INTRODUCTION: Overexpression of CD123, the alpha subunit of the IL-3 receptor, is seen in multiple hematological malignancies, including AML, BPDCN, and ALL. IMGN632 is a CD123-targeting ADC, comprising a high affinity anti-CD123 antibody coupled to a DNA-alkylating payload of the novel IGN (indolinobenzodiazepine pseudodimer) class. METHODS: Adult patients with CD123-positive R/R AML or R/R BPDCN with no more than three prior lines of therapy, were eligible. IMGN632 was given in two schedules: A) dosing day 1 and B) fractionated dosing on days 1, 4, and 8, both on a 21-day cycle. RESULTS: 74 patients (67 AML, 7 BPDCN) have received IMGN632 across nine dose-escalation cohorts on two schedules, with dosing escalated from 0.015-0.45 mg/kg on schedule A (n=61) and 0.015-0.06 mg/kg on days 1, 4, and 8 on schedule B (n=13). The median age of patients was 69 years (range 33-83). Forty-four percent had secondary AML and 70% of classifiable AML patients were ELN adverse risk (32/46). Twenty-six percent were primary refractory to frontline therapy, 32% were enrolled in first relapse, and 41% had other relapsed-refractory disease. Sixty-eight percent of patients had received prior intense therapy, including stem cell transplant in 19%. The most common treatment-emergent adverse events (AEs) were diarrhea (30%; all ≤ grade 2), febrile neutropenia (27%; all grade 3), nausea (26%; one grade 3), chills (23%; all ≤ grade 2), and lung infection (22%; ≥ grade 2). The principal treatment-related AEs were infusion-related reactions (16%; four grade 3), which included chills, nausea, diarrhea and tachycardia. None requiring treatment discontinuation. The majority of patients received premedication with dexamethasone. Three dose limiting toxicities occurred at dose levels ≥ 0.18 mg/kg (all in schedule A), including one prolonged neutropenia and two reversible veno-occlusive disease cases. Importantly, no patterns of hepatotoxicity or cytopenias occurred with doses below 0.18 mg/kg, which are doses being evaluated for combinations. The 30-day mortality from last dose was 8%. In the assessable AML population (n=66), 37 (55%) had a reduction in bone marrow blasts, and 13 (20%) achieved an objective response (3 CR, 8 CRi, 2 MLFS; Figure 1) across a wide range of doses (0.045 to 0.3 mg/kg). Of note, the majority of responders (77%) had failed prior intensive therapies (including three with prior transplant), 62% had adverse ELN risk classification (including complex karyotype, ASXL1, RUNX1, and FLT3-ITD mutations), and 23% were primary refractory. Although no MTD was determined on either schedule, based on the efficacy, safety, and PK data, the recommended phase 2 dose (RP2D) and schedule was 0.045 mg/kg given on day 1 every 21 days. In addition to a lack of significant toxicities seen with repeated dosing, and consistency of post-infusion exposures and CD123 saturation, encouraging single agent activity was seen at this level in non-secondary AML patients with a response rate of 32% (6/19; 2 CR, 3 CRi, 1 MLFS). Of seven R/R BPDCN patients, three (43%) achieved an objective responses (CR, CRi, PR), two others had stable disease and two had clinical progression. The patient with CR had previously had a partial response to SL-401, responded to CHOP, received a transplant and was refractory to decitabine with venetoclax: on IMGN632 this patient cleared bone marrow (28% to 0%) with one dose, and cleared skin (biopsy negative) and CT lesions with 2 doses. The patient with a CRi was refractory to SL-401, CLAG-M, and CLAG, and cleared bone marrow (37% to 0%), skin and CT lesions after one 0.045 mg/kg dose of IMGN632. The patient with a PR had previously had a partial response to SL-401: on IMGN632 this patient had complete clearance of bone marrow blasts (87% to 0%) and significant improvement in skin and CT lesions with one dose of IMGN632. CONCLUSIONS: In this phase 1 trial, the novel CD123-targeting ADC IMGN632 demonstrated a manageable safety profile and broad therapeutic window in high risk R/R AML and BPDCN patients. The encouraging single agent activity and safety profile, along with supporting preclinical efficacy studies, have led to the subsequent development of IMGN632 as monotherapy in patients with R/R BPDCN and MRD+ AML, and in combination with azacitidine and/or venetoclax in patients with R/R and untreated AML. Figure 1. Maximum % decrease in bone marrow blasts from baseline. Objective responses (CR, CRi, or MLFS) are shown in black. Disclosures Daver: Glycomimetics: Research Funding; Otsuka: Consultancy; Pfizer: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Celgene: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Karyopharm: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Servier: Research Funding; Agios: Consultancy; Abbvie: Consultancy, Research Funding; Jazz: Consultancy; Karyopharm: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Forty-Seven: Consultancy; Forty-Seven: Consultancy; Jazz: Consultancy; Glycomimetics: Research Funding; Incyte: Consultancy, Research Funding; Otsuka: Consultancy; Sunesis: Consultancy, Research Funding; NOHLA: Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Agios: Consultancy; Servier: Research Funding; NOHLA: Research Funding; Celgene: Consultancy. Montesinos:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees. DeAngelo:Glycomimetics: Research Funding; Blueprint: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Research Funding; Amgen, Autolus, Celgene, Forty-seven, Incyte, Jazzs, Pfizer, Shire, Takeda: Consultancy. Wang:Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Papadantonakis:Agios: Consultancy, Honoraria. Erba:Incyte: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Pfizer: Consultancy; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Agios: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Agios: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Amgen: Consultancy; Astellas Pharma: Consultancy; Astellas Pharma: Consultancy; ImmunoGen: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding. Pemmaraju:cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; incyte: Consultancy, Research Funding; celgene: Consultancy, Honoraria; samus: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding; affymetrix: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding; plexxikon: Research Funding. Lane:AbbVie: Research Funding; Stemline Therapeutics: Research Funding; N-of-One: Consultancy. Rizzieri:Celgene, Gilead, Seattle Genetics, Stemline: Other: Speaker; AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Jazz, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva: Other: Advisory Board; AROG, Bayer, Celgene, Celltron, Mustang, Pfizer, Seattle Genetics, Stemline: Consultancy; Stemline: Research Funding. Sweet:Agios: Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees. Konopleva:Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; Ascentage: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; Ablynx: Research Funding; Astra Zeneca: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Agios: Research Funding; Calithera: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Sloss:ImmunoGen: Employment. Culm-Merdek:ImmunoGen Inc: Employment. Zweidler-McKay:ImmunoGen: Employment. Kantarjian:AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; BMS: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; Astex: Research Funding.

Background: CD123 is a subunit of the interleukin 3 (IL3) receptor and is expressed on the surface of blasts in most cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). CD123 expression is often higher on leukemia cells than normal progenitors and may be enriched in residual cells surviving chemotherapy. Uniformly high CD123 is characteristic of blastic plasmacytoid dendritic cell neoplasm (BPDCN), an uncommon leukemia related to AML. Tagraxofusp (TAG, SL-401) is a recombinant protein drug consisting of IL3 fused to a truncated diphtheria toxin payload that targets CD123. Single agent TAG is approved for treatment of BPDCN. In preclinical models and in patients who received TAG, we previously found that TAG resistance in AML and BPDCN was mediated by DNA methylation and downregulation of diphthamide genes (e.g. DPH1) and subsequent resistance to diphtheria toxin (Togami, JCI 2019). TAG resistance was reversible by the hypomethylating agent azacitidine (AZA), and TAG plus AZA was more effective than either alone in xenograft models. Therefore, we performed a phase 1b trial combining TAG with AZA or with AZA and venetoclax (VEN) in patients with AML, MDS, or BPDCN. Methods: Detection of CD123 on blasts by flow or IHC was required. Eligibility included albumin ≥3.2 g/dL, normal cardiac ejection fraction, and hospitalization in cycle 1 to mitigate risks of capillary leak syndrome (CLS). The study followed a 3+3 dose escalation, plus expansion cohorts, of 28-day cycles of TAG with fixed doses of AZA or AZA-VEN. First, we tested 5 schedules of the doublet TAG (5 or 7 μg/kg/d1-5, or 7, 9, or 12 μg/kg/d1-3) with standard doses of AZA (75 mg/m2 d1-7) in newly diagnosed AML (1L), relapsed/refractory AML (R/R), or MDS with ≥10% blasts. Next, we tested 3 doses of the triplet TAG (7, 9, or 12 μg/kg/d4-6) with AZA (75 mg/m2 d1-7) and VEN (400 mg d1-21, ramp up d1-3 in cycle 1) in 1L AML, R/R AML, or R/R BPDCN. Results: 34 patients have been enrolled and 33 are evaluable (one withdrew prior to therapy). The age range is 21-86 (median 67). Median follow up is 8.4 months [95% CI, 7.1-19.1]. 