Publications by authors named "Michael K Keng"

11 Publications

  • Page 1 of 1

Adapting isotonic dose-finding to a dynamic set of drug combinations with application to a phase I leukemia trial.

Clin Trials 2021 Jan 10:1740774520983484. Epub 2021 Jan 10.

Department of Public Health Sciences, Division of Translational Research & Applied Statistics, University of Virginia, Charlottesville, VA, USA.

Background/aims: This article describes the proposed design of a phase I study evaluating the safety of ceramide nanoliposome and vinblastine among an initial set of 19 possible dose combinations in patients with relapsed/refractory acute myeloid leukemia and patients with untreated acute myeloid leukemia who are not candidates for intensive induction chemotherapy.

Methods: Extensive collaboration between statisticians and clinical investigators revealed the need to incorporate several adaptive features into the design, including the flexibility of adding or eliminating certain dose combinations based on safety criteria applied to multiple dose pairs. During the design stage, additional dose levels of vinblastine were added, increasing the dimension of the drug combination space and thus the complexity of the problem. Increased complexity made application of existing drug combination dose-finding methods unsuitable in their current form.

Results: Our solution to these challenges was to adapt a method based on isotonic regression to meet the research objectives of the study. Application of this adapted method is described herein, and a simulation study of the design's operating characteristics is conducted.

Conclusion: The aim of this article is to bring to light examples of novel design applications as a means of augmenting the implementation of innovative designs in the future and to demonstrate the flexibility of adaptive designs in satisfying changing design conditions.
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http://dx.doi.org/10.1177/1740774520983484DOI Listing
January 2021

Gilteritinib: An FMS-like tyrosine kinase 3/AXL tyrosine kinase inhibitor for the treatment of relapsed or refractory acute myeloid leukemia patients.

J Oncol Pharm Pract 2020 Jul 26;26(5):1200-1212. Epub 2020 Apr 26.

Division of Hematology/Oncology, Department of Medicine, University of Virginia, Charlottesville, USA.

Acute myeloid leukemia has recently undergone a significant transition into identifying and successfully inhibiting driver mutations leading to disease. One of the most common mutations in acute myeloid leukemia involves the protein FMS-like tyrosine kinase 3 (FLT3), which leads to ligand-independent activation of intracellular signaling cascades leading to the survival and proliferation of the acute leukemia blast cell. Preclinical studies have demonstrated the presence of two dominant types of mutations of this protein: internal tandem duplication and tyrosine kinase domain mutations. Successful inhibition of this protein has proven to be challenging. While FLT3 has been shown to be successfully inhibited and shown to improve overall survival in the frontline therapy of acute myeloid leukemia in combination with cytarabine and anthracycline, relapsed and refractory (R/R) patients have not been shown to be a successful population until recently. A phase III trial (ADMIRAL trial) demonstrated significant overall survival benefit in patients receiving gilteritinib compared to patients receiving salvage chemotherapy. This review will provide an overview of the preclinical, clinical, and practical use of gilteritinib in the treatment of patients with relapsed and refractory acute myeloid leukemia with mutation.
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http://dx.doi.org/10.1177/1078155220918006DOI Listing
July 2020

Granulocytic Sarcoma: A Rare Cause of Wrist Pain.

Ann Plast Surg 2020 07;85(1):29-32

Department of Pathology, The University of Virginia, Charlottesville, VA.

Septic, inflammatory, or crystal-induced arthritis are common etiologies of wrist pain without antecedent trauma associated with pain, loss of motion, swelling, redness, and warmth. In this report, we detail the case of granulocytic sarcoma of the wrist that presented as acute wrist pain, swelling, and limitation in motion. Granulocytic sarcoma is an exceedingly rare extramedullary tumor associated with acute myeloblastic leukemia. It may be found in any part of the body; however, upper extremity involvement is uncommon. To our knowledge, this is the first description of granulocytic sarcoma occurring in the wrist joint.
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http://dx.doi.org/10.1097/SAP.0000000000002315DOI Listing
July 2020

Enasidenib in acute myeloid leukemia: clinical development and perspectives on treatment.

