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PURPOSEStandard cytotoxic induction chemotherapy for acute myeloid leukemia (AML) results in prolonged neutropenia and risk of infection. Romyelocel-L is a universal, allogeneic myeloid progenitor cell product being studied to reduce infection during induction chemotherapy.PATIENTS AND METHODSOne hundred sixty-three patients with de novo AML (age ≥ 55 years) receiving induction chemotherapy were randomly assigned on day 0 (d0), of whom 120 were evaluable. Subjects received either romyelocel-L infusion on d9 with granulocyte colony-stimulating factor (G-CSF) starting daily d14 (treatment group) or G-CSF daily alone on d14 (control) until absolute neutrophil count recovery to 500/µL. End points included days in febrile episode, microbiologically defined infections, clinically diagnosed infection, and days in hospital.RESULTSMean days in febrile episode was shorter in the treatment arm from d15 through d28 (2.36 v 3.90; P = .02). Similarly, a trend toward decreased microbiologically defined infections and clinically diagnosed infection in the treatment arm was observed from d9 to d28 (35.6% v 47.5%; P = .09), reaching a statistically significant difference from d15 to d28 (6.8% v 27.9%; P = .002). Because of this, antibacterial or antifungal use for treatment of an infection was significantly less in the treatment group (d9-d28: 44.1% v 63.9%; P = .01). Significantly fewer patients in the treatment arm received empiric antifungals from d9 tod28 (42.4% v 63.9%; P = .02) and d15-d28 (42.4% v 62.3%; P = .02). Patients in the treatment arm also had 3.2 fewer hospital days compared with control (25.5 v 28.7; P = .001). Remission rates and days to absolute neutrophil count recovery were similar in the two groups. No patients in the romyelocel-L plus G-CSF group died because of infection compared with two patients in the control arm. No graft-versus-host disease was observed.CONCLUSIONSubjects receiving romyelocel-L showed a decreased incidence of infections, antimicrobial use, and hospitalization, suggesting that romyelocel-L may provide a new option to reduce infections in patients with AML undergoing induction therapy.

Abstract Background: Sapacitabine is a novel oral nucleoside analogue with a unique ability to induce single-strand DNA breaks after incorporation into DNA, leading to production of double-strand DNA breaks and/or G2 cell cycle arrest. In AML cell lines, the active metabolite of sapacitabine, CNDAC, is synergistic with hypomethylating agents (HMAs) particularly when treated with HMAs first. In a pilot study, there were 6 CRs and 2 PRs in 25 patients treated with sapacitabine in alternating cycles with decitabine. This global randomized phase 3 study evaluated the survival benefit of this treatment strategy vs. decitabine monotherapy. Methods: Decitabine 20 mg/m2 was administered intravenously daily x 5 days of a 4-week cycle (for the control arm and odd cycles of the study arm) alternating with sapacitabine 300 mg p.o. b.i.d. x 3 days/week x 2 weeks of a 4-week cycle (even cycles of the study arm). The safety of these doses was further evaluated in the lead-in phase of the phase 3 study to confirm the findings from the pilot study. Eligible patients were ≥70 years with untreated AML and unsuitable for or unwilling to receive standard induction chemotherapy. Patients who had received HMAs for prior MDS or MPD were excluded. Results: For 482 patients randomized to receive decitabine/sapacitabine (n=241) vs. decitabine only (n=241), randomization was stratified by the presence of antecedent MDS or MPN, peripheral white blood cell count (WBC <10,000 vs. ≥10,000) and bone marrow blast percentage (≥50% vs. < 50%). Median age was 77 years (range 70-90), and 317 patients had de novo AML (66%), 165 secondary AML (34%). WBC was ≥10,000 in 161 patients (33%) and >40,000 in 59 patients (12%); 194 patients (40%) had unfavorable cytogenetic risk by SWOG criteria. Disease characteristics were well balanced in both arms. In total, 13.7% of