40 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. Author response for 'Diagnostic utility of bronchoscopy in newly diagnosed acute leukemia patients'
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Ashleigh Keiter, John C. Byrd, Kristin Lynn Koenig, Meixiao Long, James S. Blachly, Mark E. Lustberg, Thomas P. Curley, Gregory K. Behbehani, Alice S. Mims, Tamanna Haque, Nicole Grieselhuber, Bhavana Bhatnagar, Karilyn Larkin, Shylaja Mani, Qiuhong Zhao, Sarah A Wall, Alison R. Walker, and Sumithira Vasu
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medicine.medical_specialty ,Acute leukemia ,Bronchoscopy ,medicine.diagnostic_test ,business.industry ,Medicine ,Newly diagnosed ,Radiology ,business - Published
- 2021
5. Outcomes of Bone Marrow Compared to Peripheral Blood for Haploidentical Transplantation
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Karilyn Larkin, Audrey M. Sigmund, Alice S. Mims, Patrick Elder, Nicole Grieselhuber, Ayman Saad, Yvonne A. Efebera, Qiuhong Zhao, Srinivas Devarakonda, Sarah A Wall, Ashley E. Rosko, Don M. Benson, Muhammad Salman Faisal, Justin Jiang, Sumithira Vasu, Hannah Choe, Nidhi Sharma, Naresh Bumma, Abdullah Khan, Jonathan E. Brammer, Sam Penza, Samantha Jaglowski, and Maria Chaudhry
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medicine.medical_specialty ,bone marrow ,Cyclophosphamide ,Gastroenterology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,haploidentical transplantation ,business.industry ,Incidence (epidemiology) ,allogenic transplantation ,General Medicine ,peripheral blood ,Confidence interval ,Peripheral blood ,Transplantation ,medicine.anatomical_structure ,surgical procedures, operative ,030220 oncology & carcinogenesis ,Cohort ,Medicine ,Bone marrow ,Stem cell ,business ,030215 immunology ,medicine.drug - Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) from a haploidentical (haplo) donor has emerged as a suitable alternative in the absence of a matched donor. However, haplo-HCT patients have a higher risk of graft-versus-host disease (GVHD). Hence, bone marrow (BM) stem cell source and post-transplant cyclophosphamide (PTCy) have been routinely used to help mitigate this. Due to ease of collection, peripheral blood (PB) stem cells are increasingly being considered for haplo-HCT. We retrospectively analyzed 74 patients (42 BM and 32 PB) who underwent haplo-HCT at Ohio State University from 2009 to 2018. Median age at transplant was 60 years (yrs) for BM and 54 yrs for PB, (p = 0.45). There was no difference in OS (p = 0.13) and NRM (p = 0.75) as well as PFS (p = 0.10) or GRFS (p = 0.90) between the groups. The BM cohort showed a 3-year OS rate of 63% (95% confidence interval (CI): 46–76), and 3-year PFS of 49% (95% CI: 33–63). For the PB group, 3-year OS and PFS were 78% (95% CI: 59–89) and 68% (95% CI: 49–82), respectively. There were no differences in the incidence of acute GVHD (grade II-IV) (p = 0.31) and chronic GVHD (p = 0.18). Patients receiving BM had a significantly higher risk for relapse with relapse rates by 2 years at 36% (95% CI: 22–50) vs. 16% (95% CI: 6–31) for PB (p = 0.03). The findings from this study suggest that PB is an excellent alternative to BM for haplo-HCT.
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- 2021
6. Type of prior genotoxic insult determines the genomic characteristics of therapy‐related myeloid neoplasms
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Ann-Kathrin Eisfeld, Dan Jones, Alice S. Mims, Nicole Grieselhuber, Weiqiang Zhao, Tamanna Haque, John C. Byrd, Sumithira Vasu, Bhavana Bhatnagar, James S. Blachly, Meixiao Long, Caner Saygin, Gregory K. Behbehani, Karilyn Larkin, Michael Ozga, and Alison Walker
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Myeloid ,Therapy related ,business.industry ,media_common.quotation_subject ,Smoking ,Antineoplastic Agents ,Neoplasms, Second Primary ,Hematology ,Insult ,medicine.anatomical_structure ,Mutation Rate ,Leukemia, Myeloid ,Risk Factors ,Mutation ,Cancer research ,Humans ,Medicine ,business ,DNA Damage ,media_common - Published
- 2021
7. 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
8. 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
9. 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
10. PP2A is a therapeutically targetable driver of cell fate decisions via a c-Myc/p21 axis in human and murine acute myeloid leukemia
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Alice S. Mims, Rosa Lapalombella, Nicole Grieselhuber, Min Chen, Erin Hertlein, Swagata Goswami, Rajeswaran Mani, Yo-Ting Tsai, Frank Frissora, Raymond D. Devine, Ralf Bundschuh, Logan A. Walker, Larry Beaver, Gregory K. Behbehani, Kevan Zapolnik, Pearlly S. Yan, Eileen Y. Hu, Jessica Nunes, Alison Walker, Zhiliang Xie, Chad Bennett, Chi-Ling Chiang, John C. Byrd, Sumithira Vasu, X. Mo, Karilyn Larkin, Natarajan Muthusamy, Mitch A. Phelps, and Ann Marie Ventura
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Cyclin-Dependent Kinase Inhibitor p21 ,Myeloid ,Cellular differentiation ,Immunology ,Cell fate determination ,Biology ,Biochemistry ,Proto-Oncogene Proteins c-myc ,Mice ,hemic and lymphatic diseases ,Cell Line, Tumor ,medicine ,Gene silencing ,Animals ,Humans ,Protein Phosphatase 2 ,Mice, Knockout ,Myeloid leukemia ,Cell Biology ,Hematology ,Cell cycle ,medicine.disease ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Cancer research ,Stem cell - Abstract
Dysregulated cellular differentiation is a hallmark of acute leukemogenesis. Phosphatases are widely suppressed in cancers but have not been traditionally associated with differentiation. In this study, we found that the silencing of protein phosphatase 2A (PP2A) directly blocks differentiation in acute myeloid leukemia (AML). Gene expression and mass cytometric profiling revealed that PP2A activation modulates cell cycle and transcriptional regulators that program terminal myeloid differentiation. Using a novel pharmacological agent, OSU-2S, in parallel with genetic approaches, we discovered that PP2A enforced c-Myc and p21 dependent terminal differentiation, proliferation arrest, and apoptosis in AML. Finally, we demonstrated that PP2A activation decreased leukemia-initiating stem cells, increased leukemic blast maturation, and improved overall survival in murine Tet2−/−Flt3ITD/WT and human cell-line derived xenograft AML models in vivo. Our findings identify the PP2A/c-Myc/p21 axis as a critical regulator of the differentiation/proliferation switch in AML that can be therapeutically targeted in malignancies with dysregulated maturation fate.
