeneic stem cell transplantation (SCT). Herein, we update our initial experience and report further analysis of this group of patients to determine whether there are pre-SCT prognostic factors predictive of posttransplantation relapse and survival. We reviewed the records of 68 patients who consecutively underwent transplantation at the City of Hope Cancer Center with allogeneic SCT for primary refractory AML between July 1978 and August 2000. Potential factors associated with overall survival and disease-free survival were examined. With a median follow-up of 3 years, the 3-year cumulative probabilities of disease-free survival (DFS), overall survival (OS), and relapse rate for all 68 patients were 31% (95% confidence interval [CI], 20%–42%), 30% (95% CI, 18%–41%), and 51% (95% CI, 38%–65%), respectively. In multivariate analysis, the only variables associated with shortened OS and DFS included the use of an unrelated donor as the stem cell source (relative risk, 2.23 [OS] and 2.05 [DFS]; P = .0005 and .0014, respectively) and unfavorable cytogenetics before SCT (relative risk: 1.68 [OS] and 1.58 [DFS]; P = .0107 and .0038, respectively). Allogeneic SCT can cure approximately one third of patients with primary refractory AML. Cytogenetic characteristics before SCT correlate with transplantation outcome and posttransplantation relapse.

Autologous hematopoietic stem cell transplantation (autoSCT) is an effective treatment for patients with various hematologic malignancies. Despite the significant improvement in the overall outcome, disease progression after transplantation remains the major cause of treatment failure. With longer follow-up, therapy-related myelodysplasia/acute myelogenous leukemia is becoming an important cause of treatment failure. The prognosis for these 2 groups of patients is very poor. Allogeneic hematopoietic stem cell transplantation (alloSCT) is a potential curative treatment for these patients. However, the outcome with conventional myeloablative alloSCT after failed autoSCT is typically poor because of high transplant-related mortality. In an attempt to reduce the treatment-related toxicity, we studied a reduced-intensity conditioning regimen followed by alloSCT for patients with progressive disease or therapy-related myelodysplasia/acute myelogenous leukemia after autoSCT. This report describes the outcomes of 28 patients with hematologic malignancies who received a reduced-intensity alloSCT after having treatment failure with a conventional autoSCT. Fourteen patients received a hematopoietic stem cell transplant from a related donor and 14 from an unrelated donor. The conditioning regimen consisted of low-dose (2 Gy) total body irradiation with or without fludarabine in 4 patients and the combination of melphalan (140 mg/m2) and fludarabine in 24. Cyclosporine and mycophenolate mofetil were used for posttransplantation immunosuppressive therapy, as well as graft-versus-host disease (GVHD) prophylaxis, in all patients. All patients engrafted and had >90% donor chimerism on day 100 after SCT. Currently, 13 patients (46%) are alive and disease free, 7 patients (25%) developed disease progression after alloSCT, and 8 (32%) died of nonrelapse causes. Day 100 mortality and nonrelapse mortality were 25% and 21%, respectively. With a median follow-up of 24 months for surviving patients, the 2-year probabilities of overall survival, event-free survival, and relapse rates were 56.5%, 41%, and 41.9%, respectively. Six patients (21%) developed grade III to IV acute GVHD. Among 21 evaluable patients, 15 (67%) developed chronic GVHD. We conclude that (1) reduced-intensity alloSCT is feasible and has an acceptable toxicity profile in patients who have previously received autoSCT and that (2) although follow-up was short, a durable remission may be achieved in some patients who would otherwise be expected to have a poor outcome.

To evaluate the prognostic impact of acute myeloid leukemia (AML) classifications, specimens from 300 patients with 20% or more bone marrow myeloblast cells were studied. Specimens were classified according to the French-American-British Cooperative Group (FAB), the World Health Organization (WHO), the Realistic Pathologic Classification, and a cytogenetic risk group scheme. Cases with fewer than 30% blast cells did not have a 5-year survival significantly different from cases with 30% or more blast cells, and survival was similar for the low blast cell count group and cases with multilineage dysplasia and 30% or more blasts. Categories of AML with recurrent cytogenetic abnormalities of t(15;17), t(8;21), inv(16)/t(16;16), and 11q23 showed significant differences in 5-year survival. No significant difference was identified between AMLs arising from myelodysplasia and de novo AMLs with multilineage dysplasia, but all cases with multilineage dysplasia had a worse survival than all other AMLs and other AMLs without favorable cytogenetics. FAB types M0, M3, and M4Eo showed differences in survival compared with all other FAB types, with M0 showing a significant association with high-risk cytogenetics and 11q23 abnormalities. Other FAB groups and WHO AML, not otherwise categorized subgroups did not show survival differences. These findings suggest that the detection of recurring cytogenetic abnormalities and multilineage dysplasia are the most significant features of current AML classification.