patients achieved CR, more on the study arm vs. control (16.6% vs. 10.8%). A total of 37.3% treated patients received ≥5 cycles of treatment, similar on both arms, as were 30- and 60-day death rates. Median overall survival was 5.9 months on the study arm vs. 5.7 months on control arm, which did not reach a statistically significant difference. In the subgroup of patients with <10,000 WBC (n=321), median overall survival was higher on the study arm vs. control arm (8.0 months vs. 5.8 months), as was CR rate (21.5% vs. 8.6%). Grade 3 or higher adverse events (regardless of causality) that occurred in >10% patients were thrombocytopenia, anemia, neutropenia, pneumonia, febrile neutropenia, sepsis, and disease progression. Conclusion: The regimen of sapacitabine administered in alternating cycles with decitabine was active and well tolerated but it did not significantly improve overall survival as compared to decitabine monotherapy. Further analyses are being conducted to characterize the subgroups of patients who appeared to have benefited from this treatment regimen and the potential cost savings associated with the use of an oral drug. Disclosures Kantarjian: Amgen: Research Funding; Pfizer: Research Funding; Delta-Fly Pharma: Research Funding; ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding. Goldberg: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; COTA: Employment, Equity Ownership; Pfizer: Honoraria; Ariad: Speakers Bureau; Jazz: Speakers Bureau. Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees. Strickland: Boehringer Ingelheim: Consultancy; Daiichi Sankyo: Consultancy; CTI BioPharma: Consultancy; Tolero Pharmaceuticals: Consultancy; Sunesis Pharamaceuticals: Consultancy, Research Funding; Baxalta: Consultancy; Alexion Pharmaceuticals: Consultancy; Astellas Pharma: Honoraria. Rubenstein: Alexion Pharmaceuticals: Speakers Bureau. Arellano: Cephalon Oncology: Research Funding. Schiller: bluebird bio: Research Funding; mateon therapeutics: Research Funding. Gaidano: Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Montesinos: Celgene Corporation: Honoraria, Research Funding. Rizzieri: Shire: Research Funding; Erytech: Research Funding. Subramanian: Boehringer-Ingelheim, Lilly, BMS, Astra-Zeneca, Pfizer, Biocept: Consultancy, Speakers Bureau. Buyse: IDDI: Employment, Equity Ownership. Chiao: Cyclacel LTD: Employment, Equity Ownership.

Abstract Hairy cell leukemia (HCL) is a rare B-cell malignancy, and there is a need for novel treatments for patients who do not benefit from purine analogs. Ibrutinib, an oral agent targeting Bruton tyrosine kinase in the B-cell receptor signaling pathway, is highly effective in several malignancies. Its activity in HCL was unknown, so we conducted a multisite phase 2 study of oral ibrutinib in patients with either relapsed classic or variant hairy cell leukemia. The primary outcome measure was the overall response rate (ORR) at 32 weeks, and we also assessed response at 48 weeks and best response during treatment. Key secondary objectives were characterization of toxicity and determination of progression-free survival (PFS) and overall survival (OS). Thirty-seven patients were enrolled at 2 different doses (24 at 420 mg, 13 at 840 mg). The median duration of follow-up was 3.5 years (range, 0-5.9 years). The ORR at 32 weeks was 24%, which increased to 36% at 48 weeks. The best ORR was 54%. The estimated 36-month PFS was 73% and OS was 85%. The most frequent adverse events were diarrhea (59%), fatigue (54%), myalgia (54%), and nausea (51%). Hematologic adverse events were common: anemia (43%), thrombocytopenia (41%), and neutropenia (35%). Ibrutinib can be safely administered to patients with HCL with objective responses and results in prolonged disease control. Although the initial primary outcome objective of the study was not met, the observation of objective responses in heavily pretreated patients coupled with a favorable PFS suggests that ibrutinib may be beneficial in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01841723.

