Search

The cornerstone of management in patients with acute promyelocytic leukemia (APL) is early diagnosis and prompt initiation of treatment with an all-trans retinoic acid (ATRA)-based regimen. Identification of the t(15;17)(PML-RARA) chromosomal translocation through conventional cytogenetics fluorescence in-situ hybridization (FISH) or detection of the promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) fusion through RT-PCR represent the current standard of care for diagnosing APL. However, about 1–2% of patients with APL have a variant translocation involving other fusion partners with RARα besides PML. These patients present a unique diagnostic and clinical challenge in that conventional cytogenetics in addition to FISH and/or RT-PCR for PML-RARα may fail to identify these clinically relevant genetic lesions leading to an inappropriate diagnosis and treatment. We present two cases of patients who had APL with variant translocations whose bone marrow specimens were sent to the University of Michigan for enrollment in the MI-ONCOSEQ study (HUM00067928) after standard testing failed to identify PML-RARα or t(15;17) despite a phenotypic concern for this diagnosis. In these two patients, whole exome and transcriptome profiling via the MI-ONCOSEQ platform identified a PRKAR1A-RARα fusion in one patient and ZBTB16-RARα fusion in another patient. These cases illustrate the utility of whole exome and transcriptome profiling in diagnosing variant translocations in patients in whom there is a high clinical suspicion for APL based on hematopathology review.

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.

Background Current literature has demonstrated the utility of the MRSA nasal screen as a de-escalation tool to decrease unnecessary anti-MRSA antibiotic therapy. However, data on the applicability of this test in patients with hematologic malignancy is lacking. Methods This is a single-center, retrospective cohort study of patients with acute myeloid leukemia (AML) with or without history of hematopoietic cell transplant (HCT), with pneumonia and MRSA nasal screening with respiratory cultures obtained. The primary outcome was to determine the negative predictive value (NPV) of the MRSA nasal screen for MRSA pneumonia. Secondary outcomes included sensitivity, specificity, positive predictive value (PPV) of the MRSA nasal screen and prevalence of MRSA pneumonia. Results Of 98 patients with AML and pneumonia, the prevalence of MRSA pneumonia was 4.1% with confirmed positive MRSA respiratory cultures observed in 4 patient cases. In patients with confirmed MRSA pneumonia, 3 had positive MRSA nasal screens while 1 had a false negative result, possibly due to a long lag time (21 days) between MRSA nasal screen and pneumonia diagnosis. Overall, the MRSA nasal screen demonstrated 75% sensitivity and 100% specificity, with a PPV of 100% and a NPV of 98.9%. Conclusions Given the low prevalence, empiric use of anti-MRSA therapy in those AML and HCT patients with pneumonia may not be warranted in clinically stable patients. For patients in whom empiric anti-MRSA antibiotics are initiated, nasal screening for MRSA may be utilized to de-escalate anti-MRSA antibiotics in patients with AML with or without HCT.

Background Acute leukemia with mixed-phenotype blasts is associated with poor outcomes. There are no standard treatment regimens. Due to disease heterogeneity, controversy exists over whether an AML-based, ALL-based, or a combined (hybrid) AML/ALL-based regimen is most appropriate. Materials and Methods We conducted a single-center, retrospective case series review of patients with acute leukemia with mixed phenotype blasts as described by the European Group for Immunological Characterization of Leukemia (EGIL) or the 2008 WHO classification. Patients were treated from November 2014 and December 2019 with the combination chemotherapy regimen FLAG-idarubicin-vincristine-prednisone with or without rituximab. Outcomes included induction response, time to transplant, time to relapse, overall survival, time to neutrophil or platelet recovery, infection, and duration of hospitalization. Results The median age was 68 years (range 21−77). Six patients (87.5 %) had unfavorable/complex cytogenetics. All patients achieved a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi). Estimated 1-year overall survival was 85.7 %. There were no deaths during induction, with a 22 day median duration of hospitalization for induction. Conclusion The combination of FLAG, idarubicin, vincristine, and prednisone (FLAG-VIPR) demonstrated favorable induction responses in a disease state with historically poor outcomes and should be studied in a prospective clinical trial.

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.

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.

Secondary AML is associated with a disproportionately poor prognosis, consistently shown to exhibit inferior response rates, event-free survival, and overall survival in comparison with de novo AML. Secondary AML may arise from the evolution of an antecedent hematologic disorder, or it may arise as a complication of prior cytotoxic chemotherapy or radiation therapy in the case of therapy-related AML. Because of the high frequency of poor-risk cytogenetics and high-risk molecular features, such as alterations in TP53, leukemic clones are often inherently chemoresistant. Standard of care induction had long remained conventional 7 + 3 until its reformulation as CPX-351, recently FDA approved specifically for secondary AML. However, recent data also suggests relatively favorable outcomes with regimens based on high-dose cytarabine or hypomethylating agents. With several investigational agents being studied, the therapeutic landscape becomes even more complex, and the treatment approach involves patient-specific, disease-specific, and therapy-specific considerations.

