104 results on '"David F. Claxton"'
Search Results
2. A novel clinically relevant graft-versus-leukemia model in humanized mice
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Shin Mineishi, Pan Zheng, Robert F. Paulson, W. Christopher Ehmann, Hiroko Shike, Bei Jia, K. Sandeep Prabhu, Todd D. Schell, Yi Zhang, Chenchen Zhao, Michael G. Bayerl, Hong Zheng, David F. Claxton, and Leonard D. Shultz
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0301 basic medicine ,medicine.medical_treatment ,Immunology ,Graft vs Leukemia Effect ,Mice, SCID ,Human leukocyte antigen ,Hematopoietic stem cell transplantation ,Biology ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Mice, Inbred NOD ,Granulocyte Colony-Stimulating Factor ,medicine ,Animals ,Humans ,Transplantation, Homologous ,Immunology and Allergy ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Cell Biology ,Hematopoietic Stem Cells ,medicine.disease ,Disease Models, Animal ,Leukemia, Myeloid, Acute ,Leukemia ,Haematopoiesis ,surgical procedures, operative ,030104 developmental biology ,030220 oncology & carcinogenesis ,Humanized mouse ,Cancer research ,Stem cell - Abstract
The prognosis for acute myeloid leukemia (AML) relapse post allogeneic hematopoietic stem cell transplantation (alloSCT) is dismal. Novel effective treatment is urgently needed. Clinical benefit of alloSCT greatly relies on the graft-versus-leukemia (GVL) effect. The mechanisms that mediate immune escape of leukemia (thus causing GVL failure) remain poorly understood. Studies of human GVL have been hindered by the lack of optimal clinically relevant models. Here, using our large, longitudinal clinical tissue bank that include AML cells and G-CSF mobilized donor hematopoietic stem cells (HSCs), we successfully established a novel GVL model in humanized mice. Donor HSCs were injected into immune-deficient NOD-Cg-PrkdcscidIL2rgtm1Wjl/SzJ (NSG) mice to build humanized mice. Immune reconstitution in these mice recapitulated some clinical scenario in the patient who received the corresponding HSCs. Allogeneic but HLA partially matched patient-derived AML cells were successfully engrafted in these humanized mice. Importantly, we observed a significantly reduced (yet incomplete elimination of) leukemia growth in humanized mice compared with that in control NSG mice, demonstrating a functional (but defective) GVL effect. Thus, for the first time, we established a novel humanized mouse model that can be used for studying human GVL responses against human AML cells in vivo. This novel clinically relevant model provides a valuable platform for investigating the mechanisms of human GVL and development of effective leukemia treatments.
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- 2021
3. Post-transplant cyclophosphamide alters immune signatures and leads to impaired T cell reconstitution in allogeneic hematopoietic stem cell transplant
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Chenchen Zhao, Matthew Bartock, Bei Jia, Neal Shah, David F. Claxton, Baldeep Wirk, Kevin L. Rakszawski, Myles S. Nickolich, Seema G. Naik, Witold B. Rybka, W Christopher C. Ehmann, Raymond J. Hohl, Jessica Valentin, Michelle Bernas-Peterson, Emily M. Gerber, Michele Zimmerman, Joseph A. Mierski, Shin Mineishi, and Hong Zheng
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Cancer Research ,Oncology ,Programmed Cell Death 1 Receptor ,Hematopoietic Stem Cell Transplantation ,Graft vs Host Disease ,Humans ,Hematology ,CD8-Positive T-Lymphocytes ,Cyclophosphamide ,Molecular Biology - Abstract
Despite the increased usage of post-transplant cyclophosphamide (PTCy) in allogeneic hematopoietic stem cell transplantation (allo-HSCT), our knowledge of immune reconstitution post-allo-HSCT in the setting of PTCy is limited. Adequate immune reconstitution is the key to a successful transplant. In this study, we aim to investigate the effect of PTCy on the reconstitution of each immune component; more focus was placed on the immunophenotype and functions of T cells. Using blood samples from patients who underwent allo-HSCT under regimens containing PTCy (n = 23) versus those who received no PTCy (n = 14), we examined the impact of PTCy on the post-transplant immune response. We demonstrated a distinct T cell immune signature between PTCy versus non-PTCy group. PTCy significantly delayed T cell reconstitution and affected the T cell subsets by increasing regulatory T cells (Treg) while reducing naïve T cells. In addition, we observed remarkable enhancement of multiple inhibitory receptors (TIGIT, PD-1, TIM-3, CD38, CD39) on both CD4+ and CD8+ T cells on day 30 post-transplantation in patients who received PTCy. Importantly, upregulation of PD-1 on CD8 T cells was persistent through day 180 and these T cells were less functional, manifested by reduced cytokine production upon anti-CD3/CD28 stimulation. Furthermore, we found a significant correlation of T cell immune phenotypes to clinical outcome (disease relapse and GVHD) in patients who received PTCy. Our novel findings provide critical information to understand the mechanism of how PTCy impacts immune reconstitution in allo-HSCT and may subsequently lead to optimization of our clinical practice using this treatment.
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- 2022
4. Interleukin-4 treatment reduces leukemia burden in acute myeloid leukemia
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Fenghua Qian, Brooke E. Arner, Kathleen M. Kelly, Charyguly Annageldiyev, Arati Sharma, David F. Claxton, Robert F. Paulson, and K. Sandeep Prabhu
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PPAR gamma ,Leukemia, Myeloid, Acute ,Mice ,Prostaglandin D2 ,Genetics ,Animals ,Cytokines ,Humans ,Interleukin-4 ,Molecular Biology ,Biochemistry ,Article ,Biotechnology - Abstract
Interleukin-4 (IL-4) is a signature cytokine pivotal in Type 2 helper T cell (Th2) immune response, particularly in allergy and hypersensitivity. Interestingly, IL-4 increases endogenous levels of prostaglandin D(2) (PGD(2)) and its metabolites, Δ(12)-prostaglandin J(2) (Δ(12)-PGJ(2)) and 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)), collectively called cyclopentenone PGs (CyPGs). However, the therapeutic role of IL-4 in hematologic malignancies remains unclear. Here, we employed a murine model of acute myeloid leukemia (AML), where human MLL-AF9 fusion oncoprotein was expressed in hematopoietic progenitor cells, to test the effect of IL-4 treatment in vivo. Daily intraperitoneal treatment with IL-4 at 60 μg/kg/d significantly alleviated the severity of AML, as seen by decreased leukemia-initiating cells (LICs). The effect of IL-4 was mediated, in part, by the enhanced expression of hematopoietic- PGD(2) synthase (H-PGDS) to effect endogenous production of CyPGs, through autocrine and paracrine signaling mechanisms. Similar results were seen with patient-derived AML cells cultured ex vivo with IL-4. Use of GW9662, a peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, suggested endogenous CyPGs-PPARγ axis mediated p53-dependent apoptosis of LICs by IL-4. Taken together, our results reveal a beneficial role of IL-4 treatment in AML suggesting a potential therapeutic regimen worthy of clinical trials in AML patients.
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- 2022
5. Comparison of CALGB 10403 (Alliance) and COG AALL0232 toxicity results in young adults with acute lymphoblastic leukemia
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Martin S. Tallman, Mignon L. Loh, Naomi J. Winick, Kristina Laumann, Selina M. Luger, Jennifer L. McNeer, Richard Stone, David F. Claxton, Michaela Liedtke, Kristin Coffan, Wendy Stock, Frederick R. Appelbaum, Eric Larsen, Elizabeth A. Raetz, William L. Carroll, Anjali S. Advani, Jun Yin, Stephen P. Hunger, Matthew C. Foster, Zhiguo Chen, Harry P. Erba, Meenakshi Devidas, and Richard A. Larson
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Adult ,medicine.medical_specialty ,Adolescent ,Clinical Trials and Observations ,business.industry ,Mortality rate ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Survival Rate ,Young Adult ,Regimen ,Cog ,Internal medicine ,Humans ,Medicine ,Prospective Studies ,Young adult ,Child ,business ,Prospective cohort study ,Adverse effect ,Body mass index ,Febrile neutropenia ,Aged - Abstract
Adolescents and young adults (AYAs) with acute lymphoblastic leukemia have improved outcomes when treated with pediatric-inspired regimens. CALGB 10403 was the largest prospective study to evaluate the feasibility of using a pediatric regimen in AYAs with acute lymphoblastic leukemia up to 40 years of age. This article presents the toxicity events observed in the CALGB 10403 study and compares these toxicities vs those observed among AYAs treated on the same arm of the companion Children’s Oncology Group (COG) AALL0232 study. Toxicities in CALGB 10403 were similar to those observed in COG AALL0232. Some grade 3 to 4 adverse events were more often reported in CALGB 10403 compared with COG AALL0232 (hyperglycemia, hyperbilirubinemia, transaminase elevation, and febrile neutropenia). Adverse events correlated with body mass index ≥30 kg/m2 and some with increasing age. The mortality rate in CALGB 10403 was low (4%) and similar to that in the COG AALL0232 trial. A caveat to this analysis is that only 39% of CALGB 10403 patients completed all planned protocol treatment. In COG AALL0232, although 74% of patients aged
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- 2021
6. Harnessing the power of sphingolipids: Prospects for acute myeloid leukemia
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Johnson Ung, Su-Fern Tan, Todd E. Fox, Jeremy J.P. Shaw, Luke R. Vass, Pedro Costa-Pinheiro, Francine E. Garrett-Bakelman, Michael K. Keng, Arati Sharma, David F. Claxton, Ross L. Levine, Martin S. Tallman, Myles C. Cabot, Mark Kester, David J. Feith, and Thomas P. Loughran
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Leukemia, Myeloid, Acute ,Sphingolipids ,Oncology ,Humans ,Hematology ,Ceramides ,Aged ,Signal Transduction - Abstract
Acute myeloid leukemia (AML) is an aggressive, heterogenous malignancy characterized by clonal expansion of bone marrow-derived myeloid progenitor cells. While our current understanding of the molecular and genomic landscape of AML has evolved dramatically and opened avenues for molecularly targeted therapeutics to improve upon standard intensive induction chemotherapy, curative treatments are elusive, particularly in older patients. Responses to current AML treatments are transient and incomplete, necessitating the development of novel treatment strategies to improve outcomes. To this end, harnessing the power of bioactive sphingolipids to treat cancer shows great promise. Sphingolipids are involved in many hallmarks of cancer of paramount importance in AML. Leukemic blast survival is influenced by cellular levels of ceramide, a bona fide pro-death molecule, and its conversion to signaling molecules such as sphingosine-1-phosphate and glycosphingolipids. Preclinical studies demonstrate the efficacy of therapeutics that target dysregulated sphingolipid metabolism as well as their combinatorial synergy with clinically-relevant therapeutics. Thus, increased understanding of sphingolipid dysregulation may be exploited to improve AML patient care and outcomes. This review summarizes the current knowledge of dysregulated sphingolipid metabolism in AML, evaluates how pro-survival sphingolipids promote AML pathogenesis, and discusses the therapeutic potential of targeting these dysregulated sphingolipid pathways.
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- 2022
7. Rapid Donor Identification Improves Survival in High-Risk First-Remission Patients With Acute Myeloid Leukemia
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R.L. Bayer, Jerald P. Radich, Maria Brown, M. Lynn Savoie, Bruno C. Medeiros, Harry P. Erba, John M. Pagel, Selina M. Luger, Stephen A. Strickland, Sanjay R. Mohan, Guillermo Garcia-Manero, Dennis L. Confer, David A. Rizzieri, Stephen R. Spellman, Richard Stone, Geoffrey L. Uy, David F. Claxton, Mark R. Litzow, Min Fang, Frederick R. Appelbaum, Megan Othus, Mikkael A. Sekeres, Jeffrey Chell, Bayard L. Powell, James Essell, Guido Marcucci, Anna Moseley, Richard A. Larson, and Tara L. Lin
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Adult ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Myeloid ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,ORIGINAL CONTRIBUTIONS ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Prospective Studies ,Prospective cohort study ,Oncology (nursing) ,business.industry ,Health Policy ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Cytogenetics ,First remission ,Myeloid leukemia ,Middle Aged ,medicine.disease ,Transplantation ,Leukemia, Myeloid, Acute ,Leukemia ,surgical procedures, operative ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,business - Abstract
PURPOSE: Patients with acute myeloid leukemia with high-risk cytogenetics in first complete remission (CR1) achieve better outcomes if they undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy alone. However, only approximately 40% of such patients typically proceed to HCT. METHODS: We used a prospective organized approach to rapidly identify donors to improve the allogeneic HCT rate in adults with high-risk acute myeloid leukemia in CR1. Newly diagnosed patients had cytogenetics obtained at enrollment, and those with high-risk cytogenetics underwent expedited HLA typing and were encouraged to be referred for consultation with a transplantation team with the goal of conducting an allogeneic HCT in CR1. RESULTS: Of 738 eligible patients (median age, 49 years; range, 18-60 years of age), 159 (22%) had high-risk cytogenetics and 107 of these patients (67%) achieved CR1. Seventy (65%) of the high-risk patients underwent transplantation in CR1 ( P < .001 compared with the historical rate of 40%). Median time to HCT from CR1 was 77 days (range, 20-356 days). In landmark analysis, overall survival (OS) among patients who underwent transplantation was significantly better compared with that of patients who did not undergo transplantation (2-year OS, 48% v 35%, respectively [ P = .031]). Median relapse-free survival after transplantation in the high-risk cohort who underwent transplantation in CR1 (n = 70) was 11.5 months (range, 4-47 months), and median OS after transplantation was 14 months (range, 4-44 months). CONCLUSION: Early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donor led to a CR1 transplantation rate of 65% in the high-risk group, which, in turn, led to an improvement in OS when compared with the OS of patients who did not undergo transplantation.
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- 2020
8. Multi‐dimensional analysis identifies an immune signature predicting response to decitabine treatment in elderly patients with AML
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Jeff Sivik, Chenchen Zhao, Natthapol Songdej, Todd D. Schell, Witold B. Rybka, David F. Claxton, Seema Naik, Hong Zheng, Ming Wang, W. Christopher Ehmann, Bei Jia, Raymond J. Hohl, Hui Zeng, and Shin Mineishi
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Oncology ,Male ,medicine.medical_specialty ,immune signature ,Decitabine ,CD38 ,CD8-Positive T-Lymphocytes ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,T‐cell exhaustion ,Downregulation and upregulation ,AML ,Internal medicine ,medicine ,Biomarkers, Tumor ,Cytotoxic T cell ,Humans ,Aged ,Cell growth ,business.industry ,Hematology ,biochemical phenomena, metabolism, and nutrition ,Middle Aged ,Phenotype ,Haematological Malignancy – Clinical ,Leukemia, Myeloid, Acute ,030220 oncology & carcinogenesis ,DNA methylation ,bacteria ,Female ,business ,030215 immunology ,medicine.drug ,Research Paper - Abstract
Summary Decitabine is a DNA‐hypomethylating agent that has been widely applied for the treatment of acute myeloid leukaemia (AML) patients who are elderly or unfit for intensive therapy. Although effective, the complete response rate to decitabine is only around 30% and the overall survival remains poor. Emerging data support that regulation of DNA methylation is critical to control immune cell development, differentiation and activation. We hypothesize that defining how decitabine influences the immune responses in AML will facilitate the development of novel immune‐based leukaemia therapeutics. Here, we performed phenotypic and functional immune analysis on clinical samples from AML patients receiving decitabine treatment and demonstrated a significant impact of decitabine on the immune system. T‐cell expression of inhibitory molecules was upregulated and the ability of CD8 T cells to produce cytokines was decreased upon decitabine treatment. Importantly, in an unbiased comprehensive analysis, we identified a unique immune signature containing a cluster of key immune markers that clearly separate patients who achieved complete remission after decitabine from those who failed to do so. Therefore, this immune signature has a strong predictive value for clinical response. Collectively, our study suggests that immune‐based analyses may predict clinical response to decitabine and provide a therapeutic strategy to improve the treatment of AML.