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- 2021
11. 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
12. 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
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- 2018
13. 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
14. Impact of Bone Marrow Versus Peripheral Blood on Outcomes in Haploidentical Transplantation
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Yvonne A. Efebera, Ashley E. Rosko, Sumithira Vasu, Sam Penza, Nicole Grieselhuber, Sarah A Wall, Karilyn Larkin, Samantha Jaglowski, Alice S. Mims, Maria Chaudhry, Don M. Benson, Audrey M. Sigmund, Srinivas Devarakonda, Qiuhong Zhao, Nidhi Sharma, Hannah Choe, Patrick Elder, Jonathan E. Brammer, Naresh Bumma, Abdullah Khan, Basem M. William, Ayman Saad, and Justin Jiang
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Transplantation ,medicine.medical_specialty ,Haploidentical transplantation ,business.industry ,Cell Biology ,Hematology ,Peripheral blood ,Surgery ,medicine.anatomical_structure ,Molecular Medicine ,Immunology and Allergy ,Medicine ,Bone marrow ,business - Published
- 2021
15. Impact of Chronic Graft-Versus-Host Disease on Non-Relapse Mortality and Survival
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Nicole Grieselhuber, Sam Penza, Jonathan E. Brammer, Yvonne A. Efebera, Sumithira Vasu, Maria Chaudhry, Justin Jiang, Audrey M. Sigmund, Hannah Choe, Qiuhong Zhao, Karilyn Larkin, Nidhi Sharma, Sarah A Wall, Alice S. Mims, Ashley E. Rosko, Ayman Saad, Samantha Jaglowski, Don M. Benson, Basem M. William, Srinivas Devarakonda, Patrick Elder, Naresh Bumma, and Abdullah Khan
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Transplantation ,medicine.medical_specialty ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,Gastroenterology ,Graft-versus-host disease ,Internal medicine ,medicine ,Molecular Medicine ,Immunology and Allergy ,Nonrelapse mortality ,business - Published
- 2021
16. Comparison of Bone Marrow Versus Peripheral Blood in Haploidentical Transplantation Using Post-Transplant Cyclophosphamide- a Retrospective Analysis
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Sarah A Wall, Ayman Saad, Yvonne A. Efebera, Srinivas Devarakonda, Don M. Benson, Alice S. Mims, Audrey M. Sigmund, Qiuhong Zhao, Justin Jiang, Samantha Jaglowski, Nicole Grieselhuber, Basem M. William, Nidhi Sharma, Jonathan E. Brammer, Sam Penza, Maria Chaudhry, Patrick Elder, Sumithira Vasu, Ashley E. Rosko, Hannah Choe, Naresh Bumma, and Abdullah Khan
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medicine.medical_specialty ,Platelet Engraftment ,business.industry ,Immunology ,Retrospective cohort study ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,law.invention ,Transplantation ,Leukemia ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Clinical endpoint ,Cumulative incidence ,Progression-free survival ,business - Abstract
Background: Allogeneic transplantation (allo-HCT) is a potentially curative treatment for a variety of hematologic malignancies and nonmalignant hematologic disorders. Allo-HCT from a haploidentical (Haplo) related donor has emerged as a suitable alternative in the absence of matched related donor (MRD) and matched unrelated donor (MUD). Haplo HCT patients however have higher risk of graft rejection and graft versus-host disease (GVHD). Thus, patients often receive post-transplant cyclophosphamide (PTCy), which has proven to be highly effective in reducing GVHD. While the use of peripheral blood is an attractive option due to the ease of collection and rapid peripheral blood count recovery, not much information is available on the impact of graft sources using PTCy in Haplo-HCT. This study compares outcomes of bone marrow (BM) versus peripheral blood (PB) stem cell graft for Haplo-HCT in adult patients. Methods: We performed a retrospective study of 81 adult patients who underwent Haplo-HCT at The Ohio State University from 2009 to 2018. The study endpoints were overall survival (OS), progression free survival (PFS), non-relapse mortality (NRM), relapse, engraftment, acute GVHD (grade II-IV), and chronic GVHD. All endpoints were measured from the time of transplantation. Patient, disease, and transplant-related characteristics were compared between the two groups (BM versus PB) using the Mann-Whitney U test for continuous variables, and chi-squared or Fisher's exact test for categorical variables. The probabilities of OS and PFS were calculated using the Kaplan-Meier (KM) method and compared using log-rank test. Cumulative incidence rates were estimated and compared using Gray's test accounting for competing risks. Results: We compared the outcomes of patients who received a BM graft (N=43) with those receiving a PB graft (N=38). The median age at transplant was 57 years (20-74). All patients received PTCy in addition to tacrolimus and mycophenolate in 91% of patients. Reduced intensity conditioning (RIC) was used in majority of patients (N=63, 78%). The two groups were comparable including age (median, 60 years for BM and 56 years for PB, p=0.60) and the type of conditioning regimen (79% RIC for BM, 76% RIC for PB, p=0.77). The number of CD34+ and CD3+ infused cells was higher in PB grafts (median, 8.6x106 CD34+ cells/Kg, 2.0 x108 CD3+ cells/Kg, respectively) than for BM (median, 3.7x106 CD34+cells/Kg, 0.4x108 CD3+cells/Kg, respectively). Time to neutrophil and platelet engraftment were significantly shorter in patients receiving PB versus those getting BM grafts: median 15 vs. 17.5 days, (p=0.02) and median 20 vs. 29 days (p Conclusion: Our study suggests peripheral blood for haploidentical transplant to be a good alternative to bone marrow. Similar PFS, OS and NRM were seen between the two graft sources. As expected, faster neutrophil and platelets engraftment were seen with PB due to more CD3+ and CD34+ infused, but without an increase in acute or chronic GVHD. A reduced relapse risk was observed with PB graft. Our study is small and is retrospective, but provide encouraging results. A prospective randomized controlled trial is required to confirm these results. Disclosures Chaudhry: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bumma:Sanofi: Speakers Bureau; Amgen: Speakers Bureau. Khan:Amgen: Consultancy; Janssen: Consultancy. Devarakonda:Janssen: Consultancy. Vasu:Kiadis Inc: Other: Kiadis has obtained exclusive licensing requirements from The OHio State University; Janssen: Membership on an entity's Board of Directors or advisory committees; Omeros: Membership on an entity's Board of Directors or advisory committees. Jaglowski:Novartis: Consultancy, Research Funding; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR: Consultancy. William:Seattle Genetics: Research Funding; Merck: Research Funding; Dova: Research Funding; Kyowa Kirin: Consultancy, Honoraria; Guidepoint Global: Consultancy; Incyte: Research Funding; Celgene: Consultancy, Honoraria. Mims:Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; Abbvie: Membership on an entity's Board of Directors or advisory committees; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Agios: Consultancy; Novartis: Speakers Bureau. Brammer:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Seattle Genetics: Honoraria, Speakers Bureau; Kymera: Honoraria; Verastem Oncology: Other: Travel. Saad:Amgen: Other: research support; Magenta Therapeutics: Other: Personal Fees; Incyte Pharmaceuticals: Other: Personal Fees; Orcabio: Other: research support; Kadmon: Other: research support. Efebera:Celgene: Research Funding; Ohio State University: Current Employment; Takeda: Honoraria, Speakers Bureau; Pharmacyclics: Research Funding.
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- 2020
17. Survival Implications of Opioid Use after Blood and Marrow Transplantation
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Jonathan E. Brammer, Karilyn Larkin, Qiuhong Zhao, Sam Penza, Naresh Bumma, Abdullah Khan, Nicole Grieselhuber, Ayman Saad, Yvonne A. Efebera, Samantha Jaglowski, Srinivas Devarakonda, Hannah Choe, Bradley W. Blaser, Maria Chaudhry, Ashley E. Rosko, Alice S. Mims, Ashleigh Keiter, Julianna Roddy, Patrick Elder, Basem M. William, Sarah A Wall, Sumithra Vasu, Noha N. Soror, and Don M. Benson
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medicine.medical_specialty ,education.field_of_study ,Proportional hazards model ,business.industry ,Public health ,Immunology ,Hazard ratio ,Population ,Opioid use disorder ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Internal medicine ,medicine ,Data monitoring committee ,Cumulative incidence ,Progression-free survival ,education ,business - Abstract
B ackground Premature death from opioid-related causes imposes an enormous public health burden across the United States. Between 2001 and 2016, the number of opioid-related deaths in the United States increased by 345%, from 9489 to 42 245 deaths (33.3 to 130.7 deaths per million population. Moreover, opioids may have immunosuppressive properties independent of their psychotropic effects; opioid use has been associated with increased invasive pneumococcal disease in a nested case-control study of 1233 Medicaid patients from Tennessee. In liver transplant recipients, opioid use disorder has been associated with increased mortality after transplant. The impact of opioid use disorder on patients receiving blood and marrow transplant (BMT) remains to be defined. Methods We performed a retrospective analysis of all consecutive adult patients who had BMT (autologous and allogeneic) from 1/1/2008 through 1/1/2018 at the James Comprehensive Cancer Center. Overall survival (OS) was measured from the date of transplant to the date of death, censoring at date of last follow up if alive. Progression free survival (PFS) was measured from the date of transplant to the date of disease progression or the date of death, whichever occurred first, censoring at last follow up if no event. OS and PFS were estimated by the Kaplan-Meier method and compared using the log-rank test. Opioid use (OU) was defined as a binary yes/no variable if an opioid was prescribed upon discharge from the hospital after BMT. The impact of OU, along with other patient, disease, and BMT related factors, on PFS/OS, was analyzed using Cox regression method. Results A total of 1585 patients were included in the analysis (Table 1). The median age at BMT was 58 (range=18-79) years; 59% were males; 60% had autologous transplants; and 58% were prescribed opioids upon discharge from the hospital. OU was significantly more in patients who were younger, have had allogeneic transplant, reduced intensity conditioning, had acute myeloid leukemia (AML), or higher BMT comorbidity index (CMI). On univariable analysis, OU was not associated with cumulative incidence of relapse (CIR) or PFS however it was associated with inferior OS; hazard ratio (HR)=1.25, 95% CI: 1.06-1.49; p=0.01 (Figure-1). There were no differences in CIR, PFS, or OS when autologous and allogeneic transplants were analyzed separately. Upon multivariable analysis of OS, OU lost statistical significance after controlling for age, diagnosis, type of transplant, intensity of conditioning regimen, CMI, and disease risk index (DRE). Of interest, OU independently predicted for superior OS at 100 days and 365 days post-BMT; HR=0.29, 95% CI 0.16-0.50 (p= Conclusion: Our results suggest that opioid use (OU) may have a long term negative impact on survival in BMT patients. The apparently protective effects of OU early on after BMT is elusive but may be possibly related immunomodulatory effects of opioids. A major limitation of our study is that OU is analyzed at a single time point at hospital discharge after BMT. We plan to undertake a more detailed analysis of ongoing OU after discharge and its impact on survival outcomes after BMT. Disclosures Brammer: Celgene Corporation: Research Funding; Seattle Genetics, Inc.: Speakers Bureau. Efebera:Celgene: Research Funding; Ohio State University: Current Employment; Pharmacyclics: Research Funding; Takeda: Honoraria, Speakers Bureau. Mims:Abbvie: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Agios: Consultancy; Novartis: Speakers Bureau. Chaudhry:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bumma:Sanofi: Speakers Bureau; Amgen: Speakers Bureau. Khan:Amgen: Consultancy; Janssen: Consultancy. Devarakonda:Janssen: Consultancy. Jaglowski:Novartis: Consultancy, Research Funding; CRISPR: Consultancy; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. William:Kyowa Kirin: Consultancy, Honoraria; Merck: Research Funding; Seattle Genetics: Research Funding; Incyte: Research Funding; Guidepoint Global: Consultancy; Dova: Research Funding; Celgene: Consultancy, Honoraria.
