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Summary Background Daunorubicin and cytarabine are used as standard induction chemotherapy for patients with acute myeloid leukaemia. CPX-351 is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. Primary analysis of the phase 3 trial in adults aged 60–75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia provided support for approval of CPX-351 by the US Food and Drug Administration and European Medicines Agency. We describe the prospectively planned final 5-year follow-up results. Methods This randomised, open-label, multicentre, phase 3 trial was done across 39 academic and regional cancer centres in the USA and Canada. Eligible patients were aged 60–75 years and had a pathological diagnosis of acute myeloid leukaemia according to WHO 2008 criteria, no previous induction therapy for acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned 1:1 (stratified by age and acute myeloid leukaemia subtype) to receive up to two induction cycles of CPX-351 (100 units/m2 administered as a 90-min intravenous infusion on days 1, 3, and 5; on days 1 and 3 for the second induction) or standard chemotherapy (cytarabine 100 mg/m2 per day continuous intravenous infusion for 7 days plus intravenous daunorubicin 60 mg/m2 on days 1, 2, and 3 [7+3]; cytarabine for 5 days and daunorubicin on days 1 and 2 for the second induction [5+2]). Patients with complete remission or complete remission with incomplete neutrophil or platelet recovery could receive up to tw cycles of consolidation therapy with CPX-351 (65 units/m2 90-min infusion on days 1 and 3) or chemotherapy (5+2, same dosage as in the second induction cycle). The primary outcome was overall survival analysed in all randomly assigned patients. No additional adverse events were collected with long-term follow-up, except data for deaths. This trial is registered with ClinicalTrials.gov , NCT01696084 , and is complete. Findings Between Dec 20, 2012, and Nov 11, 2014, 309 patients with newly diagnosed high-risk or secondary acute myeloid leukaemia were enrolled and randomly assigned to receive CPX-351 (153 patients) or 7+3 (156 patients). At a median follow-up of 60·91 months (IQR 60·06–62·98) in the CPX-351 group and 59·93 months (59·73–60·50) in the 7+3 group, median overall survival was 9·33 months (95% CI 6·37–11·86) with CPX-351 and 5·95 months (4·99–7·75) with 7+3 (HR 0·70, 95% CI 0·55–0·91). 5-year overall survival was 18% (95% CI 12–25%) in the CPX-351 group and 8% (4–13%) in the 7+3 group. The most common cause of death in both groups was progressive leukaemia (70 [56%] of 124 deaths in the CPX-351 group and 74 [53%] of 140 deaths in the 7+3 group). Six (5%) of 124 deaths in the CPX-351 group and seven (5%) of 140 deaths in the 7+3 group were considered related to study treatment. Interpretation After 5 years of follow-up, the improved overall survival with CPX-351 versus 7+3 was maintained, which supports the previous evidence that CPX-351 can contribute to long-term remission and improved overall survival in patients aged 60–75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia. Funding Jazz Pharmaceuticals.

Background Patients diagnosed with acute myeloid leukemia with a FLT3 mutation (FLT3+ AML) have historically had poor outcomes. While the addition of the FLT3 inhibitors to induction therapy has been shown to improve survival outcomes in FLT3+ AML, interactions and overlapping toxicities between FLT3 inhibitors and standard of care medications used during induction therapy (e.g. azole antifungals, anthracyclines) and logistical barriers have complicated their use. To avoid these concerns, our institution has opted to defer initiation of midostaurin until after completion of induction therapy. However, to our knowledge no study confirming the effectiveness of this strategy for real world FLT3 inhibitor use has been published. Methods We performed a single center, propensity-score matched, retrospective cohort study characterizing efficacy and safety of our strategy for use of FLT3 inhibitors in the treatment of FLT3+ AML. The primary outcome was median event-free survival (EFS), while secondary endpoints included median overall survival (OS), overall response rate (ORR), 30-day mortality, duration of neutropenia, duration of thrombocytopenia, consolidation cycle delays, documented infections, and all-cause hospital readmission. Results A total of 83 FLT3+ AML patients treated with intensive induction therapy were included in the study, of whom 48 were propensity-score matched and analyzed. Baseline characteristics were similar between the patients who received a FLT3 inhibitor after induction therapy and the historical control arm. Median EFS was not significantly different but compared favorably between the FLT3 inhibitor cohort and historical controls (not reached vs 8 months, p = 0.343) with 18-month EFS of 54% and 43% for the two cohorts, respectively. Similarly, no significant differences were noted with regard to median OS (not reached vs 28.7 months, p = 0.752), ORR (79.2% vs 79.2%), or safety outcomes between groups. Conclusion Compared to historical controls, addition of a FLT3 inhibitor to intensive chemotherapy post-induction may improve EFS or OS in a real world patient cohort with longer follow-up and a larger sample size. The omission of midostaurin in induction allowed for the use of an azole antifungal and the intensification of anthracycline dose may have contributed to high remission rates in both groups.