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- 2019
9. Alterations in sphingolipid composition and mitochondrial bioenergetics represent synergistic therapeutic vulnerabilities linked to multidrug resistance in leukemia
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Miki Kassai, Su-Fern Tan, Todd E. Fox, Hannah S Coalson, Li-Pin Kao, Kelsey L. McLaughlin, David J. Feith, Margaret Nelson, Mark Kester, Myles C. Cabot, David F. Claxton, Thomas P. Loughran, Kelsey H. Fisher-Wellman, and James T Hagen
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Sphingolipids ,Leukemia ,Bioenergetics ,Daunorubicin ,Cytarabine ,HL-60 Cells ,Biology ,medicine.disease ,Sphingolipid ,Biochemistry ,Article ,Drug Resistance, Multiple ,Oxidative Phosphorylation ,Mitochondria ,Multiple drug resistance ,Drug Resistance, Neoplasm ,Vincristine ,medicine ,Cancer research ,Genetics ,Humans ,Molecular Biology ,Biotechnology - Abstract
Modifications in sphingolipid (SL) metabolism and mitochondrial bioenergetics are key factors implicated in cancer cell response to chemotherapy, including chemotherapy resistance. Vinca alkaloids such as vincristine (VCR), widely used in cancer treatment, are no exception, as their beneficial actions are often supplanted by resistance. In the present work we utilized HL-60 human leukemia cells and a VCR-resistant counterpart, HL-60/VCR, as a model to determine potential interplay between SL metabolism and mitochondrial bioenergetics supportive of multidrug resistance (MDR). Relative to wild-type cells, HL-60/VCR presented with global alterations in SL composition, typified by upregulated expression of sphingosine kinase (SPHK1), which catalyzes formation of sphingosine 1-phosphate (S1P), glucosylceramide synthase (GCS), which catalyzes formation of glucosylceramides (GC), and acid ceramidase, responsible for ceramide hydrolysis. In support of these changes, VCR resistance was also characterized by increases in S1P, several molecular species of ceramide and GC, and changes in sphingomyelin (SM) molecular species. With respect to mitochondria, despite increased basal respiration in HL-60/VCR cells, direct interrogation of the mitochondrial network revealed intrinsic respiratory complex insufficiency, largely localized to complex I (CI). Importantly, forced ceramide accumulation in wild-type cells phenocopied the respiratory insufficiency observed in HL-60/VCR, and co-targeting SL metabolism and CI induced synergistic cytotoxicity in HL-60/VCR cells, as well as in other MDR leukemia models. Together, these data underscore the intimate connection between cellular sphingolipids and mitochondrial metabolism and suggest that pharmacological intervention across both pathways may represent a novel treatment strategy against MDR.
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- 2021
10. Acute Myeloid Leukemia Stem Cells: Origin, Characteristics, and Clinical Implications
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Nathaniel A, Long, Upendarrao, Golla, Arati, Sharma, and David F, Claxton
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Leukemia, Myeloid, Acute ,Neoplastic Stem Cells ,Humans ,Hematopoietic Stem Cells - Abstract
The stem cells of acute myeloid leukemia (AML) are the malignancy initiating cells whose survival ultimately drives growth of these lethal diseases. Here we review leukemia stem cell (LSC) biology, particularly as it relates to the very heterogeneous nature of AML and to its high disease relapse rate. Leukemia ontogeny is presented, and the defining functional and phenotypic features of LSCs are explored. Surface and metabolic phenotypes of these cells are described, particularly those that allow distinction from features of normal hematopoietic stem cells (HSCs). Opportunities for use of this information for improving therapy for this challenging group of diseases is highlighted, and we explore the clinical needs which may be addressed by emerging LSC data. Finally, we discuss current gaps in the scientific understanding of LSCs.
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- 2021
11. Results of a randomized phase 3 study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid leukemia (SEAMLESS)
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Pau Montesinos, Farhad Ravandi, Martha Arellano, Karen Seiter, Ellin Berman, Jessica K. Altman, Lori J. Maness, Donald P. Quick, Parameswaran Venugopal, Judy H. Chiao, Scott R. Solomon, Rakesh Gaur, Mikkael A. Sekeres, Maria R. Baer, Marc Buyse, Aleksandra Butrym, David A. Rizzieri, Stephen A. Strickland, Stuart L. Goldberg, Tapan M. Kadia, Marc Gautier, David F. Claxton, Gary J. Schiller, Gianluca Gaidano, Kebede H. Begna, Selina M. Luger, Hagop M. Kantarjian, and Xavier Thomas
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Myeloid ,Cancer Research ,medicine.medical_specialty ,Randomization ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,Phases of clinical research ,Decitabine ,sapacitabine ,Acute ,acute myeloid leukemia ,Sapacitabine ,Gastroenterology ,Article ,chemistry.chemical_compound ,Cytosine ,Rare Diseases ,acute myeloid leukemia (AML), decitabine, hypomethylation, sapacitabine, therapy ,Clinical Research ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Oncology & Carcinogenesis ,Cancer ,Aged ,therapy ,Leukemia ,business.industry ,Myelodysplastic syndromes ,Induction chemotherapy ,Evaluation of treatments and therapeutic interventions ,Hematology ,medicine.disease ,humanities ,Regimen ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Oncology ,chemistry ,Hypomethylating agent ,6.1 Pharmaceuticals ,Public Health and Health Services ,Azacitidine ,Arabinonucleosides ,business ,medicine.drug ,hypomethylation - Abstract
BackgroundAcute myeloid leukemia (AML) is fatal in elderly patients who are unfit for standard induction chemotherapy. The objective of this study was to evaluate the survival benefit of administering sapacitabine, an oral nucleoside analogue, in alternating cycles with decitabine, a low-intensity therapy, to elderly patients with newly diagnosed AML.MethodsThis randomized, open-label, phase 3 study (SEAMLESS) was conducted at 87 sites in 11 countries. Patients aged ≥70 years who were not candidates for or chose not to receive standard induction chemotherapy were randomized 1:1 to arm A (decitabine in alternating cycles with sapacitabine) received 1-hour intravenous infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 8 weeks (first cycle and subsequent odd cycles) and sapacitabine 300 mg twice daily on 3 consecutive days per week for 2 weeks every 8 weeks (second cycle and subsequent even cycles) or to control arm C who received 1-hour infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 4 weeks. Prior hypomethylating agent therapy for preexisting myelodysplastic syndromes or myeloproliferative neoplasms was an exclusion criterion. Randomization was stratified by antecedent myelodysplastic syndromes or myeloproliferative neoplasms, white blood cell count (
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- 2021
12. Sphingolipid metabolism determines the therapeutic efficacy of nanoliposomal ceramide in acute myeloid leukemia
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Charyguly Annageldiyev, Nicole R. Keasey, Emily Sullivan, Paul T. Toran, Hong Gang Wang, Regina M. Ondrasik, Su Fern Tan, Andrea L. Cote, Tye G. Deering, Todd E. Fox, David J. Feith, Brian M. Barth, Timothy J Brown, Stephan T. Stern, Mark Kester, David F. Claxton, Thomas P. Loughran, Vasiliki Papakotsi, Arati Sharma, Ross L. Levine, David B. Needle, Junjia Zhu, Sriram S. Shanmugavelandy, Aaron D. Viny, Viola Devine, Weiyuan Wang, and Jason Liao
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0301 basic medicine ,Myeloid ,Treatment outcome ,Ceramides ,Vinblastine ,03 medical and health sciences ,Drug Delivery Systems ,0302 clinical medicine ,hemic and lymphatic diseases ,Humans ,Medicine ,neoplasms ,Drug Carriers ,Sphingolipids ,Nanoliposomal Ceramide ,business.industry ,Extramural ,Myeloid leukemia ,Hematology ,medicine.disease ,Stimulus Report ,Antineoplastic Agents, Phytogenic ,Nanostructures ,carbohydrates (lipids) ,Leukemia, Myeloid, Acute ,Leukemia ,Treatment Outcome ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Liposomes ,Sphingolipid metabolism ,Cancer research ,lipids (amino acids, peptides, and proteins) ,business ,medicine.drug - Abstract
Key Points Distinct sphingolipid metabolism of AML with MDS-related changes defines unique sensitivity to nanoliposomal C6-ceramide. Vinblastine alters sphingolipid metabolism to enhance the sensitivity of AML to nanoliposomal C6-ceramide.
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- 2019
13. Acid ceramidase promotes drug resistance in acute myeloid leukemia through NF-κB-dependent P-glycoprotein upregulation
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Dhimant Desai, Mark R. Conaway, Thomas P. Loughran, Hong Gang Wang, Samy A.F. Morad, Kenichiro Doi, Xin Liu, David J. Feith, Todd E. Fox, Su Fern Tan, Mark Kester, Myles C. Cabot, David F. Claxton, Wendy Dunton, and Shantu Amin
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0301 basic medicine ,Acid Ceramidase ,Drug resistance ,030204 cardiovascular system & hematology ,Biochemistry ,adenosine 5′-triphosphate binding cassette transporter B1 ,0302 clinical medicine ,Endocrinology ,Tandem Mass Spectrometry ,hemic and lymphatic diseases ,Medicine ,multidrug resistance protein 1 ,Research Articles ,P-glycoprotein ,Acute leukemia ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Cytarabine ,NF-kappa B ,Myeloid leukemia ,Flow Cytometry ,drug therapy ,Leukemia, Myeloid, Acute ,medicine.drug ,Daunorubicin ,Cell Survival ,Blotting, Western ,Antineoplastic Agents ,HL-60 Cells ,QD415-436 ,In Vitro Techniques ,Real-Time Polymerase Chain Reaction ,03 medical and health sciences ,Humans ,cancer ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,sphingosine 1-phosphate ,Mitoxantrone ,business.industry ,Lentivirus ,Cell Biology ,030104 developmental biology ,HEK293 Cells ,Drug Resistance, Neoplasm ,biology.protein ,Cancer research ,sphingolipid ,business - Abstract
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. More than half of older AML patients fail to respond to cytotoxic chemotherapy, and most responders relapse with drug-resistant disease. Failure to achieve complete remission can be partly attributed to the drug resistance advantage of AML blasts that frequently express P-glycoprotein (P-gp), an ATP-binding cassette transporter. Our previous work showed that elevated acid ceramidase (AC) levels in AML contribute to blast survival. Here, we investigated P-gp expression levels in AML relative to AC. Using parental HL-60 cells and drug-resistant derivatives as our model, we found that P-gp expression and efflux activity were highly upregulated in resistant derivatives. AC overexpression in HL-60 conferred resistance to the AML chemotherapeutic drugs, cytarabine, mitoxantrone, and daunorubicin, and was linked to P-gp upregulation. Furthermore, targeting AC through pharmacologic or genetic approaches decreased P-gp levels and increased sensitivity to chemotherapeutic drugs. Mechanistically, AC overexpression increased NF-κB activation whereas NF-kB inhibitors reduced P-gp levels, indicating that the NF-kappaB pathway contributes to AC-mediated modulation of P-gp expression. Hence, our data support an important role for AC in drug resistance as well as survival and suggest that sphingolipid targeting approaches may also impact drug resistance in AML.
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- 2019
14. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403
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John C. Grecula, Michaela Liedtke, Kristina Laumann, Guido Marcucci, Richard A. Larson, Wendy Stock, Noreen Fulton, Mark R. Litzow, Selina M. Luger, Martin S. Tallman, Jeffrey A. Bogart, Greg Malnassy, Krzysztof Mrózek, Richard Stone, Frederick R. Appelbaum, Matthew C. Foster, Edy Parker, Anjali S. Advani, Ben L. Sanford, Jun Yin, Charles G. Mullighan, Susan Geyer, Elisabeth Paietta, Richard C. Harvey, Harry P. Erba, Clara D. Bloomfield, Cheryl L. Willman, and David F. Claxton
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Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Immunology ,Biochemistry ,Drug Administration Schedule ,Young Adult ,Risk Factors ,Acute lymphocytic leukemia ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Philadelphia Chromosome ,Obesity ,Prospective Studies ,Young adult ,Prospective cohort study ,Survival analysis ,Errata ,business.industry ,Historically Controlled Study ,Retrospective cohort study ,Cell Biology ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Survival Analysis ,Clinical trial ,Regimen ,Treatment Outcome ,Female ,business - Abstract
Retrospective studies have suggested that older adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) have better survival rates when treated using a pediatric ALL regimen administered by pediatric treatment teams. To address the feasibility and efficacy of using a pediatric treatment regimen for AYA patients with newly diagnosed ALL administered by adult treatment teams, we performed a prospective study, CALGB 10403, with doses and schedule identical to those in the Children’s Oncology Group study AALL0232. From 2007 to 2012, 318 patients were enrolled; 295 were eligible and evaluable for response. Median age was 24 years (range, 17-39 years). Use of the pediatric regimen was safe; overall treatment-related mortality was 3%, and there were only 2 postremission deaths. Median event-free survival (EFS) was 78.1 months (95% confidence interval [CI], 41.8 to not reached), more than double the historical control of 30 months (95% CI, 22-38 months); 3-year EFS was 59% (95% CI, 54%-65%). Median overall survival (OS) was not reached. Estimated 3-year OS was 73% (95% CI, 68%-78%). Pretreatment risk factors associated with worse treatment outcomes included obesity and presence of the Philadelphia-like gene expression signature. Use of a pediatric regimen for AYAs with ALL up to age 40 years was feasible and effective, resulting in improved survival rates compared with historical controls. CALGB 10403 can be considered a new treatment standard upon which to build for improving survival for AYAs with ALL. This trial was registered at www.clinicaltrials.gov as #NCT00558519.
- Published
- 2019
15. Pentostatin, Cyclophosphamide, and Rituximab Followed by Alemtuzumab for Relapsed or Refractory Chronic Lymphocytic Leukemia: A Phase 2 Trial of the ECOG-Acrin Cancer Research Group (E2903)
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Elisabeth Paietta, Zhuoxin Sun, Martin S. Tallman, Neil E. Kay, Natalie S. Callander, Sanford Kempin, Rhett P. Ketterling, Gordan Srkalovic, David F. Claxton, Gerald Gross, Joseph J. Mazza, Olga Frankfurt, and Joel N. Saltzman
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Male ,medicine.medical_specialty ,Cyclophosphamide ,Chronic lymphocytic leukemia ,Nodular Partial Remission ,Gastroenterology ,Disease-Free Survival ,Article ,Chemoimmunotherapy ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Pentostatin ,Alemtuzumab ,Aged ,business.industry ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Survival Rate ,Female ,Refractory Chronic Lymphocytic Leukemia ,Rituximab ,business ,Febrile neutropenia ,medicine.drug - Abstract
Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) may benefit from salvage chemoimmunotherapy (CIT). To explore further the use of CIT in the pre-novel agent era, ECOG-ACRIN undertook a phase 2 trial (E2903) for R/R CLL utilizing pentostatin, cyclophosphamide, and rituximab (PCR) followed by a consolidation course of alemtuzumab. This trial enrolled 102 patients with a median age of 64 years. Treatment consisted of PCR for six cycles followed by alemtuzumab for either 4 or 12 weeks depending upon the initial response to PCR. The overall response after PCR (complete remission (CR), nodular partial remission (nPR), partial remission (PR)) was 55%. Major responses (CR, or nPR) were achieved in 6%. The median overall survival (OS) and the median progression- free survival (PFS) were 28 months and 12 months respectively. The most serious non-lethal adverse events were myelosuppression, febrile neutropenia, fatigue, nausea, and hyponatremia. PCR is an effective and well-tolerated nucleoside-based regimen for heavily pretreated CLL patients with R/R disease. The addition of alemtuzumab to CLL patients with a minor response (PR) or stable disease did not result in a significant number of higher responses (CR or nPR) nor an improvement in OS.