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- 2020
18. Impact of Race and Geographic Location on Outcomes in Allogeneic Transplant
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Alice S. Mims, Audrey M. Sigmund, Sarah A Wall, Qiuhong Zhao, Ashley E. Rosko, Nicole Grieselhuber, Don M. Benson, Srinivas Devarakonda, Justin Jiang, Hannah Choe, Nidhi Sharma, Jonathan E. Brammer, Patrick Elder, Naresh Bumma, Abdullah Khan, Samantha Jaglowski, Sam Penza, Maria Chaudhry, Basem M. William, Ayman Saad, Sumithira Vasu, Karilyn Larkin, and Yvonne A. Efebera
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Referral ,business.industry ,Immunology ,Retrospective cohort study ,Cell Biology ,Hematology ,Biochemistry ,Health equity ,Underserved Population ,Cohort ,Medicine ,Residence ,Progression-free survival ,Rural area ,business ,Demography - Abstract
Introduction: Allogeneic hematopoietic stem cell transplant (allo-HCT) is a potential curative therapy for a variety of both malignant and nonmalignant hematologic disorders. However, allo-HCT is costly and requires highly specialized, technologically advanced care that is only available in select healthcare centers across the country. Due to its cost and limited availability, minority populations are at risk for healthcare disparities in access to and outcomes of allo-HCT. Prior studies have focused on the impact of health disparities, including race, and geographic residence at time of transplant, on allo-HCT outcomes with variable results. The aim of this study was to evaluate the impact of race and location of residence on outcomes of allo-HCT at one major referral institution. Methods: We performed a retrospective cohort study of patients that underwent allo-HCT at the Ohio State University from 1984 to 2018. The impact of demographic factors including race and place of primary residence were assessed. Patients were divided into race defined as Caucasian, African American (AA), and other. They were also grouped by zip code into rural, suburban, and urban groups. Rural was defined as less than 1000 people per square mile, suburban between 1000-3000 people per square mile, and urban greater than 3000 people per square mile. 2018 population estimates were used. Patients were then stratified into 7 groups based on year (yr) of transplant for analysis. 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. Primary endpoints were progression free survival (PFS) and overall survival (OS). PFS and OS were calculated using Kaplan Meier Curves and compared using log-rank test between race and residence groups. Results: A total of 1,943 patients were included in the study. Of these patients, median age at time of transplant was 50 years old (range 18-76), and 59.6% were male. AML/MDS patients made up the majority of the cohort at 46.3%, with the other most common diagnoses being non-Hodgkin's lymphoma (14.2%), acute lymphocytic leukemia (11.8%), and chronic myeloid leukemia (10.1%). Most patients (94.3%) identified as Caucasian, while 4.6% identified as AA, and 1.1% other. The majority of patients lived in a rural area at the time of transplant with 63.4% rural, 22.9% suburban, and 13.8% urban. There was no significant difference in OS or PFS between Caucasian and AA patients (Figure 1A and B; p=0.15, 0.21). Median OS for AA was 1.9 yrs [95% confidence interval (CI): 0.8-3.6] as compared to 2.3 yrs (95% CI: 1.9-2.9) for Caucasians, with 5 -yr OS of 33 vs. 42% and 10-yr OS of 21 vs. 36% for AA and Caucasian, respectively. Median PFS was 0.9 (95% CI: 0.5-2.7) and 1.3 yrs (95% CI 1.1-1.6), with 5 -yr PFS of 30 vs. 37% and 10-yr PFS of 21 vs. 32% for AA and Caucasian, respectively. There also was no significant difference in OS or PFS between rural, urban, and suburban patients (Figure 2A and 2B; p=0.39, 0.17), with median OS in the three groups 2.2 (95%CI: 1.7-2.9), 2.9 (95%CI: 1.6-4.5), and 2.2 (95% CI: 1.6-3.6) yrs, and 5-yr OS of 40 vs. 43 vs. 43% and 10-yr OS of 33 vs. 39 vs. 39%, respectively. Median PFS were 2.2 (95%CI: 1.7-2.9), 2.9 (95%CI: 1.6-4.5), and 2.2 yrs [95% CI: 1.6-3.6], with 5-yr PFS of 36 vs. 40 vs. 38% and 10-yr PFS of 30 vs. 37 vs. 35%, respectively. Conclusion: Our study suggests that once patients undergo allo-HCT, there is no significant difference in outcomes between patients based on race or residence. This finding suggests that while these underserved populations may initially have less access to specialized care for HCT, if they ultimately undergo allo-HCT, outcomes are similar to their counterparts. Our study did show a significantly lower rates of allo-HCT performed in non-Caucasian races (94% Caucasians vs 4.6% AA and 1% other), which may reflect disparities in access to care in these groups as well as a lack of donors. Further research is needed to assess the barriers for these underserved patients to undergo transplant and to help ameliorate these barriers. 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:Janssen: Membership on an entity's Board of Directors or advisory committees; Omeros: 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:Kite, a Gilead Company: Consultancy, Research Funding; Juno: Consultancy; Novartis: Consultancy, Research Funding; CRISPR: Consultancy. William:Merck: Research Funding; Celgene: Consultancy, Honoraria; Dova: Research Funding; Seattle Genetics: Research Funding; Incyte: Research Funding; Guidepoint Global: Consultancy; Kyowa Kirin: Consultancy, Honoraria. Mims:Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; 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; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Agios: Consultancy; Novartis: Speakers Bureau; 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
19. 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
20. Confronting the therapeutic misconception
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Nicole Grieselhuber, Douglas Brown, Ira J. Kodner, and Jennifer Yu
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Adult ,Therapeutic Misconception ,Physician-Patient Relations ,Informed Consent ,Psychotherapist ,business.industry ,Therapeutic misconception ,Ovariectomy ,Clinical Decision-Making ,Breast Neoplasms ,06 humanities and the arts ,0603 philosophy, ethics and religion ,Article ,03 medical and health sciences ,0302 clinical medicine ,Chemotherapy, Adjuvant ,Humans ,Medicine ,Female ,Surgery ,060301 applied ethics ,030212 general & internal medicine ,business ,Mastectomy - Published
- 2017
21. Predictors of Relapse after Haploidentical Hematopoietic Progenitor Cell Transplantation (Haplo-HCT); A Single-Institution Experience
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Ying Huang, Nicole Grieselhuber, Andrew Schaefer, Sarah A Wall, Ayman Saad, Don M. Benson, Hannah Choe, Hemant K. Parekh, Gerard Lozanski, Sam Penza, Basem M. William, Jonathan E. Brammer, Samantha Jaglowski, Alice S. Mims, Sumithira Vasu, Bradley W. Blaser, Michael Ozga, Yvonne A. Efebera, and Karilyn Larkin
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Transplantation ,medicine.medical_specialty ,business.industry ,CD33 ,Myeloid leukemia ,Cancer ,Hematology ,Disease ,medicine.disease ,medicine.anatomical_structure ,Cell transplantation ,Hematopoietic progenitor ,Internal medicine ,medicine ,Cumulative incidence ,Bone marrow ,business - Abstract
Background Haplo-HCT emerged as a reliable option for patients with high risk hematological malignancies with no HLA-matched related or unrelated donors available. Retrospective registry data suggest comparable outcomes to HLA-matched donors; however, relatively little is known regarding predictors of disease relapse following haplo-HCT. We hypothesize that attainment of full-donor CD3 and CD33 chimerism at day 30 (D30) and 100 (D100) is associated with lower incidence of relapse after haplo-HCT. Methods We undertook a retrospective analysis of 78 patients who underwent haplo-HCT at the Ohio State University James Cancer Hospital between January 2013 and December 2017. The associations between patient characteristics including CD3/CD33 donor chimerisms and the cumulative incidence rate (CIR) of relapse were evaluated using proportional sub-distribution hazards model, treating death without relapse as the competing risk. The models were built adopting a landmark analysis approach at D30 and D100. Progression-free survival (PFS) was estimated using the method of Kaplan-Meier. Results Median age at haplo-HCT was 56 (20-74) years and 68% were males. 50% had acute myeloid leukemia/myelodysplastic syndrome, and 54% had intermediate disease risk index (DRI). Most patients (85%) received reduced-intensity conditioning and 50% received bone marrow (BM) grafts. Complete (100%) CD3 donor chimerism was observed in 63 (84%) patients at D30, and subsequently 59 (95%) patients at D100. Complete CD33 donor chimerism was observed in 67 (89%) patients at D30, and subsequently 56 (88%) patients at D100. In univariable D30 landmark analysis, the CIR of relapse was significantly lower in patients who achieved complete CD3 (and CD33) chimerism compared with patients with less than complete chimerism (Figure 1A; p Conclusions Complete CD3 and CD33 donor chimerisms at D30 and D100 predict a patient's risk for relapse following haplo-HCT. We observed a strong association between CD3 chimeric status at D30 with DRI, as well suggestive that high risk disease may be associated with impaired immune reconstitution after transplant and perhaps a less robust graft vs disease effect.
