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The use of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL fusion protein have dramatically changed the clinical management and outcomes for patients with chronic myelogenous leukemia (CML)...

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.

The diagnosis of pure erythroid leukemia (PEL) can be challenging. Prompt identification of CD45+, CD34‐, CD71+, CD117+, and E‐cadherin+ erythroblasts is important. The differential diagnosis is broad and includes megaloblastic anemia.

Internal tandem duplications and tyrosine kinase mutations in the fms-like tyrosine kinase 3 (FLT3) receptor can occur in acute myeloid leukemia (AML) and portend a poor prognosis. Midostaurin, a multikinase inhibitor that targets FLT3, demonstrated a survival benefit in FLT3-mutated AML in combination with front-line chemotherapy. Despite this advancement, the use of FLT3 inhibitors in clinical practice is complicated by significant drug-drug interactions and uncertainty about optimal timing, duration, and sequencing of therapy. As monotherapy, the utility of FLT3 inhibitors was initially limited by incomplete and transient clinical responses and the development of acquired resistance. This led to the development of more potent and selective FLT3 inhibitors designed to overcome common resistance mechanisms. One of these second generation FLT3 inhibitors, gilteritinib, is now FDA-approved for the treatment of relapsed or refractory AML. Now that multiple FLT3 inhibitors are commercially available, it is important to further delineate the role of these agents in the AML population. This review aims to provide a comprehensive overview of the role of FLT3 inhibitors in AML and apply the current literature to clinical practice.

Conventional karyotyping is essential standard practice in the initial evaluation of myelodysplastic syndrome (MDS) and is the most impactful single component of the Revised International Prognostic Scoring System (IPSS-R). While single nucleotide polymorphism array (SNP-A) has demonstrated the ability to detect chromosomal defects with greater sensitivity than conventional karyotype, widespread adoption is limited by the unknown additional prognostic impact of SNP-A analysis. Here, we investigate the significance of additional SNP-A abnormalities in the setting of MDS and demonstrate differences in survival of patients with additional abnormalities, even those initially characterized as relatively lower risk either by cytogenetic score or IPSS-R. Our findings identify specific abnormalities, particularly KMT2A partial tandem duplication, that are invisible to conventional karyotype and potentially contribute to the poor prognosis of MDS patients. Furthermore, these results demonstrate the added value of SNP-A analysis in identifying patients who may benefit from more aggressive therapy, particularly those who would otherwise be classified into lower risk categories.

Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. Recent advances have resulted in an expansion of treatment options for AML, especially concerning targeted therapies and low-intensity regimens. This portion of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML focuses on the management of AML and provides recommendations on the workup, diagnostic evaluation and treatment options for younger (age

Myelodysplastic syndromes (MDS) are a heterogeneous category of myeloid neoplasms that represent the most common class of acquired bone marrow failure syndromes in adults. MDS is typically associated with a hypoproliferative macrocytic anemia, but atypical findings on initial diagnostic evaluations can raise concern for a distinct pathophysiological process and lead to the investigation of alternative etiologies. Here, we report a case of MDS with a concomitant hypoproliferative microcytic and hypochromic anemia that led to the identification of acquired hemoglobin H due to a novel somatic ATRX mutation.

BACKGROUND The introduction of tyrosine kinase inhibitor (TKI) therapy has dramatically improved outcomes for patients with chronic myeloid leukemia (CML); however, the prognosis for those who do not meet treatment milestones remains guarded. Here, we report our experience of patients with CML treated at a single center who did not achieve a complete cytogenetic response (CCyR) at 24 months. METHODS We retrospectively evaluated 305 patients who were diagnosed with CML at the University of Michigan between 2001 and 2014 and were treated with TKIs. We assessed rates of CCyR at 24 months correlated to clinical outcomes. RESULTS The majority of patients (79%) achieved CCyR at 24 months and were classified as responders. At a median follow-up of 8.1 years from TKI initiation, overall survival among responders was significantly greater than nonresponders (93% vs. 85%, P < .001). Progression to blast phase was more common in nonresponders (1.9% vs. 10.4%, P = .004). However, 34% of nonresponders (at 24 months) went on to achieve CCyR with continued TKI therapy. CONCLUSION Here, we re-demonstrate the importance of early CCyR in predicting survival and prevention of progression to blast phase. In addition, late CCyR appears to have prognostic implications, and continued TKI therapy with the goal of achieving a later CCyR may be a reasonable strategy in patients with limited alternate treatment options.

Uproleselan (GMI-1271) is a novel E-selectin antagonist that disrupts cell survival pathways, enhances chemotherapy response, improves survival in mouse xenograft and syngeneic models, and decreases chemotherapy toxicity in vivo. A phase 1/2 study evaluated the safety, tolerability, and antileukemic activity of uproleselan (5-20 mg/kg) with MEC (mitoxantrone, etoposide, and cytarabine) among patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Among the first 19 patients, no dose-limiting toxicities were observed. The recommended phase 2 dose (RP2D) was 10 mg/kg twice daily. An additional 47 patients with R/R AML were treated with uproleselan at the RP2D plus MEC. At the RP2D, the remission rate (complete response [CR]/CR with incomplete count recovery [CRi]) was 41% (CR, 35%), and the median overall survival (OS) was 8.8 months. In a separate cohort, 25 newly diagnosed patients age ≥60 years received uproleselan at the RP2D plus cytarabine and idarubicin (7 + 3). In these frontline patients, the CR/CRi rate was 72% (CR, 52%), and the median OS was 12.6 months. The addition of uproleselan was associated with low rates of oral mucositis. E-selectin ligand expression on leukemic blasts was higher in patients with relapsed vs primary refractory AML and in newly diagnosed older patients with high-risk cytogenetics and secondary AML. In the R/R cohort, E-selectin expression >10% was associated with a higher response rate and improved survival. The addition of uproleselan to chemotherapy was well tolerated, with high remission rates, low induction mortality, and low rates of mucositis, providing a strong rationale for phase 3 randomized confirmatory studies. This trial was registered at www.clinicaltrials.gov as #NCT02306291.

Background: All-trans retinoic acid (ATRA) serves as the backbone of the management of patients with acute promyelocytic leukemia (APL), with guidelines recommending the initiation of ATRA as soon as APL is suspected. As a regional referral center for patients with acute leukemia, those who are suspected of having APL are often transferred to our facility. However, many referring centers are unable to initiate treatment using ATRA. We conducted an exploratory analysis of the clinical availability of ATRA and the factors limiting access to this critical drug. Patients and Methods: The United States was divided into 6 geographic regions: Northwest, Southwest, Central, Southeast, Northeast, and the Great Lakes. Twenty hospitals were randomly selected from states within each of these regions and were surveyed as to whether they typically treated patients with acute leukemia, the availability of ATRA at their institution, and reported reasons for not stocking ATRA (if not available). Results: Less than one-third of hospitals queried (31%) had ATRA in stock. Neither the size of the hospital nor the hospital’s status as academic versus nonacademic (53% vs 31%; P=.08) influenced ATRA availability. Of the hospitals that referred patients with APL, only 14% (7/49) had ATRA readily available. Hospitals that treated patients with APL were more likely to have ATRA available than referring centers (58% vs 14%; P=.000002). Conclusions: Nearly two-thirds of the hospitals surveyed that cared for patients with acute leukemia do not have ATRA immediately available. Moreover, the vast majority of hospitals that refer patients to other centers do not have ATRA. These findings should spur investigation into the impact of immediate ATRA availability on the morbidity and mortality of patients with APL. A call by hematologists nationwide to their formulary committees is warranted to ensure that this lifesaving medication is available to patients suspected of having APL.

Supplemental Digital Content is available in the text., Objectives: Leukostasis is a life-threatening complication of acute hyperleukocytic leukemia, and is associated with substantial mortality. Management of leukostasis requires time-sensitive diagnostics and therapeutics, and leukapheresis remains a mainstay of treatment in select patients. Leukapheresis requires coordination of multi-disciplinary resources, which can prove challenging in the emergency department setting, and delays in treatment due to the complexity and coordination required are common. The objective of this study was to assess the effect of utilization of an emergency department-ICU and a multidisciplinary care pathway on outcomes of critically ill leukostasis patients presenting to the emergency department. Design: Retrospective cohort study. Setting: Single large academic medical center in the United States. Patients: Adult emergency department patients with signs and symptoms of leukostasis requiring emergent leukapheresis from 2012-2019. Interventions: Implementation of a hybrid emergency department-ICU setting (emergency critical care center) and a multidisciplinary care pathway with members from Emergency Medicine, Hematology, Blood Bank, and Clinical Pathology. Measurements and Main Results: A total of 70 patients were identified and included for analysis: 14 preemergency critical care center; 32 postemergency critical care center, premultidisciplinary care pathway; and 24 postemergency critical care center, postmultidisciplinary care pathway. A statistically significant reduction in the time from emergency department presentation to initiation of leukapheresis was observed from preemergency critical care center to postemergency critical care center, premultidisciplinary care pathway and postemergency critical care center, postmultidisciplinary care pathway (11.5 vs 7.9 vs 7.7 hr; p = 0.004). Statistically significant reductions in in-hospital mortality were observed from preemergency critical care center to postemergency critical care center, premultidisciplinary care pathway and postemergency critical care center, postmultidisciplinary care pathway (64.3% vs 21.9% vs 25.0%; p = 0.01). A trend toward decreased inpatient ICU utilization was observed, although was not statistically significant (35.7% vs 12.5% vs 25.0%; p = 0.14.) Conclusions and Relevance: Implementation of a multidisciplinary care pathway via use of an emergency department-ICU for critically ill patients with leukostasis was associated with statistically significant reductions in time to leukapheresis and in-hospital mortality. These findings suggest an emergency department-ICU model may allow for maximal resource and care coordination at the point of contact with critically ill patients and improved clinical outcomes.

Fibroblast growth factor 23 (FGF23)–induced hypophosphatemia is a rare paraneoplastic syndrome of phosphate wasting that, if unrecognized, may cause tumor-induced osteomalacia. It is classically associated with benign mesenchymal tumors but occasionally has been found in patients with other malignancies. Hypophosphatemia has been associated with acute leukemia but has not previously been reported to be due to inappropriate FGF23 secretion. Here, we describe FGF23-induced severe hypophosphatemia and renal phosphate wasting associated with a mixed-phenotype Philadelphia chromosome-like acute leukemia in a previously healthy 22-year-old man. He was found to have low serum 1,25-dihydroxyvitamin D and extremely high FGF23 levels, as well as inappropriate urinary phosphorus excretion. The hypophosphatemia improved with calcitriol and oral phosphate treatment but normalized only during chemotherapy-induced ablation of the blasts. FGF23 levels declined with a reduction in peripheral blast counts. Using real-time reverse transcription polymerase chain reaction, we found that the leukemia cells were the source of FGF23. To our knowledge, this is the first description of FGF23-induced hypophosphatemia associated with acute leukemia. We recommend that the FGF23 paraneoplastic syndrome be considered as a possible etiology of hypophosphatemia in patients with acute leukemia., A young man with refractory mixed-phenotype Philadelphia chromosome-like acute leukemia was found to have phosphaturic hypophosphatemia associated with expression of FGF23 by his leukemia cells.