- Published
- 2019
16. HOXBLINC long non-coding RNA activation promotes leukemogenesis in NPM1-mutant acute myeloid leukemia
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Qian Lai, Hongyu Ni, Shi Chen, Ying Guo, Huacheng Luo, Yi Qiu, Feng Chun Yang, David F. Claxton, Ganqian Zhu, Yang Feng, Suming Huang, Ru Feng, Jianfeng Xu, Bing Xu, Olga A. Guryanova, Stephen D. Nimer, Arati Sharma, Zhigang Zhao, Ruben A. Mesa, Wei Li, and Mingjiang Xu
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0301 basic medicine ,Transcription, Genetic ,Carcinogenesis ,General Physics and Astronomy ,Histones ,Mice ,0302 clinical medicine ,Transcription (biology) ,hemic and lymphatic diseases ,Gene expression ,Myeloid Ecotropic Viral Integration Site 1 Protein ,Promoter Regions, Genetic ,Regulation of gene expression ,Myelopoiesis ,Multidisciplinary ,Chemistry ,Gene Expression Regulation, Leukemic ,Myeloid leukemia ,Nuclear Proteins ,Chromatin ,Cell biology ,Stem-cell research ,Leukemia ,Leukemia, Myeloid, Acute ,030220 oncology & carcinogenesis ,Multigene Family ,Self-renewal ,Heterografts ,RNA, Long Noncoding ,Nucleophosmin ,Myeloid-Lymphoid Leukemia Protein ,Signal Transduction ,NPM1 ,Science ,Mice, Transgenic ,General Biochemistry, Genetics and Molecular Biology ,Article ,Acute myeloid leukaemia ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Cancer models ,Cell Proliferation ,Homeodomain Proteins ,Gene Expression Profiling ,General Chemistry ,Histone-Lysine N-Methyltransferase ,medicine.disease ,030104 developmental biology ,Mutation - Abstract
Nucleophosmin (NPM1) is the most commonly mutated gene in acute myeloid leukemia (AML) resulting in aberrant cytoplasmic translocation of the encoded nucleolar protein (NPM1c+). NPM1c+ maintains a unique leukemic gene expression program, characterized by activation of HOXA/B clusters and MEIS1 oncogene to facilitate leukemogenesis. However, the mechanisms by which NPM1c+ controls such gene expression patterns to promote leukemogenesis remain largely unknown. Here, we show that the activation of HOXBLINC, a HOXB locus-associated long non-coding RNA (lncRNA), is a critical downstream mediator of NPM1c+-associated leukemic transcription program and leukemogenesis. HOXBLINC loss attenuates NPM1c+-driven leukemogenesis by rectifying the signature of NPM1c+ leukemic transcription programs. Furthermore, overexpression of HoxBlinc (HoxBlincTg) in mice enhances HSC self-renewal and expands myelopoiesis, leading to the development of AML-like disease, reminiscent of the phenotypes seen in the Npm1 mutant knock-in (Npm1c/+) mice. HoxBlincTg and Npm1c/+ HSPCs share significantly overlapped transcriptome and chromatin structure. Mechanistically, HoxBlinc binds to the promoter regions of NPM1c+ signature genes to control their activation in HoxBlincTg HSPCs, via MLL1 recruitment and promoter H3K4me3 modification. Our study reveals that HOXBLINC lncRNA activation plays an essential oncogenic role in NPM1c+ leukemia. HOXBLINC and its partner MLL1 are potential therapeutic targets for NPM1c+ AML., Nucleophosmin (NPM1) gene mutation induces a specific gene expression program leading to acute myeloid leukaemia. Here, the authors show that mutant NPM1 activates a HOXB locus-associated long non-coding RNA which is essential for its associated oncogenic transcriptional program and leukaemia development.
- Published
- 2021
17. Improved outcome in AML relapse after allogeneic transplant with high-intensity chemotherapy followed by 2nd allogeneic stem cell transplant or donor lymphocyte infusion
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Shin Mineishi, Christopher Ehmann, David F. Claxton, Valerie I. Brown, Neal Shah, Witold B. Rybka, Joseph Mierski, Gina Mackey, Hong Zheng, Myles Nickolich, Seema Naik, Kentaro Minagawa, Baldeep Wirk, Robert J. Greiner, Kevin Rakszawski, and Brooke Silar
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Oncology ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Antineoplastic Agents ,Donor lymphocyte infusion ,Cell therapy ,Young Adult ,Internal medicine ,Statistical significance ,medicine ,Humans ,Transplantation, Homologous ,Child ,Aged ,Chemotherapy ,Hematology ,business.industry ,Cancer ,Myeloid leukemia ,General Medicine ,Middle Aged ,medicine.disease ,Survival Analysis ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Lymphocyte Transfusion ,Female ,Stem cell ,Neoplasm Recurrence, Local ,business ,Stem Cell Transplantation - Abstract
Acute myeloid leukemia (AML) relapse after allogeneic stem cell transplant (alloSCT) remains a major therapeutic challenge. While patients with longer remission after initial alloSCT are recommended to receive cell therapy (CT) such as 2ndalloSCT or donor lymphocyte infusion (DLI), survival for patients who relapse within 6 months of alloSCT has been dismal. We evaluated the outcomes of AML relapse after alloSCT to assess the impact of different treatments on long-term survival. One hundred and seventy-two patients with AML underwent alloSCT at the Penn State Cancer Institute from January 2014 to August 2019. Sixty-nine patients relapsed (median age, 60 years; range, 10–75). Of these, 4 patients underwent 2ndalloSCT, and 26 received DLI. One-year overall survival (OS) in all cases was 20.3% (95% CI: 11.8–30.4%). Patients with ECOG performance status (PS) 0–2 at relapse showed a better 1-year OS than those with PS 3–4. Median OS for patients who received chemotherapy only or chemotherapy with CT was 74 or 173.5 days, respectively (p
- Published
- 2021
18. Lenalidomide-Epoetin Alfa Versus Lenalidomide Monotherapy in Myelodysplastic Syndromes Refractory to Recombinant Erythropoietin
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Amit Verma, Selina M. Luger, Zhuoxin Sun, Puneet S. Cheema, Jaroslaw P. Maciejewski, Martin S. Tallman, Mark R. Litzow, David F. Claxton, Jessica K. Altman, Rami S. Komrokji, John M. Bennett, Alan F. List, Kathy L. McGraw, Ryan J. Mattison, Charles A. Schiffer, Andrew S. Artz, and Timothy R. Wassenaar
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0301 basic medicine ,Oncology ,Ineffective erythropoiesis ,Male ,Cancer Research ,medicine.medical_specialty ,Anemia ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Internal medicine ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Recombinant erythropoietin ,Lenalidomide ,Aged ,Aged, 80 and over ,business.industry ,Myelodysplastic syndromes ,Epoetin alfa ,ORIGINAL REPORTS ,Middle Aged ,medicine.disease ,Prognosis ,Recombinant Proteins ,Epoetin Alfa ,Survival Rate ,030104 developmental biology ,Erythropoietin ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Myelodysplastic Syndromes ,Female ,Neoplasm Recurrence, Local ,business ,medicine.drug ,Follow-Up Studies - Abstract
PURPOSE Impaired response to erythropoietin underlies ineffective erythropoiesis and anemia in myelodysplastic syndromes (MDS). We investigated whether treatment with lenalidomide (LEN), which augments erythropoietin receptor signaling in vitro, can restore and improve hemoglobin response to epoetin (EPO) alfa in patients with lower-risk, non-del(5q) MDS who have anemia that is refractory to or have low probability of benefit from treatment with recombinant erythropoietin. METHODS In a phase III, US intergroup trial, we randomly assigned patients to receive either LEN and EPO alfa or LEN alone following stratification by serum erythropoietin concentration and prior erythropoietin treatment. RESULTS A total of 195 evaluable patients were randomly assigned: 99 patients to the LEN-EPO alfa cohort and 96 to LEN alone. After four cycles of treatment, the primary end point of major erythroid response (MER) was significantly higher (28.3%) with the combination compared with LEN alone (11.5%) ( P = .004). Among 136 patients who completed 16 weeks of study treatment, 38.9% and 15.6% achieved MER, respectively ( P = .004). Additionally, minor erythroid response was achieved in 18.2% and 20.8% of patients, for an overall erythroid response rate of 46.5% versus 32.3%. Among LEN nonresponders, 38 crossed over to the addition of EPO alfa with 10 patients (26.3%) achieving a MER. Responses to the combined treatment were highly durable with a median MER duration of 23.8 months compared with 13 months with LEN alone. CONCLUSION LEN restores sensitivity to recombinant erythropoietin in growth factor–insensitive, lower-risk, non-del(5q) MDS, to yield a significantly higher rate and duration of MER compared with LEN alone (funded by the National Cancer Institute; E2905 ClinicalTrials.gov identifier: NCT02048813 ).
- Published
- 2021
19. Glucocorticoids enhance the antileukemic activity of FLT3 inhibitors in FLT3-mutant acute myeloid leukemia
- Author
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Pinyi Lu, Longgui Chen, Barbara A. Miller, Zhongming Zhao, Charyguly Annageldiyev, Melat T. Gebru, Christopher M. Dower, Jennifer M. Atkinson, Arati Sharma, Megan M. Young, Zhenyuan Tang, Hong Gang Wang, Lijun Zhang, David F. Claxton, Yuka Imamura Kawasawa, and Zhenqiu Liu
- Subjects
0301 basic medicine ,Anti-Inflammatory Agents ,Drug resistance ,Biochemistry ,Dexamethasone ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,Medicine ,Myeloid Neoplasia ,Bcl-2-Like Protein 11 ,Gene Expression Regulation, Leukemic ,Myeloid leukemia ,hemic and immune systems ,Drug Synergism ,Hematology ,Neoplasm Proteins ,Leukemia, Myeloid, Acute ,030220 oncology & carcinogenesis ,Neoplastic Stem Cells ,FLT3 Inhibitor ,Glucocorticoid ,medicine.drug ,Programmed cell death ,Immunology ,Antineoplastic Agents ,03 medical and health sciences ,Downregulation and upregulation ,Animals ,Humans ,Computer Simulation ,Benzothiazoles ,Selection, Genetic ,Glucocorticoids ,Protein Kinase Inhibitors ,Quizartinib ,Inflammation ,business.industry ,Phenylurea Compounds ,Cell Biology ,Minimal residual disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,chemistry ,fms-Like Tyrosine Kinase 3 ,Drug Resistance, Neoplasm ,Cancer research ,Myeloid Cell Leukemia Sequence 1 Protein ,business ,Apoptosis Regulatory Proteins ,Transcriptome - Abstract
FLT3 is a frequently mutated gene that is highly associated with a poor prognosis in acute myeloid leukemia (AML). Despite initially responding to FLT3 inhibitors, most patients eventually relapse with drug resistance. The mechanism by which resistance arises and the initial response to drug treatment that promotes cell survival is unknown. Recent studies show that a transiently maintained subpopulation of drug-sensitive cells, so-called drug-tolerant "persisters" (DTPs), can survive cytotoxic drug exposure despite lacking resistance-conferring mutations. Using RNA sequencing and drug screening, we find that treatment of FLT3 internal tandem duplication AML cells with quizartinib, a selective FLT3 inhibitor, upregulates inflammatory genes in DTPs and thereby confers susceptibility to anti-inflammatory glucocorticoids (GCs). Mechanistically, the combination of FLT3 inhibitors and GCs enhances cell death of FLT3 mutant, but not wild-type, cells through GC-receptor–dependent upregulation of the proapoptotic protein BIM and proteasomal degradation of the antiapoptotic protein MCL-1. Moreover, the enhanced antileukemic activity by quizartinib and dexamethasone combination has been validated using primary AML patient samples and xenograft mouse models. Collectively, our study indicates that the combination of FLT3 inhibitors and GCs has the potential to eliminate DTPs and therefore prevent minimal residual disease, mutational drug resistance, and relapse in FLT3-mutant AML.
- Published
- 2020
20. Unexpected Short-Tandem-Repeat Patterns in Posttransplant Chimerism Testing: Investigation of 3 Cases with Help from Forensic Science
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Witold B. Rybka, Kristina Gvozdjan, Shin Mineishi, Hiroko Shike, Jozef Malysz, Carolyn Fisher, Heather Casey, Zheng Hong, Mike G Bayerl, Lorie H. Kumer, Maria Baker, Carrie L. Mowery, Jennifer Tyler, Christopher Ehmann, David F. Claxton, and Seema Naik
- Subjects
Forensic Genetics ,Genetic Markers ,Male ,medicine.medical_treatment ,Clinical Biochemistry ,Locus (genetics) ,Hematopoietic stem cell transplantation ,03 medical and health sciences ,0302 clinical medicine ,HLA Antigens ,Clinical Decision Rules ,medicine ,Humans ,Transplantation, Homologous ,030216 legal & forensic medicine ,Genetic Testing ,Allele ,Alleles ,Aged ,Transplantation Chimera ,business.industry ,Biochemistry (medical) ,Hematopoietic Stem Cell Transplantation ,Middle Aged ,medicine.disease ,Lymphoma ,Chromosome 4 ,030220 oncology & carcinogenesis ,Immunology ,Microsatellite ,Trisomy ,business ,Trinucleotide repeat expansion ,Microsatellite Repeats - Abstract
Chimerism testing by short tandem repeats (STRs) is used to monitor engraftment after allogeneic hematopoietic stem cell transplantation (HSCT). Generally, STR alleles are stable and transferred from parent to child or from donor to recipient. However, 3 cases did not follow this norm. Additional work-up with help from forensic literature solved these mysteries. In case 1, the patient received HSCT from his son. The son shared STR alleles in 22/23 loci except Penta E, which was explained by repeat expansion in the son. In case 2, the patient had been in remission for 14 years after HSCT for lymphoma and developed repeat expansion in CSF1PO in granulocytes. In case 3, a pre-HSCT patient demonstrated 3 alleles, with 2 peaks taller than the third, in the FGA locus (chromosome 4). A combination of a triallelic variant and leukemia-associated trisomy 4 explained the finding. STR number variants are rare and clinically inconsequential but can overlap malignancy-associated, clinically significant changes.