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 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.

The 5-year overall survival (OS) in patients ≥ 60 years old with acute myeloid leukemia (AML) remains

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

Central nervous system (CNS) relapse in acute myeloid leukemia (AML) confers a poor prognosis. Despite the identification of risk factors for CNS relapse (e.g. hyperleukocytosis), there is no standard practice for CNS relapse risk reduction with intrathecal (IT) chemotherapy in patients. We compared outcomes of 50 patients who did not receive IT chemotherapy with 18 patients who did receive IT chemotherapy with a hyperleukocytosis at diagnosis (defined as white blood cell count ≥100,000 cells/mcL). There were three occurrences of CNS relapse, all within patients who did not receive prophylaxis. There was no difference in the incidence of CNS relapse between the patient cohorts (

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.

Background Relapsed/refractory acute myeloid leukemia (AML) confers a poor prognosis, and there is no single standard of care first-line salvage regimen. FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor) is a common salvage regimen with a favorable toxicity and efficacy profile in poor-risk AML. Materials and Methods We conducted a single-center, retrospective analysis of first relapse/primary refractory patients with AML that received salvage chemotherapy from January 2009 to July 2019. We propensity-score matched patients 1:1 (based on age at diagnosis, cytogenetic risk group, Charlson comorbidity index, de novo vs. secondary AML, and whether or not they received an allogeneic stem cell transplant in first complete remission) into 2 groups, FLAG (Group 1) or non-FLAG (Group 2) as first-line salvage regimen, with 66 patients in each group. The primary endpoint was overall response rate (complete response and complete response with incomplete hematologic recovery). Results The median patient age was 59 years (range, 19-80 years). Patients treated with FLAG had a higher overall response rate (complete response/complete response with incomplete hematologic recovery) (71.2% vs. 50.0%; odds ratio, 2.47; 95% confidence interval [CI], 1.21-5.08; P = .013), longer event-free survival (8.9 vs. 2.1 months; hazard ratio [HR], 0.58; 95% CI, 0.39-0.86; P = .005), and longer overall survival (14.2 vs. 5.9 months; HR, 0.62; 95% CI, 0.41-0.93; P = .019). Patients who received FLAG had a shorter median duration of neutropenia (22 vs. 34 days; HR, 0.43; 95% CI, 0.29-0.64; P Conclusion This analysis supports the FLAG regimen as an effective and well-tolerated salvage therapy for patients with relapsed/refractory AML.

High dose cytarabine (HIDAC) consolidation has demonstrated a survival benefit in patients with acute myeloid leukemia (AML). The increasing prevalence of obesity and the toxicity risk with this therapy renders important the quantification of potential risks with weight-based dosing in this patient population. The American Society of Clinical Oncology published recommendations on chemotherapy dosing in obese patients, but patients with leukemia were excluded from analysis. This was a retrospective comparison of safety and efficacy outcomes in obese and non-obese patients with AML who received HIDAC consolidation. Thirty-nine (41.9 %) patients received dose adjusted HIDAC in cycle 1. Nine of the 40 patients in the obese group received HIDAC dose-adjusted for obesity. The combined incidence of cycle delays, febrile neutropenia, or documented infection was 41.5 % in non-obese patients compared to 57.5 % in obese patients (p = 0.127). The median overall survival (OS) and event free survival (EFS) were not reached in both cohorts. The estimated 36-month overall survival was 76.4 % (95 % CI 0.623-0.905) in non-obese patients, compared to 66.1 % (95 % CI 0.472-0.85) in obese patients. There were no significant differences in safety or efficacy outcomes for obese versus non-obese patients who received HIDAC consolidation. For class III obesity, baseline dose-adjustments were more common.

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=

Acute myeloid leukemia is a hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and other tissues. Prognosis is poor with 5-year survival rates ranging from 5–65% depending on demographic and clinical features. Outcomes are worse for patients that have an antecedent myeloproliferative neoplasm that evolves to acute myeloid leukemia, with a survival rate of 15 mg/dL).

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.

