Search

Background Limited data exist to guide blood culture ordering in persistent febrile neutropenia (FN), resulting in substantial variation in practice. Unnecessary repeat blood cultures have been associated with patient harm including increased antimicrobial exposure, hospital length of stay, catheter removal, and overall cost. Methods We conducted a single-center study of adult hematology-oncology patients with ≥3 days of FN. The yield of blood cultures was first evaluated in a 2-year historical cohort. Additionally, a pilot pre-/postintervention study was performed in non–stem cell transplant (SCT) patients following a change in our population clinical practice guideline from a recommendation of daily blood cultures to a clinically guided approach. The primary outcome was cultures collected per days of FN after day 3 of persistent FN. Results One hundred forty-six episodes of ≥3 days of FN in 108 patients were identified during the historical period. Day 1 blood cultures were positive in 23 of 146 (16%) episodes. Blood cultures were drawn on 374 of 513 (73%) subsequent episode-days (day 2–12) and were negative in 366 of 374 (98%). After the intervention, a 53% decrease was observed in the rate of total blood cultures collected (1.4 preintervention vs 0.7 postintervention; P = .03). Blood cultures obtained after 48 hours rarely yielded clinically significant organisms. Conclusions Repeat blood cultures are low-yield in persistent FN without new clinical change. A pilot intervention in non-SCT patients successfully reduced the frequency of blood culture collection.

Background/aims This article describes the proposed design of a phase I study evaluating the safety of ceramide nanoliposome and vinblastine among an initial set of 19 possible dose combinations in patients with relapsed/refractory acute myeloid leukemia and patients with untreated acute myeloid leukemia who are not candidates for intensive induction chemotherapy. Methods Extensive collaboration between statisticians and clinical investigators revealed the need to incorporate several adaptive features into the design, including the flexibility of adding or eliminating certain dose combinations based on safety criteria applied to multiple dose pairs. During the design stage, additional dose levels of vinblastine were added, increasing the dimension of the drug combination space and thus the complexity of the problem. Increased complexity made application of existing drug combination dose-finding methods unsuitable in their current form. Results Our solution to these challenges was to adapt a method based on isotonic regression to meet the research objectives of the study. Application of this adapted method is described herein, and a simulation study of the design’s operating characteristics is conducted. Conclusion The aim of this article is to bring to light examples of novel design applications as a means of augmenting the implementation of innovative designs in the future and to demonstrate the flexibility of adaptive designs in satisfying changing design conditions.

Acute myeloid leukemia has recently undergone a significant transition into identifying and successfully inhibiting driver mutations leading to disease. One of the most common mutations in acute myeloid leukemia involves the protein FMS-like tyrosine kinase 3 (FLT3), which leads to ligand-independent activation of intracellular signaling cascades leading to the survival and proliferation of the acute leukemia blast cell. Preclinical studies have demonstrated the presence of two dominant types of mutations of this protein: internal tandem duplication and tyrosine kinase domain mutations. Successful inhibition of this protein has proven to be challenging. While FLT3 has been shown to be successfully inhibited and shown to improve overall survival in the frontline therapy of acute myeloid leukemia in combination with cytarabine and anthracycline, relapsed and refractory (R/R) patients have not been shown to be a successful population until recently. A phase III trial (ADMIRAL trial) demonstrated significant overall survival benefit in patients receiving gilteritinib compared to patients receiving salvage chemotherapy. This review will provide an overview of the preclinical, clinical, and practical use of gilteritinib in the treatment of patients with relapsed and refractory acute myeloid leukemia with FLT3 mutation.

PURPOSE: Mucosal barrier injury (MBI) occurs during periods of prolonged neutropenia in patients receiving cytotoxic chemotherapy for hematologic malignancies. This can lead to laboratory-confirmed bloodstream infections (LCBIs) and subsequent complications, including sepsis, organ failure, and possible death. There are no published prevention strategies for MBI. The purpose of our proposal was to decrease our MBI-LCBI events per month by 25%. METHODS: A multidisciplinary team was assembled to achieve this proposal. Cause-and-effect diagrams in addition to Pareto charts were used to investigate potential interventions. Using Plan-Do-Study-Act (PDSA) cycles, multiple tests of change were designed over the course of 3 years. RESULTS: The number of baseline events per month for MBI-LCBIs was 1.1. With the completion of the first PDSA cycle, the MBI-LCBI events dropped to 1.0 event per month. A second PDSA cycle involving implementation of an oral care kit improved to 0.35 events per month. This unfortunately was not sustained, and a root cause analysis demonstrated that physician noncompliance with ordering the oral kit was the main reason. After the change of a physician-driven protocol to a nurse-driven protocol, the third PDSA cycle resulted in a decrease in MBI-LCBI events to 0.89 events per month. CONCLUSION: To our knowledge, this is the first published report of an intervention to prevent MBI-LCBI events. Through a multidisciplinary approach and with quality improvement tools, we were able to demonstrate a significant reduction in MBI-LCBI events.

Acute myeloid leukemia (AML) is an aggressive, heterogenous malignancy characterized by clonal expansion of bone marrow-derived myeloid progenitor cells. While our current understanding of the molecular and genomic landscape of AML has evolved dramatically and opened avenues for molecularly targeted therapeutics to improve upon standard intensive induction chemotherapy, curative treatments are elusive, particularly in older patients. Responses to current AML treatments are transient and incomplete, necessitating the development of novel treatment strategies to improve outcomes. To this end, harnessing the power of bioactive sphingolipids to treat cancer shows great promise. Sphingolipids are involved in many hallmarks of cancer of paramount importance in AML. Leukemic blast survival is influenced by cellular levels of ceramide, a bona fide pro-death molecule, and its conversion to signaling molecules such as sphingosine-1-phosphate and glycosphingolipids. Preclinical studies demonstrate the efficacy of therapeutics that target dysregulated sphingolipid metabolism as well as their combinatorial synergy with clinically-relevant therapeutics. Thus, increased understanding of sphingolipid dysregulation may be exploited to improve AML patient care and outcomes. This review summarizes the current knowledge of dysregulated sphingolipid metabolism in AML, evaluates how pro-survival sphingolipids promote AML pathogenesis, and discusses the therapeutic potential of targeting these dysregulated sphingolipid pathways.

Variant acute promyelocytic leukemia (vAPL) is a rare leukemia characterized by rearrangement between RARα and a non-PML partner gene. This type of leukemia can be difficult to recognize by histomorphologic evaluation, particularly in patients with few or no Auer rods, and by flow cytometry, but it can be identified by distinct cytogenetic features. Herein, we report on a patient with vAPL with t(11;17)(q23;q21) who presented an initial diagnostic challenge. Detailed flow cytometry findings are presented for this rare entity. Our case study also presents novel treatment (chemotherapy in combination with venetoclax) chosen based on mechanistic data from preclinical studies.

Background: CTLA-4 blockade with ipilimumab (IPI) has modest activity in hematologic malignancies relapsed post allogeneic hematopoietic cell transplantation (allo-HCT) (Davids M, NEJM). Adding decitabine (DAC) to IPI may increase efficacy of this approach in myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), and we further asked the extent to which alloreactivity contributed to this activity. Here, we present safety (Table 1) and clinical activity (Figure 1) from a phase I, multicenter, investigator-initiated study (CTEP 10026) of DAC plus IPI in pts with R/R MDS/AML with (Arm A) and without (Arm B) prior HCT. Methods: Pts ≥ 18 y with R/R MDS (≥ 5% blasts), R/R AML or untreated secondary AML were eligible. Prior HMA was permitted but trial was later amended to exclude those with disease progression on HMA therapy within 12 weeks of study entry. Pts post allo-HCT (Arm A) were required to be > 3 mo from donor cell infusion, have no prior acute GVHD Gr III or higher, be > 2 weeks off of immunosuppression and have donor T-cell chimerism ≥ 20%. Treatment was given in 28-day cycles with a lead-in single agent DAC (cycle 0) followed by combination DAC + IPI for up to a year. DAC infusion was given at 20 mg/m2 days 1-5. IPI infusion was given at 3 mg/kg (DL0), 5 mg/kg (DL1) or 10 mg/kg (DL2) on day 1 of cycles 1-4, 5, 7, 9 and 11. DLT was defined as ≥ Gr 3 non-hematologic adverse event (AE), acute GVHD, and steroid-refractory immune-related AE within 8 weeks of first IPI dose. Results: At data cut-off, 32 of 39 enrolled pts received at least 1 dose of DAC+IPI; 4 of 7 did not move on to C1D1 due to AML-related complications. Median age was 72 y (range 29-85); 25 had AML and 7 had MDS. Median number of prior regimens was 2 (range, 0-5). Twenty of 32 pts had received prior HMA therapy. A median of 3 IPI doses were given (range, 1-8). NGS performed on screening marrows using an 88-gene panel revealed mutations most commonly in ASXL1 (n=9), RUNX1 and STAG2 (n=6 each), and DNMT3A, NRAS and TP53 (n=5 each). Arm A (Post allo-HCT): Sixteen pts received DAC+IPI across the 3 DLs (7 at DL0, 3 at DL1, 6 at DL2; dose-expansion is open at DL2). The most common treatment emergent Gr 3/4 AEs were febrile neutropenia (n=3) and AST elevation, lymphocytopenia, neutropenia, thrombocytopenia, leukopenia (n=2 each). Seven of 16 pts experienced immune-related AE, including 1 with late-onset acute GVHD Gr III (colon/liver), 4 with chronic GVHD (mild, n=2; moderate, n=1; severe n=1), and 2 with Gr 2/3 ipi-induced colitis. All immune-related AEs were reversible with steroids, except for one case of steroid refractory Gr III acute GVHD complicated by fatal septic shock (DLT at IPI 10 mg/kg). In total, 4 of 16 evaluable pts achieved response, including 3 with CR and 1 with marrow CR; 2 of 4 responders had immune-related AE. For these 16 pts, the median OS is 12.8 mo (95% CI: 7.6-NA). Arm B (transplant-naïve): Sixteen pts received DAC+IPI across the 3 DLs (4 at DL0, 3 at DL1, 6 at DL2; 3 are in dose-expansion at DL2). The most common treatment emergent Gr 3/4 AEs were lymphocytopenia, thrombocytopenia and leukopenia (n=5 each); neutropenia (n=4); and anemia, fatigue, lung infection, and febrile neutropenia (n=3 each). In 6 of 16 pts that had ≥ Gr 2 immune-related AEs, all were reversible with steroids (including Gr 3 colitis (n=1), Gr 3 dermatitis (n=2), Gr 2 pneumonitis (n=1), Gr 3 hypophysitis/Gr 2 arthritis (n=1)), except for a case of Gr 2 dermatitis (resolved)/Gr 4 immune thrombocytopenia (refractory to steroids, transfusions and IVIG) (n=1; DLT at IPI 10 mg/kg). No study treatment-related deaths were observed. Objective responses were detected in 8 of 16 evaluable pts with 3 CR, 2 CRi, and 3 marrow CR. Only 2 of 8 responders had immune-related AEs. For these 16 pts, the median OS is 18.3 mo (95% CI: 11.7-NA). Overall, 2 pts discontinued study treatment due to AE. Dose expansion continues at DL2 (MTD) in Arm A and Arm B to further establish safety and tolerability. Correlative science including immunophenotyping is ongoing and will be presented. Conclusion: In this ongoing phase 1 study in pts with R/R or secondary MDS/AML, DAC plus IPI had expected AE profile and exhibited encouraging clinical activity. The rate of immune-related toxicity was frequent but similar to prior observations with IPI 10 mg/kg for melanoma. Further, high clinical activity was observed amongst pts who did not receive allo-HCT, suggesting that an alloreactive environment may not be required to benefit from CTLA-4 blockade. Disclosures Garcia: Pfizer: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lily: Research Funding. Brunner:Astra Zeneca: Research Funding; Janssen: Research Funding; Xcenda: Consultancy; GSK: Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Jazz Pharma: Consultancy; Forty Seven, Inc: Consultancy; Celgene/BMS: Consultancy, Research Funding; Biogen: Consultancy; Acceleron Pharma Inc.: Consultancy. Neuberg:Celgene: Research Funding; Madrigal Pharmaceuticals: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding. Steensma:Takeda: Consultancy; BMS/Celgene: Consultancy; Onconova: Consultancy; Arena: Current equity holder in publicly-traded company; CRISPR: Current equity holder in publicly-traded company; Aprea Therapeutics: Research Funding; Arrowhead Pharmaceuticals: Current equity holder in publicly-traded company; Astex Pharmaceuticals, Onconova Therapeutics, Pfizer, Stemline Therapeutics, Summer Road: Consultancy; H3 Biosciences: Research Funding. Rodig:Bristol Myers Squibb: Research Funding; Merck: Research Funding; Affimed: Research Funding; KITE/Gilead: Research Funding; Immunitas: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Lindsley:Takeda Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Bluebird Bio: Consultancy; MedImmune: Research Funding. Davids:Research to Practice: Honoraria; Eli Lilly: Consultancy; Adaptive Biotechnologies: Consultancy; Novartis: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Consultancy; Gilead Sciences: Consultancy; Surface Oncology: Research Funding; MEI Pharma: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Ascentage Pharma: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Sunesis: Consultancy; Zentalis: Consultancy; Syros Pharmaceuticals: Consultancy; Janssen: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Genentech: Consultancy, Research Funding; AbbVie: Consultancy; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding. Wu:BionTech: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding. Stone:Pfizer: Consultancy; Syros: Consultancy; Stemline: Consultancy; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gemoab: Consultancy; Syndax: Consultancy, Research Funding; Macrogenics: Consultancy; Trovagene: Consultancy; Biolinerx: Consultancy; Argenix: Other; Jazz: Consultancy; Aztra-Zeneca: Consultancy; Daiichi-Sankyo: Consultancy; Astellas: Consultancy; Syntrix: Other: DSMB; Novartis: Consultancy, Research Funding; Takeda: Other: DSMB; Arog: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy; Celgene: Consultancy, Other. DeAngelo:Takeda: Consultancy; Blueprint Medicines Corporation: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Incyte Corporation: Consultancy; Abbvie: Research Funding; Glycomimetics: Research Funding; Shire: Consultancy; Autolos: Consultancy; Amgen: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Forty-Seven: Consultancy; Jazz: Consultancy. Soiffer:Rheos Therapeutics: Consultancy; Celgene: Other; Juno: Other; Alexion: Consultancy; Novartis: Consultancy; VOR Biopharma: Consultancy; Mana Therapeutics: Consultancy; Precision Bioscience: Consultancy; Cugene: Consultancy; Gilead: Consultancy; Be The Match/National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Decitabine plus Ipilimumab to be given in the context of a clinical trial