Cancer Manag Res 2019 30;11:8073-8080. Epub 2019 Aug 30.

Division of Hematology/Oncology, Department of Medicine, University of Virginia, Charlottesville, VA, USA.

Recently there has been a significant progression in the understanding of molecular mutations driving biochemical and cellular signaling changes leading to survival and proliferation of leukemia cells in patients with acute myeloid leukemia (AML). Preclinical studies have demonstrated a mutated enzyme in the citric acid cycle, isocitrate dehydrogenase (IDH), leads to the production of an oncogenic metabolite R-2-hydroxy-glutarate (R-2-HG). This causes the arrest in the differentiation of hematopoietic stem cells leading to the promotion of leukemia. Inhibitors of the IDH enzyme have been shown in preclinical studies to reduce the production of R-2-HG, resulting in terminal differentiation of leukemia blast cells. In recent phase I and II trials, the IDH2 inhibitor enasidenib has shown clinical activity in patients with relapsed and refractory (R/R) AML. This review will describe the preclinical and clinical developments of enasidenib and its Food and Drug Administration approval in R/R AML, treatment recommendations and management will be outlined.
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http://dx.doi.org/10.2147/CMAR.S162784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724422PMC
August 2019

A prospective study on urine alkalization with an oral regimen consisting of sodium bicarbonate and acetazolamide in patients receiving high-dose methotrexate.

Cancer Manag Res 2019 30;11:8065-8072. Epub 2019 Aug 30.

Division of Hematology/Oncology, Department of Medicine, University of Virginia, Charlottesville, VA, USA.

Purpose: Intravenous (IV) sodium bicarbonate is typically used in alkalization regimens for the safe use of the chemotherapeutic agent high-dose methotrexate (HDMTX). Urine parameters including urine output and pH are important in order to minimize the risk of kidney injury, which increases adverse effects and hospital length of stay following HDMTX. IV sodium bicarbonate has been on shortage, and there are limited literature describing the safety of alternative regimens.

Patients And Methods: A single institution, prospective analysis of non-Hodgkin's lymphoma and acute lymphoblastic leukemia patients receiving HDMTX for central nervous system (CNS) prophylaxis or disease. Patients received an oral (PO) regimen of sodium bicarbonate and acetazolamide to achieve a urine pH >7. This cohort was compared to a subsequent IV sodium bicarbonate control cohort. Multiple co-primary safety outcomes assessed the incidences of acute kidney injury and delayed methotrexate clearance as well as change in liver function tests. Secondary outcomes included time to urine pH, time to urine output, and length of stay.

Results: A total of 126 encounters were studied for the primary safety outcome. There was no difference between AKI incidence in patients receiving the PO alkalization regimen compared to patients receiving IV sodium bicarbonate (14.5% vs 9.3%, respectively, =0.41). There was no difference in methotrexate clearance between the PO and IV groups (26.5% vs 37.2%, respectively, =0.21). The use of PO alkalization regimen is estimated to have saved 2002 vials of IV sodium bicarbonate and was approximately US$226 less expensive per encounter.

Conclusion: This analysis supports the use of PO regimens to achieve urine alkalization necessary for safe administration of HDMTX during periods of IV sodium bicarbonate shortage. Further studies may determine optimal dosing strategies that decrease length of stay and ensure noninferiority of efficacy outcomes with PO regimens for urine alkalization with HDMTX.
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http://dx.doi.org/10.2147/CMAR.S190084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720153PMC
August 2019

Evaluation of cardiomyopathy in acute myeloid leukemia patients treated with anthracyclines.

J Oncol Pharm Pract 2020 Apr 9;26(3):680-687. Epub 2019 Sep 9.

Department of Medicine, Division of Hematology/Oncology, University of Virginia, Charlottesville, VA, USA.

