Diagnosis Of Acute Myelogenous Leukemia Research Articles

Impact of body mass index and karyotype on clinical outcomes in adolescents and young adults (AYA) with acute myeloid leukemia.

6551 Background: Acute myelogenous leukemia (AML) represents 15%–20% of leukemias in children and approximately 33% in adolescents and young adults (AYA) (1). Obesity has been associated with worse outcome in acute lymphoblastic leukemia in AYA patients (pts). To date, however, the relationship between weight and clinical outcomes in AYA pts diagnosed with AML has not been established. We investigated the impact of body mass index (BMI) along with other prognostic factors on outcomes of AYA AML pts receiving intensive chemotherapy and/or allogeneic stem cell transplant (SCT). Methods: This retrospective chart review included pts 18-39 yrs newly diagnosed with AML between 01/2006-12/2023. All pts received intensive chemotherapy with cytarabine- and anthracycline-based induction followed by consolidation chemotherapy +/- SCT. BMI was calculated using height and weight at AML diagnosis. Pts were classified by BMI into under, normal, overweight, or obese categories. AML risk classification (ELN 2022) and HCT co-morbidity index (HCT-CI) were performed. Outcomes included complete response (CR), CR with incomplete counts (CRi), overall response rates (CR+CRi), event free survival (EFS), and overall survival (OS). Results: Eighty-seven pts (median age 25 yrs, range 18-38) were identified. 44 (51%) were male; 85% were Caucasian. Per ELN 2022, 27 (31%) had favorable, 40 (46%) intermediate, and 20 (23%) adverse risk. Overall response rate to chemotherapy was 92% (CR 80%, CRi 12%). CR rate by ELN was 96%, 72% and 58%, respectively. Median OS for all pts was 788 days and per ELN risk was 1379, 569, and 595 days, respectively. Co-morbidity indices (HCT-CI) ranged from 0-5. Sixty-two percent underwent SCT. 29% relapsed. The percentage of pts alive at 2 and 5 years was 54% and 29%. Pts were categorized by BMI: underweight (BMI < 18.5, 6%), normal weight (NW) (BMI 18.5-24.9) (37%), overweight (OW)(BMI 25-29, 26%), and obese (OB) (BMI > 30, 31%) pts. Overall, there was a trend to improved outcomes in NW vs OW and OB pts. Median OS was 1006 (NW) vs 748 (OW) vs 678 (OB) days (p=0.0036 for NW vs OW/OB). Two-year OS was 63%, 52%, and 48%; 5-year OS was 38%, 26%, and 19%. The impact of BMI was dependent on AML karyotype. In favorable risk AML AYA pts, the relapse rate was 4%, 4% and 12%. Median OS was 1982 (NW), 1169 (OW), and 1256 (OB) days (p=0.0525 NW vs OW/OB). Five-year OS was 50%, 25% and 18%. The most common causes of death were GVHD-induced multi-organ failure and respiratory failure which did not correlate with HCT-CI. In intermediate and adverse risk AML, there was no difference in outcomes by BMI. Conclusions: Outcomes of favorable risk AYA AML pts following intensive chemotherapy +/- SCT was influenced by BMI with increased mortality and shorter OS in pts with high BMI (overweight and obese) as compared to normal BMI. Additional studies to confirm this finding and elucidate the underlying reasons are warranted.

Characteristics and complications of acute promyelocytic leukemia in children: an analysis of a national database

Acute promyelocytic leukemia (APL) is an uncommon subtype of acute myelogenous leukemia (AML) that was previously one of the most fatal forms of acute leukemia. With advances in diagnosis and treatment, APL has become one of the most curable myeloid leukemias. The major reason for treatment failure in APL is early death after initiation of treatment. We performed a retrospective cross-sectional analysis of the Healthcare Cost and Utilization Project 2016 and 2019 Kids’ Inpatient Database, with the diagnosis of APL or AML not in remission as defined by ICD-10-CM codes. We compared complications and outcomes associated with APL and AML (exclusive of APL) in hospitalized children in the U.S. and described yearly national incidence. The national incidence of APL was 2.2 cases per million children per year. Children with APL were more likely to have cardiopulmonary complications (OR 1.79; CI 1.20–2.67; p = 0.004), coagulation abnormalities or DIC (OR 7.75; CI 5.81–10.34; p < 0.001), pulmonary hemorrhage (OR 2.18; CI 1.49–3.17; p < 0.001), and intracranial hemorrhage (OR 10.82; CI 5.90–19.85; p < 0.001) and less likely to have infectious complications (OR 0.48; CI 0.34–0.67; p < 0.001) compared to children with AML. In-hospital mortality rates were similar in children with APL and AML (4.2% vs 2.6%; OR 1.62; CI 0.86–3.06; p = 0.13), while the median length of stay for children who died from APL was shorter compared to AML (2 (IQR: 1–7) versus 25 (IQR: 5–66) days; p < 0.05). Hemorrhagic complications occur more often, and infectious complications occur less often in hospitalized children with APL compared to AML.