The NCCN Guidelines for Acute Myeloid Leukemia (AML) provide recommendations for the diagnosis and treatment of adults with AML based on clinical trials that have led to significant improvements in treatment, or have yielded new information regarding factors with prognostic importance, and are intended to aid physicians with clinical decision-making. These NCCN Guidelines Insights focus on recent select updates to the NCCN Guidelines, including familial genetic alterations in AML, postinduction or postremission treatment strategies in low-risk acute promyelocytic leukemia or favorable-risk AML, principles surrounding the use of venetoclax-based therapies, and considerations for patients who prefer not to receive blood transfusions during treatment.

Background: Blasts and leukemic stem cells of acute myeloid leukemia (AML) as well as several other hematologic malignancies express CD123, potentially providing a target for novel therapies. Vibecotamab (XmAb14045, SQZ622) is a potent bispecific antibody targeting both CD123 and CD3 that stimulates targeted T cell-mediated killing of CD123-expressing cells, regardless of T cell antigen specificity. It is a full-length immunoglobulin molecule designed to be dosed intermittently. Methods: Patients with relapsed or refractory AML, B-cell acute lymphoblastic leukemia (B-ALL), blast phase chronic myelogenous leukemia, or blastic plasmacytoid dendritic cell neoplasm were eligible to enroll on this first-in-human, multicenter, open-label phase 1 dose-escalation study (XmAb14045-01) with standard 3+3 design. The primary objective was to estimate the maximum tolerated dose (MTD) or recommended dose and schedule of vibecotamab. Secondary objectives included safety, preliminary antileukemic activity, and pharmacokinetics/pharmacodynamics of vibecotamab. Treatment was administered weekly in 28-day cycles, using a weight-based dose with 3 escalating doses in the first week followed by escalating weekly doses. Therapy was continued for as long as tolerated and there was continuing evidence of therapeutic benefit in the opinion of the investigator. Treatment response was assessed by the 2017 European LeukemiaNet (ELN) criteria after Cycle 1 and after each odd-numbered cycle. CRS was graded using the CRS revised grading system (Lee et al., Blood, 2014). Results: At data cut-off, 104 patients with AML, 1 with B-cell ALL, and 1 with CML as their primary diagnosis have been treated at dosages from 0.003 to 12.0 µg/kg vibecotamab. Patients had a median age of 63 years and were heavily pretreated (median of 3 prior therapies [range 1-8], including 32 (30%) who had undergone prior allogeneic stem cell transplantation). The recommended initial priming dose is 0.75 µg/kg; no MTD has been identified. CRS or its component symptoms was the most common treatment-emergent adverse event (TEAE). CRS occurred in 62 of 106 patients (85% grade 1-2, 15% grade ≥3), the majority on the first dose. Additional events consistent with CRS or infusion related reaction were seen in 24% of subjects (chills, fever, tachycardia, hypotension, etc.), and they were mostly mild or moderate severity. No myelosuppression requiring dose modification or evidence of tumor lysis syndrome was seen. Response of CR (2), CRi (3) or MLFS (2) was observed in 7/51 patients (ORR=14%) treated at higher dose levels (0.75 µg/kg). Stable Disease was observed in an additional 36 patients (71%). No CR, CRi, or morphologic leukemia-free state (MLFS) responses were observed at lower doses. Antileukemic activity occurred quickly; 6 out of 7 responders achieved at least a MLFS response after first cycle. A characterization of responders versus non-responders revealed responding patients harbor a lower burden of disease and specific T-cell subtypes. No association was found between response status and CD123 target expression on AML blasts. Conclusions: Vibecotamab demonstrated evidence of antileukemic activity in heavily pretreated patients with relapsed/refractory AML treated at the ≥0.75 µg/kg doses cohorts, with a 14% response rate. CRS was the most common toxicity but was generally manageable with premedications. The study is ongoing with further optimization of dose and schedule. Biomarker data suggest a population of AML patients that are more likely to respond. Additional information will be provided at the time of the meeting. Disclosures Ravandi: Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Macrogenics: Research Funding. Stock:Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; American Society of Hematology: Honoraria; Leukemia and Lymphoma Society: Research Funding; Novartis: Research Funding; Abbvie: Honoraria, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: 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; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Honoraria. Foran:Xencor: Research Funding; H3Biosciences: Research Funding; Agios: Honoraria, Research Funding; Trillium: Research Funding; Takeda: Research Funding; Kura Oncology: Research Funding; Aptose: Research Funding; Aprea: Research Funding; Actinium: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Revolution Medicine: Consultancy. Mawad:Adaptive Biotechnologies: Speakers Bureau; Abbvie: Speakers Bureau. Blum:Celyad: Research Funding; Amerisource Bergen: Honoraria; Syndax: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Research Funding; Xencor: Research Funding. Yang:Xencor: Current Employment, Current equity holder in publicly-traded company; Jazz Pharmaceuticals: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Pastore:Novartis NIBR East Hanover New Jersey: Current Employment, Current equity holder in publicly-traded company; Memorial Sloan Kettering Cancer Center: Ended employment in the past 24 months. Johnson:Xencor: Current Employment, Current equity holder in publicly-traded company. Zheng:Xencor: Current Employment, Current equity holder in publicly-traded company; Tocagen: Ended employment in the past 24 months. Yilmaz:Pint Pharma: Honoraria; Pfizer: Research Funding; Daicho Sankyo: Research Funding. Mims:Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; Agios: Consultancy; Novartis: Speakers Bureau.

Abstract Idiopathic HES is a myeloproliferative disorder (MPD) characterized by persistent overproduction of eosinophils resulting in organ damage. In a small subset of patients (pts), the disease is caused by the FIP1L1-PDGFR-α fusion tyrosine kinase. Its expression has been associated with complete clinical responses to therapy with tyrosine kinase inhibitor (TKI) imatinib mesylate. In contrast, there is no specific therapy for pts with HES lacking FIP1L1-PDGFR-α expression and corticosteroids are used for palliation. Alemtuzumab (Campath-1H™) is a humanized rat monoclonal antibody directed against the CD52 antigen. Since CD52 is expressed on eosinophils, we evaluated its efficacy in pts with FIP1L1-PDGFR-α-negative symptomatic HES. A total of 9 pts (5 male, 4 female) received alemtuzumab in weekly cycles at the dose of 30 (8 pts) or 10 (1 pt) mg 3 times a week intravenously or subcutaneously. During the first week alemtuzumab was given in escalating doses (3→10→30mg) to assure tolerance. Median age was 53 years (range 24–70), time from HES diagnosis to alemtuzumab therapy 34 months (range 4–195), median WBC 17×109/L (range 6.9–82.4), absolute eosinophil count (AEC) 9×109/L (range 0.7–30), and bone marrow eosinophils 23% (range 10–68). Three pts had abnormal cytogenetics: del11(q23), +8, and t(5;6). Pts had received a median of 3 prior therapies (range 2–6), including corticosteroids (prednisone; n=9), imatinib (n=7), dasatinib (n=3), interferon-alpha (n=3), hydroxyurea (n=3), nilotinib (n=2), and cladribine (n=2). A total of 121 weekly cycles have been administered (median 13 cycles) thus far. A complete hematologic response (CHR; i.e. AEC normalization) was observed in 8 pts (89%) within 4 weeks of therapy; peripheral blood eosinophils were undetectable in 6 of 8 CHR pts. Follow-up bone marrow specimens were available in 3 pts while in CHR (after a median of 5.5 weekly alemtuzumab cycles) showing complete response in 2 and partial response in 1 pt. In addition, 3 pts that were on prednisone and 2 on hydroxyurea at the start of alemtuzumab discontinued them within 2 weeks into therapy. One pt had a remarkable partial response with reduction of AEC from 47.5 to 1×109/L after 8 weekly cycles of alemtuzumab; this patient was on 3g of hydroxyurea and 80mg of prednisone at the start of alemtuzumab and was able to discontinue hydroxyurea and decrease prednisone to 10mg while on alemtuzumab. Five pts who stopped alemtuzumab experienced relapse after a median time of 3.5 weeks (range, 1 to 10) and 1 relapsed while receiving alemtuzumab after 14 weekly cycles. Three pts are currently on alemtuzumab: 2 receiving 30 mg weekly as maintenance while in CHR after 8+ and 19+ weeks, respectively, and 1 with partial response is receiving 30mg 3 times a week. One relapsed pt was rechallenged with alemtuzumab and normalized AEC again. Alemtuzumab was generally well tolerated. Grade 3–4 drug-related toxicities occurred in 2 pts, 1 with neutropenia and 1 with infusion-related fever, which led to transient and complete alemtuzumab discontinuation, respectively. Two pts experienced CMV reactivation that required therapy. In summary, alemtuzumab was well tolerated and has remarkable activity in pts with FIP1L1-PDGFR-α-negative HES. Different dose schedules of alemtuzumab that include prolonged maintenance therapy are warranted to improve the response duration. Updated clinical results will be presented.

