Hemic and Lymphatic Diseases Commons^™

Personalized Neoantigen Vaccines As Early Intervention In Untreated Patients With Lymphoplasmacytic Lymphoma: A Non-Randomized Phase 1 Trial, Szymon J Szymura, Lin Wang, Tiantian Zhang, Soung-Chul Cha, Joo Song, Zhenyuan Dong, Aaron Anderson, Elizabeth Oh, Vincent Lee, Zhe Wang, Sapna Parshottam, Sheetal Rao, Jasper B Olsem, Brandon N Crumpton, Hans C Lee, Elisabet E Manasanch, Sattva Neelapu, Larry W Kwak, Sheeba K Thomas

Faculty, Staff and Student Publications

Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade lymphoma with no standard therapy. Nine asymptomatic patients treated with a first-in-human, neoantigen DNA vaccine experienced no dose limiting toxicities (primary endpoint, NCT01209871). All patients achieve stable disease or better, with one minor response, and median time to progression of 72+ months. Post-vaccine single-cell transcriptomics reveal dichotomous antitumor responses, with reduced tumor B-cells (tracked by unique B cell receptor) and their survival pathways, but no change in clonal plasma cells. Downregulation of human leukocyte antigen (HLA) class II molecules and paradoxical upregulation of insulin-like growth factor (IGF) by the latter suggest resistance mechanisms. …

Association Between Intravenous Fluids During Labor And Primary Postpartum Hemorrhage: A Retrospective Cohort Study, Belinda R Bruce, Heather L Shepherd, Saleem Ahmed Khan, Charlotte R Haunton, Julie Leask, Bradley S De Vries

Faculty, Staff and Student Publications

INTRODUCTION: There is a major research gap relating to the impact of intravenous (IV) fluids administration during labor on maternal and neonatal outcomes. It is biologically plausible that a relationship between volume of IV fluids and primary postpartum hemorrhage (PPH) exists. The primary objective of this study was to evaluate whether the administration of high-volume IV fluids during labor (≥ 2500 mL) increases the risk of primary PPH and other adverse outcomes for women with a term, singleton pregnancy, in comparison to low-volume IV fluids during labor (<2500 >mL).

MATERIAL AND METHODS: A retrospective cohort study was conducted at a …

Sotatercept For Anemia Of Myelofibrosis: A Phase Ii Investigator-Initiated Study, Prithviraj Bose, Lucia Masarova, Naveen Pemmaraju, Sharon D Bledsoe, Naval G Daver, Elias J Jabbour, Tapan M Kadia, Zeev Estrov, Steven M Kornblau, Michael Andreeff, Nitin Jain, Jorge E Cortes, Gautam Borthakur, Yesid Alvarado, Mary Ann Richie, Mackenzie H Dobbins, Selene A Mccrackin, Lingsha Zhou, Sherry A Pierce, Xuemei Wang, Allison M Pike, Guillermo Garcia-Manero, Hagop M Kantarjian, Srdan Verstovsek

Faculty, Staff and Student Publications

No abstract provided.

Acute Myeloid Leukemia With Mast Cell Differentiation Is Characterized By Interstitial Mast Cells, Complex Karyotype, Do Hwan Kim, Sa A Wang, Wei Wang, Guilin Tang, Shaoying Li, C Cameron Yin, Pei Lin, Marina Konopleva, M James You, Roberto N Miranda, Xiaoqiong Wang, Qing Wei, L Jeffrey Medeiros, Jie Xu

Faculty, Staff and Student Publications

No abstract provided.

Eculizumab For Management Of Hyperhemolysis Syndrome In Pediatric Patients With Sickle Cell Disease: A Single-Center Case Series, Ajibike Lapite, Saleh Bhar, Titilope Fasipe

Faculty, Staff and Students Publications

Chronic hemolytic anemia and vascular occlusion are hallmarks of sickle cell disease (SCD). Blood transfusions are critical for supportive and preventive management of SCD complications. Patients with SCD are at risk for hyperhemolysis syndrome (HHS), a subtype of delayed hemolytic transfusion reactions. HHS management includes intravenous immunoglobulin, corticosteroids, and avoidance of further transfusions. Not all patients respond to first-line agents. Eculizumab, which blocks terminal complement activation, has been proposed as second-line management of HHS. We describe two patients who received eculizumab for refractory HHS. In our experience, eculizumab is a safe and effective option for refractory pediatric HHS.