Racial Disparities in Telemedicine Uptake during the COVID-19 Pandemic among Patients with Hematologic Malignancies in the United States

Background: The COVID-19 pandemic impacted healthcare visit trends, transitioning care to utilize telemedicine. We aimed to investigate if the uptake in telemedicine during pandemic was equitable across racial groups for patients with hematologic malignancies. Methods: Using the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database we analyzed patients with diagnosis of acute myelogenous leukemia (AML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) or multiple myeloma (MM). Patients were categorized into treatment types within lines of therapy: outpatient (oral therapy and outpatient infusions combined with oral therapy) vs. inpatient treatments (chemotherapy, cellular therapy). Monthly visit rates were calculated as the number of visits (telemedicine or in-person [in-clinic treatment administration, vitals, and/or labs]) per active patient per 30-day standardized month. We used time-series forecasting methods on pre-pandemic monthly visit rate data (March 2016 - February 2020) to estimate projected counterfactual monthly visit rates between March 2020 - February 2021.Telemedicine uptake was descriptively analyzed over time (t). Results: We included 18,924 active patients (2,394 Black and 16,530 White) and 884,504 visits (117,673 Black and 766,831 White). 4,053 AML, 3,468 diffuse large B cell lymphoma, 1,943 follicular lymphoma, 2,151 mantle cell lymphoma, 5,926 chronic lymphocytic leukemia and 7,752 myeloma patients. Black patients had no significant reductions in in-person visit rates throughout the pandemic period compared to the projected rates. Conversely, White patients experienced an 18% (95% PI 9.9% - 25%) lower rate of in-person visits for outpatient therapy during the early pandemic (March - May 2020) (actual monthly visit rate 1.61; projected visit rate 2.0 [95% CI 1.8-2.2]). Telemedicine uptake was significantly higher for White patients compared with Black patients for all diseases and treatment categories between March 2020-February 2021 (t = 9.5, p &lt; 0.01), AML inpatient (t = 2.4, p = 0.04), MM outpatient (Figure 3C) (t = 6.0, p &lt; 0.01) and MM inpatient treatment categories (Figure 3D) (t = 2.3, p = 0.04). Conclusions: White patients had significantly higher telemedicine uptake compared with Black patients for all treatment categories. These findings challenge healthcare systems to direct efforts toward reducing the gap in healthcare access.

Use of extracellular vesicle microRNA profiles in patients with acute myeloid leukemia for the identification of novel biomarkers.

This study aimed to establish clinically significant microRNA (miRNA) sets using extracellular vesicles (EVs) from bone marrow (BM) aspirates of patients with acute myelogenous leukemia (AML), and to identify the genes that interact with these EV-derived miRNAs in AML. BM aspirates were collected from 32 patients with AML at the time of AML diagnosis. EVs were isolated using size-exclusion chromatography. A total of 965 EV-derived miRNAs were identified in all the samples. We analyzed the expression levels of these EV-derived miRNAs of the favorable (n = 10) and non-favorable (n = 22) risk groups; we identified 32 differentially expressed EV-derived miRNAs in the non-favorable risk group. The correlation of these miRNAs with risk stratification and patient survival was analyzed using the information of patients with AML from The Cancer Genome Atlas (TCGA) database. Of the miRNAs with downregulated expression in the non-favorable risk group, hsa-miR-181b and hsa-miR-143 were correlated with non-favorable risk and short overall survival. Regarding the miRNAs with upregulated expression in the non-favorable risk group, hsa-miR-188 and hsa-miR-501 were correlated with non-favorable risk and could predict poor survival. Through EV-derived miRNAs-mRNA network analysis using TCGA database, we identified 21 mRNAs that could be potential poor prognosis biomarkers. Overall, our findings revealed that EV-derived miRNAs can serve as biomarkers for risk stratification and prognosis in AML. In addition, these EV-derived miRNA-based bioinformatic analyses could help efficiently identify mRNAs with biomarker potential, similar to the previous cell-based approach.

Ongoing Phase III Randomized Trial of Salvage DFP-10917 Vs. Non-Intensive Reinduction or Intensive Reinduction for Acute Myelogenous Leukemia (AML)

Background: DFP-10917 is a deoxycytidine analogue with a novel structure. It contains a side chain cyanide (CN) group at the 2 carbon of deoxyribose that induces DNA damage in a manner unique from structurally related nucleoside analogues (eg, cytarabine, decitabine, or gemcitabine). When administered at high doses, DFP-10917 inactivates deoxyribonucleic acid (DNA) polymerase leading to S-phase arrest similar to cytarabine. When administered at low concentrations by continuous infusion, it displays an alternative, potentially advantageous, mechanism of action - DNA strand breakage leading to G2/M phase arrest and ultimately cell apoptosis. The strand breakage occurs via a spontaneous beta elimination reaction that requires no additional enzymatic activity. There is no current standard treatment for patients with relapsed/refractory (R/R) AML. Results of a completed Phase I/II study in R/R AML (D11-11002; NCT01702155) demonstrated preliminary efficacy of DFP-10917 in this indication, with a ~50% complete response (CR) rate in Phase II. Five of 14 patients who achieved CR proceeded to stem cell transplantation. Based on completed studies, risks associated with DFP-10917 are predominantly hematological (eg, neutropenia, anemia, febrile neutropenia, leukopenia, lymphopenia, thrombocytopenia). Study Design and Methods: Based on promising Phase II results, the Sponsor initiated Study D18-11141 (NCT03926624), a Phase III, randomized, controlled study to compare the rate and duration of CR in patients with AML R/R to 2-4 prior induction regimens. Patients receive either DFP-10917 or non-intensive reinduction (low-dose cytarabine [LoDAC], azacitidine, decitabine, venetoclax + LoDAC or azacitidine or decitabine) or intensive reinduction (high and intermediate dose cytarabine regimens). Patients assigned to DFP-10917 receive 6 mg/m 2/day by continuous infusion for 14 days followed by a 14-day rest period. Control treatment is administered per physician's decision. Adults aged ≥18 years with histologically or pathologically confirmed diagnosis of AML based on World Health Organization classification and adequate performance status (≤2) and organ function are eligible. Study Status: The study is ongoing at 34 study centers in the United States. As of July 2023, 162 patients were enrolled, with 82 assigned to DFP-10917. A majority of the patients are male (57.4%) and aged &amp;lt;75 years (83.3%). Overall, 44% have AML with myelodysplasia-related changes; 36% have AML not otherwise specified; and &amp;lt;20% have AML with recurrent genetic abnormalities or therapy-related myeloid neoplasms. Enrollment and management of patients were affected from 2020 to 2021 by COVID-19 restrictions. A prospectively-planned interim analysis will occur after the 150 th patient randomized is followed for &amp;gt;2 months. Based on recruitment projections, this analysis is scheduled for 09/2023. At that time, the Data Safety Monitoring Board will review an unblinded estimate of the treatment effect for the primary endpoint of CR, with the study either stopped for superiority or futility or continuing to a final analysis. If continued, the number of patients required for the final analysis will range from 300 to 450, in increments of 50, with the number determined based on the size of the interim treatment effect for the primary endpoint of CR or the secondary endpoint of overall survival.