Abstract Background : Effective therapy for classical hairy cell leukemia (c-HCL) refractory to purine nucleoside analog (PNA) treatment is limited, and there are no accepted treatment standards for variant hairy cell leukemia (v-HCL). Ibrutinib, an oral small molecule inhibitor of Bruton tyrosine kinase (BTK), has shown single-agent efficacy and acceptable tolerability in patients with various B-cell malignancies, including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's. While BTK is expressed in HCL cells, the clinical activity of ibrutinib in this disease has not been previously assessed. We conducted a single-arm, multi-center phase 2 study (NCI #9268) of single-agent ibrutinib to characterize the overall response rate (complete + partial response) and safety of single-agent ibrutinib treatment for HCL. Methods : Patients with c-HCL (unfit for or relapsed after PNA) and v-HCL (relapsed or treatment-naïve) were eligible. Enrolled patients required treatment, had ECOG ≤ 2, no active infection, and preserved end-organ function. Patients received continuous once daily ibrutinib in 28-day cycles. Using a Simon 2-stage design, the first 13 patients were treated at 420 mg daily, and a second cohort of 13 patients was accrued at the 840 mg dose-level. Ultimately, the pre-specified number of objective responses was reached at the 420 mg dose-level, and accrual to the second stage of the design continues at that dose. Response, including bone marrow biopsy with immunohistochemistry for minimal residual disease (MRD), was assessed after 8 and 12 cycles. Patients experiencing clinical benefit may continue ibrutinib until unacceptable toxicity or progressive disease. Results: As of 15 May 2016, 28 patients had been enrolled and were evaluable for response: 420 mg/day (n=15) and 840 mg/day (n=13). Enrolled patients (1 treatment-naïve v-HCL, 10 relapsed v-HCL, 17 relapsed c-HCL) included 22 male and 6 female patients with median age 65 years (range: 43-78). Relapsed patients received median 4 prior therapies (range: 1-11); all had prior PNA, 81% had prior rituximab, and 3 c-HCL patients had prior vemurafenib. Response data are summarized by dose and histology in the table. To date, the ORR is 46% [4 CR (all c-HCL) and 9 PR (6 c-HCL)], with objective responses more commonly observed in patients with c-HCL. Eight additional patients (29%) with stable disease have experienced clinical benefit (resolution of symptoms, improvement in peripheral blood cell counts) not meeting criteria for PR, most commonly attributable to persistent thrombocytopenia, and continue on treatment. At median follow-up of 22 months, 20 patients (71%) remain on treatment, 3 patients (1 v-HCL, 2 c-HCL) have progressed, 2 patients (c-HCL) with severe neutropenia at baseline (c-HCL) had early deaths from pneumonia, 1 (c-HCL) discontinued during cycle 8 for failure to resolve baseline neutropenia, and 2 other patients (v-HCL) have discontinued for adverse events. Estimated 24-month progression-free survival (PFS) was 79% (95% CI: 57-91%) and the median PFS has not been reached. Redistribution lymphocytosis was observed in patients with circulating disease at baseline. Soluble interleukin-2 receptor (sIL2R) level was increased at baseline in all c-HCL patients for whom data were available and correlated with response. In general, toxicity did not differ by dose level or disease histology. The most frequent (>10%) grade ≥3 adverse events (AEs) were lymphopenia (21%), neutropenia (18%), lung infection (18%), thrombocytopenia (14%), hypophosphatemia (11%), and hypertension (11%). Common grade 1/2 non-hematologic toxicities included myalgia (57%), diarrhea (54%), fatigue (50%), nausea/vomiting (46%), bruising (46%), and rash (46%); grade 1/2 atrial fibrillation (no grade ≥3) was observed in 5 patients. Grade ≥3 infection was observed in 25%, but no grade ≥3 bleeding AEs were reported. Conclusions: Ibrutinib can induce