21 results on '"Nicole Grieselhuber"'
Search Results
2. Impact of Opioid Use after Blood and Marrow Transplantation (BMT): A Single-Center Analysis
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Noha N. Soror, Ayman Saad, Nicole Grieselhuber, Marcin Puto, Alice S. Mims, Naresh Bumma, Abdullah Khan, Yvonne A. Efebera, Bradley W. Blaser, Karilyn Larkin, Basem M. William, Sam Penza, Maria Chaudhry, Srinivas Devarakonda, Sumithira Vasu, Ashleigh Keiter, Samantha Jaglowski, Jonathan E. Brammer, Sarah A Wall, Don M. Benson, Qiuhong Zhao, Patrick Elder, Hannah Choe, and Ashley E. Rosko
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Oncology ,Transplantation ,medicine.medical_specialty ,Marrow transplantation ,business.industry ,Opioid use ,Cell Biology ,Hematology ,Single Center ,Internal medicine ,medicine ,Molecular Medicine ,Immunology and Allergy ,business - Published
- 2021
3. The Incidence of Invasive Fungal Infections in Patients With AML Treated With a Hypomethylating Agent
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James S. Blachly, Bhavana Bhatnagar, Sumithira Vasu, Nicole Grieselhuber, Sarah A Wall, Gregory K. Behbehani, Alison R. Walker, Joseph Maakaron, Tamanna Haque, Mark E. Lustberg, Ying Huang, Michael Ozga, Karilyn Larkin, and Alice S. Mims
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Antifungal Agents ,Decitabine ,Neutropenia ,Logistic regression ,symbols.namesake ,Bronchoscopy ,Internal medicine ,medicine ,Humans ,Fisher's exact test ,Aged ,Retrospective Studies ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,Incidence ,Incidence (epidemiology) ,Myeloid leukemia ,Hematology ,Middle Aged ,medicine.disease ,Leukemia, Myeloid, Acute ,Oncology ,Hypomethylating agent ,symbols ,Female ,business ,Invasive Fungal Infections ,medicine.drug - Abstract
Background Newly diagnosed patients with acute myeloid leukemia (AML) who receive induction with a hypomethylating agent (HMA) are often neutropenic with an increased risk for invasive fungal infections (IFIs). This study analyzed the incidence and risk factors for IFIs in these patients, evaluated clinical patterns in antifungal prophylaxis, and assessed the diagnostic utility of tests in this setting. Patients and Methods We studied 117 newly diagnosed patients with AML treated with HMAs at our center, divided into groups based on concern for IFI (cIFI: all possible, probable, and proven IFIs) versus no concern for IFI. The Fisher exact test compared patients with cIFI versus without, and a multivariable logistic regression model estimated odds for cIFI. Results Sixty-seven (57%) patients had cIFI, with 48 possible IFIs, 17 probable, and 2 proven cases. There was no difference in incidence based on home zip code, but the presence of chronic obstructive pulmonary disease was highly associated with cIFI (P = .001), as was male gender (P = .01). Neutropenia at treatment initiation was borderline in significance (P = .08). In diagnostics, 9% of patients had positive serum fungal markers, and 30 patients underwent bronchoscopy, with only 27% of cases yielding positive results. There was a difference in treatment regimens between patients receiving antifungal prophylaxis with mold coverage versus without mold coverage with respect to cIFI (P = .04). Conclusions cIFI in patients with AML treated with HMAs remains significant, especially in males and those with chronic obstructive pulmonary disease, who were found to be at higher risk. This may prompt clinicians to consider anti-mold prophylaxis in this setting.
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- 2021
4. Longitudinal Survival Outcomes in Allogeneic Stem Cell Transplantation: An Institutional Experience
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Justin Jiang, Audrey M. Sigmund, Qiuhong Zhao, Patrick Elder, Don M. Benson, Sumithira Vasu, Samantha Jaglowski, Alice Mims, Hannah Choe, Karilyn Larkin, Jonathan E. Brammer, Sarah Wall, Nicole Grieselhuber, Ayman Saad, Sam Penza, Yvonne A. Efebera, and Nidhi Sharma
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Cancer Research ,allogenic transplantation ,overall survival ,progression-free survival ,graft-versus-host disease ,Oncology - Abstract
Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a potentially curative treatment for many hematological disorders, but is often complicated by relapse of the underlying disease, graft-versus-host disease (GVHD), and infectious complications. We conducted a retrospective analysis on patients undergoing allo-SCT from 1984 to 2018 to better understand how survival has changed longitudinally with therapeutic advancements made to mitigate these complications. Method: We analyzed data from 1943 consecutive patients who received allo-SCT. Patients were divided into groups (gps) based on the year (yr) of transplant. Primary endpoints were overall survival (OS), progression free survival (PFS), and GVHD-free relapse-free survival (GRFS). Secondary endpoints were the cumulative incidences of grade II–IV and grade III–IV acute GVHD (aGVHD), chronic GVHD (cGVHD), and non-relapse mortality (NRM). Results: Our study found statistically significant improvements in OS, PFS, and GRFS. Five-year PFS among the groups increased from 24% to 48% over the years. Five-year OS increased from 25% to 53%. Five-year GRFS significantly increased from 6% to 14%, but remained relatively unchanged from 2004 to 2018. Cumulative incidences of grade II–IV aGVHD increased since 2009 (p < 0.001). However, cumulative incidence of NRM decreased since 2004 (p < 0.001). Conclusions: Our data show improved OS, PFS, and GRFS post allo-SCT over decades. This may be attributed to advances in supportive care and treatments focused on mitigation of GVHD and relapse.