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- 2020
22. 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
23. 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
24. Trend in Survival in Patients Undergoing Allogeneic Stem Cell Transplantation: An Institutional Experience
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Don M. Benson, Srinivas Devarakonda, Ayman Saad, Karilyn Larkin, Jonathan E. Brammer, Nicole Grieselhuber, Yvonne A. Efebera, Patrick Elder, Audrey M. Sigmund, Qiuhong Zhao, Sam Penza, Justin Jiang, Maria Chaudhry, Nidhi Sharma, Ashley E. Rosko, Basem M. William, Naresh Bumma, Abdullah Khan, Sumithira Vasu, Samantha Jaglowski, Hannah Choe, Alice S. Mims, and Sarah A Wall
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medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Disease ,Biochemistry ,Transplantation ,Family medicine ,medicine ,Data monitoring committee ,Chronic gvhd ,In patient ,Cumulative incidence ,Progression-free survival ,business - Abstract
Introduction: Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a potentially curative treatment for many hematological malignancies and disorders. However, this potential is often impeded by several factors including relapse of the underlying disease, graft-vs-host disease (GVHD) and infectious complications. Specifically, acute GVHD continues to be a major factor in the morbidity and mortality of patients. Hence, the practice of allo-SCT is continuously evolving to mitigate these factors. In particular, advances in the conditioning regimens, GVHD prophylaxis, infectious disease monitoring and prophylaxis and supportive care not only have resulted in improved outcomes, but also have expanded potential indications for allo-HSCT. Therefore, we conducted a retrospective analysis on patients who underwent allo-SCT at The Ohio State University from 1986-2018 to better understand how survival has changed longitudinally in accordance with these therapeutic advancements. Method: We analyzed data from 1943 consecutive patients who received an allo-SCT. Patients were divided into seven groups based on the year of transplant: groups (gp) 1: 1984-1988, 2: 1989-1993, 3: 1994-1998, 4: 1999-2003, 5: 2004-2008, 6: 2009-2013, and 7: 2014-2018. The primary endpoints were overall survival (OS) and progression free survival (PFS), and log-rank test was used to compare across transplant years. The Kaplan-Meier method was used to estimate OS and PFS. The 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). Cumulative incidence rates were estimated and compared using Gray's test accounting for competing risks. Results: Across the years (1984-2018), the median age was 50.0 (range: 18-76) with 59.6% of the patients being male. Acute myeloid leukemia accounted for 36.3% of transplants, followed by non-Hodgkin lymphoma (14.2%), acute lymphoid leukemia (11.8%), chronic myeloid leukemia (10.1%), and myelodysplastic syndrome (10.0%). Fifty-five percent of patients received myeloablative conditioning. Across the groups, statistically significant improvements in PFS and OS were observed (p Conclusion: Our data shows improved overall and progression-free survival post allo-SCT over decades, which may be attributed to advances in supportive care, and GVHD and relapse mitigation therapy. The decline in NRM is also likely due to improved supportive measures such as infectious disease monitoring and prophylaxis. Nonetheless, post-transplant relapse and grade III-IV aGVHD remain prominent challenges. Therefore, future research should continue to investigate therapeutic strategies that can both reduce high grade GVHD while limiting post-transplant relapse. 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:Kiadis Inc: Other: Kiadis has obtained exclusive licensing requirements from The OHio State University; Janssen: Membership on an entity's Board of Directors or advisory committees; Omeros: Membership on an entity's Board of Directors or advisory committees. Jaglowski:CRISPR: Consultancy; Novartis: Consultancy, Research Funding; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. William:Incyte: Research Funding; Guidepoint Global: Consultancy; Dova: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Kyowa Kirin: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Mims:Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Agios: Consultancy; Abbvie: 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; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau. Brammer:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Seattle Genetics: Honoraria, Speakers Bureau; Kymera: Honoraria; Verastem Oncology: Other: Travel. Saad:Incyte Pharmaceuticals: Other: Personal Fees; Amgen: Other: research support; Kadmon: Other: research support; Orcabio: Other: research support; Magenta Therapeutics: Other: Personal Fees. Efebera:Celgene: Research Funding; Takeda: Honoraria, Speakers Bureau; Pharmacyclics: Research Funding; Ohio State University: Current Employment.
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- 2020
25. 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
26. Impact of Chronic Graft-Versus-Host Disease on Non-Relapse Mortality
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Yvonne A. Efebera, Sam Penza, Jonathan E. Brammer, Sarah A Wall, Nicole Grieselhuber, Alice S. Mims, Basem M. William, Maria Chaudhry, Patrick Elder, Karilyn Larkin, Don M. Benson, Sumithira Vasu, Ayman Saad, Samantha Jaglowski, Srinivas Devarakonda, Audrey M. Sigmund, Qiuhong Zhao, Hannah Choe, Ashley E. Rosko, Naresh Bumma, Abdullah Khan, Nidhi Sharma, and Justin Jiang
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medicine.medical_specialty ,education.field_of_study ,business.industry ,medicine.medical_treatment ,Incidence (epidemiology) ,Immunology ,Hazard ratio ,Population ,Retrospective cohort study ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Disease ,Biochemistry ,Quality of life ,hemic and lymphatic diseases ,Family medicine ,Medicine ,Data monitoring committee ,business ,education - Abstract
Introduction-Chronic graft-versus-host disease (cGVHD) poses as a major late complication of hematopoietic stem cell transplantation. The role of cGVHD as a determinant in transplant-related morbidity and mortality, infectious complications, prolonged immune suppression, and impaired patient-reported quality of life has been extensively studied. Nonetheless, numerous advances in allogeneic hematopoietic stem cell transplant (allo-SCT) in recent years have expanded the indications for allo-SCT to a broader range of patients, including previously excluded older patients. However, long-term health status of older transplant recipients is poorly studied. Notably, the incidence of cGVHD may increase with age. Therefore, the development of cGVHD and the use of immunosuppressive therapy may lead to a higher degree of non-relapse mortality (NRM) in older patients. The objective of this study was to compare the NRM in both younger and older transplant recipients with and without cGVHD. Methods-We performed a retrospective cohort study of patients that underwent allo-SCT at the Ohio State University from 1999 to 2018. Data was analyzed from 1194 patients who survived or have been followed up with by at least day (d) 180 post-transplantation, among which 373 patients had developed cGVHD. Patients were grouped based on their age into a younger and older population. The older population was defined as ≥60 (N=373, 31%) with the younger population defined as Results-The median age at allo-SCT was 53.0 yr (range: 18-76) and 61.1% were male. Acute myeloid leukemia accounted for 36.7% of transplants, followed by non-Hodgkin's lymphoma (14.8%), acute lymphoid leukemia (12.7%), and myelodysplastic syndrome (11.0%). Additionally, 58.0% received reduced-intensity conditioning regimen. The majority of stem cell donor types were match unrelated (45.3%) and match related (39.8%). Patients who had developed cGVHD by d180, regardless of age, were at higher risk of NRM compared to patients with no cGVHD (hazard ratio [HR]: 1.52, 95% confidence interval [CI]: 1.16-1.99; p=0.002). To examine the influence of age with NRM, we stratified the analysis by cGVHD status by d180. Among patients developed cGVHD by d180, in both univariable (HR 1.22, 95% CI 0.79-1.9, p=0.373) and multivariable analysis (HR: 1.17, 95% CI: 0.74-1.87; p=0.501), there was no statistically significant difference in NRM between patients ≥60 and Conclusion-This study showed that patients with cGVHD by day 180 were at higher risk for higher NRM compared to patients without cGVHD. Among cGVHD patients, there was no difference on the outcome of older patients (≥60 years old) compared to younger ones ( Disclosures Chaudhry: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bumma:Sanofi: Speakers Bureau; Amgen: Speakers Bureau. Khan:Amgen: Consultancy; Janssen: Consultancy. Devarakonda:Janssen: Consultancy. Vasu:Kiadis Inc: Other: Kiadis has obtained exclusive licensing requirements from The OHio State University; Janssen: Membership on an entity's Board of Directors or advisory committees; Omeros: Membership on an entity's Board of Directors or advisory committees. Jaglowski:Novartis: Consultancy, Research Funding; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR: Consultancy. William:Celgene: Consultancy, Honoraria; Dova: Research Funding; Guidepoint Global: Consultancy; Merck: Research Funding; Kyowa Kirin: Consultancy, Honoraria; Seattle Genetics: Research Funding; Incyte: Research Funding. Mims:Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; 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; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Novartis: Speakers Bureau; Agios: Consultancy. Brammer:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Seattle Genetics: Honoraria, Speakers Bureau; Kymera: Honoraria; Verastem Oncology: Other: Travel. Saad:Magenta Therapeutics: Other: Personal Fees; Incyte Pharmaceuticals: Other: Personal Fees; Amgen: Other: research support; Kadmon: Other: research support; Orcabio: Other: research support. Efebera:Takeda: Honoraria, Speakers Bureau; Pharmacyclics: Research Funding; Celgene: Research Funding; Ohio State University: Current Employment.