Liposomal daunorubicin/cytarabine (CPX-351) gained FDA approval for secondary AML after demonstrating improved outcomes over daunorubicin and cytarabine (7 + 3). A number of study limitations prompted a comparison of safety/efficacy of CPX-351 against regimens containing a purine analogue and high-dose cytarabine (HIDAC). This retrospective study compared complete response rates with/without count recovery (CR/CRi) between HIDAC-based regimens and CPX-351 in 169 patients with newly diagnosed sAML. The CR/CRi rate was 62.7% in the HIDAC-based therapy arm vs. 47.9% in the CPX-351 arm (

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.

This retrospective study was conducted to determine whether the number of peripherally inserted central-catheter lumens affected the rate of central-line associated bloodstream infections (CLABSIs) in adult patients with acute leukemia. The results show that CLABSI rates were not significantly different between patients with triple-lumen or double-lumen PICCs (22.1% vs 23.4%; P = .827).

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.

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

The availability of Erwinia Asparaginase has been limited across the world due to manufacturing shortages or for some countries due to the high acquisition cost, putting patients at risk for inferior outcomes. This manuscript provides guidance on how to manage hypersensitivity reactions and utilize therapeutic drug monitoring (TDM) to conserve and limit Erwinia use. The clinical and financial impact of a multidisciplinary committee are also discussed. Faced with a global Erwinia shortage, a multidisciplinary asparaginase allergy committee was created to review all hypersensitivity reactions to asparaginase therapy, staff education was performed on the management of asparaginase hypersensitivity reactions, an institution-wide premedication policy was mandated, and standardized guidelines were created for TDM. This multidisciplinary approach reduced the PEG-asparaginase to Erwinia switch rate from 21% (35 of 163) to 7% (10 of 134) (

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 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.

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.

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 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.

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

Asparaginase remains a cornerstone of ALL therapy and is one of the key contributing factors to improved outcomes in adolescent and young adult (AYA) patients treated on pediatric protocols. Asparagine depletion has been associated with improved outcomes in ALL patients; this has led to an increased emphasis on optimizing asparagine depletion in ALL patients of all ages. To ensure adequate asparagine depletion, the use of therapeutic drug monitoring of asparaginase therapy holds much promise, yet remains underutilized in practice. Data regarding asparaginase activity level monitoring and associated outcomes are reviewed, and an evidence-based asparaginase activity level monitoring algorithm is presented. Finally, unique management strategies for key asparaginase toxicities in ALL patients are discussed, as well as a discussion of novel asparaginase formulations on the horizon.

Asparaginase is commonly de-emphasized/omitted in adult acute lymphoblastic leukemia regimens due to poor tolerability, including hepatotoxicity (HTX). Adult patients (n = 100) given induction therapy containing pegylated asparaginase (PEG) from January 2008 to February 2016 were evaluated for HTX. Sixteen patients met criteria for HTX (direct bilirubin >3 g/dL). A multivariable model identified body surface area >2m2 (OR 7.40; 95% CI: 1.73–31.61, p = .007), albumin

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

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.

