Acute Myelogenous Leukemia Research Articles

Novel Small Molecule and Peptide Inhibitors of CREB in Leukemia Cells

Background: Acute Lymphoblastic Leukemia (ALL) and Acute Myelogenous Leukemia (AML) account for nearly 45% of all childhood cancer. Current therapy for acute leukemia results in significant morbidity and late complications in children. Therefore, more effective and less toxic therapies to treat leukemia are needed. Previous work in our laboratory has identified CREB (cAMP Response Element Binding Protein), a transcription factor that promotes cell proliferation and survival in acute leukemia, is overexpressed in primary ALL and AML cells and is a potential target for therapy. We have investigated small molecules and peptides to inhibit the critical interaction between the phosphorylated KID (Kinase-Inducible) domain of CREB and the KIX (KID-interacting) domain of the coactivator CBP (CREB Binding Protein). Methods: We assessed a library of previously untested alpha-mimetic compounds from ChemDiv designed to mimic interactions between α-helices and protein surfaces for predicted interaction with a shallow hydrophobic groove on the interaction surface of KIX. We interrogated the 24,737 compounds in the library using rigid-receptor ligand docking, followed by induced-fit ligand docking of the top compounds using two different software, MOE and Schrodinger's Bioluminate. The top 50 binding poses from each software's rankings were combined to yield 87 candidate alpha-mimetic molecule inhibitors. In addition to our screen of small molecules, we have designed peptide inhibitors that closely mimic the αB helix of pKID. We investigated two methods to enhance the stability and cell-penetrating ability of our peptides: hydrocarbon stapling and the utilization of a rigid scaffold from the scorpion toxin peptide BmBKTtx1. Based on the calculated binding scores and locations, the most promising chimeric peptide designs were further investigated for binding stability using 500 nanosecond molecular dynamics (MD) simulations modeling their interaction with KIX. Results: The binding poses of the final set of small molecules were visually inspected for occupation of key hotspots on the pKID:KIX interaction surface, including the location of the phosphorylation sight of KID. Of the 87 molecules and their binding poses, only 21 of them (24%) obstructed fewer than two of the three hotspots chosen for the analysis. Moreover, 80 of the molecules (92%) extended into the hydrophobic pocket, the most critical hotspot. The multi-residue construction of this pocket likely contributed to the high similarity in interaction fingerprint between these molecules and pKID; occupation of this pocket can serve as a good indicator of strong ligand binding to KIX in future assays. The most-promising peptide designs using the scorpion toxin scaffold were assessed with MD simulations and compared to a control peptide comprised primarily of the αB helix of pKID. The chimeric peptides showed increased binding stability over the control peptide with an average RMSD of 6.8Å vs. 12.5Å, illustrating the benefits of the stability afforded by the scorpion scaffold design. Several of the hydrocarbon stapled peptides were tested in vitro using fluorescence polarization (FP) assay developed by our lab (Chae et al. Bioorganic & Medicinal Chemistry Letters, 2019) and in AML HL-60 and KG-1 cells and were shown to have growth inhibitory effects by Cell-Titer Glo Assays. Discussion: These small molecules and scorpion toxin-derived peptides represent novel candidate inhibitors of the pKID:KIX interaction implicated in leukemia. Based on promising results from our in silico analyses of these inhibitors, we have obtained ten structurally diverse alpha-mimetic small molecules and three chimeric peptides and aim to test their efficacy in vitro using the FP assay. Furthermore, we will obtain high resolution cryo-EM structures of successful compounds and peptides bound to the KIX domain using a double-shell protein scaffold (Zhang et al. ACS Central Science, 2022), and use these structures for further refinement of the inhibitors. The development of new inhibitors for the pKID:KIX interaction promises to reveal insights into the structural relationship between the two domains and the basis for effective, targeted leukemia therapeutics.

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

Randomized Phase II Study to Assess the Role of Nivolumab As Single Agent to Eliminate Minimal Residual Disease and Maintain Remission in Acute Myelogenous Leukemia (AML) Patients after Chemotherapy (NCI9706 protocol; REMAIN Trial)

Randomized Phase II Study to Assess the Role of Nivolumab As Single Agent to Eliminate Minimal Residual Disease and Maintain Remission in Acute Myelogenous Leukemia (AML) Patients after Chemotherapy (NCI9706 protocol; REMAIN Trial)

Uncovering Ethnic Genomic Disparities Associated with Inferior Outcome in African Americans Diagnosed with Acute Myelogenous Leukemia

Background: African Americans (AA) have higher cancer-associated mortality than other ethnicities. AA with AML exhibit inferior overall survival (OS) to non-AA subgroups (OS=162 d vs 709 d, respectively, p=0.0001, HR=7.8) Fig 1A. In other cancers, higher genomic instability (GI) and differential oncogenic addiction contribute to AA worse outcomes; however, in AML, genetic causes of inferior outcomes are uncharacterized. In this study, we seek to investigate differential AML mut and other factors that contribute to inferior AA OS. Methods: After IRB approval, 92/250 (36.8%) available AML patients (pt) had next generation sequencing (NGS) data and were included. Mut frequencies were annotated by ethnicity [White (W) vs AA vs Hispanic (H) vs Asians (A)] and prioritized by European Leukemia Network (ELN) 2017 classification. Numeric chromosomic alterations (NCA) were extracted from metaphase karyotyping at diagnosis. Deleteriousness of mutations to protein function was calculated with sorting intolerant from tolerant (SIFT) prediction method. Chi-square and t-test evaluated differences in categorical and continuous variables respectively. Logistic binary regression was used to detect predictors for racial induced survival. SAS software was used. Results: Whites (W), AA, Hispanics (H) and Asians (A) represented 57/91 (62%), 14/91 (15%), 20/91 and (22%), 5/91 (5.4%) of the cohort, respectively. Median age was 63 (W) , 57.5 (AA) , 53 (H), 62 (A), p=NS. 60/92 (65%) were male. Median number of mut were 2.04 (W), 1.8 (AA), 2.2 (H) and 1.8 (A), p=NS. Distribution for adverse ELN-2017 defects were equivalent among AA vs non-AA except RUNX1, p=0.05. Lack of favorable mut was observed among AA. Only AA demonstrated CUX1, previously associated with DNA repair defects, and FBXW7 mut. A non-significant trend for higher NCA in AA (2.7 [W], 6.4 [AA], 3 [H] and 0.8 [A], p=0.09) was observed. Age correlated with NCA and number of mut in AML genome, p=0.02 and p=0.004. Interestingly, correlation effect was mostly driven only by AA, p=0.02 and p=0.003, respectively. SIFT score was 0.01 (W), 0.09 (AA), 0.02 (H), and 0.01 (A). These SIFT results suggest that AA mut are functionally tolerated. After adjusting for multiple factors, only canonical ELN-2017 mut, p=0.02 (OR 0.37, CI 0.16-0.8), and AA race, p=0.005 (OR 0.25, CI 0.1-0.67) increased risk of death (c-statistics=0.66) Fig.1B. Conclusions: In AA, frequency of Adverse ELN-2017 mut is similar to other races, but favorable mutations were lacking. NCA and number of AML genome mut strongly correlate with aging in AA, but not other ethnic groups. Surprisingly, SIFT score failed to demonstrate functional deleteriousness for AA mut, which suggests alternative genomic defects as a culprit for poor outcome. Acknowledging the small number of mut in our cohort, our study advances our understanding of racial disparity in AML survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prolonged Use of Eltrombopag in Patients with Severe Aplastic Anemia without Complete Response at 6 Months after Immunosuppressive Therapy