Background: Myelodysplastic syndromes (MDS) represent a heterogeneous group of malignancies that are characterized by aberrant hematopoiesis and consequently abnormal blood counts. Patients with MDS have an increased likelihood of developing acute myeloid leukemia (AML). Next generation sequencing (NGS) is currently being used to study the genetic landscapes of diverse cancer types in finer detail than has previously been possible, owing to its ease-of-use and widespread availability. Crucially, the accuracy and broad breadth of genomic coverage provided by NGS approaches may permit the study of mutations that are rare in MDS patients, yet well studied in AML or other cancer types. Based on the fact that much less is known about particular rare somatic mutations in MDS, we decided to investigate 6 genes. IDH1 and IDH2 are targetable in patients with AML. Mutations in JAK2 are found in high proportions in patients with myeloproliferative neoplasms (MPNs) or MDS/MPN overlap neoplasms. Finally, other mutations in genes such as BCOR, BCORL1, and MUTYH also occur in MDS patients with appreciable-but generally low-frequencies such that their overall impact on MDS patients is largely unknown. Methods: We utilized the Tempus LENS platform to retrospectively characterize 236 MDS patients who underwent genomic-testing with the Tempus|xT assay (DNA-seq of 595-648 genes at 500x coverage; full transcriptome RNA-seq; data accessed on 06/28/2021). The patient population was 28% female, with a median age of 71.6 years. Mutations identified included germline and/or somatic single nucleotide variants (though we only considered somatic variants in this study), insertions/deletions and copy number variations (gains defined as ≥8 copies). For a subset of patients processed at Rush University Medical Center (RUMC), we additionally performed a curated clinical investigation into laboratory variables, prognostic data, treatment history and outcomes data. Results: Within the Tempus MDS dataset, we observed a range of mutation frequencies. In total, 58 patients had mutations in at least one of either: JAK2, BCOR, IDH2, IDH1, BCORL1, and MUTYH. When comparing the observed frequencies against values that have previously been reported, mutations in these 6 genes occurred with higher frequency in our dataset while most other mutations were in accordance with the relative frequencies reported by other sources (Table 1). We observed the largest deviation from expectation for BCOR. Whereas prior reports list this mutation as occurring with a frequency of Conclusions: We identified a higher frequency of BCOR/BCORL1 mutations among patients with MDS than has been previously reported. At the same time, most other mutation frequencies were in relative accordance with existing reports. We observed complex cytogenetic abnormalities in 75% of patients for which we had extensive clinical information. Our data suggest an association between BCOR/BCORL1 mutations and complex karyotypes, a finding that may establish a prognostic role of BCOR/BCORL1 and have potential therapeutic implications. This hypothesis is, however, subject to further investigation and will require larger sample sizes that are likely to become available with the rapidly increasing utilization of next generation sequencing techniques and availability of high-quality, curated clinical information. Figure 1 Figure 1. Disclosures Hockenberry: Tempus Labs, Inc: Current Employment, Current holder of stock options in a privately-held company. Okeke: Tempus Labs, Inc: Current Employment. Mahon: Tempus Labs, Inc: Current Employment. Hassane: Tempus Labs, Inc: Current Employment. Enschede: Tempus Labs, Inc: Current Employment, Current holder of stock options in a privately-held company. Shammo: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Astra zeneca: Research Funding; CTI pharma: Research Funding; Stemline therapeutics: Research Funding; Kartos Pharma: Research Funding; Takeda: Consultancy, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Honoraria, Research Funding; Abbvie: Current holder of individual stocks in a privately-held company, Research Funding; Baxter: Current holder of stock options in a privately-held company; sanofi: Consultancy, Honoraria, Speakers Bureau; NS Pharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Apellis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Introduction Blast-phase (BP), or leukemic transformation is a rare and devastating complication of myeloproliferative neoplasms (MPNs) (primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET), and post-PV/ET myelofibrosis). Patients with BP-MPNs have a poor prognosis with a median overall survival of less than 6 months, and there is no standard treatment regimen for these aggressive diseases (Dunbar et al, Blood. 2020). The development of hypomethylating agent (HMA)/venetoclax (Ven) combination offers new hope for some with AML, but has been relatively disappointing in BP-MPN, though data are limited and retrospective (Masarova et al, Blood Adv. 2021; Gangat et al, Am J Hematol. 2021). Here, we add our experience with several common treatment regimens for BP-MPN. Methods We retrospectively analyzed data from 39 consecutive patients with BP-MPNs diagnosed from December 2008 to February 2021 who received treatment at the University of Michigan. We included all patients with a previous diagnosis of MPNs who had ≥ 20% blasts in the peripheral blood or bone marrow, and subsequently received systemic therapy. One patient with a myeloid sarcoma was included as well. Disease characteristics at time of BP-transformation were noted. Patients were divided into the following groups based on 1 st-line induction therapy: 7+3 (daunorubicin and cytarabine), FLAG (fludarabine, high-dose cytarabine and G-CSF), hypomethylating agent only (decitabine or azacitidine), and HMA/Ven. Patients were followed for 2 years post-diagnosis. Differences in induction response were assessed using the Chi-square test. Differences in overall survival were calculated using the Kaplan-Meier regression with the log-rank test. Two patients who received alternate induction therapy outside of the four groups were not included in these analyses. Results The composite BP-MPN population had a median advanced age of 69 years old and a median ECOG performance status (PS) of 1. Most (97.4%) had received systemic treatment prior to their transformation for their MPN, with 71.8% receiving hydroxyurea and 41.0% receiving ruxolitinib. The rate of response (CR, CRi, MLFS) was highest in the HMA/Ven group at 42.9%, followed by FLAG (29.4%), HMA only (11.1%), and 7+3 (0%), p = 0.033 (Table 3). Despite the higher response rate, differences in 2-year OS were not significantly different among the 4 groups: 7+3 (25.0%), FLAG (7.7%), HMA (0%), HMA/Ven (20.0%) (p=0.92, Figure 1). Median time to relapse after achieving remission ranged from 2-10 months, and did not vary significantly based on induction regimen. Patients in the HMA and HMA/Ven groups had higher incidences of death with induction at 77.8% and 28.6%, respectively (Table 3). Conclusions The highest rates of response, including complete remission, were achieved with the combination of HMA and venetoclax compared to intensive induction chemotherapy or HMA alone. However, this did not translate into significant differences in OS, which is consistent with other retrospective reports. No responses were seen with 7+3 induction, though several patients were able to go on salvaged with other therapies and subsequent allogeneic stem cell transplantation thereafter. Finally, the baseline poor ECOG PS of the HMA group and borderline ECOG PS of the HMA/Ven group also contribute to their low survival rates.Larger, prospective studies comparing currently available treatment regimens in BP-MPN would be helpful, but ultimately new therapies are desperately needed for this high-risk disease. Figure 1 Figure 1. Disclosures Bixby: Takeda: Consultancy. Talpaz: Constellation: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Grant/research support ; Celgene: Consultancy; Imago: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Introduction: Cytarabine is a backbone of intensive acute myeloid leukemia (AML) chemotherapy; yet it is associated with toxicity which precludes its use in older patients and in those with comorbidities. Aspacytarabine (BST-236) is a prodrug of cytarabine, which is inactive in its intact prodrug form until cytarabine is gradually released in the plasma and inside the cells. Due to the pharmacokinetics and metabolism of aspacytarabine, the peak toxic systemic exposure to cytarabine is decreased, resulting in reduced systemic toxicity with relative sparing of normal tissues, thus enabling delivery of high cytarabine doses to AML patients otherwise unfit to receive intensive cytarabine therapy. Presented herein are the data, including final primary endpoint analysis, from a phase 2b study that recently completed enrollment. Aims: To evaluate the efficacy and safety of aspacytarabine as a single agent for induction and consolidation therapy of newly diagnosed AML patients unfit for standard induction chemotherapy. Methods: Aspacytarabine was administered at 6-day courses of 4.5 g/m 2/d (equimolar to 3 g/m 2/d cytarabine) daily 1-hour intravenous infusions, for 1-2 induction and 1-3 consolidation courses, to AML patients age ≥75 years or otherwise unfit for intensive chemotherapy. Patients with secondary or therapy related AML, and patients who received prior hypomethylating agents (HMA) ± venetoclax therapy for a preceding condition were eligible. Primary endpoint is complete remission with complete hematological recovery (CR). Secondary and exploratory endpoints include safety, duration of response (DOR), overall survival (OS), and minimal residual disease (MRD). NCT03435848. Results: Enrollment into the study was completed in May 2021. Sixty-five newly diagnosed AML patients unfit for standard chemotherapy (median age 75 years, range 54-88 years) were treated with aspacytarabine and completed 1-4 courses (median 1 course) at doses of 4.5 g/m 2/d, including 39 patients (60%) with de novo AML and 26 patients (40%) with secondary AML. Eleven patients (17%) were previously treated for MDS/CMML with HMA (median 14 courses), including 1 patient (2%) with HMA + venetoclax. Thirty-two patients (49%) and 15 patients (23%) had adverse or intermediate European LeukemiaNet (ELN) scores, respectively. The baseline median bone marrow blasts was 43%, and 25 patients (38%) had ECOG PS 2 or 3 at enrollment (Table 1). Aspacytarabine was well-tolerated in repeated-course administration. Grade ≥3 drug-related adverse events included hematological events and infections, with, importantly, no severe gastrointestinal or neurological events. The 30-day all-cause mortality rate was 12.5% (95% CI, 5.9-23.7). Of the 65 intention-to-treat AML patients, 24 (37%) achieved a CR following 1 (17 patients) or 2 (7 patients) courses. The median time to complete neutrophil and platelet recovery were 27 days (range 11-39 days) and 26 days (range 18-40), respectively. The CR rates in de novo and secondary AML patients were 44% and 27%, respectively. Twenty-seven percent of the patients with prior HMA therapy achieved a CR, including the 1 patient with prior HMA + venetoclax treatment. The CR rates in patients at the age of ≥75 years and patients with adverse ELN scores were 35% and 34%, respectively. Of the 21 patients in CR evaluable to date for MRD analysis by multiparameter flow cytometry, 11 (52%) became MRD negative following aspacytarabine treatment. Follow up is ongoing, with a current median duration of follow up of 5.2 months. The median DOR has not yet been reached at 12 months, and median OS of responders not reached at 24 months (Figure 1). Conclusions: Aspacytarabine appears to be an effective regimen for AML with a considerable reduction of the attendant toxicities that typically are associated with standard intensive cytotoxic therapies. The results of the phase 2b study are consistent with the previously completed phase 1/2a study, which demonstrated safety and a 36% CR rate in a similar population, suggest that aspacytarabine, given as monotherapy, is generally safe and effective as a first-line therapy for AML patients who are unfit for intensive chemotherapy These data support a role for aspacytarabine as a new treatment option for older patients with AML. Furthermore, this agent may serve as a backbone for combination therapy with targeted or other chemotherapy agents, as well as in younger patients with AML. Figure 1 Figure 1. Disclosures Altman: Boehringer Ingelheim: Research Funding; BMS: Research Funding; Immunogen: Research Funding; Syros: Consultancy; GlycoMimetics: Other: Participation on an advisory board; Daiichi Sankyo: Consultancy; AbbVie: Consultancy, Other: Advisory Board, Research Funding; Fujifilm: Research Funding; Kura Oncology: Consultancy; Kartos: Research Funding; Biosight: Consultancy, Other: Travel fees, Research Funding; Astellas: Consultancy, Other: Advisory Board, Research Funding; ALZ Oncology: Research Funding; Amgen: Research Funding; Aprea: Research Funding; Theradex: Consultancy, Other: Advisory boards; Kura: Research Funding. Koprivnikar: Bristol Myers Squibb: Speakers Bureau. McCloskey: Amgen: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy; Incyte: Speakers Bureau; BMS: Honoraria, Speakers Bureau; COTA: Other: Equity Ownership. Kota: Pfizer: Consultancy; Novartis: Consultancy; Incyte: Research Funding. Emadi: Secura Bio.: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; NewLink Genetics: Research Funding; Jazz Pharmaceuticals: Research Funding; KinaRx, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Co-founder. Zuckerman: BioSight Ltd: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Orgenesis Inc.: Honoraria; Cellect Biotechnology: Honoraria; Novartis: Honoraria; Gilead Sciences: Honoraria, Speakers Bureau. Levy: Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Other: Promotional speaker; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Epizyme: Consultancy, Other: Promotional speaker; Dova: Consultancy, Other: Promotional speaker. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Wolach: Novartis: Consultancy; Amgen: Research Funding; Janssen: Consultancy; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy; Neopharm: Consultancy. Percival: AbbVie: Research Funding; Biosight: Research Funding; BMS/Celgene: Research Funding; Cardiff Oncology: Research Funding; Glycomimetics: Research Funding; Nohla therapeutics: Research Funding; Oscotec: Research Funding; Pfizer: Research Funding; Trillium: Research Funding. Roboz: Actinium: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; Jazz: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Mesoblast: Consultancy; Glaxo SmithKline: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Janssen: Research Funding; Daiichi Sankyo: Consultancy; Blueprint Medicines: Consultancy; Bristol Myers Squibb: Consultancy; Helsinn: Consultancy; Jasper Therapeutics: Consultancy; Astellas: Consultancy; Astex: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Otsuka: Consultancy; Roche/Genentech: Consultancy. Levi: AbbVie: Consultancy, Research Funding. Flaishon: BioSight Ltd.: Current Employment. Cohen: BioSight Ltd.: Current Employment. Tessler: BioSight Ltd.: Current Employment. Blumberg: BioSight Ltd.: Current Employment. Gengrinovitch: BioSight Ltd.: Current holder of individual stocks in a privately-held company. Ben Yakar: BioSight Ltd.: Current Employment. Rowe: Biosight Inc.: Consultancy.

