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Courtney D DiNardo

Guillermo Montalban-Bravo, Courtney D DiNardo
Isocitrate dehydrogenases (IDHs) are enzymes involved in multiple metabolic and epigenetic cellular processes. Mutations in IDH1 or IDH2 are detected in approximately 20% of patients with acute myeloid leukemia (AML) and induce amino acid changes in conserved residues resulting in neomorphic enzymatic function and production of an oncometabolite, 2-hydroxyglutarate (R-2-HG). This leads to DNA hypermethylation, aberrant gene expression, cell proliferation and abnormal differentiation. IDH mutations diversely affect prognosis of patients with AML based on the location of the mutation and other co-occurring genomic abnormalities...
March 15, 2018: Future Oncology
Jo Ishizawa, Kenji Nakamaru, Takahiko Seki, Koichi Tazaki, Kensuke Kojima, Dhruv Chachad, Ran Zhao, Lauren E Heese, Wencai Ma, Man Chun John Ma, Courtney D DiNardo, Sherry A Pierce, Keyur P Patel, Archie Tse, R Eric Davis, Arvind Rao, Michael Andreeff
Early clinical trials using murine double minute 2 (MDM2) inhibitors demonstrated proof-of-concept of p53-induced apoptosis by MDM2 inhibition in cancer cells, however, not all wild-type TP53 tumors are sensitive to MDM2 inhibition. Therefore, more potent inhibitors and biomarkers predictive of tumor sensitivity are needed. The novel MDM2 inhibitor DS-3032b is 10-fold more potent than the first-generation inhibitor nutlin-3a. TP53 mutations were predictive of resistance to DS-3032b, and allele frequencies of TP53 mutations were negatively correlated with sensitivity to DS-3032b...
February 28, 2018: Cancer Research
Hagop Kantarjian, Farhad Ravandi, Nicholas J Short, Xuelin Huang, Nitin Jain, Koji Sasaki, Naval Daver, Naveen Pemmaraju, Joseph D Khoury, Jeffrey Jorgensen, Yesid Alvarado, Marina Konopleva, Guillermo Garcia-Manero, Tapan Kadia, Musa Yilmaz, Gautam Bortakhur, Jan Burger, Steven Kornblau, William Wierda, Courtney DiNardo, Alessandra Ferrajoli, Jovitta Jacob, Rebecca Garris, Susan O'Brien, Elias Jabbour
BACKGROUND: Inotuzumab ozogamicin, an anti-CD22 monoclonal antibody bound to a toxin, calicheamicin, has shown single-agent activity in relapsed or refractory acute lymphoblastic leukaemia. We aimed to assess the activity and safety of inotuzumab ozogamicin in combination with low-intensity chemotherapy in older patients with acute lymphoblastic leukaemia. METHODS: We did a single-arm, phase 2 study at the MD Anderson Cancer Center (Houston, TX, USA). Eligible patients were aged 60 years or older and had newly diagnosed, Philadelphia chromosome-negative, acute lymphoblastic leukaemia, and an Eastern Cooperative Oncology Group performance status of 3 or lower...
January 15, 2018: Lancet Oncology
Amir T Fathi, Courtney D DiNardo, Irina Kline, Laurie Kenvin, Ira Gupta, Eyal C Attar, Eytan M Stein, Stephane de Botton
Importance: Enasidenib mesylate, a mutant isocitrate dehydrogenase 2 (IDH2) protein inhibitor that promotes differentiation of leukemic myeloblasts, was recently approved by the US Food and Drug Administration for use in relapsed/refractory (R/R) mutant IDH2 acute myeloid leukemia (AML). During the first study of enasidenib in humans, a minority of patients with advanced myeloid neoplasms experienced unexpected signs/symptoms of a differentiation syndrome (DS), a potentially lethal entity...
January 18, 2018: JAMA Oncology
Courtney D DiNardo, Keith W Pratz, Anthony Letai, Brian A Jonas, Andrew H Wei, Michael Thirman, Martha Arellano, Mark G Frattini, Hagop Kantarjian, Relja Popovic, Brenda Chyla, Tu Xu, Martin Dunbar, Suresh K Agarwal, Rod Humerickhouse, Mack Mabry, Jalaja Potluri, Marina Konopleva, Daniel A Pollyea
BACKGROUND: Elderly patients (aged ≥65 years) with acute myeloid leukaemia have poor outcomes and no effective standard-of-care therapy exists. Treatment with hypomethylating agents such as azacitidine and decitabine is common, but responses are modest and typically short-lived. The oral anti-apoptotic B-cell lymphoma 2 protein inhibitor, venetoclax, has shown promising single-agent activity in patients with relapsed or refractory acute myeloid leukaemia and preclinical data suggested synergy between hypomethylating agents and venetoclax, which led to this combination phase 1b study...