Systemic mastocytosis (SM) is characterized by a clonal proliferation of aberrant mast cells within extracutaneous sites. In a subset of SM cases, a second associated hematologic non-mast cell disease (AHNMD) is also present, usually of myeloid origin. Polymerase chain reaction and targeted fluorescence in situ hybridization studies have provided evidence that, in at least some cases, the aberrant mast cells are related clonally to the neoplastic cells of the AHNMD. In this work, a single nucleotide polymorphism microarray (SNP-A) was used to characterize the cytogenetics of the aberrant mast cells from a patient with acute myeloid leukemia and concomitant mast cell leukemia associated with a KIT D816A mutation. The results demonstrate the presence of shared cytogenetic abnormalities between the mast cells and myeloid blasts, as well as additional abnormalities within mast cells (copy-neutral loss of heterozygosity) not detectable by routine karyotypic analysis. To our knowledge, this work represents the first application of SNP-A whole-genome scanning to the detection of shared cytogenetic abnormalities between the two components of a case of SM-AHNMD. The findings provide additional evidence of a frequent clonal link between aberrant mast cells and cells of myeloid AHNMDs, and also highlight the importance of direct sequencing for identifying uncommon activating KIT mutations.

Multiple BCR-ABL tyrosine kinase inhibitors (TKIs) are available for the treatment of chronic myeloid leukemia in chronic phase (CML-CP), and several baseline and on-treatment predictive factors have been identified that can be used to help guide TKI selection for individual patients. In particular, early molecular response (EMR; BCR-ABL ≤10% on the International Scale at 3 months) has become an accepted benchmark for evaluating whether patients with CML-CP are responding optimally to frontline TKI therapy. Failure to achieve EMR is considered an inadequate initial response according to the National Comprehensive Cancer Network guidelines and a warning response according to the European LeukemiaNet recommendations. Here we review data supporting the importance of achieving EMR for improving patients' long-term outcomes and discuss key considerations for selecting a frontline TKI in light of these data. Because a higher proportion of patients achieve EMR with second-generation TKIs such as nilotinib and dasatinib than with imatinib, these TKIs may be preferable for many patients, particularly those with known negative prognostic factors at baseline. We also discuss other considerations for frontline TKI choice, including toxicities, cost-effectiveness, and the emerging goals of deep molecular response and treatment-free remission.

The optimal intensity of conditioning for allogeneic hematopoietic stem cell transplantation (HCT) in acute myeloid leukemia (AML) remains undefined. Traditionally, myeloablative conditioning regimens improve disease control, but at the risk of greater nonrelapse mortality. Because fludarabine with myeloablative doses of intravenous busulfan using pharmacokinetic monitoring has excellent tolerability, we reasoned that this regimen would limit relapse without substantially elevating toxicity when compared to reduced intensity conditioning. We retrospectively analyzed 148 consecutive AML patients in remission receiving T cell replete HCT conditioned with fludarabine and intravenous busulfan at doses defined as reduced (6.4 mg/kg; FluBu2, n = 63) or myeloablative (12.8 mg/kg; FluBu4, n = 85). Early and late nonrelapse mortality (NRM) was similar among FluBu4 and FluBu2 recipients, respectively (day + 100: 4 vs 0 %; 5 years: 19 vs 22 %; p = 0.54). NRM did not differ between FluBu4 and FluBu2 in patients >50 years of age (24 vs 22 %, p = 0.75). Relapse was lower in recipients of FluBu4 (5 years: 30 vs 49 %; p = 0.04), especially in patients with poor risk cytogenetics (22 vs 59 %; p = 0.02) and those >50 years of age (28 vs 51 %; p = 0.02). Overall survival favored FluBu4 recipients at 5 years (53 vs 34 %, p = 0.02), a finding confirmed in multivariate analysis (HR: 0.57; 95 % CI: 0.34–0.95; p = 0.03). These data suggest that myeloablative FluBu4 may provide equivalent NRM, reduced relapse, and improved survival compared to FluBu2, emphasizing the importance of busulfan dose in conditioning for AML.

Patients with secondary acute myeloid leukemia (sAML) have poor outcomes, with CR/CRi rates of 25-35% with standard 7 + 3 induction chemotherapy, while single center non-comparative analyses suggest promising outcomes with FLAG. We conducted a single-center, retrospective cohort study assessing outcomes in treatment-naïve patients with sAML treated with fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor (FLAG, n = 40) compared with 7 + 3 (n = 66). Median patient age was 63 years (range: 27-82) in the FLAG group and 60 years (range: 21-76) in the 7 + 3 group (P = 0.968). Patients treated with FLAG achieved higher overall response rates (CR + CRi + MLFS) compared to 7 + 3 (70% vs. 48%, P = 0.043). FLAG was well tolerated, with only one induction death (30-day mortality rate, 3% vs. 8%, P = 0.405) and no cases of cerebellar toxicity. Duration of neutropenia was significantly shorter with FLAG (median 16 vs. 23 days, P 0.001). Half of the FLAG-treated patients proceeded to consolidative therapy compared with only 27% of those who received 7 + 3 (P = 0.022). Overall survival was comparable between groups (8.5 mos, FLAG vs. 9.1 mos, 7 + 3; P = 0.798). Thus, FLAG may represent a low-cost treatment strategy in sAML that produces higher response rates and promising survival outcomes with minimal treatment-related toxicity. Further studies are required to prospectively compare FLAG to the newly FDA-approved CPX-351 in sAML.