Purpose: To determine the disease-free survival (DFS) and toxicity of administering interleukin-2 (IL-2) immunotherapy early after autologous stem-cell transplantation (ASCT) to simulate a graft versus leukemia effect observed in allogeneic transplantation. Patients and Methods: Fifty-six patients with acute myeloid leukemia in first remission received a single consolidation of high-dose cytarabine-idarubicin at a median of 1.1 month postremission with the intent to proceed to ASCT and IL-2 9 × 106 U/m2/24 h for 4 days, followed by 10 days of IL-2 1.6 × 106 U/m2/24 h on hematologic recovery. Results: Eighty-four percent of patients received the intended ASCT, and 68% of patients received IL-2 treatment. With a median follow-up of 39.4 months (range, 1.2 to 76.3 months), the 2-year cumulative probability of DFS for all 56 patients is 68% (95% confidence interval [CI], 55% to 80%) and 74% (95% CI, 57% to 85%) for the 39 patients undergoing IL-2 treatment after ASCT. The 2-year cumulative probability of DFS for favorable, intermediate, and unfavorable cytogenetics is 88% (95% CI, 59% to 97%), 48% (95% CI, 26% to 67%), and 70% (95% CI, 23% to 93%), respectively. Toxicities from IL-2 were mainly thrombocytopenia, leukopenia, fever, and fluid retention. Two septic deaths occurred during neutropenia, which includes one during consolidation and one during transplant, for an overall 4% mortality rate. Conclusion: These results suggest that a moderate dose of IL-2 after high-dose cytarabine-idarubicin–mobilized ASCT is associated with a low regimen-related toxicity and may improve DFS. A phase III study of IL-2 is now warranted.

7032 Background: Blinatumomab (blin), a bispecific T-cell engaging antibody construct, has shown improved overall survival vs SOC in pts with r/r ALL in a randomized phase 3 study ( Haematologica 2016;101:S129). To better evaluate safety, we compared AEs of blin vs SOC after adjusting for varying treatment exposure times. Methods: Adults ≥ 18 yrs with r/r ALL (refractory, 1st relapse < 1 yr, ≥ 2 relapses or relapse after transplant) were randomized to receive blin or SOC (1 of 4 predefined regimens). Blin was dosed by continuous infusion (4 wks on/2 wks off) for up to 5 cycles (9 µg/d on d1−7 in cycle 1, then 28 µg/d); up to 4 maintenance cycles (4 wks on/8 wks off) were allowed for ≤ 12 mo. Exposure-adjusted (exp-adj) event rates were calculated as no. of events*100/total exposure time (Table). Results: Median (range) no. of cycles were 1 (1−4) for SOC and 2 (1−9) for blin. The highest exp-adj rates (per 100 pt-yrs) were for pyrexia (507 SOC vs 376 blin), anemia (987 vs 229), thrombocytopenia (750 vs 126) and neutropenia (351 vs 121), all lower in blin. Febrile neutropenia (365 vs 93) and infections (1216 vs 436) were also both lower in blin (p < 0.0001). Exp-adj rates for neurologic events were 743 SOC vs 472 blin, with median time (range) to onset of 7 (1−43) d and 7 (1−190) d, respectively, and gr ≥ 3 cytokine release syndrome (CRS) rates were 0 SOC vs 10 blin. The most frequent AEs in both cycles 1 and 2 were pyrexia, nausea and anemia in both arms; CRS events decreased in the blin arm between cycles 1 and 2 (14% vs 2%). Most fatal AEs were related to infection in both arms. Conclusions: Here blin showed an AE profile consistent with that previously reported for r/r ALL, including similar rates of manageable CRS and neurologic events. Exp-adj AE rates were generally higher in SOC vs blin, including for cytopenias and infections. Clinical trial information: NCT02013167. [Table: see text]

7004 Background: Recurrent mutations in isocitrate dehydrogenase 2 (m IDH2) occur in 8-15% of AML pts. mIDH2 proteins synthesize an oncometabolite, 2-hydroxyglutarate (2HG), causing DNA and histone hypermethylation and blocked myeloid differentiation. Enasidenib (AG-221) is an oral, selective, small-molecule inhibitor of mIDH2 protein. Methods: This phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in pts with m IDH2 myeloid malignancies. Safety for all pts and efficacy outcomes for R/R AML pts from the phase 1 dose-escalation and expansion phases are reported. Results: In all, 239 pts received enasidenib. In the dose-escalation (n=113), the MTD was not reached at doses up to 650 mg daily. Median 2HG reductions from baseline were 92%, 90%, and 93% for pts receiving 100 mg daily, respectively. Enasidenib 100 mg QD was chosen for the expansion phase (n=126) based on PK/PD profiles and demonstrated efficacy. Median number of enasidenib cycles was 5 (range 1–25). Grade 3-4 drug-related investigator reported AEs included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (ie, retinoic acid syndrome; 7%). For R/R AML pts, overall response rate (ORR) was 40.3%, including 34 (19.3%) complete remissions (CR; Table). Response was associated with cellular differentiation, typically with no evidence of aplasia. Median overall survival (OS) for R/R AML pts was 9.3 months (mos). For pts who attained CR, OS was 19.7 mos. Pts who had received ≥2 prior AML regimens (n=94; 53%) had median OS of 8.0 mos. Conclusions: Enasidenib was well tolerated, induced CRs, and was associated with OS of >9 mos in pts who had failed prior AML therapies. Differentiation of myeloblasts, not cytotoxicity, appears to drive the clinical efficacy of enasidenib. Clinical trial information: NCT01915498. [Table: see text]