Background Acute myeloid leukemia patients receive anthracycline-containing induction chemotherapy. Anthracyclines cause cardiotoxicity; however, there is a paucity of data reflecting the risk of cardiotoxicity in the acute myeloid leukemia population, and risk factors for development of reduced left ventricular ejection fraction are not well established in this population. Methods A retrospective cohort study of adult acute myeloid leukemia patients receiving anthracycline-containing induction chemotherapy between March 2011 and August 2017 was performed. Baseline and all additional cardiac monitoring within one year of induction were collected. Home medications and new medication initiation were determined via the electronic health record and new outpatient prescriptions. Results Of 97 evaluable patients, 25 (25.8%) developed reduced left ventricular ejection fraction and 18 (18.6%) experienced clinical heart failure within one year of induction. The median difference from baseline to lowest left ventricular ejection fraction was −5.0 percentage points, with a range of +10.0 to −52.5. The median time to onset of reduced left ventricular ejection fraction was 27 days, at a median cumulative anthracycline dose of 270 mg/m2. No patient-specific or medication-specific factors were significantly associated with the risk of developing reduced left ventricular ejection fraction. Of 14 patients started on medical management for reduced left ventricular ejection fraction, 10 (71%) responded to therapy. Conclusions In this retrospective analysis, we observed that acute myeloid leukemia patients experienced reduced left ventricular ejection fraction more quickly and at lower doses than previously reported in the solid tumor population. Reduced left ventricular ejection fraction was at least partially reversible in most patients started on medical management. Although no factors were significantly associated with decreased cardiomyopathy risk, future assessment of cardioprotective medications may be warranted.

Daniel R Reed,1 Eric J Pierce,2 Jeremy M Sen,3 Michael K Keng11Division of Hematology/Oncology, Department of Medicine, University of Virginia, Charlottesville, VA, USA; 2Department of Medicine, University of Virginia, Charlottesville, VA, USA; 3Department of Pharmacy Services, University of Virginia, Charlottesville, VA, USACorrespondence: Michael K KengUniversity of Virginia, Department of Medicine, Division of Hematology/Oncology, 1300 Jefferson Park Avenue, West Complex, Room 6009, Charlottesville, VA 22908, USATel +1 434 924 4257Fax +1 434 244 7534Email mk2pv@virginia.eduPurpose: Intravenous (IV) sodium bicarbonate is typically used in alkalization regimens for the safe use of the chemotherapeutic agent high-dose methotrexate (HDMTX). Urine parameters including urine output and pH are important in order to minimize the risk of kidney injury, which increases adverse effects and hospital length of stay following HDMTX. IV sodium bicarbonate has been on shortage, and there are limited literature describing the safety of alternative regimens.Patients and methods: A single institution, prospective analysis of non-Hodgkin’s lymphoma and acute lymphoblastic leukemia patients receiving HDMTX for central nervous system (CNS) prophylaxis or disease. Patients received an oral (PO) regimen of sodium bicarbonate and acetazolamide to achieve a urine pH >7. This cohort was compared to a subsequent IV sodium bicarbonate control cohort. Multiple co-primary safety outcomes assessed the incidences of acute kidney injury and delayed methotrexate clearance as well as change in liver function tests. Secondary outcomes included time to urine pH, time to urine output, and length of stay.Results: A total of 126 encounters were studied for the primary safety outcome. There was no difference between AKI incidence in patients receiving the PO alkalization regimen compared to patients receiving IV sodium bicarbonate (14.5% vs 9.3%, respectively, P=0.41). There was no difference in methotrexate clearance between the PO and IV groups (26.5% vs 37.2%, respectively, P=0.21). The use of PO alkalization regimen is estimated to have saved 2002 vials of IV sodium bicarbonate and was approximately US$226 less expensive per encounter.Conclusion: This analysis supports the use of PO regimens to achieve urine alkalization necessary for safe administration of HDMTX during periods of IV sodium bicarbonate shortage. Further studies may determine optimal dosing strategies that decrease length of stay and ensure noninferiority of efficacy outcomes with PO regimens for urine alkalization with HDMTX.Keywords: non-Hodgkin’s lymphoma, acute lymphoblastic leukemia, oral alkalization, alkalization, high-dose methotrexate, chemotherapy administration

Recently there has been a significant progression in the understanding of molecular mutations driving biochemical and cellular signaling changes leading to survival and proliferation of leukemia cells in patients with acute myeloid leukemia (AML). Preclinical studies have demonstrated a mutated enzyme in the citric acid cycle, isocitrate dehydrogenase (IDH), leads to the production of an oncogenic metabolite R-2-hydroxy-glutarate (R-2-HG). This causes the arrest in the differentiation of hematopoietic stem cells leading to the promotion of leukemia. Inhibitors of the IDH enzyme have been shown in preclinical studies to reduce the production of R-2-HG, resulting in terminal differentiation of leukemia blast cells. In recent phase I and II trials, the IDH2 inhibitor enasidenib has shown clinical activity in patients with relapsed and refractory (R/R) AML. This review will describe the preclinical and clinical developments of enasidenib and its Food and Drug Administration approval in R/R AML, treatment recommendations and management will be outlined.

Purpose: Twenty percent of patients with acute myeloid leukemia (AML) undergoing induction or reinduction chemotherapy at the University of Virginia Health System from May 2011 to August 2014 had a proven or probable invasive fungal infection (IFI). The purpose of our initiative was to reduce the percentage of proven or probable IFIs in patients with AML undergoing induction or reinduction chemotherapy at the University of Virginia Health System to 10% or less by June 2017, in concordance with national averages. Methods: A multidisciplinary team was formed to lead the comprehensive quality improvement (QI) initiative. The team generated both current process state and ideal process state workflow diagrams, a cause-and-effect diagram, and a Pareto diagram to determine the most relevant etiology for proven or probable IFIs in patients with AML undergoing induction or reinduction chemotherapy. Results: Analysis led to the creation of a program standardizing antifungal prophylaxis in this patient population, along with a suggested work-up for recalcitrant fevers. Through two tests of change (Plan-Do-Study-Act cycles 1 and 2), the QI initiative was able to effectively reduce the proven or probable IFI rate to 0% since program implementation in August 2016, thus surpassing both QI initiative goals and national rates of IFI. Mean length of stay (LOS) decreased by 3.4 days, and median intensive care unit LOS decreased by 2 days. Conclusion: Creation of a standardized antifungal prophylaxis program led to a marked decrease in LOS and the proven or probable IFI rate of patients with AML undergoing induction or reinduction chemotherapy.

Background Acute myeloid leukemia, the most common acute leukemia in adults, has a poor overall survival. Studies have suggested that certain socioeconomic factors such as living in a rural or farming area are associated with worse outcomes. Since 42% of acute myeloid leukemia patients seen in our academic center reside in a rural area, we have a unique opportunity to study outcomes of patients in rural versus urban settings. Aim This analysis evaluates the effect of geography and socioeconomic factors on the biology, treatment, and overall survival of patients with acute myeloid leukemia, with the goal of understanding health care disparities. Methods and results Patient characteristics, cytogenetic data, treatment history, and overall survival were collected and analyzed to identify differences between urban and rural residency. This cohort included 42% of patients who resided in a rural area at the time of acute myeloid leukemia diagnosis. There was no difference in overall survival between the cohorts. The 1 year overall survival for the entire cohort was 47.9%. There was no difference detected in rates of adverse cytogenetics between the rural and urban cohorts. Similar numbers of patients received induction chemotherapy or proceeded to allogeneic stem cell transplant between the cohorts. Conclusions This study highlights that similar outcomes can be achieved in rural and urban patients, suggesting that intensive efforts at telehealth, education, and collaboration with local oncology practices may be beneficial.

Septic, inflammatory, or crystal-induced arthritis are common etiologies of wrist pain without antecedent trauma associated with pain, loss of motion, swelling, redness, and warmth. In this report, we detail the case of granulocytic sarcoma of the wrist that presented as acute wrist pain, swelling, and limitation in motion. Granulocytic sarcoma is an exceedingly rare extramedullary tumor associated with acute myeloblastic leukemia. It may be found in any part of the body; however, upper extremity involvement is uncommon. To our knowledge, this is the first description of granulocytic sarcoma occurring in the wrist joint.

Relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) is associated with a poor prognosis in both children and adults. Traditionally, there were limited options for salvage therapy, which consisted mostly of conventional chemotherapy. However, in the past 5 years, novel agents have changed our treatment strategies in this population. Blinatumomab, a bispecific CD19 directed CD3 T-cell engager, has shown to be effective in both minimal residual disease and R/R B-cell ALL. In R/R B-cell ALL, blinatumomab was associated with an improved median overall survival of 7.7 months vs 4.0 months with traditional chemotherapy (HR for death, 0.71; 95% CI, 0.55-0.93; P=0.01). It has distinctive side effects as compared to chemotherapy, specifically cytokine release syndrome and neurological toxicities. When compared to standard of care chemotherapy, patients have higher quality of life scores and less financial burden. Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire, blinatumomab-treated patients fared better and had a longer time to deterioration or death (global health status/quality of life subscale: HR 0.66; 95% CI 0.48-0.92; P=0.009) compared to conventional chemotherapy. Using an incremental cost effective ratio threshold of US$150,000 per quality adjusted life year, blinatumomab was determined to be more cost effective compared to chemotherapy with a probability of 73.7%. This review summarizes the current and future data with blinatumomab in R/R B-cell ALL in the adult and pediatric population.

Background: Hypomethylating agents (HMA) are well established standard of care for patients (pts) with higher-risk MDS (HR-MDS). However, approximately half of the pts do not respond to HMA therapy and most of the responders eventually lose response (HMA failure). There is no standard of care for pts after HMA failure and median overall survival (OS) post HMA failure is around 6 months (Jabbour et al. 2015). While the mutational landscapes and their role in prognosis are increasingly becoming apparent in pts with HR-MDS at diagnosis, mutational profiles at the time of HMA failure and their impact on clinical outcomes are not well understood. Here, using samples collected from a global Phase 3 trial randomizing HR-MDS pts post HMA failure to I.V. rigosertib (RGS) or physician's choice (PC) (INSPIRE: NCT02562443), we analyzed the landscape of driver mutations in HR-MDS after HMA failure and investigated the association with the clinical outcomes. Since RGS is a non-ATP-competitive small molecule RAS mimetic (Athuluri-Divakar 2016), the study also offered an opportunity to test the hypothesis whether HR-MDS pts with oncogenic RAS pathway mutations benefit from RGS. Methods: HR-MDS pts after HMA failure were randomized 2:1 to RGS or PC. All pts failed to respond to or progressed on prior HMA therapy. Bone marrow samples or peripheral blood samples were collected at the time of trial screening. Genomic DNA was sequenced by the targeted capture deep sequencing of 295 genes (median 500x). Results: 372 pts were enrolled in INSPIRE trial (248 to RGS and 124 to PC). The median age of the trial participants was 73 (range: 40-85). All pts were previously treated and with an HMA with the median duration of prior HMA therapy of 6.7 months. 64% and 28% of the pts were classified as IPSS-R very high risk or high risk, respectively, at the time of randomization. Among the 372 participants, DNA sequencing of pre-treatment samples was performed in 188 pts (51% of the participants, N = 122 in RGS arm, N = 66 in PC arm). The most frequently identified driver mutations involved ASXL1 (36%) followed by RUNX1 (24%), TET2 (23%), STAG2 (22%) and TP53 (21%). Mutations in splicing pathway genes were found in 36% of the pts. Oncogenic RAS pathway mutations were detected in 15% of the pts (NRAS = 3 %, KRAS = 2%, CBL = 4%, NF1 = 5%, PTPN11 = 3%, and 1% had multi-hit mutations). Compared to the previously untreated MDS pts (N = 446, Papaemmanuil et al. Blood 2013), mutations in ASXL1 (36% vs. 18%, P < 0.0001), BCOR (9% vs. 3%, P = 0.002), CEBPA (4% vs. 0.2%, P = 0.001), NF1 (5% vs. 0.9%, P = 0.003), RUNX1 (25% vs. 11%, P < 0.0001), STAG2 (22% vs. 5%, P < 0.0001), TP53 (21% vs. 6%, P < 0.0001), and IDH1/2 (13% vs. 7%, P =0.016) were significantly more enriched in pts with HMA failure, whereas mutations in SF3B1 (7% vs. 37%, P < 0.0001), TET2 (23% vs. 35%, P = 0.006), and splicing pathway genes (36% vs. 68%, P < 0.0001) were significantly less frequent in HMA failure pts. These results are consistent with the high-risk profiles of HMA failure pts. Frequency of oncogenic RAS pathway mutations were similar between HMA failure and previously untreated MDS pts (15% vs. 13%, P = 0.612). Correlation analysis between the types of HMA failure and gene mutations showed that TP53 mutations were significantly enriched in pts who relapsed after initial response to HMA (P = 0.001), whereas oncogenic RAS pathway mutations were significantly enriched in pts who progressed during the HMA therapy (P = 0.03). Overall, RGS did not significantly improve the overall survival (OS) of HMA failure pts compared to PC. Survival difference between RGS arm and PC arm was not observed in any subgroups stratified by the gene mutations. The only subgroup that showed improved OS with RGS compared to PC was pts with RAEB-t (median OS 7.5 vs. 3.9 months, P = 0.049). Of note, among pts with oncogenic RAS pathway mutations, no survival difference was observed between RGS and PC arms. Conclusion: High-risk gene mutations, such as TP53, ASXL1, RUNX1, and STAG2 (Ogawa. Blood 2019). were significantly enriched in MDS pts with HMA failure, suggesting their role in HMA resistance and disease progression. Identifying the mutations present de novo and with HMA failure offers the opportunity to determine prognosis based on these mutations as well as potential strategies to target these mutations with new medical entities. Disclosures Takahashi: GSK: Consultancy; Celgene/BMS: Consultancy; Novartis: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. 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. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution. Diez-Campelo: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. OffLabel Disclosure: Rigosertib for MDS patients after HMA failure

Introduction: The usage of cytogenetics and next generation sequencing (NGS) has become more prominent in recent years for risk stratification of patients (pts) with myelodysplastic syndromes (MDS). Management of these patients is a multi-faceted endeavor which requires understanding of how MDS genetics interacts with a patient's lifestyle and co-morbidities. Obesity rates in the United States continue to rise; the current rate in Virginia is 30% (Centers for Disease Control and Prevention, CDC). This study analyzed whether body mass index (BMI) at diagnosis was correlated with the number or type of MDS mutations seen on initial NGS and whether obesity influenced outcomes stratified by individual mutations. Methods: Adult pts diagnosed with MDS at the University of Virginia from August 2012 to December 2019 who had cytogenetics and NGS panels done prior to initiation of MDS therapy were included. Any patient without the aforementioned initial diagnostic information was excluded. MDS disease characteristics, treatment type, comorbidities, and patient demographics were assessed including weight, height, and BMI (categories defined per CDC) at time of diagnosis. The primary aim of this analysis was to evaluate the association of BMI with the number and type of mutations on NGS panel at diagnosis. Wilcoxon-Mann-Whitney tests were used to explore the difference in BMI by presence of 13 mutations of interest: ASXL1, DNMT3A, FLT3, IDH1, IDH2, NPM1, NRAS, SETBP1, SF3B1, SRSF2, TET2, TP53, and U2AF1. The Spearman correlation coefficient was used to assess the relationship between BMI and total number of mutations. Kaplan-Meier estimates, log rank tests, and Cox proportional hazard models were used for time-to-event analyses. All analyses were performed using SAS 9.2 (SAS Institute, Cary, NC). Results: 143 MDS pts met inclusion criteria with a median age at diagnosis of 69 (range 39-87) and 60.7% (n=88) were male. The median weight was 81.3 kg and the median BMI at diagnosis was 27.7 kg (range 16.04-52.66). There were 29 pts in the normal BMI class (20%), 4 pts in the underweight class (3%), 38 pts in the obese class (26%), and 72 pts in the overweight class (50%). By IPPS-R risk scoring system, 64 pts were low or very low risk (44%), 39 pts intermediate risk (27%), and 41 pts high or very high risk (29%). There was no difference in the median number of mutations across BMI groups with a spearman correlation coefficient of 0.05 (Figure 1). However, the median BMI was significantly lower in patients with the NPM1 mutation versus those without (p=0.04), diagnosed prior to the WHO re-classification of these patients to acute myeloid leukemia (AML). Presence of the NPM1 mutation in MDS is also associated with worse PFS and an increased hazard ratio of 9.4 (p=0.0003), likely behaving similarly to AML. In comparison, presence of the SF3B1 mutation was found to be protective wherein patients who lacked the mutation had an increased hazard ratio of 6.0 (p=0.0133). BMI alone did not predict for progression free survival (PFS) or overall survival (OS); this was also true regardless of patient residency based on zip code. However, obese patients exhibiting the NPM1 and SF3B1 had better PFS (Figure 2). Moreover, the landmark analysis indicates among patients who are alive and free of progression at 20 months after MDS diagnosis, overweight patients exhibit better PFS than normal/underweight or obese patients (p=0.0192) (Figure 3). Conclusion: While BMI in pts with MDS does not appear to predict the gross number of NGS mutations, NPM1 mutations occurred more often in pts with low BMIs. Overweight pts who did not progress by 20 months have a better PFS. Prospective and larger retrospective studies are needed to expand on the findings that BMI may have an unexplored potential in stratifying pts with newly diagnosed MDS. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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.