Background: Acute myeloid leukemia patients receive anthracycline-containing induction chemotherapy. Anthracyclines cause cardiotoxicity; however, there is a paucity of data reflecting the risk of cardiotoxicity in the acute myeloid leukemia population, and risk factors for development of reduced left ventricular ejection fraction are not well established in this population.

Methods: A retrospective cohort study of adult acute myeloid leukemia patients receiving anthracycline-containing induction chemotherapy between March 2011 and August 2017 was performed. Baseline and all additional cardiac monitoring within one year of induction were collected. Home medications and new medication initiation were determined via the electronic health record and new outpatient prescriptions.

Results: Of 97 evaluable patients, 25 (25.8%) developed reduced left ventricular ejection fraction and 18 (18.6%) experienced clinical heart failure within one year of induction. The median difference from baseline to lowest left ventricular ejection fraction was -5.0 percentage points, with a range of +10.0 to -52.5. The median time to onset of reduced left ventricular ejection fraction was 27 days, at a median cumulative anthracycline dose of 270 mg/m. No patient-specific or medication-specific factors were significantly associated with the risk of developing reduced left ventricular ejection fraction. Of 14 patients started on medical management for reduced left ventricular ejection fraction, 10 (71%) responded to therapy.

Conclusions: In this retrospective analysis, we observed that acute myeloid leukemia patients experienced reduced left ventricular ejection fraction more quickly and at lower doses than previously reported in the solid tumor population. Reduced left ventricular ejection fraction was at least partially reversible in most patients started on medical management. Although no factors were significantly associated with decreased cardiomyopathy risk, future assessment of cardioprotective medications may be warranted.
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http://dx.doi.org/10.1177/1078155219873014DOI Listing
April 2020

Reducing Time to Antibiotic Administration for Febrile Neutropenia in the Emergency Department.

J Oncol Pract 2015 Nov 28;11(6):450-5. Epub 2015 Jul 28.

Cleveland Clinic, Cleveland, OH

Purpose: Febrile neutropenia (FN) is an oncologic emergency, and prolonged time to antibiotic administration (TTA) is associated with increased hospital length of stay (LOS) and worse outcomes. We hypothesized that a febrile neutropenia pathway (FNP) quality initiative project would reduce TTA delays for febrile patients with cancer presenting to the emergency department (ED).

Methods: This prospective study compared ED FNP patients (> 18 years old), between June 2012 and June 2013 with both historical and direct admissions (DA) cohorts at a multispecialty academic center. Interventions included providing patients with FN-Alert cards, standardizing the definition of FN and recognizing it as a distinct chief complaint, revising ED triage level for FN, creating electronic FN order sets, administering empiric antibiotics before neutrophil count result, and relocating FN antibiotics to the ED. The primary outcome was TTA, with a target goal of 90 minutes after ED presentation.

Results: In total, 276 FN episodes in 223 FNP patients occurred over the 12-month study period and were compared with 107 episodes in 87 patients and 114 episodes in 101 patients in the historical and DA cohorts, respectively. Use of the FNP reduced TTA from 235 and 169 minutes in historical and DA cohorts, respectively, to 81 minutes, and from 96 to 68 minutes when the order set was not used versus used in the FNP group (P < .001 for all comparisons). Decrease in hospital LOS was not statistically significant.

Conclusion: The ED FNP is a significant quality initiative with sustainable interventions, and was able to demonstrate value by decreasing TTA compared to both historical and DA controls in cancer patients presenting to the ED.
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http://dx.doi.org/10.1200/JOP.2014.002733DOI Listing
November 2015

A drug's life: the pathway to drug approval.

Clin Adv Hematol Oncol 2013 Oct;11(10):646-55

Professor of medicine and the director of the Leukemia Program at the Cleveland Clinic Taussig Cancer Institute in Cleveland, Ohio.