Is Renal Function Equally Impacted By Hypomethylating Agents during Acute Myelogenous Leukemia Induction Therapy?

Background: Hypomethylating agents (HMA), such as azacitidine (AZA) /decitabine (DAC) plus BCL2 inhibitors are increasingly used as acute myelogenous leukemia (AML) therapy. However, side effects such as neutropenic fever, tumor lysis syndrome and acute kidney injury (AKI) are described. Although AKI induced by HMAs is infrequent, severity can result in permanent renal damage. Previous reports suggest that kidneys clear more than 50% of AZA with renal tubular acidosis and electrolytes abnormalities developing after drug exposure. To date, it is unknown whether concurrent comorbid conditions increase risk of AKI in AML patients. This study aimed to evaluate renal function overtime in patients receiving a HMAs plus venetoclax to determine each agent's ability to induce AKI. Methods: A single center retrospective, descriptive study from January 2018 to March 2022 was conducted at Baylor St. Luke's Medical Center. Patients with a confirmed diagnosis of AML, who received at least 1 cycle of venetoclax and a HMA, who were not eligible for intensive chemotherapy were included. Primary objective was incidence of AKI in AZA vs DAC during first week induction. Given potential additive impact of BCL2 inhibition on renal function, secondary objective was a subgroup analysis of patients in AZA group receiving venetoclax ≤ or >14 days. Descriptive and paired-t-test comparing baseline and daily sequential creatinine and glomerular filtration rate (GFR) were analyzed using SAS. Results: 40 AML patients were included. 25/40 (62.5%) and 15/40 (37.5%) received AZA and DAC. Baseline patient characteristics were well balanced between groups, except for differential absolute lymphocyte count (ALC) expression [3.4 K/uL vs 1.3 K/uL, in AZA treated vs DAC, p=0.01]. Patients receiving AZA developed significantly higher incidence of AKI from day 1 to day7. DAC was associated with transient significant AKI detectable only during day 5 (Fig 1A). At last follow up, incidence of irreversible renal failure was observed in 1/40 (2.5%) of AML patients. In further subgroup analysis, we sought to understand the possible nephrotoxic BCL2- inhibitor effect while combining with AZA. Patients exposed >14 days of BCL2- inhibitors developed sustained AKI throughout day 3 to day 7 [p=<0.05 for all time points], as compared to those receiving ≤14 days. No detectable differences on incidence of diabetes, heart failure, infections, and use of diuretics were found in patients exposed or not to 14 days of BCL-2 inhibitor. Conclusions: Our study demonstrates more severe and sustained worsening renal function in patients exposed to AZA than those receiving DAC. While our report recapitulates similar previous observations, we describe an important synergistic BCL-2 inhibitor effect on renal function when combined with AZA. It would be interesting to investigate whether higher than expected ALC cooperates to induce renal damage via enhanced T-cell immunity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Relationship Between Pretransplantation Nutritional Status and Outcome in Adults with Acute Myelogenous Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation

Pretransplantation nutritional status may impact outcome after allogeneic hematopoietic cell transplantation (HCT). Various simple screening tools have been developed and used to identify patients at risk of malnutrition; however, how best to use these screening tools is unclear, and their accuracy for the prediction of adverse outcomes is unknown. To investigate how these different measures contribute to outcome prediction, we examined a large cohort of adults with acute myelogenous leukemia (AML) who underwent allogeneic HCT in first or second remission at our institution between April 2006 and May 2021. We assessed the prognostic role of the Nutrition Risk Index (NRI), which combines weight loss and serum albumin, in 970 adults with AML in first or second remission who had usual body weight information available at AML diagnosis or relapse and before HCT. A low NRI at the time of conditioning for HCT was associated with higher nonrelapse mortality (hazard ratio [HR], .97; 95% confidence interval [CI], .95 to .98; P < .001) and relapse risk (HR, .98; 95% CI, .96 to .99; P < .001) and decreased relapse-free survival (HR, .97; 95% CI, .96 to .98; P < .001) and overall survival (HR, .97; 95% CI, .96 to .98; P < .001), as was a low pre-HCT serum albumin level. After multivariable adjustment, NRI, but not weight loss alone, was associated with outcome. The predictive ability of NRI was overall relatively low and comparable to that of serum albumin, with a C-statistic not exceeding .59. Taken together, our data indicate that pre-HCT level of serum albumin, an acute-phase protein recognized to more accurately reflect the severity of the inflammatory response compared with poor nutritional status, but not weight loss, is independently associated with post-HCT outcome in patients with AML. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Trends in Allogeneic Hematopoietic Cell Transplantation Utilization and Estimated Unmet Need Among Medicare Beneficiaries with Acute Myelogenous Leukemia