- Published
- 2020
21. AML chemoresistance: The role of mutant TP53 subclonal expansion and therapy strategy
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Yi Qiu, Suming Huang, David F. Claxton, and Bowen Yan
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0301 basic medicine ,Cancer Research ,Myeloid ,endocrine system diseases ,Population ,Article ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Genetics ,medicine ,Humans ,education ,Molecular Biology ,neoplasms ,education.field_of_study ,business.industry ,Hematopoietic stem cell ,Myeloid leukemia ,Cell Biology ,Hematology ,medicine.disease ,Hematopoietic Stem Cells ,Hematopoiesis ,Leukemia ,Haematopoiesis ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,Hypomethylating agent ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Neoplastic Stem Cells ,Bone marrow ,Tumor Suppressor Protein p53 ,business - Abstract
Acute myeloid leukemia (AML) is a heterogeneous clonal disease characterized by the proliferation and accumulation of myeloid blast cells in the bone marrow, which eventually lead to hematopoietic failure. Chemoresistance presents as a major burden for therapy of AML patients. p53 is the most important tumor suppressor protein that regulates cellular response to various stress. It is also important for hematopoietic stem cell development and hematopoiesis. Mutation or deletion of TP53 has been found to be linked to cancer progression, therapy-related resistance, and poor prognosis. TP53 mutation occurs in less than 10% of AML patients; however, it represents a subset of AML with therapy resistance and poor outcome. In addition, there is a subgroup of patients with low-frequency TP53 mutations. The percentage ranges from 1% to 3% of all AML patients. These patients have outcomes comparable to those of the high-frequency TP53 mutation patients. TP53-mutated clones isolated from the parental cells exhibit a survival advantage under drug treatment compared with cells with wild-type TP53, and have a higher population of leukemia stem cell (LSC) marker-positive cells, a characteristic of chemo-resistant cells. Therefore, low-frequency TP53 mutation, which is currently underappreciated, is an important prognosis factor for AML patients. Epigenetic drugs, such as hypomethylating agent and histone deacetylase inhibitors, have been found effective in targeting TP53-mutated AML. Histone deacetylase inhibitors can preferentially target the TP53-mutated subpopulation by reactivating p53-targeted genes and by eradicating LSC marker–positive cells. Therefore, combined treatment with epigenetic drugs may represent a new therapeutic strategy for treatments of TP53-mutated AML.
- Published
- 2020
22. Ceramide Analogue SACLAC Modulates Sphingolipid Levels and MCL-1 Splicing to Induce Apoptosis in Acute Myeloid Leukemia
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Todd E. Fox, Mark Kester, Hong Gang Wang, Shantu Amin, Charyguly Annageldiyev, Gemma Fabriàs, Jennifer M. Pearson, David J. Feith, Dhimant Desai, Thomas P. Loughran, José Luis Abad, Su Fern Tan, Myles C. Cabot, David F. Claxton, Arati Sharma, Abad, José Luís [0000-0002-8343-9611], Fabriàs, Gemma [0000-0001-7162-3772], Abad, José Luís, and Fabriàs, Gemma
- Subjects
0301 basic medicine ,Cancer Research ,Ceramide ,Apoptosis ,HL-60 Cells ,Mice, SCID ,Ceramides ,Transfection ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Mice, Inbred NOD ,hemic and lymphatic diseases ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Protein Isoforms ,Molecular Biology ,neoplasms ,Aged ,Cancer ,Gene knockdown ,Sphingolipids ,Acute myeloid leukemia ,Sphingosine ,Chemistry ,Myeloid leukemia ,U937 Cells ,Sphingolipid ,Xenograft Model Antitumor Assays ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,Myeloid Cell Leukemia Sequence 1 Protein ,Female ,Bone marrow ,MCL-1 - Abstract
Acute myeloid leukemia (AML) is a disease characterized by uncontrolled proliferation of immature myeloid cells in the blood and bone marrow. The 5-year survival rate is approximately 25%, and recent therapeutic developments have yielded little survival benefit. Therefore, there is an urgent need to identify novel therapeutic targets. We previously demonstrated that acid ceramidase (ASAH1, referred to as AC) is upregulated in AML and high AC activity correlates with poor patient survival. Here, we characterized a novel AC inhibitor, SACLAC, that significantly reduced the viability of AML cells with an EC50 of approximately 3 μmol/L across 30 human AML cell lines. Treatment of AML cell lines with SACLAC effectively blocked AC activity and induced a decrease in sphingosine 1-phosphate and a 2.5-fold increase in total ceramide levels. Mechanistically, we showed that SACLAC treatment led to reduced levels of splicing factor SF3B1 and alternative MCL-1 mRNA splicing in multiple human AML cell lines. This increased proapoptotic MCL-1S levels and contributed to SACLAC-induced apoptosis in AML cells. The apoptotic effects of SACLAC were attenuated by SF3B1 or MCL-1 overexpression and by selective knockdown of MCL-1S. Furthermore, AC knockdown and exogenous C16-ceramide supplementation induced similar changes in SF3B1 level and MCL-1S/L ratio. Finally, we demonstrated that SACLAC treatment leads to a 37% to 75% reduction in leukemic burden in two human AML xenograft mouse models. IMPLICATIONS: These data further emphasize AC as a therapeutic target in AML and define SACLAC as a potent inhibitor to be further optimized for future clinical development., The authors thank those who generously provided cell lines for our studies: Dr. Jacqueline Cloos and Carolien van Alphen, VU Medical Center Amsterdam (EOL-1, HEL, Kasumi-3, Kasumi-6, ME-1, ML2, MM-6, and NB4); Dr. Mark Levis, Johns Hopkins Medical Institutions (MOLM-13 and MOLM-14); Dr. Douglas Graham, Emory University (NOMO1); Dr. Xiaorong Gu, Cleveland Clinic (OCI-AML2 and OCI-AML3); Dr. Harold L. Atkins, Ottawa Hospital Research Institute (OCI-AML4); Drs. Scott Kaufmann and Mithun Shah, Mayo Clinic (SET2); and Barbara Miller, Penn State Hershey (U937-Luc2-P2A-tdTomato). The authors also thank Alex Wendling, Wendy Dunton, Emily Sullins, Matthew Schmachtenberg, and Shubha Dighe (University of Virginia), and Viola Devine (Penn State, Hershey, PA) for technical assistance; Tye Deering (University of Virginia) for his lipid expertise; and Antonio Delgado (IQAC-CSIC) for SACLAC and RBM14C12 synthesis. The authors thank Marieke Jones (University of Virginia) for her statistics expertise. The authors thank the staff of the Flow Cytometry Core at Penn State University College of Medicine (Hershey, PA). The authors thank Drs. Melissa Jurica and Arun Ghosh (University of California, Santa Cruz, CA) for providing SSA for these studies. The authors also thank Drs. Samar Alsafadi and Marc-Henri Stern (Curie Institute) for providing the vector for SF3B1 overexpression. This work was supported by the NIH under the NCI Award Number P01CA171983 (to T.P. Loughran and M. Kester), P30CA044579 (to T.P. Loughran), and under the National Institute of General Medicine Sciences Award Number T32GM007055 (to J.M. Pearson) and AEI/FEDER (grant number CTQ2017-85378-R; to G. Fabrias). Additional funding was provided to T.P. Loughran by the Bess Family Charitable Fund and a generous anonymous donor. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Published
- 2020
23. Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies
- Author
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Amriti R. Lulla, Jeffrey J. Pu, Jawad Babar, Nadia Khan, Cyril H. Benes, Lanlan Zhou, Joshua E. Allen, A. Pieter J. van den Heuvel, Ultan McDermott, Mala K. Talekar, Mathew J. Garnett, C. Leah B. Kline, Junior Hall, Wolfgang Oster, David F. Claxton, Varun V. Prabhu, David T. Dicker, Wafik S. El-Deiry, and Stephan A. Grupp
- Subjects
Boron Compounds ,0301 basic medicine ,Cell Survival ,Pyridines ,Chronic lymphocytic leukemia ,Transplantation, Heterologous ,Glycine ,Antineoplastic Agents ,Apoptosis ,Mice, SCID ,CHOP ,Pharmacology ,Biology ,Heterocyclic Compounds, 4 or More Rings ,Mice ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,Cell Line, Tumor ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Molecular Biology ,Anaplastic large-cell lymphoma ,Acute leukemia ,Bortezomib ,Imidazoles ,Drug Synergism ,Cell Biology ,medicine.disease ,Activating Transcription Factor 4 ,G1 Phase Cell Cycle Checkpoints ,Lymphoma ,Pyrimidines ,Cell Cycle News and Views ,030104 developmental biology ,Hematologic Neoplasms ,030220 oncology & carcinogenesis ,Azacitidine ,Cytarabine ,Cancer research ,Mantle cell lymphoma ,Drug Screening Assays, Antitumor ,Transcription Factor CHOP ,Reports ,Developmental Biology ,medicine.drug - Abstract
ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1-8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples. ONC201 induced caspase-dependent apoptosis that involved activation of the integrated stress response (ATF4/CHOP) pathway, inhibition of Akt phosphorylation, Foxo3a activation, downregulation of cyclin D1, IAP and Bcl-2 family members. ONC201 synergistically reduced cell viability in combination with cytarabine and 5-azacytidine in AML cells. ONC201 combined with cytarabine in a Burkitt's lymphoma xenograft model induced tumor growth inhibition that was superior to either agent alone. ONC201 synergistically combined with bortezomib in MM, MCL and ALCL cells and with ixazomib or dexamethasone in MM cells. ONC201 combined with bortezomib in a Burkitt's lymphoma xenograft model reduced tumor cell density and improved CHOP induction compared to either agent alone. These results serve as a rationale for ONC201 single-agent trials in relapsed/refractory acute leukemia, non-Hodgkin's lymphoma, MM and combination trial with dexamethasone in MM, provide pharmacodynamic biomarkers and identify further synergistic combinatorial regimens that can be explored in the clinic.
- Published
- 2018
24. Increased CD13 Expression in Acute Myeloid Leukemia–associated Early Acute Hypoxic Respiratory Failure
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Ruchi J Desai, Andry Van de Louw, Michael G. Bayerl, David F. Claxton, Coursen Schneider, and Cinda Boyer
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Adult ,Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,CD13 Antigens ,Critical Care and Intensive Care Medicine ,Flow cytometry ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Leukemic Infiltration ,Humans ,Medicine ,Young adult ,Hypoxia ,Lung ,Aged ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,Myeloid leukemia ,Middle Aged ,Hypoxia (medical) ,Flow Cytometry ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,Respiratory failure ,030220 oncology & carcinogenesis ,Acute Disease ,Cancer research ,Female ,medicine.symptom ,Respiratory Insufficiency ,business - Published
- 2017
25. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1–2 study
- Author
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Raoul Tibes, Stan Gill, Chaofeng Liu, Christoph Röllig, Stephen A. Strickland, Joseph G. Jurcic, Stuart L. Goldberg, Maria R. Baer, Alexander E. Perl, Alexander I. Spira, Andreas Neubauer, Gary J. Schiller, Mark R. Litzow, Richard A. Larson, Catherine C. Smith, Jessica K. Altman, Harry P. Erba, Mark J. Levis, Erkut Bahceci, Giovanni Martinelli, Robert K. Stuart, Eunice S. Wang, Jorge E. Cortes, David F. Claxton, Celalettin Ustun, Ellen K. Ritchie, Perl, Alexander E, Altman, Jessica K, Cortes, Jorge, Smith, Catherine, Litzow, Mark, Baer, Maria R, Claxton, David, Erba, Harry P, Gill, Stan, Goldberg, Stuart, Jurcic, Joseph G, Larson, Richard A, Liu, Chaofeng, Ritchie, Ellen, Schiller, Gary, Spira, Alexander I, Strickland, Stephen A, Tibes, Raoul, Ustun, Celalettin, Wang, Eunice S, Stuart, Robert, Röllig, Christoph, Neubauer, Andrea, Martinelli, Giovanni, Bahceci, Erkut, and Levis, Mark
- Subjects
Male ,Myeloid ,0301 basic medicine ,Gastroenterology ,chemistry.chemical_compound ,tyrosine kinase inhibitor ,0302 clinical medicine ,Recurrence ,hemic and lymphatic diseases ,Midostaurin ,Phosphorylation ,Lung ,Cancer ,Aniline Compounds ,Leukemia ,Hematology ,Middle Aged ,3. Good health ,Leukemia, Myeloid, Acute ,Infectious Diseases ,medicine.anatomical_structure ,Oncology ,Tolerability ,Pyrazines ,6.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,embryonic structures ,Retreatment ,Female ,Patient Safety ,Blood Platelets ,medicine.medical_specialty ,Maximum Tolerated Dose ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,Antineoplastic Agents ,acute myeloid leukemia ,Acute ,Neutropenia ,Article ,relapsed/refractory ,03 medical and health sciences ,Rare Diseases ,Clinical Research ,Internal medicine ,Genetics ,medicine ,Humans ,Oncology & Carcinogenesis ,FLT3 inhibition ,Aged ,Quizartinib ,business.industry ,Evaluation of treatments and therapeutic interventions ,medicine.disease ,Surgery ,030104 developmental biology ,fms-Like Tyrosine Kinase 3 ,chemistry ,Fms-Like Tyrosine Kinase 3 ,business ,Progressive disease ,Febrile neutropenia - Abstract
Summary Background Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia. Methods In this phase 1–2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations ( FLT3 mut+ ) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3 mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing. Findings Between Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3–4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (41 [16%] of 252]), fatigue (37 [15%]), elevated aspartate aminotransferase (33 [13%]), and elevated alanine aminotransferase (24 [10%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (78 [31%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission. Interpretation Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials. Funding Astellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro.
- Published
- 2017
26. Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients
- Author
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L. Gashonia, Pavel Kiselev, Kaitlin Kennard, Christina Howlett, Allison M. Winter, Andre Goy, Clive S. Zent, Danielle M. Brander, Stephen J. Schuster, Chadi Nabhan, Kenneth A. Foon, Allan-Louie Cruz, Catherine Daniel, David F. Claxton, Brian T. Hill, Alan P Skarbnik, Paul M. Barr, Colleen Timlin, K. Isaac, Nicole Lamanna, Molly Fanning, Chaitra S. Ujjani, J. Lenhart, Melissa Yacur, Bruce D. Cheson, Jeffrey J. Pu, Jakub Svoboda, S. Henick Bachow, and Anthony R. Mato
- Subjects
Adult ,Oncology ,medicine.medical_specialty ,Chronic lymphocytic leukemia ,Kaplan-Meier Estimate ,Disease-Free Survival ,Drug Administration Schedule ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Piperidines ,Chemoimmunotherapy ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Clinical endpoint ,Humans ,Progression-free survival ,Aged ,Proportional Hazards Models ,Quinazolinones ,Retrospective Studies ,Aged, 80 and over ,Sulfonamides ,business.industry ,Venetoclax ,Adenine ,Hazard ratio ,Hematology ,Middle Aged ,Bridged Bicyclo Compounds, Heterocyclic ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Pyrimidines ,Treatment Outcome ,chemistry ,Purines ,030220 oncology & carcinogenesis ,Ibrutinib ,Pyrazoles ,Idelalisib ,business ,030215 immunology - Abstract
Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence.We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS).A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06).In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.