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- 2022
5. Impact of Race and Geographic Area of Residence on Outcomes After Allogeneic Stem Cell Transplant
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Audrey M. Sigmund, Qiuhong Zhao, Justin Jiang, Patrick Elder, Don M. Benson, Ashley Rosko, Naresh Bumma, Abdullah Khan, Srinivas Devarakonda, Sumithira Vasu, Samantha Jaglowski, Alice Mims, Hannah Choe, Karilyn Larkin, Jonathan Brammer, Sarah Wall, Nicole Grieselhuber, Ayman Saad, Sam Penza, Yvonne A. Efebera, and Nidhi Sharma
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Cancer Research ,Oncology - Abstract
BackgroundAllogeneic hematopoietic stem cell transplant (allo-HCT) is a potential curative therapy for a variety of hematologic disorders. However, it requires highly specialized care that is only available at select centers across the country. Thus, minority populations are at risk for healthcare disparities in access to and outcomes of allo-HCT. Our study aimed to assess the impact of race and location of residence on outcomes of allo-HCT.MethodsWe performed a retrospective analysis of all patients who underwent allo-HCT at the Ohio State University from 1984 to 2018. Patients were divided by race (Caucasian, African American, and other) and grouped by zip code into rural, suburban, and urban groups. Primary endpoints included progression-free survival (PFS) and overall survival (OS).ResultsOf the 1,943 patients included in the study, 94.3% self-identified as Caucasian, 4.6% African American, and 1.1% other. In total, 63.4% lived in rural areas, 22.9% suburban, and 13.8% urban. There was no significant difference in OS or PFS by race (p = 0.15, 0.21) or place of residence (p = 0.39, 0.17). In addition, no difference in nonrelapse mortality, acute and chronic graft-versus-host disease (GVHD), and GVHD-free relapse-free survival (GRFS) was seen among the race or place of residence.ConclusionOur study suggests that when appropriate access to HCT is given, there is no difference in outcomes based on race, ethnicity or place of primary residence. Further research is needed to further evaluate barriers for these patients to undergo transplant and help mitigate these barriers.
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- 2021
6. Novel Targeted Therapeutics in Acute Myeloid Leukemia: an Embarrassment of Riches
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Alice S. Mims and Nicole Grieselhuber
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Cancer Research ,medicine.medical_specialty ,IDH1 ,medicine.medical_treatment ,Article ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,hemic and lymphatic diseases ,Biomarkers, Tumor ,Medicine ,Humans ,Molecular Targeted Therapy ,neoplasms ,Protein Kinase Inhibitors ,Clinical Trials as Topic ,Hematology ,business.industry ,Drug discovery ,Myeloid leukemia ,Disease Management ,DOT1L ,Clinical trial ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Bone marrow ,Disease Susceptibility ,business ,Nucleophosmin ,030215 immunology - Abstract
PURPOSE OF REVIEW: Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow that has a poor prognosis with traditional cytotoxic chemotherapy, especially in elderly patients. In recent years, small molecule inhibitors targeting AML associated IDH1, IDH2 and FLT3 mutations have been FDA approved. However, the majority of AML cases do not have a targetable mutation. A variety of novel agents targeting both previously untargetable mutations and general pathways in AML are currently being investigated. Herein, we review selected new targeted therapies currently in early phase clinical investigation in AML. RECENT FINDINGS: The DOT1L inhibitor pinometostat in KMT2A rearranged AML, the menin inhibitors KO-539 and SYNDX-5613 in KMT2Ar and NPM1 mutated AML and the mutant TP53 inhibitor APR-246 are examples of novel agents targeting specific mutations in AML. In addition, BET inhibitors, polo-like kinase inhibitors and MDM2 inhibitors are promising new drug classes for AML which do not depend on the presence of a particular mutation. SUMMARY: AML remains in incurable disease for many patients but advances in genomics, epigenetics and drug discovery have led to the development of many potential novel therapeutic agents, many of which are being investigated in on-going clinical trials. Additional studies will be necessary to determine how best to incorporate these novel agents into routine clinical treatment of AML.
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- 2021
7. Targeting DNA damage repair functions of two histone deacetylases, HDAC8 and SIRT6, sensitizes acute myeloid leukemia to NAMPT inhibition
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Samuel K. Kulp, Nicole Grieselhuber, James S. Blachly, Tierney Kauffman, Deepa Sampath, Hannah Phillips, Matthew Cannon, Lapo Alinari, Youssef Youssef, Pearlly S. Yan, Katie Williams, Larry Beaver, Lai Tzung-Huei, Steven Sher, Allison M. Mustonen, Christopher C. Coss, Alice S. Mims, John C. Byrd, Shelley Orwick, Lindsey T. Brinton, Daniel Canfield, Pu Zhang, Shaneice Mitchell, Amy Lehman, Wing Keung Chan, and Rosa Lapalombella
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0301 basic medicine ,Male ,Cancer Research ,DNA End-Joining Repair ,Indoles ,Combination therapy ,DNA repair ,Nicotinamide phosphoribosyltransferase ,Aminopyridines ,Synthetic lethality ,Hydroxamic Acids ,Article ,Histone Deacetylases ,03 medical and health sciences ,chemistry.chemical_compound ,Gene Knockout Techniques ,Mice ,0302 clinical medicine ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Animals ,Humans ,Sirtuins ,Nicotinamide Phosphoribosyltransferase ,Acrylamides ,business.industry ,Myeloid leukemia ,Recombinational DNA Repair ,HDAC8 ,Phenylbutyrates ,Xenograft Model Antitumor Assays ,Non-homologous end joining ,Repressor Proteins ,Haematopoiesis ,Leukemia, Myeloid, Acute ,030104 developmental biology ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Cytokines ,business ,DNA Damage - Abstract
Purpose: Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors (NAMPTi) are currently in development, but may be limited as single-agent therapy due to compound-specific toxicity and cancer metabolic plasticity allowing resistance development. To potentially lower the doses of NAMPTis required for therapeutic benefit against acute myeloid leukemia (AML), we performed a genome-wide CRISPRi screen to identify rational disease-specific partners for a novel NAMPTi, KPT-9274. Experimental Design: Cell lines and primary cells were analyzed for cell viability, self-renewal, and responses at RNA and protein levels with loss-of-function approaches and pharmacologic treatments. In vivo efficacy of combination therapy was evaluated with a xenograft model. Results: We identified two histone deacetylases (HDAC), HDAC8 and SIRT6, whose knockout conferred synthetic lethality with KPT-9274 in AML. Furthermore, HDAC8-specific inhibitor, PCI-34051, or clinical class I HDAC inhibitor, AR-42, in combination with KPT-9274, synergistically decreased the survival of AML cells in a dose-dependent manner. AR-42/KPT-9274 cotreatment attenuated colony-forming potentials of patient cells while sparing healthy hematopoietic cells. Importantly, combined therapy demonstrated promising in vivo efficacy compared with KPT-9274 or AR-42 monotherapy. Mechanistically, genetic inhibition of SIRT6 potentiated the effect of KPT-9274 on PARP-1 suppression by abolishing mono-ADP ribosylation. AR-42/KPT-9274 cotreatment resulted in synergistic attenuation of homologous recombination and nonhomologous end joining pathways in cell lines and leukemia-initiating cells. Conclusions: Our findings provide evidence that HDAC8 inhibition- or shSIRT6-induced DNA repair deficiencies are potently synergistic with NAMPT targeting, with minimal toxicity toward normal cells, providing a rationale for a novel–novel combination-based treatment for AML.