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- 2020
27. 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
28. 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
29. Relationship of Tacrolimus Concentration and Incidence of Acute Graft-Versus-Host Disease after Allogenic Stem Cell Transplantation
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Nicole Grieselhuber, Alice S. Mims, Basem M. William, Qiuhong Zhao, Samantha Jaglowski, Nidhi Sharma, Yvonne A. Efebera, Ayman Saad, Bin Ni Ni, Sumithira Vasu, Hannah Choe, Sam Penza, Maria Chaudhry, Karilyn Larkin, Patrick Elder, Ashley E. Rosko, Jonathan E. Brammer, Srinivas Devarakonda, Sarah A Wall, Don M. Benson, Naresh Bumma, and Abdullah Khan
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Transplantation ,medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,Hazard ratio ,chemical and pharmacologic phenomena ,Hematology ,Lower risk ,Gastroenterology ,Tacrolimus ,Calcineurin ,surgical procedures, operative ,immune system diseases ,Internal medicine ,medicine ,Cumulative incidence ,Methotrexate ,business ,medicine.drug - Abstract
Introduction Acute graft versus host disease (aGVHD) remains a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT). Preventing GVHD without impairing the graft-versus-tumor effect remains an important goal for successful allo-HSCT. Tacrolimus (TAC), a calcineurin inhibitor that prevents T-cell activation, is commonly used as aGVHD prophylaxis. The influence of TAC has proved effective for preventing aGVHD after allo-HSCT. There is also variability in the serum concentrations of TAC and very little is known on the impact of early (first 4 weeks) TAC levels on aGVHD incidence. Methods Data were analyzed for 707 consecutive patients undergoing allo-HSCT at the Ohio State University between 2002- 2016. All patients received standard prophylaxis with TAC daily and methotrexate on days +1, +3, +6, and +11 post allo-HSCT. Tacrolimus dose was adjusted to achieve a target serum level of 5-12 ng/ml. Fine and Gray's proportional hazard models accounting for competing risks were used to evaluate the association between TAC levels and outcome of aGVHD, cGVHD, GVHD-free/relapse-free survival (GRFS),and relapse. Cox proportional hazard models were used for the association with OS. Results The mean weekly TAC concentrations at weeks 1, 2, 3 and 4 were 8.0, 9.7, 11.3 and 10.5 ng/mL, respectively. The cumulative incidence of grades II–IV aGVHD was 40% at day 100 and 45% at day 180 post HSCT. In univariable analysis, high TAC level at week 1 was associated with lower grade II-IV aGVHD (Hazard ratio (HR), 0.96; p = 0.006). We examined the effect of week 1 TAC levels categorized into tertiles ( 8.95 ng/ml). Higher level of TAC (>8.95 ng/ml) was associated with lower risk of aGVHD (Figure 1a). In multivariable analysis, week 1 TAC levels > 5.85 ng/ml remained associated with a lower risk of grade II-IV aGVHD. However, only levels of 5.85-8.95 ng/ml were associated with statistically significant lower risk with HR=0.75, p=0.04 compared to the lower group ( 7.2 ng/ml (HR: 0.78, p=0.03). The CI of cGVHD was 41% at 1 year post-allo-HSCT. Week 2 TAC level >10.6 ng/ml was associated with an increased risk of relapse (HR, 1.37, p=0.043) (Figure 1b). The cumulative incidence of relapse at 1, 3 and 5 year post allo-HSCT was 33%, 38% and 40%, respectively. TAC levels at weeks 1, 2, 3 and 4 were not associated with OS. The 1, 3 and 5 year GRFS was 21%, 14% and 12%.TAC levels at any week were not associated with GRFS. Conclusion Achieving mean whole-blood level of tacrolimus between 6.0-9.0 ng/ml within the first week post-allogenic bone marrow transplantation may reduce the risk of aGVHD.