Background: Clostridium difficile infection (CDI) is a major complication facing patients undergoing autologous stem cell transplantation (ASCT) and can be associated with increased morbidity and length of stay (LOS). Various institutional and multicenter studies have reported incidence rates in this population ranging from less than 5% to more than 10% in this high-risk population. CDIs are not only problematic for individual patient care, but CDI also negatively impact hospital resource utilization by increasing post-transplant LOS. A prospective quality improvement study was initiated at the University of Virginia (UVA) to decrease CDI. Methods: To decrease CDI rate, a multidisciplinary team comprised of oncology and infectious diseases physicians, pharmacists, and nurses was formed. The group used quality improvement principles to identify and target areas of greatest significance. Retrospective chart review was done of 65 consecutive patient ASCT encounters from June 2016 to July 2017 to establish the baseline cohort. For each of these encounters, extensive patient demographics, clinical, and inpatient event data were collected. Analysis of the data identified 17% CDI rate (n=11) in the 30-day period following ASCT. The aim of study was to decrease the CDI rate by 33%. The team used qualitative and quantitative tools to understand factors contributing to CDI, including: process map and a priority matrix categorizing potential interventions based on impact and ease of implementation. A statistical process control chart (p-chart with 3 sigma limits) depicted rates of CDI in the baseline cohort and intervention groups. Results: The baseline CDI rate was 17%. Three Plan-Do-Study-Act (PDSA) cycles of interventions were implemented; post-intervention data were collected and analyzed. From August 2017 to June 2018, the first PDSA cycle consisted of eliminating ciprofloxacin prophylaxis between T+0 and count recovery (which was standard of care) due to hypothesis that the prophylactic antibiotic itself was leading to increases in CDIs. The first PDSA cycle resulted in an increased CDI rate of 19% (n=12) and worsening of sepsis events. Ciprofloxacin prophylaxis was reinstituted. A second PDSA cycle was executed between July 2018 and January 2020 incorporating ultraviolet (UV) light equipment into existing post-discharge cleaning practices, resulting in a decreased CDI rate of 9% (n=11). A third PDSA cycle was conducted from February 2020 through current (July 2021) and added a 2-step C. diff PCR and toxin assay into testing protocols, leading to a further CDI rate decrease to 7% (n=9). P-chart depicting CDI reduction is shown in Figure 1. A significant difference in CDI incidence was found comparing patients before and after implementation of UV light cleaning practices (p Conclusions: This prospective study surpassed the goal to reduce CDI by 33% by using quality improvement methods to drive a clinically significant special cause variation reduction in the 30-day CDI incidence after ASCT and a trend towards decreased LOS at UVA. This study not only improved patient care, but likely represents increased patient quality of life and cost savings. Future PDSA cycles are scheduled and may include other cancer patients beyond those receiving ASCT. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background For patients receiving high dose cytarabine (HiDAC) at the University of Virginia Health System between 10/2019 and 10/2020, median length of stay (LOS) from time of clinic appointment to hospital discharge exceeded the expected standard treatment time (119.4 hours vs 112 hours). Despite the final dose of chemotherapy being scheduled for completion by 9:00 am on the planned day of discharge, only 50% of patients receiving HiDAC were successfully discharged by 12:00 pm (3 hours post-chemotherapy completion). Though there are no national standards for duration of inpatient stay for planned chemotherapy, LOS that extends beyond the standard treatment time results in increased cost, overutilization of hospital resources, delayed admissions for future patients, and patient dissatisfaction. Methods A multidisciplinary team of licensed providers, pharmacists, and nurses was formed. Due to inconsistency in admission times, the team focused on the percentage of patients discharged by 12:00 pm as a surrogate marker for LOS. The aim was to increase the percentage of patients discharged by 12:00 pm to 65%. Reviewing the baseline data revealed an unstable process with a 3-sigma XmR statistical process control chart. The team developed current and ideal process state maps, a Pareto chart, and a priority matrix to determine an action plan. The most common identified causes for delay in discharge included: lack of standardized discharge checklist, discharge order placed after 10:00 am, medications dispensed from the outpatient pharmacy after 11:00 am, licensed providers not prioritizing patients who were pending discharge, and medication reconciliation not completed prior to day of discharge. Results From 10/2020 to 5/2021, the first PDSA cycle focused on standardizing the discharge process to correct the instability in the process. A discharge checklist was created based on the ideal process map, which allowed providers to have a consistent process at discharge. A 3-sigma XmR chart demonstrated a newly stable process and an increase in percentage of patients discharged by 12:00 pm to 58% (14 of 24). The second PDSA cycle from 6/2021 to 8/2021 addressed the high impact/easy effort interventions identified in the priority matrix: providers completed medication reconciliation the day before discharge, prioritized seeing HiDAC discharge patients first during morning rounds, and ensured discharge orders were placed prior to completion of the last chemotherapy infusion. Following these interventions, the percentage of patients discharged by 12:00 pm increased to 66% (4 of 6). Conclusions Using quality improvement methodology, a multidisciplinary team developed an action plan for patients receiving HiDAC that has increased the percentage of patients discharged by 12:00 pm. This outcome may lead to decreased length of stay, reduced hospitalization costs, and increased bed availability for other hematology/oncology patients. Further PDSA cycles are planned and will focus on the pharmacy medication delivery service, and continuous evaluation of the process is ongoing. Figure 1 Figure 1. Disclosures El Chaer: Amgen: Honoraria, Research Funding.

Most drugs used in standard regimens for acute lymphoblastic leukemia (ALL) were developed more than 30 years ago. Since that time, several new drugs have been developed and incorporated into ALL treatment. In spite of this, novel therapeutic approaches are still needed to improve outcomes for high-risk or relapsed ALL. This manuscript discusses newer treatment strategies, including purine nucleoside analogs, monoclonal antibodies, antibody drug conjugates, mammalian target of rapamycin (mTOR) inhibitors, proteasome inhibitors, histone deacetylase (HDAC) inhibitors, hypomethylating agents, spleen tyrosine kinase inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, Janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibitors, anti-programmed cell death protein (anti-PD-1) antibodies, mitogen-activated protein kinase (MEK) inhibitors, CXCR4 antagonists, poly (ADP-ribose) polymerase (PARP) inhibitors, and FMS-like tyrosine kinase 3 (FLT3) inhibitors. Additionally, this manuscript discusses the impact of diagnostic approaches on management of ALL. Specifically, minimal residual disease is increasingly felt to be important and will likely dramatically impact the care of ALL patients in the near future.

There are no national standards for time between patient arrival and the initiation of scheduled chemotherapy (time to chemotherapy [TTC]). Delays in this process have a negative impact on patient care and the use of health care resources. At the University of Virginia Cancer Center, mean TTC in 2015 was 12.1 hours and mean length of stay (LOS) was 5.45 days at baseline. We formed a multidisciplinary team that participated in ASCO’s Quality Training Program. We aimed to improve TTC by 10% over 6 months. We used Plan-Do-Study-Act (PDSA) cycles as quality improvement (QI) models and used XmR charts to evaluate the interventions. The first PDSA cycle involved amending the chemotherapy consent process; mean TTC and LOS improved to 9.3 hours and 4.65 days, respectively. The second PDSA cycle involved shifting pharmacist review of chemotherapy orders to before admission rather than after patient arrival. Mean TTC remained at 9.4 hours (net 22% improvement from baseline) and LOS improved to 4.33 days (net 21% improvement). Our team surpassed the 10% improvement goal for TTC. This QI project faced a few limitations. Our baseline data set was a retrospective cohort review. In addition, oncology patients have a wide range of individual clinical needs that may have an impact on TTC. Delays in TTC have an impact on oncologic care at many medical centers. Our project highlights the need for guidance on this issue. We recommend that other institutions form multidisciplinary teams and also use QI tools to assess delays and implement changes.

Introduction: Cytogenetics and next generation sequencing (NGS) have become standard of care for initial diagnosis for patients (pts) with acute myeloid leukemia (AML). Obesity rates in the United States continue to rise and the relationship of obesity to outcomes and NGS results in AML is not well defined. This study analyzed if body mass index (BMI) at diagnosis was correlated with the number or type of myeloid mutations seen on initial NGS and whether obesity influenced outcomes stratified by individual mutations. Methods: Adult pts newly diagnosed with AML at the University of Virginia from 3/2015 to 4/2020 who had cytogenetics and NGS panel completed prior to initiation to therapy were included. Pts without initial diagnostic information or incomplete diagnostic information were excluded. AML disease characteristics, treatment type, and comorbidities were assessed including weight, height, BMI (categories defined per CDC) at the time of diagnosis. The primary aim of this analysis was to test the association of BMI with the number and type of mutations on NGS panel at diagnosis. A logistic regression model was used to explore the relationship between 9 mutations of interest including NPM1, FLT3, TP53, RUNX1, ASXL1, IDH1,IDH2, TET2, and DNMT3A. Spearman's rank correlation test was used to investigate impact of BMI on number of mutations found on NGS. Non parametric tests using Mann-Whitney-U to explore the relationship between type of mutation and BMI. An alpha level ≤ 0.05 was used to determine significance. Relapse free survival (RFS) was estimated for the different BMI groups by the Kaplan-Meier method. Results: 176 AML pts met inclusion criteria with a median age of 66 (range 18-95) and 60.2% (n=106) were male. The median weight was 83.6 kg and median BMI at diagnosis was 28 kg/m2 (range 18.1-52.4). There were 54 pts in the normal or underweight category (30.7%), 59 pts in the overweight category (33.5%), 63 pts in the obese class (35.8%). By ELN criteria, 10.2% pts were favorable (n=18), 42% pts were intermediate (n=74), and 47.7% pts were adverse (n=84). The majority of pts received induction with anthracycline and cytarabine (66.5%, n=117), 21% patients received a hypomethylating agent (HMA) (n=37), and 12.5% of patients received palliative care or low intensity treatment (n=22).)There was no difference in the median number of mutations across BMI groups with a spearman correlation of -0.1 (p value 0.2, Figure 1) with a median number of 2 mutations across all weight groups. Patients in underweight or normal weight groups were more likely to have a TP53 mutation than patients in higher weight classes HR 3.5 (95% CI 1.7-7.3; p = 0.04, Figure 1). BMI did not predict presence of the other 8 mutations. TP53 mutation status was associated with decreased RFS and OS as expected, specifically there was no protective effect of BMI on TP53. However, obese and overweight TP53 negative patients trended better with improved RFS and OS compared to the lower weight classes (Figure 2). When risk stratified for BMI alone, patients with higher BMIs had an improved trend in RFS and OS (Figure 3). Conclusion: BMI in pts with newly diagnosed AML does not appear to predict for the gross number of NGS mutations. However, TP53 mutations occurred more often in patients with low or normal BMI compared to overweight patients. Obese and overweight patients trended with improved RFS and OS compared to the lower weight classes. Prospective and larger retrospective studies are needed to expand on the findings that BMI may have unexplored potential in stratifying AML pts at diagnosis. Figure 1 Disclosures Keng: Agios: Other.

Background: Rural communities may not have access to adequate health care, but the effect of geographic residence on patient outcomes and molecular characteristics of acute myeloid leukemia (AML) is poorly understood. Several studies have investigated the effect of various demographics (such as race, gender, zip code) and environmental exposures on the development and outcome of AML. Evidence is lacking to suggest a link between genetic abnormalities and residence. Methods: A single center, retrospective chart review was conducted on patients with AML diagnosed between 9/2015 and 8/2018. Consecutive patients with a new diagnosis of AML and a clinical next generation sequencing panel (Illumina TruSight Myeloid 54 gene panel) performed during their initial leukemia workup were included. Patients were excluded if they had APML or CML in blast crisis. Data collected included demographic information (including zip code), smoking history, BMI, cytogenetic data, treatment regimen, and overall survival. Patients were grouped into urban and rural subsets based on their county of residency as described in the National Center for Health Statistics 2013 Urban-Rural Classification Scheme for Counties. Zip codes were used to extrapolate socioeconomic data including education and income level. Cytogenetic data was used to risk stratify patients per ELN criteria. Mutational profile, cytogenetics and overall survival (OS) were compared between the groups. Mutations analyzed were limited to ASXL1, DNMT3A, FLT3, IDH1, IDH2, NPM1, NRAS, TET2, and TP53, as these are often used in medical decision making. Multivariate logistic regression was conducted to evaluate differences between the groups. Time to event data were analyzed using log-rank tests, Kaplan-Meier method, and Cox proportional hazard regression model. Results: 113 patients were included in this study. Median age of the entire cohort was 66.3 years old. 59% (n = 67) were male. 24% (n = 27) of patients were from a rural area; 76% (n = 86) were from an urban area. There was no difference in median age, race, prior MDS or MPN, number of patients who underwent chemotherapy or number of patients who underwent allogeneic stem cell transplant (ASCT) as demonstrated in Table 1. Patients from both cohorts also had similar risk cytogenetics (urban cohort: favorable: n = 5, 5.8%; intermediate: n = 35; 40.7%; adverse: n=46; 53.5%; rural cohort: favorable: n = 3, 11.1%; intermediate: n = 14; 51.9%; adverse: n = 10, 37%; p = 0.282). In the rural cohort, 15% of patients reported income below the poverty level; in the urban cohort, 10.2% reported income below the poverty level (p < 0.0001). Fewer patients in the rural cohort were high school graduates as compared to the urban cohort (82.7% versus 87.8%, p < 0.0001). Rural patients traveled an average of 145 miles for treatment; urban patients traveled 57 miles (p < 0.0001). Mutation frequency is described in Table 2. ASXL1 mutation was more frequent in the urban cohort as compared to the rural cohort (p = 0.032). There was no difference in frequency of other mutations between the cohorts. The 2 year survival rate was 46% (n = 52) for the cohort; 2 year survival rate for the rural cohort was 70% (n = 19) and for the urban cohort was 38% (n = 33) (p = 0.011; Figure 1). 53 patients (urban: n =39, 66.1%; rural: n = 14, 77.8%; p = 0.35) underwent induction chemotherapy. Rural patients who underwent induction chemotherapy had an improved OS as compared to urban patients who underwent induction chemotherapy (p = 0.005). Conclusion: In this single center retrospective study, our data demonstrates: 1. Urban patients had an increased frequency of ASXL1 mutations; 2. Rural patients were more likely to live below the poverty level and not graduate high school; 3. Rural patients traveled a greater distance for treatment; 4. OS was improved in rural patients in this limited cohort. Our rural patients may have improved OS due to our close co-management with rural centers. These studies suggest that the biology of the AML is not worse in the rural cohort and intensive efforts at access, remote monitoring, and communication with local physicians may result in outcomes similar to urban patients. Further studies will be investigating improving access to leukemia and transplant care for patients with AML. Disclosures Balkrishnan: Merck and Company: Consultancy. Keng:Agios: Membership on an entity's Board of Directors or advisory committees.