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- 2021
8. Effect of Early Post-Transplantation Tacrolimus Concentration on the Risk of Acute Graft-Versus-Host Disease in Allogenic Stem Cell Transplantation
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Don M. Benson, Jonathan E. Brammer, Nicole Grieselhuber, Karilyn Larkin, Nidhi Sharma, Naresh Bumma, Qiuhong Zhao, Abdullah Khan, Patrick Elder, Samantha Jaglowski, Alice S. Mims, Bin Ni, Hannah Choe, Yvonne A. Efebera, Srinivas Devarakonda, Sam Penza, Maria Chaudhry, Basem M. William, Ayman Saad, Marcin Puto, Ashley E. Rosko, Sumithira Vasu, and Sarah A Wall
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Cancer Research ,medicine.medical_specialty ,chemical and pharmacologic phenomena ,Lower risk ,Gastroenterology ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,allogeneic stem cell transplantation ,Internal medicine ,hemic and lymphatic diseases ,graft versus host disease ,medicine ,Cumulative incidence ,tacrolimus ,relapse ,business.industry ,Myeloid leukemia ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Tacrolimus ,Calcineurin ,Transplantation ,stomatognathic diseases ,Graft-versus-host disease ,surgical procedures, operative ,Oncology ,Quartile ,030220 oncology & carcinogenesis ,business ,030215 immunology - Abstract
Acute graft versus host disease (aGVHD) remains a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT). Tacrolimus (TAC), a calcineurin inhibitor that prevents T-cell activation, is commonly used as a GVHD prophylaxis. However, there is variability in the serum concentrations of TAC, and little is known on the impact of early TAC levels on aGVHD. We retrospectively analyzed 673 consecutive patients undergoing allo-HSCT at the Ohio State University between 2002 and 2016. Week 1 TAC was associated with a lower risk of aGVHD II–IV at TAC level ≥ 10.15 ng/mL (p = 0.03) compared to the lowest quartile. The cumulative incidence of relapse at 1, 3 and 5 years was 33%, 38% and 41%, respectively. TAC levels at week 2, ≥ 11.55 ng/mL, were associated with an increased risk of relapse (p = 0.01) compared to the lowest quartile. Subset analysis with acute myeloid leukemia and myelodysplastic syndrome patients showed significantly reduced aGVHD with TAC level ≥ 10.15 ng/mL at week 1 and a higher risk of relapse associated with week 2 TAC level ≥11.55 ng/mL (p = 0.02). Hence, achieving ≥10 ng/mL during the first week of HCT may mitigate the risk of aGVHD. However, levels (>, 11 ng/mL) beyond the first week may be associated with suppressed graft versus tumor effect and higher relapse.
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- 2021
9. Genomic analysis of cellular hierarchy in acute myeloid leukemia using ultrasensitive LC-FACSeq
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Tzyy-Jye Doong, Nicole Grieselhuber, Nyla A. Heerema, Gerard Lozanski, Cecelia R. Miller, Karilyn Larkin, Tierney Kauffman, Rosa Lapalombella, Arletta Lozanski, John C. Byrd, Clara D. Bloomfield, Casey Cempre, Shelley Orwick, Bhavana Bhatnagar, Alice S. Mims, Lynne V. Abruzzo, Gregory K. Behbehani, Eileen Hu, Virginia M. Goettl, Alison Walker, Steven Sher, Pu Zhang, Caner Saygin, Jordan N. Skinner, James S. Blachly, Jadwiga Labanowska, and Deedra Nicolet
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0301 basic medicine ,Adult ,Male ,Cancer Research ,Biology ,Somatic evolution in cancer ,Article ,Acute myeloid leukaemia ,Immunophenotyping ,Clonal Evolution ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,medicine ,Biomarkers, Tumor ,Humans ,Cancer genetics ,Aged ,Aged, 80 and over ,Myeloid leukemia ,Hematopoietic stem cell ,Correction ,Hematology ,Genomics ,Amplicon ,Middle Aged ,medicine.disease ,Flow Cytometry ,Hematopoietic Stem Cells ,Prognosis ,Haematopoiesis ,Leukemia ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,DNA methylation ,Mutation ,Cancer research ,Neoplastic Stem Cells ,Female ,Stem cell ,Follow-Up Studies - Abstract
Hematopoiesis is hierarchical, and it has been postulated that acute myeloid leukemia (AML) is organized similarly with leukemia stem cells (LSCs) residing at the apex. Limited cells acquired by fluorescence activated cell sorting in tandem with targeted amplicon-based sequencing (LC-FACSeq) enables identification of mutations in small subpopulations of cells, such as LSCs. Leveraging this, we studied clonal compositions of immunophenotypically-defined compartments in AML through genomic and functional analyses at diagnosis, remission and relapse in 88 AML patients. Mutations involving DNA methylation pathways, transcription factors and spliceosomal machinery did not differ across compartments, while signaling pathway mutations were less frequent in putative LSCs. We also provide insights into TP53-mutated AML by demonstrating stepwise acquisition of mutations beginning from the preleukemic hematopoietic stem cell stage. In 10 analyzed cases, acquisition of additional mutations and del(17p) led to genetic and functional heterogeneity within the LSC pool with subclones harboring varying degrees of clonogenic potential. Finally, we use LC-FACSeq to track clonal evolution in serial samples, which can also be a powerful tool to direct targeted therapy against measurable residual disease. Therefore, studying clinically significant small subpopulations of cells can improve our understanding of AML biology and offers advantages over bulk sequencing to monitor the evolution of disease.