Impact Of Patient Demographics And Neighborhood Socioeconomic Variables On Clinical Trial Participation Patterns For Nhl, Chijioke Nze, Clark R Andersen, Amy A Ayers, Jason Westin, Michael Wang, Swaminathan Iyer, Sairah Ahmed, Chelsea Pinnix, Francisco Vega, Lynne Nguyen, Lorna Mcneill, Loretta J Nastoupil, Kehe Zhang, Cici X Bauer, Christopher R Flowers

Faculty, Staff and Student Publications

Prior studies have demonstrated that certain populations including older patients, racial/ethnic minority groups, and women are underrepresented in clinical trials. We performed a retrospective analysis of patients with non-Hodgkin lymphoma (NHL) seen at MD Anderson Cancer Center (MDACC) to investigate the association between trial participation, race/ethnicity, travel distance, and neighborhood socioeconomic status (nSES). Using patient addresses, we ascertained nSES variables on educational attainment, income, poverty, racial composition, and housing at the census tract (CT) level. We also performed geospatial analysis to determine the geographic distribution of clinical trial participants and distance from patient residence to MDACC. We examined 3146 consecutive …

Chronic Eosinophilic Leukemia With A Novel Jak1 Mutation Responds Well To The Jak1/2 Inhibitor Ruxolitinib, Qing Wei, Jie Xu

Faculty, Staff and Student Publications

No abstract provided.

Costs And Impact Of Disease In Adults With Sickle Cell Disease: A Pilot Study, Sophie Lanzkron, Nicole Crook, Joanne Wu, Sarah Hussain, Randall G. Curtis, Derek Robertson, Judith R. Baker, Diane Nugent, Amit Soni, Jonathan C. Roberts, Megan M. Ullman, Julie Kanter, Michael B. Nichol

Cardeza Foundation for Hematologic Research

We assessed the feasibility to estimate illness burden in adults with SCD, investigated factors associated with health-related quality of life (HRQoL), and estimated societal burden. We recruited 32 participants and collected data on fatigue, HRQoL, and work productivity and activity impairment via patient survey. Health care utilization was abstracted for the 12 months before enrollment using medical chart review. Mean age was 36.7 years; 84.4% of participants had hemoglobin SS or Sβthal0 disease, and 81.3% reported chronic pain (experiencing pain on ≥3 days per week in the past 6 months). Mean EQ-5D-3L visual analogue scale score was 63.4 and the …

Daratumumab In Transplant-Eligible Patients With Newly Diagnosed Multiple Myeloma: Final Analysis Of Clinically Relevant Subgroups In Griffin, Ajai Chari, Jonathan L Kaufman, Jacob Laubach, Douglas W Sborov, Brandi Reeves, Cesar Rodriguez, Rebecca Silbermann, Luciano J Costa, Larry D Anderson, Nitya Nathwani, Nina Shah, Naresh Bumma, Sarah A Holstein, Caitlin Costello, Andrzej Jakubowiak, Tanya M Wildes, Robert Z Orlowski, Kenneth H Shain, Andrew J Cowan, Huiling Pei, Annelore Cortoos, Sharmila Patel, Thomas S Lin, Peter M Voorhees, Saad Z Usmani, Paul G Richardson

Faculty, Staff and Student Publications

The randomized, phase 2 GRIFFIN study (NCT02874742) evaluated daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM). We present final post hoc analyses (median follow-up, 49.6 months) of clinically relevant subgroups, including patients with high-risk cytogenetic abnormalities (HRCAs) per revised definition (del[17p], t[4;14], t[14;16], t[14;20], and/or gain/amp[1q21]). Patients received 4 induction cycles (D-RVd/RVd), high-dose therapy/transplant, 2 consolidation cycles (D-RVd/RVd), and lenalidomide±daratumumab maintenance (≤ 2 years). Minimal residual disease–negativity (10−5) rates were higher for D-RVd versus RVd in patients ≥ 65 years (67.9% vs 17.9%), with HRCAs (54.8% vs 32.4%), and with gain/amp(1q21) (61.8% vs 28.6%). D-RVd showed a …