remission in both c-HCL and v-HCL patients, including heavily pre-treated patients, but complete remissions have only been observed in c-HCL to date. The drug is generally well-tolerated during long-term administration, and durable clinical benefit is observed in the majority of treated patients even when objective response criteria are not met. Table 1. Table 1. Figure 1. Figure 1. Disclosures Jones: Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lozanski:Stemline Therapeutics Inc.: Research Funding; Beckman Coulter: Research Funding; Genentech: Research Funding; Boehringer Ingelheim: Research Funding.

Background: Guadecitabine is a next generation subcutaneous (SC) hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a phase 2 study of guadecitabine in 206 AML patients. International guidelines recommend a minimum of 4 to 6 cycles of HMA treatment to gain maximum benefit, but some suggest that treatment may not be beneficial if no response was observed after 4 cycles. No prospective studies have confirmed the correlation between an HMA number of cycles with response and survival using landmark methodology. We present here the results of landmark response and survival analyses based on number of cycles and whether patients had an objective response or not. M ethods: Landmark response (CR, CRi, or CRp based on 2003 IWG criteria, grouped together as composite CR or CRc), and overall survival (OS) analyses for patients alive at or beyond month 3 and month 5 (time of planned start of cycle 4 and cycle 6 respectively) were conducted. Landmark OS was compared between patients who received at least 4 or 6 cycles and those who did not. The landmark methodology avoids the bias of early deaths before cycles 4 and 6 attributing a survival benefit in those who did not die early and were able to get more cycles. We also compared the result in responding and non-responding patients to see if survival benefit was restricted to responding patients only. Results: The study completed enrolment with 206 AML patients: 103 patients (50%) for each of Treatment Naïve (TN) unfit for intensive chemotherapy, and relapsed/refractory (r/r) AML. Median age was 68.5y (range 22-92y), ECOG PS ≥2 in 26%, poor risk cytogenetics in 41%, secondary AML in 26%, and median baseline BM blasts % was 40% in the total AML population. 108 patients (52.4%), and 155 patients (75%) received <4 and <6 cycles respectively. The primary reasons for treatment discontinuation before 4 and 6 cycles respectively (% from the total population of 206 patients) were early progression (20.4, and 30.6%), and early death (12.6%, and 17%). However, 9.7% and 14% discontinued treatment before 4 or 6 cycles respectively as a result other less objective reasons such as patient decision, investigator decision, or adverse events which might have been manageable without treatment discontinuation. The landmark analysis population included 161 patients for 4-cycle analysis, and 133 for the 6-cycle analysis. In those patients, there were no major differences in baseline characteristics between those who received at least 4 or 6 cycles and those who did not. In the landmark analysis comparing those who received at least 4 cycles (97 patients) and those who did not (64 patients), CRc rate was 62% vs 25% (p < 0.0001) and median OS was 13.7 m vs 6.1 respectively (HR 0.53, 95% CI 0.37-0.75, p 0.0003). In the landmark analysis comparing those who received at least 6 cycles (51 patients) and those who did not (82 patients) the CRc rate was 82.4% vs 35.4% (p < 0.0001), and median OS of 19.9 m vs 8.8 m respectively (HR 0.42, 95% CI 0.27-0.64, p <0.0001). The results were consistent when TN and r/r AML patients were analyzed separately. More interestingly the landmark OS benefit in patients who received at least 4 or 6 cycles was also evident in patients who did not have an objective CRc. Patients with no CRc who received at least 4 cycles had a median OS of 8 