Background Eltrombopag (EPAG) could improve the efficacy of immunosuppressive therapy (IST) consisted by antithymocyte immunoglobulin (ATG) and cyclosporin (CsA) in untreated severe aplastic anemia (SAA) patients. This study explored whether patients with SAA could benefit from continuous use of EPAG beyond 6 months. Methods From February 2018 to October 2021, 92 Chinese patients who were 2 years of age or older with a new diagnosis of acquired SAA and were not eligible for front-line hematopoietic stem-cell transplantation were collected in the China Eastern Cooperation Group for Anemia (CECGA). Patients were treated with rabbit ATG (r-ATG) based IST consisting of CsA. Patients over 12 years old and aging 6-11 years old took EPAG orally at dose of 75mg and 37.5mg once daily, respectively; EPAG was administered with 1.25 mg per kilogram per day for patients with age distribution between 2 and 5 years. Generally, all patients were treated with EPAG at least 6 months. The lack of response at 6 months, relapse, HSCT, development of a clonal hematologic disease including myelodysplastic syndrome, and acute myelogenous leukemia, or disease- or treatment-related death are regarded as events in event free survival (EFS). Results The median age was 38 (2-78) years, with 18 patients (20%) under 18 years old and 21 patients (43%) over 60 years old. In the whole cohort, 61 patients (66%) were diagnosed as SAA and 31 patients (34%) with very severe aplastic anemia (vSAA). At 3, 6 and 12 months, the actuarial overall response rates (ORR) were 55% (51 of 92), 73% (67 of 92) and 81% (60 of 74) and complete response (CR) rates were 11% (10 of 92), 20% (18 of 92) and 34% (25 of 74), respectively. 18 patients (20%) who achieved CR within 6 months were under steady state. In 49 patients with PR at 6 months, 14 (35%) of 40 patients who were continuously exposed to EPAG improved to CR within 6.5 (3 ~ 10) months of median time after 6 months. Among 25 patients who failed at 6 months, 11 patients continued to use EPAG, and 5 patients (45%) improved responses with extended median time of 3 (1 ~ 6) months after 6 months (Figure 1). The cumulative effect curve showed that 93% and 58% of all 12 months remission and CR occurred within 6 months. In patients with PR and NR at 6 months, the better 2-year event free survival (EFS) was found in whom continued to use EPAG (75% vs. 26%, P=0.001) (Figure 2). Discussion EPAG plus IST were used to treat previously untreated SAA patients in prospective studies. The ORR and CR rate at 6 months were 68% ~ 94% and 26% ~ 58%, respectively [1, 2]. We found that 93% of all 12 months remission occurred within 6 months for patients treated with IST and EPAG. It is suggested that EPAG should be used in sufficient dosage at least 6 months. It has been reported that patients with CR and PR were present with better OS of 100% and 92%, while OS of non-responders was 47% (P=0.0016), effect was demonstrated as a predictor for 4-year OS [3]. For patients with PR and NR at 6 months in our study, it was found that not only the response rates, but also the 2-year EFS were improved by continuous usage of EPAG, compared to them discontinued EPAG. In conclusion, additional EPAG to IST mainly take effect within 6 months. Continuous administration of EPAG could improve the hematologic response and EFS in patients without achieving CR at 6 months. REFERENCE [1]. Townsley DM, Scheinberg P, Winkler T, et al., Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia. N Engl J Med, 2017. 376(16): p. 1540-1550. [2]. Peffault de Latour R, Kulasekararaj A, Iacobelli S, et al., Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia. N Engl J Med, 2022. 386(1):11-23. [3]. Assi R, Garcia-Manero G, Ravandi F, et al., Addition of Eltrombopag to Immunosuppressive Therapy in Patients with Newly Diagnosed Aplastic Anemia. Cancer, 2018. 124(21):4192-4201. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Association between Patient-Reported Social Determinant of Health Outcomes and a Social Genomics Profile in Allogeneic Hematopoietic Cell Transplantation: A Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis

Introduction Patient-reported outcomes (PROs) capture the subjective experience of a patient's social and environmental context, providing a firsthand account of this and other social determinants of health (SDOH). An individual's socioenvironmental context is linked to a wide array of health outcomes, including for patients undergoing hematopoietic cell transplantation (HCT) [1, 2]. Social genomics, the study of socioenvironmental effects on human gene expression, offers a framework for understanding these complex biobehavioral relationships [3]. The conserved transcriptional response to adversity (CTRA) is a genomic biomarker characterized by increased expression of pro-inflammatory genes and decreased innate anti-viral gene expression [4]. The CTRA profile has been associated with psychosocial adversity and is predictive of clinical outcomes in HCT, and thus may be a means to map the biologic sequelae of social hardship [2, 4]. The objective of this study was to examine the association of pre-transplant CTRA profile with psychosocial PROs in allogeneic HCT recipients. Methods A cross-sectional analysis of data from a subset of participants enrolled on a prior CIBMTR study testing the feasibility of centralized collection of PROs in allogeneic HCT [5] was completed. For the present analysis, eligible patients from this larger cohort were those aged >18 years with baseline (pre-HCT) PRO measures and available pre-transplant banked biospecimens. PROs included the 36-Item Short Form Health Survey (SF-36) and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT). Descriptive analyses of patient-, disease-, and transplant-related characteristics were prepared. CTRA was derived from banked whole blood specimens using RNA sequencing. Transcript-per-million values of the 47 indicator genes were log2 transformed and analyzed using mixed effects linear regression models testing relative average gene expression levels to standardized PRO score controlling for age, sex, race, malignant versus non-malignant disease, and performance status. Results A total of n=140 patients representing 8 transplant centers in the United States were included. Patient characteristics are depicted in Table 1. The median age was 55 years (range 18-75y), 44% were female, and 90% identified as White. A majority (96%) of patients had a hematologic malignancy diagnosis, with acute myelogenous leukemia (AML) being most common (35%). There were statistically significant associations between lower CTRA gene expression and higher FACT-BMT total scores (β-coefficient -0.041 difference in log2 CTRA RNA abundance/SD PRO score, p-value=0.003) social well-being (β-coefficient -0.058 difference in log2 CTRA RNA abundance/SD PRO score, p-value=0.0001), physical well-being, (β-coefficient -0.031 difference in log2 CTRA RNA abundance/SD PRO score, p-value=0.031) and FACT-G scores (β-coefficient -0.042 difference in log2 CTRA RNA abundance/SD PRO score, p-value=0.003) as depicted in Figure 1. This corresponds to a 10.7%, 14.8%, 8.2%, and 11.1% difference, respectively, in CTRA gene expression per 4-SD range of variation in each PRO. Conclusions Patient reports of socioenvironmental experience were associated with the CTRA immunoregulatory pattern in adult allogeneic HCT recipients, with social well-being emerging as the most significant domain. This finding is consistent with prior literature and supports the importance of social well-being and community context in the setting of allogeneic HCT. Heightened CTRA expression could provide a potential molecular mechanism for social gradients in HCT outcomes, although this was not experimentally tested in this study. Further research and intervention that targets this pathway could support optimal multidimensional outcomes in this high-risk population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Combination Therapy of Eltrombopag and Cyclosporine a Improves Hematopoiesis in Patients with Lower-Risk Myelodysplastic Syndrome

Objective: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal myeloid disorders characterized by ineffective hematopoiesis and cytopenias, with variable risks of progression to acute myelogenous leukemia (AML). Peripheral blood cytopenias are the major sources of morbidity and mortality for lower-risk MDS (LR-MDS) pts.The strategies guided by risk stratification tools are different for HR- and LR-MDS. The treatment options for cytopenias in IST non-responders, especially thrombocytopenia, are limited. Such pts are prone to a high risk of bleeding. Eltrombopag (EPAG) is an orally administered nonpeptide thrombopoietin (TPO) receptor agonist. The single-agent activity of EPAG was demonstrated in 44-47% of pts with LR-MDS . In this study, we investigated the efficacy and safety of the combination of EPAG and CysA in LR-MDS in a non-randomized phase II investigator-initiated trial. Method(s):Pts with a diagnosis of LR-MDS by WHO 2016 classification and IPSS-R as low to intermediate-risk group with hemoglobin (Hb) <9.0 g/dL, or RBC transfusion-dependence (at least four units of RBC at 8 weeks prior to enrollment); platelet count <20×109/L or platelet transfusion dependence; were enrolled. http://www.chictr.org.cn/ identifier: ChiCTR2000035473. The primary objective of this IIT was to evaluate the response to this regimen based on IWG-MDS 2006 criteria. Results All the 31 pts were evaluated for response at the primary endpoint. Among them, 21 (67.7%) pts achieved treatment response in at least one eligible lineage with an objective response rate (ORR), 4 (12.9%) pts achieved a CR, 5 (16.1%) pts achieved bi-lineage responses (HI-PE R), 11 (24.3%) pts achieved platelet lineage responses (HI-P R), and 1 (3.2%) patient achieved erythroid lineage response (HI-E R). ANC did not increase significantly at the primary endpoint compared to the baseline; however, altered ANC was a response of CR pts. The median time to response was 8 (range, 2-24) weeks, irrespective of whether the pts had a platelet or erythroid response.Of the 21 pts eligible for an erythroid lineage response,10 pts (47.6%) had responded by the endpoint and the platelet response rate was 64.5% (20/31). The median increase in Hb levels and platelets was from 60.4±18.2 g/L to 68.0±21.2 g/L (P=0.015) and from 12.3±11.2×109/L to 32.5±37.3×109/L (P=0.003) (Figure 1). The median DORs of HI-E and HI-P were not achieved, but the response rates of erythroid and platelet lineages in 20 months were 80.0% and 70.6%, respectively (Figure 2). The RBC and platelet transfusion-dependent rate decreased from 42.9% (9/21) to 28.6% (6/21) (P=0.334) and from 58.0% (18/31) to 25.8% (8/31)We also performed targeted next-generation exome sequencing of 80 genes associated with myeloid malignancies in 21 pts. Among them, 18 showed a total 19 somatic mutations (Figure 3). TET2,and ANKRD11 were detected in 3 responding pts,and KMT2D was detected in 3 responding pts. Pts with adverse prognostic genes, such as ASXL1, ARSR2, U2AF1, KIT, and ETV6, did not exhibit a hematological response. Somatic mutations in DHX9 and ROBO1 were associated with BM failure, as detected in responding pts. All 31 pts were evaluated for toxicity, and the treatment was found to be well-tolerated. The most commonly reported adverse events (AEs) of any grade were nausea (6/31,19.4%), elevated liver transaminases (4/31,12.9%), and headache (3/31,9.7%); no severe AEs had been reported until the cutoff date. One MDS-SLD patient who received CR at 3 weeks experienced deep venous thrombosis of the lower extremity after 9 months of medication, thereby requiring dose interruption. After anticoagulant therapy, the platelet count was still 65×109/L. One MDS-U case who received HI-P had increased BM blasts from 3.2% to 15.4% for 4 months. Another MDS-U case received HI-E and HI-P, and the chromosome was changed from normal karyotype to -7/del (20q) chimeric karyotype for 9 months after administration of the drugs. However, the hematological response was maintained for 16 months until the cutoff date for data collection. Conclusions: Our results indicated that the addition of Epag to CysA is well-tolerated and is an effective treatment for LR-MDS. These ORR are better than CysA monotherapy, especially HI-P. Also, the hematological responses are durable, although continued Epag administration might be necessary. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of Qualified Dedicated APL Leukemia Specialist and Simplified Treatment Algorithm on Early Deaths in APL, a Monocenter Experience