Hairy Cell Leukemia Variant And Who Classification Correspondence Re: 5th Edition Who Classification Haematolymphoid Tumors: Lymphoid Neoplasms, Michael Grever, Leslie Andritsos, Mirela Anghelina, Evgeny Arons, Versha Banerji, Jacqueline Barrientos, Seema A Bhat, James Blachly, Alessandro Broccoli, Timothy Call, Claire Dearden, Sascha Dietrich, Monica Else, Narendranath Epperla, Andrei Fagarasanu, Brunangelo Falini, Francesco Forconi, Alessandro Gozzetti, Paul Hampel, David J Hermel, Sunil Iyengar, James B Johnston, Gunnar Juliusson, Robert J Kreitman, Francesco Lauria, Gerard Lozanski, Christopher C Oakes, Sameer A Parikh, Jae Park, Graeme Quest, Kanti Rai, Farhad Ravandi, Tadeusz Robak, Kerry A Rogers, Alan Saven, John F Seymour, Tamar Tadmor, Martin S Tallman, Constantine S Tam, Enrico Tiacci, Xavier Troussard, Bernhard Wörmann, Clive S Zent, Thorsten Zenz, Pier Luigi Zinzani

Faculty, Staff and Student Publications

No abstract provided.

Plasmacytoid Dendritic Cells Control Homeostasis Of Megakaryopoiesis, Florian Gaertner, Hellen Ishikawa-Ankerhold, Susanne Stutte, Wenwen Fu, Jutta Weitz, Anne Dueck, Bhavishya Nelakuditi, Valeria Fumagalli, Dominic Van Den Heuvel, Larissa Belz, Gulnoza Sobirova, Zhe Zhang, Anna Titova, Alejandro Martinez Navarro, Kami Pekayvaz, Michael Lorenz, Louisa Von Baumgarten, Jan Kranich, Tobias Straub, Bastian Popper, Vanessa Zheden, Walter Anton Kaufmann, Chenglong Guo, Guido Piontek, Saskia Von Stillfried, Peter Boor, Marco Colonna, Sebastian Clauß, Christian Schulz, Thomas Brocker, Barbara Walzog, Christoph Scheiermann, William C Aird, Claus Nerlov, Konstantin Stark, Tobias Petzold, Stefan Engelhardt, Michael Sixt, Robert Hauschild, Martina Rudelius, Robert A J Oostendorp, Matteo Iannacone, Matthias Heinig, Steffen Massberg

Faculty, Staff and Student Publications

Platelet homeostasis is essential for vascular integrity and immune defence1,2. Although the process of platelet formation by fragmenting megakaryocytes (MKs; thrombopoiesis) has been extensively studied, the cellular and molecular mechanisms required to constantly replenish the pool of MKs by their progenitor cells (megakaryopoiesis) remains unclear3,4. Here we use intravital imaging to track the cellular dynamics of megakaryopoiesis over days. We identify plasmacytoid dendritic cells (pDCs) as homeostatic sensors that monitor the bone marrow for apoptotic MKs and deliver IFNα to the MK niche triggering local on-demand proliferation and maturation of MK progenitors. This pDC-dependent feedback loop is crucial for MK …

Innate And Adaptive Immune Responses That Control Lymph-Borne Viruses In The Draining Lymph Node, Carolina R. Melo-Silva, Luis J. Sigal

Department of Microbiology and Immunology Faculty Papers

The interstitial fluids in tissues are constantly drained into the lymph nodes (LNs) as lymph through afferent lymphatic vessels and from LNs into the blood through efferent lymphatics. LNs are strategically positioned and have the appropriate cellular composition to serve as sites of adaptive immune initiation against invading pathogens. However, for lymph-borne viruses, which disseminate from the entry site to other tissues through the lymphatic system, immune cells in the draining LN (dLN) also play critical roles in curbing systemic viral dissemination during primary and secondary infections. Lymph-borne viruses in tissues can be transported to dLNs as free virions in …

Stat5b Mutations In Myeloid Neoplasms Differ By Disease Subtypes But Characterize A Subset Of Chronic Myeloid Neoplasms With Eosinophilia And/Or Basophilia, C Cameron Yin, Wayne Tam, Serena M Walker, Amandeep Kaur, Madhu M Ouseph, Wei Xie, Olga K Weinberg, Peng Li, Zhuang Zuo, Mark J Routbort, Simon Chen, L Jeffrey Medeiros, Tracy I George, Attilio Orazi, Daniel A Arber, Adam Bagg, Robert P Hasserjian, Sa A Wang