Acute myeloid leukemia (AML) is sustained by small populations of leukemia stem cells (LSCs) that can resist available treatments and represent important barriers to cure. Although previous studies have shown increased signal transducer and activator of transcription (STAT)3 and STAT5 phosphorylation in AML leukemic blasts, the role of Janus kinase (JAK) signaling in primary AML compared with normal stem cells has not been directly evaluated. We show here that JAK/STAT signaling is increased in LSCs, particularly from high-risk AML. JAK2 inhibition using small molecule inhibitors or interference RNA reduced growth of AML LSCs while sparing normal stem cells both in vitro and in vivo. Increased JAK/STAT activity was associated with increased expression and altered signaling through growth factor receptors in AML LSCs, including receptor tyrosine kinase c-KIT and FMS-related tyrosine kinase 3 (FLT3). Inhibition of c-KIT and FLT3 expression significantly inhibited JAK/STAT signaling in AML LSCs, and JAK inhibitors effectively inhibited FLT3-mutated AML LSCs. Our results indicate that JAK/STAT signaling represents an important signaling mechanism supporting AML LSC growth and survival. These studies support continued evaluation of strategies for JAK/STAT inhibition for therapeutic targeting of AML LSCs.

Introduction This study aims to analyse treatment outcomes, disease control and toxicity in patients with chloromas referred for radiation therapy (RT). Methods Medical records were retrospectively reviewed for 41 patients with chloromas treated with RT at our institution. Results Twenty-five patients were treated with palliative intent, whereas sixteen received RT as a component of curative intent therapy in addition to systemic chemotherapy with or without haematopoietic stem cell transplant (HSCT). All patients received RT for chloroma (median dose 24 Gy). Median survival was 5.4 months after RT (95% confidence interval (CI) 3.5–12.6 months), and no significant difference in overall survival was identified based on prior treatment with systemic chemotherapy alone or HSCT. Patients treated with curative intent had a median survival of 26.2 months (95% CI 6.1–48.9 months) and a Kaplan–Meier estimate of 15% overall survival at 5 years. At the end of the study follow-up period, 38 patients were dead and three patients treated with curative intent remained alive. After palliative RT, 44% of patients experienced partial relief and 48% experienced complete symptomatic improvement without significant acute toxicities. Conclusions RT provides timely symptom palliation for patients with chloromas with minimal morbidity, but the prognosis remains poor. Long-term remission can be achieved in selected patients with salvage chemotherapy and HSCT.

This study aims to analyse treatment outcomes, disease control and toxicity in patients with chloromas referred for radiation therapy (RT).Medical records were retrospectively reviewed for 41 patients with chloromas treated with RT at our institution.Twenty-five patients were treated with palliative intent, whereas sixteen received RT as a component of curative intent therapy in addition to systemic chemotherapy with or without haematopoietic stem cell transplant (HSCT). All patients received RT for chloroma (median dose 24 Gy). Median survival was 5.4 months after RT (95% confidence interval (CI) 3.5-12.6 months), and no significant difference in overall survival was identified based on prior treatment with systemic chemotherapy alone or HSCT. Patients treated with curative intent had a median survival of 26.2 months (95% CI 6.1-48.9 months) and a Kaplan-Meier estimate of 15% overall survival at 5 years. At the end of the study follow-up period, 38 patients were dead and three patients treated with curative intent remained alive. After palliative RT, 44% of patients experienced partial relief and 48% experienced complete symptomatic improvement without significant acute toxicities.RT provides timely symptom palliation for patients with chloromas with minimal morbidity, but the prognosis remains poor. Long-term remission can be achieved in selected patients with salvage chemotherapy and HSCT.

