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Patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) represent a heterogeneous population and therefore there is no standard of care first salvage regimen. We conducted a multicenter, retrospective analysis to compare chemotherapy (e.g. HyperCVAD, MOAD, Larson/CALGB-9511, etc.) to novel agents (blinatumomab or inotuzumab) in first salvage. The primary endpoint, overall survival (OS), was not significantly different among treatment arms, with a median OS of 10.6 months with chemotherapy and 10.1 months with novel therapy (

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

PEG-asparaginase is a key component in treatment regimens for acute lymphoblastic leukemia (ALL). Major side effects include thrombosis and bleeding; however, there is currently no consensus on methods to prevent these complications. In this multi-center retrospective cohort study of 101 adults, we compared two prophylaxis strategies: cryoprecipitate and fresh frozen plasma (Cryo/FFP) versus cryoprecipitate and antithrombin (ATIII). The overall incidence of venous thromboembolism (VTE) was not significantly different between the two groups (19.7% for Cryo/FFP and 8.6% in Cryo/ATIII,ip/i = 0.17), and neither was grade ≥3 bleeding (3% for Cryo/FFP and 11.4% for Cryo/ATIII,ip/i = 0.18). Given the significant cost associated with ATIII without a clear benefit, a careful benefit and risk analysis should be considered before utilizing ATIII as a prophylaxis strategy to prevent thrombosis or bleeding following asparaginase administration.

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.