Introduction Aplastic anemia is a challenging disease to treat due to its rarity and severity. The current standard of care for severe and very severe aplastic anemia includes consideration of frontline allogeneic stem cell transplant (ASCT) in patients who are under 40 years of age and have an HLA-matched sibling. For patients who do not meet this criteria, immunosuppressive therapy (IST) consisting typically of horse antithymocyte-globulin (ATG) and cyclosporine (CsA) is considered, with recent data supporting the addition of eltrombopag. The main risks of IST are infusion reactions, serum sickness, kidney injury, and infection. While it is generally well tolerated in younger patients, older patients have historically been treated with transfusion support alone due to concerns for higher complications. Unfortunately, data to support clinical decisions regarding these concerns is limited, with small studies showing that reduced dosing or attenuated doses of ATG with or without CsA is safe and can be effective. At the University of Michigan, we have been treating older patients with attenuated doses of ATG +/- CsA since the late-2000s and have recently added eltrombopag to our standard of care. Herein, we present the results of our experience using IST to treat aplastic anemia, specifically presenting our outcomes in patients over 60 years old at the time of initiation of IST. Methods We used the Electronic Medical Record Search Engine (EMERSE) to query patients with aplastic anemia who were treated at the University of Michigan between 1995 and 2021. Patients included in our analysis were diagnosed with idiopathic aplastic anemia or hepatitis-associated aplastic anemia, were 18 years or older at the date of initiating IST, were treated with IST first-line, had adequate physician follow up at the University of Michigan, and were reported as being complaint with IST. Patients diagnosed or with high concern for hypoplastic myelodysplastic syndrome (MDS) were excluded in addition to those who received treatment for paroxysmal nocturnal hemoglobinuria (PNH). Statistical analysis was performed using SPSS Statistics v.27 (IBM, 2020). Results We identified 62 patients aged 18 - 60 and 54 patients over 60 years old who met inclusion criteria. Descriptive statistics of the two cohorts are available in Table 1. All patients in our study received horse ATG in addition to cyclosporine. 63% of patients over 60 received full dose horse ATG (20mg/kg for 5 days) and 37% received attenuated horse ATG (20mg/kg for 5 days), while 46% received eltrombopag as part of their IST. OS was superior in patients 18-60 receiving IST with median OS NR vs. 2760 days (Figure 1; p=0.009). In patients over 60, no difference in OS was observed in those who received attenuated (3646 days) vs. full dose IST (2760 days) (Figure 2, p=0.83). Lastly, no difference in median OS was seen in patients > 60 years old who received eltrombopag compared to those who did not (2821 vs 2760 days, Figure 3, p=0.795). Using a Chi-squared test, no statistically significant differences in rates of PR at 12 months, CR at 12 months, primary refractory disease, febrile neutropenia within 6 months of IST, bacterial infections within 6 months IST, and viral infections within 6 months of IST were noted between those who received dose attenuated ATG and those who received full dose ATG in patients > 60. PR in older patients was 48% (12) and 36% (9) at 3 and 12 months with eltrombopag, compared to 40% (10) and 36% (9) without. CR in older patients was 12% (3) and 16% (4) with eltrombopag at 3 and 12 months, compared to 12% (3) and 12% (3) without. In patients > age 60 who received dose attenuated IST, the addition of eltrombopag did not affect OS (Figure 4). A trend toward better OS was seen in patients 18-60 who received eltrombopag, but this was not statistically significant (Figure 5). Discussion In conclusion, we present our experience using IST to treat aplastic anemia at the University of Michigan. Dose attenuated IST has been proposed as a potential option for elderly patients, but we found no significant difference in OS, rates of response, or rates of infection between patients who received full dose and those who did not. There was also a trend toward improved survival with the addition of eltrombopag in younger patients, but additional follow up time is needed. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. Recent advances have resulted in an expansion of treatment options for AML, especially concerning targeted therapies and low-intensity regimens. This portion of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML focuses on the management of AML and provides recommendations on the workup, diagnostic evaluation and treatment options for younger (age

Objectives The incidence of Clostridium difficile infection (CDI) in adults with malignancy is 7%-14% compared with 1%-2% in the general hospitalized population. Despite the increased incidence of CDI in this population, a major concern is the propensity of CDI to recur, leading to delays in therapy impacting outcomes. We conducted a retrospective case-control study to identify risk factors for recurrent CDI (rCDI) and to determine the impact of rCDI on adult patients with a haematological malignancy. Methods Adult haematology patients with CDI from June 2010 to December 2014 were divided into two groups: rCDI and non-rCDI. Multivariable models using logistic regression were constructed to identify risk factors for rCDI. Results A total of 100 patients in our study yielded a 41% recurrence rate. CDI impacted chemotherapy significantly more in the rCDI group (53.7% versus 11.9%, P

Introduction: RARA-positive (RARA+) AML patients represent a subset of non-APL AML characterized by high RARA expression levels, which can be identified by a novel blood-based biomarker test that predicts sensitivity to SY-1425, an oral selective RARα agonist (McKeown, Cancer Discovery 2017; Vigil, ESH 2017). Approximately 30% of relapsed/refractory (R/R) AML patients are RARA+, similar to the prevalence in newly diagnosed (ND) unfit AML (Vigil, ESH 2017). Evidence of synergistic activity of SY-1425 with azacitidine (aza) in preclinical models supported clinical development of the combination (McKeown, Haematologica 2018), which is currently being evaluated in RARA+ R/R AML and ND unfit AML (NCT02807558). Early data of SY-1425 in combination with aza demonstrated a high CR rate and a rapid onset of response in RARA+ ND unfit AML (Cook, ASH 2018; de Botton, ESH 2019), supporting evaluation of the combination in a RARA+ R/R cohort. Initial data for the RARA+ R/R AML cohort are presented here. Methods: RARA+ R/R AML patients enrolled on the trial received aza at 75 mg/m2 IV/SC daily on days 1-7 followed by SY-1425 at 6 mg/m2/day PO in divided doses twice daily on days 8-28 of each 28-day cycle. Objectives included characterization of activity by overall response rate (ORR) per IWG criteria, characterization of composite complete response rate, time to response, overall survival (OS), and evaluation of safety. Results: A total of 28 patients were treated, with data available through 27 May 2020 reported here. Baseline characteristics included 13 (46%) male, median age 74 (30-87), and 12 (43%) with marrow blasts > 30%. Patients were heavily pretreated with 12 (43%) having received 3 or more prior regimens, including 19 (68%) with prior HMA and/or venetoclax treatment; 17 (61%) with prior HMA; and 9 (32%) with prior venetoclax in combination with HMA or LDAC. Nine (32%) patients were reported as both HMA and venetoclax naïve. Two (7%) had received prior allogenic stem cell transplant. Time on treatment was up to 6.5 months. 17 (61%) patients had discontinued treatment, most commonly due to progressive/resistant disease (29%). Among the 20 response-evaluable patients, the ORR was 20% with 4 pts having an IWG response; 3 (15%) attaining a CRi, all at the first response assessment at Cycle 2 Day 1, and 1 (5%) achieving MLFS at Cycle 3 Day 1. Two patients discontinued treatment approximately 1 month after initial response and the other 2 responders (1 CRi and 1 MLFS) continued treatment. Of those who did not achieve an IWG response, 7 (35%) achieved reductions in bone marrow blasts ≥25% not meeting criteria for IWG response, 8 (40%) had stable disease, and 1 (5%) had disease progression. Median OS for all treated patients (n=28) was 5.9 months (95% CI: 3.8, NE). The AE profile of the combination is consistent with that previously reported for single-agent SY-1425 or aza in AML. Most common AEs (all grades/causality) included nausea (39%), constipation (29%), pyrexia (29%), and fatigue, hypertriglyceridemia, diarrhea and vomiting (25% each). Hematologic AEs ≥ grade 3 included thrombocytopenia (18%), anemia (18%), febrile neutropenia (14%) and neutropenia (7%). The majority of non-hematologic AEs were low grade. The most frequent SAEs included febrile neutropenia, pyrexia and sepsis (11% each). Conclusions: SY-1425 in combination with aza was generally well-tolerated with clinical responses observed in this heavily pretreated relapsed/refractory AML population. The early OS estimate is encouraging, especially given the prevalence of HMA +/- venetoclax prior treatment in the study population. SY-1425 in combination with aza shows potential as a novel regimen for the treatment of RARA+ R/R AML. Disclosures Stein: Celgene Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy; Abbvie: Consultancy; Seattle Genetics: Consultancy; Syndax: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Biotheryx: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cluzeau:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: 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; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Liesveld:Onconova: Other: data safety monitoring board; Abbvie: Honoraria. Rousselot:Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy; Incyte: Consultancy, Research Funding. Rizzieri:Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Acrobiotech: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Karyopharm: Honoraria, 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; AROG: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees. Braun:Daiichi Sankyo: Honoraria; Servier: Research Funding. Bixby:GlycoMimetics: Research Funding. Roboz:Pfizer: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Astex: Consultancy; Amphivena: Consultancy; Agios: Consultancy; Abbvie: Consultancy; Array BioPharma: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Eisai: Consultancy; Jazz: Consultancy; Roche/Genentech: Consultancy; Sandoz: Consultancy; Actinium: Consultancy; Argenx: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; AstraZeneca: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Takeda: Consultancy; Trovagene: Consultancy; Cellectis: Research Funding; Jasper Therapeutics: Consultancy; Epizyme: Consultancy; Helsinn: Consultancy; MEI Pharma: Consultancy. Kelly:Syros Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Volkert:Syros Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Zhou:Syros Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company; Incyte: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Kang-Fortner:Syros Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Roth:Syros Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.