Allogeneic hematopoietic cell transplantation (alloHCT) is a resource-intensive procedure and the sole potentially curative treatment available for patients with acute myelogenous leukemia (AML). Although Medicare coverage may help address a major financial barrier to accessing alloHCT, there remains an unmet need for alloHCT owing to sociodemographic disparities. This study examined trends and factors associated with the utilization of alloHCT and the estimated unmet need for alloHCT among Medicare beneficiaries with AML. This retrospective cohort study included patients (age 65 to 74 years) with a diagnosis of AML identified in Medicare claims data from 2010 through 2016. To study trends in utilization, transplantation rates were calculated as the number of patients who underwent alloHCT within 180 days and 1 year of diagnosis (numerator) divided by the total number of patients with AML within each diagnosis year (denominator). A multivariable logistic regression was used to identify factors associated with the likelihood of undergoing alloHCT within 1 year of diagnosis. Two approaches were applied to estimate the unmet need for alloHCT. The first approach used claims data to identify the potential need for alloHCT among patients who achieved complete remission for at least 90 days. The second approach used established National Marrow Donor Program (NMDP) methodology, which considers estimates of risk level, response to treatment, comorbidity, and early mortality, to identify the potential and unmet need for alloHCT. The overall estimated need and unmet need from 2010 to 2015 and over different time periods were evaluated for both approaches. The alloHCT rate within 180 days of diagnosis increased from 8% in 2010 to 15.8% in 2016 (P < .001), and the 1-year alloHCT rate also increased over time, from 11.9% in 2010 to 20.0% in 2015 (P < .001). The likelihood of undergoing alloHCT within 1 year of diagnosis was associated with diagnosis year, age, race, geographic region, Elixhauser Comorbidity Index, and population-level median household income. Between 2010 and 2015, the claims data approach estimated a lower potential need for alloHCT compared with the NMDP methodology estimate (27% versus 36%); both approaches estimated that 43% to 44% of patients with a potential need for alloHCT had an unmet treatment need. Despite the differences in estimated potential need between the 2 approaches, both showed a sustained unmet need but with a downward trend over time. Our data show that utilization of alloHCT has increased over time among Medicare beneficiaries with AML. Two approaches of need analysis were conducted for validation of estimated need and unmet need for alloHCT using claim-identified remission status, given the lack of cytogenetics and molecular information in claims data. Both approaches to estimating the unmet need for alloHCT found a downward trend over time; however, there are differences in utilization of alloHCT by age, race, geographic region, comorbidity, and socioeconomic status, indicating disparities in access to alloHCT among Medicare beneficiaries with AML. This suggests the need for policy efforts, research, and continued education to improve access to alloHCT and to close the gap between the actual utilization of alloHCT and the unmet need.

Comparison of classification techniques in the diagnosis of acute myelogenous leukemia

The leukemia blood cell discriminates from other blood cells by geometrical structure and cellular material by hematologist with microscope. In conventional color imaging system, the granular region in leukemia cells classify false negatively by experts due to micro geometrical and morphological changes in leukemia cell. Hence, a computer aided decision support system (CADSS) employs for automatic classification of leukemia blood cells. This paper gives the comparative study of various methods of classification of Acute Myelogenous Leukemia (AML) with improved accuracy and their results are compared. In this paper, the classification techniques such as Convolutional Neural Networks (CNN), Support Vector Machines (SVM), Fraction Black-Widow Optimized Neural Network (FB-NN), Deep CNN with Arithmetic Optimization and Hybrid Convolutional Bi-LSTM based RNN are made with blood microscopic images, in which according to measures, Deep CNN with Arithmetic Optimization has the best accuracy.

Trends in Allogeneic Hematopoietic Cell Transplantation Utilization and Estimated Unmet Need Among Medicare Beneficiaries with Acute Myeloid Leukemia