Context Novel treatment approaches for patients with secondary acute myeloid leukemia (AML) are urgently needed. Secondary AML constitutes about 25-30% of AML and it has been observed that patients with secondary AML have worse responses rates to chemotherapy, increased rates of relapse, and worse overall survival compared to patients with de novo AML. Objective Our long-term goal is to develop more effective therapeutic options for patients with secondary AML. Our objectives in this study are: (i) to demonstrate synergy between cytarabine and venetoclax in secondary AML cell lines and patient-derived samples, (ii) to elucidate the mechanism of this synergy, (iii) functional characterization of Bcl-2 family proteins by BH3 profiling performed on secondary AML cell lines and patient samples. Results Synergy was demonstrated between cytarabine and venetoclax in secondary AML and de novo AML cell lines (Molm13, MV4;11, SKM-1; ML-2) using both an MTT cell viability assay and a flow-cytometry based Annexin-V assay, quantified by the computer software Compusyn. BH3 profiling of these cell lines indicated a dependence on both Bcl-2 and Mcl-1. Interestingly, SKM-1 showed sole dependence on Mcl-1. In SKM-1 cells, western blotting showed increased expression of Mcl-1 after treatment with venetoclax for 8 hrs and decreasing Mcl-1 expression with time (8hrs–72hrs) after treatment with cytarabine. Combination treatment for 24-48 hrs led to Mcl-1 expression that was similar to or less than Mcl-1 expression in control cells. Synergy between cytarabine and venetoclax was confirmed in patient samples. Importantly, BH3 profiling showed that patient samples exhibited dependence on Bcl-2 or both Mcl-1 and Bcl-2. Conclusions There is significant synergy between cytarabine and venetoclax in both de novo and secondary AML cell lines as well as patient samples. One of the potential mechanisms of this synergy is abrogation of Mcl-1 upregulation. Secondary AML exhibits variable functional dependence on Mcl-1 and Bcl-2. These findings support the clinical investigation of cytarabine and venetoclax in patients with secondary AML as well as the use of BH3 profiling as a potential predictive biomarker. Acknowledgements This work was supported by the NIH R01 CA-217141 and AACR Bayer Innovation and Discovery Award to Z. Nikolovska-Coleska.

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.

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 (

Introduction Acute myeloid leukemia (AML) is a heterogeneous clonal hematopoietic neoplasm. The cytogenetic changes associated with AML affect the response rate and survival and are one of the most important independent prognostic factors. AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM accounts for 1% to 2% of all forms of AML and has been associated with a younger age at diagnosis, a poor response to standard induction chemotherapy, and very poor long-term prognosis. Patients and Methods We performed a single-center, retrospective cohort study comparing the outcomes with hypomethylating agent (HMA) plus lenalidomide to those with standard intensive induction therapies for newly diagnosed and relapsed/refractory AML with inv(3). Results Of the 15 patients, 4 (26.7%) had received lenalidomide and HMA as primary therapy. The overall response rate (ORR) was 100% for the 4 patients who had received lenalidomide with HMA as first-line induction therapy. The ORR was 27.3% (3 of 11) for the patients who had received other induction regimens (P = .0256). The duration of response for first induction therapy was an average of 7.4 months after lenalidomide plus an HMA and a mean of 1.5 months after induction with other chemotherapy regimen (P = .057). The ORR for induction and reinduction therapy was also assessed, with an ORR of 21.4% (6 of 28) for alternative chemotherapy regimens and an ORR of 75% (6 of 8) for induction and reinduction with lenalidomide plus HMA (P = .0046). Conclusions The high ORR and reasonable duration of response could allow for potentially curative allogeneic hematopoietic cell transplantation for these patients with high-risk AML. Our initial data suggest that lenalidomide plus HMA is a promising approach for patients with AML with inv(3).

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.

Context: The current standard of care for Ph+ ALL is concurrent chemotherapy or corticosteroids with a TKI, followed by an allogeneic transplant for those who are eligible and have attained complete morphologic remission. However, recent studies have suggested that transplant may not be necessary for all patients with Ph+ ALL, especially those who achieve CMR after induction. Objective: Our objective is to analyze the outcomes and characteristics of patients with Ph+ ALL treated within our institution who did not undergo allogeneic stem cell transplant. Design: We conducted a retrospective cohort study of patients with Ph+ ALL who did not undergo allogeneic stem cell transplant treated at the University of Michigan between 2007 and 2019. Main Outcome Measures: The primary outcome measurements of our study were overall survival (OS) and event-free survival (EFS). Results: 31 patients were identified in our database and met eligibility criteria. 30/31 patients received an upfront TKI (20 received dasatinib, 9 received imatinib, and 1 received ponatinib). 11 patients had molecular testing, and 4 had an IKZF1 mutation. The median OS was 388 days, with a median EFS of 247 days. 7 patients were deemed medically eligible for transplant but did not undergo transplant for reasons including patient preference and lack of an adequately matched donor. The median OS was 372 days for these 7 patients. 10/31 patients achieved CMR, with a median time to CMR of 148.5 days. The median OS in patients who achieved CMR was 551 days. The median OS for those who survived at least 50 days after diagnosis was 494 days. Cox regression analysis found an HR of.129 [0.020–0.841] for initial induction with hyperCVAD + TKI and an HR of 10.177 [1.209–85.677] with dexamethasone, vincristine, and TKI. No significant difference in OS was observed based on the choice of TKI. All patients who achieved CR experienced relapse or death during follow-up. Conclusions: Our results reveal poor outcomes in non-transplanted patients with Ph+ ALL and support the current standard of care utilizing concomitant chemotherapy and TKI with allogeneic transplant in those who are medically eligible.