- Published
- 2017
27. Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience
- Author
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Sunita D. Nasta, Jakub Svoboda, Pavel Kiselev, Tatyana Feldman, Paul M. Barr, Daniel Porter, Jeffrey J. Pu, Nicole Lamanna, David F. Claxton, Clive S. Zent, Chadi Nabhan, Alison R. Sehgal, Gurbakhash Kaur, Andrew M. Evens, Spencer Henick Bachow, Anthony R. Mato, Bruce D. Cheson, Andre Goy, Lauren E. Strelec, Chaitra S. Ujjani, Daniel J. Landsburg, Alexandra Vandegrift, Stephen J. Schuster, Danielle M. Fitzpatrick, Brian T. Hill, Alan P Skarbnik, and Christina Howlett
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Chronic lymphocytic leukemia ,Immunology ,Salvage therapy ,Antineoplastic Agents ,Kaplan-Meier Estimate ,Biochemistry ,Disease-Free Survival ,Cohort Studies ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Piperidines ,Internal medicine ,medicine ,Humans ,Aged ,Proportional Hazards Models ,Quinazolinones ,Retrospective Studies ,Aged, 80 and over ,Salvage Therapy ,Proportional hazards model ,business.industry ,Adenine ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Surgery ,Discontinuation ,Leukemia ,Pyrimidines ,Treatment Outcome ,chemistry ,Purines ,030220 oncology & carcinogenesis ,Ibrutinib ,Toxicity ,Disease Progression ,Pyrazoles ,Female ,Idelalisib ,business ,030215 immunology - Abstract
B-cell receptor kinase inhibitor (KI) therapy represents a paradigm shift in chronic lymphocytic leukemia (CLL) management, but data on practice patterns after KI discontinuation and optimal sequencing are limited. We conducted a multicenter, retrospective, comprehensive analysis on 178 patients with CLL (ibrutinib = 143; idelalisib = 35) who discontinued KI therapy. We examined responses, toxicity, post-KI therapies, and overall survival (OS). Patients had a median of 3 prior therapies (range 0-11); del17p (34%), p53 mutation (27%), del11q (33%), and complex karyotype (29%). Overall response rate (ORR) to first KI was 62% (complete response 14%). The most common reasons for KI discontinuation were toxicity (51%), CLL progression (29%), and Richter transformation (RT) (8%). Median progression-free survival (PFS) and OS from KI initiation were 10.5 and 29 months, respectively. Notably, initial KI choice did not impact PFS or OS; however, RT portended significantly inferior OS (P = .0007). One hundred fourteen patients received subsequent salvage therapy following KI discontinuation with an ORR to subsequent KI at 50% and a median PFS of 11.9 months. Median PFS in KI-intolerant patients treated with an alternate KI was not reached vs 7 months for patients with CLL progression. In summary, these data demonstrate that toxicity was the most common reason for KI discontinuation, that patients who discontinue KI due to toxicity can respond to an alternate KI, and that these responses may be durable. This trial was registered at www.clinicaltrials.gov as #NCT02717611 and #NCT02742090.
- Published
- 2016
28. Clofarabine followed by haploidentical stem cell transplant using fludarabine, busulfan, and total-body irradiation with post-transplant cyclophosphamide in non-remission AML
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Kosuke Miki, Kevin Rakszawski, Shin Mineishi, Seema Naik, Henry N. Wagner, David F. Claxton, and Hiroko Shike
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Transplantation Conditioning ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,03 medical and health sciences ,0302 clinical medicine ,Adenine nucleotide ,hemic and lymphatic diseases ,Internal medicine ,Humans ,Medicine ,Clofarabine ,Busulfan ,Cyclophosphamide ,Adenine Nucleotides ,business.industry ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Hematology ,Total body irradiation ,Combined Modality Therapy ,Tumor Burden ,Fludarabine ,Transplantation ,Leukemia, Myeloid, Acute ,Treatment Outcome ,surgical procedures, operative ,030220 oncology & carcinogenesis ,Transplantation, Haploidentical ,Arabinonucleosides ,business ,Immunosuppressive Agents ,Vidarabine ,030215 immunology ,medicine.drug - Abstract
Approximately 30-40% of patients with acute myeloid leukemia (AML) experience induction failures. In these patients who do not achieve remission with two cycles of standard induction therapies, the probability of achieving remission with subsequent inductions is very limited. Hematopoietic stem cell transplantation (HSCT) is the only curative option for these patients, but high relapse rate and transplant-related mortality often preclude them to proceed to transplant. Thus, AML not in remission at time of HSCT remains a huge unmet need in current HSCT practice, particularly if the patient does not have an HLA-matched donor identified by the time of two induction failures. We used clofarabine cytoreduction immediately followed by fludarabine (Flu) and busulfan (Bu) × 3 with total-body irradiation (TBI) conditioning (Flu/Bu3/TBI) for haploidentical peripheral blood stem cell transplant with post-transplant cyclophosphamide for two cases of refractory AML with a very high tumor burden at transplant and achieved complete remission by day + 30 in both cases.
- Published
- 2018
29. Chemotherapy selection pressure alters sphingolipid composition and mitochondrial bioenergeticsin resistant HL-60 cells
- Author
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Miki Kassai, Samy A.F. Morad, Li-Pin Kao, Traci S. Davis, Noha Abdelmageed, Gemma Fabriàs, Thomas P. Loughran, José L. Abad, Sarah Spiegel, Su Fern Tan, David J. Feith, Todd E. Fox, Mark Kester, Kelsey H. Fisher-Wellman, Matthew R. MacDougall, Myles C. Cabot, David F. Claxton, Fabriàs, Gemma, and Fabriàs, Gemma [0000-0001-7162-3772]
- Subjects
0301 basic medicine ,Ceramide ,Daunorubicin ,Cell Survival ,Cell ,Immunoblotting ,Apoptosis ,HL-60 Cells ,QD415-436 ,030204 cardiovascular system & hematology ,Ceramides ,Biochemistry ,Mass Spectrometry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Sphingosine ,medicine ,Ceramidases ,Humans ,Research Articles ,Cancer ,Sphingolipids ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Cell Biology ,Sphingolipid ,Amides ,Mitochondria ,Acid Ceramidase ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Sphingosine kinase 1 ,Mitochondrial biogenesis ,Glucosyltransferases ,Drug resistance ,Cancer research ,biology.protein ,Fatty Acids, Unsaturated ,Lysophospholipids ,medicine.drug - Abstract
The combination of daunorubicin (dnr) and cytarabine (Ara-C) is a cornerstone of treatment for acute myelogenous leukemia (AML); resistance to these drugs is a major cause of treatment failure. Ceramide, a sphingolipid (SL), plays a critical role in cancer cell apoptosis in response to chemotherapy. Here, we investigated the effects of chemotherapy selection pressure with Ara-C and dnr on SL composition and enzyme activity in the AML cell line HL-60. Resistant cells, those selected for growth in Ara-C- and dnr-containing medium (HL-60/Ara-C and HL-60/dnr, respectively), demonstrated upregulated expression and activity of glucosylceramide synthase, acid ceramidase (AC), and sphingosine kinase 1 (SPHK1); were more resistant to ceramide than parental cells; and displayed sensitivity to inhibitors of SL metabolism. Lipidomic analysis revealed a general ceramide deficit and a profound upswing in levels of sphingosine 1-phosphate (S1P) and ceramide 1-phosphate (C1P) in HL-60/dnr cells versus parental and HL-60/Ara-C cells. Both chemotherapyselected cells also exhibited comprehensive upregulations in mitochondrial biogenesis consistent with heightened reliance on oxidative phosphorylation, a property that was partially reversed by exposure to AC and SPHK1 inhibitors and that supports a role for the phosphorylation system in resistance. In summary, dnr and Ara-C selection pressure induces acute reductions in ceramide levels and large increases in S1P and C1P, concomitant with cell resilience bolstered by enhanced mitochondrial remodeling. Thus, strategic control of ceramide metabolism and further research to define mitochondrial perturbations that accompany the drug-resistant phenotype offer new opportunities for developing therapies that regulate cancer growth., This work was supported by National Institutes of Health Grant P01 CA171983 and by a grant from the Brody Brothers Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare that they have no conflicts of interest with the contents of this article.
- Published
- 2019
30. Impact of ruxolitinib on myelofibrosis patients post allogeneic stem cell transplant—a pilot study
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David F. Claxton, Junjia Zhu, Jeffrey J. Pu, Michael G. Bayerl, Joyson Poulose, Jozef Malysz, and Julie Fanburg-Smith
- Subjects
Male ,Oncology ,medicine.medical_specialty ,Ruxolitinib ,Transplantation Conditioning ,Pilot Projects ,Article ,Internal medicine ,Nitriles ,Humans ,Transplantation, Homologous ,Medicine ,Myelofibrosis ,Janus Kinases ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,medicine.disease ,Pyrimidines ,Primary Myelofibrosis ,Pyrazoles ,Female ,Stem cell ,business ,medicine.drug - Published
- 2019
31. Downregulation of CD73 associates with T cell exhaustion in AML patients
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Charyguly Annageldiyev, Yaxian Kong, Robert F. Paulson, Hong Zheng, Chenchen Zhao, Bei Jia, Hui Zeng, Joseph S. Fotos, K. Sandeep Prabhu, Arati Sharma, and David F. Claxton
- Subjects
0301 basic medicine ,Adult ,Male ,Cancer Research ,TIGIT ,medicine.medical_treatment ,T cell ,T-Lymphocytes ,Down-Regulation ,Biology ,GPI-Linked Proteins ,Transfection ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,AML ,PD-1 ,medicine ,Cytotoxic T cell ,Humans ,Molecular Biology ,5'-Nucleotidase ,Aged ,T cell exhaustion ,Aged, 80 and over ,Tumor microenvironment ,lcsh:RC633-647.5 ,Research ,CD28 ,lcsh:Diseases of the blood and blood-forming organs ,Hematology ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immune checkpoint ,Leukemia, Myeloid, Acute ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,CD73 ,Female - Abstract
Background Successful treatment for acute myeloid leukemia (AML) remains challenging. Inhibiting immune checkpoint to enhance anti-tumor response is an attractive strategy for effective leukemia therapeutics. CD73 is a recently recognized immune checkpoint mediator that is highly expressed on tumor cells and stromal cells in tumor microenvironment. The ectonucleotidase activity of CD73 catalyzes AMP to adenosine, which subsequently inhibits anti-tumor immune responses. In this study, we aim to explore the effect of CD73 in AML. Methods Peripheral blood samples collected from patients with newly diagnosed AML (n = 27) were used in this study. CD73 expression on each immune cell component was examined by flow cytometry. Phenotypic study of CD73-expressing T cells and analysis of the correlation between CD73 and other immune checkpoints were performed using flow cytometry-based assays. Functional status of CD73+ vs. CD73− T cells was assessed in an in vitro cytokine release assay upon CD3/CD28 antibody stimulation. Results In contrast to the long recognized immune suppressive effect of CD73-adenosine signaling in tumor tissue, we made a striking observation that in AML, CD73 expression on CD8 T cells associates with an increased immune response. CD73+ CD8 T cells are more functional, whereas CD73− CD8 T cells exhibit features of exhaustion manifested by high expression of inhibitory receptors such as PD-1 and TIGIT, increased intracellular expression of Eomes, reduced capacity of cytokine production, and high susceptibility to apoptosis. Conclusions Our data highlight the potential of CD73 as a double-edged sword in anti-leukemia immunity and argue strongly for the combinational treatment by adding immune checkpoint inhibitors to the CD73-targeting approaches.
- Published
- 2019
32. Therapy of acute myeloid leukemia: therapeutic targeting of tyrosine kinases
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Joseph Cioccio and David F. Claxton
- Subjects
0301 basic medicine ,Cell Survival ,medicine.medical_treatment ,Antineoplastic Agents ,Therapeutic targeting ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Malignant cells ,Animals ,Humans ,Pharmacology (medical) ,Molecular Targeted Therapy ,Protein Kinase Inhibitors ,Cell survival ,Cell Proliferation ,Pharmacology ,business.industry ,Myeloid leukemia ,General Medicine ,Janus Kinase 2 ,Leukemia, Myeloid, Acute ,Proto-Oncogene Proteins c-kit ,030104 developmental biology ,fms-Like Tyrosine Kinase 3 ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,business ,Tyrosine kinase - Abstract
Tyrosine kinases (TKs) drive cell survival and proliferation in many normal and malignant cell types. TKs are frequently mutated in acute myeloid leukemia (AML) and hence are increasingly targeted. The management of AML has dramatically improved because of TKI-targeted treatment.This review provides a biological background for TK inhibitors (TKIs) in AML and reviews their use in the clinic. TK expression and mutation in AML are explored with a focus on TKs associated with specific AML subsets and treatment outcomes. TKIs that specifically target FLT3, c-Kit, and Jak2 are discussed. TKI targeting of specific genes mutated in individual cases and general 'untargeted' use of these agents are highlighted. Lastly, the mechanisms TKI drug resistance in AML are exploredThe use of TKIs in the clinic is improving outcomes for many patients. An improved understanding of tyrosine kinase biology and the expanding use of TKIs are likely to dramatically improve outcomes in the coming decade. TKIs and other targeted agents could gradually supplant the use of cytotoxic chemotherapy for AML.
- Published
- 2019
33. Eomes
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Bei, Jia, Chenchen, Zhao, Kevin L, Rakszawski, David F, Claxton, W Christopher, Ehmann, Witold B, Rybka, Shin, Mineishi, Ming, Wang, Hiroko, Shike, Michael G, Bayerl, Jeffrey M, Sivik, Todd D, Schell, Joseph J, Drabick, Raymond J, Hohl, and Hong, Zheng
- Subjects
Cohort Studies ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Humans ,Induction Chemotherapy ,CD8-Positive T-Lymphocytes ,Receptors, Immunologic ,Prognosis ,Promoter Regions, Genetic ,T-Box Domain Proteins ,Survival Analysis - Abstract
Acute myeloid leukemia (AML) is a devastating blood cancer with poor prognosis. Immunotherapy targeting inhibitory pathways to unleash the antileukemia T-cell response is a promising strategy for the treatment of leukemia, but we must first understand the underlying molecular mechanisms. Eomesodermin (Eomes) and T-bet are both T-box transcription factors that regulate CD8
- Published
- 2018
34. Bone marrow CD8 T cells express high frequency of PD-1 and exhibit reduced anti-leukemia response in newly diagnosed AML patients
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Witold B. Rybka, Shin Mineishi, Todd D. Schell, Bei Jia, Hong Zheng, Michael G. Bayerl, W. Christopher Ehmann, David F. Claxton, Hiroko Shike, Raymond J. Hohl, Syed Rizvi, and Liru Wang
- Subjects
Male ,0301 basic medicine ,Programmed Cell Death 1 Receptor ,Gene Expression ,Bone Marrow Cells ,Newly diagnosed ,CD8-Positive T-Lymphocytes ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Text mining ,Correspondence ,Gene expression ,medicine ,Humans ,Cytotoxic T cell ,business.industry ,Hematology ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Immunohistochemistry ,Leukemia, Myeloid, Acute ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Bone marrow ,business - Published
- 2018
35. Characteristics of early acute respiratory distress syndrome in newly diagnosed acute myeloid leukemia
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Junjia Zhu, Ruchi J Desai, Andry Van de Louw, and David F. Claxton
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Respiratory complications ,ARDS ,medicine.medical_treatment ,macromolecular substances ,Acute respiratory distress ,Newly diagnosed ,03 medical and health sciences ,Leukocyte Count ,0302 clinical medicine ,Risk Factors ,hemic and lymphatic diseases ,Internal medicine ,White blood cell ,medicine ,Humans ,Hospital Mortality ,Aged ,Retrospective Studies ,Mechanical ventilation ,Respiratory Distress Syndrome ,business.industry ,Incidence ,Myeloid leukemia ,Hematology ,Middle Aged ,Pennsylvania ,medicine.disease ,Survival Rate ,Intensive Care Units ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Female ,business ,Early phase ,030215 immunology - Abstract
Acute respiratory complications occur frequently during the early phase of acute myeloid leukemia (AML) but information on the most severe form, acute respiratory distress syndrome (ARDS), is lacking. We retrospectively analyzed 280 patients with newly diagnosed AML in order to describe the incidence, risk factors and early mortality associated with ARDS within 15 d. Univariate and then multivariate analysis were performed. ARDS developed in 9% of patients and was associated with 64% day-30 mortality. White blood cell count on admission was an independent risk factor for ARDS (OR = 1.007, 95% CI = 1.001-1.012, p = .012) with a moderate prediction ability (AUC 0.704, p = .001). Other variables were associated with ARDS in univariate but not in multivariate analysis: body mass index (p = .06), transfusions (p = .001) and sepsis (p .0001). Leukemia-specific complications and documented infections were the most frequent ARDS etiologies and were sometimes associated, with no clear distinctive temporal pattern.