January 12, 2018: Lancet Oncology
Prajwal Boddu, Hagop Kantarjian, Farhad Ravandi, Guillermo Garcia-Manero, Gautam Borthakur, Michael Andreeff, Elias J Jabbour, Christopher B Benton, Courtney D DiNardo, Marina Konopleva, Naval Daver, Keyur Patel, Koichi Takahashi, Rashmi Kanagal-Shamanna, Jorge Cortes, Tapan Kadia
No abstract text is available yet for this article.
January 17, 2018: Leukemia & Lymphoma
Prajwal Boddu, Hagop M Kantarjian, Guillermo Garcia-Manero, Farhad Ravandi, Srdan Verstovsek, Elias Jabbour, Gautam Borthakur, Marina Konopleva, Kapil N Bhalla, Naval Daver, Courtney D DiNardo, Christopher B Benton, Koichi Takahashi, Zeev Estrov, Sherry R Pierce, Michael Andreeff, Jorge E Cortes, Tapan M Kadia
Secondary acute myeloid leukemia (s-AML) includes therapy-related AML and AML evolving from antecedent hematological disorder (AHD). s-AML arising after treating AHD likely represents a prognostically distinct, high-risk disease category. In this study, treated s-AML (ts-AML) was defined by: (1) prior diagnosis of myelodysplasia, myeloproliferative neoplasm, or aplastic anemia and (2) at least 1 therapy for that diagnosis. ts-AML was categorized by age (< or ≥60 years), and each cohort assessed for response rates and overall survival (OS) on various treatment regimens...
July 25, 2017: Blood Advances
Koichi Takahashi, Feng Wang, Hagop Kantarjian, Xingzhi Song, Keyur Patel, Sattva Neelapu, Curtis Gumbs, Latasha Little, Samantha Tippen, Rebecca Thornton, Courtney D DiNardo, Farhad Ravandi, Carlos Bueso-Ramos, Jianhua Zhang, Xifeng Wu, Guillermo Garcia-Manero, P Andrew Futreal
Recent studies have revealed that clonal hematopoiesis of indeterminate potential (CHIP) is an important risk factor for therapy-related myeloid neoplasms (t-MNs). CHIP is currently defined as a clonal hematopoietic population carrying somatic point mutations in 1 of the leukemia-associated genes. Patients with t-MNs often present with chromosomal abnormalities in addition to somatic point mutations. It remains unclear whether chromosomal abnormalities can cooccur with point mutations as part of CHIP. Here we report that 3 of 14 patients with t-MNs had low amplitude but detectable chromosome arm-level copy number alterations (CNAs) in the peripheral blood samples that were taken at the time of their primary cancer diagnosis and before exposure to therapy...
June 27, 2017: Blood Advances
Courtney D DiNardo, Caitlin R Rausch, Christopher Benton, Tapan Kadia, Nitin Jain, Naveen Pemmaraju, Naval Daver, Wendy Covert, Kayleigh R Marx, Morgan Mace, Elias Jabbour, Jorge Cortes, Guillermo Garcia-Manero, Farhad Ravandi, Kapil N Bhalla, Hagop Kantarjian, Marina Konopleva
INTRODUCTION: Venetoclax (VEN), a selective BCL2 inhibitor, has single-agent activity in relapsed and refractory (R/R) acute myeloid leukemia (AML), and efficacy in lower intensity combinations for treatment-naïve elderly AML patients. VEN treatment combinations in R/R AML have not been previously reported. METHODS: All R/R myeloid patients (including AML, myelodysplastic syndrome (MDS), and blastic plasmacytoid dendritic cell neoplasm (BPDCN)) treated with VEN combinations in the salvage setting were reviewed...
March 2018: American Journal of Hematology
Rita Assi, Hagop M Kantarjian, Guillermo Garcia-Manero, Jorge E Cortes, Naveen Pemmaraju, Xuemei Wang, Graciela Nogueras-Gonzalez, Elias Jabbour, Prithviraj Bose, Tapan Kadia, Courtney D Dinardo, Keyur Patel, Carlos Bueso-Ramos, Lingsha Zhou, Sherry Pierce, Romany Gergis, Carla Tuttle, Gautam Borthakur, Zeev Estrov, Rajyalakshmi Luthra, Juliana Hidalgo-Lopez, Srdan Verstovsek, Naval Daver
Ruxolitinib and azacytidine target distinct disease manifestations of myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPNs). Patients with MDS/MPNs initially received ruxolitinib BID (doses based on platelets count), continuously in 28-day cycles for the first 3 cycles. Azacytidine 25 mg/m2 (Day 1-5) intravenously or subcutaneously was recommended to be added to each cycle starting cycle 4 and could be increased to 75 mg/m2 (Days 1-5) for disease control. Azacytidine could be started earlier than cycle 4 and/or at higher dose in patients with rapidly proliferative disease or with elevated blasts...