Introduction: Allogeneic hematopoietic cell transplantation (alloHCT) is the only potentially curative treatment available for acute myelogenous leukemia (AML). It is a medically complicated and resource intensive procedure for which there are patient-, provider- and system-related factors that may impact its utilization. While Medicare coverage for alloHCT may help address a major financial barrier to access, there is still an unmet need due to other factors. This study intended to examine trends and factors associated with utilization of alloHCT and to estimate unmet need for alloHCT among Medicare beneficiaries with AML.Methods: This retrospective cohort study included all patients with a diagnosis of AML identified in the Medicare claims data from 2010 through 2016. Primary patient selection criteria included: primary or secondary diagnosis of AML, age limit (65-74), and continuous enrollment (for at least 180 days after AML diagnosis in Part A and Part B fee-for-service programs).To study trends in utilization, the transplant rates were calculated as the number of patients who received an alloHCT within 180 days and one year of diagnosis (numerator) divided by the total number of patients diagnosed with AML within each diagnosis year (denominator). Transplant rates within one year of diagnosis were further adjusted by patient characteristics, including age group, sex, race, residential region, and Elixhauser Comorbidity Index (ECI). A multivariable logistic regression was utilized to identify factors associated with the likelihood of receiving alloHCT within one year of diagnosis.Two approaches were applied to estimate unmet need for alloHCT. The first approach (Approach 1) used claims data to identify the potential need for alloHCT among patients who achieved complete remission for at least 90 days; patients who achieved 90-day remission but did not receive alloHCT at any time point were considered to have unmet need.In the second approach (Approach 2), the total number of patients diagnosed with AML in the claims data was run through the National Marrow Donor Program (NMDP) methodology , which takes estimates of risk level, response to treatment, comorbidity, and early mortality into consideration. Overall estimated need and unmet need from 2010-2015 and over different time periods were evaluated for both approaches.Results: Among the 5,974 patients diagnosed with AML from March 1, 2010 through June 30 th, 2016, 1226 patients (21%) received an alloHCT by the end of 2016. Trend analysis results suggest that utilization of alloHCT increased from 2010 to 2016 (P < 0.0001) (Figure 1). The likelihood of receiving alloHCT within one year of diagnosis was found to be associated with diagnosis year, age, race, geographic region, ECI, and population-level median household income (Table 1).Both approaches estimated that approximately 36% of the diagnosed patients were in need of alloHCT between 2010 and 2015. The overall unmet need was estimated as 59% and 43% based on the claims data approach and the NMDP methodology, respectively. Despite the differences in estimated unmet need between the two approaches, the unmet need for alloHCT was found to trend down over time (Figures 2 & 3).Discussion and Conclusions:Medicare coverage facilitates access to the health care system and receipt of health services when a need for treatment or care is recognized. Utilization of alloHCT has increased over time among Medicare beneficiaries with AML. However, there are persistent differences in utilization of alloHCT by age, race, geographic region, comorbidity, and socioeconomic status, indicating disparities in access to alloHCT among this population. The results of estimated need and unmet need for alloHCT may be affected by the lack of cytogenetics and molecular information in administrative claims. To minimize this limitation, we used NMDP methodology for validation and found a similar estimation of potential need for alloHCT and downward trend in unmet need. Although the unmet need for alloHCT for AML has improved over time, policy efforts, research, and continued education are needed to close the gap between the actual utilization of alloHCT and unmet need for this potentially curative treatment. [Display omitted] DisclosuresSaber: Govt. COI: Other.

Molecular Biomarker Testing and Targeted Therapy Patterns in Patients with Acute Myelogenous Leukemia (AML) in Community Health Systems in the United States: A Real-World Data Analysis

Molecular Biomarker Testing and Targeted Therapy Patterns in Patients with Acute Myelogenous Leukemia (AML) in Community Health Systems in the United States: A Real-World Data Analysis

COVID-19 Pandemic Highlights Health Disparities in Latinos in San Diego

Introduction:Minority healthcare disparities are well known in many areas of medicine. Higher mortality has been reported in minorities with different cancer types despite adjusting for income or education. In hematological malignancies the trend persists. Despite favorable prognostic factors upon diagnosis of acute myelogenous leukemia, the mortality risk for Latinos and African Americans is higher by 12% and 7%, respectively. Both incidence and mortality in acute lymphoblastic leukemia are highest in Latinos. In Hodgkin's Lymphoma, Latino and African American adolescents and young adults have a higher risk of death at 35% and 62%, respectively.The COVID-19 pandemic has drawn attention to the immense disparities in healthcare outcomes in minority communities. Disproportionate rates of hospitalization and death related to COVID-19 have been reported across the nation, highlighting the stark consequences of historic racial and economic injustices. With these findings comes a call to action and an urgency to create systemic change to promote health equity.Methods:Patients hospitalized at any Scripps Health hospital in San Diego County from March 1, 2020 to July 30, 2020 with a PCR confirmed diagnosis of COVID-19 and blood type were included in the analysis (n = 316). Demographic, laboratory and clinical data were extracted from the electronic medical record and included age, ethnicity, BMI, sex, medications, co-morbidities, blood type, white blood cell count, lymphocyte count, hemoglobin, platelets, ESR, CRP and D-dimer. Outcomes of interest included length of say (LOS), intensive care unit (ICU) admission, intubation and mortality. Analysis was performed with an a priori predictor of Latin American ethnicity. Linear regression analysis of LOS, logistic regression of other variables and age-adjusted regression was done. Demographic characteristics that were predictive in univariate analysis with p< 0.1 were included in a multiple regression model for each outcome with Latin American ethnicity as a predictor. If the potentially predictive demographic characteristic maintained trends toward significance (p<0.1), the predictor was retained in the model to produce the final regression results for each outcome.Results:Hospitalized COVID patients were predominantly male, obese (BMI 30.6) and average age was 63 years. 69.3% of patients were Hispanic. 65.51% of patients were diabetic, 26.27% had chronic kidney disease and 23.10% had congestive heart failure. Additional patient characteristics are included in Table 1. Median length of hospital stay was 16.5 days, 59% were admitted to the ICU, 37% were intubated, and 27% died. Blood type was not found to be a predictor of outcomes. The odds ratio (OR) of age adjusted LOS for Latinos was 1.01 days (p-value 0.60), 1.06 for ICU admission (p-value 0.80) and 0.82 for death (p-value 0.50). After adjusting for age and other potentially predictive characteristics, Hispanic ethnicity was not predictive of poor outcomes.Conclusion:In this retrospective analysis of patients hospitalized for COVID-19 in San Diego County, there was a strikingly high rate of hospitalizations in Latino patients. While the 2019 United States Census estimates the Latino population in San Diego to be 34.1%, Latinos comprised nearly 70% of patients hospitalized with COVID-19 in the Scripps Health system. Despite the high rate of admissions in Latino patients, Latin American ethnicity was not a predictor of poor outcomes as previously reported in other populations. The underlying etiology of the high rates of COVID-19 hospital admission in Latinos is likely multifactorial due to overcrowding, lack of access to healthcare and higher prevalence of chronic illness as demonstrated by our cohort's increased incidence of co-morbid conditions.DisclosuresNo relevant conflicts of interest to declare.