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- 2020
10. BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor
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Yan Ma, Lianbo Yu, Elizabeth Baskin, Matthew Cannon, Todd Ewing, Laura Sanftner, Katie Williams, Shaneice Mitchell, Zachary A. Hing, Garson Tsang, Christina Tantoy, Hamid Rezaei, Nicole Grieselhuber, John C. Byrd, Marika Nespi, Rosa Lapalombella, David M. Lucas, Deepa Sampath, Adhirai Marimuthu, Songyuan Shi, Jason Walters, Ben Powell, Heidi Carias, Gaston Habets, Ewy Mathé, Tzung Huei Lai, Ken C. Dong, Robert A. Baiocchi, Larry Beaver, Jennifer A. Woyach, Jiazhong Zhang, Virginia M. Goettl, James S. Blachly, Wayne Spevak, Lapo Alinari, Hatice Gulcin Ozer, Lindsey T. Brinton, Chao Zhang, Prabha N. Ibrahim, Paul Severson, Dalia El-Gamal, Bonnie K. Harrington, Gideon Bollag, Bernice Matusow, Ying Zhang, Amy Lehman, and Rafe Shellooe
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0301 basic medicine ,BRD4 ,Pyridines ,Chronic lymphocytic leukemia ,Antineoplastic Agents ,Cell Cycle Proteins ,Mice, SCID ,Biology ,Article ,BET inhibitor ,Mice ,03 medical and health sciences ,immune system diseases ,Cell Line, Tumor ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Pyrroles ,Epigenetics ,Cell Proliferation ,Gene Expression Regulation, Leukemic ,Gene Expression Profiling ,breakpoint cluster region ,Nuclear Proteins ,Isoxazoles ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Xenograft Model Antitumor Assays ,Bromodomain ,Gene expression profiling ,030104 developmental biology ,Oncology ,Cancer research ,Epigenetic therapy ,Signal Transduction ,Transcription Factors - Abstract
Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is overexpressed in CLL and is enriched proximal to genes upregulated or de novo expressed in CLL with known functions in disease pathogenesis and progression. These genes, including key members of the B-cell receptor (BCR) signaling pathway, provide a rationale for this therapeutic approach to identify new targets in alternative types of cancer. Additionally, we describe PLX51107, a structurally distinct BET inhibitor with novel in vitro and in vivo pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in preclinical models of CLL. Herein, the discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers. Significance: To date, functional studies of BRD4 in CLL are lacking. Through integrated genomic, functional, and pharmacologic analyses, we uncover the existence of BRD4-regulated core CLL transcriptional programs and present preclinical proof-of-concept studies validating BET inhibition as an epigenetic approach to target BCR signaling in CLL. Cancer Discov; 8(4); 458–77. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 371
- Published
- 2018
11. Effect of Age on Outcomes of Allogeneic Transplantation in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome
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Nicole Grieselhuber, Marcos de Lima, Karilyn Larkin, Justin Jiang, Jonathan E. Brammer, Samantha Jaglowski, Audrey M. Sigmund, Qiuhong Zhao, Maria Chaudhry, Naresh Bumma, Abdullah Khan, Srinivas Devarakonda, Alice S. Mims, Nidhi Sharma, Sam Penza, Yvonne A. Efebera, Hannah Choe, Ashley E. Rosko, Sumithira Vasu, Patrick Elder, Sarah A Wall, Don M. Benson, and Ayman Saad
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Oncology ,medicine.medical_specialty ,Allogeneic transplantation ,business.industry ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Biochemistry ,hemic and lymphatic diseases ,Internal medicine ,medicine ,In patient ,business - Abstract
Background: Allogeneic stem cell transplantation (allo-SCT) has become an increasingly important consolidation treatment option for patients with acute myeloid leukemia (AML) and as upfront therapy for patients with high-risk myelodysplastic syndrome (MDS). Although the median age at diagnosis for both diseases is above 65 years, studies evaluating allo-SCT as treatment option for patients aged 65 years or older are limited. Further, as the population ages, the number of patients above 65 years considered for allo-SCT will continue to rise. Thus, the aim of our current investigation was to analyze outcomes based on age in AML/MDS patients Methods: A retrospective analysis was performed for all AML/MDS patients who received allo-SCT between January 1984 and December 2018 at our institution. Primary endpoints included progression free survival (PFS) and overall survival (OS). PFS was counted from the day of transplantation to relapse or death. OS was defined as survival from the day of allo-SCT until death from any cause, with censoring of patients known to be alive at the time of last follow-up. PFS and OS were calculated using Kaplan Meier Curves. Secondary endpoints included cumulative incidences of grade II-IV and III-IV acute GVHD (aGVHD), chronic GVHD (cGVHD), relapse, and non-relapse mortality (NRM). Cumulative incidence rates of aGVHD, cGVHD, relapse, NRM were estimated and compared using Gray's test accounting for competing risks. Results: The cohort consisted of 900 AML/MDS patients, with 150 patients ≥65 years and 750 patients The median time from diagnosis to transplantation was 176 days (range: 55-4920) for age Conclusion: Overall, our study suggests similar outcomes for elderly patients undergoing allo-HCT as compared to their counterparts, which is in line with prior studies. This likely is due to advancements in the transplant field, including the development of RIC and alternative donors, which have allowed greater access to transplant for older adults. Utilization of allo-HCT is feasible and should be considered for AML/MDS patients ≥65 years. Further research is underway to evaluate the important determinants of health status in older patients undergoing allo-HCT and to ultimately help predict NRM (BMT CTN 1704). Figure 1 Figure 1. Disclosures Bumma: Amgen, Sanofi: Speakers Bureau; Janssen, Oncopeptides, Sanofi: Consultancy. Vasu: Seattle Genetics: Other: travel support; Boehringer Ingelheim: Other: Travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Jaglowski: Takeda: Consultancy; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy; Novartis: Consultancy, Research Funding. Mims: Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Kura Oncology: Consultancy; Leukemia and Lymphoma Society: Consultancy; Glycomemetics: Research Funding; Aptevo: Research Funding; Xencor: Research Funding; Daiichi-Saynko: Consultancy. Brammer: Celgene: Research Funding; Seattle Genetics: Speakers Bureau; Kymera Therapeutics: Consultancy. Saad: Incyte Pharmaceuticals: Consultancy; careDx: Consultancy; Amgen: Research Funding; Kadmon: Research Funding; OrcaBio: Research Funding; Magenta Therapeutics: Consultancy. de Lima: Miltenyi Biotec: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.