Introduction: Thrombotic events are a frequent complication in patients with malignancy due to increased tissue factor expression and activation of hemostatic mechanisms by both host cells and cancer tissues. Patients with acute myeloid leukemia (AML) are at risk of venous thromboembolism (VTE) not only because of their malignancy but also because of prolonged hospitalizations, immobility, and the need for central venous access. Profound thrombocytopenia is an expected complication, due to myelosuppressive chemotherapy as well as from underlying marrow-infiltrative disease. This results in difficult prophylactic and treatment decisions where providers must carefully balance the risk of thrombosis and bleeding. There are no published consensus guidelines regarding appropriate use of prophylaxis in patients with leukemia. Methods: A retrospective chart review was completed on AML patients receiving induction or consolidation chemotherapy or treatment for relapsed disease admitted to the University of Virginia from October 2011 through September 2017. Patients with acute promyelocytic leukemia were excluded. Clinical data from 142 patients over a total of 667 hospital admissions were reviewed. The following data was collected: demographics (including age, sex, and race), clotting events, clot location, type of line placed, treatment of clot, and bleeding events. Bleeding events were defined according to International Thrombosis and Hemostasis criteria. χ2 analysis was performed to compare categorical values. Results: Twenty-nine of 142 (20.4%) AML patients were diagnosed with VTE. None of the patients had a prior history of clot or diagnosis of clotting disorder. Thrombosis occurred more commonly during induction therapy, 13 of the 29 events (45%), compared to other stages in their treatment (p value=0.37). Of the thromboses occurring during induction, 14 clotting events (48%) were central line associated, 4% (5/125) of thrombosis occurred in peripherally inserted central lines, 10% (5/51) in temporary internal jugular central lines and 2% (4/165) in tunneled central lines (p value=0.99). The average platelet count at the time of clot was 61 K/µl. Most patients were not on prophylaxis at the time of their clotting event (93.1% vs 6.9%; p value= Patients who received therapeutic anticoagulation had a comparable rate of bleeding compared to patients who were not on anticoagulation (31.6% vs 40.8%; p value= 0.44). Patients who were treated for VTE (n=19) had 2 major bleeds and 4 clinically relevant non-major bleeds. Patients who did not receive treatment for their VTE event (n=10) had 1 major bleed and 3 minor bleeding events. Conclusion: Our study identified a 20.4% incidence of VTE in AML patients, occurring more frequently during induction chemotherapy and in patients without prior thrombotic history.The clots were most commonly catheter associated and the highest rate of clot occurred with temporary internal jugular lines. Importantly, we found that when patients were treated with anticoagulation, their incidence of bleed did not exceed the general incidence of bleeding (43%) seen during the time period of the analysis. Average platelet count at VTE diagnosis was 61 K/µL, which is above most institutions' thresholds for use of pharmacologic VTE prophylaxis including patients with acute leukemia. Given that only two patients in our study were receiving prophylaxis at the time of VTE and that bleeding rates were similar with full therapeutic anticoagulation, this suggests prophylaxis is important, safe, and is potentially neglected in patients with acute leukemia. This highlights an area of potential improvement in decreasing VTE in patients that can safely receive prophylaxis and is the basis for future prospective safety trials exploring the use of prophylaxis in this patient population. Disclosures No relevant conflicts of interest to declare.

Introduction: Higher risk MDS is a serious disease associated with poor survival with hypomethylating agents (HMAs) the standard of care in patients ineligible for stem cell transplantation. Unfortunately, HMAs are only effective in 30-40% of patients with duration of response typically shorter than 1.5 years (Fenaux, Lancet Oncol 2009) leading to evaluation of combination therapies to improve outcomes in higher risk MDS. Inhibition of both histone deacetylation and DNA hypermethylation has been shown to induce re-expression of silenced genes in myeloid malignancies in a synergistic fashion. Studies have evaluated HMAs in combination with HDACi but the results have been disappointing due to increased toxicity and early discontinuations. Pracinostat, a potent oral Class I, II, IV HDAC inhibitor, has been studied in combination with standard dose azacitidine in a prior Phase 2 study in 102 patients with untreated IPSS intermediate-2/high risk MDS (Garcia-Manero, Cancer 2017). Pracinostat was administered at 60 mg/day on 3 alternate days/week for 3 weeks/month, with step down dose to 45 mg in case of poor tolerability. Toxicity, primarily cytopenias, nausea, vomiting and fatigue resulted in early discontinuations and insufficient treatment exposure, potentially leading to diminished efficacy and no observed benefit of the pracinostat/azacitidine combination. This follow-up study is evaluating a lower dose of pracinostat (25% reduction) in combination with standard dose azacitidine with the goal of reducing toxicity, decreasing early discontinuations, and improving outcomes. Methods: The primary objective of this Phase 2, two-stage study at 24 sites is to determine the safety/tolerability and efficacy of the pracinostat/azacitidine combination in patients with IPSS-R high-/very high-risk MDS previously untreated with HMAs. Up to 40 subjects were to enroll in Stage 1, treated with pracinostat at 45 mg, 3 days each week for 3 consecutive weeks, followed by 1 week of rest, along with azacitidine at the standard dose of 75 mg/m2 for 7 days of each 28-day cycle. Study drugs are to be administered until disease progression or intolerable toxicity, avoiding early discontinuation ( Results: At the time of the interim analysis (25 May 2018), 39 patients had received ≥1 dose of study treatment and 20 were evaluable for assessment of early discontinuations. Median age was 67 years, 69% were male, and 59% had high-risk MDS. Of the 20 evaluable patients, 2 patients (10%) discontinued prior to the end of Cycle 3 due to AEs (1 febrile neutropenia, Day 45 and 1 fungal infection, Day 90). In 18 subjects evaluated for response at the end of Cycle ≥2, the ORR was 28% (1 complete response, 4 partial responses). Most common Grade ≥3 AEs in the 33 patients with >1 week follow-up were decreased neutrophil count (33%), anemia (30%), febrile neutropenia (27%), and dyspnea (12%). Non-hematologic AEs of fatigue and gastrointestinal events were reduced in this initial group of patients relative to that seen in the prior study. Conclusions: The interim analysis of this study evaluating the efficacy and safety of pracinostat + azacitidine in patients with IPSS-R high-/very high-risk MDS revealed a discontinuation rate and an efficacy response rate meeting the predefined thresholds to allow for expansion of the study. These findings suggest that a reduced dose of pracinostat may allow patients to remain on treatment longer, thus increasing the likelihood of a treatment response. Based on these data, the study IDMC approved expansion of this study to enroll 60 evaluable patients. Updated data, including 6 months efficacy data on the initial cohort, will be presented. Disclosures Khaled: Alexion: Consultancy, Speakers Bureau; Daiichi: Consultancy; Juno: Other: Travel Funding. Ramies:MEI Pharma, Inc: Employment. Mappa:Helsinn Healthcare: Employment. Atallah:Jazz: Consultancy; BMS: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy; Novartis: Consultancy.

Background: High dose methotrexate (MTX) is an important agent in the prevention and treatment of cancer in the central nervous system. Administration of this drug requires alkalization of the urine, which traditionally includes the use of intravenous (IV) sodium bicarbonate (bicarb). In May 2017, IV bicarb was on national shortage; at the University of Virginia, pharmacists and physicians designed an oral (PO) regimen using bicarb and acetazolamide to ensure patients could continue receiving MTX. As there are limited published data, we aimed to assess the safety and the impact on time to start of MTX. Methods: Retrospective chart review was done 5/2016-4/2017 to establish a baseline time to methotrexate. In a prospective analysis, data was collected from May 2017 to May 2018 on all patients who received MTX. For patients receiving the PO regimen, bicarb 2,600 mg PO 6 times daily and acetazolamide 250 mg PO every 6 hours were the initial doses and titrated to maintain a urine pH greater than or equal to 7. The primary endpoint was time to MTX for patients with planned admissions who start MTX upon meeting urine pH and output parameters. Secondary endpoints included incidence of acute kidney injury (AKI) and delayed methotrexate clearance for all patient encounters. AKI was defined using Kidney Disease Improving Global Outcomes criteria. Delayed MTX clearance was defined based on failure to meet goal levels based on published chemotherapy protocols. χ2 analysis was completed on categorical variables. A statistical process control chart (p-chart) depicted time to MTX. Results: A total of 162 patient encounters were included in the analysis. The median age of patients receiving oral bicarb was 51 years (range 21-69) and was 51 years (range 21-63) for patients receiving IV bicarb. Eighty-six encounters were planned admissions that started MTX when urine parameters were met and received either IV (n=32) or PO bicarb (n=54). In these patients median time from admission to MTX was 8.4 vs 7.9 hours, respectively. Figure 1 shows consecutive patients receiving MTX prior to, during, and after resolution of the IV bicarb shortage; there is less variability and fewer outliers in the MTX start time when exclusively administering the PO regimen during the shortage. For the secondary analysis an additional 76 encounters with either unplanned admissions or predetermined MTX start time on subsequent day to admission were analyzed for safety outcomes. The rate of AKI was 14.5% vs 8.9% in the PO vs IV groups, respectively (p=0.28). There was no difference in incidence of delayed methotrexate clearance with 26.5% of patients in PO group vs 25.3% patients in IV group (p=0.87). Length of stay was slightly increased in patients who received PO vs IV alkalization (3.78 vs 3.15 days). Conclusion: Our alternative oral bicarb and acetazolamide urine alkalization regimen appears safe in patients receiving MTX and allowed for continued treatment of patients during a national IV bicarb shortage. Time to start of MTX was decreased with implementation of PO regimen, and there appeared to be a more predictable start time for MTX. While not significant, the higher incidence of AKI in PO group warrants further analysis. Future efforts include using oral outpatient alkalization prior to inpatient admission to work towards improving length of stay. Disclosures No relevant conflicts of interest to declare.