- Published
- 2018
36. Myeloid sarcoma of the thyroid
- Author
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Jozef Malysz, Monika Joshi, Elizabeth Cottrill, David F. Claxton, and Dana Goldenberg
- Subjects
medicine.medical_specialty ,Medical psychology ,business.industry ,Graduate medical education ,Psychological intervention ,Workload ,030204 cardiovascular system & hematology ,Middle Aged ,03 medical and health sciences ,Leukemia, Myeloid, Acute ,0302 clinical medicine ,Otorhinolaryngology ,030220 oncology & carcinogenesis ,Family medicine ,Medicine ,Survey data collection ,Humans ,Observational study ,Female ,Sleep (system call) ,Thyroid Neoplasms ,Sarcoma, Myeloid ,business - Abstract
Graduate medical education programs typically set up call under the assumption that residents will have similar experiences. The terms black cloud and white cloud have frequently been used to describe residents with more difficult (black) or less difficult (white) call experiences. This study followed residents in the department of head and neck surgery during call to determine whether certain residents have a significantly different call experience than the norm. It is a prospective observational study conducted over 16 months in a tertiary care center with a resident training program in otolaryngology. Resident call data on total pages, consults, and operative interventions were examined, as well as subjective survey data about sleep and perceived difficulty of resident call. Analysis showed no significant difference in call activity (pages, consults, operative interventions) among residents. However, data from the resident call surveys revealed perceived disparities in call difficulty that were significant. Two residents were clearly labeled as black clouds compared to the rest. These residents did not have the highest average number of pages, consults, or operative interventions. This study suggests that factors affecting call perception are outside the objective, absolute workload. These results may be used to improve resident education on sleep training and nighttime patient management in the field of otolaryngology and may influence otolaryngology residency programs.
- Published
- 2017
37. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis
- Author
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Pavel Kiselev, Christina Howlett, Allison M. Winter, Chaitra S. Ujjani, Colleen Dorsey, Sunita D. Nasta, Jakub Svoboda, Clive S. Zent, Brian T. Hill, Alan P Skarbnik, Jeffrey Pu, Bruce D. Cheson, Spencer Henick Bachow, Anthony R. Mato, Krista Isaac, Andre Goy, Paul M. Barr, Meghan C. Thompson, Stephen J. Schuster, Colleen Timlin, Kaitlin Kennard, Chadhi Nabhan, David F. Claxton, Daniel J. Landsburg, Nicole Lamanna, and Danielle M. Brander
- Subjects
Adult ,Male ,medicine.medical_specialty ,Drug-Related Side Effects and Adverse Reactions ,Chronic lymphocytic leukemia ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Piperidines ,Internal medicine ,Clinical endpoint ,Medicine ,Humans ,Chronic Lymphocytic Leukemia ,Survival rate ,Protein Kinase Inhibitors ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Adenine ,Retrospective cohort study ,Hematology ,Middle Aged ,medicine.disease ,Prognosis ,Leukemia, Lymphocytic, Chronic, B-Cell ,Discontinuation ,Clinical trial ,Survival Rate ,Pyrimidines ,chemistry ,030220 oncology & carcinogenesis ,Ibrutinib ,Disease Progression ,Acalabrutinib ,Pyrazoles ,Female ,business ,030215 immunology ,Follow-Up Studies - Abstract
Clinical trials that led to ibrutinib’s approval for the treatment of chronic lymphocytic leukemia showed that its side effects differ from those of traditional chemotherapy. Reasons for discontinuation in clinical practice have not been adequately studied. We conducted a retrospective analysis of chronic lymphocytic leukemia patients treated with ibrutinib either commercially or on clinical trials. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. This multicenter, retrospective analysis included ibrutinib-treated chronic lymphocytic leukemia patients at nine United States cancer centers or from the Connect® Chronic Lymphocytic Leukemia Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival. Six hundred sixteen ibrutinib-treated patients were identified. A total of 546 (88%) patients were treated with the commercial drug. Clinical trial patients were younger (mean age 58 versus 61 years, P=0.01) and had a similar time from diagnosis to treatment with ibrutinib (mean 85 versus 87 months, P=0.8). With a median follow-up of 17 months, an estimated 41% of patients discontinued ibrutinib (median time to ibrutinib discontinuation was 7 months). Notably, ibrutinib toxicity was the most common reason for discontinuation in all settings. The median progression-free survival and overall survival for the entire cohort were 35 months and not reached (median follow-up 17 months), respectively. In the largest reported series on ibrutinib- treated chronic lymphocytic leukemia patients, we show that 41% of patients discontinued ibrutinib. Intolerance as opposed to chronic lymphocytic leukemia progression was the most common reason for discontinuation. Outcomes remain excellent and were not affected by line of therapy or whether patients were treated on clinical studies or commercially. These data strongly argue in favor of finding strategies to minimize ibrutinib intolerance so that efficacy can be further maximized. Future clinical trials should consider time-limited therapy approaches, particularly in patients achieving a complete response, in order to minimize ibrutinib exposure.
- Published
- 2017
38. Modification of sphingolipid metabolism by tamoxifen and N-desmethyltamoxifen in acute myelogenous leukemia—Impact on enzyme activity and response to cytotoxics
- Author
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Todd E. Fox, Su Fern Tan, David J. Feith, Brian M. Barth, Myles C. Cabot, Mark Kester, David F. Claxton, Samy A.F. Morad, and Thomas P. Loughran
- Subjects
medicine.medical_specialty ,Ceramide ,N-Desmethyltamoxifen ,HL-60 Cells ,Article ,chemistry.chemical_compound ,Internal medicine ,Stilbenes ,Tumor Cells, Cultured ,medicine ,Humans ,Molecular Biology ,Sphingolipids ,biology ,Sphingosine ,Cytotoxins ,Estrogen Antagonists ,Cell Biology ,Lipid signaling ,Lipid Metabolism ,Antiestrogen ,Sphingolipid ,Enzyme Activation ,Leukemia, Myeloid, Acute ,Phosphotransferases (Alcohol Group Acceptor) ,Tamoxifen ,Endocrinology ,chemistry ,Sphingosine kinase 1 ,Cancer research ,biology.protein ,medicine.drug - Abstract
The triphenylethylene antiestrogen, tamoxifen, can be an effective inhibitor of sphingolipid metabolism. This off-target activity makes tamoxifen an interesting ancillary for boosting the apoptosis-inducing properties of ceramide, a sphingolipid with valuable tumor censoring activity. Here we show for the first time that tamoxifen and metabolite, N-desmethyltamoxifen (DMT), block ceramide glycosylation and inhibit ceramide hydrolysis (by acid ceramidase, AC) in human acute myelogenous leukemia (AML) cell lines and in AML cells derived from patients. Tamoxifen (1–10 μM) inhibition of AC in AML cells was accompanied by decreases in AC protein expression. Tamoxifen also depressed expression and activity of sphingosine kinase 1 (SphK1), the enzyme-catalyzing production of mitogenic sphingosine 1-phosphate (S1-P). Results from mass spectroscopy showed that tamoxifen and DMT (i) increased the levels of endogenous C16:0 and C24:1 ceramide molecular species, (ii) nearly totally halted production of respective glucosylceramide (GC) molecular species, (iii) drastically reduced levels of sphingosine (to 9% of control), and (iv) reduced levels of S1-P by 85%, in vincristine-resistant HL-60/VCR cells. The co-administration of tamoxifen with either N-(4-hydroxyphenyl)retinamide (4-HPR), a ceramide-generating retinoid, or a cell-deliverable form of ceramide, C6-ceramide, resulted in marked decreases in HL-60/VCR cell viability that far exceeded single agent potency. Combination treatments resulted in synergistic apoptotic cell death as gauged by increased Annexin V binding and DNA fragmentation and activation of caspase-3. These results show the versatility of adjuvant triphenylethylene with ceramide-centric therapies for magnifying therapeutic potential in AML. Such drug regimens could serve as effective strategies, even in the multidrug-resistant setting.
- Published
- 2015
39. Phase I/II Study of Clofarabine, Etoposide, and Mitoxantrone in Patients With Refractory or Relapsed Acute Leukemia
- Author
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Witold B. Rybka, W. Christopher Ehmann, David F. Claxton, and Kamal Kant Singh Abbi
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Gastroenterology ,Refractory ,Recurrence ,Acute lymphocytic leukemia ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Clofarabine ,Etoposide ,Neoplasm Staging ,Mitoxantrone ,Acute leukemia ,Adenine Nucleotides ,business.industry ,Remission Induction ,Myeloid leukemia ,Hematology ,Middle Aged ,medicine.disease ,Transplantation ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Oncology ,Female ,Arabinonucleosides ,business ,medicine.drug - Abstract
Background Clofarabine, a second-generation nucleoside analogue, was studied in combination with etoposide and mitoxantrone in acute leukemia. Patients and Methods In the phase I portion of this study clofarabine was given 20 or 25 mg/m2 daily for 5 days (Days 2-6) with etoposide 100 mg/m2 from day 1 to 5 and mitoxantrone 8 mg/m2 from day 1 to 3. The dose-limiting toxicity was myelosuppression, and dose level 1, with clofarabine 20 mg/m2 daily for 5 days was identified as the phase 2 dose. In total, 22 patients with relapsed or refractory acute myeloid leukemia (n = 18) and acute lymphocytic leukemia (n = 4) were treated. Results Five of 22 patients (23%) achieved complete response (CR), and 3 (13%) achieved CR with incomplete platelet recovery; an overall response rate of 36%. Median overall survival was 167 days (range, 22-1327 days). For 2 patients this regimen represented an effective bridge to allogeneic stem cell transplantation. Conclusion Clofarabine in combination with etoposide and mitoxantrone is tolerable and shows significant activity in relapsed and refractory acute leukemia in adults.
- Published
- 2015
40. Pyoluteorin derivatives induce Mcl-1 degradation and apoptosis in hematological cancer cells
- Author
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Hong Gang Wang, Christopher M. Dower, Kenichiro Doi, Qiang Liu, Shen Shu Sung, Krishne Gowda, David F. Claxton, Shantu Amin, Jyh Ming Lin, and Thomas P. Loughran
- Subjects
Models, Molecular ,Cancer Research ,Time Factors ,Cell Survival ,Molecular Conformation ,Antineoplastic Agents ,Apoptosis ,Pharmacology ,Bcl-2-associated X protein ,Phenols ,Cell Line, Tumor ,hemic and lymphatic diseases ,Animals ,Humans ,Protein Interaction Domains and Motifs ,Pyrroles ,Cytotoxicity ,bcl-2-Associated X Protein ,biology ,Bcl-2 family ,Drug Synergism ,Biological activity ,Xenograft Model Antitumor Assays ,Tumor Burden ,Cell biology ,Disease Models, Animal ,bcl-2 Homologous Antagonist-Killer Protein ,Oncology ,Drug Resistance, Neoplasm ,Hematologic Neoplasms ,Proteolysis ,Cancer cell ,biology.protein ,Myeloid Cell Leukemia Sequence 1 Protein ,Molecular Medicine ,Female ,Stromal Cells ,Pharmacophore ,Bcl-2 Homologous Antagonist-Killer Protein ,Research Paper ,Protein Binding - Abstract
Mcl-1, a pro-survival member of the Bcl-2 protein family, is an attractive target for cancer therapy. We have recently identified the natural product marinopyrrole A (maritoclax) as a novel small molecule Mcl-1 inhibitor. Here, we describe the structure-activity relationship study of pyoluteorin derivatives based on maritoclax. To date, we synthesized over 30 derivatives of maritoclax and evaluated their inhibitory actions and cytotoxicity toward Mcl-1-dependent cell lines. As a result, several functional groups were identified in the pyoluteorin motif that significantly potentiate biological activity. A number of such derivatives, KS04 and KS18, interacted with Mcl-1 in a conserved fashion according to NMR spectroscopy and molecular modeling. KS04 and KS18 induced apoptosis selectively in Mcl-1-dependent but not Bcl-2-dependent K562 cells through selective Mcl-1 down-regulation, and synergistically enhanced apoptosis in combination with ABT-737. Moreover, the intraperitoneal administration of KS18 (10 mg/kg/d) and ABT-737 (20 mg/kg/d) significantly suppressed the growth of ABT-737-resistant HL-60 xenografts in nude mice without apparent toxicity. Overall, we identified the pharmacophore of pyoluteorin derivatives that act as potent and promising Mcl-1 antagonists against Mcl-1-dependent hematological cancers.
- Published
- 2014
41. Blimp-1 impairs T cell function via upregulation of TIGIT and PD-1 in patients with acute myeloid leukemia
- Author
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Witold B. Rybka, Hui Zeng, Liuluan Zhu, Ming Wang, Raymond J. Hohl, Neil Palmisiano, Bei Jia, Jianhong Zhang, Michael G. Bayerl, W. Christopher Ehmann, Todd D. Schell, Yaxian Kong, Hong Zheng, and David F. Claxton
- Subjects
Adult ,Male ,Transcriptional Activation ,0301 basic medicine ,Cancer Research ,TIGIT ,T-Lymphocytes ,medicine.medical_treatment ,T cell ,Programmed Cell Death 1 Receptor ,lcsh:RC254-282 ,Flow cytometry ,Young Adult ,03 medical and health sciences ,Immune system ,PD-1 ,Acute myeloid leukemia (AML) ,medicine ,Humans ,Receptors, Immunologic ,Molecular Biology ,Transcription factor ,Aged ,T cell exhaustion ,medicine.diagnostic_test ,Gene Expression Regulation, Leukemic ,lcsh:RC633-647.5 ,Chemistry ,Research ,Myeloid leukemia ,lcsh:Diseases of the blood and blood-forming organs ,Hematology ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Blimp-1 ,Up-Regulation ,Leukemia, Myeloid, Acute ,Leukemia ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,Oncology ,Cancer research ,Cytokines ,Female ,Positive Regulatory Domain I-Binding Factor 1 - Abstract
Background T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) and programmed cell death protein 1 (PD-1) are important inhibitory receptors that associate with T cell exhaustion in acute myeloid leukemia (AML). In this study, we aimed to determine the underlying transcriptional mechanisms regulating these inhibitory pathways. Specifically, we investigated the role of transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) in T cell response and transcriptional regulation of TIGIT and PD-1 in AML. Methods Peripheral blood samples collected from patients with AML were used in this study. Blimp-1 expression was examined by flow cytometry. The correlation of Blimp-1 expression to clinical characteristics of AML patients was analyzed. Phenotypic and functional studies of Blimp-1-expressing T cells were performed using flow cytometry-based assays. Luciferase reporter assays and ChIP assays were applied to assess direct binding and transcription activity of Blimp-1. Using siRNA to silence Blimp-1, we further elucidated the regulatory role of Blimp-1 in the TIGIT and PD-1 expression and T cell immune response. Results Blimp-1 expression is elevated in T cells from AML patients. Consistent with exhaustion, Blimp-1+ T cells upregulate multiple inhibitory receptors including PD-1 and TIGIT. In addition, they are functionally impaired manifested by low cytokine production and decreased cytotoxicity capacity. Importantly, the functional defect is reversed by inhibition of Blimp-1 via siRNA knockdown. Furthermore, Blimp-1 binds to the promoters of PD-1 and TIGIT and positively regulates their expression. Conclusions Our study demonstrates an important inhibitory effect of Blimp-1 on T cell response in AML; thus, targeting Blimp-1 and its regulated molecules to improve the immune response may provide effective leukemia therapeutics. Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0486-z) contains supplementary material, which is available to authorized users.