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- 2021
12. Correction: Genomic analysis of cellular hierarchy in acute myeloid leukemia using ultrasensitive LC-FACSeq
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Cecelia R. Miller, Alice S. Mims, Tierney Kauffman, Virginia M. Goettl, Gregory K. Behbehani, Jadwiga Labanowska, Clara D. Bloomfield, Pu Zhang, Nicole Grieselhuber, Lynne V. Abruzzo, Eileen Hu, Caner Saygin, Gerard Lozanski, Jordan N. Skinner, Casey Cempre, Alison Walker, Steven Sher, John C. Byrd, Karilyn Larkin, Bhavana Bhatnagar, Nyla A. Heerema, Tzyy-Jye Doong, James S. Blachly, Rosa Lapalombella, Deedra Nicolet, Arletta Lozanski, and Shelley Orwick
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Cancer Research ,Oncology ,Hierarchy (mathematics) ,Cancer genetics ,Myeloid leukemia ,Hematology ,Computational biology ,Biology - Published
- 2021
13. Trametinib for the treatment of IGHV4-34, MAP2K1-mutant variant hairy cell leukemia
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Cynthia Timmers, Kerry A. Rogers, Jeffrey A. Jones, Nicole Grieselhuber, Leslie A. Andritsos, Julie W. Reeser, Sameek Roychowdhury, Aharon G. Freud, Christopher C. Oakes, Mirela Anghelina, Dan Jones, Gerard Lozanski, David M. Lucas, James S. Blachly, Michael R. Grever, and Katie Williams
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0301 basic medicine ,Trametinib ,Cancer Research ,Mutation ,Chemotherapy ,Chemistry ,medicine.medical_treatment ,Mutant ,Hematology ,medicine.disease ,medicine.disease_cause ,Uncommon disorder ,Article ,03 medical and health sciences ,Leukemia ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,MAP2K1 ,medicine ,Cancer research ,Hairy cell leukemia - Abstract
Variant hairy cell leukemia (vHCL) is an uncommon disorder accounting for 10% of all HCL cases [1]. The difference in therapeutic response to chemotherapy between patients with classic HCL (cHCL) a...
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- 2017
14. Outcomes of the cyclophosphamide, vincristine, prednisone (CVP) +/- rituximab (R-CVP) regimen in older patients with newly diagnosed Ph- acute lymphoblastic leukemia
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Alison Walker, Bhavana Bhatnagar, Gregory K. Behbehani, Nicole Grieselhuber, Caner Saygin, Karilyn Larkin, John C. Byrd, Sumithira Vasu, Meixiao Long, James S. Blachly, and Alice S. Mims
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Cancer Research ,medicine.medical_specialty ,Newly diagnosed ,Gastroenterology ,Older patients ,Prednisone ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Cyclophosphamide ,R-CVP Regimen ,Aged ,Aged, 80 and over ,business.industry ,Age Factors ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Ph+ acute lymphoblastic leukemia ,Treatment Outcome ,Oncology ,Cyclophosphamide/vincristine ,Vincristine ,Rituximab ,business ,medicine.drug - Published
- 2019
15. Longitudinal Survival Outcomes in Allogeneic Stem Cell Transplantation: An Institutional Experience
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Sarah A Wall, Nicole Grieselhuber, Ayman Saad, Karilyn Larkin, Nidhi Sharma, Srinivas Devarakonda, Alice S. Mims, Justin Jiang, Don M. Benson, Basem M. William, Yvonne A. Efebera, Audrey M. Sigmund, Qiuhong Zhao, Hannah Choe, Naresh Bumma, Abdullah Khan, Patrick Elder, Jonathan E. Brammer, Sam Penza, Maria Chaudhry, Samantha Jaglowski, Sumithira Vasu, and Ashley E. Rosko
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Oncology ,Transplantation ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology ,Stem cell ,business - Published
- 2021
16. Improvement in Survival of AML and MDS Patients Following Allogeneic Transplant: A Long-Term Institutional Experience
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Hannah Choe, Nicole Grieselhuber, Sarah A Wall, Don M. Benson, Alice S. Mims, Karilyn Larkin, Audrey M. Sigmund, Srinivas Devarakonda, Qiuhong Zhao, Patrick Elder, Ashley E. Rosko, Samantha Jaglowski, Justin Jiang, Yvonne A. Efebera, Sumithira Vasu, Sam Penza, Naresh Bumma, Abdullah Khan, Maria Chaudhry, Nidhi Sharma, Ayman Saad, Basem M. William, and Jonathan E. Brammer
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Immunology ,medicine ,Cell Biology ,Hematology ,business ,Biochemistry ,Term (time) - Abstract
Introduction: Allogeneic stem cell transplant (allo-SCT) plays a key role in the post-remission therapy for acute myeloid leukemia (AML) patients due to its high rates of efficacy as compared to alternate therapies. For patients with relapsed/refractory AML and those with high-risk myelodysplastic syndrome (MDS), it remains the sole curative option. However, these patients continue to have significant obstacles for successful transplant including risk for relapse of underlying disease, graft versus host disease (GVHD), and infectious complications. Outcomes of allo-SCT in these patients have improved over time with the evolution of practice of allo-SCT, including modifications of transplant conditioning regimens, supportive care, and earlier recognition of transplant complications. Our study sought to assess the trends in survival in AML and MDS patients undergoing allogeneic transplant at The Ohio State University from 1984-2018. Methods: We analyzed data from 900 consecutive patients who received an allo-SCT (705 AML and 195 MDS). The patients were stratified into 7 different groups based on year of transplant using 5 year increments; group (gp) 1 included 1984-1988, gp 2 1989-1993, gp 3 1994-1998, gp 4 1999-2003, gp 5 2004-2008, gp 6 2009-2013, and gp 7 2014-2018. Progression free survival (PFS) and overall survival (OS) were utilized as primary end points. PFS and OS were calculated using Kaplan Meier Curves. Secondary endpoints included cumulative incidences of grade II-IV and III-IV acute GVHD (aGVHD), chronic GVHD (cGVHD), and non-relapse mortality (NRM). Cumulative incidence rates were estimated and compared using Gray's test accounting for competing risks. Results: Median age at transplant was 52 years (yrs) old (range 18-76) and 55.6% were male. Patients having myeloablative (MA) conditioning regimen comprised 57.6% of the cohort. From 1984 to 2018, there was a statistically significant improvement in both PFS and OS (Figure 1 a and b; p Conclusion: Our study demonstrates significant improvement over the past several decades in survival in AML and MDS patients undergoing