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.

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.

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.

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

B lymphoblastic leukemia (B-ALL) in adults has a higher risk of relapse and lower long-term survival than pediatric B-ALL, but data regarding genetic prognostic biomarkers are much more limited for adult patients. We identified 70 adult B-ALL patients from three institutions and performed genome-wide analysis via single nucleotide polymorphism (SNP) arrays on DNA isolated from their initial diagnostic sample and, when available, relapse bone marrow specimens to identify recurring copy number alterations (CNA). As B-cell developmental genes play a crucial role in this leukemia, we assessed such for recurrent deletions in diagnostic and relapse samples. We confirmed previous findings that the most prevalent deletions of these genes occur in CDKN2A, IKZF1, and PAX5, with several others at lower frequencies. Of the 16 samples having paired diagnostic and relapse samples, 5 showed new deletions in these recurrent B-cell related genes and 8 showed abolishment. Deletion of EBF1 heralded a significant negative prognostic impact on relapse free survival in univariate and multivariate analyses. The combination of both a CDKN2A/B deletion and an IKZF1 alteration (26% of cases) also showed a trend toward predicting worse overall survival compared to having only one or neither of these deletions. These findings add to the understanding of genomic influences on this comparably understudied disease cohort that upon further validation may help identify patients who would benefit from upfront treatment intensification.

This study evaluated the impact of antibacterial prophylaxis with levofloxacin in relapsed/refractory acute myeloid leukemia (AML) patients. This was a retrospective, single-center, cohort study. Adult patients with relapsed/refractory AML admitted for reinduction chemotherapy between November 1, 2006 and June 15, 2015 were screened for inclusion. A protocol initiating levofloxacin prophylaxis was implemented on December 1, 2013. Patients receiving hypomethylating agents (decitabine/azacitidine) were not administered antibacterial prophylaxis and thus not included in this analysis. Patients receiving broad spectrum antibiotics on day 1 of reinduction chemotherapy or receiving another antibacterial agent for prophylaxis were also excluded. Ninety-seven patients were included in the control group (no prophylaxis), while 48 patients received levofloxacin prophylaxis. Patients in the prophylaxis group received levofloxacin 500 mg once daily on day 1 of chemotherapy and continued until neutrophil recovery (or hospital discharge or death). There was a reduction in the rate of bacteremia in the prophylaxis group (37.5 %) compared to the control group (53.6 %, p = 0.0789), largely due to a reduction in gram-negative bacteremia (2.1 vs. 21.6 % respectively, p = 0.001). No difference was found between prophylaxis and the control groups in the incidence of neutropenic fever, incidence of multidrug resistance, length of hospital or ICU stay, or mortality. Levofloxacin prophylaxis reduced the rate of infections overall in adult patients with relapsed/refractory AML, without increasing rates of multidrug-resistant organisms.