Introduction: BST-236 (aspacytarabine), a novel pyrimidine antagonist, is a cytarabine prodrug designed to deliver high cytarabine doses with reduced systemic toxicity. BST-236 pharmacokinetics and metabolism reduce peak systemic exposure to free cytarabine and enable intensive treatment to patients otherwise unfit for intensive therapy. An open label phase 2b study, following a completed phase 1/2a dose escalation study, is ongoing. Enrolled are newly-diagnosed acute myeloid leukemia (AML) patients unfit for standard therapy, including patients with treatment-related AML or AML secondary to myelodysplastic syndrome (MDS) with prior exposure to hypomethylating agents (HMA). Aims: To evaluate the efficacy and safety of BST-236 induction and consolidation in AML patients unfit for standard induction therapy. Methods: BST-236, at a dose of 4.5 g/m2/d (containing 3 g/m2/d of cytarabine), is evaluated as a first-line induction and consolidation therapy in newly-diagnosed AML patients unfit for standard chemotherapy. Patients with secondary AML, previously treated with HMA, as well as patients with therapy-related AML, are eligible. Each BST-236 induction and consolidation course consists of 6 daily 1-hour intravenous infusions. Results: To date, in the phase 1/2 and phase 2 studies, 42 AML patients were treated with BST-236, of whom 20 newly-diagnosed AML patients unfit for standard chemotherapy (median age 73 years) completed 1-4 courses of 4.5 g/m2/d BST-236. Of these, 40% had de novo AML and 60% had secondary AML. Thirty percent of patients were previously treated with HMA for MDS (median 10 courses), and 10% received prior chemo- or radiotherapy. The median baseline bone marrow blast percentage was 38 (range 13-94), and 35% and 53% of patients had intermediate or adverse European LeukemiaNet (ELN) score, respectively. BST-236 is safe and well-tolerated in repeated-course administration. Grade >2 adverse events include mainly hematological events and infections, with no other drug-related typical high-dose cytarabine events such as severe mucositis or cerebellar toxicity. Related serious adverse events include only cytopenia and pneumonia. The 30-day mortality rate is 7%. The complete remission (CR) rate in the evaluable patients to date who received 4.5 g/m2/d BST-236 is 50% in the de novo patients, 20% in secondary AML patients, and 20% in patients with prior HMA treatment. Forty-three percent of patients with adverse cytogenetics attained a CR, including 1 of 3 patients with a TP53 mutation. The median number of courses for reaching a CR is 1, and notably, all patients with bone marrow remission achieved complete hematological recovery within 36 days. BST-236 consolidation was well-tolerated and did not result in increased toxicity, enabling full count recovery. While none of the patients have undergone stem cell transplant, considered ineligible by the treating investigator, responses to BST-236 were durable and median overall survival (OS) for responders is not reached at 23 months (Figure 1A). Median OS for secondary AML patients was 6.8 months, and not reached for the de novo AML patients (Figure 1B). Follow up is ongoing with additional patients enrolling on study; updated analysis of response, minimal residual disease (MRD), duration of response, and OS will be presented at the meeting. Conclusions: The cumulative clinical data suggest that BST-236 as a single agent treatment is a safe and efficacious induction and consolidation therapy for patients who are unfit for standard intensive chemotherapy, including patients with adverse cytogenetics and prior exposure to HMA. The data may establish BST-236 as a new intensive therapy backbone of AML and may, for the first time, allow older adults deemed unfit for standard intensive induction and consolidation therapy, to benefit from an intensive treatment. Disclosures Altman: Genentech: Research Funding; Novartis: Consultancy; Syros: Consultancy; Theradex: Other: Advisory Board; Agios: Other: advisory board, Research Funding; Glycomimetics: Other: Data safety and monitoring committee; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Kura Oncology: Other: Scientific Advisory Board - no payment accepted, Research Funding; BioSight: Other: No payment but was reimbursed for travel , Research Funding; AbbVie: Other: advisory board, Research Funding; Fujifilm: Research Funding; Kartos: Research Funding; Celgene: Research Funding; Boehringer Ingelheim: Research Funding; ImmunoGen: Research Funding; Amgen: Research Funding; Aprea: Research Funding; Amphivena: Research Funding; Janssen: Consultancy; Immune Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy; ASH: Consultancy; Cancer Expert Now: Consultancy; PeerView: Consultancy; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; PrIME Oncology: Consultancy; France Foundation: Consultancy. Luger:Ariad: Research Funding; Biosight: Research Funding; Kura: Research Funding; Onconova: Research Funding; Agios: Honoraria; Acceleron: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Daiichi-Sankyo: Honoraria; Hoffman La Roche: Research Funding; Loxo Oncology: Honoraria. Koprivnikar:Amgen: Speakers Bureau; Novartis: Speakers Bureau; Alexion: Speakers Bureau; BMS: Speakers Bureau. Kota:Novartis: Consultancy, Honoraria; Incyte: Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Honoraria; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical, Company Ltd, Cambridge, MA, USA: Honoraria; Xcenda: Honoraria. Emadi:Jazz Pharmaceuticals: Research Funding; NewLink Genetics: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; KinaRx: Other: co-founder and scientific advisor. Bhatnagar:Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees; KaryoPharm Therapuetics: Research Funding; Cell Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bixby:GlycoMimetics: Research Funding. Burch:Janssen: Other: paid speaker. Wolach:Amgen: Other: Fees for lectures and Consultancy; Janssen: Other: Fees for lectures and Consultancy; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Fees for lectures and Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Other: Fees for lectures and Consultancy; Astellas: Consultancy, Honoraria, Other: Fees for lectures and Consultancy; Pfizer: Consultancy, Honoraria. Levi:Abbvie Inc: Consultancy, Research Funding. Flaishon:BioSight Ltd.: Current Employment. Tessler:BioSight Ltd.: Current Employment. Gengrinovitch:BioSight Ltd.: Current Employment. Ben Yakar:BioSight Ltd.: Current Employment. Rowe:Pluristem ltd: Consultancy.

Background: CFI-400945 is a potent, selective, orally administered, first-in-class inhibitor of the serine/threonine kinase, Polo-like kinase 4 (PLK4). PLK4 is a highly conserved master regulator of centriole duplication, and is critical for maintenance of genomic integrity. Aberrant expression of PLK4 results in a number of effects including the centrosome amplification often seen in aneuploid cancers, pointing to a potentially causative role for PLK4 in genome instability and cancer progression. A Phase 1 study has been completed evaluating CFI-400945 as a monotherapy in solid tumors, showing a tolerable safety profile and promising signs of activity. As acute myeloid leukemia (AML) is a disease characterized by genomic instability, it is of significant interest as a potential indication for the clinical evaluation of CFI-400945. pre-clinical studies, CFI-400945 showed potent activity towards leukemia cell lines and primary human samples in vitro, as well as marked efficacy in two subcutaneous models of leukemia, specifically the MV4-11 FLT3-ITD AML. A Phase 1 trial in AML was initiated at the Princess Margaret Cancer Center in 2018, and of six patients evaluable for response, two (33%) achieved complete remission (CR), and 3 patients (50%) had stable disease (with one patient having a 78% reduction in marrow blast count) [re: Murphy et al, ASH 2020]. These promising results have led to a plan for an expanded trial examining CFI-400945 in AML, particularly focused on complex karyotype (CK). Study Design and Methods: The study will have 4 parts, Part 1A (1A): a single agent dose escalation portion, Part 1B (1B): a food effect portion once the MTD of 1A is determined, and combinations with azacitidine (2A), and decitabine (2B). For parts 1A and 1B, patients with relapsed and/or refractory AML, MDS, or CMML after >1 prior therapy will be included. Patients with MDS or CMML must have progressed or had a lack of response after at least 4 cycles of hypomethylating agents. For parts 2A and 2B, patients should have relapsed and/or refractory AML or untreated MDS or CMML. Untreated patients who decline or are ineligible for intensive therapy may be included. The study will use a standard 3 + 3 design. The maximum tolerated dose (MTD) will be defined as the dose level where the number of dose limiting toxicities (DLTs) is Biomarker Selection and companion Diagnostics: No biomarker based pre-selection of patients. PD evaluations will include blast reduction and markers of mitosis. Study Treatment and Endpoints: Part 1: Each cycle will be 28 days (21 days on/7 days off). Starting does of CFI-400945 will be 32mg po. Once the MTD of 1A is determined, 1B will explore the food effect of a high fat meal on the PK of CFI-400945 at the MTD. 2A and 2B will explore the combination of CFI-400945 with standard dose of either azacitidine (2A) or decitabine (2B). The starting dose of CFI-400945 will be 32mg po for 21 days on/7 off. The DLTs will be defined as NCI CTCAE V5.0 Grade >3 related non-hematologic event(s) occurring during cycle 1 or prolonged pancytopenia in the presence of a hypocellular bone marrow > day 42 without evidence of disease. The efficacy endpoints for AML, MDS, and CMML include the overall response rate, and the CR rate per standard criteria. The aim of the food effect part of the study is the asses the effect of high fat food on the PK of CFI-400945. The safety endpoint is the incidence of treatment emergent adverse events. PK endpoints include evaluations of parameters such as half-life, AUC, etc. Exploratory endpoints include eval of minimal residual disease, genomic alterations and other molecular features associated with response and biological effects of PLK4 inhibition. Disclosures Jonas: Amgen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GlycoMimetics: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Sigma Tau: Research Funding; Jazz: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy; Tolero: Consultancy; Treadwell: Consultancy; Forty Seven: Research Funding; Accelerated Medical Diagnostics: Research Funding; AROG: Research Funding; Daiichi Sankyo: Research Funding; F. Hoffmann-La Roche: Research Funding; Forma: Research Funding; Genentech/Roche: Research Funding; Hanmi: Research Funding; Incyte: Research Funding; LP Therapeutics: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding. Bixby:GlycoMimetics: Research Funding. Brandwein:Pfizer: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Astellas: Honoraria; Taiho: Honoraria; Roche: Honoraria; Jazz Pharmaceuticals: Honoraria. Michelson:Treadwell Therapeutics: Consultancy. Bray:TIO Discovery: Current Employment; Treadwell Therapeutics: Current Employment. Roberts-Thomson:Treadwell Therapeutics: Current Employment. Borthakur:BioTherix: Consultancy; FTC Therapeutics: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; PTC Therapeutics: Consultancy; Argenx: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; BioLine Rx: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; BioLine Rx: Consultancy; PTC Therapeutics: Research Funding; Curio Science LLC: Consultancy; Cyclacel: Research Funding; GSK: Research Funding.

Background Despite fungal prophylaxis, invasive mold infections (IMIs) are a significant cause of morbidity and mortality in patients with acute myeloid leukemia (AML) receiving remission induction chemotherapy. The choice of antifungal prophylaxis agent remains controversial, especially in the era of novel targeted therapies. We conducted a retrospective case–control study to determine the incidence of fungal infections and to identify risk factors associated with IMI. Methods Adult patients with AML receiving anti-Aspergillus prophylaxis were included to determine the incidence of IMI per 1000 prophylaxis-days. Patients without and with IMI were matched 2:1 based on the day of IMI diagnosis, and multivariable models using logistic regression were constructed to identify risk factors for IMI. Results Of the 162 included patients, 28 patients had a possible (n = 22), probable, or proven (n = 6) diagnosis of IMI. The incidence of proven or probable IMI per 1000 prophylaxis-days was not statistically different between anti-Aspergillus azoles and micafungin (1.6 vs 5.4, P = .11). The duration of prophylaxis with each agent did not predict IMI occurrence on regression analysis. Older age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.004–1.081; P = .03) and relapsed/refractory AML diagnosis (OR, 4.44; 95% CI, 1.56–12.64; P = .003) were associated with IMI on multivariable analysis. Conclusions In cases that preclude use of anti-Aspergillus azoles for prophylaxis, micafungin 100 mg once daily may be considered; however, in older patients and those with relapsed/refractory disease, diligent monitoring for IMI is required, irrespective of the agent used for antifungal prophylaxis., The risk for proven or probable breakthrough invasive mold infections (IMI) in acute myeloid leukemia (AML) patients undergoing induction chemotherapy was not different between patients receiving micafungin or anti-aspergillus azoles. Older patients and those with relapsed or refractory AML were at the highest risk of breakthrough IMI.

Key Points This is the first report of successful treatment of therapy-resistant leptomeningeal T-PLL with intrathecal alemtuzumab. Intrathecal alemtuzumab is a potentially safe and efficacious therapeutic alternative for treatment of leptomeningeal T-PLL.

Pediatric high-grade glioma (HGG, WHO Grade III and IV) is a devastating brain tumor with a median survival of less than two years. PDGFRA is frequently mutated/ amplified in pediatric HGG, but the significance of this finding has not been fully characterized. We hypothesize that alterations of PDGFRA will promote distinct prognostic and treatment implications in pediatric HGG. In order to characterize the impact of PDGFR pathway alterations, we integrated genomic data from pediatric HGG patients (n=290) from multiple pediatric datasets and sequencing platforms. Integration of multiple human datasets showed that PDGFRA mutation, but not amplification, was associated with older age in pediatric HGG (P=

Effective practice of precision medicine in oncology relies on identifying and targeting unique characteristics of individual cancers. Coupling functional analysis with genomic screening will further enhance the selection of efficacious cancer therapies. Cancer is a heterogeneous disease that is defined by distinct capabilities, one of which is the evasion of apoptosis, controlled by the antiapoptotic protein members, Bcl-2, Bcl-xL, Mcl-1, and Bfl-1. These antiapoptotic proteins have become validated therapeutic targets, as manifested by the FDA-approved venetoclax, a selective Bcl-2 inhibitor, and several other molecules in clinical trials that target Mcl-1 and Bcl-xL. One of the translational challenges lies in predicting functional antiapoptotic dependence in a patient’s cancer and discriminating responders from nonresponders to Bcl-2 family targeted therapy. We have successfully characterized an updated array of Bcl-2 family antagonists, consisting of peptides and selective small-molecule BH3-mimetics via in vitro binding assays and functional analysis using model cell lymphoma cell lines. With this selective set of chemical tools, we employed the BH3 profiling assay across a wide spectrum of hematologic and solid tumor cell lines in order to functionally dissect survival dependence. To validate the results of BH3 profiling, we performed treatments with BH3-mimetics and analyzed their ability to induce apoptosis, which further demonstrated how cancers can be differentiated and targeted based on antiapoptotic dependence. The obtained data suggest that hematologic cancer cell lines mainly rely on Mcl-1 and Bcl-2 for survival and commonly undergo apoptosis in response to single-agent inhibitors of these proteins. Solid tumor cell lines are more dependent upon Bcl-xL and Mcl-1 and certain cell lines display increased involvement of Bfl-1. These cell lines undergo apoptosis when exposed to a combination of Bcl-xL/Mcl-1 inhibitors. Single agent-responsive solid tumor cell lines are less common but can be identified by BH3 profiling. This approach was successfully applied to primary patient samples to validate clinical utility. Further applications of dynamic BH3 profiling were explored to demonstrate how various FDA-approved therapies can alter antiapoptotic dependencies and aid in the design of rational combination therapies with BH3-mimetics. This work lays a translational foundation in the field of precision medicine by incorporating Bcl-2 protein family targeting into potential personalized cancer treatments. Citation Format: Karson J. Kump, Matthew Lieberman, Rita A. Avelar, Charles Foucar, Malathi Kandarpa, Antonio Di Cristofano, Russell J. Ryan, Sami N. Malek, Ryan A. Wilcox, Dale L. Bixby, Tycel J. Phillips, Moshe Talpaz, Analisa DiFeo, Zaneta Nikolovska-Coleska. Precision medicine strategy to elucidate and target Bcl-2 prosurvival proteins in a wide spectrum of cancers [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 10.