February 2018: American Journal of Hematology
Brittany Knick Ragon, Courtney D DiNardo
PURPOSE OF REVIEW: Over the past decade, the pathogenic role of mutations in isocitrate dehydrogenases (IDH) 1 and 2, affecting approximately 20% of patients with AML, has been defined, allowing for the development of specific therapeutic strategies for IDH-mutant AML. In this review, the landscape and progress of targeted therapeutics aimed at IDH mutations in AML and related myeloid malignancies will be described. RECENT FINDINGS: Since 2013, several mutant IDH-targeted inhibitors have been developed, and nearly a dozen clinical trials have opened specifically for IDH-mutant hematologic malignancies...
December 2017: Current Hematologic Malignancy Reports
Maliha Khan, Jorge Cortes, Tapan Kadia, Kiran Naqvi, Mark Brandt, Sherry Pierce, Keyur P Patel, Gautam Borthakur, Farhad Ravandi, Marina Konopleva, Steven Kornblau, Hagop Kantarjian, Kapil Bhalla, Courtney D DiNardo
(1) Runt-related transcription factor 1 (RUNX1) mutations in acute myeloid leukemia (AML) are often associated with worse prognosis. We assessed co-occurring mutations, response to therapy, and clinical outcomes in patients with and without mutant RUNX1 (mRUNX1); (2) We analyzed 328 AML patients, including 177 patients younger than 65 years who received intensive chemotherapy and 151 patients >65 years who received hypomethylating agents. RUNX1 and co-existing mutations were identified using next-generation sequencing; (3) RUNX1 mutations were identified in 5...
July 26, 2017: International Journal of Molecular Sciences
Nicholas J Short, Hagop Kantarjian, Farhad Ravandi, Xuelin Huang, Lianchun Xiao, Guillermo Garcia-Manero, William Plunkett, Varsha Gandhi, Koji Sasaki, Naveen Pemmaraju, Naval G Daver, Gautam Borthakur, Nitin Jain, Marina Konopleva, Zeev Estrov, Tapan M Kadia, William G Wierda, Courtney D DiNardo, Mark Brandt, Susan M O'Brien, Jorge E Cortes, Elias Jabbour
The purine nucleoside analogues clofarabine and fludarabine are active in acute myeloid leukemia (AML). We conducted a phase I/II randomized study of idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FIA) for relapsed or refractory AML. Clofarabine 15 mg/m(2) was identified as the recommended phase II dose. Eighty-one patients were assigned using adaptive randomization to CIA (n = 48) or FIA (n = 33). The complete response (CR)/CR without platelet recovery rate did not differ between CIA and FIA (38% versus 30%, respectively; p = ...
July 18, 2017: Leukemia & Lymphoma
Elias Jabbour, Nicholas J Short, Farhad Ravandi, Xuelin Huang, Lianchun Xiao, Guillermo Garcia-Manero, William Plunkett, Varsha Gandhi, Koji Sasaki, Naveen Pemmaraju, Naval G Daver, Gautam Borthakur, Nitin Jain, Marina Konopleva, Zeev Estrov, Tapan M Kadia, William G Wierda, Courtney D DiNardo, Mark Brandt, Susan M O'Brien, Jorge E Cortes, Hagop Kantarjian
BACKGROUND: Fludarabine and clofarabine are purine nucleoside analogues with established clinical activity in patients with acute myeloid leukemia (AML). METHODS: Herein, the authors evaluated the efficacy and safety of idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FIA) in adults with newly diagnosed AML. Adults with newly diagnosed AML who were deemed suitable for intensive chemotherapy were randomized using a Bayesian adaptive design to receive CIA (106 patients) or FIA (76 patients)...