Background Post-remission therapies for patients with AML such as high-dose cytarabine (HiDAC) and allogeneic stem cell transplant (alloSCT) have led to improved outcomes for younger patients, but disease recurrence remains prevalent with ~40% 5-year OS. CD33 is a cell surface receptor expressed in ~90% of AML, representing a promising target for therapy. Vadastuximab talirine (33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Methods This phase 1b dose-escalation study (NCT02326584) evaluates the safety and anti-leukemic activity of 33A in combination with consolidation therapy (HiDAC) or as a single agent for maintenance therapy. AML patients (ECOG status 0-1) must be in 1st remission (CR or CRi) after standard induction therapy and be able to receive HiDAC (consolidation cohort) or be in 1st remission and have completed planned post-remission therapies, either chemotherapy and/or alloSCT (maintenance cohort). For maintenance post-alloSCT, patients were between Day 60 and 100 post-transplant without significant GVHD. Prior to HiDAC administration (3 gm/m2 q12h Day 1, 3, 5), 33A is given on Day 1 for up to 4 cycles (28-day cycle). For maintenance therapy, 33A is given as a single agent on Day 1 for up to 8 cycles (6-wk cycle). Results Consolidation cohort: 21 patients (57% male) with a median age of 52 years (range, 21-64) were treated with 5, 10, or 20 mcg/kg of 33A with HiDAC. Patients received a median of 2 cycles (range, 1-4). As anticipated, all patients experienced Grade 4 myelosuppression. At 20 mcg/kg, 1 DLT (lack of recovery of platelets [25K] and/or ANC [500] by Day 42) occurred in Cycle 1. At 10 mcg/kg, no DLTs were observed but delay of subsequent cycles of treatment occurred in 4 of 10 patients, primarily due to thrombocytopenia. No DLTs were observed in the 8 patients treated at 5 mcg/kg and 1 non-hematologic-related dose delay was reported (otitis externa). Non-hematologic treatment-emergent adverse events (AE) in ≥25% of patients regardless of relationship included nausea (38%) and fatigue (33%). No infusion-related reactions (IRRs) or events of veno-occlusive disease were reported. The 30- and 60-day mortality rates were 0%. Of the 19 efficacy evaluable patients, 15 (79%) have maintained remission, 18 patients are alive and 3 patients (14%) remain on treatment. Reasons for treatment discontinuation were completion of planned consolidation therapy (38%), AE (thrombocytopenia, 14%), leukemic relapse (5%), and other non-AE (29%). Nine patients (43%) went on to receive an alloSCT. Maintenance cohort: 22 patients (41% male) with a median age of 45.5 years (range, 23-71) have been treated with 5 mcg/kg of 33A. Patients were a median of 6.2 months from diagnosis (range, 3.4-21.5); 12 patients completed chemotherapy-based treatment alone and 10 patients completed standard chemotherapy with an alloSCT in 1st remission. Patients received a median of 3 cycles (range, 1-6); no DLTs were reported. AEs reported in ≥15% of patients were fatigue (41%), neutropenia (41% [36% ≥G3]), nausea (36%), thrombocytopenia (36% [27% ≥G3]), diarrhea, dyspnea, headache, and vomiting (18% each); no IRRs were observed. Of the 20 efficacy evaluable patients, 15 (75%) have maintained remission. Reasons for treatment discontinuation were AEs (41%, primarily myelosuppression), leukemic relapse (14%), completion of planned therapy (9%), and other non-AE reasons (19%); 4 patients (18%) remain on treatment. Median OS is not yet reached and 19 patients are alive. Pharmacokinetic data in patients receiving post-remission therapy with 33A demonstrate that exposure appears to be greater than in patients with active disease, possibly due to a decrease in target-mediated disposition. Conclusions 33A can be safely administered in combination with HiDAC and as monotherapy in the post-remission setting. In combination with HiDAC, non-hematologic toxicities of 33A were consistent with effects reported with HiDAC alone. As a single agent, 33A administered as maintenance post-chemotherapy and/or alloSCT results in predictable on-target myelosuppression, with mild non-hematologic adverse effects. Disclosures Yang: Seattle Genetics: Research Funding. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Advani:Seattle Genetics: Consultancy, Research Funding. Walter:Emergent Biosolutions: Consultancy; Seattle Genetics: Research Funding; CSL Behring: Research Funding; Celator Pharmaceuticals: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Pfizer: Consultancy; Amphivena Therapeutics, Inc.: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Covagen AG: Consultancy; Agios: Consultancy; Arog: Research Funding. Faderl:Seattle Genetics: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; Celator Pharmaceuticals: Research Funding; BMS: Research Funding; Ambit Bioscience: Research Funding; Karyopharm: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; JW Pharma: Consultancy; Amgen: Speakers Bureau. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Erba:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding; Agios: Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; Juno: Research Funding; Jannsen: Consultancy, Research Funding; Ariad: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Gylcomimetics: Other: DSMB; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Celator: Research Funding. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Merck: Other: Advisory Board participation; Celgene: Consultancy, Research Funding; Bexalata: Other: Advisory Board participation. Levy:Amgen: Speakers Bureau; Jansen: Speakers Bureau; Millennium: Speakers Bureau; Seattle Genetics: Research Funding. Wood:Pfizer: Honoraria, Other: Laboratory Services Agreement; Amgen: Honoraria, Other: Laboratory Services Agreement; Juno: Other: Laboratory Services Agreement; Seattle Genetics: Honoraria, Other: Laboratory Services Agreement. Feldman:Seattle Genetics: Employment, Equity Ownership. Voellinger:Seattle Genetics: Employment, Equity Ownership.