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.

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

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).

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.

Context Secondary AML (sAML) represents up to 30% of total AML cases and is associated with a poor porgnosis. Response rates to traditional chemotherapy regimens are poor. Prior studies have shown that both fludarabine, high-dose cytarabine, and granulocyte colony stimulating factor (FLAG) and HMA-based regimens (e.g. decitabine ± venetoclax) can provide favorable responses with lower treatment related toxicities than traditional regimens such as 7+3 or CPX-351. Objective The purpose of this study was to compare response rates in patient with sAML receiving 10-day decitabine ± venetoclax to FLAG. Design Single-center retrospective cohort study of patients with sAML starting induction therapy at Michigan Medicine between January 2014 and July 2019. Setting Academic Medical Center. Patients or other participants Adult patients with sAML receiving first induction. Exclusion criteria as follows: receipt of prior therapy for this AML occurrence, or prior use of hypomethylating agent for antecedent hematologic disorder. Main outcome measures Complete response/Complete response with incomplete count recovery (CR/CRi) Results The median age was 73 (range, 37–80) in the decitabine ± venetoclax group and 67 (range, 27–82) in the FLAG group (p = 0.037). There was numerically lower but statistically similar CR/CRi rate in patients treated with decitabine ± venetoclax compared to FLAG (40 vs. 62%, p = 0.076). More patients in the decitabine ± venetoclax group achieved MLFS (25% vs. 1%, p = 0.002). The median overall survival was comparable in both groups (11.1 months, decitabine ± venetoclax vs. 9.5 months, FLAG; p = 0.472). There was a higher incidence of documented infections (20% vs. 55%, p = 0.01) with FLAG, despite days to absolute neutrophil count recovery being longer with decitabine ± venetoclax (median, 34 vs. 19 days; p Conclusions Response rates after FLAG and decitabine ± venetoclax are comparable and translate to similar overall survival in the sAML population in this real-world, single-center retrospective review. Larger studies are necessary to elucidate benefits of the individual regimens in the sAML patient population.

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.

7510 Background: CPX-351 (Vyxeos; daunorubicin and cytarabine liposome for injection), a dual-drug liposomal encapsulation of cytarabine [C] and daunorubicin [D], is approved by the FDA and EMA for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Primary analysis of the pivotal phase 3 study (NCT01696084) that formed the basis for these approvals evaluated patients (pts) aged 60-75 y with newly diagnosed high-risk/secondary AML and found that CPX-351 significantly improved median overall survival (OS) vs conventional 7+3, with a comparable safety profile. Here, we report the prospectively planned final 5-y follow-up results from this phase 3 study. Methods: Pts were randomized 1:1 to receive ≤2 induction cycles of CPX-351 (100 units/m2 [C 100 mg/m2 + D 44 mg/m2] as a 90-min infusion on Days 1, 3, 5 [2nd induction: Days 1, 3]) or 7+3 (C 100 mg/m2/d continuously for 7 d + D 60 mg/m2 on Days 1-3 [2nd induction: 5+2]). Pts achieving complete remission (CR) or CR with incomplete platelet or neutrophil recovery could receive up to 2 consolidation cycles. Pts could receive a hematopoietic cell transplant (HCT) at the physician’s discretion. Pts were followed until death or up to 5 y following randomization. Results: In total, 309 pts were randomized to CPX-351 (n = 153) or 7+3 (n = 156). The survival rate at 5 y was higher for CPX-351 vs 7+3 (18% vs 8%; Table). Among pts who died, the most common primary cause of death was progressive leukemia in both arms (CPX-351: 56%; 7+3: 53%). After a median follow-up of 60.65 mo, improved median OS with CPX-351 vs 7+3 was maintained: 9.33 vs 5.95 mo; Kaplan-Meier (KM) OS curves plateaued at ~30 mo. HCT was received by 53 (35%) vs 39 (25%) pts after CPX-351 vs 7+3; among these pts, the survival rate at 5 y was higher for CPX-351 vs 7+3 (52% vs 23%), and median OS landmarked from the HCT date was not reached for CPX-351 vs 10.25 mo for 7+3 (Table). Conclusions: After 5 y of follow-up, improved OS was maintained in this phase 3 study, supporting that CPX-351 has the ability to produce or contribute to long-term remission and survival in older pts with newly diagnosed high-risk/secondary AML. Clinical trial information: NCT01696084 . [Table: see text]

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.