m vs 5.4 m in those who did not (HR 0.63, 95% CI 0.40-0.98,p 0.04). Patients with no CRc who received at least 6 cycles had a median OS of 12.9 vs 8 m in those who did not (HR 0.40, 95% CI 0.17-0.94, p 0.03). Summary/Conclusions: In a prospective phase 2 study of 206 TN and r/r AML patients treated with the HMA guadecitabine, patients who were alive at or beyond 3 and 5 months who continued treatment for at least 4 or 6 cycles respectively achieved a highly significant response and survival benefit compared to those who discontinued treatment before cycle 4 or 6. The survival benefit was evident even in patients who did not have an objective response. Reasons for treatment discontinuation should be weighed carefully before stopping HMA treatment with guadecitabine before 4 or 6 cycles in AML patients to maximize response and survival benefit. Failure to achieve an objective response after 4 cycles should not be a reason for treatment discontinuation as long as patient can still benefit. Disclosures Yee: MedImmune: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Research Funding; Hoffman La Roche: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millennium: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Roboz:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: 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; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees. O'Connell:BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Griffiths:Boston Scientific: Consultancy; Boston Scientific: Consultancy; Abbvie, Inc.: Consultancy; Persimmune: Consultancy; Genentech, Inc.: Research Funding; Novartis Inc.: Consultancy; Novartis Inc.: Consultancy; New Link Genetics: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Partner Therapeutics: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; New Link Genetics: Consultancy; Abbvie, Inc.: Consultancy, PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Onconova Therapeutics: Other: PI on a clinical trial; Partner Therapeutics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Persimmune: Consultancy; Celgene, Inc: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Genentech, Inc.: Research Funding. Stock:Daiichi: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Savona:AbbVie: Membership on an entity's Board of Directors or advisory committees; Selvita: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ravandi:Macrogenix: Consultancy, Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Xencor: Consultancy, Research Funding. Daver:Astellas: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Forty-Seven: Consultancy; Incyte: Consultancy, Research Funding; Servier: Research Funding; Incyte: Consultancy, Research Funding; NOHLA: Research Funding; Jazz: Consultancy; Glycomimetics: Research Funding; NOHLA: Research Funding; Abbvie: Consultancy, Research Funding; Agios: Consultancy; Celgene: Consultancy; Sunesis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astellas: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Forty-Seven: Consultancy; Agios: Consultancy; Otsuka: Consultancy; Jazz: Consultancy; Immunogen: Consultancy, Research Funding; Glycomimetics: Research Funding; Sunesis: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Karyopharm: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Otsuka: Consultancy; Celgene: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Servier: Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding. Jabbour:AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Adaptive: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Su:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Kantarjian:Pfizer: Honoraria, Research Funding; Astex: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; Takeda: Honoraria; Immunogen: Research Funding; Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; BMS: Research Funding; Ariad: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding.