Background CD33is expressed in approximately 90% of AML cases, representing a promising target despite age, prior therapies, or mutational heterogeneity. Vadastuximab talirine (33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Upon binding, 33A is internalized and transported to the lysosomes where PBD dimer is released via proteolytic cleavage of the linker, crosslinking DNA, and leading to cell death. Methods The dose-escalation portion of this phase 1 study (NCT01902329) was designed to evaluate the safety, tolerability, pharmacokinetics, and antileukemic activity of 33A as monotherapy. After dose escalation, 40 mcg/kg was identified as the recommended monotherapy dose. Eligible patients (ECOG status 0-1) in this expansion cohort must have had CD33-positive AML and considered ineligible for or declined conventional induction/consolidation. 33A monotherapy was administered outpatient IV every 3 weeks for up to 2 cycles, followed by optional low-dose maintenance treatment for patients who achieved a CR/CRi. Investigator assessment of response was per IWG criteria; CRi required either platelet count of ≥100,000/µL or neutrophils of ≥1,000/µL (Cheson 2003). Results Twenty-seven treatment naive patients (48% male) with a median age of 74 years (range, 67-89) were treated with 40 mcg/kg of 33A. Most patients had intermediate (70%) or adverse (26%) cytogenetic risk by MRC and 48% of patients had underlying myelodysplasia. Twenty-four patients were considered unfit for intensive therapy and 3 patients declined intensive therapy. At baseline, patients had a median of 47% BM blasts. Three patients remain on treatment. The most common Grade 3 or higher adverse events (AE) were thrombocytopenia (44%), febrile neutropenia (41%), anemia (33%), fatigue, and pneumonia (19% each). Other common treatment-emergent AEs regardless of relationship to 33A were decreased appetite, diarrhea, fatigue, peripheral edema, thrombocytopenia (44% each), febrile neutropenia (41%), dizziness (37%), anemia, chills, cough, dyspnea, and epistaxis (33% each). The 30- and 60-day mortality rates were 0% and 15%. Of the 26 efficacy evaluable treatment naive patients, 6 patients (23%) achieved a best clinical response of CR, 8 (31%) achieved CRi, and 5 patients (19%) achieved a morphologic leukemia-free state. Most remissions were achieved after 1 cycle and were observed in many patients with adverse risk including underlying myelodysplasia (6/12, 50%), FLT3/ITD+ (3/4, 75%), and in patients ≥75 years of age (8/12, 67%). Of the responding patients with available minimal residual disease (MRD) data, 6 of 13 (46%) achieved MRD negativity by flow cytometry. In patients who achieved at least a CRi, the median time to full count recovery from first dose was 6.1 weeks for neutrophils (≥1,000/µL) and 5.1 weeks for platelets (≥100,000/µL). Median OS continues to evolve with 10 patients (37%) alive at the time of this data cut. Pharmacokinetic data for treatment naive patients is consistent with previously reported results; 33A exhibits rapid elimination consistent with target-mediated drug disposition. Conclusions In an expansion cohort of 33A monotherapy at 40 mcg/kg, AEs observed were generally manageable and commonly associated with on-target myelosuppression. 33A has demonstrated favorable antileukemic activity as a single agent with 54% achieving a CR+CRi in this high risk treatment naive older AML population, more than doubling the response rate expected with standard non-intensive therapies such as hypomethylating agents or low-dose cytarabine. The rapid clearance of marrow blasts, high rate of MRD-negative remissions, and low early mortality rate are encouraging. These data support exploration of 33A in combination with standard induction, consolidation, and pre- and post-transplant regimens. Disclosures Stein: Celgene: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Bexalata: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Celgene: Consultancy, Research Funding; Merck: Other: Advisory Board participation. Kovacsovics:Seattle Genetics: Research Funding. Levy:Seattle Genetics: Research Funding; Jansen: Speakers Bureau; Amgen: Speakers Bureau; Millennium: Speakers Bureau. Erba:Daiichi Sankyo: Consultancy; Jannsen: Consultancy, Research Funding; Celator: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Juno: Research Funding; Astellas: Research Funding; Ariad: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Pfizer: Consultancy; Agios: Research Funding; Novartis: Consultancy, Speakers Bureau; Gylcomimetics: Other: DSMB; Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Sunesis: Consultancy. Jillella:Seattle Genetics: Research Funding. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Stein:Novartis: Consultancy; Seattle Genetics: Research Funding; Agios Pharmaceuticals: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding. Faderl:Astellas: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Celator Pharmaceuticals: Research Funding; BMS: Research Funding; Ambit Bioscience: Research Funding; Karyopharm: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; JW Pharma: Consultancy; Amgen: Speakers Bureau. DeAngelo:Baxter: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Ariad: Consultancy; Celgene: Consultancy. Ho:Seattle Genetics: Employment, Equity Ownership. O'Meara:Seattle Genetics: Employment, Equity Ownership. Voellinger:Seattle Genetics: Employment, Equity Ownership. Advani:Seattle Genetics: Consultancy, Research Funding.