Introduction: A dangerous consequence of chemotherapy used to treat patients with hematologic malignancy is the breakdown of intestinal and oral mucosa known as MBI (mucosal barrier injury). In the setting of neutropenia, this can lead to life-threatening laboratory confirmed blood stream infections (LCBI) from translocation of bacteria. This results in increased length of stay, ICU admissions, and decreased quality of life for patients. Sparse evidence exists to guide clinicians on interventions to help prevent and treat MBI and reduce its complications. Methods: In an attempt to reduce MBI-LCBI events, a multidisciplinary team including oncology physicians, nurses, and pharmacists was assembled. A retrospective chart review from 1/2015 to 12/2015 was completed to establish a baseline for MBI-LCBI rate. This rate was calculated by dividing the number of MBI-LCBI events by total number of patients on the malignant hematology wards receiving inpatient chemotherapy treatment. The average MBI-LCBI rate was 0.01. While there is no published national average MBI-LCBI rate, we aimed to decrease this rate by 75%. LEAN principles were applied to approach the problem. A statistical process chart (p-chart) was used to depict rates of MBI-LCBI in baseline cohort and intervention groups. Results: The baseline MBI-LCBI rate was found to be 0.01. Through LEAN methodology with analysis of an A3 and outlining "5 whys," a number of root causes leading to increased MBIs were identified. These included: accessibility of necessary supplies needed for compliance with standard work, availability of the oral care kits, importance of on-going education related to appropriate care and maintenance practices. The multidisciplinary team focused on 2 main interventions to improve MBI-LCBI rate. One Plan Study Do Act (PDSA) cycle was completed and post intervention data was analyzed. In March of 2016 the first intervention implemented was a robust education plan for nursing, including instructions for grading mucositis based on WHO criteria and completing through oral assessments marking the first PDSA cycle. Through further analysis of an A3, oral care was identified as a potential intervention in decreasing MBIs. A second intervention of oral care bundle, consisting of sodium bicarbonate mouth wash, artificial saliva, scheduled nursing oral assessments and teeth brushing, was implemented on May of 2016. After one year of implementation of PDSA cycle 1 the MBI rate (0.003 MBI-LCBIs per month) was reduced by 70% from baseline (Figure 1). This was not sustainable and ultimately after completion of first cycle in March of 2018 the average MBI-LCBI rate was found to be 0.009 which was still reduced from the baseline event rate of 0.01 MBI-LCBI per month. Conclusions: Through a multidisciplinary effort, the rate of MBI-LCBIs were able to be reduced through interventions in both education of nursing and physician staff and focus on oral care in patients. While there was initially significant success, it is apparent towards the end of PDSA cycle 1 there was difficulty with sustainability. There was a reduction in the number of oral care bundle ordered and therefore currently a second PDSA cycle is underway with a nurse driven oral care order set. Further focus in prevention, sustainability support structures (nurse driven protocol implementation) and reducing MBI rate is important in decreasing morbidity and mortality in this patient population. Disclosures No relevant conflicts of interest to declare.

Febrile neutropenia (FN) is an oncologic emergency, and prolonged time to antibiotic administration (TTA) is associated with increased hospital length of stay (LOS) and worse outcomes. We hypothesized that a febrile neutropenia pathway (FNP) quality initiative project would reduce TTA delays for febrile patients with cancer presenting to the emergency department (ED).This prospective study compared ED FNP patients (18 years old), between June 2012 and June 2013 with both historical and direct admissions (DA) cohorts at a multispecialty academic center. Interventions included providing patients with FN-Alert cards, standardizing the definition of FN and recognizing it as a distinct chief complaint, revising ED triage level for FN, creating electronic FN order sets, administering empiric antibiotics before neutrophil count result, and relocating FN antibiotics to the ED. The primary outcome was TTA, with a target goal of 90 minutes after ED presentation.In total, 276 FN episodes in 223 FNP patients occurred over the 12-month study period and were compared with 107 episodes in 87 patients and 114 episodes in 101 patients in the historical and DA cohorts, respectively. Use of the FNP reduced TTA from 235 and 169 minutes in historical and DA cohorts, respectively, to 81 minutes, and from 96 to 68 minutes when the order set was not used versus used in the FNP group (P.001 for all comparisons). Decrease in hospital LOS was not statistically significant.The ED FNP is a significant quality initiative with sustainable interventions, and was able to demonstrate value by decreasing TTA compared to both historical and DA controls in cancer patients presenting to the ED.

Several prognostic scoring systems have been developed to risk stratify patients with myelodysplastic syndromes (MDS) [1–7]. The International Prognostic Scoring System (IPSS) has been the most wid...

This study aimed to identify the rate and impact of vancomycin-resistant enterococcal (VRE) bacteremia in patients with acute myeloid leukemia (AML) receiving induction chemotherapy (IC). Thirty-seven (10.6%) of 350 patients had VRE bacteremia during IC, with increasing rates of VRE bacteremia over the course of the study period. The overall complete remission (CR) rate for the cohort was 73%, and there was no difference in CR rate between the VRE bacteremia and non-VRE bacteremia cohorts (70% vs. 73%, p = 0.70). Unadjusted median overall survival (OS) was 12.8 months, and differed significantly between those with and without VRE bacteremia (7.1 months vs. 13.1 months, respectively; p = 0.03). The presence of VRE bacteremia during IC for AML was independently associated with increased all-cause mortality (hazard ratio 1.72, 95% confidence interval 1.13–2.63, p = 0.01).

In the United States, drugs and medical devices are regulated by the US Food and Drug Administration (FDA). A drug must undergo rigorous testing prior to marketing to and medical use by the general public. The FDA grants marketing approval for drug products based on a comprehensive review of safety and efficacy data. This review article explains the history behind the establishment of the FDA and examines the historical legislation and approval processes for drugs, specifically in the fields of medical oncology and hematology. The agents imatinib (Gleevec, Novartis) and decitabine (Dacogen, Eisai) are used to illustrate both the current FDA regulatory process-specifically the orphan drug designation and accelerated approval process-and why decitabine failed to gain an indication for acute myeloid leukemia. The purpose and construct of the Oncologic Drugs Advisory Committee are also discussed, along with examples of 2 renal cell cancer drugs-axitinib (Inlyta, Pfizer) and tivozanib-that used progression-free survival as an endpoint. Regulatory approval of oncology drugs is the cornerstone of the development of new treatment agents and modalities, which lead to improvements in the standard of cancer care. The future landscape of drug development and regulatory approval will be influenced by the new breakthrough therapy designation, and choice of drug will be guided by genomic insights.

BACKGROUND: Clostridium difficile infection (CDI) is the most important cause of nosocomial infectious diarrhea and has been not well studied in patients with neutropenia who have hematologic malignancies in the United States. Previous studies suggest patients undergoing induction chemotherapy for acute myeloid leukemia (AML) are at a high risk of contracting CDI, but these patient's clinical and disease characteristics are not described. This study reports CDI rates and disease characteristics in AML patients at the University of Virginia (UVA). METHODS: A retrospective chart review of 126 consecutive patients undergoing induction or re-induction chemotherapy for AML at UVA from July 2011 to December 2015 was conducted. The primary endpoint was to determine the rate of CDI within ninety days of chemotherapy initiation. CDI was defined by a Clostridium difficile positive PCR in the presence of diarrhea. Secondary endpoints include patient characteristics, comorbidities, risk factors, and disease specific indices associated with CDI. Statistical methods include nonparametric Wilcoxon test, Fisher's exact test, and Holm's sequential Bonferroni procedure as appropriate. Statistical significance was defined as p-value RESULTS: Of 126 patients, 31 patients (24.6%) with AML had CDI. 8 patients (25.8%) had one recurrent episode of CDI, 2 patients (6.4%) had two recurrences, and 2 patients (6.4%) had more than two recurrences. 25 patients (80.6%) underwent CT abdominal imaging specifically for the CDI episode, revealing 2 patients (8%) with typhilitis. 2 patients (6.4%) developed toxic megacolon, but no patients underwent colectomy. There was no CDI specific mortality in these 31 patients. During the same 4 year timespan, an additional 27 patients with hematologic malignancies other than AML were identified. These two cohorts (AML and non-AML CDI patients) were not statistically different in terms of patient demographics (age, gender, BMI), medical comorbidities (tobacco use, asthma, COPD, cardiac disorders, CKD, and rheumatologic conditions), and CDI characteristics (recurrences, prior antibiotics prophylactic and treatment regimens, PPI medication usage, CDI treatment regimen and treatment duration, development of typhilitis and toxic megacolon, and mortality). The only statistically significant difference is the presence and increased duration of neutropenia in the AML CDI patient cohort (p-value < 0.001). DISCUSSION: The study concludes that the incidence of CDI in patients with AML undergoing induction chemotherapy is greater than hospitalized patients without AML as reported in the literature. However, when compared to a matched cohort of hospitalized patients with non-AML hematologic malignancies, the incidence of CDI is similar between these two groups. This result is striking as AML induction chemotherapy regimens are typically more intense, resulting in more profound and longer neutropenia. Even with increased cytopenias, the CDI rate and disease characteristics are not affected when AML CDI patients are compared to non-AML CDI patients. This suggests that cytopenias should not be the focus for CDI patients, rather hematologic malignancies as whole lead to increased CDIs and heightened awareness is warranted when caring for patients with hematologic malignancies and complaints of diarrhea. Patients in both AML and non-AML CDI cohorts have relatively favorable outcome, with no patient mortality attributable to CDI. Further studies are needed to evaluate what, if any, predictive risk factors can increase CDI in the setting of AML. Disclosures No relevant conflicts of interest to declare.

BACKGROUND: Invasive fungal infections (IFI) occur in 5% to 40% of patients with hematologic malignancies, most commonly in patients with acute myeloid leukemia (AML). Historically, at the University of Virginia (UVA), antifungal prophylaxis was not routinely used in patient undergoing induction chemotherapy for AML. With an antifungal treatment naïve patient cohort, this study had the unique opportunity to examine if specific patient characteristics, comorbidities, or diagnostic criteria were predictive for the development of an IFI. METHODS: A retrospective chart review of 126 consecutive patients undergoing induction or re-induction chemotherapy for AML at UVA from July 2011 to December 2015 was conducted. The primary endpoint was to determine the rate of probable or biopsy proven IFIs within ninety days of chemotherapy initiation as characterized by the European Organization for Research and Treatment of Cancer/Invasive Fungal Cooperative Group and the National Institute of Allergy and Infectious Disease Mycoses Study Group criteria. Secondary endpoints include patient comorbidity and disease specific indices associated with IFI. Each induction or re-induction regimen was counted as a distinct event. Statistical methods include pairwise Wilcoxon tests, univariate analyses, and Kruskal-Wallis tests. Statistical significance was defined as a p-value RESULTS: Of 126 patients, there were a total of 176 distinct induction or re-induction events. Thirty-eight patient events (22%) received antifungal prophylaxis with fluconazole per attending physician preference. In patients (n=102, 81%) who did not receive antifungal prophylaxis during induction, there were a total of 19 (19%) patients with probable/proven IFI. There was a significant association with probable/proven IFI in regards to decreased bone marrow cellularity (p-value 0.018). There were no correlations between probable/proven IFI and body mass index, age of diagnosis, gender, nicotine abuse, length of neutropenia, cytogenetics, and bone marrow blast percentage. In the antifungal prophylaxis cohort, 3 patients (8%) had probable/proven IFI. Another aspect reviewed is the potential concept of an immune reserve ratio (IRR). The IRR is the percentage of the bone marrow core cellularity divided by blasts - representing the bone marrow functionality at the time of leukemia diagnosis or relapse. IRR was 1.9 vs 1.4 vs 1.2 (p-value 0.038) for none vs possible vs probable/proven IFI cohorts. DISCUSSION: This study reveals that decreased bone marrow cellularity and decreased IRR may be used to predict which AML patients undergoing induction chemotherapy are at higher risk of developing an IFI. Traditional risk factors, such as tobacco use, length and degree of neutropenia, were not found to be significant in this review. Other patient co-morbidities, such as hypertension, COPD, and chronic kidney disease, and AML disease specific characteristics, such as cytogenetic and bone marrow blasts, also did not demonstrate clinical significance. To date, studies have not developed a method to quantify a patient's immune reserve at the time of AML diagnosis and risk of IFI. The IRR attempts to use the ratio of bone marrow cellularity and blasts as a surrogate marker of functional immune activity. This review suggests that the IRR is highly correlative of IFI development. Future studies need to be performed to validate this prospectively. UVA is currently conducting a prospective clinical trial examining the utility of IRR to predict IFI in adults with AML induction chemotherapy. Disclosures No relevant conflicts of interest to declare.