Faculty, Staff and Student Publications

STAT5B has been reported as a recurrent mutation in myeloid neoplasms with eosinophilia, but its overall frequency and importance across a spectrum of myeloid neoplasms are largely unknown. We conducted a multicenter study on a series of 82 myeloid neoplasms with STAT5B mutations detected by next-generation sequencing. The estimated frequency of STAT5B mutations in myeloid neoplasms was low, <0.5%, but mutations were detected in all categories of such neoplasms, including myelodysplastic syndrome (MDS, 28%), acute myeloid leukemia (AML, 26%), myelodysplastic/myeloproliferative neoplasm (MDS/MPN, 18%), Philadelphia chromosome-negative classic MPN (12%), systemic mastocytosis (1%), and, with a notably high frequency, chronic eosinophilic leukemia, not otherwise specified (CEL-NOS, 15%). STAT5B mutations occurred preferentially in the SH2 domain (95%), involved 12 different codons, with the N642H hotspot being the most common (78%). Co-mutations were present in all cases and clonal hierarchy analysis showed that STAT5B mutations tended to be subclonal in AML, MPN, and MDS, but frequently dominant/co-dominant in CEL-NOS (83%), followed by MDS/MPN (40%). Across the group, eosinophilia and/or basophilia were common (41%), frequently observed in cases in which STAT5B mutations were detected at initial diagnosis (P<0.0001), with a high variant allele frequency (median 42.5%, P=0.0001), as a dominant/ co-dominant clone (P<0.0001), involving the canonical N642H (P=0.0607), and associated with fewer co-mutations (P=0.0009). Our data show that the characteristics and importance of a STAT5B mutation differ among myeloid neoplasms, but if present as a dominant mutation and detected at initial diagnosis, it appears to be a driver mutation in a subgroup of chronic myeloid neoplasms, preferentially promoting a proliferation of eosinophils and basophils.

Immune Infiltration At The Primary Tumor Is Associated With Clinical Outcome Of Patients With Extranodal Extension Of Lymph Node Metastasis In Oral Cancer, Chieko Michikawa, Frederico O Gleber-Netto, Curtis R Pickering, Xiayu Rao, Jing Wang, Andrew G Sikora, Jeffrey N Myers, Mitchell J Frederick

Faculty, Staff and Student Publications

Background: Extranodal extension (ENE) of lymph node metastasis is one of the most reliable prognostic indicators for patients with locally advanced oral cancer. Although multiple reports have found a close relationship between immune infiltration of tumors and patient clinical outcomes, its association with ENE is unknown.

Methods: We identified 234 human papillomavirus-negative (HPV-) oral cavity squamous cell carcinoma (OSCC) patients in The Cancer Genome Atlas and investigated the immune infiltration profiles of primary tumors and their association with survival.

Results: Hierarchical clustering analysis clearly classified the overall immune infiltration status in OSCC into high immune or low immune groups. The …

A Phase 1/2 Study Of Pepinemab In Children, Adolescents, Or Young Adults With Recurrent Or Refractory Solid Tumors: A Children’S Oncology Group Consortium Report (Advl1614), Emily Greengard, Robin Williams, Branden Moriarity, Xiaowei Liu, Charles G Minard, Joel M Reid, Terrence Fisher, Elizabeth Evans, Desa Rae Pastore, Maurice Zauderer, Stephan Voss, Elizabeth Fox, Brenda J Weigel

Faculty, Staff and Students Publications

PURPOSE: Pepinemab, a humanized IgG4 monoclonal antibody, targets the SEMA4D (CD100) antigen to inhibit binding to its high-affinity receptors (plexin B1/PLXNB1, plexin B2/PLXNB2) and low-affinity receptor (CD72). SEMA4D blockade leads to increased cytotoxic T-cell infiltration, delayed tumor growth, and durable tumor rejection in murine tumor models. Pepinemab was well tolerated and improved T cell infiltration in clinical studies in adults with refractory tumors. SEMA4D was identified as a strong candidate proto-oncogene in a model of osteosarcoma. Based on these preclinical and clinical data, we conducted a phase 1/2 study to determine the recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics, and …

A Multicenter Study Of Venetoclax-Based Treatment For Patients With Richter Transformation Of Chronic Lymphocytic Leukemia, Paul J Hampel, Mahesh Swaminathan, Kerry A Rogers, Erin M Parry, Jan A Burger, Matthew S Davids, Wei Ding, Alessandra Ferrajoli, Jonathan M Hyak, Nitin Jain, Saad S Kenderian, Yucai Wang, William G Wierda, Jennifer A Woyach, Sameer A Parikh, Philip A Thompson