- Published
- 2017
42. Therapeutic inhibition of BCL-2 and related family members
- Author
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David F. Claxton and Michelle A Levy
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Cell ,Antineoplastic Agents ,Apoptosis ,Pharmacology ,Biology ,Bioinformatics ,Targeted therapy ,03 medical and health sciences ,chemistry.chemical_compound ,Neoplasms ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Molecular Targeted Therapy ,Bh3 mimetics ,Sulfonamides ,Venetoclax ,Intrinsic apoptotic pathway ,General Medicine ,Bridged Bicyclo Compounds, Heterocyclic ,Small molecule ,Survival Rate ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Proto-Oncogene Proteins c-bcl-2 ,Drug Design - Abstract
BCL-2 proteins are key players in the balance of cell life and death. Their roles in the development and biology of cancer have been well established and continue to be investigated. Understanding the mechanisms by which these proteins regulate apoptosis has led to the development of small molecule targeted therapies that act to overcome the cell's ability to evade programmed cell death. Areas covered: The biology of the intrinsic apoptotic pathway is reviewed with attention to the varied roles of the anti-apoptotic members of the BCL-2 family. BH3 profiling is reviewed. Historical therapeutic agents are addressed, and currently investigated BH3 mimetics are described with attention to clinical significance. The limitations of BCL-2 family targeted drugs with regard to on-target and off-target toxicities are explored. Agents under development for targeting MCL-1 and other BCL-2 family members are discussed. Expert opinion: ABT-199 (venetoclax) and other BH3 mimetics have entered the clinical arena and show promising results in both hematologic and solid malignancies. Use of agents targeting this system will likely expand, and likely a number of malignant diseases will be successfully targeted resulting in improved treatment responses and patient survival.
- Published
- 2017
43. Genome-wide mapping of histone H3K9me2 in acute myeloid leukemia reveals large chromosomal domains associated with massive gene silencing and sites of genome instability
- Author
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Evgenya Y. Popova, David F. Claxton, Sergei A. Grigoryev, Thomas P. Loughran, Nikki Keasey, Abigail Harris-Becker, and Anna C. Salzberg
- Subjects
0301 basic medicine ,Transcription, Genetic ,Cellular differentiation ,Gene Expression ,lcsh:Medicine ,Biochemistry ,Proto-Oncogene Mas ,Hematologic Cancers and Related Disorders ,Histones ,White Blood Cells ,Database and Informatics Methods ,0302 clinical medicine ,Animal Cells ,hemic and lymphatic diseases ,Medicine and Health Sciences ,lcsh:Science ,Multidisciplinary ,Chromosome Biology ,Chromosome Mapping ,Myeloid leukemia ,Cell Differentiation ,Hematology ,Genomics ,Myeloid Leukemia ,Genomic Databases ,Chromatin ,Chromosomal Aberrations ,Cell biology ,Leukemia, Myeloid, Acute ,Histone ,Oncology ,030220 oncology & carcinogenesis ,Histone methyltransferase ,Translocations ,Epigenetics ,Cellular Types ,Research Article ,Acute Myeloid Leukemia ,Heterochromatin ,Immune Cells ,Immunology ,Bone Marrow Cells ,Biology ,Research and Analysis Methods ,Polymorphism, Single Nucleotide ,Genomic Instability ,03 medical and health sciences ,Histone H3 ,Leukemias ,DNA-binding proteins ,Genetics ,Humans ,Gene Regulation ,Gene Silencing ,Blood Cells ,lcsh:R ,Cancers and Neoplasms ,Biology and Life Sciences ,Computational Biology ,Proteins ,Cell Biology ,Genome Analysis ,Biological Databases ,030104 developmental biology ,Cancer research ,biology.protein ,lcsh:Q ,K562 Cells ,Granulocytes ,K562 cells - Abstract
A facultative heterochromatin mark, histone H3 lysine 9 dimethylation (H3K9me2), which is mediated by histone methyltransferases G9a/GLP (EHMT2/1), undergoes dramatic rearrangements during myeloid cell differentiation as observed by chromatin imaging. To determine whether these structural transitions also involve genomic repositioning of H3K9me2, we used ChIP-sequencing to map genome-wide topography of H3K9me2 in normal human granulocytes, normal CD34+ hematopoietic progenitors, primary myeloblasts from acute myeloid leukemia (AML) patients, and a model leukemia cell line K562. We observe that H3K9me2 naturally repositions from the previously designated “repressed” chromatin state in hematopoietic progenitors to predominant association with heterochromatin regions in granulocytes. In contrast, AML cells accumulate H3K9me2 on previously undefined large (> 100 Kb) genomic blocks that are enriched with AML-specific single nucleotide variants, sites of chromosomal translocations, and genes downregulated in AML. Specifically, the AML-specific H3K9me2 blocks are enriched with genes regulated by the proto-oncogene ERG that promotes stem cell characteristics. The AML-enriched H3K9me2 blocks (in contrast to the heterochromatin-associated H3K9me2 blocks enriched in granulocytes) are reduced by pharmacological inhibition of the histone methyltransferase G9a/GLP in K562 cells concomitantly with transcriptional activation of ERG and ETS1 oncogenes. Our data suggest that G9a/GLP mediate formation of transient H3K9me2 blocks that are preserved in AML myeloblasts and may lead to an increased rate of AML-specific mutagenesis and chromosomal translocations.
- Published
- 2017
44. Maritoclax induces apoptosis in acute myeloid leukemia cells with elevated Mcl-1 expression
- Author
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Brian M. Barth, Thomas P. Loughran, Krishne Gowda, Shantu Amin, Qiang Liu, Hong Gang Wang, David F. Claxton, and Kenichiro Doi
- Subjects
Male ,Cancer Research ,Stromal cell ,Daunorubicin ,Mice, Nude ,Antineoplastic Agents ,Apoptosis ,Bone Marrow Cells ,Pharmacology ,Biology ,Piperazines ,Nitrophenols ,Downregulation and upregulation ,Cell Line, Tumor ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Pyrroles ,neoplasms ,Sulfonamides ,Biphenyl Compounds ,Myeloid leukemia ,Drug Synergism ,Hematopoietic Stem Cells ,medicine.disease ,Coculture Techniques ,Mice, Inbred C57BL ,Myeloid Cell Leukemia Sequence 1 Protein ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Oncology ,Drug Resistance, Neoplasm ,Heterografts ,Molecular Medicine ,RNA Interference ,Bone marrow ,Stromal Cells ,Research Paper ,medicine.drug - Abstract
Acute myeloid leukemia (AML) is one of the deadliest leukemias for which there is an urgent and unmet need for the development of novel treatment strategies. Multiple drug resistance mechanisms mediate poor drug response and relapse in patients, and a selective Mcl-1 inhibitor has been speculated to be a promising agent in the treatment of AML. Here, we describe that maritoclax, a small molecule Mcl-1 inhibitor, induces Mcl-1 proteasomal degradation without transcriptional downregulation. Maritoclax killed AML cell lines and primary cells with elevated Mcl-1 levels through selective Mcl-1 downregulation, and synergized with ABT-737 to overcome Mcl-1-mediated ABT-737 resistance. Maritoclax was more effective than daunorubicin at inducing leukemic cell death when co-cultured with HS-5 bone marrow stroma cells, while being less toxic than daunorubicin against HS-5 stroma cells, primary mouse bone marrow cells, and hematopoietic progenitor cells. Moreover, maritoclax administration at 20 mg/kg/d intraperitoneally caused significant U937 tumor shrinkage, as well as 36% tumors remission rate in athymic nude mice, without apparent toxicity to healthy tissue or circulating blood cells. In summary, our studies suggest that maritoclax belongs to a novel class of Mcl-1 inhibitors that has the potential to be developed for the treatment of AML.
- Published
- 2014
45. PIGN gene expression aberration is associated with genomic instability and leukemic progression in acute myeloid leukemia with myelodysplastic features
- Author
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Yuka Imamura Kawasawa, David F. Claxton, Michael G. Bayerl, Joseph J. Drabick, Niklas Finnberg, Sara Shimko, Raymond J. Hohl, Thomas Abraham, Jeffrey J. Pu, Witold B. Rybka, Anna C. Salzberg, Robert A. Brodsky, W. Christopher Ehmann, Abigail Sido, Hong Gang Wang, Prashanth Gokare, Emmanuel K. Teye, Wafik S. El-Deiry, and Ping Xin
- Subjects
0301 basic medicine ,Genome instability ,Oncology ,Gerontology ,Male ,medicine.medical_specialty ,Gene Expression Array ,Cell Cycle Proteins ,Spindle Apparatus ,Models, Biological ,leukemogenesis ,Protein expression ,Genomic Instability ,03 medical and health sciences ,Bone Marrow ,Internal medicine ,Gene expression ,MDS ,AML with myelodysplasia-related changes (AML-MRC) ,Medicine ,Humans ,Transcriptional activity ,Hematology ,business.industry ,Gene Expression Regulation, Leukemic ,Gene Expression Profiling ,Phosphotransferases ,Myeloid leukemia ,Computational Biology ,Nuclear Proteins ,Exons ,Sequence Analysis, DNA ,Genes, p53 ,Introns ,Gene expression profiling ,Leukemia, Myeloid, Acute ,030104 developmental biology ,Cell Transformation, Neoplastic ,Gene Knockdown Techniques ,Myelodysplastic Syndromes ,Mutation ,Disease Progression ,Female ,business ,PIGN gene expression aberration ,Signal Transduction ,Research Paper - Abstract
// Emmanuel K. Teye 1, 2 , Abigail Sido 1, 2 , Ping Xin 1, 2 , Niklas K. Finnberg 3 , Prashanth Gokare 3 , Yuka I. Kawasawa 4, 5, 6 , Anna C. Salzberg 4, 5, 6 , Sara Shimko 1, 2 , Michael Bayerl 7 , W. Christopher Ehmann 1, 2 , David F. Claxton 1, 2 , Witold B. Rybka 1, 2, 7 , Joseph J. Drabick 1, 2 , Hong-Gang Wang 8 , Thomas Abraham 9, 10 , Wafik S. El-Deiry 3 , Robert A. Brodsky 11 , Raymond J.Hohl 1, 2 , Jeffrey J. Pu 1, 2, 7 1 Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, Pennsylvania, USA 2 Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA 3 Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA 4 Institute for Personalized Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA 5 Department of Pharmacology, Penn State University College of Medicine, Hershey, Pennsylvania, USA 6 Department of Biochemistry and Molecular Biology, Penn State University College of Medicine, Hershey, Pennsylvania, USA 7 Department of Pathology, Penn State University College of Medicine, Hershey, Pennsylvania, USA 8 Department of Pediatrics, Penn State University College of Medicine, Hershey, Pennsylvania, USA 9 Department of Neural and Behavioral Science, Pennsylvania State University, Hershey, Pennsylvania, USA 10 Microscopy Imaging Facility, Pennsylvania State University, Hershey, Pennsylvania, USA 11 Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Correspondence to: Jeffrey J. Pu, email: jeffreypu@gmail.com Keywords: PIGN gene expression aberration, MDS, AML with myelodysplasia-related changes (AML-MRC), genomic instability, leukemogenesis Received: November 25, 2016 Accepted: January 11, 2017 Published: February 07, 2017 ABSTRACT Previous studies have linked increased frequency of glycosylphosphatidylinositol-anchor protein (GPI-AP) deficiency with genomic instability and the risk of carcinogenesis. However, the underlying mechanism is still not clear. A randomForest analysis of the gene expression array data from 55 MDS patients (GSE4619) demonstrated a significant (p = 0.0007) correlation (Pearson r =-0.4068) between GPI-anchor biosynthesis gene expression and genomic instability, in which PIGN, a gene participating in GPI-AP biosynthesis, was ranked as the third most important in predicting risk of MDS progression. Furthermore, we observed that PIGN gene expression aberrations (increased transcriptional activity but diminished to no protein production) were associated with increased frequency of GPI-AP deficiency in leukemic cells during leukemic transformation/progression. PIGN gene expression aberrations were attributed to partial intron retentions between exons 14 and 15 resulting in frameshifts and premature termination which were confirmed by examining the RNA-seq data from a group of AML patients (phs001027.v1.p1). PIGN gene expression aberration correlated with the elevation of genomic instability marker expression that was independent of the TP53 regulatory pathway. Suppression/elimination of PIGN protein expression caused a similar pattern of genomic instability that was rescued by PIGN restoration. Finally, we found that PIGN bound to the spindle assembly checkpoint protein, MAD1, and regulated its expression during the cell cycle. In conclusion, PIGN gene is crucial in regulating mitotic integrity to maintain chromosomal stability and prevents leukemic transformation/progression.