Introduction: Acute Promyelocytic Leukemia (APL) is a highly curable subtype of Acute Myelogenous Leukemia (AML). Since the incorporation of all-trans-retinoic acid ATRA and arsenic trioxide (ATO) survival rates for APL are reported to be >90% in clinical trials. Despite this, there is a discrepancy in survival rates in general practice, mainly due to significant early deaths (ED). Some national registries report 20-30% of patients die during induction. Major factors contributing to ED are due to rarity of the disease, advanced age, underlying comorbidities, lack of written guidelines for induction, delay in diagnosis, and physician experience level. Herein, we report our observations on the incorporation of a simple treatment algorithm and management by leukemia/APL experts on ED. Methods: Retrospective monocenter analysis of ED in APL patients who underwent induction therapy from 4/2007 to 3/2022. All APL patients who underwent induction therapy were stratified into 2 treatment groups. Patients in group 1 treated from 4/2007-12/2009 and 1/2014- 6/2017 by a hematologist without an algorithm. Group 2 patients were treated from 1/2010-12/2013 and 7/2017-03/2022 by an APL leukemia specialist using a written algorithm. Induction rate mortality was compared between both groups. The algorithm was a two-page set of guidelines directed at preventing or treating the major causes of early death. Institutional review board approval was obtained for this review. Results: Between 4/2007 and 3/2022, n=62 patients were analyzed. A total of n=5 patients were excluded from the study; n=3 passed away or were transitioned to hospice care prior to starting any form of induction therapy and n=2 were Jehovah's Witnesses who refused all blood products. A total of n=57 patients were stratified into their respective groups. Across all groups (n=10, 17.5%) reported ED, median age 68 (range 20-81), (n=6, 60%) patients >60 years of age. Group 1 consisted of n=23 patients, median age 53 (range 20-78), (n=12, 52.2%) were male, and (n=9, 39.1%) were high risk (WBC > 10,000/mm3). Incidence of ED was (n=9, 39.1%) from disseminated intravascular coagulation DIC (n=3), differentiation syndrome DS (n=4), multi-organ failure (n=1), infection (n=1). ATRA was initiated at suspicion of APL diagnosis in (n=23, 100%) of patients. ATRA given alone in (n=1, 4.3%) patients, combined with ATO in (n=8, 34.8%), with chemotherapy in (n=19, 82.6%), and (n=5, 21.7%) with ATO/ATRA/chemotherapy. Group 2 consisted of n=34 patients, median age 51 (range 10-88), (n=14, 41.2%) were male, (n=10, 41.2%) were reported as high risk. There were (n=1, 2.9%) reported ED from DIC. ATRA was initiated at suspicion of APL diagnosis in (n=34, 100%) of patients. ATRA was given alone in (n=7, 20.6%) patients, combined with ATO in (n=17, 50%) and chemotherapy in (n=8, 23.5%). ATRA/ATO/chemotherapy was administered in (n=6, 17.6%). Conclusions: Results of this retrospective study showed that a simplified treatment algorithm and management by APL experts decreased early death rates from 39.1% to 2.9%. This data is promising and has important implications for both academic centers and community practices.

Lncrna Famlf-2 Inhibits Acute Lymphoblastic Leukemia Apoptosis through the p38 MAPK Signaling Pathway

Background:Acute lymphocytic leukemia (ALL) is a hematologic malignancy caused by the clonal proliferation of immature lymphocytes. Long noncoding RNAs (lncRNAs) are involved in the pathogenesis and progression of ALL. Our previous study identified Familial acute myelogenous leukemia related factor (FAMLF) from a AML pedigree. There are at least three splice variants from FAMLF, referred as FAMLF-1, FAMLF-2 and FAMLF-3. We have shown higher expression of FAMLF-1 was related to a higher complete remission (CR) rate, and shorter relapse free survival (RFS) in AML. Another FAMLF variants, FAMLF-2 is highly expressed in ALL, and the potential mechanism of FAMLF-2 in regulating ALL progression is unclear. This study aims to investigate the functional and mechanistic roles of FAMLF-2 in ALL. Methods:The expression of FAMLF-2 was detected by real-time PCR (Q-PCR) in peripheral blood of ALL patients (N=85) and healthy controls (N=60). The full length of FAMLF-2 was obtained by 5' and 3' rapid amplification of the cDNA ends (RACE). FAMLF-2 subcellular location in Jurkat cells was detected by lncRNA FISH, nuclear/cytoplasmic RNA fractionation, and qPCR. The proliferation and apoptosis of Jurkat cell were determined by CCK-8 and flow cytometry experiments in vitro. RNA-seq was performed to study the molecular mechanism of FAMLF-2 in regulating ALL cell apoptosis. Results:The FAMLF-2 mRNA expression and in ALL patients was significantly higher than those in the normal individuals (P=0.000). The expression of FAMLF-2 was positively correlated with percentage of peripheral blood blasts (P=0.032). The ALL patients with higher FAMLF-2 expression had significantly poor overall survival (P=0.036). We defined a 2393-bp full-length transcript of FAMLF-2, and examined the subcellular localization of FAMLF-2, which showed that FAMLF-2 predominately resides in the nucleus of Jurkat cells. The cell proliferation was inhibited, and cell apoptosis was induced when FAMLF-2 were down-regulated in Jurkat and Nalm6 cells, whereas the overexpression of FAMLF-2 showed the opposite results. We analyzed the RNA-seq data of the knockdown and overexpression of FAMLF-2 in Jurkat cells, and the GSEA analysis suggested that FAMLF-2 knockdown was associated with "MYC TARGETS V1", "MYC TARGETS V2" pathways. The knockdown of FAMLF-2 in Jurkat cells upregulated the expression of p-P38 and downregulated the expression of c-Myc, bcl-2. Conclusion: Taken together, our study indicate that FAMLF-2 inhibits the apoptosis of ALL through the p38 MAPK signaling pathways, which might act as a prospective prognostic biological marker for ALL. Keywords: Acute lymphocytic leukemia, Long noncoding RNAs, FAMLF-2, apoptosis, p38 MAPK Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Trial in Progress: Tagraxofusp-Based Therapy to Eradicate Measurable Residual Disease of Acute Myelogenous Leukemia Prior to Allogeneic Hematopoietic Cell Transplantation