We report the diagnostic challenges and the clinical course of a patient with an extraordinary presentation of B-lymphoblastic leukemia (B-ALL) with eosinophilia. We identified a novel ZBTB20-JAK2 gene fusion as a chimeric RNA transcript using the Archer platform. This gene fusion from the same patient was recently identified by Peterson et al. (2019) at the genomic level using a different sequencing technology platform. The configuration of this gene fusion predicts the production of a kinase-activating JAK2 fusion protein, which would normally lead to a diagnosis of Philadelphia chromosome–like B-ALL (Ph-like B-ALL). However, the unusual presentation of eosinophilia led us to demonstrate the presence of this gene fusion in nonlymphoid hematopoietic cells by fluorescence in situ hybridization (FISH) studies with morphologic correlation. Therefore, we believe this disease, in fact, represents blast crisis arising from an underlying myeloid neoplasm with JAK2 rearrangements. This case illustrates the difficulty in differentiating Ph-like B-ALL and myeloid/lymphoid neoplasm with eosinophilia and gene rearrangements (MLN-EGR) in blast crisis. As currently defined, the diagnosis of MLN-EGR relies on the hematologic presentations and the identification of marker gene fusions (including PCM1-JAK2, ETV6-JAK2, and BCR-JAK2). However, these same gene fusions, when limited to B-lymphoblasts, also define Ph-like B-ALL. Yet, our case does not conform to either condition. Therefore, the assessment for lineage restriction of gene rearrangements to reflect the pathophysiologic difference between B-ALL and MLN-EGR in blast crisis is likely a more robust diagnostic approach and allows the inclusion of MLN-EGR with novel gene fusions.

Treatment of acute myeloid leukemia (AML) among the elderly is challenging because of intolerance of intensive therapy and therapy-resistant biology. Hypomethylating agents (HMAs) are commonly used, with suboptimal outcomes. Vadastuximab talirine is a CD33-directed antibody conjugated to pyrrolobenzodiazepine (PBD) dimers. Preclinically, HMAs followed by vadastuximab talirine produced upregulated CD33 expression, increased DNA incorporation by PBD, and enhanced cytotoxicity. A combination cohort in a phase 1 study (NCT01902329) assessed safety, tolerability, and activity of vadastuximab talirine with HMAs. Those eligible had Eastern Cooperative Oncology Group status 0 to 1 and previously untreated CD33-positive AML, and declined intensive therapy. Vadastuximab talirine was administered intravenously at 10 μg/kg on last day of HMA (azacitidine or decitabine) infusion in 4-week cycles. Among 53 patients treated, the median age was 75 years. Patients had adverse (38%) or intermediate (62%) cytogenetic risk. Median treatment duration was 19.3 weeks. No dose-limiting toxicities were reported. The majority of adverse events were a result of myelosuppression, with some causing therapy delays. Thirty- and 60-day mortality rates were 2% and 8%, respectively. The composite remission rate (complete remission [CR] and CR with incomplete blood count recovery) was 70%. Fifty-one percent of remissions were minimal residual disease-negative by flow cytometry. Similarly high remission rates were observed in patients with secondary AML, aged at least 75 years, and with adverse cytogenetic risk. Median relapse-free survival and overall survival were 7.7 and 11.3 months, respectively. Compared with historical data for HMA monotherapy, the combination of vadastuximab talirine with HMAs produced a high remission rate, but was accompanied by increased hematologic toxicity.

Purpose CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 drug ratio into leukemia cells to a greater extent than normal bone marrow cells. Prior clinical studies demonstrated a sustained drug ratio and exposure in vivo and prolonged survival versus standard-of-care cytarabine plus daunorubicin chemotherapy (7+3 regimen) in older patients with newly diagnosed secondary acute myeloid leukemia (sAML). Patients and Methods In this open-label, randomized, phase III trial, 309 patients age 60 to 75 years with newly diagnosed high-risk/sAML received one to two induction cycles of CPX-351 or 7+3 followed by consolidation therapy with a similar regimen. The primary end point was overall survival. Results CPX-351 significantly improved median overall survival versus 7+3 (9.56 v 5.95 months; hazard ratio, 0.69; 95% CI, 0.52 to 0.90; one-sided P = .003). Overall remission rate was also significantly higher with CPX-351 versus 7+3 (47.7% v 33.3%; two-sided P = .016). Improved outcomes were observed across age-groups and AML subtypes. The incidences of nonhematologic adverse events were comparable between arms, despite a longer treatment phase and prolonged time to neutrophil and platelet count recovery with CPX-351. Early mortality rates with CPX-351 and 7+3 were 5.9% and 10.6% (two-sided P = .149) through day 30 and 13.7% and 21.2% (two-sided P = .097) through day 60. Conclusion CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML. The safety profile of CPX-351 was similar to that of conventional 7+3 therapy.

Vadastuximab talirine (SGN-CD33A, 33A) is an antibody-drug conjugate consisting of pyrrolobenzodiazepine dimers linked to a monoclonal antibody targeting CD33, which is expressed in the majority of acute myeloid leukemia (AML) patients. This phase 1 study evaluated the safety, pharmacokinetics, and preliminary activity of vadastuximab talirine and determined the recommended monotherapy dose in patients with relapsed or refractory AML. Additional expansion cohorts tested vadastuximab talirine in specific subpopulations of relapsed AML, and in a cohort of older, treatment-naive patients. Patients received vadastuximab talirine IV on day 1 (5-60 µg/kg) or on days 1 and 4 (20 µg/kg) of 21-day cycles. A total of 131 patients (median age, 73 years [range, 26-89 years]) had intermediate I-II (48%) or adverse (34%) risk by European LeukemiaNet classification; 50% of patients had underlying myelodysplasia. Two dose-limiting toxicities (grade 2 pulmonary embolism and grade 4 hypocellular marrow) occurred during dose finding. Most adverse events (AEs) were consistent with myelosuppression; nonhematologic AEs included fatigue, nausea, and diarrhea. The 30-day mortality was 8%. At the recommended monotherapy dose of 40 µg/kg, the complete remission + CRi rate was 28% (5 of 18 patients); 50% of patients who responded achieved minimal residual disease negativity. In patients across dose levels who achieved CR or CRi, the median time to full count recovery was 6.4 weeks for neutrophils (≥1000/µL) and 10.6 weeks for platelets (≥100 × 109/L). Vadastuximab talirine demonstrates activity and a tolerable safety profile as a single agent in patients with AML. The recommended monotherapy dose of vadastuximab talirine is 40 µg/kg. This trial was registered at www.clinicaltrials.gov as # NCT01902329.

Introduction Relapse remains a significant challenge towards improving survival after allogeneic hematopoietic transplantation (HCT) for Acute Myeloid Leukemia (AML) not in remission or possessing poor cytogenetic/molecular features. Insights from murine pre-clinical studies demonstrate a central role for CD8+ dendritic cells in cross-presentation of leukemia associated antigens (LAA) in mediating GVL without aggravating acute Graft-versus-Host Disease (aGVHD)(Toubai, Blood 2013). We posited that enhancing LAA cross-presentation with exogenous Type I Interferon (pegIFNα) would promote GVL response and reduce rates of relapse after HCT. Methods We initiated a prospective, phase I/II, clinical trial of pegIFNα administration after myeloablative conditioning for prevention of relapse in pts with detectable AML at time of HCT (resistant to induction) or with cytogenetic/molecular features conferring high relapse risk and poor survival. Pts received up to four doses of 90mcg or 180mcg pegIFNα SubQ on d -1 and d 14, 28, 42 after PBSC or BMT. aGVHD prophy was tacrolimus + MTX or MMF. The primary endpoint was to determine the incidence of relapse in pts receiving the phase II dosage of pegIFNα. We hypothesized that 30 pts assigned to the same dose would provide 80% power to detect a difference between a promising day 180 relapse rate of 40% versus a rate of 60%. Results A total of 30 pts received study treatment at a median age of 60 years (17-72). Conditioning was myeloablative FluBu (n=9), CloBu (n=20) or FluCyTBI (n=1). At time of HCT, AML was detected in 28 pts and 2 pts enrolled for poor cytogenetic/molecular risk, complex/monosomal karyotype (n=1) and FLT3-ITD+ (n=1). There was no DLT at 90mcg (n=3) and one DLT (graft failure) after escalation to 180mcg (n=27). pegIFNα was well tolerated with ≥3 doses administered to 87% of pts. ≥Grade 3 SAEs during treatment include acute kidney injury(n=1), engraftment failure(n=1), bone pain/weakness(n=1), hypotension(n=1) and hypoxemia (n=1). 29 pts (97%) experienced primary engraftment and bone marrow exam at d 30 revealed CR in 100% of pts. Thirteen pts (43%) experienced infection. Grade II-IV aGVHD and grade III-IV aGVHD occurred in 35% (20 – 56%) and 11% (4 – 30%) by day 180. The incidence of TRM was 11% (3-30%) at day 180 and 19% (8-41%) at 1-yr. The day 180 (and 1-yr) incidence of relapse was 39% (24 – 60%) in the overall cohort and 36% (20 – 58%) in 27 pts treated at the phase II dose. At a median follow up of 19 months, the 1-yr OS was 42% (27 – 65%). Conclusion These data provide initial evidence of clinical translation for pegIFNα when administered prophylactically in an AML cohort at high risk for relapse. Type I Interferon did not significantly alter toxicity or aGVHD risk and produced relatively low rates of relapse suggesting a robust GVL response. The role of type 1 IFN in reducing clinical relapse and its underlying biological mechanisms warrants additional study.