allo-SCT. Major factors that likely contribute to improvement in outcomes throughout the years include adjustments in conditioning regimens and GVHD prophylaxis, earlier recognition of complications as well as improved management, and improved general supportive care. Overall, while outcomes have improved significantly throughout the years, post-transplant relapses remains the leading cause of transplant failure in this group. Preventing relapse post-transplant represents a continued target for research today. Disclosures Chaudhry: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bumma:Amgen: Speakers Bureau; Sanofi: Speakers Bureau. Khan:Amgen: Consultancy; Janssen: Consultancy. Devarakonda:Janssen: Consultancy. Vasu:Omeros: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Kiadis Inc: Other: Kiadis has obtained exclusive licensing requirements from The OHio State University. Jaglowski:CRISPR: Consultancy; Novartis: Consultancy, Research Funding; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. William:Kyowa Kirin: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Guidepoint Global: Consultancy; Incyte: Research Funding; Seattle Genetics: Research Funding; Merck: Research Funding; Dova: Research Funding. Mims:Novartis: Speakers Bureau; Agios: Consultancy; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Abbvie: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board. Brammer:Seattle Genetics, Inc.: Speakers Bureau; Celgene Corporation: Research Funding. Efebera:Celgene: Research Funding; Pharmacyclics: Research Funding; Takeda: Honoraria, Speakers Bureau; Ohio State University: Current Employment.
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- 2020
17. Diagnostic utility of bronchoscopy in newly diagnosed acute leukemia patients
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Meixiao Long, Thomas P. Curley, Kristin L. Koenig, Alison Walker, Nicole Grieselhuber, Shylaja Mani, James S. Blachly, Alice S. Mims, Bhavana Bhatnagar, Mark E. Lustberg, Sarah A Wall, Gregory K. Behbehani, Karilyn Larkin, John C. Byrd, Sumithira Vasu, and Tamanna Haque
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Cancer Research ,Acute leukemia ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Newly diagnosed ,Airway disease ,Oncology ,Bronchoscopy ,Internal medicine ,Induction therapy ,Medicine ,Acute respiratory failure ,business - Abstract
e19510 Background: Over 40% of newly diagnosed acute leukemia patients receiving induction therapy develop acute respiratory failure. Bronchoscopy is a valuable tool for evaluating airway disease, but its diagnostic yield in this setting has not been fully explored. Methods: We performed a retrospective chart review of 75 newly diagnosed acute leukemia patients who had bronchoscopies. Data recorded prior to bronchoscopy included age, diagnosis, induction treatment regimen, chest imaging, assisted ventilation, duration of neutropenia and antibiotic therapy and microbiological studies. Bronchoalveolar lavage (BAL) cultures were sorted by organism, as well as by other pathologic findings. The primary outcome was antibiotic change supported by culture data. Results: The study population is summarized in the table. Induction regimen backbones included 7+3 (51), 7+4+ATRA (2), decitabine (12), hyperCVAD (2), AYA (3), other (1) and none (4); 18 patients were treated on clinical trial. Average days of neutropenia was 10.92 and average days of antibiotic therapy was 10.57. Thirty-eight patients had chest infiltrates, 11 received NIPPV, and 17 were mechanically ventilated. We identified 24 patients with +BAL studies. Of these, 37.5% (9) had + blood, urine or sputum studies before bronchoscopy, but only 3 had cultures positive for the same organism as the BAL. Of 51 patients with –BAL studies, 33.3% (17) had prior negative cultures. Infections were most commonly bacterial (15, 62.5%), followed by viral (5, 20.8%) and fungal (4, 16.7%). The most common organisms were rhinovirus, vancomycin sensitive Enterococcus (4, 16.7% each) followed by VRE, Candida albicans and MRSA (2, 8.3% each). Five patients (6.7%) had alveolar hemorrhage. Of the 24 patients with +BAL cultures, bronchoscopy findings supported changing antibiotics in 18. In contrast, antibiotics were changed in 16 patients without +BAL cultures. Conclusions: We investigated the utility of bronchoscopy on AL patients during their initial admission. BAL cultures were positive in 32% of newly diagnosed AL patients undergoing bronchoscopy. However, +BAL cultures identified a new organism in 87.5% and guided antibiotic therapy in 75% of these patients. Further studies will be needed to establish predictors of bronchoscopy findings in this patient population. [Table: see text]
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- 2020
18. Type of prior genotoxic insult determines the genomic characteristics of therapy-related acute myeloid leukemia
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Karilyn Larkin, Gregory K. Behbehani, Meixiao Long, Dan Jones, John C. Byrd, Sumithira Vasu, Nicole Grieselhuber, Weiqiang Zhao, Michael Ozga, Bhavana Bhatnagar, James S. Blachly, Alison R. Walker, Alice S. Mims, Tamanna Haque, and Caner Saygin
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Insult ,Cancer Research ,Oncology ,business.industry ,media_common.quotation_subject ,Cancer research ,Cancer therapy ,Medicine ,Cytotoxic T cell ,Therapy-Related Acute Myeloid Leukemia ,business ,Complication ,media_common - Abstract