Intro: Acute myeloid leukemia (AML) is a heterogeneous clonal hematopoietic neoplasm. The cytogenetic changes associated with AML impact response rate and survival, and is one of the most important independent prognostic factors. AML with inv(3)(q21.3q26.2) or; GATA2, MECOMaccounts for 1-2% of all forms of AML. This form is associated with a younger age at diagnosis, poor response to standard induction chemotherapy, and very poor long-term prognosis with an overall survival of Methods: We conducted a single-center, IRB-approved, retrospective cohort analysis of 939 patients who received therapy for AML at the University of Michigan between March 2005-June 2018. 15/939 (1.6%) patients tested positive for inv(3)(q21.3q26.2), and they were divided into two cohorts: a lenalidomide-based regimen or other chemotherapy induction approaches. Data abstraction of patient, disease and treatment-related variables was performed through manual chart review. The primary outcome was overall response rate (ORR), reported as the combination of complete remission (CR) and complete remission with incomplete count recovery (CRi). Secondary endpoints included overall survival (OS), 30- and 60-day mortality, event free survival (EFS), and duration of response. All data were analyzed using SPSS software, version 24.0 (SPSS, Inc., Chicago, IL). Results: In total, 15 patients were positive for inv(3)(q21.3q26.2) and underwent treatment at the University of Michigan. 4/16 (25%) received lenalidomide and HMA as primary therapy. Patient demographics and lab values at diagnosis are shown in Table 1. 4/4 (100%) of patients receiving lenalidomide with HMA as first line therapy achieved CR/CRi while 3/11 (27.3%) of patients receiving other chemotherapeutic agents initially achieved CR/CRi (p=0.0256). Duration of response was numerically longer in patients receiving lenalidomide-based therapies (7.4 months vs. 1.45 months; p=0.057). Primary and secondary outcomes in patients receiving lenalidomide plus HMA and other chemotherapies are shown in Table 2. 2/13 patients requiring salvage therapy received lenalidomide with HMA. Both of these patients achieved CR/CRi, while 3/11 (27.3%) of patients receiving other chemotherapy achieved CR/CRi. Combining initial and salvage inductions, 6/6 (100%) achieved CR/CRi with lenalidomide with HMA versus 6/22 (27.3%) with other chemotherapy (p=0.0025). Discussion: AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOMis notorious for a poor response to standard induction chemotherapy and a reported remission rate of 10-20% with traditional chemotherapy (Raya et al. Hematology 2015;20(8):435-441).In this cohort, all patients who received lenalidomide with or without a HMA achieved CR/CRi compared to 27% of patients receiving other chemotherapy. Importantly, the median duration of response with lenalidomide and HMA was longer than traditional chemotherapy, although not statistically significant, likely due to the small sample size. The high ORR and reasonable duration of response could allow for potentially curative alloHCT in these high-risk AML patients. Our study is limited by the small sample size due to the rarity of this AML subtype, but the initial data suggests that lenalidomide plus HMA is a promising approach for patients with AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM. A multicenter, prospective trial should be considered to compare the efficacy of traditional cytotoxic chemotherapy approaches versus lenalidomide plus HMA to improve outcomes in this subtype of AML. Disclosures Bixby: GlycoMimetics: Research Funding.

Background: Outcomes for the treatment of AML with conventional induction chemotherapy (eg, 7+3 cytarabine/daunorubicin regimen) are poor for older adults and those with high-risk/secondary AML. CPX-351 (Vyxeos®), a dual-drug liposomal encapsulation of cytarabine and daunorubicin in a synergistic ratio, was approved by the US FDA in 2017 for the treatment of adults with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes and is currently under review by the EMA. A large randomized, open-label, multicenter, phase 3 study (ClinicalTrials.gov #NCT01696084) evaluated the efficacy and safety of CPX-351 versus conventional 7+3 chemotherapy in adults aged 60-75 y with newly diagnosed, high-risk/secondary AML (Lancet JE, et al. J Clin Oncol. 2018). In this study, CPX-351 significantly improved median overall survival (OS; primary endpoint) versus 7+3 (9.56 vs 5.95 mo; HR = 0.69 [95% CI: 0.52-0.90]; 1-sided P = 0.003), as well as event-free survival (EFS; 2.53 vs 1.31 mo; HR = 0.74 [95% CI: 0.58-0.96]; 2-sided P = 0.021). CPX-351 was also associated with higher rates of complete remission (CR; 37.3% vs 25.6%; 2-sided P = 0.040) and CR or CR with incomplete platelet or neutrophil recovery (CR+CRi; 47.7% vs 33.3%; 2-sided P = 0.016) versus 7+3, which likely contributed to the higher rate of patients undergoing hematopoietic cell transplantation (HCT) with CPX-351 (34.0% vs 25.0%; 2-sided P = 0.098). HCT is a potentially curative therapy, and the higher rate of HCT observed in the CPX-351 arm could therefore have an impact on long-term survival outcomes. To better understand the contribution of HCT and treatment with CPX-351 versus 7+3 to survival, exploratory analyses using a time-dependent proportional hazards model were performed to evaluate survival in patients who underwent HCT and assess the impact of treatment with CPX-351 versus 7+3 on survival independent of HCT status. Methods: Patients were randomized 1:1 to receive up to 2 induction cycles with CPX-351 (100 units/m2 [cytarabine 100 mg/m2 + daunorubicin 44 mg/m2] on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (cytarabine 100 mg/m2/d continuously for 7 d [2nd induction: 5 d] + daunorubicin 60 mg/m2 on Days 1-3 [2nd induction: Days 1-2]). Patients achieving CR or CRi could receive up to 2 consolidations with CPX-351 (65 units/m2 [cytarabine 65 mg/m2 + daunorubicin 29 mg/m2] on Days 1 and 3) or 5+2 (as in 2nd induction). Patients could receive HCT at the discretion of the treating physician. Results: A total of 309 patients were enrolled in the study (CPX-351: n = 153; 7+3: n = 156), and baseline characteristics were balanced between arms. A total of 52 (34.0%) patients in the CPX-351 arm and 39 (25.0%) in the 7+3 arm underwent HCT; most were 60-69 y of age (CPX-351: 69.2%; 7+3: 84.6%), had ECOG performance status ≤1 (CPX-351: 92.3%; 7+3: 94.9%), and were in CR (CPX-351: 57.7%; 7+3: 48.7%) or CRi (CPX-351: 19.2%; 7+3: 12.8%). Median time to HCT from first study dose was similar with CPX-351 (114.5 d) and 7+3 (113.0 d). Similar to the primary endpoint analysis, median OS landmarked from the time of HCT was significantly improved with CPX-351 versus 7+3 (not reached vs 10.25 mo; HR = 0.46 [95% CI: 0.24-0.89]). Further, in the current exploratory analyses in which HCT was treated as a time-dependent covariate, the HRs remained strongly in favor of CPX-351 versus 7+3 for OS (HR = 0.71) and EFS (HR = 0.74), with the upper bounds of the 95% CIs below 1.0 (Table). These results suggest CPX-351 may be associated with prolonged OS and EFS that is independent of HCT. The adverse event profile of CPX-351 was generally consistent with the known safety profile of conventional 7+3. Grade 3-5 adverse events reported in ≥10% of patients in the CPX-351 or 7+3 cohorts included febrile neutropenia (68.0% vs 70.9%), pneumonia (19.6% vs 14.6%), and hypoxia (13.1% vs 15.2%). Early mortality rates with CPX-351 and 7+3, respectively, were 5.9% and 10.6% at Day 30 and 13.7% and 21.2% at Day 60. Conclusions: Treatment with CPX-351 was associated with significantly longer median OS and EFS, as well as a higher proportion of patients achieving remission and undergoing HCT, compared with conventional 7+3 chemotherapy in this population of older patients with newly diagnosed, high-risk/secondary AML. Further, while it is expected that HCT had a positive impact on survival in this study, exploratory analyses suggest that CPX-351 produced positive OS and EFS outcomes independent of HCT. Disclosures Lin: Jazz Pharmaceuticals: Honoraria. Cortes:Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding. Ritchie:NS Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; ARIAD Pharmaceuticals: Speakers Bureau; Astellas Pharma: Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Pfizer: Consultancy, Research Funding. Stuart:Sunesis Pharmaceuticals: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Agios: Research Funding; Astellas: Research Funding; Bayer AG: Research Funding; Celator/Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding. Strickland:Tolero Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas Pharma: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding. Bixby:GlycoMimetics: Research Funding. Kolitz:Magellan Health: Consultancy, Honoraria. Schiller:bluebird bio: Research Funding; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wieduwilt:Leadiant: Research Funding; Reata Pharmaceuticals: Equity Ownership; Merck: Research Funding; Shire: Research Funding; Amgen: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. Ryan:University of Rochester: Patents & Royalties; AbbVie: Equity Ownership. Ryan:Jazz Pharmaceuticals: Employment, Other: Stock and stock options. Chiarella:Celator/Jazz Pharmaceuticals: Employment, Equity Ownership. Louie:Jazz Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Uy:GlycoMimetics: Consultancy; Curis: Consultancy.