Allogeneic hematopoietic cell transplantation (HCT) has been increasingly used in the setting of FMS-like tyrosine kinase-3 (FLT3)-mutated AML. However, its role in conferring durable relapse-free intervals remains in question. Herein we sought to investigate FLT3 mutational status on transplant outcomes. We conducted a retrospective cohort study of 262 consecutive AML patients who underwent first-time allogeneic HCT (2008-2014), of whom 171 had undergone FLT3-ITD (internal tandem duplication) mutational testing. FLT3-mutated AML was associated with nearly twice the relapse risk (RR) compared with those without FLT3 mutation 3 years post-HCT (63% vs 37%, P

Latent HIV infection of long-lived cells is a barrier to viral clearance. Hematopoietic stem and progenitor cells are a heterogeneous population of cells, some of which are long-lived. CXCR4-tropic HIVs infect a broad range of HSPC subtypes, including hematopoietic stem cells, which are multi-potent and long-lived. However, CCR5-tropic HIV infection is limited to more differentiated progenitor cells with life spans that are less well understood. Consistent with emerging data that restricted progenitor cells can be long-lived, we detected persistent HIV in restricted HSPC populations from optimally treated people. Further, genotypic and phenotypic analysis of amplified env alleles from donor samples indicated that both CXCR4- and CCR5-tropic viruses persisted in HSPCs. RNA profiling confirmed expression of HIV receptor RNA in a pattern that was consistent with in vitro and in vivo results. In addition, we characterized a CD4high HSPC sub-population that was preferentially targeted by a variety of CXCR4- and CCR5-tropic HIVs in vitro. Finally, we present strong evidence that HIV proviral genomes of both tropisms can be transmitted to CD4-negative daughter cells of multiple lineages in vivo. In some cases, the transmitted proviral genomes contained signature deletions that inactivated the virus, eliminating the possibility that coincidental infection explains the results. These data support a model in which both stem and non-stem cell progenitors serve as persistent reservoirs for CXCR4- and CCR5-tropic HIV proviral genomes that can be passed to daughter cells., Author summary People who are effectively treated with antiretroviral medication harbor persistent forms of HIV that are integrated into the cellular genome. While HIV is cytopathic to most cells, transcriptionally silent, latent forms do not express toxic HIV gene products and can survive in the host for years. When conditions change, the latent virus can be activated to reinitiate infection. Because of the capacity for virus to spread, cure of HIV will require that we identify and eradicate all cells harboring functional HIV provirus. CD4+ T cells are abundant and easily identified as harboring proviral genomes. However, rare cell types that express HIV receptors, such as bone marrow hematopoietic progenitor and stem cells can also be infected by the virus potentially serving as barriers to cure strategies. We found that HIV can infect and persist in progenitor sub-types that were previously thought to be short lived, which expands the types of cells that can support reservoir formation. In addition, we found that HIV can spread by proliferation and cellular differentiation without the need for viral gene expression and virion production that could reveal the infection to the immune system. A deeper understanding of viral reservoirs is critically important for developing strategies that will succeed in viral eradication.

Follicular lymphoma (FL) constitutes the second most common non-Hodgkin lymphoma in the western world. FL carries characteristic recurrent structural genomic aberrations. However, information regarding the coding genome in FL is still evolving. Here, we describe the results of massively parallel exome sequencing and single nucleotide polymorphism 6.0 array genomic profiling of 11 highly purified FL cases, and 1 transformed FL case and the validation of selected mutations in 102 FL cases. We report the identification of 15 novel recurrently mutated genes in FL. These include frequent mutations in the linker histone genes HIST1H1 B-E (27%) and mutations in OCT2 (also known as POU2F2; 8%), IRF8 (6%), and ARID1A (11%). A subset of the mutations in HIST1H1 B-E affected binding to DNMT3B, and mutations in HIST1H1 B-E and in EZH2 or ARID1A were largely mutually exclusive, implicating HIST1H1 B-E in epigenetic deregulation in FL. Mutations in OCT2 (POU2F2) affected its transcriptional and functional properties as measured through luciferase assays, the biological analysis of stably transduced cell lines, and global expression profiling. Finally, multiple novel mutated genes located within regions of acquired uniparental disomy in FL are identified. In aggregate, these data substantially broaden our understanding of the genomic pathogenesis of FL.

Introduction: Aspacytarabine (BST-236) is a prodrug of cytarabine, a backbone of acute myeloid leukemia (AML) therapy. Due to its unique pharmacokinetics and metabolism, treatment with aspacytarabine evades peak exposure to free cytarabine, which reduces non-hematological toxicity and enables delivery of high-dose cytarabine also to patients unfit for standard therapy. Data from a completed phase 1/2a and an ongoing phase 2b studies in AML patients unfit for standard therapy, including patients with AML secondary to therapy and myelodysplastic syndrome (MDS) with prior exposure to hypomethylating agents (HMA), demonstrate promising single-agent efficacy and safety of aspacytarabine as a potential first-line AML treatment for this challenging population. Aims: To evaluate the efficacy and safety of aspacytarabine in AML patients unfit for standard induction therapy. Methods: A completed phase 1/2a study and an ongoing phase 2b study evaluate the efficacy and safety of aspacytarabine as a single-agent therapeutic for AML. The phase 1/2a, dose-escalation study enrolled newly-diagnosed patients unfit for standard therapy and patients with relapsed/refractory AML. Patients were treated with 0.3-6 g/m2/d aspacytarabine in 6 dose-escalating cohorts. The ongoing multi-center phase 2b study expands the subgroup of newly-diagnosed AML patients unfit for standard therapy, to evaluate the efficacy and safety of aspacytarabine as a first-line therapy for this population. Secondary AML patients, treated with HMA, chemotherapy, or radiotherapy for a prior condition, are allowed. Patients in the phase 2b study are treated with the selected aspacytarabine dose of 4.5 g/m2/d, containing approximately 3 g/m2/d of cytarabine. Each aspacytarabine treatment course (induction and consolidation) consists of 6 1-hour daily intravenous infusions. Results: To date, 34 AML patients, median age 76 years, received at least 1 dose of aspacytarabine, including 30 patients unfit for standard induction therapy due to age or comorbidities. Overall, 25 patients completed 1 course of aspacytarabine, 4 patients completed 2 courses, 1 patient completed 3 courses, and 1 patient completed 4 courses of aspacytarabine. Three patients (in the phase 1/2a study) did not complete the first course. Aspacytarabine was safe and well-tolerated in repeated-course administration, including in older and unfit patients. Adverse events included mainly hematological "on-target" events with no drug-related mucositis or cerebellar toxicity. Twenty-one patients were newly-diagnosed with AML, either de novo or secondary to MDS or therapy. The patient population was characterized by older age (median 76 years, range 67-88 years), and the majority (67%) of patients had secondary AML, including 10 patients (48%) who were previously treated with HMA (median of 10 courses) or radiotherapy. The median baseline bone marrow blast percentage of this population was 75, and 43% and 48% had intermediate or adverse European LeukemiaNet (ELN) cytogenetic score, respectively. Despite these poor-prognostic characteristics, the 30-day mortality rate in the group of patients receiving ≥4.5 g/m2/d aspacytarabine was 7%. The combined complete remission (CR) rate of all doses was 33%, including 1 patient reaching a CR with partial platelet recovery (CRp). The CR rate in patients treated with at least 4.5 g/m2/d aspacytarabine is 36%, with median time for complete hematological recovery of 27 days (range 21-30) following induction and consolidation. Notably, among the 7 patients who reached a CR/CRp (median age 77), 3 secondary AML patients reached a CR, including 2 patients with prior exposure to HMA (5 and 10 courses) and 1 with prior exposure to radiotherapy (Table 1). Duration of response and overall survival follow up is ongoing and will be presented at the meeting. Conclusions: The accumulating clinical data suggest that aspacytarabine is safe and efficacious for the treatment of AML patients who are unfit for standard induction therapy, including patients with prior exposure to HMA, which may establish aspacytarabine as a new therapeutic backbone for AML, either as a single agent or in combination with targeted therapy. Disclosures Altman: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Biosight: Other: US Lead; Novartis: Consultancy; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cancer Expert Now: Consultancy; France Foundation: Speakers Bureau; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Luger:Seattle Genetics: Research Funding; Pfizer: Honoraria; Onconova: Research Funding; Kura: Research Funding; Jazz: Honoraria; Genetech: Research Funding; Daichi Sankyo: Honoraria; Cyslacel: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Agios: Honoraria. Kota:Takeda: Honoraria; Xcenda: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Flaishon:BioSight Ltd.: Employment. Tessler:BioSight Ltd.: Employment. Gengrinovitch:BioSight Ltd.: Employment. Ben Yakar:BioSight Ltd.: Employment. Rowe:BioSight: Consultancy.

Leukemic myeloblasts expressing E-selectin ligand (E-sel ligand) adhere to E-selectin on bone marrow endothelium resulting in environment-mediated drug resistance (EMDR). Uproleselan, a potent E-selectin inhibitor, disrupts the adhesion of AML cells in the bone marrow, re-sensitizing blasts to the cytotoxic effects of chemotherapy. Retrospective data demonstrated that E-sel ligand expression in AML patients is higher in relapsed disease compared to newly diagnosed AML, is more commonly seen in biologically adverse risk patients, and is present on leukemic stem cells (Chien et al ASH 2018). Preliminary data from a phase 1-2 trial of uproleselan combined with mitoxantrone, etoposide, cytarabine (MEC) chemotherapy in R/R AML demonstrated enhanced survival in patients with E-sel ligand expression on AML cells of > 10% compared to lower levels (DeAngelo et al ASH 2018). In order to more fully understand the relationship of E-sel ligand to the activity of uproleselan, we examined the clinical variables of patients with both high (> 10%) and low E-sel ligand levels in comparison to the total population of patients treated on the phase 1-2 trial. Uproleselan, combined with MEC chemotherapy was studied in 66 patients with relapsed and/or refractory AML. The expression level of E-sel ligand on the surface of AML cells (blasts/leukemic stem cells (LSCs)) in the bone marrow was measured by a flow cytometric assay using the HECA 452 antibody that recognizes a functional trisaccharide domain shared by sialyl Lea and sialyl Lex and known to bind to E-selectin. Data on E-sel ligand was available in 36 patients at study entry in the phase 1-2 study and E-sel ligand was detectable on blasts in all patients. E-sel ligand on LSCs was demonstrated at levels ≥ 10% in 22 patients (61%) and at levels < 10 % in 14 patients (39%). Overall, the clinical characteristics confirmed a highly resistant population of R/R AML patients (see table) with 79% categorized as either poor risk by the European Prognostic Index (EPI) for first salvage therapy or ≥ second salvage, with an expected 1 year survival of less than 20% (Breems et al JCO 2005, Giles et al Cancer 2005). Although the sample size was small (n=36), substantially more patients with high E-sel ligand had achieved an initial remission and were in relapse (68%) whereas low E-sel ligand patients were more likely to be primary refractory (57%) (p=0.17). Patients with high E-sel ligand were more likely to have adverse ELN risk disease (55%) compared to low E-sel ligand patients (28%) (p=0.053). These data are consistent with previous findings demonstrating that higher E-sel ligand expression contributes to clinical chemotherapy resistance, particularly increasing the risk of relapse, whereas alternative resistance mechanisms may more commonly contribute to primary resistance. Importantly, the 45% response rate and 12.7 months median overall survival (OS) in the high E-sel ligand patients suggests that E-selectin inhibition by uproleselan contributed to their significantly improved outcomes when compared to the historically dismal outcomes with standard of care alone in these poor risk R/R AML patients. Table. Disclosures DeAngelo: Incyte Corporation: Consultancy; Celgene Corporation: Consultancy; Pfizer, Inc.: Consultancy; GlycoMimetics: Research Funding; AbbVie, Inc.: Research Funding; Takeda Pharmaceuticals: Consultancy; Shire: Consultancy; Amgen: Consultancy; Blue Print Medicines: Consultancy, Research Funding; Jazz Pharmaceuticals, Inc.: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Jonas:AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding; AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Amgen, GlycoMimetics: Other: Travel expenses. Liesveld:Abbvie: Membership on an entity's Board of Directors or advisory committees; Onconova: Other: Data safety monitoring board. Advani:Pfizer: Honoraria, Research Funding; Glycomimetics: Consultancy, Research Funding; Amgen: Research Funding; Kite Pharmaceuticals: Consultancy; Abbvie: Research Funding; Macrogenics: Research Funding. Marlton:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. O'Dwyer:Onkimmune: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlycoMimetics Inc: Research Funding; BMS: Research Funding. Fogler:GlycoMimetics Inc: Employment, Equity Ownership. Magnani:GlycoMimetics Inc: Employment, Equity Ownership. Chen:GlycoMimetics: Employment. Feldman:GlycoMimetics Inc: Employment. Thackray:GlycoMimetics Inc: Employment. Becker:AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; Accordant Health Services/Caremark: Consultancy; The France Foundation: Honoraria.