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- 2020
30. 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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Hannah K. Choe, Maria Chaudhry, Sarah A Wall, Naresh Bumma, Abdullah Khan, Yvonne A. Efebera, Srinivas Devarakonda, Sumithira Vasu, Nicole Grieselhuber, Ayman Saad, Patrick Elder, Don M. Benson, Jonathan E. Brammer, Qiuhong Zhao, Karilyn Larkin, Samantha Jaglowski, Basem M. William, Bin Ni, Sam Penza, Nidhi Sharma, Alice S. Mims, and Ashley E. Rosko
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0301 basic medicine ,medicine.medical_specialty ,Thymoglobulin ,business.industry ,Incidence (epidemiology) ,medicine.medical_treatment ,Immunology ,Hazard ratio ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Lower risk ,Biochemistry ,Transplantation ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Internal medicine ,Acute lymphocytic leukemia ,medicine ,Cumulative incidence ,business ,030215 immunology - Abstract
Introduction: Acute graft versus host disease (aGVHD) remains a leading cause of morbidity and mortality in allogeneic hematopoietic stem marrow transplant (allo-HSCT), with rates ranging from 30% to 70%. Preventing GVHD without impairing the graft-versus-tumor effect remains an important goal for successful allo-HSCT. Tacrolimus (TAC), a calcineurin inhibitor that prevents T-cell activation, is commonly used as aGVHD prophylaxis. The influence of TAC has proved effective for preventing aGVHD after allo-HSCT. There is also variability in the serum concentrations of TAC and very little is known on the impact of early (first 4 weeks) TAC levels on aGVHD incidence. Given the immunologic events that lead to aGVHD, which occur within the first few days after transplant, we sought to assess whether early TAC levels were associated with aGVHD. Methods: Data were analyzed for 707 consecutive patients undergoing allo-HSCT at the Ohio State University between 2002- 2016. All patients received standard prophylaxis with TAC daily and methotrexate at a dose of 5mg/m2 on days +1, +3, +6, and +11 post allo-HSCT. Patients received anti-thymoglobulin (ATG) if receiving stem cells from an unrelated/mismatch related donor. The TAC target range was 5-12 ng/mL averaged over a 7-day period. The primary outcome of interest was the incidence of aGVHD and its association with the mean weekly TAC levels. Secondary endpoints included incidence of chronic GVHD (cGVHD), relapse and overall survival (OS). Fine and Gray's proportional hazard models accounting for competing risks were used to evaluate the association between TAC levels and outcome of aGVHD, cGVHD and relapse. Cox proportional hazard models were used for the association with OS. Mean weekly TAC levels were included in the analyses as continuous variables and then divided into tertiles. A multivariable model adjusted for confounding factors. Results: Among the 707 patients, median age was 53 years (range: 19-75) and 60.7% were male. In all, 68% patients received reduced-intensity conditioning and the remaining 32% received myeloablative conditioning. The median age of donors was 34 years (range: 18-81) with 74.7% male. Of the donors, 36.9% were match related and 55.9% match unrelated. Peripheral blood was the stem cell source for 90.2% of the patients. A total of 449 (63.5%) patients received ATG. The diagnosis included acute myeloid leukemia (36.3%), non-Hodgkin lymphoma (16.41%), myelodysplastic syndrome (11.7%), and acute lymphoblastic leukemia (11.88%). The mean weekly TAC concentrations at weeks 1, 2, 3 and 4 were 8.0, 9.7, 11.3 and 10.5 ng/mL, respectively. The cumulative incidence of grades II-IV aGVHD was 40% (95% confidence interval (95% CI): 36%-43%) at day 100 and 45% (95% CI: 41%-48%) at day 180 post-transplant. In univariable analysis, high TAC level at week 1 was associated with lower grade II-IV aGVHD (Hazard ratio (HR), 0.96; 95%CI, 0.93-0.99; p = 0.006). We examined the effect of week 1 TAC levels categorized into tertiles (< 5.85, 5.85-8.95 and >8.95 ng/ml). Higher level of TAC (>8.95 ng/ml) was associated with lower risk of aGVHD (Figure 1a). In multivariable analysis, week 1 TAC levels > 5.85 ng/ml remained associated with a lower risk of grade II-IV aGVHD. However, only levels of 5.85-8.95 ng/ml were associated with statistically significant lower risk with HR=0.75 95% CI, 0.57-0.98; p=0.04 compared to the lower group (7.2 ng/ml (HR: 0.78, 95%CI: 0.62-0.98; p=0.03). The cumulative incidence of cGVHD was 41% (95% CI: 37%-44%) at 1 year post-allo-HSCT. Since GVHD is closely intertwined with the graft-versus-tumor effect, we examined whether early TAC levels influenced the risk of disease relapse. TAC levels at week 1 were not associated with relapse. However, week 2 TAC level >10.6 ng/ml was associated with an increased risk of relapse in multivariable analysis (HR, 1.37, CI, 1.01-1.85, p=0.043) (Figure 1b), after adjusting for confounding variables. The cumulative incidence of relapse at 1, 3 and 5 year post allo-HSCT was 33%, 38% and 40%, respectively. TAC levels at weeks 1, 2, 3 and 4 were not associated with OS. Conclusion: Achieving mean whole-blood level of tacrolimus between 6.0-9.0 ng/ml within the first week post-allogenic bone marrow transplantation may reduce the risk of aGVHD. Disclosures Rosko: Vyxeos: Other: Travel support. Vasu:Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: Clinical trial support. Jaglowski:Kite: Consultancy, Other: advisory board, Research Funding; Juno: Consultancy, Other: advisory board; Novartis: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding. William:Techspert: Consultancy; Guidepoint Global: Consultancy; Defined Health: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy. Mims:Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Jazz 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; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Brammer:Bioniz Therapeutics, Inc.: Research Funding; Viracta Therapeutics, Inc.: Research Funding; Verastem, Inc: Research Funding. Saad:Actinium Pharma Inc: Consultancy; Amgen: Other: Research Support; Kadmon: Other: Research Support; OrcaBio: Other: Research Support. Efebera:Janssen: Speakers Bureau; Akcea: Other: Advisory board, Speakers Bureau; Takeda: Honoraria.
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- 2019
31. 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
32. Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia
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Amy Lehman, James S. Blachly, Bonnie K. Harrington, Virginia M. Goettl, Katie Williams, Deepa Sampath, Alice S. Mims, Nicole Grieselhuber, Karl N. Kirschner, Shaneice Mitchell, William Senapedis, Rosa Lapalombella, Pu Zhang, Justin T. Breitbach, Shelley Orwick, Yerdanose Asemelash, Shuai Dong, Sally E. Henderson, Karilyn Larkin, John C. Byrd, Matthew Cannon, Vinay K. Puduvalli, Pankaj Sharma, Erkan Baloglu, Tzung Huei Lai, and Larry Beaver
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0301 basic medicine ,Myeloid ,Nicotinamide phosphoribosyltransferase ,Aminopyridines ,Apoptosis ,HL-60 Cells ,Mice, SCID ,Biology ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Mice, Inbred NOD ,hemic and lymphatic diseases ,Cell Line, Tumor ,medicine ,Cytotoxic T cell ,Animals ,Humans ,Enzyme Inhibitors ,Nicotinamide Phosphoribosyltransferase ,Acrylamides ,Myeloid Neoplasia ,Myeloid leukemia ,Hematology ,medicine.disease ,Xenograft Model Antitumor Assays ,Haematopoiesis ,Leukemia ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Cytokines ,NAD+ kinase ,K562 Cells ,K562 cells - Abstract
Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD+ and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mitochondrial respiration and glycolysis and induced apoptosis in AML subtypes independent of mutations and genomic abnormalities. These actions occurred mainly through the depletion of NAD+, whereas genetic knockdown of p21-activated kinase 4 did not induce cytotoxicity in AML cell lines or influence the cytotoxic effect of KPT-9274. KPT-9274 exposure reduced colony formation, increased blast differentiation, and diminished the frequency of leukemia-initiating cells from primary AML samples; KPT-9274 was minimally cytotoxic toward normal hematopoietic or immune cells. In addition, KPT-9274 improved overall survival in vivo in 2 different mouse models of AML and reduced tumor development in a patient-derived xenograft model of AML. Overall, KPT-9274 exhibited broad preclinical activity across a variety of AML subtypes and warrants further investigation as a potential therapeutic agent for AML.
- Published
- 2018
33. 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
- Author
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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
- Subjects
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
34. Cytopenias after Chimeric Antigen Receptor T-Cells (CAR-T) Infusion; Patterns and Outcomes
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Nicole Grieselhuber, Basem M. William, Ashley E. Rosko, Sarah A Wall, Andrew Schaefer, Meixiao Long, Alice S. Mims, Samantha Jaglowski, Don M. Benson, Tara Hoelscher, Zebulun Purdin, Misty Lamprecht, Bradley W. Blaser, Yvonne A. Efebera, Sumithira Vasu, Sam Penza, Karilyn Larkin, Hannah Choe, Joseph E. Maakaron, Jacquela Robinson, Caner Saygin, and Jonathan E. Brammer
- Subjects
Transplantation ,medicine.medical_specialty ,Cyclophosphamide ,Anemia ,business.industry ,Hematology ,Filgrastim ,Neutropenia ,medicine.disease ,Gastroenterology ,Fludarabine ,Chemoimmunotherapy ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Absolute neutrophil count ,business ,Progressive disease ,medicine.drug - Abstract
Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) have poor treatment outcomes when treated with traditional chemoimmunotherapy. Superior outcomes have been observed with the 2 CAR-T cell products approved by the US FDA; tisagenlecleucel (CTL109) and axicabtagene ciloleucel (Axi-cel) with 12 months overall survival rates of 49% and 59% respectively. The 2 major acute toxicities of these therapies are cytokine release syndrome (CRS) and neurotoxicity. The incidence of grade 3 or higher neutropenia, anemia, and thrombocytopenia was 78%, 43%, and 38% in patients treated with axi-cel. Little is known regarding the patterns and outcomes of these cytopenias. Here we present our preliminary experience on the patterns and outcomes of cytopenias in 32 patients who received commercially-available CAR-T cell therapy at our institution. We retrospectively reviewed all DLBCL patients receiving either CTL109 or axi-cel between January and September 2018 at our institution. All patients received a conditioning regimen of low-dose cyclophosphamide and fludarabine, followed by CAR-T infusion. Persistent cytopenias were defined as incomplete absolute neutrophil count ( The median age of patients was 59 years (range, 23-80); 63% were male, 4 patients (13%) received CTL109 and 28 (87%) received axi-cel. Twenty-two patients (69%) had a 3 month follow up imaging for assessment of response, of whom 7 patients (32%) achieved complete response (CR), 6 patients (27%) achieved partial response (PR), and 9 patients (41%) had progressive disease (PD). Persistent neutropenia was observed in 3 patients (9%), while persistent thrombocytopenia was seen in 21 cases (65%) and persistent anemia was the most common with a frequency of 72% (23/32 cases). Median time to neutrophil, platelet and Hb recoveries were 11 days (range, 5-218 days), 59.5 days (range, 4-241 days), and 76 days (range, 0-218 days), respectively. Filgrastim was used in 15 (47%) patients to facilitate neutrophil recovery. Twenty-three patients (72%) experienced neurotoxicity, of whom 11 (34%) had grade 3-4 toxicity. The frequency of CRS was 94% (29 out of 32 patients), with grade 3-4 CRS observed in 4 cases (12.5%). We observed no significant association between CRS and persistent cytopenias. In our preliminary series of 32 patients, persistent anemia and thrombocytopenia were more common than neutropenia after CAR-T cell therapy. However, most of these patients required growth factor support for neutrophil recovery. Longer duration of follow up is necessary to determine the impact of persistent cytopenias on outcomes and survival after CAR-T cell therapy.