18 received TAG-AZA (5 1L AML, 9 R/R AML, 4 MDS); 15 received TAG-AZA-VEN (9 1L AML, 3 R/R AML, 3 R/R BPDCN). An MTD was not reached, and the recommended phase 2 dose of TAG was determined to be 12 μg/kg/d x3d in each combination. Adverse events (AEs) were as expected for TAG or AZA+/-VEN. Grade 3+ AEs in >10% included neutropenia (30%), thrombocytopenia (27%), anemia (18%), febrile neutropenia (18%), ALT increase (12%), and bilirubin increase (12%). Eleven of 33 (33%) experienced CLS: 8 (24%) were grade 2, 2 grade 3 (6%), and 1 grade 4 (3%). One treatment-related death occurred in a 79 year-old with AML receiving TAG-AZA-VEN who experienced tumor lysis syndrome followed by CLS and multiorgan system failure during cycle 1. Eight of 9 patients (89%) with previously untreated AML (ages 59-81, median 74; 7 of 9 ELN adverse risk) who received TAG-AZA-VEN achieved best response of complete response (CR, n=5) or complete response with incomplete count recovery (CRi, n=3), at TAG doses of 7 (n=2), 9 (n=1), or 12 μg/kg/d x3d (n=6). The 8 with CR/CRi included two AMLs with TP53 mutation and adverse karyotype, and three with secondary AML, two which had concomitant mature pDC expansion, a.k.a. "pDC-AML" (Xiao, Blood 2021). At the time of data cut off, 4 of 8 have gone to allogeneic stem cell transplantation (alloSCT) and 3 remain on therapy. Three patients with relapsed/refractory BPDCN (all had prior single agent TAG) received TAG-AZA-VEN and 2 of 3 responded (CRc=1, CRi=1), who both went to alloSCT. Four patients with previously untreated MDS and ≥10% blasts received TAG-AZA. 3 of 4 responded (all 3 with TP53 mutation) with CR (n=2) and marrow CR (n=1), and two went to alloSCT. Among 14 patients with 1L (5) or R/R (9) AML on TAG-AZA, and 3 with R/R AML on TAG-AZA-VEN, one with 1L AML (17p- and complex karyotype) achieved a CRi on TAG-AZA. Responses in all groups included patients with high and low CD123 by central flow. Conclusions: Combining TAG with AZA or AZA-VEN is feasible, with expected TAG or AZA+/-VEN toxicities. CLS is an important consideration for TAG, requiring monitoring and early implementation of supportive care. The activity of TAG-AZA-VEN in previously untreated AML and R/R BPDCN, and of TAG-AZA in MDS are encouraging, including in high-risk AML/MDS subtypes such as TP53 mutated. These data support continued development of TAG combinations in CD123+ malignancies. Figure 1 Figure 1. Disclosures Lane: Qiagen: Consultancy, Honoraria; N-of-One: Consultancy, Honoraria; Stemline Therapeutics: Research Funding; AbbVie: Research Funding. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Garcia: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Prelude: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stone: AbbVie: Consultancy; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Astellas: Membership on an entity's Board of Directors or advisory committees; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Boston Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Foghorn Therapeutics: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Gemoab: Membership on an entity's Board of Directors or advisory committees; Actinium: Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Aprea: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Macrogenics: Consultancy. Winer: Novartis: Consultancy; Takeda: Consultancy; Abbvie: Consultancy. Mughal: Oxford University Press, Informa: Other: financial benefit and/or patents ; Stemline: Current Employment, Current holder of stock options in a privately-held company. Brooks: Stemline Therapeutics: Current Employment. Konopleva: KisoJi: Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Rafael Pharmaceuticals: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Ascentage: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; Agios: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Ablynx: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Cellectis: Other: grant support; Calithera: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Forty Seven: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding. Pemmaraju: DAVA Oncology: Consultancy; Springer Science + Business Media: Other; Samus: Other, Research Funding; MustangBio: Consultancy, Other; Incyte: Consultancy; Clearview Healthcare Partners: Consultancy; LFB Biotechnologies: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Blueprint Medicines: Consultancy; Roche Diagnostics: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Celgene Corporation: Consultancy; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Affymetrix: Consultancy, Research Funding; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Protagonist Therapeutics, Inc.: Consultancy; Sager Strong Foundation: Other; Daiichi Sankyo, Inc.: Other, Research Funding; Cellectis S.A. ADR: Other, Research Funding; Aptitude Health: Consultancy; CareDx, Inc.: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy.

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.