- Published
- 2016
46. Oral sapacitabine for the treatment of acute myeloid leukaemia in elderly patients: a randomised phase 2 study
- Author
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Parameswaran Venugopal, Elias Jabbour, Stephen A. Strickland, Karen Seiter, Martha Arellano, Gary J. Schiller, Steven Coutre, David F. Claxton, Wendy Stock, Selina M. Luger, Lori J. Maness, Meir Wetzler, Stuart L. Goldberg, Hagop M. Kantarjian, William Plunkett, Stefan Faderl, Judy Chiao, and Guillermo Garcia-Manero
- Subjects
Male ,medicine.medical_specialty ,Neutropenia ,Administration, Oral ,Phases of clinical research ,Kaplan-Meier Estimate ,Sapacitabine ,Cytosine nucleoside ,Disease-Free Survival ,Drug Administration Schedule ,Article ,Group B ,law.invention ,Cytosine ,chemistry.chemical_compound ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Humans ,Aged ,Aged, 80 and over ,business.industry ,Anemia ,Pneumonia ,medicine.disease ,Thrombocytopenia ,Surgery ,Leukemia, Myeloid, Acute ,Oncology ,Tolerability ,chemistry ,Female ,Arabinonucleosides ,business ,Febrile neutropenia - Abstract
Summary Background Available treatments for acute myeloid leukaemia (AML) have limited durable activity and unsatisfactory safety profiles in most elderly patients. We assessed the efficacy and toxicity of sapacitabine, a novel oral cytosine nucleoside analogue, in elderly patients with AML. Methods In this randomised, phase 2 study, we recruited patients with AML who were either treatment naive or at first relapse and who were aged 70 years or older from 12 centres in the USA. We used a computer-generated randomisation sequence to randomly allocate eligible patients to receive one of three schedules of oral sapacitabine (1:1:1; stratified by a history of AML treatment): 200 mg twice a day for 7 days (group A); 300 mg twice a day for 7 days (group B); and 400 mg twice a day for 3 days each week for 2 weeks (group C). All schedules were given in 28 day cycles. To confirm the safety and tolerability of dosing schedules, after 20 patients had been treated in a group we enrolled an expanded cohort of 20–25 patients to that group if at least four patients had achieved complete remission or complete remission with incomplete blood count recovery, and if the 30 day death rate was 20% or less. Our primary endpoint was 1-year overall survival, analysed by intention-to-treat (ie, patients who have received at least one dose of sapacitabine) in those patients who had been randomly allocated to treatment. This trial is registered with ClinicalTrials.gov, number NCT00590187. Results Between Dec 27, 2007, and April 21, 2009, we enrolled 105 patients: 86 patients were previously untreated and 19 were at first relapse. Of the 60 patients randomly allocated to treatment, 1-year overall survival was 35% (95% CI 16–59) in group A, 10% (2–33) in group B, and 30% (13–54) in group C. 14 (13%) of 105 patients died within 30 days and 27 (26%) died within 60 days. The most common grade 3–4 adverse events were anaemia (eight of 40 patients in group A, 12 of 20 patients in group B, and 15 of 45 patients in group C), neutropenia (14 in group A, 10 in group B, 11 in group C), thrombocytopenia (24 in group A, 12 in group B, and 22 in group C), febrile neutropenia (16 in group A, nine in group B, and 22 in group C), and pneumonia (seven in group A, five in group B, and 10 in group C). The most common grade 5 events were pneumonia (two in group A, one in group B, and three in group C) and sepsis (six in group A, three in group B, and one in group C). Seven deaths were thought to be probably or possibly related to sapacitabine treatment. Interpretation Sapacitabine seems active and tolerable in elderly patients with AML. The 400 mg dose schedule had the best efficacy profile. Future investigations should aim to combine sapacitabine with other low-intensity therapies in elderly patients with AML. Funding Cyclacel Limited.
- Published
- 2012
47. Acid ceramidase is upregulated in AML and represents a novel therapeutic target
- Author
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Jong K. Yun, Dhimant Desai, Brian M. Barth, Thomas P. Loughran, Andy Awwad, Mark Kester, Hong Gang Wang, Stephen D. Turner, Xin Liu, Samy A.F. Morad, Edward H. Schuchman, Kenichiro Doi, David J. Feith, Arati Sharma, Ross L. Levine, Junjia Zhu, Todd E. Fox, Su Fern Tan, Alden Dewey, Myles C. Cabot, David F. Claxton, Barbara Spitzer, Mithun Vinod Shah, Shantu Amin, and Jason Liao
- Subjects
0301 basic medicine ,Gerontology ,Oncology ,Time Factors ,Acid Ceramidase ,Apoptosis ,0302 clinical medicine ,Sphingosine ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,Molecular Targeted Therapy ,Enzyme Inhibitors ,leukemia ,Myeloid leukemia ,humanities ,3. Good health ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Leukemia ,Leukemia, Myeloid, Acute ,myeloid cell leukemia sequence 1 protein ,030220 oncology & carcinogenesis ,Female ,RNA Interference ,Signal Transduction ,Research Paper ,medicine.medical_specialty ,Cell Survival ,Ceramide breakdown ,Antineoplastic Agents ,HL-60 Cells ,Ceramides ,Transfection ,Gene Expression Regulation, Enzymologic ,Unmet needs ,03 medical and health sciences ,Internal medicine ,medicine ,Overall survival ,Biomarkers, Tumor ,Animals ,Humans ,ceramide ,sphingosine 1-phosphate ,Dose-Response Relationship, Drug ,business.industry ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,Transplantation ,Mice, Inbred C57BL ,030104 developmental biology ,Lysophospholipids ,business - Abstract
// Su-Fern Tan 1 , Xin Liu 2 , Todd E. Fox 3 , Brian M. Barth 4 , Arati Sharma 2 , Stephen D. Turner 5 , Andy Awwad 2 , Alden Dewey 2 , Kenichiro Doi 6 , Barbara Spitzer 7 , Mithun Vinod Shah 8 , Samy A.F. Morad 9, 10 , Dhimant Desai 11 , Shantu Amin 11 , Junjia Zhu 2 , Jason Liao 2 , Jong Yun 2, 11 , Mark Kester 3 , David F. Claxton 2 , Hong-Gang Wang 2, 12 , Myles C. Cabot 9 , Edward H. Schuchman 13 , Ross L. Levine 7 , David J. Feith 1, 14 , Thomas P. Loughran, Jr 1, 14 1 Department of Medicine, University of Virginia, Charlottesville, VA, USA 2 Penn State Hershey Cancer Institute, Hershey, PA, USA 3 Department of Pharmacology, University of Virginia, Charlottesville, VA, USA 4 Department of Molecular, Cellular, and Biomedical Sciences, University of New Hampshire, Durham, NH, USA 5 Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, USA 6 Department of Pathology, Osaka City University Medical School, Osaka, Japan 7 Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA 8 Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA 9 Department of Biochemistry and Molecular Biology, East Carolina University, Brody School of Medicine, Greenville, NC, USA 10 Department of Pharmacology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt 11 Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA 12 Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, USA 13 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt. Sinai, New York, USA 14 University of Virginia Cancer Center, Charlottesville, VA, USA Correspondence to: Thomas P. Loughran, Jr, email: tploughran@virginia.edu Keywords: acid ceramidase, myeloid cell leukemia sequence 1 protein, ceramide, sphingosine 1-phosphate, leukemia Received: May 20, 2016 Accepted: October 13, 2016 Published: November 4, 2016 ABSTRACT There is an urgent unmet need for new therapeutics in acute myeloid leukemia (AML) as standard therapy has not changed in the past three decades and outcome remains poor for most patients. Sphingolipid dysregulation through decreased ceramide levels and elevated sphingosine 1-phosphate (S1P) promotes cancer cell growth and survival. Acid ceramidase (AC) catalyzes ceramide breakdown to sphingosine, the precursor for S1P. We report for the first time that AC is required for AML blast survival. Transcriptome analysis and enzymatic assay show that primary AML cells have high levels of AC expression and activity. Treatment of patient samples and cell lines with AC inhibitor LCL204 reduced viability and induced apoptosis. AC overexpression increased the expression of anti-apoptotic Mcl-1, significantly increased S1P and decreased ceramide. Conversely, LCL204 induced ceramide accumulation and decreased Mcl-1 through post-translational mechanisms. LCL204 treatment significantly increased overall survival of C57BL/6 mice engrafted with leukemic C1498 cells and significantly decreased leukemic burden in NSG mice engrafted with primary human AML cells. Collectively, these studies demonstrate that AC plays a critical role in AML survival through regulation of both sphingolipid levels and Mcl-1. We propose that AC warrants further exploration as a novel therapeutic target in AML.
- Published
- 2016
48. T-Cell Immunoglobulin and ITIM Domain (TIGIT) Associates with CD8+ T-Cell Exhaustion and Poor Clinical Outcome in AML Patients
- Author
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Jianhong Zhang, Liuluan Zhu, W. Christopher Ehmann, Witold B. Rybka, Todd D. Schell, Melissa R. George, Yaxian Kong, David F. Claxton, Hong Zheng, and Hui Zeng
- Subjects
0301 basic medicine ,Adult ,Antigens, Differentiation, T-Lymphocyte ,Male ,Cancer Research ,Myeloid ,medicine.medical_treatment ,T cell ,Apoptosis ,Biology ,Lymphocyte Activation ,03 medical and health sciences ,Young Adult ,TIGIT ,medicine ,Cytotoxic T cell ,Humans ,Treatment Failure ,RNA, Small Interfering ,Receptors, Immunologic ,Aged ,Middle Aged ,medicine.disease ,Transplantation ,Leukemia ,Leukemia, Myeloid, Acute ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,Oncology ,Immunology ,Cytokines ,Female ,RNA Interference ,CD8 ,T-Lymphocytes, Cytotoxic - Abstract
Purpose: T-cell immunoglobulin and immunoreceptor tyrosine–based inhibitory motif (ITIM) domain (TIGIT) is a recently identified T-cell coinhibitory receptor. In this study, we aimed to determine the clinical impact of TIGIT in patients with acute myelogenous leukemia (AML) and dissect the role of TIGIT in the pathogenesis of leukemia progression. Experimental Design: TIGIT expression on T cells from peripheral blood collected from patients with AML was examined by flow cytometry. The correlation of TIGIT expression to clinical outcomes, including rate of complete remission and relapse post-allogeneic stem cell transplantation (alloSCT) in AML patients, was analyzed. Phenotypic and functional study (cytokine release, proliferation, killing, and apoptosis) of TIGIT-expressing T cells were performed. Using siRNA to silence TIGIT, we further elucidated the regulatory role of TIGIT in the T-cell immune response by dissecting the effect of TIGIT knockdown on cytokine release and apoptosis of T cells from AML patients. Results: TIGIT expression on CD8+ T cells is elevated in AML patients and high-TIGIT correlates with primary refractory disease and leukemia relapse post-alloSCT. TIGIT+ CD8+ T cells display phenotypic features of exhaustion and exhibit functional impairment manifested by low production of cytokines and high susceptibility to apoptosis. Importantly, their functional defects are reversed by TIGIT knockdown. Conclusions: TIGIT contributes to functional T-cell impairment and associates with poor clinical outcome in AML. Our study suggests that blockade of TIGIT to restore T-cell function and antitumor immunity may represent a novel effective leukemia therapeutic. Clin Cancer Res; 22(12); 3057–66. ©2016 AACR.
- Published
- 2015
49. Outpatient consolidation treatment with clofarabine in a phase 2 study of older adult patients with previously untreated acute myelogenous leukemia
- Author
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Martha Arellano, Stefan Faderl, Roger M. Lyons, Harry P. Erba, Janice Gabrilove, David F. Claxton, Dirk Huebner, Tibor Kovacsovics, Pritesh J. Gandhi, and Hagop M. Kantarjian
- Subjects
Male ,Antimetabolites, Antineoplastic ,Cancer Research ,medicine.medical_specialty ,Neutropenia ,Gastrointestinal Diseases ,Nausea ,Phases of clinical research ,Hypokalemia ,Article ,Drug Administration Schedule ,Myelogenous ,Internal medicine ,Outpatients ,Ambulatory Care ,medicine ,Humans ,Clofarabine ,Adverse effect ,Aged ,Inpatients ,Adenine Nucleotides ,business.industry ,Consolidation Chemotherapy ,Pneumonia ,Hematology ,Acute Kidney Injury ,Length of Stay ,Middle Aged ,medicine.disease ,Surgery ,Leukemia, Myeloid, Acute ,Oncology ,Quality of Life ,Vomiting ,Female ,Arabinonucleosides ,medicine.symptom ,business ,Febrile neutropenia ,medicine.drug - Abstract
This report describes outpatient (OP) administration of clofarabine in older patients ( ≥ 60 years) with untreated acute myelogenous leukemia (AML). Overall, 112 patients underwent clofarabine induction. Clofarabine was administered to 35 OPs for a total of 72 OP cycles, with 81% of these cycles representing consolidation treatment. Median length of hospital stay was 0 – 6 days and 5 – 25 days across OP and inpatient (IP) cycles, respectively. The most common adverse events (AEs) were nausea, vomiting, diarrhea, febrile neutropenia, edema, hypokalemia and pneumonia. The overall frequency of treatment-emergent grade ≥ 3 AEs and serious AEs was generally not diff erent with IP or OP administration of clofarabine. No deaths were reported within 30 days following OP or IP consolidation cycles. In the appropriately selected older patient, OP administration of clofarabine consolidation appears feasible, is as well tolerated as IP administration and has potential to contribute to the quality of life in elderly patients with AML.
- Published
- 2011
50. Targeted Indocyanine-Green-Loaded Calcium Phosphosilicate Nanoparticles for In Vivo Photodynamic Therapy of Leukemia
- Author
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Sriram S. Shanmugavelandy, Brian M. Barth, Thomas P. Loughran, James M. Kaiser, Trevor M. Goff, Nicole A. DiVittore, David F. Claxton, Christopher O. McGovern, James H. Adair, Erhan I. Altinoglu, Mark Kester, Daniza Crespo-Gonzalez, and Nicole R. Keasey
- Subjects
Calcium Phosphates ,Indocyanine Green ,medicine.medical_treatment ,Childhood cancer ,General Physics and Astronomy ,chemistry.chemical_element ,Photodynamic therapy ,Calcium ,Substrate Specificity ,Mice ,chemistry.chemical_compound ,In vivo ,Cancer stem cell ,Cell Line, Tumor ,hemic and lymphatic diseases ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,General Materials Science ,Molecular Targeted Therapy ,Leukemia ,Photosensitizing Agents ,Singlet Oxygen ,business.industry ,Silicates ,General Engineering ,Reproducibility of Results ,food and beverages ,Cancer ,medicine.disease ,Endocytosis ,Proto-Oncogene Proteins c-kit ,Photochemotherapy ,chemistry ,Immunology ,Disease Progression ,Neoplastic Stem Cells ,Cancer research ,Female ,business ,human activities ,Indocyanine green - Abstract
Leukemia is one of the most common and aggressive adult cancers, as well as the most prevalent childhood cancer. Leukemia is a cancer of the hematological system and can be divided into a diversity of unique malignancies based on the onset of the disease as well as the specific cell lineages involved. Cancer stem cells, including recently identified leukemia stem cells (LSCs), are hypothesized to be responsible for cancer development, relapse, and resistance to treatment, and new therapeutics targeting these cellular populations are urgently needed. Nontoxic and nonaggregating calcium phosphosilicate nanoparticles (CPSNPs) encapsulating the near-infrared fluoroprobe indocyanine green (ICG) were recently developed for diagnostic imaging and drug delivery as well as for photodynamic therapy (PDT) of solid tumors. Prior studies revealed that specific targeting of CPSNPs allowed for enhanced accumulation within breast cancer tumors, via CD71 targeting, or pancreatic cancer tumors, via gastrin receptor targeting. In the present study, ICG-loaded CPSNPs were evaluated as photosensitizers for PDT of leukemia. Using a novel bioconjugation approach to specifically target CD117 or CD96, surface features enhanced on leukemia stem cells, in vitro ICG-CPSNP PDT of a murine leukemia cell line and human leukemia samples were dramatically improved. Furthermore, the in vivo efficacy of PDT was dramatically enhanced in a murine leukemia model by utilizing CD117-targeted ICG-CPSNPs, resulting in 29% disease-free survival. Altogether, this study demonstrates that leukemia-targeted ICG-loaded CPSNPs offer the promise to effectively treat relapsing and multidrug-resistant leukemia and to improve the life of leukemia patients.
- Published
- 2011
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