BACKGROUND Secondary AML (sAML) that develops after an antecedent hematologic disorder or exposure to genotoxic therapy is associated with a poor prognosis and historical long-term survival rates of 5-10% (Granfeldt Østgård et al. 2015). Liposomal daunorubicin and cytarabine (CPX-351) was recently FDA approved for the treatment of sAML, based on a randomized phase III trial that found a higher complete remission (CR) rate, event-free survival (EFS), and overall survival (OS) with CPX-351 compared to 7+3 chemotherapy (Lancet et al. 2018). Retrospective studies conducted in this patient population suggest that high-dose cytarabine (HIDAC)-based regimens may also be safe and effective in sAML (Vulaj et al. 2018, Talati et al. 2018). With an average wholesale price of up to $150,000 for induction, CPX-351 represents a large financial burden when compared to HIDAC-based regimens. Because HIDAC-based regimens employ older, generic medications, and sAML is a relatively rare diagnosis, it is unlikely these two induction strategies will be compared prospectively. This real-world, multicenter study retrospectively compared clinical outcomes in patients with sAML receiving CPX-351 and HIDAC-based regimens. METHODS Adult patients with newly diagnosed sAML treated between January 2013 and January 2019 from 7 academic medical centers (University of Michigan n=73, MD Anderson Cancer Center n=27, Barnes Jewish Hospital n=22, University of North Carolina n=21, Huntsman Cancer Institute n=9, University of Rochester n=9, Indiana University n=8) were divided into 2 cohorts based on induction regimen: HIDAC-based or CPX-351. Demographics, disease characteristics, and outcomes were collected in accordance with the institutional review board approved protocol. The primary endpoint of composite complete response/complete response with incomplete count recovery (CR/CRi) as well as secondary efficacy endpoints were defined using 2003 International Working Group Criteria. For the primary endpoint, a sample of 96 patients was established a priori as necessary to demonstrate non-inferiority of HIDAC-based regimens using a non-inferiority margin of 7.5% and historical CR/CRi rates or 65% and 47.7% for HIDAC-based and CPX-351 respectively. Chi-square or Fisher's exact tests were utilized to evaluate dichotomous variables. Continuous variables were analyzed via Student's t-test or Mann-Whitney U test. Kaplan-Meier analysis with log-rank test was performed to estimate progression-free survival (PFS) and overall survival (OS). RESULTS A total of 169 patients were included (HIDAC-based: n=75; CPX-351: n=94). HIDAC-based regimen distribution was as follows: fludarabine/cytarabine ± G-CSF (n=73) and clofarabine/cytarabine ± G-CSF (n=2). Baseline characteristics were well balanced (table 1) with the exception of a higher Charlson Comorbidity Index in patients who received HIDAC-based therapy. The median age of all patients was 67 years and the majority of patients had sAML due to an antecedent hematologic disorder. CR/CRi rate was numerically higher and non-inferior with HIDAC-based therapy (62.7%) compared with CPX-351 (47.9%) (p=0.002 [one-sided for non-inferiority]). Median OS was 10.06 vs 10.59 months and median EFS was 5.56 vs 4.11 months with HIDAC-based regimens compared with CPX-351, respectively. Thirty-day mortality (1.3 vs 8.5%; p=0.039) and confirmed infection in induction (56% vs 74.5%; p=0.012) were significantly higher with CPX-351. Additionally, the time to absolute neutrophil count (ANC) and platelet count (PLT) recovery in CR/CRi were significantly longer with CPX (ANC: 18 vs 35.5 days; p CONCLUSIONS HIDAC-based regimens yield CR/CRi rates that are non-inferior to CPX-351 in patients with sAML with similar EFS and OS. In a primarily elderly population, HIDAC-based therapy demonstrates greater tolerability with lower induction mortality, infection rates, and a more favorable duration of cytopenias. With non-inferior efficacy, better tolerability, and significantly lower cost, HIDAC-based regimens may be preferred to CPX-351 in patients with sAML. Disclosures Klaus: Jazz Pharmaceuticals: Other: Advisory Board, Speakers Bureau. Clark:Elliott Benson Research: Consultancy. Pettit:Samus Therapeutics: Research Funding.

This article reviews recent clinical experiences with first-line and second-line second-generation BCR-ABL inhibitors and discusses considerations for selection of therapy for patients with chronic-phase chronic myeloid leukemia.We reviewed recent publications on PubMed and abstracts from major congresses relevant to the topic.Therapeutic options for front-line treatment have increased with the approval of two second-generation BCR-ABL inhibitors, dasatinib and nilotinib. Both agents are also treatment options for patients with resistance or intolerance to front-line imatinib. More recently, bosutinib, ponatinib, and omacetaxine have also been approved for patients with resistance or intolerance to prior therapy.Expanded treatment options coupled with rapidly changing treatment guidelines have led to numerous questions regarding the selection and monitoring of therapy. Common concerns include how to best select therapy based upon patient-specific comorbidities, monitoring and interpretation of treatment outcomes, and optimization of dosing when side effects occur.

Summary: Long-lived reservoirs of persistent HIV are a major barrier to a cure. CD4+ hematopoietic stem and progenitor cells (HSPCs) have the capacity for lifelong survival, self-renewal, and the generation of daughter cells. Recent evidence shows that they are also susceptible to HIV infection in vitro and in vivo. Whether HSPCs harbor infectious virus or contribute to plasma virus (PV) is unknown. Here, we provide strong evidence that clusters of identical proviruses from HSPCs and their likely progeny often match residual PV. A higher proportion of these sequences match residual PV than proviral genomes from bone marrow and peripheral blood mononuclear cells that are observed only once. Furthermore, an analysis of near-full-length genomes isolated from HSPCs provides evidence that HSPCs harbor functional HIV proviral genomes that often match residual PV. These results support the conclusion that HIV-infected HSPCs form a distinct and functionally significant reservoir of persistent HIV in infected people. : HIV causes an infection that persists even when optimal therapy is used. Zaikos et al. provide evidence that HIV-infected progenitor cells from the bone marrow can amplify virus through normal cellular growth pathways in some treated people. Keywords: HIV, latency, reservoir, virus, persistence, clonal, hematopoietic, human, defective, infectious

Activating mutations in the FMS-like tyrosine kinase-3 (FLT3), a tyrosine kinase receptor important in haematopoiesis, are among the most common molecular aberrations in acute myeloid leukaemia (AML), occurring in 30% of adult patients (Levis & Small 2003). Common FLT3-activating mutations include FLT3 internal tandem duplications (FLT3-ITDs), detected in about 23% of AML patients, and point mutations within the tyrosine kinase domain, found in about 8% (Levis & Small 2003). These mutations result in a constitutively active FLT3 receptor, leading to growth factor–independent proliferation and survival of leukaemic cells and conferring poor prognosis (Levis & Small 2003). Clinical studies of single-agent first-generation FLT3 inhibitors have demonstrated clinical activity, with responses that are typically short-lived and mostly partial or complete responses with incomplete haematopoietic recovery. This may be due to suboptimal potency and/or pharmacokinetics, leading to insufficient or transient target inhibition, or concomitant c-kit inhibition (Knapper 2011). Recently, high potency second-generation FLT3 inhibitors (eg, quizartinib) have shown substantial efficacy as monotherapy, suggesting a potency threshold for clinical benefit (Knapper 2011). The validation of FLT3-ITD as a therapeutic target has rekindled interest in developing and testing new potent FLT3 inhibitors in AML patients with FLT3-ITD mutations (Smith et al, 2012). Ponatinib is a novel, orally administered tyrosine kinase inhibitor (TKI) and a potent pan–BCR-ABL1 inhibitor (O’Hare et al, 2009). Based on results in patients with chronic myeloid leukaemia (CML) and Philadelphia chromosome–positive acute lymphoblastic leukaemia (Ph+ ALL) in phase 1 and phase 2 clinical trials (Cortes et al 2012a, Cortes et al (2012b), ponatinib (45 mg once daily) has been approved in the United States for the treatment of patients with CML and Ph+ ALL that is resistant or intolerant to prior TKI therapy. Preclinical studies revealed that ponatinib also potently inhibits FLT3, leading to apoptosis of leukaemic cell lines carrying the FLT3-ITD mutation and tumour regression in xenograft models, suggesting the potential for activity in patients with AML (Gozgit et al, 2011). Additionally, ponatinib appears to retain activity against the clinically-relevant quizartinib-resistant mutant FLT3-ITD F691L (Smith et al, 2013). Here we report the first clinical experience with ponatinib in 12 AML patients included in the phase 1 study. Methods are described in the on-line supporting information. The median age of these patients was 49 (30-72) years. The median time from diagnosis to treatment was 1 year. Patients received a median of 3 (1-7) prior therapies; 58% had received 3 or more prior therapies (Table I and Table S1). Mutational analysis in a central laboratory confirmed the presence of FLT3-ITD in 7 patients (58%). Three additional patients did not have an adequate DNA sample at study entry; however, they had a history of FLT3-ITD mutation—as reported by the investigator—and they are included in the FLT3-ITD mutation– positive group for these analyses. Three patients (all FLT3-ITD mutation positive) were previously treated with one or more FLT3 inhibitors (sorafenib, quizartinib, and/or IMC-EB10); one patient progressed on IMC-EB10 and had a partial response to sorafenib, one patient had a complete response to sorafenib and a partial response to quizartinib, and one patient had a partial response to quizartinib. Seven patients (70%) with FLT3-ITD mutation were FLT3 inhibitor– naive (Table I). The median treatment duration was 52 (10-173) days. At the time of analysis, all patients had discontinued ponatinib: 5 (42%) due to death (all unrelated to ponatinib), 3 (25%) due to adverse events (AEs: unrelated central nervous system [CNS] haemorrhage, possibly related acute pancreatitis, unrelated graft vs host disease), 2 (17%) due to progressive disease (PD), and 2 (17%) due to investigator decision (Table I). Table 1 Selected baseline characteristics, treatment duration, response, and reasons for discontinuation by individual patients with AML Nine patients experienced at least one treatment-related AE. The most common treatment-related AEs occurring in 2 or more patients were pancreatitis (n=3) and petechiae (n=2). Three patients experienced a treatment-related serious AE (SAE) of pancreatitis (all grade 2), which was a dose-limiting toxicity in this trial (Cortes et al, 2012a). Pancreatitis resolved in 2 patients after dose interruption, lasting 3 days in one patient and 8 days in the other. These 2 patients continued therapy at a reduced dose (30 mg) and were subsequently re-escalated to 45 mg without recurrence. The third patient discontinued therapy per investigator decision. Additional details regarding treatment-emergent AEs and SAEs can be found in Table S2. Seven patients died during the study for reasons not related to ponatinib: disease progression (n=3), multiorgan failure (n=2), pneumonia and sepsis (n=1), and CNS haemorrhage (n=1) (Table I). Ponatinib had an acceptable safety profile in this small group of patients with refractory AML, similar to that observed in patients with CML and Ph+ ALL. Few treatment-related AEs were reported; the most common was pancreatitis, which was manageable, and re-challenge with ponatinib was possible in most cases. The geometric mean maximal concentration and area under the curve of single-dose ponatinib at day 1, cycle 1 in AML patients were 97 nM and 1441 nM*h, respectively, similar to findings across all 31 patients receiving 45 mg ponatinib (98.8 nM and 1360.1 nM*h). The overall response rate (RR, partial remission or better) was 3/12 (25%): 2 patients achieved complete remission with incomplete blood count recovery and one patient experienced partial remission (Table I, Fig 1). These 3 responders carried FLT3-ITD mutations and were all FLT3 inhibitor–naive; the duration of ponatinib treatment in these patients was 3 to 6 months. Among 10 patients with FLT3-ITD mutations, RR was 3/10 (30%). Among 7 patients with FLT3-ITD mutations who were FLT3 inhibitor–naive, RR was 3/7 (43%). Three patients (2 FLT3-ITD negative) had stable disease, as they did not meet criteria for complete/partial remission or PD; however, peripheral blood blasts in 2 of these patients decreased considerably (~60-90%) during the first treatment cycle. The RR reported with quizartinib in phase 1 testing was 30% (Cortes et al, 2009) and 10% with sorafenib (Borthakur et al, 2011). Although the sample size reported here is small, these results suggest that ponatinib has clinical activity in AML patients with FLT3-ITD, requiring confirmation in a larger cohort of patients and with additional focus on optimization of response (eg, combination therapy) and response durability. Figure 1 Course of the disease in 3 responders during ponatinib treatment

To further our understanding of the genetic basis of acute myelogenous leukemia (AML), we determined the coding exon sequences of ∼ 18 000 protein-encoding genes in 8 patients with secondary AML. Here we report the discovery of novel somatic mutations in the transcriptional corepressor gene BCORL1 that is located on the X-chromosome. Analysis of BCORL1 in an unselected cohort of 173 AML patients identified a total of 10 mutated cases (6%) with BCORL1 mutations, whereas analysis of 19 AML cell lines uncovered 4 (21%) BCORL1 mutated cell lines. The majority (87%) of the mutations in BCORL1 were predicted to inactivate the gene product as a result of nonsense mutations, splice site mutation, or out-of-frame insertions or deletions. These results indicate that BCORL1 by genetic criteria is a novel candidate tumor suppressor gene, joining the growing list of genes recurrently mutated in AML.