Febrile neutropenia (FN) can occur at any time during the course of a malignancy, especially hematologic malignancies, from diagnosis to end-stage disease. The majority of FN episodes are typically confined to the period of initial diagnosis and active treatment. Because of suppressed inflammatory responses, fever is often the sole sign of infection. As FN is a true medical emergency, prompt identification of and intervention in FN can prolong survival and improve quality of life. This article reviews FN in the setting of hematologic malignancies, specifically myelodysplastic syndromes and acute leukemias, providing an overview of the definition of fever and neutropenia, diagnostic approach, categories of risk/risk assessment, management in patients at low and high risk, and prophylaxis of infections.

Purpose: Constitutive signal transducer and activator of transcription 3 (STAT3) activity, observed in ∼50% of acute myelogenous leukemia cases and associated with adverse treatment outcome, is down-regulated by arsenic trioxide (ATO). Heat shock protein (HSP) 90 is a molecular chaperone involved in signal transduction pathways. We hypothesized that HSP90 inhibitors will potentiate ATO effect on constitutive STAT3 activity and cell killing. One concern was that the effect of ATO and HSP90 inhibitors will result in up-regulation of HSP70, a protein known to inhibit apoptosis. Experimental Design: We have used a semimechanistic pharmacodynamic model to characterize concentration-effect relationships of ATO and HSP90 inhibitors on constitutive STAT3 activity, HSP70 expression, and cell death in a cell line model. Results: Pharmacodynamic interaction of ATO and three HSP90 inhibitors showed synergistic interactions in inhibiting constitutive STAT3 activity and inducing cell death, in spite of a concurrent synergistic up-regulation of HSP70. Conclusions: These preliminary results provide a basis for studying the combined role of ATO with HSP90 inhibitors in acute myelogenous leukemia with constitutive STAT3 activity.

Another Summer Olympics has passed and we, like many, trudged into work bleary-eyed each morning, having stayed up late the previous night to watch our favorite events, from swimming to track and f...

Background The International Prognostic Scoring System (IPSS) has been the most widely used risk assessment tool to predict clinical outcome in MDS. Recently, the revised IPSS (IPSS-R) was introduced to allow a greater discriminating capacity in assessing cytogenetic abnormalities and cytopenias and further refines prognostication. However, like the IPSS, the IPSS-R was developed in pts with primary MDS and its utility in pts with secondary (s)MDS is unclear. Material and Methods We conducted an IRB-approved analysis of 765 pts diagnosed with MDS (per 2008 WHO criteria) and evaluated at the Cleveland Clinic between 9/1998 and 1/2013. IPSS-R was calculated as described previously (Greenberg et al, Blood 2012). Cytogenetic risk subgroups were per IPSS-R. Overall survival (OS) was measured from the time of diagnosis to time of death or last follow up. Time-to-event analyses were performed by the Kaplan-Meier method, and curves were compared with the 2-tailed log rank test. Differences among variables were evaluated by the chi-square test and Mann-Whitney U test for categorical and continuous variables, respectively. Results We identified 56 pts (7%) with sMDS: 14 (25%) pts had prior antecedent hematologic disorder, 32 (57%) had prior radiation therapy, and 10 (18%) received prior chemotherapies. Eleven pts (20%) were untreated and 45 pts (80%) received treatment: 17 (30%) with single agent 5-azacitidine, 12 (21%) with supportive measures, 9 (16%) with hematopoietic stem cell transplant (HSCT), and 7 (11%) with other therapies. For all pts, the median age was 66 years (range, 24-81). Median white blood cell count at diagnosis was 3.8 k/mL (range, 0.9-179.7), median absolute neutrophil count (ANC) was 2.2 k/mL (range, 0.1-145.6), median hemoglobin was 9.6 g/dL (range, 0.4-14), median platelet count was 65 X 103/mL (range, 4-460), and median bone marrow blasts was 5% (range, 0-26). The distribution of cytogenetic categories based on IPSS-R criteria was similar in pts with sMDS [2 (4%) very good, 28 (50%) good, 8 (14%) intermediate, 10 (18%) poor and 8 (14%) very poor] compared to primary MDS [28 (4%) very good, 351 (50%) good, 109 (15%) intermediate, 84 (12%) poor and 137 (19%) very poor]. IPSS-R risk categories in pts with sMDS [3 (5%) very low, 15 (27%) low, 11 (20%) intermediate, 15 (27%) high, and 12 (21%) very high] compared to primary MDS [75 (11%) very low (P = 0.15), 221 (31%) low (P = 0.3), 162 (23%) intermediate (P = 0.3), 145 (20%) high (P = 0.1), and 106 (15%) very high (P = 0.1)] were also similar. With a median follow up of 18.4 months (m, range, 1.8-104.6), the median OS for sMDS pts was not reached for very low risk pts, 31.6 m for low risk, 13.7 m for intermediate risk, 27.3 m for poor risk and 39 m for very poor risk (P = 0.15, Figure 1). Conclusion Although pts with sMDS had similar cytogenetic and IPSS-R risk categories compared to those with primary MDS, the IPSS-R did not predict for OS in sMDS pts. The lack of predictability of IPSS-R could be because that most of our pts with sMDS received therapy including HSCT. A new prognostic module to predict the outcome of pts with sMDS who are receiving treatment is needed. Disclosures: No relevant conflicts of interest to declare.

Background Febrile neutropenia (FN) is an oncologic emergency associated with high morbidity and mortality, particularly in patients (pts) with hematologic malignancies. Delays in antibiotic administration, which can occur in busy emergency departments (EDs), lead to worse outcomes. We instituted a FN pathway (FNP) in the Cleveland Clinic (CC) ED to reduce antibiotic delays. Methods This prospective study comparing patients from 06/12 - 06/13 to historical pts from 02/10 - 05/12, represented a collaboration among cancer center, ED, infectious disease, pharmacy, and electronic medical record representatives. Fever was defined as temperature >38°C either at home or in the ED, while neutropenia as absolute neutrophil count Results In total, 137 consecutive FN episodes in 115 pts with hematologic malignancies occurred during the 12 month study period, 63 episodes in 44 pts in the historical cohort. All pts were triaged and treated using the ED FNP, but use of the specific FN order set was variable: episodes were thus classified as treated per the order set (n=53) or not (n=84 – pts still received antibiotics, but not necessarily per the order set). Overall 60% of pts (n=89) were male and the median age at the time of first ED encounter was 59 years (range 20-88). Cancers were: non-Hodgkin lymphoma (38%), acute myeloid leukemia (21%), other leukemias (15%), and myelodysplastic syndromes (8%). Compared to historical pts, FNP study pts had a higher median ANC (2.0 vs. 0.2, p Comparing the two FNP groups treated or not treated per the order set, those treated using the order set had shorter times to antibiotics being ordered (median 28.0 vs. 60.5 minutes, p0.28). Conclusion The FNP significantly decreased time from ED registration to all set time-points, including time to antibiotics by almost three-fold, compared to historical controls in pts with hematologic malignancies. Rate of hospitalization was significantly lower, and ICU and length of stay numerically lower. The FNP is an effective clinical tool to provide prompt antibiotic administration to FN pts and likely represents a significant mechanism for improved outcomes and cost-savings to patients with hematologic malignancies presenting with FN. Disclosures: No relevant conflicts of interest to declare.

Background Smoking is a risk factor for development of MDS and for overall survival. The pathogenesis of MDS is a multi-step process with both environmental and genetic influences. The link between smoking and MDS is thought to be mediated by organic solvents in tobacco. We identified specific molecular abnormalities associated with smoking exposure in MDS patients (pts). Methods 151 MDS pts seen from 2000-2012 with complete smoking and molecular data were included. Correlations and univariable comparisons were performed using Fisher’s Exact, Chi-square, Kruskal-Wallis, or Wilcoxon rank sum tests. Poisson regression models were used to assess associations between the number of mutations present and demographic and clinical factors. Analysis was performed using next-generation targeted deep gene sequencing with 22 common gene mutations, selected based on the frequency observed in a cohort of MDS patients analyzed by whole exome sequencing. Mutations were considered individually and in functional groups: methylation (TET2, IDH1, IDH2), histone modification (ASXL1, EZH2), and gene splicing (SRSF2, U2AF1, SF3B1). Paired DNA (tumor vs. CD3+ lymphocytes) produced raw sequence reads aligned using Burrows-Wheeler Aligner (BWA). Variants were detected using the Broad Institute's Best Practice Variant Detection GATK toolkit. Results Median age at MDS diagnosis was 68 years (range 20-85); 42% were female; and 77% had de novo MDS. IPSS (low, Int-1, Int-2, high) and IPSS-R (very low, low, int, high, very high) categories were: 26%, 44%, 22%, 7% and 10%, 40%, 19%, 18%, 13%, respectively; IPSS-R cytogenetic categories were: very good (60 (p=0.003), and in particular fewer mutations in methylation-associated genes (p=0.0001). In multivariable analysis that adjusted for IPSS-R cytogenetics, older age (p=0.0005) and greater smoking history/exposure (p=0.002) were both associated with more mutations. Current and ex-smokers and heavier smoking exposure (>20 pack years) were also associated with worse survival (p=.03 and .01, respectively), though current or ex-smokers with Conclusion Smoking is associated with a greater number of molecular abnormalities in MDS pts, and may generate a distinct mutational signature pattern, particularly along histone acetylation pathways. This study identifies specific environmentally-mediated pathways in the multistep pathogenesis of MDS. Disclosures: No relevant conflicts of interest to declare.