In the United States, drugs and medical devices are regulated by the US Food and Drug Administration (FDA). A drug must undergo rigorous testing prior to marketing to and medical use by the general public. The FDA grants marketing approval for drug products based on a comprehensive review of safety and efficacy data. This review article explains the history behind the establishment of the FDA and examines the historical legislation and approval processes for drugs, specifically in the fields of medical oncology and hematology. The agents imatinib (Gleevec, Novartis) and decitabine (Dacogen, Eisai) are used to illustrate both the current FDA regulatory process-specifically the orphan drug designation and accelerated approval process-and why decitabine failed to gain an indication for acute myeloid leukemia. The purpose and construct of the Oncologic Drugs Advisory Committee are also discussed, along with examples of 2 renal cell cancer drugs-axitinib (Inlyta, Pfizer) and tivozanib-that used progression-free survival as an endpoint. Regulatory approval of oncology drugs is the cornerstone of the development of new treatment agents and modalities, which lead to improvements in the standard of cancer care. The future landscape of drug development and regulatory approval will be influenced by the new breakthrough therapy designation, and choice of drug will be guided by genomic insights.
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October 2013

Febrile neutropenia in hematologic malignancies.

Curr Hematol Malig Rep 2013 Dec;8(4):370-8

Cleveland Clinic Taussig Cancer Institute, Leukemia Program, 9500 Euclid Avenue, R35, Cleveland, OH, 44118, USA.

Febrile neutropenia (FN) can occur at any time during the course of a malignancy, especially hematologic malignancies, from diagnosis to end-stage disease. The majority of FN episodes are typically confined to the period of initial diagnosis and active treatment. Because of suppressed inflammatory responses, fever is often the sole sign of infection. As FN is a true medical emergency, prompt identification of and intervention in FN can prolong survival and improve quality of life. This article reviews FN in the setting of hematologic malignancies, specifically myelodysplastic syndromes and acute leukemias, providing an overview of the definition of fever and neutropenia, diagnostic approach, categories of risk/risk assessment, management in patients at low and high risk, and prophylaxis of infections.
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http://dx.doi.org/10.1007/s11899-013-0171-4DOI Listing
December 2013

The race for survival in myelodysplastic syndromes.

Leuk Lymphoma 2013 Feb 16;54(2):219-20. Epub 2012 Oct 16.

Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH 44195, USA.

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http://dx.doi.org/10.3109/10428194.2012.726724DOI Listing
February 2013

Synergism between arsenic trioxide and heat shock protein 90 inhibitors on signal transducer and activator of transcription protein 3 activity--pharmacodynamic drug-drug interaction modeling.

Clin Cancer Res 2007 Apr;13(7):2261-70

Roswell Park Cancer Institute and State University of New York at Buffalo, Buffalo, New York 14263, USA.

Purpose: Constitutive signal transducer and activator of transcription 3 (STAT3) activity, observed in approximately 50% of acute myelogenous leukemia cases and associated with adverse treatment outcome, is down-regulated by arsenic trioxide (ATO). Heat shock protein (HSP) 90 is a molecular chaperone involved in signal transduction pathways. We hypothesized that HSP90 inhibitors will potentiate ATO effect on constitutive STAT3 activity and cell killing. One concern was that the effect of ATO and HSP90 inhibitors will result in up-regulation of HSP70, a protein known to inhibit apoptosis.

Experimental Design: We have used a semimechanistic pharmacodynamic model to characterize concentration-effect relationships of ATO and HSP90 inhibitors on constitutive STAT3 activity, HSP70 expression, and cell death in a cell line model.

Results: Pharmacodynamic interaction of ATO and three HSP90 inhibitors showed synergistic interactions in inhibiting constitutive STAT3 activity and inducing cell death, in spite of a concurrent synergistic up-regulation of HSP70.

Conclusions: These preliminary results provide a basis for studying the combined role of ATO with HSP90 inhibitors in acute myelogenous leukemia with constitutive STAT3 activity.
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http://dx.doi.org/10.1158/1078-0432.CCR-06-2468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715964PMC
April 2007