7515 Background: Therapy-related AML (tAML) is a long-term complication of cytotoxic cancer therapy. It is characterized by adverse genetics and inferior survival outcomes when compared to de novo AML. A proposed mechanism in tAML pathogenesis includes treatment-induced selection of clones harboring pre-existing mutations (i.e. clonal hematopoiesis, CH). We hypothesize that genotoxic therapies used to treat prior malignancy drive leukemogenesis through different mechanisms leading to unique clonal compositions. Methods: AML patients (pts) treated at The Ohio State University between 2015-2018 were included. Genetic profiling was performed using Miseq Illumina platform with a 49-gene targeted sequencing panel at our clinical laboratory. Results: We studied 337 AML pts (Table), of whom 53% had smoking history. Mutations involving ASXL1 were more common in smokers vs non-smokers (14% vs 5.8%, p= .001), while JAK2 mutations were more common in non-smokers (8% vs 1.2%, p= .003). Regarding specific genotoxic therapies and mutations in tAML, we investigated common CH-associated mutations including DNMT3A, TET2, and ASXL1 (DTA mutations). In tAML pts, those exposed to radiotherapy experienced a higher frequency of DTA (52% vs 27%, p= .05), NPM1 (21% vs 0%, p= .002), and SRSF2 (15% vs 0%, p= .01) mutations, and conversely, a lower incidence of TP53 mutations (21% vs 46%, p= .04). Pts with history of cytotoxic chemotherapy had a lower incidence of DTA mutations, including those who received platinum agents (8% vs 49%, p= .005) and taxanes (7% vs 52%, p< .001), but had a higher incidence of TP53 mutations (75% vs 25%, p< .001 for platinum; 53% vs 25%, p= .04 for taxanes). Similarly, alkylators and anthracyclines were associated with lower incidence of DNMT3A (0% vs 20%, p= .009) and ASXL1 (0% vs 12.5%, p= .04) mutations. Conclusions: Different genotoxic agents demonstrate unique effects in leukemia development. Our data suggest that CH clones with DTA mutations may be enriched with smoking and radiotherapy, while cytotoxic chemotherapy may confer a higher incidence of TP53 mutations. Given the adverse prognosis of TP53 mutated AML, identification of pre-existing CH clones might influence treatment selection in solid tumor pts receiving anticancer therapy. [Table: see text]
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- 2020
19. NPM1 mutations Using Deep Amplicon Sequencing and Broad Next Generation Sequencing at the Time of Complete Remission Is Informative to Predicting Risk of Relapse Following Intensive Chemotherapy
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Alison Walker, Nyla A. Heerema, Nicole Grieselhuber, Charles Thomas Gregory, Shelley Orwick, Bhavana Bhatnagar, Gregory K. Behbehani, James S. Blachly, John C. Byrd, Karilyn Larkin, Alice S. Mims, and Apollinaire Ngankeu
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Oncology ,medicine.medical_specialty ,NPM1 ,business.industry ,medicine.medical_treatment ,Immunology ,Complete remission ,Cell Biology ,Hematology ,Impedance threshold device ,Biochemistry ,Chemotherapy regimen ,DNA sequencing ,medicine.anatomical_structure ,Internal medicine ,Mutation (genetic algorithm) ,medicine ,Bone marrow ,business ,Neoadjuvant therapy - Abstract
Introduction: NPM1 gene mutations are a common molecular aberration in acute myeloid leukemia (AML). In the absence of concurrent high FLT3-ITD ratio mutations (>0.5), NPM1 mutations typically associate with higher complete remission (CR) rates following intensive induction chemotherapy. NPM1 mutations have been shown to be stable markers of persistent disease or impending relapse during CR or complete remission with incomplete count recovery (CRi). Given the clinical implications that persistent NPM1 mutations can have during CR/CRi, we used Deep Amplicon sequencing on CR/CRi bone marrow (BM) samples collected from adult de novoNPM1-mutated AML patients to determine the ability of NPM1 mutations at both a high and lower sensitivity next generation sequencing methods and also the presence of additional clonal abnormalities on relapse risk. Methods: We performed targeted next generation sequencing (NGS) analysis in addition to NPM1 Deep Amplicon sequencing on paired BM or blood samples collected from 38 newly diagnosed NPM1-mutated AML patients during CR/CRi after successful induction (1-2 courses of 7 + 3) and, if available, at relapse. NPM1 mutated NGS libraries were prepared using a KAPA HyperPlus Kit (Roche, Pleasanton, CA) and xGen Lockdown Probes (IDT, Coralville, IA). Libraries were sequenced using the Illumina HiSeq 4000 (Illumina, San Diego, CA). GATK's MuTect2 was used to perform variant calling. Variant allele frequency (VAF) cut-off for the NGS panel was 0.05 (5%) with the exception of hotspot variants in IDH1 (R132) and IDH2 (R140) where variants detected to a level of 0.01 (1%) were included. The VAF cut off used for NPM1 Deep Amplicon sequencing was 0.00012 (0.012%). Results: Targeted NGS analysis and NPM1 Deep Amplicon sequencing had exceptional concordance at the level of detection of VAF= 0.05 (Figure 1). Of 38 patients, 23 patients had undetectable NPM1 mutations as analyzed through NPM1 Deep Amplicon sequencing of whom 9 (38.1%) relapsed. In contrast, 15 patients were positive by NPM1 Deep Amplicon sequencing and 9 (60%) relapsed. Only 4 patients had detectable persistent NPM1 mutations after induction according to both detection techniques and two of these relapsed. We next examined the potential impact of clearing both NPM1 mutation and co-occurring mutations together on relapses (Figure 2). A total of 15 patients cleared all of their clonal abnormalities and 5 (27%) relapsed. In contrast, of the 23 patients who did not clear the NPM1 mutation and/or another co-occurring mutation at remission, 14 (61%) have relapsed. Eleven of the relapsed patients had relapse samples available of whom all had persistent NPM1 mutation at this time. Paired CR/CRi and relapsed samples showed acquisition or recurrence of several other mutations, most notably FLT3-ITD, IDH1, and IDH2 which are all targetable with small molecule therapeutics. Conclusions: The use of Deep Amplicon sequencing to identify NPM1 mutations at a lower detection threshold compared to standard NGS techniques was more sensitive, but did not appear to fully inform relapse rates in NPM1-mutated AML patients after receipt of induction therapy. The appearance of other AML-associated mutations, identified together with NPM1 at time of remission, was more frequent among patients relapsing. These pilot data provide support for concurrent assessment of Deep Amplicon sequencing together with a broad standard NGS AML mutational assay to further enhance risk stratification of NPM1-mutated patients. Additionally, while NPM1 clones are present in all patients examined at the time of relapse, persistence or development of targetable clones justifies repeat broad NGS sequencing at this time. Figure Disclosures Bhatnagar: Novartis and Astellas: Consultancy, Honoraria; Cell Therapeutics, Inc.: Other: Research support; Karyopharm Therapeutics: Other: Research support. Mims:Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Behbehani:Fluidigm corporation: Other: Travel funding. Byrd:Novartis: Other: Travel Expenses, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S.