November 15, 2017: Cancer
Rashmi Kanagal-Shamanna, Sanam Loghavi, Courtney D DiNardo, L Jeffrey Medeiros, Guillermo Garcia-Manero, Elias Jabbour, Mark J Routbort, Rajyalakshmi Luthra, Carlos E Bueso-Ramos, Joseph D Khoury
A subset of patients with familial platelet disorder with propensity to myeloid malignancy and germline RUNX1 mutation develops hematological malignancies, often myelodysplastic syndrome/acute myeloid leukemia, currently recognized in the 2016 WHO classification. Patients who develop hematologic malignancies are typically young, respond poorly to conventional therapy, and need allogeneic stem cell transplant from non-familial donors. Understanding the spectrum of bone marrow morphologic and genetic findings in these patients is critical to ensure diagnostic accuracy and develop criteria to recognize the onset of hematologic malignancies, particularly myelodysplastic syndrome...
October 2017: Haematologica
Eytan M Stein, Courtney D DiNardo, Daniel A Pollyea, Amir T Fathi, Gail J Roboz, Jessica K Altman, Richard M Stone, Daniel J DeAngelo, Ross L Levine, Ian W Flinn, Hagop M Kantarjian, Robert Collins, Manish R Patel, Arthur E Frankel, Anthony Stein, Mikkael A Sekeres, Ronan T Swords, Bruno C Medeiros, Christophe Willekens, Paresh Vyas, Alessandra Tosolini, Qiang Xu, Robert D Knight, Katharine E Yen, Sam Agresta, Stephane de Botton, Martin S Tallman
Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ∼12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies...
August 10, 2017: Blood
Courtney D DiNardo, Richard M Stone, Bruno C Medeiros
In this review, we focus on three key areas in acute myeloid leukemia (AML) developmental therapeutics: FLT3 inhibitors, IDH inhibitors, and drugs that may be particularly beneficial in secondary AML.
2017: American Society of Clinical Oncology Educational Book
Prajwal Chaitanya Boddu, Hagop M Kantarjian, Farhad Ravandi, Guillermo Garcia-Manero, Srdan Verstovsek, Elias J Jabbour, Koichi Takahashi, Kapil Bhalla, Marina Konopleva, Courtney D DiNardo, Maro Ohanian, Naveen Pemmaraju, Nitin Jain, Sherry Pierce, William G Wierda, Jorge E Cortes, Tapan M Kadia
BACKGROUND: The development of newer strategies to improve outcomes for older patients with secondary acute myeloid leukemia (s-AML) is a critical unmet need. Establishing baseline metrics for evaluating newer approaches is important. METHODS: s-AML was defined as 1 or more of the following: a history of an antecedent hematologic disorder (AHD), a diagnosis of therapy-related acute myeloid leukemia (AML), and AML with karyotype abnormalities characteristic of myelodysplastic syndrome...
August 15, 2017: Cancer
Suresh K Agarwal, Courtney D DiNardo, Jalaja Potluri, Martin Dunbar, Hagop M Kantarjian, Rod A Humerickhouse, Shekman L Wong, Rajeev M Menon, Marina Y Konopleva, Ahmed Hamed Salem
PURPOSE: The effect of posaconazole, a strong cytochrome P450 3A (CYP3A) inhibitor and commonly used antifungal agent, on the pharmacokinetic properties of venetoclax, a CYP3A substrate, was evaluated in patients with acute myeloid leukemia to determine the dose adjustments needed to manage this potential interaction. METHODS: Twelve patients received 20- to 200-mg ramp-up treatment with oral venetoclax and 20 mg/m2 of intravenous decitabine on days 1 through 5, followed by 400 mg of venetoclax alone on days 6 through 20...
February 2017: Clinical Therapeutics
Koichi Takahashi, Feng Wang, Hagop Kantarjian, Denaha Doss, Kanhav Khanna, Erika Thompson, Li Zhao, Keyur Patel, Sattva Neelapu, Curtis Gumbs, Carlos Bueso-Ramos, Courtney D DiNardo, Simona Colla, Farhad Ravandi, Jianhua Zhang, Xuelin Huang, Xifeng Wu, Felipe Samaniego, Guillermo Garcia-Manero, P Andrew Futreal
BACKGROUND: Therapy-related myeloid neoplasms are secondary malignancies that are often fatal, but their risk factors are not well understood. Evidence suggests that individuals with clonal haemopoiesis have increased risk of developing haematological malignancies. We aimed to identify whether patients with cancer who have clonal haemopoiesis are at an increased risk of developing therapy-related myeloid neoplasms. METHODS: We did this retrospective case-control study to compare the prevalence of clonal haemopoiesis between patients treated for cancer who later developed therapy-related myeloid neoplasms (cases) and patients who did not develop these neoplasms (controls)...
January 2017: Lancet Oncology
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