Protein Energy Malnutrition Significantly Increases Mortality and Adverse Outcomes in Acute Myelogenous Leukemia (AML) Patients with Neutropenic Fever: Findings of a Nationwide Inpatient Sample Analysis

Introduction: Neutropenic fever is a major cause of morbidity and mortality in all malignancies, especially acute leukemia. Protein energy malnutrition (PEM) is also a well-established risk factor for overall cancer related mortality. Acute myelogenous leukemia (AML) patients are frequently afflicted with neutropenic fever due to protracted neutropenia and community acquired, nosocomial, and opportunistic infections. They are also commonly malnourished due to poor oral intake, cachexia from underlying disease, and the toxicity of chemotherapy. To date, few studies have attempted to link neutropenic fever and PEM outcomes in AML. We thus aim to explore the prevalence and outcome of PEM in patients with AML and neutropenic fever. Methods: The Nationwide Inpatient Sample (NIS) database for 2016 and 2017 was searched for patients with primary discharge diagnosis of AML who had NF. This group was divided based on the presence or absence of PEM. The primary outcome was a comparison of inpatient mortality between the groups. Secondary outcomes included diagnosis of sepsis, mean total hospital charges (THC) and mean length of hospital stay (LOS). Outcomes were compared using multivariate regression analysis adjusting for sociodemographic and hospital characteristics and Charlson comorbidity index as a marker of severity. Results: A total of 10145 admissions met the inclusion criteria with AML and NF. Among the included patients, 1700 (16.7%) had PEM. Patient with PEM were significantly older (58.1 vs 55.2 years of age, p&amp;lt;0.001) but had no significant difference in sex (52.0 vs 55.0% females, p=0.308) and racial distribution, compared with patients without PEM. Overall, 825 (8.1%) hospitalizations had inpatient mortality. Patients with PEM had significantly higher adjusted odds ratio (aOR) of mortality (aOR: 2.00, 95% CI 1.335 - 2.998), developing sepsis (aOR: 2.06, 95% CI 1.514 - 2.812), as well as increase mean difference in LOS(8.6 days, 95% CI 5.77 - 11.37) and THC (105,600 USD 95% CI 57,000 - 154,000), compared to patients without PEM. Conclusion: PEM is associated with a significantly adverse outcome in patients with febrile neutropenia-- an almost double mortality rate and increased risk of complications like sepsis, increased LOS, and hospital costs. Neutropenic patients are markedly susceptible to fulminant systemic infections from various sources. PEM furthers this risk via weakening of host defenses including natural barriers and both innate and acquired immunity. Furthermore, in neutropenic patients with systemic infections, malnutrition may delay and impede wound healing along with immune responses which often contributes to a protracted course and adverse outcome. Nutrition in neutropenia has garnered limited attention, with some randomized trials showing limited to no benefit of the "neutropenic diet" in patients while depriving them of essential macro- and micronutrients. Nonetheless, current management guidelines for malnutrition in malignancies, particularly acute leukemias, are sparse. The profound impact of malnutrition in febrile neutropenia patients warrants further study, and we thus recommend further attention to screening practices and management strategies alongside primary treatment for malignancy and infection. Disclosures No relevant conflicts of interest to declare.

Selection of allogeneic hematopoietic cell transplant donors to optimize natural killer cell alloreactivity

Natural killer (NK) cells are potent mediators of the graft versus leukemia phenomenon critical to the success of allogeneic hematopoietic cell transplantation. Central to calibrating NK effector function via their interaction with class I human leukocyte antigens are the numerous inhibitory killer Ig-like receptors (KIR). The KIR receptors are encoded by a family of polymorphic genes, whose expression is largely stochastic and uninfluenced by human leukocyte antigens genotype. These features provide the opportunity to select hematopoietic cell donors with favorable KIR genotypes that confer enhanced protection from relapse via NK-mediated graft versus leukemia. Over the last 2 decades, a large body of work has emerged examining the use of KIR genotyping to stratify potential donors based on anticipated NK alloreactivity. Overall, these results support KIR-based donor selection for patients undergoing allogeneic hematopoietic cell transplantation for a diagnosis of acute myelogenous leukemia. Despite this, the underlying factors that control NK cell responsiveness are not completely understood, and opportunities remain to refine donor selection using NK cell receptor genotyping. In this review, we will summarize the relevant findings with respect to KIR genotyping as a selection parameter for allogeneic hematopoietic cell donors and address practical considerations with respect to KIR-based selection of donors for patients with myeloid neoplasia.

DNA Methylation Markers in the Diagnosis and Prognosis of Common Leukemias

An effective and accurate diagnostic method for leukemia has not yet been developed. Using genome‐wide methylation profiling and machine learning methods, we evaluated the utility of CpG methylation status to differentiate blood from patients with acute lymphocytic leukemia (ALL) or acute myelogenous leukemia (AML) from normal blood. We constructed a diagnostic prediction model that can differentiate ALL and AML blood from normal blood as well as ALL blood from AML blood with high diagnostic specificity and sensitivity by utilizing a CpG methylation panel. We then developed a methylation‐based survival classifier with 23 CpGs for ALL and 20 CpGs for AML that could successfully divide patients into high‐risk and low‐risk groups, with significant differences in clinical outcome in each leukemia type. These methylation markers have outperformed existing methods in their high sensitivity and specificity for diagnosis of ALL and AML, and have implications for the prediction of prognosis and treatment selection.Support or Funding InformationGuangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, ChinaUsing 11 markers, the methylation profile can differentiate subtype of leukemia and normal blood. Unsupervised hierarchical clustering and heatmap associated with ALL, AML and normal blood.Figure 1Methylation markers can predict five‐year overall survival of patients. A. AML training set (n=125); B. AML validation set (n=55); C. ALL training set (n=55); and D. ALL validation set (n=34).Figure 2

New advances in targeted therapy and immunotherapy of acute myelogenous leukemia

Acute myelogenous leukemia (AML) is a highly heterogeneous malignant hematologic disease, and it is mainly treated with traditional chemotherapy, but the efficacy is limited and the patients with worse performance status and comorbidities can not be treated with chemotherapy. Gene changes play an important role in the diagnosis and prognosis of AML, and these gene changes also provide targets for molecular targeted therapy. Meanwhlie, immunotherapy has achieved certain curative effects in AML and has a promising prospect. In this review, targeted therapy and immunotherapy of AML reported in 61st American Society of Hematology (ASH) Annual Meeting are summarized. Key words: Leukemia, myelogenous, acute; Immunotherapy; Gene change; Molecular targeted therapy

DNA methylation markers in the diagnosis and prognosis of common leukemias

The ability to identify a specific type of leukemia using minimally invasive biopsies holds great promise to improve the diagnosis, treatment selection, and prognosis prediction of patients. Using genome-wide methylation profiling and machine learning methods, we investigated the utility of CpG methylation status to differentiate blood from patients with acute lymphocytic leukemia (ALL) or acute myelogenous leukemia (AML) from normal blood. We established a CpG methylation panel that can distinguish ALL and AML blood from normal blood as well as ALL blood from AML blood with high sensitivity and specificity. We then developed a methylation-based survival classifier with 23 CpGs for ALL and 20 CpGs for AML that could successfully divide patients into high-risk and low-risk groups, with significant differences in clinical outcome in each leukemia type. Together, these findings demonstrate that methylation profiles can be highly sensitive and specific in the accurate diagnosis of ALL and AML, with implications for the prediction of prognosis and treatment selection.

Acceleration of AML Progression By Cigarette Smoke Exposure or Condensate Exposure and Associated DNA Methylation Alterations

Subsets of acute myelogenous leukemia (AML) are characterized by molecular alterations with prognostic significance, however, little is known about how modifiable behaviors, such as cigarette smoking, intersect with genetic factors. Mutations rendering the Fms-like tyrosine kinase 3 (FLT3) constitutively active, such as internal tandem duplication (ITD), are associated with refractory disease and therapy resistance. Inhibition of the FLT3 kinase shows some benefit in this population, as highlighted by the FDA approvals of midostaurin and gilteritinib, but overall outcomes remain poor. Cigarette smoke exposure (CSE) also marks a population of patients with poor prognosis. Current and former smokers who develop AML are known to have worse survival as compared to never smokers (Alfayez M., et al. ASCO 2019), but the impact of FLT3 mutation and subsequent associated treatment response has not been studied. Also, the underlying mechanism of how history of cigarette smoking influences leukemia biology and response to therapy is poorly understood. In order to model a history of smoking in AML patients, NOD-SCID mice (n=25) were exposed to CSE using a smoking robot for 2 hours, 5 days/week, for 2 weeks. Mice were then inoculated via tail-vein injection with luciferase tagged human FLT3-ITD cells and leukemia burden was monitored through noninvasive imaging. CSE continued through the duration of the experiment, post engraftment. Control "non-smoking" mice (n=15) were only injected with leukemia cells. Within one week post leukemic introduction, a significant increase in leukemic burden as measured by bioluminescence was apparent in mice exposed to CSE versus control mice (P-value&lt;0.0001). To model the impact of smoking cessation upon diagnosis of AML in patients, experiments were modified to halt CSE once leukemic engraftment was detectable by non-invasive imaging. Smoking cessation versus continuous smoke exposure yielded reduced relative leukemic burden. Mice with continuous smoke exposure had higher rates of leukemia compared to mice who ceased smoking (n=10) one week prior (P-value =0.0064). These rapid changes in leukemic burden suggest that CSE may prime the microenvironment to promote leukemia progression or directly affect leukemia cells. To address the latter possibility, human AML cells were exposed to cigarette smoke condensate (CSC), which contains the chemicals present in cigarettes, for two weeks before introducing the cells into mice. A significant increase in leukemic burden was observed in mice injected cells exposed to CSC compared to mice injected with unexposed leukemia cells (P-value &lt;0.001), highlighting a direct role for the chemicals in cigarettes on in vivo leukemia proliferative factors. Smokers are known to carry altered global DNA methylation signatures that persist decades after quitting. To measure DNA methylation changes in the in vivo models described above, we examined spleens of non-smoking and smoke exposed mice by reduced representative bisulfite sequencing (RRBS). Sequences were mapped to either the human or mouse genome, (enabling identification of leukemia specific versus microenvironment specific alterations) and were compared in the smoking and non-smoking mice. Over 200 genes exhibited significant DNA methylation alterations in their promoter regions. Genes involved in RNA polymerase activity and chromatin remodeling were highly represented amongst those with altered DNA methylation. The clinical significance of our observations was confirmed in a cohort of 58 treatment naïve FLT3-ITD AML patients at MD Anderson receiving intensive induction therapy: 41 never smokers and 17 ever smokers. Smokers had significantly reduced survival as compared to the never smokers (median overall survival of 18 vs 23 months, P-value 0.0092). Collectively our findings indicate that short-term CSE is sufficient to alter DNA methylation patterns and accelerate the early progression of FLT3-ITD AML in vivo. Smoking cessation upon diagnosis may slow leukemic growth relative to smoking throughout AML therapy prompting the consideration of behavioral interventions for smokers with AML. Improved understanding of the mechanism of leukemic progression and drug resistance from CSE is expected to lead to improved treatment paradigms designed for patients with a history of cigarette smoking. Disclosures Konopleva: Genentech: Honoraria, Research Funding; Kisoji: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents &amp; Royalties; Ablynx: Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding. Jabbour:Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding. DiNardo:agios: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; jazz: Honoraria; medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; daiichi sankyo: Honoraria; syros: Honoraria; celgene: Consultancy, Honoraria.