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- 2019
20. PHASE I DOSE-ESCALATION STUDY OF VENETOCLAX PLUS BEAM FOLLOWED BY AUTOLOGOUS STEM CELL TRANSPLANT (ASCT) FOR CHEMORESISTANT, RELAPSED/REFRACTORY, OR HIGH-RISK NON-HODGKIN'S LYMPHOMA (NHL); PRELIMINARY RESULTS
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Alice S. Mims, Nicole Grieselhuber, Basem M. William, Sarah A Wall, Yvonne A. Efebera, J. Robinson, Samantha Jaglowski, A. Rosko, Marcin Puto, Don M. Benson, Kami J. Maddocks, R. Von Derau, Robert A. Baiocchi, James S. Blachly, Lapo Alinari, H. Choe, Karilyn Larkin, B. Blaser, Bhavana Bhatnagar, Qiuhong Zhao, Sabarish Ayyappan, Narendranath Epperla, S. Devarakonda, J. Maakaron, Sumithira Vasu, A. Saad, Sam Penza, Beth Christian, Jonathan E. Brammer, and M. Chaudhry
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Oncology ,Cancer Research ,medicine.medical_specialty ,Venetoclax ,business.industry ,Hematology ,General Medicine ,medicine.disease ,Non-Hodgkin's lymphoma ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Relapsed refractory ,medicine ,Dose escalation ,Stem cell ,business - Published
- 2019
21. Trametinib for the Treatment of IGHV4-34, MAP2K1 Mutant Variant Hairy Cell Leukemia
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Julie W. Reeser, Nicole Grieselhuber, Cynthia Timmers, Michael R. Grever, Kerry A. Rogers, David M. Lucas, Weiqiang Zhao, Aharon G. Freud, Mirela Anghelina, Jeffrey A. Jones, Gerard Lozanski, Leslie A. Andritsos, James S. Blachly, and Sameek Roychowdhury
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0301 basic medicine ,Oncology ,Bendamustine ,medicine.medical_specialty ,Immunology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Hairy cell leukemia ,Cladribine ,Trametinib ,business.industry ,Melanoma ,Leukemia cutis ,Cell Biology ,Hematology ,medicine.disease ,Rash ,Leukemia ,030104 developmental biology ,030220 oncology & carcinogenesis ,medicine.symptom ,business ,medicine.drug - Abstract
Background: Mutations of MAP2K1, which encodes MEK1, have been identified in up to half of patients with variant Hairy Cell Leukemia (vHCL).[Waterfall et al., Nat Gen 2014, Mason et al., Leukemia & Lymphoma 2016], and have been associated with vHCL with IGHV4-34 gene usage, which This form of HCL tends to have a worse prognosis than classic HCL or wild type vHCL (Arons et al., Blood 2009), with inferior responses to chemotherapy and shorter durations of remission. Trametinib, an oral inhibitor of MEK1 and MEK2, is FDA approved for treatment of patients with BRAF p.V600E mutant melanoma. We hypothesized that this MEK inhibitor would have activity in MAP2K1 mutant vHCL. Case Report: The patient is a 52 year old man with a history of CD25+, BRAF wildtype, IGHV4-34 usage vHCL diagnosed in 2005. His previous treatments included cladribine, BL22, pentostatin/rituximab, splenectomy, single agent rituximab, ibrutinib, bendamustine/rituximab, and allogeneic transplantation from a matched unrelated donor. The patient experienced disease relapse day +350 post transplant when he developed skin nodules as well as a generalized skin rash. The skin rash appeared clinically consistent with acute GVHD. However, when biopsies of both the skin nodules and skin rash were performed he was found to have relapsed vHCL. He was consented for paired tumor and germline next generation sequencing with a 25-gene amplicon panel which revealed a somatic MAP2K1 K57N mutation that has been shown to constitutively activate MEK [Marks et al., Cancer Res 2008]. As the patient had exhausted the majority of available treatment options, he was prescribed trametinib 2 mg po daily (commercial supply, according to approved melanoma dosing). Within a week of therapy initiation his skin nodules were markedly diminished in size and his generalized rash had resolved. He did develop a new acneiform rash over his face consistent with drug toxicity. This was managed with topical agents with improvement and did not require a dose reduction. Disease restaging following cycle 2 of therapy showed near complete resolution of skin nodules, with disappearance of visible skin rash. Repeat bone marrow biopsy showed unchanged hairy cell index. Skin biopsies were repeated and phospho-ERK (T202/Y204) staining of skin biopsies pre- and post-trametinib were performed (Figure 1). This showed diminished lymphocyte involvement on H&E staining with a decrease in p-ERK expression on immunostaining, indicative of decreased signaling downstream of MEK and consistent with on target trametinib effects. As of this writing, the patient has remained on trametinib for 12 weeks with no recurrence of leukemia cutis rash. Discussion: MEK inhibition with the oral MEKi trametinib is a well tolerated therapy with clinical activity in MAP2K1 mutant vHCL. Additional studies of this agent are warranted. Optimal dose and duration of therapy will need to be explored in prospective clinical trials. Figure 1 Skin biopsies pre- and post-trametinib. (A)(C) H&E staining shows diminished lymphocyte involvement. (B)(D) PhosphoERK immunostaining shows decrease of phosphoERK expression. Bar = 500 μm Figure 1. Skin biopsies pre- and post-trametinib. (A)(C) H&E staining shows diminished lymphocyte involvement. (B)(D) PhosphoERK immunostaining shows decrease of phosphoERK expression. Bar = 500 μm Disclosures Andritsos: Hairy Cell Leukemia Foundation: Research Funding. Anghelina:Hairy Cell Leukemia Foundation: Research Funding. Lozanski:Boehringer Ingelheim: Research Funding; Beckman Coulter: Research Funding; Genentech: Research Funding; Stemline Therapeutics Inc.: Research Funding. Jones:Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.
- Published
- 2016
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