Background Numerous studies convincingly demonstrate that measurable residual disease (MRD) in AML at time of allogeneic cell transplantation (alloHCT) is a powerful, independent predictor of subsequent relapse. Attempts to eradicate AML MRD pre-transplant with consolidation chemotherapy have been unsuccessful, with reported MRD conversion rates as low as 20% (Appelbaum et al., Blood 2019). Tagraxofusp is an IL-3 truncated diphtheria toxin recombinant protein that binds CD123 with high affinity. Preliminary data using tagraxofusp as consolidation therapy in AML patients has demonstrated good tolerability (Lane et al., Blood 2017). Pathways of resistance to tagraxofusp have been identified preclinically as loss of the intracellular target for diphtheria toxin, diphthamide, through methylation of an enzyme involved in diphthamide synthesis. Treatment with a hypomethylating agent has the potential to restore expression of diphthamide and increase tagraxofusp sensitivity in AML cells (Togami et al., J Clin Invest 2019). Design This is a single-arm, open-label, multi-center phase Ib/II clinical trial to evaluate the safety and effectiveness of tagraxofusp +/- azacitidine in AML patients who are in first or second remission with detectable MRD and are planned to undergo alloHCT. MRD will be measured by multi-dimensional flow cytometry with sensitivity of 0.02% (Hematologics). Patients will be enrolled in a modified 3+3 dose escalation design with two cohorts: cohort A) tagraxofusp 12 mcg/kg IV qday on days 1-5; and cohort B) azacitidine 75 mg/m2 subq qday on days 1-5 plus tagraxofusp 12 mcg/kg qday on days 8-12. Patients achieving MRD-negativity after cycle 1 will proceed to alloHCT. If a patient remains MRD-positive, an additional cycle of investigational therapy will be administered. All patients will proceed to alloHCT after no more than 2 cycles of investigational therapy. Both cohorts contain a dose escalation and a dose expansion phase. Cohort B will open if cohort A is not efficacious. Up to 44 participants will be enrolled in this trial at University of California Los Angeles and University of California San Francisco (two constituent sites of the University of California Hematologic Malignancies Consortium). Objectives The primary objective is to estimate the rate of conversion from MRD-positive pre-investigational therapy to MRD-negative after 1 or 2 cycles of investigational therapy. Key secondary objectives include to determine the safety of tagraxofusp +/- azacitidine in this patient population and to evaluate if adverse effects of this investigational therapy lead to delays in alloHCT. Exploratory objectives will involve use of single cell RNA sequencing to investigate if response to investigational therapy is predicted by leukemia-specific biomarkers and to evaluate if putative cell surface markers (inferred from RNA detection) are associated with MRD persistence. Main Outcomes The primary endpoint is MRD status after 1 or 2 cycles of investigational therapy. Key secondary endpoints include dose-limiting toxicities (any grade 4 or 5 non-hematologic toxicity or any grade 3 or greater hematologic toxicity at day 42) and number of days between investigational therapy and alloHCT. Conclusions There is an unmet need to improve outcomes in AML with detectable MRD pre-transplant. The strategy in this study is to employ tagraxofusp as an alternative mechanism of action to eradicate chemo-resistant AML cells responsible for subsequent relapse. In order to mitigate any potential resistance the residual leukemia population may have against tagraxofusp, azacitidine will be added to optimize the likelihood for MRD negativity and the possibility for improved outcomes after alloHCT. This study was sponsored by the ASH CRTI. References Appelbaum J, Loeb A, Gardner K, et al. Additional Cytotoxic Chemotherapy Is Unlikely to Eliminate Measurable Residual Acute Myeloid Leukemia (AML). Blood. 2019;134(Supplement_1):260-260. Lane AA, Sweet KL, Wang ES, et al. Results from Ongoing Phase 1/2 Trial of SL-401 As Consolidation Therapy in Patients with Acute Myeloid Leukemia (AML) in Remission with Minimal Residual Disease (MRD). Blood. 2017;130(Supplement 1):2583-2583. Togami K, Pastika T, Stephansky J, et al. DNA methyltransferase inhibition overcomes diphthamide pathway deficiencies underlying CD123-targeted treatment resistance. J Clin Invest. 2019;129(11):5005-5019. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Predictive Ability of Coronary Artery Disease on Age Acceleration and Clinical Outcome in Adult Acute Myelogenous Leukemia

Background: Aging is strongly associated with hematologic malignancies. Chronological age (CA) fails to explain biological and clinical outcome differences among AML patients (pt) at same age. Phenotypic age (PA) has gained momentum to predict cause-specific mortality in individuals sharing similar CA. Age acceleration (AA), resulting from the difference between phenotypic or methylation age (MA) and CA correlates with all-cause mortality. Similarly, Clonal Hematopoiesis of indeterminate Prognosis (CHIP) is associated with AA [PMID: 34050697]. CHIP mutations (mut) may be inherited into AML from preexisting immortalized/transformed cells. Cells harboring CHIP induce inflammation and "accelerate" vascular complications [i.e coronary artery disease (CAD)]. In this study, we seek "proof of clinical concept" for an association between AA and AML outcome when accounting for the presence or not of CAD. Methods: After IRB approval, AML pt were selected to estimate PA based on "proposed score 9 clinical biomarker's score" [PMID: 29676998] including albumin, creatinine, glucose, c-reactive protein, lymphocyte percent, red cell mean cell volume, red distribution width, alkaline phosphatase, white blood count). PA was calculated at AML onset. Difference between PA and CA was recorded as Delta PA-CA. Positive and negative delta PA-CA were considered as AA vs rejuvenation. Given the association between inflammation, CAD and CHIP, we performed individual correlation survival analysis accounting for phenotypic age in AML pt with and without CAD. Descriptive statistics, univariate and multivariate analysis were performed using SAS software. Results: 81/253 (32%) AML pt were available. Pearson correlation revealed that in pt without CAD, PA negatively correlated with survival (R= -0.31, p= 0.04), an effect not observed among AML pt with established CAD (R= -0.10, p=0.52). With AML pt lacking CAD [42/81(51%)] representing our population of interest, median CA, PA and MA among pt with (N=31) or without (N=11) AA was 53 years (y) v 49, p=0.5, 84 v 44, p= 0.0001 and 79 v 44, p=0.0001. WBC was 27 K/uL v 32.4 K/uL, p=0.5, in pt with and without AA. Favorable (fav) ENL-2017 was 33% vs 18%, p=0.1, Int 11% vs 18%, p=NS and unfav 56% v 64%, p=NS in pt with and without AA. Overall survival (OS) was 439 d vs not reached (NR), in pt with and without AA, p=0.03, HR=6.5 CI 2.2-19.4. Multivariate cox regression considering ELN-2017 classification, age and PA revealed that only AA was independent predictor of outcome, p=0.03, HR-1.02, CI=1.002-1.03. Conclusions: AA is associated with inferior AML outcome without overt CAD. In our proof of concept cohort, and acknowledging small sample size, AA supersedes ENL-2017 classification and CA as predictors of inferior outcome in AML. Our study adds insight on how AA based on epigenetic clock estimation potentially influences not only leukemogesis, but also renders organ function inability to survive AML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Dexamethasone during Leukemia Induction Therapy to Reduce Incidence of Acute Myelogenous Leukemia Relapse