Introduction: SY-1425 (tamibarotene) is an orally available, synthetic retinoid in Phase 2 development for non-APL AML and MDS patients (pts) positive for the RARA and/or IRF8 biomarkers of RARA pathway activation (McKeown et al, Cancer Discovery, 2017). Biomarker-selected pts treated with SY-1425 single agent showed myeloid differentiation, improved blood counts and reduced bone marrow blasts, and treatment was generally well tolerated with manageable and/or reversible side effects (Jurcic et al, ASH 2017). SY-1425 showed evidence of combination activity in preclinical models. Synergy was observed with HMAs, with DNA damage and apoptosis in vitro, and in an AML PDX model the combination of SY-1425 and azacitidine (Aza) demonstrated increased tumor reduction, deeper, more durable responses and improved survival relative to Aza or SY-1425 alone (McKeown et al, ASH 2016). SY-1425 induced CD38 expression in preclinical models and the combination with daratumumab (Dara), a CD38 targeting antibody indicated for multiple myeloma (MM), induced immune-mediated cell death ex vivo (Austgen et al, AACR 2017). SY-1425 also increased CD38 expression in bone marrow blasts in AML/MDS pts (Jurcic et al, ASH 2017). These data support the ongoing investigation of the efficacy and safety of SY-1425 in non-APL AML and MDS pts, in combination with Aza or Dara (NCT02807558). Methods: Biomarker positive (Bm+), unfit pts with newly-diagnosed (ND) AML received SY-1425 + Aza. The SY-1425 + Aza combination arm was recently expanded to include biomarker negative pts. Bm+ pts with relapsed/refractory (R/R) AML or R/R higher-risk MDS received SY-1425 + Dara. All enrolled pts received SY-1425 at 6 mg/m2/day PO with twice daily dosing. Aza (75 mg/m2 IV/SC) and Dara (16 mg/kg IV) were dosed as approved in MDS and MM, respectively. Objectives included characterization of activity by overall response rate (per IWG), duration of response, event-free, relapse-free and overall survival, hematologic improvement, and assessment of safety. For pts treated with SY-1425 + Dara, the kinetics and magnitude of CD38 increases were evaluated on peripheral blasts using a centralized assay. Results: With 10 ND AML pts currently enrolled to receive SY-1425 + Aza, 6 were Bm+. Data through 9 July 2018 were available for 5 Bm+ pts, 4 (80%) male and median age 76 years (64-83). Pts were reported to have poor (3 pts) and intermediate (2 pts) ELN genetic risk. Median time on treatment was 25.4 weeks (9.7-42.1). Early clinical responses at 4 weeks (C2D1) were reported in 4 of 5 pts. Best responses were CR (1 pt), CRi (1 pt) and PRi (2 pts), defined as PR with incomplete blood count recovery. A 5th pt with ND AML developing from prior CMML with 2 distinct blast populations had stable disease (AML blasts), but with CR of CMML marrow blasts by flow at 8 weeks (C3D1). 2 pts remained on treatment, including 1 with CR at 9 months (C10D1). 3 pts discontinued due to PD/lack of efficacy (2 pts) and AE (1 pt). 10 Bm+ pts have enrolled to receive SY-1425 + Dara. Data were available for 4 pts (3 R/R AML and 1 R/R MDS), 4 (100%) female and median age 60 years (36-68). Pt risk was poor (2 pts) and intermediate (1 pt) per ELN for AML, and good (1 pt) per IPSS-R for MDS. Median time on treatment was 5.9 weeks (0.7-8.9). 1 of 3 evaluable pts achieved a PRi at 4 weeks (C2D1) but progressed at C3D1. Initial data demonstrate that 3 of 4 pts showed an increase in CD38 expression levels in peripheral AML blasts as early as 3 days following SY-1425 treatment, up to 2.6-fold by 1 week. All 4 pts discontinued treatment due to disease progression. AEs (most common, all causality) reported in >2 pts receiving SY-1425 combination treatment included febrile neutropenia (44%), and hypertriglyceridemia, pruritus, abdominal pain and peripheral edema (33% each). Overall, AEs, including AEs ≥ grade 3 and SAEs, were consistent with those of single agent SY-1425, Aza or Dara. Conclusion: SY-1425 in combination with Aza in non-APL AML shows preliminary evidence of clinical activity with early objective responses observed. CD38 expression increased in 3 of 4 pts with R/R AML or R/R MDS within 3 days of SY-1425 treatment and reduction in marrow blasts was observed in 1 pt treated with SY-1425 in combination with Dara. No new safety signals have been identified with either combination regimen. In summary, early data suggest SY-1425 in combination has clinical potential in pts with non-APL AML and MDS. Updated results will be presented. Disclosures Cook: Syros Pharmaceuticals: Consultancy. Liesveld:Abbvie: Honoraria; Onconova: Other: DSMB. Rizzieri:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: 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; Incyte: 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; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy. Stein:Novartis: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy; Bayer: Consultancy. Roboz:Argenx: Consultancy; Jazz Pharmaceuticals: Consultancy; AbbVie: Consultancy; Astex Pharmaceuticals: Consultancy; Cellectis: Research Funding; Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Astex Pharmaceuticals: Consultancy; Cellectis: Research Funding; Sandoz: Consultancy; Bayer: Consultancy; Otsuka: Consultancy; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Eisai: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; AbbVie: Consultancy; Roche/Genentech: Consultancy; Pfizer: Consultancy; Orsenix: Consultancy; Celgene Corporation: Consultancy; Roche/Genentech: Consultancy; Orsenix: Consultancy; Argenx: Consultancy; Janssen Pharmaceuticals: Consultancy; Eisai: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Aphivena Therapeutics: Consultancy; Aphivena Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; Sandoz: Consultancy. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Jurcic:Actinium Pharmaceuticals, Inc: Research Funding; Daiichi-Sankyo: Research Funding; Forma Therapeutics: Research Funding; Syros Pharmaceuticals: Research Funding; AbbVie: Consultancy, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Research Funding; Genetech: Research Funding; Incyte: Consultancy; Celgene: Research Funding; Astellas: Research Funding. Raza:Kura Oncology: Research Funding; Geoptix: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Research Funding; Janssen: Research Funding; Onconova: Research Funding, Speakers Bureau; Syros: Research Funding. Bixby:GlycoMimetics: Research Funding. Cortes:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Arog: Research Funding. Stephens:Syros Pharmaceuticals: Employment, Equity Ownership. Volkert:Syros Pharmaceuticals: Employment, Equity Ownership. Kang:Syros Pharmaceuticals: Employment, Equity Ownership. Di Tomaso:Syros Pharmaceuticals: Employment, Equity Ownership. Roth:Syros Pharmaceuticals: Employment, Equity Ownership.

Background Binding of E-selectin (E-sel) to sialyl Lex on the leukemic cell surface activates cell survival pathways and promotes chemotherapy resistance in AML. Expression of the E-sel ligand (E-sel-L) is associated with increased relapse and poor survival. Uproleselan (GMI-1271), a novel E-sel antagonist, disrupts cell survival pathway activation, enhances chemotherapy response and protects from toxicity with improved survival in vivo. We added uproleselan to mitoxantrone, etoposide, cytarabine (MEC) chemotherapy for R/R AML patients (pts) and to cytarabine and idarubicin (7+3) induction for older, treatment naïve (TN) AML pts. Here we report on final outcomes and correlative studies. Methods A Phase (Ph) 1/2 trial evaluated safety and efficacy of escalating doses of upro (5-20 mg/kg) combined with MEC in pts with R/R AML. The recommended Ph 2 dose (RP2D) was 10 mg/kg. Ph 2 added pts ≥60 yrs with TN AML treated with upro and 7+3. Uproleselan was given 24 hrs prior, every 12 hrs during and 48 hrs post chemotherapy. Responders could receive consolidation therapy (1 cycle MEC or 1-3 cycles IDAC) with uproleselan. Baseline E-sel-L expression on AML blasts (CD45+,SSC) and leukemic stem cells (LSC, CD34+CD38-CD123+) in blood and bone marrow (BM) was assessed by flow cytometry, for percentage of blasts binding to E-sel-Fc chimeric protein and HECA452 (antibody to sialyl Lex). Post-induction measurable residual disease (MRD-/MRD+) was assessed locally. Results 91 pts were enrolled (Ph 1 R/R=19; Ph 2 R/R=47. TN=25). Median age in R/R pts was 59 yrs (26-84) with 22/66 (33%) primary refractory, 22 (33%) CR1 Median age in TN pts was 67 yrs (60-79). 48% had adverse risk (ELN) and 52% secondary AML (sAML). Uproleselan was well tolerated, with no increase in adverse events, no Grade 3/4 mucositis, and mortality 8% (30d) and 12% (60d). CR/CRi was 72% (all), and 69% (sAML). 5/9 (56%) evaluable pts were MRD-. 19/25 (76%) proceeded to further anti-leukemic therapy; 11 (44%) proceeded to SCT. Median (95% CI) EFS, OS, and remission duration were 9.2 m (3.0-12.6), 12.6 m (9.9-NR), and 10.4 m (7.1-17.8) respectively; 1-year OS was 52%. For sAML, median (95% CI) EFS and OS were 7.7 m (1.1-9.5) and 10.5m (4.4-NR), respectively. For TN/MRD-, 1-year OS was 60%. E-sel-L was detectable on BM blasts in all 24 evaluable pts: median expression 31% (2-92) of blasts. In a subset of MRD evaluable pts (N=8), E-sel-L expression was higher in those who were MRD+ (35% vs 8%). In BM blasts (Figure N=24), LSC expression of E-sel-L correlated with blast E-sel-L (R2=0.87, p Conclusion The addition of uproleselan to chemotherapy was well tolerated, with low oral mucositis rates, high remission rates, high MRD- and transplant rates, and promising survival outcomes in pts with R/R and TN AML. High E-sel-L expression is associated with improved remission and survival with uproleselan treatment in R/R AML. Phase III studies in pts with R/R and (older) TN AML are underway. Figure. Figure. Disclosures DeAngelo: Shire: Honoraria; Amgen: Consultancy; BMS: Consultancy; ARIAD: Consultancy, Research Funding; Blueprint Medicines: Honoraria, Research Funding; Takeda: Honoraria; Glycomimetics: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Amgen: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Glycomimetics: Research Funding; Blueprint Medicines: Honoraria, Research Funding; Pfizer Inc: Consultancy, Honoraria; Shire: Honoraria; BMS: Consultancy; Takeda: Honoraria; Incyte: Consultancy, Honoraria; Pfizer Inc: Consultancy, Honoraria; ARIAD: Consultancy, Research Funding. Jonas:Glycomimetics: Research Funding; Genentech/Roche: Research Funding; Celgene: Consultancy, Research Funding; Accelerated Medical Diagnostics: Research Funding; Daiichi Sankyo: Research Funding; Incyte: Research Funding; Esanex: Research Funding; Tolero: Consultancy; Kalobios: Research Funding; LP Therapeutics: Research Funding; Amgen: Consultancy; Pharmacyclics: Research Funding; Forma: Research Funding; AbbVie: Consultancy, Research Funding. Liesveld:Onconova: Other: DSMB; Abbvie: Honoraria. Bixby:GlycoMimetics: Research Funding. Advani:Glycomimetics: Consultancy; Novartis: Consultancy; Amgen: Research Funding; Pfizer: Honoraria, Research Funding. Marlton:GlycoMimetics: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. O'Dwyer:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Onkimmune: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Glycomimetics: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees. Fogler:GlycoMimetics: Employment, Equity Ownership. Wolfgang:GlycoMimetics: Employment, Equity Ownership. Magnani:GlycoMimetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Thackray:GlycoMimetics: Employment, Equity Ownership. Becker:GlycoMimetics: Research Funding.