Background For patients who are less than 65 years with newly diagnosed AML, standard induction treatment is continuous infusion cytarabine for 7 days and an anthracycline for 3 days (7+3). Although a high percentage of patients achieve an initial CR by morphologic criteria, some requiring a 2nd induction, a significant number of patients are either primarily resistant to treatment or achieve a morphologic CR but with flow cytometric or molecular evidence of minimal residual disease (MRD). CD33, a cell surface antigen, is expressed in approximately 90% of AML, representing a promising target of therapy regardless of genetic or mutational heterogeneity. Vadastuximab talirine (33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Upon binding, 33A is internalized and transported to the lysosomes where PBD dimer is released via proteolytic cleavage of the linker, crosslinking DNA, and leading to cell death. Addition of 33A to 7+3 chemotherapy could result in enhanced and deeper (MRD negative) remissions, resulting in reduced relapse rates and improved overall survival. Methods This phase 1b study (NCT02326584) evaluated the safety and antileukemic activity of escalating doses of 33A in combination with 7+3 induction therapy (cytarabine 100 mg/m2 and daunorubicin 60 mg/m2). AML patients (ECOG status 0-1) must be eligible to receive induction therapy. 33A is given on Days 1 and 4 concomitantly with the combination treatment. Response assessments occur on Days 15 and 28; investigator assessment of response is per IWG criteria (Cheson 2003). A 2nd induction regimen and post-remission therapies were per investigator choice and did not include additional administration of 33A. MRD was assessed centrally by bone marrow examination using a multi-parametric flow cytometric assay at Days 15 and Day 28. Results To date, 42 patients (36% male) with a median age of 45.5 years (range, 18-65) have been treated with 10+10 (n=4) and 20+10 (n=38) mcg/kg of 33A. Most patients had intermediate (40%) or adverse (43%) cytogenetic risk by MRC criteria and 17% of patients had secondary AML. As expected, all patients experienced Grade 4 myelosuppression. In patients who achieved CR or CRi, the estimated median time to count recovery from Day 1 of therapy was 33 days for neutrophils (≥1K) and 35 days for platelets (≥100K). Three DLTs (lack of recovery of platelets [25K] and/or ANC [500] by Day 42) occurred at the 20+10 mcg/kg dose level, which was determined to be the maximum tolerated dose (MTD) of 33A in combination with 7+3. No non-hematologic treatment emergent adverse events (AEs) ≥Grade 3 were reported in >15% of patients; Grade 1 or 2 non-hematologic AEs occurring in >15% of patients were nausea (55%), diarrhea (33%), constipation (31%), decreased appetite (19%), fatigue (19%), and vomiting (17%); no infusion-related reactions occurred. No veno-occlusive disease (VOD) or significant hepatotoxicity was observed. The 30- and 60-day mortality rates were 0% and 7%, respectively. Of the 40 efficacy evaluable patients, best responses include 24 CR (60%), 7 CRi (18%), and 4 morphologic leukemia-free state (10%) with a CR+CRi (CRc) rate of 78%; 94% of CR or CRi responses occurred with 1 cycle of induction therapy. Twenty-three of 31 (74%) patients attaining CR or CRi achieved MRD negative status. Median OS is not yet reached; 36 patients were alive at the time of this data cut with 6 patients (14%) still on treatment. Pharmacokinetic data demonstrate rapid elimination of 33A. Conclusions 33A can be safely combined with 7+3 with acceptable count recovery and the recommended phase 2 dose is 20+10 mcg/kg on Days 1 and 4. An alternate schedule of single-day dosing on Day 1 is under investigation and enrollment continues. Extramedullary AEs, including hepatic toxicity, and induction mortality rates were similar to reported rates for 7+3 alone in this AML population. A high remission rate within the 1st induction cycle was observed, the majority of which were MRD negative. Disclosures Erba: Sunesis: Consultancy; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy; Amgen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Pfizer: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Celator: Research Funding; Daiichi Sankyo: Consultancy; Jannsen: Consultancy, Research Funding; Gylcomimetics: Other: DSMB; Agios: Research Funding; Astellas: Research Funding; Juno: Research Funding. Levy:Millennium: Speakers Bureau; Amgen: Speakers Bureau; Jansen: Speakers Bureau; Seattle Genetics: Research Funding. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Celgene: Consultancy, Research Funding; Merck: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Bexalata: Other: Advisory Board participation. Advani:Seattle Genetics: Consultancy, Research Funding. Faderl:JW Pharma: Consultancy; Amgen: Speakers Bureau; Karyopharm: Consultancy, Research Funding; Ambit Bioscience: Research Funding; BMS: Research Funding; Celator Pharmaceuticals: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Celgene: Consultancy, Research Funding. Smith:Seattle Genetics: Research Funding; Celgene: Consultancy, Speakers Bureau. Wood:Juno: Other: Laboratory Services Agreement; Seattle Genetics: Honoraria, Other: Laboratory Services Agreement; Pfizer: Honoraria, Other: Laboratory Services Agreement; Amgen: Honoraria, Other: Laboratory Services Agreement. Walter:Covagen AG: Consultancy; Astra-Zeneca: Consultancy; Amphivena Therapeutics, Inc.: Consultancy, Research Funding; Pfizer: Consultancy; Abbvie: Research Funding; Amgen: Research Funding; Celator Pharmaceuticals: Research Funding; CSL Behring: Research Funding; Seattle Genetics: Research Funding; Emergent Biosolutions: Consultancy; Agios: Consultancy; Arog: Research Funding. Yang:Seattle Genetics: Research Funding. Feldman:Seattle Genetics: Employment, Equity Ownership. Voellinger:Seattle Genetics: Employment, Equity Ownership. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding.