Background The IDSA and NCCN guidelines recommend continuing IV anti-pseudomonal (IVPSA) therapy until neutrophil recovery (i.e., an ANC > 500 cells/mm3) in high-risk acute myeloid leukemia (AML) patients with febrile neutropenia (FN). This recommendation is based on expert opinion and the current practice should be re-evaluated given the emergence of multi-drug-resistant organisms and high rates of Clostridium difficile infection (CDI) in this population. The purpose of this study was to evaluate whether IVPSA antibiotics could be safely de-escalated or discontinued in high-risk AML patients with FN following implementation of a guideline. Methods This single-center, pre–post quasi-experimental study included patients with AML receiving induction chemotherapy hospitalized between September 2015 to February 2018. Patients in the intervention group were compared with a historical cohort of patients admitted before implementation of the guideline. The primary outcome was the incidence of suspected or documented bacterial infection after antibiotic de-escalation in the intervention group (or meeting criteria for de-escalation in the historical control group). Secondary outcomes included the incidence of CDI, IVPSA Days of Therapy (DOTs), hospital length of stay (LOS), and mortality. Patients in the intervention group were evaluated for antibiotic de-escalation on day 5 of FN and antibiotics were discontinued if patients were afebrile, hemodynamically stable, and without evidence of infection irrespective of their ANC (or de-escalated to fluoroquinolone prophylaxis in relapsed/refractory disease). In clinically stable patients with suspected or documented bacterial infection, antibiotics were continued for a defined duration per indication as outlined in the guideline. Results A total of 93 patients were included in the analysis. Baseline demographics were similar between the two groups with the exception of more relapsed/refractory patients in the intervention group. Patients in the intervention group had similar clinical outcomes and lower rates of CDI and IVPSA DOTs (see Figure 1). Conclusion In high-risk AML patients with FN, an antibiotic de-escalation guideline reduced the incidence of CDI and IVPSA antibiotic DOTs without adversely affecting clinical outcomes. Disclosures All authors: No reported disclosures.