Background: Dexamethasone is an anti-inflammatory steroid used with chemotherapy to prevent nausea/vomiting. Dexamethasone reduces chemo-resistance through inhibition of cytokine production and proliferation via nuclear factor kappa B (NF-kB) dependency. NF-kB is a pro-inflammatory transcription factor. When inactivated, NF-kB complexes are sequestered by inhibitors of kappa-B (I-kB) in the cytoplasm. Upon activation, NF-kB dimers translocate to the nucleus, activating kB responsive DNA. In AML, it has been found that NF-kB is highly activated, suggesting it is an integral part of AML biology. Approximately, 40% of patients diagnosed with AML have demonstrated increased activity of NF-kB and enhanced chemoresistance. In this study, we investigate the effect of dexamethasone given as adjuvant antiemetic prophylaxis on clinical AML outcome. Methods: A single-center, retrospective, descriptive study, from May 2015 to September 2021, was conducted in AML adult cohort admitted for induction therapy at Baylor St. Luke's Medical Center. Dexamethasone exposure was defined as a dose at least 8 mg daily for a total of 5-7 days during induction therapy and consolidation. Primary endpoint was clinical efficacy including event free survival (EFS) and overall survival (OS). Secondary endpoints were complete remission (CR) in patients receiving dexamethasone vs. not. Statistical analysis using SAS software included descriptive and inferential statistics. Results: 106 patients were evaluated. 47 (44.3%) were exposed to dexamethasone. Median age was 61 years (21-88) vs 55 years (26-82), p=0.03. ELN-2017 distribution among dexamethasone exposed vs. those who were not was in favorable 32% vs 15%, intermediate 32% vs 26 % and unfavorable 37% vs 58%. EFS was 745 days (d) vs. 164 d, in patients receiving dexamethasone vs. not, p=0.0001, HR=0.31, CI=0.16-0.54 (Fig 1). Subgroup analysis by ELN-2017 classification demonstrated that superior EFS was driven by intermediate risk, p=0.0004, HR=01, CI= 0.03-0.3 (Fig 2). In de novo AML, EFS was not reached (NR) vs 162d in AML patients dexamethasone exposed vs. not exposed (p=0.0001, HR=0.12, CI=0.05-0.29). Similarly, for secondary AML, EFS was 1,322 d vs 199 d, in dexamethasone exposed vs not exposed, p=0.05, HR=0.37, CI=0.14-0.92. CR/CRi was 60 % vs 40.2% for patients dexamethasone vs. not, p=0.2. With EFS, as outcome of interest, cox regression model was constructed accounting for age, ELN-2017 classification, and dexamethasone exposure demonstrating that favorable ELN-2017 (p=0.004; HR=0.17; CI=0.05-0.58) and exposure to dexamethasone (p=0.001; HR=3.7, CI=1.6-8.2) interacted to induce superior EFS. Conclusions: Dexamethasone exposure is associated with significant lower relapse risk in adult diagnosed with AML receiving induction. Our study is "proof of concept” for dexamethasone activity against AML. Albeit activity seems restricted to intermediate ENL-2017 subgroup, mitigation of relapse risk seems wide among de novo and secondary AML. Clinical studies are needed to reconfirm our findings and to uncover the inflammatory pathways targeted by dexamethasone leading to anti-leukemia effect. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clonal Evolution of t(8;21) Coexisting with t(9;22) in a Blastic Transformation of Chronic Myeloid Leukemia

Abstract Introduction/Objective Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by chromosomal translocation t(9;22) and the production of the fusion protein BCR-ABL1. The clinical course of the disease is characterized by a chronic phase, accelerated phase, and blast phase. One of the criteria for the progress of chronic phase to accelerated phase is the presence of cytogenetic anomaly additional to t(9;22). The blast phase of CML usually presents as acute myelogenous leukemia (AML); however, its characteristics are different from de novo AML. One of the most common subtypes of de novo AML with balanced translocation is AML with t(8;21). Here, we present a case of the blast phase of CML that presents t(8;21). Methods/Case Report The peripheral blood from a 51-years-old-man presenting with fatigue and splenomegaly showed leukocytosis, mild anemia, marked neutrophilia with left shift, monocytosis, basophilia, and &amp;lt;1% blasts. Flow cytometry identified an increase in granulocyte events with the left shift. Chromosome studies detected t(9;22) by karyotyping and FISH. BCR-ABL1 transcript was detected at 41.98% on the International Scale by RT-PCR, consistent with chronic myeloid leukemia (CML). The following bone marrow biopsy confirmed a diagnosis of the chronic phase of CML with &amp;lt;5% myeloblasts. After a year of treatment with imatinib, the patient developed marked leukocytosis, anemia, and thrombocytopenia. Flow cytometry detected an immature cell population comprising ~50% of total cells positive for CD117, CD34 (partial), CD13 (dim), and CD33. A few blasts were also positive for cMPO and negative for CD14, CD64, TdT, Glycophorin A, cytoplasmic CD3, CD19, and other markers. BCR-ABL1 transcript was detected at 56.45% on the International Scale by RT-PCR. Chromosome analysis revealed all cells (20/20) exhibiting t(8;21) leading to a fusion between RUNX1 and RUNX1T1 genes with a maintained t(9;22). FISH analysis confirmed t(8;21) and t(9;22). These findings were consistent with a blast phase of CML. Results (if a Case Study enter NA) NA Conclusion Progression of CML is frequently accompanied by cytogenetic evolution. However, the development of t(8;21) in Ph+ clones is extremely rare. Only six cases have been previously reported. Misidentifying this blast phase of CML (in the absence of a clinical history of the chronic phase of CML) as AML with recurrent genetic abnormalities is a potential pitfall we should be aware of.