Faculty, Staff and Student Publications

Patients with chronic lymphocytic leukemia (CLL) who develop Richter transformation (RT) have a poor prognosis when treated with chemoimmunotherapy regimens used for de novo diffuse large B-cell lymphoma. Venetoclax, a BCL2 inhibitor, has single-agent efficacy in patients with RT and is potentially synergistic with chemoimmunotherapy. In this multicenter, retrospective study, we evaluated 62 patients with RT who received venetoclax-based treatment outside of a clinical trial, in combination with a Bruton tyrosine kinase inhibitor (BTKi; n=28), rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=13), or intensive chemoimmunotherapy other than R-CHOP (n=21). The best overall and complete response rates were 36%/25%, 54%/46%, and …

Astrocytic Slc4a4 Regulates Blood-Brain Barrier Integrity In Healthy And Stroke Brains Via A Ccl2-Ccr2 Pathway And No Dysregulation, Qi Ye, Juyeon Jo, Chih-Yen Wang, Heavin Oh, Jiangshan Zhan, Tiffany J Choy, Kyoung In Kim, Angelo D'Alessandro, Yana K Reshetnyak, Sung Yun Jung, Zheng Chen, Sean P Marrelli, Hyun Kyoung Lee

Faculty, Staff and Student Publications

Astrocytes play vital roles in blood-brain barrier (BBB) maintenance, yet how they support BBB integrity under normal or pathological conditions remains poorly defined. Recent evidence suggests that ion homeostasis is a cellular mechanism important for BBB integrity. In the current study, we investigated the function of an astrocyte-specific pH regulator, Slc4a4, in BBB maintenance and repair. We show that astrocytic Slc4a4 is required for normal astrocyte morphological complexity and BBB function. Multi-omics analyses identified increased astrocytic secretion of CCL2 coupled with dysregulated arginine-NO metabolism after Slc4a4 deletion. Using a model of ischemic stroke, we found that loss of Slc4a4 exacerbates …

Profiling The Activity Of The Para-Caspase Malt1 In B-Cell Acute Lymphoblastic Leukemia For Potential Targeted Therapeutic Application, Firas M Safa, Terri Rasmussen, Lorena Fontan, Min Xia, Ari Melnick, Adrian Wiestner, Patricia Lobelle-Rich, Jan A Burger, Yara Mouawad, Hana Safah, Erik K Flemington, Nakhle S Saba

Faculty, Staff and Student Publications

B-cell acute lymphoblastic leukemia (B-ALL) remains a hard-to-treat disease with a poor prognosis in adults. Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a para-caspase required for B-cell receptor (BCR)-mediated NF-κB activation. Inhibition of MALT1 in preclinical models has proven efficacious in many B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma and diffuse large B-cell lymphoma. We sought to examine the role of MALT1 in B-ALL and determine the biological consequences of its inhibition. Targeting MALT1 with both Z-VRPR-fmk and MI-2 efficiently kills B-ALL cells independent of the cell-of-origin (pro, pre, mature) or the presence of the Philadelphia …

Proteomics For Optimizing Therapy In Acute Myeloid Leukemia: Venetoclax Plus Hypomethylating Agents Versus Conventional Chemotherapy, Eduardo Sabino De Camargo Magalhães, Stefan Edward Hubner, Brandon Douglas Brown, Yihua Qiu, Steven Mitchell Kornblau

Faculty, Staff and Student Publications

The use of Hypomethylating agents combined with Venetoclax (VH) for the treatment of Acute Myeloid Leukemia (AML) has greatly improved outcomes in recent years. However not all patients benefit from the VH regimen and a way to rationally select between VH and Conventional Chemotherapy (CC) for individual AML patients is needed. Here, we developed a proteomic-based triaging strategy using Reverse-phase Protein Arrays (RPPA) to optimize therapy selection. We evaluated the expression of 411 proteins in 810 newly diagnosed adult AML patients, identifying 109 prognostic proteins, that divided into five patient expression profiles, which are useful for optimizing therapy selection. Furthermore, …

Altered Platelet-Megakaryocyte Endocytosis And Trafficking Of Albumin And Fibrinogen In Runx1 Haplodeficiency, Fabiola Del Carpio-Cano, Guangfen Mao, Lawrence E. Goldfinger, Jeremy Wurtzel, Liying Guan, Mohammad Afaque Alam, Kiwon Lee, Mortimer Poncz, A. Koneti Rao