Although only 5000 new cases of chronic myeloid leukemia (CML) were seen in the United States in 2009, this neoplasm continues to make scientific headlines year-after-year. Advances in understanding the molecular pathogenesis coupled with exciting developments in both drug design and development, targeting the initiating tyrosine kinase, have kept CML in the scientific limelight for more than a decade. Indeed, imatinib, a small-molecule inhibitor of the leukemia-initiating Bcr-Abl tyrosine kinase, has quickly become the therapeutic standard for newly diagnosed chronic phase-CML (CP-CML) patients. Yet, nearly one-third of patients will still have an inferior response to imatinib, either failing to respond to primary therapy or demonstrating progression after an initial response. Significant efforts geared toward understanding the molecular mechanisms of imatinib resistance have yielded valuable insights into the cellular biology of drug trafficking, enzyme structure and function, and the rational design of novel small molecule enzyme inhibitors. Indeed, new classes of kinase inhibitors have recently been investigated in imatinib-resistant CML. Understanding the pathogenesis of tyrosine kinase inhibitor resistance and the molecular rationale for the development of second and now third generation therapies for patients with CML will be keys to further disease control over the next 10 years.

HIV causes a chronic infection characterized by depletion of CD4(+) T lymphocytes and the development of opportunistic infections. Despite drugs that inhibit viral spread, HIV infection has been difficult to cure because of uncharacterized reservoirs of infected cells that are resistant to highly active antiretroviral therapy (HAART) and the immune response. Here we used CD34(+) cells from infected people as well as in vitro studies of wild-type HIV to show infection and killing of CD34(+) multipotent hematopoietic progenitor cells (HPCs). In some HPCs, we detected latent infection that stably persisted in cell culture until viral gene expression was activated by differentiation factors. A unique reporter HIV that directly detects latently infected cells in vitro confirmed the presence of distinct populations of active and latently infected HPCs. These findings have major implications for understanding HIV bone marrow pathology and the mechanisms by which HIV causes persistent infection.

Given its relative rarity, it may at first seem surprising that chronic myeloid leukemia (CML) has garnered so much attention over the last decade. Yet, the advances in molecular pathogenesis that have been derived from studying this leukemia have clearly benefited all of oncology. Moreover, the strides in drug design and development that have also ensued around CML have given rise to what others have called a molecular revolution in cancer therapy. While a majority of patients with chronic phase CML (CP-CML) have an excellent durable response to imatinib (Gleevec, Novartis, Basel, Switzerland), a clear minority will unfortunately have signs of primary or secondary resistance to therapy. Significant efforts geared toward understanding the molecular mechanisms of imatinib resistance have yielded valuable insights into the biology of drug trafficking into and out of cells, epigenetic control of cellular processes, alterations in enzymatic structures, and the rational structural-based design of small molecule enzyme inhibitors. This review will describe the efforts at understanding the pathogenesis of imatinib resistance and the molecular rationale for the development of second- and now third-generation therapies for patients with CML.

Imatinib is one of the most potent cancer therapeutic agents identified to date. Before the introduction of this tyrosine kinase inhibitor (TKI), 5-year survival in chronic myeloid leukemia (CML) was approximately 40%-60%, but since the introduction of imatinib, overall survival has increased to approximately 90% for patients with chronic-phase disease. However, nearly one fifth of patients are intolerant or resistant to imatinib, resulting in patients with persistent or progressive disease. Recent research has identified a number of additional compounds that more efficiently inhibit the Abl tyrosine kinase and additional kinases that potentially play a role in imatinib resistance. The advent of dasatinib and nilotinib has provided additional options for patients with progressive disease. A number of phase II clinical trials have recently demonstrated that these second-generation TKIs are well tolerated and effective in patients with Philadelphia chromosome-positive (Ph+) leukemias. Recent clinical trial developments raise questions regarding the proper dosage and schedule of these newer agents as well as the timing of their use in the treatment of patients with CML. Additionally, the development of nonoverlapping resistance patterns with sequential drug exposure argues for the possibility of a drug selection scheme that might limit the development of resistant disease. As the era of personalized medicine has begun to take shape in the 21st century, the addition of newer TKIs might facilitate this trend in the treatment of Ph+ leukemias.