Mocravimod, a Selective Sphingosine-1-Phosphate Receptor Modulator, in Allogeneic Hematopoietic Stem Cell Transplantation for Malignancy

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the sole curative option for patients with acute myelogenous leukemia. Outcomes are limited by leukemia relapse, graft-versus-host disease (GVHD), and abnormal immune reconstitution. Mocravimod (KRP203) is an oral sphingosine-1-phosphate receptor (S1PR) modulator that blocks the signal required by T cells to egress from lymph nodes and other lymphoid organs. Mocravimod retains T cell effector function, a main differentiator to immunosuppressants. In preclinical models, mocravimod improves survival by maintaining graft-versus-leukemia (GVL) activity while reducing GVHD. In patients undergoing allo-HSCT for hematological malignancies, mocravimod is postulated to prevent GVHD by redistributing allogeneic donor T cells to lymphoid tissues while allowing a sufficient GVL effect in the lymphoid, where malignant cells usually reside. The primary objective of this study was to assess the safety and tolerability of mocravimod in patients undergoing allo-HSCT for hematologic malignancies. Secondary objectives were to determine the pharmacokinetic profiles of mocravimod and its active metabolite mocravimod-phosphate in this patient group, as well as to assess GVHD-free, relapse free survival at 6 months after the last treatment. In this 2-part, single- and 2-arm randomized, open-label trial, we evaluated the safety, tolerability, and pharmacokinetics of mocravimod in allo-HSCT recipients (ClinicalTrials.gov identifier NCT01830010). Patients received either 1 mg or 3 mg mocravimod per day on top of standard of care GVHD prophylaxis with either cyclosporine A/methotrexate or tacrolimus/methotrexate. We found that mocravimod can be safely added to standard treatment regimens in patients with hematologic malignancies requiring allo-HSCT. Mocravimod resulted in a significant reduction of circulating lymphocyte numbers and had no negative impact on engraftment and transplantation outcomes. Our results indicate that mocravimod is safe and support a larger study to investigate its efficacy in a homogeneous acute myelogenous leukemia patient population undergoing allo-HSCT.

Clofarabine and Busulfan Myeloablative Conditioning in Allogeneic Hematopoietic Cell Transplantation for Patients With Active Myeloid Malignancies

Patients with refractory or relapsed and refractory myeloid malignancies have a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning (MAC) in patients with active, chemotherapy-refractory myeloid disease is historically associated with high rates of relapse and nonrelapse mortality (NRM). A MAC regimen combining clofarabine with busulfan (Clo/Bu4) has been reported to exhibit antileukemic activity with acceptable toxicity in patients age ≤70 years. Here we describe the clinical outcomes of a real-world population of patients with active myeloid malignancies undergoing allogeneic HCT with Clo/Bu4 MAC. In a single-center retrospective descriptive analysis, we identified patients who underwent HCT for myeloid malignancies not in remission using Clo/Bu4 MAC between 2012 and 2020. We report event-free survival (EFS) and overall survival (OS), cumulative incidences of relapse and NRM, and the incidence and severity of acute and chronic graft-versus-host disease (GVHD). We identified 69 patients with a median age of 60 years (range, 22 to 70 years). Most patients had relapsed/refractory or primary refractory acute myelogenous leukemia (AML; n=55) or refractory myelodysplastic syndrome (MDS; n=12); 1 patient had chronic myelogenous leukemia, and 1 patient had a blastic plasmacytoid dendritic cell neoplasm. Fifty patients (72.5%) had complete remission at day 100 post-transplantation. Two-year EFS and OS were 30% (95% confidence interval [CI], 20% to 44%) and 40% (95% CI, 29% to 54%), respectively. Patients with AML had a 2-year EFS and OS of 28% (95% CI, 18% to 44%) and 38% (95% CI, 27% to 54%), respectively; those with MDS had a 2-year EFS and OS of 47% (95% CI, 25% to 88%) and 56% (95% CI, 33% to 94%), respectively. The cumulative incidence of relapse at 2 years was 39% (95% CI, 27% to 51%) for all patients, including 45% (95% CI, 31% to 58%) in the patients with AML and 18% (95% CI, 2% to 45%) in those with MDS. NRM at 2 years was 31% (95% CI, 20% to 42%), including 27% (95% CI, 15% to 39%) in patients with AML and 35% (95% CI, 10% to 63%) in those with MDS. The total incidence of acute GVHD (aGVHD) of any severity was 80%, and the incidence of grade III-IV aGVHD was 22%. In patients who achieved remission, those who required systemic immunosuppression for aGVHD (58%) had poorer 2-year EFS (29% versus 54%; P=.05) and 2-year OS (39% versus 70%; P=.04) compared to those who did not. The 2-year cumulative incidence of chronic GVHD was 44% (95% CI, 28% to 58%). Clo/Bu4 MAC followed by allogeneic HCT for patients with active myeloid malignancies is an effective transplantation strategy for patients up to age 70, particularly those with advanced MDS. The high incidence of and poor outcomes associated with aGVHD highlight the importance of optimizing preventative strategies.

WIN Symposium 2022 - Abstract Poster Presentations.

WIN Symposium 2022 - Abstract Poster Presentations.

Single Institute Experience – Linear Accelerator Based Total Body Irradiation Using Volumetric Modulated Arc Therapy Planning in Standard Size Linear Accelerator Room

<h3>Purpose/Objective(s)</h3> To share experience of linear accelerator based total body irradiation (TBI) with volumetric modulated arc therapy (VMAT) in a standard size linear accelerator room <h3>Materials/Methods</h3> 30 patients aged 2-18 years (between 2018-2021) were treated with TBI as conditioning for bone marrow transplant (BMT)using VMAT based plan on our linear accelerator in a standard sized linear accelerator room. Indication of BMT was – acute lymphoblastic leukemia, acute myelogenous leukemia, chronic myeloid leukemia, myelodysplasia, aplastic anemia etc. Patient selection involved assessment regarding need of anesthesia, details of previous radiation, details of conditioning regimen for scheduling, organs dysfunction, adequate counselling and written consent from parents. With or without anesthesia, patients were immobilized using full body vacloc, head rest, brain orfit cast and knee rest. Position was supine, hands by side. Both head first (HF) and feet first (FF) scans were acquired if body length was more than 120 cm (for 120 cm, HF scan alone was acquired). A wire was placed on thigh to aid fusion of HF and FF scans for plan evaluation. Fiducials at three levels and optically stimulated luminescent dosimeter for dose monitoring were placed. Dose was 2-4 Gy single fraction and 12-13.2Gy/6 fractions (twice daily over 3 days, with 6 hours gap) based on chemotherapy conditioning regimen- delivered to 14 and 16 patients respectively. The planning objective was 90-100% coverage and dose max less than 120%. For multifraction plans, target was mean dose to lungs and kidney less than 10 Gy and 8Gy respectively. VMAT plans were generated with 3-5 iso-centers with fixed couch vertical and lateral values and changing longitudinal value, ensuring only longitudinal couch movement. Plan was made using 6MV energy and 5-9 arcs and 3 cm overlap between fields (avoid over joints to prevent effusion and over lungs to reduce lung dose) <h3>Results</h3> Mean PTV V95 – 93% (92-96%), Dmax – 115% mean (109%-120%). Mean lung dose (for 12-13.2Gy plans) was 9.4Gy/ (9-10 Gy), kidney mean dose was 7.8Gy (7.5-8 Gy). Mean monitor units in the plans were 1120 for complete arc and 690 for partial arcs. Treatment was delivered in strict aseptic precautions, under cover of steroids and antiemetics - in presence of radiation oncologist and physicist. Cone beam CT scan was used for position verification before and after treatment. The mean duration of treatment was 75 mins (range 60-90 minutes). 18 patients had grade 2 nausea and vomiting, one had knee joint effusion. No other side effects were reported. All transplants were successful except one reported graft versus host disease. <h3>Conclusion</h3> The procedure needs careful planning and delivery. It is feasible and possible to deliver TBI using VMAT in a standard sized linear accelerator room and should be offered to patients requiring the same.

Analysis of disparities in time to allogeneic transplantation in adults with acute myelogenous leukemia

AbstractAlthough alternative donors extend transplant access, whether recipient ancestry affects the time to allogeneic transplant is not established. We analyzed the likelihood of clinically significant delays to allograft by patient ancestry in 313 adult patients with acute myelogenous leukemia (AML) who underwent transplantation. Non-European ancestry patients (n = 99) were more likely than Europeans (n = 214) to receive HLA-mismatched donor allografts (45% vs 24%). Overall, the median time from transplant indication to allograft was 127 days (range, 57-1683). In multivariable analysis, non-Europeans had an increased risk of prolonged indication to transplant time >180 days owing to significant delays in indication to consult >90 days and consult to transplant >120 days. Compared with recipients of HLA-matched unrelated donors (URDs), HLA-mismatched adult donor recipients were at an increased risk of delayed indication to transplant, whereas HLA-identical sibling and cord blood recipients were at a lower risk. Subanalysis showed more indication to transplant delays >180 days in non-European (44%) vs European (19%) 8/8 URD recipients. Finally, the pandemic further exacerbated delays for non-Europeans. In summary, although non-European patients with AML are less likely to receive 8/8 URDs as expected, if they do, their transplants are delayed. HLA-identical siblings and cord blood facilitate the fastest transplants regardless of patient ancestry, whereas other adult donor transplants are delayed. Strategies to mitigate referral barriers, hasten donor evaluation, and use all alternative donor sources are critical to ensure timely transplantation for patients with AML.

Hepatosplenic mucormycosis due to Rhizomucor pusillus identified by panfungal PCR/sequencing of ribosomal ITS2 and LSU regions in a patient with acute myelogenous leukemia: A case report.

Angioinvasive Rhizomucor pusillus infection with dissemination to the liver and spleen is exceedingly uncommon, representing less than 1% of reported cases of mucormycosis. Diagnosis of mucormycosis is often difficult using conventional methods that rely on broad-based non-septate hyphae present on histologic examination and morphological identification of the cultured organism. Our laboratory also uses an in-house panfungal molecular assay to rapidly diagnose invasive fungal infection when conventional methods do not provide definitive results. Herein we present a case of disseminated mucormycosis with hepatosplenic involvement in a 49-year-old female with acute myelogenous leukemia following induction chemotherapy. But in this case repeated tissue biopsy cultures were negative. R. pusillus infection was diagnosed using an in-house panfungal PCR/sequencing assay based on dual priming oligonucleotide primers. New molecular assays facilitate prompt diagnosis of invasive fungal infections.

Evaluation the role of CD34 in patients with acute myeloid leukemia

Acute myeloid leukemia (AML) is the most common leukemia among the adult population and accounts for about 80% of all cases, and its characterized by clonal expansion of immature “blast cells” in the peripheral blood and bone marrow. The stem cell marker CD34 is expressed by leukemia blasts only for a subset of patients with acute myelogenous leukemia (AML). The aim of this study is to determine the role of CD34 in AML and its relationship with the parameters of complete blood (CBC). A total of (60) venous blood sample from patients and (30) control their ages ranged between 18 and 66 years, the samples was collected from Baghdad medical city hospital. Sera from all participants were tested to assessment CD34 level by ELISA. In the current study, CD34 in patients and control groups show a significant difference in relation with AML patients at p-value (&lt;0.001). The levels of CD34 in the patients were 0.55 ± 0.03, whereas it's significantly increased to 0.81 ± 0.05 in the control. Also we found the majority of patients presented with subtype M3 38.3% of total patients.