References1 Riaz W, Zhang L, Horna P, et al. Blastic plasmacytoid dendritic cell neoplasm: update on molecular biology, diagnosis, and therapy. Cancer Control 2014; 21: 279-289. 2 Frankel AE, Woo JH, Ahn C, et al. Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients. Blood 2014; 124: 385-392. 3 Sun W, Liu H, Kim Y, et al. First pediatric experience of SL-401, a CD123-targeted therapy, in patients with blastic plasmacytoid dendritic cell neoplasm: report of three cases.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive malignancy previously known as blastic natural killer cell lymphoma, CD4+CD56+ hematodermic neoplasm, or agranular CD4+ NK cell leukemia. BPDCN has recently been classified as the malignant counterpart of plasmacytoid dendritic cells (pDCs), the most common dendritic cell subset in peripheral blood. Clinical outcomes in BPDCN are poor, with median survival of less than 12 months. The pathogenesis and genetic changes associated with pDC transformation are largely unknown, and the optimal treatment for this disease is unclear. Loss of the CDKN2A locus on 9p21 is the most common copy number alteration, and the sole targeted sequencing effort reported to date focused only on somatic mutations in TP53 and TET2 (Jardin et al. Br J Haem 2011). The goal of this study was to characterize the genetics of BPDCN by next-generation sequencing of all exons of 219 genes known to be recurrently mutated in hematologic malignancies. We sequenced a discovery cohort of seven adult patients with BPDCN, and confirmed the somatic status of single nucleotide variants (SNVs) and insertion-deletions (InDels) not present in dbSNP using paired germline tissue where available. All cases met World Health Organization criteria for pathological diagnosis of BPDCN. We confirmed the presence of TET2 (4 of 7 patients) and TP53 (1 of 7) mutations in BPDCN, and noted that the overall mutational spectrum was overlapping with previously sequenced hematologic neoplasms. Specifically, we observed mutations in ASXL1 (in 2 patients: K586* and an InDel causing a frameshift at S795), IDH2 (R140Q), KRAS (G13D), ABL1 (T315I), ARID1A (R1721*), GNA13 (E313*), U2AF1 (Q157L), and SRSF2 (P95L) that have been reported in myeloid and mature B cell neoplasms. Also of interest was an IRF8 R404W mutation; IRF8 is a transcription factor that drives pDC development and germline loss of IRF8 in humans is associated with dendritic cell deficiency. The most striking finding was the presence of premature stop, frame shift, and splice site mutations in the splicing factor ZRSR2 on chromosome Xp22.1 in 4 of 7 (57.1%) BPDCNs. ZRSR2 mutations were present in 71-84% of sequence reads at their respective locations, consistent with homo/hemizygous alterations in a dominant clone. Xenografting of one BPDCN that harbored a ZRSR2 premature stop mutation resulted in leukemia engraftment that retained the ZRSR2 mutation. From a validation cohort of 32 additional adult and pediatric BPDCNs, ZRSR2 mutations were present in 11 cases, for a total of 15 of 39 (38.5%) patients. Ten of 15 mutations were premature stop, frame shift, or splice site, while the remaining were missense variants. ZRSR2 is recurrently mutated in MDS and AML but at a much lower frequency (1-5%), and ZRSR2 mutations have not been described as characteristic of any other malignancy. Thus, ZRSR2 mutations are approximately 10-fold more prevalent among BPDCNs as compared to MDS or AML, indicating a unique association between BDPCN and ZRSR2 mutation. BPDCN is predominantly a disease of the male sex, both in previous studies and in our cohort (28 males among 36 patients, 77.8%). In a prior report (Yoshida et al. Nature 2012), 12 of 12 cases of MDS with ZRSR2 nonsense and frame shift mutations were male. All 10 cases of BPDCN with ZRSR2 nonsense, frame shift, and splice site mutations in our cohort were male (P=0.076 by two-sided Fisher’s exact test). Thus, we hypothesize that BPDCN may be more common in males because of a gene dosage effect related to the chr.X location of ZRSR2. There was also a trend toward an association between ZRSR2 loss-of-function mutation and age ≥65 (P=0.068). There was no statistically significant difference in overall survival between patients with and without mutations in ZRSR2, although we were limited by the small cohort size and the heterogeneity of therapies received. We conclude that loss of ZRSR2 function is specifically associated with pDC transformation and leukemogenesis, as well as male sex and older age. Further studies to confirm these findings in additional cohorts and define the mechanism linking ZRSR2 mutation with BPDCN are underway. Disclosures: DeAngelo: Ariad, Novartis, BMS: Consultancy. Neuberg:Synta Pharmaceuticals: Trust owns stock; I am a Trustee Other.