Background Binding of E-selectin (E-sel), an adhesion molecule expressed in the vasculature of the bone marrow, to sialyl Lex on the leukemic cell surface activates cell survival pathways and promotes chemotherapy resistance in AML. GMI-1271 is a novel E-selectin antagonist that disrupts activation of cell survival pathways, enhances chemotherapy response with improved survival in mouse xenograft and syngeneic models and protects from chemotherapy toxicity in vivo (Becker 2013; Winkler 2013, 2014, 2016). We added GMI-1271 to salvage with MEC for relapsed/refractory AML patients or to induction with 7+3 for older treatment naïve (TN) AML patients. Methods A Phase (Ph) 1 trial escalated GMI-1271 (5-20 mg/kg) combined with MEC (mitoxantrone, etoposide, cytarabine) in pts with R/R AML, to evaluate safety, tolerability and anti-leukemic activity. Dose limiting toxicity (DLT) was defined as persistent cytopenias in the absence of disease or any Grade 3-5 non-hematologic toxicity beyond day 42. The recommended Ph 2 dose (RP2D) of GMI-1271 was 10 mg/kg. A Ph 2 study then enrolled 47 pts with R/R AML for GMI-1271 plus MEC chemotherapy. Responders could receive 1 cycle of consolidation with GMI-1271 plus MEC. We also enrolled a separate Ph 2 cohort of 25 pts ≥60 yrs with TN AML for GMI-1271 (10 mg/kg) plus cytarabine and idarubicin (7+3). Two cycles of induction were allowed. Responders could receive 3 cycles of consolidation with GMI-1271 plus intermediate dose cytarabine. Prior treatment of MDS was allowed; for R/R disease prior SCT was allowed. GMI-1271 was given 24 hrs prior, then every 12 hrs during and for 48 hrs post chemotherapy. E-sel ligand expression on leukemic blasts in blood and bone marrow was assessed by flow cytometry, for the percentage of blasts binding to E-sel-Fc chimera and HECA452 (antibody to sialyl Lex). Results 91 pts were enrolled (Ph 1 R/R=19; Ph 2 R/R=47, TN=25). Median age for R/R pts was 59 yrs (range 26-84) and 62% were males. Prior AML history included 32% primary refractory, 33% CR1 Median age for TN pts was 67 yrs (range, 60-79) 56% were males, and 32% had high-risk CG. 56% had secondary AML (sAML), 43% of sAML had prior hypomethylating therapy. GMI-1271 was well tolerated, adverse events were typical for AML induction in the TN population, and Grade 3/4 mucositis was not seen. 30 and 60 d mortality were 8 and 12%, respectively; two deaths were from sepsis before response assessment and one involved persistent disease. Median time to ANC 500 was 28d (range 21-63). 8 pts required two induction courses, and 4 (16%) proceeded to SCT by data cut-off. The CR/CRi rate was 68% (73% for de novo and 64% for sAML) and ORR was 80%. Median OS and DFS are not yet reached; median follow up is 6 mos. Median E-sel ligand expression (binding to HECA452) at baseline was 31% (range, 2-92%) of bone marrow blasts. Conclusion The addition of GMI-1271 to chemotherapy was well tolerated with high remission rate, low induction mortality, and low rate of mucositis suggesting improved tolerance of chemotherapy. In R/R AML, correlative studies showed blasts expressing the E-sel ligand were predictive of response. Initial survival outcomes are promising and updated survival outcomes will be presented at ASH. FDA granted Breakthrough Therapy Designation to GMI-1271 for treatment of adults with R/R AML and randomized trials are planned. Disclosures DeAngelo: Amgen: Consultancy, Research Funding; BMS: Consultancy; Immunogen: Honoraria, Research Funding; Celgene: Research Funding; ARIAD: Consultancy, Research Funding; Blueprint Medicines: Honoraria, Research Funding; Incyte: Consultancy, Honoraria; Glycomimetics: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals U.S.A., Inc.: Honoraria; Shire: Honoraria; Pfizer Inc.: Consultancy, Honoraria, Research Funding. Jonas: Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie, Celgene, Daiichi Sankyo, Pharmacyclics, Genentech/Roche, Glycomimetics, Esanex, Kalobios: Research Funding; Rigel: Consultancy. Liesveld: Seattle Genetics: Honoraria; Onconova: Honoraria. Advani: Pfizer: Consultancy; Takeda/ Millenium: Research Funding. O'Dwyer: Onkimmune Ltd: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; GlycoMimetics Inc: Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Magnani: GlycoMimetics, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Thackray: GlycoMimetics, Inc.: Employment, Equity Ownership. Becker: GlycoMimetics, Inc.: Research Funding.

Summary This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60-min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. Dose escalation proceeded using a standard ‘3 + 3’ design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m 2 , respectively. On schedule A, hepatotoxicity was dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target-specific activity of pevonedistat. In conclusion, administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed.

SummaryChromosomal translocations affecting mixed lineage leukemia gene (MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Finally, we demonstrate the efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification.