Hematology Commons^™

Contribution Of The Oral And Gastrointestinal Microbiomes To Bloodstream Infections In Leukemia Patients, Stephanie Mcmahon, Pranoti Sahasrabhojane, Jiwoong Kim, Samantha Franklin, Chia-Chi Chang, Robert R Jenq, Andrew E Hillhouse, Samuel A Shelburne, Jessica Galloway-Peña

Faculty, Staff and Student Publications

Bloodstream infections (BSIs) pose a significant mortality risk for acute myeloid leukemia (AML) patients. It has been previously reported that intestinal domination (>30% relative abundance [RA] attributed to a single taxon) with the infecting taxa often precedes BSI in stem cell transplant patients. Using 16S rRNA amplicon sequencing, we analyzed oral and stool samples from 63 AML patients with BSIs to determine the correlation between the infectious agent and microbiome composition. Whole-genome sequencing and antimicrobial susceptibilities were performed on all BSI isolates. Species-level detection of the infectious agent and presence of antibiotic resistance determinants in the stool (

Targeted Therapy With The Mutant Idh2 Inhibitor Enasidenib For High-Risk Idh2-Mutant Myelodysplastic Syndrome, Courtney D Dinardo, Sangeetha Venugopal, Curtis Lachowiez, Koichi Takahashi, Sanam Loghavi, Guillermo Montalban-Bravo, Xuemei Wang, Hetty Carraway, Mikkael Sekeres, Ameenah Sukkur, Danielle Hammond, Kelly Chien, Abhishek Maiti, Lucia Masarova, Koji Sasaki, Yesid Alvarado, Tapan Kadia, Nicholas J Short, Naval Daver, Gautam Borthakur, Farhad Ravandi, Hagop M Kantarjian, Bhumika Patel, Amy Dezern, Gail Roboz, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

The isocitrate dehydrogenase enzyme 2 (IDH2) gene is mutated in ∼5% of patients with myelodysplastic syndrome (MDS). Enasidenib is an oral, selective, mutant IDH2 inhibitor approved for IDH2-mutated (mIDH2) relapsed/refractory acute myeloid leukemia. We designed a 2-arm multicenter study to evaluate safety and efficacy of (A) the combination of enasidenib with azacitidine for newly diagnosed mIDH2 MDS, and (B) enasidenib monotherapy for mIDH2 MDS after prior hypomethylating agent (HMA) therapy. Fifty patients with mIDH2 MDS enrolled: 27 in arm A and 23 in arm B. Median age of patients was 73 years. The most common adverse events were neutropenia (40%), …

Concomitant Targeting Of Flt3 And Btk Overcomes Flt3 Inhibitor Resistance In Acute Myeloid Leukemia Through The Inhibition Of Autophagy, Weiguo Zhang, Guopan Yu, Hongying Zhang, Mahesh Basyal, Charlie Ly, Bin Yuan, Vivian Ruvolo, Sujan Piya, Seemana Bhattacharya, Qi Zhang, Gautam Borthakur, Venkata Battula, Marina Konopleva, William G Rice, Michael Andreeff

Faculty, Staff and Student Publications

Strategies to overcome resistance to FMS-like tyrosine kinase 3 (FLT3)-targeted therapy in acute myeloid leukemia (AML) are urgently needed. We identified autophagy as one of the resistance mechanisms, induced by hypoxia and the bone marrow microenvironment via activation of Bruton tyrosine kinase (BTK). Suppressing autophagy/BTK sensitized FLT3- mutated AML to FLT3 inhibitor-induced apoptosis. Furthermore, co-targeting FLT3/BTK/aurora kinases with a novel multikinase inhibitor CG-806 (luxeptinib) induced profound apoptosis in FLT3-mutated AML by co-suppressing FLT3/BTK, antagonizing autophagy, and causing leukemia cell death in FLT3-wildtype AML by aurora kinase-mediated G2/M arrest and polyploidy, in addition to FLT3 inhibition. Thus, CG-806 exerted profound anti-leukemia …

Targeting Glutaminase Is Therapeutically Effective In Ibrutinib-Resistant Mantle Cell Lymphoma, Lingzhi Li, Lei Nie, Alexa Jordan, Qingsong Cai, Yang Liu, Yijing Li, Yuxuan Che, Jovanny Vargas, Zhihong Chen, Angela Leeming, Wei Wang, Yixin Yao, Michael Wang, Vivian Changying Jiang

Faculty, Staff and Student Publications

Mantle cell lymphoma (MCL) is an incurable B-cell non-Hodgkin lymphoma characterized by frequent relapses. The development of resistance to ibrutinib therapy remains a major challenge in MCL. We previously showed that glutaminolysis is associated with resistance to ibrutinib. In this study, we confirmed that glutaminase (GLS), the first enzyme in glutaminolysis, is overexpressed in ibrutinib-resistant MCL cells, and that its expression correlates well with elevated glutamine dependency and glutaminolysis. Furthermore, we discovered that GLS expression correlates with MYC expression and the functioning of the glutamine transporter ASCT2. Depletion of glutamine or GLS significantly reduced cell growth, while GLS overexpression enhanced …

Mini-Hyper-Cvd Plus Inotuzumab Ozogamicin, With Or Without Blinatumomab, In The Subgroup Of Older Patients With Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphocytic Leukaemia: Long-Term Results Of An Open-Label Phase 2 Trial, Elias Jabbour, Nicholas J Short, Jayastu Senapati, Nitin Jain, Xuelin Huang, Naval Daver, Courtney D Dinardo, Naveen Pemmaraju, William Wierda, Guillermo Garcia-Manero, Guillermo Montalban Bravo, Koji Sasaki, Tapan M Kadia, Joseph Khoury, Sa A Wang, Fadi G Haddad, Jovitta Jacob, Rebecca Garris, Farhad Ravandi, Hagop M Kantarjian

Faculty, Staff and Student Publications

Background: The outcome of older patients with B-cell acute lymphocytic leukaemia is inferior to that in younger patients due to the adverse disease biology and their inability to tolerate intensive therapy. We aimed to study the long-term outcomes of inotuzumab ozogamicin with or without blinatumomab in combination with low-intensity chemotherapy in these patients.

Methods: For this open-label phase 2 trial, patients aged 60 years or older with newly diagnosed, Philadelphia-chromosome negative, B-cell acute lymphocytic leukaemia, and an ECOG performance status of 3 or lower were eligible. This study was conducted at the University of Texas MD Anderson Cancer Center. The …

A Phase 2 Study Of Nivolumab Combined With Ibrutinib In Patients With Diffuse Large B-Cell Richter Transformation Of Cll, Nitin Jain, Jayastu Senapati, Beenu Thakral, Alessandra Ferrajoli, Philip Thompson, Jan Burger, Sreyashi Basu, Tapan Kadia, Naval Daver, Gautam Borthakur, Marina Konopleva, Naveen Pemmaraju, Erin Parry, Catherine J Wu, Joseph Khoury, Carlos Bueso-Ramos, Naveen Garg, Xuemei Wang, Wanda Lopez, Ana Ayala, Susan O'Brien, Hagop Kantarjian, Michael Keating, James Allison, Padmanee Sharma, William Wierda

Faculty, Staff and Student Publications

Richter transformation (RT) is a rare complication of chronic lymphocytic leukemia (CLL) that has dismal outcomes. Upregulation of PD-1/PD-L1 drives immunological evasion in patients with RT. We hypothesized that combining nivolumab, a PD-1 blocking antibody, with the BTK inhibitor (BTKi) ibrutinib could potentiate tumor-cell killing. We conducted an investigator-initiated phase 2 clinical trial to assess the efficacy of combined nivolumab and ibrutinib in patients with diffuse large B-cell lymphoma (DLBCL) RT and CLL. Patients included were ≥18 years of age with adequate hepatic and renal function. Patients received nivolumab every 2 weeks of a 4-week cycle for a maximum of …

Five-Year Follow-Up Of Zuma-1 Supports The Curative Potential Of Axicabtagene Ciloleucel In Refractory Large B-Cell Lymphoma, Sattva S Neelapu, Caron A Jacobson, Armin Ghobadi, David B Miklos, Lazaros J Lekakis, Olalekan O Oluwole, Yi Lin, Ira Braunschweig, Brian T Hill, John M Timmerman, Abhinav Deol, Patrick M Reagan, Patrick Stiff, Ian W Flinn, Umar Farooq, Andre H Goy, Peter A Mcsweeney, Javier Munoz, Tanya Siddiqi, Julio C Chavez, Alex F Herrera, Nancy L Bartlett, Adrian A Bot, Rhine R Shen, Jinghui Dong, Kanwarjit Singh, Harry Miao, Jenny J Kim, Yan Zheng, Frederick L Locke

Faculty, Staff and Student Publications

In phase 2 of ZUMA-1, a single-arm, multicenter, registrational trial, axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated durable responses at 2 years in patients with refractory large B-cell lymphoma (LBCL). Here, we assessed outcomes in ZUMA-1 after 5 years of follow-up. Eligible adults received lymphodepleting chemotherapy followed by axi-cel (2 × 106 cells per kg). Investigator-assessed response, survival, safety, and pharmacokinetics were assessed in patients who had received treatment. The objective response rate in these 101 patients was 83% (58% complete response rate); with a median follow-up of 63.1 months, responses were ongoing in 31% …

Sirolimus Versus Cyclosporine A In Patients With Primary Acquired Pure Red Cell Aplasia: A Prospective Cohort Study, Yuan Yang, Zengwei Tang, Yuzhou Huang, Qinglin Hu, Shuqing Wang, Jiang Ji, Yali Du, Chen Yang, Miao Chen, Shimin Hu, Bing Han

Faculty, Staff and Student Publications

No abstract provided.

Impact Of Early Relapse Within 24 Months After First-Line Systemic Therapy (Pod24) On Outcomes In Patients With Marginal Zone Lymphoma: A Us Multisite Study, Narendranath Epperla, Rina Li Welkie, Pallawi Torka, Geoffrey Shouse, Reem Karmali, Lauren Shea, Andrea Anampa-Guzmán, Timothy S Oh, Heather Reaves, Montreh Tavakkoli, Kathryn Lindsey, Irl Brian Greenwell, Emily Hansinger, Colin Thomas, Sayan Mullick Chowdhury, Kaitlin Annunzio, Beth Christian, Stefan K Barta, Praveen Ramakrishnan Geethakumari, Nancy L Bartlett, Alex F Herrera, Natalie S Grover, Adam J Olszewski

Department of Medicine Faculty Papers

Progression of disease within 24 months (POD24) from diagnosis in marginal zone lymphoma (MZL) was shown to portend poor outcomes in prior studies. However, many patients with MZL do not require immediate therapy, and the time from diagnosis-to-treatment interval can be highly variable with no universal criteria to initiate systemic therapy. Hence, we sought to evaluate the prognostic relevance of early relapse or progression within 24 months from systemic therapy initiation in a large US cohort. The primary objective was to evaluate the overall survival (OS) in the two groups. The secondary objective included the evaluation of factors predictive of …

Impact Of Clonal Plasma Cells In Autografts On Outcomes In High-Risk Multiple Myeloma Patients, Oren Pasvolsky, Denái R Milton, Mikael Rauf, Sassine Ghanem, Adeel Masood, Ali H Mohamedi, Mark R Tanner, Qaiser Bashir, Samer Srour, Neeraj Saini, Paul Lin, Jeremy Ramdial, Yago Nieto, Guilin Tang, Hans C Lee, Krina K Patel, Partow Kebriaei, Sheeba K Thomas, Donna M Weber, Robert Z Orlowski, Katy Rezvani, Richard Champlin, Elizabeth J Shpall, Pei Lin, Muzaffar H Qazilbash

Faculty, Staff and Student Publications

Most patients with multiple myeloma (MM) undergoing autologous hematopoietic stem cell transplantation (autoHCT) eventually relapse, perhaps due to the presence of clonal plasma cells (CPC) in the autograft. We conducted a retrospective analysis to evaluate the impact of CPC in the autograft on the outcomes of high-risk chromosomal abnormalities (HRMM) patients undergoing autoHCT between 2008 and 2018. Patients were divided into CPC+ or CPC- in the autograft by next-generation flow cytometry (NGF). There were 75 CPC + autografts (18%) and 341 CPC- (82%). The CPC + group was less likely to achieve MRD-negative complete remission post-transplant (11% vs. 42%; p < 0.001). Median progression free survival (PFS) and overall survival (OS) were (12.8 vs. 32.1 months) and (36.4 vs. 81.2 months) in the CPC + and CPC- groups, respectively (both p < 0.001). Also in the subset of patients with MRD-negative ≥VGPR prior to autoHCT, those with CPC + autografts had inferior PFS (HR 4.21, p = 0.006) and OS (HR 7.04, p = 0.002) compared to CPC-. In multivariable analysis, the degree of CPC positivity in the autograft was independently predictive of worse PFS (HR 1.50, p = 0.001) and OS (HR 1.37, p = 0.001). In conclusion, both the presence and degree of CPC in the autograft were highly predictive of inferior PFS and OS.

Impact Of Lyophilization On Porcine Hemoglobin Properties., Mustafa Almosawi

College of Arts & Sciences Senior Theses

Blood transfusion is the single most often performed lifesaving procedure in hospitals worldwide. Unfortunately, packed red blood cells (RBCs) used for transfusion can only be stored for 42 days at 4 °C before being discarded due to irreversible damage that occurs during storage. Any reduction in available RBCs for an extended period can lead to blood shortages. To increase the shelf-life of RBCs, we investigated freeze-drying (lyophilizing) in the presence of the non-toxic sugar trehalose as a method for long-term preservation. However, the oxidative stress of the lyophilization and storage processes can compromise the functionality of these cells, and the …

Dna Methylation Analysis Is Used To Identify Novel Genetic Loci Associated With Circulating Fibrinogen Levels In Blood, Julie Hahn, Jan Bressler, Arce Domingo-Relloso, Ming-Huei Chen, Daniel L Mccartney, Alexander Teumer, Jenny Van Dongen, Marcus E Kleber, Dylan Aïssi, Brenton R Swenson, Jie Yao, Wei Zhao, Jian Huang, Yujing Xia, Michael R Brown, Ricardo Costeira, Eco J C De Geus, Graciela E Delgado, Dre'von A Dobson, Paul Elliott, Hans J Grabe, Xiuqing Guo, Sarah E Harris, Jennifer E Huffman, Sharon L R Kardia, Yongmei Liu, Stefan Lorkowski, Riccardo E Marioni, Matthias Nauck, Scott M Ratliff, Maria Sabater-Lleal, Tim D Spector, Pierre Suchon, Kent D Taylor, Florian Thibord, David-Alexandre Trégouët, Kerri L Wiggins, Gonneke Willemsen, Jordana T Bell, Dorret I Boomsma, Shelley A Cole, Simon R Cox, Abbas Dehghan, Andreas Greinacher, Karin Haack, Winfried März, Pierre-Emmanuel Morange, Jerome I Rotter, Nona Sotoodehnia, Maria Tellez-Plaza, Ana Navas-Acien, Jennifer A Smith, Andrew D Johnson, Myriam Fornage, Nicholas L Smith, Alisa S Wolberg, Alanna C Morrison, Paul S De Vries

Faculty, Staff and Student Publications

Background:

Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined by inter-individual differences in DNA methylation at CpG sites, and vice versa.

Methods:

We performed an epigenome-wide association study (EWAS) of circulating fibrinogen levels in 18,037 White, Black, American Indian, and Hispanic participants representing 14 studies from the CHARGE consortium. Circulating leukocyte DNA methylation was measured in 12,904 participants using the Illumina 450K array, and in 5,133 participants using the EPIC array. Each study performed an EWAS of fibrinogen using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific …

Epigenetic Age Acceleration Among Survivors Of Pediatric Medulloblastoma And Primitive Neuroectodermal Tumor, Rachel D Harris, Melissa A Richard, Maria Monica J Gramatges, Kevin Wilhelm, Michael E Scheurer, Philip J Lupo, Austin L Brown

Faculty, Staff and Students Publications

Survivors of childhood central nervous system (CNS) tumors experience early-onset aging-related phenotypes. DNA methylation (DNAm) age is an emerging epigenetic biomarker of physiologic age and may be predictive of chronic health conditions in long-term survivors. This report describes the course of epigenetic age acceleration using post-diagnosis blood samples (median: 3.9 years post-diagnosis; range: 0.04–15.96) from 83 survivors of pediatric CNS tumors. Epigenetic age acceleration was detected in 72% of patients, with an average difference between chronologic and dnam age of 2.58 years (95% Ci: 1.75–3.41, p < 0.001). Time from diagnosis to sample collection correlated with the magnitude of epigenetic age acceleration.

Development And Validation Of A Patient-Reported Outcome Measure To Assess Symptom Burden After Chimeric Antigen Receptor T-Cell Therapy, Xin Shelley Wang, Samer A Srour, Tito Mendoza, Meagan Whisenant, Ishwaria Subbiah, Elizabeth Gonzalez, Mona Kamal, Shu-En Shen, Charles Cleeland, Partow Kebriaei, Katayoun Rezvani, Sattva Neelapu, Sairah Ahmed, Elizabeth Shpall

Faculty, Staff and Student Publications

This cross-sectional study aimed to develop and validate a patient-reported outcomes (PROs) assessment tool to assess symptom burden and daily functioning in patients after chimeric antigen receptor (CAR) T-cell therapy, the MD Anderson Symptom Inventory (MDASI-CAR). The items were generated based on literature review, content elicitation interviews with patients, and clinician's review. The patients completed the MDASI core and module, single-item quality-of-life (QoL) measure and Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29). The psychometric validation analysis was based on the acceptability after item reduction process. The final 10 MDASI-CAR module items included tremors, fever/chills, headache, balance, dizziness, attention, difficulty speaking, coughing, …

Anti-Factor Xa Level Monitoring For Enoxaparin Prophylaxis And Treatment In High-Risk Patient Groups, Lucie Sikes, Kipson Charles, Abigail Antigua, Rima Patel, Selina Imboywa, Pheba Cherian

HCA Healthcare Journal of Medicine

Monitoring anti-factor Xa levels is a controversial topic in the inpatient setting due to resource utilization and unclear conditional guideline recommendations regarding this practice. Enoxaparin dosing in certain high-risk patient populations such as those with low body weight, obesity, renal insufficiency, and pregnancy has not been determined. The objective of this review was to assess the safety and efficacy of enoxaparin monitoring via anti-factor Xa levels in high-risk patient populations.

The PubMed database was searched for articles related to low-molecular-weight heparin monitoring. Randomized controlled trials and meta-analyses that evaluated the safety and efficacy of enoxaparin prophylaxis and treatment in patients …

Interrogating Bromodomain Inhibitor Resistance In Kmt2a-Rearranged Leukemia Through Combinatorial Crispr Screens, Shaela Wright, Jianzhong Hu, Hong Wang, Judith Hyle, Yang Zhang, Guoqing Du, Marina Y Konopleva, Steven M Kornblau, Mohamed Nadhir Djekidel, Wojciech Rosikiewicz, Beisi Xu, Rui Lu, Jun J Yang, Chunliang Li

Faculty, Staff and Student Publications

Bromo- and extra-terminal domain inhibitors (BETi) have exhibited therapeutic activities in many cancers. However, the mechanisms controlling BETi response and resistance are not well understood. We conducted genome-wide loss-of-function CRISPR screens using BETi-treated KMT2A-rearranged (KMT2A-r) cell lines. We revealed that Speckle-type POZ protein (SPOP) gene (Speckle Type BTB/POZ Protein) deficiency caused significant BETi resistance, which was further validated in cell lines and xenograft models. Proteomics analysis and a kinase-vulnerability CRISPR screen indicated that cells treated with BETi are sensitive to GSK3 perturbation. Pharmaceutical inhibition of GSK3 reversed the BETi-resistance phenotype. Based on this observation, a combination therapy regimen inhibiting both …

Targeting Of Epigenetic Co-Dependencies Enhances Anti-Aml Efficacy Of Menin Inhibitor In Aml With Mll1-R Or Mutant Npm1, Warren Fiskus, Christopher P Mill, Christine Birdwell, John A Davis, Kaberi Das, Steffen Boettcher, Tapan M Kadia, Courtney D Dinardo, Koichi Takahashi, Sanam Loghavi, Michael J Soth, Tim Heffernan, Gerard M Mcgeehan, Xinjia Ruan, Xiaoping Su, Christopher R Vakoc, Naval Daver, Kapil N Bhalla

Faculty, Staff and Student Publications

Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single-cell RNA-Seq, ChiP-Seq, ATAC-Seq, RNA-Seq, RPPA, and mass cytometry (CyTOF) analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. Notably, MI-mediated genome-wide, concordant, log2 fold-perturbations in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. MI treatment also reduced the number of AML cells expressing the stem/progenitor cell signature. A …

Mechanisms Of Response And Resistance To Combined Decitabine And Ipilimumab For Advanced Myeloid Disease, Livius Penter, Yang Liu, Jacquelyn O Wolff, Lin Yang, Len Taing, Aashna Jhaveri, Jackson Southard, Manishkumar Patel, Nicole M Cullen, Kathleen L Pfaff, Nicoletta Cieri, Giacomo Oliveira, Seunghee Kim-Schulze, Srinika Ranasinghe, Rebecca Leonard, Taylor Robertson, Elizabeth A Morgan, Helen X Chen, Minkyung H Song, Magdalena Thurin, Shuqiang Li, Scott J Rodig, Carrie Cibulskis, Stacey Gabriel, Pavan Bachireddy, Jerome Ritz, Howard Streicher, Donna S Neuberg, F Stephen Hodi, Matthew S Davids, Sacha Gnjatic, Kenneth J Livak, Jennifer Altreuter, Franziska Michor, Robert J Soiffer, Jacqueline S Garcia, Catherine J Wu

Faculty, Staff and Student Publications

The challenge of eradicating leukemia in patients with acute myelogenous leukemia (AML) after initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either after allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naïve setting. Integrative transcriptome-based analysis of 304 961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells. Clinical responses were …

Molecular Mechanisms Of Ferroptosis And Updates Of Ferroptosis Studies In Cancers And Leukemia, Hiroki Akiyama, Bing Z Carter, Michael Andreeff, Jo Ishizawa

Faculty, Staff and Student Publications

Ferroptosis is a mode of cell death regulated by iron-dependent lipid peroxidation. Growing evidence suggests ferroptosis induction as a novel anti-cancer modality that could potentially overcome therapy resistance in cancers. The molecular mechanisms involved in the regulation of ferroptosis are complex and highly dependent on context. Therefore, a comprehensive understanding of its execution and protection machinery in each tumor type is necessary for the implementation of this unique cell death mode to target individual cancers. Since most of the current evidence for ferroptosis regulation mechanisms is based on solid cancer studies, the knowledge of ferroptosis with regard to leukemia is …

Swi/Snf Blockade Disrupts Pu1-Directed Enhancer Programs In Normal Hematopoietic Cells And Acute Myeloid Leukemia, Courtney Chambers, Katerina Cermakova, Yuen San Chan, Kristen Kurtz, Katharina Wohlan, Andrew Henry Lewis, Christiana Wang, Anh Pham, Milan Dejmek, Michal Sala, Mario Loeza Cabrera, Rogelio Aguilar, Radim Nencka, H Daniel Lacorazza, Rachel E Rau, H Courtney Hodges

Faculty, Staff and Students Publications

UNLABELLED: In acute myeloid leukemia (AML), SWI/SNF chromatin remodeling complexes sustain leukemic identity by driving high levels of MYC. Previous studies have implicated the hematopoietic transcription factor PU.1 (SPI1) as an important target of SWI/SNF inhibition, but PU.1 is widely regarded to have pioneer-like activity. As a result, many questions have remained regarding the interplay between PU.1 and SWI/SNF in AML as well as normal hematopoiesis. Here we found that PU.1 binds to most of its targets in a SWI/SNF-independent manner and recruits SWI/SNF to promote accessibility for other AML core regulatory factors, including RUNX1, LMO2, and MEIS1. SWI/SNF inhibition …

Clinical Outcomes Associated With Npm1 Mutations In Patients With Relapsed Or Refractory Aml, Ghayas C Issa, Aram Bidikian, Sangeetha Venugopal, Marina Konopleva, Courtney D Dinardo, Tapan M Kadia, Gautam Borthakur, Elias Jabbour, Naveen Pemmaraju, Musa Yilmaz, Nicholas J Short, Abhishek Maiti, Koji Sasaki, Lucia Masarova, Sherry Pierce, Koichi Takahashi, Guilin Tang, Sanam Loghavi, Keyur Patel, Michael Andreeff, Kapil Bhalla, Guillermo Garcia-Manero, Farhad Ravandi, Hagop Kantarjian, Naval Daver

Faculty, Staff and Student Publications

Mutations in Nucleophosmin 1 (NPM1) are associated with a favorable prognosis in newly diagnosed acute myeloid leukemia (AML), however, their prognostic impact in relapsed/refractory (R/R) settings are unknown. In a retrospective analysis, we identified 206 patients (12%) with mutated NPM1 (NPM1c) and compared their outcomes to 1516 patients (88%) with NPM1 wild-type (NPM1wt). NPM1c was associated with higher rates of complete remission or complete remission with incomplete count recovery compared with NPM1wt following each line of salvage therapy (first salvage, 56% vs 37%; P < .0001; second salvage, 33% vs 22%; P = .02; third salvage, 24% vs 14%; P = .02). However, NPM1 mutations had no impact on relapse-free survival (RFS) and overall survival (OS) with each salvage therapy with a median OS following salvage 1, 2 or 3 therapies in NPM1c vs NPM1wt of 7.8 vs 6.0; 5.3 vs 4.1; and 3.5 vs 3.6 months, respectively. Notably, the addition of venetoclax to salvage regimens in patients with NPM1c improved RFS and OS (median RFS, 15.8 vs 4.6 months; P = .05; median OS, 14.7 vs 5.9 months; P = .02). In conclusion, NPM1 mutational status has a minimal impact on prognosis in relapsed or refractory AML; therefore, novel treatment strategies are required to improve outcomes in this entity.

Venetoclax For Acute Myeloid Leukemia In Pediatric Patients: A Texas Medical Center Experience, Adriana Trabal, Amber Gibson, Jiasen He, David Mccall, Michael Roth, Cesar Nuñez, Miriam Garcia, Meredith Buzbee, Laurie Toepfer, Aram Bidikian, Naval Daver, Tapan Kadia, Nicholas J Short, Ghayas C Issa, Farhad Ravandi, Courtney D Dinardo, Guillermo Montalban Bravo, Sofia Garces, Andrea Marcogliese, Hana Paek, Zoann Dreyer, Julienne Brackett, Michele Redell, Joanna Yi, Guillermo Garcia-Manero, Marina Konopleva, Alexandra Stevens, Branko Cuglievan

Faculty, Staff and Student Publications

The BCL-2 inhibitor venetoclax improves survival for adult patients with acute myeloid leukemia (AML) in combination with lower-intensity therapies, but its benefit in pediatric patients with AML remains unclear. We retrospectively reviewed two Texas Medical Center institutions' experience with venetoclax in 43 pediatric patients with AML; median age 17 years (range, 0.6-21). This population was highly refractory; 44% of patients (n = 19) had ≥3 prior lines of therapy, 37% (n = 16) had received a prior bone marrow transplant, and 81% (n = 35) had unfavorable genetics KMT2A (n = 17), WT1 (n = 13), FLT3-ITD (n = 10), …

A Phase 2 Study Of Interleukin-22 And Systemic Corticosteroids As Initial Treatment For Acute Gvhd Of The Lower Gi Tract, Doris M Ponce, Amin M Alousi, Ryotaro Nakamura, John Slingerland, Marco Calafiore, Karamjeet S Sandhu, Juliet N Barker, Sean Devlin, Jinru Shia, Sergio Giralt, Miguel-Angel Perales, Gillian Moore, Samira Fatmi, Cristina Soto, Antonio Gomes, Paul Giardina, Leeann Marcello, Xiaoqiang Yan, Tom Tang, Kevin Dreyer, Jianmin Chen, William L Daley, Jonathan U Peled, Marcel R M Van Den Brink, Alan M Hanash

Faculty, Staff and Student Publications

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic transplantation. In experimental models, interleukin-22 promotes epithelial regeneration and induces innate antimicrobial molecules. We conducted a multicenter single-arm phase 2 study evaluating the safety and efficacy of a novel recombinant human interleukin-22 dimer, F-652, used in combination with systemic corticosteroids for treatment of newly diagnosed lower gastrointestinal acute GVHD. The most common adverse events were cytopenias and electrolyte abnormalities, and there were no dose-limiting toxicities. Out of 27 patients, 19 (70%; 80% confidence interval, 56%-79%) achieved a day-28 treatment response, meeting the prespecified primary endpoint. Responders …

Pd-L1 + Macrophages Are Associated With Favorable Features In Primary Mediastinal (Thymic) Large B-Cell Lymphoma, Raphael E Steiner, Edwin R Parra, Francisco Vega, Lei Feng, Jason R Westin, Sattva S Neelapu, Paolo Strati, Michael R Green, Christopher R Flowers, Luisa M Solis, Ignacio I Wistuba, Sairah Ahmed, Ranjit Nair, Fredrick B Hagemeister, Mansoor Noorani, Mario L Marques-Piubelli

Faculty, Staff and Student Publications

Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a rare, aggressive subtype of non-Hodgkin lymphoma and has a complex inflammatory microenvironment. Although most patients can be cured with standard-of-care immunochemotherapy, patients who have disease relapse have an unfavorable prognosis. Pre-treatment prognostic biomarkers in PMBCL are needed. In this retrospective study, we analyzed the clinical features and outcomes of PMBCL patients and their association with immune cell subpopulations identified by multiplex immunofluorescence at initial diagnosis. Two different antibody panels were used to assess macrophages in tissue biopsy specimens collected before the initiation of induction therapy. Twelve PMBCL patients, including five patients …

Dna Damage Response-Related Proteins Are Prognostic For Outcome In Both Adult And Pediatric Acute Myelogenous Leukemia Patients: Samples From Adults And From Children Enrolled In A Children's Oncology Group Study, Stefan E Hubner, Eduardo S De Camargo Magalhães, Fieke W Hoff, Brandon D Brown, Yihua Qiu, Terzah M Horton, Steven M Kornblau

Faculty, Staff and Student Publications

The survival of malignant leukemic cells is dependent on DNA damage repair (DDR) signaling. Reverse Phase Protein Array (RPPA) data sets were assembled using diagnostic samples from 810 adult and 500 pediatric acute myelogenous leukemia (AML) patients and were probed with 412 and 296 strictly validated antibodies, respectively, including those detecting the expression of proteins directly involved in DDR. Unbiased hierarchical clustering identified strong recurrent DDR protein expression patterns in both adult and pediatric AML. Globally, DDR expression was associated with gene mutational statuses and was prognostic for outcomes including overall survival (OS), relapse rate, and remission duration (RD). In …

The Evolution Of Acute Lymphoblastic Leukemia Research And Therapy At Md Anderson Over Four Decades, Elias Jabbour, Nicholas J Short, Nitin Jain, Fadi G Haddad, Mary Alma Welch, Farhad Ravandi, Hagop Kantarjian

Faculty, Staff and Student Publications

Progress in the research and therapy of adult acute lymphoblastic leukemia (ALL) is accelerating. This analysis summarizes the data derived from the clinical trials conducted at MD Anderson between 1985 and 2022 across ALL subtypes. In Philadelphia chromosome-positive ALL, the addition of BCR::ABL1 tyrosine kinase inhibitors (TKIs) to intensive chemotherapy since 2000, improved outcomes. More recently, a chemotherapy-free regimen with blinatumomab and ponatinib resulted in a complete molecular remission rate of 85% and an estimated 3-year survival rate of 90%, potentially reducing the role of, and need for allogeneic stem cell transplantation (SCT) in remission. In younger patients with pre-B …

Towards A Biomarker For Acute Arterial Thrombosis Using Complete Blood Count And White Blood Cell Differential Parameters In Mice, Hee Jeong Jang, Dawid Schellingerhout, Jiwon Kim, Jinyong Chung, Dong-Eog Kim

Faculty, Staff and Student Publications

There is no blood biomarker diagnostic of arterial thrombosis. We investigated if arterial thrombosis per se was associated with alterations in complete blood count (CBC) and white blood cell (WBC) differential count in mice. Twelve-week-old C57Bl/6 mice were used for FeCl3-mediated carotid thrombosis (n = 72), sham-operation (n = 79), or non-operation (n = 26). Monocyte count (/µL) at 30-min after thrombosis (median 160 [interquartile range 140-280]) was ~ 1.3-fold higher than at 30-min after sham-operation (120 [77.5-170]), and twofold higher than in non-operated mice (80 [47.5-92.5]). At day-1 and -4 post-thrombosis, compared with 30-min, monocyte count decreased by about …

Treatment Outcomes For Newly Diagnosed, Treatment-Naïve Tp53-Mutated Acute Myeloid Leukemia: A Systematic Review And Meta-Analysis, Naval G Daver, Shahed Iqbal, Camille Renard, Rebecca J Chan, Ken Hasegawa, Hao Hu, Preston Tse, Jiajun Yan, Michael J Zoratti, Feng Xie, Giridharan Ramsingh

Faculty, Staff and Student Publications

Background: TP53 mutations, which are present in 5% to 10% of patients with acute myeloid leukemia (AML), are associated with treatment resistance and poor outcomes. First-line therapies for TP53-mutated (TP53m) AML consist of intensive chemotherapy (IC), hypomethylating agents (HMA), or venetoclax combined with HMA (VEN + HMA).

Methods: We conducted a systematic review and meta-analysis to describe and compare treatment outcomes in newly diagnosed treatment-naïve patients with TP53m AML. Randomized controlled trials, single-arm trials, prospective observational studies, and retrospective studies were included that reported on complete remission (CR), CR with incomplete hematologic recovery (CRi), overall survival (OS), event-free survival (EFS), …

Corrigendum To 'The Hemophilia Joint Health Score Version 21 Validation In Adult Patients Study: A Multicenter International Study' [Research And Practice In Thrombosis And Haemostasis, 6/2, (2022) E12690], Adrian Minford, Leonardo R Brand Ao, Maha Othman, Christoph Male, Rezan Abdul-Kadir, Paul Monagle, Andrew D Mumford, Dorothy Adcock, Björn Dahlbäck, Predrag Miljic, Maria T Desancho, Jun Teruya

Faculty, Staff and Students Publications

This corrects the article "The Hemophilia Joint Health Score version 2.1 Validation in Adult Patients Study: A multicenter international study" in volume 6, e12690.

The Immunomodulating Effects Of Morphine Dependence And Withdrawal In A Rat Model, Mark Stoll

Annual Research Symposium

Would you like to know what happens to the immune system during opioid drug withdrawal?