Background: SL-401 is a targeted therapy directed to the interleukin-3 receptor (CD123), a target overexpressed on blastic plasmacytoid dendritic cell neoplasm (BPDCN) and other hematologic malignancies. BPDCN is an aggressive hematologic malignancy of unmet medical need that often presents in bone marrow and skin, and may also involve lymph nodes and viscera. Long-term outcomes after treatment with chemotherapy have been very poor, with median overall survival from diagnosis of ~12 months, highlighting the need for novel therapies. Results from the Phase 2 trial of SL-401 in patients with BPDCN are reported here. Methods:This multicenter, single-arm Phase 2 trial of patients with BPDCN includes a lead-in (stage 1) and expansion (stage 2). In stage 1, patients with BPDCN or relapsed or refractory (r/r) AML received SL-401 as a daily IV infusion at 7, 9, 12, or 16 ug/kg/day for days 1-5 of a 21 day cycle. In stage 2, patients with BPDCN receive SL-401 at the dose determined in stage 1. Results: As of 7/25/16, 29 patients with BPDCN have received SL-401, including 16 first-line and 10 relapsed/refractory (r/r) adults and 3 pediatric patients (under compassionate use). The 26 adult patients (9+17 in stages 1&2) received SL-401 at 7 ug/kg (n=3 [stage 1]) or 12 ug/kg (n=23 [6+17 in stages 1&2]). The median adult age was 69 years (range: 29-82 years). In stage 1, 12 ug/kg was the highest tested dose for BPDCN; MTD was not reached in BPDCN. Results in AML (r/r) patients will be reported separately. The most common treatment-related AEs, all grades, were transient transaminase elevation (54%) and hypoalbuminemia (38%). Transient thrombocytopenia was also noted (19%). The most common ≥ Grade 3 treatment-related AEs were transient transaminase elevation (42%) and thrombocytopenia (19%). Two stage 1 patients developed capillary leak syndrome (CLS): gr 5 (7 ug/kg) and gr 4 (12 ug/kg). Safety precautions, including monitoring of albumin levels and body weight, were successfully implemented to minimize risk of severe CLS, which has not occurred in patients with BPDCN since adoption. Twenty-one of 26 adult patients were evaluable for response (response assessment from 3 recently treated patients are pending; 1 patient was discontinued for as yet unspecified reasons; and 1 patient treated at 7 ug/kg was not evaluable for response due to AE); median follow-up for evaluable patients was 6.9 months (range: 0.6-17.6 months). An 86% (18/21) ORR was observed in evaluable adult BPDCN patients. ORR in evaluable patients was 100% (14/14) in first-line and 57% (4/7) in r/r BPDCN. Of these, 92% (11/12) of first-line patients treated at 12 ug/kg had a CR (n=8) or clinical CR (CRc: a CR in non-skin organs with gross reduction in cutaneous lesions and residual microscopic skin disease) (n=3). 75% (9/12) of these patients remain progression free for 3+ to 16+ months (ongoing), including 4 patients who remain on SL-401 in remission (for 3+ to 12+ months [up to 16+ cycles], ongoing) and 5 additional patients who experienced a major response on SL-401 (3 CR, 1 CRc, 1 PR) and were then successfully bridged to stem cell transplant (SCT; 3 auto-SCT and 2 allo-SCT) and all remain progression free for 3+ to 16+months (ongoing) since first SL-401 dose. Notably, a patient with r/r BPDCN was recently bridged to allo-SCT following CRc on SL-401. Conclusions: SL-401 demonstrates robust single agent activity in BPDCN, including 86% ORR in all-lines, with multiple CRs, in evaluable patients. Six patients, including 1 r/r patient, have proceeded to SCT after achieving a major response from SL-401, and an additional 7 patients remain on SL-401 for up to 12+ months, ongoing. The SL-401 side effect profile remains manageable, and no unexpected AEs have emerged with increased treatment duration, drug exposure, and patient enrollment. Response duration, progression-free and overall survival data continue to be encouraging and updated data will be presented. Clinical trial information: NCT02113982. Disclosures Lane: N-of-1: Consultancy; Stemline Therapeutics: Research Funding. Sweet:Ariad: Consultancy, Speakers Bureau; Incyte Corporation: Research Funding; Pfizer: Speakers Bureau; Karyopharm: Honoraria, Research Funding; Novartis: Consultancy, Speakers Bureau. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Wang:Immunogen: Research Funding; Incyte: Speakers Bureau. Chen:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. McDonald:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Lancet:Quantum First: Consultancy; Pfizer: Research Funding; Seattle Genetics: Consultancy; Novartis: Consultancy; Biopath Holdings: Consultancy; ERYtech: Consultancy; Karyopharm: Consultancy; Baxalta: Consultancy; Kalo Bios: Consultancy; Celgene: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Boehringer-Ingelheim: Consultancy; Amgen: Consultancy. Kantarjian:Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding.