Abstract Background: Blasts and leukemic stem cells of acute myeloid leukemia (AML) as well as several other hematologic malignancies express CD123, potentially providing a target for novel therapies. XmAb14045 (also known as SQZ622) is a potent bispecific antibody targeting both CD123 and CD3 that stimulates targeted T cell-mediated killing of CD123-expressing cells, regardless of T cell antigen specificity. It is a full-length immunoglobulin molecule designed to be dosed intermittently, in contrast to smaller constructs that are referred to as "DART" or "BiTE" bispecific antibodies that require a continuous infusion. Methods: Patients with relapsed or refractory AML, B cell acute lymphoblastic leukemia (B-ALL), blast phase chronic myelogenous leukemia, or blastic plasmacytoid dendritic cell neoplasm were eligible to enroll on this first-in-human, multicenter, open-label phase 1 dose-escalation study (XmAb14045-01) with standard 3+3 design. The primary objective was to estimate the maximum tolerated dose (MTD) or recommended dose and schedule of XmAb14045. Secondary objectives included safety, preliminary antileukemic activity, and pharmacokinetics/pharmacodynamics of XmAb14045. Treatment was administered weekly in 28 day cycles, using a weight-based dose with a single dose level in Part A and, in Part B, an initial priming dose on Day 1 followed by an escalated dose on subsequent weeks. Premedication to prevent cytokine release syndrome (CRS) was instituted as needed and included a steroid, acetaminophen, and diphenhydramine. Patients were premedicated at all XmAb14045 doses ≥0.075 µg/kg. Therapy was continued for as long as tolerated and there was continuing evidence of therapeutic benefit in the opinion of the investigator. Treatment response was assessed by the 2017 European LeukemiaNet (ELN) criteria after Cycle 1 and after each odd-numbered cycle. CRS was graded using the CRS revised grading system (Lee et al., Blood, 2014). Results: At data cut-off, 64 patients have been treated to date, 63 with relapsed/refractory AML and 1 with B-ALL. Patients had a median age of 61 years and were heavily pretreated (median of 3 prior therapies [range 1-8], including 19 [30%] who had undergone prior allogeneic stem cell transplantation). The recommended dose for Part A was 1.3 µg/kg after a single dose-limiting toxicity of Grade 4 CRS at 2.3 µg/kg; no MTD has been identified. CRS or its component symptoms was the most common treatment-emergent adverse event (TEAE). CRS episodes began within approximately 1-4 hours of the start of drug infusion and occurred in 49 of 64 patients (77%). Seven patients (11%) developed Grade ≥3 CRS, the majority of these on the first dose. There were no CRS-related deaths. Excluding CRS-related events, additional TEAEs occurring in >10% of patients included fatigue (31%), febrile neutropenia (30%), peripheral edema (30%), cough (23%), elevated hepatic transaminases (19%; all recovered without sequelae), pneumonia (17%), stomatitis (14%), hyperglycemia (13%), and sepsis (11%). No myelosuppression requiring dose modification or evidence of tumor lysis syndrome was seen. In Part A, single agent antileukemic activity was documented with a best response of CR (2) or CRi (1) in 3/13 AML patients (CR/CRi rate 23%) treated at the two highest dose levels studied to date (1.3 and 2.3 µg/kg weekly); no CR, CRi, or morphologic leukemia-free state (MLFS) responses were seen at lower doses. Antileukemic activity occurred quickly; all responders had achieved at least an MLFS response after 4 doses (1 cycle). Two responders were bridged to stem cell transplantation, and the third was ineligible for medical reasons but remains in remission at 14+ weeks after initiating therapy. Conclusions: XmAb14045 demonstrated evidence of antileukemic activity in heavily pretreated patients with relapsed/refractory AML treated in Part A at the 1.3 and 2.3 µg/kg doses administered once weekly, with a 23% CR/CRi rate. CRS was the most common toxicity but was generally manageable with premedications. The study is ongoing with further optimization of dose, schedule, and premedication regimen for CRS anticipated during accrual to dose escalation cohorts in Part B. ClinicalTrials.gov Identifier: NCT02730312 Disclosures Ravandi: Xencor: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Jazz: Honoraria; Sunesis: Honoraria; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Orsenix: Honoraria; Xencor: Research Funding; Orsenix: Honoraria; Jazz: Honoraria; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding. Foran:Xencor, Inc.: Research Funding; Agios: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Mawad:Swedish Cancer Institute: Employment. Blum:Astellas: Consultancy; Pfizer: Consultancy; Boehringer Ingelheim: Research Funding; Forma: Research Funding; Xencor: Research Funding; Tolero: Research Funding. Saville:Xencor, Inc.: Employment, Equity Ownership. Johnson:Xencor, Inc.: Employment, Equity Ownership. Vanasse:Novartis: Employment, Equity Ownership. Ly:Xencor, Inc.: Employment, Equity Ownership. Mims:Novartis: Consultancy; 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.