Paired Analyses of AML at Diagnosis and Relapse By Single-Cell RNA Sequencing Identifies Two Distinct Relapse Patterns

Introduction: Despite achievement of complete remission (CR) following chemotherapy, Acute Myelogenous Leukemia (AML) relapses in the majority of adult patients. While relapsed AML is almost always clonally related to the disease at diagnosis, the actual molecular and cellular contributors to chemotherapy resistance and to AML relapse remain incompletely understood. Some molecular determinants of relapse have been identified in genomic, epigenetic and proteomic aberrations, while cellular relapse reservoirs have been identified in leukemia stem cells as well as in more mature leukemic cell compartments. Here, we set out to determine the cellular composition, gene mutation status and gene expression of paired AML specimens procured at diagnosis and at relapse aiming at a better understanding of the AML relapse process. Methods: We employed the drop-seq 3' single cell RNA sequencing (scRNA-seq) method (Macosko 2015) with minor modifications to analyze the mRNA expression in single cells derived from 12 paired AML specimens procured at diagnosis and at relapse from prior CR. We obtained scRNA-seq data on 1000-2000 single cells per sample detecting approximately 2000-3000 unique molecular identifiers (UMIs) and 800-1500 genes per cell. Using WES or panel-based sequencing we determined mutations in known driver genes. Subsequently, we optimized novel methods for detection and mapping of mutated driver genes to individual cells using mutation specific PCR conditions and novel bioinformatics approaches. We annotated scRNA-seq expression profiles of the diagnosis and relapsed AML specimens individually using publicly available data for cell type-specific RNA markers derived from sorted normal cell populations and further compared the scRNA-seq data to scRNA-seq data of 5 pooled normal human bone marrows generated for this study. Results: Through analyses of scRNA-seq data of paired diagnosis and relapse AML specimens via principle components analyses (PCA) or t-distributed stochastic neighbor embedding (t-SNE) we detected varying degrees of separation of cell clusters in all cases analyzed indicative of substantial changes in single cell gene expression between AML diagnosis and relapse. A few of these observed cluster shifts were paralleled by gain or loss of mutated genes (e.g. FLT3-ITD) at relapse while most others lacked obvious clonal genomic markers. Through subsequent comparison of the expression similarities of single AML cells to sorted normal human bone marrow cells we detected two distinct AML relapse patterns: i) a pattern of relapse suggesting simple leukemia regrowth as evidenced by similar proportions of leukemia cells mapping onto discrete normal bone marrow cells (e.g. monocyte-like or GMPs or CMPs), and, ii) a pattern of relapse whereby the gene expression of relapsed cells (but not diagnosis cells) had similarity to normal hematopoietic cells that are conventionally placed more apical in the classical hematopoiesis differentiation cascade (HSCs, MPPs, CMPs; a phenotypic shift to immaturity). In addition, no leukemia sample mapped to just one classically defined bone marrow cell type but instead to multiple cell types, suggesting that most AML leukemia cells harbor aberrant hybrid cell gene expression patterns. Finally, we detected quantitative shifts in T cells and NK cells in some samples at relapse, which will be analyzed in greater detail. Conclusions: The comparative analysis of scRNA-seq data of paired AML specimens procured at diagnosis and relapse, identifies frequent and previously unrecognized changes in gene expression in leukemia cells at relapse. Through a comparison of gene mutation and gene expression at single cell resolution we identify two distinct AML relapse patterns in adult AML. Disclosures No relevant conflicts of interest to declare.

A Rare Presentation of Acute Myelogenous Leukemia: A Case Report of Vaginal and Uterine Myeloid Sarcoma from Iran

Myeloid or granulocytic sarcoma is an extramedullary tumor of immature granulocytic cells. This condition is rare and has a challenging diagnosis, relying on a high index of suspicion as well as radiology, histology, immunophenotyping, and molecular analyses. We herein report a case of a 25-year-old woman presented with vaginal bleeding and a large pelvic mass involving the vaginal and uterus. A biopsy and immunohistochemical examination of the mass revealed granulocytic sarcoma, and a subsequent bone marrow biopsy confirmed the diagnosis of acute myelogenous leukemia. The patient was treated based on the standard chemotherapy followed by allogeneic bone marrow transplantation from her full-matched sibling donor. After a 9-months follow-up, there was no notable complication, and the patient is now completely disease-free. Granulocytic sarcoma of the cervix is rare, and awareness of this entity is required for timely diagnosis and effective treatment.