Inv(16)(p13q22)/t(16;16)(p13.1;q22) is one of the most common chromosomal mutations found in human acute myeloid leukemia (AML). This inversion on chromosome 16 creates a fusion gene CBFb-MYH11 and leads to the expression of a fusion protein CBFβ-SMMHC. Expression of Cbfβ-SMMHC (CM) in a conditional Cbfb-MYH11 knock-in mouse model (Cbfb+/56M/Mx1-Cre) leads to development of spontaneous AML with the acquisition of additional genetic and epigenetic alterations. In order to further understand the underlying mechanism(s) driving leukemogenesis and identify predictive biomarkers during disease progression, we performed RNA-seq to track changes of transcriptiome in time series peripheral blood samples using illumina HiSeq sequencer. A cohort of 16 mice were included in the experiment, 9 out of which are CM conditional knock-in mice and the remaining 7 are controls. Peripheral blood samples were collected before the induction of CM expression as the "0" time point samples. After induction, peripheral blood samples were collected at 1, 2, 3.5, 4.5, 5.5 and 6.5 month (experimental end point) after induction, and leukemic samples were collected when mice were moribund as the "end" time point samples. Between 3.5 and 6.5 months, 6 out of 9 CM knock-in mice in this cohort had succumbed to lethal leukemia. Total RNA was isolated for mRNA and microRNA (miR) sequencing library preparation. The mapped sequencing read counts were annotated to genes and differential expression was compared using edgeR. False discovery rate (FDR) were used to adjust for multiple comparisons. Genes with adjusted P value (FDR) 2 were considered differentially expressed genes. Unsupervised clustering analysis revealed that all diseased mice showed unique disease-related mRNA and miRNA signatures at the end point. The disease-related signatures were absent in all control mice and the three CM conditional knock-in mice that did not develop leukemia. We found that 2,032 mRNA genes and 106 miRs were significantly up-regulated whereas 2,926 mRNA genes and 121 miRs were significantly down-regulated at the leukemia end point. Principal component analysis revealed that the disease-related changes occur quite early, at 1-2 month after induction. Among the earliest changes, miR-126-3p and miR-126-5p, previously reported to be associated with human inv(16) AML, were significantly up-regulated (log fold change =2.09 and 2.36 respectively; p< 0.0001) at 1 month and increased progressively throughout leukemia progression (log fold change = 4.11 and 4.45; p< 0.0001). DAVID gene ontology (GO) analysis of genes negatively correlated with miR-126 expression showed significant enrichment for mitotic cell cycle and cell division GO pathways. In addition, dynamic changes in a number of predicted miR-126 targets were seen during disease progression. We reasoned that high miR-126 expression might contribute to AML progression. Lentiviral miR-126 knock-down in AML LSK (Lin-/Sca1+/cKit+) cells from CM induced mice led to increased apoptosis and reduced quiescence in vitro. To assess the role of miR-126 in leukemia progression in vivo, we then designed a novel CpG-miR-126 inhibitor (Zhang et al, submitted). Mice transplanted with CM+ AML and treated with with anti-miR126 (5 mg/kg, daily, 30 days) had a significant delay in leukemia progression and enhanced survival (control 42% survival v.s. anti-miR-126 80% survival at 70 days; n=7-10), supporting the notion that high miR-126 contributes to disease growth. Further mechanistic investigation of miR-126 function during inv(16) AML progression are ongoing. In conclusion, transcriptome analysis of time series samples during spontaneous leukemia progression allows identification of disease-related changes and early increase of miR-126 as a potential biomarker. Further functional validation is expected to provide mechanistic insights and rational for targeting miR-126 in inv(16) AML. Disclosures Stein: Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding.

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.