Abstract 1487 The presence of VRE bacteremia in hematopoietic stem cell transplant recipients portends a worsening clinical course and poor overall survival (Avery et al; BMT, 2005). The impact of VRE bacteremia on outcome in AML patients (pts) receiving induction chemotherapy (IC) has not been established. We conducted an IRB-approved retrospective study of AML pts who received cytarabine-based IC at Cleveland Clinic between 2000–2008 to determine VRE rates and effect on complete remission (CR) and overall survival (OS). Data on age at AML diagnosis (dx), gender, diabetes, smoking history, history of antecedent hematological disorder, pathologic classification, hematologic parameters at dx and at VRE occurrence, metaphase cytogenetics (per CALGB/Alliance 8461), precedingnon-VRE bacteremias, invasive fungal infection (IFI), time from dx and induction to VRE and number of VRE infections, complete remission (CR) and overall survival (OS) were collected from our AML database. The association of these factors with VRE bacteremia was assessed using Fisher's exact test, the Cochran-Armitage trend test and Wilcoxon rank sum test. The impact of VRE bacteremia on OS was assessed using a 2:1 matched-pairs analysis based on gender and year of dx (+ 3 years), and factors known to influence outcome: age at dx (+ 5 years), etiology, and cytogenetic risk. The timing of VRE was also accounted for in the matching. Frailty models, which included a term for WBC at dx, were use to assess the impact of VRE bacteremia while taking into account both the impact of WBC and the paired nature of the data. Of 350 pts evaluable for analysis, the median age at dx was 57 years (range 19–88); 192 (55%) were male; 114 (33%) had secondary AML; median baseline WBC was 10.4K/mL (range, 0.48–550); cytogenetic risk distribution was favorable (14%), intermediate (54%), and unfavorable (32%); 45% were current or former smokers; 17% had a history of diabetes; and 7% had IFI. With the exception of IFI (16% in pts with VRE versus 6% in non-VRE pts, p=.04) there were no significant differences in these factors between the two groups (all p>.08). Of 37 pts (9.8%) who had documented VRE bacteremias during IC, the median interval from the start of IC to VRE infection was 17 days (range, 9–58). The majority (89%) of VRE bacteremias occurred in pts receiving IC between 2005 and 2008 (infection rate of 22%, 33/152) while only 4 infections occurred in 198 pts treated between 2000 and 2004 (infection rate of 2%). One plausible explanation for this epidemiologic shift could be the frequent use of fluoroquinolone prohylaxis to prevent neutropenic fever, which became routine in 2004. The overall CR rate for the cohort was 73%; 70% in VRE pts and 73% in non-VRE pts (p=0.7). Median follow-up was 72.2 months (range 1.1–145.4). Unadjusted median OS for the entire cohort was 12.8 months (95% C.I. 10.6–15.9); 7.1 months (95% C.I. 3.9–16.5) for VRE pts and 13.1 months (95% C.I. 11.2–16.3) for non-VRE pts (p=0.13, Figure 1A). Using the 2:1 matching to adjust for the impact of age, etiology, and cytogenetics, VRE pts had a significantly inferior OS compared to non-VRE pts even after adjusting for WBC at dx (p=0.04 and.80, respectively, Figure 1B). Mutivariableanalyses confirmed this association. In conclusion, VRE bacteremia in pts undergoing IC for AML is an independent risk factor for worse OS. The routine use of fluoroquinoloneprophylaxis is likely contributing to the increased prevalence of VRE bacteremia. Consideration should therefore be given to escalating VRE appropriate antibiotic care in these patients sooner and in the post-remission setting. Figure 1. Survival from Diagnosis A. All patients B. VRE cases and matched controls Figure 1. Survival from Diagnosis . / A. All patients . / B. VRE cases and matched controls Disclosures: Saunthararajah: Cleveland Clinic Innovation: patent application for oral THU-decitabine., patent application for oral THU-decitabine. Patents & Royalties. Advani:Genzyme: Honoraria, Research Funding; Immunomedics: Research Funding. Maciejewski:NIH: Research Funding; Aplastic Anemia&MDS International Foundation: Research Funding.

Abstract 4947 Background Recent advances in the treatment of multiple myeloma (MM) have significantly improved overall survival. With MM patients living longer, there is a constant need to find better therapeutic options, especially when patients are refractory to conventional agents, and are not eligible for experimental therapeutics in clinical trials. We evaluated treatment with single-agent high-dose cyclophosphamide (HDCy) in a cohort of heavily pre-treated patients with relapsed/refractory MM. Methods All the patients were previously treated for active MM at the University of Southern California (USC), Los Angeles, CA. Cyclophosphamide was administered at 1.2 gm/m2 in D5W intravenous (IV) over 1 hour every 3 hours for a total of 4 doses. Mesna was given to prevent urinary adverse events from cyclophosphamide as 4 gm/m2 in 1000 ml D5W IV to run at 50 ml/hr for 20 hours, starting 15 minutes prior to the first dose of cyclophosphamide. Patients were given pre-medications with 5HT3 antagonists an steroids. Treatment was administered in the in-patient setting and patients were discharged after the last dose of cyclophosphamide. Treatment was repeated every 4 weeks, if well-tolerated and continued response. Growth factor support was provided to the patients, as needed. Response to treatment was assessed after each 4-week cycle according to the International Uniform Response Criteria for MM. Results Seven patients (4 females, 3 males) were treated on this regimen with a median age of 53 years (range 34-61 yrs). These patients included 3 Hispanics (43%), 2 Asians (29%), 1 Caucasian (14%) and 1 African-American (14%). MM subtype was IgG disease in 3, IgA in 2, and light-chain only in 2 patients. Advanced stage disease (>stage 1) at the time of diagnosis as per the Durie Salmon (DS) staging system was present in 71% of the patients, while 3 patients (43%) had advanced stage disease as per the International Staging System (ISS). Four patients (57%) had lytic bone disease at the time of diagnosis, while only 1 patient was a non-secretor. Five of these patients (71%) never received an autologous stem cell transplant (ASCT) as a part of their MM treatment. Median number of therapies in these patients was 5 (range 4-8), while median number of therapies prior to high-dose cyclophosphamide (HDCy) were 3 (range 2-7). Median number of cycles of HDCy administered to the patients was 2 (range 1-5). Overall Response Rate (ORR = CR+PR) was 29% (n=2) with 1 patient achieving CR and 1 patient achieving VGPR. Four patients (57%) had stable disease (SD) and 1 patient had progressive disease (PD). Thus, the overall clinical benefit (CR+PR+SD) was seen in 6 out of the 7 patients (86%). Median time to best response was 5 weeks (range 4-10 weeks). Median time to progression was 16 weeks (range 8-24 weeks). Most common adverse events were cytopenias and fatigue, but were easily manageable with supportive care on an out-patient basis. Conclusions Despite improvement in therapeutic regimens for MM, it remains an incurable disorder. There is a constant need to develop regimens for treatment of relapsed/refractory MM patients that are efficacious and well-tolerated. We report the use of single-agent HDCy in heavily pre-treated MM patients. Despite the small number of patients studied, we have noted meaningful clinical benefit with a manageable toxicity profile. This warrants further investigation into developing therapeutic regimens with high-dose cyclophosphamide. Disclosures No relevant conflicts of interest to declare.

Abstract 4895 Background Multiple myeloma (MM) remains an incurable cancer. Several biological and environmental factors have been considered to contribute to its pathogenesis, but so far no clear etiology is known. It remains undetermined if geographical differences and variability in environmental factors influences biological behavior and clinical presentation of MM patients. In depth research into the regional and demographic variation of these characteristics has not yet been done. To evaluate the impact of environmental influences we compared MM disease characteristics in two distinct geographical regions. Methods Patients with plasma cell disorders seen in the malignant hematology clinics of the University of Southern California (USC), Los Angeles, CA and the Multiple Myeloma Program Clinic at the Roswell Park Cancer Institute (RPCI), Buffalo, NY were included in this analysis. Demographic and disease-related clinical characteristics at the time of diagnosis of active MM were evaluated. Chi-square test or Mann-Whitney U test were used where appropriate. A 0.05 nominal significance level was used in all hypothesis testing. Results One hundred and sixty patients at USC and 170 patients at RPCI were studied. Among these, 140 and 144 had active MM at the time of diagnosis, respectively. The median age at diagnosis was 58 years (range 20-85) and 60 years (range 35-83), and males represented 48% and 52 % of the patients, respectively in the two geographic locations. Predominant patient race was Hispanic at USC (54%) and Caucasian at RPCI (92%). Advanced stage disease (>stage 1) was present in 87% and 85% patients, respectively as per the Durie Salmon (DS) staging and 53% and 48%, respectively as per the International Staging System (ISS). IgG MM was the most common subtype in both locations, but there were a higher number of patients on the West coast with LCO disease (22% vs. 10%). Lytic lesions were noted at the time of diagnosis in 59% of the patients at USC and 78% of the patients at RPCI while non-secretory MM was noted in 9% and 10% of the patients, respectively. There was a statistically significant difference between the patient populations in the two geographical regions with respect to median age at diagnosis (p=0.048), patient race (p Conclusions Despite widespread heterogeneity amongst MM patients, variations in disease characteristics amongst geographically distinct regions have not been studied systematically. Our investigation represents the first attempt to compare patient characteristics from the West and East coasts of USA. We observe several demographic and clinical characteristics that were significantly different between the two populations that could not be explained based on ethnic influences of the study population. These differences in clinical characteristics may represent undefined environmental influences that are unique to geographic location of the patient(s) and can potentially influence disease biology. Our pilot observation will need validation in a larger patient population to better understand the influences mediated by environmental factors and geographic diversity on clinical and biological behavior of the disease. Disclosures No relevant conflicts of interest to declare.

Abstract 4875 Background Study of ethnic disparities in various malignancies has revealed variation in treatment patterns as well as clinical outcomes. In multiple myeloma (MM) patients, ethnic disparities and clinical variability has been recorded in Caucasian, African-American and Asian populations. Such an analysis has not yet been undertaken for patients with Hispanics decent. Since this is the fastest growing ethnic subgroup in USA, it is increasingly important to investigate the variations in disease that may specifically define this population from MM patients of other ethnic backgrounds. We studied a large cohort of MM patients with Hispanic decent seen at our institution and compared them with the Caucasians (the most predominantly reported MM patient population), to better define biological characteristics and survival in this subgroup. Methods Patients with plasma cell disorders seen at the University of Southern California were included in the analysis. Demographic, mortality and disease-related clinical characteristics at the time of diagnosis of active MM were evaluated. Chi-square test or Mann-Whitney U test were used where appropriate. A 0.05 nominal significance level was used in all hypothesis testing. Results Plasma cell disorders in 160 patients were studied. Among these, 140 had active MM at the time of diagnosis. Patients were divided into Hispanic (H; 54%), Caucasian (C; 21%), African-American (AA; 14%), Asian (A; 6%), and other (O; 5%) subgroups based on race. Median age at diagnosis amongst Hispanic patients was 57 yrs (range 20-85), with 49% males. Advanced stage (>stage 1) disease was observed in 87% and 55% of these patients based on the Durie Salmon (DS) staging system and the International Staging System (ISS), respectively. Renal dysfunction was noted at diagnosis in 9% patients. IgG disease was the most common MM subtype (57%) and kappa light chain involvement was more common than lambda light chain (61% vs. 39%). Presence of bone lesions was noted in 65% of the Hispanic patients, while 8% had non-secretory MM. Median serum M spike at diagnosis was 2.3 gm% (range 0-26.7) and median bone marrow (BM) plasmacytosis at diagnosis was 24.5% (range 1%-100%). Majority of Hispanic patients (89%) never received an autologous stem cell transplant (ASCT) and only 21% ever participated in a clinical trial. Immunomodulatory drugs (IMiDs) were used in 55% and proteasome inhibitors (PI) in 44% of the Hispanic patients over the course of their disease. Median overall survival (OS) amongst Hispanic MM patients was 4.1 yrs (95% CI 3.1, 8.1). Further investigation involved comparison of these characteristics between our Hispanic (n=75) and Caucasian (n=30) patients. Among the demographic parameters, we observed a statistically significant difference between the 2 ethnic groups with respect to median age at diagnosis (H; 57 vs. C; 64, p=0.01). Hispanics had 61% patients Conclusions Studies of ethnic disparities remain an important area of evaluating management needs of specific patient populations as well as optimal triaging of healthcare resources. There is limited information on biological parameters of disease, clinical management information and survival outcome of Hispanic patients with MM. Here we present disease characteristics and treatment outcomes in this fast growing ethnic subgroup. Although our experience is limited to a single center, it reflects the changing population demographics of USA. We observed important disparities in patient demographics such as young age at diagnosis, as well as variable treatment patterns such as decreased ASCT in Hispanic population. Although several parameters may influence these patterns, our initial indications warrant systematic evaluation in larger patient cohorts. These studies are timely and will help in better understanding of ethnic influences on disease biology and clinical behavior. Disclosures No relevant conflicts of interest to declare.