Cardeza Foundation for Hematologic Research

Platelet α-granules have numerous proteins, some synthesized by megakaryocytes (MK) and others not synthesized but incorporated by endocytosis, an incompletely understood process in platelets/MK. Germ line RUNX1 haplodeficiency, referred to as familial platelet defect with predisposition to myeloid malignancies (FPDMMs), is associated with thrombocytopenia, platelet dysfunction, and granule deficiencies. In previous studies, we found that platelet albumin, fibrinogen, and immunoglobulin G (IgG) were decreased in a patient with FPDMM. We now show that platelet endocytosis of fluorescent-labeled albumin, fibrinogen, and IgG is decreased in the patient and his daughter with FPDMM. In megakaryocytic human erythroleukemia (HEL) cells, small interfering RNA …

Effect Of Aspirin Versus Low-Molecular-Weight Heparin Thromboprophylaxis On Medication Satisfaction And Out-Of-Pocket Costs: A Secondary Analysis Of A Randomized Clinical Trial, Nathan N O'Hara, Katherine P Frey, Deborah M Stein, Joseph F Levy, Gerard P Slobogean, Renan Castillo, Reza Firoozabadi, Madhav A Karunakar, Joshua L Gary, William T Obremskey, Rachel B Seymour, Joseph Cuschieri, C Daniel Mullins, Robert V O'Toole, Metrc

Faculty, Staff and Student Publications

BACKGROUND: Current guidelines recommend low-molecular-weight heparin for thromboprophylaxis after orthopaedic trauma. However, recent evidence suggests that aspirin is similar in efficacy and safety. To understand patients' experiences with these medications, we compared patients' satisfaction and out-of-pocket costs after thromboprophylaxis with aspirin versus low-molecular-weight heparin.

METHODS: This study was a secondary analysis of the PREVENTion of CLots in Orthopaedic Trauma (PREVENT CLOT) trial, conducted at 21 trauma centers in the U.S. and Canada. We included adult patients with an operatively treated extremity fracture or a pelvic or acetabular fracture. Patients were randomly assigned to receive 30 mg of low-molecular-weight heparin (enoxaparin) …

Dynamic Imaging Of Blood Coagulation Within The Hematoma Of Patients With Acute Hemorrhagic Stroke, Muhammad E Haque, Seth B Boren, James Mills, Kerry G Schneider, Maria Parekh, Stuart M Fraser, Ivo Bach, Praveen Hariharan, Pamela J Zelnick, Felix S Guerra Castanon, Asim Naveed, Muhammad Tariq, Octavio D Arevalo, Khader M Hasan, Miguel Escobar, Xiurong Zhao, Clark Sitton, Ponnada A Narayana, James C Grotta, Jaroslaw Aronowski, Sean I Savitz

Faculty, Staff and Student Publications

BACKGROUND: The dynamics of blood clot (combination of Hb [hemoglobin], fibrin, and a higher concentration of aggregated red blood cells) formation within the hematoma of an intracerebral hemorrhage is not well understood. A quantitative neuroimaging method of localized coagulated blood volume/distribution within the hematoma might improve clinical decision-making.

METHODS: The deoxyhemoglobin of aggregated red blood cells within extravasated blood exhibits a higher magnetic susceptibility due to unpaired heme iron electrons. We propose that coagulated blood, with higher aggregated red blood cell content, will exhibit (1) a higher positive susceptibility than noncoagulated blood and (2) increase in fibrin polymerization-restricted localized diffusion, …

Recurrent Nontraumatic Subgaleal Hematomas In A Pediatric Patient With Sickle Cell Disease, Irtiza N Sheikh, Olayinka Okeleji, Rabya Afzal, Eliana Bonfante, Monica Kodakandla, Neethu M Menon

Faculty, Staff and Student Publications

Spontaneous subgaleal hematoma in pediatric patients with sickle cell disease (SCD) is a rare occurrence that can present with symptoms mimicking ischemic stroke, a known complication of SCD. However, unlike ischemic stroke, subgaleal hematoma is nonlethal and can be managed conservatively without major sequelae. Here, we present the case of an adolescent with SCD who presented with 2 episodes of subgaleal and epidural hematomas, 2 years apart. The latter episode occurred while on crizanlizumab, an anti-P-selectin antibody, approved for use in SCD in 2019 to reduce the number of acute pain crises. We demonstrate the diagnosis of subgaleal hematoma and …

The Remission Status Of Aml Patients After Allo-Hct Is Associated With A Distinct Single-Cell Bone Marrow T-Cell Signature, Anna Mathioudaki, Xizhe Wang, David Sedloev, Richard Huth, Aryan Kamal, Michael Hundemer, Yi Liu, Spyridoula Vasileiou, Premal Lulla, Carsten Müller-Tidow, Peter Dreger, Thomas Luft, Tim Sauer, Michael Schmitt, Judith B Zaugg, Caroline Pabst