- Published
- 2019
35. Levofloxacin Prophylaxis for Autologous Stem Cell Transplant: A Second Look
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Nicole Grieselhuber, Christina Liscynesky, Karilyn Larkin, Yvonne A. Efebera, Zeinab El Boghdadly, Alice S. Mims, Meixiao Long, Sam Penza, Sarah A Wall, Basem M. William, Jonathan E. Brammer, Bradley W. Blaser, Samantha Jaglowski, Don M. Benson, Hannah Choe, Ashley E. Rosko, Joseph E. Maakaron, and Sumithira Vasu
- Subjects
Melphalan ,Transplantation ,medicine.medical_specialty ,business.industry ,Hematology ,medicine.disease ,Lymphoma ,03 medical and health sciences ,0302 clinical medicine ,Antibiotic resistance ,Levofloxacin ,030220 oncology & carcinogenesis ,Internal medicine ,Relative risk ,Bacteremia ,medicine ,Stem cell ,business ,Multiple myeloma ,030215 immunology ,medicine.drug - Abstract
Introduction Autologous stem cell transplant patients (ASCT) are at risk for bacterial. Antibacterial prophylactic strategy is variable among centers. Fluoroquinolone prophylaxis in ASCT patients has not been found to add a survival benefit. We performed a retrospective review of patients undergoing ASCT with and without bacterial prophylaxis to compare endpoints of interest. Methods At our institution, patients undergoing ASCT for multiple myeloma (MM) receive levofloxacin 500 mg daily as prophylaxis, while lymphoma patients do not. We retrospectively examined MM or lymphoma patients undergoing ASCT between July of 2015 and 2018 for bacteremia episodes. MM patients received melphalan and lymphoma patients received BEAM. All patients received growth factor support. Clinical and microbial data was recorded and analyzed using SPSS. Results In total, 172 patients underwent ASCT for lymphoma and 343 for MM. Seventeen percent (30/172) of lymphoma patients and 5.5% (19/324) of MM patients had febrile neutropenic episodes associated with bacteremia. Relative risk was 3.1 [1.83 – 5.43, p Discussion Fluoroquinolone prophylaxis resulted in less blood stream infection episodes but more breakthrough infections with resistant isolates. There was no statistically significant difference between the rates of CDI infections despite a trend to lower incidence in the prophylaxis group. Bacteremia was more difficult to treat for the resistant isolates. There were two infection-related mortalities in the prophylaxis group. In the era of antimicrobial resistance, further reevaluation of the utility of fluoroquinolone prophylaxis should be carefully weighed against the risks.
- Published
- 2019
36. CD37 Expression in Acute Myeloid Leukemia Provides New Target for Directed Therapy
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Nicole Grieselhuber, John C. Byrd, Bonnie K. Harrington, Karilyn Larkin, Erin Guth, and Natarajan Muthusamy
- Subjects
0301 basic medicine ,biology ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Immunotherapy ,Biochemistry ,CD19 ,Flow cytometry ,03 medical and health sciences ,030104 developmental biology ,Immunophenotyping ,Cytokine ,biology.protein ,medicine ,Cancer research ,Stem cell ,Antibody ,business - Abstract
Background: Acute myeloid leukemia (AML) is a disease for which there is an urgent need for therapy that is more effective and less toxic. Antibody based therapy has been of limited success due to both the lack of consistent immunophenotype in AML as well as the overlap with normal hematopoetic stem cells (HSCs). CD37 is a tetraspanin best characterized for its role in B-cell development and immune response (Van Spriel et al., 2004, 2009, 2012), recently shown to be expressed on AML cells but not in normal HSCs (Pereira et al.,2015). Debio 1562 (formerly IMGN529) is a potent antibody drug conjugate (ADC) directed at CD37, comprised of the antibody K7153A linked to the microtubule inhibitor (DM1) and has already demonstrated tolerability and efficacy in early phase clinical trials in lymphoid malignancies. We evaluated the expression of CD37 across primary AML samples as well as the activity of Debio 1562 in both in vitro and in vivo AML model systems. Methods: MTS assays were used to assess relative viability in AML cell lines with (THP1, OCI-AML3) or without (KG-1a) CD37 expression. Cells were treated with either the ADC, the payload conjugated to an isotype antibody (Iso-DM1) or a vehicle control for 72 hours. After determining the IC50 for each cell line, flow cytometry annexin V/PI was performed to assess apoptosis and cell death. THP-1 and OCI-AML3 CD37 knock out cell lines were created using an inducible CRISPR Cas9 system and evaluated by MTS and annexin V/PI following confirmation of knockdown of CD37 expression. Primary AML samples were obtained to assess CD37 expression by flow cytometry using K7153A-PE and separately used to evaluate direct cytotoxicity in an in vitroassay. Peripheral blood mononuclear cells from newly diagnosed AML patients were treated with either therapy, cells were harvested after 72 hours and subsequently stained with CD2/CD19/CD45 as well as EdU to assess degree of proliferation and analyzed using flow cytometry with the addition of Countbright beads to measure absolute cell counts. In vivo therapy evaluations were performed in NSG mice were engrafted with the THP1 cell line, and then treated with either the ADC, Iso-DM1 or vehicle. The mice were treated twice weekly with 10mg/kg given IP, for 7 total doses. The mice were monitored for overall survival. Results: Analysis of the TCGA database shows AML patients with higher levels of CD37 transcripts had lower overall survival (p Conclusions: CD37 is expressed across a wide range of AML subtypes, and higher transcript levels of CD37 expression is associated with decreased survival. Despite the majority of primary samples showing minimal to modest expression of the protein when compared to B lymphocytes, CD37 is an efficient target on AML cells using Debio 1562. Additional studies are ongoing to evaluate the mechanism of CD37 trafficking in myeloid cells as well as the ability to upregulate this important target. This work provides rationale for phase I clinical trials of Debio 1562 in AML patients, as well as demonstrating CD37 as a potential target for other CD37 Immunotherapies. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
- Published
- 2018
37. Impact of Cytokine Release Syndrome on Outcomes after T-Cell Replete Peripheral Blood Haploidentical Donor Transplantation
- Author
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Nicole Grieselhuber, Sam Penza, Maria Chaudhry, Marcin Puto, Ashley E. Rosko, Sumithira Vasu, Bradley W. Blaser, Hannah K. Choe, Bhavana Bhatnagar, John L Vaughn, Sarah A Wall, Basem M. William, Yvonne A. Efebera, Alison Walker, Don M. Benson, Samantha Jaglowski, Karilyn Larkin, Julianna Roddy, Alice S. Mims, Caner Saygin, Joseph Coleman, Steven M. Devine, Meixiao Long, and Jonathan E. Brammer
- Subjects
business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Sepsis ,Transplantation ,Leukemia ,Cytokine release syndrome ,medicine.anatomical_structure ,ABO blood group system ,otorhinolaryngologic diseases ,medicine ,Bone marrow ,business ,Busulfan ,medicine.drug - Abstract
Background: Haploidentical hematopoietic cell transplantation (haplo-HCT) is an advancing and potentially curative therapy for patients with hematologic malignancies when the availability of HLA-matched donors are limited. The common source for haplo-HCT is donor bone marrow, but peripheral blood (PB) haplo-HCT is an emerging and less invasive option with similar survival outcomes. However, multiple series showed an increased incidence of culture negative fever early after haplo-HCT, which has been attributed to cytokine release syndrome (CRS) and more commonly observed with PB haplo-HCT. In this study, we investigated the incidence and impact of CRS on clinical outcomes and financial toxicity in PB haplo-HCT patients treated at a single center. Methods: A total of 40 patients who underwent PB haplo-HCT in the Ohio State University between Jan 2015 - Dec 2017 were included. CRS was defined and graded based on the criteria proposed by Lee, et al (Blood, 2014). Symptoms occurring before day +14 were included, patients with a documented infection (e.g. positive culture data) and clinical suspicion of sepsis were excluded. Overall survival (OS) was defined as the time from transplantation until death. Transplant-related mortality (TRM) was defined as death before day +28 from any cause and patients who died after day +28 with no evidence of disease. Results:. The median age at HCT was 53 years (range, 19 to 74), 63% were male. The most common diagnosis was acute myeloid leukemia (47.5%), followed by lymphoma (22.5%), acute lymphoblastic leukemia (7.5%) and myelodysplastic syndrome (7.5%). Two patients had undergone previous autologous HCT. At the time of haplo-HCT, 62% of patients were in complete remission, 38% had relapsed/refractory disease. Donor was the child in 58%, sibling in 24% and parent in 18% with an antigen match ratio of 5/10 in 50%, 6/10 in 30%, 7/10 in 12.5%, 8/10 in 7.5%. Mismatch for sex and ABO blood group were seen in 50% and 45%, respectively. Twenty percent of patients received myeloablative conditioning with fludarabine/busulfan/thiotepa, while 80% received reduced-intensity regimen with fludarabine/cyclophosphamide/total body irradiation. The incidence of CRS was 85%, including grade 1-2 CRS in 77.5% and grade 3-4 CRS in 7.5%. Time to the onset of CRS was Conclusions: CRS is commonly observed after PB haplo-HCT and usually manifests with fever within 48 hours of cell infusion. We observed favorable survival outcomes in patients who experienced mild CRS, which may suggest an association between mild CRS and graft-versus-leukemia effect. A minority of patients developed severe CRS requiring intensive care unit support, which was associated with poor OS, high TRM, prolonged hospital stay and increased financial toxicity. Further studies investigating biomarkers that can predict the development of severe CRS might enable the incorporation of CRS prophylaxis (e.g. with tocilizumab) into standard conditioning regimens for PB haplo-HCT. Disclosures Vasu: Boehringer Ingelheim Inc: Membership on an entity's Board of Directors or advisory committees. Mims:Novartis: Consultancy; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Devine:Kiadis Pharma: Consultancy. Jaglowski:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Juno: Consultancy.