Faculty, Staff and Students Publications

Acute myeloid leukemia (AML) is a hematologic malignancy for which allogeneic hematopoietic cell transplantation (allo-HCT) often remains the only curative therapeutic approach. However, incapability of T cells to recognize and eliminate residual leukemia stem cells might lead to an insufficient graft-versus-leukemia (GVL) effect and relapse. Here, we performed single-cell RNA-sequencing (scRNA-seq) on bone marrow (BM) T lymphocytes and CD34+ cells of 6 patients with AML 100 days after allo-HCT to identify T-cell signatures associated with either imminent relapse (REL) or durable complete remission (CR). We observed a higher frequency of cytotoxic CD8+ effector and gamma delta (γδ) T cells in …

Hematopoietic Stem Cells With Granulo-Monocytic Differentiation State Overcome Venetoclax Sensitivity In Patients With Myelodysplastic Syndromes, Juan Jose Rodriguez-Sevilla, Irene Ganan-Gomez, Feiyang Ma, Kelly Chien, Monica Del Rey, Sanam Loghavi, Guillermo Montalban-Bravo, Vera Adema, Bethany Wildeman, Rashmi Kanagal-Shamanna, Alexandre Bazinet, Helen T Chifotides, Natthakan Thongon, Xavier Calvo, Jesús María Hernández-Rivas, Maria Díez-Campelo, Guillermo Garcia-Manero, Simona Colla

Faculty, Staff and Student Publications

The molecular mechanisms of venetoclax-based therapy failure in patients with acute myeloid leukemia were recently clarified, but the mechanisms by which patients with myelodysplastic syndromes (MDS) acquire secondary resistance to venetoclax after an initial response remain to be elucidated. Here, we show an expansion of MDS hematopoietic stem cells (HSCs) with a granulo-monocytic-biased transcriptional differentiation state in MDS patients who initially responded to venetoclax but eventually relapsed. While MDS HSCs in an undifferentiated cellular state are sensitive to venetoclax treatment, differentiation towards a granulo-monocytic-biased transcriptional state, through the acquisition or expansion of clones with STAG2 or RUNX1 mutations, affects HSCs' …

The Lymphoma Epidemiology Of Outcomes Cohort Study: Design, Baseline Characteristics, And Early Outcomes, James R Cerhan, Matthew J Maurer, Brian K Link, Andrew L Feldman, Thomas M Habermann, David L Jaye, W Richard Burack, Timothy J Mcdonnell, Francisco Vega, Jennifer R Chapman, Sergei Syrbu, Kiran R Vij, Giorgio Inghirami, John P Leonard, Leon Bernal-Mizrachi, Umar Farooq, Thomas E Witzig, George J Weiner, Yucai Wang, Juan P Alderuccio, Susan L Slager, Melissa C Larson, Shaun M Riska, Brianna J Gysbers, Julianne J Lunde, Tanner W Reicks, Amy A Ayers, Colin B O'Leary, Kathleen J Yost, Hongfang Liu, Grzegorz S Nowakowski, Jia Ruan, Dai Chihara, Jean L Koff, Carla Casulo, Carrie A Thompson, Jonathon B Cohen, Brad S Kahl, Loretta J Nastoupil, Izidore S Lossos, Jonathan W Friedberg, Peter Martin, Christopher R Flowers

Faculty, Staff and Student Publications

To address the current and long-term unmet health needs of the growing population of non-Hodgkin lymphoma (NHL) patients, we established the Lymphoma Epidemiology of Outcomes (LEO) cohort study (NCT02736357; https://leocohort.org/). A total of 7735 newly diagnosed patients aged 18 years and older with NHL were prospectively enrolled from 7/1/2015 to 5/31/2020 at 8 academic centers in the United States. The median age at diagnosis was 62 years (range, 18-99). Participants came from 49 US states and included 538 Black/African-Americans (AA), 822 Hispanics (regardless of race), 3386 women, 716 age <40 >years, and 1513 rural residents. At study baseline, we abstracted clinical, …

Safety, Efficacy And Determinants Of Response Of Allogeneic Cd19-Specific Car-Nk Cells In Cd19+ B Cell Tumors: A Phase 1/2 Trial, David Marin, Ye Li, Rafet Basar, Hind Rafei, May Daher, Jinzhuang Dou, Vakul Mohanty, Merve Dede, Yago Nieto, Nadima Uprety, Sunil Acharya, Enli Liu, Jeffrey Wilson, Pinaki Banerjee, Homer A Macapinlac, Christina Ganesh, Peter F Thall, Roland Bassett, Mariam Ammari, Sheetal Rao, Kai Cao, Mayra Shanley, Mecit Kaplan, Chitra Hosing, Partow Kebriaei, Loretta J Nastoupil, Christopher R Flowers, Sadie Mae Moseley, Paul Lin, Sonny Ang, Uday R Popat, Muzaffar H Qazilbash, Richard E Champlin, Ken Chen, Elizabeth J Shpall, Katayoun Rezvani

Faculty, Staff and Student Publications

There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted a phase 1/2 trial of cord blood-derived natural killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19+ B cell malignancies. The primary objectives were safety and efficacy, defined as day 30 overall response (OR). Secondary objectives included day 100 response, progression-free survival, overall survival and CAR19/IL-15 NK cell persistence. No notable toxicities such as cytokine release syndrome, neurotoxicity or graft-versus-host disease were observed. The day 30 and day 100 OR rates were …

Gamma Delta T Cells In Acute Myeloid Leukemia: Biology And Emerging Therapeutic Strategies, Adishwar Rao, Akriti Agrawal, Gautam Borthakur, Venkata Lokesh Battula, Abhishek Maiti

Faculty, Staff and Student Publications

γδ T cells play an important role in disease control in acute myeloid leukemia (AML) and have become an emerging area of therapeutic interest. These cells represent a minor population of T lymphocytes with intrinsic abilities to recognize antigens in a major histocompatibility complex-independent manner and functionally straddle the innate and adaptive immunity interface. AML shows high expression of phosphoantigens and UL-16 binding proteins that activate the Vδ2 and Vδ1 subtypes of γδ T cells, respectively, leading to γδ T cell-mediated cytotoxicity. Insights from murine models and clinical data in humans show improved overall survival, leukemia-free survival, reduced risk of …

A Phase 1/2 Study Of Mini-Hyper-Cvd Plus Venetoclax In Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia, Nicholas J Short, Elias Jabbour, Nitin Jain, Jayastu Senapati, Lewis Nasr, Fadi G Haddad, Zhenhua Li, Yu-Chih Hsiao, Jun J Yang, Naveen Pemmaraju, Maro Ohanian, William G Wierda, Guillermo Montalban-Bravo, Gautam Borthakur, Lina Han, Lianchun Xiao, Xuelin Huang, Regina Abramova, Min Zhao, Rebecca Garris, Marina Konopleva, Farhad Ravandi, Hagop Kantarjian

Faculty, Staff and Student Publications

Preclinical studies suggest that Bcl-2 inhibition with venetoclax has antileukemic activity in acute lymphoblastic leukemia (ALL) and may synergize with conventional chemotherapy. We designed a phase 1/2 clinical trial to evaluate the safety and efficacy of low-intensity chemotherapy in combination with venetoclax in adults with relapsed or refractory ALL. Patients received the mini-hyper-CVD regimen (dose-attenuated hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with methotrexate and cytarabine) in combination with venetoclax (200 mg or 400 mg daily) on days 1 to 14 in cycle 1 and on days 1 to 7 in consolidation cycles. Twenty-two patients were treated. The median number of …

Incidence And Predictors Of Post-Thrombotic Syndrome In Patients With Proximal Dvt In A Real-World Setting: Findings From The Garfield-Vte Registry, Paolo Prandoni, Sylvia Haas, Meg E Fluharty, Sebastian Schellong, Harry Gibbs, Eric Tse, Marc Carrier, Barry Jacobson, Hugo Ten Cate, Elizaveta Panchenko, Peter Verhamme, Karen Pieper, Gloria Kayani, Lord A Kakkar

Faculty, Staff and Student Publications

Although substantial progress has been made in the pathophysiology and management of the post-thrombotic syndrome (PTS), several aspects still need clarification. Among them, the incidence and severity of PTS in the real world, the risk factors for its development, the value of patient's self-evaluation, and the ability to identify patients at risk for severe PTS. Eligible participants (n = 1107) with proximal deep-vein thrombosis (DVT) from the global GARFIELD-VTE registry underwent conventional physician's evaluation for PTS 36 months after diagnosis of their DVT using the Villalta score. In addition, 856 patients completed a Villalta questionnaire at 24 months. Variable selection …