- Published
- 2018
38. NAMPT Inhibitor KPT-9274 Selectively Targets Self-Renewal Capacity in Acute Myeloid Leukemia
- Author
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William Senapedis, Shelley Orwick, Shaneice Mitchell, Alice S. Mims, Nicole Grieselhuber, Rosa Lapalombella, Deepa Sampath, Erkan Baloglu, James S. Blachly, Justin T. Breitbach, Bonnie K. Harrington, John C. Byrd, Matthew Cannon, Vinay K. Puduvalli, Pankaj Sharma, Yerdanos Asemelash, Amy Lehman, and Virginia M. Goettl
- Subjects
Myeloid ,IDH1 ,business.industry ,Immunology ,Nicotinamide phosphoribosyltransferase ,Myeloid leukemia ,Combination chemotherapy ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,chemistry.chemical_compound ,Leukemia ,medicine.anatomical_structure ,chemistry ,Cancer research ,Medicine ,NAD+ kinase ,Stem cell ,business - Abstract
Acute Myeloid Leukemia (AML) is a heterogeneous disease that is characterized by an accumulation of neoplastic myeloid precursor cells in the bone marrow. Recently, multiple agents targeting AML associated mutations in FLT3, IDH1 and IDH2 have been developed. However, a majority of AML patients lack these mutations. Therefore, development of a novel therapeutic approach broadly relevant to AML would be attractive. The clonal capacity of AML cells is maintained by leukemic initiating cells (LICs), which possess self-renewal capabilities and are resistant against cytotoxic combination chemotherapy. Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step in the generation of NAD+, which is an important enzymatic cofactor and serves as a metabolite required for cellular respiration. LICs show a higher energy turnover rate than normal cells and are heavily reliant on oxidative phosphorylation. This suggests that energy generation processes, such as NAD+ biosynthesis, are critically required in myeloid malignancies. Thus, targeting the regeneration of NAD+ offers an attractive alternative therapeutic strategy in AML. Unlike many targeted therapies that are limited to one genetic subtype of AML, targeting regeneration of NAD+ via NAMPT inhibition could be relevant to a much broader patient population based upon metabolic differences between tumor and normal cells. We show that inhibition of NAMPT using the agent KPT-9274 induces loss of glycolytic and mitochondrial activity, more specifically a depleted total spare reserve capacity (p Disclosures Mims: Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Baloglu:Karyopharm Therpeutics: Employment. Senapedis:Karyopharm Therapeutics: Employment.
- Published
- 2018
39. 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
- Subjects
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
40. The Novel BET Inhibitor PLX51107 Has In Vitro and In Vivo Activity Against Acute Myeloid Leukemia
- Author
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Alison Walker, Nicole Grieselhuber, Bonnie K. Harrington, Alice S. Mims, Bhavana Bhatnagar, Virginia M. Goettl, Ramiro Garzon, William Blum, Rosa Lapalombella, Rebecca B. Klisovic, David M. Lucas, Shaneice Mitchell, James S. Blachly, John C. Byrd, Shelley Orwick, and Sumithra Vasu
- Subjects
0301 basic medicine ,Severe combined immunodeficiency ,Myeloid ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,BET inhibitor ,03 medical and health sciences ,Leukemia ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,In vivo ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Cytarabine ,B cell ,medicine.drug - Abstract
Background: Acute myeloid leukemia (AML) has very poor long-term survival with traditional therapies. AML has a diverse pathogenesis and likely represents multiple different diseases. Various epigenetic effector proteins are altered in AML by mutation, over-expression, or compartmental displacement and these changes maintain transcriptional programs important for leukemogenesis. The bromodomain and extra-terminal domain (BET) proteins, including BRD2, BRD3 and BRD4, play roles in many cellular functions important to leukemogenesis, such as super-enhancer function, transcriptional elongation, histone acetylation and cell cycle progression. In particular, AML cells depend on BRD4 for expression of the pro-survival proteins MYC and BCL2. BRD4 has therefore become an attractive target for novel therapeutics. PLX51107 is a novel BET inhibitor with a unique binding mode in the acetylated lysine binding pocket of BRD4 that differentiates it from other compounds under investigation. Our group has previously shown this compound to have antineoplastic activity in models of aggressive B cell malignancies. We have now investigated the anti-leukemic properties of PLX51107 in both in vitro and in vivo models of AML. Results: PLX51107 treatment potently reduced viability and proliferation of the human AML cell lines MV4-11, MOLM-13, OCI-AML3, and Kasumi-1, with IC50 of 0.17, 1.8, 0.2 and 0.2 μM, respectively. We then evaluated the in vitro activity of PLX51007 in primary human AML samples. PLX51107 inhibited the proliferation of primary human AML cells co-cultured with HS5 stromal cells. For nearly all samples tested (n=9), the IC50 of PLX51007 was less than 1 μM (average = 0.41 μM, range 0.039 - 1.5 μM). Notably, PLX51107 showed efficacy across a broad range of AML risk groups, including samples with adverse risk features such as 11q23 abnormalities and FLT3-ITD mutations. In comparison, for the same AML samples, the average IC50 for JQ1 was 0.71 μM (range 0.02 - 3.3 μM) and for cytarabine was 3.5 μM (range 0.33 to >10 μM). Furthermore, PLX51107 treatment reduced the clonogenicity of primary AML cells. Following incubation of AML cells in 1 μM PLX51107, there was significantly decreased colony formation (p We next examined the efficacy of PLX51107 in vivo, utilizing luciferase labeled MV4-11 AML cells xenotransplanted into NOD / SCID / IL2rgnull (NSG) immunodeficient mice. Daily oral dosing with 20 mg/kg PLX51107 resulted in prolonged survival (median 47 days) compared to vehicle treated control animals (median 30 days, p< 0.001). Weekly measurement of bioluminescence showed decreased disease burden in PLX51107 treated mice. In addition, human peripheral blood CD45 / CD33 double positive cells were significantly decreased in treated animals. Histologic analysis conducted at day 16 showed decreased leukemic burden in the bone marrow of the PLX51107 treated animals. In addition, examination of tissues from moribund mice at time of euthanasia demonstrated fewer leukemia cells in the spleen, liver and bone marrow. Conclusions: Collectively, our results show pre-clinical activity of PLX51107 in AML, supporting further development of this compound in clinical trials for relapsed or refractory myeloid malignancies. We are currently working to define downstream targets of PLX51107 action and developing patient derived AML xenografts to further characterize the in vivo effects of PLX51107. Disclosures Walker: Gilead Sciences: Research Funding. Bhatnagar:Karyopharm: Research Funding.
- Published
- 2016
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